THE ALKALOIDS Chemistry and Pharmacology VOLUME 36
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THE ALKALOIDS Chemistry and Pharmacology Edited by Arnold Brossi Narionul Instirures of Health Bethesda, Maryland
VOLUME 36
Academic Press, Inc. Hurcourt Brace Jouanouich, Publishers
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92
x
7
h
r
J
3
2
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50-5522
CONTENTS
CONTRIBUTORS .......................................................... PREFACE ................................................................
ix xi
Chapter I . Alkaloids of Slwchnos and Gardneria Species NORIOAIMI,SHIN-ICHIRO SAKAI, A N D YOSHIOBAN
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Srrychnos Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Gardneria Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Pharmacology of Gardneria Alkaloids. ............................... References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I 2 47 62 62
Chapter 2. Lead Tetraacetate Oxidation in Alkaloid Synthesis OSAMUHOSHINO A N D BUNSUKE UMEZAWA I. 11. 111. IV. V. VI. VII.
............. Introduction Aporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-Homoaporphines.. . . . . . . Homoproaporphines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Morphinandienones and Homomorphinandienones .................... Isopavines and Homoisopavines . . . . Benzo[c]phenanthridines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IX. X. XI. XII. XIII.
Tetrahydroprotoberberines ................... Indole Alkaloids ................................................... Oxoaporphines ............................. Lead Tetraacetate-Mediated Hydroxylation of lsoquin Miscellaneous Reactions .....................................
............................ V
70 72 83 90 91 94 95 96 97 98 I10 Ill 126 130
vi
CONTENTS
Chapter 3. Canthin-6-one Alkaloids TAlCHl OHMOTO A N D KAZUOKOIKE
I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Natural Occurrence. . . . . . . . . . . . . . . . . . . 111. Structural Elucidation . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . 1V. "C-NMR Spectroscopy . . . . . ....................... V. Synthesis . . . . . . . . . . . . . . . . . . VI. Biosynthesis.. . . . . . . . . . . . . . ....................... V11. Bioassay and Pharmacology . ....................... References . ....................................
135 136 I37 154 I55 164 I65 167
Chapter 4 . Phenethylisoquinoline Alkaloids TETSUJl KAMETAN1 A N D MASUOKOlZLlMl 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I I . Structural Elucidation, Chemical Reaction, and Stereochemistry of Phenethylisoquinoline Alkaloids. .................................... Ill. Biosynthesis . . . . . . . . . . . . . . . ....................... IV. Synthesis.. . . . . . . . . . . . . . . . . ..... V. Pharmacology ........................ References . . . . . . . . . . . . . . . . .......................
172 173 200 202 219 220
Chapter 5. Alkaloids of the Calabar Bean SEIICHI
TAKANO A N D KUNlO OCASAWARA
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Structures of the Alkaloids ......................................... 111. Synthesis of the Alkaloids .......................................... IV. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
225 225 226 247 249
Chapter 6. Chemistry of Melanins PROTA, PARIS SVORONOS, A N D RAIMONDO CRIPPA, VACLAV HORAK,GIUSEPPE LESZEK WOLFRAM
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
................................................ Ill. Synthetic Melanins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Isolation, Purification, and Characterization .......................... V. Structure and Chemical Properties.. ................................. 11. Natural Melanins..
254 256 268 279 283
vii
CONTENTS
VI. Spectroscopic Characterization ..................................... Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CUMULATIVE INDEX OF TITLES. . . . . . . . . . . . . INDEX ............. . . . . . . . . . . . . . . . . . . . . . . .
....
297 307 3 12
325 33 I
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CONTRIBUTORS
Numbers in parentheses indicate the pages on which the author’s contributions begin.
NORIOAIMI( I ) , Faculty of Pharmaceutical Sciences, Chiba University, Chiba 260, Japan YOSHIOBAN(I), Hokkaido University, Sapporo 060, Japan RAIMONDO CRIPPA(253), University of Parma, Parma, Italy VACLAVHORAK (253), Georgetown University, Washington, D.C. 20057 OSAMUHOSHINO (69), Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12, Shinjuku-ku, Tokyo 162, Japan TETSUJIKAMETANI* (171), Institute of Medicinal Chemistry, Hoshi University, Tokyo, Japan KAZUOKOIKE( 1 3 9 , School of Pharmaceutical Sciences, Toho University, Chiba 274, Japan MASUOKOIZUMI(171), Fujigotemba Research Laboratories, Research Management Department, Chugai Pharmaceutical Co. Ltd., Toshimoku, Tokyo 171, Japan KUNIOOGASAWARA (225), Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980, Japan TAICHIOHMOTO ( 1 3 3 , School of Pharmaceutical Sciences, Toho University, Chiba 274, Japan GIUSEPPE PROTA(253), Universita di Napoli, Napoli, Italy SHIN-ICHIRO SAKAI( I ) , Faculty of Pharmaceutical Sciences, Chiba University, Chiba 260, Japan PARISSVORONOS (253), Queensborough College of the City University of New York, Bayside, New York I1364 SEIICHITAKANO(225), Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980, Japan BUNSUKE UMEZAWA* (69), Department of Pharmaceutical Sciences, Science University of Tokyo, Shinjuku-ku, Tokyo, Japan LESZEKWOLFRAM (253), Clairol Company, Stamford, Connecticut 06922
* Deceased ix
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PREFACE
An overlap of information concerning indole alkaloids, which are presented in the chapter on “Alkaloids from Strychnos and Gardneria Species,” with material presented in Volume 34 in the chapter on “African Strychnos Alkaloids,” is incidental, and offset by including alkaloids from Gardneria species here. A review of chemically important reactions which fertilized alkaloid chemistry is continued here with the chapter on “Lead Tetraacetate Oxidation in Alkaloid Synthesis” by the late Professor Bunsuke Umezawa from Tokyo University. The three dozen alkaloids presented in the chapter on “Canthin-6-one Alkaloids,” which are prevalent in the plant families Rutaceae and Simaroubaceae, are grouped together for the first time. The chapter on “Phenethylisoquinoline Alkaloids,” which appeared for the first time in Volume 14 of this treatise, has been updated. It again shows the great complexity of this group of alkaloids which are separated into seven subgroups. “Alkaloids of the Calabar Bean” reviews and updates this topic, including pharmacological properties. “Chemistry of Melanins” reviews for the first time a family of black pigments occurring in skin and hair and derived from the amino acids, dopa, and tryptophan. This chapter will be most useful to those working in this exciting and practically unexplored field. Most contributions to this volume are by Japanese scientists, making it almost a special Japanese issue. Arnold Brossi
xi
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- Chapter
1
-
ALKALOIDS OF STRYCHNOS AND GARDNERIA SPECIES N O R ~A Oi
~ AND i
SHIN-~CHIRO SAKAI
Fuculry of Phurmuceuticul Sciences Chibu University Chihu 260. Jupun
Y O S H ~BAN O Hokkuido University Supporo 060, Jupon I. introduction .....................
................................................
I
I I . Slrvcknos Alkaloids.. ............................................. 111. Gtrrdneriu Alkaloids ........................................ IV. Pharmacology of Gardtwriu Alkaloids.. . ............................... References.. .............................................................
62
..... 62
I. Introduction
There have already appeared many chapters on Strychnos alkaloids, including those of calabash curare, in previous volumes (1-6) of this treatise. Although extensive studies on Strvchnos alkaloids were carried out and many of the main structural classes of alkaloids were determined by the mid- 1960s, various types of new alkaloids have since been found and efficiently characterized, sometimes even from small pieces, of herbarium specimens of Strychnos plants. In this chapter, alkaloids isolated from Strychnos species are presented in tabular form (see Table 11). Most recent papers on these subjects simply describe the structures of new alkaloids as determined primarily by spectral methods. Therefore, detailed description concerning structure elucidation of individual alkaloids seems unnecessary. Coverage of the literature starts from around 1965. In line with this principle, the Strychnos alkaloids tabulated by M. Hesse (7,8)are included only when they were reported to be newly found in other species of Strychnos. Thus, I
'THE AI.KAI.OIDS. VOI.. 36 Copyright (0 1989 hy Acadcmic Prc\\. Inc. All right\ ol' reproduction in any limn rcrervrd.
2
NOR10 AIM1 E T A L
TABLE I PLANTTAXONOMY OF THE FAMILY LOGANIACEAE Tribe Gelsemieae Loganieae Spigelieae Antonieae Strychneae Potalieae
Genus (number of species) Gelsemiurn (3), Mostuea ( 8 ) Loganiri (25). Geniostoma (40). Lohordia (25) Spigelia (50). Cynoctonum (6). Mitrasacme (40) Usteria ( I ) , Antonia ( I ) , Norrisia (2) Strychnos (150). Gurdneria (3,Neubergia (10-12) Fagruetr ( 3 5 ) . Potcilia ( l ) , Anthocleisra (14)
some important Strychnos alkaloids may be absent from Table 11, for these alkaloids, readers should consult the elaborate publications by Hesse cited above. It may be appropriate to mention here that two monographs contain chapters which exhibit an enormous collection of alkaloids of Sfrychnos species (9). Furthermore, several excellent reviews have been published on African ( / U - / 2 ) , Central and South American, ( / 3 , / 4 ) and . Asian (/5-2U), species of Srrychnos. The second part of this chapter covers Grirdneriri alkaloids, which are included in this treatise for the first time. The family Loganiaceae consists of about 500 species of plants, and these plants are classified into six tribes and 17 genera ( 2 / )(Table 1). As shown in Table I , tribe Strychneae includes Grrrdtwrirr. the alkaloid-rich genus of this family. As far as we know, no clear-cut results have been obtained concerning the alkaloidal constituents in the genus N e i i h r g i i , the remaining group of the tribe Strychneae.
11. Shychnos Alkaloids
The list of Strychnos alkaloids (Table 11) indicates the following items: (1) name, (2) structure, (3) molecular formula, (4) molecular weight, (5) melting point, (6) specific rotation, (7) scientific name of the source plant, (8) locality of the habitat of the plant (abbreviations: As, Asia: Af, Africa; and Am, Central or South America), and (9) literature citations. The alkaloids are grouped according to the main skeletal structural classes, which are basically presented in order of generally accepted biogenetic sequence (9,22). (Text continues on p. 47.)
TABLE I1 (Continued) ~
Structure
Alkaloid
Diplocerine 16-Epidiplocerine Strychnorubigine (9-Methoxyisositririkine) ( IhR)-lsositosinkine
R=H @-Me a R=H V-Me a R = OMe R=H
Molecular formula
MW
rnp 1°C)
126- I27
la10
_
Species
_
_
_
_
_
_
Location
_
~~
Ref.
S . gussn'eikri Exell.
Af
24, 27
S . gussweileri Exell.
Af
2s
S . rubiginusa DC.
Am
28
S . kasengoensis
Af
181
~
m
4 4 4
c c c
m
f , %
R
01
5
- 0
N N cio
m
x
N
N
b l
N
m * I *
TABLE 11 (Continued)
Alkaloid
Structure
C-Mavacurine
Molecular formula
MW
mp (T)
Specie5
[el0
S. amuzonicu KrukotT S diurrriruns Ducke S.,frmsii Ducke S. murrophvllu B. Rodr.
Location
Ref.
Am Am Am Am Am Am
.i7 37 37 37 37
S.pou$olio DC. S. subrorduru Spruce S. scheffleri Gilg. S. ro.r!/eru Roh. Schomb. S.uoriuhilis de Wild.
As Am Am Af Am Af
38 37 37 39 37 40
S. scheffleri Gilp. S. uuriuhr1i.s de Wild.
Af Af
39
S . melinoniuno Baill. S. mirscherlichii Rich. Schomb. var. omupensis KrukofF et Barneby
S
nrrs-uomiru
L.
37
CH,OH C-Fluorocurine
40
E E
E L
< < < a < < < <
L L L L
7
Z
s
I
o
1
TABLE I1 (Continued) Molecular formula
Structure
Alkaloid
MW
mp ( " 0
[alD
Specie5
Ref.
Location
Ri
2
R,
R,
?I-Epi-O-methylkrihinr
H
OMe
H
C ~ I H ~ ~ N Z338 O?
10-Hydroxy-2I-epi0-methylkrihine 10-Hydroxy-?I-0methylkrihine Krihine
OH
OMe
H
C:[H26N203
OH
H
OMe
C:IHX,NZO~ 354
OH
H
C ~ ~ H Z ~ N 324 ~OZ
H
OH
H
R3
354
S . dale de Wild. S. elaeorurpo Gilg. ex
Af Af
42 42
176-180 (dec)
Leewenherg S. derussato (Pappe) Gilg.
Af
41
145-148
S. decussata (Pappe) Gilg.
Af
41
S. dale de Wild
Af
4 2 . 49
S. elaeocurpa Gilg. ex
Af
4 2 . 49
Leewenherg S. spinosu Lam. S. dale de Wild. S. elaeocurpu Gilg. ex Leewenherg
Af Af Af
46 42 42
or
H
2
?I-0-Methylkrihine
H
H
OMe
C2,H:,N:O2
33X
Akagerine lactone
Strychnohirsutine
Tetrahydrostrychnohirsutine
3.4.5.6-tetrahydro
C>~H~:N?OI338
184- I86
S. drcrrssura (Pappe) Gilg.
Af
48
C,9H?oN:O: 304 C I ~ H ~ P N ? O308 Z
141- 143 221-223
S. hirsrrra Spruce ex Benth. S. hirsutu Spruce ex Benth.
Am Am
50 50
(continued)
TABLE I1 (Continued) Alkaloid
Decuwne
Structure
R = H
Molecular formula
MW
mp ( T I
203-205
[alD
Specie5
S.dale de Wild. S.decusmu (Pappe) Gilg. S. elueocurpu Gilg. ex
L
0
K
IO-Hydroxy-3.14dihydrodecussine
= H, 3.14-dihvdro
R = OH. 3.14-dihydro
78-82
Leewenberg S. floribunda Gilg. S. dulr de Wild. S. deciissuru (Pappel Gilg. S. elueocurpu Gilg. ex Leewenberg S. decussoru (Pappe) Gilg.
Location
Ref.
Af Af Af
Sl 5 1 . /43 51
Af Af Af Af
43, 44 51 51 51
Af
51
2
M
-
6
d
0
C
N
.
L
10
Q Q <
C
-
-
O
11
TABLE I1 (Continued) Alkaloid
Structure
Molecular formula
MW
mp ( T I
[UlD
Species
Af
Strellidimine
6.7-Dihydroflavopereirine
Location
S. r~snmbarrnsisGilg.
Af
Ref
187
145
K
11
26'
11
IP
FN 13
a m m
C
,-,-I-
C
d d d
L
14
b d
L1-
r.0
o N O m
m m
4::
16
+; +
2) r
m
I
P
P
.I
-m
17
P
I?
0
5 r_ ; . I
r
c
3
ci
X
I
4'
a 0 N
TABLE I1 (Continued) Alkaloid
W
Molecular formula
Structure
MW
N"-Deacelyl- 17-0-acetyl- 18-hydroxyisorctuline N'-Deacetyl-IX-hydroxyiborrlulinc I X-Hydroxyiwrcluline Strychnopivoline N-Oxyrelulinc
OH
354
on
312
n n
354 322 354
N1-Dracetyl-lX-acetoxyirorelu-
OAC
line I I-Methoxyretuline I I-Methoxyiwrelulinc
Strychnozairine
mp ("C)
[alD
Species
Location
Ref.
S. hrnninpsii Gilg.
.%f
65
247-2511
S. henninpsii Gilg.
Af
62
24s-248
J. hmningsii Gilg. S. uuriirbilis de Wild. S. ampruneuru Gilg.
Af Af Af
65 60 Y2. 154
338
S . kusenguenri.\
Af
/8/
n
352
S. kosenguensis
Af
/8/
H
352
S. kosenparnsis
Af
181
S. uariuhilis de Wild
Af
/47
n
i78-1~0
t 145" ( M e O H )
19
c m
E
d
ti
20
m m
Strychnospermine Na-Acetyl-12-hydroxy- I Imethoxystrychnosplendine Na-Acetylstrychnosplendine
O-Methyl-N"-acetylstrychnorplendine
H OH
H H
OMe OMe
H OH
Cz:H?xNzO, Cz:H?xNzOq
36X 400
?ox-xw
AC
242-244
- 141" ICHCII)
Ac
OH
H
H
H
C:iH?e,N?Oi
354
173-175 155-1?7
+ 1 ? 1 " ICHCIi)
Ac
AC
OMe
H
H
H
C x H i x N i 0 1 36X
S. psilospermo F. v . Muell S.frndlcri Sprague et Sandwith S. urrrl[wro Solered S . / r n d l r r i Sprague et Sandwith S. s/it.fflrrr Gilg. S . ocrtlrara Solered
Au\t Am
102. / W 77. 78
Af Am
79 77, 78
Af Af
1 .Y 76
H H
H H
H H
CivH?jN:O?
370 312
S. shc/&ri Gilg. S . taba.wana Sprque et Sandwith S . .splrndrn.r Gilg. S . s p l m d ~ r Gilg. ~.~
H
H
H
H
CzlHy,N:O?
33X
S. splrndrn.! Gilg.
Af
81
H
H
OMc
OH
Cz?HxNz04
3x4
S. brasiliozri.\ (Sprcng.) Mart.
Am
7.1
Rz
RT
R4
Rq
OH
H
H
H
Splendoline Strychnorplendine
COCH~OH OH H OH
Nd-Acetyl-3-deoxyisostrychnorplendine 12-Hydroxy-l I-methoxy\permostrychnine
Ac
AC
Af Am
3Y
Af Af
XI. 144
80
82. R.3, /44
272-273
-217" ICHCIII
N
RI
Na-Acetyl-isostrychnosplendine Ac
C~IH?~N~O 354 ]
S. splendens Gilg.
Af
83. M ,
S. aruleara Solered
Af
76
I44
(continued)
rn
t-kI 0
z-a r
N
-a
- r
22
2k
R ? % ? 4 4 4
R $ R 4
2 4
5 E
L L E
E
E L E
E 4 4 4
L E 4
2-
-
4 4
I.
d
v
r
+
C.
c
+
c
c,
P
r
r I r
I Y.
r
2 2
-
x
r 1 r
c
23
4
L
i
4 4
L
E
4
E L L +
z 2
z
5
z
...
z C
x
4 4 4 4
2 3s z
3
z
z
24
I
u "I
"
2 E
N P
25
26
i i
J
i i i
i r
<<
i i i i i
22
g2
I
I
e o
e
z
z
z
z
27
z
I I
0
zT
28
d x z I
I
x
0 n
x I
I
0
Y x
n0
x
z
0
L
C
<<<
L
29
e 2 0
CZX
x
I
0
x
2 0
I
2
crx
I sO L
I
X i ,
I
I L
8I
30
I
s C
I
I C
I
I
C
ti
u Y
0
31
TABLE I1 (Continued)
”N
21 .22-a-Epoxy-3,4dimethoxy-Nmethyl-srrpseudostrychnine 2 I.??-a-Epoxy-14hydroxy-2.3dimcthoxy-N-methyl.~r~--pceudortrychnine 21 .??-u-Epoxy-C hydroxy-3-methoxy-N methyl-Ariv p\eudostrychnine ?I.??-u-Epoxy-I4hydroxy-4-methoxyN-mefhyl-.srcpseudostrychnine ?I,22-a-Epoxy-l4hydroxyicajine 21 22-a-Epoxy-14hydroxynovacine ?I .??-a-Epoxy-?methoxy-N-methylscc-p\eudostrychnine 21 .22-a-Epoxy-4methoxy-N-methylsur-pseudostrychnine ?I .??-a-Epoxynovacine
Molecular formula
Structure
Alkaloid
MW
mp I T 1
[alD
Specie\
Location
Ref
H
Af
IIY
ti
OH
AT
IIY
OMe
on
H
Af
114. I I Y
H
H
OMe
0H
AT
IIY
n
n
n
OH
266-268 ldecl
+3”
Af
114
OMe
OMe
H
OH
251-253
+3”
Af
112. 114.
H
OMe OMe
OMe
OM^
H
116. 117
OMe
H
H
n
H
H
OMe
H
OMe
OMC
n
H
265-267 (decl
239-241
+I?”
AT
114
Af
I19
Af
l I 2 . 114. 116.
117. 110.
2 I.2?-a-Epoxyvomicine
H
H
on
122
H
252-???
+11?”
Af
114. I19
cxJ($
CHOH 3
II
I
AF
IM 186
5 . nigrirunu Bak.
Af
1Z.i
S. niprifrrnrr Bak.
Af
12.3
Af
Brafouledine Isobrafouledine
I I1
Ki
R?
Ri
I X-Dehydro- 10hydroxynigritanin
on
n
n
CuiHuN40
464
174-176
18-Dehydronigntanin
H
n
H
C,oH+tNj
450
226-228
W
+46.8" IEtOH)
(continued)
34
0 I
y:,
4
e
35
TABLE I I (Continued) Molecular Alkaloid
Structure
N-Methylusamharensine Usambarensine lO.IO'-Dimethoxy3u. 17u-Z-tetrahydrousambarensine 10. IO'-DimethoxyN4'-methyl-3u.17u-Z-tetrahydrousambaremine
W
HO
m
Isustrychnufoline lsustrychnophylline
@*-Me.
R I = R?
=
formula
H
= R2 = H S'.h'.I7u.N-tetrahydro.lV-Z.R1 = R2
=
OMe
N~-Me.19-5'.6'.17'a,N-tetrahydruZ,R1= Rz = OMe
mp ("C)
IUIU
Specie\
Location
Ref
447
S. i~sumharmsirtiilg.
Af
/30. / 3 /
432 CzyH2xN4 C I I H I L N I O ~ 4%
S. idsomhuren3iJ Gilg. S. dole de Wild.
Af Af
/30-/32
C12HirN40:
S. du/r de Wild.
AT
/84
CIOHIINI
RI
MW
510
/84
Strychnofoline Slrychnophylline
17s
H
216
S. usumhormsir Gilg. S. urmnborensis Gilg.
Af Af
/33, 134 133
Me-N
Me-N
I
Jdnu\\lne A Jdnurvnc B
(continued)
TABLE I1 (Continued) Alkaloid
W
m
Afrocuranne
Structure
Molecular formula
MW
mp K )
[UlD
Species
Location
Ref
E d
s
6
L
6 4
ji
.< 6 4 6 6 4 6 6 6 6
L E L E L L L E L 4
F
4
39
I
Alkaloid
Structure
Bimor-C-alkaloid H
K
=
Risnor-C-alkaloid H di-N-oxide
R
=
Ri\nor-C-alkaloid H mono-N-oxide C-Toxifcrinc I (loxifcrinc V l
ti. R' = O H
H. K '
OH Nh.Nh'-dioxide R = H. R ' = on =
Nh-0 R
R'
:
=
OH
Nh.h"' -dimethyl
Molecular lormula
MW
mp ('CI
lnlD
Specie,
Location
Ref
Af Af
M. Y / 35. 36
Af Af
3 S 36
Af Af
8.5
Am Am
/ Y / . 1%
JS
15
IY4
Matopensine Matopensine N-oxide
C-Alkaloid D
Nh-0
CMHIXNIO? h 0 X
S. n r i r ~ ~ / i ~liii ~r/i~
Af
1x1
Af
181
Am
I Y Z , 19.1
(continued)
42
L
L I1
0
Y
I1
r
b
b
c
-
C-Alkaloid G
11: R = H. R' = OH
C-Alkaloid E
11:
R
= R' =
OH
W P
,ine V Caracurine V
C a r a c u r i n e I1
.chocurine
Af
85. Y I 62 110. 140
Am At' At'
/YO 136 140
Af Af
AS 1411
Am
/Y/J
At'
Af
Caracurinc V di-hi-oxide
Nh-0. Nh -0
Caracurine V mono-hi-oxide
Nh-0
Caracurine I I
TABLE I1 (Conrinued) Molecular Structure
Alkaloid Caracurine I1 dimethosalt Dolichocurine
formula
MW
mp 1°C)
lull)
Specie, S. rox!lrro Rob. Schomb S.do/ic~horlysriGilg. ex
Nd.Nh-dimethyl
Location
Ref.
Am Af
/9/ 35
Onochie et Hepper
R
C-I6
c-22
c-16'
I?'-Hydroxyisostrychnohiline lsostrychnobiline
OH
P-H
a-H
a-H
CIUH~~NJOI 630
S. uoriuhili, de Wild.
Af
/4/
H
0-H
a-H
a-H
Cj~HjhNjOi 614
S. u o r i ~ h i l i sde Wild.
Af
66, 72.
Strychnohiline Dehydroisostrychnohiline
H
S. uoriohi/;.%de Wild.
Af
66. 72
U-n
CJUHJ~N.IO: 614 CNHJJN~O: h i ?
S . hosuimrn\i.%
Af
181
/4/
H
Not indicated u-H I6.I'l-dchydro
Sangucine Rindline Rouhamine
(\tructure unhnownl (5tructure unknown)
Strychnochrornine
(structure unkonwnl
Strychnocarpine
CI~HI:NJO: C:aHl,,N?Or
ClnH2:NzO:
634 426 299
298
350 214-216
20?-?10
+ 1Y4" ICHCIII
S. rwju Baill. S . hmninxsii GiIg. S. dPcirsrirru (Pappel Gilg. S. Jiorrhrindn Ciilg. S. p o . ~ ~ w r i l r Exell. ri
S. rlurocorpo Gilg. ex Leewenherg S. fiorihrmda Gilg.
Af Af Af Af Af
112. 142 88 51
Af
(6
Af
43, 44
43 24
(continued)
TABLE I1 (Continued) Structure
Alkaloid
Molccular fbrmula
MW
mp ("C)
1C11D
spcc1c\
Location
Ref.
R
Af
Dinklageine
l46. lR7
OH Strychnovoline
"
R = H
For other plants containing angustine and related alkaloids. see Ref. I52.
177-17X
f98" IMcOH)
S. d i i i k l i i y ~ Gilg. i
Af
1x2
I . ALKALOIDS OF S T R Y C H N O S A N D G A R D N E R I A
47
(Text continues from p. 2.) Some of the molecular formulas and molecular weights are calculated from the proposed structure; thus, they are not always fully evidenced by elemental analysis of other experimental data in the literature cited. As for taxonomy, the Latin name adopted in the original literature is recorded. No effort was made to take into account different opinions about synonyms or other scientific names.
111. Gardneriu Alkaloids
As is described in the introduction (Section I), genus Gardneria is included in the tribe Strychnae. Five species in Japan and Taiwan have been collected and their alkaloids chemically studied by the present authors (Sakai and Aimi). All species are lianas, and they seem to be divided into two groups based on morphological similarities of the inflorescences: the first group consists of two species, Gardneria nutans Sieb. et Zucc. and G. insularis Nakai, which have only one to three flowers in an inflorescence, while the other group, including G. multiJlora Makino, G. Shimudui Hayata (restricted to Taiwan), and G. lii~kirrrn.si.s Hatsushima, have three to ten flowers in a congested inflorescence (156). This classification is also obtained from comparison of alkaloid constituents. Plants of the G. nutans group (Japanese name Horai-kazura) contain gardnerine (1)and gardneramine (4) (see Scheme I ) as the main bases and gardnutine (2), hydroxygardnutine (3), and 18-hydroxygardnerine (5) as minor constituents. From the viewpoint of oxidation state of the indole moiety, gardnerine (l),gardnutine (2), hydroxygardnutine (3), and hydroxygardnerine (5) are indoles, and gardneramine (4) is an oxindole. Thus, plants of the G. nutans group contain both indole and oxindole alkaloids. On the other hand, plants of the G. mulriJora group (Japanese name Chitose-kazura) contain gardneramine (4) as the main base, and all the accompanying alkaloids are oxindoles. No traces of indole alkaloids were found in the plants of the latter group (159). Structures and physical properties of Gardneria alkaloids are shown in Table 111. Structures of the main alkaloids of G. nutans and chemical correlation among three of them, 1,2,and 3, are shown in Schemes I and 2 (157,164). The position of the methoxy group on the aromatic! ring was determined by comparison of UV spectra with that of IO-methoxy-1,2,3,4,5,6,12, 12b-octahydroindoloquinolizidine. The absolute configuration of this
X
48
I1 C
I T
I1 Z
I 0
M v,
s:
c,
49
I
z, ii
g
f "
c;'
I
R
I
E E
c
3
XZ
0
A0
2
3
n
3
3
' A
2
3
c
3
3
3
I
2
'j '6
n
3
3
2
Alkaloid N
CH2OH CH:
Exorncthylene compound
Cardfloramine IX-Demethoxy-
OH
CH:OMe
160
CH20Me
166
RI
R:
CHzOMc
H
H
Me
119EIgdrdiloramine
OMe
C::H!JOIN~ C2 I H ~ ~ O : JN
396
3%
159- I60
-24x" (CHCIII
I?.
mrrlr@ora
Makino G. nrrrlriflora Makino
165. I77 165
52
Me 0.
NOR10 AIM1 E T A L
q
,I H
Gardnerine (11
10
M
e
Ho
q
H
Me H
Gardnutine ( 2 1
Hydroxygardnutine ( 3 1
OH
‘OH
Gardneramine ( 4 )
HYdroxygardnerine (5)
SCHEME 1. Gardneria alkaloids isolated from Gardneria nutons Sieb. et Zucc.
Gardrierine ( 1 1
Gardnutine ( 2 )
\
11 H B r / A c O H 21
Zn/AcOH
SCHEME 2. Chemical correlation of Gardneria alkaloids.
group of alkaloids was determined chemically as shown in Scheme 3; compound 10 derived from 1was identical with the sample derived from ajmaline (11)of known absolute configuration. (158, 162). The structure of gardneramine (4), one of the main bases of G. nutans and also G. multiJIora, was chemically investigated (160, 166). The full structure of this alkaloid, including the location of methoxy groups on the
I . ALKALOIDS OF STRYCHNOS A N D GARDNERIA
53
HOCH,
q
10
"I
n
--q SCHEME 3
Me0 \Zl' 11'
19'
I8
11
Me0
32
aromatic ring and the configuration of double bond in the side chain, was established by X-ray crystallography of gardnerarnine cyanobromide (12) (C24H2XN30SBr. mp 2 14°C) (161). The absolute configuration was also determined, as indicated on page 58. The characteristic features of the structure of gardneramine are (1) the presence of an irninoether group that can be regarded as a masked oxindole, and (2) 2 orientation of the side chain double bond. With respect to the latter feature, gardneramine (4) was the first example of a natural indole alkaloid possessing a Z double bond between C I 9and C20. It is noteworthy that an accompanying minor alkaloid, 18-demethoxygardneramine (U), is the base with the conventional E-type double bond. Chemical removal of the rnethoxy function at C-18 of gardnerarnine (4) to
54
NOR10 AIM1 ET A L .
give 19-epi-l8-demethoxygardneramine(17) was effected as shown in Scheme 4.
M
e
O
a
Me0
dil HCI
OCH,
, OH
Me0
CI
J 1 3
Meo + IMeo OM
OMe
Me0
Br CI 14
CI
15
Me0
I6
CI
- Meo@6kL Me0
17
SCHEME 4
Comparative NMR studies were made for (I9 Z)-18-demethoxygardneramine (17) and natural (19 E)-demethoxygardneramine (18). Irradiation of the C-18 methyl protons of 18 caused a 9% enhancement of the signal strength of C-I5 H . while no enhancement was observed for the corresponding signals of 17 (164). "C N M R was also useful for clarification of geometry. The signals arising from C-IS and C-21 of 18 are observed at 629.8 and 649.4, respectively, while the corresponding signals of 17 appear at 636.8 and 646.5. These data indicate a y effect due to the C-18 methyl group on C-1.5 in compound 18 and the lack of such effect in compound 17;this observation proved to have important diagnostic value in solving the problem of Z or E geometry at C-19 (170). Similar observations of I3C-NMR chemical shifts were obtained for a pair of geometrical isomers, 19 and 20 (170), to establish the same regularity. Isomer 19 was prepared from 2 by Wolff-Kishner reduction, and 20 was obtained from 3 via the corresponding aldehyde (Scheme 5).
55
I . ALKALOIDS OF S T R Y C H N O S A N D G A R D N E R I A
ti Cp
7
-7
qcno Me H
H
reduction,
Me 0
1
0
7
H
MnO2, NHzNHz*HzO, KOH
Me 0
I 3 : R = CI120H
Me0
20
R
SCHEME 5
Plants of the G . multijloru group do not contain gardnerine (1) or its derivatives, which are characterized by their typical indole chromophore. The main constituent, gardneramine (41, and various accompanying alkaloids are all at the oxidation level of oxindole. As shown in Table 111, thirteen monomeric and two dimeric Gurdneriu alkaloids have been isolated, and most of the structures were elucidated through chemical correlation with the established structure of 4 (165,166,169,f72). Chitosenine (21) is an amorphous base isolated from G . multijloru whose name comes from the Japanese word for this plant, Chitosekazura. Chitosenine (21) consumed 1 mol equiv NaI04 to give the norketone (22), and 21 also gave the acetonide (23) on reaction with acetone under the usual conditions (Scheme 6). Mesylate 24 afforded oxirane derivative 25 in an aprotic solvent, while in a protic solvent iminoether 26 was generated. The UV and CD spectra of 26 were superimposable on those of gardneramine (4), supporting the assigned structure. Other minor G . multijloru alkaloids, alkaloids I, J, L, M, and N, together with gardfloramine, which possesses a methylene dioxy group on the aromatic ring, were also isolated (169).
56
NOR10 AIM1 ET A L
“
‘
O
N ?
Meo%
22
m
d’
CH
21
MsCI/Py
I DM F Me0
24
26
SCHEME 6
The structure of gardfloramine has recently been established as formula 27 by the use of X-ray crystallography. It is interesting to note that 27 has a pattern of oxidation on the aromatic ring different from that of gardneramine (4) and all other trimethoxylated Gardnevia alkaloids (177). Two bis-type indole alkaloids, gardmultin (28) and demethoxygardmultine (29). are contained in G . multiflorrr. Reduction of 28 with NaBH4 in acetic acid gave the dihydro derivative (30) (Scheme 7). Compound 30 is an a-amino alcohol, and oxidative cleavage of 30 by use of H I 0 4 gave chitosenine norketone (22) and gardneramine (4). The UV spectrum of 28 is quite similar to the absorption curve obtained from graphical sum-
I . ALKALOIDS OF S T R Y C H N O S A N D G A R D N E R I A
57
OMe
27
M=oq Meo
NaBH4
,,OCHi
ACOH
Me0 OMe
6Me
30
28
OMe
22
SCHEME 7
28
11HCOzH 2 ) -OH
-
A
t BuOK
t BuOH
SCHEME 8
'8
58
NOR10 AIM1 E T A L
mation of the respective curves of 21 and of 1,2-dihydrogardneramine, which was generated by reduction of 4 with NaBH4 and AcOH. The ethereal part of 28 was cleaved with formic acid, and subsequent hydrolytic removal of the formyl group gave compound 31 (Scheme 8). Gardmultine (28) was recovered when the 0-mesylate of 31 (i.e., 32) was treated with alkali. The 'H-NMR signal arising from the C-18' methyl group on the chitosenine part of gardmultine (28) is observed at 60.88 as a doublet. This anomalous high-field chemical shift can be explained by the anisotropic
Gardneramine Cyanobromide (12)
effect due to the aromatic ring in the other half, the gardneramine moiety. This was an important clue leading to elucidation of the stereostructure of gardmultine (28). The correctness of the elucidated structure was confirmed by Silverton and Akiyama (173) by means of X-ray analysis. Demethoxygardmultine (29) has a RI value closely similar to that of gardmultine (28) on thin-layer chromatography. Also their U V spectra, 'H-NMR spectra, and mass spectral fragmentation are quite similar, and the behavior of the alkaloids toward various acids is also similar. A n 'H-NMR signal arising from the 18-vinyl methyl group appeared at a highly shielded position (60.88). indicating that the molecular construction and the orientation of the C-19'-C-20' double bond were the same as those of gardmultine (2 8 ).The E configuration of the ethylidene group in the gardneramine moiety (lower half in the depicted structure) was elucidated by "C-NMR analysis in a similar way as described above (172). Conversion ofgardnerine (1) to pelirine (33) was attempted as shown in
59
1. ALKALOIDS OF S T R Y C H N O S A N D G A R D N E R I A
A cOCH2
AcOCHz 11
M e 0w " ' 2 NazCO3 I ~ ~a 0 % ~ K- C N
tBuOCl
" Hzo
'
Me0 35
I
HOCH t
M
e
nO o
q
H
I
HOCHt
I
I H
SCHEME 9
Scheme 9. Pelirine is a 2-acyl indole alkaloid isolated from RirwwlJirr pertikrttsis. Its structure was proposed as 33' (174) in which the position of the methoxyl group on the aromatic ring and CI, stereochemistry remained to be determined. Gardnerine acetate (34) was treated with cyanogen bromide in methanol to give 35. A series of reactions involving oxidation with t-BuOCI, decyanation with AcOH. N-methylation, and ultimate deacetylation afforded compound 38, possessing the same molecular formula as pelirine (33).The ultraviolet absorption maximum of 38 was observed at 344.5 nm, bathochromically shifted by about 16 nm from the literature value (328 nm) for 33. This suggested that the methoxyl group of 33 should be at the C-I0 position. I n agreement with this conclusion, the structure of pelirine was determined to be IO-methoxy-16epiaffinine (33) by means of X-ray crystallography (178). The conversion of gardnerine (1) to ochropine (39). a 2-acyl indole alkaloid isolated from the stem bark of Oclirositr p o w r i (175). was also carried out to establish structure 39 for the latter alkaloid. The reaction sequence is shown in Scheme 10. The nitrile function of 43 was converted to the carbomethoxy grouping by methanolysis. C-D ring cleavage with BrCN gave an epimeric mixture of C-3 hydroxyls which was then subjected to Cornforth oxidation to furnish 4.Decyanation of 46 and
60
NOR10 AIM1 ET A L MeOtC
M
e
Me
O N-,
CHI q ti Me 0 the
39
I
44
R1
H
H
40
CH20H
H
Me
41
CHO
H
Me
42
CH=NH
H
Me
13
CN
H
Me
-
aq T HBFr- C NN atCOI
R2 R 3
Gardnerine ( 1 ) CH20H
q -Me MeOtC
MeO
MeOtC
the 0
no
46:
R = CN
41:
R= H
39:
R = Me
45
SCHEME10
SCHEME I1
I . ALKALOIDS OF S T R Y C H N O S AND G A R D N E R l A
Me0
__*
mea
61
me 0
h 2 R 5
R= OH
50
R = OH
51
R = OCOCH3
53
R = OCOOCH3
54
52
SCHEME 12
reductive methylation of the resulting amino group g’ave the desired alkaloid, ochropine (39) (/7/). Lounasmaa and Koskenen proposed a biosynthetic scheme of a Gelsemium alkaloid, koumine (48,), from unnatural 18-hydroxydeoxysarpagine (49) as shown in Scheme I I (179). An I I-methoxylated congener corresponding to 49 is 18-hydroxygardnerine (51, a compound already known from leaves of G. nutcins and also obtained from hydroxygardnutine (3)through reduction with lithium aluminum hydride. By using 5 as the starting material, a biomimetic laboratory conversion to 1 1 methoxykoumine (55) was performed (180) (see Scheme 12). Treatment of 18-hydroxygardnerine (5) with methyl chloroformate afforded a C-D-cleaved compound (50) (Scheme 12). Following acetylation of the hydroxyl group of 50, the resulting ally1 acetate (51) was treated with sodium hydride to generate indole anion. Subsequent addition of triphenylphosphine and palladium acetate gave rise to a hepta cyclic compound (52) as a result of bond formation between C-7 and C-20 via a rr-ally1 complex of palladium. Under the same conditions carbonate 53 also afforded 52, though with a slightly lower yield. Compound 52, which possesses the fundamental skeletal construction of koumine (48). was then reduced with lithium aluminum hydride to the secondary amine (54). Subsequent oxidation with lead tetraacetate gave the target molecule I 1-methoxykoumine (55). All the physical data including U V , IR,
62
NOR10 AIM1 E T A L
T A B L E IV ACUTETOXICITY OF Gnrdnc.ritr ALKALOIDS I N MICE
Alkaloid
iv
iP
Gardneramine (4) 18-Demethoxygardneramine Alkaloid 1 Gardnerine (1) Gardnutine (2) Hydroxygardnutine (3)
I42
I84
I 50
-
128
-
69 49
I26
I20
300
300
‘H-NMR, and ”C-NMR spectra clearly indicated that the resulting compound (55) had the structure shown. CD spectral comparison of natural koumine (48) and the synthetic I I-methoxykoumine ( 5 5 ) proved that their absolute stereochemistry is identical.
IV. Pharmacology of Gardneria Alkaloids Gardneramine (4) exhibits a mild central depressive effect, while the comparable effect of gardnerine (1) is much weaker. A medium grade of acute toxicity was found for Grirdnrriri alkaloids. Low toxicity was observed for hydroxygardnutine (3). which should be compared with that of gardnutine (2) (176) (Table IV).
1. H. L. Homes. in “The Alkaloids” (R. H. F. Manske and H. L . Holmes, eds.) Vol. I, p. 375. Academic Press, New York, 1950. 2. H. L . Holmes, in “The Alkaloids” (R. H. F. Manske and H. L. Holmes, eds.). Vol. 2, p 513. Academic Press, New York, 1952. 3. J. B. Hendrickson, in “The Alkaloids” ( R . H. F. Manske ed.), Vol. 6 , p. 179. Academic Press, New York, 1960.
4. A. R. Battersby and H . F. Hodson. in “The Alkaloids” ( R . H. F. Manske, ed.), Vol. 8, p. S15. Academic Press, New York, 1965: G. F. Smith ihid, p.592. 5 . A. R. Battersby and H. F. Hodson. in “The Alkaloids” (R. H. F. Manske and H . L. Holmes, eds.), Vol. I I . p. 189. Academic Press, New York. 1968.
I . ALKALOIDS OF STRYCHNOS AND GARDNERIA
63
6. G. Massiot and C. Delaude, in “The Alkaloids” (A. Brossi, ed.). Vol. 34, p. 211. Academic Press, San Diego, 1988. 7. M. Hesse, “Indolalkaloide in Tabellen.” Springer-Verlag. Berlin, 1964. 8. M. Hesse, “lndolalkaloide in Tabellen, Ergaenzungrwerk.” Springer-Verlag. Berlin, 1968. 9. N. G. Bisset, in “Indole and Biogenetically Related Alkaloids” ( J . D. Phillipson and M. H., Zenk, eds.), p.27. Academic Press, London, 1980: M. V. Kisakurek, A. J. M. Leewenherg, and M. Hesse. in “Alkaloids: Chemical and Biological Perspectives” (S. W. Pelletier, ed.), Vol. 1, p. 211. Wiley (Interscience), New York, 1983. 10. N. G. Bisset and A. J. M. Leeuwenberg. Lloydiu 31, 208 (1968). 1 I . N. G. Bisset and J. D. Phillipson, Llovdiu 34, 1 (1971). 12. R. Verpoorte, Phurm. Weekhl. 113, 1249 (1978). 13. B. A. Krukoff, Lloydiu 35, 193 (1972). 14. G. B. Marini-Bettolo, K. A . Geneesk. Bergie 43, 185 (1981). 15. N. G. Bisset, Lloydia 29, 1 (1966). 16. N. G. Bisset and M. C. Woods, Llovdia 29, 172 (1966). 17. N. G. Bisset, Lloydiu 35, 95 (1972). 18. N. G. Bisset, Lioydiu 36, 179 (1973). 19. N. G. Bisset, Lbydiu 37, 62 (1974). 20. N. G. Bisset, Lloydia 39, 263 (1976). 21. A. Enpler. “Syllabus der Pflanzenfamilien.” Vol 2. Borntraeger. Berlin. 1964. 22. S. I. Heimberger and A. I. Scott, J. Chem. Soc.. Chem. Commun.. 217 (1973). 23. C. Coune and L. Angenot. Pluntu Med. 34, 53 (1978). 24. C. Coune, Plunt. Med. Phytother. 12, 106 (1978). 25. C. A. Coune and L. J. G. Angenot, Herb. Hung. 19, I89 (1980). 26. A. Petitzean. P. Rasoanaivo, and J. P. Razafintsalama, Phytochemistry 16, 154 (1977). 27. C. Coune and L. J . G. Angenot, Phytochemistry 17, 1447 (1978). 28. G. B. Marini-Bettolo, C. Galeffi, M. Nicoletti. and 1. Messana, Phytochemistry 19,992 ( I 980). 29. C. Galeffi, M. Nicolletti, 1. Messana, M. Patamia, and G. B. Marini-Bettolo, flunfu Med. 39, 208 (1980). 30. A. A. Olaniyi, W. N . A. Rolfsen. and R. Verpoorte, Plunta Med. 43, 353 (1981). 31. N. G. Bisset, K. H. C. Baser, J. D. Phillipson. L. Bohlin. and F. Sandberg, Lloydiu40, 546 (1977). 32. A. R. Battershy, R. Binks, H. S. Hodson, and D. A. Yeowell. J. Chem. Soc.. 1848 (1960). 33. A. R. Battersby and D. A. Yeowell. J. Chem. SOC.4419 (1964). 34. L. Angenot. Pluntu Med. 27, 24 (1975). 35. R. Verpoorte. M. J. Verziljl. and A. B. Svendsen, Pluntu Med. 44, 21 (1982). 36. K. H. C. Baser, N. G. Bisset, and P. J. Hylands, Phytochernistry 18, 512 (1979). 37. G. B. Marini-Bettolo. Furmuco, Ed. S c i . 25, I50 (1970). 38. A. Gugginsherg, M. Hesse, H. Schmid, and P. Karrer. Helu. Chim. Actu 49, I (1966). 39. M. Caprasse and L. Angenot, Pluntu Med. 42, 364 (1981). 40. M. Tits, M. Franz. D. Tavernier. and L. Angenot. Pluntu Med. 42, 371 (1981). 41. W. N. A. Rolfsen, A. A. Olaniyi, and P. Hylands, J. N u t . Prod. 43, 97 (1980). 42. W. Rolfsen, L. Bohlin, S. K. Yehoah. M. Geeveratne. and R. Verpoorte. Pluntu Med. 34, 264 (1978). 43. R. Verpoorte, F. T . Joosse, H. Groenink, and A. B. Svendsen. Pluntu Med. 42, 32 ( 1981 ). 44. R. Verpoorte, Pluntu Med. 39, 236 (1980).
64
NOR10 AIM1 ET A L
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I . ALKALOIDS OF STRYCHNOS A N D G A R D N E R I A
65
83. M. Koch, M. Plat, B. C. Das, E. Fellion, and J . LeMen, Ann. Pharm. Fr. 27, 229 ( 1969). 84. M. Koch, M. Plat, B. C. Das, and J . LeMen, Bull. Soc. Chim. Fr., 3250 (1968). 85. R. Verpoorte, H. Groenink, and A. Baerheim Svendsen, Planiu Med. 39, 388 (1980). 86. H. King, J. Chem. Soc., 955 (1949). 87. C. G . Casinovi, G. B. Marini-Bettolo, and N . G. Bisset, Naiitre (London) 193, 1178 (1962). 88. J. S. Grossert, J. M. Hugo, M. E. von Klemperer, and F. L. Warren, J. Chern. Soc.. 2812 (1965). 89. N. G. Bisset and J . D. Phillipson, J. Phorm. Phurmacol. 23, 244s (1971). 90. G. B. Marini-Bettolo, E. Miranda delle Monache, S. E. Giuffra, and C. Galefti, Gazz. Chim. Ital. 101, 971 (1971). 91. R. Verpoorte, E. W., Koda, H. van Doorne, and A . B. Svendsen, Planiu Med. 33,237 ( 1978). 92. M. Koch, J. Garnier, and M. Plat, Ann. Pharm. Fr. 30, 229 (1972). 93. A. Penna, M. A. Iorio, S. Chiavarelli, and G. B. Marini-Bettolo, Gazz. Chim. Ital. 87, 1163 (1957). 94. F. Delle Monache, E. Corio, and G. B. Marini-Bettolo, Ann. I s t . Super. Saniia 3, 564 (1967). 95. C. Galefti. M. A. Ciasca Rendian. E. M. delle Monache, A. Villar del Fresno. and G. B. Marini-Bettolo. J. Chrornutogr. 45, 407 (1969). 96. R. Starfati, M. Pais, and F.-X. Jarreau, Phyiochemisiry 9, I107 (1970). 97. A. W. Hill, Bull. Misc. Inf., R . Boi. Card.. 195 (1917). 98. H. G. Boit and L. Paul, Naturwissenschaften 47, 136 (1960). 99. H. T. Chang, Yu.-I. Tung, and C. C. Lou. Acia Pharm. Sin. 10, 365 (1963). 100. J. Pelletier and J. B. Caventou, Ann. Chim. Phys. 10, 142 (1819). 101. N. G. Bisset and M. D. Walker, Phyiochemistry 13, 525 (1974). 102. F. A. L. Anet, G. K. Hughes, and E. Ritchie, Ausi. J. Chem. 6 , 58 (1953). 103. F. H. Shaw and I. S. de la Lande, Ausi. J. Exp. B i d . Med. Sci. 26, 199 (1948). 104. J. Pelletier and J . B. Caventou, Ann. Chirn. Phys. 8, 323 (1818). 105. N. G. Bisset and P. Fousche, J. Chromaiogr. 37, 172 (1968). 106. G. B. Marini-Bettolo, M. A. Ciasca. C. Galeffi, N . G. Bisset, and B. A , . Krukoff, Phyiochemistry 11, 381 (1972). 107. N. G. Bisset and J . D. Phillipson, J. Phorrn. Phurmacol. 25, 563 (1973). 108. F. Sandberg, K. Roos, K. J . Ryberg, and K. Kristianson. Teiruhedron Lett., 6217 ( 1968). 109. F. Sandberg, K. Roos, K. J . Ryrberg, and K. Kristianson, Acia Pharm. Suec. 6 , 103 ( 1969). 110. N. G. Bisset and A. K. Choudhury, Phyfochemisiry 13, 265 (1974). 111. C. Galefti, M. Nicoletti, 1. Messana, and G. B. Marini-Bettolo, Tetruhedron 35, 2545 ( 1979). 112. K. Kambu, C. Coune, and L. Angenot, Plunia Med. 37, 161 (1979). 113. N. G. Bisset, C. G. Casinovi, C. Galeffi. and G. B. Marini-Bettolo, Ric. Sci.. Parie 2: Sez. B 35, 273 (1965). 114. N. G. Bisset, B. C. Das, and J . Parello, Teiruhedron 29, 4137 (1973). 115. N. G. Bisset and A. K. Choudhury, Phyiochemisiry 13, 259 (1974). 116. F. Jaminet, Lejeunia 15, 9 (1951). 117. F. Jaminet, J. Pharm. Belg. [N.S.] 8, 449 (1953). 118. N. G. Bisset, C. R . Hehd. Seances Acud. Sci. 261, 5237 (1965). 119. N. G. Bisset and A. A. Khalil. Phytochemisiry 15, 1973 (1976).
66
NOR10 AIM1 ET A L
120. W. F. Martin, H. R. Bentley. J . A. Henry, and F. S. Spring. J. Chem. Soc., 3603 (1952). 121. N. G. Bisset. A. K . Choudhury, and M. C. Walker, Phytochemistry 13, 255 (1974). 122. N . G. Bisset, Tetrahedron Lett.. 3107 (1968). 123. J . U. Oguakwa, C. Galeffi, I. Messana, R. L. Bua, M. Nicolletti, and G. B. Marini-Bettolo, Gazz. Chim.Itczl. 108, 615 (1978). 124. L. Angenot. C. Coune, and M. Tits, J. Pharm. Belg. 33, I I (1978). 125. L. Dupont. J. Lamotte-Brasseur, 0. Dideberg, H. Campateyne, M. Vermeire, and L. Angenot. Acta Crystallogr., Sec,t. B B33, 1801 (1977). 126. M. Koch and M. Plat, C. R. Seances Acud. Sci.. Ser. C 273, 753 (1971). 127. L. J . G. Angenot. C. A. Coune, M. J . G. Tits. and K. Yamada, Phytochemistry 17, 1687 (1978). 128. M. Caprasse. D. Tavanier, and L.. Angenot. J. Pharrn. BeIg. 38, 211 (1983). 129. C. Richard, C. Delaud, L. LeMen-Olivier, and J . LeMen, Phytochemistry 17, 539 (1978). 130. L. J. G. Angenot and N. G. Bisset, J. Pharm. Belg. 26, 585 (1971). 131. C. A. Coune, L. J. Angenot, and J. Denoel, Phytochemistry 19, 2009 (1980). 132. 0. Dideberg, L. Dupont, and L. Angenot, Acta Crystallogr., Sect. B B31, 1571, (1975). 133. L. Angenot, Plant. Med. Pkyrother. 12, 123 (1978). 134. 0. Dideberg, J. Lamotte-Brasseur, L. Dupont. H. Campsteyne, M. Vermeire, and L. Angenot. Acta Crystallogr., Sect. B B33, 1796 (1977). 135. R. Verpoorte and A. B. Svendsen, Llciydia 39, 357 (1976). 136. R. Verpoorte, E. W. Kodde, and A. Baerheim-Svendsen, Planta Med. 34, 62 (1978). 137. F. Delle Monache. P. T. Aldo. and G. B. Marini-Bettolo, Tetrahedron Lett., 2009 (1969). 138. H. Asmis. P. Waser, H. Schmid, and P. Karrer, Helu. Chim. Actu 38, 1661 (1955). 139. M. J. G. Tits and L. Angenot. Plrrnta Med. 34, 57 (1978). 140. R. Verpoorte and A. B. Svendsen, J. Pharm. Sci. 67, 171 (1978). 142. J. Larnatte. L. Dupont, 0. Dideberg, K. Kambu. and L. Angenot, Tetrahedron Lett., 4227 (1979). 143. L. R. McGee, G. S. Reedy, and P. N. Confalone. Te/rrihedron Lett. 25, 2115 (1984). 144. M. Koch. M. Plat, and J . LeMen, Tetruhedron 25, 3377 (1969). 145. L. Angenot and A. Denoel, Pluntu Med. 23, 226 (1974). 146. A. L. Skaltsounis, S. Michel. F. Tillequin, and M. Koch, Tetruhedron Lett. 25, 2783 (1984). 147. M. Tits, D. Tavernier, and L. Angenot. Phytochemistry 24, 205 (1985). 148. F. C. Ohiri, R. Verpoorte. and A. B. Svendsen, Plantu Med. 50, 446 (1984). 149. J . Leclercq and L. Angenot. PIantu Med. 50, 457 (1984). 150. M. Caprasse. L. Angenot. D. Tavernier. and M. J. 0. Anteunis, Plantu Med. 50, 131 (1984). 151. T. Y. Au, H. T. Cheung, and S. Sternhell. J . Chem. Soc.. Perkin Trans. 13 (1973). 152. J. D. Phillipson and S. R. Hemmingway, Plzytochemistry 13, 973 (1974). 153. N. G. Bisset and J . D. Phillipson. Phytochemistty 13. 1265 (1974). 154. R. Verpoorte. A. B. Svendsen, and F. Sandbert, Actu Phurm. Sitec. 12, 455 (1975). 155. R. Verpoorte and F. Sandberg. Ac./ci Pliurm. Sitec. 8, I19 (1971). 156. J . Haginiwa. S. Sakai, A. Kubo, and T . Hamamoto, Yakrigcikrr Zasshi 87, 1484 (1967). 157. S. Sakai, A. Kubo. and J . Haginiwa. Tetruhedron Lett., 1485 (1969). 158. S. Sakai. A. Kubo. T. Hamamoto. M. Wakabayashi, K . Takahashi. Y. Ohtani, and J. Haginiwa. Tetrcihedron Lett.. 2057 (1971). 159. J . Haginiwa. S. Sakai. A. Kubo. K. Takahashi, and M. Taguchi. Yakugakrt Zasshi 90, 219 (1970).
I . ALKALOIDS OF S T R Y C H N O S A N D G A R D N E R I A
67
160. S. Sakai, N . Aimi, A. Kubo, M. Kitagawa, M. Shiratori. and J. Haginiwa, Tetruhedon Lett., 2057 (1971). 161. N . Aimi, S . Sakai, Y. litaka, and A. Itai, Tetruhedron Lett.. 2061 (1971). 162. S. Sakai, A . Kubo, T . Hamamoto, M. Wakabayashi, K. Takahashi, H. Ohtani, and J. Haginiwa. Chem. Pharm. Bull. 21, 1783 (1973). 163. S. Sakai, A. Kubo, K. Katano, N . Shinma, and K. Sasago, Yukugaku Zasshi93, I165 (1973). 164. S. Sakai, N. Aimi, K. Katano, H. Ohhira. and J. Haginiwa, Yukrcgaku Zasshi 94, 225 (1974). 165. S. Sakai, N. Aimi, K. Yamaguchi, H . Ohhira. K . Hori, and J. Haginiwa, Tetruhedron L e t f . . 715 (1975). 166. S. Sakai, N . Aimi, K. Yamaguchi, E. Yarnanaka. and J . Haginiwa. Tetruhedron Lett.. 719 (1975). 167. S. Sakai, N . Aimi. A. Kubo, M. Kitagawa, M. Hanasawa, K. Katano. K. Yamaguchi, and J. Haginiwa, Chew?.Pharm. Bull. 23, 2805 (1975). 168. S. Sakai, Heterocycles, 4, 131 (1976). 169. S . Sakai. N . Aimi, K. Yamaguchi, K. Hori. and J . Haginiwa. Yukugukir Zusshi97, 399 (1977). 170. N. Aimi, K. Yamaguchi, S . Sakai, J. Haginiwa. and A. Kubo, Chem. Pharm. Bull. 26, 3444 (1978). 171. S . Sakai, Y. Yamamoto, and S . Hasegawa. Chern. Phcinn. Bull. 28, 3454 (1980). 172. S . Sakai, N. Aimi, K. Yamaguchi, E. Yarnanaka, and J. Haginiwa, J . Chem. Soc., Perkin Trans. 1, 1257 (1982). 173. J. V. Silverton and T. Akiyama, J . Chem. Soc.. Perkin Truns. 1, 1263 (1982). 174. A. K. Kiang and A. S. C. Wan, J . Chem. Soc.. 1394 (1960); J . A. Weisbach and B. Douglas, Chem. I n c . (London). 623 (1965). 175. B. Douglas, J . L. Kirkpatrick, B. P. Mappre. and J. A. Weisbach. Aust. J . Chem. 17, 246 ( 1964). 176. M. Harada, Y. Ozaki. S . Murayama. S . Sakai. and J. Haginiwa, Yakrcguku Zasshi 91, 997 (1971); M. Harada. Y. Ozaki, and H. Ohno, Chem. Phurm. Bull. 27, 1069 (1979): Y. Ozaki, Ph.D. Dissertation, Chiba University (1983). 177. S. Sakai, N . Aimi, K. Yamaguchi, K . Ogata, and J . Haginiwa. Chem. Pharm. Bull. 35, 453 (1987). 178. A. S . C . Wan, M. Yokota, K. Ogata. N. Aimi, and S . Sakai, Heferocycles 26, 1211 (1987). 179. M. Lounasmaa and A. Koskinen. Pluntu Med. 44, 120 (1982). 180. S. Sakai, E. Yamanaka, M. Kitajima. M. Yokota, N . Aimi, S . Wongseripipatana, and D. Ponglux. Tetrahedron Lett. 38, 4585 (1986). 181. P. Thepenier, M. J. Jacquier, G . Massiot. L. LeMen-Olivier, and C. Delaude, Phytochemistry 23, 2659 (1984). 182. S . Michel, A . L. Skaltsounis. F. Tillequin, M. Koch, and L. A. Assi. J . N u t . Prod. 48, 86 (1985). 183. G . Massiot, P. Thepenier, M. J. Jacquier, C. Delaude. and L. LeMen-Olivier, Tetruhedron Lett. 26, 2441 (1985). 184. R. Verpoorte, G . Massiot, M. J. Jacquier, P. Thepenier. and L. LeMen-Olivier. Tetruhedron L e f t . 27, 239 (1986). 185. P. Forgacs, A. Jehanno. J . Provost. C . Thal, J. Guilhem. C. Pascard, and C. Moretti, Phytochemistry 25, 969 (1986). 186. S . Michel, F. Tillequine. and M. Koch, J . N u t . Prod. 49, 452 (1986). 187. s. Michcl, F. Tillequin. and M. Koch. J . C / J C , I ISoc... J. Chcm. C’ommun., 229 (19x7).
68
NOR10 AIM1 E T A L
188. D. Tavanier, W. Zhang, L. Angenot, M. Chierici-Tits, and J. Leclercq, Phytochem i s t y 26, 557 (1987). 189. S. I. Heimberger and A. 1. Scott, J. Chem. Soc.. Chem. Commun.. 217 (1973). 190. H. Asmis, H. Schmid. and P. Karrer. Helu. Chim. Acra 37, 1983 (1954). 191. H. King, J. Chem. Soc., 3263 (1949). 192. G. B. Marini-Bettolo, M. A. Jorio, A. Pimenta, A. Ducke, and D. Bovet, Gazz. Chim. Ira/. 84, 1161 (1954). 193. J. Kebre, H. Schmid, P. Waser, and P. Karrer, Helu. Chim. Acra 36, 345 (1953). 194. A. Pimenta, M. A. Jorio, K. Adank, and G. B. Marini-Bettolo, Guzz. Chim. Ira/. 84, I147 (1953). 195. K. Adank, D. Bovet, A. Ducke, and G. B. Marini-Bettolo, Gnzz. Chim. Iiul. 83, 966 (1953). 196. H. Wieland, K . Baehr, and B. Witkop, Justrrs Liebigs Chem. A n n . 547, 156 (1941). 197. G. B. Marini-Bettolo, P. de Berredo Carneiro, and G. C. Casinova, Gazz. Chim. Ira/. 86, I148 (1956). 198. G. B. Marini-Bettolo, M. Lederer, M. A. Jorio, and A. Pimenta, Gazz. Chim. Ira/. 84, 1155 (1954). 199. F. A. L. Anet and R. Robinson, J. Chem. Soc., 2253 (1955). 200. N. G. Bisset, J. Bosly, B. C. Das, and G. Spiteller, Phytochemis/ty 14, 141 1 (1975). 201. J. Bosly, J . Phurm. B d g . 6 , 150, 243 (1951). 202. M. Spiteller-Friedmann and G. Spiteller, Justirs Liebigs Ann. Chem. 712, 179 (1968). 203. R. Verpoorte and A. B. Svendsen. Phytochemistry 13, 201 1 (1974).
- Chapter 2 LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS OSAMU
HOSHINOA N D BUNSUKE UMEZAWA' Fuculiy of Phurniuc~euticulSciences Science University of Tokyo Shinjuku-ku, Tokyo, Japan
I. Introduction............................................................................. ......
70 72 A . From I-Benzyl-l,2,3,4-tetrahydro-6-methoxy-2-methylisoquinolin-7-ols72 B. From I-Benzyl-l,2,3,4-tetrahydro-7-methoxy-2-methylisoquinolin-6-ols78 C . From I -Benzyl-1,2,3,4-tetrahydro-6-methoxy-2-methylisoquinolin-5-ols 80 D. From 1,2,3,4-Tetrahydro-l-(3-hydroxy-4-methoxybenzy1)isoquinolines 82 83 Ill. C-Homoaporphines ......................................................................... A. From 1,2,3,4-Tetrahydro-6-methoxy-1-phenethylisoquinolin-7-ols 83 B. From 1,2,3,4-Tetrahydro-7-methoxy-I-phenethylisoquinolin-6-ols ....... 87 C. From 1,2,3,4-Tetrahydro-6-methoxy-I-phenethylisoquinolin-5-ols ....... 89 IV. Homoproaporphines ................ ...................... 90 91 V. Morphinandienones and Homom V1. lsopavines and Homoisopavines 94 95 VII. Benzo[c]phenanthridines .................................................................. VIII. 10-Hydroxy-2,3,9-trimethoxydibenzopyrrocoline .................................. 96 IX. Tetrahydroprotoberberines .......... 97 X. Indole Alkaloids ............................................................................. 98 A. Yohimbine Alkaloids ......................... .......................... ............... 98 103 C. Ajmaline Alkalo ................................................ 104 D. Iboga Alkaloids ................................................ 106 XI. Oxoaporphines ..... ........................... ................. 110 Ill A. Aporphines and C-Homoaporphines 112 112 B. Homoproaporphines ................................................................... I I3 120 D. Cularidines ............................................ ........ .. ...... .. 121 F. Simple Isoquinolines and I-Benzylisoquinolines...... ............... ......... 124 G . Spirobenzylisoquinolines ............................................................. 125 XIII. Miscellaneous Reactions ............................................ ...................... 126 130 References 11. Aporphines ....................................................................................
t Deceased M a y 24, 1988. 69
THE ALKALOIDS. VOL. 36 All
Copyrighi C 19x9 by Academic Press. Inc. right\ of reproduction in any form reserved.
70
OSAMU HOSHINO A N D B U N S U K E UMEZAWA
I. Introduction
Lead tetraacetate (LTA) has been one of the most important oxidants in organic synthesis ( 1 4 ) . Representative types of reactions on a variety of functionalities mediated by LTA are dehydrogenation, oxidative decarboxylation, oxidative demethylation, oxidative fragmentation, and bridged aziridine formation among others. One prominent feature of LTA is displayed in the formation of so-called o- or p-quinol acetates when applied to phenols ( 5 ) . The acetates have been a fascinating target for the study of molecular migrations since they are cyclohexadienones incorporating an allylic acetate moiety ( 6 ) . With respect to reactivity, whereas phenols are nucleophilic, the acetates are electrophilic. In other words, umpolung of the former is achieved with the aid of LTA. Since the mid-1950s, phenol oxidative coupling (7) has been actively applied to the synthesis of many types of alkaloids, with considerable progress being achieved especially in the field of isoquinoline alkaloids (8-ff).As to aporphine synthesis, employment of new reagents such as vanadium oxyfluoride (12) greatly improved yields as compared to classical methods such as oxidation with potassium ferricyanide and ferric chloride. In the early 1970s, our attention was directed to the Wessely acetoxylation (13). LTA oxidation of phenolic tetrahydroisoquinolines was exploited in our laboratory to give the corresponding p-quinol acetates, which were proved to be the reactive intermediates for the aporphine synthesis (14-15); that is, when an electron-rich benzene ring was present in a given p-quinol acetate, C-C bond formation occurred intramolecularly on its acid treatment. Since many isoquinoline alkaloids incorporate a guiacol moiety, we first tried to oxidize the most accessible 6-methoxy- and 7-methoxy- 1,2,3,4tetrahydroisoquinolinols (types A and B) with LTA. Later, tetrahydroisoquinolinols of type C were also used. In spite of Wessely’s statement (16) that LTA oxidation of both vanillin and isovanillin affords the corresponding o-quinol acetates, for a while we were able to obtain not the o-quinol acetate 2 from corypalline (1) but the p-quinol acetate 3 (17). At the outset of our study (18), LTA oxidation of isocorypalline (4) gave no isolable o-quinol acetate 5 , 4-acetoxyisocorypalline (6) being isolated instead. Recently, however, we solved the seeming discrepancy by modifying the choice of the solvent in LTA oxidation (f9,20).As expected, LTA oxidation of 1 in dichloromethane (CH2CI2)at 0°C gave 2, treatment of which with acetic acid (AcOH) furnished 3 (Scheme I ) . Analogously, it was confirmed that I ,2,3,4-tetrahydro-5-hydroxy-6-methoxyand 8-
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
"' HW
N
M
e
71
Me
Me0
Me
s
' OH
n=l, 2 R - H , OMe, R1 = R 2 = 0 M e , R ~ R~ + =OCH.~
hydroxy-7-methoxy-2-methylisoquinolines (7 and 8) gave the corresponding o-quinol acetates 9 and 10 by LTA oxidation. As for the mechanistic details of the formation of the o- and p-quinol acetates, Harrison and Norman (21) have provided a full discussion. Thus, appropriate p- or o-quinol acetates are used for successful synthesis of some isoquinoline
1
3
2
L'&N M e M e 0m N M e L MA c Oe
Me&
NMe
W
M
OH
7
9
8
10
R e a g e n t s : a . Pb(OAc)4, AcOH;b. P b ( O A c I 4 , CH2CI2;c. A ~ O H ;t i . 30°c
SCHEME I
e
72
OSAMU HOSHINO AND BUNSUKE UMEZAWA
alkaloids (22,23), and other characteristic reactions caused by LTA oxidation are nicely applied to the synthesis of some indole alkaloids as reviewed in this chapter.
11. Aporphines
Aporphine synthesis is classified in this section into four subsections A,
B, C, and D according to the location of the guiacol-type oxygenation pattern. A. FROM I-BENZYL-I ,2,3,4-TETRAHYDRO-6METHOXYlSOQUlNOLIN-7-OLS
Aporphine synthesis via a p-quinol acetate was first achieved in our laboratory (14,15). LTA oxidation in AcOH of (&)-codamine (11) gave a p-quinol acetate (12)(Scheme 21, the structure of which was characterized by spectroscopic means. Treatment of acetate 12 with acetic anhydride in the presence of concentrated sulfuric acid gave (+)-0-acetylthaliporphine
MH
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y
-
-..H M e
a
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e
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o
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-
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I
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e
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Me
OMe
' OMe
12
Me0
'
OMe
13
l4
OMe
OMe
17
16
Reagents: a. Pb(OAd4, A c O H ; b . Ac20, c.H+04;
d . LIAIH4, T H F ; e. CH2N2. MeOH
SCHEME 2
Id
OMe
15 c . LINHCI, MeOH;
e
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
73
(13) and a diastereomeric mixture of (~)-4-acetoxy-O-acetyIthaliporphines (14) in 18 and 8% yield, respectively. Hydrolysis of 13 gave (+)-thaliporphine (16). Although 14 was resistant to hydrogenolysis, its reduction with lithium aluminum hydride (LAH) also gave 16. The intermediate responsible for the above conversion of 14 to 16 seemed to be a quinone methide (15) (24, hydride addition to which completed the reaction. Methylation of 16 with diazomethane led to (+)-glaucine (17) (Scheme 2). Later, we carefully reexamined the reaction (25).Thus, in addition to the improved yield (32.4%) of 13, (+)-4p- and (*)-4a-acetoxy-Oacetylthaliporphines (18 and 19) were obtained separately. Diastereomer 18 was a key compound leading to (?)-cataline (357) (26) (see Section XILA). LTA oxidation followed by analogous treatment of (f)-l-(3,4methylenedioxybenzyl) congener 20 afforded (+)-0-acetyldomesticine (22) and (+)-4p- and (+)-4a-acetoxy-O-acetyldomesticines(23 and 24) in 18,4.7, and 5.5% yield, respectively, via 21. Similar hydrolysis of 22 gave (+)-domesticine (25), methylation of which with diazomethane led to (+)-nantenine (26) (27). Interestingly, LTA oxidation of 11 in a mixture of trifluoroacetic acid (TFA) and CH2C12was shown to give 16 and 27 in 10 and 20.2% yield, respectively (25) (Scheme 3).
16
21
26
25
Reagents: a . P b ( O A c ) 4 , AcOH; b . A q O , C . H $ q
;
c . 4NHCI. dioxane;
d . C H L N ~ ,MeOH; e . Pb(OAc)4, CF3COOH, CHfil2
SCHEME 3
74
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
The above-mentioned procedure inevitably resulted in the formation of 0-acetylaporphines. Hence their hydrolysis was prerequisite for the synthesis of natural aporphines. In addition, formation of the undesirable 4-acetoxyaporphines was a problem. Hara et af. (28) found a useful procedure to solve the problem. TFA in CH2Cl2 was confirmed to be the most effective reagent for the desired cyclization. LTA oxidation in AcOH of 11 gave p-quinol acetate 12, treatment of which with TFA in CH2C12 led to (+)-thaliporphine (16) in 96% yield. Similarly, (+)-domesticine (25) was prepared in 83.6% yield via 21 derived from 20. As expected, no 4-acetoxyaporphines were detected in the reaction. By the same procedure, (?)-l-hydroxy-2,9,10, I I-tetramethoxyaporphine (29) was obtained in 48% yield from the corresponding (*)- 1,2,3,4-tetrahydro2-methylisoquinolin-7-01 (28) (Scheme 4). Aporphines having various oxygenation patterns in ring D were also synthesized by a similar' methodology (29). Starting from (+)-1-(4benzyloxy-3-methoxybenzy1)- and (~)-I-(3-benzyloxy-4-methoxybenzy1)- 1,2,3,4-tetrahydro-6-methoxy-2-methylisoquinolin-7-ols (30 and 31),
75
2. L E A D TETRAACETATE O X I D A l I O N IN ALKALOID SYNTHESIS
(&)-lo-and (t)-9-benzyloxy-aporphines(32 and 33) were obtained in 48 and 44% yield, respectively. Hydrogenolysis of 32 and 33 gave (2)-bracteoline (34) and (2)-isoboldine ( 3 3 , respectively. On the other hand, methylation of 32 and 33 afforded (?)- 10- and (?)-9-benzyloxy-trimethoxyaporphines 36 and 37, debenzylation of which led to (+)-10-hydroxy1,2,9-trimethoxyaporphine(38) and (?)-N-methyllaurotetanine (39). respectively (Scheme 4). Furthermore, LTA oxidation followed by similar treatment of (k)-I ,2,3,4-tetrahydro-6-methoxyI -(3-methoxybenzyl)-2-methylisoquinoh-7-01 (40) gave (2)-isothebaine (41) and so-called lirinine, (*I- I hydroxy-2,9-dimethoxyaporphine(42), in 22 and 53% yield (30). As for lirinine, however, nonidentity of 42 with natural lirinine (31) was confirmed (30) and the originally proposed structure (i.e., 42) for the alkaloid was revised to (-)-3-hydroxy-l,2-dimethoxyaporphine (43) (32,331. Methylation of 42 with diazomethane gave (*)-I ,2.9-trimethoxyaporphine (44)(Scheme 5 ) . Analogously, (k)-l-hydroxy-2,1O-dimethoxy9-phenoxyaporphine (46) was obtained in 49% yield from (*)-I ,2,3,4tetrahydro-6-met hoxy- 1 -(4-methoxy-3-phenoxybenzyl)-2-methylisoquinolin-7-01 (45). Reductive dephenoxylation of 46 with sodium in liquid ammonia (34) gave (+)-l-hydroxy-2,IO-dimethoxyaporphine(47). methylation of which afforded (?)-I ,2,IO-trimethoxyaporphine(48).
40
43
42
41
C
44 Reagents:
(1.
Pb(OAc4, ACOH; b . CF3COOH, CH2C12;
c . CH2N2, MeOH
SCHEME 5
76
OSAMU HOSHlNO AND BUNSUKE UMEZAWA
Methylation of 46 with diazomethane led to (+)-I ,2, IO-trimethoxy-9phenoxyaporphine (49), reductive dephenoxylation of which caused concomitant demethylation (35)to lead to (?)-2,IO-dimethoxyaporphine (50) (30) (Scheme 6).
'
MHO e
Me0
y
M "H
e
a,b
'
M
Me0
:
p
M "He
M
'
:
Me0
I
F
M
...eH
'
OPh
45
P h 'C6H
Mep /
Me0
\
"H NMe
Me M
Me0
e
y
MH
%
e
:
\
Me0
OPh
50
I /y
' 48
49
Reagents :
M ".H e
(I.
P b ( O A c 4 , ACOH ; b. CFSOOH, CH$12,
C'.
Na, liq.NHj,
toluene,
-78OC;
If.
CH2N2, MeOH
SCHEME 6
Recently, Szantay et af. (36) obtained (&)-isoboldine (35) in 14% yield accompanied by a small amount of (+)-salutaridine (52)(see Section V) on LTA oxidation of (&)-reticuline (51)in the presence of trichloroacetic acid (Scheme 7 ) . Surprisingly, TFA treatment in CH2C12of the p-quinol acetate derived from (+)- I-benzyl-8-chloro- 1,2,3,4-tetrahydroisoquinolin-7-ols gave three products (37,38),in spite of the expectation that the reaction might afford 8-chloromorphinandienones 58 and 59 only. Thus, (?)-8-chlorocodamine (53) and (+)-8-chloro- I -(3,4-methylenedioxybenzyl)congener (54) (39,40) gave (+)-4P-hydroxythaliporphine (27)and (+)-4p-hydroxydomesticine (55)in 23 and 6% yield, respectively. The other products, (+)-9-chloroisopavines (56 and 57) and (+)-8-~hloromorphinandienones(58 and 59), are described in Sections V and VI.
M:p ':? M:p '$ 77
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
M
/H
Me
'
y Me
(I
0
Me0
OH
+
"H
%: M
I lrMe
'
51
Me0
0
35
*..H
b, c
52
"H
+
Me@ H
0
R
'
R
R
53 54
I IJMe
CI
'
R=Me
R + R=CH2
CI
Me0
+
R
27 55
58 59
56 51
R e a g e n t s : a. P b ( O A d 4 , C C I p O H , CtipZI2, - 7 8 ' C ;
b . Pb(OAc)4, &OH;
c . CF$OOH,
CHfi12
SCHEME7
Coutts et al. (41) reported that LTA oxidation in AcOH of (+)-2-trifluoroacetyl- 1,2,3,4-tetrahydro-6-methoxy- I -(3,4,5-trimethoxybenzyl)isoquinolin-7-01 (60) gives p-quinol acetate 61, TFA treatment in CH2C12of which affords in 35% yield (+)-6-trifluoroacetyl-l-hydroxy-2,9,10,1 Itetramethoxynoraporphine (62). Further methylation of 62 with methyl iodide and sodium hydride gave (2))-6-trifluoroacetyl-I,2,9,10, I 1pentamethoxynoraporphine (63) (Scheme 8). The above reaction was applied to the synthesis of noraporphines (42). LTA oxidation in CH2C12 of (+)-2-trifluoroacetyl-1,2,3,4-tetrahydro-l(3,4-dimethoxybenzyl)isoquinolin-7-ol64 gave the relatively stable o-quinol acetate 66, which was converted to p-quinol acetate 67 on treatment with AcOH (43). Similar oxidation in AcOH of 64 gave the same p-quinol acetate 67. Treatment of both quinol acetates 66 and 67 with TFA in CH2Clz afforded (+)-6-trifluoroacetyl- 1 -hydroxy-2,9,10trimethoxynoraporphine (68) in 61 and 65% (43) yield, respectively. Similarly, (~)-2-trifluoroacetyl-l,2, 3, 4-tetrahydro-l-(3, 4-methylenedioxybenzyl) congener 65 was converted to (+)-6-trifluoroacetylnoraporphine 70 in 21% yield via o-quinol acetate 69. Removal of the trifluoroacetyl group was effected by aqueous potassium carbonate in hot
78
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
R e a g e n t s : a . P b ( O A d 4 , AcOH; b. CF3COCH, C y C 1 2 ; c. Pb(OAc14, CH2Cb; d . AcOH; e . a q . K 2 C 0 3 , MeOH,A; f . NaH, Me1
SCHEME 8
methanol. Thus, (2)-wilsonine (71)and (+)-nordomesticine (72)were prepared near quantitatively from 68 and 70, respectively, while (?)-norglaucine (75)and (*)-nornantenine (76) were obtained via 73 and 74 (42) (Scheme 8).
B. FROMI-BENZYL-I ,2,3,4-TETRAHYDRO-7-METHOXY2-METHYLISOQUlNOLIN-6-OLS
We confirmed that LTA oxidation in CHzClz of (+)-1,2,3, 4-tetrahydro- 7-methox y - I - (3 ,4dimethox ybenzyl)- 2 -meth ylisoquinolin-6-01 (77)gives quantitatively the corresponding reactive o-quinol acetates 81 as a diastereomeric mixture (Scheme 9) and that treatment of the quinol acetates with acetic anhydride containing concentrated sulfuric acid
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
79
produces (+-)-0-acetylpredicentrine(82) in 3 1.8% yield (44,45).Similarly, (?)-I ,2,3,4-tetrahydro-l-(3,4-methylenedioxybenzyl)congener 78 was converted to (2)-0-acetylisodomesticine (83) in 16.1% yield. Hydrolysis of 82 and 83 with potassium hydroxide in methanol gave (*)-predicentrine (84) and (?)-isodomesticine (851, methylation of which with diazomethane gave (?)-glaucine (17) and (*)-nantenine (26), respectively. Analogously, (?)- 1-(3-benzyloxy-4-methoxybenzyl)- and ( 2 ) 144benzyloxy -3 - methoxybenzy1)- I ,2,3,4- tetrahydro-7-methoxy-2-methylisoquinolin-6-01s (79 and 80) were convertible to (?)-O,O-diacetylboldine (86) and (2)-2,10-diacetoxy-1,9-dimethoxyaporphine (87) in 41.7 and 36.9% yield, respectively. Hydrolysis of 86 and 87 afforded (-+)-boldine (88) and (?)-2,lO-dihydroxy-l,9-dimethoxyaporphine(89) (Scheme 9). The cleavage of an aryl benzyl ether by an acetyl carocation is well documented (46). When a mixture of concentrated sulfuric acid and acetic anhydride was diluted in a given solvent, a dramatic change in products was observed, and a new route to catechol-type aporphines was thus developed (47). Acid treatment of o-quinol acetate 81 derived from 77 was conducted in CHzClz to afford (2)I ,2-diacetoxy-9,10-dimethoxyaporphine(90) and (+-)-0-acetylpredicentrine(82) in 13.2 and 18.5% yield, respectively (Scheme 10). Hydrolysis of 90 with 1096 hydrochloric acid gave (*)-1,2dihydroxy-9,IO-dimethoxyaporphine(911, whereas methylation (48)of 90 with diazomethane furnished directly (?)-glaucine (17). The same reaction as above in acetonitrile was more favorable for the formation of the diacetoxyaporphine 90. Thus, 90 and 82 were formed in 52 and 15% yield, respectively. A highly efficient synthesis of the (*)-diacetoxyaporphine 90 was achieved by conducting the reaction in a 2.5-fold volume of
M:yM:
80
RO
OSAMU HOSHINO AND BUNSUKE UMEZAWA
'
Me0
Reagents:
'
(1.
P b ( 0 A c l q . CH2C12; 1 , .
c .
IO'hHCI, ( 1 . CH2Ni,
A r L O , c . H - 5 0 q . CH2C120r CHJCN.
hWOH
SCHEME 10
acetonitrile, the yield being raised to 63.5%. Analogously, the o-quinol acetate derived from 78 was converted to (*)-I ,2-diacetoxy-9,10methylenedioxyaporphine (92)in 70.9% yield. On the other hand, the o-quinol acetate 81 derived from 77 when treated with concentrated sulfuric acid in methanol unexpectedly afforded two diastereomeric mixtures of p-quinol methyl ethers 93 and 4-methoxylated compound 94 in 40 and 12.4% yield, respectively (49) (Scheme 11). Treatment of 92 with acetic anhydride containing concentrated sulfuric acid ensured cyclization to give (5)-0-acetylthaliporphine (13)in 60% yield. Similarly, (?)-0-acetyldomesticine (22)was also prepared in 71.8% yield from the p-quinol methyl ether 95,which was formed together with 96 on LTA oxidation of 78 (50).
c. FROMI -BENZYL-1,2,3,4-TETRAHYDRO-6-METHOXY2-METHYLlSOQUlNOLIN-5-OLS
The above-mentioned procedure for aporphine synthesis starting from 7- and 6-tetrahydroisoquinolinolswas applied to tetrahydroisoquinolin-501s (Scheme 12). LTA oxidation in CH2CI2of (*)-1,2,3,4-tetrahydro-6methoxy-l-(3,4-dimethoxybenzyl)-2-methylisoquinolin-5-ol (97)was per-
81
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
Me0 m ?e '
'
RO
'
a
'ti
A
OMe C
RO
OR
-
e
'
M e o $ M e i I F
RO
R
81
77 78
'W Y
'
RO
R
e
' R
94
R=Me
96
R=Me
R +R=CH
2
OR
13 22 R e a g e n t s : a . Pb(OAc)q, CH2C12; b . MeOH, c.%SOq;
C.
A c ~ O , c.HzSq,
SCHEME1 1
97 100
R=Me R
+
R=CH 2
98 101
99 102
R e a g e n t s : a . Pb(OAc)q, CH2CI2; b . CF3COOH. C H Z C I ~
SCHEME12
82
OSAMU HOSHINO A N D B U N S U K E UMEZAWA
formed to give a diastereomeric mixture of the o-quinol acetates 98, TFA treatment in CHzClz of which furnished (+)-3-hydroxy-2,9,10-trimethoxyaporphine (99) in 73% yield. Similarly, (?)-l-(3,4-methylenedioxybenzyl) congener 100 led to (+)-3-hydroxy-9,lO-methylenedioxyaporphine (102) in 87% yield via o-quinol acetate 101 (51 32). D. FROM1,2,3,4-TETRAHYDRO-l-(3-HYDROXY-4-METHOXYBENZYL)ISOQUINOLINES
LTA oxidation of (+)-laudanine (103) under the above conditions readily gives the o-quinol acetate 104, TFA treatment of which as usual produces two compounds ( 5 3 3 ) ;one is (?)-N-methyllaurotetanine (39) (17% yield) and the other (?)-I ,2,3,4-tetrahydro-I-hydroxy-6,7-dimethoxy-2-methylisoquinoline (105) (56% yield) (Scheme 13). The yield of the former was raised to 23% on LTA oxidation of 103 in a mixture of TFA and CH2Cl2. On the other hand, treatment of o-quinol acetate 104
c
M e 0W
N
+
M
e
OH
105
Me OAc
106 111 112
115 116
Reagents: a. Pb(OAC)U, CH2CI2; b. CF3COOH. CH2Ch;
C.
Pb(OAc4, CF3COOH. CH2C12;
d . Ac20, c . H2SO4; e. 5%KOH-MeOH; f . C y N 2 , MeOH
SCHEME13
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
83
with acetic anhydride containing concentrated sulfuric acid gave (*)-Oacetyl-N-methyllaurotetanine(106) in 37% yield, hydrolysis of which with 5% methanolic potassium hydroxide led to 39. Analogously, (?)-Oacetylcassythicine (111) and (?)-9-acetoxy-l,2,3, lo-tetramethoxyaporphine (112) were obtained in 45 and 80% yield, respectively, via o-quinol acetates 109 and 110 derived from (t)-6,7-methylenedioxy- and (9-2,3,4-trimethoxy-1,2,3,4-tetrahydro-1-(3-hydroxy-4-methoxybenzyl)2-methylisoquinoline (107 and 108). Hydrolysis of 111 and 112 as above gave (t)-cassythicine (113) and (?)-9-hydroxy-l,2,3, Io-tetramethoxyaporphine (114), methylation of which with diazomethane afforded (+)-dicentrine (115) and (+)-thalicsimidine (116), respectively (54) (Scheme 13).
111. C-Homoaporphines
Appropriate phenolic 1,2,3,Ctetrahydro- I-phenethylisoquinolinesgave miscellaneous C-homoaporphines by the same methodology as mentioned in Section 11. A. FROM1,2,3,4-TETRAHYDR0-6-METHOXY-IP H EN ETH Y LlSOQU I N O L l N-7-OLS LTA oxidation in AcOH of (+)-l-homoveratryl-l,2,3,4-tetrahydro-6methoxy-2-methylisoquinolin-7-ol(117) readily afforded p-quinol acetate 120, treatment of which with acetic anhydride including concentrated sulfuric acid produced (?)-l-acetoxy-2,10, I I-trimethoxy-Chomoaporphine (123) in 16% yield. Similarly, (?)-0-acetylkreysigine (125) was obtained in 18% yield from (t)-1-(3,4,5-trimethoxyphenethyl)isoquinolin-7-ol (119). In both cases, 4-acetoxy-C-homoaporphines 126 and 128 were not isolated. Hydrolysis of 123 and 125 with 4 N hydrochloric acid in methanol gave (~)-l-hydroxy-2,1O,ll-trimethoxy-Chomoaporphine (129) and (?)-kreysigine (131), respectively ( 5 5 3 6 ) . Similar treatment of p-quinol acetate 121 derived from (?)-l-(3,4-methylenedioxyphenethyl) congener 118 gave (+)-I-acetoxy-10,I I-methylenedioxy-2-methoxy-C-homoaporphine (124) accompanied by a small amount of its 4-acetoxy product 127, the yield of 124 being 15.6% (27). Hydrolysis of 124 with 5% aqueous potassium carbonate in methanol produced (?)-1-hydroxy-10, 1 1-methylenedioxy-2-methoxy-C-homoaporphine ( WO) (Scheme 14).
84
1 19 R =OMe,
OSAMU HOSHINO AND BUNSUKE UMEZAWA
R1 =Me
129 130 131 R e a g e n t s : a . Pb(OAd4, AcOH; b . Ac20. c.H2SQ;
c . 4 N H C I , MeOH; d . 5 % a q . K 2 C O 3 , MeOH
SCHEME14
A modification of the above procedure gave three types of products, C-homoaporphines 129-131, homoproaporphines 132 and 133 (see Section IV), and homomorphinandienones 134 and 135 (except for 118; see Section V) (57). LTA oxidation in AcOH of (t)-I-phenethyltetrahydroisoquinolin-7-01 117 gave a p-quinol acetate 120, TFA treatment of which in CHzClz produced the (*)-C-homoaporphine 129 in 44.2% yield. Similarly, the (+)-C-homoaporphines 130 and 131 were prepared in 55 and 35.2% yield, respectively, from the (*)-I-phenethyltetrahydroisoquinolin-7-01s 118 and 119 (Scheme 15). In the case of C-homoaporphines, as for aporphines (see Section 11), various kinds of C-homoaporphines with a hydroxyl group in the D ring were obtained, accompanied by (+-)-homoproaporphines 132, 142, and 133 and ( t)-homomorphinandienones 143-145, starting from (?)-1(benzyloxyphenethy1)- 1, 2, 3, 4-tetrahydro-6-methoxy-2-methylisoquinolin-7-01s. LTA oxidation followed by TFA treatment of (*)-l-(4-benzyloxy-3-methoxyphenethy1)-I , 2, 3, 4-tetrahydro-6-methoxy-2-methylisoquinoh-7-01 (l36) gave (*)1 I-benzyloxy- I-hydroxy-2,IO-dimethoxy-C-homoaporphine (l39) in 39.3% yield. In a similar way, (*)-l-(3-benzyloxy-4methoxyphenethy1)- and (*)I-(4-benzyloxy-3,5-dimethoxyphenethy1)1,2,3,4-tetrahydro-6-methoxy-2-methylisoquinolin-7-ols (137 and l38) led to (*)10-benzyloxy- 1-hydroxy-2,l I-dimethoxy-C-homoaporphine (140) and (*)-0-benzylmultifloramine (141) in 29.6 and 27.3% yield, respectively (57) (Scheme 15).
85
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
NMe
h . ~
117 R = H , 118 R = H ,
138
HO
Rl=R2=Me
I29
R , + R 2 =CH2
130
11s R=OMe, 136 R:H. 137 R = H ,
a.b
R =R =Me 1 2
R 1 = B n , R2=Me R,=Me, R =Bn 2
R=OMe, R 1 = B n , R2=Me
132
134
131
133
139 140 141
132
135 143 144 145
142 133
BnzCH C H 2 6 5 R e a g e n t s : a . Pb(OAcIl), ACOH; b . CF3COOH. CHZCIZ;
c. Pb(OAc4, CF3COOH. AcOH
SCHEMEI5
Catalytic debenzylation of the (&)-0-benzyl-C-homoaporphines139141 afforded (+)-l, 11-dihydroxy-2,lO-dimethoxy- and (?)-I, 10-dihydroxy-2,ll -dimethoxy-C-homoaporphines (146 and 147) and (+)-multirespectively (Scheme 16). Methylation of 139-141 with floramine (la), diazomethane gave (+)-1l-benzyloxy-l,2,10-trimethoxy-, (+)-lobenzyloxy-1,2,1l-trimethoxy-, and (+)-I l-benzyloxy-1,2,10,12-tetramethoxy-C-homoaporphines (149, 150, 151), similar catalytic debenzylation of which led to (+)-1 l-hydroxy-l,2,10-trimethoxy-and (+)-lO-hydroxy-l,2,1I-trimethoxy-C-homoaporphines (152 and 153) and (+)-0-methylmultifloramine (154), respectively (57). When LTA oxidation was carried out in a mixture of AcOH and TFA (4 : 1 by volume), the product distribution pattern changed considerably; namely, the yield of C-homoaporphines decreased, whereas that of homoproaporphines and/ or homomorphinandienones somewhat increased (see Sections IV and V). Thus, the (+)-C-homoaporphines 129,130, and 131 were formed in 19, 7.5, and 10% yield, respectively, from 117-119 (57) (Scheme 15). Interestingly, LTA oxidation in AcOH and subsequent TFA treatment of (+)-1,2,3,4-tetrahydro-6-methoxy-I-(3-methoxyphenethyl)-2methylisoquinolin-7-01 (155) afforded (*)-1-hydroxy-2,lO-dimethoxy-Chomoaporphine (156) in 1 I % yield (Scheme 17), a (+)-homomorphinandienone 157 being the major product (30) (see Section V). p-Quinol acetates 161-163 of (+)-8-chloro- 1,2,3,4-tetrahydr0-6-meth-
86
OSAMU HOSHINO A N D B U N S U K E UMEZAWA
148 R = R , = H , R =Me 2
147 R = R = H , Rl=de
148 R=OMe,
Rl=H,
R =Me 2
139
a
R=H, R1=6n R2 =Me
140 R = H ,
Rl=Me R2=Bn
141
R1
R=OMe, R1=Bn R, =Me
OR2
149 R = H ,
R =Bn, 1 R =Me
2
Bn=CH C H 2 6 5
150 . - -R = H ,
151 R e a g e n t s : a. Pd-C,
R.=Me, R =Bn 2 R=OMe, I? = B n , 1 R =Me 2
'
H2, MeOH, H';
152 R=R1=H,
R,=Me
153 R =R2=H,
R 1=Me
154 R=OMe, R =Me 2
R 1:H,
b . C b N 2 , MeOH
:pe8
SCHEME16
OMe
MeDH JMe
a,b \
+
Me0
\
e
12"'
e
155 Reagents:
I
156 a.
157
Pb(OAC)Q, ACOH; b . CF3COOH, CH2C12
SCHEME17
oxy- I-phenethylisoquinolin-7-01s158-160 were treated with TFA in CH2C12 to give three types of products (except for 160) (37,38) (Scheme 18) as in the case of (5)-l-benzyl congeners (see Section 11,A). Thus, (*)-I ,4P-dihydroxy-2.10, I I-trimethoxy- and (?)-I ,4P-dihydroxy-l0,11
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
+
87
IS6 167
170 171 R e a g e n t s . a . Pb(OAc)q, A c O H ; b . C F ~ C O O H , c H z c l z
SCHEME 18
methylenedioxy-C-homoaporphines(164 and 165) were formed in 30 and 17% yield, respectively, besides (t)-9-chlorohomoisopavines 166-168 and (+-)-9-chlorohomomorphinandienones 169-171 (see Sections V and VI). With 160, however, the corresponding C-homoaporphine was not obtained.
B. FROM1,2,3,4-TETRAHYDRO-7-METHOXY-1PHENETHYLISOQUINOLIN-6-OLS
As in the case of 1-benzyl congeners, LTA oxidation in CHzClz of (+)- 1,2,3,4-tetrahydro-7-methoxyI -( 3,4-dimet hoxyphenethyl)-2-methyl-
isoquinolin-6-01 (172) was found to give quantitatively o-quinol acetate 175, the structure of which was readily determined by spectroscopy. However, treatment of the unpurified o-quinol acetate 175 with acetic anhydride containing concentrated sulfuric acid produced (?)-2-acetoxy1,lo, 1 1-trimethoxy-C-homoaporphine(178) in 25.3% yield, accompanied by a comparable amount of a biphenyl compound (181) (58). The
88
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
yield of 178 was raised to 55.6% by use of BF,.Et,O instead of concentrated sulfuric acid. Similarly, o-quinol acetate 176 derived from (+)-1-(3,4-methylenedioxyphenethyl) analog 173 led to (?)-2-acetoxy-l methoxy- 10, I I methylenedioxy-C-homoaporphine (179) in 62% yield together with a biphenyl compound 182. The best choice of cyclization reagents was found to be a combination of acetic anhydride and concentrated sulfuric acid or BF,.Et,O in nitromethane, the yield of 178 being raised to 80.2 or 78.6%. Hydrolysis of 178 and 179 with 10% hydrochloric acid in methanol afforded (L)-l,lO,l 1-trimethoxy- and (?I-I-methoxy10,l I -methylenedioxy-2-hydroxy-C-homoaporphines (183 and 184), respectively. Methylation of 183 with diazomethane led to (?)-1,2,10,11tetramethoxy-C-homoaporphine (185) (58) (Scheme 19). OAC
Reagents: u . Pb(OAcb, CHZC12, b . AC20, c.H2SQ,or c.HzS04
or
B%.Et2O, CHIN%;
EF3.EtzO; c . Ac20,
d . lO",CI;
e . C H ~ N Z .MeOH
SCHEME19
It is noteworthy that when the o-quinol acetate 177 derived from 174 was treated with acetic anhydride containing concentrated sulfuric acid, the product was (+)-C-homoaporphine 180, whose stereostructure was confirmed to be 186 by X-ray crystallographic analysis of a methiodide of 180 (59). Furthermore, 186 was heated at 60°C to give a more stable stereoisomer, which should be 187.
2. L E A D TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
M A e0c
M “ e0 P
M.+I e
p
Me Me0
M
89
*.+I e
Me
‘
Me0
OMe
‘ OMe
186
187
c. FROMI ,2,3,4-TETRAHYDRO-6-METHOXY-IPHENETHYLlSOQUlNOLlN-5-OLS
l-Phenethyltetrahydroisoquinolin-5-ols, as in the case of I-benzyl congeners, gave 3-hydroxy-C-homoaporphines (51,52). LTA oxidation in CHzC12 and subsequent TFA treatment of (*)-I ,2,3,4-tetrahydro-6methoxy-l-(3,4-dimethoxyphenethyI)-2-methylisoquinolin-5-01(188) afforded (t)-3-hydroxy-2,1O,ll-trimethoxy-C-homoaporphine (194) in 91% yield via o-quinol acetate 191 (Scheme 20). Similarly, (?)-2-methoxy10,l I-methylenedioxy- and (?)-2,lO,I I ,12-tetramethoxy-3-hydroxy-Chomoaporphines (195 and 196) were obtained in 87 and 90% yield, respectively, from (-+)-1-(3,4-methylenedioxyphenethyl)and (-+)-l-(3, 4,
OH Me0 /
b R
Fe /
R1 O
188 189 190
R:H,
R 1 =Me
R = H , R ~ + 1R =CH 2 R=OMe, R =Me
1
Reagents:
a.
191 192 193 Pb(0Ac)Q. CH2Cb; b . CF3COOH. CH2C12
SCHEME 20
194 195 196
90
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
5 - trimethoxyphenethyl) - I , 2 , 3 , 4 - tetrahydro - 6 - methoxy - 2 - methyliso-
quinolin-5-01s (189 and 190) through o-quinol acetates 192 and 193.
IV. Homoproaporphines As mentioned in Section 111, we found that LTA oxidation in AcOH and subsequent TFA treatment of the (?)-I-phenethyltetrahydroisoquinolin-7-01s 117 and 136 afforded (2)I-hydroxy-2,lO-dimethoxyhomoproaporphine (132) in 6.9 and 15.5% yield, respectively, which corresponded to dienone I1 (601, as well as (k)-C-homoaporphines 129 and 139 and (2)-homomorphinandienones 134 and 143 (see Section V) (57) (Scheme 15). The stereostructure of dienone I1 was determined as 197 by an X-ray crystallographic analysis of its derivative (57,61,62).For another spiroisomer named dienone I, the naturally occurring (2)-kreysiginone ( 6 3 , the above experiment in turn established the correct stereoI-phenethyltetrahydrostructure as 198. In an analogous manner, the (*)isoquinolin-7-01s 137 and 138 afforded (?)- I0-benzyloxy-l-hydroxy-2methoxyhomoproaporphine (142) and ( 5 ) -12-methoxykreysiginone (133) in 11.4 and 15.9% yield, respectively, together with (k)-C-homoaporphines 140 and 141 and (?)-homomorphinandienones 144 and 145 (see Sections 111 and V) (Scheme 15).
M8e
Me
0
0
0
bMe
197
198
On the other hand, LTA oxidation in a mixture of AcOH and TFA of (+)-1-phenethyltetrahydroisoquinolin-7-ols caused no appreciable improvement in the yields of (2)-homoproaporphines ( 5 7 ) . Thus, 119 and 138 gave 133 in 15 and 10% yield, respectively. Dienone I1 197 was obtained in 31 and 18% yield, respectively, from 117 and 136, whereas 142 was produced in 16% yield from 137 (Scheme 15).
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
91
In contrast to the above results, TFA treatment of p-quinol acetate 200 of ( 5 ) -1-(4-methoxyphenethyI)-tetrahydroisoquinolin-7-o1199 proceeded smoothly to give (+)-l-hydroxy-2-methoxyhomoproaporphine(201) in 98% yield (64). Alternatively, treatment of 200 with acetic anhydride containing concentrated sulfuric acid produced (*)-l-acetoxy-2methoxyhomoproaporphine (202) and the (?)-4@-acetoxylated homoproaporphine 203 (see Section XII,B) in 53 and 5% yield, respectively (Scheme 21).
OAr
199
200
201
\
Reagents: a . Pb[OAd4, AcOH; b . CF3COOH. CH2CI2;
C.
Ac20, C.H2504
SCHEME 21
V. Morphinandienones and Homomorphinandienones Szantay et al. (34) succeeded in a biomimetic synthesis of (+-)-salutaridine (52) in 2.7% overall yield from (2)-reticuline (51) with the aid of LTA oxidation conducted in CHzClz in the presence of trichloroacetic acid, with (+-)-isoboldine (35) also being formed (Scheme 7 ) . Since morphinandienone 52 (65) is an important precursor to morphine, the above synthesis is quite interesting in spite of the low yield.
92
OSAMU HOSHINO AND BUNSUKE UMEZAWA
Endeavors to increase the yield were actively made by the same group (66,67). LTA oxidation of (5)-N-acylnorreticulines 204-206 under strictly defined conditions gave (+-)-N-acylnorsalutaridines207-209 in 18 to 40% yield (Scheme 22). Hydrolysis of (+)-N-formylnorsalutaridine (208) with 18% hydrochloric acid gave (+)-norsalutaridine (210), the Eschweiler-Clarke methylation of which produced 52 (36). LTA oxidation of (+)-6'-halogeno-N-acylnorreticulines211-214 also gave (2)I-halogeno-N-acylnorsalutaridines 215-218, LAH reduction of which furnished (+-)-salutaridinol (219) (66,67). On the other hand, TFA treatment of the p-quinol acetates of (?)-8-chlorocodamine (53) and congener 54 gave (+)-8-chloro-O-methylflavinantine(58) and (+-)-8-chloroamurine (59) in 3 and 6% yield, respectively (37,38), together with (+)-4phydroxyaporphines 27 and 55 and (+)-9-chloroisopavines 56 and 57 (see Sections I1 and VI) (Scheme 7).
Me
211 X=CI, 212 X=CI, 213 X-Br, 214 x = B r ,
R=COOEt R-CHO R=COOEt R=CHO
215 216 217 218
219
R e a g e n t s : u . Pb(OAc)4, CC13COOH, CHzCb, -25OC; b . 18%HCI;
c. CH20, HCOOH; d. LiAIH4, T H F
SCHEME 22
93
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
Recently, we found that TFA treatment in CHzClzof o-quinol acetates 66 and 69 derived from 64 and 65 at low temperatures gave the corresponding (+)-morphinandienones 220 and 221 besides (+)-aporphines 68 and 70 (Scheme 23). The ratio of morphinandienone and aporphine was approximately 1 : 1 in the reaction of o-quinol acetates 66 and 69 in acetonitrile at -25°C for 5 min (43).
68 70
66 69
220 221
R e a g e n t s : a . Pb(OAcI4, CH2C12; 0 . CF3COOH, CH3CN, - 2 5 ° C
SCHEME 23
TFA treatment of the p-quinol acetate derived from (?)- I-phenethyltetrahydroisoquinolin-7-01155 was carried out to give (*)-2,6-dimethoxyhomomorphinandienone (157) in 45% yield, with the C-homoaporphine 156 also being produced (30)(Scheme 17). Analogously, 117 and 119 gave (?I-demethoxy-0-methylandrocymbine (134) and (*)-0-methylandrocymbine (135) in 3.3 and 23.1% yield, respectively (57), the (+)-Chomoaporphines 129 and 131, and the (+)-homoproaporphines 132 and 133 being produced at the same time (see Sections 111 and IV) (Scheme 15). Similar treatment of the (2)I-benzyloxyphenethyltetrahydroisoquinolin-7-01s 136-138 produced (+)-3-benzyloxy-2,6-dimethoxy-and (+)-2benzyloxy-3,6-dimethoxyhomomorphinandienones(143 and 144) and (*)-0-benzylandrocymbine (145) in 6.1, 0.3, and 12.2% yield, respectively. The (+)-C-homoaporphines 139-141 and the (+)-homoproaporphines 132, 142, and 133 were also formed, illustrating the general trend for this kind of reaction (57) (Scheme 15). LTA oxidation in a mixture of AcOH and TFA ( 4 : 1 by volume) was favorable for the formation of homomorphinandienones (57). (+)-0Methylandrocymbine (135) was obtained in 26% yield from 119. Although (?)-kreysigine (131) and (+)- 12-methoxykreysiginone (133) (see Sections 111 and IV) were formed as products, the yield by this method was comparable to that of the thalium(II1) trifluoroacetate oxidation reported
94
OSAMU HOSHINO A N D B U N S U K E UMEZAWA
by Schwartz et al. (68). Analogously, the (2)-1-phenethyltetrahydroisoquinolin-7-01s 117 and 136-138 gave the (+)-homomorphinandienones 134, 143, 144, and 145 in 16, 14, 5, and 13% yield, respectively. In the former three cases, the only by-products were the (?)-homoproaporphines 132 and 142 (see Section IV), whereas in the latter both (2)-C-homoaporphine 141 (see Section 111) and (-+)-homoproaporphine 133 were formed (Scheme 15).Similar TFA treatment of p-quinol acetate 163 of the (k)-8-chlorotetrahydroisoquinolin-7-ol 160 gave (2)-8-chloro0-methylandrocymbine (171)in 45% yield in addition to a small amount of (k)-9-chlorohomoisopavine 168 (37,38) (Scheme 18).
VI. Isopavines and Homoisopavines
In early studies, we reported that LTA oxidation in CHzClz of the 78 affords a diastereomeric mixture of the (+)-4-acetoxy compounds 222 and 223, treatment of which with concentrated hydrochloric acid in ethanol gives (*)-2,3,8trimethoxy- and ( ~)-8-methoxy-2,3-methylenedioxy-7-hydroxyisopavines (224and 225)in 70 and 54% overall yield, respectively (69) (Scheme 24). Later, we confirmed that the oxidation of 77 and 78 gives the reactive (?)- 1 -benzyltetrahydroisoquinolin-6-ols77 and
R e a g e n t s : a . Pb(0Ac)q. CH2Ch; b . c . H C I , EtOH;
c. 3OoC or ACOH; d . C y N 2 , MeOH
SCHEME 24
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
95
o-quinol acetates, which are thermally isomerized to a diastereomeric mixture of separable (t)-4a- and (+)-4/3-acetoxytetrahydroisoquinolin-601s (19). Recently, TFA treatment in CH?CI2 instead of concentrated hydrochloric acid in ethanol was confirmed to be effective, as judged by the uniform reproducibility (70). Methylation of the (+)-isopavines 224 and 225 with diazomethane produced (5)-Omethylthalisopavine (226) and (+)-reframhe (227) (69). More recently, Meyers et af. (71) reported that (-)-isopavines 224 and 225 and (-)-O-methylthalisopavine (226) may be prepared starting from the corresponding (+)-tetrahydroisoquinolin-6-ols77 and 78 by similar methodology. Similar treatment (see Section I1 ,A) of the 8-chlorotetrahydroisoquinolin-7-01s 53 and 54 gave (?)-2,3,7-trimethoxy- and (?)-7-methoxy2,3-methylenedioxy-9-chloro-8-hydroxyisopavines(56 and 57) in 4 and 7% yield, respectively (37,38) (Scheme 7). Quite analogously, (*)-2,3,7trimethoxy-, (?)-7-methoxy-2, 3-methylenedioxy-, and (?)-2, 3, 4, 7-tetramethoxy-9-chloro-8-hydroxyhomoisopavines(166, 167, and 168) were obtained from the ( ?)-8-chloro- 1-phenethyltetrahydroisoquinolin-7-ols 158-160 in 17, 16, and 9% yield, respectively (37,38) (Scheme 18).
VII. Benzo[c]phenanthndines Kametani et al. (72,731 achieved a biomimetic synthesis of a ben~ ~ [ c l p h e n a n t h r i d i nfrom e the tetrahydroprotoberberine (74-76). Thus, Hofmann degradation of (+)-lO-hydroxy-2,3,I I-trimethoxytetrahydroprotoberberine (228) gave methine base 230, which on LTA oxidation followed by treatment with acetic anhydride containing concentrated sulfuric acid afforded the (+)-8, I2-diacetoxybenzo[c]phenanthridine 232 (Scheme 25). (+)-5,6-Dihydro-2,3,8,9-tetramethoxy-5-methylbenzo [clphenanthridine (234) was readily obtained from 232 on treatment with concentrated hydrochloric acid in boiling ethanol and subsequent methylation of the resulting benzo[c]phenanthridine 233 with diazomethane. The methine base 231 derived from 229 was similarly transformed to (+)-cis-8-acetoxy-4b,5,6.IOb-tetrahydro-9-methoxy-5methyl-2,3-methylenedioxybenzolc.lphenan~~~e (235). hydrolysis of which gave (+)-cis-4b,5,6,10b-tetrahydro-8-hydroxy-9-methoxy-5-methyl-2,3-methylenedioxybenzo[c]phenanthridine (236). Methylation of 236 with diazomethane partly caused dehydrogenation, giving dihydronitidine (237) in addition to the tetrahydro compound 238. The conversion of dihydronitidine (237) to nitidine (239) has already been reported (77).
96
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
Reagents:
a . 2O%KOH-Me0H.A; b . Pb(OAc),,
AcOH;
C.
ACZO, C.H2SQq;
d . c . H C I , E t 0 H . A ; e. CH2N2, MeOH
SCHEME 25
Although LTA oxidation was not involved in the original report, Hanaoka et al. (78) accomplished a biomimetic synthesis of sanguilutine (240) and dihydrosanguilutine (241) by sequential treatment of (t)-2,3,9,10,12-pentamethoxytetrahydroprotoberberine(389), which is derivable from (+)-corytencine (384) by LTA oxidation (see Section XII1,C) (Scheme 26).
VIII. 10-Hydroxy-2,3,9-trimethoxydibenzopyrrocoline
Although it is only one example, Blasko ef al. (79) reported the formation of IO-hydroxy-2,3,9-trimethoxydibenzopyrrocolineby LTA oxidation of N-nor- 1-benzyltetrahydroisoquinoline. LTA oxidation in CHzClz of (*)-N-norlaudanine (242)in the presence of TFA and trifluoroacetic anhyride (TFAA) (9 : 1 by volume) gave (+)-lO-hydroxy-2,3,9trimethoxydibenzopyrrocoline (243)in 16.5% yield (Scheme 27).
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
97
bMe
240
Me
'
OMe
bH
384
389
241 SCHEME26. Synthesis of sanguilutine (240) and dihydrosanguilutine (241).
243 R e a g e n t s : a . P b ( O A d 4 , C F ~ O H - ( C ~ C O ) Z( 9 O: 1 ) , C H E I z , -ZO°C
SCHEME27
IX. Tetrahydroprotoberberines Cushman and Dekow (80)performed a synthesis of (+)-canadine (246) by oxidative decarboxylation on LTA treatment (Scheme 28). Thus, LTA oxidation in a mixture of AcOH and dimethylformamide of (-C)-cis-2,3methylenedioxy- 8-0x0- 9,lO- dimethoxy- 13- carboxytetrahydroprotoberberine (244) in the presence of cupric acetate gave berlambine (245) in 65% yield. Aluminum hydride reduction of 245 afforded (?)-canadhe (246) in 63% yield.
98
OSAMU HOSHINO AND BUNSUKE UMEZAWA
244
245
246
Reagents: a . Pb(0Ac)u. Cu(0AcI2, AcOH, Me2NCHO;
b. LiAIHu, A I C I j , Et2O
SCHEME 28
X. Indole Alkaloids In the case of tetrahydro-P-carboline alkaloids, a remarkable solvent effect is observed. Namely, LTA oxidation in AcOH causes tetradehydrogenation, whereas in CHzClzthe acetoxyindolenine is produced. A. YOHIMBINE ALKALOIDS
I . Epimerization at C-3 LTA oxidation in warm AcOH of yohimbine (247) was first discovered by Hahn et al. (81)to give tetradehydroyohimbine (248) in 50 to 60% yield (Scheme 29). Bader et al. (82) utilized the reaction to invert the absolute configuration at C-3, i.e., 3R + 3 s . Thus, LTA oxidation in AcOH of 3-epi-a-yohimbine (249) gave a tetradehydro compound 250, sodium borohydride reduction of which effected the partial inversion to give a-yohimbine (rauwolscine) (251). Similarly, deserpidinediol (252) and reserpinediol (253) were transformed to 34sodeserpidinediol (254) and 3-isoreserpinediol (255) (Scheme 29). LTA oxidation-mediated epimerization of indole alkaloids has also been performed. Brown et al. (83) synthesized (+)-dihydroisositsirikine (258) and (+)-dihydrocorynantheine (259) by epimerization at C-3 on LTA oxidation followed by sodium borohydride reduction of the (+)-compound 256 and (+)-hirsutine (257) (Scheme 30). Interestingly, Barzai-Beke et d.(84) found that LTA oxidation of indolo[2,3-a]quinolizidine cyanoacetate 260 gives a mixture of the corresponding iminium salts 261 and enamine 262. When the mixture in CH*Clz solution is allowed to stand at room temperature, iminium salt 263, epimeric with 261, is produced (Scheme 31).
T a 5
99
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
H H"
H"
Meme'
241
MeOOC'
248
bH
MeOOC
249
,
,
6H
MeOO
250
OH
MeOO
251
AH
.a H,' 3
a
..+I H.
HOHZ
&e
252 253
H H.'
H"
. HOHZ
AH
OH
-. H
HOCHf
W e
b
e
254 255
R=H R=We
Reagents: a . Pb(OAc),,, AcOH; 0 . NaBH,,,
MeOH
SCHEME 29
2. Oxindoles
Finch et al. (85) investigated the LTA oxidation in CHzClz of reserpiline (264) to obtain 7-acetoxy-7H-reserpiline (265). Further treatment of the latter with dilute methanolic AcOH furnished isoreserpiline oxindole carapanaubine (266) (Scheme 32). Similarly, aricine (267), tetrahydroalstonine (268), pseudoyohimbine (269), yohimbine (247), reserpine (270), methyl reserpate (271), isoreserpine (272), and methyl isoreserpate (273) were converted to the respective 7-acetoxy-7H-yohimbinoid alkaloids 274-281, respectively (Scheme 33). 7-Benzoyloxy methyl 7H-isoreserpate (282) was also obtained on lead tetrabenzoate oxidation. AcOH treatment of 7-acetoxy-7H-yohimbinoid alkaloids bearing a cis D-E ring juncture gave the corresponding oxindole alkaloids, whereas a similar reaction of the alkaloids bearing a trans D-E ring juncture, such as 276 and 277, did not occur. In the reaction,
H H.'
.-H
MeOO H
256
H
258
yxt ye a. b
H He''
"Et
HMeOOC tl
ti,'
'
MeOOC
257
'
~e
259
Reagents:
(1.
Pb(OAc$,
AcOH; b . NaBHq, MeOH
SCHEME 30
__I_
H'MeOO
260
N
b1261 qH 262
Et
MeOOCAN
26 3 R e a g e n t s : a . P b ( O A c 4 , AcOH; I , .
SCHEME 31
CH2CI2, room temp.
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
264
101
265 R e a g e n t s : u . Pb(OAc),,,
C H ~ C I ~b ;. ACOH, MeOH
SCHEME 32
267 R - 0 M e 268 R
274 215
SCHEME 33A
therefore, the trans D-E ring juncture in 7-acetoxy-7H-yohimbinoid alkaloids was unfavorable for the formation of oxindoles. Furthermore, it is noteworthy that C-3 a-H epimerizes during oxindole formation. Thus, 7-acetoxy-7H-reserpine (278) and 7-acetoxy methyl 7H-reserpate (279) were transformed to isoreserpine oxindole B (285) and methyl isoreserpate oxindole B (286), which were identical with those derived from 281 on similar treatment. LTA oxidation in methanol of isoreserpine (272) gave 7-methoxy-7H-isoreserpine (287). In contrast to the 7-acetoxy congener, however, treatment of the latter with dilute methanolic AcOH produced no reaction, the starting material being recovered unchanged.
102
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
M bnne
278 279
/ :::
6Me
SCHEME 338
3. Pseudoindoxyls
Finch et a / . (86, 87) synthesized pseudoindoxyls by base treatment of 7-acetoxy- or 7-aroyloxy-7H-yohimbinoidalkaloids. 7-Benzoyloxy, 7(p-anisoyloxy), and 7-(m-bromobenzoyloxy) methyl 7H-isoreserpates (282, 283, and 284) and 7-(rn-bromobenzoyloxy)-7H-isoreserpiline(289) were obtained by oxidation of methyl isoreserpate (273) and isoreserpiline (288) with the corresponding lead tetraaroates in CH2Cl2.Treatment of 7-(m-bromobenzoyloxy)-7H-isoreserpiline(289) with methanolic sodium methoxide afforded isoreserpiline pseudoindoxyl(290), which was identical with the yellow alkaloid of Rauwolia uomitoria Afzel. Similarly, aricine (267), tetrahydroalstonine (268), and methyl isoreserpate (273) were converted to their pseudoindoxyls 291-293 (Scheme 34).
103
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS OCOAr
Me H-‘
..~e
..Me
‘
MeOO
289
288
RT c, b
.H
H H.’.
.Me
H.’
R
Q
g
H---
‘O
I+-
-..H
MeOOC MeOO
290
Ar=mBrCsHq
..Me
MeOOC h
0
e
293
R e a g e n t s : a . Pb(OCOHqGBr-rn)q,
CH2C12; b . NaOMe, MeOH.6;
c. P b ( O A c 4 , CH2C12
SCHEME34
7-Hydroxy-7H-yohimbine (294) derived from 7-acetoxy-7H-yohimbine (277) on hydrolysis, underwent rearrangement to give yohimbine pseudoindoxyl(295) on treatment with 2 N potassium hydroxide in boiling methanol, whereas treatment with methanolic hydrochloric acid gave the hydrochloride of A’-dehydroyohimbine (296) (Scheme 35). Treatment of 7-acetoxy-7H-ajmalicine (298) derived from ajmalicine (297) with methanolic sodium methoxide led to ajmalicine pseudoindoxyl (299). For structural determination of the pseudoindoxyl alkaloids by mass spectroscopy, Finch et al. (88) prepared 3-deuterio-, 14,14-dideuterio-, 3,5,6trideuterio-, and 3,14,14-trideuterioajmalicinepseudoindoxyls by the same methodology as above.
B. “INVERTED”YOHIMBINOID ALKALOIDS Inversion of the A-B ring of yohimbinoid alkaloids was achieved (87,89,90).Yohimbine dihydropseudoindoxyl (300). which was available by sodium borohydride reduction of yohimbine pseudoindoxyl(295), was treated with 2 N hydrochloric acid in boiling methanol to give “inverted”
, 3 ”is
104
OSAMU HOSHIND A N D B U N S U K E UMEZAWA
295
MeOOC -*
Hd
MeOOC’
294
: OH
\
”is MeOOC’ AH
d
tr-.
___Ic
.Me
H” MeOOC
Me00
297
‘
c.
\ 0
O
298 R e a g e n t s : a . 2N NaOH, M e 0 H . A ;
H.MeOOC
299 b . HCI, MeOH, A:
Pb(OAc14, CH2CI2; d . NaOMe, M e 0 H . A
SCHEME 35
yohimbine (301) (Scheme 36). Analogously, ajrnalicine dihydropseudoindoxy1 (302) was transformed to “inverted” ajmalicine (303). On the other hand, partial epirnerization at C-3 was found to occur in the reaction when a given dihydroindoxyl involved cis D-E ring fusion. Several “inverted” alkaloids prepared by this method have been reported (87).
C. AJMALINEALKALOIDS Bartlett el al. (91) reported the use of oxidative demethylation of LTA. When 2 I-deoxyajrnaline- 17-0-acetate (304) was oxidized with LTA ( I equiv) in acetic anhydride, 2-hydroxy-2I-deoxyajmaline-17-0-acetate (305) was produced. However, LTA oxidation (excess of the oxidant) in benzene of the acetate 304 proceeded via oxidative demethylation to (306), which was also give l-demethyl-A’-2 I-deoxyajmaline-l7-O-acetate
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
105
M eOOc.'->
300
301
OH
bH
303
302
R e a g e n t s : a . 2NHCI. M e 0 H . A
SCHEME 36
obtainable on further LTA oxidation in benzene of the hydroxyacetate 305 (Scheme 37). 21-Deoxyajmaline and 2-hydroxy-2I-deoxyajmaline-17epi-O-acetates (307 and 308) and diacetylajmaline (309) were similarly converted to their indolenines (92). Taylor et al. (93) applied the reaction to the synthesis of dihydrovomilenine (310), which is derived from vomilenine (311) on hydrogenation. L T A oxidation of diacetylajmaline (309) as above led to I-demethyl-A'-ajmaline-17-0-acetate (310) and I-demethyl-A'-ajmalineI7,2 I -0,O-diacetate (312). The former was identical with dihydrovomilenine (Scheme 37). Sakai er af. (94) elucidated the absolute configuration of garderine (313) by two routes including interrelation of 313 with ajmaline (316) on LTA oxidation (Scheme 38). In one route, oxidation in benzene of 17,21dideoxy- I-demethylajmaline (314) derived from garderine (313) gave 17,21-dideoxy-1-demethyl-I ,Zdehydroajmaline (315), which was identical with the 1,2-dehydroajmaline derived from ajmaline (316). In the other, demethoxy- I -demethyl- I -mesyl- 19,20-dihydro compound 319 was also prepared via 318 by demethylation of 21-deoxyisoajmalol A 317 on LTA oxidation.
106
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
QAc OAc
305 b
q
304
306
J A
31 1
309
R e a g e n t s : a . P b ( O A c ) q ( l e q . ) , A p O ; b . Pb(OAC)4. CsHs
SCHEME 37
Although not pertaining to ajmaline alkaloids, an interesting result, in which formation of an indolenine on LTA oxidation seems to be a key step, has been reported by Moore and Rapoport (95). LTA oxidation followed by pyrolysis of deacetylgeissovelline and deacetyldihydrogeissovelline (320 and 321) gave eight-membered lactams 322 and 323 (Scheme 39).
D. ZSOGA ALKALOIDS Nagata et ul. (96) were the first to synthesize a highly strained bridged aziridine 1-aza-tricyclo[3.2.1 .O?.’]-octane” ring system, which is known to be a hypothetical intermediate (97) in alkaloid chemistry. The bridged aziridines 325-327, readily available near quantitatively on LTA oxidation in benzene of 4-aminomethylcyclohexenes 324 (6,s-unsaturated primary amines), were susceptible to acylation with acid anhydrides, giving the corresponding acylated isoquinuclidine (Scheme 40). Based on this methodology, Nagata e t ul. (98,99) succeeded in a total synthesis of several lhogu alkaloids. “
107
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
Me H
Me
313
314
Et ISOAJMALIME
316
I
H
q-j 313
hs
H"
.€t
H
H
317
318
319 Ms=MeS02
R e a g e n t s : a . Pb(OAcI,,, G H s ; b . p - M e C 6 H 4 q C l , p y r i d i n e ; c . LiAIHq; d . M s C I , p y r i d i n e
SCHEME 38
Me
320 321
xX = ..'H 'Et
R e a g e n t s : a . Pb(OAc14, ACOH. C & , :
b. 1 8 0 - 2 0 0 ° C ( 0 . i m r n H g ~
SCHEME 39
108
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
Reagents: ri.Pb(OAcIq, C6H6; I ) .
3-indoleacetic a n h y d r i d e ; c . a q . K 2 C 0 3 , MeOH;
d . 0 p p e n a u e r oxidation,
('.
I I - M ~ C ~ H Q S % H4%. , A
SCHEME 40
Treatment of 325 with 3-indolylacetic anhydride gave the acylated isoquinuclidine ester 328, which was hydrolyzed to give the hydroxyisoquinuclidine 329. Oppenauer oxidation followed by treatment of 329 with p-toluenesulfonic acid in benzene brought about cyclization to give the lactam tosylate 331, which was convertible to (*)-desethylibogamine (332). Similarly, LTA oxidation of cis-3-ethyl-5-amino~ethylcyclohexene yielded the bridged aziridine 326, which was transformed to (+)-ibogamine (333). (2)-Epiibogamine (334) was also synthesized via 327 starting from trans-3-ethyl-5-aminomethylcyclohexene(Scheme 40). Shortly afterward, Hirai et al. (100) reported an improved synthesis of 333. The lactam tosylate 335 led to 333 in one step, and the former proved to be a key intermediate for the synthesis of (2)-coronaridine (336) (Scheme 41). Narisada et al. (101) directed their attention to oxidative fragmentation (337) by LTA. Thus, LTA oxidation of (~)-7-oxo-l8-hydroxyibogamine in a mixture of methanol and tetrahydrofuran gave the methoxy ketolactam 338 accompanied by an acetoxyindolenine 339. The methoxy ketolactam 338 was converted to (+)-velbanamine (340) and (-+)-isovelbanamine (341) in several steps (Scheme 41). The scope of the bridged aziridine synthesis was further investigated by Nagata et al. (102). LTA oxidation in benzene of 5-aminocycloheptene
109
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
m@$€t MeOOC
m(&p/ t' OTS
33 6
H
335 Ts=p-toluenesulfonyl
qt 333
a
OH
b
H
3 39 331
340 341
R-OH, R, =Et R:Et,
Y'OH
R e a g e n t s : a . A I H ? r e d u c t i o n ; b . Pb(OAc),,
MeOH, T H F
SCHEME 41
(342) gave the bridged aziridine 343 (Scheme 42). Treatment of 343 with diethyl pyrocarbonate proceeded smoothly to give the cleaved product 344, LAH reduction of which led to (+)-2-hydroxytropane (345).
34 2
E344 345
34 3 R e a g e n t s : a. P ~ ( O A C ) ~a ,n h y d r o u s K2CO3, ( E t O C O ) 2 0 , CsHg, Et20;
SCHEME 42
C.
G y ; b. LiAIH4, T H F
R=Rl=COOEt R=Me, R1 =H
110
OSAMU HOSHINO AND BUNSUKE UMEZAWA
XI. Oxoaporphines Recently, Castedo et al. (103) applied LTA oxidation to the synthesis of oxoaporphines. LTA oxidation in AcOH of (+)-glaucine (17) gave 0-methylatheroline (oxoglaucine) (346)and dehydroglaucine (347)in 69 and 7- 10% yield, respectively, the former being formed almost quantitatively on LTA oxidation of the latter. Compound 346 was also prepared by the similar reaction of cataline (357)(104). Furthermore, a green zwitterionic compound, corunnine (348), was synthesized on heating of 346 (f03).Blask6 et al. (79) also obtained 0-methylatheroline (346)on LTA oxidation in CH2CI2 of (+)-tetrahydropapaverine (349) in the presence of a 9 : 1 mixture of TFA and TFAA, the yield being 24.1%. Quaternization of 346 with methyl iodide followed by sodium borohydride reduction furnished (+)-7-hydroxy-1,2,9,10-tetramethoxyaporphine (350) (Scheme 43).
348
357 a
Me
Me
'
Me
17
d, e
349
350 Reagents: a . Pb(OAc)q, AcOH; b . Pb(OAc4 ; c. Pb(OAc4, CF3COOH(CF3CO)zO ( 9 : 1 ) , CH2CI2, -2OOC; d . Mel, CH3CN;
NaBN,, MeOH; f . 150°C
SCHEME 43
e.
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
111
Nimgirawath and Taylor (105) reported an analogous experiment. Synthesis of liriodenine (352) was achieved in 27% yield by LTA oxidation of dehydroushinsunine (351) (Scheme 44). Similarly, aluminum hydride reduction followed by LTA oxidation of N-methoxycarbonyl- or N-ethoxycarbonyl-dehydrostephalagine(353or 354) afforded atherospermidine (355) (106).
353 R = M e
354 R = E t
35 5
R e a g e n t s : a . Pb(OAc)Q, AcOH; b. LiAIHq,AICI3, T H F
SCHEME 44
XII. Lead Tetraacetate-Mediated Hydroxylation of Isoquinoline Alkaloids As mentioned above (see Section II,A), a diastereomeric mixture of (?)-4p- and (~)-4a-acetoxy-O-acetylthaliporphines (18 and 19) was formed as a by-product on acid treatment of the p-quinol acetate derived
112
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
from (+)-codamine (11) (14,15). This experimental result suggests the possibility that LTA oxidation followed by a similar acid treatment of (+)- 1 -hydroxy-2-methoxyaporphinescould promote acetoxylation at C-4 and that isoquinoline alkaloids incorporating a 1,2,3,4-tetrahydro-6methoxyisoquinolin-7-01 moiety in their skeletons could undergo the same reaction. This section deals with the realization of this possibility. A N D C-HOMOAPORPHINES A. APORPHINES
The stereoselective synthesis of (+)-cataline (357) was achieved (25,26,107) by the use of LTA oxidation. LTA oxidation in AcOH of (+)-thaliporphine (16) gave quantitatively (?)-4P-acetoxythaliporphine (356), acetylation of which afforded (?)-4~-acetoxy-O-acetyIthaliporphine (18) in 79.2% yield (Scheme 45). Hydrolysis of 356 with 10% hydrochloric acid gave (?)-4P-hydroxythaliporphine (27), methylation of which with diazomethane furnished (?)-cataline (357) in 86.5% overall yield. As mentioned below, (2)-cataline (357) was also prepared from (+)-srilankine (362). Interestingly, a ready exchange of 4P-acetoxyl and 4P-methoxyl groups in (+)-aporphine 356 was observed (108,109).Treatment of 356 with methanol alone led to (+)-1-hydroxy-2,4P,9,10tetramethoxyaporphine (358) in a high yield. Similar stereoselective acetoxylation at C-4 in C-homoaporphines was performed (38). Thus, (+)-C-homoaporphines 127 and 128 were converted quantitatively to (+)-2,lO,ll-trimethoxy- and (+)-2-methoxy10,ll-methylenedioxy-4P-acetoxy- I -hydroxy-C-homoaporphines (359 and 360), respectively (Scheme 45). Recently, (+)-srilankine (362) was synthesized by the same methodology (107). LTA oxidation in AcOH of (+)-predicentrine (84) gave (+)-4P-O-acetylsrilankine(361), hydrolysis of which with 10% hydrochloric acid afforded (+)-srilankine (362) in 20% overall yield (Scheme 46). On the other hand, LTA oxidation in CHzClz of 84 produced as expected a diastereomeric mixture of o-quinol acetates 363, treatment of which with acetic anhydride including concentrated sulfuric acid stereoselectively led to (+)-2,4P-O,O-diacetylsrilankine(364) in 70% yield. Hydrolysis of diacetate 364 with 10% hydrochloric acid gave (+)-srilankine (362) in 79% yield (about 55% overall yield from 84). Further methylation of 362 with diazomethane gave (?)-cataline (357) in 83% yield.
B. HOMOPROAPORPHINES Acetoxylation at C-4 in a homoproaporphine also proceeded stereoselectively (64). LTA oxidation in AcOH of the (?)-homoproaporphine
113
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
MHOe
'
Me
'
o
p
M
e
a
M
I
Me0
Me
:
p
M
e
i
\
' Me
16
Me
l
p
M
e
'
Me
R =R1 =H
127 128
R=Me R+R=CH2
359 R=Me 360 R + R=CH2
358
R e a g e n t s : a . Pb(OAc)4, AcOH; b . A c 2 0 , p y r i d i n e ; c. 10:HCI;
d . CH2N2, MeOH; e. MeOH
SCHEME 45
201 gave the corresponding p-quinol acetate 365, treatment of which with acetic anhydride containing concentrated sulfuric acid led to (?)-I ,4Pdiacetoxy-2-methoxyhomoproaporphine(203) in 94% yield (Scheme 47). Dienone-phenol rearrangement was not observed under the conditions described above.
C. TETRAHY DROPROTOBERBERIN ES
AND
OXYPROTOBERBERINES
LTA oxidation of four tetrahydroprotoberberines has been investigated ( f f 0 , I l f ) Namely, . LTA oxidation in AcOH of (2)-govanine (366) and ( 2 ) IO-hydroxy-2,3,ll-trimethoxytetrahydroprotoberberine (369) afforded the corresponding p-quinol acetates 367 and 370 quantitatively. Treatment of acetate 367 with acetic anhydride including concentrated sulfuric acid gave only (~)-2,5p-diacetoxy-3,10,1 I-trimethoxytetrahydroprotoberberine (368) in 90.9% yield, whereas that of acetate 370 resulted in acetoxylation at C-13 to lead to (*)-10,13aand (?)-10,13P-diacetoxy-
114
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
361 b
a4 Me0
6Me
363
bMe
364
Reagents: a . Pb(OAd4, AcOH; b . 10%HCI; c . Pb(OAc)4, CH2C12; d . A c 2 0 , c.HzSO4
SCHEME 46
201
36 5 Reagents: a. Pb(OAc)4, AcOH; b . A c 2 0 , c.H2S04
SCHEME 47
203
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
369
115
eH R e a g e n t s : u . Pb(OAcIq, AcOH. I , .
A c P , c.Ii2Mq
SCHEME 48
2,3,11-trimethoxytetrahydroprotoberberines(371 and 372) in 12 and 35% yield, respectively (Scheme 48). Hydrolysis of the diacetate 368 with concentrated hydrochloric acid gave (t)-2,5p-dihydroxy-3,10,1 I-trimethoxytetrahydroprotoberberine (373), methylation of which with diazomethane afforded (?)-5phydroxy-2,3,1O,ll-tetramethoxytetrahydroprotoberberine(374) (Scheme 49). Methanolysis of diacetate 368 with aqueous potassium hydroxide in methanol proceeded smoothly to give (?)-3,5a,IO,ll- and (+)-3,5p,IO,I 1tetramethoxy-2-hydroxytetrahydroprotoberberines (375 and 376), while that of the two diastereomeric diacetates 371 and 372 led to (+)-lohydroxy-2,3,11,13a-tetramethoxytetrahydroprotoberberine(377) as a sole product. On the other hand, LTA oxidation in AcOH of (?)-discretine (378) gave an inseparable mixture of (?)-5a-and (~)-5~-acetoxy-3-hydroxy-2,10,11trimethoxytetrahydroprotoberberines (379 and 380) in 30% yield (in a ratio of 5 : l l ) , 25% of the starting material 378 being recovered unchanged. Hydrolysis of the mixture with concentrated hydrochloric acid effected separation to give (-+)-3,5a- and (-+)-3,5P-dihydroxy-2,10, I Itrimethoxytetrahydroprotoberberines (381 and 382) in 20 and 48% yield,
1 I6
:%
OSAMU HOSHINO AND BUNSUKE UMEZAWA
H"
Me% R
0
a
\
H'
/
'
Me Me
H"
0
OMe
OMe
Me
Me
375 376
368
R-OMe, R1=H R = H , R1 - 0 M e
Me
\ Me
371 372
R = O A ~ ,R ~ = H
OH Me
3 77
R = H , R~ =OAC
R e a g e n t s : a. C.HCI; b . CI-$N2, MeOH; c . S % a q . K O H , MeOH
SCHEME 49
respectively. Methylation of the dihydroxy compounds 381 and 382 with diazomethane yielded (*)-5a- and (~)-Sp-hydroxy-2,3,10,11tetramethoxytetrahydroprotoberberines (383 and 374), respectively (Scheme 50). Unexpectedly, LTA oxidation in AcOH of (+)-corytencine (384) proceeded in a different manner to give a rearranged product, (?)12-acetoxy-9-hydroxy-2,3,lO-trimethoxytetrahydroprotoberberine(386), and the usual acetoxylated product, (+)-13p-acetoxy-l I-hydroxy-2,3,10trimethoxytetrahydroprotoberberine (387) in 5 I .9 and 12.5% yield, respectively. The novel rearrangement via p-quinol acetate 385 was termed tetrahydroisoquinoline oxidative rearrangement by Hara et al. (111,112). Acetylation or methylation of 386 gave diacetate 388 or (2)-2,3,9,10,12pentamethoxytetrahydroprotoberberine (389). Hydrolysis of the 13pacetate 387 with concentrated hydrochloric acid gave (?)-I 1,13pdihydroxy-2,3,IO-trimethoxytetrahydroprotoberberine(390), methylation of which with diazomethane afforded (?)-13p-hydroxy-2,3,IO,lltetramethoxytetrahydroprotoberberine (391) (Scheme 5 I ) .
117
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
Me0
378
Me 'Q-OMeOMe
OMe
379
RZOAC, R ~ = H
381
R:OH,
380
H - H , R~ =OAC
382
R = H , R, =OH
R1 =H
/
Me Me
R e a g e n t s : a . Pb(OAc14, AcOH;
b . c . H C I ; c. CH2N2, MeOH
SCHEME 50
'
Me
38r
384
Me
OAc
'
AC
OMe
m e
308
309
Reagents: u . Pb(0Ac)Q. ACOH; b . A c 2 0 . p y r i d i n e , C.
CHIN*.
MeOH, d . C.HCI'
SCHEME 51
390
R H
391
R-Me
I18
OSAMU HOSHINO AND BUNSUKE UMEZAWA
As stated in Section I, LTA oxidation in CH2Cl2of 1,2,3,4-tetrahydro7-methoxy-2-methylisoquinolin-6-ols has been established to give the corresponding reactive o-quinol acetates ( / 9 , 2 0 ) .Benzene ring acetoxylation via such o-quinol acetates has been carried out successfully ( I / . 3 , / / 4 ) .LTA oxidation in CH2Cl2 of (*)-discretine (378) and ( 2 ) corytencine (384) gave the corresponding o-quinol acetates 392 and 393, treatment of which with acetic anhydride containing concentrated sulfuric acid promoted acetoxylation at the benzene ring to give (*)-3,4diacetoxy-2,10, I I - and (*)-I I , 12-diacetoxy-2,3,10-trimethoxytetrahydroprotoberberines (394 and 396) in 65.6 and 47.2% yield, respectively (see also Section XII,F). Hydrolysis followed by methylation of the diacetates 394 and 396 gave (+)-2,3,4,10,1I - and (~)-2,3,10,11,12-pentamethoxytetrahydroprotoberberines (395 and 397) (Scheme 52).
AT b
Me0
OMe
w'
H
0
a
392
'
0
Me
Me
394
Me Me
R=Rl=Ac
R =R1=Me
R e a g e n t s : a . Pb(OAc)q, CH2C12; b . AC20, c.H2S0,,; c . H C I , MeOH; d . CI+Nz,
C.
MeOH
SCHEME52
The stereochemistry of the two quaternary protoberberium salts, (+)-berberastine (398) and (+)-thalidastine (399), except the sign of specific rotation, remained uncertain, owing to their paucity as well as instability. To solve these problems, Zarga and Shamma (I15) utilized
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
I19
LTA-mediated hydroxylation and postulated the absolute configurations of 398 and 399 on the basis of the identical sign of specific rotation exhibited by (+)-5a-hydroxyjatrorrhizine (400). the synthesis of which was unambiguously performed as follows. LTA oxidation of (+)-tetrahydrojatrorrhizine (401) gave a diastereomeric mixture of 5-monoacetates (402), hydrolysis of which with 10% hydrochloric acid led to 33- and 5a-alcohols 403 and 404 in a ratio of 1 : 2. Alcohol 404 was oxidized with iodine in hot ethanol to furnish the quaternary protoberiberium iodide 400 (Scheme 53).
R e a g e n t s : a . Pb(OAc14, ACOH; b . 10:HCI;
C.
12, EtOH, t3
SCHEME 53
Boar ef r d . ( 1 16, 1 1 7 ) established the 2-acetoxylation of enamides 405 by use of LTA oxidation (Scheme 54). Dorn rt (11. (118) applied the reaction to oxyprotoberberines to achieve the synthesis of (*)-I3P-hydroxytetrahydroprotoberberines, the key step being C-13 acetoxylation. LTA oxidation in benzene of CH2C12 of 2,3-dimethoxy-, 2,3,lO,Iltetramethoxy-, and 2,3-methylenedioxy-9,IO-dimethoxy-oxyprotoberberines (406,407, and 245) led to the corresponding 13-acetoxy-oxyprotoberberines 408, 409, and 410 in 62, 55, and 71% yield, respectively. Successive reduction of 409 and 410 with LAH and sodium borohydride gave (?)-13/3-hydroxyxylopinine (391) and (2)-ophiocarpine (411) in 60 and 52% yield, respectively (Scheme 54).
120
OSAMU HOSHINO A N D B U N S U K E UMEZAWA
405
245
411
41 0
R + R z O C H P , Rl=R2=OMe R3-H
Reagents; a . Pb(OAc),,, C.
LiAIH,,,
R + R = O C H P . Rl=R2:OMe R3=H
C6H6; b . Pb(OAcb, CHZC12;
T H F ; d . NaBHq, MeOH
SCHEME 54
Further, LTA oxidation of the 13-acetoxy-oxyprotoberberines was confirmed to give the 8,13-dioxo- 13a-oxygenated berbines ( 1 18). On LTA oxidation in CHCl3 of 409, (+)-13a-ethoxy- and (?)-13a-hydroxy-8,13dioxo-2,3.10,1 I-tetramethoxyberbines (412 and 413) were obtained in 40 and 46% yield, respectively (Scheme 55). The former (412) was yielded as the sole product when the LTA oxidation products were pretreated with absolute ethanol in the presence of p-toluenesulfonic acid. Analogously, LTA oxidation followed by treatment of 410 with methanol and p-toluenesulfonic acid resulted in the sole production of (+)-9,10,13a-trimethoxy-2.3-methylenedioxy-8. I3-dioxoberbine (414) in 92% yield. Exchange of 13a-methoxyl and 13a-hydroxyl groups occurred readily. Thus, threatment of 414 with hydrochloric acid led to ( 2 ) 13a-hydroxy-8,13dioxoberbine (415) in 88% yield. Treatment of the latter with 10% ammonium hydroxide caused ring-alteration to lead to (%)-chilenine(416) in 66% yield (Scheme 55).
D. C U L A R I D ~ N E S De Lera P t al. (119) achieved the synthesis of limousamine (421) by the use of LTA oxidation. LTA oxidation in AcOH of cularidine (417)
2. LEAD TETRAACETATE OXIDATION I N ALKALOID SYNTHESIS
Reagents:
121
a . Pb(0Ac)q. CHC13; b . EtOH, p-MeCbHqS03H; c. MeOH, p-MeC6HqS03H; d . C.HCI; e . 100,aq.NH3
SCHEME 55
proceeded as usual to give the corresponding p-quinol acetate, treatmen of which with acetic anhydride containing concentrated sulfuric acid gavc a diastereomeric mixture of cularidine 4,7-diacetates (418 and 419) (38% yield) together with cularidine acetate (420) (32% yield). Hydrolysis of thc former with 2% aqueous sodium carbonate ensured separation to give 4p and 4a-hydroxycularidines (421 and 422); 421 corresponded to limousamine, 422 to epilimousamine. Methylation of 421 with diazornethane led to the known compound 0-methyllimousamine (423) (Scheme 56).
E. ERYTHRINA ALKALOIDS Application of LTA oxidation to the synthesis of Erythrinri alkaloids was reported by Mondon and Seidel (120). Although attempts to introduce an acetoxyl group to C-6 in 424 were unsuccessful, cis and trans dimers 425 and 426 were obtained in a ratio of I : 1 (Scheme 57). Recently, two groups that performed LTA oxidation of erysovine (427) and erysodine (428) report mutually contradictory results. As I I oxygenated Erythrinu alkaloids are relatively scarce, their ready preparation from the abundant alkaloids 427 and 428 deserved special attention. According to Abdullah et uf. (/2/), LTA oxidation in AcOH of 427 proceeded stereospecifically to give quantitatively 1 la-acetoxyerysovine
122
OSAMU HOSHINO A N D B U N S U K E UMEZAWA
+
.$ Me0
OMe
420
418 R - O A C , R , = H 419 R =H , R~ =OAC
417
421 422
423
RZH, R ~ = O H R = O H , R,=H
R e a g e n t s : a . Pb(OAc)4, AcOH; b . A c 2 0 , c.H2S0,,;
c . 21aq.Na2COj,
THF; d . CHZNZ
SCHEME 56
424
425
R=
426
Me0
Reagents: a . Pb(OAc),,, AcOH
SCHEME 57
'
123
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
(429), whereas that of 428 gave a diastereomeric mixture of the corresponding o-quinol acetates 430 in virtually quantitative yield. Treatment of the quinol acetates 430 with acetic anhydride containing concentrated
sulfuric acid unexpectedly promoted acetoxylation at C-17 to give two isomeric products 431 (major) and 432. The desired acetoxylation at C-1 1 was achieved under acetylation conditions. Thus, 1 1p-acetoxy-Oacetylerysodine (433) was produced in 10% yield on treatment of the o-quinol acetates 430 with acetic anhydride in pyridine (Scheme 58). The report by Sarragiotto et (11. (122) sharply contrasted that by Abdullah et C J / . (121) LTA oxidation in AcOH of 427 gave the corresponding p-quinol acetafe, treatment of which with acetic anhydride in the presence of concentrated sulfuric acid led to four I I-acetoxylated and ( 3 R . I IS)-l I-acetoxy-3, 15-diacetylerysovine (434 products, (3R,IlR)and 436) and (3S,IlR)- and (3S,IIS)-l l-acetoxy-3,15,-diacetyl-3epierysovine (435 and 437) in 17,6, 13, and 0.5% yield, respectively. LTA oxidation in CHzClzof 428 gave the corresponding o-quinol acetates 430. However, decomposition of the acetates prior to their expected rearrangement prevented further development (Scheme 58).
431
R-OAC,
432 R - H I
433
R ~ = H
R1 :OAc R e a g e n t s : a . Pb(OAc),.
AcOH; b . P b ( O A c $ , CH2CI2;
A C ~ c, . H 2 m q ; d . A q O , p y r i d i n e
SCHEME58
C
124
OSAMU HOSHINO AND BUNSUKE UMEZAWA
F. SIMPLE ISOQUINOLINES A N D I-BENZYLISOQUINOLINES Benzene ring acetoxylation via the o-quinol acetate has been developed in our laboratory (113,114). LTA oxidation in CHzClzof isocorypalline (4) gave o-quinol acetate (5) (Scheme I ) , treatment of which with acetic anhydride including concentrated sulfuric acid afforded 5-acetoxy-6-0acetylisocorypalline (438) in 19.4% yield. Hydrolysis of 438 with concentrated hydrochloric acid in methanol afforded a 5,6-diol hydrochloride, methylation of which with diazomethane led to tehaunine (439) in 22.1% yield. Similarly, (*)-N-rnethylsalsoline (440) and (?)-1,2,3,4-tetrahydro7-methoxy-l-(4-methoxybenzyl)-2-methylisoquinolin-6-ol(441) were transformed to (2))-O-rnethylgigantine(444)and (*)-tetrahydrotakatonine (445) in 4 and 0.48% yield, respectively, via 442 and 443 (Scheme 59).
c,d Me m
m
R M
e
a'b
re&NMe
R
Me0 R
4 440 441
438 442 443
R=H R=Me R=p-MeOC6H4CH 2
Reagents: a. Pb(OAc),,,
439 444 445
CH2C12; b . A c 2 0 , c.H2S04;
c. c . H C I , MeOH; d . CH2N2, MeOH
SCHEME 59
Recently, Gozler et al. (123) proposed the stereostructure 1,4cis - 1,2,3,4-tetrahydro - 4,6 - dihydrox y - 7 -met hox y - 1 - (3,4- dimethoxybenzyl)-2-methylisoquinoline (446) for (+)-roemecarhe. However, the stereostructure was revised to 449 based on the synthesis of 446 (124). Namely, two epirneric acetates, (*)-I ,4-cis- and ( + ) - I ,4-trans-4-acetoxy- I ,2,3,4tetrahydro-6-hydroxy-7-methoxy1-( 3,4-dirnethoxybenzyl) -2-methyliso quinolines (447 and 448),previously prepared via a thermal isomerization of the corresponding o-quinol acetates (19), were used for synthesis of (L)-roemecarine and its epimer (Scheme 60). Hydrolysis of 447 and 448 with 5% methanolic potassium hydroxide proceeded with retention of the configuration at C-4 to give the authentic (+)-1,4-cis- and ( + ) - I ,4-~ransdiols 446 and 449. As a result, structure 446 was inconsistent with natural roemecarine on the basis of 'H-NMR spectral comparison, while 449 was identical with the alkaloid with respect to spectroscopic data. De Lera et al. (125) applied the above acetoxylation method to the
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
125
e
Me
Me :H, R1 =OAc
bMe
77
448
R=OAC, R , = H
446
R e a g e n t s : u . Pb(OAc)q, CH2C12; b . 3OoC or AcOH; C.
S%KOH-MeOH
SCHEME 60
synthesis of a key intermediate leading to 4-hydroxysarcocapnine (126) and other oxidized isocularine alkaloids (127). LTA oxidation in CHzCl? of (?)-I-(2-bromo-3,4-dimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy2-methylisoquinolin-8-01 (450) gave the corresponding o-quinol acetate 451, the CHzClz solution of which was stirred at room temperature to give a 1 :9 diastereomeric mixture of the (?)-4-acetoxy-l,2,3,4-tetrahydroisoquinolin-8-01s 452 (Scheme 61). Ullmann reaction of 452 resulted in cyclization to give a diastereomeric mixture of (+)-4-acetoxyisocularines, hydrolysis of which gave the (+)-4-hydroxy compounds 453 and 454. The minor diastereomer 453 was identified as natural 4-hydroxysarcocapnine. Yagonine (455) and aristoyagonine (456) were obtained by further manipulation of 453 and 454 (Scheme 61).
G . SPIROBENZYLISOQUINOLINES Application of LTA-mediated hydroxylation to the synthesis of spirobenzylisoquinoline alkaloids has been reported by Blasko ot cil. (128). 2,3,9-Trimethoxy- and 9-methoxy-2,3-methylenedioxy-lO-hydroxy-8keto-spirobenzylisoquinolines(457 and 458) underwent acetoxylation at C-13ontreatment of LTA in AcOH to afford the corresponding syn-13-
126
OSAMU HOSHINO A N D BUNSUKE UMEZAWA
‘..H
Me0
-0
(1
‘H
\
Br
450
-
*yj
Me%
\
’
’
OMe
Me
451
Me
-.
Br
’
1452
OMe
Me
OMe
+ hAeo2NM R.
455
e% M e ;
Me
\ /
453 R = O H ,
M e 0 7 MeQ
454
R1 = H
R = H , R1 :OH
Med
-
456 Me0
Reagents: a . Pb(OAdq, CH2C12; b . CH2C12, room t e m p . ; c. K C 2 C u O , pyridine, 1 6 5 O C ; d . aq.Na2C03, MeOH; e .
4,
DDQ, G H 6 . A ; f . Ba(OHI2, MeOH
SCHEME61
acetoxyspirobenzylisoquinolines459 and 460 in 72 and 70% yield, respectively (Scheme 62). A small amount of quinodiacetates 461 and 462 were always formed. Hydrolysis of 459 and 460 with 5% hydrochloric acid gave the syn-13-hydroxyspirobenzylisoquinolines 463 and 464, respectively. On the other hand, treatment of 459 with potassium tert-butoxide in hot methanol or ethanol promoted a n alkoxide introduction to C-13 giving syn-2,3,9,13-tetramethoxyor syn-13-ethoxy-2,3,9-trimethoxy-l0hydroxy-8-keto-spriobenzylisoquinoline(456 or 466) in 45 or 21.2% yield, together with N-methylcorydaldine (467) (36% yield). XIII. Miscellaneous Reactions As mentioned in Section VI, acid treatment of the p-quinol acetates of 53 and 54 and 158-160 gave the corresponding chloroisopavines (Scheme 7) and homoisopavines (Scheme 18). though yields are low. These
I27
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
\ Me 0
Me
467 Hd
463 464
R-Me R
+
R=CH2
R e a g e n t s : a . Pb(OAc)ll, A c O H ; b . 5:HCI;
c. MeOH or EtOH, tBu0K.d
SCHEME 62
findings suggested the formation of bicyclo- 1 -azanonanes or decanes by acid treatment of p-quinol acetates derived from N-benzyl or phenethyltetrahydroisoquinolinols.Eventually, TFA treatment of p-quinol acetates 473 and 474 derived from 468 and 469 was performed to give (*I-dibenzoI-azabicyclo [3.3.Ilnonanes 478 and 479 in moderate yields (Scheme 63). In an analogous manner, the homologs 480-482 were prepared from p-quihol acetates 475-477 of (?)-N-phenethyl congeners 470-472. On the other hand, (+)-7-hydroxy-bicyclo-1 -azanonane 486 was obtained by acid treatment of the 4-acetoxy compound 485 via o-quinol acetate 484 derived from 483 on LTA oxidation (129). A synthesis of bistetrahydroisoquinolines using p-quinol acetate 3 and 8.8a-epoxy p-quinol 495 was performed (130-132). Reaction of 3 corypalline (1) (130),isocorypalline (4), and 6- and 7-tetrahydroisoquinolinols (131) and subsequent acetylation gave substituted bistetrahydroisoquinolines 487-492 (Scheme 64). Interestingly, similar treatment of 3 with 5-tetrahydroisoquinolinolgave a C-0 coupling dimer (493) in addition to a C-C coupling dimer (494). On the other hand. bistetrahydroisoquinolyl ethers 496-499, which were formed by intermolecular C-0 coupling. were obtained by treatment of 8,8a-epoxy p-quinol 495 with tetrahydro-
128
OSAMU HOSHlNO A N D BUNSUKE UMEZAWA
Reagents
u
Pb(oAc)4. AcOH, 0
c
PblOACh,, CH2CI2,
CFJCOOH, CH2Ch, 11.
neat, room lemp
SCHEME 63
"
"
m
N
M
e
"
b. c
& :..Me
M ti e o m N M e
R
1
3 487
400 AcO
,
Me0 c A
o
'/
g
e
+
491
g
s
, ,JO "Me f
aNMe AcmN
R - AC
492
R
e
AC Me
494
493 Reagents.
(1.
Pb(OAcIq, ACOH. b .
tetrahydroisoquinolinols, CFjCOOH,
CH2C12; ('. A c 2 0 , p y r i d i n e
SCHEME 64
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
/
3
1
" HO ' O
W
N Me
bR
496
129
495
.=-mNMe 497 .
M
M e m N M e
-
R e a g e n t s : a . Pb(OAc14, AcOH; b . 3 . 5 % H 2 0 2 , N a O H , MeOH;
c . tetrahydroisoquinolinols, LiOH, H 2 0 , M q N C H O , 5Ooc
SCHEME 65
isoquinolinols under basic conditions (132) (Scheme 65). Such results might provide a novel route for synthesis of bisbenzyltetrahydroisoquinoline alkaloids. More recently, conversion of corypalline (1) and (*)-l-benzyl-6methoxytetrahydroisoquinolin-7-01(500) to isocorypalline (4) and ( *1- I benzyl-7-methoxytetrahydroisoquinolin-6-ol(509) was accomplished via p-quinol ethers (133). Thus, P-quinol ethers 502 and 503 (134) derived from P-quinol acetate 3 were reduced with sodium borohydride to give 6-alkoxy-tetrahydroisoquinolinols504 and 505 in 88 and 54% yield, respectively (Scheme 66). On the other hand, p-quinol acetate 501 was treated with isopropanol in the presence of BF,.Et20 to give two diastereomeric mixtures of p-quinol ethers 506 and (+)-4,6-diisopropoxytetrahydroisoquinolin-7-01 (507) in 14 and 18% yield, respectively. Similar reduction of 506 as above gave (+)-6-isopropoxytetrahydroisoquinolin-7-01508, which was also obtained by catalytic hydrogenolysis of 507. Methylation and dealkylation of 504-505 and 508 gave isocorypalline (4) and (+)-l-benzyltetrahydroisoquinolin-6-ol509, respectively.
130
OSAMU HOSHINO AND BUNSUKE UMEZAWA
Acknowledgments
The authors are grateful to Drs. H. Mishima and H . Hara for valuable suggestions with respect to the manuscript.
RFFERENCES
I . R. Criegee, in “Oxidation in Organic Chemistry” ( K . B. Wiberg, ed.), Part A, p. 277. Academic Press, New York, 1965. 2. M. Lj. MihailoviC and 2. Cekovid, in “The Chemistry of The Hydroxyl Groups” ( S . Patai, ed.), Part I . p. 533. Wiley (Interscience), New York, 1971. 3. M. Lj. MihailoviC and R. E. Partch, in “Selective Organic Transformations” (B. S . Thyagarajan. ed.). Vol. 2, p. 97. Wiley (Interscience), New York. 1972. 4. R. N. Bulter, in “Synthetic Reagents” ( J . S. Pizey, ed.), Vol. 3, p. 277. Ellis Horwood, London, 1977. 5. J . D. Loudon. Prog. Org. Chem. 5, 51 (1961). 6. B. Miller. in “Rearrangements of Molecular Migrations” (B. S. Thyagarajan, ed.), Vol. I . p. 247. Wiley (Interscience). New York, 1968.
2. LEAD TETRAACETATE OXIDATION IN ALKALOID SYNTHESIS
131
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- Chapter 3 CANTHIN-6-ONE ALKALOIDS TAICHIOHMOTOA N D KAZUOKOIKE School of Pharmaceutical Sciences Toho University 2-2-1 Miyama, Funabashi, Chiha 274, Japan
I. Introduction .............
....................................................
11. Natural Occurrence ............................................................ 111. Structural Elucidation .................................
135
................ 137 ................155
References ..........
................................. ................................................................
165 167
I. Introduction In 1952, Haynes et a f .( 1 ) isolated an alkaloid from Pentaceras australis (Rutaceae) grown in Australia. This alkaloid, with the molecular formula Cl4HRN2O,was named canthin-6-one (1). Giesbrecht et a f . (2) later isolated a new type of alkaloid, 3-methoxycanthin-2,6-one(2), from Simaba cuspiduta of Brazil. Then Ohmoto and Koike (3) isolated 3-methylcanthin-5,6-dione(picrasidine L, 3) and picrasidine M (4), a dimeric alkaloid having a canthin-5,6-dione and p-carboline structure, for the first time from Picrasma quassioides. Most of the over 30 alkaloids which belong to the above four types are found exclusively in the families Rutaceae and Simaroubaceae of the order Rutales. As for other plants, alkaloids of these types have been isolated only from the families Amaranthaceae and Caryophyllaceae of the order Centrospermae and the family Malvaceae of the order Malvales. All plants mentioned above are dicotyledons. Steglich et al. (4) isolated a substance with bitter taste, infractopicrin (S),from Cortinarius infiactus in the family Cortinariaceae. 135
THEALKALOIDS VOL 36 Copyright 19x9 by Acddemic Pre\c Inc All right\ o f reproduction in any form reserved
136
TAICHI OHMOTO AND KAZUO KOIKE
Ri SCtb (6) H (7)
(8)OCHs
Fh H OCHs OCHs
Several kinds of P-carboline derivatives have been isolated from fungi since the first isolation of canthin-6-one alkaloids from this toadstool. Taylor ( 5 ) reviewed some of the canthin-6-one alkaloids such as canthin-6-one (l), 4-methylthiocanthin-6-one (6),5-methoxycanthin-6-one (7), and 4,5-dimethoxycanthin-6-one(8). Cordell ( 6 ) , Joule (7), and Saxton (8-12) summarized several other canthin-6-one alkaloids.
11. Natural Occurrence
Thirty-five canthin-bone alkaloids have been isolated from 36 species of plants and a species of toadstool. Twenty-nine of the 35 alkaloids have been isolated from species in the family Simaroubaceae. These com-
3. CANTHIN-6-ONE ALKALOIDS
137
pounds form an important group from a chemotaxonomical point of view. Three other alkaloids have been isolated from cell cultures of Ailanthus altissima of the family Sirnaroubaceae. The nearly 100 species of the family Simaroubaceae are distributed mainly in the tropics, and only a few species grow wild in subtropical and temperate zone areas. The wood, seeds, and bark of the plants are used in folk medicine as stomach, antiarnebic, antimalarial, antihelminthic agents, and so on. The canthin-6one alkaloids in the Simaroubaceae are found together with quassinoids and P-carboline alkaloids. Large amounts of alkaloids occur in the root bark and bark, and lesser amounts are found in the heartwood and wood. Names, formulas, sources, etc. of natural canthin-6-one alkaloids are summarized in Table I.
111. Structural Elucidation
All the canthin-6-one alkaloids isolated from plants, except canthin-6one itself which has a simple structure, are oxidized at any position from C-1 to C-11 of the skeleton to form hydroxy and/or methoxy derivatives. Many canthin-6-one and canthin-2,bdione derivatives are weakly basic and produce salts with 10% mineral acid, but 3N-substitution products of canthin-2,6-dione have no basicity. The IR spectra of canthin-6-one alkaloids show characteristic absorptions arising from the lactam group in the region between 1632 and 1695 cm-' depending on the position of functional groups. The compounds are optically inactive. Canthin-2, 6-dione and canthin-5,6-dione derivatives give strong, characteristic yellowish green fluorescence in organic solvents. Details of structural elucidation are discussed as follows. Canthin-6-one ( I )
Canthin-6-one (1)has been isolated from 25 of the 36 species of plants in Table I and from cell cultures of Ailanthus altissima (13-16). Canthin-6one is one of the most widely distributed alkaloids in plants. It has been reported ( 1 7 ) that 1 is contained in 9 of 33 species in the genus Rhododendron of the family Ericaceae of China. Readers are referred to Volume 8 (p. 249) of this treatise for its structure (5). Canthin-6-one N-Oxide (9)
Canthin-6-one N-oxide (9) has been isolated from the wood (18), root bark (19), and cell cultures (13,15) of Ailanthus altissirna. By comparing the chemical shifts of H-2 in the 'H-NMR spectra of the N-oxides of
TABLE I CANTHIN-6-ONE ALKALOIDS A N D THEIROCCURRENCE ~
Compound Canthin-6-one (1)
Formula
mp P.3
C , ~ H ~ N Z O 162- I63
Source Fagara mayu Fagara viridis (syn. Fagara fuscopilosa) Fagara zanthoxyloides Pentaceras australis Zanihoxylum belizense Zanthoxylum coreanum Zanihoxylum dipetalum (syn. Fagara dipeiala) Zanihoxylum elephantiasis (syn. Zanthoxylum aromaticum, Fagara elephuniiasis) Zanthoxylum Jlavum Zanthoxylum ovalifolium Zanthoxylum suberosum (syn. Zanthoxylum dominianurn) Zanthoxylum sp. (yet unnamed) Ailanthus aliissimu (syn. Ailanihus grandulosa) Ailanthus altissima cell culture Ailanthus excelsa Brucea antidysenterica Hannoa klaineana Odyendea gabonensis (syn. Quassia gabonensis) Picrasma crenata
Family
Ref.
Rutaceae Rutaceae
62-64 65
Rutaceae Rutaceae Rutaceae Rutaceae Ru taceae
66 1 67 68 69
Rutaceae
70- 72
Rutaceae Rutaceae Rutaceae
73 74,75 76
Rutaceae Simaroubaceae
77,78 18,19,22-24,79
Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae
13-16 25 46,47,80 81 37
Simaroubaceae
5
-
Canthin-6-one N-oxide (9)
244-245
1-Hydroxycanthin-6-one (10)
220
1-Methoxycanthin-6-one (11)
250-25 1
W
\c
I-Methoxycanthin-6-one N-oxide iU)
CIsHION203
2-Hydroxycanthin-6-one (13)
Ci4HaN~02
4-Hydroxycanthin-6-one (14) 4-Methoxycanthin-6-one (15)
Ci4HaN~02 ClcHinND2
220-221
4-Methylthiocanthin-6-one ( 6 ) 5-Hydroxycanthin-6-one (16)
C i,H 1nN20S C14HaN202
252.5-253.5 256-258 (dec.)
256-251
Picrasma excelsa (syn. Quussicr jamaicenese) Picrasma javanica Picrasma quassioides (syn. Picrasma ailanthoides) Quassia africana (syn. Simaba africana) Simaba multi~ora Soulamea pancheri Hibiscus syriacus Ailanthus altissima Ailanthus altissima cell culture Ailanthus altissimu Ailanthus altissima cell culture Ailanthus giraldii Ailanthus altissima Ailanrhus altissima cell culture Ailonthus e.rcelsa Brucea antidysenterica Hannoa klaineana Soulamea pancheri Ailanthus alrissima Ailanthus altissima cell culture Ailanthus altissimu cell culture Quassia kerstingii Ailanthus altissimu cell culture Charpentiana obovata Drymaria cordata Pentaceras australis Sirnarouba amara Ailanthus altissima cell culture
Sirnaroubaceae
53,82
Sirnaroubaceae Sirnaroubaceae
83 50,84
Sirnaroubaceae
55
Sirnaroubaceae Sirnaroubaceae Malvaceae Simaroubaceae
85
Sirnaroubaceae
20 13,15,16 21 18,19.22 13-16 25 26 27.87 28 19 13.15 13.15 29 13,15 32 33 31 34 13,15
Simaroubaceae Sirnaroubaceae Sirnaroubaceae Sirnaroubaceae Sirnaroubaceae Simaroubaceae Sirnaroubaceae
Sirnaroubaceae Amaranthaceae Caryophyllaceae Rutaceae Simaroubaceae
28 86 18,19 13,15
(continued)
TABLE I (Continued) Compound
L 0
Formula
mp CC)
5-Methoxycanthin-6-one (7)
Ci5HioNzOz
237-238
5-Hydroxymethyicanthin-6-one (17) 8-Hydroxycanthin-6-one (18)
CIcH,,N,O2 C14HsN202
246-247 >300
9-Methoxycanthin-6-one (19)
C i5H ioNzOz
175-176
10-Hydroxycanthin-6-one (20)
CiiH&"02
288-293 (dec.)
10-Methoxycanthin-6-one (21) 11-Hydroxycanthin-6-one (amarorine)
C I ~ H I O N Z O ~175-178 323-325 CI4HgN2O2
(22)
11-Methoxycanthin-6-one (amoridine) (2.3) I -H ydrox y- 1 1-methox ycanthin-6-one (24)
C15HION202 237-238 CISHIoN~O,
-
Source
Family
Ref.
Peniaceras australis Zanihoxylum carbibaeum Zanihoxylum elephaniiasis Ailanthus excelsa Burcea aniidysenierica Odyendea gabonensis Picrasma excelsa Picrasma quassioides Ailanthus uliissimu Ailanihus excelsa Odyendea gabonensis Pierreodendron kersiingii Simaba muliipora Simaba cuspidaia Simaba multipora Eurycoma longifolia Simaba muliipora Simaba mulripora Amaroria soulameoides (syn Soulamea soulameoides) Brucea anridysenierica Quassia kersiingii Amaroria soulameoides
Rutaceae Rutaceae Rutaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae
35 88 72 25 47 37 53,82 84 36 25 37,38 39 40 2 41 43 42 42 44,45
Simaroubaceae Simaroubaceae Simaroubaceae
46 29 44
Brucea antidysenrerica
Simaroubaceae
26,47
Brucea antidysenterica
Simarou baceae
26
Soulamea pancheri Brucea antidysenterica Picrasma quassioides
Simaroubaceae Simaroubaceae Simaroubaceae
28 46 48
Simaroubaceae Simaroubaceae
53 49-52,54
Simaroubaceae Simaroubaceae
37 55
258 (dec.)
Picrasma excelsa Picrasma quassioides (syn. P. ailanthoides) Odyendea gabonensis Quassia africana (syn. Simaba africana) Ailanthus altissima cell culture Simaba multijora Simaba cuspidata Simaba multij7ora Samadera indica
Simaroubaceae Simaroubaceae Simaroubaceae Simaroubaceae
13,15 42 2 42 56
280-290 (dec.)
Simaba mulfijlora
Simaroubaceae
42
>330
274 (dec.)
Picrasma quassioides Quassia amara Picrasma quassioides
Simaroubaceae Simaroubaceae Simaroubaceae
3,57,58 59 48
294-295 (dec.) 171-172 (dec.) 199-200 (dec.) >350
Picrasma quassioides Picrasma quassioides Picrasma quassioides Cortinarius infractus
Simaroubaceae Simaroubaceae Simaroubaceae Corinariaceae
3 48 61 4
1 I-Hydroxy-I-methoxycanthin-6-one
(25) 1 , I I-Dimethoxycanthin-6-one(26)
4-Hydroxy-5-rnethoxycanthin-6-one (picrasidine Q ) (27) 5-Hydroxy-4-methoxycanthin-6-one (nigakinone) (28)
-
217-220 (dec.) 286-289 224-225
4,5-Dimethoxycanthin-6-one (8)
145-146
4,5-Dihydrocanthin-6-one (29) Canthin-2,6-dione (31) 3-Methoxycanthin-2,6-dione (2)
128 290-305 (dec.) >330
f 5-Methoxycanthin-2,6-dione (indacanthinone) (30) lO-Hydroxy-3-rnethoxycanthin-2,6dione (32) 3-Methylcanthin-5,6-dione (picrasidine L) (3) 3-Methyl-4-methoxycanthin-5,6-dione (picrasidine 0) (33) Picrasidine M (4) Picrasidine N (34) Picrasidine U (35) Infractopicrin ( 5 )
142
TAICHI OHMOTO AND KAZUO KOIKE
canthind-one (l),4,5-dimethoxycanthin-6-one(8), and pyridine, it was found that the N-oxides showed an approximately 0.5-ppm high-field shift relative to 1,8, and pyridine. On this basis, compound 9 was assumed to be a 3-oxide. Haynes et a/. ( I )obtained 9 by oxidizing 1 with hydrogen peroxide. Ohmoto et a / . (18) obtained 9 through oxidizing 1 with m-chloroperbenzoic acid and further converted 9 to 1through hydrogenation with palladium on carbon. On the basis of these results, structure 9 was confirmed.
I-Hydroxycanthin-6-one (10) 1-Hydroxycanthin-6-one (10) has been isolated from the root bark (20) and cell cultures (13,m 6 ) of Ailanthus altissima and from the heartwood (21) of A. giraldii. By comparison of the mass spectra and splitting patterns in the 'H-NMR spectra of 5-hydroxycanthin-6-one (16) and 8-hydroxycanthin-6-one (U), 10 was estimated to be the I-hydroxyl derivative. Through direct comparison between methylated 10 and I methoxycanthin-6-one (ll),structure 10 was confirmed. I-Methoxycanthin-6-one (11) I-Methoxycanthin-6-one (11) has been isolated from the root bark (19,221, wood (18), stem ( 2 3 , and leaves (24) of A. altissima, its cell culture (14-16), the root bark of A. excelsa (25), the ground wood of Brucea antidysenterica (26), the root of Hannona klaineana (27), and Soulamea pancheri (28). Based on results of comparisons between 4-methoxy- I -methoxycarbonyl-P-carboline obtained by oxidizing 11 (18)
4iT&hoxy-1iW.hoxycarbony 1-o-carboline
3. CANTHIN-6-ONE ALKALOIDS
I43
with KMn04 and I methoxycarbonyl-P-carboline together with comparison of the chemical shifts of H-3 in the 'H-NMR spectra of I-ethyl4-methoxy-p-carboline and I -ethyl-P-carboline, structure 11 was determined. 1-Methoxycanthin-&one N-Oxide (12)
1-Methoxycanthin-6-one N-oxide (12) has been isolated from the root bark of A. aftissima (19) and its cell culture (15). High-resolution MS proved that the number of oxygens in 12 was larger than that of 11 by one. Also, through a comparison of the 'H-NMR spectra of 11 and 12, Ohmoto et a / . assumed that this compound would be the N-oxide derivative. Ohmoto et a / . (18) then made a direct comparison of natural product 12 with a synthetic compound obtained by oxidizing 11 with m-chloroperbenzoic acid and determined structure 12 for I-methoxycanthin-6-one N-oxide.
2-Hydroxycanthin-6-one (13) and 4-Hydroxycanthin-6-one (14)
Both 2-hydroxy- (13) and 4-hydroxycanthin-6-one (14) have been isolated from cell cultures of A. altissima (13,f5),and 13 has also been isolated from the stem bark of Quassia kerstingii (29). From the facts that the mass spectra of both 13 and 14 show an mlz 236 ion and that both compounds show the same fragmentation pattern, formed by losing CO then HCN from the molecular ion, it was supposed that they are hydroxycanthin-6-ones. Crespi-Perellino et al. (13,151 compared the 'H-NMR spectrum of 13 with those of 1 and 10 and supposed 13 to be the
Ri
Fh
(13)
OH
H
(14)
H
OH
144
TAICHI OHMOTO A N D KAZUO KOIKE
1- or 2-hydroxyl derivative. In addition, acetylated 13 did not agree with l-acetoxycanthin-6-one, and structure 13 was determined. As 'H-NMR spectral data for the indole ring and positions 1 and 2 of 14 did not differ from those of 1, the substituent effect on the chemical shift of H-5 was in accordance with the known substituent effect on acetylated 14 (30),and, according to Nelson and Price (31), a hydroxyl derivative obtained from 4-methylthiocanthin-6-one (6) with alcoholic alkali agreed with 14. Based on these findings, structure 14 was determined. 4-Methoxycanthin-6-one (15)
4-Methoxycanthin-6-one (15) has been isolated from the bark of both the stem and root of Charpentiera obouata (Amaranthaceae) (32) and the aerial parts of Drymariu cordata (Caryophyllaceae) (33).This is one of the compounds not found in the families Rutaceae and Sirnaroubaceae. Its UV and IR spectra proved that it was a canthin-6-one alkaloid, and the 'H-NMR spectrum confirmed the methoxyl function. As natural 15 was identical with an authentic compound synthesized by Nelson and Price (31), structure 15 was determined.
4-Merhylthiocanthin-6-one (6) 4-Methylthiocanthin-6-one (6) is one of the first canthin-6-one alkaloids isolated from the bark (stem, root, branch, and sapling) and wood of Pentaceras australis (31)together with 1 and 7 (5).Readers are referred to Volume 3 (p. 249) of this treatise for its structure (5). 5-Hydroxycanthin-6-one (16)
5-Hydroxycanthin-6-one (16) has been isolated from the root bark of Simarouba umara (34) and from cell cultures of A . alrissima (12,15). Since its UV spectrum was similar to that of 5-methoxycanthin-6-one (25), Lassak et a f .(34)assumed it to be 4- or 5-hydroxycanthin-6-one. The prominent peak at M+-56 (mlz 180, Mf-2CO) in the mass spectrum supported structure 16 having an OH adjacent to the carbonyl group. The final confirmation of structure 16 was made through direct comparison of methylated 16 with authentic 7.
3. CANTHIN-6-ONE ALKALOIDS
I45
5-Methoxycanthind-one (7)
5-Methoxycanthin-6-one (7)has been found in the bark (stem, root, branch, and sapling) and leaves of Pentaceras australis (35). This compound has also been found in three species of Rutaceae including P . australis, five species of Simaroubaceae, and one species of Caryophyllaceae. The number of species of plants containing 7 is second only to those containing 1. Readers are referred to Volume 3 (p. 249) of this treatise for its structure (5). 5-Hydroxymethylcanthin-6-one( I 7)
5-Hydroxymethylcanthin-6-one (17)has been isolated from the root bark of A . altissima (36).This is the only canthin-6-one alkaloid which has a hydroxymethyl function. In the 'H-NMR spectrum the signal arising from the methylene protons (6 4.60, 2H, dd, J = 5.7 and 1.2 Hz) in C&OH showed long-range coupling with an aromatic proton (6 8.02, l H , t, J = 1.2 Hz) at position 4 o r 5 . It also showed coupling with a hydroxyl proton (6 5.56, l H , t, J = 5.7 Hz). On this basis, 17 was supposed to be a 4- or 5-hydroxymethyl alkaloid. Through comparisons of the 'H-NMR spectrum of 17 with that of 1 and that of acetylated 17, structure 17 was determined.
8-Hydroxycanthind-one (18)
8-Hydroxycanthin-6-one (18)has been isolated from the root bark of Ailanthus excelsa (25), the trunk (37) and stem bark (38) of Odyendea gabonensis, the stem bark of Pierreodendron kerstingii (39), and the wood of Simaba multifora (40).The bathochromic shift caused by alkali addition shown in the UV spectrum together with MS data suggested that
146
TAlCHl OHMOTO A N D KAZUO K O l K E
18 would be a hydroxycanthin-6-one alkaloid. Since a doublet I6 8.08 and 8.78 (each d, J = 4.9 Hz) and 6 6.97 and 8.12 (each d, J = 10.6 Hz)] arising from two isolated pairs of vicinal protons at H-l and H-2 as well as H-4 and H-5 is observed in the 'H-NMR spectrum, the hydroxy group should be located in ring A of the benzenoid nucleus. Moreover, since continuous three aromatic protons of ABC-type exist, the hydroxy group should be located at position 8 or 1 I . Comparison of the 'H-NMR spectra of 1 and 18 confirmed structure 18. 9-Methoxycanthin-6-one (19) 9-Methoxycanthin-6-one (19) has been isolated from the bark of Simabu cuspidata (2) and the stem bark of Simaba mufrijlora (41). From IR, U V , high-resolution MS (M+ at mlz 250.0735), and 'H-NMR (6 3.99, 3H, s), it was supported that 19 was a methoxycanthin-6-one. From the fact that there are two isolated pairs of vicinal protons (H-l and H-2; H-4 and H-5) in the 'H-NMR spectrum, it is obvious that the methoxyl group does not exist in ring C or D. In addition, the lower field proton H-8 (6 8.13, I N , d , J = 2 Hz) in ring A does not show ortho coupling. These findings led to determination of structure 19.
10-Hydroxycanthin-6-one (20) and 10-Methoxycanthin-6-one (21) Both I0-hydroxy- (20) and 10-methoxycanthin-6-one (21) have been isolated from the wood of S. muftijlora (42),and 20 has also been isolated from the root of Eurycoma longifolia (43). The U V spectrum of 20 shows a large bathochromic shift (76 nm) on alkali addition. Both the UV and IR spectra of 20 resemble those of 18. Acetylation and methylation of 20 produce the monoacetate and monomethyl ether, respectively. In the 'H-NMR spectrum of 20, two isolated pairs of vicinal protons in rings C and D and 1 , 2, 4-trisubstituted aromatic protons are observed. From these observations Arisawa et a f . (42) concluded that the hydroxyl function should associate with position 9 or 10. The position was fixed by the interlocking evidence, and structure 20 was determined. There was an increase in the molecular ion of 14 mass units in the mass spectrum of 21 as compared to 20 and the appearance of a new signal (6 3.91, 3H, s)
3. CANTHIN-6-ONE ALKALOIDS
147
R
(203 R=H (21) R = C k
arising from the methoxyl function in the 'H-NMR spectrum of 21, but otherwise both the UV and 'H-NMR spectra of 20 and 21 were alike. Thus, 21 was assumed to be the monomethyl ether of 20. Direct comparison of methylated 20 and naturally produced 21 supported structure 21. 11-Hydroxycanthin-6-one (Amarorine, 22) and 11 -Methoxycanrhin-6-one (Amaroridine, 23)
Both 1l-hydroxy- (22) and 1 I-methoxycanthin-6-one (23) have been isolated from the bark and wood of Amaroria soulameoides (44,45), and 22 has also been isolated from the stem of Brucea antidysenterica (46)and the stem bark of Quassia kerstingii (29). Since the UV spectrum of 22 showed a bathochromic shift on alkali addition, it was supposed that 22 had a phenolic hydroxyl group, and, together with findings from the studies on the IR and 'H-NMR spectra, Clarke et al. (44) assumed 22 to be a hydroxycanthin-bone derivative. When 22 was methylated, 23 was produced. Since the 'H-NMR spectra of both 22 and 23 showed pairs of aromatic vicinal protons at H-1 and H-2 as well as H-4 and H-5 and three coupled aromatic protons of the ABC type on ring A, it was concluded that the functional group should be attached to position 8 or 1 1. Through X-ray crystallographic studies on the monohydrate of 22, Clarke et af. assigned structure 22 to the compound having a hydroxyl function and structure 23 to the compound having a methoxyl function (44). Incidentally, 22 obtained from B . antidysenterica formed 11-O-bromobenzoylcanthin-6-one, X-ray analysis of which supported structure 22 (46).
(22) R=H (23) R=C%
148
TAICHI OHMOTO AND KAZUO KOIKE
I-Hydroxy-1I-methoxycanthin-6-one (24) and I 1 -Hydroxy-l-methoxycanthin-6-one (25)
Both I-hydroxy-1 l-methoxy- (24)and 1I-hydroxy-l-methoxycanthin6-one (25) have been isolated from the wood of B. antidysenterica (26, 47). In addition, 24 has been isolated from its root bark (47) and 25 from Soulamea pancheri (28). The UV spectrum of 24 shows a bathochromic shift on addition of alkali, and its mass spectrum shows the molecular ion at mlz 266 (M+, 100%). These facts support the supposition that 24 is a canthin-6-one alkaloid which has a hydroxyl and a methoxyl substituent. Since the 'H-NMR spectrum shows aromatic proton signals, a pair of vicinal protons at H-4 and H-5, a singlet at H-2, and three protons from H-8 through H-10, it is assumed that this compound is either 24 or 25. The 'H-NMR spectrum of 24 is not the same as that of 25, and irradiation of 11-OCH3induced an NOE (20%) of the H-10 signal but did not affect the H-2 signal. Based on these findings, structure 24 was determined. Structure 25 was determined after comparison of the 'H-NMR spectral data of 25 and those of 24 and from the NOE observed (H-2, 20%) by irradiation of l-OCH3 of acetylated 25.
Ri (24) (25)
Rz
H Cl-b Cl-b H
I , I I-Dimethoxycanthin-&one (26)
1,11-Dimethoxycanthin-6-one (26) has been isolated from the stem of B. antidysenterica (46). The IR and UV spectra indicate a typical canthin-6-one structure, the 'H-NMR spectrum shows two methoxyl signals [a 4.00 and 4.16 (each 3H, s)], and the high-resolution mass spectrum also suggests a dimethoxycanthin-6-one alkaloid. Since the 'H-NMR spectrum shows the presence of aromatic protons at H-4 and H-5, three protons on ring A, and also a IH singlet, it was considered that one of the two methoxyl groups is attached to either C-1 or C-2 and the other methoxyl to C-8 or C-1 I . NOE experiments on 26 revealed that irradiation of l-OCH3 and lI-OCH3 induced 12 and 13% enchancement at H-2 and H-10, respectively. From these facts, structure 26 was determined.
149
3. CANTHIN-&ONE ALKALOIDS
4-Hydroxy-5-methoxycanthin-6-one (Picrasidine Q , 27) Picrasidine Q (27) has been isolated from the root wood of Picrasmu quassioides (48).The IR spectrum of 27 shows a hydroxyl group, and its UV spectrum shows the typical absorption arising from the canthin-6-one chromophore. Its 'H-NMR spectrum shows a methoxyl group, a pair of ortho-coupled signals at H-1 and H-2, and signals of four continuous aromatic protons at H-8 through H-11. It is understood, therefore, that the hydroxyl and methoxyl substituents are located at positions 4 and 5, respectively. Methylated 27 is identical with 8 but is not identical with authentic 28. On the basis of these facts, structure 27 was determined.
cw 0
OH Cl-b
m
5-Hydroxy-4-methoxycanthin-6-one (nigakinone, 28) and 4,5Dimethoxycanthin-&one (8) Both nigakinone (28) and 4,5-dimethoxycanthin-6-one(8) have been isolated from the heartwood (49,501, stem (51), and wood (52) of P. quassioides and from the wood of P . excelsa (53). In addition, 8 has been isolated from the wood of P . quassioides (syn. P . ailanrhoides; 54), the trunk bark of Odyendea gabonensis (371, and the root bark of Quassia
4,5-dihydroxycanthind-one
0ocI-b l-cnethoxycarbony 1-o-carboline
150
TAICHI OHMOTO AND KAZUO KOIKE
africana (55). Acetylation of 28 gave the monoacetate, and direct comparison between methylated 28 and authentic 8 proved that they were fully identical. In addition, the CO absorption shown in the IR spectrum of 28 differs from that of 8 in wave number, that is, 28 and 8 show absorptions at 1632 and 1663 cm-', respectively. KMn04 oxidation of 28 produces 1-methoxycarbonyl-P-carboline.From these facts, structure 28 was determined. Incidentally, there is a report (17) which states that 28 is contained in 17 of 33 species of the genus Rhododendron of the family Ericaceae grown in China and 8 in 28 species of this genus.
4,5-Dihydrocanthin-6-one(29)
4,5-Dihydrocanthin-6-one(29) has been isolated only from cell cultures of A. altissima (13,15).Its mass spectrum shows the molecular ion at mlz 222, and the fragmentation pattern is very similar to that of canthin-6-one, with some differences; e.g., [M - HIf and [M - H - CO]' have higher intensity than the fragments obtained from 1, and 29 is larger than 1 by two mass units. The 'H-NMR spectrum of 29 shows the same data as that of 1 at the indole ring and positions 1 and 2, but aromatic protons at positions 4 and 5 have been substituted with two multiplets [6 3.22 and 3.49(each 2H)] which correspond to the methylene group, and hence structure 29 was determined. Further evidence was obtained by Haynes et al. when they synthesized 29 through reduction (HJRaney Ni or Zn plus AcOH) of 1(I).
S-Methoxycanthin-2,6-dione (Indacanthinone, 30), 3-Methoxycanthin-2,6-dione (2), Canthin-2,6-dione (31), (32) and IO-Hydroxy-3-methoxycanthin-2,6-dione Indacanthinone (30) was the first compound isolated as a canthin2,6-dione alkaloid from the wood of Samadera indica (56). 3Methoxycanthin-2,6-dione(2), canthin-2,6-dione (31), and lO-hydroxy-3methoxycanthin-2,6-dione (32) have been isolated from the wood of Simaba multiJora (42), and 2 has been also isolated from the bark of S. cuspidata ( 2 ) .Compounds 30, 2, 31, and 32 give intense yellowish green fluorescence in solution with organic solvents. Their UV spectra strongly
3. CANTHIN-6-ONE ALKALOIDS
I51
fluorescence in solution with organic solvents. Their UV spectra strongly resemble those of canthin-6-one alkaloids. The mass spectrum of 30 proves the molecular formula C ~ S H ~ O NIt~has O ~been . made clear from the 'H-NMR spectrum and measurement of methoxyl groups by Zeisel's method that one of the three oxygens in the formula belongs to a methoxyl group. The IR and mass spectra of 30 suggest it has two CO groups. One of them shows a -NHCO- function and weak basicity. By allowing SO2 gas to pass through the orange-red solution of 30 prepared in an organic solvent, the solution is decolorized, regaining the orange-red color on aeration. Reactions between 30 and POC13 result in substitution of the enol O H with Cl to form the chlorine-containing compound (CI5H9N2O2CI). When the cool chloroform solution of 30 absorbs bromine, the bromine-containing compound (ClsH9N202Br),which shows the same UV spectrum as that of 30, is produced. These facts strongly support structure 30. The UV spectra of 2, 31, and 32 are similar to that of 30. MS of these three compounds shows parent ions at mlz 266 (CI5Hl0N2O3),mlz 236 ( C I S H ~ N ~ Oand ~ ) , mlz 282 (CI5HION2O4), respectively. The 'H-NMR spectrum of 2 shows, in addition to a methoxyl signal (6 4.20, 3H, s), a pair of doublets which are assigned to H-4 and H-5 and a proton signal (6 7.26, IH, s) which is assigned to H-1. In addition it indicates the existence of four aromatic protons on ring A. On the basis of these findings, structure 2 was determined. Compound 31 is produced through reduction of 2 with sodium hydrogen sulfide. Direct comparison indicates that this synthetic product is identical with naturally produced 31. Thus, structure 31 was determined. On the other hand, Giesbrecht et al. (2) made comparisons among the signals arising from N-OCH3 of 2 (6 64.8). C-OCH3 of 2-methoxypyridine (6 53.1), and N-OCH3 of pyridone (6 64.7)
152
TAlCHl OHMOTO A N D KAZUO KOIKE
and determined structure 2. The 1R spectrum of 32 indicates the existence of a hydroxyl group (3440 cm-I), and acetylation of 32 produces the monoacetate. By comparing the 'H-NMR spectra of the monoacetate and lO-acetoxycanthin-6-0ne, structure 32 was determined.
3-Mefhylcanfhin-5,6-dione(Picrasidine L , 3) Picrasidine L (3) has been isolated from the root bark ( 3 ) ,root (57), and wood (58) of P . quassioides and from the wood of Quassia umara (59). The compound reported as 3-methylcanthin-2,6-dione was identified as 3 by Ohmoto and Koike (3).The compound isolated from the wood of Q . amara (59) was also corrected from 3-methylcanthin-2,6-dioneto 3 (60). The I3C-NMR spectrum of 3 indicates the existence of two carbonyl carbons (6 156.34 and 169.79). The UV spectrum of 3 resembles that of 2; however, while addition of acid or base produces no change in the UV spectrum of 2, addition of acid causes a large hypochromic shift in U V spectrum of 3, though base induced no subsequent change. 'H-NMR spectral data of 3 reveal four vicinal protons which are positioned at H-8 through H-1 1 of ring A , a pair of ortho-coupled signals at H-1 and H-2, a methyl proton signal (6 3.98, 3H, s), and an olefinic proton signal (H-4, 6 5.98, l H , s); hence, structure 3 was proposed. The synthetic product obtained by methylation of 16 completely agrees with natural 3, and thereby structure 3 was confirmed.
3-Methyl-4-methoxycanthin-5,6-dione (Picrasidine 0 , 33)
Picrasidine 0 (33) has been isolated from the root wood of P . quassioides (48).The UV spectrum shows, like 3, a hypochromic shift on addition of acid. The 'H-NMR spectrum shows signals arising from a methyl (6 3.82, 3H, s) and a methoxyl (6 4.26, 3H, s) but lacks the aromatic proton at H-4, and hence structure 33 was proposed. Since the synthetic compound obtained through methylation of 28 agrees with naturally produced 33, structure 33 was confirmed.
3. CANTHIN-&ONE ALKALOIDS
153
Picrasidines M (4), N (34), and U (35)
Picrasidine M (4) has been isolated from the root bark of P . quassioides (3) and picrasidines N (34) and U (35) from the root wood of the same plant (48,61).All three compounds emit the strong yellowish fluorescence specific to canthin-5,bdiones in organic solvents. From elemental analyses of 4 and 34 their molecular formulas were obtained: 4, C29HZZN404; 34, C30H24N404. While the IR spectrum of 4 shows an absorption band arising from an amino group at 3420 cm-', 34 does not show this absorption. In the 'H-NMR spectrum of 4, signals of the AzBztype [6 3.72 ( 2 H , t, J = 7.1 Hz) and 4.77 (2H, t, J = 7. I Hz)] are observed, and hence a -CH2CH2-unit should be present. Two methoxyl signals [6 3.97 (3H, s) and 4.13 (3H, s)] are observed, and aromatic proton signals are also observed at H-3' (6 7.99, l H , s), H-8 through H-1 1 , and H-5' through H-7'; hence, it has been suggested that 4 is a compound in which the canthin-5,6-dione and I-ethyl-4,8-dimethoxy-P-carbolinestructures are found together between N-3 and C-1'. Compound 4 gives 5acetoxycanthin-bone and 4,8-dimethoxy-I-vinyl-~-carbolinewhen treated with acetic anhydride. Methylation of 5-acetoxycanthin-6-one produces 7. From direct comparison among synthesized 5-
154
TAICHI OHMOTO AND KAZUO KOlKE
methoxycanthin-6-one and 7 and synthesized 4,8-dimethoxy-l-vinyl-Pcarboline and respective authentic samples, structure 4 was determined. The IR and 'H-NMR spectra of compound 34 lack signals of an NH proton of the indole moiety in the p-carboline structure, but otherwise they are very much similar to those of 4. Compound 34 produces when 5-acetoxycanthin-6-one and 4,9-dimethoxy-I-vinyl-~-carboline treated with acetic anhydride, and hence structure 34 was determined. Comparison between the 'H-NMR spectrum of 35 and that of 4 shows a lack of an H-4 signal in the former but an increase in the methoxyl signal by one. Otherwise the patterns of both spectra are the same. Cleavage of 35 with acetic anhydride produces 5-acetoxy-4-methoxycanthin-6-one and 4,8-dimethoxy-I-vinyl-P-carboline, and hence structure 35 was determined.
Infractopicrin ( 5 )
Infractopicrin (5) has been isolated as a bitter substance from the fruiting bodies of Cortinurius infractus ( 4 ) . The IR and U V spectra suggest that 5 is a canthin-6-one alkaloid. Its 'H-NMR spectrum shows the existence of a -CH2CH2CH2-group [6 2.47 (2H, m), 3.22 (2H, t t , J = 6 and 0.6 Hz), and 4.96 ( 2 H , t , J = 6 Hz)]. Its mass spectrum shows mlz 36 and 38 ions, whose existence was confirmed by chlorination. Thus, structure 5 was determined.
IV. 13C-NMR Spectroscopy Over 30 canthin-6-one alkaloids have already been isolated, and their structures have been determined. There are not many reports, however, which mention that "C-NMR spectroscopy was used for structural
3. CANTHIN-bONE ALKALOIDS
155
determination (2, 3, 48, 89, 90). The reason for this seems to be that, although canthin-6-one alkaloids have low molecular weights, they have many tertiary carbons, and this, together with two nitrogen atoms in the molecule, makes it difficult to assign the carbon atoms causing chemical shifts in I3C-NMR spectrum. Koike and Ohmoto (90) measured I3C-IH shift correlation two-dimensional NMR (91) for the first time and clearly assigned proton-bearing carbons (Fig. I). Koike and Ohmoto then assigned the chemical shifts in the "C-NMR spectra of canthin-6-one alkaloids using spin-spin coupling between 13C and 'H. They obtained a spin-spin network (Fig. 2) between I3C and 'H and coupling constants ( ' J , Table 11; 'f and ' J , Table 111) using protoncoupled "C NMR and the long-range selective decoupling (LSPD) method (92). Thus, assignment of all carbon atoms in canthin-6-one alkaloids have been established (Table IV). By comparing ring C of 1 with its model compound, pyridine, it is seen that spin-spin coupling constants of the two are very similar (Fig. 2). Both carbonyl carbons at position 6 of 1 and in acrylic acid, which is the model compound of 1, have very large 3J values for vicinal trans coupling (Fig. 2), and this fact also strongly supports the assignment of carbon atoms in canthin-6-one alkaloids. Investigation of substituent effects of 11,28, and 8 revealed that C-2 in the ortho position and C-16 in the para position in 11, which possesses a substituted methoxyl group at position 1 , showed about 14 ppm and 7 ppm high-field shifts, respectively, as compared with 1. Substituent effects owing to oxygen functional groups at positions 4 and 5 were shifted about 6 ppm upfield for C-15 in 28 and about 3 ppm upfield for C-15 in 8. Another observation disclosed that C-4 in 8, which is produced by substituting a methoxyl for a hydroxyl group at position 5 in 28, showed an approximately 10 ppm down-field shift (90).
V. Synthesis
A. SYNTHESIS OF CANTHIN-6-ONES Cook et al. (93,94) obtained lactam 37a, in 82% yield, by refluxing Nb-benzyltryptamine (36a) and 2-ketoglutaric acid in toluene in the presence of p-toluenesulfonic acid. Then they oxidized 37a with SeOz in dioxane. As a result, loss of the Nb-benzyl group and aromatization of ring C proceeded simultaneously, and canthin-6-one (1) was successfully synthesized in 33% yield. Under similar conditions, using Nb-benzyl tryptophan methyl ester (36b), 2-methoxycarbonylcanthin-6-one (38) was
N
Y
m
w
a d
-LT
I'
7
R
-f
a
m
157
3. CANTHIN-6-ONE ALKALOIDS
Hy7 JH f 0
14.1
FIG. 2. Spin network of 1, pyridine, and acrylic acid ( J , Hz).
synthesized in 66% yield, forming 37b on its way. Rosenkranz ef ul. (95) synthesized Nb-succinyltryptophan (39a) from tryptophan and succinic acid. They 39a was added to polyphosphoric acid, V205, and P0Cl3, and the mixture was heated at 115°C. Thus, 1was synthesized in one step at 75% yield. 4-Ethylcanthin-6-one (40) was synthesized by the same method (Scheme I). In addition, there are reports of the following syntheses: 4,5dimethoxycanthin-6-one (8) from 1-methoxymethyl-P-carbolineand succhic acid anhydride (96), 1 using 4-oxo-l,4,6,7,12,12b-hexahydroindo
TABLE I1 ONE-BOND "C-'H COUPLING CONSTANTS (Hz) FOR COMPOUNDS 1, 11, 28, A N D 8 Carbon 1 2 4 5 8 9 10
II I-OCHI 4-OCH3 5-OCH,
1
11
28
8
165. I 179.7 165.1 168.0 168.5 162.1 162.1 162.1
178.6 164.0 168.0 168.7 160.0 160.0 160.0 145.5 -
164.0 179.0 -
164.0 178.6
-
168.0 160.0 160.0 160.0 146.7 145.7
168.0 160.0 160.0 160.0 146.5
u
W
m
9 10
II
12
dd 'J(C-9, H-1 I ) dd 'J(C-lo, H-8) ddd *J(C-11, H-10) 'J(C-11, H-9)
13
t
14
'J(C-13. H-9) 'J(C-13, H-11) dd ?J(C-14, H-1) 'J(C-14, H-2)
15
8.8 8.8
'J(C-13, H-9) 'J(C-13, H-11) d 'J(C-14, H-2)
8.0
8.0 1.5
8.0
t
6.0 6.0
t
3.7 8.1 8.1 8.1
t
'J(C-16, H-2) 'J(C-16. H-5) 1-OCHS 4-OCH' 5-OCH'
'J(C-12, H-10) 'J(C-12, H-8)
1.5
t
'J(C-15, H-I) 'J(C-1.5, H-4) 16
6.0 6.0
8.1
t
'J(C-12, H-10) ~J(c-12, H-8)
-$
8.1
dd )J(C-9, H-11) dd 'J(C-lO, H-8) ddd *J(C-Il, H-10) 'J(C-11, H-9)
8.1
1 I .4
11.4
d 'J(C-15, H-4)
t 'J(C-16, H-2) 'J(C-16, H-5) q
8.8 8.8 8.0
8.0
11.0 11.0
dd 'J(C-9, H-l I ) dd 'J(C-lo, H-8) ddd 'J(C-11, H-10) 'J(C-11, H-9) t ' ~ ~ ( c - 1 H-10) 2, 'J(C-12, H-8) t 'J(C-13, H-9) 'J(C-13, H-11) dd *J(C-14, H-I) 'J(C-14, H-2) d ?I(C-15, H-I) d 'J(C-16, H-2)
1.5 8.0
dd 'J(C-9, H-11) dd 'J(C-lo, H-8) ddd 'J(C-11, H-10) 'J(C-ll, H-9)
6.0 6.0
'J(C-12, H-10) 'J(C-12, H-8)
8.0 8.0
'J(C-13, 'J(C-13, dd 'J(C-14, 'J(C-14, d 'J(C-15,
8.0 8.0
8.0 8.0 1.5
8.0
t
6.0 6.0
t
3.5 8.0 8.0
12.5
H-9) H-11)
8.0 8.0
H-I) H-2)
3.5 8.0
H-I)
8.0
d 'J(C-16, H-2)
12.8
I60
TAICHI OHMOTO A N D KAZUO KOIKE
TABLE IV "C-NMR SPECTRAL DATA(ppm) FOR COMPOUNDS 1, 11, 28, A N D 8 Carbon
1
11
28
8
I 2 4 5 6 8 9 10 I1 12 13 14 15 16 I-OCH3 4-OCHj 5-OCHz
115.37 144.84 138.57 127.98 158.21 116.29 129.84 124.69 121.61 123.33 138.24 128.99 130.91 135.23 -
152.23 130.69 138.69 124.61 160.21 116.73 129.59 125.66 124.37 123.88 138.17 130.18 130.83 128.70 56.70 -
113.70 144.11 142.68 139.60 156.27 115.22 129.62 124.65 122.39 124.20 137.38 127.96 124.82 133.46 60.51 -
114.89 144.48 152.05 139.35 157.43 116.24 130.01 124.59 121.78 123.96 138.22 129.15 127.61 132.71 61.17 61.04
-
pCH3 1
4.4
O+OC&
[2,3-a]chinolizine and NaNOz (97), and 1 using naturally produced eburnamonine and Se (98). Moreover, Hagen and Cook (99) synthesized 3-0x0-9-methoxycarbonyl indolizino[8,7-b]indole (41) from tryptamine hydrochloride and dimethyl a-ketoglutamate in refluxing methanol. As
161
3. CANTHIN-bONE ALKALOIDS
tryptamine : W tryptophan : Rco(x1
3 6 3 : RH 331: Fi4JX-b
7 days
37a : RH 3ib: m
1: W
38:
rn
SCHEME I
illustrated in Scheme 2, they obtained 1-methoxycanthin-6-one by treatment of 41 with dichlorodicyanobenzoquinone (DDQ) and followed by hydrolysis, methylation, and cyclization.
2) WQ dioxane,
A 11 SCHEME2
162
T A l C H l OHMOTO AND KAZUO KOIKE
P
I
UJ
2
1
I
2
FIG. 3. UV spectra of 3 and 16. ~, EtOH; ...... 16 in EtOH + CHI.
B.
3 in Et0H;---,
3 in EtOH
+ HCI; -.-.-,16
in
S Y N T H E S I S OF C A N T H I N - 5 , 6 - D I O N E S
UV spectra of canthin-5,6-dione alkaloids 3 and 33, which were isolated by Ohmoto and Koike (3,48) from Picrasma quassioides, showed a characteristic absorption between 400 and 500 nm. This absorption was hypochromically shifted under acidic conditions. The UV spectrum of 3 in acidic solvents resembles that of 5-hydroxycanthin-6-one (16) (Fig. 3). This fact, that is, that 3 undergoes chemical shift in acidic solvents, indicates that the carbonyl at position 5 of the canthin-5,ddione skeleton in 16 is protonated, producing 42a. On the basis of the above observations, Ohmoto and Koike refluxed 16 and 33 with dimethyl sulfate in acetone and synthesized 3 and 28 (Scheme 3).
I63
3. CANTHIN-6-ONE ALKALOIDS
'H
+
d
7
'ab
w
56?
acetone,
w
M
0 3 : RSI 28: rn
16: RH
33: F#x)b
42a: Mi
a :F#x)b
SCHEME 3
Similarly, Matus and Fischer (100) heated I-alkyl-p-carboline with an excess of dialkyl oxalate and synthesized canthin-5,6-dione derivatives in 20-65% yield (Scheme 4). Catalytic hydrogenation of Nb-benzylcanthin5,ddione (43a) produces 16. Based on these reactions, the structures of canthin-5,bdione derivatives were elucidated (Scheme 5 ) . YOOR2
R,J
q
q
N CbR
+
R 43aH b
H
c H dCH3 e C& f C &
g
H
COO&
Fb
RI H
M
H
C& C&
47
C-kFl-l
64
H n %
OcH3CA-k SCHEME 4
o=f&& Ph
=AD
0
42
44 20 39
C&
H H H
yield (%)
29
0j-q
0
OH
16
43a SCHEME 5
164
TAICHI OHMOTO AND KAZUO KOIKE
VI. Biosynthesis It was hypothesized that the biosynthetic pathway to canthin-6-one alkaloids started from tryptophan as a precursor and produced tryptamine on the way to canthin-6-one (1) (101) (Scheme 6). Anderson et al. (103) established, for the first time, the method of tissue cultivation of Ailanthus altissima using cell and cell suspension cultures. It was recognized that yield of 1 from tissue cultures was 100 to 1000 times higher than the content of 1 in the plant body. From feeding experiments using cell suspension cultures and providing ~ - [ m e t h y l e n e ' ~ C ] tryptophan as the precursor, production of radioactive 1, 10, and 11 was confirmed. The rate of production gradually increased in accordance with the length of feeding time (16,102).
H
H
tryptophan
tryptamine
0canthin-ne
SCHEME 6
Similarly, Crespi-Perellino et al. (13,15), using cell cultures of A. altissima and providing L-, D-, and D,L-[methylene-'4C]tryptophanas the precursor, carried out tracer experiments and proved the biosynthetic pathway to canthin-6-one alkaloids to be as follows (Scheme 7): tryptophan + P-carboline-I-propionic acid + 4,5-dihydrocanthin-6-one(29) + canthin-6-one (1) + I-hydroxycanthin-6-one (10)+ I-methoxycanthin-6one (11) + I-methoxycanthin-6-one 3-oxide (12).In the biosynthetic pathway to canthin-6-one alkaloids, oxidation proceeds stepwise. The hydroxyl group at position 1 of canthin-6-one is methylated, and 11 is readily formed; this formation is considered to be a transmethylation promoted by a specific enzyme. Anderson et al. (103) carried out feeding experiments with cell cultures and obtained radioacof A. altissima and ~-[methylene-'~CImethionine tive 14. They supposed, therefore, that L-methionine would become S-adenosylmethionine and associate with transmethylation of 10 to produce 11. In accordance with growth of the cell culture, radioactive 11 gradually increases; hence, they stated that the 0-methyltransferase acts at the last stage of synthesis.
3. C A N T H I N - b O N E ALKALOIDS
165
SCHEME 7
VII. Bioassay and Pharmacology Over twenty canthin-6-one alkaloids have been bioassayed in the following areas. The antimicrobial activities of 1and 11against 1 I kinds of bacteria were almost negligible compared to that of streptomycin (70,87). Activities of 1 on various bacterial and fungal strains were investigated, and it was found that in general the activity was strong toward fungi relative to bacteria (66,86,104). When the hydroxyl group of the canthin-6-one nucleus was changed to a methoxyl group, the antibacterial activity decreased (70). Both 8 and 28 inhibited growth of Staphylococcus aureus and its drug-resistant strains (50). As it is well known that Ailanthus altissima (23) and Eurycoma longfolia (43) are used as febrifuges and antimalarial agents among folk medicines in Southeast Asian countries, their antimalarial and amebicidal activites were measured. Several quassinoids in such plants showed activity but 1,11,18,21, and 31 did not (23,43).The amebicidal activity of quassin and 1 was determined by bioassay using axenic Entamoeba histolytica. While the EDSovalue of quassin was 0.5 pg/ml, that of 1was as large as 23 pg/ml (82,105).
166
TAICHI OHMOTO AND KAZUO KOIKE
The antiherpes activity of four kinds of canthin-6-one alkaloids was assayed biologically together with 10 P-carboline derivatives. Among these compounds, 8 and 28 had activity on a level with that of acyclovir, the control. It was noticed, however, that the therapeutic ratio was small (106).
As part of a search for antitumor agents in plants, testing of cytotoxic activity has been caried out in uitro with three kinds of cell systems. In the guinea pig keratinocyte (GPK) system, 1, 7, 9, and 11 did not show statistically significant cytotoxic activity (14) in GPK epithelial cells as judged from inhibition of DNA synthesis. In the P388 lymphocytic leukemia system, both 22 and 26 had cytotoxic activity (45,46). In the nasopharynx (KB) system, none of the compounds 1, 7, 11, and 18 showed full cytotoxic activity (25). Compounds 20,21, and 22 had weak activity (42,45). The activities of 16 canthin-6-one alkaloids, including 1, 7, and 11, which were already reported, and 13 other synthetic compounds were assayed biologically. The results indicated that 22 and 26 had the strongest activity (26). When the structure-cytotoxicity relationship was investigated, it was found that compounds such as 22 and 26 which were oxidized at position C-10 or C-11 of ring A showed strong cytotoxic activities. It was also noted that activity was reduced by replacing the hydroxy group in 11-hydroxy derivatives with methyl ether or ester (26,45). Compounds 1 and 2 manifested phototoxicity on bacteria and fungi on irradiation with near-UV light (320-400 nm). Both compounds inhibited mitosis of Chinese hamster ovary cells and induced chromosomal changes. It was apparent that the two compounds could be photosensitizers, though their activities were weaker than 8-methoxypsoralen, the control (107). With the inhibitory activity against cyclic adenosine monophosphate phosphodiesterase as an index, in uitro bioassay of the activity of 21 canthin-6-one alkaloids was carried out. The strongest inhibitory activities were detected with 4, 17, and 27 among the compounds tested. The activities shown by 10,28, and 34 were the same, twice as strong, and 15 times as strong, respectively, as the activity of papaverine, the control. Acetylation and methylation of the hydroxy derivatives of canthin-6-one decreased activity (108,109). The rate of blood flow in the stomach and intestine of rabbits was assayed in uiuo by the hydrogen clearance method. Compounds 1,28, and 29 increased the blood flow rate in the intestine by 15, 25, and 35%, respectively. In the stomach, however, 1 increased the rate by only lo%, and 28 decreased it (110).
3. CANTHIN-6-ONE ALKALOIDS
I67
REFERENCES
1 . H. F. Haynes, E. R. Nelson, and J. R. Price, Ausr. J. Sci. Res., Ser. A 5, 387 (1952). 2. A. M. Giesbrecht, H. E. Gottlieb, 0. R. Gottlieb, M. 0. F. Goulart, R. A. De Lima, and A. E. G. Sant’ana, Phyrochemisrry 19, 313 (1980). 3. T. Ohmoto and K. Koike, Chem. Pharm. Bull. 33, 3847 (1985). 4. W. Steglich, L. Kopanski, M. Wolf, M. Moser, and G. Tegtmeyer, Terrahedron L e f t . 25, 2341 (1984). 5 . W. I. Taylor, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. 8, p. 249. Academic Press, New York, 1965. 6. G. A. Cordell, “Introduction to Alkaloids: A Biogenetic Approach,” p. 619. Wiley, New York, 1981. 7. J. A. Joule, in “The Alkaloids” (J. E. Saxton, ed.), Vol. I , p. 156. Royal Society of Chemistry, London, 1971. 8. J. E. Saxton, in “The Alkaloids” (M. F. Grundon, ed.), Vol. 7, p. 183. Royal Society of Chemistry, London, 1977. 9. J. E. Saxton, in “The Alkaloids” (M. F. Grundon, ed.), Vol. 8, p. 154. Royal Society of Chemsitry, London, 1978. 10. J. E. Saxton, in “The Alkaloids” (M. F. Grundon, ed), Vol. 9, p. 152. Royal Society of Chemistry, London, 1979. 1 1 . J. E. Saxton, in “The Alkaloids” (M. F. Grundon, ed.), Vol. 11, p. 145. Royal Society of Chemistry, London, 1981. 12. J. E. Saxton, Nat. Prod. Rep., 591 (1987). 13. N. Crespi-Perellino, A. Guicciardi, G. Malyszko, and A. Minghetti, J . Nar. Prod. 49, 814 (1986). 14. L . A. Anderson, A. Harris, and J. D. Phillipson, J. Nar. Prod. 46, 374 (1983). 15. N. Crespi-Perellino, A. Guicciardi. G. Malyszko, E. Arlandini, M. Ballabio, and A. Minghetti, J. Nar. Prod. 49, 1010 (1986). 16. L. A. Anderson, C. A. Hay, M. F. Roberts, and J . D. Phillipson. Planr Cell Rep. 5,387 (1986). 17. Laboratory of Medicinal Plants, Institute of Materia Medica, Chinese Academy of Medical Sciences, Acra Eor. Sin. 19, 257 (1977). 18. T. Ohmoto, K. Tanaka, and T. Nikaido, Chem. Pharm. EiiII. 24, 1532 (1976). 19. T. Ohmoto, K. Koike, and Y. Sakamoto, Chern. Pharm. EIIII. 29, 390 (1981). 20. E. Varga, K. Szendrei, J. Reisch, and G. Maroti, Fitoterapia 52, 183 (1982). 21. S . A. Khan and K. M. Shamsuddin, Phytochemisfry 20, 2062 (1981). 22. E. Varga, K . Szendrei, J. Reisch, and G. Maroti, PIanra Med. 40, 337 (1980). 23. D. H . Bray, P. Boardman, M. J. O’Neill, K . L . Chan, J . D. Phillipson, D. C. Warhurst, and M. Suffness, Phytorher. Res. 1, 22 (1987). 24. C. Souleles and R. Waigh, J. Nar. Prod. 47, 741 (1984). 25. G. A. Cordell, M. Ogura, and N. R. Farnsworth, Lloydia 41, 166 (1978). 26. N. Fukamiya, M. Okano, T. Aratani, K. Negoro, Y. M. Lin. and K. H. Lee, Planfa Med. 53, 140 (1987). 27. L . Lumonadio and M. Vanhaelen, Phyrochemisrry 23, 453 (1984). 28. B. Viala, Thesis, Universite de Paris-Sud, Centre d’Orsay, France (1971). 29. G. R. Pettit, S. B. Singh, A. Goswami, and R. A. Nieman, Tetrahedron 44,3349 (1988). 30. L. M. Jackman and S. Sternhell, “Application of NMR Spectroscopy to Organic Chemistry,” 2nd ed., p. 202. Pergamon, New York, 1969.
168
TAICHI OHMOTO A N D KAZUO KOIKE
E. R. Nelson and J. R. Price. ANSI.J. Sci. Res. Ser. A 5, 768 (1952). P. J. Scheuer and T. R. Pattabhiraman, Lloydia 28, 95 (1965). W. S. Chen, Acta D o t . Sin. 28, 450 (1986). E. V. Lassak, J . Polonsky, and H. Jacquemin, Phytochemistry 16, 1126 (1977). E. R. Nelson and J. R. Price, Aust. J. Sci. R e s . , Ser. A 5, 563 (1952). T. Ohmoto and K. Koike, Chem. Pharm. Bull. 32, 170 (1984). P. Forgacs, J. Provost, and A. Touche, Planta Med. 46, 187 (1982). P. G. Waterman and S. A. Ampofo, Plurrttr M i d . 50, 261 (1984). S. A. Ampofo and P. G. Waterman, J . Nut. Prod. 48, 863 (1985). M. Arisawa, A . Fujita, N . Morita, A. D. Kinghorn, G. A. Cordell, and N. R. Farnsworth. Planta Med. 51, 348 (1985). 41. J. Polonsky, J. Gallas, J. Varenne, J. Prance, C. Pascard, H. Jacquemin, and C. Moretti, Tetrahedron Leu. 23, 869 (1982). 42. M. Arisawa, A. D. Kinghorn, G. A. Cordell, and N. R. Farnsworth, J. Nut. Prod. 46, 222 (1983). 43. K. L. Chan, M. J. O'Neill, J. D. Phillipson, and D. C. Warhurst, Planta Med. 52, 105 (1986). 44. P. J. Clarke, K. Jewers. and H. F. Jones, J . Chem. Soc. Perkin Trans. I , 1614 (1980). 45. S. S. Handa. A. D. Kinghorn. G. A . Cordell. and N. R. Fransworth, J. Nut. Prod. 46, 359 (1983). 46. N. Fukamiya, M. Okanao. T. Aratani, K. Negoro, A. T. McPhail, M. Ju-ichi, and K. H. Lee, J. Nut. Prod. 49, 428 (1986). 47. A. Harris. L. A. Anderson, J. D. Phillipson, and R. T. Brown, Planta Med., 51, 151 (1985). 48. T. Ohmoto and K. Koike, Chem. Pharm. Bull. 33, 4901 (1985). 49. Y. Kimura, M. Takido, and S. Koizumi, Yakugaku Zosshi 87, 1371 (1967). 50. J. S. Yang, S. R. Luo. X. L. Shen, and Y. X. Li, Acta Pharm. Sin. 14, 167 (1979). 51. Y. Kondo and T. Takemoto, Chem. Pharm. Bull. 21, 837 (1973). 52. T. Ohmoto and K . Koike, Chem. Pharm. Bull. 32, 3579 (1984). 54. N. Inamoto, S. Masuda, 0. Simamura. and T. Tsuyuki, Bull. Chem. Soc. J p n . 34,888 ( 1961). 55. L. Lumonadio and M. Vanhaelen, J. Nut. Prod. 49, 940 (1986). 56. V. S. lyer and S. Rangaswami, Curr. Sci. 41, 140 (1972). 57. T. Ohmoto and K. Koike, Chem. Pharm. Bull. 30, 1204 (1982). 58. J. S. Yang and D. Gong, Acfu Chim. Sin. 42, 679 (1984). 59. P. Barbetti. G. Grandolini, G. Fardella, and I. Chiappini, Planta Med. 53, 289 (1987). 60. G. G r a n d o h i , private communication. 61. K. Koike and T. Ohmoto, Phytochemistry 27, 3029 (1988). 62. I. A. Benages, M. E. A. De Juarez, S. M. Albonico, A. Urzua, and B. K. Cassels, fhvtochemistry 13, 2891 (1974). 63. E. M. Assem, 1. A. Benages, and S. M. Albonico, Planta Med. 48, 77 (1983). 64. P. R. Torres and B. K. Cassels, A n . Asoc. Quirn. Argent. 63, 187 (1975). 65. F. Fish and P. G . Waterman, Phytochemistry 10, 3325 (1971). 66. 0. 0. Odebiyi and E. A . Sofowora. Planto Med. 36, 204 (1979). 67. S. Najiar. G. A. Cordell. and N. R. Farnsworth, Phytochemistry 14, 2309 (1975). 68. C. M. Kim and 1. 0. Huh, Korean J . Phurmucogn. 12, 5 (1981). 69. F. Fish, A. I. Gray, and P. G. Waterman, Phytochemistry 14, 2073 (1975). 70. L. A . Mitscher, H. D. H. Showalter, M. T. Shipchandler, R. P. Leu and J. L . Beal, Lloydiu 35, 177 (1972). 71. F. Fish. A. I. Gray, and P. G. Waterman, 1.Phurm. Pharmcol. 28, Suppl., 69p (1975). 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.
3. CANTHIN-&ONE ALKALOIDS
169
A. T. Awad, J. L. Beal, S. K. Talapatra, and M. P. Cava, J. Pharm. Sci.56,279 (1967). P. G. Waterman, Phytochemistry 15, 578 (1976). S. K. Talapatra, S. Dutta, and B. Talapatra, Phytochemistry 12, 729 (1973). H. K. Desai, D. H. Gawad, T. R. Govindachari, B. S. Joshi, P. C. Parthasarathy. K. S . Ramachandran, K. R. Ravindranath, A. R. Sidhaye. and N. Viswanathan, Indian J. Chem. Sect. B 14B, 473 (1976). 76. G. B. Guise, E. Ritchie, R. G. Senior, and W. C. Taylor, Aust. J. Chem. 20, 2429 (1967). 77. J. R. Cannon, G . K. Hughes, E. Ritchie, and W. C. Taylor, Aust. J. Chem. 6, 86 (1953). 78. J. Vaquette, A. Cave, and P. G . Waterman, Plunta Med. 35, 42 (1979). 79. K. Szendrei, T. Korbely, H. Krenzien. J. Reisch. and I. Novak, Herha Hung. 16, 15 (1977). 80. A Harris, L . A. Anderson, and J. D. Phillipson, J. Pharm. Pharmacol. 33, 17p (1981). 81. L. Lumonadio and M. Vanhaelen, Phytochemistry 23, 2121 (1984). 82. A. H a m s and J. D. Phillipson. J. Pharm. Pharmacol. 34, 43p (1982). 83. T. Ohmoto, K. Koike, and K. Kageil, Shoyakugaku Zasshi 41, 338 (1987). 84. T . Ohmoto and K. Koike, Chem. Pharm. Bull. 31, 3198 (1983). 85. M. Arisawa, A. Fujita, N. Morita, P. J. Cox, R. A. Howie, and G. A. Cordell, Phytochemistry 26, 3301 (1987). 86. M. Yokota, H. Zenda, T. Kosuge, and T. Yamamoto. Yakugakrr Zusshi 98, 1508 (1978). 87. L. Lumonadio, M. Vanhaelen, and M. J. Devleeschouwer, Fitotempiu 57,291 (1986). 88. D. D. Casa and M. Sojo, J. Chem. Soc. C , 2155 (1967). 89. N. Fukamiya, M. Okano, T. Aratani, K. Negoro, A. T. McPhail. M. Ju-ichi, and K. H. Lee, J . Nat. Prod. 49, 4281 (1986). 90. K. Koike and T. Ohmoto, Chem. Pharm. Bull. 33, 5239 (1985). 91. A. Bax, “Two Dimensional Nuclear Magnetic Resonance in Liquids.” Delft Univ. Press. Reidel, Dordrecht, 1982. 92. H. Seto, T. Sasaki, H. Yonehara, and J. Uzawa, Tetrahedron Lett. 18, 923 (1978). 93. 0. Campos, M. DiPierro. M. Cain. R. Mantei, A. Gawish, and J. M. Cook, Heterocycles 14, 975 (1980). 94. M. Cain, 0. Campos, F. Guzman, and J. M. Cook, J . A m . Chem. Soc. 105,907 (1983). 95. H. J . Rosenkranz, G. Botyos, and H. Schmid. Justus Liehigs Ann. Chem. 691, 159 (1966). 96. L. A. Mitscher, M. Shipchandler, H . D. H . Showalter. and M. S. Bathala, Heterocycles 3, 7 (1975). 97. R. Oehl, G. Lenzer, and P. Rosenmund, Chem. Ber. 109, 705 (1976). 98. M. F. Bartlett and W. 1. Taylor, J . A m . Chem. Soc. 82, 5941 (1960). 99. T. J . Hagen and J . M. Cook, Tetrahedron Lett. 29, 2421 (1988). 100. I. Matus and J. Fishcer, Tetrahedron Lett. 26, 385 (1985). 101. R. Hegnauer, in “Chemical Plant Taxonomy“ (T. Swain, ed.), p. 410. Academic Press, New York, 1963. 102. L. A. Anderson, M. F. Roberts, and J. D. Phillipson, Plant Cell Rep. 6, 239 (1987). 103. L. A. Anderson, C. A. Hay, J. D. Phillipson, and M. F. Roberts, Plunt Cell Rep. 6,242 (1987). 104. T. Ohmoto and Y. 1. Sung, Shoyakugaku Zasshi 36, 307 (1982). 105. A. T. Keene, A. Horris, J. D. Phillipson, and D. C. Warhurst. Planta Mad. 52, 278 (1986). 106. T. Ohmoto and K. Koike, Shoyakugaku Za.tshi 42, 160 (1988). 72. 73. 74. 75.
170
TAICHI OHMOTO AND KAZUO KOIKE
107. G. H. N . Towers and Z. Abramowski. J . Nur. Prod. 46, 576 (1983). 108. Y. I. Sung, K. Koike, T. Nikaido, T. Ohmoto, and U. Sankawa. Chem. Pharm. Bull. 32, 1872 (1984). 109. T. Ohmoto, T . Nakaido, K. Koike, K. Kohda, and U. Sankawa, Chem. Pharm. Bull. 36, 4588 (1988). 110. T. Ohmoto, Y. I. Sung, K. Koike, and T. Nikaido, Shoyakuguku Zasshi 39,28 (1985).
- Chapter 4 PHENETHYLISOQUINOLINE ALKALOIDS TETSUJ I KAMETANI~ Institute of Medicinal Chemistry Hoshi Universiry Tokyo. Japan
MASUOKOIZUMI Fujigoremha Research Lahorarories Chugai Pharmaceuriccil C o . . Ltd. Shizuoka, Japun I. Introduction ......... ........
.................................
i72
11. Structural Elucidation, Chemical Reaction, and Stereochemistry of
Phenethylisoquinoline Alkaloids .......................................................... .................. A. Simple Phenethylisoquinolines. .......
173 173
C. Bisphenethylisoquinolines ............................................... D. Homoproaporphines .................................................. E. Homoaporphines.... ............... ....................................................... ................. F. Homoerythrina Alkaloids ............. G. Dibenz[dflazecines ................................................................ H. Miscellaneous ............................................... Ill. Biosynthesis ......................... .......... .............. A. Androcymbines ... ............ ............................................................ B. Homoaporphines............. ........................... s ..............................
191 191
189
194
195 197 198
200 200 200 20 1 20 1 202 IV. Synthesis .................................................... 202 A. Phenol Oxidation ......................................................................... 206 B. Nonphenolic Oxidation .... .............. 208 C. Anodic Oxidation ................................................. D. Lead Tetraacetate Oxidation via Quinol Acetates ................... ........... 208 209 E. Photolytic Cyclodehydrobromination ........... ............ F. Asymmetric Synthesis .............. ................ ............., ........... ........... 213 214 G. Miscellaneous Methods. ........... V. Pharmacology ..................................... ...... ................. ....................... 219 220 References .....................................
' Deceased. 171
THE ALKALOIDS, VOI.. 36 Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.
172
TETSUJI KAMETANI A N D MASUO KOIZUMI
I. Introduction
The chapter on phenethylisoquinoline alkaloids that appeared in Volume 14 of this treatise reviewed the literature up to the middle of 1972 ( I ) . In the succeeding years covered in this review (1972-1988) significant advances have been made in all aspects of study regarding this family of alkaloids. Phenethylisoquinoline alkaloids are classified into seven major alkaloid groups based on structural differences: simple I-phenethylisoquinolines (l),homomorphinanedienones (2), bisphenethylisoquinolines (3), homoproaporphines (4), homoaporphines (9, homoerythrines (6), and dibenz[dflazecines (7)which are related to benzylisoquinoline alkaloids. Although tropolone and Cephalotaxus alkaloids also belong to the
0
R1
2
1
Me-N
3
8
4
7
5
R3 a4 6 10
2
1
173
4. PHEN ETHY LISOQUINOLIN E ALKALOIDS
phenethylisoquinoline alkaloid group, these alkaloids are not included in this chapter since they were reviewed earlier (2). This chapter is organized in the same manner as the preceeding reviews, listing the alkaloids according to structure. Some sections that were prominent in the last review are absent or received scantily, because little new information has appeared, whereas new sections have been added or others expanded when warranted. Synthesis of the alkaloids is discussed in a separate section; this arrangement seemed desirable since some of the synthetic approaches are applicable to more than one ring system. Nearly 40 new phenethylisoquinoline alkaloids have been isolated and characterized since the last review in Volume 14 of this treatise (I). These alkaloids are listed in Table I together with their botanical sources and physical properties.
11. Structural Elucidation, Chemical Reaction, and Stereochemistry of
Phenethylisoquinoline Alkaloids A. SIMPLE PHENETHYLISOQUINOLINE ALKALOIDS Of the simple phenethylisoquinoline alkaloids dysoxyline (8), (S)-( +)homolaudanosine (9), and (-)-isoautumnaline (lo), 8 and 9 were isolated from Dysoxyfum lenticeflare Gillespie (3):Alkaloid 10 was isolated from Colchicum ritchii R.B. ( 4 ) . Alkaloids 8 and 9 were identified as simple I-phenethylisoquinolinesby means of their mass spectra. The parent ions of 8, mlz 355 (CzlHz5NO4), and 9 mlz 371 (C22H24N04), differ by 16. Both compounds show a base peak at mlz 206 resulting from the loss of a phenethyl radical from the parent ion. A similar loss of the C-1 benzyl radical produces the base peak
8 ’ 7 7 ’
0@R5 R3
0
R4
g : 9 : 10: 11:
R1 Me Me H Me
R2 Me Me Me
H
R3
R4
-cHzMe Me
Me Me MO Me
R5 R6 H BOH H IIH OH OH MH
I74
LT.
r"
I
I75
'D
TABLE I (Continued) UV Compound
Colchiritchine (14). CmH21N04
CC-20 11.5). C ~ I H ? I N O S
rnp ("C)
Amorphous
2 10-2 12
[aid")"
t207 10.I5,MeOH)
Amax,
nm
(log d
213 l4.4ld 241 (4.08) 277 (3.701
243 (4.27) 280 13.781
IR ymrr. c m ~ l 16fdY
1630 1610
1665 1635 1605
'H NMR 6. pprn I .4M IH.m.H-I2Pl' I .7M 1 H.m.H-6P)
2.341 IH.m.H-5P) 2.42( 1H.m.H-6a) 2.821 IH.m.H-5al 2.85(2H,m.H-I3uP) 3.?7(IH.m.H-l2a) 3.67(3H,s.OMel 4.08(3H.s.OMe) 4.1 1IIH.m.H-71 5.93 5.97l?H.d,Jl.4.OCHzOl 6.27( 1H.s.H-4) 6.3 I ( 1 H.s.H-81 6.81lIH.r.H-I I 1
2.9M3H.r.NMe)' 3.79(3H.r.OMel 4.14(3H.s.OMe) 5.95(2H,r.OCHzO) 6.261IH.s.Ar-H) 6.48(IH.s.olefinic H ) 6.75( 1H.r.olefinic H)
Source Colchirum rirrhii R.B.
Ref. 4
h
cml r
Lo
0
PI ci
N
I
*
N n
I78
a
N
I
N
?
179
0 I
t
%
TABLE I (Conrinued)
Source
Compound lolantamine 1271. C I P H ~ ~ N O ~
215-216
-
+ II 2 (CHCIII
3350 1650 1630
Ref.
2.38(3H.s.NMe)' 3.78(3H,s,OMe) 6.451 IH.s.Ar-HI
Merendpro jolonrue
I5
2.37OH.r.NMe)' 3.5 II3H.s.OMel 3.78(3H.s.OMe) 3.79( IH,c,H-I2) 6.46(1H.s.Ar-H1
Colrhiciim Iurerrm
I6
lhon
231-232
-96 (MeOHl
m
228 (3.891'' 272 (4.051
0
Me0
Jolanline (31). C20H27N04
269-270
-
2lod 2x5
Me0
3535 1677 1667 1617 1600
3400 1650 1630 I600 1460
Baker
Merendero jolonrae
17
+
0
N P
N I
N
181
WX N19 0 -
I
N ICi I
0
r? N
... "I
I82
E m
m
Merenderine (491, C ~ ~ H Z J N O S
CC-24 (501. CiiH25NOr
Colrhirunr szouirsii
Amorphous
245-249
249 (3.901 281 (3.601
342W
276(3.28Ih 284 (3.301
3320h
Colchrrum
23
5.24
cornigerum
Hornoerythrina alkaloids
Holidinine (52). CloH27NOd
164-165
t Y 1 (1.03. CHCI31
1580
1480
3.25(3H,a.OMel' 3.76(3H.a.OMe) 3.93(3H.s.OMel 5.5h(lH.H-I1 5.581 IH.s.OH1 6.631IH.s,Ar-Hl
Phdline 5p. afT.
25
HO
Meo% Me0 P' (continued)
TABLE 1 (Continued)
Compound Comosidine 671, C ~ U H ~ N O ?
mp 1°C)
143-145
[alDI")"
+72 (0.17. CHCIi)
Uv A,,,. nm (log el
1R ymrx. cm
236 (3.%lh 283 (3.511
1610h 1580
'H NMR
1515 1469
-
2.7-Dihydrohomoerysotrine 1.541. CroHyNOi
Amorphous
-
- I18 (0.58. CHChl
e
3-Epi-2.7-d1hydrohomoerysotrine (53).
CmW?7NOi
Amorphou,
+ I ? ? (0.50. CHCIjl
282 (3.481h 259 (3.021
-
6 . ppm
Source
3.7646H.s.OMel' 3.84(3H.s.OMel 6 . W IH.s.Ar-HI 6.07(IH,s.Ar-Hl
Phellinr sp. aff. Phpllirle wmim
IRCM IH.q.H-4,,1' ?.68(3H,a,OMeI 3.76(3H.s.OMel 3.8213H.s.OMeI 5.241IH.m.H-II 6.561 1H.s.H-18) 6.89( IH.>.H-I5)
CeptluloroxllJ hurringrotiiu
I .58( IH.I.H-4,, )' ?.78( IH.q.H-4,,1 3.19(3H.r.OMe) 3.7713H.r.OMel 3.83I3H.b.OMel 5.25f IH.m.H-I I 6 . 6 3 1H.s.H-18) 6.74( 1H.s.H-151
Ref. 25.33
Labill.
3'
260 (hydrochloride)
+75 ( I . ? , EtOHl
242 (3.681 291 (3.65)
1615h 1495
I480 I44?
I .55(preudo-t.J4,,.4,q IZ,J3,4,, I 1 .H-4,,IC 2.53( IH.q,J?H-4,,,) 3.?7(s.OMe) ?.76( IH.d.Jl0.H-I) 5.86(?H.OCHzOl 6.021 1H.m.H-2) 6.?6( IH,b.Ar-H)
[email protected])
Phelline
?.85(3H,s,OMe)' 3.3X 1H.rn.H-3) 5. I512H.d.JI .4.OCH?O) 5.30(q1J 10.1.8 S.hl(d.JI0) 6.27( 1H.s.H-18) 7.lO(lHs.H-lY
Phelline
33
comu.w
Labill.
MeO" Alkaloid 6 (59). C I V H ? I N O ~
I26
t 6 3 (1.8. EtOH)
243 (3.691 292 (3.67)
1620h 1500
1489 1465
Wilconine (601. C20HzcN04
150-151
-51.4 (0.55, CHCI,)
281 13.41)h 258 (2.75) 233 (3.901
1610" 1?80
1460 1120
'
I .67( IH,q.H-4,,)' 2.96OH.s.OMe) 3.1 I(IH.m,H-4,,,) 3.76(6H.s.OMe) 3.84( IH.rn.H-3,, 1 5.864 IH.d.Jl0.5.H-Il 6.CfAIH.rn.H-2) 6.?3( IH.s.Ar-H) 6.82(lH.s.Ar-H)
33
comoscr
Labill.
Crphrrloroxrrs
34
wlsoniunu
(continued)
TABLE 1 (Continued) UV Am,,.
nm
Compound
mp ("C)
Lalol")"
(log C)
IR ymrr.cm
'
'H NMR 6 . PPm
Epiwilsonine (61). CmH25N04
103-104
t60.7 (0.S5,CHCI?)
281 13.44)h 2sn 12.77) 233 13.92)
1.701IH.q.H-4,,)' 3.1411 H . m .H-4,, ) 3.2913H.s.OMe) 3.3MIH.m.H-3,,) 3.7913H.s.OMe) 3.8013H.s.OMe) ?.77IlH.q.H-I) 6.041 1H.m.H-2) 6.611 IH.s.Ar-H) 6.981 IH.s.Ar-H)
Dibeoz[dJlszednes Dysazecine 166). C ~ I H ~ S N O ~
217-219 (picrate)
t 8 3 10.22. EtOH)
230 (4.18Ih 291 (3.861
2.1013H.s.NMe)' A ?.MlIH.td.JI1.3) 3.8213H.s.OMe) 3.92(3H.s.OMe) 5.961IH.d.JI.O 5.981IH.d.JI . 5 ) 6.521IH.a.Ar-H) b.S3( 1H.s.Ar-H) 6.76OH.s.Ar-H)
r
O
Me0 '@-Me
0 Me
Source Crpholoroxrrs nil5uniuno
Ref. 34
Miscellaneous alkaloids Holidine (67). CigH24N203
Amorphous
+I75 (1.0. CHCI71
233 (3.931b 272 0.631
1714h 1580
1.66(IH.dd.ll?.H-4,,)' 2.70( 1H.dd ,J 12.3.H-4,, ) 3.14(IH,m.H-3) 3.22(3H.s.OMe) 3.99(3H.s.COOMel 5.70(1H.H-I) 7 . W I H.s,Ar-H) 8.50( IH,s,Ar-Hl
Phelline sp.
232 (3.99)h 272 (3.651
3350h 1680
I .68(lH.dd.llZ.H-4,,)' 2.68(IH.dd.J12,3.H-4.,) 3.13(IH.m.H-3) 3.23(3H.s.OMe) 5.69(2H.s.NHz) 5.79( I H.H-I 1 7.94( IH.s.Ar-H) 8.34( IH,s,Ar-HI
P h e l l i n ~sp.
MeOOC
25
aff.
MeO" Phellinarnide (68).C I R H ~ ~ N K ~
206
+I80 (1.0. CHCI3)
25
aff.
(continued)
TABLE I (Continued)
Source
Compound I1 I4
Phellibilidine (69). C I ~ H ~ ~ N O ~
- 1 1 (1.0. CHCI,)
213 (4.02) 298 (3.11)
3570 3400 2930 1715
1610 1450
1.4M 1H,dd.J12H-4,,)'~m 3.36(3H,s.OMe) 3.58(I H,s.OH) 3.61(IH.m,H-3) 4.34.4. IZ(ZH.Zd.Jl2.H-181 5 . 5 3 1H.rn.H- I ) 5.70(IH.s.H-l5)
Helline
1.5MIH.dd.J12.H-4,,)'J 1.97( IH.m.Hb) 2.56(1H.dd,J12.3.5,H-4,q) 2.W 1H.d.J16.Ha) 3.4 I(3H.s.OMel 3 . W 1H Im.H-3,") 3.82(IH.d.J12.H-18) 3.96(1H,d.J12.H-18) 5.54(1H.rn.H-I) 5.6M 1H.s.H- 15)
Hrfline billiardierr
Ref. 26
billrardreri
% O MeO" lsophellibilidine (70). C,,H23NO4
(Concentration. solvent).
132
EtOH. ' CDCll.
+204 (1.2, CHCI,i
MeOH. ' D20.
' CF,COOH.
213 (3.98$' 280 13.34)
KBr.
-
CHCI,. ' CD6. 400 MHz.
' 270 MHz. ' 100 MHz.
60 MHz.
26
189
4. PHENETHYLISOQUINOLINE ALKALOIDS
in the mass spectra of benzylisoquinolines. The difference of 16 amu between 8 and 9 is explained by the presence of a methylenedioxy group in 8 and two methoxy groups in 9. The difference is confirmed by the presence of ions derived from the cleavage of the C-7‘-C-8’ bond in 8 at mlz 135 and in 9 at mlz 151. The ‘H-NMR spectra are in full agreement with structures 8 and 9. The circular dichroism (CD) spectra obtained from 8 and 9 each showed positive Cotton effects near 280 and 240 nm. Since the CD spectrum of (S)-( +)-laudanosine contains bands of a similar sign at these wavelengths, the absolute configuration for alkaloids 8 and 9 must be ( S ) (3). The diphenolic isoquinoline (lo), CZIH27N05,was obtained together with the known isomeric base (-)-autumnaline (11). The ‘H-NMR spectrum of 10 differed from that of 11 only by a slight shift of the H-5 and H-8 absorptions. This indicated that the isomerism resided in ring A, more specifically in the relative positions of the methoxy and hydroxy substituents. Complete NOE studies of 10 and 11 conclusively established the substitution pattern in rings A and C in each case (4).
B. HOMOMORPHINANEDIENONES A N D ANALOGS I . Androcymbine-Type Alkaloids Three alkaloids, namely alkaloids CC-10 (12) and CC-20 (15) and collutine (13), were isolated from Colchicum cornigerum (5) and Colchicum luteum ( 6 ) , respectively. Recently, a fourth alkaloid, colchiritchine (14), was isolated from Colchicum ritchii ( 4 ) .
RS
12: 13: 14 : 15 : 16 : 11: 18:
R1 H
R2 Me Me Me -CH,-CH2Me H Me Me Ma Me
R3 Me H Me Me Me Me Me
R4 I ~ 4H “H
R5 HMe Me H ~ f i HMe 4I-I Me 4 4 Me IIH Me
The IR spectra of these alkaloids showed the characteristic absorptions of a cross-conjugated dienone system, and their U V spectra were similar to that of androcymbine (16). Their similarity to 16 was also evident from the mass spectra of CC-10 and collutine which established the molecular formula CZIHZ5NO5. Alkaloid CC-10 is thus isomeric with androcymbine (16) and with collutine (13), but it was chromatographically different from both. Since methylation of 12 and 13 with diazomethane yielded 18, an
190
TETSLJJI KAMETANI A N D MASUO KOIZUMI
enantiomer, 0-methylandrocymbine (171, was obtained by similar methylation of 16. The mass spectrum of CC-20 confirmed the structure and also established the molecular formula CzlHzlNOs that is two hydrogens less than that of 12 and 13. This is due to the presence of a methylenedioxy group in CC-20, also confirmed in the 'H-NMR spectrum which showed signals for one aromatic methoxy, one vinylic methoxy, and an N-methyl group. It must be stressed that the 'H-NMR spectrum of CC-20 was virtually identical with that of 16, apart from obvious differences in the methoxy and methylenedioxy regions. The combined data lead to structure 15 for alkaloid CC-20. The spectral data of colchiritchine (14) was identical with that of CC-20, apart from the absence of an N-methyl group ( 4 ) . 2. Alkaloid CC-2 and Szovitsidinr Alkaloid CC-2 (19) and szovitsidine (21) were isolated from Colrhicum cornigerum (5) and Colchicum szovitsii (7), respectively. The molecular formula of alkaloid CC-2 is C21H27N05, corresponding to four hydrogens more than present in CC-20. Structure 19 was determined for CC-2 in the following way. The absorption at 3536 cm-' in its IR spectrum was assigned to an alcoholic hydroxy group because the U V spectrum was unchanged on addition of strong base. The 'H-NMR spectrum showed signals corresponding to one N-methyl, one aromatic methoxy, one methoxy attached to saturated carbon, one methylenedioxy group, and one aromatic proton. The coupled signals present correspond to HC (6 4.5, d, J = 4 Hz), H B (6 5.9, t, J = 4 Hz), and HA (6 6.4, m); this set of signals is closely similar to the three protons (HA, HB, HC) in kreysiginine (20).Irradiation of HC in the spectrum of CC-2 caused the HB signal to collapse to a doublet (J = 4 Hz), indicating a cis relationship between HA and HB.
19:R= H
20
21
Mild oxidation of CC-2 with manganese dioxide afforded a conjugated enone, C21H2SNOS,showing the allylic nature of the original hydroxy group. Furthermore, the 'H-NMR spectrum of the enone was identical with that of the oxidation product of 19; in particular, the signal for HA
4. PHENETHYLISOQUINOLINE ALKALOIDS
191
now appeared as a triplet (6 4.12, J = 8 Hz), which supported the presence of the methylene group at the carbon adjacent to the OMe group. The foregoing information is best accommodated by structure 19 for alkaloid CC-2. Rigorous structural proof came from X-ray crystallographic studies ( 2 7 ) . The data reported on szovitsidine (21) are not sufficiently complete to unambiguously assign its structure. It may be assumed that szovitsidine is a reduced derivative of 0-methylandrocymbine (17) whose structure, including absolute stereochemistry, was previously elucidated together with that of androcymbine (16) (28). C. BISPHENETHYLISOQUINOLINES The new bisphenethylisoquinoline alkaloid is jolantinine 22, which was isolated from Merederu joluntue (8).The structure of (22) was determined by IR, 'H-NMR, and mass spectroscopy.
22
D. HOMOPROAPORPHINES Colchicum kesselringii Rgl. gave seven alkaloids, kesselridine (23) ( l o ) , regelamine (24) (1I ) , kesselringine (25) (12). regeline (26) ( 1 3 , regelinone (32) (18), isoregelinone (33) (20), and jolantimine (34) ( 1 9 ) , whereas Colchicum luteum afforded t h e alkaloids luteidine (28) ( 1 6 ) and luteicine (29) ( 9 ) . Jolantamine (27) (15) and jolantine (31) ( 1 7 ) were isolated from Merendsru joluntue, and trigamine (30) was obtained from Merendera triginu (Adams) (14).This group comprises several types of compounds. They differ in the nature of ring D and consequently in their U V , IR, and NMR spectroscopic properties. When there is a keto group at C-12 or C-13 of ring D, it may form a cyclic half-acetal bridge with the phenolic
192
TETSUJI KAMETANI A N D MASUO KOIZUMI
I2 S4 : Me H R1
Me H R2
26: M e
Me
M
s
R2 0
HO
12
'
M
e
R 27: H 28: ome
0
0
M$HO ?-Me
-
g 8
R'P
Ho'
M
MeO H
Ho 29
30
31
R OH 33 : - O H
32:
group at C-1. The half-acetal hydroxyl can be free or etherified with a methyl group. Moreover, the double bond in ring D can be in the cis or trans configuration to the hydrogen at C-6A. Reduction of regelamine (24) in ethanol containing sodium gave the ring-cleavage products 35 and. 36. Sodium borohydride reduction of jolantamine (27) and subsequent hydrogenation in the presence of Raney nickel gave 36 (29,301. Treatment of kesselringine (25) and regeline (26) with acetic anhydride containing sodium acetate gave the acetates 39 (12) and 40 (13),respectively. On the other hand, treatment of 26 with acetic anhydride containing sulfuric acid gave 37 (12). Methylation of 26 with dimethyl sulfate gave 43 (13). Furthermore, methylation of 25 with diazomethane afforded 26, which was hydrolyzed with acid to 24. Treatment of 25 with butanol and hydrochloric acid furnished 38. Acetylation of 26 with acetic anhydride gave 40, while treatment of 24 or 26 with acetyl chloride or acetic anydride gave 42. Treatment of 25 with benzyl chloride gave 41 (31). Reduction of luteidine (29) by sodium borohydride or hydrogenation in the presence of Raney nickel gave tetrahydroluteidine (44), whereas Wolff-Kishner reduction of 28 gave the cyclopropane 45. Cyclization of 28 in acetic acid containing hydrogen chloride gas gave the acetal46 (16).
35: R = O H 36:R=H
R1 31: Ac 38: H
R2 Me Bu
R3 Ac H
R1
39: Ac 4 0 : Me 41 : Bz 42: M e
R2 R3 M e Ac Me Ac M e Bz Ac Ac
R4 Me Me Ph
Me
43
194
TETSUJI KAMETANI A N D MASUO KOIZUMI 28
46
The structure of all the alkaloids were established spectroscopically, and typical examples are described here. The elemental analysis and the mass spectrum of kesselringine (25) established the molecular formula C19H25N04.The UV spectrum showed that kesselringine contains one aromatic ring. In the UV spectrum measured in alkaline ethanol, the bands at 292 and 231 nm underwent a bathochromic shift by approximately 10 nm and showed hypochromicity, indicating the presence of a free phenolic group. According to the IR spectrum, the alkaloid possesses a hydroxy group but no 0x0 group. The 'H-NMR spectrum of kesselringine exhibits one N-methyl group, one aliphatic methoxy group, a multiplet arising from one proton of the OCH type, and a singlet arising from the isolated aromatic proton. Consequently, kesselringine is a homoproaporphine alkaloid with a phenolic group at C-2. A phenolic hydroxy group at C-1 forms the ketal group. Since the ketal group is located at C-12 on ring D, the secondary hydroxy group must be in the axial position, as shown in the 'H-NMR analysis, and, consequently, in the quasi-cis position to the vicinal methoxy group in the ketal. Kesselringine shows negative Cotton effects in its CD spectrum at 250 and 300 nm and a positive Cotton effect at 220 nm. By analogy with proaporphine alkaloids, it is assumed that kesselringine has the (6aR,8aS,1 IS, 12R) configuration. E. HOMOAPORPHINES
The alkaloids 0-methylkreysigine (47) (21),szovitsamine (48) (22),and merenderine (49) (23) were isolated from Colchicum szouitsii. A fourth alkaloid, CC-24 (50), was isolated from Colchicum cornigerum (5,24).The chemical behavior of 50 has not been described. All four alkaloids were
'
47: 48: 49: 50:
R2 0
I95
4. PHENETHYLISOQUINOLINE ALKALOIDS
R1 Me Me
RZ
Me H
H H
Me
51:H
Me
H
R3 R1 OMe I I H OMe I I H OH IIH OMe ' I H OH - H
M R3
presented as optical antipodes of known alkaloids; in particular, the ( R ) form of merenderine (49) was identical with the (S)form of floramultine (51).
F. HOMOERYTHRINA ALKALOIDS
Cephalotaxus harringtonia (32) gave two alkaloids, 3-epi-2,7dihydrohomoerysotrine (53) and 2,7-dihydrohomoerysotrine (54), whereas Cephaloraxus wilsoniana (34) afforded wilsonine (60) and epiwilsonine (61). Alkaloids 57, 58, and 59 were isolated from Phelline comosa Labill. (3.9, and holidinine (52) and comosidine (57) were isolated from Phelline sp. aff. (25). The spectroscopic properties of the homoerythrina skeleton parallel those of the Erythrina group. The IR and 'H-NMR spectral characteristics are similar, particularly in rings A and B. The stereochemistry at C-3 may be assigned from chemical shift and coupling constants. Elemental analysis and mass spectroscopy of two isomeric alkaloids, 3-epi-2,7-dihydrohomoerysotrine (53) and 2,7-dihydrohomoerysotrine (54) established the molecular formula CzaHz7N03.Their spectroscopic properties closely resembled schelhammericine (55) except that the 'H-NMR spectra revealed the presence of two aromatic methoxy groups instead of a methylenedioxy group as in 55. Distinction between the two epimers on the basis of 'H-NMR data was made as follows. In the (3s) methoxy group of 53, the methoxy resonance occurs at 6 2.68, with a quartet for the axial C-4 proton near 6 1.80. In the (3s) methoxy group of 54, the methoxy resonance occurs at 6 3.19 with an apparent triplet for the axial C-4 proton at 6 1.58. The configuration at C-5 is considered the same as that in 55, since their optical rotations are of the same magnitude (32). In the same way, the physical and spectral data of holidinine (52) indicate that one of the methoxy groups of comosivine (56) is replaced by a hydroxy group (25). Alkaloid 57 (C20H27N03) was found to differ from 6,7-dihydrohomoerythramine (58) in that it contained two aromatic methoxy groups in place
196
TETSUJI KAMETANI A N D MASUO KOIZUMI
52: 53: 54: 55: 56:
R1 R2 R3 OMeMe H H Me Me H Me Me H -C&OMeMe Me
R4 R5 H OMe OMeH H OMe OMeH H OMe
R1 R2 5 7 : Me Me 58 : -CH~-
R2
R4
of the methylenedioxy group. The C-3 proton was, from 'H-NMR coupling constants, found to be axial, and structure 57 was consistent with the data. The configuration at C-5 is assumed, although its CD curve is the inverse of that of 58 in the 235 nm region. Structure 58 corresponds to 6,7-dihydrohomoerysotrine (33). The epoxy alkaloids 59 (CI9HZINO4) and 61 (C20H2SN04)exhibited similar physical and spectral characteristics. Both contain an allylic methoxy group, a disubstituted double bond, and para-oriented aromatic protons; however, the former alkaloid contains a methylenedioxy group and the latter two aromatic methoxy groups. Their IR spectra show no hydroxy or carbonyl group, suggesting that the fourth oxygen atom is contained in a ring. The mass fragmentation patterns of the two alkaloids are almost identical, showing that they differ only in the aromatic substituents. Structures 59 and 61 were assigned to the two alkaloids on the basis of spectroscopic evidence and chemical transformations.
4. PHENETHYLISOQUINOLINE ALKALOIDS
197
R20
OH MeO"
2 R1 R2 6 2 : Me Me 6 3 : -CH2-
R1 R2 64:Me Me 65: -CH2-
Reduction of 61 with lithium aluminum hydride gave the alcohol 62 with preservation of the double bond. The positions of both the double bond and the hydroxy group were evident from the 'H-NMR and mass spectral data of 62. The downfield shift experienced by the proton at C-14 (6 1.36) could be accounted for if the hydroxy group were at C-6 near the aromatic proton at C-14. Similar reduction of 59 gave the corresponding alcohol 63. Catalytic reduction of 61 led to alcohol 64, and spectral data revealed that isomerization of the double bond had occurred. Similar reduction of 59 gave the alcohol 65, which exhibited spectroscopic properties similar to those of 64. That the original alkaloids 59 and 61 contained a 6,7-epoxy group was concluded from the reduction experiments, but the stereochemistry of the epoxide remains uncertain. Alkaloid 61 was later isolated from a different plant along with its C-3 epimer 60. The name wilsonine was given to 60, and 3-epiwilsonine to 61.
G.
DIBENZ[df]AZECINES
A new dibenz[df]azecine is dysazecine (66), which was isolated from Dysoxylum lenticellare (3). The mass spectrum of 66 established the molecular formula C21H25N04 and suggested the presence of a nitrogen atom in the large heterocyclic ring. The 'H-NMR spectrum of 66 revealed four noncoupled aromatic protons, one methylenedioxy group, two methoxy groups, and an N-methyl group in a uniquely shielded position (6 2.10). The I3C-NMR spectrum shows the presence of four oxygenated
198
TETSUJI KAMETANI AND MASUO KOIZUMI
10
Me0 0-
Me 66
quaternary aromatic carbons (6 144.7- 148.3), four quarternary aromatic carbons (6 133.0-135.4), four protonated aromatic carbons ortho to oxygens (6 107.5-1 12.8), and five aliphatic methylene groups (two dishielded by the nitrogen at 6. 49.6 and 59.0, and three resonating between 6 27.8 and 30.5). The narrow ranges of the chemical shifts within some groups precludes individual assignments in the absence of model compounds. By analogy to dysoxyline (8) and schelhammericine (55), dysazecine is a dibenz[d,flazecine with a three-carbon bridge between nitrogen and the methylenedioxy phenyl ring. Spectral data do not distinguish between this molecule and that in which the third methylene group connects the dimethoxyphenyl with the nitrogen, and further work is required to settle this point. The CD spectrum of 66 is dominated by strong (0 > lo4) Cotton effects at 295 nm (positive) and 232 nm (negative). Since 66 contains no chiral carbon, its optical activity arises solely from the inherently nonsymmetric diphenyl ring system held in one chiral conformation. The literature contains a report on the transformation of schelhammeridine to optically active, bridged biphenyls which differ from 66 by the absence of both methoxy groups and the presence of a chiral C-7 hydroxy function (35). The ( R ) chirality for the biphenyl system was associated with a positive Cotton effect at 290 nm in the ORD spectrum of these compounds (35). This assignment seems in agreement with the signs of the Cotton effect generally observed in the CD spectra of optically active biphenyls. The combined data lead to structure 66 for dysazecine.
H. MISCELLANEOUS 1 . Holidine and Phellinamide
Two new alkaloids, holidine (67) and phellinamide (68), were isolated from Phelline sp. aff. P . lrrcida along with several other homoerythrinan
4. PHENETHYLISOQUINOLINE ALKALOIDS
199
and related alkaloids (25).The mass spectra of holidine and phellinamide and C18H23N302, established their molecular formulas as C19H24N203 respectively. Their spectroscopic properties closely resembled each other. The 'H-NMR spectrum of 68 revealed the presence of an amide group in place of a methyl ester group in 67. Hydrolysis of the amide group of 68 with 1 N hydrochloric acid followed by esterification with diazomethane afforded a compound identical in all respects to 67. This chemical correlation confirms that the configurations at C-3 and C-5 are the same in both alkaloids. These data lead to structures 67 and 68 for holidine and phellinamide, respectively.
6 7 : R=OMe
68: R= NH,
H
MeO" 69
70
2. Phellihilidine and Isophellibilidine Helline hilliardieri afforded two new alkaloids, phellibilidine (69) and isophellibilidine (70), respectively (26). The mass spectrum of 70 shows it to be isomeric with 69 (CI7HZ3NO4). Moreover, several common peaks were found in the spectra of 69 and 70, indicating the same partial structure. The IR absorption at 3380 cm-' for 70 agrees with the presence of a hydroxy group; the absorption at 1745 cm-' can be attributed not to an unconjugated ester or &lactone but rather to an a,p-unsaturated
200
TETSUJI KAMETANI A N D MASUO KOIZUMI
lactone, which is also compatible with the U V and 'H-NMR data. The 'H-NMR spectrum of 70 discloses the presence of two trisubstituted double bonds in addition to a methoxy group and two protons of an AB system. Reduction of 69 and 70 with lithium aluminum hydride did not lead to the same compound: 69 gave rise to diol71 while 70 afforded trio1 72. The above data for phellibilidine and isophellibilidine lead to proposed structures 69 and 70 and to assignment of the pseudoequatorial orientation to the methoxy group at C-3.
72
71
111. Biosynthesis
Although biosynthesis of the phenethylisoquinoline alkaloids has not yet been studied in full, that of androcymbines, homoaporphines, and homoerythrinans has been examined by work with radioactive tracers. In this section tracer experiments as well as hypothetical biogenetic routes in the synthesis of the phenethylisoquinoline alkaloids are discussed. A. ANDROCYMB~NES Extensive tracer experiments show that tropolone alkaloids of the species Colchicum are derived from the I-phenethylisoquinoline system (73) by way of the dienone O-methylandrocymbine (16) (36). These findings, when combined with results of the earlier work (37), support the sequence shown.
B. HOMOAPORPHINES Specifically I4C-labeled I-phenethylisoquinolineswere administered to Kreysigia rnultijlora plants, and the alkaloids were isolated and degraded to unambiguous sequences. The results show that the C-homoaporphine
20 1
4. PHENETHYLISOQUINOLINE ALKALOIDS
-I-
-
16
73
no
::qo NHCOMe
skeleton of 50 originates from autumnaline (73), probably by ortho-para phenol coupling. Taxonomic interest in these findings was related to the biosynthesis of colchicine (74) in Cofchicurn autumnale (38).
C. HOMOERYTHRINA A N D DIBENZ[~,JAZECINE ALKALOIDS Tracer experiments suggest that schelhammeridine (78) of the species Schelhammera is derived from the 1-phenethylisoquinoline 75 by way of
the dibenz[df]azecine 76a and dienone 77 (39).
Me 71
76a
77
70
D. HOLIDINE A N D PHELLINAMIDE Holidine (67) and phellinamide (68) probably originate from the reaction of ammonia with aldehydes 80 and 81 formed by cleavage of the aromatic
202
TETSUJI KAMETANI A N D MASUO KOIZUMI
67 : R=OMe 68: R=NH,
81
80
79
ring of homoerythrinan precursors such as 79 (25).The hypothesis shown was proposed by Barton (26).
IV. Synthesis This section describes various synthetic methods, each of which gives rise to a different type of phenethylisoquinoline alkaloid, depending on reactivity and reaction conditions. A. PHENOLOXIDATION One-electron withdrawing inorganic reagents have been used to perform biomimetic syntheses of phenolic phenethylisoquinoline alkaloids. In order to obtain androcymbine compounds of type 85, the diphenolic isoquinoline 82a was subjected to phenol oxidation with manganese dioxide. The homoaporphine 83a coupled at the ortho-ortho position to the hydroxy group was the only product formed under these reaction
R2 82
a
b c d e
83
Rl
R2
R3
OH H OMe H H
Me Me Me H M e
Me Me Me Me H
R2 OH Me H Me OMeMe H Me OMeH on ~e R1
a
b C
d e
t
85
84
R3
OMe OMe OMe OH OMe
n
R1
R3
b
H OMe OMeOMe
c
OMeH
a
a~
b
R1 R2 H OMeMe
4. PHENETHYLISOQUINOLINE ALKALOIDS
203
conditions (40).Although diphenolic oxidative coupling reactions play an important role in the biosynthesis of alkaloids (41), the synthetic utility of the above reaction has been limited owing to low yield. Therefore, attention has been directed toward utilization of monophenolic substrates in an attempt to develop effective intramolecular coupling methods for use in alkaloid synthesis. Efficient syntheses of different alkaloids have resulted from intramolecular oxidative coupling of monophenolic isoquinolines using vanadium oxytrifluoride (VOF3)in trifluoroacetic acid (TFA). Thus, treatment of 82b and 82c with VOF3-TFA gave homoaporphines 83b and 83c and homoproaporphines 84b and 84c, with dienone 84b undergoing a dienone-phenol rearrangement in concentrated sulfuric acid to give the homoaporphine 83e (42).As model enzymatic reaction, phenol oxidation of the hydrochloride of 82d with cuprous chloride and oxygen in pyridine gave (+)-kreysiginone (84c) and isomer 84a, while 82e-hydrochloride provided ortho-ortho (830, ortho-para (83d), and para-para (85a) coupled products (43,44). The colchicine precursor 0-methylandrocymbine (85b) seemed a particularly challenging synthetic goal for applying the new procedure, since previous attempts to prepare the alkaloid by oxidative coupling of diphenol 82a had met with failure (45).Treatment of phenethylisoquinoline 82c with diborane in T H F , followed by two-electron oxidation using thallium(II1) trifluoroacetate gave, after removal of the blocking group with anhydrous sodium carbonate in refluxing methanol, (+)-0methylandrocymbine (85b) in 20% overall yield (46). The existence of homoerythrina alkaloids has been anticipated from biosynthetic considerations. Homoerythrina dienone 77 was synthesized in the following way. Oxidation of the diphenolic isoquinoline 86 with vanadium oxytrichloride in methylene chloride afforded the expected prohomoerythrinadienone 87 (47),which was transformed to the imine 88 in quantitative yield by 1 N sodium hydroxide at 0°C. Sodium borohydride reduction of the iminium chloride of 88 gave 76. Oxidative phenolic coupling of 76 with potassium hexacyanoferrate in methylene chloride afforded homoerythrina dienone 77 in 45% yield and homoerysodienone 89a in 15% yield (48). Moreover, the lactam dienone 91 was prepared in excellent yield by oxidation of the N-acyltetrahydroquinoline 90 with potassium ferricyanide (49). Reduction of the lactam carbonyl group of 91 would afford the required homoerythrina dienone 89a, but this could not be achieved in the presence of interfering functional groups. Consequently, lactam 91 was protected by benzylation, and reduction of the product with sodium borohydride gave a mixture of epimeric lactam dienols 92a in 70% overall
IL-
0
T
T
T
\ /
Or'
p L
W
m
204
t
E
b
m
m m
k0 \ /
gb n q
::a+
j
Me0
+ Z
0
OMe 90
a: X=O b:X=H,
P
MeO
\
R1 0
91
0 R4 76
a b c d e
R1 H
R2
02
Me Me Me Me
Me
H
H 02
R3 Me Me Me Me H
0
89 a : R=H b : R=0z
92 M
MR Me0
0 H
R4 H H Bz 0z Me
X HI 0 2
0 HZ H2
206
TETSUJI KAMETANI A N D MASUO KOlZUMl
yield. Further reduction of 92a with lithium aluminum hydride afforded the corresponding base 92b. Jones oxidation of 92b gave dienone 89b, which was treated with aqueous TFA to give the required phenolic dienone 89a in virtually quantitative yield (50). On the other hand, reductive cleavage of the dienone lactam 91 with chromium(I1) chloride gave the dibenz[df]azecine 76b in 87% yield. Protection of 76b by benzylation gave lactam 76c, which was reduced to amine 76d with lithium aluminum hydride. Deprotection of 76d by hydrogenolysis afforded the diphenolic dibenz[d,Aazecine 76a, a likely biosynthetic precursor of the Schelhammera alkaloids. Oxidation of the diphenol76a by potassium ferricyanide in the two-phase system gave the expected 5,7-fused dienone 77 in 61% yield (50). Reaction of the N-oxide 93a with cuprous chloride in methanol gave the homoaporphine 83d. Compound 93b provided (?)-kreysiginone (84a) under similar reaction conditions (51).
0
R2
93 R1
R2
a
H
Me
b
Me
H
B. NONPHENOLIC OXIDATION The use of phenolic oxidative coupling for in uitro synthesis of isoquinoline alkaloids has as a whole proved disappointing, although it still is considered to be a key step in the biosynthesis of these compounds. In recent years, it has been shown that phenolic ethers may efficiently be coupled by reagents such as vanadium oxytrifluoride (VOF3), thallium tristrifluoroacetate (TTFA), and ruthenium(1V) tetrakis(trifluor0acetate) (RUTFA), thus providing more rewarding routes to phenethylisoquinoline alkaloids.
207
4. PHENETHYLISOQUINOLINE ALKALOIDS
Treatment of N-trifluoroacetylisoquinoline 94a with VOF3 in trifluoroacetic acid gave the homoerythrina dienone 96a in 64% yield along with homoaporphine 97. Similarly 94b gave 95a in 50% yield and 96b in 42% yield, and 94c gave 95c in 3% yield along with 96a (52). Similar oxidation of 94d with VOF3 gave 96d in 65% yield, which when treated with 1 M sodium hydroxide in methanol yielded imine 98. Reduction of the imine hydrochloride with sodium borohydride in ethanol gave the dibenz[d,f]azecine 76e (53).
94
9s a , c
Ei
R2 me Me
R3 me Me
me
EZ
me
me
me
EZ
R1 me
w
a,b.d
97
Me
?
96d
6
Me 98
Nonphenolic is quinolines 99a,b were subject d to oxidatia with TTFA (54) and with RUTFA (55) to give the homoaporphines 100a,b. Moreover, oxidation of 99c with TTFA in trifluoroacetic acid gave lOOc, while 99d provided 101 under the same conditions. Treatment of 101 with sulfuric acid resulted in smooth dienone-phenol rearrangement with concomitant debenzylation to give an 81% yield of (2)-multifloramine (83e) (56).
208
TETSUJI K A M E T A N I A N D MASUO KOIZUMI
R30
0 Me
0 R3
99 a b C
d
100 a , b , c
R1
R2
R3 Me
Me Me Bz Bz
H OMe Me OMe Me OMe Bz
Me0 0
99d
M
~
o
$
?
-
~
~
Me 0 101
C. ANODIC OXIDATION Although diphenols have not yet been coupled electrochemically, their methyl ethers have recently been coupled with considerable success. Yields have been high, and the reactions seem remarkably clean. Oxidation of the hydrochloride of 102 was carried out on a graphite anode in water using tetraethylammonium perchlorate as the electrolyte. Potentials were controlled at 0.7 V. The dienone 103 was obtained in 23% yield (57). Similar anodic oxidation of 94a gave the homoaporphine lOOa (58).
D. LEADTETRAACETATE OXIDATION V I A QUINOL ACETATES Treatment of the quinol acetates derived from 5-, 6-, or 7-hydroxytetrahydroisoquinolines with lead tetraacetate (LTA) in acid gives different types of alkaloids. LTA oxidation of 7-hydroxy bases 82b,c,f,g in acetic
209
4. PHENETHYLISOQUINOLINE ALKALOIDS
102
103
acid gave the p-quinol acetates 104,which were treated with concentrated sulfuric acid-acetic anhydride to give O-acetylhomoaporphines 105a,b,c,d (59-61). On the other hand, treatment of p-quinol acetates 104b,c,g with trifluoroacetic acid gave the homomorphinandienones 106b,c,gand the hornoproaporphines 84a,b,calong with homoaporphines (62,63). Oxidation of 5-hydroxyisoquinolines 107a,b,c with LTA in dichloromethane gave the o-quinol acetate 108 which was converted with trifluoroacetic acid to the 3-hydroxyhomoaporphine 109 (64,65).Treatment of o-quinol acetate 111 prepared from 6-hydroxyisoquinoline 110 with acetic anhydride in the presence of an acid (concentrated sulfuric acid, boron trifluoride, or trifluoroacetic acid) gave the 2-hydroxyhomoaporphine 112 (66).
E. PHOTOLYTIC CYCLODEHYDROBROMINATION Since the total synthesis of O-methylandrocymbine (17)was accomplished via a photolytic cyclodehydrobromination reaction of a 1 4 2 bromophenethyl)-7-hydroxyisoquinoline(67), many phenethylisoquinoline alkaloids have been synthesized by this reaction. Irradiation of the bromoisoquinoline 113a,b with a Hanovia 450-W mercury lamp, using a Pyrex filter, in the presence of an excess of sodium hydroxide and sodium hydrogen sulfite gave alkaloid CC-24 (83a)(68) and the homoaporphine 114 (69), respectively. The first total synthesis of dysazecine (66) was accomplished in the following way (70). Irradiation of bromoamide 115 in methanol in the presence of sodium hydroxide with a 1 0 0 - W high-pressure mercury lamp gave cyclicamide 116a, which was reduced with diborane to the amine 116c. Conversion of 116a to dysazecine was achieved by allowing 116a to react with methyl iodide and potassium carbonate in ethanol to give the O-rnethyl derivative 116b. Reduction of 116b with sodium borohydride
M He
_j
R1
'
OR3
0
R2
H
-CH2-
g
O M e Bz
'
0
OR3
R4
R2
82 R1
Rl
0
R2
f
-
% M:e-
104
105
R3
R2
Me
+
106
R3
R4
a b c d
Me Me OMeMe Me H -CH2O M e Bz M e
R1 '
0 P
H
-
0 0 R3 04
M
e
21 I
4. PHENETHYLISOQUINOLINE ALKALOIDS
107 R1
a
b C
R2
108
109
R3
H H
Me Me -CH2OMe Me Me
O
\
AcO Me%-Me
MOO OMe OMe
110
112
111
0 R4
OMe 113 Rl
a
b
R2
Me H -CHz-
R3
R4
OH Me H H
R1
R2
83a : Me H 114 : -CHz-
R3
OH H
R4 Me
H
212
TETSUJI KAMETANI A N D MASUO KOIZUMI
115
116
a
b c
R H Me Me
X 0 0 H,
and boron trifluoride-etherate in tetrahydrofuran afforded the expected amine 116c. N-Methylation of 116c with formaldehyde and sodium borohydride gave (+)-dysazecine (66). An application of the photolytic cyclodehydrobromination reaction to bromoamide 117 gave the 1 1-membered ring lactams 118 and 119, which could be useful compounds for the synthesis of homoaporphines (71). Cyclization of 119 with phosphorous oxychloride in acetonitrile afforded the expected homoaporphine 120 in excellent yield (72).
117 Rl a
on
b c d e
OH Owe
on
119
R4 RS OMeOMe
n -ocn,o-
H ti OMeOMe O m e o n OMeOMe Omen
OH H H
118
R2 R3 OMe n
H
RS 120
213
4 . PHENETHYLISOQUINOLINE ALKALOIDS
The dibenzazecine 122a was readily prepared by a photocyclization reaction of bromophenol 121. Reduction of 122a with diborane gave the secondary amine 122b, which was converted to the dienone 123 by Birch reduction. Cyclization of 123 on heating in 5% hydrochloric acid afforded the desired compound 124a, and subsequent 0-methylation of 124a with an excess of diazomethane gave 124b (73).
122
121
a
b
123
X=O X=H,
124
a
R=H
b
R=Me
F. ASYMMETRIC SYNTHESIS Two asymmetric syntheses of phenethylisoquinolines have been reported. Simple exchange between isoquinoline 125 and imine 126 gave the chiral formamidine 127. Methylation of 127 with tert-butyllithium gave the lithiated formamidine, which was alkylated with 3,4-dimethoxyphenethyl iodide and hydrazinolyzed to give the (S)-( -)-isoquinoline 128 in 95% enantiomeric excess (e.e.) (74). The e.e. of 128 was determined by chiral-column HPLC analysis, as developed by Pirkle and applied to chiral N-heterocycles and other amines (75). Reaction of aldehyde 129 and ylide 130,derived from 3,4,5-trimethoxybenzyltriphenylphosphonium chloride obtained by treatment of the salt in T H F with n-butyllithium, afforded the trans-alkene 131 which was
214
TETSUJI KAMETANI A N D MASUO KOlZUMl
J
L -0uo
OMe 125
126
127
128
catalytically reduced to urethane 132a. When 132a was treated with an excess of methyllithium in THF, the reaction proceeded in acceptable chemical yield and without loss of optical purity to give base 132b (76). Conversion of 132b to homoprotoberberine 133 was accomplished by treatment of the hydrochloride of 132b with formaldehyde using an established procedure (77). The spectroscopic properties of 133 were the same as those already reported (77), and the optical purity was 81.9% based on published data. Compound 132c, prepared by reduction of 132a with lithium aluminum hydride, was treated with thallium(II1) trifluoroacetate to give (S)-O-methylkreysigine (51) in 27% chemical yield and 84% e.e.
G . MISCELLANEOUS METHODS The adduct 135 was formed in high yield when dichlorocarbene was generated by phase-transfer catalyzed decomposition of chloroform in the presence of the oxyberberine 634. Reduction of 135 with lithium aluminum hydride in hot THF lead to an enlargement of ring C with formation of the vinylic chloride 136 (78). On the other hand, N carboethoxydehydroaporphine 137 was reacted with dichlorocarbene under the same conditions to give adduct 138. Its reduction with lithium aluminum hydride followed by catalytic hydrogenation gave homodicentrine (139) in 63% overall yield from 137 (79). The benzyne reaction of the bromoisoquinoline 140 was examined by using sodium methylsulfinylmethanide, and dibenz[b,g]azecine 141 was obtained (80,81). An attractive modification appeared to be the expansion of the central ring of (+)-homoargemonine (143), since it seemed possible that 143 could be a representative of a new, as yet undiscovered alkaloid class originating from a I-phenethyltetrahydroisoquinolineprecursor. The synthesis of 143 was accomplished by reaction of the 1,2dihydroisoquinoline 142 and formic acid-phosphoric acid (82). Stereo-controlled total synthesis of homoerythrina alkaloids was accomplished by the new method and proved a useful tool for the synthesis
8
+
OMe
OMe OMe
134
137
135
138
136
139
217
4. PHENETHYLISOQUINOLINE ALKALOIDS
Me0 " O
W
N
-
B
Me
-
OH
CH,SCH,
bOMe
h
OMe
140
Me0
0
M
e
141
A
0
e
7
Me
M
e
Me0
0
g
) 143
&
y
)
M
e OMe
MeO OMe 142
of these alkaloids. When enone 144 was reduced with tetra-n-butylammonium borohydride, alcohol 145 was produced stereoselectively (a: b, 6 : I ) in 80% yield. On the other hand, reduction of 144 with sodium borohydride-cerium(II1) chloride gave the alcohol 145 as a major product (a : b, 1 : 5) in 81% yield. Methylation of 145a with methyl iodide afforded 0-methyl ether 14% in 44% yield. The isomeric alcohol 145b similarly gave the O-methyl ether 145d in 73% yield. Reduction of 145c with lithium aluminum hydride-aluminum chloride ( 1 : 1) in T H F gave 55, which was identical with schelhammericine. Similar reduction of the isomeric 0methyl ether 145d afforded 3-epischelhammericine (146)(83). Reduction of the enone 147 with sodium borohydride-cerium(II1) chloride in methanol gave a 2 : 1 mixture of the unsaturated alcohols,
2
A
fP
A
0
A0
0
A0
0
ZZ==
0000
1010
99
A
A0 0
0
?!P @
A
219
4. PHENETHYLISOQUINOLINE ALKALOIDS
which were separated after methylation to the O-methyl derivatives 148a (54% yield) and 148b (25% yield). Reduction of 148a with aluminum hydride gave amine 149, whose spectral data were identical to those of alkaloid A. Similarly 148b gave 6,7-dihydrohomoerythraline(58) (84).
V. Pharmacology Simple I-phenethylisoquinolineswere studied extensively by Brossi et af. at Hoffmann-La Roche. The results of their studies led to the discovery of (+)-1-(4’-chlorophenethyl)-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline (150a), whose hydrochloride was clinically evaluated as an analgesic under the generic name methopholine. The compound was found to be a clinically effective analgesic with a potency similar to that of codeine. Although the general toxicity of methopholine was excellent (851, the compound was never marketed owing to the formation of cataracts in dogs during chronic toxicity studies, later found not to be drug related. The chemistry and pharmacology of methopholine was summarized (86) and chemical details reported (87).
Meo2-M
Me0
/
.Me
Cl
Cl
150a
1 Sob
It was later found that the analgesic effect of methopholine rested entirely with the (R)-(-) antipode (150b), in retrospect a better drug (88). The story of methopholine is a classic example of how structure-activity relationships should be resolved early, and the enantiomers studied, before a decision on which compound to be developed is reached. Chlorinated analogs of methopholine were found to have antitussive activity (89),also resting with the ( R ) isomer.
220
TETSUJI KAMETANI AND MASUO KOIZUMI
Recently, dysoxyline (8) and (S)-( +)-homolaudanosine (9)were demonstrated to have significant cardiac effects as assayed using isolated atrial muscles of the rat by Aladesanmi and Ilesanmi (90).
Acknowledgments
The author (M.K.) is most grateful to Dr. A. Brossi, Department of Health and Human Services, National Institutes of Health, who carefully read and made critical comments on various portions of the manuscript. Thanks are also due Professor Dr. Toshio Honda, Institute of Medicinal Chemistry, Hoshi University, Tokyo, for critical reading of the text. The author is extremely grateful for family support and especially acknowledges Miss Namie Koizumi for preparing all the drawings and typing the manuscript.
REFERENCES
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4. PHENETHYLISOQUINOLINE ALKALOIDS
22 1
16. N. L . Mukhamedyarova, M. K. Yusupov, and M. G . Levkovich, Khim. Prir. Soedin. 354 (1976). 17. Kh. Turdikulov, V. D. Nguyon, and M. K. Yusupov, Khim. Prir. Soedin. 555 (1976). 18. M. K . Yusupov, A. M. Usmanov, A. K . Kasimov, and Kh. Turdikulov, Khim. Prir. Soedin. 867 (1977). 19. D. A. Abdullaeva, M. K. Yusunov, A. K. Kasyrnov, N. VanDau, and K. A. Aslanov, Khim. Prir. Soedin. 12 (1976). 20. A. M. Usmanov and M. K. Yusupov, Khim. Prir. Soedin., 195 (1981). 21. M. K . Yusupov, B. N . DinhThi, and Kh. A. Aslanov, Khim. Prir. Soedin. 11, 526 (1975). 22. M. K. Yusupov, N . DinhThi, Kh. A. Aslanov, and A. S. Sadykov, Khim. Prir. Soedin. 11, 109 (1975). 23. A. A. Trozyan, M. K . Yusupov, and Kh. A. Aslanov, Khim. Prir. Soedin. 11, 527 (1975). 24. A. K . Kasimov, E. Kh. Timbekov, M. K. Yusupov. and Kh. A. Aslanov. Khim. Prir. Soedin. 11, 230 (1977). 25. N. Langlois, J. Razafimbeld. R. Z. Andriamialisoa, J . Pusset. and G. Chauviere, Heterocycles 22, 2453 (1984). 26. D. H. R . Barton, R. D. Bracho, C. J . Potter, and D. A. Widdowson, J . Cliem. Soc.. Perkin Trans. I , 2278 (1974). 27. A. F. Cameron and C. Hannaway, J . Chem. Soc., Perkin Trans. 2 , 1002 (1973). 28. A. R. Battersby, R. B. Herbert, L. Pijewska, F. Santavy, and P. Sedmera, J. Chem. Soc., Perkin Trans. I , 1736 (1972). 29. M. K . Yusupov, D. A. Abdullaeva, F. G . Kamaev, and A. S. Sadykov, Dokl. Akad. Nauk Uzb. SSR, 51 (1976). 30. E. Kh. Timbekov, A. K . Kasimov, D. A. Abdullaeva, M. K . Yusupov, and Kh. A. Aslanov, Khim. Prir. Soedin. 328 (1976). 31. M. K. Yusupov, N . L. Mukhamedyarova, A. S. Sadykov, L. Dolejs, P. Sedmera, and F. Santavy, Collect. Czech. Chem. Comnrun. 42, 1518 (1977). 32. R. G. Powell, Phytochemistry 11, 1467 (1972). 33. N. Langlois, B. C. Das, P. Potier, and L. Lacombe, Bull. Soc. Chim. Fr. 3535 (1970). 34. R. G. Powell, K . L. Mikolajczak, D. Weisleder, and C. R. Smith, Jr., Phytochemistry 11, 3317 (1972). 35. S . R. Johns, J . A. Lamberton, A. A. Sioumis, and H. Suares, Aust. J. Chem. 22, 2203 ( 1969). 36. A. R. Battersby, R. B. Herbert, E. McDonald, R. Rarnage, and J . H. Clements, J. Chem. Soc. Perkin Trans. I , 1741 (1972). 37. A. R . Battersby, R. B. Herbert, E. McDonald, R. Ramage. and J . H . Clements, Chem. Cornmun. 603 (1966). 38. A. R . Battersby, P. Bohler, M. H. G . Munro, and R. Ramage. J. Chem. Soc., Perkin Trans. I , 1399 (1974). 39. A. R. Battersby, E. McDonald, J . A. Milner, S. R. Johns, J . A. Lamberton, and A. A. Sioumis, Tetrahedron Lett. 3419 (1975). 40. T. V. P. Rao, Curr. Sci. 45, 453 (1976). 41. W. 1. Taylor and A. R. Battersby, eds., “Oxidative Coupling of Phenols.” Dekker. New York. 42. S . M. Kupchan. 0. P. Dhingra, and C.-K. Kim, J . Org. Chem. 41, 4049 (1976); 43,4076 (1978). 43. T. Karnetani, Y. Satoh. M. Takemura, Y. Ohta, M. Ihara. and K. Fukumoto, Heterocycles 5, 175 (1976).
222
TETSUJI KAMETANI AND MASUO KOIZUMI
44. T. Kametani, M. lhara, M. Takemura, Y. Satoh, H. Terasawa, Y. Ohta. and K. Fukumoto, J. A m . Chem. Soc. 99, 3805 (1977). T. Kametani, H. Yagi, F. Satoh. and K. Fukurnoto, J. Chem. Soc. C. 271 (1968). M. A. Schwartz, B. F. Rose, and B. Vishrnuvajiala, J. A m . Chem. Soc. 95,612 (1973). J . P. Marino and J . M. Sarnanen. Tetruhedron Letr. 45.53 (1976). J. P. Marino and J . M. Samanen, J. Org. Chem. 41, 179 (1976). E. McDonald and A. Suksamrarn. Tetrcihedron Letr. 4421 (1975); J . Chem. Soc.. Perkin Truns. I , 440 (1978). 50. E. McDonald and A. Suksamrarn, J. Chem. Soc.. Perkin Trcrns. 1 , 434 (1978). 51. T. Kametani. M. Ihara, M. Takemura, and Y. Satoh, Heterocycles 14, 817 (1980). 52. S. M. Kupchan, 0. P. Dhingra. and C.-K. Kim, J. Org. Chern. 41, 4047 (1976). 53. S. M. Kupchan, 0. P. Dhingra. and C.-K. Kim, J . Chrrn. Soc,., Chem. Commun. 847 (1977); J . Org. Chem. 43, 4464 (1978). 54. F. R. Hewgill and H. C. Pass, Aitst. J . Chem. 38, 555 (1985). 55. Y. Landais, D. Rambault, and J . P. Robin, Tetruhedron Letr. 28, 543 (1987). 56. E. C . Taylor, J. G. Andrade. G. J. H . Rall, and A. Mckillop, J. A m . Chem. Soc. 102, 6513 (1980). 57. J. M. Bobbitt, I. Noguchi, R. S. Ware. K. N. Chiong, and S. J . Huang, J. Org. Chem. 40, 2924 (1975). 58. S. M. Kupchan, 0. P. Dhingra, C.-K. Kim. and V. Kameswaran, J. Org. Chem. 43, 2521 (1978). 59. 0. Hoshino, T. Toshioka, and B. Umerawa, J. Chem. Soc. Chem. Commun. 740 (1972); Chem. Phurm. Bull. 22, 1307 (1974). 60. 0. Hoshino, H. Hara, N . Serizawa, and B. Umezawa, Chem. Phurm. Bull. 23, 2048 (1975). 61. H. Hara, 0. Hoshino, and B. Umezawa, Heterocycles 5 , 213 (1976). 62. H. Hara, 0. Hoshino, and B. Umezawa, J. Chem. Soc. Perkin Truns. 1 . 2657 (1979). 63. H. Hara, 0. Hoshino, B. Umezawa, and Y. litaka, Heterocycles 7 , 307 (1977). 64. H. Hara, H. Shinoki, 0. Hoshino, and B. Umezawa, H e t e r o c y l e s 20, 2155 (1983). 65. H. Hara, H. Shinoki, T. Komatsu, 0. Hoshino. and B. Urnezawa, Chem. Pharm. Bull. 34, 1924 ( 1986). 66. 0. Hoshino, K. Kikuchi, H. Ogose, B. Umezawa, and Y. litaka, Chem. Pharm. Bull. 35, 3666 (1987). 67. T. Kametani, Y. Satoh, S. Shibuya, M. Koizumi. and K. Fukumoto, J. Org. Chem. 36, 3733 (1971). 68. T. Kametani, Y. Satoh. and K. Fukurnoto, Tetrcrhedron 29, 2027 (1973). 69. T. Govindachari. K. Nagarajan, S. Rajeswari. H. Suguna, and B. R. Pai, H e l u . Chim. Actu 60, 2138 (1977). 70. H. Tanaka. Y. Takamura. K. Ito, K. Ohira. and M. Shibata, Chc,m. Phcmii. B d . 32, 2063 (1984). 71. 0. Hoshino. H. Ogasawara. A. Takahashi, and B. Umezawa, Heteroc.ycles 23, 1943 (1984). 72. 0. Hoshino, H. Ogasawara. A. Takahashi, and B. Urnezawa. Heteroc,ycles 25, 15.5 (1987). 73. H. Tanaka. Y. Takamura, and M. Shibata. Chem. Phorm. Bull. 34, 24 (1986). 74. A. I. Meyers. M. Boes. and D. A. Dickrnan, Angew. Chem.. I n ! . Ed. Engl. 23, 458 (1984). 75. W. H. Pirkle and C. I. Welsh, J . Org. Chon. 49, 13X (1984). 76. Z. Czanocki. D. B. MacLean. and W . A. Szarek. J . Chem. Soc.. Chem. Commrrn. 493 (1984): Can. J . Chem. 65, 23.56 (1987). 45. 46. 47. 48. 49.
4. PHENETHYLISOQUINOLINE ALKALOIDS
223
77. A. Brossi and S. Teitel, Hclu. Chiin. Actu 52, 1228 (1969). 78. G. Manikumar and M. Shamma. J . Org. Chem. 46, 386 (1981). 79. J . L. Castro, L. Catedo, and R. Riguera. T ( > t r t i h d r o nLett. 1561 (1985); J . Org. Chc>in. 52 3579 (1987). 80. S. Kano, T. Ogawa, T . Yokomatsu. E. Komiyama, and S. Shibuya, Telrcihedron Lett. 1063 (1974). 81. S. Kano, E. Komiyama, T. Ogawa. Y. Takahashi. T . Yokomatsu. and S. Shibuya. Chem. Pharm. Bull. 23, 2058 (1975). 82. F. R. Stermitz and D. K. Williams, J. O r g . Chem. 58, 2099 (1978). 83. Y. Tsuda, S. Hosoi. T . Ohshima. S. Kaneuchi. M. Murata. F. Kiuchi. J. Toda. and T . Sano. Chem. Phurm. B1~11.33, 3574 (1985). 84. Y. Tsuda and M. Murata, Tetruhedron Lett. 27, 3385 (1986). 85. H. Besendorf. B. Pellmont, H. P. Bachtold, and A. Studer. Experientiu 18, 446 (1962). 86. A. Brossi, H. Besendolf, L. A. Pirk. and A. Reiner, in “Medical Chemistry” (J. de Stevens, ed.), Vol. 5, pp. 281-330. Academic Press. New York, 1965. 87. A. Brossi. H. Besendorf, B. Pellmont. M. Walter, and 0 . Schnider. H d u . Chim. Actu 43, 1459 (1960). 88. A. Brossi and F. Burkhardt, Helu. Chitn. Actti 44, 1558 (1961). 89. A. Rheiner, Jr. and A. Brossi. E.rpc.ric,ntiu 20, 488 (1964). 90. A. J . Aladesanmi and 0 . R. Ilesanmi. J . Ncit. Prod. 50, 1041 (1987).
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- Chapter 5 ALKALOIDS OF THE CALABAR BEAN SEIICHI TAKANO A N D KUNIO OGASAWARA Phurmuceuticul Instilute Tohoku Universitv Aohayumu, Sendui 980. Japan
I . Introduction .......
.................. ................................................................. HI. Synthesis of the Alkaloids .................................................................. ........... A. Brief Outline of Syntheses Established prior to 1970 B. Syntheses after 1971 ..................................................................... IV. Pharmacology.. ................................................................... .......................................... References 11. Structures of the
225 225 226 226 226 247 249
I. Introduction
The alkaloids of the Calabar bean (Physostigmu uenenosum) were reviewed in Volumes 2 ( I ) , 8 (2), 10 ( 3 ) ,and 13 (4) of this treatise, covering the period up to 1970. In the intervening years no new alkaloids have been discovered. However, considerable advances have been made in both the synthesis and pharmacology of the alkaloids. A number of syntheses including entirely new approaches and an enantiocontrolled route as well as the first total synthesis of racemic geneserine have been accomplished. In addition, the remarkable enantiospecificity in pharmacological activities such as antiacetylcholinesterase and analgesic activities has been recognized. This chapter outlines investigations reported during the period from 1971 to the end of 1988, focusing mostly on synthesis.
11. Structures of the Alkaloids
Isolation of seven alkaloids from the Calabar bean is reported to date (Fig. I). Of these, the structures of (-)-calabatine (6) (C17H~5N~03) 225
THE ALKALOIDS. VOL 76 Copyright 0 1989 hy Academic !‘re\\. Inc All right\ of reproduction in any form renerved
226
SEIICHI T A K A N O A N D K U N l O OGASAWARA
(-)-physostigmine (1)
MeycoQ&J HO
(-)-norphysostigrnine (2)
M HeO N
C
o
e
,
I H Me
N 0'
(-)-eseramine (3)
(-)-calabatine (6);C17H,503N, Me (-)-calabacine ( 7 ) ;C17H,503N,
Me
(-)-physovenine (4)
(-)-geneserine (5)
FIG. I . Alkaloids isolated from the Calabar bean.
and (-)-calabacine (7) (C17H25NZ03) have not been determined since their isolation was reported in 1963 ( 5 ) . 111. Synthesis of the Alkaloids
A. BRIEFOUTLINE OF SYNTHESES ESTABLISHED PRIOR TO 1970 Of the five alkaloids with known structures, physostigmine (l),eseramine (3), and physovenine (4) have been synthesized (1-4). Since the conversion of physostigmine (l),a principal alkaloid, to physovenine (4) (6) and geneserine ( 5 ) (7,8) has also been established, synthesis of the former implies acquisition of the latter two alkaloids in a formal sense. Up to 1970, the synthesis of geneserine ( 5 ) was not reported because its structure had been considered to be the N-oxide of physostigmine (1)until 1969 (9-11) since its first isolation in 1915 (12). The four approaches to the synthesis of physostigmine (1) may be classified into four types based on the key step employed: (i) the Fischer indolization route, (ii) the indole alkylation route, (iii) the oxindole alkylation route [including synthesis of physovenine (411, and (iv) the oxidative indolization route (1-4) (Scheme 1).
B.
S Y N T H E S E S A F T E R 1971
There have been more than 10 syntheses of physostigmine (1) and related alkaloids reported since 1971. They include entirely new ap-
227
5. ALKALOIDS OF THE CALAEAR BEAN
(i) Fischer indolization route
1
EtMgBr Me1
L+
rNHNH2
R
O
e
N
p
(ii) lndole alkylation route
h
-
t
(iii) Oxindole alkylation route
Hlo
I
1
h
9
EtONa CICHzCN
,
Me Me
Me
physostigmine (1)
13
(iv) Oxidative indolization route
\
aq. K3Fe(CN)6 I H I
14
Me Me 15
SCHEME I . Outline of syntheses established prior to 1970.
proaches to construct the alkaloid framework, the first enantiocontrolled synthesis of natural (-)-physostigmine (l), and the first total synthesis of racemic geneserine ( 5 ) . It should be pointed out that the same intermediate 27 of geneserine (9,which could be obtained by (v) the isochromanone route or by (vi) the radical cyclization route, may be used not only for geneserine (5) but also for physostigmine (1)and physovenine (4) (Scheme 2). Improved syntheses based on classical routes such as the Fischer indolization route and the oxindole alkylation route have also been reported. The former could provide substantial amounts of the racemic alkaloids, while the latter made possible the practical production of both the natural and the unnatural enantiomers of the alkaloids with the development of a highly efficient method for resolving the racemic intermediate. The latter may be particularly interesting from the pharma-
228
SEIICHI TAKANO A N D KUNIO OGASAWARA
(iii) Enantiocontrolled route
Y
M e o w22c N
lhv Me
H2
1) LDA 2) hydrolysis 3) alkylation
I
C02Et 20
17
18
Me physostigrnine (1)
I
I
Me Me 25
k 27
4
I
F-
I
Me 29
t
BuaSnH
26 (v) lsochrornanone route
I
I
Me Me TfO24 (iv) 1,3-Dipolar addition route
I
Me 28 (vi) Radical cyclization route
SCHEME 2. Outline of syntheses established after 1971.
5. ALKALOIDS OF THE CALABAR BEAN
229
cological point of view, since the enantiospecificity of biological activities has been recognized in recent pharmacological investigations of physostigmine (1) and related alkaloids. The syntheses established after 1971 are outlined chronologically in the order in which they were developed.
I . Synthesis of Physostigrnine a. Synthesis of Racemic Physostigrnine via the Photochemical Route. The photochemical valence isomerization of 1,2-dihydronaphthaIenes to l,la,2,6b-tetrahydrocycloprop[b]indenes (e.g., 30 + 31) is well established (13). Ikeda and co-workers applied this photochemical rearrangement to 1,2-dihydroquinoline derivatives and observed that the same type of reaction took place in these heterocycles to give rise to cycloprop[blindoles in moderate yields (e.g., 32 + 33) (14). This finding was immediately exploited in a synthesis of racemic physostigmine (1)by the same authors (15). Unfortunately, the key reaction did not proceed in good yield with the appropriate substrate for construction of the natural product; nevertheless, an entirely new approach to the alkaloid was established.
30
C02Et
32
31
CO,Et 33
Photolysis of 1,2-dihydroquinoline 19, obtained in 47% yield from 6-methoxy-4-methylquinoline 34 by the Reissert reaction (16), in ethanol in a Pyrex tube afforded the endo-cyanocycloprop[b]indole 20 in 10% yield as a single product. On alkaline hydrolysis 20 furnished the furo[2,3-b]indole 38 in 69% yield. Formation of 38 was assumed to occur by sequential hydrolysis to the anion 35, ring opening to the indolenine 36, hydrolysis of the cyano group, and recyclization as shown in Scheme 3 . After N-methylation of 38 with methyl iodide in a sealed tube, the resulting 39 was heated with methylamine to give the lactam 40 which was reduced with LiAIH4 to give racemic esermethole (41) in 25% overall yield from 38. Conversion to 41 to racemic physostigmine (1) in two steps had already been established (1,2).
230
SEllCHI TAKANO AND KUNIO OGASAWARA
Me
hv,
CN
KCN, 47%
EtOH, Pyrex tube 2"C.g h
I
34
CO,Et
I
CO,Et
19 10% KOH
M
aq. EtOH 120-130 "C
35
20
e
o
e
C
N
36
Meocfb Me1
YHo H
37
38
Me 39
25%
69%
acetone 60 "C sealed tube 4.5 h
Me Me 40
100%
(f)-eserrnethole (41) 100%
SCHEME 3. Synthesis of racemic physostigmine. The lkeda approach
b. Synthesis of Racemic Physostigmine via the Acyliminium Route. In 1978, Wijnberg and Speckamp (17) disclosed a new approach to racemic physostigmine (1)employing acyliminium cyclization (18)as the key step, a route which they developed by themselves. The synthesis devised by these authors did not start from an indole derivative but from the succinimide 47 corresponding to the A-C framework of the alkaloid. In order to avoid the difficulties encountered in the preparation of the nitrated imide 48 starting from the nitrated precursor, the introduction of the nitro group was performed at a later stage. Thus, 3-ethoxybenzaldehyde (42) was first converted to the imide 47 in 60% yield via a sequence
-[
j
23 1
5. ALKALOIDS OF THE CALAEAR BEAN
E t O D C H O
E t O m N C 0 2 E t
KCN
E0 t&0 ;2Et
+
TiCI,
\
42
MeOH, 43
92%
co
cone. HCI
E W , y L L O z H
IL4h
30 min
11 44
n AcCl
45
CH3NHz b
46 (76% from 43) 1) Mel, K,C03 2) NaBH,
fum HN03
D
conc HCI. Me
Me 48: Rl=N02, R2=H
47
O’C, 4h
49: Rl=H, R2=NO2
50: X=Y=O 51 : X=H, OH, Y=O 52: X=O, Y=H, OH
16
LiAIH,
-EtoQ&AoI OHC
Me AcO-
J
53
Me CHO 54 74%
““6 \
I H I
known-
physostigmine (1)
Me Me (k)-eserethole (55)
SCHEME 4. Synthesis of racemic physostigmine. The Speckamp approach
232
SEIICHI TAKANO AND KUNIO OGASAWARA
of five steps (19). Nitration of 47 with fuming nitric acid in acetic acid gave the desired nitro-imide 48 in 40% yield accompanied by the regioisomer 49 in 25% yield. Alkyiation of 48 with methyl iodide in the presence of potassium carbonate occurred regioselectively at the benzylic carbon to afford the single product 50 in 85% yield. Reduction of 50 with sodium borohydride in the presence of hydrochloric acid (NaBH4/Ht), the conditions established by Speckamp and co-workers (18,20), occurred at the more crowded site in a 3 : 1 selection to give a mixture of the regioisomers from which the desired carbinol-lactam 51 could be obtained in 60% yield after separation of the regioisomer 52 by recrystallization. After catalytic hydrogenation of 51, the resulting amine 16 was treated with acetic formic anhydride at 0°C to give the tricyclic N8-formyl compound 54 in 74% yield in one step via concomitant formation of the acyliminium intermediate 53 and cyclization. On reduction with LiAIH4 54 furnished racemic eserethole 55 in 74% yield which had previously been converted to racemic physostigmine (1) (1,2) (Scheme 4). c. Synthesis of Racemic Physostigmine via the Fischer Indolization Route. As apparent from the first synthesis of physostigmine (1) by Robinson and co-workers in the early 1930s (21), the Fischer indolization approach is one of the most straightforward routes to construct the alkaloid framework. In 1975, Rosenmund and Sotiriou reported the synthesis of ethyl 3-formylbutyrate (61) and its transformation to the physostigmine framework by the Fischer indolization reaction (22). In 1979, Rosenmund and Sadri disclosed a synthesis of racemic physostigmine (1) starting from the same aldehyde 61 and employing a slight modification of the established procedure (23). The synthesis seemed to be very practical since the conversion could be carried out neatly from the aldehyde (61) in good overall yield. Ethyl 3-formylbutyrate (61) was prepared in 15% overall yield from ethyl crotonate (56) by sequential hydrobromination, cyanation, reductive amination with N,N'-diphenylethylenediamine(59) in the presence of Raney nickel catalyst, and acid-catalyzed hydrolysis as shown in Scheme 5. The phenylhydrazone 63 obtained from 61 with the phenylhydrazine 62 was stirred in ethanolic hydrogen chloride at 40°C for 90 min, followed by alkaline hydrolysis of the initially produced indolenium ester 64 to yield the tricyclic lactone 66 in one step in 72% yield via the hydroxyindolinecarboxylate 65 after acid work-up. Condensation of 66 with methylamine followed by reduction of the resulting lactam 67 with LiAIH4 afforded racemic eserethole (55) in 82% yield (Scheme 5). Although yield of the starting aldehyde 61 requires improvement, this synthesis seems to be quite practical since it could be carried out neatly in 59% overall yield
233
5 . ALKALOIDS OF THE CALABAR BEAN
\/&yoEf HBr-AcOH 0
. moEt .yF;02E KCN
0-5 "C, 3 h
0
Br
56
CN 0
96%EtOH 75 o c
57 98%
58 42-45%
P h N H b N H P h 59
20% HCI
AcOH, MeOH Raney nickel
U
H2
0
OHC
60
61
35%overall
EtoYl \
62
N-NH2 Me
. Eton N-N-
A C 0 2 E t
HC'
63
EtOH -40 "C, 90 min then 40% KOH acid work up
I
Me
. ; ~\ c No 2OH- ] Me 65
Eton%~ --. known
\
Me 66
-
I
I
Me 64
b
N N I H I Me Me 67
(+)-physostigmine (1)
O
72% from 6 1
SCHEME 5. Synthesis of racemic physostigmine. The Rosenmund approach.
in three steps to give eserethole (55). Conversion of 55 to physostigmine (1) had already been established (1,2). d. Synthesis of Natural (-)-Physostigmine via the Enantiocontrolled Route. Alkaloids used in medicine such as (-)-physostigmine (1)occur in nature in one specific enantiomeric form, and generally only the specific enantiomer shows biological effects. Enantiocontrol is, therefore, a critical factor in the synthesis of biologically active natural compounds.
234
SEIICHI TAKANO A N D KUNIO OGASAWARA
The first enantiocontrolled synthesis of the natural ( - ) enantiomer of physostigmine (1)was achieved by Takano and co-workers in 1982 (24)by employing the chirality transfer method they established (25). Starting from (-)-(S)-0-benzylglycidol (21) (26). accessible efficiently in large amounts from D-mannitol (271, the synthesis involved stereoselective methylation of the chiral lactone (69) in the key step where the original chirality of the starting material was efficiently transferred to the chiral quaternary center of the alkaloid with the requisite stereochemistry. The synthesis, however, is unsatisfactory due to nonregioselectivity in the nitration step at a later stage. Condensation of 21 with the phenylacetonitrile (22) followed by alkaline hydrolysis afforded the y-lactone 69 in 63% overall yield as an 1 : 1 epimeric mixture. Methylation of the lithium enolate 70 generated in situ from 69 furnished a 8 : 1 mixture of the lactones 23 and 71 which were readily separated by a single column chromatography step to give 23 in 80% yield together with an 11% yield of the unwanted epimer 71. The observed overwhelming formation of the former lactone (23) indicated that the alkylation occurred mainly on the side remote from the benzyloxymethyl group of the enolate intermediate 70. After removal of the unwanted group of 23, the chiral lactone 72 obtained was transformed to the lactam 73 in 78% overall yield. On nitration with copper(I1) nitrate in acetic anhydride (28) 73 yielded a mixture of three regioisomers 74, 75, and 76 from which the requisite amine 77 could be isolated in a pure state in 38% overall yield by chromatographic separation from the unnecessary regioisomers after catalytic hydrogenation. Treatment of 77 with LiAIH4 afforded the tricyclic aminal 79 with the alkaloid framework directly in 60% yield via concomitant reductive cyclization. Reductive methylation of 79 with 30% formalin and sodium cyanoborohydride gave (-)-esermethole (41) which was further converted to (-)-eseroline (15), the penultimate intermediate of (-)-physostigmine (1) (29), on exposure to boron tribromide in rnethylene chloride (Scheme 6). Since an efficient synthesis of (+)-(R)-0-benzylglycidol (21) (30)has also been established, the pharmacologically interesting unnatural (+)-physostigmine (1) may also be obtained by the same methodology. e. Synthesis of Racemic Physostigmine via the Intramolecular 1,3Dipolar Addition Route. An ingenious synthesis of racemic physostigmine (1) by a fundamentally new methodology making use of an intramolecular 1.3-dipolar cycloaddition was devised in 1983 by Smith and Livinghouse (31). These authors retrosynthetically dissembled the alkaloid into an unprecedented olefin-formamidine l ,3-dipolar species like 25 (Scheme 7). Assemblage of the alkaloid framework based on their
o x O B n
-.
LDA
235
5 . ALKALOIDS OF THE CALABAR BEAN
.
Meo&OBn
M e o W C N
21
KOH-EtOH M e 0 acid work up
\
68
22
69 OBn 63% overall
THF, -78 "C-rt
LDA
Me1 THF -78 "C-rt
I
OBn
23 1)
71
H,/Pd-C, HClOd (cat)
2) KOH-MeOH, then NalO, then NaBH,. acid work up
180 "C sealed tube
72
Me
73
0,
Me 72% 76
19%
5-10 "C
Me
75
Me 74 I
I
t
Me 378 0
77
38%
SCHEME 6. Synthesis of (-)-physostigmine. The Takano approach
OBn
236
SEIICHI TAKANO A N D K U N I O OGASAWARA
25
1 SCHEME
7
retrosynthetic analysis was realized by employing organosilicon chemistry which allowed concurrent generation of the expected formamidine 1,3-dipolar intermediate and internal cycloaddition toward the nonactivated double bond in a single operation. The aminoolefin (82) obtained from the acetanilide 80 in a three-step sequence of reactions was converted to the formamide 83 in 88% yield by sequential formylation and methylation. Treatment of 83 with methyl trifluoromethanesulfonate followed by trimethylsilylmethylamine gave the formamidine 84 in 77% yield. Methylation of 84 with methyl trifluoromethanesulfonate, followed by exposure of the resulting salt (24) to tetra-n-butylammonium fluoride brought about a facile generation of the 1,3-dipolar species 25 and concurrent intramolecular cyclization to furnish racemic eserethole (55) in 70% yield (Scheme 8). This method may be widely applicable to the synthesis of numerous natural products which contain the pyrrolidine ring. f. Synthesis of Racemic Physostigmine via the Isochromanone Route. Fukumoto and co-workers (32) discovered an interesting tandem electrocyclic [3,3]-sigmatropic rearrangement giving rise to high yields of the 4,4-disubstituted isochroman-3-ones when the allyl esters of certain benzocyclobutenecarboxylic acids were heated under reflux in o-dichlorobenzene. As shown in Scheme 9, reaction of the benzocyclobutene 26 proceeded with concurrent generation of the o-quinodimethane intermediate 86, electrocyclic cyclization to the keteneacetal 87, and [3,3]-sigmatropic rearrangement to furnish the isochromanone 26 in a single operation. Utilizing the isochromanone 26, the same authors obtained intermediate 95 (8)common to the synthesis of the Calabar bean alkaloids physostigmine (1)as well as physovenine (4) and geneserine (5). Thus, 4-allyl-6-methoxy-4-methylisochroman-3-one (26) obtained in 100% yield from the thermolysis of allyl 1,2-dihydro-5-methoxy-lmethylbenzocyclobutene-1-carboxylate(86) in o-dichlorobenzene, was first reduced to the diol88 with LiAIH4 (Scheme 10). After having trapped one of two hydroxy groups of 88 selectively as the bromoether 89 on treatment with N-bromosuccinimide in tetrahydrofuran, the remaining benzylic alcohol group was first oxidized with Jones reagent to give the
237
5 . ALKALOIDS OF THE CALABAR BEAN
Y-COCH, H ..
80 1) BnOCHO
Me
Me
24
-.
25
“‘a&)
known
(&)-physostigmine(1)
\
I H I Me Me W-eserethole f551
SCHEME8. Synthesis of racemic physostigmine. The Livinghouse approach.
L
85
86
[3,3]-sigmatropic reaction
87
M
e
O
V
26
SCHEME9. Tandem sigmatropic formation of the isochromanone (26) from the benzocyclobutene (85).
238
SEIICHI T A K A N O A N D K U N I O OGASAWARA
;;;"M 0 ;e 0 -
26
\
___)
M
e
O
\
OH 88
q
y(oJ,
OH 89
+ Br
Me
H 94
Y O
90 : X=H 91: X=OH 92: X=N3
ii
93
95
96
Mead known
\
HVo' R
?
Me
97: R=C02Me 77: R=H
\
-
(f)-physostigmine (1)
I H I Me Me (t)-esermethole (41)
SCHEME 10. Synthesis of racemic physostigmine. The Fukumoto approach.
aldehyde 90 which then was further oxidized with sodium chlorite in the presence of sulfamic acid (33) to produce the carboxylic acid 91 in 81% overall yield from 88. The Curtius-type reaction using diphenylphosphoryl azide (34) 91 furnished the carbamate 93 in quantitative yield in one step. When the Curtius process was carried out under standard conditions (35)via the corresponding acyl azide intermediate 92, the yield of 93 was decreased to 48%. Compound 93 was then converted to the key oxindole 95 in satisfactory overall yield by sequential reductive cleavage of the bromoether bond with zinc-copper and oxidation of the resulting alcohol 94 with pyridinium dichromate. Oxidative cleavage of the double bond of 95 with sodium periodate and osmium tetroxide followed by reductive amination of the resulting aldehyde with methylamine hydrochloride and sodium cyanoborohydride
5 . ALKALOIDS OF THE CALABAR BEAN
239
afforded the lactam carbamate 97 via concommitant intramolecular nucleophilic cleavage of the imide bond of 96 by the secondary amino group in the molecule (36). Selective cleavage of the carbamate bond using a complex of dimethyl sulfide and aluminum chloride (37) gave the known amino lactam 77, in 40% overall yield from 95, whose conversion to physostigmine (1) had already been accomplished (24). Although this synthesis required rather lengthy steps from the starting isochromanone 26, the reported overall yield of the final product was not low. As mentioned in Sections II,B,2,b and III,B,3,a, it should be mentioned that the intermediate lactam 95 was utilized by the same authors as the key intermediate in the synthesis of two other Calabar bean alkaloids, physovenine (4) and geneserine (5). g. Synthesis of Racemic Physostigmine via the Improved Oxindole Alkylation Route. Total synthesis of physostigmine (1) by Julian and Pikl in 1935 (38) was accomplished from the cyano-oxindole 13 by catalytic reduction to the amine 99, its three-step conversion to 100, followed by reductive cyclization to eserethole (55) using sodium in ethanol. This reductive cyclization required large amounts of sodium and ethanol which made the original method very impractical. However, Yu and Brossi (39) established an improved version of the Julian synthesis using the methoxy analog (98) of Julian's starting material 13. Thus, the carbamate 102, obtained quantitatively from amine 101, was refluxed with LiAlH4 in tetrahydrofuran to afford racemic esermethole (41) in 82% yield in one step by concurrent reduction of the carbamate group and reductive cyclization. Similarly, they also achieved direct conversion of the cyanide 98, the precursor of the amine 101, to N'-noresermethole (103) in 80% yield. Racemic esermethole (41) could also be obtained in 80% yield from 103 by carbamoylation followed by reduction of the resulting 104 with LiAlH4 (Scheme 1 I ) . Synthesis of N'-noresermethole (103) also implies a formal synthesis of eseramine (3), since the conversion of 103 to 3 had previously been established (40).
h. Synthesis of Natural (-)- and Unnatural (+)-Physostigmine via the Improved Oxindole Alkylation Route. Prior to the above-mentioned efficient synthesis of racemic esermethole (41) and N'-noresermethole (103), Schonenberger and Brossi (41) developed an efficient method for resolution of racemic N'-noresermethole (103) obtained by the original Julian method (38). Reaction of racemic N'-noresermethole (103) with (-)-(S)-( I -phenylethyl)isocyanate afforded the less polar (+)-urea 106 and the more polar (-)-urea 105 in 37 and 40% yield, respectively, after chromatographic separation of the product obtained as a mixture of diastereomers. The ureas 105 and 106 decomposed cleanly in refluxing
240
SEIICHI T A K A N O A N D KUNIO O G A S A W A R A
I
Me 13: R=Et 98: R=Me
Me
99 : Rl=Et, R,=H 1 0 0 : R,=Et, R,=Me 101 : R,=Me, R,=H 1 0 2 : R,=Me, R,=CO,Et
I
I Me
R,
(f)-esermethole (41): R,=R,=Me (f)-eserethole (55): R,=Et, R,=Me (k1-N I-noresermethole (103 ): Rl=Me, R,=H
104: R,=Me. R,=CO,Et
SCHEME 1 1 . Synthesis of racernic physostigmine. The Brossi approach.
I M sodium pentyloxide in n-pentyl alcohol within 1 hr, affording as the basic materials (+)-N'-noresermethole (103) and (-)-N'-noresermethole (103), respectively, which were isolated as the oxalate salts. Since an improved method which could efficiently produce racemic N'-noresermethole (103) had been established by the same authors' group Me 1) (3-PhCHNCO (104) M e I.
MeoO+~
0
0 J Me ,
\
YHY Me H (?)-lo3
2) separation
\
H Me
Meoom Me
and Me* CONHCHPh
(-)-lo5
\
y ye.
NH Me CONHCHPh (+)-lo6
MeooqJ *
(+)-lo5 nC5H11 0 N a nC5H1 10H,reflux
YHN Me H
(+)-lo3
Me Me (+)-esermethole (41): R=Me (+)-eseroline(15): R=H (+)-physostigmine (1): R=MeNHCO
SCHEME 12. Synthesis of (+)-physostigmine. The Brossi approach.
24 I
5. ALKALOIDS OF THE CALABAR BEAN
(see Section III,B, 1 ,g) both enantiomers of physostigmine (1) became readily available in large amounts applying the resolution method described here. Thus, the fumarate salt of (+)-N'-noresermethole (103), obtained from the less polar urea 106, was treated with formaldehyde and triethylamine followed by sodium borohydride to afford (+)-esermethole (41) in 62% yield by reductive methylation. The unnatural (+) enantiomer of physostigmine (1) could be obtained in 73% overall yield from 41 by de-0-methylation with boron tribromide followed by carbamoylation of the resulting (+)-eseroline (15) with methyl isocyanate (42) (Scheme 12). The same authors' group also disclosed a practical synthesis of natural (-)-physostigmine (1) starting from the fumarate of ( -)-N'noresermethole (103) obtained from the more polar urea 105 by employing a slightly different procedure which could also produce pharmacologically interesting N'-substituted-N'-norphysostigmines and another Calabar bean alkaloid, (-)-eseramine (3) (43). Thus, the fumarate of ( - ) - N ' noresermethole (103) was first treated with benzyl bromide in the presence of sodium hydrogen carbonate to give (-)-N'-benzyl- 1noresermethole (107) which was then converted to Nl-benzylnorphysostigmine (1) in 48% overall yield by sequential de-0-methylation to 108 and its carbamoylation to 109. Hydrogenolytic debenzylation of 109 using palladium hydroxide on carbon afforded (-)-N'-norphysostigmine (110), in 72% yield, which furnished natural (-)-physostigmine (1)in 63% yield on reductive methylation with formalin and sodium borohydride. Natural (-)-eseramine (3) was obtained in 98% yield on carbamoylation of 110 with methyl isocyanate (Scheme 13). Because derivatives of both natural
(-)-lo6
nC5H1, ONa nC5Hl 10H, reflux
-UqJI H I Me H
(-)-lo3
107: R=Me 108: R=H 109: R=MeNHCO
110: R=H
(-)-physostigmine (1): R=Me (-)-eseramine (3): R=MeNHCO
SCHEME 13. Synthesis of (-)-physostigmine. The Brossi approach.
242
SEIICHI TAKANO AND KUNIO OGASAWARA
and unnatural antipodes of physostigmine (1) as well as eseroline (3) are expected to exhibit interesting physiological activities, this synthesis may be particularly useful for pharmacological investigations. 2. Synthesis of Physovenine Since physostigmine (1) is known to be transformed to physovenine (4) ( 6 ) , the aforementioned syntheses of physostigmine (1) imply formal routes to 4. However, two direct syntheses of racemic physovenine (4) have been established since 1970. a. Synthesis of Racemic Physovenine via the Indole Alkylation Route. Although alkylation of the oxindole 29 with ethylene oxide in the presence of sodium ethoxide produced the primary alcohol 111 which was convertible to physovenine (4) via 113 (44), it has been reported that reaction of the Grignard derivatives of the corresponding indole derivative 112 failed to yield the product with physovenine framework 114 on treatment with alkylating agent (45) (Scheme 14). However, Onaka (46)
MeomMe -Meoe 0
L l
\
N Me 29
O
NaOEt in EtOH
\
y
o
Me 111
NdEtOH
I
H 112
MeMgl R, 113: R,=R,=Me
Me (+)-physovenine (4)
114: R,=Bn, R,=H SCHEME
14
first succeeded in obtaining the intermediate 117 of physovenine (4), though in low yield, by alkylating the Grignard derivative generated from 5-methoxy-3-methylindole(115) with ethylene oxide. Thus, treatment of 115 with methylmagnesium iodide followed by an excess amount of ethylene oxide in ether at room temperature afforded directly the tricyclic aminoacetal 117 in 13% yield after chromatographic purification. Treat-
5. ALKALOIDS OF THE CALABAR BEAN
243
ment of 117 with methyl iodide in the presence of sodium hydride gave the known compound 113, in 36% yield, which had previously been converted to racemic physovenine (4) (44) (Scheme 15).
MeowMe MeMgl
then
H
Et,O,
7
rt. 4 h
116
115
known
.
(+)-physovenine (4)
k 117: R=H (13%) 1 1 3 : R=Me (36%)
SCHEME15. Synthesis of racemic physovenine. The Onaka approach.
b. Synthesis of Racemic Physovenine by the Isochromanone Route. Fukumoto and co-workers synthesized racemic physovenine (4) using the same intermediate 95 used in the synthesis of physostigmine (1) (8a).Ozonolysis of 95, obtained from the isochromanone 26,followed by reduction of the ozonide mixture with sodium borohydride gave the diol 118 as a diastereomeric mixture with concomitant reduction of the imide carbonyl group in the molecule. On treatment with p-toluenesulfonic acid in methylene chloride the mixture furnished the tricyclic carbamate 119 in 86% overall yield from 95. Reduction of 119 with LiAIH4 did not yield the desired N-methyl derivative 113 but the secondary amine 117. The latter could be transformed to amine 113 in excellent overall yield on reductive methylation with formalin and sodium cyanoborohydride. Cleavage of the methyl ether group of 113 with boron tribromide followed by treating the resulting phenol 120 with methyl isocyanate afforded racemic physovenine (4) in 83% yield (Scheme 16). 3 . Synthesis of Geneserine
a. Synthesis of Racemic Geneserine via the Isochromanone Route. Since the first isolation of geneserine (5) by Polonovski in 1915 (12), it was not until 1969 that its structure was determined unambiguously as a tetrahydro- 1,2-oxazine by Hootele based on physicochemical examination which ruled out the originally proposed structure 121, the N-oxide of physostigmine (1) (9,10). However, Brossi and co-workers
244
SEIICHI TAKANO AND KUNIO OGASAWARA
95
118
113: R,=R2=Me 1 1 9 : R,=Me. R,=CO,Me 117: R,=Me, R,=H 1 2 0 : R,=H, R,=Me (*)- physovenine (4): R,=MeNHCO, R,=Me
SCHEME 16. Synthesis of racemic physovenine. The Fukurnoto approach.
later found that the N-oxide 121 really did exist as the salt 121a with the stereochemistry shown (X = CI) when geneserine (5) was treated with acid. They also observed that the salt reverted to geneserine (5) on exposure to base, indicating the intervention of an indolenium intermediate 122 under both acidic and basic conditions. Similarly, genesoline (5; MeNHCO = H) formed the N-oxide structure (121; MeNHCO = H) on exposure to acid (11) (Scheme 17). Although it was possible to transform physostigmine (1) to geneserine (5) by simple oxidation (7,8,11), the first total synthesis of racemic geneserine (5) was accomplished in 1986 by Fukumoto and co-workers using the same oxindole intermediate 95 used for the synthesis of
Me 5
121
122
121a
SCHEME 17
245
5. ALKALOIDS OF THE CALABAR BEAN
physostigmine (1) and physovenine (4) (47). Since selective manipulation of the methyl groups was found to be very difficult in later stages of the synthesis, 95 was first exposed to the complex generated from dimethyl sulfide and aluminum bromide (37) to afford the phenol-lactam 123a by spontaneous de-0-methylation and decarbomethoxylation. Double alkylation of 123a with methyl iodide in the presence of sodium hydride followed by de-0-methylation of the resulting dimethyl-lactam 123b with boron tribromide gave the N-methylphenol 123c which was treated with methyl isocyanate to furnish the carbamate 124 in satisfactory overall yield. Cleavage of the vinyl bond of 124 followed by reductive hydroxylamination of resulting aldehyde 125 afforded the hydroxylamine 126 in good overall yield. Finally, partial reduction of 126 with diisobutylaluminum hydride furnished directly racemic geneserine (5) via spontaneous cyclization of the carbinol amine intermediate 127, although the conversion ratio was not high (-35%). The yield of the final step was 75% based on consumption of the starting material (Scheme 18).
1) Me,SAIBr3 2) NaH,Mel
MeNCO
3) BBr3 C0,Me
R2
123a : R1=R2=H 123b : Rl=R2=Me 123C : Rl=H, R,=Me
95
M
e
N
H
C
O
e
1) Na10,-0s04
M e b $ C ) e / ; O H
2) MeNHOH,NaBH3CN I
Me
'
N
O
I
Me
1 2 4 : X=CH2 1 2 5 : X=O
L
'
126
127
J
(f)-geneserine (5)
SCHEME 18. Synthesis of racemic geneserine. The Fukumoto approach
246
SEIICHI TAKANO AND KUNIO OGASAWARA
b. Synthesis of Racemic Geneserine via the Radical Cyclization Route. Synthetically, the isochromanone route seemed to be far from practical since it took too many steps to reach the key intermediate l23b from the starting material via the chromanone intermediate 26 even though interesting chemistry was involved. Recently, a much shorter and more concise route to the key intermediate 123b was devised by Jones and co-workers (48) that exploits intramolecular radical cyclization as the key step. The unsaturated amide 28 obtained from the nitrobenzene 128 in three steps was cyclized to give the known oxindole 29 (44) in 63% yield via the radical intermediates 129 and 130 on treatment with 1 equiv of tri-n-butyltin hydride in refluxing toluene (49). Treatment of 29 with ally1 bromide in the presence of lithium hexamethyldisilazide afforded the key intermediate 122 of the Fukumoto synthesis in 88% yield (Scheme 19).
28
129
MeomM ' y o Me 29
130
Fukumoto synthesis -
\
+ (+)-geneserine (5)
y o Me 122
SCHEME 19. Synthesis of racernic geneserine. The Jones approach
This method, however, is still not practical from a synthetic point of view, because a much more efficient synthesis of 29 and an equivalent oxindole 12 of the Jones synthesis had already been established in 1935 by Julian and Pikl starting from p-ethoxyacetanilide (131) and employing the intramolecular Friedel-Crafts reaction in the synthesis of physostigmine (1) (38,44)(Scheme 20).
247
5 . ALKALOIDS OF THE CALABAR BEAN
1 ) Na. Me,SO,.
EtO
,
'Q,,,
A 2.
xylene
2) KOH, aq. EtOH
*
EtO0BrLMe
\
3) CH3CHBrCOBr
N
H
Me
131
132
O
alkylation "
O ' mN IM O e
I Me
Me 133
80%from 1 3 1
12: R=Et 29: R=Me
SCHEME 20. Synthesis of the 3-methyloxindoles. The Julian approach.
IV. Pharmacology The well-known pharmacological effects of (-)-physostigmine (1) are based on inhibition of acetylcholinesterase (50). (-)-Physostigmine (1)is used clinically in the treatment of glaucoma (51) and myasthenia gravis (52) and for protection against organophosphate poisoning (53).It has also been reported that oral and intravenous administration of (-)-physostigmine (1) significantly improved memory in patients with Alzheimer's disease (54). However, opposite results have also been reported (55). Brossi and co-workers (43)examined the anticholinesterase activity of (-)-N1-norphysostigmine (110), (-)-eseramine (3), and other N'substituted analogs of (-)-physostigmine (1) which were prepared readily by their synthetic method (39,4143).Among these (-)-NI-norphysostigmine (110) was found to be as potent as (-)-physostigmine (1). In uitro inhibition of acetyl- (AChE) and butyryl- (BChE) cholinesterases was also examined using carbamate analogs of (-)-physostigmine (l),and the carbamates 134,135, and 136 were all more than three times more potent against human plasma BChE than (-)-physostigmine (1) (56). Enantiomeric comparison of the physiological activities of natural (-) and unnatural (+) enantiomers of physostigmine (1) together with related compounds has also been investigated by Brossi and co-workers (57). It was found that unnatural (+)-1 inhibits acetylcholinesterase from electric eel considerably less than natural (--)-1, but the unnatural antipode exhibits lower toxicity (57) and blocks the open channel of the nicotinic
248
SEIICHI T A K A N O A N D K U N I O OGASAWARA
134 : R=n-octyl 135 : R=n-butyl 136 : R=benzyl
"3" Me Me 139a
138 137 : X=H 140 : X=Br
Me' 'd 139b
acetylcholine receptor (42). Furthermore, the unnatural antipode was found to prevent organophosphate-induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamoylation (58). (-)-Eseroline (W), a major metabolite of (-)-physostigmine (l),was found to be an analgesic with a potency similar to that of natural morphine (59). This finding prompted an extensive pharmacological comparison of both enantiomers of eseroline (15) and derivatives which became readily available through the development of an efficient synthesis of (-1 and (+) enantiomers of N'-noreseroline (15) ( 3 9 , 4 1 4 3 ) . Brossi and co-workers (60)found that both enantiomers of eseroline (15) bind to opiate receptors of rat brain membranes with equal affinity and show opiate agonist properties as inhibitors of adenylate cyclase in uiuo. They confirmed, however, that only (-)-eseroline (15) shows potent narcotic activity enantiospecifically similar to that of morphine, but neither (+)-eseroline (15) nor natural forms of both N'-noreseroline (137) and the open dihydroseco analog 138 show analgesic effects (60,61). Eseroline (15) in solution is extremely sensitive to autooxidation, forming red dyes, with rubreserine (139) as the major constituent (62). In relation to pharmacological investigations, Brossi and co-workers unambiguously determined its structure by X-ray diffraction analysis as a resonance hybrid of the mesomers 139a and 139b (60). (- )-7-Bromoeseroline (140), prepared from (-)-physostigmine (1) by sequential bromination with N-bromosuccinimide and alkaline hydrolysis, was reported to be a potent, centrally acting analgesic, with excellent oral activity and stability, and superior to morphine in its antinoceptive effects in rodents with significantly reduced side effects (63).
5. ALKALOIDS OF THE CALABAR BEAN
249
Acknowledgments
We thank Drs. Masahiro Yonaga and Kozo Shishido for helpful suggestions and Miss Reiko Ono for preparation of the manuscript. We are also grateful to Dr. Arnold Brossi who gave us valuable reference articles and kind suggestions.
REFERENCES
1. L. Marion, in “The Alkaloids” (R. H. F. Manske. ed.). Vol. 2. pp. 438-450. Academic
Press, New York, 1952. 2. E. Coxworth, in “The Alkaloids” (R. H. F. Manske. ed.), Vol. 8. pp. 27-46. Academic Press, New York, 1965. 3. B. Robinson, in “The Alkaloids” (R. H. F. Manske and H. L. Holmes eds.). Vol. 10. pp. 383-401. Acadmic Press, New York, 1967. 4. B. Robinson, in “The Alkaloids” (R. H. F. Manske and H. L. Holmes. eds.). Vol. 13, pp. 213-226. Academic Press, New York, 1971. 5. W. Doepke, Nutirru~i,s.sen.sc~iiuftrn 50, 713 (1963). 6. M. Polonovski and M. Polonovski, B i t / / . Soc. Cliirn. Fr. 141 23, 335 (1918). 7. M. Polonovski and M. Polonovski, Bid1 So(,. Clrirn. (41 37, 744 (1925). 8. a . K. Shishido, K. Hiroya. H. Komatsu. and K. Fukumoto. J. Chern. Soc., Perkin Trans. 1 . 2491 (1987): b. M. Nakagawa, K. Yoshikawa. and T. Hino. J. A m . Chern. Soc. 97, 6496 (1975). 9. C. Hootele, Tetrulirdron Lett., 2713 (1969); F. G. Riddell, D. A. R. Williams, C. Hootele, and N. Reid, J. Chern. Soc. B . 1739 (1970). 10. B. Robinson and D. Moorecroft. J. Chem. Soc. C. 2077 (1970). I I . Q . 3 . Yu, H. J . C. Yeh, A. Brossi, and J . L. Flippen-Anderson, J. Nut. Prod. (in press). 12. M. Polonovski and C. Nitzberg, Brill. Soc. Chirn.Fr. 141 17, 244 (1915). and references therein. 13. D. A. Seeley, J. A m . Chern. Soc. 94, 4378 (1972); H. Heimgartner. H.-J. Hansen and H. Schmid, Helu. Cliirn. Actci 55, 3005 (1972). 14. M. Ikeda, S. Matsugashita, and Y. Tamurd,J. Chem. Soc.. Perkin Trcins. 1 . 2587 (1976); M. Ikeda, S. Matsugashita. F. Tabusa, and Y. Tamura. ibid.. I166 (1977). 15. M. Ikeda, S. Matsugashita, and Y. Tdmura. J . Cheni. Soc.. Perkin Trcrns. 1 . 1770(1977). 16. F. D. Popp, L. E. Katz, C. W. Klinowski. and J . M. Wefer. J. O r g . Chern. 33, 4477 (1968). 17. J . B. P. A. Wijnberg and W. N. Speckamp, Tetruhedron 34, 2399 (1978). 18. H. Hiemstra and W. N. Speckamp, in “The Alkaloids” (A. Brossi. ed.), Vol. 32, pp. 271-339. Academic Press, San Diego, California. 1988. 19. K. Sen and P. Bagchi, J. Org. Chem. 20, 845 (1955). 20. J. C. Hubert, J . B. P. A. Wijnberg, and W. N. Speckamp, Tetruliedron 31, 1437 (1975). 21. R. Robinson and H. Suginome, J. Cliern. Soc.. 298. 304 (1932): F. E. King, M. Liquori, and R. Robinson. ihid., 1475 (1933); F. E. King. R. Robinson. and H. Suginome, ihid.. 1472 (1933). 22. P. Rosenmund and A. Sotiriou, Chern. Ber. 108, 208 (1975). 23. P. Rosenmund and E. Sadri, Liehigs A n n . Cliern., 927 (1979).
250
SEIlCHl TAKANO .4ND KUNIO OGASAWARA
24. S . Takano, E. Goto. M. Hirama, and K. Ogasawara, Chem. Pharm. Bull. 30, 2641 ( 1982). 25. S. Takano and K. Ogasawara, J. Syrith. O r g . Chem. J p n . 40, 1037 (1982): S. Takano, Pure Appl. Chem. 59, 353 (1987). 26. S. Takano, M. Akiyama. and K. Ogasawara. Synthesis, 503 (1985). 27. S . Takano and K. Ogasawara, J. S y n t h . O r g . Chem. J p n . 45, 1157 (1987). 28. F . A. Carey and R. M. Giuliano, J. O r g . Chem. 46, 1366 (1981). 29. M . Polonovski and C. Nitzberg, Bull. Soc. Chim. Fr. [4/ 19, 33 (1916). 30. S. Takano. K. Seya, E. Goto. M. Hirama, and K. Ogasawara. Synthesis, I16 (1983). 31. R. Smith and T. Livinghouse. J. O r g . Chem. 48, 1554 (1983): Tetruhedron 41, 3559 (1985). 32. K. Shishido. E. Shitara, K. Fukumoto, and T. Kametani, J . A m . Chem. Soc. 107, 5810 (1985). 33. B. 0. Lindgren and T. Nilsson, Actu Chem. Sctrnd. 27, 888 (1973). 34. K. Ninomiya, T. Shioiri, and S. Yamada. Tetruhedron 30, 2151 (1974). 35. A. Arrieta. J. M. Aizpurua. and C . Palomo, Tetruhedron Lett. 25, 3365 (1984). 36. D. L. Flynn, R. E. Zelle, and P. A. Grieco, J. Org. Chem. 48,2424 (1983). 37. M. Node, K. Nishide, M. Sai, K. Fuji, and E. Fujita, J . Org. Chem. 46, 1991 (1981). 38. P. L. Julian and J. Pikl. J. Am. Cheni. Soc. 57, 563 (1935). 39. R.-S. Yu and A. Brossi. Heterocycles 27, 1709 (1988). 40. B. Robinson, Chem. Ind. (London), 87 (1965): J . Chem. Soc. 3336 (1965). 41. B . Schonenberger and A. Brossi, Helu. Chim.Actu 69, 1486 (1986). 42. R.-S. Yu and A. Brossi. Heterocycles 27, 745 (1988). 43. R.-S. Yu, J. R. Atack, S. I. Rapoport, and A. Brossi, J. M e d . Chem. 31, 2297 (1988). 44. R. B . Longmore and B. Robinson, C h e m . Ind. (London), 1297 (1965). 45. R. B. Longmore and B. Robinson, Collect. Czech. Chem. Commrrn. 32, 2184 (1967). 46. T. Onaka, Tetruhedron L e t t . . 4391 (1971). 47. K. Shishido, K. Hiroya, H. Komatsu. K. Fukumoto, and T. Kametani, J. Chem. Soc., C h e m . Commrm., 904 (1986); J . C h e m . Soc.. Perkin Truns. 1 . 2491 (1987). 48. C . Wright, M. Shulkind. K. Jones, and M. Thompson, Tetruhedron L e t t . 28, 6389 (1987). 49. K. Jones, M. Thompson, and C . Wright, J. Chem. Soc., Chem. Commun., 904 (1986). 50. G. B. Koelle, in "The Pharmacological Basis of Therapeutics" (R. S. Goodman and A. Gilman, eds.), 5th ed., pp. 445-466. Macmillan. New York, 1975. 51. Uj. Axelsson, Actci Ophthalmol., Suppl. 102, 1 (1969). 52. M. B. Walker. Proc. R. Sor. M e d . 1, 1200 (1934). 53. S. S. Deshpande, G. B. Viana, F . C . Kauffman, D. L . Rickett, and E. X. Albuquerque, Fundam. Appl. To.roco1. 6, 566 (1986). 54. R. C . Mohs, B. M. Davis, C . A. Johns, A. A. Mathe, B. S. Greenwald, T. B. Horvath, and K. L. Davis, Am. J . Psychiutry 142,28 ( 1 9 8 3 , and references therein: R. C. Mohs, B. M. Davis, B. S. Greenwald, A. A. Mathe, C. A. Johns, T. B. Horvath, and K. L. Davis, J. A m . Gerintr. Soc. 33, 749 (1985). and references therein: S. A. Beller, J. E. Overall, and A. C. Swann, Psychopharmacology 87, 147 (1985). and references therein. 55. C. Caltagirone, G. Gainotti, and C. Masullo, In/. J. Neurosci. 247 (1982). and references therein: S. Jatkowitz. Ann. Nerrrol. 14, 690 (1983), and references therein: A. Agnoli, N. Martucci, V. Manna, L. Conli, and M. Fioravanti, Clin. Neurophormucol. 6, 311 (1983). 56. Q.3. Yu, J. R. Atack, S. I. Rapoport, and A. Brossi, FEBS L e t t . 234, 127 (1988). 57. A. Brossi, B. Schonenberger. 0. E. Clark, and R. Ray, FEBS Lett. 201, 3708 (1986). 58. M. Kawabuchi, A. F. Boyne, S. S. Deshpande. W. M. Cintra, A. Brossi, and E. X. Albuquerque, Synripse 2, 139 (1988).
S. ALKALOIDS OF THE CALABAR BEAN
25 I
59. S. Fiirst, T. Friedmann, A . Bartolini, R . Bartolini, P. Aiello-Malmberg. A . Galli. G . T. Somogyi, and J . Knoll, Eur. J . Phurmocol. 83, 233 (1982). 60. B . Schonenberger, A . E. Jacobson, A. Brossi, R . Streaty. W. A . Klee, J . L. Flippen-Anderson, and R . Gilardi, J . M e d . Chem. 29, 2268 (1986). 61. A . Brossi, J . Nut. Prod. 48, 878 (1985). 62. J . 0 . Jobst and 0 . Hesse, Ann. Chem. Phorm. 129, 115 (1864). 63. E. J. Glamkowski, R . R. L . Hamer. Y . Chiang, K. W. Locke, F. P. Huger, R. S. Hsu. and G . C . Helsley, Ahstr. Pup. 197th ACS-Meet., Am. Chem. Soc.. M e d . Chem. Sect. No. 28, (1988).
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- Chapter 6 CHEMISTRY OF MELANINS RAIMONDO CRIPPA University of Parma Parma. Itulv
VACLAVHORAK Georgetonv University Washington, D . C . 20057
GIUSEPPE PROTA University of Naples Naples. Italy
PARISSVORONOS Queensborough College of fhe Cify University of N e w York Bayside, N e w York I I364
LESZEKWOLFRAM Clairol Company Stamford, Connecticut 06922
I. Introduction .................................................. 11. Natural Melanins ............................ A. Occurrence ....................................................................... B. Biosynthetic Studies .................... 111. Synthetic Melanins .................................................................. A. Enzymatic Synthesis .................................................. B. Autooxidation ................................................ C. Electrochemical Synthesis ............................................................. D. Photochemical Synthesis .............................. IV. Isolation, Purification, and A. Isolation and Purification ............................................................... B. Solubility and Solubilization. C. Analysis and Standardization ........................... V. Structure and Chemical Properties ....................................................... A. Elemental Composition B. Degradation ...................................................................... C. Nondegradative Methods .............................. 253
254
268 272 272 277 279 279 280 282 283 284 285 287
THE ALKALOIDS. VOL. 36 Copyright 0 1989 hy Academic Press. Inc. All rights of reproduction in any form reserved.
254
RAIMONDO CRIPPA E T A L .
VI. Spectroscopic Characterization.. .......................................................... A. Ultraviolet-Visible and Infrared Spectroscopy .................................. B. X-Ray Diffraction and Rayleigh Scattering of Mossbauer Radiation Studies ....................................................................................... C . Mossbauer Spectroscopy ....... D. NMR Spectroscopy ...................................................................... E. Electronic Structure ..................................................................... Appendix.. .......................................................................................
297 297 298 300 30 I 30 1 304 307 312
I. Introduction Monoterpenoid indole alkaloids are the largest group of alkaloids whose tryptophan origin involves structural variations of the pyrrole moiety, as well as hydroxylated and etherified benzene rings (I). These compounds may be viewed as structural links between the indole alkaloids and the largest and most important family of polymeric alkaloids, the melanin pigments derived from 5,6-dihydroxyindole. Unlike indole alkaloids, however, the latter pigments originate from phenylalanine, tyrosine, and 3,4-dihydroxyphenylalanine(dopa). Melanin is an omnibus term that describes a large family of natural and synthetic phenolic-quinonoid pigments of diverse origin and chemical nature (2). It is clear that while there are several operational and descriptive definitions of “melanin,” there is no unequivocal physicochemical definition. This, however, has not been an obstacle in attempts to elucidate the pattern of melanin reactivity and to probe its physical characteristics. In fact, experimental information gathered over the years suggests a number of common features which are not overridden by either the diversity of pigment origin or the heterogeneity of structure. Natural melanins are generally differentiated by their origin, e.g., bovine eye, melanoma, sepia melanin. They usually occur in the form of granular particles, the melanosomes, and are secretory products of pigment-producing cells, the melanocytes. Synthetic melanins are named after the compound from which they were prepared via chemical or enzymatic oxidation (e.g., d,l-dopa, 5,6-dihydroxyindole, catechol melanin). Melanins are classified according to their chemical structure into the insoluble black eumelanins (poly-5,6-indole quinones) and the alkalisoluble red phaeomelanins (polydihydrobenzothiazines). Nicolaus (3) includes another group, the homoaromatic phenolic allomelanins (per-
6. CHEMISTRY OF MELANINS
255
ylenequinone derivatives), which are often not polymers and are not, therefore, included in this review. The frequently cited resistance of eumelanins to either chemical or enzymatic digestion (4-6) has helped to convey an image of melanin as an inert material. Such inertness, though, cannot be justified by the fact that on exposure to a variety of reagents the material remains obstinately black, insoluble, or shows a virtually undisturbed intrinsic ESR signal. On the contrary, melanins display an impressive range of chemical properties by acting as effective redox (electron exchange) polymers, ion exchangers, and radical scavengers and by showing a strong tendency to bind with aromatic and lipophilic compounds. Unlike those of most alkaloids, reactions of the insoluble melanins are heterogeneous in character and involve both the surface and the interior of the melanin particles. Whereas in living organisms alkaloid molecules diffuse to receptor sites, melanosomes, owing to their immobility, are targets for molecules that diffuse toward them. Many biological functions of melanins, such as camouflage and skin photoprotection, depend on the physicochemical properties of the pigment, whose structure is of special interest to physicists with respect to spectroscopic and conductivity characteristics. Melanins have been a subject of interest as far back as Aristotles’ Historia Animalia. Since the landmark publications by Nicolaus ( 3 , 7 ) ,a large volume of experimental results have been reviewed by many authors with emphasis on special aspects. The chemistry of melanin precursors has been summarized in various articles on catecholamines (8-21), adrenochromes (22),and aminochromes (23). A variety of reviews approach melanins from the medical and biochemical (24-73) point of view, in particular in relation to malignant melanoma. Several articles are restricted to discussion of melanogenesis and biosynthesis (24-38), sunlight and pigmentation (39,40), as well as growth and regulation (4f- 4 3 , structure (25,36,37,46-54),and binding of melanins (55-57). The nature of mammalian colors (58,59)and skin (60-63, hair (64,65),and cell pigments (40,46,54) has also been updated. Several reviews have dealt with specific topics such as electron spin resonance (ESR) ( 7 4 , free radicals ( 7 3 , and chemiluminescence (76). The diversity of melanin functions and their biological and applied significance have been the subject of frequent international meetings and workshops bringing together chemists, biochemists, biologists, physicists, and researchers in medicine ( 7 7 ) . The aim of this chapter is to provide a concise, yet comprehensive and up-to-date review of the field of melanins, with particular emphasis on the chemical, physical, and biosynthetic aspects of these important and
256
RAIMONDO CRIPPA E T A L .
ubiquitous pigments. The abbreviations used in the text are alphabetically listed and appropriate struchres given in the Appendix at the end of the chapter.
11. Natural Melanins
A. OCCURRENCE Early studies of melanins and melanogenesis were aimed toward investigation of the coloration observed in cuts or injuries of several plant tissues, such as potatoes and mushrooms. In the nineteenth century tyrosinase, the enzyme acting on tyrosine to produce red and black coloration, was first extracted from Russula nigreans (78), and it was later isolated from various invertebrates such as insects and cephalopods (79). It soon became apparent that most of the black pigment found in animals originates in processes involving this enzyme. Tyrosinase is nowadays known to catalyze the biosynthesis of not only black but also brown, yellow, reddish brown, and carrot-red pigments (e.g., in hair) (80). Optical phenomena that include diffraction, light scattering, and interference have been identified as additional factors that broaden the palette of natural colors, such as blue eyes in animals and the spectacular color pattern in the peacock’s tail (81). There is now evidence that melanin pigmentation is mainly determined by two chemically distinct but biogenetically related types of pigments. One of them is the dark, insoluble eumelanins that are produced from the tyrosinase-catalyzed oxidation of tyrosine, and the other is the alkalisoluble phaeomelanins that originate from an altered eumelanin pathway through the intervention of cysteine. There exist, however, a variety of hybrid pigments that exhibit structural features as well as chemical and physical properties of both the eu- and phaeomelanins. Unlike the case
1
R :COOH
2
R = COOH
6. CHEMISTRY OF M E L A N I N S
257
for eumelanins, the occurrence of phaeomelanins is restricted to certain types of yellow or reddish hair and feathers and is often accompanied by the presence of the biogenetically related trichochromes, such as the orange-red trichochrome B (1) and C (2). The most common sources of natural melanins are summarized in Table I. There was no intention, however, to make the list complete. The topic and/or results of the quoted papers are also given. A discussion of biosynthetic studies of melanins follows.
B. BIOSYNTHETIC STUDIES A substantial body of evidence accumulated in recent years indicates that both eu- and phaeomelanins as well as the structurally related trichochromes are biogenetically related. The metabolic pathways diverge at later stages after the formation of common intermediates (57).In early steps of biosynthesis, largely worked out by Raper ( 1 5 4 , tyrosine via dopa is enzymatically converted to dopaquinone. The subsequent fate of the latter is largely a result of its intrinsic reactivity as affected by the environment. In the case of natural melanogenesis, the biochemical environment of the site is under genetic control. Available evidence indicates that dopaquinone behaves in a similar fashion in uiuo in a biological system (e.g., in skin or hair follicle melanocytes) or in uitro, ultimately producing an insoluble black pigment. This process, shown in Scheme 1, involves a sequence of oxidation steps, cyclization of dopaquinone, rearrangement of dopachrome, and polymerization of 5,6dihydroxyindole (DI). In phaeomelanin-forming melanocytes the intervention of sulfhydryl compounds, such as cysteine ( 1 5 3 , causes a switch of the mechanism toward production of sulfur-containing pigments. The in uitro nonenzymatic reaction of dopaquinone with the sulfhydryl compounds is very fast and yields three isomeric monoadducts, 2-, 5-, and 6-cystein-S-yldopa (3,4, and 5 respectively), and a bis-adduct, 2,5-bis-cystein-S,S-yldopa (6) isolated in a ratio of 14 : 74 : 1 : 5 (156). This finding is consistent with the dominant role of 5-Cysdopa in the biosynthesis of phaeomelanins with the contribution of 2-Cysdopa and 2,5-bis-Cysdopa to the heterogeneity of these pigments. Homogeneous synthetic pigments are accessible through oxidation of a single isomer such as 5-Cysdopa. Thus, in vitro biosynthetic studies of the conversion of this isomer to phaeomelanins (157,158) suggest that the reaction involves an oxidative ring closure of the cysteine residue to give an unstable o-quinoneimine intermediate; this can either give rise to the dihydrobenzothiazine by exchange of redox states with the starting
TABLE I COMMON SOURCES OF NATURAL MELANINS Occurrence Banan as Brain, frog Cell, mast Eyes, cattle
N
m 'A
Eyes, frog Eyes, human
Eyes, mice Eyes, shrimp Feathers, chicken Feathers, turkey
Notes Semiconductor studies Study of hydrolysis products Eumelanins inhibit ESR signal ascribed to superoxide dismutase U V irradiation studies Pyrrole, phenylacetonitrile. phenols, indoles, catechol, and derivatives are isolated on pyrolysis Affinity toward manganese Efficiency of radical production is threefold greater than from synthetic melanin produced by oxidation of 3,4-dihydroxyphenylalanine Fe'* complexation Nitro Blue Tetrazolium reduction under aerobic conditions is catalyzed by cetyltrimethyl ammonium bromide Free radical production enhanced with Rose Bengal as photosensitizer Kinetics of interactions with 02Metal affinity studies Characterization via pyrolysis-gas chromatography Semiconductor characterization Kinetics of interactions with 0 2 Affinity of TI' Irradiation did not produce detectable amounts of 0 2 1R studies at various pH and water of hydration content Spectroscopic comparison between melanins of blue and brown eyes Semiconductor properties Binding of chlorpromazine and chloroquine in r h o Kinetics of interaction with 02Free radical production enhanced with Rose Bengal as photosensitizer Derivatives of 5-S-cysteinyldopa and 2-S-cysteinyldopa were isolated Solubility studies using aromatic solvents Light scattering and absorption spectrum of alkaline solution
Ref. 82 83 84 85 86 87 88 89-91 92 93 94 95 96 82 94 97 98 99 100 82 101 94 93 102 103 104
Fungi Fur, animal Grape pomace Hair, hamster Hair, human
Hair, horse
Effect of persulfate oxidation ”C-NMR studies Use of heavy metal salts for fur hide treatment Complexation with Co” enhanced carrot and onion germination Melanogenesis is inhibited by melatonin UV or heat exposure produces strong ESR radical signals Affinity toward manganese Permanganate oxidation of eumelanins yields pyrrole-2,3,5-tricarboxylicacid, while HI hydrolysis of phaeomelanins yields 3-amino-4-hydroxyphenylalanine Melanin isolation review Melanin isolation and characterization via solubilization Isolation via enzymatic digestion with PSF 2019 proteinase Free radical production enhanced with Rose Bengal as photosensitizer ESR studies show the relation of melanin to heredity, race, and area of living ESR studies under various conditions of temperature, pH. and light irradiation Fluorescein studies show distinction between yellow and black hair melanins Method for quantitative determination of eu- and phaeomelanins Comparison of physical and chemical properties of black and red hair melanins Determination of various metals in hair by atomic absorption and flame photometry after low-temperature ashing Genetic interactions between brown and red pigments Review on fine structure Review Isolation and characterization via degradation with various reagents Quantitative determination Characterization via pyrolysis-gas chromatography Semiconductor studies Study of hydrolysis products
I05 106 I07 108 109 110 87 111 112 113 114 93 115 116 98 117 118 119 120 50 40,63 121
122 96 82 83
(continued)
TABLE I (Continued) Occurrence Hair, mouse
h) 0 m
Hair, rabbit Hair, sheep and goat Hair, wild boar Humic acids, soil Melanoc ytes Melanoma
Notes Sulfur level decreased as hair color changed from black to yellow to white Purification procedure via treatment with HCI Ultrastructural and cytochemical study Magnesium dependence and hair graying Study of dopachrome oxidoreductase and tyrosinase activity Correlation between melanin charge and intensity of ESR signal of irradiated hair Sulfur level decreased as hair color changed from black to yellow to white Study of hydrolysis products Eumelanins yield 2,4,5-tricarboxypyrrole on KMnO, or HI treatment EPR spectrometric evaluation of melanin content Eumelanins yield 2,4,5-tricarboxypyrrole on KMnO, or HI treatment Chemiluminescence studies during photooxidation Semiconductor studies Ultrastructural composition of eumelanins and phaeomelanins in animals Mechanism of melanogenesis Permanganate oxidation of eumelanins yields pyrrole-2,3,5-tricarboxylic acid, while HI hydrolysis of phaeomelanins yields 3-amino-4-hydroxyphenylalanine Method for quantitative determination of eu- and phaeomelanins Effect of UV radiation @Coirradiation studies Effect of tert-butylcatechol Review on regulation of melanization and growth of melanoma cells
Ref. 123 !24 125 126 127 128 123 83 102 129 102 130 131 132 133 111 117 134 135 136 41
Melanoma, hamster Melanoma. mice
Pearl Sepiomelanin Skin, frog Skin, human
N
Skin, monkey Tobacco hornworm larva Wool, pigmented
I4C investigation of the role of amino acids in melanogenesis
137
Growth inhibition by butyric acid and DMSO FT-IR studies show the presence of both eu- and phaeomelanins Purification procedure via HC1 ESR studies NaBHJNaOH treatment yields 5,6-dihydroxyindole-2-carboxylic acid Review EPR studies of irradiated epithelium cells Method based on remittance spectroscopy for estimating the pigment amount Description of ointments for melanin inhibition Study of the oxidation mechanism of S-S and S-H bonds by X-ray photoelectron spectroscopy Enzymatic eumelanin reduction after exposure to 4-terf-butyl catechol Mechanism of decolorization study Review Melanin metabolism review Study of UV role in inducing melanogenesis Solubilization studies
138 139 124 140 141 54 142 143 144 145 146 147 27,28,3/,6063 44
Effect of cationic surfactants ESR studies of irradiated fibers ESR study of reduced melanins Review
151 152 153 27
148
149,150
SCHEME 1. Overall view of metabolic pathways leading to the formation of eumelanins and phaeomelanins (175).
263
6. CHEMISTRY OF MELANINS
OH
CH / CH /\ NH2 COOH
o-’” OH
CH< CH
\
SCH,CH
k,‘COOH
,NHZ
LCOOH
SCHzCH,
COOH
4
OH
HA‘ HOOC-
cHcHzs6f C H i \ CH
/\
SCH,CH 0 N H 2 ‘COOH
NHz COOH
6
5
material or undergo rearrangement with or without decarboxylation to give the corresponding 1,4-2H-benzothiazines. Which of these paths prevails depends on a number of parameters such as pH, oxygen tension, and the presence of metal ions (159). Very little is known about the chemistry of later steps of in v i m phaeomelanogenesis beyond the benzothiazine stage. Radiotracer studies (160) and model experiments (161)suggest that the alanyl side chain of the postulated intermediates does not take part in the polymerization process, which probably proceeds via an enamine-imine type condensation of the 1,4-thiazine ring system rather than by oxidative coupling at positions 2 and 8 and subsequent ring closure of the alanyl side chain as previously suggested by Minale at ul. (162,163). A detailed account of the regulatory mechanism of melanogenesis (164) with special reference to skin and hair pigmentation addresses the divergence of the metabolic pathways leading either to eu- or phaeomelanins. Since both nonenzymatic reactions involving dopaquinone, the cyclization and the addition of the sulfur nucleophiles, are very rapid, the outcome of melanogenesis depends on the thiol content of the melanocyte, with formation of mixed (hybrid) pigments possibly resulting (165,166).Study of the effects of thiol compounds and glutathione-related enzymes on the skin of different colored mice showed consistency with this view. Thus, the lowest level of glutathione reductase activity was associated with eumelanin type pigmentation, the highest with phaeomelanin-producing melanocytes (167).
264
RAIMONDO CRIPPA ET A L .
The cysteinyldopas required for pigment formation can be derived either by direct addition of cysteine to dopaquinone or via enzymatic hydrolysis of glutathionedopas (34, 168). Which of these pathways prevails in uiuo is not clear, owing to lack of information on the distribution of cysteine glutathione (GSH) in different compartments of the melanocytes (169). It was determined that under physiological conditions the enzymatically generated dopaquinone reacts with GSH in a fashion similar to cysteine to yield the corresponding adducts, 2-, 5-, and 6-glutathion-S-yldopas ( 1 70) in comparable relative yields (12, 76, and 5%, respectively). Moreover, both 5-Cysdopa and 5-glutathionyldopa have been found in melanoma tissues (171), which also seem to contain the hydrolytic enzyme y-glutamyltranspeptidase and a peptidase capable of converting the latter to the former ( 1 72). y-Glutamyltranspeptidase has been detected in normal and malignant melanocytes using biochemical and histochemical methods (173,174). Evidence suggests that certain heavy metal ions, commonly found in pigmented tissues, play an important role in melanogenesis (175). Of particular interest is the finding that copper and, to a lesser degree, zinc, cobalt, and iron have the ability to catalyze the rearrangement of dopachrome to 5,6-dihydroxyindole(s), which is a key regulatory step in the biosynthesis of eumelanins. HPLC analysis of incubation mixtures after decomposition of dopachrome in the absence of oxygen has shown that metal ions affect not only the kinetics of the rearrangement but also the ratio of DI to 5,6-dihydroxyindole-2-carboxylicacid (DICA). As a rule, in the absence of metal ions the reaction leads mainly to DI, while in the presence of metal ions the rearrangement is mainly directed toward DICA formation (Scheme 2) ( 1 76-178).
H H
H 5,6-dihydroxyindole
(DI)
5,6-dihydroxyindole-zcarboxylic acid (DICA)
SCHEME 2. Rearrangement of dopachrome to 5,6-dihydroxyindole (DI).
265
6. CHEMISTRY OF MELANINS
Some reports associate the rearrangement of dopachrome to DI in melanoma with an enzyme distal from tyrosinase (1 79-182) characterized as an oxidoreductase (183). Owing to the preliminary nature of the supporting experiments, however, the regulatory effect may be associated with the catalytic effect of metal ions rather than that of the new enzyme (184). Metal ions also affect the polymerization of 5,6-dihydroxyindole(s) in the early stages leading to the formation of melanochrome(s). Knowledge of the structure and mechanism of formation of the latter compound is of paramount importance in understanding the chemistry of melanization processes and has, therefore, attracted a good deal of attention since 1948, when Mason (185) first detected this intermediate and tentatively identified it as 5,6-indolequinone arising from the oxidation of DI. This structure was later questioned by Beer el al. (186), who showed that the absorption spectrum of melanochrome was more consistent with that of a DI dimer or oligomer. Subsequent attempts to establish the structure of melanochrome did not proceed far because of the untractable nature of the material (187). However, based on model studies and partly on
HoQT
O@J:
t
o’6
O 0
/ n
HO
I
-
H’
om 0
H
H’
SCHEME3. Mechanism of polymerization of 5.6-dihydroxyindole according to Bu’lock and Harley-Mason (188).
266
RAIMONDO CRIPPA E T A L
theoretical grounds, Bu'lock and Harley-Mason (188) suggested that formation of melanochrome involves condensation of 5,6-indolequinone at positions 3 and 7 (Scheme 3). Since then this mode of polymerization has been widely accepted as a chemical background for most speculations concerning the structure of natural and biosynthetic melanins (7,37,56). Recently Prota and co-workers (189) have succeeded in isolating a melanochrome using an improved procedure that involves metalcatalyzed oxidation of Dl at pH 7. Dithionite reduction followed by acetylation with acetic anhydride produced a mixture of leucomelanochrome acetate oligomers, with the symmetrical 2,2'-dimer, 7, as the major component. Mild alkaline hydrolysis under anaerobic conditions gave the parent compound 8, which underwent rapid autooxidation to a blue-purple pigment with a chromophore identical to that of the oxidation product of DI. This process suggests that the DI-derived melanochrome is a quinone derived from 8.
R
7 8 9
R
R = H ;R'=Ac R = H ; R ' = H R = CH, ; R ' = AC
0R
R'O R
/
OR'
In a similar study the metal-catalyzed oxidative polymerization of DICA (190,191) in which position 2 is occupied produced dirners and trimers 13-15 coupled at positions 4 and 7. The observation is interesting considering that natural eumelanins appear to contain a substantial proportion of DICA-derived units (7,37,192). However the presence of
267
6. CHEMISTRY OF MELANINS
ROU')-COOCH,
RO
H
COOCH,
13
RO
Ro Op T $ C H O O C H
,
,
RO i&COOCH /
\
'
I
COOCH,
H
15
R
= Ac
R ROo Q T L H O O C H ,
14
these units in the polymer backbone was, until recently. little understood, because, unlike DI, DICA is relatively stable to autooxidation and is a very poor substrate of tyrosinase. The findings that in the presence of metal ions the rearrangement of dopachrome leads mainly to DICA and that its subsequent polymerization is also susceptible to metal catalysis provide, for the first time, a plausible explanation for the incorporation of these units into eumelanins. Unlike metal catalysis, oxidative coupling by tyrosinase gave the 2,4-dimer 10 rather than the 2,2'-dimer 7. Similar results were obtained with 5,6-dihydroxy-l-methylindole, readily available by oxidative cyclization of epinephrine (193). Oxidation and subsequent acetylation gave dimers 9 and 11 and a trimer, 12, arising from coupling at positions 2 and 4. These results are of particular interest since they demonstrate the tendency of the 5,6-dihydroxyindole system to undergo oxidative coupling at positions 3 and 7, as commonly believed. As far as the mechanism of polymerization of 5,6-dihydroxyindoles is concerned, kinetic experiments (184,194) and pulse irradiation studies (190) suggest that coupling proceeds via oxygen-centered semiquinone radicals. If confirmed, such reactive intermediates may account for the complexity of the later stages of melanogenesis and the heterogeneity of natural and synthetic melanins. On the whole, these biosynthetic studies have provided considerable insight into the chemistry of both the early and later stages of melanogenesis, including the structural characterization of melanochrome(s).
268
RAIMONDO CRIPPA ETAL
The subsequent conversion of these intermediates to eumelanins is still far from being well understood and represents a major focus for further work aimed at a definite understanding of the structure of both natural and synthetic melanins.
111. Synthetic Melanins
Synthetic melanins can serve as model compounds in attempts to understand the chemistry and biochemistry of natural melanogenesis. Four different methods of synthesis are discussed in this section: in uitro enzymatic, autooxidative, electrochemical, and photochemical. The in uirro enzymatic method is the most closely related to natural melanogenesis. Certainly, drawing a parallel between autooxidative and natural melanogenesis and their products is much more objectionable. However, both the enzymatic and autooxidative methods are the most effective in the preparation of large (gram) quantities of melanins. The other two, the electrochemical and photochemical methods, are valuable tools in studies of the melanization processes, especially in identifying individual steps such as the redox and electron transfer processes. At this time, though, they do not represent practical methods for the artificial synthesis of melanins. This section includes a list of various artificial melanins classified by substrate (Table II), as well as a discussion of the four synthetic methods mentioned above.
A. ENZYMATIC SYNTHESIS Eumelanins and phaeomelanins (165,204) have generally been prepared by reacting different starting materials (such as catecholamines and related compounds) in the presence of commercially available mushroom tyrosinase (see Scheme 1, Section 11). Mushroom tyrosinase (241-244), a tetramer of molecular weight 125,000, is a metalloenzyme (245,246) that carries a coupled binuclear copper active site capable of catalyzing two distinct reactions: ( I ) hydroxylation of tyrosine to dopa (cresolase activity) and (2) subsequent two-electron oxidation to dopaquinone (catecholase activity). The first reaction, which is the rate-determining step in melanogenesis, is characterized by a time lag before the beginning of oxygen consumption. This induction period can be shortened by the addition of a catalytic amount of dopa and related metabolites (215,247)
TABLE I1 SYNTHETIC MELANINS Substrate ADR BZQ BZQ-2M-31 CAT
Dopa
Notes studies Oxidation (NADH) and reduction [K3Fe(CN),,2,6-dichlorophenolindophenol] Mechanism of action in photosensitized reactions Reversible two-electron reduction at a carbon paste electrode Study of electrode processes on a mercury electrode X-Ray diffraction studies Studies on the inhibitory effects of thiols on melanization Oxidases are inhibited by copper chelators and ions with affinity toward copper atoms ESR studies of chloroquine-melanin complexes Cu2+ complexation Melanins prepared at higher pH retain a higher percentage of pyrrole units than those prepared by acid treatment Polarographic study of melanin reaction with HzOz Interaction studies with depigmenters Chemiluminescence measurements of degraded melanin Effect of cysteine on oxidation by mushroom tyrosinase Mechanism of action of melanin in photosensitized reactions Quantitative fluorometry method Oxidation-reduction studies ESR of chloroquine-melanin complexes X-Ray diffraction studies of melanin prepared by autooxidation or via mushroom tyrosinase ESR resonance studies IR and ESR studies Presence of less uncyclized side chains than dopamine-melanin Identification of intermediates leading to melanin prepared via NaI04 or mushroom tyrosinase Involvement of superoxide ions in oxidation of NADH via melanin Mossbauer study of melanin interaction with ferric ions
Ref. 195 196 197 198 199 200 201 202 203 204 205 206 207 208 196 209 210 202 199 211 212 213 215 216 217 (continued)
TABLE I1 (Continued) Substrate
Dopa, cysteinyl
IND ND DI Tetrahydroxybiphenylylenedi(ethy1amine)
TYR
Notes
Ref.
Kinetics of first step of melanization process to dopachrome Pulse radiolysis investigation of oxidation of melanin precursors Oxidation [K,Fe(CN)6, Ce(S0,)J and reduction (ascorbic acid, Na2S204)studies Oxidation (NADH) and reduction [K3Fe(CN)6,2,6-dichlorophenolindophenol,cytochrome c ] studies Identification of 5-hydroxydopa as intermediate in melanogenesis via tyrosinase Interaction with p-rerr-butylcatechol Catalysis of melanization via polyamine-copper complexes Melanogenesis inhibition by thiol group Presence of stable free radicals Pulse radiolysis investigation of oxidation of melanin precursors Effect of cysteine on oxidation accomplished via mushroom tyrosinase ESR studies Greater content of uncyclized side chains than dopa-melanin Involvement of superoxide ions in oxidation of NADH by melanin Oxidation (NADH) and reduction [K3Fe(CN),,2,6-dichlorophenolindophenol] studies Use of melanin in treating psoriasis Oxidation (NADH) and reduction [K3Fe(CN),,2,6-dichlorophenolindophenol] Quantitative determination via damping of polarographic maximum of O2 Reaction with Fe" ascorbic acid/EDTA to yield melanin Role of dopachrome oxidoreductase Melanin formation via microsomes in presence of an NADPH-generating system and molecular oxygen Study of melanin formation via polyphenol oxidase
218 219-221 195,222,223 224 225 226 228 229 230 220,221 209 231,232 214 217 195 233 195 234 235 236 23 7 238
Identification of 5-hydroxydopa as intermediate in melanogenesis via tyrosinase Effect of cysteine on oxidation via mushroom tyrosinase Study of intermediates in melanogenesis using tyrosinase No melanization occurs with mammalian tyrosinase ESR and IR studies
225 209 216,239 240 213
6. CHEMISTRY OF MELANINS
27 1
as well as ferrous ions. The peculiarity that there is no induction period when the substrate is dopa or another o-dihydroxyphenol is interpreted via a mechanism involving a change in the oxidation state of the two copper atoms at the active site (Scheme 4)(248).Copper-chelating agents (20/,208,230),cyanide, and benzoic acid (244)inhibit tyrosinase activity. The pH optimum for the enzyme is 6-7. Enzyme activity is assayed by the oxidation of tyrosine to dopaquinone which is monitored at 280 nm [0.001 change of absorbancy increase per minute represents one activity unit (249)]or at 475 nm (250).
SCHEME 4. Proposed mechanism of hydroxylation and oxidation of phenolic substrates to o-quinones (245).
Dopa, dopamine, and tyrosine have been the most common substrates in the preparation of synthetic eumelanins. In a typical experiment the enzyme (15 ml of solution of 30 mg of enzyme in 100 ml Sorensen's buffer, pH 7) and L-dopa (150 mg) in pH 7 buffer (500 ml) are kept with access to air for 2 weeks (153); stirring, bubbling air through the mixture, and raising the temperature up to 38°C accelerate the process. Melanin is separated by filtration, fractional sedimentation, or, more efficiently, by centrifuging (500 to 100,000 g ) , especially after acidification (pH < 3.5) (see Section IV) (251).Samples are further purified by repeated resuspension and centrifugation or dialysis (252). A synthetic phaeomelanin can be easily obtained by the tyrosinasecatalyzed oxidation of L-tyrosine or L-dopa in the presence of excess L-cysteine at pH 6.8 followed by chromatography of the acid-soluble fraction on a Sephadex column. This procedure leads to the isolation of four major reddish brown pigments that are similar to natural
272
RAIMONDO CRIPPA E T A L .
phaeomelanins isolated from hair and feathers. Another procedure involves the tyrosinase-cata!yzed oxidation of the intermediary cysteinedopa adducts, especially 5-S-cysteinyldopa, in the presence of a catalytic amount of L-dopa. Enzymatic copolymerization of dopa and 5-S-cysteinyldopa led to products with both eu- and phaeomelanin properties. Thus, reaction of a 0.5 mM solution of both components (various ratios used) and mushroom tyrosinase (4 mg, 2230 units/mg) in pH 6.8 buffer (40 ml) was completed in 4 hr and was followed by acidification (pH 3.5) (165). B. AUTOOXIDATION
Melanins have been prepared by air oxidation of dopa and other substrates (including catechol) (21I ) in alkaline medium (pH > 8). These melanins are described by the base used in the synthetic procedure, such as NaOH-melanin, ammonia-melanin, diethylamine-melanin (212), to characterize eventual structural differences. In a typical experiment (253) air was bubbled for 3 days through a solution of d,I-dopa (10 g) in deionized water (2 liters) adjusted with concentrated ammonia to pH 8; 3.5 g of a precipitate was formed after acidification to pH 2, which was then washed with 10 mM hydrochloric acid and deionized water. Melanogenesis by autooxidation of 5,6-dihydroxyindole proceeds much more rapidly than that of dopa and is further accelerated (reaction time of a few minutes) by a number of heavy metal ions such as Cu(II), Zn(II), or Fe(III), which commonly occur in pigmented tissues (194). Metalcatalyzed autooxidation of 5,6-dihydroxy-2-carboxylic acid (DICA) using Co(II1) at slightly alkaline pH proceeds rapidly to give a dark brown melanin (192). C. ELECTROCHEMICAL SYNTHESIS In the 1980s electrochemical studies provided a fundamentally new mechanistic insight into the early stages of the melanization processes. Cyclic voltammetry of several catecholamines identified and clarified the cascade of chemical steps that precede the final polymerization of the respective 5,6-indolequinones. These studies allowed the identification of each electron-transfer process and determination of the rate constants of the coupled chemical (nonoxidative) reactions. Furthermore, the voltammetric data established a background for the quantitative determination of catecholamines using a selective amperometric detector in combination with liquid chromatography (LCEC technique) (254). The tendency of this class of compounds to absorb at electrode surfaces (such as platinum) allowed the determination of
6 . CHEMISTRY OF MELANINS
273
catecholamine concentrations at the 5 x lo-' M or 10 ppb level (255). Relevant electroanalytical data that serve in the detection and determination of important catecholamines and related compounds (see Appendix for clarification of abbreviations) are presented in Table 111. Several of the references provide information on the mechanism of the anodic electrode processes. Several publications on electrochemical mechanistic studies of the oxidative transformations of catecholamines followed the contribution by R. N . Adam's group (256)and involved a-methyldoparnine, a-methylnoradrenaline, dopamine (257), a-rnethyldopa, 5,6-dihydroxy-2-methylindole (258), and dopa (259). These studies (257) (Scheme 5), which confirmed the validity of the melanization scheme by Mason and Raper (Ref. 7, p. 50), explored the pH effect on the sequence of events that characterize the electrooxidation of catecholamines. Thus, the cyclic voltammogram in 1 M HC104(pH 0.6) shows only peaks corresponding to the catechol-quinone redox couple as the protonation of the amino group prevents the cyclization step. At pH 6.36, however, the cyclization products appear as a new redox couple that corresponds to the respective dihydroindole product. This process is of particular biological significance since the rate of cyclization of the oxidized form of catecholamines is a major factor in determination of catecholamine toxicity. Such toxicity results from competitive reactions of the oxidized quinonoid form of the catecholamines with sulfhydry1 groups of some essential enzymes. Thus, the fast cyclizing N-methylsubstituted catecholamines are less toxic than the unsubstituted ones that cyclize more slowly. Moreover, E l l ? potentials (rotating carbon electrode) of catecholamines were successfully correlated with their cytotoxicity (279),justifying the importance of the electron-transfer step. At an even higher pH (>7.68) the absence of a cathodic peak estimates the half-life of the corresponding quinone to be of the order of tens of milliseconds (257). The darkening around the anode is considered evidence for an electrochemically accomplished rnelanogenesis. The electrocatalytic effect (oxidation of NADH) observed with a glassy carbon electrode coated with polymer containing dopamine (covalently attached to a polyrnethyl methacrylic matrix) is analogous to bulk reactions of melanins (see Section V). The overall electrochemical behavior, however, indicates a very slow reaction involving only a few monolayers (280). No direct electron transfer between melanin particles suspended in aqueous buffers and electrodes has been observed. This allowed the use of the polarographic method in monitoring the concentration changes of TIt3and Fe+3mediators reacting with D,L-dopa melanin (210).Moreover,
E J
l . P
TABLE Ill ELECTROANALYTICAL OXIDATION DATAOF VARIOUSCATECHOLAMINES A N D RELATED COMPOUNDS Compounds DA, dopa DA, NADR, ADR, A-MNADR, IPNADR A-MDA, A-MNADR, DA A-MD, 5,6-DHMI Dopa ADR, NADR ADR, DA, NADR, SER. A-MDA, dopa NADR, ADR, DA ADR, NADR, DA, DHBA, dopa ADR, NADR NADR, dopa, DA, MTAM, VMA, ADR, HMVA, SER, 5HI-3AA
Isolation~electrochemicaldetection
Ref.
M or 10 ppb Polarographic three-electrode cell system; detection limit 5 x Cyclic voltammetry; planar carbon paste electrode Cyclic voltammetry; carbon paste electrode in I M HCIO, Cyclic voltammetry; carbon paste electrode in I M HCIO, Cyclic voltammetry; carbon paste electrode Polarography after KIOl oxidation HPLC; carbon paste electrode; detection limit 0.4-0.6 ng/ml HPLC with electrochemical detector: detection limits (in fmol): NE, 80; E. 180; DA, 200 HPLC with amperometric detector Polarography after air oxidation Polarography on carbon fibers, graphite powder, polyester resin, and glass tubes; SCE and Ag/AgCI used as reference electrodes; range of 200-570 mV
255
256 25 7 258 25 9 260 26 I 262 263 264 265
ADR, NADR, IPNADR, A-MD DA, NADR Dopa, DA, ADR, NADR ADR, NADR, DA, DOE, dopa, DHEPH NADR. DA, ADR, DHBA NADR, ADR, DA UA Dopa, UA, AA UA SHI-3AA, dopa, 6-HDA, 6-ADA, DA, NADR, AA NADR, dopa, DA, ADR, DHBA, SER, DHPAA, VMA, MN, NMN, CRT, N ;;1 HMVA,A-MD DA, SAL, ADR, NADR -
Differential pulse polarography using glassy carbon, SCE, and auxilliary Pt electrodes Double pulse voltammetry using Pt surfaces HPLC with electrochemical detection Three-electrode polarography system; El:?range 0.33-0.22 V/ECS HPLC with amperometric detector; wax impregnated carbon paste detector electrode; E +0.5 V vs. Ag/AgCI Reversed-phase liquid chromatography with thin-layer amperometric detector operated at +0.720 V vs. AgiAgCl HPLC with direct electrochemical oxidation; detection limit I pg HPLC with sandwich-type thin-layer cell and carbon paste, graphite, glassy carbon, gold, platinum, and mercury as working electrodes HPLC with electrochemical detection Liquid chromatography with sandwich-type thin-layer cell
266 267 268 269 270
HPLC with electrochemical detector; detection limits 0.05-0.20 ng
2 76
HPLC with electrochemical detector HPLC with amperomrtric detector (review)
277 2 78
271 2 72 273 2 74 2 75
276
RAIMONDO CRIPPA ET A L
2H'
+
2e-
1
R" H
HO H
melanoid pigment
SCHEME 5. Electrochemical oxidation of catecholamines to melanoid pigments (257).
the formation of hydrogen peroxide during the enzymatic and autooxidative melanogeneses (in I M KOH) was also monitored with dc polarography (264). This study suggests the following reaction scheme:
277
6. CHEMISTRY OF MELANINS
The charge-transfer processes between chlorpromazine cation radicals (CPZ'.) and catecholamines were studied spectrochemically in order to determine the biological function of chlorpromazine (281). Electrochemical oxidation of the neurotransmitter serotonin (SER, which carries a single phenolic group) produced polyhydroxylated compounds and the corresponding quinones (282) which are the most potent neurotoxins known.
D. PHOTOCHEMICAL SYNTHESIS Catecholamines are thermodynamically and photochemically unstable compounds that yield aminochromes and melanins on photooxidation (283-285) (Scheme 6 ) . Thus, irradiation (254 nm) of oxygen-saturated dilute solutions of adrenaline, isoprenaline, and noradrenaline produced the corresponding aminochromes in 65, 56, and 35% yield, respectively (285). Longer irradiation produced melanins, thus providing evidence for the photolabile character of aminochrome (284). Studies of the action spectrum confirmed the excited state of the catecholamine as the primary
catecholamine
catecholamine-quinone
indoline
Tested compounds NADR
R1
R2 = H
R3
ADR
R1 = O H
R2
R3 = CH)
DA
R1 = H
R2 = H
R3 = H
Dopa
R1
=
R2 = COOH
R3
=
H
IPNADR
R1
= OH
R2
=
H
R3
=
(CH3)zCH
EP
R1 = H
R2
=
H
R3 = CHJ
= OH
H
=
H
=
H
R3 aminochrome
J melanin
+
0 O
m
.
"
:
R3
+
H o Q ) 7 J :
HO
R'
indole-quinone
SCHEME6 . Thermochemical decomposition of catecholamines (284).
278
RAIMONDO CRIPPA E T A L
factor in the transformation processes. N-Substituted catecholamines were found to react more rapidly than the corresponding N-unsubstituted ones (284). A method was established (286) for detecting the presence of radicals during the protolysis of catecholamines and for assigning the hyperfine structures of the corresponding o-semiquinone anion radicals. An investigation of the oxidation of melanin precursors in the presence of azide radicals using pulse radiolysis has been reported (219). Thus, dopa and cysteinyldopa yielded first the unstable semiquinones that disproportionated to a quinone-quinol complex. The quinones decayed to more stable products; dopaquinone produced dopachrome while cysteinyldopa-quinones rearranged to benzothiazine isomers. Photooxidation of various melanin precursors, e.g., DI, has been studied in connection with investigation of the mechanism of the immediate pigment darkening, i.e., natural skin tanning (287). The experiments were performed both under physiological conditions (phosphate buffer, pH 7) and in organic solvents (methanol). These studies can generally be characterized as preliminary, and only a few conclusions can be drawn. Experiments in aqueous media showed significant competition between the primary photochemical and autooxidative processes. Irradiation of all
cH3c00fx2
CHICOO
\
CH,COO
16
17
OCOCH, CH,COO CHJCoo
CHICOO
I&/
CH3COO
CHICOO
\
CH,COO
2
\j
c
H
CH, 20
3
6. CHEMISTRY OF MELANINS
279
investigated compounds (DI, M-DI, and their 0,O-diacetyl- and 0.0dimethyl derivatives) in methanol produced different colors and yielded complex mixtures of unidentified products (288). The one identified process was a photo-Fries rearrangement of the 5,6-diacetoxyindole to 5-acetoxy-7-acetylindole (289). U V irradiation of N-methyl-DI using a Pyrex glass filter yielded a mixture of products with low conversion (290). Acetylation and chromatographic separation on silica gel TLC plates produced two isomeric triacetoxy-I-methylindoles (16 and 17), two pentaacetoxybisindolyls (19 and 20), as well as 5,6-diacetoxyindole (18) identified by NMR and mass spectroscopy. The structures of the photooxygenation products reveal the marked tendency of the indole moiety to undergo light-catalyzed oxygenation at the 2 , 4 , and 7 positions. The reaction conceivably involves interaction of the semiquinone radicals with triplet oxygen to give peroxide products which, together with the semiquinones, take part in the highly complex polymerization processes.
IV. Isolation, Purification, and Characterization
A. ISOLATION A N D PURIFICATION Selection of the procedure that will lead to the isolation and purification of natural melanins depends on the source material. Generally melanins are minor components of tissues and rarely exist in the free state, as in sepia ink (granules with dimensions of -0.2 pm (Ref. 7, p. 60). According to a widely used procedure, the tissue is homogenized in a blender and the protein components solubilized by extensive hydrolytic treatment with mineral acids, such as concentrated HCI at room temperature for 7 days [sepiomelanin, melanoma (Ref. 7, p. 92) and eye melanin (Ref. 7, p. I O l ) ] or boiling 6 N HCI. Such drastic conditions (204,291)lead to considerable alteration of the pigment as evidenced by the evolution of carbon dioxide. Thus, permanganate oxidation of acid-treated eumelanins, either natural or synthetic, gives much lower yields of pyrrole-2,3,5-tricarboxylicacid (PTCA) than the corresponding untreated pigments (II I). This suggests that the COz liberated during acid treatment arises from loss of the carboxyl group at position 2 of the indole or pyrrole rings (204,292).Thus, development of milder procedures is desirable. In the favorable case of cephalopod ink, minimal damage can be achieved by mechanical separation of the pigment granules, followed by a short treatment with 0.5 N MCl at room temperature and extensive
280
RAIMONDO CRIPPA E T A L
sonication in deionized water (291). Alternatively, insoluble melanin granules have been disaggregated using various solubilization processes (293) which provide a method for the separation of proteins and other extraneous material from melanin particles. Pigmented epidermal appendages such as hair, wool, and feathers have been widely used in the harvesting of melanins and are solubilized via various techniques such as acid hydrolysis (102,f 1 2 ) , alkaline degradation (294), or phenolthioglycollic acid extraction (295). The extent of structural modification that results from these rather drastic procedures should be taken into consideration when such samples are used in further studies. Recently, however, much milder isolation techniques (114,296)based on enzymatic digestion of keratin at ambient temperature and neutral pH have been attempted. Gel permeation chromatography has been used in studies of watersoluble melanins. Several fractions were separated from allomelanin from Aspergillus niger on Sephadex G gels (Ref. 7 , p. 131). Similarly, humic acids were separated into three fractions on Sephadex G-75 (297).
B. SOLUBILITY A N D SOLUBILIZATION The relatively poor solubility of natural and synthetic eumelanins (Table IV) is a considerable obstacle in structural determination. The rate of particle sedimentation in aqueous suspensions of synthetic melanins is
TABLE IV SOLUBILITY OF NATIVE MELANINS" Solvent
Squid
octopus
Dog
Man
Concentrated sulfuric acid Liquid ammonia Phenol 15% Sodium hydroxide Formic acid Dimethylformamide Dimethyl sulfoxide Ethylene chlorohydrin Basic sodium borohydride Dilute hydrogen peroxide/ammonia Solulene
5 5 5 4-5 5 5 5 5 4
4 5 5 4-5 5 5 5 4 4 I
4 5 5 4-5 4 5 4 4 4
I
4 5 5 4-5 4 5 4 4 4 1
1
1
I
I
1
" Solubilities range from 5 (totally insoluble) to I (totally soluble). Data are experimental observations by L. J . Wolfram and M . A. Berthiaume.
6 . CHEMISTRY OF MELANINS
28 I
generally accelerated by lowering the pH. This effect results from decreased solvation of the hydrophilic groups and formation of large agglomerates resulting from hydrophobic interactions of the individual indole units. Detailed studies using static and dynamic light scattering methods revealed the existence of two distinct pH ranges: one between pH 3.4 and 7.0 where the aggregation was slow (20 hr and fractal dimensions of 2.23) and another below pH 3.4 where the aggregation was fast (30 min and fractal dimensions 1.8). The fractal nature of the aggregates accounts for the relative stability of melanin suspensions (298). The different hydration and ionization states were correlated with the dielectric property of melanins (299).The dielectric constants and specific conductivities of melanin suspensions followed the sequence acidic > neutral > basic pH and showed dependence on the time of hydration. The solubilization of eumelanins has been attempted under a variety of conditions. Table IV summarizes the results obtained with some native melanins (300). A melanin is considered completely solubilized if the solution does not scatter light. So far only two approaches have been successful, one of which is based on treating the pigment with Solulene 100 (0.1 M solution of dimethyl-n-dodecyl-n-undecyl ammonium hydroxide in toluene; incubation for 2.5 hr at 75°C). Such solutions were used in the characterization and quantitative determination of melanins (124,301). The extinction coefficient (absorption at 400 nm) for hair melanin was of the order of 3000 M - ' cm-' per indole unit, while that of melanoma melanin was only about 70% that of synthetic dopa melanin (124). The mechanism of the Solulene solubilization process is unknown, and degradation of the pigment cannot be excluded. Interestingly, full neutralization of the melanin solution in Solulene with acetic acid did not precipitate the pigment (302). The second approach to solubilization involves treatment of natural melanosomes and synthetic melanins with a dilute solution of hydrogen peroxide at pH 9-10 (303). The solubilized melanin precipitates under acidic conditions and is readily redissolved in basic media. There is only a slight increase in the carboxyl content, suggesting only limited degradation of the pigment. The fact that melanins can be solubilized in both polar and nonpolar media is a clear manifestation of the ability of the melanin structure to accommodate highly diverse demands on its solvation characteristics. Melanin solubilization provides a unique opportunity for determination of molecular weights. Three approaches using various melanin preparations have been attempted (300,303,304).These included viscosity, gel permeation chromatography, and vapor pressure osmometry. Surprisingly the molecular weights were lower than expected, ranging between
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1100 and 6000 irrespective of melanin origin (sepia, dopa-tyrosinase, or autooxidative 5,6-dihydroxyindole). The molecular weights of melanin samples solubilized by the oxidative method were not much different from those of Solulene-solubilized ones. Thus, the melanin prepared oxidatively from human hair had a molecular weight of about 10,000 (vapor phase osrnornetry) (303) and is generally unaffected by the length of oxidation time, between 10 and 1440 min (302).
C. ANALYSIS A N D STANDARDIZATION The semiquantitative and quantitative methods discussed in this section are based on the optical properties of melanins in both the transmission and reflection mode, and they may require solubilization and/or partial degradation of the samples (305).The melanin content in tissues has been determined visually (306) following treatment with Fe" and potassium ferricyanide (307) and by reflectance (308)and remittance (143) methods. For fluorimetric determination of melanins (melanoma cells), the sample is solubilized with alkaline hydrogen peroxide (pH 7.8, 100°C, 30 min); the excitation wavelength is 410 nm, emission 500 nm (148). Fairly good chemical stability of melanins has been determined in gravimetric determinations after separation from all other constituents of melanosomes with acid digestion (6 N HCI, I O O T , 72 hr) (110). Methods based on quantitative markers combined with TLC and HPLC (using an electrochemical detector) have been developed both for eu- and phaeomelanins. Thus, for eumelanins the marker is pyrrole-2,3,5-
TABLE V MOLECULAR WEIGHTSOF SOLUBILIZED MELANINS" Solubilization time (min)
MNh
MW
10 30 60 120 240 480 1,440
2,100 2,700 2,200 3,900 2,020 2,530 1,930
3,100 5.400 6,200 (14,700) 6,340 6,100 4.500
" L. J . Wolfram and M. A. Berthiaume. unpublirhed experimental data. Number average molecular weight. ' Weight average molecular weight.
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tricarboxylic acid produced by permanganate oxidation, for phaeomelanins the aminohydroxyphenylalanine produced by hydrolysis with hydroiodic acid (149). Yields of analytical markers vary significantly for melanins of different origin and are generally low. They are particularly useful, however, in estimating the relative ratios of eumelanins to phaeomelanins in mixed o r hybrid pigments (150). The free radical properties of melanins suggest an obvious marker, and ESR signals have been used for both identification and characterization of melanins in tissues and body fluids (309).
V. Structure and Chemical Properties The understanding of melanin structure has been attempted via analytical and biosynthetic approaches. The analytical one originally explored by Nicolaus (3,7,310) has led to the development of a number of useful methods for characterizing natural and synthetic melanins in terms of elemental composition. functional groups, and structural features of the pigment backbone. These methods helped in the elucidation of the partial polymeric structure of the eumelanin sepiomelanin (3) seen below.
COOH
0
284
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Some properties of both eu- and phaeomelanins such as insolubility, heterogeneity, and unusuai spectral properties have been an obstacle in obtaining information on both structures and chemical properties. The biosynthetic approach, which originated with Raper’s pioneering studies in the 1920s (154), has provided information on the ultimate monomeric precursors of eu- and phaeomelanins. Thus, eumelanins are considered as polymers or copolymers resulting from the oxidative coupling of 5,6-dihydroxyindole (DI) and 5,6-dihydroxyindole-2carboxylic acid (DICA), while phaeomelanins are derived from the oxidative cyclization of cysteinyldopa adducts via the intermediate 1 ,Cbenzothiazines. Since the melanin precursors are known and since the mode of interactions to form the pigment is not unlimited, one might expect that the chemical reactivity pattern of melanin should reflect that of its precursors. The results of investigations suggest that this is indeed the case, and, thus, the long-held view of the chemical inertness of this material is being rapidly abandoned. A. ELEMENTAL COMPOSITION The content and relative ratios of heteroelements have been used as criteria in the differentiation of melanin families. Even in the same family, however, the content of heteroatom(s) depends on the origin (156). Thus, the nitrogen content for eumelanins ranges from 5.18% for one synthetic dopa-melanin to 12.13% for melanoma melanin (Ref. 7, p. 97) (9.42% N calculated for 5,6-indolequinone homopolymer). For phaeomelanins the sulfur and nitrogen content varies between 10 and 12% and between 7 and 9%, respectively (Ref. 7, p. 116) (10.26% S and 8.97% N calculated for the cysteinyldopa homopolymer). The empirical formula and particularly the carbon/sulfur (US) ratio have been useful in determining the degree of heterogeneity of hybrid melanins, i.e., the ratio of dihydroxyindole versus cysteinyldopa units. Thus, in one investigation (118) the C/S ratio for black hair melanin was found to be 40, while for red hair melanin the C/S ratio was 7. These data suggest the presence of some cysteinyldopa units even in black hair melanins. Furthermore, the higher content of oxygen in a synthetic melanin compared to the expected C8H5N02for poly(DI), [C9H5N04for poly(DICA)] suggests the presence of more hydroxyls or carboxyls in the melanin structure. The minimum sulfur content in skin was found to vary with hair color, owing to dissimilation of sulfur in the skin during hair growth (123).
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The presence of proteins is one of the major factors contributing to pigment heterogeneity in native melanins. Depending on the source of the pigment and the method of melanin isolation, the quantity of melanoproteins vary widely from as little as 4.3% (113) to as high as 55.8% (118). No difference between the amino acid compositions of the hydrolysates from black and red hair melanoproteins was detected. The content of melanoproteins varies according to the method of isolation, but the degree of subsequent removal by acid hydrolysis has not, in our view, been satisfactorily validated. The heteroatom count of melanin preparations is affected to a much lesser extent by the bound metals such as Na, K , Ca, Mg, Fe, Zn, Cu, Cr, Pb, Mn, Cd, and Sr determined in human hair and skin (119). Neutron activation analysis of melanins isolated from dark human hair and banana peels gave evidence for the presence of Au, Br, Sb, Ag, Fe, Zn, Co, Cr, Ni, and Hg (311). B. DEGRADATION The conventional spectrophotometric techniques (UV-visible, IR, NMR) are of limited use in structural determination of melanins. Consequently , an array of degradation techniques that yield easily identifiable, low molecular weight fragments has been developed. Many of these methods were developed in the 1950s and 1960s and are documented by Nicolaus (7). The degradation methods are classified as reductive, oxidative, pyrolytic, and photochemical, and recent findings are described below.
I . Reductive Methods Melanins have been degraded reductively via catalytic hydrogenation, as well as with hydriodic acid and sodium borohydride. Thus, sepiomelanin at 150°C with hydrogen and palladium in ethanol produced 5,6-dihydroxyindole (Ref. 7, p. 81). On the other hand, under surprisingly mild conditions (0. I N NaOH/NaBH4) sepiomelanin and biosynthetic eumelanins gave 5,6-dihydroxyindole-2-carboxylicacid (14/). Degradation with hydriodic acid was found to be a specific method in the identification of phaeomelanins (117); aminohydroxyphenylalanine, the degradation product identified by HPLC, is characteristic for melanins derived from 5-S-cysteinyldopa. Owing to the chemical nature of the reagent this degradation involves both reductive and hydrolytic processes. No effect on the number of 5,6-dihydroxyindole units in the melanin polymer was observed on reduction with ascorbic acid or sodium dithionite (222).
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RAIMONDO CRIPPA ET A1
2. Oxidative Methods Melanins have been aerobically degraded to a number of pyrrolecarboxylic acids with alkali hydroxides either by high-temperature fusion (above 200°C) (Ref. 7, p. 80) or in boiling dilute aqueous solution (e.g., 4% NaOH) (Ref. 7, p. 81). This finding may support the hypothesis that carboxyl-substituted pyrrole moieties (e.g., 2,3,5-pyrroletricarboxylic acid) represent one constituent of the melanin structure (Ref. 7, p. 85). It is much more likely, however, that the majority of the pyrrolecarboxylic acids result from oxidative-hydrolytic degradation of the 5,6dihydroxyindole moieties of the melanin. This process parallels the oxidative degradation of 5,6-indole-2-carboxylic acid with peracetic acid (Ref. 7, p. 80) which also leads to pyrrole-2,3,5-tricarboxylicacid. Alkali fusion (308°C) of several eumelanins and allomelanins isolated from animals and plants (312) produced 5,6-dihydroxyindole and 3,4dihydroxybenzoic acid. A more detailed study using sodium hydroxide degradation of both natural and synthetic melanins revealed the formation of two different components: one (the more stable under the reaction conditions used) which absorbs in the visible region and a second absorbing in the U V region. It was speculated that the former is composed of stacks of planar monomer units and that the latter represents the “core” of the polymer providing the protective function against the harmful U V radiation (313). A number of studies have been devoted to the truly oxidative degradation of all types of melanins. Generally, eumelanins undergo oxidative degradation in several stages for which various reagents, such as hydrogen peroxide and potassium permanganate, have been utilized. Hydrogen peroxide oxidation in mild alkaline (pH 9-10) media first solubilizes melanin with no obvious structural change (see Section IV). It is the second stage, the bleaching process, which is most probably associated with the oxidative breakdown of the polymer structure. Complete bleaching of melanin in specimens embedded in paraffin or polystyrene is possible in 1-3 hr at 37°C in a mixture of benzyl alcohol (20 ml), acetone (10 ml), 10% hydrogen peroxide (5 ml), and 25% ammonia (4 drops). Results are identical to those obtained after 24-48 hr of oxidation in 10% hydrogen peroxide (314). Oxidative degradation can be terminated at the solubilization stage by decomposition of the excess hydrogen peroxide (Pt-black, catalase). Acidification (pH <2) causes precipitation and leaves only a faint color in the supernatant. Such melanin (MFA) retains the chromatic characteristics of the intact pigment as indicated by both its color and ESR signal but accounts for only 60-65% of the weight of the starting material. Similar
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weight recoveries have been obtained for a range of natural and synthetic melanins. Treatment of MFA with hydrogen peroxide under conditions used for solubilization results in no further significant weight loss. It appears that melanin, whether native or synthetic, may be constituted of two major fractions, only one of which (the MFA component) bears the color and the ESR signal (300). At present, the nature of the two components can only be speculated. Thus, one may wonder whether the colorless material originates in the “dead” pathway of melanogenesis. Pyrrolecarboxylic acids are the final products of oxidative degradation of eumelanins. The origin, reaction conditions, as well as the isolation and identification techniques used are the factors responsible for the different ratios of di-, tri-, and tetracarboxylic acids formed (7). Thus, untreated sepiomelanin and a number of synthetic melanins oxidized via KMN04 showed the following trend in the relative ratios of pyrrolecarboxylic acids: 2,3,5 >> 2,3 = 2,3,4,5. The same samples after decarboxylation at 200°C followed the sequence 2,3,5 > 2,3 > 2,5 = 2,4 = 2,3,4,5. The decrease in 2,3,5 triacids and the increase in 2,3 diacids are attributed to the loss of carboxyl groups owing to the thermal treatment (7). Resistance to further oxidative degradation uhder specific experimental conditions may substantially influence the ratio of the individual pyrrolecarboxylic acids formed (315). 3. Other Degradation Methods
Photooxidation of adrenochrome melanin under oxygen at high pressure led to its degradation and formation of low molecular weight products (316). Natural black (human hair, bovine eyes) and synthetic (tyrosine, dopa, and dopamine) melanins were investigated by Curie point pyrolysis-gas chromatography-mass spectrometry (86,96).The pigments were characterized by different ratios of degradation products identified as aromatic hydrocarbons, phenols, catechols, pyrroles, and indoles. The amount of ash in karakul lamb wool was correlated to its color, with black producing the most (3.9%) and white the least (1.2%). Similar studies showed a correlation with the calcium content (317.3f8).
c. NONDEGRADATIVE METHODS I . Redox System One of the most characteristic functional properties of melanins is their ability to exchange electrons with reducing and oxidizing agents; this accounts for their existence in both the oxidized quinone and reduced
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RAIMONDO CRIPPA ET A L
quinol forms, respectively. Unlike oxidative and reductive degradations, these processes merely involve a reversible exchange of two electrons and two protons. Typically, Ti3+,Fe3+,ascorbic acid (2101, Fe(CN):-, sodium hydrosulfite, NADH and NADPH, cytochrome c, dichlorophenolindophenol ( 2 2 3 , nitroxide free radicals ( 3 / 9 ) ,and Nitro Blue Tetrazolium (320)undergo exchange of oxidation states with aqueous melanin suspensions. Eumelanins can act either as electron acceptors or electron donors in a fashion similar to that of a large number of electronexchanging synthetic polymers characterized by the quinone-quinol functionality (322). ESR is the method used extensively to characterize directly changes in the oxidation state of melanins (75). Spectrophotometric or electrochemical methods have been useful in monitoring concentration changes of the reagents-mediators (oxidants, reductants). The electrochemical method allows the monitoring of nontransparent suspensions without separating the melanin that does not exchange electrons with the electrode. Owing to the presence of acidic groups in melanins (carboxyls, phenolic groups) positively charged reagents react faster than anions or neutral species, especially in basic media. Thus, cationic nitroxides react much faster than anionic ones, and the reaction is twofold faster at pH 10 than pH 5 . The slow reaction with Nitro Blue Tetrazolium is dramatically accelerated in the presence of a cationic detergent (92). Generally reduction of both natural black wool and synthetic L-dopa and tyrosine melanins results in a lighter color and changes in the ESR spectra (/53).Relatively minor changes are observed on treatment with mild reducing agents [ascorbic acid/water, sodium borohydride/ aluminum chloride/diglyme, sodium borohydride/ferric chloride/diglyme, homogeneous high-pressure catalytic hydrogenation using tris(tripheny1phosphine)chlororhodium in chloroform]. Much more significant changes are observed under the drastic condition4 of Birch reduction (sodium in liquid ammonia). Interestingly, products of the reduction in nonaqueous media show an increased free radical content, while the reverse is observed when aqueous media are used. Mechanistically, the quinone-quinol forms in melanins are coupled via the relationship Melred
Mel,,
+ 2n e - + 2n H'
where n is an integer. Experimentally, however, this relationship has never been examined quantitatively in order to determine coupled irreversible chemical processes such as cross-linking or carbon-carbon bond cleavage.
6. CHEMISTRY OF MELANINS
289
The populations and role of semiquinone states assumed to be responsible for the characteristic ESR signal have been extensively studied by ESR spectrometry for all types of melanins (75). The increase in the free radical content after reduction of melanins in nonaqueous media may indicate an increased population of semiquinones (153) and/or quinhydrone-type complexes. In such a case a maximum intensity signal should be observed with half-oxidized-half-reduced melanin. Both reduction and oxidation processes have been found to be biphasic. Thus, in kinetic studies of the reduction of synthetic d,l-dopa melanin with Ti3+ and oxidation with Fe3+, respectively, a fast first electron-exchange step was followed by a slow second step (210). Whereas the quinone-quinol relationship involves an exchange of two electrons, only 0.5 electrons were accounted for the fast reaction step between d,l-dopa melanin and Ti3+; similarly, only 0.02 electrons per indole unit was exchanged with Fe3+(210). From the 25: 1 ratio for the fast reduction versus oxidation steps, it was concluded that melanin in an air atmosphere exists predominantly in the quinonoid form. This finding was further supported by an experiment in which reduced d,l-dopa melanin was partially reoxidized by air. The biphasic character of the electron-exchange processes was interpreted as the difference in reaction mechanisms involving the surface and the core of the melanin granules. Using the oxidation-reduction capacities obtained for the fast electron-exchange processes, one-fourth of the indole units were found at the particle surface. Assuming the same fast rate of electron exchange in both the oxidation and reduction, respectively, the slow diffusion of the reagent (Ti3+,Fe” , and H+)in and out of the melanin particle is believed to control the rate in the second phase. Alternatively, the slow step may represent an electron transfer between the outside indole units exchanging electrons with the reagent and the indole units of the particle interior, combined with a diffusion of protons. This mechanism resembles processes which characterize electron transfer in redox-conducting polymeric films of similar chemical structure deposited at solid electrodes (322). Whereas only 0.02 electron per indole unit was exchanged in the fast Fe3+ oxidation process, long exposure of d,I-dopa melanin resulted in total consumption of two electrons. This observation was associated with an oxidative cross-linking step involving two hydrogen atoms (210). Unlike the Fe3+-oxalate oxidation, the potassium ferricyanide one in pH 7.2 buffer afforded 0.25 electrons per indole unit. When the reaction with potassium ferricyanide was allowed to proceed to completion (time not specified) about 0.75 electrons per indole unit were exchanged, again suggesting deeper structural changes.
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RAIMONDO CRIPPA ET A L
The electron-exchange properties of melanins have been studied with a number of special reagents in order to elucidate the electron exchange mechanism itself and the role of the melanin redox properties in biological systems. It was thus found that nitroxide radicals were reversibly reduced by melanins in the dark (319)and that the redox equilibria were altered on irradiation (see Section VI). Moreover, the reduction of nitroxides (R2N0.)was inhibited by oxygen. The equilibrium
K
=
[Mel,,] [R2NOH]/[Mel,,~][R2N0.]
and the reaction rates were determined quantitatively. Melanins such as d,I-dopa melanin, phaeomelanin, and retinal pigment slowly reduced Nitro Blue Tetrazolium in aqueous dimethylformamide (aeorobic conditions, pH 7.4) (320). The reaction was strongly accelerated by cationic detergents (e.g., cetyltrimethyl ammonium bromide) with no significant photoeffect (92). Hydrogen peroxide, which oxidatively degrades eumelanins, undergoes disproportionation with catechol melanin to produce oxygen and water (205). Of particular significance to biological systems is the reaction of melanins with oxygen. The effect of external factors on this reaction, e.g., pH, illumination with visible light, temperature, and catalase, has been studied in detail (323). Melanins (d,I-dopa and bovine eye melanin) were studied in their native, reduced (sodium borohydride in 12% sodium hydroxide), oxidized (potassium ferricyanide in pH 6.8 buffer), and methylated (first reduced with sodium borohydride, then reacted with dimethyl sulfate) forms, and the reaction was monitored via ESR. The rates of oxygen uptake were, generally, higher with illumination. Over the pH range 5.5-1 1.9 the rates increased more than three orders of magnitude, while the free radical intensity fourfold. The sodium-reduced d,l-dopa melanin reacted faster (up to two orders of magnitude at low pH) while the methylated substrates slower (one order of magnitude). Activation energies for reaction with oxygen determined for the dark and photoactivated processes were 10 and 5 kcal/mol, respectively. However, only a negligible difference in the oxygen consumption rates for untreated and ferricyanide-oxidized melanin has been found. Results of the study of the effect of hydrogen peroxide and catalase suggest processes leading to hydroxylated melanins via a hydroperoxide intermediate rather than a quinole to quinone oxidation:
The studies aimed toward the examination of the role of melanins in
6 . CHEMISTRY OF MELANINS
29 I
living systems (especially the processes involving NADH, NADPH, and cytochrome c ) (223) are directly linked to their redox properties. Generally, the chemical changes of melanins, both natural and synthetic, were monitored via ESR, while concentration changes of the reactants were determined spectrophotometrically. In a way similar to reactions reported earlier, the electron-transfer processes were found to be strongly irradiation dependent (both by visible and U V light). The following equations characterize the mechanism of NADH oxidation with melanin (324):
+ NADH + H ' C
MelFed+ NAD' Melred+ 0: C Mel,,, + HzOz NAD' + 2 HzO NADH + H' + HzOZ
Mel,,
In this system the rate of NADH oxidation was increased by eliminating H202 using catalase. In addition to direct electron exchange, melanins exhibit interesting properties characteristic of electron-transfer agents (223).Thus, synthetic dopa, dopamine, adrenaline, adrenochrome, and hydroquinone melanins accelerated the oxidation of NADH with Fe(CN):-. (optimum pH 5.5-8.5) and 2,6-dichlorophenolindophenol-Cu?'. The rate with all three components present was higher than the combined rates of oxidation of NADH with either reagent alone (68,195). Interestingly, the 1 : 2 molar ratio of NADH oxidized and Fe(CN)63- reduced was approximately the same irrespective of the amount of the melanin used. The reversible character of the entire system was documented by the rate decrease after addition of any of the reaction products [Fe(CN):- and NAD']. The use of various reagents as cooxidants (e.g., KMn04, benzoquinone, iodine, and ferric chloride) enhanced the oxidation of NADH and decreased the reduction of ferricyanide (325).
2. Acid Functional Groups Information on the acidic functional groups of melanins was obtained by acid o r base titrations (326).Melanins were prepared by autooxidation of the precursors in the presence of bases (such as sodium hydroxide, ammonia, diethylamine, and glutathione). Since incorporation of highly nucleophilic bases in the polymeric matrix is quite likely, it is not surprising that the resulting titration curves showed large differences for samples of different origin. In addition, the results were also influenced by the titration procedure itself (e.g., the waiting time) most probably because of the biphasic mechanism. The titration curves were characteristic for both reversible and irreversible processes; the latter involved reactions other than proton exchange, such as the loss of bases attached by coulombic forces and of absorbed carbon dioxide following treatment
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RAIMONDO CRIPPA ET A L
with acids. The titration curves are unique for each melanin type and, therefore, are well-suited for characterization and differentiation purposes. The amino acid composition of pigmented wool melanins was determined, and the effect of cationic surfactants on the reduction of bleeding of wool in alkaline solution was explained on the basis of neutralization of the carboxyl groups in melanins by the cationic surfactants (327). 3 . Derivatization Melanins have been derivatized with various reagents in processes involving both phenolic and carboxyl functional groups. The native phenolic functional groups of melanins have been methylated with diazomethane directly. Samples with higher numbers of methoxy groups were prepared by reducing the quinone functionalities with sodium borohydride prior to methylation with dimethyl sulfate. Such derivatized melanins underwent oxidation by oxygen (in the dark, pH 10.5) 10 times slower compared to the native sample (Ref. 7, p. 80; 323) A similar effect was observed on methylation of the phenolic groups in humic acids (327). The reverse trend was observed, however, with a methylated melanin on illumination (pH <9). Natural and synthetic melanins carry different contents of carboxylic groups that represent residual carboxyls which originated from the monomer acids (e.g., dopa, TYR). The carboxyl groups in melanins were esterified using methanol/hydrochloric acid or diazomethane, the latter reagent also methylating the phenolic groups. The content of carboxyls in the native melanin was increased after treatment with hydrogen peroxide, suggesting an oxidative degradation of the polymeric backbone and cleavage of some carbon-carbon bonds (212). 4 . Interaction with Light
Although the visual manifestation of the interaction of melanins with light has been considered as one of its cornerstone characteristics for a long time, it is only relatively recently that more fundamental inquiries into the nature of light absorption have been made. The results of these investigations not only broadened our understanding with regard to melanin color but also opened intriguing vistas in the area of the photoprotection mechanism. The absorption spectrum of melanin throughout the UV and visible range is quite structureless and intensifies with decreasing wavelength. There is no evidence of any distinctly absorbing chromophores related to an extended conjugation of the macromolecular welectron system (36). Modification of the extent of conjugation is thought to be a factor (5) in
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293
altering the quanta1 energies required for light absorption and, thus, in modulation of the color of melanin (i.e., black eumelanin, highly conjugated; phaeomelanin, less conjugated). A somewhat different view of the interaction of melanin with light has been taken by McGinness and Proctor (315) who explained these effects in terms of an amorphous semiconductor theory. In these terms melanin is black because the absorbed light is not reradiated but is instead captured and converted to rotational and vibrational energy (photon-phonon coupling). The relatively featureless spectrum of melanin, from the UV through the visible and into the IR, means that such photon capture is available for any energy level between these spectral limits. In this sense, the melanin can be considered “black” not just in the visible region. On the other hand, Wolbarsht et al. (328) discount the importance of atomic o r molecular absorption and suggest that melanin acts as a light trap because it is an efficient light scatterer. Both the light optical density of melanin and the overall shape of the absorption spectrum can be accounted for by multiple scattering of the Rayleigh type. A counter argument is based on the experimental observation (30/,304) that solutions of melanin, which show no evidence of scattering, exhibit a very similar absorption spectrum. In fact, the optical density (OD) can be fitted (329) to the following expression derived from the amorphous semiconductor theory:
ODZ”’ = K E0 ”’(Z
- 1)
where Z equals 1.242/AEo(dimensionless), Eo is the optical bandgap in eV, A the vacuum wavelength in pm. z a dimensionless independent variable, and K a constant. This relationship appears to hold for both euand phaeomelanins with bandgaps in the range of 1.0-1.3 eV. Thus, evidence points toward a strong intrinsic optical absorption in the melanin moiety mediated, in the case of melanin particles (melanosomes), by Mie-type scattering which tends to suppress the wavelength dependence. Photoprotection is believed to be one of the major biological functions of melanin pigments (39). The spectral absorbance characteristics of melanin qualify it as a potential sunscreen but both the localization of the pigment and the particulate mode seem somewhat inconsistent with conventional sunscreening functions. It appears, however, that melanin can effectively participate in mediating the harmful effects of sunlight by an array of photoinduced chemical reactions resulting in consumption of molecular oxygen (330,331) o r by scavenging active oxygen species (332,333) such as superoxide anion and Hz02. In biological systems, superoxide and hydrogen peroxide are formed in small quantities during normal processes. Both species are known to
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produce several biological effects, most of which are deleterious to tissues. While the cell defense mechanisms are adequate to remove these active oxygen species under normal conditions, with exposure to UV light, their concentration increases (333),and thus the role of an in situ residing quencher such as melanin becomes important. It should be pointed out, however, that although melanin can act as a free radical quencher and protectively mediate the decomposition of active oxygen species, melanin itself may become energetically overloaded into a toxic state (334). There exists evidence of melanin’s augmenting the radiative damage to cells (335)and of phaeomelanin’s role in sunlight-induced skin cancer (336). The process of photoinduced interaction of melanin with molecular oxygen is accompanied by photobleaching (301,304,331). Using ESR measurements the rates of photooxidation of eumelanin and phaeomelanin have been found to be comparable. In other reports, however (337), phaeomelanin has been found to be more resistant toward photobleaching than eumelanin. A similar pattern of reactivity has been noticed in photo- and chemical oxidation of these two pigments in their native milieu (hair) (338). A relatively recent finding has been that of melanin fluorescence (339,340). This is an important observation in view of earlier reports denying this aspect of light-melanin interaction. Gallas and Eisner (340) focused their study on identifying the fluorophores and stress the linkage to the ESR signal. A significant rise in fluorescence was observed on solubilization of melanin, a process which is unlikely to augment the intensity of the ESR signal (339), thus contradicting this concept. The presence of a spin trap represents a further step toward understanding the interaction of light with melanins. Eumelanins, both natural (bovine eye) and synthetic (dopa), were studied in the presence of spin traps, such as 5,5-dimethyl-l-pyrrolineI-oxide (2f1). From the structure of the spin trap adducts, hydrated electrons and hydrogen atoms are postulated as products of melanin photolysis. This reaction occurs with short-wavelength U V light and in basic media; at pH 7, however, photoionization dominates over photolysis. It is also suggested that the chromophore responsible for these processes is commonly the hydroxylsubstituted aromatic ring, not necessarily derived specifically from dopa. Commonly, light enhances the rate of many reactions, probably because of the increased population of radicals and/or other favorable changes in the structure of melanin molecules. Thus, photoinduced changes have been reported in redox equilibria established between melanin and nitroxides (Section IV) (319); these may result from a photochemical effect on redox potentials of either one or both com-
6. CHEMISTRY OF MELANINS
295
ponents. A substantial increase has been reported in the rate of oxidation of NADH by melanin under U V irradiation (roughly fourfold after 100 min) and in the presence of oxygen when compared with the reaction under dark and anaerobic conditions (324). Additional information on the interaction of melanins with light and oxygen was obtained from mechanistic studies of the effect of Rose Bengal acting as an anionic sensitizer (93,141). These studies included natural eumelanins (bovine eye) and phaeomelanins (red hair, chicken feathers) as well as synthetic dopa melanin. An enhancement of the rate of radical formation was observed both in the presence (factor of several hundred) and, interestingly, in the absence of oxygen (factor of twenty). Under anaerobic conditions the Rose Bengal, reversible free radical promotion depends on the concentration of both the photosensitizer and melanin and is quenched by oxygen, suggesting a triplet state of the dye. Under aerobic conditions a mechanism involving singlet oxygen is postulated based on the quenching effect of low concentrations of azide and the rate enhancement with DzO. Whereas catalase had no effect, superoxide dismutase increased consumption of oxygen by about 50% (341). 5 . Complexation and Binding
Melanins bind both metal cations and organic species, the latter often carrying positive charge(s). The processes are controlled by ion-exchange and/or hydrophobic interaction mechanisms and are essential in the various biological functions of melanins. The ion-exchange capacity of fungal phenolic polymers (allomelanins) found in soil is believed to play an important biological role both as a source and in the translocation of metal ions (e.g., Fe, Cu) in nature (342). Binding of organic compounds characterized by high affinity to melanins is used to explain the toxicity of chlorpromazine and chloroquine (343). Other medicinal aspects may involve affinity and binding of various molecules to melanins in substantia nigra and in malignant melanoma cells. Natural melanins always contain a certain amount of metals (see Section V,A). Studies of metal binding by both native (bovine eye) and synthetic melanins (with paraquat as a reference ion) provided data on the relative affinities of metals to melanins (95). These studies confirmed the ion-exchange properties of melanins that result from the presence of carboxyls as well as the cooperative effect of the neighboring nitrogen atom and phenolic groups. Similar to the case of other ion exchangers, the affinity for melanin increases with valency of the cation and atomic number of the element (Cs’ >> Li’, Ba” >> Mg”). However, the exceedingly high affinity found for Pb’+ when compared with similar
296
RAIMONDO CRIPPA ET A L
divalent ions suggests the possible contribution of other factors. The equal affinity found for native and synthetic melanins indicates that the proteins present in native melanins play a minor role in the binding of metals (95). Detailed study of the affinity of Mn’+ was prompted by the fact that occupational exposure to manganese affects the nervous system and, in particular, nerve cells in substantia nigra. Using S4Mnand autoradiographic techniques, the highest binding was found for bovine eye melanin (1.33 pmol/mg; corresponding to one Mn atom per 4.8 indole units), the lowest for synthetic DA melanin (0.15 pmol/mg) (87). Complexation of grape pomace melanin with metals (Co”, Mn”) enhanced its effectiveness in carrot and onion germination (108). Binding studies combined with ESR spectroscopy provided deep mechanistic insight into the nature of the interaction of the metal ions with melanin. This technique allowed the identification of chelation of di- and trivalent diamagnetic metal ions by the o-semiquinone radical centers (253);this interaction often results in an increase of the total free radical concentration. Studies carried out over a broad pH range demonstrated different binding mechanism of ions below and above pH 7. At lower pH binding involved primarily carboxyl groups or complexation with a bidentate nitrogen-carboxyl ligand. At higher pH binding involved mainly phenolic hydroxyls. The binding capacity varied for melanins of different origin: the number of reactive sites in a bovine eye melanin was less than that in synthetic melanins (203). Organic compounds used in binding studies with melanins were mostly bases, often positively charged (quarternary ammonium cations). Paraquat and diquat studied both in uitro and in uiuo were found to bind strongly to eye melanin, and the cation-exchange mechanism was fully identified (344). A systematic structure-affinity study was reported for a series of heterocyclic compounds and synthetic d,I-dopa melanin (345).The structural variables of the substrate molecules were basicity, extent of the 7~ system, and planarity of the molecule (346).Relative affinities determined from adsorption in pH 7 phosphate buffer followed the sequences pyridine << quinoline < acridine Series I: Series 11: quinoline < 2-methylquinoline < 2,6-dimethylquinoline Series 111: iminostilbene > 9-methyliminostilbene > 9,lOdimethyliminostilbene Thus, the extent of the r-electron system in series I, the 7~ system and basicity in series 11, and the steric factors and degree of buckling of the central ring in series 111 are the determining factors for the affinity toward
6 . CHEMISTRY OF MELANINS
297
melanin. These results are consistent with the expected stabilities of the charge-transfer complexes between the respective heterocycle, the .rr-donor, and the oxidized melanin, a .rr-acceptor. The practical consequences of this structure-affinity relationship suggest applications in the development of drugs which may selectively target melanocytes (such as melanoma cells) o r drugs with low toxicity that are not accumulated in melanin-containing tissues, such as eyes. Analysis of experimental data from binding studies of chloroquine, chlorpromazine, paraquat, and Nil’ using Scatchard plots support the concept of more than one binding site participating in these processes (343). VI. Spectroscopic Characterization
A. ULTRAVIOLET-VISIBLE A N D INFRARED SPECTROSCOPY The history of spectroscopic investigations of melanins attests to many attempts to obtain UV-visible and IR spectra with sufficient resolution to allow structural determinations. In the UV-visible range, the insolubility of natural eumelanins and the scarce solubility (at high pH) of artificial ones produces problems of scattered light, which prevent structural spectrophotometric determinations by traditional means. Typical spectra of both eu- and pheomelanins in the range 180-700 nm are characterized by a monotonic increase of the absorbance with decreasing wavelength coupled with one or more barely detectable shoulders that possibly reflect relative amounts of the various monomers present in the pigment. Solid films of eumelanins show spectra even less resolved (347). Despite the poor resolution, such spectra can provide comparative parameters in terms of optical absorbance ratios at selected wavelengths attempts to characterize melanins of different origin. An original approach to the absorbing and scattering properties of melanin granules, leading to a light-trap role in uiuo, was suggested by Wolbarsht r t ul. (328). Their hypothesis takes into account the effects arising from Rayleigh scattering (by the molecules) and Mie scattering (by the melanosomes) and, through a semiquantitative treatment, provides a model of the overall optical properties based on multiple scattering and multiple absorption with consequent high optical density. The proposed absorption mechanism of melanin as an amorphous semiconductor (315) with phonon coupling to excited electronic states helps to explain the efficient absorption of internally scattered light. A strong dependence of this effect on the hydration state further improves the description of this
298
RAIMONDO CRIPPA ET At-.
peculiar optical behavior (348). A more detailed discussion of the interaction of melanins with light is presented in Section V . The infrared characterization of melanins in the fingerprint region gives fairly good results when performed using very “dilute” KBr pellets (99). The sensitivity of the method allowed the study of protonation and deprotonation of titrable groups at different pH, thus monitoring the binding of iron to various chelating functional groups and allowing the comparison of natural and various synthetic melanins (99,349,350).Table V lists the IR vibration bands for various synthetic and natural melanins. 1R analysis of hydration in melanins was performed on samples dried at different temperatures (99). Spectra of samples of synthetic L-dopa melanin heated under reduced pressure (2 X lo-’ torr) at 400 K and 670 K show a decrease of the bands in the water absorption regions (3400, 1600, and 600 cm-’) and a concomitant increase of the background (mainly at shorter wavelengths) attributed to light scattering. Simple analysis of the transmittance T over a path of length x in a medium containing only spherical scatterers of radius r gives T =
e-yx
where y = n i k is the scattering coefficient. The scattering area ratio k is a function of the ratio rlA. The theory gives, for small particles, y a K4 (Rayleigh scattering) and, for larger particles, y A-$ (Mie scattering) when $ approaches zero. For L-dopa melanin $ equals 1.26. This value cannot be explained by the use of simplified approximations, thus reflecting the complex distribution of shapes and sizes of the pigment granules. Such studies on natural pigments are rather limited owing to the possible interference of proteins and other strongly bound cellular components to the IR spectra of melanins.
B. X-RAYDIFFRACTION A N D RAYLEIGH SCATTERING OF MOSSBAUER RADIATION STUDIES Early X-ray diffraction studies on melanins gave evidence of only a short range order in the arrangement of the indole rings with the appearance of a lamellar structure with an average interlayer spacing of about 3.4 A (351). Reinvestigation of this subject was recently made possible through the introduction of a new technique, Rayleigh scattering of Mossbauer radiation (RSMR) (352). This diffraction technique has an extremely high energy resolution (AEIE and provides both detailed structural and dynamic information. The spectra show a broad structured peak centered at Q = 1.78 A-‘ arising mainly from interlayer distances
TABLE V VIBRATION BANDSA N D CHARACTERISTIC IR ABSORPTION REGIONS FOR SYNTHETIC A N D NATURAL MELANINS ~~
~
L-Dopa melanin
Dopamine melanin
Sepia melanin
~
~~
Eye melanin
V
Vibrational band
(cm-')
N - H - NH2 symmetrical and asymmetrical stretching OH - H bonded stretching ( H 2 0 ,carboxylic, phenolic) N - H - NH3' stretching Aliphatic C - H stretching
3400-3500 3440 3200 2930 2860 2700-2500 I700 I600 I600 1400 1400 1300-1200 900-730 600
Carboxylic H-bonded OH stretching C = 0 COOH stretching OH bending (HzO) Carboxylate ion asymmetrical stretching Carboxylate ion symmetrical stretching Carboxylic C - 0 stretching or OH bending Aromatic C - H bending OH librations (HzO)
pH2
+ + + + +
pH 10
pH2
+
+
+
pH 10
+
+ +
+ + +
+ +
+
+
+
t
+ +
+
+ +
+ +
+ +
+
+ +
pH2
+ +
+
pH2
pH 10
+
+
+ +
+
+
+ +
+
+
+ +
+
pH 10
+ +
+
+ +
+ + + +
+ +
+ +
+
+ + + +
+ +
+ +
300
RAIMONDO CRIPPA E T A L
and a broad second peak at Q = 5.4 k 'corresponding to intermolecular distances. The total curve is affected by the contribution of water coordinated to the melanin, which is responsible for the inelastic part of the spectrum. Consequently, the net radial distribution function deduced from the elastic part reflects the atomic distribution of the melanin structure alone. The main peaks correspond to the average bond lengths (C-N, C=O, C-C) in the melanin monomer (1.45 A), to distances between next-nearest neighbors (2.4 A), to the perpendicular interlayer spacing between indole planes (3.4 A), and to distances between atoms in adjacent layers occupying different positions in each monomer unit (4.4 The assignment of currently unidentified peaks may provide additional valuable structural information. The dynamics of the system are typical of a layered structure characterized by large anisotropies in the bonding forces. The mean square displacements measured along the direction of interlayer bonds < u: >, is one order of magnitude greater than that measured for bond distances in the monomer plane, < u i >. This result is confirmed by the large difference between the Debye temperatures 13, and 811 for motions perpendicular and parallei to the monomer planes (0, = 109.5 K , 1911 = 456 K), reflecting the strong anisotropy of the thermal vibrations. The X-ray diffraction curve for lyophilized melanosomes gives a radial distribution function similar to the curve obtained for a synthetic melanin (90). Thus, a peak at 3.4 A corresponds to the distance between indole planes, and two peaks are assigned to distances between first and second neighboring atoms, respectively. Other peaks, not observed in pure melanin, are assigned to distances relative to the protein matrix. Smallangle X-ray investigations confirmed the presence of periodicity in melanoproteic organelles (353). The results of recent X-ray studies of melanin films prepared from 5,6-dihydroxyindole (DI) are consistent with a pentameric structure with the DI units being linked at the 7 and 4 positions and twisted in a helix with a 180" repeat at each end (354).
A).
C. MOSSBAUER SPECTROSCOPY The ion-exchange capability of various types of melanins allows binding of the 57Feisotope, the most common probe used in Mossbauer spectroscopy. This method has proved to be a useful and accurate technique in the investigation of molecular and supramolecular structures of melanins. Both natural sepia and bovine eye melanins, as well as synthetic d,l-dopa melanin, were subjected to such studies (39,349,355).
6. CHEMISTRY OF MELANINS
30 1
Generally, the Mossbauer spectra show characteristics consisting of two components: two Zeeman sextets and a central quadrupole doublet. Studies performed at variable temperatures report a redistribution of the intensities between the components with a temperature-dependent line broadening. The results suggest that, in all samples, melanins occur in the form of very small paracrystalline particles with a broad size range and showing a superparamagnetic behavior. D. NMR SPECTROSCOPY The ability of NMR spectrometers to operate in the cross-polarization/ magic angle spinning mode is a powerful tool for structural elucidation of insoluble materials (356). Natural abundance solid-phase I3C-NMR spectra could be obtained for synthetic L-dopa eumelanin. The inordinate number of resonance signals, however, prevented definitive assignments of the peaks to specific carbons. Subsequently Chedekel et al. (357)used this technique to study the conversion of specifically labeled L-dopa and 5,6-dihydroxyindole to melanin. In the enzymatically produced melanin the I3C-NMR spectrum identified unequivocally the benzylic carbon of I-dopa as the C-3 carbon in the DI (or its carboxyl derivative) repeating unit. In the melanin formed by autooxidation, however, the C-3 carbon was in the form of both a pyrrolelike and a carbonyl carbon. Eumelanins produced in a similar way from DI showed no presence of carbonylcarrying structural units. These results also strongly suggest that the polymerization step involves predominantly the 4 and 7 positions of the indole. Recent work by Aime and Crippa (358) shows that spectral features differentiate samples according to their various sources and that different functionalities present in eumelanins can be identified. E. ELECTRONIC STRUCTURE Despite the lack of knowledge of the precise molecular structure of melanins, many of their physical properties can be understood in terms of the electronic structure. Thus, the optical and electrical behaviors of melanins and melanosomes, which are consistent with the role observed or hypothesized in uiuo, can be interpreted in terms of the formalism of the solid-state theory. Pullman and Pullman were the first to perform a calculation of the band structure for an idealized indole-5,6-quinone polymer, and their results enabled the prediction of an exceptional electron-accepting ability arising from extension of the lowest empty band in the bonding energy region
302
RAIMONDO CRIPPA E T A L
(359). The possibility that melanins are intrinsic semiconductors was investigated experimentally in order to explain their properties, such as conductivity, photoconductivity, as well as the light and temperature dependence of the paramagnetism. Unfortunately, inconsistencies emerged between the models and experimental data. An analysis of this problem led McGinness (360) to suggest that such discrepancies could be worked out by appiication of theories on the electronic structure of amorphous materials proposed by Mott (361). The application of these new ideas yielded a model of melanin granules as hypothetical solid-state devices that might assume many physiological roles. The quantum mechanical solution of the random-square well model for the single particle wave function yields a set of energy levels different from those of crystals. For amorphous materials, the density of states is gaussian and the states under the peak are extended (i.e., the electron has the same probability of being found anywhere in the solid). On the contrary, the states under the tails are localized, and the electrons are restricted to a local volume. In this picture the mobility of the electrons in localized states depends on tunneling or phonon-assisted hopping. The resulting conductivity is not dependent on a gap in the density of states, as in the case of crystals, but is based on the mobility of electrons in localized states. For this reason the concept of “mobility gaps” substitutes the usual term “band gaps.” Many simplified reviews on this topic have been published, and readers are referred to the detailed treatment of the theory by Cohen (362).A short account of the concept is presented by Davis and Mott (363). Thus, one can test the validity of the model and calculate the most important parameters of the energy band structure of melanins. Experiments using a different approach gave somewhat different results. Working with melanin suspensions in 0.1 M hydrochloric acid, Strzelecka obtained an Eo value 1.4 eV and was able to reveal the presence of a band of states at the Fermi level (364). Despite the discrepancies, attributed to differences in the nature of the samples (melanins are very sensitive to degree of hydration and pH) the experiments confirm the consistency of the proposed model and provide useful data for further interpretation of the physical properties of melanins. Typical figures are (+ = 10-’2-10-’’ R-’ cm-’; (EF - Ev)= 1 eV, and Eo = 1.4-3.4 eV for synthetic melanins from L-dopa and hydroquinone (365) and for natural melanins extracted from bovine eyes, hair, and banana peels (82). The threshold switching in melanins and melanosomes, a rather exotic property of amorphous semiconductors, was studied by McGuiness et al.,
6. CHEMISTRY OF MELANINS
303
who demonstrated that it can happen at biologically attainable electrical field strengths (366-368). Study of the alteration of both the conductivity and threshold switching characteristics after doping of melanins with other molecules of biological importance and coupled with lowtemperature specific heat determinations (369) suggested the doping molecules as the carriers contributing to the conduction states. These findings support the hypothesis of a relation between electronic properties and cellular functions of inelanosomes as nonlinear energy transduction devices operating by phonon-electron coupling mechanisms (3f5).This biophysical model justifies the observed transition from a cytoprotective state at low energy input rates to a cytotoxic state at the high energy input rates. Strictly connected with these ideas are experiments on the absorption and dispersion of sound waves in melanins (370). A resonance absorption was found at I MHz, and a rather sophisticated theoretical interpretation allowed correlation of the shear spectrum with the presence of partially ordered structures. Particularly interesting is the observation that hydrated melanins and melanosomes are exceptionally “black” materials with respect to ultrasound absorption. More strictly related to the organization of pigmented tissues are studies on the electrical charge and/or polarization storage in melanins (which can consequently be classified as bioelectrets). This effect was discovered in synthetic melanins (365) but was also found in pigment epithelium-choroid complexes (371). Experiments performed via the thermally stimulated depolarization current (TSDC) technique showed a large depolarization current in the physiological temperature range in fresh pigmented eye tissue. This result can be explained only by preferential displacement of opposite charges or by natural orientation of electric dipoles in melanin molecules. The biological relevance of this peculiar histological feature is still not fully understood. It should be noted that the role of occular pigmentation is possibly more complex than believed on the basis of simple light absorption mechanisms. A fast photostable electrical response of the eye caused by melanin was identified (372), but its significance for vision processes is still doubtful. The possible biophysical consequences of the introduction of new physical models of melanins are stimulating and puzzling at the same time. New fields of investigation are open to test these models, in particular, the role of melanins in the inner ear and the functional significance of neuromelanin in the brain. Theoretical hypotheses on this last topic (373,374) are based on the electronic structure and physicochemical behavior of such pigments.
304
RAIMONDO CRIPPA E T A I
F. ESR SPECTROSCOPY Historically melanins were among the first biological molecules submitted to ESR investigations (375). The origin of their paramagnetism was debated for several years, but the presence of stable free radicals was almost always considered as the probable cause for the ESR signal. The classic publication by Blois et al. (376) provided definitive data on the spectral characteristics (including the g value, linewidth, temperature dependence, and magnetic interactions with Cu2+and confirmed both the presence of trapped free radicals and the close similarity between natural squid melanin and various synthetic preparations. More recently, the problem received great attention in an attempt to correlate the free radical properties of melanins to their chemical structure, biosynthesis, and possible physiological role in cells and tissues (75). 1 . Characteristics of ESR Spectra
The small differences in the ESR spectra of a large number of natural and synthetic eumelanins studied under various physical conditions were attributed to preparation and experimental conditions. Common parameters of the spectra are a single, slightly asymmetrical line that is nonhomogeneously broadened, without hyperfine coupling; g -2.004 and AH4-10 G,concentration 4-10 x lo” spins/g, corresponding to 1 radical per 3000 monomers of an average molecular weight of 200. The presence of residual protein moieties or metal ions (e.g., Zn, Cu, Fe in concentrations of 25-950 pg/g in samples extracted from bovine eyes) in natural eumelanins does not influence the ESR lineshape or intensity. Saturation recovery measurements gave values of relaxation times TI ranging between 10 and 20 sec, depending on the type of melanin and experimental conditions (377). All these experiments were performed on dried eye melanin or frozen suspensions. At present, no firmly based experimental data exist on TI and T2 for melanin under physiological conditions, primarily because of the strong dependence of the microwave saturation on the oxygen pressure. The effect of temperature on the paramagnetism (378), which was doubtful earlier, was recently definitely established both with regard to the spin concentration and linewidth on samples of suspended material. It was, moreover, correlated to temperaturedependent equilibria between diamagnetic groups (quinone, hydroquinone, or their donor-acceptor complexes) and their paramagnetic counterparts (biradicals and semiquinone radicals). All the spectral characteristics point to the presence of immobilized semiquinones as the simple radicals that originate the paramagnetism in melanins (S = l/2).This view is also supported by many experiments
305
6. CHEMISTRY OF MELANINS
involving oxidizing and reducing agents and the pH dependence of free radical concentration. The redox properties of many melanins were tested with various reactants, but their consequences on ESR spectral intensities are not unequivocal (75,324). However, it is still reasonable to attribute to melanins a scavenging ability for OH., H-, e-aq and other radicals, owing to the presence of various electron-exchange groups (379). The influence of pH on free radical concentrations is, on the other hand, well established and is due to the equilibrium (380) MQ
+ MQH2 $ 2
MQ-.
+ 2 H‘
As an example, the ratios of radical concentrations in aqueous suspensions of natural melanins at pH 1,7, and 14 are 0.5, 1 , and 7 respectively (309). Moreover differences in g values and linewidth were also found at different pH values, indicating the presence of various ionizable forms of the free radicals. However, at present, exact determinations of the pK, for melanins are subject to experimental difficulties owing to the appearance of irreversible changes during the titration with H+ and to the pH-dependent shift of the oxidation state (326). Equilibrium among the various forms of ionizable groups on melanins can also explain the well-known effects of metal ions on ESR spectral features. Diamagnetic ions generally enhance the ESR spectrum by a factor varying between 1.2 and 9. The equilibrium MQ
+
MQHz
2 H’
+ 2 MQ
2 1”’ ‘
2 MQ . I“+
(where I indicates a metal ion) can justify the finding that the extent of radical formation depends on the complexation ability of a particular ion. A concomitant broadening of the spectral line was noted with ions that possess a nuclear moment. The decrease of the ESR intensity observed with paramagnetic ions, originally reported by Blois et al. (376) with Cu” and also studied with synthetic and natural melanins ( 2 0 3 , has a different physical explanation. The formation of complex(es) places the ion in close proximity to the free radical, and the consequent strong magnetic interaction quenches the signal drastically. Details on the theoretical treatment of this phenomenon in melanins have been reported by Sarna et al. (381). Characteristics of the ESR spectra of phaeomelanins are quite different and deserve some comment. The usual spectrum is composed of a triplet with g = 2.0052, a value typical of immobilized radicals with hyperfine splitting due to nitrogen ( I = 1). Accurate measurements were accomplished on synthetic cysteinyldopa melanins (382) at various pH in DzO
306
RAIMONDO CRIPPA ET A L .
and in the presence of metal ions. All results point to the presence of semiquinonimine radicals. The most important consequence of such detailed studies is the definitive assignment of the ESR spectral characteristics of natural melanins, considered copolymers of dopa- and cysteinyldopa-derived monomers, as suggested by Prota (34).In a comparative study of synthetic melanins, prepared with different ratios of dopa and cysteinyldopa as starting materials, and natural malanins, it was possible to demonstrate the presence of both 0 , O - and p-N,Osemiquinones and semiquinonimine free radicals (382) in ratios directly related to the chemical composition.
2. Efiect of Light on Free Radicals Studies of the absorption of electromagnetic radiation in both the UV and visible regions by melanins resulted in an enhanced population of radicals being characterized by ESR. The absorption of light by melanin suspensions induces transient free radicals at wavelengths throughout the visible and UV region. They differ slightly from intrinsic radicals, showing a more complex ESR spectrum, with a higher g value, broader linewidth, and, possibly, a shorter T I .This induced population consists of two components, one characterized by a low yield (of the order of 1-2%) and a decay time of a few seconds and the other with a decay time of a few milliseconds that accounts for about 50% of the signal (252).The complex kinetics, temperature independent for the fast decay component, probably involve physical effects such as electron tunneling mechanisms and is further complicated by pH and oxygen pressure dependence, as suggested by accurate measurements with spin traps and superoxide dismutase (383, indicating the formation of 02--in transient equilibria under light. The transient nature of the light-induced radicals with the first half-life (time resolution 0.1 sec) of around 1 sec (384-386) was confirmed in more detailed studies (252). Using a pulse photolysis system (time resolution 0.2 msec), the existence of a slow (half-life 5 sec, second-order kinetics, large temperature dependence) and fast (chemical lifetime 50 msec, no temperature dependence) decaying spectral component was revealed. During continuous irradiation the contribution of the fast decaying component is dominant (50- 100 times), and the process shows characteristics of a singlet-triplet intersystem crossing mechanism. The entire photoexcitation process, which is considered by some to have relevance to the photoprotective action of melanins, is formulated as follows: Q
+ QH* 2
singlet
+ triplet -+
QH.
+ QH. + Q + QH?
where Q, QH2, and QH. represent quinone, quinol, and semiquinone units of the polymer, respectively.
307
6. CHEMISTRY OF MELANINS
During photolysis of phaeomelanins biologically active OH. and 0 2 - . are produced in concentrations about 100 times higher than in eumelanins. Nanosecond laser-flash photolysis indicates a photoionization of the excited state of the molecule producing a phaeomelanin radical action and hydrated electrons (387) that are responsible for the reduction of molecular oxygen to 0 2 - .The . biological and pathological implications of the deexcitation pathways of melanins are discussed in a review by Chedekel (388) with particular emphasis on the consequences of the formation of HPETEs during the photodegradation of phaeomelanins in the presence of arachidonic acid. These reactions open new areas in the study of the physiopathology of human skin cancer under sunlight irradiation. The Appendix lists the abbreviations that were used throughout the chapter.
Appendix
Abbreviation AA
Compound name
Structure CH,OH
Ascorbic acid
I
HO
6-ADA
6-Aminodopamine
ADR
Adrenaline (epinephrine)
OH
CHCHZNHCH3
I
OH
A-MD
y z
a-Methyldopa
H ~ ~ H ~ - : - C O O H
HO
\
CH3
(conrinued)
308
RAIMONDO CRIPPA E T A L .
Appendix (Continued)
Abbreviation A-MDA
Compound name
Structure
a-Methyldopamine
CH,CHNH,
I
CH 3
A-MNADR
a-Methylnoradrenaline
/
CHCHNH,
I I
HO CH,
BZQ
Benzoquinone
BZQ-2M-31
2-(2-Methyl-3-indolyI)benzoquinone
CAT
Catechol
CPZ
Chlorpromazine
CRD
Carbidopa
CRT
Creatinine
309
6 . CHEMISTRY OF MELANINS
Appendix (Continued)
Abbreviation DA
Compound name Dopamine (3-hydroxytyramine)
Structure H 0 ~ C H z C H z N H z HO
DHBA
3,4-Dihydroxybenzylamine
DHEPH
3.4-Dihydroxyephedrine
DI
5.6-Dihydroxyindole HO H
DICA
5.6-Dihydroxyindole-2-carboxylicacid COOH
H
3,4-DHMA
p
OH
3.4-Dihydroxymandelic acid
OH
CHCOOH
I
OH
5.6-DH MI
5.6-Dihydroxy-2-methylindole
DHPAA
3,4-Dihydroxyphenylacetic acid H o ~ C H z C o o H HO
DOE
Dioxethedrine
OH
OH
CHCHNHCH~CH,
I
I
OHCH,
3 10
RAIMONDO CRIPPA ET A L
Appendix (Continued)
Abbreviation Dopa
Compound name Dopa (3.4-dihydroxyphenylalanine)
Structure HODHz;".f"oH HO
EPH
Ephedrine
EPI
Epinine (deoxyepinephrine)
OH
OH
0 ~H,CH ,NHCH,
6-HDA
p
OH
6-H ydrox ydopamine
OH
CH ,CH,NHCH,
5HI-3AA
5-Hydroxyindole-3-acetic acid H
HMVA
Homovannilic acid
,COOH
CH H J p,01
HO
HQ
IND
Indole
IPADR
N-lsopropyladrenaline
OH
OH
@
CH CH ,NCH
I
OH
I
CH(CH,),
31 1
6. CHEMISTRY OF MELANINS
Appendix (Continued)
Abbreviation IPNADR
Compound name
N-Isopropylnoradrenaline(isoproterenol. isoprenaline)
Structure OH
OH
>-=
LHCH,NHCH(CH,), I OH
M-DI
HO
MN
Metanephrine
6"
CH,O
CHCHZNHCH,
I
OH MTAM
3-Methox ytyramine
CH30
OH
@
CH,CH,NH,
NMN
Normetanephrine (3-0-methylnoradrenaline)
CH30
$H CHCH ZNH 2
I
OH NADR
Noradrenaline (norepinephrine)
SAL
Salsoline
(continued)
312
RAIMONDO CRIPPA ET A L
Appendix (Continued)
Abbreviation
Compound name
SALOL
Salsolinol
SER
Serotonin
TRP
Tryptophan
TYR
Tyrosine
VMA
Vanillylmandellic acid
Structure
CH COOH
I
OH UA
Uric acid
REFERENCES
I . J . E. Saxton, ed., "Indoles," Part 4. Wiley. New York, 1983.
2. M. Thomas. in "Moderne Methoden der Pfanzen Analyse" ( K . Paech and M. V. Tracey, eds.), Vol. 4. p. 661. Springer-Verlag. Berlin, 1955. 3. R. A. Nicolaus, in "Methodicum Chimicum" (F. Korte and M. Goto, eds.), Vol. 11, Part 3 , p. 190. Academic Press, New York. 1978.
6. CHEMISTRY OF MELANINS
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CUMULATIVE INDEX OF TITLES
Aconitum alkaloids, 4, 275 (1954), 34,95 (1988)
diterpenoid, 7,473 (1960) CI9diterpenes, 12,2 (1970) Czoditerpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, experimental antitumor activity of acronycine, 21, I ( 1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8,789 (1965). 11,41 (1968) Alkaloid structures spectral methods, study, 24,287 (1985) unknown structure minor alkaloids, 5, 301 (1955). 7, 509 (1960) unclassified alkaloids, 10,545 (1967), 12,455 (1970). 13, 397 (1971),14,507 (1973). 15, 263 (1975). 16, 511 (1977) Alkaloids in Cannabis safivu L.. 34, 77 (1988) the plant, 1, 15 (1950). 6, l(1960) Alkaloids from African Sfrychnos, 34, 21 1 (1988) Ants and insects, 31, 193 (1987) Aspergillus, 29, 185 (1986) Guafteria,35, 1 (1989) Pauridiuntha species, 30,223 (1987) Tabernaemontana, 27, I (1986) AIstonio alkaloids, 8, 159 (1965). 12, 207 (1970), 14, 157 (1973) Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960), 11, 307 (1968). 15, 83 (1975). 30, 251 (1987) Amphibian alkaloids, 21, 139 (1983) Analgesics, 5, I (1955) Anesthetics, local, 5, 21 1 (1955) Anthranilic acid, related to quinoline alkaloids, 17, I05 (1979). 32, 341 (1988) Antimalarials, 5, 141 (1955) Antitumor alkaloids, 25, 1 (1985) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4, 119 (1954). 9, 1 (1967), 24, 153 (1985) Arisfolochia alkaloids, 31, 29 (1987) Aristoieliu alkaloids, 24, I13 (1985) Aspidosperma alkaloids, 8, 336 (1965), 11,205 (1968). 17, 199 (1979) Azafluoranthene alkaloids, 23, 301 (1984) 325
326
CUMULATIVE INDEX OF TITLES
Bases simple, 8, I (1965) simple indole, 10, 491 (1967) Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954). 10, 402 (1967) Bisbenzylisoquinoline alkaloids, 4, 199 (1954), 7,439 (1960), 9, 133 (1967). 13, 303 (1971). 30, I (1987) occurrence, 16, 249 (1977) structure. 16, 249 (1977) pharmacology, 16, 249 (1977) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981) Buxus alkaloids, steroids, 9, 305 (1967), 14, 1 (1973) Cactus alkaloids, 4, 23 (1954), 21, 255 (1983) Calabar bean alkaloids, 8,27 (1965). 10,383 (1967). 13,213 (1971) Calabash curare alkaloids, 8,515 (1969, 11, 189 (1968) Calycanthaceae alkaloids, 8,581 (1965) Camptothecin, 21, 101 (1983) Cancentrine alkaloids, 14,407 (1973) Capsicum species, pungent principle of, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971), 26, I (1985) Carboline alkaloids, 8, 47 (1965). 26, I (1985) P-Carboline congeners and ipecac alkaloids, 22, 1 (1983) Cardioactive alkaloids, 5,79 (1955) Celestraceae alkaloids, 16, 215 (1977) Cephalotuxus alkaloids. 23, 157 (1984) Chemotaxonomy of papaveraceae and fumariaceae, 29, 1 (1986) Chinese medicinal plants, alkaloids. 32, 24 I (1988) Chromone alkaloids. 31,67 (1987) Cinchona alkaloids, 14, 181 (1973). 34, 331 (1988) chemistry, 3, 1 (1953) Colchicine, 2,261 (1952). 6,247 (1960). 11,407 (1968). 23, I (1984) Configuration and conformation, elucidation by X-ray diffraction, 22, 51 (1983) Corynantheine, yohimbine, and related alkaloids, 27, 131 (1986) Cularine alkaloids, 4, 249 (19541, 10,463 (1967). 29, 287 (1986) Curare-like effects. 5, 259 (1955) Cyclic tautomers of tryptamines and tryptophans, chemistry and reactions. 34, 1 (1988) Cyclopeptide alkaloids, 15, 165 (1975)
Daphniphyllum alkaloids, 15,41 (1975). 29, 265 (1986) Delphinirrm alkaloids, 4, 275 (1954)
diterpenoid. 7, 473 (1960) Clo-diterpenes. 12, 2 (1970) Czu-diterpenes, 22, 136 (1970) Dibenzazonine alkaloids, 35, 177 (1989) Dibenzopyrrocoline alkaloids, 31, 101 (1987) Diplorrhyncus alkaloids, 8, 336 (1965) Clg-Diterpene alkaloids Aconitirm. 12, 2 (1970)
CUMULATIVE INDEX O F TITLES Delphinium, 12, 2 (1970) Garrya, 12, 2 (1970) structure, 17, I(1970) synthesis, 17, I(1979) Czo-Diterpene alkaloids Aconitum, 12, 136 (1970) chemistry, 18,99 (1981) Delphinium, 12, 136 (1970) Garrya, 12, 136 (1970) Distribution of alkaloids in traditional Chinese medicinal plants, 32, 241 (1988) Diterpenoid alkaloids Aconitum. 7,473 (1960), 12,2 (1970) Delphinium. 7,473 (1960), 12, 2 (1970) Gurrya, 7,473 (1960). 12, 2 (1960) general introduction, 12, xv (1970) Cly-diterpenes,12, 2 (1970) Czo-diterpenes,12, 136 (1970) Eburnamine-Vincamine alkaloids, 8, 250 (1965), 11, 125 (1968),20, 297 (1981) Elaeocarpus alkaloids, 14,325 (1973) Elucidation, by X-ray diffraction structural formula, 22,51 (1983) configuration, 22,51 (1983) conformation, 22, 5 1 (1983) Enamide cyclizations. application in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and in uifro, 18, 323 (1981) Ephedra bases, 3, 339 (1953), 35, 77 (1989) Ergot alkaloids, 8, 726 (1965), 15, 1 (1975) Erythrina alkaloids, 2,499 (1952), 7, 201 (1960). 9,483 (1967). 18, I (1981) Erythrophleum alkaloids, 4, 265 (1954). 10,287 (1967) Eupomafia alkaloids, 24, I (1985) Forensic chemistry, alkaloids, 12, 514 (1970) by chromatographic methods, 32, I (1988) Galhulimima alkaloids, 9,529 (1967), 13, 227 (1971) Garrya alkaloids diterpenoid, 7,473 (1960) C I VV-diterpenes, 12, 2 (1970) Czo-diterpenes,12, 136 (1970) Geissospermum alkaloids, 8, 679 (1965). 33, 84 (1988) Gelsemiurn alkaloids, 8,93 (1965). 33,83 (1988) Glycosides, monoterpene alkaloids, 17,545 ( 1979) Haplophyron cirnicidum alkaloids, 8, 673 ( 1965) Hasubanan alkaloids, 16, 393 (1977).33, 307 (1988) Holarrhena group, steroid alkaloids, 7 , 319 (1960) Hunferia alkaloids, 8, 250 (1965)
327
328 fbogu alkaloids,
CUMULATIVE INDEX OF TITLES
8, 203 (1965).11,79 (1968)
Imidazole alkaloids, 3,201 (1953),22,281 (1983) Indole alkaloids, 2,369 (1952).7,I (1960),26,1 (1985) distribution in plants, 11, I (1968) simple, including P-carbolines and P-carbazoles, 26,I (1985) Indole bases, simple, 10,491 (1967) Indolizidine, simple and quinolizidine alkaloids, 28, 183 (1986) 2,2'-Indolylquinuclidine alkaloids, chemistry, 8, 238 (1965).11,73 (1968) In uirro and microbial enzymatic transformation of alkaloids, 18,323 (1981) Ipecac alkaloids, 3,363(1953).7,419(1960).13,189 (1971).22,I (1983) P-Carboline alkaloids, 22,1 (1983) Isolation of alkaloids, I, I (1950) lsoquinoline alkaloids, 7,423 (1960) biosynthesis 4,1 (1954) "C-NMR spectra, 18, 217 (1981) simple isoquinoline alkaloids, 4,7 (1954),21,255 (1983) Isoquinolinequinones. from actinomycetes and sponges, 21,55 (1983) Kopsia alkaloids, 8, 336 (1965)
Local anesthetics, alkaloids, 5,21 1 (1955) Localization of alkaloids in the plant. 1, 15 (1950),6, I (1960) Lupine alkaloids, 3,119 (1953).7,253 (1960).9,175 (1967),31, I16 (1987) Lycopodium alkaloids, 5,265(1955).7,505 (1960),10,306 (1967),14,347 (1973),26,241
(1985) Lythraceons alkaloids, 18,263 (1981), 35,I55 (1989) Mammalian alkaloids, 21,329 (1983) Marine alkaloids, 24, 25 (1985) Maytansinoids, 23,71 (1984) Melodinus alkaloids, 11,205 (1968) Mesembrine alkaloids. 9,467(1967) Metabolic transformation of alkaloids, 27,323 (1986) Microbial and in v i m enzymatic transformation of alkaloids, 18,323 (1981) MitraRynu alkaloids. 8, 59 (1965).10, 521 (1967),14, 123 (1973) Monoterpene alkaloids, 16,43I (1977) glycosides, 17,545 (1979) Morphine alkaloids. 2, I (part I , 1952),2,161 (part 2,1952), 6, 219 (1960),13, I (1971) Muscarine alkaloids, 23,327 (1984) Mydriatic alkaloids, 5, 243 (1955) a-Naphthaphenanthridine alkaloids, 4,253(1954).10,485(1967) Naphthyl isoquinoline alkaloids. 29,141 (1986) Narcotics. 5, 1 (1955) "C-NMR spectra of isoquinoline alkaloids, 18, 217 (1981) Nuphuralkaloids, 9,441 (1967).16,181 (1977),35,215 (1989) Orhrosiu alkaloids, 8, 336 (1965).11,205 (1968) Ourcitpurici alkaloids, 8, 59 (1965).10,521 (1967) Oxaporphine alkhloids, 14,225 (1973)
CUMULATIVE INDEX OF TITLES
329
Oxazole alkaloids, 35, 259 (1989) Oxindole alkaloids, 14, 83 (1973) Papaveraceae alkaloids, 10,467 (1967). 12, 333 (1970). 17, 185 (1979) pharmacology, 15, 207 (1975) toxicology, 15,207 (1975) Pavine and isopavine alkaloids, 31, 317 (1987) Penfaceras alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids, 19, 193 ( 1981) P-Phenethylamines, 3, 313 (1953). 35,77 (1989) Phenethylisoquinoline alkaloids, 14, 265 (1973) Phthalideisoquinoline alkaloids. 4, 167 (1954). 7,433 (1960). 9, I17 (1967). 24, 253 (1985) Picralima alkaloids, 14, 157 (1973) Picralima nifida alkaloids, 8, I19 (1965). 10, 501 (1967) Piperidine alkaloids, 26, 89 (1985) Plant systematics, 16, I (1977) Pleiocurpu alkaloids, 8, 336 (196.5). 11, 205 (1968) Polyamine alkaloids, putrescine, spermidine. spermine, 22,85 (1983) Pressor alkaloids, 5 , 229 (19%) Profoberherine alkaloids. 4, 77 (1954). 9,41 (1967). 28,95 (1986), 33, 141 (1988) Protopine alkaloids. 4, 147 (1954). 34, 181 (1988) Pseudocinchona alkaloids, 8, 694 (1965) Putrescine and related polyarnine alkaloids, 22, 85 (1983) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960). 11,459 (1968). 26, 89 (1985) Pyrrolidine alkaloids, 1,91 (1950). 6, 31 (1960), 27, 270 (1986) Pyrrolizidine alkaloids, 1, 107 (1950), 6, 35 (1960), 12, 246 (1970). 26, 327 (1985) Quinazolidine alkaloids, see Indolizidine Alkaloids Quinazoline alkaloids, 3, 101 (1953), 7, 247 (1960), 29,99 (1986) Quinazolinocarbolines. 8,55 (1965). 21, 29 (1983) Quinoline alkaloids other than Cinchona. 3, 65 (1953). 7, 229 (1960) related to anthranilic acid, 17, 105 (1979). 32, 341 (1988) Rau~wlJiaalkaloids, 8, 287 (1965) Reissert synthesis of isoquinoline and indole alkaloids, 31, I (1987) Reserpine, chemistry, 8, 287 (1965) Respiratory stimulants, 5, 109 (1955) Rhoeadine alkaloids, 28, I (1986)
Salamandra group, steroids, 9,427 (1967) Scelefiuim alkaloids, 19, 1 (1981) Senecio alkaloids, see Pyrrolizidine alkaloids Secoisoquinoline alkaloids, 33,231 (1988) Securinega alkaloids, 14,425 (1973) Sinomenine, 2, 219 (19.52)
330
CUMULATIVE INDEX OF TITLES
Solanum alkaloids chemistry. 3 , 247 (1953)
steroids, 7,343, (1960). 10, I(1967). 19, 81 (1981) Sources of alkaloids, 1, I (1950) Spectral methods, alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids, 22, 85 (1983) Spermine and related polyamine alkaloids, 22, 85 (1983) Spirobenzylisoquinoline alkaloids, 13, 165 (1971) Sponges, isoquinolinequinones, 21,55 (1983) Stemona alkaloids. 9, 545 (1967) Steroid alkaloids Apocynaceae, 9, 305 (1967), 32, 79 (1988) Bu.rirs group, 9, 305 (1967). 14, 1 (1973). 32, 79 (1988) Holarrhena group, 7, 3 I9 (1960) Salamandru group, 9,427 (1967) Solanumgroup, 7, 343 (1960), 10, 1 (1967), 19, 81 (1981) Verulrum group, 7,363 (1960). 10, 193 (1967), 14, 1 (1973) Stimulants respiratory, 5, 109 (1955) uterine. 5, 163 (1955) Structural formula, elucidation by X-ray diffraction, 22, 51 (1983) Strychnos alkaloids. 1,375 (part 1-1950).2, 513 (part 2-1952), 6, 179 (1960), 8, 515. 592 (1965). 11, 189 (1968). 34,21 I (1988) Sulfur-containing alkaloids. 26, 53 ( 1985) Tuxus alkaloids, 10,597 (1967) Toxicology, Papaveraceae alkaloids. 15, 207 ( 1975) Transformation of alkaloids. enzymatic, microbial and in uifro. 18, 323 (1981) Tropane alkaloids, 1,271 (1950). 6, 145 (1960). 9, 269 (1967). 13, 351 (1971), 16, 83 (1977). 33, 1 (1988) Tropoloisoquinoline alkaloids. 23, 301 (1984) Tropolonic Colrhicum alkaloids, 23, I (1984) Tylophoru alkaloids. 9, 517 (1967) Uterine stimulants. 5, 163 (1955) Verufrrrrn alkaloids
chemistry, 3,247 (1952) steroids, 7, 363 (1960). 10, 193 (1967). 14, I ( 1973) “Vinca” alkaloids, 8,272, (1965)-11, 99 (1968) Voucungu alkaloids. 8, 203 (1965). 11, 79 (1968) X-Ray diffraction, elucidation of structural formula. configuration, and conformation, 22, 51 (1983) Yohimbe alkaloids. 8, 694 (1965) Yohirnbine alkaloids. 11, 145 (1968). 27, 131 (1986). see also Coryantheine
INDEX Amarorine. 140, 147 Aminohydroxyphenylalanine, 285 Androcymbine-type alkaloids, 189 biosynthesis of, 200 Angustidine. 13 Angustine, 13 Angustoline. 13 Antirhine, 1 1 Aricine, 99 Aristoyagonine, I25 Atherospermidine, 1 1 1
A
N-Acetyl-3-deoxyisostrychnosplendine. 21 0-Acetyldomesticine, 80 0-Acetylkreysigine, 83 0-Acetylhenningsoline, 23 0-Acetylisoretuline, 17 N-Acetylisostrychnosplendine,21 0-Acetyl-N-methyllaurotetanine, 83 N-Acetylnorreticuline, 92 oxidation of, 92 0-Acetylpredicentrine, 79 0-Acetylretuline, 17 0-Acetylsrilankine, 112 N-Acetylstrychnosplendine, 21 Acet yltabascanine, 19 0-Acetylthaliporphine, 72, 80 Afrocurarine, 38 Ajmaline, 105 Ajmaline alkaloids, by LTA oxidation of, 104 Akagerine, 7 Akagerine lactone, 9 Alkaloid 1, 185 Alkaloid 6, 185 A-Alkaloid H, 40 C-Alkaloid A, 42 C-Alkaloid D, 41 C-Alkaloid E, 43 C-Alkaloid F, 42 C-Alkaloid G , 43 C-Alkaloid K , 39 CC-2 alkaloid, 190 CC-I0 alkaloid, 175, 189 CC-20 alkaloid, 176, 189 CC-24 alkaloid, 183 Allomelanins, 254 Alstonine, 5 Alvimine, 19 Alviminine, 25 Amaroridine. 140, 147
B Benzophenanthridines, by oxidation of berbines, 95 0-Benzylmultifloramine, 84 N'-Benzylnoresermethole, 24 I Berberastine, I18 Bisnor-C-alkaloid H , 40 Di-N-oxide of 40 Mono-N-oxide of. 40 Bisnordihydrotoxiferine, 39 N-oxide of, 39 Bispheneth ylisoquinolines, I72 Boldine, 79 Bracteoline, 75 Brafouledine, 33 7-Bromoeseroline. 24X Brucine, 26 Brucine N-oxide, 26
C Calabacine, 226 Calabar bean, alkaloids of, 225 Calabatine, 225 33 1
332 C-Calabassine, 22 Camptoneurine, I I Canadine, 97 Canthin-2,6-dione, 141, 150 Canthin-6-one, 135, 137, 138. 161 biosynthesis of, 164 NMR-spectroscopy of, 154 pharmacology of, 165 synthesis of, 155 Canthin-6-one N-oxide, 137, 139 Caracurine II,43 Caracurine V , 43 Di-N-oxide of, 43 Mono-N-oxide of, 43 Carapanaubine, 99 Cataline, 73. I12 Catecholamines, electrochemical oxidation of. 276 thermolytic decomposition of, 277 Chilenine, 120 Chitosenine, 50 structure proof, 55 8-Chloroamurine, 92 8-Chlorocodarnine, 76, 92 9-Chloroisopavines, 92 8-Chloro-0-rnethylandrocymbine. 94 8-Chloro-O-methylflavinantine, 92 Codamine, oxidation of, 72 Colchiritchine, 176 Colchitrichine, 190 Collutine, 175, 189 a-Colubrine, 26 P-Colubrine, 27 Comosidine, 184, 195 Comosivine, 195 Condylocarpine, 16 Coronaridine, 108 Corunnine, 110 Corypalline, 127 Corytencine, 116, I18 Cularidine, 120 Cularidines, by LTA oxidation of, 120 C-Curarine I , 43 N-Cyano-sec-pseudocolubrine.3 I N-Cyano-sec-pseudostrychnine,3 I N-Cyan-sec-pseudobrucine, 3 I Cysteinyl-dopa. 263
INDEX
D N-Deacet yl- I8-acetoxyisoretuline, I8 Deacetylgeissovelline, 106 N-Deacetyl-18-hydroxyisoretuline,18 N-Deacetylisoretuline, 18 N-Deacetylretuline, 18 Decussine, 10 1,2-Dehydroajrnaline, 105 2,16-Dehydrodiaboline, 23 Dehydroglaudine, I10 18-Dehydro- 10-hydroxynigritanin, 33 18-Dehydronigritanin, 33 Dehydrostrychnobiline, 44 Dehydroushinsunine, I I I Demethoxy-0-methylandrocyrnbine,93 0-Demethylsilanine, 25 Deoxysarpagine, 60 18-Deoxy Wieland-Gumlich aldehyde, 17 Descarbomethox ydi h ydrogambirtan nine. 13 Deserpidinediol, 98 Desethylibogamine, 108 Diaboline, 23 5,6-Diacetoxyindole, 279 Diacetylajmaline, I05 Dibenz[df]azecines, 172 Dibenzopyrrocolines, by LTA oxidation of isoquinolines, 96 4,5-Dihydrocanthin-6-one, 141, I50 Dihydrocorynantheine, 98 3,14-Dihydrodecussine, 10 2,7-Dihydroerysotrine, 184, 195 6.7-Dihydroflavopereirine, 12 6.7-Dihydrohornoerysotrine196 Dihydroisosilirikine, 98 Dihydrornilenine, 105 Dihydronitidine, 95 Dihydrosanguilutine, 96 4,5-Dihydroxycanthin-6-one, 149 1.2-Dihydroxy-9, 10-dimethoxyaporphine, 79 5.6-Dihydroxyindole, polymerization of, 265 5,6-Dihydroxyindole-2-carboxylicacid, from melanin, 285 Dihydrousambarensine. 35 18, 19-Dih ydrousambaridine, 34 Dihydrovornilenine, 105
333
INDEX
2.10-Dimethoxyaporphine,76 I , ] I-Dimethoxycanthin-6-one, 141, 148 4,5-Dimethoxycanthin-6-one, 136, 141, 149 18-Dimethoxygardfloramine, 5 1 Dimethoxygardmultine, 5 1 18-Dimethoxygardneramine, 49 Dimethoxy-hr-methyltetrahydrousambarensine, 36 10,I I-Dimethoxystrychnobrasiline,22 Dimethoxytetrahydrousambarensine,36 Dimethylgardneramine, 49 Dinklageine, 46 Diplocerine, 4 Discretine, 115, 118 Dolichantoside, 3 Dolichocurine, 44 Domesticine. 73 Dopachrome, rearrangement of, 264 Dysazecine, 186, 197 Dysoxyline. 173, 174, 198
E
F Floramultine, 195 Fluorocurarine, 15 C-Flurocurine, 7
G Garderine, 105 Gardfloramine, 5 1 structure proof, 56 Gardmultine, 51 Gardneramine, 49 structure proof, 52 N-Oxide of, 49 Gardneramine c yanoborohydride, X-ray analysis of, 53,58 Gilrdneria alkaloids, 1,47 chemical correlation of, 52 NMR studies of, 54 pharmacology of, 61 Gardnerine, 48 Gardnutine, 49 Geneserine, 226 synthesis of, 243 structure of salt, 244 Glaucine, 73, 79, I10 Govanine, 113
Ellipticine, 1 I 3-Epi-2,7-dihydroerysotrine, 184, 195 16-Epidiplocerine, 4 Epilimousamine, 121 21-Epi-0-methylkribine, 8 17-Epi-0-methyl-I I-methoxydiaboline, 23 Epiwilsonine, 186, 195 H 2 1,22-Epoxy-4,14-dihydroxy-3-methoxy-NMethyl-sec-pseudostrychnine, 3 1 Henningsamine, 23 Epoxynovacine, 32 Henningsoline, 23 Epoxypseudostrychnins, 32 Hirsutine, 98 Epoxyvomicine, 32 Holidine, 183, 187, 198 Ericsonine, 6 biosynthesis of. 201 Erysodine, 121 Holidinine, 195 Erysovine, 121 Holstiline, 29 Erythrina alkaloids, Holstiine, 29 by LTA oxidation of, 121 Homoaporphines, 90. 112. 172 Eseramine, 226 by LTA oxidation of, 90 Eserethole, 231, 237 Homoerythrina alkaloids, 172 Esermethole, 235 biosynthesis of, 201 Eseroline, 235, 241 Homoisopavines, pharmacology of, 248 by LTA oxidation of isoquinolines. 94 16-Ethoxystrychnine, 28 Homolaudanosine, 173, 174 Eumelanins, 254
334
INDEX
Hornornorphinandienones. 91, 172 by LTA oxidation, 90 Hornoproaporphines, 172 biosynthesis of, 200 10-Hydroxyakagerine, 7 I-Hydroxycanthin-6-one, 139, 142 2-Hydroxycanthin-6-one. 139, 143 4-Hydroxycanthin-6-one, 139, 143 5-Hydroxycanthin-6-one. 139 8-Hydroxycanthin-6-one. 140, 145 10-Hydroxycanthin-6-one,140, 146 I I-Hydroxycanthin-6-one. 140, 147 3-Hydroxy-a-colubrine, 28 2-Hydroxy-2I-deoxyajrnaline,104 3-Hydroxydiaboline, 24 10-Hydroxy-3, 14-dihydrodecussine, 10 3-Hydroxy- I ,2-dirnethoxyaporphine, 75 10-Hydroxy-2 I-epi-0-rnethylkribine, 8 Hydroxygardnerine, 48 Hydroxygardnutine, 49 14-Hydroxyicajine. 29 16-Hydroxyisoretulinal, 17 18-Hydroxyisoretuline, 18 Hydroxyisostrychnobiline, 44 Hydroxyjatrorrhizine. I 19 Hydroxylation of isoquinolines, by LTA, 1 1 1 140, I-Hydroxy-l I-rnethoxycanthin-6-one, 148 4-Hydroxy-5-rnethoxycanthin-6-one, 141, I49 5-Hydroxy-4-rnethoxycanthin-6-one. 141, 149 I I-Hydroxy-I-rnethoxycanthin-6-one, 14I , I48 IO-Hydroxy-3-rnethoxycanthin-2,6-dione, I50 12-Hydroxy- I I-rnethoxydiaboline, 24 12-H ydroxy-1 1methoxy-N-methyl-secpseudostrychnine, 29 12-Hydroxy-1I-rnethoxysperrnostrychnine, 21 4-Hydroxy-3-rnethoxystrychnine, 27 12-Hydroxy-1I-rnethoxystrychnobrasiline, 22 12-Hydroxy- 1 I-rnethoxystrychnofendlerine, 22 10-Hydroxy- 17-0-rnethylakagerine, 7 5-Hydroxyrnethylcanthin-6-one, 140, 145 14-Hydroxynovacine, 30
12-Hydroxyretulinal, 17, 18 4-Hydroxysarcocapine, I25 4-Hydroxystrychnine, 27 15-Hydroxystrychnine, 27 4-Hydroxythaliporphine, 76, 112 2-Hydroxytropanes, 109
I Iboga alkaloids, by LTA oxidation of, 106 Ibogarnine, 108 Icajine, 30 Icajine N-oxide, 30 Indacanthinone, 141, I50 Infractopicrin, 135, 141, 154 Inverted Yohirnbinoid alkaloids, 103 Isoauturnnaline, 173, 175 Isoboldine. 75 Isobrafouledine, 33 Isocorypalline, 124, 129 Isodolichantoside, 3 Isodornesticine. 79 Isornalindine, 14 Isopavines, by LTA oxidation, 94 Isophellibilidine, 188, 199 Isoregelinone. 181 Isoreserpine, 99 Isoreserpinediol. 98 Isoretulinal, 17 Isoretuline, 17 Isorosibiline, 15 Isositosirikine, 4 Isosplendine, 22 Isosplendoline, 22 Isostrychnine, 25 Isostrychnobiline, 44 Isostrychnofoline, 36 Isostrychnopentarnine, 34 Isostrychnophylline, 36 Isostrychnosplendine, 22 Isothebaine, 75 Isovelbanarnine, 108
J Janussine A,B, 37 Jobertine, 23
INDEX Jolantamine, 180, 191 Jolantimine, 181 Jolantine, 180, 191 Jolantinine, 177, 191
K Kesselridine. 178, 191 Kesselringine, 179. 191 Koumine, 60 Kreysigine, 83 Kreysiginine, 190 Kreysiginone, 90 Kribine, 8
L Laudanine, oxydation of with LTA, 82 Lead tet raacetate, Oxidation of isoquinolines, 69 Limousamine, 120 Lirinine, 75 Liriodenine, 11 I Luteicine, 178 Luteidine, 180, 192
M Macusine B, 5 Malindine, 14 Matopensine, 41 N-oxide of,41 C-Mavacurine, 6 Melanins, analysis of, 282. 284 biosynthesis of,257 complexation of, 295 definition of, 254 degradation of,285 derivatization of, 292 isolation of, 279 occurrence of, 256 oxidation of, 286 solubility of,280 spectroscopic characterization of,297
335
synthetic melanins, 268 X-ray diffraction analysis of,298 Melanochromes. 266 Melinonine E, 14 Merendrine, 183 3-Methoxycanthin-2,6-dione, 135, 141, 150, 162 3-Methoxycanthin-5,6-dione,I35 5-Methoxycanthin-2.6-dione.141, 150, 162 I-Methoxycanthin-6-one, 139, 142 I-Methoxycanthin-6-one N-oxide, 139, 143 4-Methoxycanthin-6-one, 139, 144 5-Methoxycanthin-6-one. 136, 140. 145 9-Methoxycanthin-6-one1 140. 146 10-Methoxycanthin-6-one. 140, 146 11-Methoxycanthin-6-one. 140, 147 10-Methoxy-0-demethylsilanine. 25 I I-Methoxydiaboline. 24 1 I-Methoxyisoretuline, 18 3-Methox y-N-meth yl-secpseudostrychnine, 30 1 I-Methoxyretuline, 18 10-Methoxysilanine, 25 16-Methoxystrychnine, 28 1 I-Methoxystrychnofendlerine,22 1 I-Methoxy Wieland-Gumlich aldehyde, 24 0-Methyl-N-acetylstrychnosplendine, 2I 0-Methylandroc ymbine, 93, I90 N-Methylantirhine, I 1 0-Methylatheroline, I10 3-Methylcanthin-5,6-dione. 141, 152 N-Methylcoralydine, 126 0-Methyldihydromacusine B. 5 O-Methylgigantine, I24 Methylisoresepate, 99 0-Methylkreysigine, 182. 194 21-0-Methylkribine, 8 N-Methyllaurotetanine, 75. 80 0-Methyllimousamine, 120 0-Methylmacusine B, 5 3-Methyl-4-methoxycanthin-5,6-dione, 152 17-@Methyl- 1 1methoxy Wieland-Gumlich aldehyde, 24 0-Methylmultifloramine. 85 Methylreserpate, 99 N-Methylsalsoline, 124 N-Methyl-sec-pseudo-b-colubrine, 30 0-Methylthalisopavine, 95 4-Methylthiocanthin-6-one, 136, 139, 144 N-Methylusambarensine,36
336
INDEX
Morphinandienones, 91 Multifloramine. 85
N Nigakinone, 141, 149 Nigritanin, 34 Nitidine, 95 N'-Noreserrnethole, 240 Nor-C-fluorocurarine. 15 Normacusine B, 5 N'-Norphysostigmine, 24 I N'-Norphysostigrnine, 226 Norsalutaridine, 92 Novacine, 30
0
Ochropine, 59 Ophiocarpine, I19 Oxindoles, by LTA oxidation, 99 Oxoaporphrines, by LTA oxidation of, 110 I7-Oxoellipticine, 1 I Oxoglaucine, 110 N-Oxyretuline, 18
P Pelirine, 58 Pentaacetoxybisindolyls,279 Phaeomelanins, 254 Phellibilidine, 188, 199 Phellinarnide, 187. 198 Phenethylisoquinoline alkaloids, 171 synthesis of, 202 pharmacology of, 219 I-Phenethylisoquinolines,83 Physostigrnine. 226 synthesis of, 229 pharmacology of, 247 Physostigrnine N-oxide, 244 Physovenine, 226 synthesis of, 242 Picrasidine L,M. 135 Picrasidine L.Q.M.N.U. 141. 152. 153
Picrasidine 0.152 Predicentrine, 79, I12 Protostrychnine, 25 Pseudobrucine, 28 Pseudoindoxyls, 102 Pseudostrychnine, 28 Pseudoyohimbine, 99 Pyrrolcarboxylic acids, from melanin, 287
R Rauwolscine, 98 Regelarnine, 178, 191 Regeline, 179, 191 Regelinone, 181 Reserpiline, 99 Reserpine, 99 Reserpinediol, 98 Retulinal, 17 Retuline, 17 Rindline, 29, 45 Roernecarine, 124 Rosibiline, 15 Rouharnine. 45 Rubreserine, 248 S
Salutaridine, 76, 91 Salutaridinol, 92 Sangucine, 45 Sanguilutine, 96 Schelharnrnericine, 195, 198 Sepiornelanin, 283 Serpentine, 5 Spermostrychnine, 20 Spirobenzylisoquinolines, by LTA oxidation of, 125 Splendoline, 21 Srilankine. I12 Strellidimine. 12 Strychnine, 27 Strychnine N-oxide, 27 Strychnobaridine, 35 Strychnobiline, 44 Strychnobrasiline. 22 Strychnocarpine, 46 Strychnochromine, 45
337
INDEX Strychnofluorine, 15 Strychnofoline, 37 Strychnohirsutine, 9 Strychnopentamine, 34 Strychnophylline, 37 Strychnopivotine, 18 Strychnorubigine, 4 Stryrhnos alkaloids, I Strychnosiline, 20 Strychnospermine. 21 Strychnosplendine, 21 Strychnovoline, 46 Strychnoxanthine, 55 Strychnozairine, 19 Szovitsamine, 182. 194 Szovitsidine, 177, 190
Trichochromes B.C, 256 Trigamine, 179 1,2,9-Trimethoxyaporphine.75 1.2.10-Trimethoxyaporphine.75 Tsilanimbine. 17 Tsilanine. 25 Tubotaiwine, 16
U Usambarensine, 36 Usambaridines, 34 Usambarine. 34
V T Tabascanine, 19 Tehaunine, 124 Tetradehydroyohimbine, 98 Tetrahydroakatonine, I24 Tetrahydroalstonine. 99 Tetrahydroberbines, by LTA oxidation decarboxylation, 97 Tetrahydrojatrorrhizine, I 19 Tetrahydrostrychnohirsutine,9 Thalidastine, 118 Thaliporphine, 73,74 Thaliprophine, 1 1 1 Toxiferine, 43 C-Toxiferine 1, 40
Velbanamine, 108 Vomicine. 30 Vomilenine. 105
W Wieland-Gumlich aldehyde, 24 Wilsonine, 78, 185. 195
Y Yagonine, 125 Yohimbe alkaloids, 98 Yohimbine, 99
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