Advances in Asymmetric Synthesis, Volume 1, Volume 1 (Advances in Asymmetric Synthesis)

135
,0

HH

o

76d

81%,98%ee

NBu4F 100% 100% HQ.

„o^cx

79a CICOPh, Et3N 92% DMAP, CH2CI2

I f) y j ^

>

95%

,0 h< r

^

J-NH 78

CICOOBu1, Et3N DMAP, CH2CI2

.CL . ^ 0 ,

fTW

H+, 100%

o-

^ o

79b

O

Scheme 30.

Y HO

79a: R = Ph 79b: R = t-BuO

NaHMDS

/

-30°C

\

Y ^ /

78a:

R< = A c ,

R2 = TES

78b: Fh = R2= Troc 0.5% HCI 25°C,36h

Taxol

89% Zn/AcOH/MeOH 60°C, 1h 80a: R = Ph, R! = Ac, R2 = TES, 93°/ 80b: R = 'BuO, By = R2 = Troc, 95°/

Scheme 31.

90%

Taxotere

136

IWAO OJIMA

V. MISCELLANEOUS ASYMMETRIC TRANSFORMATIONS WITH CHIRAL P-LACTAMS A. Asymmetric Aldol Reaction

We investigated the aldol reaction of 70, which would create two chiral centers at the C-3 position of the p-lactam and at its side chain. The approach of these aldehydes should be from the opposite side of the 4-styryl group, but the stereochemistry at the side chain and the stereoselectivity of the reaction were not easily predictable. It was found that the reactions of 70 with 2-methylpropanal, butanal, and 3-methylbutanal, proceeded smoothly at -100 °C to give products in high chemical yields with >99% de.20 When Af-(4-bromophenyl)-p-lactam (70-Br) was employed, the reaction also gave the corresponding product with >99% de in 97% yield. At first, we naturally assumed that these products were simple aldols (81).20 However, to our surprise, the X-ray crystallographic analysis of one of the products (R = isopropyl; Af-4-bromophenyl) revealed that it was a unique spiro-P-lactam (82-Br).20 1H, 13C NMRs and 2D NMR measurements (i.e., COSY, CSCM, NOESY), for 82a-82c and 82-Br clearly showed that all the products had the same spiro-P-lactam skeleton.20 It is apparent that the initially formed aldol 82 (lithium salt) is rearranged to the spiro-p-lactam as illustrated in Scheme 32. In order to determine the absolute configuration of the newly formed chiral center at the side chain, the spiro-P-lactam 82a (R = /-Pr) was converted to the corresponding N,N'-spiro-P-lactam (86a-/?) via hydrogenation, reaction with trimethylsilyl iodide (TMSI), and modified Birch reduction as shown in Scheme 33. 57 The stereochemistry of 86a-/? was determined on the basis of 2D NMR analysis; namely the NOESY spectrum of 86a-/? clearly showed that the isopropyl group at C4' of oxazolidinone moiety was in the opposite side of the hydrogen at C4 of the p-lactam moiety. Thus, the configuration at the newly formed chiral center (CI') at the side chain of 86a-/? was unambiguously determined to be R.20'21 This assignment is consistent with the X-ray crystallographic analysis for 82-Br, which has an R configuration at the side chain.

cD^ep^H

"Nv O'

70

R

1

2. R 2 CHO

R1= -CH 2 Ph -C 6 H 4 -Br-p (70-Br)

V

82a: R 2 = (CH 3 ) 2 CH-

>99% d.e. (96%)

82b: R2 = CH 3 CH 2 CH 2

>99% d.e. (92%)

82c: R 2 = (CH 3 ) 2 CHCH 2

>99% d.e. (95%)

Scheme 32.

The fi-Lactam Synthon Method

137

TMSI N

O'

\ /

83a

P h

CHCI3lA 89%

Ph

Li/NH3 THF/t-BuOH y / ' 69%

°

1

84a

H2 00% Pd(OH)2/C

We also looked at the participation of the chiral 4-phenyloxazolidinone moiety in asymmetric induction. Thus, 70 was converted to 3-amino-(}-lactam (87) through hydrogenation and modified Birch reduction, and then to 3-imino-p-lactam (88). The aldol reaction of 88 with 3-methylpropanal in a manner similar to that for the formation of 82, gave the desired aldol product (90) with 90% de (Scheme 34). The

J

\~f

1.H2,Pd/C

A— N. 70

W

,Ph 2. Li/NH3 .Ph 2.Li/NH THF/t-BuOH -78°C

J— NH

_PJC ] HO_T 100%

Y-f J—NH

87

89%

1.LiHMDS,-78°C TMSCI, -78°C-r.t. 2. LiHMDS, -97°C (CH3)2CHCHO 3. 2N HCI

Ph E t O . I NaH || 86a-S

Scheme 34.

82%

138

IWAO OJIMA

Scheme 35.

stereochemistry at CI' was unambiguously determined by converting 90 to the spirobicyclic |3-lactam 86a-S followed by the NOESY analysis [viz., it turned out that the newly formed chiral center (CI') of 86a-5 was 5]. It should be noted that the NMR spectra of the minor isomer coincided with those of 86a-/?. Consequently, it is found that (1) the P-lactams, 70 and 88, give opposite configurations with each other at the newly formed chiral centers (CT) of the side chain, and (2) a simple (3-lactam skeleton such as 88 possesses relatively high stereogenecity (90% de) in this aldol reaction. Possible mechanisms which can accommodate these findings are proposed in Scheme 35. In the Newman projections of the cyclic transition states for the aldol reaction of 2-methylpropanal with lithium (3-lactam enolates, the top position is the least hindered in the case of 88, and thus the bulky isopropyl group takes this position to give S configuration. On the other hand, the top position is very crowded in the case of 70 because of the 4-phenyl groyp of the oxazolidinone moiety, and thus the isopropyl group can no longer occupy this position to give the R configuration. B. Unique Rearrangements of Chiral 3-Oxazolidinyl-p-lactams

In the course of our study on the transformations of chiral 3-oxazolidinyl-(3lactams, we discovered novel rearrangements of these p-lactams. This section describes these rearrangements and discusses possible mechanisms.

Thefi-LactamSynthon Method

139

Scheme 36.

First, the 4-styryl-p-lactam (71a) was converted to the corresponding 4-hydroxymethyl-p-lactam (92) by ozonolysis followed by sodium borohydride reduction in 85% overall yield (Scheme 36).69 Next, 92 was treated with excess sodium methoxide (10 equiv) in methanol at refluxing temperature, with the intention of converting 92 to the lactone (93). However, contrary to our prediction, a bicyclic diazolidinone (94) was obtained in nearly quantitative yield, which consisted of a single stereoisomer (Scheme 37).69 When the reaction was carried out in methanol in the presence of a catalytic amount of sodium methoxide (0.3 equiv), the initially expected lactone (93) was formed in 95% yield.69 This lactone (93) was also obtained in quantitative yield by using a catalytic amount of sulfuric acid in refluxing n-butanol.69 When the lactone (93) was treated with excess sodium methoxide (10 equiv) in refluxing methanol, 94a was obtained in quantitative yield. Thus, 93 is likely to be a key-intermediate for

Ph

-<

V Ph

V

CH3

NaOCH3(10eq.)

-^rzr t CH OH,

H^"OH

O

3

i^^N^\

I

Bn 92

NaOCH3 (0.3 eq CH3OH,

94a or H2SO4 (cat.) n-BuOH, 100%

95% U

V I

i ,N-

9G%

NaOCH3 (10 eq.) CH 3 OH, 100%

:. C H 3 N H

Ri

93

Scheme 37.

140

IWAO OJIMA

95

93

.Ph

Ph Ph

Ph*.

^

?

L-*H

j

•

I

N-

I "

Me

5.

96

Scheme 38.

the formation of 94a. The structures of 93 and 94a were elucidated by X-ray crystallographic analyses.69 A likely mechanism for these rearrangements is proposed in Scheme 38.69 As Scheme 38 illustrates, the 4-hydroxymethyl of 92 becomes alkoxide on treatment with sodium methoxide, and the alkoxide attacks intramolecularly the P-lactam carbonyl to cleave the p-lactam ring, forming the lactone (93) stereospecifically. Under acidic conditions, protonation takes place on the p-lactam carbonyl oxygen, and the 4-hydroxymethyl group attacks the P-lactam carbonyl, opening the p-lactam ring to give 93 with complete stereospecificity. When the base is used in excess, methoxide ion attacks the chiral oxazolidinone moiety to open the ring, generating the alkoxide ion and a methyl carbamate moiety (95). The alkoxide (95) then undergoes lactone exchange to form another alkoxide-bearing morpholinone moiety (96). Finally, the alkoxide ion abstracts the amine proton and the amide thus generated attacks the carbamate moiety, all intramolecularly, to give the bicyclic diazolidinone (94a). According to the proposed mechanism (Scheme 38), methoxide ion attacks the oxazolidinone moiety of 93 to generate 95. If this is indeed the case, 3-oxazolidinyl-

The ^-Lactam Synthon

141

Method

CH3O,

97

CH3O,

o

^o

Scheme 39.

P-lactams not bearing the 4-hydroxymethyl group might undergo the same type of rearrangement to yield the corresponding bicyclic diazolidinones. In order to examine this hypothesis, we carried out the reaction of the 4-styryl(3-lactam (71a) with excess sodium methoxide in refluxing methanol. The reaction indeed gave the expected rearrangement product, 94b (Scheme 39), but in somewhat reduced isolated yield (50%).69 A substantial amount of cinnamaldehyde was recovered, which indicates the occurrence of a retro-imine condensation process. This side reaction may well be ascribed to the competing methoxide attack on the (i-lactam carbonyl to open the (J-lactam ring first, promoting the retro-imine condensation. Nevertheless, the major pathway is to generate 97, which then rearranges to form the morpholinone intermediate (98), which is very similar to 96 (Scheme 38). This reaction gives only one stereoisomer as well. The structure was elucidated by chemical correlation of 94b to 94a through conversion of the styryl moiety to the hydroxymethyl group via ozonolysis followed by sodium borohydride reduction.69 Consequently, it is demonstrated that ^-lactams are useful chiral precursors for the asymmetric synthesis of heterocycles. The asymmetry of the chiral |J-lactams is successfully transferred to the chiral centers in the final hetero-bicyclic products. Since the 1- and 4-substituent on the p-lactam ring and the substituent in oxazolidinyl moiety can readily be modified, the novel rearrangements may serve as new and useful methods for the asymmetric synthesis of a variety of oxazabicyclo[4.3.0] systems.

142

IWAO OJIMA

VI. CONCLUSION This chapter has described a unique synthetic method, the "(5-Lactam Synthon Method" (p-LSM) developed in our laboratory, which is based on the use of enantiomerically pure p-lactams as useful synthetic intermediates. The first generation p-LSM is based on the facile reductive cleavage of the N-C 4 bond of enantiomerically pure 4-aryl-p-lactam esters, which are obtained through the [2+2] cycloaddition of azidoketene or other achiral ketenes to chiral imino esters followed by diastereomer separation. The method has been applied to biologically active oligopeptide syntheses and extremely stereoselective labeling of dipeptides. The second generation p-LSM is based on the control of absolute configurations by asymmetric synthesis. The newer features in the second generation method include: • enantio- as well as diastereoselective [2+2] cycloaddition of chiral ketenes to imines or imino esters; • enantioselective chiral ester enolate-imine cyclocondensation; • stereoselective alkylations through the Type 1 and the Type 2 chiral P-lactam enolates; • dissolving metal reduction conditions for the N-C4(Ar) bond cleavage; and • hydrolytic cleavage of the N-C(O) bond, which is applicable to any enantiomerically pure p-lactams. These reactions proceed with extremely high selectivity and constitute the basis for various subsequent transformations. The second generation p-LSM has been applied to: (1) the asymmetric syntheses of non-protein amino acids, and their dipeptides and derivatives, which are very important as key structures in enzyme inhibitors as well as modifiers of biologically active peptides; and (2) the highly efficient and practical synthesis of Taxol, Taxotere, and their analogs which are highly potent anticancer agents. The applicability of the P-LSM can be further expanded. For example, the highly stereoselective aldol reaction gives novel spirobicyclic-P-lactams, and the unique skeletal rearrangements provide new routes to a variety of heterocyclic compounds. Although the p-lactam skeleton is just a four-membered cyclic amide, it has been giving us unexpectedly rich organic chemistry and still more is expected to come in the future.

ACKNOWLEDGMENTS This work has been supported by grants from the National Institute of Health (NIGMS). Generous support from Rhone-Poulenc Rorer, Indena, SpA, Ajinomoto Co., Inc., and the Center for Biotechnology at Stony Brook, which is sponsored by the New York State Science

Thefi-LactamSynthon Method

143

& Technology Foundation, is also gratefully acknowledged. The author would like to thank Drs. Hauh-Jyun C. Chen, Xiaogang Qiu (George Chiu), Yazhong Pei, Ivan Habus, Mangzhu Zhao, Martine Zucco, Kazuaki Nakahashi, and Thierry Briguard; Takeo Komata, Young Hoon Park, Chung Ming Sun, Olivier Duclos, Scott D. Kuduk, and Edward Ng for their dedication and fruitful collaboration in his research laboratory at Stony Brook. He also thanks Dr. Naoto Hatanaka, Shigemi Suga, and Rumiko Abe for their excellent collaboration in the discovery and initial development of the first generation P-Lactam Synthon Method at the Sagami Chemical Research Center.

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39. Jung, M. J. In Chemistry and Biochemistry of Amino Acids; Barrett, G. C. Ed.; Chapman and Hall: New York, 1985; p. 227. 40. Ramalingam, K.; Woodard, R. W. Tetrahedron Lett. 1985,26,1135. 41. Walsh, J. J.; Metzler, D. E.; Powell, D.; Jacobson, R. A. J. Am. Chem. Soc. 1980,102,7136. 42. Paul, P. K. C ; Sukumar, M.; Bardi, R.; Piazzesi, A. M ; Valle, G.; Toniolo, C ; Balaram, P. J. Am. Chem. Soc. 1986,108, 6363, and references cited therein. 43. e.g., (a) DeBoer, C.; Caron, E. L.; J. W. Hinman, J. W. J. Am. Chem. Soc. 1953, 75, 499; (b) Hinuma, Y.; Kuroya, M.; Yajima, T.; Ishihara, K.; Hamada, S.; Watanabe, K.; Kikuchi, K. /. Antibiotics 1955, A8,148; (c) Haskell, T. H.; Ryder, A.; Frobardt, R. P.; Fusari, S. A.; Jakubowski, Z. L.; Bartz, Q. R. J. Am. Chem. Soc. 1958,80,743; (d) Hanessian, S.; Haskell, T. H. Tetrahedron Lett. 1964,2451. 44. Pandey, R. C ; Meng, H.; Cook, Jr., J. C ; Rinehart, Jr., K. L. J. Am. Chem. Soc. 1977, 99,5203, and references therein. 45. (a) Hartwig, W.; Schollkopf, U. Liebigs Ann. Chem. 1982, 1952; (b) Groth, U.; Chiang, Y.-C; Schollkopf, U. Liebigs Ann. Chem. 1982, 1756; (c) Groth, U.; Schollkopf, U.; Chiang, Y.-C. Synthesis 1982, 864; (d) Groth, U.; Schollkopf, U. Synthesis 1983, 37. 46. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 705, 5390, and references cited therein. 47. Karady, S.; Amato, J. S.; Weistock, L. M. Tetrahedron Lett. 1984,25,4337. 48. Sinclair, P. J.; Zhai, D.; Reibenspies, J.; Williams, R. M. J. Am. Chem. Soc. 1986,108,1103. 49. Georg, G. I.; Guan, X.; Kant, J. Tetrahedron Lett. 1988,29,403. 50. Schollkopf, U.; Hausberg, H.-H.; Segel, M ; Reiter, U.; Hoppe, I.; Seanger, W.; Lindner, K. Liebigs Ann. Chem. 1981,696. 51. e.g., (a) For a review, Hart, D. J.; Ha, D.-C. Chem. Rev. 1989, 89,1447; (b) Georg, G. I.; Kant, J.; Gill, H. S. J. Am. Chem. Soc. 1987,109,1129; (c) Ha, D.-C; Hart, D. J.; Yang, T.-K. J. Am. Chem. Soc. 1984,106,4819; (d) Hart, D. J.; Kanai, K.; Thomas, D. G.; Yang,T. K. J. Org. Chem. 1983,48, 289. 52. The reactions of the corresponding zinc enolates have been extensively studied by van Koten et al., e.g., (a) van der Steen, F. H.; Kleijn, H.; Jastrzebski, J. T. B. H.; van Koten, G. Tetrahedron Lett. 1989,30,765; (b) van der Steen, F. H.; Jastrzebski, J. T. B. H.; van Koten, G. Tetrahedron Lett. 1988, 29, 2467; (c) Jastrzebski, J. T. B. H.; van der Steen, F. H.; van Koten, G. Rec. Trav. Chim. Pays-Bas 1987,106,516. However, the best enantioselectivity so far attained in the zinc enolate-imine condensation process is 50% ee. 53. (a) Whitesell, J. K.; Chen, H.-H.; Lawrence, R. M. J. Org. Chem. 1985,50,4663; (b) Whitesell, J. K.; Lawrence, R. M. Chimia 1986, 40, 318; (c) Schwartz, A.; Madan, P.; Whitesell, J. K.; Lawrence, R. M. Org. Synth. 1990, 69,1. 54. For similar discussion in aldol reactions, see (a) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E. Tetrahedron Lett. 1987, 28, 39; (b) Evans, D. A.; Nelson, J. V; Taber, T. R. In Topics in Stereochemistry. Stereoselective Aldol Condensations; Allinger, N. L.; Eliel, E. L.; Wilen, S. H. (Eds.); Wiley: New York, 1982; Vol. 13. 55. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543. 56. Zhao, M. Dissertation; State University of New York at Stony Brook, 1991. 57. Rich, D. H. J. Med. Chem. 1985, 28, 263. 58. (a) Joulin, P.; Castro, B.; Nisato, D. J. Chem. Soc. Perkin Trans. 11987,1177; (b) Yanagisawa, H.; Kanazaki, T.; Nishi, T. Chem Lett. 1989,687; (c) Koot, W-J.; Ginkel, R. V.; Kranenburg, M.; Hiemstra, H.; Louwrier, S.; Moolenaar, M. J.; Speckamp, W. N. Tetrahedron Lett. 1991,32,401; (d) Takemoto, Y; Matsumoto, T.; Ito, Y; Terashima, S. Tetrahedron Lett. 1990, 31, 111; (e) Kunieda, T.; Ishizuka, T.; Higuchi, T.; Hirobe, M. J. Org. Chem. 1988, 53, 3381. 59. e.g., (a)Ito, Y; Kamijo,T.; Harada,H.;Terashima, S.Heterocycles 1990,30,299; (b) Kobayashi, Y; Takemoto, Y; Ito, Y; Terashima, S. Tetrahedron Lett. 1990, 31, 3031; (c) Matsumoto, T.; Kobayashi, Y; Takemoto, Y; Ito, Y; Kamijo, T; Harada, H.; Terashima, S. ibid. 1990,31,4175;

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60. 61.

62. 63. 64.

65.

66. 67.

68. 69.

IWAO OJIMA (d) Iizuka, K.; Kamijo, T.; Harada, Akahane, K.; Kubota, T.; Umeyama, H.; Ishida, T.; Kiso, Y. J. Med. Chem. 1990,33, 2707. Ojima, I.; Park, Y. H.; Sun, C. M.; Brigaud, T.; Zhao, M. Tetrahedron Lett. 1992,33,5737. (a) Wiernik, P. H.; Schwartz, E. L.; Strauman, J. J.; Dutcher, J. P.; Lipton, R. B.; Paietta, E. Cancer Research 1987,47,2486; (b) Annual Report to the Food and Drug Administration: Taxol, IND 22850. NSC 125973; February 1989. Division of Cancer Treatment, NCI, Bethesda; (c) Workshop on Taxol and Taxus: Current and Future Perspectives; June 1990; Division of Cancer Treatment, NCI, Bethesda. Proceedings of the Second National Cancer Institute Workshop on Taxol and Taxus, September 1992; Alexandria, VA. Denis, J.-N.; Greene, A. E.; Gurnard, D.; Gu6ritte-Voegelein, F ; Mangatal, L.; Potier, P. J. Am. Chem. Soc. 1988,110, 5917. Bombardelli, E.; De Bellis, P.; Foti, V; Pace, R.; Zini, G.; Gabetta, B. In Proceedings of the Second National Cancer Institute Workshop on Taxol and Taxus, September 1992; Alexandria, VA. (a) Senilh, V; Gufritte, F ; Gurnard, D.; Colin, M.; Potier, P. C. R. Seances Acad. Sci. Ser. 2 1984, 299, 1039; (b) Guentte-Voegelein, F ; Senilh, V; David, B.; Gurnard, D.; Potier, P. Tetrahedron 1986,42,4451; (c) Mangatal, L.; Adeline, M. T; Gu6nard, D.; Gu6ritte-Voegelein, F. ibid. 1999,45,4111. Colin, M ; Gurnard, D.; Gu6ritte-Voegelein, F ; Potier, P. Eur. Pat. Appl. EP 253,738, 1988: Chem. Abstr. 1988,109, 22762w. Leading papers in the SAR study of taxol analogs, see (a) Gu6ritte-Voegelein, F ; Gu6nard, D.; Lavelle, F ; Le Goff, M. T..; Mangatal, L.; Potier, P. /. Med. Chem. 1991,34,992; (b) Swindell, C. S.; Krauss, N. E. J. Med. Chem. 1991,34,1176; (c) Mathew, A. E.; Mejillano, M. R..; Nath, J. P.; Himes, R. H; Stella, V. J. J. Med. Chem. 1992,35,145. Holton, R. A. Eur. Pat. Appl. EP 400,971,1990: Chem. Abstr. 1990,114,164568q. Ojima, I.; Pei, Y Tetrahedron Lett. 1992,33, 887.

Chiral Organoboranes Based on a-Pinene

147

ASYMMETRIC SYNTHESES VIA CHIRAL ORGANOBORANES BASED ON cc-PINENE

Herbert C. Brown and P. V. Ramachandran

I. Introduction II. Versatile Organoboranes III. Asymmetric Hydroboration A. Diisopinocampheylborane (IpC2BH) B. Applications of IpC2BH C. Mechanism of Hydroboration D. Monoisopinocampheylborane (IpcBH2) E. Applications of IpcBH2 F. Other Hydroborating Agents IV. A General Asymmetric Synthesis A. Optically Active Boronic Esters B. Borinate Esters C. Applications of Boronate and Borinate Esters

Advances in Asymmetric Synthesis Volume 1, pages 147-210. Copyright © 1995 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-699-1 147

148 149 152 152 153 156 156 159 160 160 161 162 163

148

HERBERT C. BROWN and P. V. RAMACHANDRAN

V. Asymmetric Homologation A. Alternatives for Asymmetric Hydroboration of 2-Substituted-l-Alkenes . B. Three-Carbon Homologation C. Broad Scope of Organoborane Chemistry VI. Asymmetric Allyl-and Crotylboration A. B-Allyldiisopinocampheylborane B. #-Methallyldiisopinocampheylborane C. 3,3-Dimethylallyldiisopinocampheylborane D. (Z)-3-Methoxyallyldiisopinocampheylborane E. Comparison of Chiral Auxiliaries F. B-(E)- and (Z)-Crotyldiisopinocampheylborane G. B-2'-Isoprenyldiisopinocampheylborane H. Applications of Allyl-and Crotylboration VII. Asymmetric Enolboration VIII. Asymmetric Reduction A. Ipc2BH and IpcBH2 B. Alpine-Hydride® C. 5-Isopinocampheyl-9-borabicyclo[3.3.1]nonane(Alpine-Borane ) . . . . D. fi-ChlorodiisopinocampheylboraneCIpciBClDIP-Chloride™) E. Modified Reagents F. ZMso-2-ethylapopinocampheyl-9-borabicyclo[3.3.1 ]nonane (Eapine-Borane) G. Lithium (ZMso-2-ethylapopinocampheyl-9-borabicyclo[3.3.1 ]nony 1) Hydride (Eapine-Hydride) H. Z?-Chlorodiiso-2-ethylapopinocampheylborane (Eap2BCl) IX. Asymmetric Cleavage of meso-Epoxides X. Conclusions Acknowledgments References and Notes

169 170 172 172 173 174 175 176 176 177 178 179 180 183 183 184 185 185 189 197 200 201 202 203 203 205 205

I. INTRODUCTION The synthesis of mammoth molecules with an assembly of asymmetric centers remains a major challenge for organic chemists. These challenges are being overcome with ingenuity and, as an added bonus, new reactions and reagents become available. Yet, until 1961 organic chemists yearned for reactions which could achieve high optical yields, reactions that are readily conducted today. The dreams a synthetic organic chemist once had are well expressed in the words of the late Professor R. B. Woodward in Perspectives in Organic Chemistry published in 1956. ... The real problem, and the great opportunity, in this area lies in the synthesis of molecules or systems which possess the capacities of the enzymes for direction, facilitation, and control of organic reactions. There is no reason to suppose thatrichrewards are not to be found in this direction...

Chiral Organoboranes Based on a-Pinene

149

Almost four decades later, organic chemists have made exceptional progress in the area of asymmetric synthesis via molecules which possess almost enzyme-like capabilities.1 Synthetic chemists have significantly reduced the importance of classical resolutions in their strategies for synthesis of optically active compounds. Realizing >90% ee after a synthetic step is becoming commonplace in many types of reactions. While planning the synthesis of a target molecule with an assemblage of asymmetric centers, organic chemists design their approaches much differently than was the case several decades ago. Especially noteworthy is the fact that asymmetric syntheses are becoming more reagent-controlled rather than substratecontrolled. The progress made in the methodologies, whether using stoichiometric or catalytic reagents, frequently involves organometallic chemistry. In these approaches to asymmetric synthesis, the boron atom occupies a unique position attributed to the characteristics of this element. Organoboranes prepared from readily available chiral auxiliaries are viable, cost-effective, alternatives to many catalytic procedures for executing a synthetic step. The progress that we and others have made in asymmetric synthesis via organoboranes is now so large that it is no longer possible to review them completely in a chapter such as this. This work has been reviewed several times in the past and the reader's attention is called to some of these reviews.2 Herein, we have attempted to highlight the more significant successes that have been achieved in our laboratories. Wherever possible, we have referred to the work of other research groups. We have also included representative examples of the applications of our methodologies from the current literature to give the reader an idea of their efficiency. We have not delved into the details of similar or comparable procedures of other researchers since they have been reviewed elsewhere. Most of our research is based on a-pinene or pinene-derived materials as the chiral inducer. Though we have at times achieved better results with other terpenes as the chiral auxiliary, we have not included them in this review, but have referred to them in the appropriate sections.

II. VERSATILE ORGANOBORANES It was serendipity that we discovered the remarkably facile addition of diborane in ether solvents to alkenes and alkynes (Eq. I).3 V=c'

+

H-B'

-H-C-C-B^

(1)

A systematic study followed which revealed the major characteristics of hydroboration as described below:4 1. Reactions are essentially instantaneous and quantitative (Eq. 2).

150

HERBERT C. BROWN and P. V. RAMACHANDRAN >B =\ 3/=\

OH

(2)

BH3

2. The addition proceeds in an anti-Markovnikov manner (Eq. 3). BH 3 ^

R,

[O]

)3B

~R^ ^ \ 3 \X" ^0

•

H

(3)

3. The reaction involves a cis addition of the H-B bond (Eq. 4).

_/

^>

4.

HB

AB(

\

[O]

^

OH

(4)

The addition takes place preferentially from the less hindered side of the double bond (Eq. 5).

A> -*- A X *

(5) 0.4%

99.6%

B.

5. No rearrangements of the carbon skeleton have been observed (Eq. 6). / [O]

HB

(6)

6. Most functional groups can tolerate hydroboration (Eqs. 7, 8). CH 2 =CHCH 2 C0 2 R

CH2=CHCH2CN

•

•*

^B-CH 2 CH 2 CH 2 C0 2 R

(7)

^B-CH 2 CH 2 CH 2 CN

(8)

This reaction was initially received with very little enthusiasm by the referees of the original communication. But, unlike other new chemical reactions, the hydroboration reaction and the chemistry of organoboranes almost immediately became a useful and powerful tool in the arsenal of the organic chemist.5 Special selectivities and substitution with retention made the organoboranes a very attractive alternative in the beginning but an indispensable necessity later. The initial skepticism was

Chiral Organoboranes Based on a-Pinene

151

cis, cis; cis, trans; trans, trans, etc.

RCH 2 CN

RR'CHOH

Chart 1. The versatile organoboranes: substitution with retention (The broken arrow indicates a reaction not yet demonstrated experimentally.)

replaced with an unbridled enthusiasm. For the uninitiated, the misconceptions and fears of using air- and moisture-sensitive materials were alleviated by several books and reviews on simple techniques for using them safely.6 Our exploration of the hydroboration reaction led us to the point where we applied it to new situations and this gave birth to several new reagents and reactions, indeed to a modern miracle—discovery of the remarkable versatility of organoboranes.7 The versatility of organoboranes is indicated in Chart 1. Over two decades, we developed simple operating procedures with emphasis on the reactions of synthetic utility. An unexpected feature revealed by these studies is that the great majority of the substitution reactions of organoboranes proceed with complete retention of configuration in the organic group that is transferred from boron to some other element or group.8 For a detailed insight of the retention reactions of organoboranes, see our earlier reviews.2,7,8

152

HERBERT C. BROWN and P. V. RAMACHANDRAN

III. ASYMMETRIC HYDROBORATION Originally we carried out the hydroboration of oc-pinene to study the sensitivity of the pinene structure toward rearrangement during hydroboration.9 The reaction proceeded without rearrangement. But it was a surprise that it proceeded to the dialkylborane stage and then ceased. Apparently, the steric requirements of this group are so large that only two such bulky groups can attach themselves to boron. The formation of diisopinocampheylborane (Ipc2BH) provided an optically active hydroborating agent. The failure of this reagent to react with a third molecule of oc-pinene made it clear that this could be used only for the hydroboration of a less hindered alkene, such as cw-2-butene. This seminal experiment marked the beginning of a practical asymmetric synthesis and a new era in organic chemistry.9 A. Diisopinocampheylborane (lpc2BH)

In the above reaction, Ipc2BH was prepared by treating a known quantity of oc-pinene and sodium borohydride in diglyme at 0 °C with a stoichiometric amount of trifluoroborane-etherate (BF3EE) and maintaining the reaction mixture at 0 °C for 4 h.9 Since the oc-pinene commercially available is of 92% ee, the maximum induction that can be obtained after the reaction is also 92%. The induction obtained in the primal experiment, 87% ee, was spectacular, considering the poor ee that was the norm for reactions of this kind in 1960 (Eq. 9).

.*)2BH

DG 1+ B H 3 •

(9) H (/?)-(-)-, 87% ee

0°C

93% ee

ci c! c & 1 HO • ^

H

98.4% ee

HCT

:^

H

92.3% ee

93% ee

Figure 1.

H, 83% ee

Chiral Organoboranes Based on a-Pinene

153

oo ao 0 Bnz

Q 0 tf Q O £99% ee

£99% ee

>99%ee

Bnz >99%ee

83% -> £99% ee

Figure 2.

After completing our systematic exploration of organoboranes, we revisited this reaction for the development of our proposed program of general asymmetric synthesis. We undertook yet another systematic study, now for the preparation of Ipc2BH and learned to make it in >99% ee. We observed a significant dissociation of Ipc2BH to IpcBH2 and a-pinene in solution.10 Our study revealed that the above dissociation could be largely suppressed by the addition of 15% excess of ocpinene.11 Later we achieved the preparation of optically pure crystalline Ipc2BH from a-pinene of 92% ee by treating the terpene with a borane-methyl sulfide complex in THF at 0°C. 12 Asymmetric hydroboration of prochiral olefins with this crystalline material at -25 °C followed by oxidation provided optically active alcohols. In the case of cw-olefins, the product s^c-alcohols were obtained in excellent ee (Figure l). 13 The reaction proved to be general for most types of ds-olefins, including heterocyclic olefins (Figure 2). I4 B. Applications of lpc2BH

The exceptional ability of Ipc2BH to hydroborate ds-alkenes has been applied for the preparation of key intermediates in several multistep syntheses. Representative examples from the literature are shown below. Thus, Uskokovic' and co-workers used this reagent for the elegant synthesis of loganin (Figure 3),15 and the Corey-lactone intermediate for prostaglandin synthesis (Figure 4).16 Corey and Noyori employed Ipc2BH for the synthesis of PGF2a17 Ruttiman and Mayer hydroborated safranol isoprenylmethylether with (+)- and (-)- Ipc2BH for the synthesis of the carotenoids (3/?,37?)-, (3S,3'S)- and (3#,3'S; meso)-zeaxanthins via a Wittig reaction (Figure 5).18 Starting from (+)-camphor Ruttiman and co-workers synthesized (3S,5/?,3'S,57?)-capsorubin, a carotenoid found in the red paprika Capsicum annuum. The key step in this synthesis is the asymmetric hydroboration of the

CH, (+Mpc2BHt [0] H3C

y

5

MeQ

\ / i ~ ^ ~^\ff

OH

AcO""-

H^OH

?H3

H3C

2C

„

CHQ

0'P~ D "8 l u c o s e

HO C02Me

C02Me Figure 3.

C02Me

9H

C02Me MsCl NaOH*

rf

cr 0M

W" K ' O Figure 4.

,CH2PPh3Cl

.CHO

[3S,3\S]-Zeaxanthin Figure 5. 154

Chiral Organoboranes Based on a-Pinene

155

\ 3. Chromatography

(+)-Camphor

> |

Capsorubin

Figure 6.

unsaturated ketal which is followed by an aldol condensation to provide the target molecule (Figure 6).19 A. E. Greene exploited the asymmetric hydroboration and continued with two highly selective three-carbon annelations for the stereocontrolled synthesis of a linearly fused triquinane, (+)-hirsutic acid (Figure 7).20 Though Ipc2BH is not efficient for the asymmetric hydroboration of 2-substituted-1-alkenes, it does demarcate two alkyl groups of extremely different steric requirements. Masamune revealed this aspect by synthesizing both epimers of a precursor of tylonolide, the aglycone of tylosin which is a member of the 16-membered polyoxomacrolide antibiotics (Figure 8). Even at room temperature, the hydroboration provided the product in >96% ee.21

H

V^ ~~il

MeOOC

N

"^

i

y PH

(+)-Ipc2BH [O] MeOOC

HOOC H O (+)-Hirsutic acid

Figure 7.

156

HERBERT C. BROWN and P. V. RAMACHANDRAN

TBDMS

TBDMS

Figure 8. C. Mechanism of Hydroboration

The high success achieved by Ipc2BH in asymmetric hydroboration of cw-olefins and its dismal performance for other classes of olefins attracted theoretical chemists to study this reaction. Accordingly, Houk and co-workers studied the hydroboration reaction using a combination of MM2 force-field and ab initio calculations.22 Recently, Egger and Kreese analyzed the origin of the regio- and stereoselectivity in asymmetric hydroborations by MNDO methodology and made a search of alternative hydroborating agents for those classes of olefins that resist asymmetric hydroboration.23 D. Monoisopinocampheylborane (IpcBhh)

When Ipc2BH was used for the asymmetric hydroboration of those classes of alkenes other than cw-olefins, the optical inductions realized were poor. Evidently,

Table 1. Asymmetric Hydroboration of Olefins with lpc2BH Class

?

IV

Olefin 2-Methyl-l-Alkenes cw-Alkenes trans-Alkencs Trisubstituted Alkenes

-20 >99 -20 -20

157

Chiral Organoboranes Based on a-Pinene

the effectiveness of the asymmetric hydroboration reaction depends upon a fit between the steric requirements of the alkyl groups of the olefin and the hydroborating agent. While cfr-olefins could be hydroborated in up to 100% ee, 2-methyl1-alkenes,frvms-alkenes,and trisubstituted alkenes could be hydroborated in only -20% ee (Table 1). Apparently, the steric requirements of 2-methyl-l -alkenes are too low to provide a good steric fit with the reagent. On the other hand, trans- and trisubstituted olefins appear larger than the reagent can handle. This led to a search for asymmetric hydroborating agents with less steric bulk on the boron. We discovered that monoisopinocampheylborane (IpcBH2) partially solves the problem. However, the synthesis of the reagent was not straightforward. Hydroboration of oc-pinene cannot be stopped at the monoalkylborane stage.24 Hence IpcBH2 was synthesized via an indirect route. As in the case of Ipc2BH, we developed various methods for preparing pure IpcBH2.25 It was detected that Ipc2BH reacts readily withterf-aminesto displace one mole of oc-pinene to form the IpcBH2-amine complex. The most successful of these is the treatment of Ipc2BH with one-half equivalent of AWAW-tetramethylethylenediamine (TMEDA) to provide the crystalline IpcBH2-TMEDA complex (Aldrich: Alpine-Boramine ™). IpcBH2 can then be conveniently liberated with BF3EE which removes TMEDA by precipitating it as a solid complex (Figure 9).26 IpcBH2 was then found to be a useful reagent for the asymmetric hydroboration of fnms-alkenes (Figure 10)27 and trisubstituted alkenes (Figure ll). 2 8 The reactions are carried out at -25 °C in THE These results suggest that increasing the steric bulk of the alkenes might improve the optical induction realized in hydroborations with IpcBH2. Accordingly, a more favorable match between the alkene and the hydroborating agent was apparently achieved in the hydroboration of phenyl trisubstituted alkenes (Figure 12).29 However, superior results have now been obtained by the technique of recrystallization of the dialkylboranes formed in the hydroboration (Section IV.A). Thus IpC2BH and IpcBH2 are complementary to each other and together handle three of the four classes of alkenes with good to excellent asymmetric induction (Table 2).

4 r ^

+ 2 BH3.SMe2

^ 2 TMED

2IpcBH2 2>99% ee

2BF 3 *-

I x-N^NHjBIpc ipcBHi'N' I £99% ee

Figure 9.

2

H0»7\ H 73% ee

HO^ H (*M+X 92% ee

75% ee

75% ee

Figure 70.

(5)-( + ),53%ee

(«)-(+)-, 62% ee

(I

V%^+>"'

^ M ^ *

Figure 11.

(25,35)-(-)82% ee

(25, 55)-(+)85% ee

(15,2/?)-(+)85% ee

Figure 72. 158

(15,2J?)-(+)97% ee

Chiral Organoboranes Based on a-Pinene

159

Table 2. Asymmetric Hydroboration of Olefins with lpc2BH and lpcBH2 %ee

requirements

Increasing steric

Class

Olefin 2-Methyl-l-Alkenes cis-Alkenes trans-Alkents Trisubstituted Alkenes

Ipc2BH -20 >99 -20 -20

IpcBH2 -1 -25 70-90* 60->99 a

Note: "Upon crystallization of the initial product the ee is upgraded to > 99%.

Though we planned to explore more hindered asymmetric hydroborating agents for the hydroboration of the Class I olefins, we discovered that we could obtain the desired asymmetric boron intermediates by applying the homologation procedures developed by Matteson and co-workers. These are discussed later (Section V). E. Applications of IpcBhh

Numerous applications of IpcBFb have been made in our general asymmetric synthesis program (Section IV). Organic chemists have utilized this reagent in

Mintsulfide

Me P-Bourbonene

Figure 13.

Me Periplanone B

160

HERBERT C. BROWN and P. V. RAMACHANDRAN

V - *

)2BH HB2(

HB 2 r 4-Icr2BH

2-Icr2BH

LimBH

| Lgf2BH

Figure 14.

several syntheses. For example, Schreiber applied this reagent in the synthesis of cryptone,30 a precursor for germacrene-D,31 mintsulfide,31 p-bourbenene,31 and periplanone-B (Figure 13). 32 F. Other Hydroborating Agents In the quest for finding the correct fit between the alkene and the borane reagent, we prepared and studied several dialkylboranes derived from several other terpenes, such as carene,33 longifolene, 34 and limonene 35 (Figure 14). Unfortunately, none of them proved as successful as cc-pinene.33 Recently, Masamune and co-workers synthesized an optically active dialkylborane, 2,5-dimethylborolane, starting from 2,5-dibromohexane.36 The reaction sequence involved a resolution step. (+)-Prolinol and (-)-valinol were used to obtain opposite enantiomers of the reagent. This reagent hydroborated three of the four classes of alkenes in excellent ee. Again the 2-alkyl-l-olefins resisted successful asymmetric hydroboration. Unfortunately, the effort required to synthesize the reagent appears to have hindered its application.

-o-

B H 2,5-Dimethylborolane

IV. A GENERAL ASYMMETRIC SYNTHESIS

Thus the reactions of Ipc2BH or IpcBFfc with suitable alkenes provide dialkyl or trialkylboranes in high ee. It was now desirable to test the conversion of these chiral organoboranes into pure enantiomers as shown in Chart 1. It was also desirable to recycle the chiral auxiliary (oc-pinene) and to use the R*B<, free of the chiral auxiliary for further modification. We successfully achieved both of these aims in our program directed to the development of a general asymmetric synthesis via chiral organoboranes.

161

Chiral Organoboranes Based on a-Pinene A. Optically Active Boronic Esters

Since the alkyl group on boron is most efficiently utilized in transformations with boronic esters, these esters have emerged as important organoborane intermediates in asymmetric synthesis. Of particular importance is the facile formation of carbon-carbon bonds. Accordingly, much effort has been devoted to developing newer methods for preparing optically pure boronic esters. Previously, it had been noticed that the products of hydroboration of alkenes with IpcBH2 were often solids—derivatives of diborane itself, IpcHBH2BHIpc. It was then discovered that simple recrystallization provides products of essentially 200% optical purity.37 These products on treatment with acetaldehyde release a-pinene to provide the boronic ester without loss of optical activity. Therefore, it is now possible to obtain the hydroboration products, Ipc2BR* and IpcR*BH, and the derived boronic esters R*B(OR')2 in essentially 100% ee (Figure 15).38 An alternate approach for obtaining optically pure boronic esters via asymmetric hydroboration consists of an optical upgradation of the initial boronates by treating them with a chelating agent to furnish a crystalline material. This is then recrystallized to yield the boronic ester derivatives in essentially optically pure form.39 This method of optical upgrading can also be applied to borinic esters. Thus norbornene, upon hydroboration with Ipc2BH, produces a product of 83% ee. This trialkylborane, exo-norbornyldiisopinocampheylborane, eliminates one a-pinene moiety upon treatment with moist acetaldehyde. Treatment of the borinate with (S)-(+)pyrrolidinemethanol forms a chelate which, upon recrystallization, yields the chelated borinic ester in >99% ee (Figure 16). Yet another method of enriching the initial hydroborated product was discovered by us recently. The controlled treatment of the initial product of lower ee with less than one equivalent of benzaldehyde undergoes a kinetic resolution liberating a-pinene selectively from one isomer, thus providing the boronate ester in essen-

.^ , . 2 | X + BH3.SMe2

THF —

'

^

,*)2BH

92% ee

21X1

(EtO)2B^^\

+ H--T

2

CH3CHO

' • «25"°C/36h " " : r>r I

97% ee Figure 15.

H**I

162

HERBERT C. BROWN and P. V. RAMACHANDRAN

Ipc

moist CH3CHO

••/^s/^R

l.dilHCl 2. CH3CHO

\.

tt—: 2. crystallize

£b.r

-

>99%ee

OEt

Figure 16.

Ipc B PhCHO ^ I p c (leg) THF, r t ' <1 min

Ipc2BH >99%ee Ipc

Ipc

I

,B,

91.5%

OBnz

8.5%

36h

0.8 eq 0 B n z 97% ee (15, 25) (crystallize: >99% ee)

l a r g e i y [ ( I / ? , 2 /?);/?]

Figure 17. tially 100% ee (Figure 17).40 Thus, the above hydroborated product from norbornene, upon treatment with 1.8 equiv benzaldehyde, liberates 1.8 equiv of oc-pinene providing the boronate in 97% ee. A simple crystallization of the boronic derivative gives the product in >99% ee. Preparation of optically active boronate esters using the Matteson homologation procedure is discussed in Section V. B. Borinate Esters

Though most of the general asymmetric syntheses utilize boronate esters, there are certain reactions that proceed via the borinate esters. In such cases, the boronates are converted to the borinates by reacting with an alkylmetal followed by treatment with ethereal HC1 or acid chlorides (Eq. 9).41 R*B(OR)2 + R'Li

LiR*R'B(OR)2

HC1/EE

R*R'BOR

(9)

Chiral Organoboranes Based on a-Pinene

163

...*B

jkBHo

olefin-1

[Q]^

R*OH 53->99%ee

[O]

R*OH >99%ee

R* I crystallize H

EtO

I ^„BR

+

I ,«*\

l.olefm-2 2.CH3CHO

crystalline dimers >99%ee

Figure 18.

Alternately, the borinates can be synthesized by successive hydroboration of two appropriate alkenes with IpcBH2, followed by treatment with aldehyde to eliminate oc-pinene (Figure 18).42 Crystallization of the initially formed IpcR*BH upgrades the optical purity of thefinalproduct. C. Applications of Boronate and Borinate Esters

There is an ever-increasing number of reactions that are carried out using chiral boronate esters which can be readily converted into the lithium monoalkylborohydride without loss of optical activity by treatment with lithium aluminum hydride.42 These optically active monoalkylborohydrides in turn can be readily transformed into R*BH2, R*BHC1, R*BC12 and similar derivatives (Figure 19).42 These can then be used as such for hydroboration followed by transformations of the organoboranes as in Chart 1, the important difference now being that we obtain optically active products after every transformation (Chart 2). Thus, Ipc2BH provides an entry into

HX LiR*BH3

2HX 3HX

Figure 19.

R*BH2 + H2 R*BHX + H2 R*BX2 + H2

164

HERBERT C. BROWN and P. V. RAMACHANDRAN as, as; as, trans; trans, trans, etc. R*CH=CHCH=CHR

R*OH R*CH2OH

R*C02H

R*CECR

R*RNH

R*CH2C02Et

fra/w-R*COCH=CHR

R*CH2CN

R*RCHOH

Chart 2. A general synthesis of pure enantiomers via asymmetric hydroboration. (The broken arrow indicates reactions not yet demonstrated experimentally.)

a huge number of optically active boronate esters that can be utilized for a general method of asymmetric synthesis. The optically active borinic and boronic esters prepared as above have been successfully converted into a-chiral aldehydes, acids, amines, oc-chiral cis- and frans-olefins, a-chiral acetylenes, p-chiral esters, ketones, etc. A complete survey of all of these reactions would be unduly space consuming, so we limit the discussions to a few representative examples. ct-Chiral Aldehydes

The treatment of chiral 2-alkyl-l,3,2-dioxaborinanes with methoxy(phenylthio)methyllithium (MPML) followed by HgCh furnishes the homologated a-methoxyalkyl derivatives which, upon oxidation with hydrogen peroxide in a pH 8 buffer, are smoothly converted to the corresponding chiral aldehydes (Figure 20).43 These aldehydes can also be prepared from chiral boronates available via the Matteson homologation procedure (Section V).44

Chiral Organoboranes Based on a-Pinene

165

LiCH(OMc)SPh - • R*CHO HgCl2 3.[0]

BMS

R*CH2OH

I H 2 Cr0 4 , H 2 0, EE

R*C02H

Figure 20.

a-Chiral Acids

The aldehydes from the above reaction can be reduced with BMS to the corresponding p-chiral alcohols. Oxidation of these aldehydes by chromic acid, using our two-phase oxidation system, provides the a-chiral acids (Figure 20).43'44 a-Ch/ra/ Amines

pri-Amines. Conversion of the optically active boronic esters to amines is achieved by converting the boronate to a borinate ester by treatment with methyl lithium and acetyl chloride, followed by reaction with hydroxylamine-O-sulfonic acid (Eq. 10).45 Me I

MeLi

o—'

CH3COCI

1. NH2OSQ3H -OAc

R*'

2. H 2 0

R*NH2

(10)

sec-Amines. Reaction of organic azides with alkyldichloroboranes is an established procedure for the synthesis of sec-amines.46 The availability of chiral dichloroboranes from chiral boronates by treatment with LAH followed by three equivalents of HC1 in EE,43 or directly by treatment of the boronates with BCI3,47 provides an excellent route to chiral sec-amines (Eq. II).48 RN - „ / ~ A BCl, „ „ „ ' R*Bx } "R^CKCHjhq'

R* 1 CI—B-N-R CI N2

cl

R* 1

N R

l.H 2 0

* -r - ric5jr

R*NHR

(11)

CI

a-Chiral Ketones Chiral ketones are an important class of compounds in their own right and as intermediates in the elaboration of more complex structures. The synthesis of various types of a-chiral ketones can be achieved without difficulty using tested procedures.

166

HERBERT C. BROWN and P. V. RAMACHANDRAN R*B(OR)2 + R'Li R*RBOR

LiR*R'B(OR)2

•

R*R'BOR

1. HCl2COMe (DCME) 2. LiO-f-Bu 3. H 2 0 2 , pH 8

!

y

•

8

;m

>

£ 99% ee

\ ^

f

> 99% ee

> 99% ee

Figure 21. Alkanones. The conversion of the chiral borinate esters to an a-chiral ketone is achieved41 by the DCME (a,a-dichloromethyl methyl ether) reaction (Figure 21).49 The versatility of this approach is exemplified by the synthesis of the optically active alarm pheromone of the ant, manica mutica (Figure 22).50

Alkenones. The procedure for a-chiral ketones is very general, and an appropriately substituted alkenyllithium can be used for the synthesis of a-chiral a'fnmy-alkenyl ketones (Figure 21).51 a-Chiral alkenones can also be prepared from borinates prepared via the hydroboration of terminal acetylenes with IpcR*BH. Treatment of the thus formed trialkylborane with acetaldehyde provides the borinates, which are converted by the DCME reaction to alkenones (Figure 23).52

Alkynones. The standard procedure for the preparation of a-chiral ketones was utilized for the synthesis of a-chiral a'-alkyny 1 ketones by the reaction of alkynyllithium with the chiral borinates (Figure 21).53 OEt \

(

JBIpc2 . B. ^ .B. j£ CH3CHO > £ !PC 1. LAH J?, IPC J H -a-Pinene* J 'H 2. H2C=CH2* J 'H

I

II

CH3CHOL. " VV^ O^OEt E t 1.DD CME CME V \ >^^N*X ^ ^ „ >99%ee -<x-Pinene* , H 72.[0] mi . \H\ pheromone of the ant l'*H manica mutica Figure 22.

Chiral Organoboranes Based on a-Pinene

167 R*

IpcBHR*

«^WCH, .99% ee ~25 C

lpc

B

" wH

SM*U

/ Y Q H ,

R* E t 0

O

"\ / 1. Cl2CHOCH3, Et3COLi m R* /=< 2. H202, pH 8 H n-C4H9

/H /==\ H n-C4H9 \

Figure 23.

a-C/i/ra/ Olefins

The synthesis of both (£)- and (Z)-olefins can be achieved from a chiral boronate using procedures established during our organoborane program.54

(Z)-Olefins. * IpcBR*H prepared by the hydroboration of an olefin using IpcBRb is treated in steps with (1) a terminal acetylene, (2) acetaldehyde, and (3) iodine in the presence of sodium methoxide to provide (Z)-alkenes in high yields and ee (Figure 24). 54

(E)-Olefins. cc-Chiral (E)-alkenyl boronates can be prepared by treating IpcR*BH with 1-bromoalkyne followed by, in steps, (1) acetaldehyde, (2) aqueous sodium hydroxide, and (3) trimethylene glycol. This boronate on protonolysis with acetic acid yields optically pure (2s)-olefins (Figure 25). 54 These procedures are superior to our earlier procedure for the preparation of oc-chiral (E)-alkenes starting from R*B(Thx)H.55

l

/

R*

/i-C H OCH^ V°—\

IpcBHR* ' - 4—9 " • ,99% ee

,H

CH3CHO

W /\-C

4

H

9

R* EIO-B'

H

hNaOMe,

Figure 24.

" w "

^9%ee

168

HERBERT C. BROWN and P. V. RAMACHANDRAN R* / Ipc—B n-C4H9CsCBr^A^ "v IpcBHR* -25 °C £99% ee Br R* l.NaOMe/MeOH,H20 2. HO(CH2)3OH '

R* H ,"

w

EtO—B ~ \ /H CHaCftO^—

n-C4H9

Br

H

H

B

/1-C4H9

AcOH ^ reflux

R* \ /

n-C4H9

H /

H

>99% ee \

/1-C4H9

JO

Figure 25.

a-Chiral Acetylenes

We utilized the chiral boranes synthesized from chiral boronates for the synthesis of chiral internal acetylenes as shown in the following scheme (Figure 26).55 Chiral terminal acetylenes were prepared by a two-step process. First, lithium (trimethylsilyl) acetylide was treated as above to form an a-chiral trimethylsilyl acetylene. This was then desilylated by treatment with aqueous sodium hydroxide.56 fi-Chiral Esters, Nitrites, and Ketones

We prepared 2?-R*-9-BBN by treating the chiral boranes with 1,5-cyclooctadiene followed by thermal isomerization. No loss of chirality was observed during this isomerization. Once this was achieved, the syntheses of p-chiral esters, nitriles, and ketones were simple (Figure 27).57

R*BH2 +

LiCsCR

X-HHLi+

/

R*

MeOH,

R* I -B—C*C—R

I2

-78 °C

I

H

_ „ „ R * ~nC « C - H

Figure 26.

OMe

*-R*—C«C—R

OMe

«* r, r, n-w aq NaOH/MeOH R*—C«C—SiMe, — •

R*

Chiral Organoboranes Based on oc-P/nene

169 l.f-BuONa,-15°C 2.BiCH 2 C0 2 Et * R*CH2C02Et

*-<3>

R*BH2 +

l./-BuONa,-15°C *-R*CH 2 CN 2. C1CH2CN l./-BuONa,-78°C 2. BrCH2COR'

R*CH2COR'

Figure 27.

V. ASYMMETRIC HOMOLOGATION Matteson and his co-workers developed an ingenious and elegant procedure for the preparation of cc-chiral boronate esters via an asymmetric homologation.58 Thus the reaction of cyclic boronate esters derived from pinanediol with preformed dichloromethyllithium, LiCHCh, at -100°C, followed by transfer of the organic group from boron to carbon induced by anhydrous ZnCh, provides the asymmetric boronate ester with > 99% enantioselectivity (Figure 28). While the Matteson procedure provides a method for the synthesis of many optically pure compounds that cannot be achieved via direct hydroboration, it has certain drawbacks. The rigorous requirement for inconvenient temperatures, such as -100 °C, for the preformation of LiCHCh and the difficulty in recycling the chiral auxiliary, pinanediol, limited the scaling-up of this procedure. We overcame these limitations by utilizing LiCHCh prepared in situ and carrying out the reaction at -78 °C.59 Procedures were also developed for recycling the pinanediol chiral auxiliary without loss of optical activity.60 We applied the chiral boronates produced by the modified procedure to the synthesis of aldehydes, acids, amines, ketones, etc. using our established procedures (Figure 29 and 30).44 Again, it is very satisfying to notice that this procedure is also an asymmetric synthesis via chiral organoboranes based on a-pinene. The chiral auxiliary, pi-

LiCHCl; C12HC 0 - , ZnCl, . b~ V-B; W (S) 20-25 M o c °C k* -100 °C

R-B

V

e1

Li*

n ! ,°-\ R-C-B (•) H

R' U

,

20-25°C» -UC1

CI ! / H R.M R-C " r - B -: \ j '(S) - 7 8^° C; H ^

H n ^ ^ B / 7s) " ^ R ~ 9 ^ B \ <S) o i P " R' °

R

Figure 28.

H R-C-OH R^C-OH R'

170

HERBERT C. BROWN and P. V. RAMACHANDRAN I.UAIH4

.LiCHCl2,-78°C 2. anh. ZnCl2 ' 3.RMgXorRLi 1. LiCH(OMe)SPh THF,-55°C R

B > V V 2.Hjp2 u 3 loJ *

2. NaOMe* 3. H 3 0 +

R

'\>H

H2CrQ4

^CHOEE-H20 £94% ee

R

.Ry £94% ee

F/gcire 29.

x

R'V. R

94-99% >%de

.MeLi,EE,-78°C 2. HCl-MeOH '

°

| ^

R

*'wH 0 M e x < Xx

R^^B I

Me 1. NH2OS03H 2. H 2 0, OH"

DCME [O] R O 94-99% ee

NH2

94-99% ee

Figure 30. nanediol, is derived from oc-pinene by a catalytic oxidation using OSO4.61 Matteson has reviewed his work on several occasions.62 He has applied the chiral boronates derived via homologation chemistry to the synthesis of insect pheromones,63a'b sugars630 amino acids,63d,e etc. Our established synthetic schemes can also be applied to the boronates prepared via Matteson's homologation procedure, the syntheses of which are difficult to realize via asymmetric hydroboration (Chart 3). A, Alternatives for Asymmetric Hydroboration of 2-Substituted-1 -Alkenes Matteson's homologation helped to circumvent a major deficiency in our asymmetric hydroboration procedure. Using a one-carbon homologation of oc-chiral boronates, we are now in a position to synthesize the boronates that cannot be obtained in high ee via the direct hydroboration of 2-substituted-l-alkenes. We applied this homologation procedure to our oc-chiral boronates prepared from asymmetric hydroboration and succeeded in the synthesis of (5-chiral boronate esters (Figure 3l). 59a ' 64

cis, as., cis, trans; trans, trans , etc. RR'HC*CH=CHCH=CHR" I RR'HC*OH

RR'HC

RR*HC*CH2OH

RR'HC*C02H

RR,HC*CK2CH=CH2 **RRHC*CSCR" -*

" RR'HC*COR"

RR'HC*CSCH

>' RR,HC*CH2COR" / RR'HC*CH2C02Et

/ /RR'HCCR^OH*.

rra/w-RR'HC*COCH=CHR" 1

,

RR HC*CR,,HOH

RR'HC*CH2CN

Chart 3. A general synthesis of pure enantiomers via asymmetric homologation. (The broken arrows indicate reactions not yet demonstrated experimentally.)

H

/

*

|

LiCH2Cl {insil situ)

J

ro

U+

O s J THF, -' £99% ee (from asym. hydroboration or asym. homologation)

B

_^O - 0 ^ /

B

80-93% £99% ee

^

asymmetnc 1hydroboration (only 20% ee)

Figure 31. 171

l.-78°Ctort 2.rt, 18hor reflux, THF, 1.5 h

172

HERBERT C. BROWN and P. V. RAMACHANDRAN

"^ - —

/°""A R*B

)

[LiCH2Cl]

*•

O—'

V

/ / MH]

^

[LiCH 2 Cl]

Li

XX

o

R*(CH 2 ) 3 B

/

o—f \

>/

VX

/ _[LiCH2CI]

V

/ | \

R*(CH 2 ) 2 B

/

\

/ ( \ Figure 32.

The above P-chiral boronates can now be utilized for further reactions of organoboranes to prepare p-chiral molecules. Another homologation of the above P-chiral boronates provides Y-chiral boronates, and a third homologation, 8-chiral boronates (Figure 32). Now we can use these (3-, y- and 8-chiral boronates for the general asymmetric synthesis as shown in Chart 3. B. Three-Carbon Homologation

The utility of the Matteson homologation procedure for the synthesis of medium ring boracyclanes has been established. We synthesized up to 12-membered boracyclanes starting from borinane, increasing the ring size one carbon at a time.59b Recently we have developed a three-carbon homologation process utilizing (achloro)allyllithium generated in situ from allyl chloride and LDA at -78 °C (Figure 33).65 C. Broad Scope of Organoborane Chemistry

The easy synthesis of chiral boronate esters by hydroboration with Ipc2BH or IpcBH2, or by Matteson's homologation procedure, has expanded the scope of asymmetric synthesis to an unimaginable extent. We have now achieved the synthesis of 34 optically pure boronates via hydroboration. Since both enantiomers of oc-pinene are readily available, we can synthesize 68 pure enantiomers. A

Chiral Organoboranes Based on oc-P/nene

O

, +

^ ^

c\ ^

173

l.LDA,-78°C 2.-78°C->rt'

U

B

-(>o OR

[H]

B-OR

Figure 33.

comparable number should be easily synthesized via asymmetric homologation. This doubles the number of optically active boron intermediates to 136. A simple one-carbon homologation doubles the number of compounds to 272. A second homologation could triple the original number (408). A third sequence makes a total of 544 pure enantiomers. We have shown 24 major reactions in Chart 3 (other, less important reactions are also known). Each of the above boronates can undergo the 24 major reactions in the chart. This makes a total of 13,056 optically pure compounds. Many of the functional groups contained in some of these 13,056 compounds can be transformed to new functional groups. Thus one is now capable of synthesizing more than 100,000 pure enantiomers using simple organoborane chemistry. Based on our successes in a relatively short period of time, we believe that greater success awaits those willing to undertake new applications of this chemistry. Needless to say, this chemistry is still very young.

VI. ASYMMETRIC ALLYL-AND CROTYLBORATION The art of asymmetric synthesis has become highly sophisticated in conformationally nonrigid systems, especially in those C-C bond forming reactions such as aldol additions.66 These reactions constitute one of the fundamental bond constructions in biosynthesis. Among such condensations, allylic organometallic reactions producing homoallylic alcohols have attained considerable importance since the product contains an alkene moiety which could be further transformed into other functional groups (Figure 34). Asymmetric synthesis has attained special importance in the synthesis of macrolide and ionophore antibiotics with a plethora of stereodefined v/c-diols or P-methyl alcohols.67 Here, not only the enantioselectivity, but the diastereoselectivity of the reaction is highly important. Accordingly, numerous searches for the

174

HERBERT C. BROWN and P. V. RAMACHANDRAN OH

R

" ^ , / 1 M ,r-M _RCHO^ R-^X^ — R^X^H

R' R2

R1'

R2

R1'

>V

\ J—

r-M

•

R2

°

R1'

R2

Figure 34.

most efficient reagent that can achieve both these selectivities in a single step have been made. Several groups have developed different alkylmetallation reactions using different metal atoms and chiral auxiliaries. These have been reviewed in the literature on several occasions. 68 Chiral organoboranes have revealed their uniqueness and advantages for achieving these desired transformations. A.

£?-Allyldiisopinocampheylborane

Two decades ago Mikhailov pointed out that allylboron derivatives, in marked contrast to the behavior of saturated trialkylboranes, undergo a fast addition to carbonyl groups with allylic rearrangement (Figure 35). 69

3<^NSs^MgBr+

BF3

^ \ / > 3 B

+ 3MgBrF

68% yield ^ s s ^ ^ ) 3 A l 2 B r 3 + BF3

•

^ \ ^

) 3 B

+ A1F3 + AlBr3

78% yield R

R

.

B

1

>v

RCHO ?

)2

J

^B(0"

Figure 35.

_

3HOH

Chiral Organoboranes Based on a-Pinene

175

R. W. Hoffmann used a chiral auxiliary derived from camphor to achieve a simple asymmetric synthesis (Eq. 12).70 The optical yields were only moderate. Accord-

v/

v/ OH ^

D

- ^ - ^

RCHO, ^ ^ R - ^ - ^ > 36 - 86% ee R = Me, Et, Ph etc.

ingly, we decided to test our chiral inducer, oc-pinene, for allylboration. This turned out to provide another major application of Ipc2B- in organic synthesis. The synthesis of Ipc2BAll was simple and the reaction with aldehydes at -78 °C, followed by either alkaline hydrogen peroxide or ethanolamine work-up, provides the homoallylic alcohols in very good yields in very high enantiomeric excesses (Figure 36).71 Roush and co-workers achieved allylborations with tartrate esters and amides as chiral directors.72 We synthesized several derivatives of Ipc2BAll and all of them proved highly successful, as described below. B. 0-Methallyldiisopinocampheylborane

This reagent was readily prepared from Ipc2BOMe by treatment with methallyllithium.73 The reagent produced methallyl alcohols in very high ee that are valuable intermediates for the elaboration into more complex acyclic compounds (Figure 37). For example, the epoxidation and iodocyclizations proceed with excellent diastereoselectivity.

)2BOMe

Ipc2BH £99% ee

^ X ^ Ipc2BAll £99% ee

Ipc2BOMe £99% ee

* t C ^ | l 4!L£_ «.,/>"<*> JOL Et20

> > H H4 ,OH 93% ee

H"^CH 3 Figure 36.

176

HERBERT C. BROWN and P. V. RAMACHANDRAN Li+ )2BOCH3

CH3CHO Ipc2BOMe, £99% ee

yx

^ B Q vj>Y

90% ee

Figure 37.

C.

3,3-Dimethylallyldiisopinocampheylborane

Artemesia alcohol, an "irregular" acyclic monoterpene isolatedfromArtemesia annua L. and Artemesia herba-albai with the unconventional non-head-to-tail union of isoprene units attracted our attention. We envisaged the synthesis of this terpene via an allylboration reaction using the 3,3-dimethylallyl derivative. The synthesis of this reagent involves a simple hydroboration of 1,1-dimethylallene, and allylboration normally provides products in 89-96% ee with predictable configuration (Figure 38).74 D.

(Z)-3-Methoxyallyldiisopinocampheylborane

The success of the above allylborations led us to (Z)-y-methoxyallyldiisopinocampheylborane since we observed the need for this type of reagent for several

) 2 BOR*

(+)-artemesia alcohol, 96% ee

Figure 38.

Chiral Organoboranes Based on a-Pinene

\77

QCH, Li—-OCH 3

,*)2BOCH3 ^ J

sKs™

IpC2B0Me

ICH3CHO

Q H

'

,) 2 BOR*

OCH3 90% ee, 98.5% syn

Figure 39.

natural product syntheses, especially certain carbohydrates and antibiotics. Synthetic access to this reagent was made possible by the reaction of the lithium salt of allyl methyl ether with 5-methoxydiisopinocampheylborane, followed by treatment with BF3EE. The reaction of this reagent with aldehyde exhibits a high selectivity for the ^jn-alcohols in high ee (Figure 39).75 E. Comparison of Chiral Auxiliaries

Though a-pinene proved highly successful as the chiral auxiliary in asymmetric allylborations, we have shown that reagents preparedfromother terpenes, such as 2-carene, yield even better enantioselectivity.76 Since this review primarily deals with those reagents derived from a-pinene, this is mentioned only for comparison purposes. Again, this review would be incomplete without mentioning some of the excellent allylborating agents developed by contemporary researchers (Figure 40).77 To provide a correct comparison, it became desirable to obtain quantitative data on the relative rates of the allylboration reaction for the various structural types that have been utilized. The glycol derivatives related to the Hoffmann chiral auxiliary proved to be very slow. Consequently, such derivatives cannot be used at low temperatures to enhance the enantioselectivities of the reaction. Roush's tartrates are much better, reacting within 15 min. at -78 °C. The surprise was our Ter2BAll reagents 8-10. The reactions were instantaneous at -100 °C when the reagents were free of the magnesium salts (from allyl magnesium chloride).78 A comparison of the ee achieved by various allylborating reagents for a selected series of aldehydes are presented in Table 3. 76

178

HERBERT C. BROWN and P. V. RAMACHANDRAN

V

S02Me

EtQ.

\ A „ Q—-BA11

lO-^BAll

EtO.

Ph

3nz

N BA11

0 2 BA11

Figure 40.

F.

&-(£)- and (Z)-Crotyldiisopinocampheylborane

Based on our successes with various allylborating agents, there was no reason for us not to believe that crotylborations would also be highly successful with our

Table 3. Comparison of the ee Achieved by Various Allylborating Agents in Figure 40 % ee Achieved Aldehyde

b

1°

2

acetaldehyde

86

96

n-butyraldehyde

72

96

i-butyraldehyde

70

94

cyclohexanecarboxaldehyde pivalaldehyde

45

88

C

3

4

d

Se

6'

7*

79

94

93

96

95

85

96

87

97

88

96

97

82

96

86

97 97

98

acrolein benzaldehyde

88 68

77

71

95

85 77

8*

9

W

>99

>99

£99

96

98

£99

96

98

699

>99 96

>99 98

>99 £99

96

98

>99

77c

Notes: Hoffmann reagent. *Reetz reagent. * Ttoush reagent (l). ** ^Roush reagent (2). *Masamune reagent (1) 77d ^Masamune reagent (2).77e *Corey reagent.™ AIpc2BAll at -100 °C.76 '4-Icr2BAll at 100 °C.76 ^2-Icr2BAllat-100°C.76

Chiral Organoboranes Based on a-Pinene \ >

/ '

kn*M -78°Cto-45°C r

K+

179

" \ _ / N '

MpcaBOMe IBF3.EE

IpcaB-

Ipc2B-

1. r-BuOK 2. n-BuLi -78 °C to -45 °C

1. Ipc2BOMe 2. BF3.EE

Figure41.

reliable chiral auxiliary, a-pinene. However, the fast equilibrium of pure (E)- and (Z)-crotylboron derivatives via a borotropic rearrangement involving the 1-methallyl compound as an intermediate offered potential problems for the synthesis of pure isomers of the crotyl derivatives. Fortunately, the timely publication of a procedure by Schlosser to prepare f-butylpotassium aided in the synthesis of isomerically pure crotylpotassium.79 Practical procedures were developed for the synthesis of pure Ipc2Bct£ and IpciBCrt2 (Figure 41).80 The reaction of these derivatives with aldehydes achieved asymmetric crotylboration with remarkable optical and geometric efficiencies. Consequently, it is now possible to synthesize each of the four possible isomers of p-methylhomoallylic alcohols (Figure 42).80 G.

£-2'-lsoprenyldiisopinocampheylborane

Our success with crotylpotassium persuaded us to prepare the 2?-2'-isoprenyldiisopinocampheylborane from isoprenylpotassium and 5-methoxydiisocampheylborane. Condensation of this reagent with aldehydes provided isoprenylated chiral alcohols (Figure 43).81 This methodology was applied for an efficient one-pot synthesis of both enantiomers of the bark beetle Ips paraconfusus Lanier, ipsenol, and ipsdienol. This simple synthesis is in sharp contrast to multistep syntheses (13 and 17 steps) by Mori.82

d

> 'ipcjB-

"lpc2B-

Ipc2B

CH3CHO,-78°C OH

OH

CH,

CH,

Figure 42.

'ipc^B-

180

HERBERT C. BROWN and P. V. RAMACHANDRAN

XXXs [/?]-(+)-Ipsenol

XxJL* [5]-(+)-Ipsdienol

Figure 43.

We used either oxidative (alkaline hydrogen peroxide) or ethanolamine work-up to isolate the product alcohols after allyl- and crotylboration reactions. The first procedure leaves isopinocampheol as a side product which should be removed carefully to obtain the pure product. Though ethanolamine complexes with borinates to form solids, the reaction with Ipc2BOR* fails to precipitate all of the borinates in a reasonable time thus making quantitative isolation difficult. A solution to these problems was found when we treated the initial reaction product with acetaldehyde to recycle the a-pinene chiral auxiliary, followed by treatment with triethanolamine. However, more recently we have observed that 8hydroxyquinoline reacts with Ipc2BOR* to form a crystalline adduct that can be easily separated from the product chiral alcohols.83 H. Applications of Allyl- and Crotylboration

The success of any new reagent or reaction can be easily measured by examining the citations in Science Citation Index for applications of the reagent. We see a cornucopia of publications utilizing our reagents for the stereospecific synthesis of a wide variety of compounds, an almost unparalleled enthusiasm in welcoming new reagents. This in turn is a heart-warming application of our initial hydroborating agent Ipc2BH..We have compiled some of the key applications of our allylborating agents from the literature in Table 4. Representative examples of the uniqueness of the crotylboration are shown in Figures 44,45, and 46. The synthesis of the Ci-Cio fragment of nystatin Ai (Figure 44) portrays the application of allyl and crotylboration in macrolide syntheses. Repetitive use of the reagent provides the product in the necessary geometry in very high ee.91 We remind the readers that the applications of allyl- and crotylboration presented in Table 4 are those which are based on our reagents. Hoffmann,68 Roush,72 and

OBnz uonz

OBnz O H

(-)-Ipc2BAU

XHO

OBnz O T B S |(-)-Ipc2BAll

(-)-Ipc2BAll

OBnz O T B S OTBS

DBnz OTBS OH

kA^l^CHO

OBnz OTBS OTBS OH

O

M

OTBS OTBS

0 * \

Figure 44.

OR R = HorTBDMS

r^^ OH Milbemycin E Spiroacetals

r

r'Y 1 ^°vl T j o 17^11 H

%

li

Leu^° |H9 1

HO k

DL OMe

Figure 45. 181

1

Milbemycin E 1

1 1

V 2 B v ^ * ^

+

fco^

OH R = H,OAc Avermectin A2a Spiroacetal

" OMe [R = (g-L-olcandrosyl)2]

Figure 46.

Table 4. Literature Citations of the Applications of Allyl and Crotylboration No.

Reagent Used

Target Molecule

Major Author

1 2 3 4 5 6 7

Ipc2BAll Ipc2BAll Ipc2BCrt£ Ipc2BCrt£ Ipc2BCrtZ Ipc2BAUOMeZ Ipc2BAll

Prostanoids Mycoticin A & B Avermectin Milbemycin E Calcimycin Carbomycin 1,3-Polyols (Euparotium pilosum) Nystatin Al Cytochalasin D Avermectin Bla FK-506 Histrionicotoxin Nikkomycin B HMG-Co A reductase inhibitor Calyculin A-H Polymethoxy-1-alkenes (Scytonema ocellatum) syn- 1,3-Polyols Monocerin ethers Fusarentin ethers Routiennocin (-)-Calicheamicinone Calyculin A (-M/vO-GABOB (3-Amino acids

15 16

Ipc2BAU Ipc2BCrt£ Ipc2BCrt£ Ipc2BCrtZ Ipc2BAll Ipc2BCrt£ Ipc2BAll Car2BAU Ipc2BCrtZ Ipc2BAll

17 18

Ipc2BAU Car2BAll

19 20 21 22 23

Ipc2BAll Ipc2BAll Ipc2BCrtZ Ipc2BAll Ipc2BCrt

8 9 10 11 12 13 14

182

YearPubl.

Ref.

Truesdale Schreiber Thomas Thomas Boeckman Wuts Nakata

1985 1987 1987 1987 1987 1988 1989

84 85 86 87 88 89 90

Nicolaou Thomas Ley Ireland Stork Barrett Renaut

1989 1990 1990 1990 1990 1990 1990

91 92 93 94 95 96 97

Smith Mori

1991 1991

98 99

Wang Simpson Simpson Ley Nicoalou Barrett Bubnov Bates

1992 1992 1992 1992 1992 1992 1992 1993

100 101 101 102 103 104 105 106

Chiral Organoboranes Based on a-Pinene


Rl

(-)-Ipc2BOTf

Ri

f

/-Pr2NEt, CH2C12

183

l ^ p i

T OBIpc2 (Z)

T OBIpc2

£97 : <3

1 R 2 C H O

2. H 2 0 2 ' 45-99%

W

OH O (and)

66-93% ee 95:5 - 98:2 syn:anti selectivity

Figure 47.

several others have explored applications of the Hoffmann and Roush allyl- and crotylboration reagents in organic synthesis. Interested readers must consult those articles for the results achieved.

VII. ASYMMETRIC ENOLBORATION Stereoselective aldol reactions have been known for quite some time.107 Of all the elements studied for application in enolization reactions, boron offers special advantages and has been used extensively.108 Asymmetric enolboration received considerable attention this past decade and several researchers developed different chiral auxiliaries to induce diastereoselectivities and enantioselectivities in the reaction. Paterson treated Ipc2BH with trifluoromethanesulfonic acid to prepare the corresponding triflate, IpC2BOTf, for asymmetric enolboration. This reagent turned out to give good to excellent optical yields in providing diastereoselective, enantioselective aldol products (Figure 47). n o Paterson has applied this reagent for the synthesis of a number of natural products.111

VIII. ASYMMETRIC REDUCTION Asymmetric reduction of the ubiquitous carbonyl group occupies a position of prime importance in asymmetric synthesis.112 The optically active alcohol products, if not the desired end product, serve as starting materials for many syntheses. Selection of an appropriate chiral reducing agent for the particular type of ketone in hand often posed major difficulty a decade ago. Though asymmetric reduction has been known for decades,113 it was only around 19&0 that good reagents finally became available. Much of the thrust in the research on asymmetric reduction has

184

HERBERT C. BROWN and P. V. RAMACHANDRAN

1. Acyclic

2

6. oc-Keto esters

O

2. Cyclic

O

7. P-Keto esters

O

3. Aralkyl

4. Heterocyclic

5. a-Halo

>6 C^ Q

*OEt 8. Acyclic conjugated enones

Q

O

9 CyClic conjugated enones

ft

0

10- Conjugated ynones

c^ 0^' N

O

Figure 48.

occurred in the last decade. Again, the development of chiral reducing agents was also complicated by the nature of the ketones. While some reagents showed exceptional promise for the reduction of certain classes of ketones, they failed miserably for the asymmetric reduction of other classes of ketones. Data were rarely reported for those less favorable applications. Consequently comparisons became difficult. We divided the ketones of interest into 10 different classes, selecting a representative member of each class, with the hope of making possible the systematic study of asymmetric reduction and the development of reagents that could effectively handle each of these classes of ketones (Figure 48). 114 The possibility of synthesizing optically active organoboranes by hydroborating suitable optically active terpenes led us to examine the possibility of achieving asymmetric reduction of prochiral ketones with chiral organoboranes and borohydrides derived from such organoboranes. A. lpc2BH and lpcBH 2

Although Ipc2BH and IpcBtfe are excellent chiral hydroborating agents, as described earlier, they proved unsatisfactory as chiral reducing agents for prochiral ketones (Figure 49).115'116 This is to be expected because a ketone would be similar to class I olefins in steric requirements and, as discussed earlier, both of these reagents fail to achieve the asymmetric hydroboration of this class of olefins in satisfactory ee.

185

Chiral Organoboranes Based on a-Pinene

I Ha

Ipc2BH IpcBH2

M

13.4% ee, S 22% ee, S

37.5% ee, 5 37% ee, 5

19.8% ee, S 21%ee,S

9%ee,S 15%ee,S

Figure 49.

B. Alpine-Hydride®

Another chiral reducing agent derived from a-pinene, lithium-£-3-pinanyl-9-borabicyclo[3.3.1]nonyl hydride (Aldrich: Alpine-Hydride®) also proved ineffective in transferring chirality to the product alcohols (Figure 50).117 C. 0-lsopinocampheyl-9-borabicyclo[3.3.1 Jnonane (Alpine-Borane®)

The reactions of trialkylboranes with carbonyl compounds under forcing conditions (150 °C) are known in the literature.118 M. M. Midland and co-workers demonstrated the chiral version of this reaction by establishing B-isopinocampheyl9-borabicyclo[3.3.1 ]nonane (Aldrich: Alpine-Borane®) as thefirstsuccessful chiral organoborane reducing agent. He utilized it to prepare a number of deuterated alcohols by reduction of the deuteroaldehydes, RCDO, in essentially optically pure

«0>

BG> Alpine-Hydride O

Ph

HO 29% ee, R

I .H

36% ee, R

Figure 50.

20% ee, R

186

HERBERT C. BROWN and P. V. RAMACHANDRAN

o

+ HB;

^

99% ee,/?

Figure 51.

form (Figure 51).119 The steric environment of the pinane moiety makes the reactions quite facile at room temperature. The reductions involve a MeerweinPondorf-Verley (MPV)120 type of process, with a six-membered transition state, and the chiral auxiliary, oc-pinene, is readily recovered from the reaction mixture (Eq. 13).118 The kinetics of the reaction are bimolecular and the hydride transfer is believed to be the rate limiting step.121

k^a — - T O P*B

V

<S^^

(13)

B

I

The opposite enantiomer of the deuterated alcohol can be prepared either by treating the deuterated aldehydes with Alpine-Borane prepared from the opposite enantiomer of oc-pinene or by treating aldehydes with deuterated Alpine-Borane, preparedfromdeuterated 9-BBN and the original enantiomer of oc-pinene (Figure 52). The tritiated alcohols can also be prepared using this procedure. This development has simplified studies using radiolabeled materials.122 Scope of Alpine-Borane Reductions

Alpine-Borane fails to reduce simple prochiral ketones, such as acetophenone and 3-methyl-2-butanone. However, certain reactive carbonyls, such as oc,($-acetylenic ketones,123 oc-keto esters, and oc-halo ketones, can be converted to the corresponding alcohols in very high ee with Alpine-Borane (Figure 52).124 Acyl cyanides are rapidly reduced by Alpine-Borane to cyanohydrins, converted

187

Chiral Organoboranes Based on a-Pinene

*o

!.*B0) X

HO H H 0

PIT ^ D

V£

100% ee, S

Alpine-Borane

-O <&®J>

HOA

VH

D Ph 100% ee, R

Figure 52.

in situ by NaBIVcobaltous chloride to the 1,2-amino alcohols of high ee.125 This aspect makes Alpine-Borane a chemoselective reagent. For example, Alpine-Borane can selectively reduce an aldehyde in the presence of a ketone, or reduce an acetylenic ketone in the presence of an ordinary ketone.126 The poor selectivity in the reduction of simple ketones with Alpine-Borane is presumed to be due to a concurrent dehydroboration of the reagent in slow reductions followed by an achiral reduction of the carbonyl group by the 9-BBN produced in this stage (Figure 53).127 This problem can be overcome by minimizing the dissociation either by conducting the reductions in high concentrations at room temperature, or at greatly elevated pressures (Table 5) 128 However these procedures are still impractical for the reduction of unactivated ketones.128

«o 0

0 ow

fast

T

T

X

R^S' active

inactive

Figure 53.

HERBERT C. BROWN and P. V. RAMACHANDRAN

188

Table 5. Asymmetric Reduction of Prochiral Ketones with Alpine-Borane® 6000 atm Reaction Time, h % Yield, IsoL % ee (6000 atm)

Ketone 2-octanone 3-methyl-2-butanone 3,3-dimethyl-2-butanone acetophenone 3-acetylpyridine a-tetralone a,a,a-trifluoroacetophenone

24 24 216 24 36 72 72

63 47

63 90

57 67 0 87 90 52 18

no reaction

80 67 43 46

% ee (1 atm)

100 100 89 54

Applications of Alpine-Borane One class of ketone whose asymmetric reduction has found much application in organic synthesis is the oc,|3-acetylenic ketones. This is due to the fact that once the reduction is complete, the acetylenic moiety provides a reactive center for further modifications. Fortunately, Alpine-Borane can asymmetrically reduce this class of ketones very effectively. Hence many applications have been made of this reagent. Synthesis of Japanolure, the Japanese beetle pheromone,129 and a corticosteroid intermediate130 are representative examples of the applications of Alpine-Borane in synthesis (Figure 54). Japanolure is a good example of the desirability of asymmetric synthesis since the presence of as little as 1% of the wrong enantiomer causes a 50% decrease in the activity.

o

QHn, OMe H

H 97%ee Japanolure

C.H 8n17

^J

H 97% ee

Corticosteroid

SiMe3

intermediate

Figure 54.

Chiral Organoboranes Based on a-Pinene

189

Alpine-Borane is the only organoborane reagent that handles unhindered acetylenic ketones effectively. Another very efficient reagent capable of achieving this reduction is Noyori's Binal-H, prepared by modifying lithium aluminum hydride with Binaphthol.131 Alpine-Borane scores better due to the low cost and the ease of reaction conditions (neat, RT). Further examples of the applications of Alpine-Borane include (-)-Pestalotin,132 Pseudomonic acid,133 Prelog-Djerassi lactone,134 mevinic acid subunits,135 prosynthon C-14 for LTB4,136 and the hydroxypentenoic acid isolated from the aquatic plant Lemma trisulcaP1 D. #-Chlorodiisopinocampheylborane (lpc2BCl/ DIP-Chloride™)

Another method examined for increasing the rate of reduction was a change in the electronic environment of the boron atom. Our investigations had indicated that sterically hindered R2BCI derivatives are more stable toward dissociation than R3B. Accordingly, we synthesized B-chlorodiisopinocampheylborane (Aldrich: DIPChloride™) which proved extremely efficient for the reduction of aralkyl ketones (Figure 55).138 The synthesis can be achieved by treating Ipc2BH with hydrogen chloride in ethyl ether or via the direct hydroboration of oc-pinene with monochloroborane. The former is the preferred procedure since commercial oc-pinene is optically enriched during the preparation of Ipc2BH. Aralkyl Ketones DIP-Chloride shows extraordinary consistency in the reduction of aralkyl ketones with predictable stereochemistry.138 Testing the reagent for a series of substituted aralkyl ketones showed that representative substituents do not affect the chiral outcome (Table 6). DIP-Chloride has found many applications in synthesis with the reduction of aralkyl ketones as a key step (see page 194).

>*WBH HClinEE

0°C

xTL^

THF

» 1A/» "25 °C

(-)-Ipc2BCl (-)-DIP-Chloride

5h

(HOCH2CH2)2NH \ / - * - IpcB-^NH EE

Figure 55.

HO.

»H

72% yield, 98% ee, S

Table 6. Asymmetric Reduction of Substituted Acetophenones with (-)-DIP-Chloride™ at-25 °C Ketone

X-Ph-COCHi X

%eea

Isomer**

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

2-Fluoro 3-Fluoro 4-Fluoro 2-Chloro 3-Chloro 4-Chloro 4-Bromo 4-Iodo 2-Nitro 3-Nitro 4-Nitro 3-Cyano 4-Cyano 2-COOHc 4-COOH 2-COOMe 4-COOEt 4-CONH2 4-CONEt2 2-Me 3-Me 4-Me 4-f-Bu 2-OHe 3-OH 4-OH 2-OLie 4-OLi 2-OMe 3-OMe 4-Me 2-CF3 3-CF3 4-CF3 4-NH2C 4-NHCOCF3

95 96 96 96 97 98 96 97 96 96 94 96 97 25 97 94 97 95 95 96 96 94 96 81 97 10 90 90 92 96 94 94 95 96 89 85

S S S S S S S S S S S S S

*d S S*

s s s s s s s R S

s R S S S S S S

s s s

Notes: aee Determined as their MTPA or MCF derivative on a capillary GC ^Determined by comparison of authentic sample or by analogy of earlier results. c Ketone:reagent:: 1:2. ^Determined by conversion to the lactone and comparing the rotation. 'Reaction proceeds by an initial chelate formation.

190

Chiral Organoboranes Based on a-Pinene

191

O

+

ci I H 0-B-OEt ^X.

NaQH

*-

H OH ^ X . + EtOH + Na[B(OH)4] + NaCl

Figure 56.

The original work-up procedure for DIP-Chloride reductions involved a nonoxidative removal of the boron by-product as the diethanolamine complex. However, the presence of this complex caused difficulty in scale-up of the reactions. A recent report on a large-scale application stated difficulty in isolating the product. 139 Moreover, disposal of the voluminous precipitate may cause environmental problems. Hence we have developed a considerably improved work-up procedure for the isolation of product alcohols after reduction. 140 The new procedure involves treatment of the reaction mixture following reduction with a molar equiv of acetaldehyde at room temperature. This achieves the complete elimination of the second unit of oc-pinene from the reagent. The oc-pinene is recovered completely by collecting in vacuum and the product is obtained by a simple hydrolysis of the chloroborate ester, R*0(EtO)BCl (Figure 56). Mechanism of Reduction The tentative mechanism for reduction of ketones with DIP-Chloride provides a predictability of configuration of product alcohols (Figure 57). This has been used for predicting configurations of products in synthetic schemes 141 and for the

H^OH

favored R

less favored

L

Rs

H

OH

Rs

Figure 57.

RL

192

HERBERT C. BROWN and P. V. RAMACHANDRAN O \

^

\

H

)-Ipc2BCl EE,-25°C ~ER

\

O

^

£>H \

4%ee

H. JOH (-)-Ipc2BCl EE, -25 °C

32% ee H HL

UJ 4 >JOH

II

95% ee

Figure 58.

correction of erroneous assignments.142 Superior reagents were later developed based on this proposed mechanism (Section VIII.E). a-Hindered Ketones

Aliphatic ketones do not yield good enantioselection with DIP-Chloride. 2-Butanone and 3-methyl-2-butanone are reduced in 4% and 32% ee, respectively. However, the mechanism of reduction suggested that hindered ketones could be reduced in very high ee. Indeed, the reduction of 3,3-dimethyl-2-butanone with DIP-Chloride provides the corresponding alcohol in 95% ee (Figure 58).143 This aspect was utilized by Bolm and Ewald in the synthesis of hindered pyridyl alcohol for use in the nickel catalyzed addition to enones144 and chalcones.145 Bolm and co-workers and later Chelucci and Soccolini prepared hindered amino alcohols for the chiral auxiliary in diethylzinc additions to aldehydes.146147

H

Ph

.OH

98% ee H . ,*OH ^ ,Ph n-C 8 H 17 ^ Hv/OH

n-G

u

>99%ee

97% eg

n-C8Hn H

96% ee

y>OH

>QQ% £99% ee^

Figure 59.

H

•I

>QQ<&^ £99% ee •

«OH

I

Chiral Organoboranes Based on a-Pinene

193

As mentioned earlier, Alpine-Borane fails to enantiospecifically reduce hindered acetylenic ketones, which on occasion constitute a key step in certain syntheses. For example, reduction of such a hindered acetylenic ketone is a key step in the synthesis of 1,3-disubstituted bromoallenes,148 (+)-asteriscanolide,149 and (+)-sterpurene.150 Accordingly, the capability of DIP-Chloride to reduce highly reactive hindered ketones, such as hindered oc,p-acetylenic ketones, was examined. DIPChloride behaved beautifully (Figure 59). Such hindered ketones are not reduced in satisfactory ee by any of the other chiral reducing agents currently available. Perfluoroalkyl Ketones

Fluorinated compounds are gaining importance in organic, medicinal, biological, and agricultural chemistry.151 This has prompted several chemists to seek means of preparing fluorinated compounds in enantiomerically pure form. Application of DIP-Chloride for the reduction of perfluoroalkyl ketones provide the products in very high ee.152 Both aromatic and aliphatic ketones are reduced with equal efficiency. One significant feature in the reduction of fluoroalkyl ketones is the fact that the reduction products possess the opposite configuration compared to the hydrogen analogs. Apparently, the combined electronic and steric effects of the fluorine atoms alter the course of the reduction (Figure 60). Acyl Silanes

Aliphatic acylsilanes undergo facile reduction with DIP-Chloride to provide 1-silylated alcohols in high ee (96-98%) and in good isolated yields (59-67%) (Eq. 14).153 a-Acetoxysilanes undergo thermal rearrangement to produce silyl acetates with migration of the alkyl groups from silicon to carbon. Upon treatment with hydrogen peroxide, these are desilylated to the corresponding chiral alcohols. A

Figure 60.

194

HERBERT C. BROWN and P. V. RAMACHANDRAN O

.*02BC1

H

v0H

IT ^SiR' 3

SiR'3

(14)

R = Me, R' = Me: 96% ee R = Et, R=Me: 98% ee R = /-Pr R' = Me: 98% ee R = Me, R' = /i-Bu: 96% ee R = Me, R' = i-Pr: 98% ee

recent review by Panek highlighted the uniqueness of DIP-Chloride for the reduction of silyl ketones.154 Olefinic Ketones

Reduction of olefinic ketones gave encouraging results. Prostaglandin intermediates, such as iodovinyl ketones, are reduced in 85% ee (Eqs. 15,16).155 Together, Alpine-Borane and DIP-Chloride satisfactorily handle 6 of the 10 classes of ketones.

(15) (5) 85% ee

1

DIP-Chloride THF,-25°C,5h'

(16) (S) 76% ee

Applications of DIP-Chloride

DIP-Chloride is being used more and more in organic synthesis involving the reduction of aralkyl ketones. The application of DIP-Chloride in the first enantioselective synthesis of the currently widely used antidepressant, Af-methyl-y-[4-trifluoromethyl]phenoxy]benzenepropanamine hydrochloride (fluoxetine hydrochloride, Eli Lilly: Prozac®), is outlined in Figure 61. 156 We also synthesized the analogs of this serotonin and norepinephrine uptake inhibitor, tomoxetine and nisoxetine.15-6 Using our procedure, Kung and co-workers prepared iodinated derivatives of tomoxetine and evaluated them in radioligand binding assays in order to develop selective radioactive ligands for the study of presynaptic monoamine uptake sites.157 Another representative application of DIP-Chloride is found in the synthesis of (l/?,35)-l-(aminomethyl)-3,4-dihydroxy-3-phenyl-l//-2-benzopyran, a potent and selective Dl agonist and its enantiomer (Figure 62). Pharmacological study of the enantiomers show that all of the dopaminergic activity resided exclusively in the 1/?,3S enantiomer.158

NHMe-HCl 100% ee /?-(-)-Fluoxetine hydrochloride PROZAC - Racemate: Eli Lilly

Figure 61.

J^^)2BC\

98% ee

1/?, 35

Figure 62. 195

R = Br, Aplysiatoxin R = H, Debromoaplysiatoxin (Highly Inflammatory Agents and Tumor Promoters)

Figure 63.

Table 7. Literature Citations of the Applications of Alpine-Borane and DIP-Chloride No.

Reagent Used

Target Molecule

Major Author YearPubl.

1 2 3 4 5 6 7

Alpine-Borane Alpine-Borane Alpine-Borane Alpine-Borane Alpine-Borane Alpine-Borane Alpine-Borane

Midland Johnson Midland Midland Uskokovic Burke Stille

1980 1981 1984 1985 1988 1989 1989

129 130 132 134 133 135 136

8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

Alpine-Borane DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride DIP-Chloride

Japanolure Corticosteroid Pestalotin Prelog-Djerassi lactone Pseudomonic acid Mevinic acid Hydroxypentenoic acid (Lemma trisulca) Prosynthon C-14 (LTB4) Fluoxetine (Prozac) Tomoxetine Nisoxetine Aplysiatoxins Styrene oxides Selective D-l agonist Chiral auxiliaries Hindered amino alcohols Reduced haloperidol Descarbamoylcalicheamicinone (+)-Motneine Hindered amino alcohols Dolastatin 10 PAF antagonists

Laggeri Brown Brown Brown Yamamura Moberg DeNinno d'Angelo Bolm Jaen Danishefsky Rey Chelucci Shioiri Thompson

1990 1988 1988 1988 1989 1989 1990 1990 1990 1991 1991 1991 1992 1992 1992

137 156 156 156 162 165 158 141 144-46 159 161 167 147 160 163-64

196

Ref

Chiral Organoboranes Based on a-Pinene

197

As mentioned earlier, DIP-Chloride is unique in reducing hindered ketones and has been utilized for this purpose. Application of DIP-Chloride is also described to synthesize new chiral auxiliaries for use in other reactions by d'Angelo.141 Jaen and co-workers synthesized reduced haloperidol using DIP-Chloride.159 Shiori compared eight different chiral reducing agents for a key step in the synthesis of (S)-Dolaphenin, the C-terminal unit of Dolastatin 10, and found that DIP-Chloride gave the best results.160 Danishefsky applied this reagent for the synthesis of descarbamoylcalicheamicinone.161 Yamamura prepared Aplysiatoxins using DIPChloride for the reduction of an aralkyl ketone (Figure 63).162 A Merck group described the use of DIP-Chloride for the synthesis of PAF-antagonists L659,989163 and MK-287.164 Other applications of DIP-Chloride include synthesis of polymer-supported styrene-oxides,165/?-alkoxyphenethanols,166 and (+)-motneine.167 A summary of the key applications of Alpine-Borane and DIP-Chloride from the literature is presented in Table 7. E. Modified Reagents

DIP-Chloride satisfactorily handles five of the ten classes of ketones that we had set to conquer in the beginning (Figure 64). Alpine-Borane handles a sixth class, oc,P-acetylenic ketones. Hence our search for a more effective reagent continued. Our tentative mechanism for the chiral reduction gave some pointers for further modification. First, modifications in the reagent, keeping a-pinene as the chiral auxiliary, were examined. Reagents substituting for the chlorine atom in DIPChloride with other halogen atoms were easily prepared as shown in Eqs. 17-19. The results of chiral reduction were mixed (Table 8).155 The mechanism of reduction suggested that one pinane unit is sufficient for inducing chirality. Accordingly, a study was next made of the effect of the second

32%ee,S

98% ee, S

95% ee, R

98% ee, S 92% ee, S

70% ee, R

No reduction

or-* 5 x HO

81%ee,S

H

H

\,H

36%ee,S

Figure 64.

Ha^H

21%ee,/?

<^

198

HERBERT C. BROWN and P. V. RAMACHANDRAN Table 8. Reaction of Diisopinocampheylhaloboranes with Representative Ketones Alcohol Products, % ee Reagent

Acetophenone

3-Methyl-2-butanone

Ipc2BF Ipc2BCl Ipc2BBr Ipc2BI

65 98 98 no reduction

30 32 28 poor reduction

Ipc2BH

HX •

Ipc2BX

( X = CI, Br, F)

-H 2

Ipc2BH

Ipc2BCl

1/2 X2 £-• - 1/2 H2 l/3SbF3

+~

CH2C12

Ipc2BX

(X = Br, I)

Ipc2BF + l/3SbCl3

(17) (18)

(19)

pinane unit by substituting the pinane group with halo groups or alkyl groups of increasing steric requirements. The monoisopinocampheyldihaloboranes were synthesized as shown in Eqs. 20-23 and were used for chiral reductions. They reacted with aralkyl ketones to form the corresponding halides. Our representative alkyl ketone, 3-methyl-2-butanone, was reduced to alcohols in -50% ee and poor yields (Table 9).155 Kaufmann tested some of these reagents as asymmetric Diels-Alder reaction catalysts with poor results.168 IpcBH2

IpcBH2

2HX •*-2H2

-H,

IpcBX2 (X = C1,F)

m

IpcBX2 (X = Br)

(21)

Table 9. Reaction of Isopinocampheyldihaloboranes with Representative Ketones Alcohol Products, % ee Reagent

III

Acetophenone

3-Methyl-2-butanone

no reaction chloride formed bromide formed

59 43 bromide formed

Chiral Organoboranes Based on a-Pinene

199

a-Pincne x 2 B H ' S M e 2 >

MShF

IpcBX2

*»

^ ^

^2)

(X = a B r )

lpcBF2 + SbX3

(23)

The alkylmonoisopinocampheylchloroboranes were synthesized as shown in Eqs. 24-26.

HC1/EE,0°C LiRBHa

"HE

|Ol > B % R HC1/EE

W

"

RBH2

^

^

^

fvfB>R

o°c ' ^

(24)

R = Me, Et, i-Pr, f-Bu

H

.

CI

CI

-As

ThxBHCl*SMe2

iCN*^ Thx

We were surprised to see that increasing the steric requirements of the alkyl group showed a clear effect on the chiral outcome in reductions (Table 10).169 This was not suggested by the tentative mechanism. Evidently, the mechanism needs to be looked into in detail. The ee of the product from the reduction of the representative aralkyl ketone, acetophenone, increased with increasing steric requirement of the alkyl group until the configuration of the product alcohol was reversed in the case of the terf-butyl group as the substituent. Alkyl ketones did not show much Table 10. Reduction of Representative Ketones with Alkylisopinocampheylhaloboranes, RIpcBCI RIpcBCl

Alcohol Products, % ee

R

Acetophenone

3-Methyl-2-butanone

Me Et

r-Bu

15 33 81 84 98 96°

Thx

83fl

48 36 25 28 32 44 18

i-Pr

Cyp Ipc

Note: "Alcohol of opposite configuration was obtained.

200

HERBERT C. BROWN and P. V. RAMACHANDRAN

A DIP-Chloride

'

H

VH

W"98% < *

CI

pn ^TPh^^ THF, -25 °C ,-BuIpcBCl

W-96%ce

Figure 65. dependency on the steric requirement of the alkyl group on the boron atom. This study revealed that f-butylisopinocampheylchloroborane can be used as a complimentary reagent for producing optically active aralkyl alcohols of opposite configuration in very high ee. Thus we can obtain either enantiomer of aralkyl alcohols by treating the ketone with the appropriate reagent, DIP-Chloride or f-BuIpcBCl (Figure 65); both reagents are prepared from the same enantiomer of oc-pinene. F.

£-lso-2-ethylapopinocampheyl-9-borabicyclo[3.3.1]nonane (Eapine-Borane)

The above modifications did not achieve any major improvement in % ee for the products in the reduction of those classes of ketones where DIP-Chloride fails. A closer look into the proposed mechanism suggested that the % ee could probably be improved by having a group of larger steric requirement at the 2-position of apopinene, e.g. 2-ethylapopinene (Figure 66, R' = Et).170 This chiral auxiliary falls within the realm of this chapter since it can be easily synthesized from oc-pinene. #-(Iso-2-ethylapopinocampheyl)-9-borabicyclo[3.3.1 ]nonane (Eapine-Borane) was prepared using a procedure identical to the preparation of Alpine-Borane (Eq. 27) and our hypothesis was tested by treating the new reagent with acetylenic ketones. The results showed improvements over Alpine-Borane in those cases tested (Table ll). 171 However, we realized that we had not chosen the correct test subject. Alpine-Borane gave very high ee for the reduction of oc,|3-acetylenic ketones. It is a difficult task to improve the % ee that is already > 80-90%. Though we did achieve some improvements over that, it was not explicit and not adequate to support our hypothesis.


HB' }J ^ neat, 65 °C, 6 h

XJS>

^N.

XB^*J/

(27) R = Me, Alpine-Borane R = Et, Eapine-Borane

Chiral Organoboranes Based on a-Pinene

R' = bulkier than Me

Figure 66.

Table 11. Comparison of Asymmetric Reduction of Representative cc,P-Acetylenic Ketones at 25 °C with Alpine-Borane and Eapine-Borane Alcohol Products, %ee Ketone 3-butyn-2-one l-octyn-3-one 3-hexyn-2-one 3-nonyn-2-one 5-methyl-3-hexyn-2 •one 4-phenyl-3-butyn-2- one

Alpine-Borane

Eapine-Borane

11 88 80 82 88 82

82 96 88 88 88 89

G. Lithium (£-lso-2-ethylapopinocampheyl-9-borabicyclo[3.3.1 ]nonyl) Hydride (Eapine-Hydride)

Alpine-Hydride, however, is not a very successful teagent. This gave us the opportunity to test our hypothesis in an environment where the ee is usually poor. The theory was upheld by the corresponding borohydride reagent prepared from ethylapopinene, lithium (2Mso-2-ethylapopinocampheyl-9-borabicyclo[3.3.1]nonyl) hydride, Eapine-Hydride (Eq. 28).172 Considerable improvements were realized for the reduction of simple aliphatic ketones, such as 2-octanone, over the parent reagent, Alpine-Hydride (Table 12).

O' R = Me, Alpine-Hydride R = Et, Eapine-Hydride

o

.A. ,"VH

R ' -R' THF,-100°C

R

"^

R

.

(28)

202

HERBERT C. BROWN and P. V. RAMACHANDRAN Table 12. Comparison of Asymmetric Reduction of Representative Ketones with Alpine-Hydride and Eapine-Hydride Alcohol Products, % ee Alpine-Hyride Ketone 2-octanone 3-methyl-2-butanone acetylcyclohexane acetophenone 2-chloroacetophenone

Eapine-Hydride

-78 °C

-78 °C

-100 °C

33 36 27 20 4

70

11 11 80 61 48

70 56

H. £-Chlorodiiso-2-ethylapopinocampheylborane (Eap2BCI)

The best results thus far supporting this hypothesis was obtained with £-chlorodiiso-2-ethylapopinocampheylborane, Eap2BCl. This reagent is excellent for the chiral reduction of all those ketones that are handled very effectively by DIP-Chloride. In addition, it also handles aliphatic ketones of intermediate steric requirements, such as 3-methyl-2-butanone (95% ee) and acetylcyclohexane (97% ee) (Figure 67, Table 13).173 We now have a reagent in hand that reduces more classes of ketones in very high ee than any other reagent. Indeed, Alpine-Borane, DIP-Chloride and Eap2BCl handle 8 of the 10 classes.114 We do not foresee any major difficulty in synthesizing reagents with increased steric requirement at the 2-position of apopinene that can handle all classes of ketones.

^

,*)2BC1

H2BCl.SMe2 CH2C12, —\36h RT,

EE,-25°C,2d 1. 2. RT, HN(CH2CH2OH)2

Eap2BCl

EapB^NH

OY

95% ee (S) 60% yield

Figure 67.

Chiral Organoboranes Based on a-Pinene

203

Table 13. Reduction of Prochiral Ketones With Eap2BCI in EE at - 2 5 °C Class of Ketone114 1 1 2 3 4 5 6 7 8 9 10

Representative Ketone 3-methyl-2-butanone acetylcyclohexane 2,2-dimethylcyclopentanone acetophenone acetylpyridine 2-chloroacetophenone methyl benzoyl formate ethyl benzoyl acetate f/ms-4-phenyl-3-buten-2-one 2-cyclohexen-1 -one 4-phenyl-3-butyn-2-one

%ee IpaBCl

Conflg. %ee EapiBCl

32 26 98 98 92 96 50 no reduction 81 36 21

(R) (R)

95 97 £99 £99 £99 £99 70

(S) (S) (R)

82 74 33

<S) (S) (S) (S) (S)

Recently, Itsuno174 and Corey175 independently showed the catalytic application of organoboranes in asymmetric reduction. Corey isolated and identified the catalyst, now known as CBS catalyst.

IX. ASYMMETRIC CLEAVAGE OF MFSO-EPOXIDES The cleavage of C-0 bonds with boron reagents, especially haloboranes, is known.176 Use of mono- and dialkylhaloboranes achieves a more selective bond rupture.177 We carried out a systematic study of the asymmetric version of this reaction for the ring cleavage of mero-epoxides using mono- and diisopinocampheylhaloboranes and successfully accomplished the preparation of 1,2-halohydrins in good to excellent ee.178 We found that diisopinocampheyliodoborane is the best suited reagent to achieve the cleavage in high ee. The reaction occurs in an tfrtfc'-periplanar manner, with an SN2 type reaction pathway (Eq. 29). I P ^ Q L J ^

(-)-Ipc2BI peniane,-100 °C, 0.5 h

\ \ ^ I J N

1. n2-BuCHO 2.(HOCH2CH2)2NH

\ \ ^ L^^J.^

(29)

95 - £99% ee

This reaction sequence provides highly valuable optically active difunctionalized compounds for asymmetric synthesis.

X. CONCLUSIONS The reaction of a-pinene with borane, just another routine reaction during the study of the characteristics of hydroboration, turned out to be one of those grandiose

204

HERBERT C. BROWN and P. V. RAMACHANDRAN Asymmetric hydroboration )2BH

Asymmetric homologation

Asymmetric hydroboration ^BH 2

\ t /

Asymmetric enolboration

BO Asymmetric reduction

J 2 BC1 Asymmetric ( ring-opening' of epoxides

Asymmetric reduction ^)2BCrt

)2BC1 Asymmetric reduction

Asymmetric crotylboration

Asymmetric allylboration

Chart 4. a-Pinene, the super chiral auxiliary.

reactions that is any researcher's dream. a-Pinene turned out to be a very fortuitous choice as a chiral auxiliary for asymmetric synthesis. It satisfies most of the conditions that are tests for an excellent chiral auxiliary, such as: (1) Both isomers of a-pinene are readily available in very high ee; optical upgradation of the commercial material is easily attained during hydroboration. (2) The preparation of the reagents and the reaction conditions in most of the reactions are very simple and convenient. (3) The work-up is easy. (4) The chiral auxiliary is readily recovered in all of the reactions in an easily recyclable form without loss of any optical activity. (5) A tentative mechanism is known for all of the reactions which helps in modification, wherever necessary. (6) The configuration of the products can be predicted based on the mechanism; exceptions are rare. (7) The scaling up of the reactions is easy. (8) Most important of all, the enantiomeric excesses as achieved in most reactions are very high. Enantiomeric excesses in the range of > 95% are obtained for (1) the asymmetric hydroboration of three of the four classes of olefins; the product from the fourth (Class I olefin) can be obtained indirectly via asymmetric homologation; (2) in the general asymmetric synthesis via boronates and borinates obtained from hydrobo-

Chiral Organoboranes Based on a-Pinene

205

ration and homologation; (3) in asymmetric homologation; (4) in asymmetric allyland crotylboration; (5) in asymmetric reductions; (6) in asymmetric enolborationaldol reactions; and (7) in the cleavage of epoxides. To our knowledge, there is no other chiral auxiliary and reaction parallel to a-pinene and its hydroboration that is capable of achieving so many different types of asymmetric reactions in such high efficiency (Chart 4). This asymmetric synthesis via chiral organoboranes is truly general.

ACKNOWLEDGMENTS Financial assistances from the National Institutes of Health, National Science Foundation, Office of Naval Research, and the United States Army Research Office are gratefully acknowledged. We wish to also acknowledge the major contributions to this program by a remarkable group of co-workers whose names appear in the references.

REFERENCES AND NOTES 1.

2.

3. 4. 5.

6.

7. 8. 9. 10. 11. 12. 13. 14. 15.

For reviews on asymmetric synthesis see: (a) Aitken, R. A. Asymmetric Synthesis, Chapman and Hall: New York, 1992; (b) Morrison, J. D. Ed. Asymmetric Synthesis, Academic: New York, 1983-85; Vol. 1-5; (c) Morrison, J. D.; Mosher, H. S.Asmmetric Organic Reactions, American Chemical Society: Washington, DC, 1976; (d) Apsimon, J. W.; Sequin, R. R Tetrahedron 1979, 35,2797; (e) Apsimon, J. W.; Collier, T. L. Tetrahedron 1986,42, 515; (f) Seebach, D. Angew. Chem. Int. Ed Engl. 1990,29,1320; (g) Corey, E. J. Pure andAppl. Chem. 1990,62,1209. (a) Brown, H. C ; Ramachandran, P. V. Pure andAppl. Chem. 1994,66,201; (b) Brown, H. C ; Singaram, B. Proc. Ind. Acad. Sci. 1988,100,119; (c) Brown, H. C ; Singaram, B. Ace. Chem. Res. 1988,21,287; (d) Srebnik, M.; Ramachandran, P. V. Aldrichim. Acta 1987,20,9; (e) Brown, H. C ; Jadhav, R K.; Singaram, B. Modern Synthetic Methods', Scheffold, R. Ed.; Springer-Verlag: Heidelberg, 1986; p. 307; (0 Matteson, D. S. Synthesis 1986,973. Brown, H. C ; Subba Rao, B. C. J. Am. Chem. Soc. 1956, 78,5694. Brown, H. C. Hydroboration; Benjamin: New York, 1962. (a) Brown, H. C. Boranes in Organic Chemistry, Cornell University Press: Ithaca, New York, 1972; (b) Brown, H. C. Current Trends in Organic Chemistry; H. Nozaki, Ed.; Pergamon Press: New York, 1983; p. 247. (a) Brown, H. C ; Kramer, G. W.; Levyi A. B.; Midland, M. M. Organic Syntheses via Boranes: Wiley-Interscience: New York, 1975; (b) Shriver, D. F. The Manipulation of Air-Sensitive Compounds; McGraw-Hill: New York, 1969; (c) Lane, C. F. Aldrichim. Acta 1977,10, 11; (d) Gill, G. B.; Whiting, D. A. ibid. 1986, 79, 31. Brown, H. C. Pure &. Appl. Chem. 1976,47,49. Brown, H. C ; Singaram, B. Pure & Appl. Chem. 1987,59, 879. Brown, H. C ; Zweifel, G. / . Am. Chem. Soc. 1961,83,486. Brown, H. C ; Moerikofer, A. W. J. Am. Chem. Soc. 1962,84,1478. Brown, H. C ; Yoon, N. M. Isr. J. Chem. 1977, 75,12. (a) Brown, H. C ; Singaram, B. J. Org. Chem. 1984,49,45; (b) Brown, H. C ; Joshi, N. N. ibid. 1988,53,4059. Brown, H. C ; Jadhav, P. K.; Desai, M. C. J. Org. Chem. 1982,47,5065. Brown, H. C ; Prasad, J. V. N. V. J. Am. Chem. Soc. 1986,108,2049. Partridge, J. J.; Chadha, N. K.; Uskokovfe, M. R. /. Am. Chem. Soc. 1973,95,532.

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16. 17. 18. 19.

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20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38 . 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.

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58. Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. J. Am. Chem. Soc. 1986,705, 810. 59. (a) Brown, H. C ; Singh, S. M ; Rangaishenvi, M. V. J. Org. Chem. 1986,57,3150; (b) Brown, H. C ; Phadke, A. S.; Rangaishenvi, M. V. J. Am. Chem. Soc. 1988, 770,6263. 60. Brown, H. C ; Rangaishenvi, M. V. J. Organomet. Chem. 1988,358,15. 61. (a) Matteson, D. S.; Ray, R. Tetrahedron Lett. 1980,27,449; (b) idem J. Ind. Chem. Soc. 1982, 59,119. 62. Matteson, D. S. Ace. Chem. Res. 1988,27, 294; (b) Chem. Rev. 1989, 89,1535; (c) Pure and Appl. Chem. 1991,63,339. 63. (a)Matteson, D. S.; Sadhu, K. M.J. Am. Chem. Soc. 1983,105,2077; (b)Matteson, D. S.; Sadhu, K. M.; Peterson, M. L. ibid. 1986,108,810; (c) Matteson, D. S.; Peterson, M. L. J. Org. Chem. 1987,52,5116. (d) Matteson, D. S.; Beedle, E. C. Tetrahedron Lett. 1987,28,4499; (e) Matteson, D. S.; Beedle, E. C ; Christenson, E.; Dewey, M. A.; Peterson, M. L. J. Labelled Compd. Radiopharm. 1988,25,675. 64. Brown, H. C ; Naik, R. G.; Bakshi, R. K.; Pyun, C ; Singaram, B. J. Org. Chem. 1985,50,5586. 65. Rangaishenvi, M. V.; Brown, H. C. Tetrahedron Lett. 1990,31,7115. 66. (a) Ley, S. V; Merritt, A. T. Nat. Prod. Rep. 1992,9,243; (b) Danishefsky, S. J. Aldrichim. Acta 1986,19,59; (c) Masamune, S.; Choy, W. Aldrichim. Acta 1982,75,47. 67. (a) Hoffmann, R. W. Angew. Chem. Int. Ed. Engl. 1992,31,1124; (b) Martin, S. E; Guinn, D. E. Synthesis 1991,245; (c) Hoffmann, R. W. ibid. 1987,26,489; (d) Masamune, S. Angew. Chem. Int. Ed Engl. 1985,24,1. 68. (a) Hoffmann, R. W. Angm C7u?m. Int. Ed. Engl. 1982,27,555; (b) Yamamoto, Y. Ace. Chem. Res. 1987,20,243; (c) Yamamoto, Y. Aldrichim. Acta 1987,20,45. 69. Mikhailov, B. M. Organometal. Chem. Rev. A. 1972,8,1. 70. Hoffmann,' R. W.; Herold, T. Chem. Ber. 1981,774,375. 71. Brown, H. C ; Jadhav, P. K. J. Am. Chem. Soc. 1983,105,2092. 72. Roush, W. R. in Trends in Synthetic Carbohydrate Chemistry; Horton, D.; Hawkin, L. D.; Garvey, M. C. eds., American Chemical Society, Washington, D.C. 1989. 73. Brown, H. C ; Jadhav, P. K.; Perumal, P. T. Tetrahedron Lett. 1984,25,5111. 74. Brown, H. C ; Jadhav, P. K. Tetrahedron Lett. 1984,25,1215. 75. Brown, H. C ; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc. 1988,110,1535. 76. Brown, H. C ; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.; Racherla, U. S. J. Am. Chem. Soc. 1990, 772, 2389. 77. (a) Reetz, M. T.; Zierke, T. Chem. Ind. 1988,663; (b) Roush, W. R.; Walts, A. E.; Hoong, L. K. /. Am. Chem. Soc. 1985,707,8786; (c) Roush, W. R.; Banfi, L. ibid. 1988,770,3979; (d) Garcia, J.; Kim, B. M.; Masamune, S. J. Org. Chem. 1987,52,4831; (e) Short, R. P.; Masamune, S. J. Am. Chem. Soc. 1989,777,1892. (f) Corey, E. J.; Yu, C.-M.; Kim, S. S. /. Am. Chem. Soc. 1989, 777,5495. 78. Brown, H. C ; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990,55,1868. 79. Fujita, K.; Schlosser, M. Helv. Chim. Acta 1982,65,1258. 80. (a) Brown, H. C ; Bhat, K. S. J. Am. Chem. Soc. 1986, 708,293; (b) idem 5919. 81. Brown, H. C ; Randad, R. S. Tetrahedron 1990,46,4463. 82. (a) Mori, K. Tetrahedron 1976,32,1101; (b) Mori, K. Tetrahedron Lett. 1976,1609. 83. Brown, H. C ; Racherla, U. S.; Liao, Y; Khanna, V. V. J. Org. Chem. 1992,57,6608. 84. Truesdale, L. K.; Swanson, D.; Sun, R. C. Tetrahedron Lett. 1985,26,5009. 85. Schreiber, S. L.; Goulet, M. J. Am. Chem Soc. 1987, 709, 8120. 86. Merifield, E.; Steel, P. G.; Thomas, E. J. J. Chem. Soc. Chem. Commun. 1987,1826. 87. Khandekar, G.; Robinson, G. C ; Stacey, N. A.; Steel, P. G.; Thomas, E. J.; Vather, S. J. Chem. Soc. Chem. Commun. 1987,877. 88. (a) Boeckman, Jr., R. K.; Charette, A. B.; Asberom, T; Johnston, B. H. J. Am. Chem. Soc. 1987, 709,7553; (b) idem 1991, 775,5337. 89. Wuts, P. G. M.; Bigelow, S. S. /. Org. Chem. 1988,53,5023.

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90. Nakata, T.; Suenaga, T.; Nakashirna, K; Oishi, T. Tetrahedron Lett. 1989,30, 6529. 91. (a)Nicolaou,K.C; Abn,K.H. Tetrahedron Lett. 1989,30,1217;(b)Nicolaou,K.C.;Groneberg, R. D.; Stylianides, N. A.; Miyazaki, T. J. Chem. Soc. Chem. Commun. 1990,1275. 92. (a) Merifield, E.; Thomas, E. J. /. Chem. Soc. Chem. Commun. 1990, 464; (b) Thomas, E. J.; Watts, J. P. ibid. 467. 93. (a) Mariin, D. D.; Grice, P.; Kolb, H. C ; Ley, S. V; Madin, A. Synlett. 1990,326. (b) Ley, S. V; Armstrong, A.; Martin, D. D.; Ford, M. J.; Grice, P.; Knight, J. G.; Kolb, H. C ; Madin, A.; Marby, C. A.; Mukherjee, S.; Shaw, A. N.; Slawin, A. M. Z.; Vile, S.; White, A. D.; Williams, D. J.; Woods, M. J. Chem. Soc. Perkin Trans. 11991,667. 94. Ireland, R. E.; Wipf, P.; Roper, T. D. J. Org. Chem. 1990,55,2284. 95. Stork, G.; Zhao, K. J. Am. Chem. Soc. 1990, 772,5875. 96. (a) Barrett, A. G. M.; Lebold, S. J. Org. Chem. 1990, 55, 5818; (b) idem 1991, 56, 4875; (c) Barrett, A. G. M.; Malecha, J. W ibid. 1991,56, 5243. 97. Barth, M.; Bellamy, F. D.; Renaut, P.; Samreth, S.; Schuber, F. Tetrahedron 1990,46, 6731. 98. Smith, A. B.; Duan, J. J.-W; Hull, K. G.; Salvatore, B. A. Tetrahedron Lett. 1991,32,4855. 99. Mori, Y; Kohchi, Y.; Noguchi, H.; Suzuki, M. Tetrahedron 1991,47,4889. 100. Wang, Z.; Deschenes, D. J. Am. Chem. Soc. 1992,114,1090. 101. Dillon. M. P.; Simpson, T. J.; Sweeney, J. B. Tetrahedron Lett. 1992,33,7569. 102. Martin, D. D.; Kotecha, N. R.; Ley, S. V; Mantegani, S.; Menedez, J. C ; Organ, H. M.; White, A. D. Tetrahedron 1992,48,7899. 103. Smith, A. L.; Hwang, C.-K.; Pitsinos, E.; Scarlato, G. R.; Nicolaou, K. C. J. Am. Chem. Soc. 1992,774,3134. 104. (a) Barrett, A. G. M.; Edmunds, J. J.; Hendrix, J. A.; Horita, K.; Parkinson, C. J. J. Chem. Soc. Chem. Commun. 1992,1236; (b) Barrett, A. G. M.; Edmunds, J. J.; Horita, K.; Parkinson, C. J. ibid. 1238. (c) Barrett, A. G. M.; Edmunds, J. J.; Hendrix, J. A.; Malech, J. W; Parkinson, C. J. ibid. 1240. 105. Bubnov, Yu. N.; Lavrinovich, L. I.; Zykov, A. Yu.; Ignatenko, A. V. Mendeleev Commun. 1992, 86. 106. Bates, R. B.; Gangwar, S. Tetrahedron: Asym. 1993,4,69. 107. For reviews on the aldol reactions, see: (a) Heathcock, C. H. in ref. 1 (c) Vol. 3, Chapter 2; (b) Evans, D. A.; Nelson, J. V; Taber, T. R.; Top. Stereochem. 1982,13,1. 108. For reactions of achiral boron enolates, see: (a) Fenzl, W.; Koster, R. Liebigs Ann. Chem. 1975, 1322; (b) Brown, H. C ; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. 7. Am. Chem. Soc. 1989, 777, 3441. (c) Evans, D. A.; Nelson, J. V; Vogel, E.; Taber, T. R. ibid. 1981, 103, 3099; (d) Masamune, S.; Mori, S.; Van Horn, D.; Brooks, D. W. Tetrahedron Lett. 1989, 1665. 109. For the asymmetric aldol reactions of enolborinates using different chiral auxiliaries, see: (a) Corey, E. J.; Choi, S. Tetrahedron Lett. 1991, 32, 2857; (b) Enders, D.; Lohray, B. B. Angew. Chem. Int. Ed. Engl. 1988,27,581; (c) Masamune, S.; Choy, W; Kerdesky, F. A.; Imperiali, B. J. Am. Chem. 1981,103,1566; (d) Evans, D. A.; Bartroli, J.; Shih, T. L. ibid. 1981,103, 2127. 110. Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C ; McClure, C. K.; Norcross, R. D. Tetrahedron 1990,46,4663. 111. Paterson, I. Pure and Appl. Chem. 1992,64,1821. 112. (a) Ref. 1 (b) Vol. 2, Chapters 2-5; (b) Midland, M. M. Chem. Rev. 1989,89,1553; (c) Brown, H. C ; Ramachandran, P. V. Ace. Chem. Res. 1992,25,16. 113. Ref. 1(c) Chapter 5. 114. Brown, H. C ; Park, W S.; Cho, B. T; Ramachandran, P. V J. Org. Chem. 1987,52,5406. 115. Brown, H. C ; Mandal, A. K. J. Org. Chem. 1977,42, 2996. 116. Brown, H. C ; Mandal, A. K. /. Org. Chem. 1984,49, 2558. 117. Krishnamurthy, S.; Vogel, S.; Brown, H. C. J. Org. Chem. 1977,42,2534. Alpine-Hydride® is a Trademark of Aldrich Chemical Company.

Chiral Organoboranes Based on a-Pinene

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118. Mikhailov, B. M ; Bubnov, Yu. N.; Kiselev, V. G. J. Gen. Chem. U. S. S. R. (Engl. Transl.) 1966, 36,65. 119. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979,101, 2352. 120. Wilds, A. L. Org. React. 1944,2,178. 121. Midland, M. M.; Zderic, S. A. J. Am. Chem. Soc. 1982,104, 525. 122. (a) Floss, H. G.; Lee, S. Ace. Chem. Res. 1993, 26, 116; (b) Shibuya, M.; Chou, H.-M.; Fountoulakis, M.; Hassam, S.; Kim, S.-U.; Kobayashi, K.; Otsuka, H.; Rogalska, E.; Cassady, J. M.; Floss, H. G. J. Am. Chem. Soc. 1990,112, 297. 123. Midland, M. M.; McDowell, D. C ; Hatch, R. L.; Tramontano, A. /. Am. Chem. Soc. 1980,102, 867. 124. Brown, H. C ; Pai, G. G. J. Org. Chem. 1985,50,1384. 125. Midland, M. M.; Lee, P. E. J. Org. Chem. 1985,50, 3237. 126. Midland, M. M.; Tramontano, A.; Kazubski, A.; Graham, R.; Tsai, D. J.-S.; Cardin, D. B. Tetrahedron 1984,40, 1371. 127. Midland, M. M.; Petre, J. E.; Zderic, S. A.; Kazubski, A. J. Am. Chem. Soc. 1982,104, 528. 128. Midland, M. M.; McLoughlin, J. I.; Gabriel, J. J. Org. Chem. 1989,54,159. 129. (a) Midland, M. M.; Tramontano, A. Tetrahedron Lett. 1980, 21, 3549; (b) Midland, M. M.; Nguyen, N. H. J. Org. Chem. 1981,46,4107. 130. Johnson, W. S.; Frei, B.; Gopalan, A. S. /. Org. Chem. 1981,46,1513. 131. Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem. Soc. 1984,106,6709. 132. Midland, M. M.; Graham, R. S. J. Am. Chem. Soc. 1984,106,4294. 133. Banish, J. C ; Lee, H. L.; Mitt, T.; Pizzolato, G.; Baggiolin, E. G.; Uskokovic, M. R. J. Org. Chem. 1988, 53, 4282. 134. Tsai, D. J.-S.; Midland, M..M. J. Am. Chem. Soc. 1985,107, 3915. 135. Burke, S. D.; Takeuchi, K.; Murtiashaw, L. W.; Liang, D. W. M. Tetrahedron Lett. 1989,30,6299. 136. Laggeri, P.; Giacomo, M. D.; Azzolina, O.; Verceri, D.; Pirillo, D. J. Chem. Res. (S). 1990, 358. 137. Tueting, D. R.; Echavarren, A. M.; Stille, J. K. Tetrahedron 1989,45, 979. 138. Brown, H. C ; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem. Soc. 1988, 111, 1539. DIP-Chloride™ is a Trademark of Aldrich Chemical Company. 139. Mathre, D. J.; Jones, T. K.; Xavier, L. C ; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Jones, E. T.; Hoogsteen, K.; Basum, M. W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751. 140. Ramachandran, P. V.; Teodorovfc, A. V.; Rangaishenvi, M. V; Brown, H. C. J. Org. Chem. 1992, 57, 2379. 141. Potin, D.; Dumas, F ; d'Angelo, J. J. Am. Chem. Soc. 1990,112, 3483. 142. Oberlender, R. A.: Nichols, D. E.; Ramachandran. P. V.: Srebnik. M. J. Pharm. Pharmacol. 1987, 39, 1055. 143. Brown, H. C ; Chandrasekharan, J.; Ramachandran, P. V. J. Org. Chem. 1986, 57, 3394. 144. Bolm, C ; Ewald, M. Tetrahedron Lett. 1992,35, 5011. 145. Bolm, C. Tetrahedron: Asym. 1991, 2, 701. 146. Bolm, G; Zehnder, M.; Bur, D. Angew. Chem. Int. Ed Engl. 1990,29, 205. 147. Chelucci, G.; Soccolini, F Tetrahedron: Asym. 1992,3,1235. 148. Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984,25, 3055. 149. Wender, P. A.; Ihle, N. C ; Correia, C. R. D. J. Am. Chem. Soc. 1988,110, 5904. 150. Gibbs, R. A.; Okamura, W. H. J. Am. Chem. Soc. 1988,110,4062. 151. Bravo, P.; Resnati, G. Tetrahedron: Asym. 1990,1, 661. 152. Ramachandran, P. V.; Teodorovic, A. V.; Brown, H. C. Tetrahedron 1993,49, 1725. 153. (a) Soderquist, J. A.; Anderson, C. L.; Miranda, E. I.; Rivera, I; Kabalka, G. W. Tetrahedron Lett. 1990, 31, 4677; (b) Buynak, J. D.; Strickland, J. B.; Lamb, G. W.; Khasnis, D.; Modi, S.; Williams, D.; Zhang, H. J. Org. Chem. 1991,56,7076. 154. Crillo, P. F ; Panek, J. S. Org. Prep. Proc. Int. 1992,24, 555. 155. Brown, H. C ; Ramachandran, P. V. Unpublished results.

210

HERBERT C. BROWN and P. V. RAMACHANDRAN

156. Srebnik, M ; Ramachandran, P. V; Brown, H. C. J. Org. Chem. 1988,53, 2916. 157. Chumpradit, S.; Kung, M.-R; Panyachodpun, C ; Prapansiri, V.; Foulon, C ; Brooks, B. P.; Stephen, A. S.; Tejani-Butt, S.; Frazer, A.; Kung, H. F. J. Med. Chem. 1992, 35,4492. 158. DeNinno, M. P.; Schoenleber, R.; Asin, K. E.; MacKenzie, R.; Kebabian, J. W. J. Med Chem. 1990, 33, 2948; (b) DeNinno, M. P.; Perner, R. J.; Morton, H. E.; Domenico, Jr. S. D. J. Org. Chem. 1992,57,7115; (c) DeNinno, M. P.; Schoenleber, R.; Perner, R. J; Lijewski, L.; Asin, K. E.; Britton, D. R.; MacKenzie, R.; Kebabian, J. W. J. Med. Chem. 1991,34, 3461. 159. Jaen, J. C ; Capruthe, B. W.; Priebe, S.; Wise, L. D. Pharm. Res. 1991,8,1002. 160. Irako, N.; Hamada, Y; Shioiri, T. Tetrahedron 1992,48,7251. 161. Yamashita, D. S.; Rocco, V. P.; Danishefsky, S. J. Tetrahedron Lett. 1991,32, 6667. 162. Toshima, H.; Yoshida, S.; Suzuki, T.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1989, 30, 6721. 163. Thompson, A. S.; Tschaen, D. M.; Simpson, P.; McSwine, D. J.; Little, E. D.; Verhoeven, T. R.; Shinkai, I. Tetrahedron Lett. 1990,31, 6953. 164. Thompson, A. S.; Tschaen, D. M.; Simpson, P.; McSwine, D. J.; Reamer, R. A.; Verhoeven, T. R.; Shinkai, I. J. Org. Chem. 1992,57,7044. 165. Antonsson, J.; Jacobsson, U.; Moberg, C ; Rakos, L. J. Org. Chem. 1989,54,1191. 166. Everhat, E. T; Craig, J. C.7. Chem. Soc. Perkin Trans. 11991,1701. 167. Rey, A. W.; Szarek, W. A.; Maclean, D. B. Can. J. Chem. 1992, 70, 2922. 168. Bir, G.; Kaufmann, D. Tetrahedron Lett. 1987,28, 111. 169. Brown, H. C ; Srebnik, M.; Ramachandran, P. V. J. Org. Chem. 1989,54,1577. 170. Brown, H. C ; Ramachandran, P. V. J. Org. Chem. 1989,54,4504. 171. Brown, H. C.; Ramachandran, P. V.; Weissman, S. A.; Swaminathan, S. J. Org. Chem. 1990,55, 6328. 172. Ramachandran, P. V.; Brown, H. C ; Swaminathan, S. Tetrahedron: Asym. 1990,1,433. 173. Brown, H. C ; Ramachandran, P. V.; Teodorovie, A. V; Swaminathan. S. Tetrahedron Lett. 1991, 32,6691. 174. Itsuno, S.; Sakurai, Y; Ito, K.; Hirao, A.; Nakahara, S. Bull. Chem. Soc. Jpn. 1987, 60, 395. 175. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,109, 5551. 176. Bhat, M. V.; Kulkarni, S. U. Synthesis 1983, 249. 177. Guindon, Y; Therien, M.; Girard, Y; Yoakim, C. J. Org. Chem. 1987, 52,1680. 178. Joshi, N. N.; Srebnik, M.; Brown, H. C. / Am Chem. Soc. 1988,110, 6246.

ENANTIOSELECTIVE SYNTHESIS OF BIOACTIVE NATURAL PRODUCTS: EXAMPLES IN THE FIELD OF INSECT CHEMISTRY

Kenji Mori I. Introduction A. Purpose of Enantioselective Synthesis in Insect Chemistry B. Methods for Enantioselective Synthesis II. Synthesis of Juvenile Hormones A. Synthesis of the Enantiomers of JH III B. Synthesis of the Enantiomers of JH I III. Synthesis of Antifeedants A. Synthesis of the Enantiomers of Polygodial . B. Synthesis of the Enantiomers of O-Methyl Pisiferic Acid IV. Pheromone Synthesis to Solve the Structural Problems A. Synthesis of the Enantiomers of Trogodermal and Related Compounds B. Synthesis of the Enantiomers of Lineatin C. Synthesis of the Enantiomers of Lardolure D. Synthesis of the Enantiomers of Periplanone-A

Advances in Asymmetric Synthesis Volume 1, pages 211-269. Copyright © 1995 by JAI Press Inc. Allrightsof reproduction in any form reserved. ISBN: 1-55938-699-1 211

212 212 214 214 215 218 218 224 224 227 . 227 227 233 233

212

KENJI MORI

V. Pheromone Synthesis to Clarify the Stereochemistry-Bioactivity Relationships . . 239 A. Synthesis of the Enantiomers of exo-Brevicomin 239 B. Synthesis of the Enantiomers of Sulcatol 239 C. Synthesis of the Enantiomers of Ipsenol and Ipsdienol 243 D. Synthesis of the Enantiomers of Dihydroactinidiolide 248 E. Synthesis of the Enantiomers of Disparlure 248 E Synthesis of Japonilure 254 G. Synthesis of All the Stereoisomers of the German Cockroach Pheromone . . 254 H. Synthesis of the Enantiomers of Olean 261 I. Synthesis of the Tsetse Fly Pheromone 261 VI. Conclusion 267 Acknowledgment 267 References 267

I. INTRODUCTION A. Purpose of Enantioselective Synthesis in Insect Chemistry

Natural organic compounds are usually produced by organisms in enantiomerically pure states. Then, why is it necessary to synthesize pure enantiomers of natural products? The enantioselective synthesis of sucrose is not an easy task at present, while sucrose is abundant and very cheap. In the case of insect bioregulators, however, they are isolated in only limited amounts due to the difficulty in securing a large number of insects except the silkworm. In fact, the availability of the silkworm moth was the reason why the study of ecdysones, pheromones, and brain hormones was initiated with that insect. The scarcity of materials for the study of insect bioregulators generally makes it difficult to fully assign their structures, especially their absolute stereochemistry. Insect pheromones, in particular, are usually volatile oils, and therefore their structures cannot be solved by X-ray analysis. Accordingly, their enantioselective syntheses by starting from compounds with known absolute configuration are often the only method to determine their stereostructures. Another important purpose of enantioselective synthesis in insect chemistry is to provide both the natural and unnatural enantiomers to clarify the stereochemistrybioactivity relationships. Especially in the case of insect pheromones, such diverse and unusual relationships as shown in Scheme 1 could be unveiled by the synthesis of both enantiomers.1 It is well established among bioactive natural products that usually the naturally occurring pure enantiomers are entirely responsible for bioactivity. Many of the chiral pheromones belong to group A of Scheme 1. In this group of pheromones, only one enantiomer is bioactive, and no inhibitory action can be observed with the inactive antipode. Other unusual cases exist, however, as shown in groups B to J.

Enantioselective Synthesis in Insect Chemistry 0 Only one enantiomer is bioactive, and the antipode does not inhibit the action of the pheromone.

213

H) Only o n e enantiomer is bioactive, but its antipode inhibits the action of the pheromone.

^CHO gypsy moth

western pine beetle

pharaoh's ant

(disparlure)

(faranal)

(exo-brevicomin)

etc.

] Only one enantiomer is bioactive, but its diastereomer inhibits the action of the pheromone.

] The natural pheromone is a single enantiomer, but its diastereomer is also equally active.

maritime pine scale (natural pheromone)

(unnatural but active)

Diastereomers at the chiral center with * are inhibitors.

All the stereoisomers are bioactive.

[F] Even in the same genus different species use different enantiomers.

nC18H37-^(CH2)7/^Y^ Ips paraconfusus

German cockroach

Ips calligraphus [(-)-ipsdienol]

((+)-ipsdienol]

| Both the enantiomers are required for bioactivity. OH

I

OH

O Only one enantiomer is as active as the natural pheromone, but its activity can be enhanced by the addition of a less active stereoisomer.

Gnathotrichus sulcatus ((+)-sulcatoll

((-)-sulcatol]

X H O ^ ^ ^^ (natural pheromone)

^ ^

^-^

XHO

(unnatural and less active)

red flour beetle

[Q One enantiomer is active on male insects,

Q] Only the meso-isomer is active.

while the other is active on females. nC

-Haar (fl) t

i2H25

(CH^^n-C^H^ tsetse fly

(Glossina pallidipes)

(S) ?

olive fruit fly [ (-)-oloan ) [ (+)-olean ]

Scheme 1. Relationship between stereochemistry and pheromone activity.

In group B, only one enantiomer is active, and the inactive antipode inhibits the action of the correct enantiomer. Especially in the case of the Japanese beetle pheromone, as studied by Tumlinson, racemate lacks bioactivity due to the strong inhibition caused by the wrong enantiomer.

214

KENJI MORI

In the case of serricornin (the cigarette beetle pheromone) and stegobinone (the drugstore beetle pheromone), a single stereoisomer is bioactive, while its diastereomer inhibits the action of the pheromone (group C). In group D, the natural pheromone of the maritime pine scale is a single enantiomer, but its diastereomer is equally active. If the stereoselectivity of the pheromone receptor is low, then all the stereoisomers are bioactive (group E) as in the case of the German cockroach pheromone. Ipsdienol is the pheromone belonging to group F. Different species of Ips bark beetles use different enantiomers, and the chirality of the pheromone is very important in establishing and maintaining a particular Ips species. Sulcatol is the pheromone in group G, which requires both enantiomers for pheromone activity, as exemplified by the ambrosia beetle Gnathothrichus sulcatus. Groups H, I, and J are also interesting. Especially in the case of the olive fruit fly pheromone, its /^-isomer is active on males, while the other is active on females. Only the meso-isomer of the tsetse fly pheromone is bioactive. As summarized above, the relationships between stereochemistry and pheromone activity are complicated enough to evoke new challenges to biologists. B. Methods for Enantioselective Synthesis

Every chemist knows that there are three methods for the preparation of optically active compounds: derivation from optically active natural compounds, optical resolution, and asymmetric synthesis. Except for the case of resolution at the stage of the final product, all enantioselective syntheses must employ enantiomerically pure precursors, which have to be prepared by one of the three methods mentioned above. We can use not only chemical methods but also biological ones to achieve optical resolution or asymmetric synthesis.2-4 I will discuss later the use of biochemical methods for enantioselective synthesis as illustrated by the syntheses of individual bioactive natural products.

II. SYNTHESIS OF JUVENILE HORMONES Since 1967 when Roller et al. isolated juvenile hormone I (JH I) as the pivotal hormone to regulate the metamorphosis of insects by keeping their juvenile characters, many different syntheses of (±)-JH I and the racemates of other JH's were reported to date.5 In continuation of our synthetic efforts in this area, we became interested in synthesizing JH's enantioselectively. Enantiomerically pure natural (+)-JH III and unnatural (-)-JH III were synthesized in 1987.6 We then synthesized (+)-JH I and (+)-JH II,7 as well as (+)-JH 0,8 (-)-JH I,9 and (+)-4-methyl JH I.10 As can be seen from Scheme 2, the key reactions in these syntheses were

Enantioselective Synthesis in Insect Chemistry

1r L C

>

215

(+)-4-Me JH I

Scheme 2. Summary of the synthesis of juvenile hormones (JH's).

asymmetric reductions with yeasts and asymmetric hydrolysis with pig liver esterase. Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed the natural (+)-isomer to be about 5 x 103 times more active than its antipode by the Galleria wax test.11 The enantiomers of JH I were also bioassayed by Sakurai et al. on allatectomized fourth instar larvae of the silkworm (Bombyx mori\ and the natural (+)-JH I was about 1.2 x 104 times more active than the unnatural isomer.12 The importance of chirality in JH activity was thus firmly established through our enantioselective synthesis of JH's. Let us now discuss the synthesis of JH III and that of JH I in more detail. A. Synthesis of the Enantiomers of JH III

Prior to our own work, there were three reports on the synthesis of the enantiomers of JH III with obscure enantiomeric purity.13"15 Scheme 3 summarizes our synthesis of JH III reported in 1987.6 Reduction of the prochiral diketone 1 with baker's yeast yields the (S)-hydroxy ketone 2 of 98-99% ee. The corresponding acetate 3 was submitted to Baeyer-Villiger oxidation to give e-lactone 4, which could be purified by recrystallization to give the enantiomerically pure material. Reduction of 4 with lithium aluminum hydride furnished triol 5, which was proved to be of -100% ee by HPLC analysis of the corresponding bis-MTPA ester. The triol 5 was then converted to acetylenic ester 6 in the usual manner. The Michael addition of thiophenol to 6 yielded a separable mixture of 7 and 8. Treatment of 7

baker‘s yeast

A%O I C,H,N

MCPBA

sucrose, H,O 4

NO,

I

(99%)

5

C,H,NHBr,

f”,

,

(want)

-

(87%)

n-BuLi

ClCO*Me (85%)

NaNH, I liq. NH, (72”/0)

6

MeMgBr

(91Yo)

\

7

L

J

\

Cul (71%) 9

8

( 8 4 : 16)

0 1) LiAIH, (90%) 2) n-BuLi, TsCl

LiBr

CO,Me NaH. n-Buli

(EtO),POCI, NaH w

0 11 Me2CuLi

C02Me

7570AcOH F

(98%)

(40%, 4 steps) 10

\

11

12aR=H 12b R = (R)-MTPA OR

12C R = (S)-MTPA

(+)-JH 111

12a

1) A 5 0 ICH ,N ,

CO,M~

b

2) Par,

(quant)

OAC

NaOMe IMeOH t (83%)

14

Scheme 3. Synthesis of the enantiomers of JH111.

(-)-JH 111

218

KENJI MORI

with methylmagnesium bromide and cuprous iodide gave 9. Chain elongation of 9 to 10 was followed by methylation with lithium dimethylcuprate to give 11. Deprotection of 11 gave dihydroxy ester 12a, which was enantiomerically pure as checked by the HPLC analysis of 12b and 12c. The natural (+)-JH III was obtained by the ring closure of the monomesylate 13, while the unnatural (-)-JH III was prepared from 12a via acetoxy bromide 14. The enantiomeric purity of our synthetic JH HI was carefully estimated as follows. The NMR non-equivalence induced by (/?)-(-)-2,2,2-trifluoro-l-(9-anthryl)ethanol upon its addition to (+)-JH III or its (-)-isomer was sufficiently large at 400 MHz as shown in Figure 1. The 400 MHz *H NMR spectrum of (±)-JH III in the presence of the chiral solvating agent showed the splitting of the triplet due to the proton at C-10 into a pair of two triplets (A8 = 0.035 ppm). Both (+)- and (-)-JH III were enantiomerically pure (-100% ee). B. Synthesis of the Enantiomers of JH I

The structure of (+)-JH I demands the preparation of the hydroxy ketone 16 as the starting material for its synthesis (Scheme 4).7 Yeast reduction of a prochiral 1,3-diketone such as 15 with two different alkyl groups at C-2 was known to yield a diastereomeric mixture of two hydroxy ketones like 16 and 17. After some screening experiments, we found that Pichia terricola KI 0117 reduces 15 diastereo- and enantioselectively to give the desired 16 of 99% ee. By starting from 16, the synthesis of both (+)- and (-)-JH I was accomplished as shown in Scheme 4. Thanks to the crystalline nature of 18 and 19, we could recrystallize them to secure enantiomerically pure (-100% ee) materials. Methanolysis of 19 was followed by acetonide formation to give 20, whose enantiomeric purity was confirmed to be -100% ee by HPLC analysis of 24. In the same manner for the synthesis of JH III, 20 was converted to 23a via 21 and 22. The enantiomeric purity of 23a was checked as its MTPA esters, 23b and 23c. Finally, 23a yielded (+)-JH I, the naturally occurring enantiomer. For the synthesis of unnatural (-)-JH I, the antipodal hydroxy ketone 16' was prepared from 16 via 25 and 26. Conversion of 16' to (-)-JH I could be carried out smoothly and the enantiomeric purity of the intermediates was checked by the HPLC analysis of 24'. Although'three other syntheses of the enantiomers of JH I have been published, none of them provided enantiomerically pure materials.16"18

III. SYNTHESIS OF ANTIFEEDANTS Some plants produce compounds which protect the producers by acting as antifeedants against pest animals including insects.19 Because these antifeedants specifically inhibit the feeding activities of the pest animals, their chemical investigation is one of the topics in plant protection. We became interested in synthesizing

DL- • k ^ \ ^ V \ / V C 0 2 M e OH

\!L N C F .

jA^__ j V '' I !.«

JJ II

»' I.S

''''»'"• I.I

ID

JU 'I

I'

(R)

(S)- /|vNJvNjv C 0 2 M e

/j^JvsA^0^^ °vH H

OH

JC

if ^CF3

I.I

3

va

^J

AM

CF

UL

_A_

l.S

i.«

I.I

I.I

i.

Figure 7. Determination of the enantiomeric purity of JH III by 1 H NMR analysis (400 MHz, CDCI3). 219

02gcocl Pichia tenicola KI 0117 glucose,H20

0 4 152

0

(86%)

-

b

HO

+o[

C5H5N O2 (72%)

+HO+O]

N N

0

Me,CO.TsOH

L ,

P

(90%)

111"

21

I

23a R=H

22

b R=((R)-MTPA) c R=((S)-MTPA)

L

,I+*.

HO

O M i OMTPA 24

T

P

A

-

1)M~O.E~N/CH,CI,

23a

L

2)NaOMelMeOH (79%)

(+)-JH I

-

1)NaBH,TTHF 2)-or' .TsOH

4 0

h,

16

N,

C5H5N (84%)

0Q

O 16'

H

24

3)NaOMe/MeOH 4)Si02,chromatog.

25

-

M e20 C,& &, , )

(80%)

0

1)PDC,MS3NCHzCIz

2)dil. AcOH

26

2'

(-)-JH I

Scheme 4. Synthesis of the enantiomers of JH1.

24'

HOQO 2

1) 1-BuSi(Me),CI

NaCECH

2) LDA I THF - H M Z Me1 (72%)

liq NH, (99%)

cuso, xylene heat

TBSO

---

(51%) @ C0,MeC0,Me

N N N

e

quinoline I pentane

2) aq HF / MeCN 3) MPLC

27

HO

'+,, 28 (26%)

1 ) DBU / THF, heat

C0,Me

TfCI, DMAP

2) H,/Pd - C

(8W/O)

HO

29 (26%)

(86%)

30

31

+

- gyHflH - P (COCI),. DMSO

1) H 2 I Pd - C

E5N I CH2CI2

2) LIAIH,

(73%)

% ' H

'5-H

(63%)

32

Ho

(-)-Polygodial

N

N W

-

C0,Me

1) DBU / THF

28

2)TfCI, DMAP CH,CI,

CHO H,/Pd-C

, 33

-P

C0,Me

'%H

34

Scheme 5. Synthesis of the enantiomers of polygodial.

____)

(+)-Polygodial

224

KENJI MORI

the enantiomers of terpenoidal antifeedants in enantiomerically pure forms so as to evaluate their bioactivities. Polygodial (see Scheme 5), a sesquiterpene with antifeedant activity against insects, and 0-methyl pisiferic acid (see Scheme 6), a diterpene with antifeedant activity against mite, were chosen as our targets, and their enantiomers were synthesized.20,21 Biological studies showed that the enantiomers of polygodial were both active as the antifeedant,22 while only the naturally occurring (+)-0-methyl pisiferic acid was bioactive as the mite antifeedant.23 A. Synthesis of the Enantiomers of Polygodial

(-)-Polygodial was first isolated from Polygonum hydropiper as a hot-tasting substance against human tongues. It was also isolated from Warburgia stuhlmanni, and shown to possess antifeedant activity against some pest insects. Many different syntheses of (±)-polygodial had been reported at the time when we undertook its enantioselective synthesis. The driving force to carry out our synthesis was Kubo's claim that the specific absolute configuration of the antifeedant appeared to govern the hotness of its taste.24 Our synthetic strategy was to use the hydroxy group of 2 as the handle to facilitate the enantioselective synthesis (Scheme 5). 20 The DielsAlder reaction between 27 and dimethyl acetylenedicarboxylate yielded a mixture of two stereoisomers, which could be separated after desilylation to give 28 and 29. Further functional group transformation of 29 via 30, 31, and 32 furnished the naturally occurring (-)-polygodial. The other isomer 28 was converted to the unnatural (+)-isomer of polygodial. Starting from the hydroxy ketone 2, both the enantiomers of polygodial could be synthesized by taking advantage of the nonstereoselective nature of the Diels-Alder reaction. Both (+)- and (-)-polygodial showed identical biological properties such as hot taste to human tongues, antifeedant activity against insects, and pisicidal activity against fishes.22 B. Synthesis of the Enantiomers of O-Methyl Pisiferic Acid

(+)-0-Methyl pisiferic acid (Scheme 6) was first isolated from the leaves of Chamaecyparis pisifera. In 1984, Marumo and his co-workers demonstrated the bioactivity of this diterpene acid to inhibit the hatching of the two-spotted spider mite, Tetranychus urticae. This inhibition was partly due to the antifeedant activity of the acid. Because the two-spotted spider mite is a serious pest to many crops, we became interested in synthesizing the enantiomers of this diterpene. Scheme 6 summarizes our synthesis of the enantiomers of 0-methyl pisiferic acid by starting from the hydroxy ketone 2.21 Here again we used the hydroxy group of 2 as the handle to facilitate the enantioselective synthesis. P-Keto ester 35 was converted

Go

1) DHP, TfoH

HO

THPO a

2) (MeO),CO NaH, KH

2

NaOMe

t

t

(93%)

35

(quant.)

THPO

(85%)

36

-Po

MeO,C

CSO

1) TsOH / MeOH THPO

HO

t

2) TsOH / CH ,,

+

37

N N

wl

38 (51%)

1) aq KOH

38

Me0,C

2) H,O+ 3) CHZN,

1) TfCI. DMAP

*)Hz/Pt02 ___)

Ho

*$

,

0 3)CrO,

40

39 (14%)

Po p:Ho

kozc

k0,C

NaH

DDQ

____)

t, H

(64%)

(70%)

'a

41

HCQMe

tFc

~

5

(94%)

&M

H2 I Pd-C

-.,ii

b

&M

1) Me,SO,,

-

HSO, I EtOAc ,.**

5

(69%)

H

&

KzC034

HOZC

2) PBuOK I DMSO

t

(58%)

1

N N 0

Fl

%

(+)-OMethyl pisiferic aad

39

(-)- Isomer

Scheme 6. Synthesis of the enantiomers of 0-methyl pisiferic acid.

I

Enantioselective Synthesis in insect Chemistry

227

via 36 into a stereoisomer^ mixture of bicyclic keto esters 37. Treatment of 37 with /7-toluenesulfonic acid, first in methanol and then in benzene, gave a separable mixture of 38 and 39. The lactone 38 was converted into keto ester 41 via 40. The bicyclic ester 41 furnished the naturally occurring 0-methyl pisiferic acid. The unnatural (-)-isomer was synthesized from 39 via 41'. Only (+)-0-methyl pisiferic acid exhibited strong activity against the mite, Tetranychus urticae, with LD50 dose of 62.5 ppm, while the (-)-isomer was inactive even at the 250 ppm level.23

IV. PHEROMONE SYNTHESIS TO SOLVE THE STRUCTURAL PROBLEMS As briefly mentioned earlier in this chapter, enantioselective synthesis proved to be extremely useful in pheroinone chemistry in solving structural problems in general and stereochemical problems in particular.25 In this section, four examples of such enantioselective syntheses of pheromones will be discussed. A. Synthesis of the Enantiomers of Trogodermal and Related Compounds

The absolute configuration of a pheromone can be determined by synthesizing its enantiomers and evaluating their chiroptical and/or biological properties. If the chiroptical properties such as [OC]D value and ORD/CD spectrum of the natural pheromone are known, then comparison of these with the corresponding data of the synthetic material is possible, allowing one to assign the absolute configuration of the natural product. My own work in 1973 first demonstrated the usefulness of this type of appro^ph as shown in Scheme 7.26 In 1969 Silverstpin and his co-workers isolated (-)-43 as the female-produced sex pheromone of the dermestid beetle, Trogoderma inclusum. By starting with (5)-2-methylrl-butanpl (42), I synthesized (S)-43, which was dextrorotatory. The naturally occurring (-)-43 was therefore (/?)-43.26 The genuine pheromone of the beetles of Trogoderma species was later shown to be trogodermal, the aldehyde corresponding to 43. Both (/?,Z)-trogodermal27 and its (^Zj-isomer28 were synthesized from (J?)-citronellol. Only the (/?)-isomer showed strong pheromone activity.28'29 B. Synthesis of the Enantiomers of Lineatin

Lineatin is the female-produced aggregation pheromone of the striped ambrosia beetle, Trypodendron lineatum. In 1977, Silverstein and his co-workers proposed two possible structures for it. Our synthesis of their racemates as shown in Scheme 8 enabled us to assign the correct structure to lineatin.30 The key step was the separation of 47 and 48.

KENJI MORl

228

(71%)

(46%)

1 ) HC&(CH2)PTHP n-BuLi / THF-HMPA c 2) TsOH / MeOH

B -r

OH

(32%)

H, I

Pd-BaSO, b

Quinoline, MeOH

-

HO-

(85%)

(8-43

[cI]~' +5.31"(CHCI,)

Natural 43 = levorotatory

:.

Natural 43 =

on (m-43

L"I----

U

f

(R.2)-Trogodermal

(R)-Citronellol O

H

C

,

,

i

(S,Z)-Trogodermal

Scheme 7. Synthesis of trogodermal and related compounds.

We then synthesized the enantiomers of lineatin as shown in Scheme 9.31The first step was the cycloaddition of dichloroketeneto isoprene to generate cyclobutane compounds. Ketone 49 was converted to racemic hydroxy lactone 50, which was resolved by employing 51 as the resolving agent. Because the absolute configuration of 51 was knuwn, the absolute configuration of 52 could be established by X-ray analysis. Biologically active (+)-lineatin was synthesized from 52, while 53 afforded biologically inactive (-)-lineatin. The naturally occurring lineatin was shown to be the (+)-isomer of 100% ee by GC analysis with a chiral stationary phase.32It should be noted that the chromatographicseparation of 52 from 53 was quite successful, giving both 52 and 53 in pure states.

Q

hv AcO

AcO

C6H6

0

(60%)

45

44

KCN L 7

7

TsOH (91.5%)

EtOH

(93%)

N N

PCC

ro

Li(s-Bu),BH

-

____)

o*o

CtiZCI, (75%)

46

47 1) AcZO I CSHSN

2) AcOH - HZO

47

48

Q-

LDA

____)

HO"'

ti OLJ

AcOP

TMSCl

Ac0"'qTMs

1) 0,I CH2CIz

2) Ph,P 3) AcOH

1) MeMgl

*

+ 2) dil HCI

4) CH,Nz

5) N W

H$I , TsOH

(t)- Lineatin

OMe

0

(k)- lsolineatin

Scheme 8. Synthesis of (Wineatin and its isomer.

+

( 86.5% )

cj+ 0

AcOH distilln.

49 ( 39% )

OH 1) (C,H,NH),Cr,O, I CH,CI, SO, chromatog.

2) (n-Bu),NF I THF ( 40% )

50

Removed from the lactone by chromatog.

2) MPLC sepn. ( 88% )

conc. HCI ___)

MeOH

( 86% )

HO\"' ( 56% )

I

52 (X-ray)

(+) - Lineatin

N W

N

(-) - Lineatin

55

Scheme 9. Synthesis of the enantiomers of Iineatin.

Enantioselective Synthesis in Insect Chemistry

233

C. Synthesis of the Enantiomers of Lardolure

In 1982, Kuwahara et al. isolated lardolure (Scheme 11) as the aggregation pheromone of the acarid mite, Lardoglyphus konoi, which is a primary pest for stored products such as dried meat and fresh meal. They identified the pheromone as 1,3,5,7-tetramethyldecyl formate by synthesizing its diastereomeric mixture, which was found to be bioactive. The synthetic mixture consisting of the eight diastereomers of (±)-lardolure showed seven peaks when analyzed by capillary GC, and the peak exhibiting the shortest retention time coincided with that of the natural lardolure. In order to establish the relative configuration of lardolure, we carried out three different syntheses of lardolure as shown in Scheme 10.33 The central idea of the synthesis was to use cis hydrogenation of substituted phenols as the key step to establish the syn relative configuration between the methyl groups of the target lardolure molecule. By the routes shown in Scheme 10, 1,3-^yn-, 1,3,5-5-yn-, and 5,7-5,yn-(±)-lardolure were prepared and analyzed by capillary GC to reveal the fact that all of them exhibited the peak due to the natural lardolure. The natural pheromone was therefore thought to have the &\\-syn relative configuration. We then accomplished the synthesis of (l/?,3/?,5/?,7/?)-(-)-lardolure and its antipode as shown in Scheme 11,34 Optical resolution of the lactone 55 yielded (+)and (-)-59 via 56, 57 and 58. The absolute configuration of (-)-59 as depicted in Scheme 11 was proved by its conversion to the known (-)-60. The key building block (-)-61 was prepared from (+)-59. Alkylation of methyl (S)-3-hydroxypentanoate (62: prepared by a biochemical method35) with (-)-61 gave the anfi-alkylation product 63, which was converted to (l/?,3/?,5/?,7/?)-(-)-lardolure. Similarly, (-)-59 and (#)-62 furnished (lS,3S,5S,7S)-(+)-lardolure. Only (l#,3/?,5/?,7/?)-(-)-lardolure was bioactive against Lardoglyphus konoi and Carpoglyphus lactis. In addition, (-)-lardolure showed the same ORD curve as that of the natural pheromone. The antipodal (+)-lardolure was an inhibitor of the pheromone of L. konoi, while it did not inhibit the action of the pheromone of C. lactis.36 D. Synthesis of the Enantiomers of Periplanone-A

The name "periplanone-A" was first given to a compound isolated by Persoons et al. for the pheromone component produced by female American cockroach, Periplaneta americana. In 1978, they proposed structure 64 for it, and demonstrated its facile rearrangement to a stable and biologically inactive compound 65 (Scheme 12).37,38 The structure 65 was supported by a synthesis of its racemate from 66 and 1,3-butadiene.39 The correct structure of Persoons's compound was shown to be not 64 but 68, which was the thermal decomposition product of the genuine pheromone 67 (now this is called periplanone-A).40 An X-ray analysis of 69 was the key to solve the problem.40 The compound 68 isolated by Persoons turned out to be a stable and biologically inactive one in its pure form. Therefore 68

Q-N

w

P

1 )H,/Raney-Ni

+Zh2&= (940/0)

(51%)

4=4 l)N2H4, KOH

L 2)HCO2H

0

HO

54

&1 )H,/Raney-Ni

OH

(66%)

0

(98%)

(63% from 54)

m

O

1.3-sym(+)-Lardolure

&O

55

G

(66%)

H

0

HCO2H

AMgBr T

s

o

U

O

H Li,CuCI,/THF (51%)

N

W

ul

4-

l)MeOH, H,SO,,

____+

&OH

U

O

, ,O TsO CJJJ

O

-

1)TsCI/C,H,N

&OH 2)Nal/Me,CO

(8ZYo from 55)

(93%)

0

55

H

1,3,5-~yn-(+)-Lardolure

LiAIH,

2)TsCVC,H,N

C

(81Y0)

J 0

THF (50%)

-

U

3)HCOZH (6l Yo)

Scheme 10. Determination of the relative configuration of lardolure.

O

C

H

5,7-~yc-(k)-Lardolure

O

+O

(91Yo)

55

D --

n02

hO+

OH

\ /

COCl

SiO, chromatog.

C5H5N

56 (mixture)

1)K,CO$MeOH

2)dil HCI

2)dil HCI (27% from 56)

-

-

-

1)CH,N,

(+)-59 1 )MOMCI-(CPr),NEt/CH,CI, 2)LiAIH,

l)CFsCO3H

___t

HOC , -oH HO2C

2

(33% from 56)

(-)-59

2)PDC

Me0,C

2)NaOH 3)TsOH

''0 '

0 (-)-60

OH &CO,Me

(92% from (+)-59)

-

OMS -

1)LiAIH,

2)MsCI

C5H5N

~

-

(-)-61

OH

63

(79%)

-

-

-

1 )LiAIH,

O

--

M

--

O

--

-OH 2)HCIIMeOH M

(91%)

(62% from 63)

Scheme 11. Synthesis of the enantiomers of lardolure.

(-)-Lardolure

rearrangement

C02Me

** -a0

64

65

N

w

a

66

NaBH, / MeOH

heat, 220°C (71%)

(80%)

DMSO,(COCI),, EtsN / CHZCI2

67

(Periplanone-A)

68

(87%)

(Isoperiplanone-A)

Scheme 12. Periplanone-A and isoperiplanone-A.

69

(X-ray analysis)

Enantioselective Synthesis in Insect Chemistry

239

was given the name "isoperiplanone-A". A concise review is available concerning this structural problem.42 Both the enantiomers of the genuine American cockroach pheromone, periplanone-A (67), were synthesized as shown in Scheme 13.40 Only its (-)-enantiomer was bioactive. The synthesis started from (/?)-3-cyclohexene-l-carboxylic acid (70) obtained by optical resolution, and the silyl enol ether 71 was converted to 72 and 73. (-)-Periplanone-A, the naturally occurring enantiomer, was synthesized from 72, while 73 eventually yielded the unnatural (+)-periplanone-A. In the present synthesis, a single enantiomer of the acid 70 served as the starting material for both the enantiomers of periplanone-A.

V. PHEROMONE SYNTHESIS TO CLARIFY THE STEREOCHEMISTRY-BIOACTIVITY RELATIONSHIPS As mentioned earlier, successful syntheses of enantiomerically pure pheromones allowed us to clarify the complicated stereochemistry-pheromone activity relationships. In order to obtain clear-cut and meaningful biological results, it was absolutely necessary tp synthesize both the enantiomers of high ee in amounts sufficient for bioassay. A. Synthesis of the Enantiomers of exo-Brevicomin

In 1973, I chose exo-brevicomin (Scheme 14) as my first target to clarify the relationship between absolute configuration and pheromone activity. e*0-Brevicomin was isolated in 1968 as the aggregation pheromone of the western pine beetle, Dendroctonus brevicomis. Its structure, 7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1] octane, manifested itself to be a chiral molecule. Its absolute configuration was not known. The isolation paper in 1968 reported that its 0.05% hexane solution showed no optical rotation between 350 and 250 nm. This statement was surprising to me because £*0-brevicomin is a highly dissymmetric molecule. My synthesis as shown in Scheme 14 was completed and published in 1974.43 The enantiomers of tartaric acid were chosen as the starting materials, and the two chiral centers of tartaric acid were brought into the target enantiomers without racemization. The enantiomers of £jt0-brevicomin were, of course, with optical rotatory power. Only {\R,5S,1 R)-(+yexo-bxsv'\comm exhibited the pheromone activity (see Scheme l). 44 Many different enantioselective syntheses of ejctf-brevicomin have been published since then.1,45'46 B. Synthesis of the Enantiomers of Sulcatol

Sulcatol is the male-produced aggregation pheromone of Gnathotrichus sulcatus, an economically important ambrosia beetle in North America. About 0.5 mg

1) LiAIH, I Et2O

KI,, NaHCO, aq

-

2) MnO, I CH2CI,

CH2C12 PPTS / CH2CIz

0

C02H

(85V0 from 70)

(R)-70

N

P

0

Do

LDA

OSiMe, MeLi , ZnCI,

~

Me,SiCI / THF E E O ~

(98%)

I E ~ O EEO’

E E O ~ 71

(91% from 71)

&Ph KH ,18crown-6 72

THF (80%)

72(43%)

73(17%)

*

I osi

1) 1-BuMe,SiCI , LiN(SiMe,),

imidazole I DMF

+

*

b

MoOs.HMPA.CsH5N TH F

7

2) 35% H202 I THF

2) PPTS I EtOH

(67%)

(59%)

(86%)

osi

+

1

I

1) ICH2CI , MeLi I Et20 N

P,

2) (mBu),NF I THF

I Similarly : 73

(-)-Periplanone-A

-*

__2. __t

(+)-Periplanone-A

Scheme 13. Synthesis of the enantiomers of periplanone-A.

I

Macdonalds epoxy ketone

1 ) EtOH / H+ I _

?02H H y HqOH

2) Me1 - Ag2O

(95%) C02H D-(-)-Tartaricacid FH,CO,Me MeOCH HCOMe CH2CO2Me

702Et MeOtH HqOMe C02Et

l e q KOH (72%)

FH~OTS Me0C.H HYOMe CH,OTs

1) LiAIH,

2)TsCl

(55%)

qH,CO,H MeOYH

HFoMe

-

CH,CO2Me

Ft

2) Ba(OH), (32%)

jc

MeOYH HYOMe (CH,),COMe

C Q

(670'0)

FH2CH20Ts MeOYH HFOMe

1) LiAIH, 2) TsCl ____t 3) LiBr

(44%)

CH2C02Me

(70.5%)

h,

NaOEt

MeOCH HtOMe CH2CN

~

DMSO

1) B,H, 2)TsCl

N P

1) MeCOCH,CO,Et

tH2CN NaCN

.

?

OHCOYH

AcOH

HYOCHO (CH,),COMe

MeOH

HCI (84%)

5'

MeOCH HC!OMe &H,CH2Br

-q 1) NaOH

2) HCI (1 1%)

6

(+) - ex0 - Brevicomin

L-(+)-Tartaricacid

(-) - exo - Brevicomin

Scheme 14. Synthesis of the enantiomers of exo-brevicomin.

Enantioselective Synthesis in Insect Chemistry

243

of the pheromone was isolated from the boring dust of this timber pest, and identified as a 65/35 mixture of (S)-6-methyl-5-hepten-2-ol and its (/?)-isomer. I thought that only a single isomer of it might be responsible for the pheromone activity, like in the case of ejco-brevicomin, and undertook the synthesis of both the enantiomers of sulcatol. Scheme 15 summarizes my 1975 synthesis.47 The starting materials were the enantiomers of glutamic acid. Lactol 74 was converted to sulcatol by a Wittig reaction. In my later synthesis, by employing microorganisms for the preparation of the enantiomers of the chiral building block 75, both the enantiomers of sulcatol were synthesized as shown in Scheme 16.48,49 Many other syntheses of this pheromone were reported.50,51 Bioassay of my samples in Canada revealed an interesting fact that both the enantiomers were necessary for the expression of the pheromone activity (see Scheme l). 52 C. Synthesis of the Enantiomers of Ipsenol and Ipsdienol

(S)-(-)-Ipsenol and (S)-(+)-ipsdienol were first isolated as the pheromone components of the California fivespined ips (Ips pamconfusus). It was later found that another bark beetle, Ips calligraphus, employs (/?)-(-)-ipsdienol as the pheromone. In the case of ipsdienol, the difference in the absolute configuration of the pheromone is therefore important in maintaining the segregation of the species. Even in the same species, enantiomerism plays a role in the case of ipsdienol. In California, the male pine engraver, Ips pini, produces (7?)-(-)-ipsdienol as the major aggregation pheromone, while its antipode worked inhibitory against the pheromone action. On the East Coast of the United States, however, Ips pini affords (5)-(+)-ipsdienol. This interesting phenomenon was studied at the receptor cell level by an electrophysiological method to reveal the existence of two distinct types of receptor cells: one keyed to (S)-(+)-ipsdienol and the other keyed to its antipode.53 My 1975 synthesis of (-)-ipsenol was achieved by starting from (S)-leucine, and established its absolute configuration as S.54 The synthesis was later modified as shown in Scheme 17.55 Cleavage of the epoxy ring of 76 with the Grignard reagent prepared from chloroprene yielded ipsenol. The first synthesis of optically active ipsdienol was completed in 1976 by starting from (/?)-glyceraldehyde acetonide.56 The synthesis, however, was lengthy and inefficient giving the final product of about 32% ee. Our 1991 synthesis of ipsdienol was efficient enough, and afforded the enantiomers of high purity (> 96% ee) by starting from the enantiomers of serine (Scheme 18).57 In this synthesis, serine was converted to epoxy ester 77, which was treated with the Grignard reagent prepared from chloroprene to give 78. Ipsdienol could be synthesized from 78 in four steps. Many other enantioselective syntheses of ipsenol and ipsdienol have been reported to date.58'59

HO2C (R)-(-)-Glutarnic acid

Raney Ni I EtOH (49%)

(quanf.)

(48%)

rnp 85 - 86"

N

P P

Q,

i-BuAIH / THF

-

(73%)

74

Ph,P=CMe,

DMSO

(20%)

U

O

*.

H

(9-Sulcatol

____)

H02C

2

-

___t_

(R)-Sulcafol

Scheme 15. The 1975 synthesis of the enantiomers of sulcatol.

02N

^ V - C 0 2 H , DCC

Saccharomyces O

OH

6a/7/V KI0116

Jl^CCfeEt '

•

(80%)

02f/

X/C0 2 Et

DMAP/CH2CI2

2) Recrysfn

(S)-75 (-96% e.e.)

1)DHP,TsOH

'-a

NOo

QH

KOH

OC

- N 0 2 aqTHF-EtOH /^—C02Et (45 o /o f r o m i m p u r e

>k/C°2Et

' 75)

"" (S)-75

'

2) LiAIH4/Et20 3) TsCI/C5H5N (89%)

(100% e.e.) m.p. 38.5-39.0°C WgP+26.1»(CHCI3)

ti^MgBr , Cul/THF

1)

OTHP rs

2) AcOH/aq THF (82%)

D-Glucose

Zoogloea ramigera •

EtOH, H 2 S0 4 H

H CH2CI2

>

PHB OH

OH •

(R)-75

(fl)-Sulcatol

(100% e.e.) Scheme 16. The 1981 -1987 synthesis of the enantiomers of sulcatol.

245

dil H,S04

I

OH

OTHP

1) EDH, H+

G C ( ) ? H

NaNO, (S)- Leucine

-

(57%)

2) DHP, TsOH

LcozEt

(85%)

KOH / HZO

N

P 0

Cull THF 76

-

1) LiAIH,

(50%)

( R ) - lpsenol

Scheme 17. Synthesis of the enantiomers of ipsenol.

2) TSCl ICSHSN

3) AcOH / aq THF

- 8,64K

Me,SO,

1 ) HBr. NaNO,

NH2

___T)

2) KOH I NaOH

H04C02H

(53%)

(9-Serine

C0,Me

OH N P

18-crown-6 (78%)

e B,Co2Me CuBrMeS I THF 77

f-BuSi(Me),CI imidazole I DMF

Ph3P=CMe2

OTBS

toluene

78

u

(n-Bu),N F

OTBS

(94%)

(R)-lpsdienol

______) ____) ____)

(R)-Serine

(66%)

(S)-lpsdienol

Scheme 18. Synthesis of the enantiomers of ipsdienol.

DME (58% from 78)

248

KENJI MORI D. Synthesis of the Enantiomers of Dihydroactinidiolide

Dihydroactinidiolide is a component of the queen recognition pheromone of the red imported fire ant (Solenopsis invicta). Its (S)-(+)-isomer is a component of the essential oil of a Japanese plant "matatabi", (Actinidia polygama), and works as an attractant against Felidae animals such as cats and lions. Our 1986 synthesis (Scheme 19) started from the same hydroxy ketone 2 used for JH synthesis, and provided both the enantiomers of dihydroactinidiolide.60 Iodolactonization of the olefinic acid derived from 79 was followed by removal of the THP protective group to give two diastereomeric iodolactones 80 and 81, which were separated by chromatography. (S)-Dihydroactinidiolide was synthesized from 80, while 81 was converted to the (/?)-isomer. Bioassay proved the latter to be the active pheromone component.61 A short and more efficient synthesis of (S)-dihydroactinidiolide was accomplished recently as shown in Scheme 20.62 Pig liver esterase (PLE)-mediated asymmetric hydrolysis of (±)-82 furnished (fi)-83 and (S)-82 with -90% enantiomeric purity. Purification of (5)-82 via the corresponding crystalline 3,5-dinitrobenzoate (S)-84 yielded (S)-83 in almost enantiomerically pure state.63 The chirality transfer at C-1 of (5)-83 to C-3 by means of orthoester Claisen rearrangement gave 85, which was converted to (S)-dihydroactinidiolide. By employing (i?)-83 as the starting material, (/?)-dihydroactinidiolide can be synthesized. There are some other syntheses of optically active dihydroactinidiolide.64 E. Synthesis of the Enantiomers of Disparlure

(7/?,8S)-(+)-Disparlure is the female-produced sex pheromone of the gypsy moth, Lymantria dispar. Its antipode, (7S,8/?)-(-)-isomer, inhibits the action of the pheromone to some extent (see Scheme 1). Three different syntheses of disparlure achieved by our group illustrate the three reliable methods in enantioselective synthesis. Our 1976 synthesis as shown in Scheme 21 started from L-(+)-tartaric acid, and afforded 5.2 g of (+)-disparlure and 7.9 g of the antipode.65 An intermediate 86 in the brevicomin synthesis (see Scheme 14) was used also in the present synthesis, and both the enantiomers of disparlure were derived from 86 by changing the order of the carbon-chain extension. Accordingly, the cheap and naturally occurring (+)-tartaric acid could be used as the common starting material. The next synthesis published in 1981 was based on the Sharpless asymmetric epoxidation as shown in Scheme 22.66 Allylic alcohol 87 was submitted to the Sharpless epoxidation to give epoxy alcohol 88 (84% ee), which was purified by recrystallization of the corresponding 3,5-dinitrobenzoate 89. The tosylate derived from 89 was treated with an organocopper reagent to give (+)-disparlure.

baker's yeast sucrose, H 2 E

(70-79Vo)

9

HO

0

%

9 # .

9849% ee

pcHoNaBH,

TH PO

b

EtOH-THF

(66%)

1) NaBH,/EOH

-

1) DHP,TsOH 2) HCOSt. NaOMe 3)mBuSH, TsOH

b

(SSYO)

(87%) 1) KOH

MeC(OEt), EtC02H, hea'i"

(96%)

-

2) CdCO,. HgCldEtOH

C02Et

3) TsOWMeOH

b

-

2) aq NaHCO,, 12-Kl/Eb0

N

P

a

1) LiNPr',, PhSef3r

THF-HMPA (80%)

80 (49%)

81 (30%)

(78%)

2)H202 (46%)

(R)-Dihydroactinidiolide

Scheme 19. The 1986 synthesis of the enantiomersof dihydroactinidiolide.

(9-Dihydroactinidiolide

p +p

PLE phosphate buffer (pH 7.5)

.

*

(rt) - 82

20%MeOH 2°C. 3 days

%

( R ) - 83 93% e.e.

(9-82 87% e.e.

OH

N

wl 0

, (s)-M 2 99% e.e.

MeOH / CH2C12 [ 37% from (k)- 821

9

EtC02H, A

MeOH / H,O

85

(75%)

99% e.e.

>o

*'5,

.

(quant.)

LiOH

(93%)

(s) - 83

2

MeC(OEt),

1) LDA. PhSeBr

THF/HMPA

~

2) H202,AcOH I THF

(59%)

(S)- Dihydroactinidiolide

Scheme 20. The 1993 synthesis of the enantiomers of dihydroactinidiolide.

L - (+) - Tartaric acid

86

(56.5%) I

1) H,/

Pd

R=H. R=THP

I

R=H, R=Ts I

(+) - Disparlure

\-. ",

..-

G

THPO'"

cn N

O

H h P P h , (goo/.)

"7 " ' l)Hz/Pd (90%

2) TsCl

THPO"'

TsOH

THPO"'

MeOH

N

(76%)

R=H. R=Ts

HO'"

(-) - Disparlure

Scheme 27. Synthesis of the enantiomers of disparlure.

(+)diethy1tartrate Ti(OLPr)4,t-BuOOH

koH

Lc

L

H

~

) THF-NH, (46%)

)

~

~

~

~

(92%) c

~

CH2C12, -23"C, 46 h

~

I

87

0 1) K,CO, I MeOH

2) TsCl I CSH5N Recryst'n

(65%) 88

89

(84%e.e.)

(84Yo)

(-100% e.e.)

[Me(CH,) J,CuLi Et20-toluene

H"

(6Wo) (+)-Disparlure

Scheme 22. Synthesis of (+I-disparlure by asymmetric epoxidation.

(83%)

254

KENJI MORI

The third one was reported in 1992, and based on an enzymatic asymmetric process (Scheme 23).67 Treatment ofmeso-cpoxy diacetate 90 with pig pancreatic lipase (PPL) yielded optically active monoacetate 91 (90% ee), which could be purified to give crystalline 92 of -100% ee. The enantiomerically pure 92 is a versatile building block to prepare epoxy pheromones just by extending the carbon chain. (+)-Disparlure was synthesized from 92 as shown in Scheme 23. (+)-Disparlure was synthesized in many different ways.68'69 F. Synthesis of Japonilure

Japonilure is the female-produced sex pheromone of the Japanese beetle, Popillia japonica. (J?,Z)-(-)-Japonilure is the natural pheromone. Male response is strongly inhibited by small amounts of the (S,Z)-(+)-isomer, and the racemate is biologically inactive (see Scheme 1). Among many published syntheses of japonilure,70'71 our 1983 synthesis is shown in Scheme 24.72 Reduction of keto ester 93 with lithium aluminum hydride in the presence of Darvon alcohol (Chirald®) 94 gave 95 with 78.6% ee. This enantiomeric purity was insufficient for the expression of full pheromone activity. The ester 95 was hydrolyzed, and the resulting acid was found to give crystalline salt 96. Its recrystallization yielded pure 96, which finally furnished enantiomerically pure (/?,Z)-(-)-japonilure. This process was employed, with a small modification, for the multi-kg synthesis of (/?,Z)-japonilure. G. Synthesis of All the Stereoisomers of the German Cockroach Pheromone

3,11 -Dimethy 1-2-nonacosanone and 29-hydroxy-3,11 -dimethy-2-nonacosanone are the female-produced wing-raising pheromones of the German cockroach, Blattella germanica. Our synthesis in 1978 of all of the possible stereoisomers of them was achieved by starting from (/?)-citronellol (92% ee).73 Bioassay of the synthetic products revealed all of them to be bioactive.74 However, comparison of the IR spectra, [OC]D values, and mp's of the samples with those of the natural products showed (3S,llS)-ketones to be the natural ones. This fact was finally confirmed by the mixture mp test of the (3S,llS)-ketone with the natural 3,11-dimethy 1-2-nonacosanone. Due to the scarcity of the naturally occurring hydroxy ketone, no mixture mp test could be executed in the case of the hydroxy ketone. Because the enantiomeric purity of (ft)-citronellol used in 1978 was only 92% ee, we developed a new synthesis of all of the four isomers of 3,11-dimethy 12-nonacosanone by starting from purer materials [(/?)-citronellol with -100% ee and ethyl (/?)-3-hydroxybutanoate with -100% ee].75 Schemes 25-27 show the summary of our 1990 synthesis.75 The key step as illustrated in Scheme 26 was the

PPL I(i-Pr)20

*

phosphate buffer (pH 7) O'C, 4.5 h 90

(*Bu)qNF

o,c

"*

OAC

1) TBDPSCI I CH2C12 DMAP - Et3N

OH

2)K2C03/MeOH

C 91

(71%)

-

1) DNBCI Et20

o'ECYBDPS

(98%)

CgHgN

(98%) 2) Recryst'n

90%e.e.

1) TsCI ICH2C12

o'\'h. "

DMAP - Et3N

THF

2) (pC9H1g)2Culi

(92%)

Et20 -

*

o\%"

&SH5

(+)-Disparlure

-4O'C, 15 min (65%)

Scheme 23. Synthesis of (+)-disparlure through an enzymatic process.

DNB=

-C

0

I CIC(CH2)2C02Me

LiAIH4 / EtpO

*

Me(CH2)flECSiMe3

AIC13 / CH2C12 -4O'C (70%)

Me(CH2)f&C L C 0 2 M e

93

-100--65'C

1) NaOH

y

-

Me(CH,),C=C

dil HCI h C o ;iH,

\

\

96 m.p. 90-91'C

(65%)

H2 I Pd-CaC03

-

L

C5H 2, quinoline

(R,Z)-Japonilure (72%)

(82%)

95 (78.6% e.e.)

4) Recryst'n

(97'0)

OH

2) dil HCI

Me(CH2)7C=C j C 0 2 M e

*

HO, Me PhCH, -,C-&CH,NMe, Ph 94

(-100% e.e.)

Scheme 24. Synthesis of (-1-japonilure.

1 ) TsCl I C,H,N

OH (R)-Citronellol

2) NaBH,

&d

2, Me(CH2),5MgBr

3) TsCI I C,H,N

(CH2)17Me

Li2CuCI, I THF

( 79% overall )

-

-

Nal

,AoTs Me,CO

Me(CH2),

( 85% ) 1) LiAIH, I Et,O

1 ) NaCN I DMSO N

uco2H\

OTs 2) NaOH I aq. EiOH

wl

v

2) MOMCI, ( kPr),rEt (93% )

( 83% )

Li,CuC14 I THF

AoMoM 2) NaBH, 3)TsCIIC5H5N

\

T

S

O

A

O

M

O

M

2) dil. HCI

( 79% )

3) TsCl I C,H,N

(73%) Nal Me(CH2)17L

O

T

S

4

Me,CO ( 82% )

(497

Scheme 25. Synthesis of the German cockroach pheromone (1).

1) 2eq. LDA

CO,E~

Me1 / THF-HMPA OH &CO,Et

2) 2eq. LDA /THF

1) LiAIH, / Et2O

*

2) TsCl / C5H5N

3) NH,CI aq.

( 96% )

4) EtOCH=CH,, TsOH ( 46% )

+Ts

Nal , NaHCO,

MeCOCH,CO,Me

Me,CO

K,CO, / Me,CO-DMF

D-

( 93% )

*

( 79% ) 1) aq. AcOH / THF

KOH

*

2) SiO, chromatog. 73% 1 TBSCI

OTBS

imidazole / DMF ( 25%)

\

-

.

=

(5S,6R)-98

(81%) TBSCI

imidazole I DMF

OH

( 87% )

( 40% )

Scheme 26. Synthesis of the German cockroach pheromone (2).

(5R, 6R)-98

NaH

( 5S, 6R )-98

0

OTBS ~

C02Me

CO(OMe), dioxane (91% 1

K2C03I MeCOEt

*

(S)-97

( 61% overall )

I84% 1

(96%)

(93 ?4 )

( %Yo)

( 3S, 1 1 S )-3,ll-Dimethyl-2-nonacosanone

m.p. 47.0-47.5"C.

[=]Ag +5.52' ( hexane)

Scheme 27. Synthesis of the German cockroach pheromone (3). (continued)

(m-97

+ (5S6R1-98

___) ___)

(S)-97 +

(5R,6R)-98

-

0

(R)-97 + (5R, 6R)-98

( 3S,1 1 R )-isomer (CH2)71, ( CH2)17Me m.p. 40.5-41.O"C. +5.51" ( hexane)

[=]Ag

____)L

__._)

N

m

&-

_____)_

%

(CH2)7/

i

( CH2),,Me

j ~ ( " ~ 2 . ' ( CH2)17Me 7 r

____)

( 3R911s )-isomer

m.p. 40.5-41.0"C.

[=]a1-5.31"( hexane)

( 3R, 11 R )-isomer

m.p. 47.0-47.5%. [&' -5.44" ( hexane)

Scheme 27. (continued)

Enantioselective Synthesis in Insect Chemistry

261

chromatographic separation of (5/?S,6/?)-6-hydroxy-5-methyl-2-heptanone to give pure (5R,6R)- and (5S,6/?)-98. All of the four enantiomerically pure isomers of 3,ll-dimethyl-2-nonacosanone were confirmed to be bioactive.75 Katsuki and Yamaguchi were the only others who synthesized enantiomerically pure (35,115)-3,11 -dimethy 1-2-nonacosanone.76 H. Synthesis of the Enantiomers of Olean

Olean (l,7-dioxaspiro[5.5]undecane) is the major component of the sex pheromone produced by the female olive fruit fly (Bactrocera oleae, formerly Dacus oleae). Our first synthesis of the enantiomers of olean (Scheme 28) used two molecules of (5>malic acid to construct a molecule of olean.77'78 Deprotection of 99 yielded crystalline (45,65,105)-100 with two equatorial hydroxy groups, whose structure was proved by an X-ray analysis. This diol 100 was oxidized to diketone 101, the reduction of which with L-selectride® produced diaxial diol 102. The structure 102 was also proved by an X-ray analysis. When 102 was treated with acid, it isomerized to more stable (4/?,6/?,10/?)-100 with two equatorial hydroxy groups. Thus, the hydroxy groups were used as the handle to fix the conformation of spiroacetals. Deoxygenation of 100 gave olean. In our second synthesis, only a molecule of (S)-malic acid was incorporated into a molecule of olean (Scheme 29).77,79 Deprotection of 103 gave a separable mixture of (4S,6fl)-104 and (45,65)-105. (S)-Olean was synthesized from (45,65)-105 by deoxygenation. Conversion of (45,65)-105 to its antipode, (4/?,6/?)-105, was executed by a three-step sequence via 106 and (4R,6R)-104. (/?)-01ean was derived from (4/?,6/?)-105. Bioassay of the enantiomers of olean revealed the surprising fact that the /^-isomer was active on males, while the other was active on females. The female olive fruit flies produce (±)-olean, which was proved to be active by the field test.80 There are some other syntheses of olean and related compounds.81 I. Synthesis of the Tsetse Fly Pheromone

15,23-Dimethylpentatriacontane was identified as the sex-stimulant pheromone produced by the female tsetse fly. Scheme 30 summarizes our synthesis of the three possible stereoisomers of 15,23-dimethylpentatriacontane.82 (/?)- Citronellic acid (-100% ee) was converted to the enantiomers of 107, the terminal part of the target molecule. Alkylation of the dianion derived from methyl acetoacetate with 107 afforded 108. This was further alkylated with 107, and the product was converted to the desired 13,23-dimethylpentatriacontane. Bioassay of the three isomers revealed only the meso-isomer to be bioactive.83

OH k C 0 Z H

HO,C (S) - Malic acid

-

1) BH,.THF

2) M e 0 3 PPTS

1) AcCl

2) EtOH

EQC E C O , H

3) NaOEt / EtOH

(7 1%)

N

1) LiAIH, / EbO

*

BF,. E1 2 0

OH EtozC+o+oMe

+

3) Nal, NaHCO, / Me,CO

3 (quant.)

n-BuLi / THF

S

(70%)

(60%)

0 x 0 EtOZC

mSr-ua.., oXo

0 x 0

2) TsCI / CSHSN

/,

(55%)

Me,CO-H,O (87%)

H O G -

n-BuLi

(MeN ,O !), &

Li/EtNH2 t-BUOH, THF

(Me,N),POCI OF;(NMe,),

HO THF I TMEDA (4S,6S,lOs) - 100 (8lY')

(73%)

(S)- Olean

n

99

t

N

m W

&o

PCC / CH2C12 (80%)

LiB(s-Bu),H

(58%) 0 101

~

I

-4

@$,,

dilHTl

OH

(60%)

(4R,6S,lOR) - 102

1 ) (Me,N),POCI 2) Li / EtNH,

t-BuOH, THF

(4R,6R,lOR) - 100

Scheme 28. Synthesis of the enantiomers of olean (1).

( R ) - Olean

HO HO,C

known

Ph TsO&

(S)-Malic acid

Ph

LiBr, NaHCO,

0 x 0

DMF THF

(97”/0)

N

0

P

OEE

mBuLi / THF

CUCI,

CUO

Me,CO - HO ,

(83%)

Ph

(86 7%)

(83%) SO, chromatog.

*

&+& HO

103

(4S,6R) - 104

(4S,65) - 105

&J

n - BuLi

(Me,N),POCI (45,6S)- 105

DME - TMEDA ( 8S0/0)

O.P(NMe,),

II 0

r-----l Li I EtNH, ____)

f-BUOH, THF (64y0)

(S) - Olean

(92% e.e.)

(82%)

N CT

wl

I

q&

)-&

_____)

LB i (:,”’;3H

(71“/o)

0

,

106 Li I EtNH,

(4R.6S) - 104

4I

mBuLi

(Me,N),POCI

TS0;w;y

HO (4R,6R) - 105

DME - TMEDA (85 4%)

*

1-BuOH. THF (72%)

(R) - Olean

(>99.5% e.e.)

Scheme 29. Synthesis of the enantiomers of olean (2).

O.P(NMe,),

II

0

1) LiAIH4

5 ) OH-

I

(4-107

1) 0 3

1) LiAIH4 ~

&oTs

L ~ ~ C U C I ~Me(CH2111

2) TsCl

-

2) NaBH4

Me(CH2)9y

3) TsCl 4) Nal

(@-Or

(5)-Io7

-

C0,Me Me(CH2),,'(CH,),k

,

Me(CH2), A(cH2)31 (5)-107

(R)- or (5)-107

K2C03/DMF

108

0

(CH,),

Me

Me(CH2), A ( C H 2 ) 4 K / ' "C0,Me H2"3y

0

NaOH, H20

(13R, 2 3 4

(135. 23s)

(25% overall yield)

(37% overall yield)

Me(CH2)i1 A(CH2)4A(CH2)4A(CH2)l

I rneso-l5,23-DimethyIpentatriacontane 1 [59% from (4-1081

Scheme 30. Synthesis of the tsetse fly pheromone.

,Me

Enantioselective Synthesis in Insect Chemistry

267

VI. CONCLUSION I reviewed our works since 1973 in the enantioselective synthesis of natural products related to insects. Out of 23 syntheses discussed, 10 of them utilized optically active natural products as the starting materials. Optical resolution was the key strategy in four cases. Among them, three employed chemical resolution, and one used an enzymatic method. Ten syntheses were based on asymmetric synthetic reactions. Biochemical reduction and hydrolysis were very useful (8 out of 10), while an asymmetric epoxidation and an asymmetric hydride reduction also proved to be useful. It therefore seems to me that the best method for one's specific purpose must be carefully chosen so as to synthesize enantiomerically pure products. In retrospect, my adherence to the preparation of highly pure enantiomers was the key to unveil the unprecedented and complicated stereochemistry-bioactivity relationships in pheromone perception among insects. Development of synthetic methods for enantiomerically pure pheromones is not only of academic interest. It is also of practical value as is exemplified in the commercialization of pheromone traps for the Japanese beetles, which can be attracted only by the correct and pure enantiomer of the pheromone.

ACKNOWLEDGMENT I acknowledge with thanks the contribution of my past and present co-workers whose names appear in the references. Special thanks are due to entomologists who helped me to put my chemical results in appropriate biological contexts. The works reviewed were mainly supported by the Japanese Ministry of Education, Science, and Culture, and also by several chemical and pharmaceutical industries.

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268 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

KENJI MORI Kindle, H.; Winistorfer, M.; Mori, K. Experientia 1989, 45, 356-360. Sakurai, S.; Ohtaki, T.; Mori, H.; Fujiwhara, M.; Mori, K. Experientia 1990, 46, 220-221. Suzuki, Y; Imai, K.; Marumo, S.; Mitsui, T. Agric. Biol Chem. 1972, 36, 1849-1850. Imai, K.; Marumo, S.; Ohtaki, T. Tetrahedron Lett. 1976, 1211-1214. Schooley, D. A.; Bergot, M. J.; Goodman, W.; Gilbert, L. I. Biochem. Biophys. Res. Commun. 1978, 81, 743-749. Loew, P.; Johnson, W. S. J. Am. Chem. Soc. 1971, 93, 3765-3766. Faulkner, D. J.; Petersen, M. R. J. Am. Chem. Soc. 1971, 93, 3766-3767. Prestwich, G. D.; Wawrzenczyk, C. Proc. Natl. Acad. Sci. USA 1985, 82, 5290-5294. van Beek, T. A.; de Groot, Ae. Reel. Trav. Chim. Pays-Bas 1986,105, 513-527. Mori, K.; Watanabe, H. Tetrahedron 1986, 42, 273-281. Mori, K.; Mori, H. Tetrahedron 1986,42, 5531-5538. Asakawa, Y; Dawson, G. W.; Griffiths, D. C ; Lallemand, J.-Y; Ley, S. V.; Mori, K.; Mudd, A.; Pezechk-Leclaire, M.; Pickett, J. A.; Watanabe, H.; Woodcock, C.; Zhang, Z.-n. J. Chem. Ecol. 1988,74,1845-1855. Wada, K. Personal communication to Mori, K. as cited by Mori, H. Doctoral Dissertation (the University of Tokyo) 1989, pp. 48-49. Kubo, I.; Ganjian, J. Experientia 1981, 37, 1063-1064. Mori, K. In Techniques in Pheromone Research', Hummel, H. E.; Miller, T. A. Eds.; Springer Verlag: New York, 1984, pp. 323-370. (a) Mori, K. Tetrahedron Lett. 1973,3869-3872; (b) Mori, K. Tetrahedron 1974,30,3817-3820. Mori, K.; Suguro, T.; Uchida, M. Tetrahedron 1978, 34, 3119-3123. Mori, K; Kuwahara, S.; Levinson, H. Z.; Levinson, A. R. Tetrahedron 1982, 38, 2291-2297. Levinson, H. Z.; Levinson, A. R.; Mori, K. Naturwissenschaften 1981, 67, 480-481. (a) Mori, K.; Sasaki, M. Tetrahedron Lett. 1979, 1329-1332; (b) Mori, K.; Sasaki, M. Tetrahedron 1980, 36, 2197-2208. (a) Mori, K.; Uematsu, T.; Minobe, M.; Yanagi, K. Tetrahedron Lett. 1982, 23, 1921-1924; (b) Mori, K.; Uematsu, T.; Minobe, M.; Yanagi, K. Tetrahedron 1983, 39, 1735^1743. Schurig, V; Weber, R.; Klimetzek, D.; Kohnle, U.; Mori, K. Naturwissenschaften 1982, 69, 602-603. Mori, K.; Kuwahara, S. Tetrahedron 1986,42, 5545-5550. Mori, K.; Kuwahara, S. Tetrahedron 1986, 42, 5539-5544. Mori, K.; Mori, H; Sugai, T. Tetrahedron 1985, 41, 919-925. Kuwahara, Y; Matsumoto, K.; Wada, Y; Suzuki, T. Appl. Entomol. Zool. 1991, 26, 85-89. Talman, E.; Verwiel, P. E. J.; Ritter, F. J.; Persoons, C. J. Isr. J. Chem. 1978,17, 227-235. Persoons, C. J.; Verwiel, P. E. J.; Ritter, F. J.; Nooyen, W. J. J. Chem. Ecol. 1982, 8, 439^51. Mori, K.; Igarashi, Y Tetrahedron 1990, 46, 5101-5112. (a) Kuwahara, S.; Mori, K. Tetrahedron Lett. 1989, 30, 7447-7450; (b) Kuwahara, S.; Mori, K. Tetrahedron 1990, 46, 8083-8092. Persoons, C. J.; Ritter, F. J.; Verwiel, P. E. J.; Hauptmann, H.; Mori, K. Tetrahedron Lett. 1990, 31, 1747-1750. Mori, K.; Kuwahara, S.; Igarashi, Y Pure Appl. Chem. 1990, 62, 1307-1310. Mori, K. Tetrahedron 1974, 30, 4223^227'. Wood, D. L.; Browne, L. E.; Ewing, B.; Lindahl, K.; Bedard, W. D.; Tilden, P. E.; Mori, K.; Pitman, G. B.; Hughes, P. R. Science 1976,192, 896-898. Mori, K. In The Total Synthesis ofNatural Products; ApSimon, J., Ed.; John Wiley & Sons: New York, 1981; Vol. 4, pp. 150-153. Mori, K. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley & Sons: New York, 1992; Vol. 9, pp. 407-424. Mori, K. Tetrahedron 1975, 31, 3011-3012. Mori, K. Tetrahedron 1981, 37, 1341-1242.

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269

Mori, K.; Puapoomchareon, P. Liebigs Ann. Chem. 1987, 271-272. Ref. 45, pp. 119-120. Ref. 46, pp. 280-285. Borden, J. H.; Chong, L.; McLean, J. A.; Slessor, K. N.; Mori, K. Science 1976,192, 894-896. Mustaparta, H.; T0mmeras, B. A.; Lanier, G. N. J. Chem. Ecol. 1985,11, 999-1007. Mori, K. Tetrahedron Lett. 1975, 2187-2190. Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35, 933-940. Mori, K. Tetrahedron Lett. 1976, 1609-1612. Mori, K.; Takikawa, H. Tetrahedron 1991, 47, 2163-2168. Ref. 45, pp. 113-117. Ref. 46, pp. 301-303. Mori, K.; Nakazono, Y. Tetrahedron 1986, 42, 283-290. Tumlinson, J. H. personal communication to Mori, K., dated October 30, 1986. Mori, K.; Khlebnikov, V. Liebigs Ann. Chem. 1993, 77-82. Mori, K.; Puapoomchareon, P. Liebigs Ann. Chem. 1991, 1053-1056. Ref. 46, pp. 356-359. (a) Mori, K.; Takigawa, T.; Matsui, M. Tetrahedron Lett. 1976, 3953-3956; (b) Mori, K.; Takigawa, T; Matsui, M. Tetrahedron 1979, 35, 833-837. (a) Mori, K.; Ebata, T. Tetrahedron Lett. 1981, 22, 4281^284; (b) Mori, K.; Ebata, T. Tetrahedron 1986, 42, 3471-3478. Brevet, J.-L.; Mori, K. Synthesis 1992, 1007-1012. Ref. 45, pp. 146-150. Ref. 46, pp. 87-94. Ref. 45, pp. 141-143, Ref. 46, pp. 238-242. Senda, S.; Mori. K. Agric. Biol. Chem. 1983, 47, 2595-2598. (a) Mori, K.; Suguro, T; Masuda, S. Tetrahedron Lett. 1978, 3447-3450; (b) Mori, K.; Masuda, S.; Suguro, T. Tetrahedron 1981, 37, 1329-1340. Nishida, R.; Fukami, H. Mem. Coll. Agric, Kyoto Univ. 1983, No. 122, 1-24. Mori, K.; Takikawa, H. Tetrahedron 1990, 46, 4473-4486. Katsuki, T; Yamaguchi, M. Tetrahedron Lett. 1987, 28, 651-654. Mori, K.; Uematsu, T; Watanabe, H.; Yanagi, K.; Minobe, M. Tetrahedron Lett. 1984, 25, 3875-3878. Mori, K.; Uematsu, T; Yanagi, K.; Minobe, M. Tetrahedron 1985, 41, 2751-2758. Mori, K.; Watanabe, H., Yanagi, K.; Minobe, M. Tetrahedron 1985, 41, 3663-3672. Haniotakis, G.; Francke, W.; Mori, K.; Redlich, H.; Schurig, V. J. Chem. Ecol. 1986, 12, 1559-1568. Ref. 46, pp. 466-468. Kuwahara, S.; Mori, K. Agric. Biol. Chem. 1983, 47, 2599-2606. McDowell, P. G.; Hassanali, A.; Dransfield, R. Physiol. Entomol. 1985,10, 183-190.

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AN EVOLUTIONARY PERSPECTIVE OF MICROBIAL OXIDATIONS OF AROMATIC COMPOUNDS IN ENANTIOSELECTIVE SYNTHESIS:

HISTORY, CURRENT STATUS, AND PERSPECTIVES

Tomas Hudlicky and Josephine W. Reed

I. Introduction II. History of Cyclohexadiene cw-Diols III. Cyclohexadiene c/s-Diols in Synthesis A. Survey of Literature B. Symmetry-Based Design of Enantiodivergent Syntheses C. Evolution of a General Method D. Future Prospects IV. Conclusions Acknowledgments Note Added in Proof References and Notes

Advances in Asymmetric Synthesis Volume 1, pages 271-312. Copyright © 1995 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 1-55938-699-1 271

272 274 276 276 281 286 302 303 307 307 308

272

TOMAS HUDLICKY and JOSEPHINE W. REED

I. INTRODUCTION This is the story of the evolution of our research program to its present state of accomplishment in biocatalytic methods of synthesis1 based on the metabolites derived from aromatic compounds. In 1986 we were fortunate to have Dr. Larry Kwart join our research group. Larry, who had studied with Ernest Wenkert at Rice University and later with David Gibson (then at the University of Texas), brought with him a rare talent for the mixed discipline of synthetic and bioorganic chemistry. His synthetic expertise allowed him to appreciate the artistic side of the preparation of large molecules; on the other hand, his experience in Gibson's laboratories led him to question the efficiency with which chemists were able to assemble their targets. While in our group, he carried out experiments in traditional organic synthesis and as a hobby pursued research connected to the mechanism of the biooxidation of aromatic compounds. Throughout his stay with us Larry incessantly questioned design aspects of our total syntheses, which at that time led mostly to racemic products. He suggested that we use the enzymatic oxidation of aromatic compounds to access a large chiral pool of synthons. We were reluctant to change our ways, but ultimately we did. We are grateful to Larry for his determination and convincing arguments; his help in getting our group over the activation barrier of embracing a new idea was invaluable. Our relationship continues to this day, and through him we have formed a relationship with the personnel at Genencor International, Inc., in South San Francisco. Any new idea in any field of human endeavor faces slow acceptance. The energy of its inceptor is taxed by long-term disbelief, continuous doubt, or perhaps even an outright rejection. So it has been with the introduction of microbially or enzymatically derived chiral synthons by such pioneers as Bryan Jones2 and Charles Sih3 to the community of synthetic organic chemists. That particular group of scientists, known to all for its constant internal strife and disagreement on most issues, viewed the intervention of prokaryotic organisms or enzymes isolated from lower mammals with outright disdain, especially as any bacterium could do a far better job at a chemical transformation than all the top-seated organic chemists put together. During the past 30 years synthetic practitioners have slowly learned their lesson. The field of biocatalysis1 has widened considerably as new players have entered with new ideas and applications. It is safe to say that biocatalysis—a relatively new area with old origins4 that provides for a highly effective combination of microbiology, molecular biology, and organic synthesis—is now a permanent and rapidly evolving subdiscipline of organic synthesis. Because of its simple and efficient methodology, biocatalytic approaches are far superior to strictly synthetic ventures in the preparation of chiral drugs, pesticides, and other compounds.5 Those synthetic chemists who continue to insist that forty-plus-step syntheses have practical merits will soon cease to evolve unless they adapt to changing trends.

f^/r^°

lower organisms

organisms

^~

W> ^ > H 2

This is the story of a class of compounds that were unknown 30 years ago: d,s-cyclohexadiene-l,2-diols l,6"9 metabolites of the bacterial metabolism of aromatic compounds, a process studied as long as 100 years ago. 910 Unlike their mms-isomers (2) produced by the oxidative metabolism of arenes by higher organisms,11 the ds-diols are of more immediate interest to the synthetic chemist because of the uneven disposition of their molecular surfaces. Space-filling models of each compound show clearly that only in the ds-isomer there exists a facial bias for an approaching reagent that will ultimately lead to selectivity in ensuing chemical transformations. When we initiated our work with cyclohexadiene diols in early 1987, it was this quality that piqued our interest and formed the basis for our symmetry-based design of synthesis. We were not the first12 nor are we likely to be the last with new ideas on the use of these magnificent chiral compounds. The pages that follow offer a personal glimpse at the initiation of this research in our group. Although recent literature coverage is included, the chapter is written with the intent to describe the evolution of our own program, not necessarily to provide an exhaustive review of the literature. This task has been accomplished already by several authors of excellent reviews,13 which continue to appear14 at a rate commensurate with the increase in the number of publications in this area. There is no doubt that the future will deliver still more imaginative applications of the metabolites of biodegradation of aromatic compounds.

274

TOMAS HUDLICKY and JOSEPHINE W. REED

II. HISTORY OF CYCLOHEXADIENE C/S-DIOLS Historically, the study of the degradation of aromatic compounds by soil microorganisms dates to the beginning of this century with a report by Stormer,15 who isolated Bacillus hexacarbororum from cultures grown in the presence of toluene and xylene. Oxidation of benzene to catechol was subsequently reported by several investigators16-18 as early as 1913.16 cw-Cyclohexadiene-l,2-diols were isolated for the first time by Gibson, who studied the metabolism of benzene, halobenzenes, and alkylbenzenes by the soil bacterium Pseudomonas putida.6,7 In a series of closely related papers, the Gibson group showed that bacterial metabolism of arenes proceeds via cyclohexadienediols 1 to catechols 3, which then undergo further oxidation to muconates. Many excellent reviews have been published on the biodegradation of aromatic compounds.8'9 In the mutant species P putida 39D (Pp39D) the conversion of 1 to 3 is arrested, and cis-dio\s accumulate in the fermentation broth. This pathway contrasts sharply with that invoked for enzymes of higher species. Catechols are biosynthesized by P450-type enzymes presumably via arene oxides, and several diverse pathways may be envisioned, as shown in Figure 2. Studies of these systems are documented in the literature by Jerina.19 Through years of study, Gibson was able to identify the components of the enzyme, toluene dioxygenase, which consists of three subunits as depicted in Figure 3. He was able to express its production in E. coli, creating a highly efficient organism, JM109, the use of which leads to more efficient accumulation of diols.8a'b'20 Gibson has proposed dioxetane 7 as an intermediate in the pathway leading to the cw-diols, and his theory has been supported by 18 0 incorporation into the diol.21 For a synthetic chemist, the most valuable information concerns the type of organism, induction parameters for the enzyme, the medium for growth, and the projected yield. This information is available both in the primary literature6'7'22 and in several excellent reviews.8 To summarize the practical aspects of diol production, Pp39D and related species are the best choice for monocyclic aromatics and seem to tolerate a wide variety of substituents. Benzene, toluene, chlorobenzene, and bromobenzene have been found to act as inducers of dioxygenase production and are usually used as such with other substrates. Noninducing substrates produce diols at lower yield. Beijerenchia 8/36 has been shown to oxidize biphenyl-type substrates.23 Naphthalene dioxygenase NCIB/11 is suited for fused R I

R 1

i^Y°" ^s,i. i

yOH

- li\

R = H, M e, Et, CI Br

I!•J- \m 3

Figure 1. Bacterial oxidation of arenes.

Microbial Oxidations of Aromatic Compounds

275

Figure 2. Eukaryotic biooxidation of arenes.

polycyclic hydrocarbons,24 including heterocyclic compounds such as indole, which can be converted to indigo via dioxygenation with E. coli HB101 containing the expression of plasmid NAH7 from Pseudomonas putida PpG7.24b Two compilations have appeared in recent dissertation literature, listing over 120 examples of diols prepared from aromatic substrates.25 From the laboratories of Boyd, Crout, Dalton, Gibson, Ribbons, Roberts, Hudlicky, and other researchers, new compounds are being reported continually; these should stimulate the imaginations of synthetic chemists toward more diverse targets.26"38 Table 1 provides a quick glimpse at the diversity of structures that can be obtained by a simple enzymatic transformation based on a suitable match-up of an organism and a substrate.

TOI i vyi-/ ( |; O X yg c n a }

151,000

02 ^ >) \

154,000

46,000

^

/ ISP T 0 L \ / Fcrrcdoxin TOL \ / Reductase-.™ \ / NAD ( (tod C,C2) ) ( (lodB) ) ( (todA) ' )( \ ISP TOL / \ Fcrredoxin TOI y \ Rcductase T0I / \ N A D H

*Us Pp39D E. coli JM 109

Figure 3. Function of toluene dioxygenase.

+ H+

276

TOMAS HUDLICKY and JOSEPHINE W. REED Table 1. Recently Isolated c/s-Diol Metabolites of Aromatic Compounds OH CH

kOH

^OH

8 26 X=H,CI,Br

927

OH

OH kOH

/

1 1 4 32

H0 2 C s

AOU

kOH

1 2 30

1129

OH

1028

1331

X)H

HO1 OH

15"

1629

X =0,S

OH

1734

1935 HQ.

20™

2127

(CO,H

2238

The absolute stereochemistry of diols derived from toluene39a'b and naphthalene390 has been established in the pioneering work of Gibson. The methods used to elucidate the structures of new metabolites range from chemical correlations,26'27 ,30 NMR analysis of Mosher esters, and X-ray crystallography.

III. CYCLOHEXADIENE C/S-DIOLS IN SYNTHESIS A. Survey of Literature

In 1987, Ley published a short synthesis of (±)-pinitol from benzene via the meso-diol (1, R = H) derived by microbial oxidation.12 At that time interest in using the meso-diol from benzene in synthesis was confined to industrial programs at ICI,

Microbial Oxidations of Aromatic Compounds

277

a company that also furnished the compound to academic investigators. Our group initiated its synthetic ventures in 1986; our first paper appeared in 198841 (see Section III.B). About the same time, many other investigators also began reporting on various transformations involving initially the diols derived from benzene, toluene, and chlorobenzene, available through donations from ICI or their own efforts with commercially available microbial strains. Today many of the diols are commercially available.42 It is interesting to note that there was almost no reaction to the ds-cyclohexadienediols in the synthetic community even though the structures of various metabolites have appeared continuously from the laboratories of Ribbons43 and others in the 1970s and 1980s. Recent reviews published on the synthetic utility of diene diols all do an excellent job in pointing out the versatility of these synthons.13"14 Because this chapter is intended to provide a personalized review of the accomplishments from our own laboratory, and since it would be redundant to review the entire literature, the major types of transformations that have been reported for these diols have been arranged in groups with the major contributors in each area listed for easy literature retrieval of information. The most recent review as of this writing is that of S. Brown and T. Hudlicky; it contains literature coverage in the area of synthesis through April 1993.13b An obvious use of cyclohexadiene cw-diols has surfaced in the area of cyclitol synthesis. As Figure 4 indicates, this strategy relies on peripheral oxygenation with control of regio- and stereochemistry. In the free diol, epoxidation takes place in a syn fashion;44 in cyclic protected forms (carbonates or acetonides), it leads to anti stereochemistry.4513 Similarly corresponding diols can be obtained with Os04.45b'46

jb> OH

HOT

^OH

OH

23

6>I

^

26

n. b^ cr R 1

^OH ^OH

24

X = (CH3)2,0

27

''

R = H,Me,Cl,Br k()H

I I O ^ ^ - N•Oil OH

25

HO'

•a Y

OH

Figure 4. Conduritol synthesis. (From Refs. 44, 45, 47, 48.)

^OH 28

278

T O M A S H U D L I C K Y a n d JOSEPHINE W . REED 9H


30

31 X = (CH3)2,0

•

6H

R*=Plr^^S

32

Figure 5. Cyclitol or inositol synthesis. (From Refs. 45, 47, 49.)

When R is a group other than hydrogen, the products are homochiral and have been used in exhaustive syntheses of cyclohexanetetrols or conduritols. When R is a halogen, the vinyl halide can be reduced and the resulting olefin subjected to further oxidation along the same principles. In the case of the diol from benzene, opening of the epoxide can be accomplished with chiral nucleophiles leading to resolved products, as in Ley's synthesis of homochiral compounds (Figure 5).47 Amino conduritols are accessible via either nucleophilic opening of epoxides with nitrogenous nucleophiles46,50 or the [4 + 2] cycloaddition of acyl nitroso compounds.51"53 This latter strategy has been exploited also in the applications to aminocyclitol (conduramine) synthesis (Figure 6). Full oxidative cleavage of double bonds at either the diene or the monoolefin has led to tetrose57'58a and hexose derivatives, and ultimately also to their aza analogs50,59 as shown in Figure 7 (see sections II.B and C). Cycloaddition chemistry has been exploited in the preparation of cyclopropanes,60,61a cyclobutanes,61a and Diels-Alder adducts.34,56,61,62 In unsymmetrical dienes, such as those derived from a halobenzene, full regiochemical control is seen with polarized dienophiles such as acyl nitroso compounds. Figure 8 shows some illustrative examples of cycloaddition products. Transition-metal-mediated transformations have surfaced. The cyclohexadiene cw-diols containing halogens

X

X 1

>Y°

•V^OR

0'

(l

R4*

I

R

JyOR R2N1

33

*"

X

OH 01

jl

35

34

QC *R>

36

Figure 6. Aminocyclitol synthesis. (From Refs. 34; 49; 51 a,c,d; 54; 55; 56.)

Microbial Oxidations of Aromatic Compounds

^"*NoH

279

HO'

37

38

OH

39

40

0H

Figure 7. Carbohydrate synthesis. (From R§fs. 50, 57, 58.)

have been transmetallated and converted to alkyl and aryl derivatives.65 This becomes an extremely useful method in those cases where the corresponding cis-diol might not be available by biooxidation (Figure 9). Iron complexes of diols and their transformation lead to efficient chirality transfer and will see applications to total syntheses.66 The meso-dio\ derived from benzene has been used in the synthesis of polymers (Figure 9).67

CO 2 R

T\

41

X = R = R,= R2=

H,F,Cl,Br,CF 3 ,CH=CH 2 H,C(CH 3 ) 2 Me,Ph,H,Cl Me,Ph,H,Cl,C0 2 Et

42

Figure 8. Cycloaddition chemistry. (From Refs. 34; 41; 56; 60; 61; 62a,b,c; 63; 64.1

280

TOMAS HUDLICKY and JOSEPHINE W. REED

6c

(1) M

(2) E+ 1

46 X = Cl,Br E = OCR,SnR3,Ph,CH=CH2,etc.

OKt MeO. *(CO)3 R(J

MeO'

47

OR

48

Figure 9. Transition-metal-mediated transformations. (From Refs. 65a,b,c; 66; 67.)

Most recently the use of the meso-dio\ derived from benzene has been coupled with lipase resolution to furnish enantiodivergent access to such compounds as conduritols,48'51b conduramines,51a and shikimic acid esters68 (Figure 10). This brief overview provides a general idea of the types of chemical transformations performed to date with cyclohexadiene cw-diols. Notably absent from the efforts seem to be two features. First, a big-picture, system-oriented design of classes of compounds rather than the synthesis of isolated members has not been formulated. Second, save for our own efforts, almost no applications of these synthons to the efficient preparation of larger molecules have appeared. The chemistry of these diols has not yet reached the full potential in synthetic applications. The elements of key reactions all exist and have been documented, but the two criteria above have so far been addressed only by our research group. It is the purpose of the next section of this chapter to enlighten the reader to the natural sequence of events that led to increasingly more sophisticated applications, and to pave the way for truly exhaustive and system-oriented applications to come.

ox — ox OH

X)H

'VAOH

OH

OH

49

OAc

50

Figure 10. Lipase resolution of meso-diols. (From Refs. 51a, 68.)

Microbial Oxidations of Aromatic Compounds

281

B. Symmetry-Based Design of Enantiodivergent Syntheses

During the 1980s our research group was engaged in the design of general synthetic methodologies for the preparation offive-memberedcarbo- and heterocyclic compounds.69 Such topics were popular during this era; however, few investigators concerned themselves with the design of truly exhaustive methods of synthesis that would approach an entire class of compounds rather than isolated members. Organic synthesis eventually evolved to a level where a desired target could be attained in a stereocontrolled fashion, and often with the desired absolute stereochemistry as well. Unfortunately, few if any attempts at a unified approach toward entire groups of natural products were apparent. Nature offers a beautiful model for this endeavor in the biogenetic schemes for terpene and alkaloid synthesis, in which individual members are derived from a common intermediate by series of transformations that address subtle differences in regio- and stereochemistry. It is no doubt Nature's strategy that motivated my mentors—Ernest Wenkert, the late Robert V. Stevens, and Wolfgang Oppolzer—to think along the same lines in designing natural product syntheses. Wenkert designed a general protocol for indole alkaloid synthesis based on his vision of biogenesis and synthetic connectivity in the context of available methodology of the period.70 Stevens produced a general method of synthesis using a strategy that addressed the general substitution pattern of those alkaloids containing a five-membered pyrroline nucleus.71 Oppolzer's use of the ene reaction in terpene and alkaloid syntheses led to approaches that took into account regio- and stereochemical differences among members of a general class of natural products.72 Guided by these principles we designed general methods of annulation that were amenable to the synthesis of both linear and angular triquinanes as well as to the preparation of analogous nitrogenous and oxygen-containing compounds. The methodology was based on topological connectivity of targets and emphasized the consideration of individual reagents and steps as dimensions of the actual synthesis. These concepts have been reviewed and exemplified in a number of approaches to terpenes and alkaloids containing five-membered rings.585'69,73 These methods, while efficient and general, lacked the final level of sophistication, namely that of asymmetric design. We eventually solved this problem by commencing our synthetic ventures with optically pure materials.69'73'74 However, the ultimate accomplishment in efficient synthetic protocol involves the conversion of achiral materials to either of the two enantiomers of the final target. Given that enantiomers are identical compounds in every respect except for properties related to symmetry, any method that targets two enantiomers of a chiral compound should address the equivalence of the two pathways in energy.74 In other words, both approaches must be as close as possible to identical in expended effort. The enzymatic oxidation of aromatic compounds provides the necessary introduction of asymmetry. The enzyme toluene dioxygenase evolved to recognize one of the chiral possibilities, that is, a bias toward one-half of an unsymmetrical

282

TOMAS HUDLICKY and JOSEPHINE W. REED

Figure 11. Proenantiotopic differentiation. (Note: D- and L-configurations are arbitrarily assigned.)

molecule such as 51 depicted in Figure 11. The outcome of enzymatic oxidation cannot be duplicated by the use of an "enantiomerically opposite" enzyme because none exists. However, further functionalization of one enantiomer may lead to projected intermediates in which a net inversion appears to have taken place. The resolution or desymmetrization of meso compounds follows the same principle. on

OH

CXX - ^ (XX OH

49 (meso)

OAc

50 (homochiral)

The key question with regard to the principles of enantiodivergent design is: If the monoacetate 50 was available only as one enantiomer, would it be possible to "switch" the two groups in such a way as to create the other enantiomer? In practice this is impossible as the compound would have to be symmetrical at some point. However, since the phenomenon is important only at the stage of a target, then a number of steps may be inserted into the sequence so that only one of those steps would serve as the equivalent of the enantiomeric switch. For example, if the intent is to convert 50 to the enantiomeric pair 53a and 53b (Figure 12), then the switch can be accomplished by adjusting the order of operations which remain nearly identical otherwise. In this example there is an additional step of protection which renders the two pathways nonidentical with respect to energy expenditures. Cyclohexadiene diols are amenable to this analysis in several ways. Consider the three compounds below. Each is unsymmetrical, and 55 and 56 are homochiral. The dotted line represents the "proenantiotopic" plane of symmetry indicating that events taking place on either side of it will ultimately lead to enantiomerically

Microbial Oxidations of Aromatic Compounds

283 NH2

alkylation OH

SN2

"

hydrolysis

f|Ssf^\/

"

U-cA 6H

OCX oV

en

\ (protection)

53a

?" hydrolysis

•

alkylation

•

SJM2

( l l ^ \ /

LA.A NH2

53b

Figure 12. Principle of functional differentiation.

distinct products. Enone 56 contains an additional plane of "latent symmetry" because of reaction site differentiation. In addition to differentiated functionalities (i.e., oxidation states of CI and C4), either olefin or diol can be cleaved and/or interconnected to furnish enantiomeric products from 56 (Figure 13). In this instance the pathways are energetically equivalent. ci

-ee
54

KMn04

56

I04

HX^0"

H+

OHC.

Js*r OH

OH

OH

56

H+

I04

KMn0 4

57a

HO, CHO

HO1

6H

57b

Figure 13. Principle of reaction site differentiation.

284

TOMAS HUDLICKY and JOSEPHINE W. REED

C 1. 0 3 2. H + 3. Corey-Winters

X,

XHO

Figure 14. Design of enantiomeric cyclohexenes.

This principle can also be applied to the synthesis of enantiomeric cyclohexanes as illustrated in Figure 14. In this instance, the functional equivalence dictates the use of an extra step in one pathway. It will be seen in later examples that such equivalence is only important at the end of the synthesis. Thus, the longer the synthetic sequence the more opportunities exist for an "enantiomeric switch." In other words, more operations provide more opportunities for the mathematical commutation principles of substitution of the order of reagents in any given sequence of an identical outcome in all criteria except for symmetry. The concept of proenantiotopic symmetry is similar to that of reflexivity proposed by Bertz.75 It differs, however, in that the outcome of enantiodivergent operations is a function of incipient chemical steps and their order in sequence. For concise discussion of these principles the reader should consult a recent series of chapters by Hudlicky,74 Wender,76aandBertz.76b The most successful example of the enantiodivergent synthesis is that of (+)- and (-)-pinitols (32a and 32b). In this approach, the proenantiotopic plane was drawn to indicate identical reflective symmetry in the starting diol and the two enantiomers. The hypothetical enantiomer of la is related to the reflection of the desymmetrizing element (CI atom) across the proenantiotopic plane by a switch of the substituent, such as the methoxy substituent in 32a/b. Theoretically, the "switch" could be accomplished by the exchange of those groups that constitute proenantiotopic reflection, that is, exchange the methoxy and the hydroxy groups as shown above (from C6 to C5. for example). The starting material for the synthesis is diol la and enantiodivergence is accomplished by "switching" the order of steps, as

CI

JV° H

H->41

--[-—j-— V-s, 0H la

^yOH ^~

^X^,...

^ p ^OH l b CI

[4->l|

OH

Oil |6->5]

HO*'

|5-»6.|

4^^011

"0^^-s^OH

»~

• OH

Oil

32b

32a

CI

a

f

1. epoxidation

55

c

non-enantiomersHO'

59

6-'

OH

60

2. hydrolysis 3. reduction 1 4. diol formation

I 2. reduction 3. epoxidation 1 4. hydrolysis

OH

OH

I MeOr

di

' diol « formation r * ^ T * °\ V/ / 1.

I ^y"

Y

-+

enantiomers

»~

u

V HO'

OH

0 H

OH

OH

\,

JL

-*

enantiomers

MeOr>^N)H

•

I

HO''

•

OH

62

I

>^\)H 1

OH 32a

32b Figure 15. Enantiodivergent synthesis of pinitols. 285

286

TOMAS HUDLICKY and JOSEPHINE W. REED

shown in Figure 15. Thus the very first step defines either the cw-diol or epoxide formation and thus the final outcome. In this synthesis all steps are absolutely identical, and enantiodivergence is accomplished solely by changing the order of individual steps according to the defined symmetry requirements.74 For this reason the order of steps should be considered as an important dimension of a reaction sequence. With the application of the above principles, the synthetic strategy is complete and attention can be devoted entirely to execution of system-oriented design of an entire class of molecules. The next section shows some of the advances we have made toward this goal. C. Evolution of a General Method Principles of Design

Cyclohexadienediols such as 1 are exceptional substrates that offer a wealth of possible transformations, a few of which are: (1) Each hydroxyl group can be x

1

selectively protected, and subsequent reactions such as Claisen rearrangement and intramolecular Diels-Alder reaction can be carried out; (2) The polarized diene allows sequential functionalization with OH, NR, SH, SR, N3, or OR groups; (3) The diene and its component olefin allow cycloaddition chemistry (4+2,4+3,6+4, 2+2,2+1,2+3, etc.); (4) Either of the olefins or the diol allow cleavage to dicarbonyl compounds, whose reclosure leads to sugars; and (5) The free diol and its protected form allow syn and and discrimination, respectively, of facial selectivity for subsequent transformations. In order to execute the design properly for any member of a given class, the planner must control the topology as well as topography of the targets.69'77 Regio-, stereo-, and enantiocontrol are topographical qualities, whereas the type of compound represents a topological variant. The guidelines that we have evolved to utilize can best be exemplified on the carbohydrate/cyclitol class of compounds. The relationship between 63 and 64 is a topological one, and the two classes of compounds may be interconverted provided selective cleavage of one of the six diol units can be accomplished (Figure 16). The topography of either molecule is subject to precise control of regio- and stereochemical events. For example, dihydroxylation or epoxidation of the free diol (1) as opposed to its acetonide (55) would lead to syn versus anti relative stereochemistry of the next center, which in turn will control the next one, and so on.

Microbial Oxidations of Aromatic Compounds

287

)ii

O

V_y

55 hindering effectnext center anti

directing effect— next center syn

peripheral oxidation

6

5

Al ^OH f**f |2

partial peripheral oxidation

^ ^ J \ ) H

reductive

4

cyclization

selective cleavage

*

HO^S^OH

reductive cyclization

64 carbohydrates

63 cyclitols

Figure 16. Topological relationship between cyclitols and carbohydrates.

The regiochemistry of oxygenation is controlled by the electronics of the polarized diene system—calculations indicate and experiments confirm that the chloro olefin is deficient in electron content and therefore the C4-C5 olefin is the first to interact with electrophilic reagents.45'46 The type of sugar (i.e., tetrose, pentose, hexose) is addressed by the controlled loss of two, one, or zero carbons from the diene diol unit 1, as shown in Figure 17. These principles have been defined in detail in recent publications.45,46'50 The heterosugars (and heterocyclitols) are defined by the placement of heteroatoms, usually nitrogen. To control entry into each class of compounds another dimension is required—that of the placement of heteroatoms. on

no

OH

Oil

.on

HO,

on

HO'

on

70 aza sugar (endocyclic nitrogen)

amino sugar (exocyclic nitrogen)

72 amino cyclitol (exocyclic nitrogen)

288

TOMAS HUDLICKY and JOSEPHINE W. REED OH

ozonolysis (loss of 2 carbons)

OH(T

°

65 X

rVV U > A 55

tetrose

o

Ll 3

HO

°

2(loss sis of 1ycarbon) - ozonol

^VV

OHC. J ^ r / \ OH

67 1. hydroxylation

^~ 2. ozonolysis (no carbon loss) QHC 69 hexose

F/gi/re 17. Design of carbohydrate synthesis.

Figure 18 outlines schematically what is required to reach each of these classes from chlorocyclohexadiene diol. This strategy assumes that the order of introduction of peripheral substituents, their stereochemistry, and their protected or unprotected nature are already controlled.50 What remains then is the decision on which of the six sides of the cyclohexane ring is cleaved and which of the peripheral groups is free to cyclize onto the carboxylate or aldehyde generated by such cleavage. For example, ozonolysis of 73 and the cyclization of a nitrogen substituent onto the CI carboxylate generates the aza sugar nucleus 74, in contrast to the amino sugar 76, which would result from a cyclization of C4 hydroxy 1 onto the C1 carboxylate. The cyclization of CI hydroxy 1 onto C5 yields similarly amino hexose 79, whereas

tc 80

-„,xc 6H

si

9"

oc 82

Microbial Oxidations of Aromatic Compounds

^""> I 1. epoxidation 2. R2N' *

77 amino sugar

289

reductive cleavage

; - A > ^'A ccyclization y

R2rT Y

70b aza sugar

v

II r>n HN^^^y^ JX^V^SOH HO

OH

HO

NH2

79 amino sugar

Figure 18. Design of topologically controlled amino sugar and aza sugar synthesis.

closure of the nitrogen substituent onto CI gives a five-membered-ring aza sugar 70b. A different substitution pattern of amino sugar is attained in 77 via C1-C5 cyclization of the hydroxyl group (Figure 18). We have realized this strategy in the synthesis of aza sugars, described in several recent papers.50'78 For cyclitols, inositols, and all of their derivatives the peripheral nitrogen is introduced either by ammonolysis of an epoxide45'46'50 or by [4+2] nitrosyl addition.51'52,54 It should be apparent at this point that any combination of functional groups or atoms in any regio-, stereo- and indeed enantiomeric composition should be accessible by judicious planning. The sequences can be reduced to a few steps increasing the efficiency of the overall synthesis. The analysis presented above was constructed conceptually over five or six years of research. It evolved both from the concepts acquired during the terpene and alkaloid syntheses mentioned in the following sections69 and from the simple applications that initiated our entry into the biocatalysis field. For chronological reasons and for clarity, we now outline the applications in the order of their actual accomplishment to show that the full recognition of the above analytical reasoning was only recently achieved with the sugars and cyclitols as targets.

TOMAS HUDLICKY and JOSEPHINE W. REED

290

83a 83b

R=H R = C(CH 3 ) 2

55

86

85

Figure 19. Synthesis of prostanoid synthon. (From Refs. 41, 79, 80.) Terpenes

Our first application of the use of cylohexadiene diols was in 1986 and utilized the diol (prepared by Larry Kwart) derived from toluene by means of the organism Pp39D donated to us by Professor David Gibson. We envisioned a simple ozonolysis of the diene to produce a homochiral enone (85) through aldol condensation as shown in Figure 19.41 After extensive experimentation (and almost six years later) a better synthesis of 85 became availablefromthe diolfromchlorobenzene via erythruronolactone 8680

88

HO^

Figure 20. Synthesis of PGE20C and specionin.

6Et

Microbial Oxidations of Aromatic Compounds

291

83a 90b

Figure 21. Synthons for perhydroazulene terpenes.

and Borchardt's Wittig reaction.81 Enone 85 is an intermediate in Johnson's synthesis82 of PGE2OC (87), and it synthesis constitutes a formal synthesis of PGE2OC (Figure 20). Later it served as a key intermediate in our synthesis of specionin (88),79 which combined [2+3] annulation technology69 with the use of this chiral pool synthon. Diol 83a was also converted to its fully saturated diastereomeric diols 89, which when separated and cleaved provided, through cyclization, the enantiomeric aldehydes that may have potential in the synthesis of hydroazulene sesquiterpenes (Figure 21).41 The application of diol 91 derived from styrene was expressed in the synthesis of zeylena (95) via an intramolecular Diels-Alder reaction of the internal diene with cinnamyl ester and adjustment of the vinyl group to the oxidation state of benzyl alcohol (Figure 22).83

*xT^^vh 91

92

Figure 22. Synthesis of zeylena.

TOMAS HUDLICKY and JOSEPHINE W. REED

292

The exo-diene unit in the styrene diol was "protected" by a [4+2] cycloaddition with diazodicarboxylate in which the ester group was designed so as to suffer easy removal (trichloroethyl, trimethylsilyl ethyl). The C3 alcohol was inverted via the Mitsunobu protocol, connecting for the first time the manifold of frajw-arene diols from the cw-isomers. The deprotection of pyrazine 93 regenerated the endocyclic diene system, which underwent a facile Diels-Alder reaction to afford 94 and was converted to zeylena by additional adjustments of the styrene double bond. Alkaloids During the early to mid-eighties our group designed and implemented a [4+1] annulation method for pyrrolizidine alkaloid synthesis58'69,84 based on the azidediene cycloaddition and the subsequent rearrangement of the vinyl aziridine. The details of the development and overall results of this methodology has been summarized in a recent review.585'69 The alkaloids that were attained by this method—supinidine, isoretronecanol, and trachelanthimidine—wereracemic, and the chemistry of the arene cw-diols provided the necessary means of rendering the method asymmetric (Figure 23). The recognition of the proenantiotopic plane of symmetry in erythruronolactone also provided for enantiodivergent design of the more highly oxygenated heliotridane triols (Figure 24).58a Depending on the locality (a vs. b; Figure 18) of the first transformation (i.e., reaction site differentiation principle), either of the dienic azides 102 or 103 became available via more or less identical pathways. These compounds were then converted to enantiomeric pyrrolizidine triols 106a and 106b, respectively, via azide-diene cycloaddition and subsequent selective vinylaziridine-pyrroline rearrangement.583 In 1990 advances made in the synthesis of amino conduritol54 permitted the application of acyl nitroso [4+2] cycloaddition technology to the synthesis of homochiral lycoricidine as shown in Figure 25,55 The cycloaddition and reduction of the oxazine provided the four contiguous chiral centers, and Heck coupling

or^° 99

97

98

100

101a R = E 101bR = CH2OH

Figure 23. Pyrrolizidine alkaloid synthesis.

^.^Ab

•X-:i

86

102

104

»—OH

106a

106b

Figure 24. Enantiodivergent synthesis of trihydroxyheliotridanes.

110 pancratistatin

109 lycoricidine

Figure 25. Synthesis of lycoricidine. 293

TOMAS HUDLICKY and JOSEPHINE W. REED

294

furnished, in analogy with the published effort of Chida,85 the lycoricidine skeleton that was easily elaborated to the alkaloid in a total of nine steps from chlorobenzene. This work serves as an advanced model study for an eventual approach to a more complex alkaloid, the antitumor substance pancratistatin (110), now nearing completion in our laboratories. Finally in 1992, the solution of topological switch between the aza sugars (containing an endocyclic nitrogen) and amino conduritol (with an exocyclic nitrogen atom) provided the means to rapid synthesis of a newly reported alkaloid, kifunensine (111), Figure 26.78

"endo-N"

OH

OH

6H

111 kifunensine

109 lycoricidine

Figure 26. Topological control of synthesis of aza sugars and conduramines.

HO

Figure 27. Synthesis of kifunesine.

OH

Microbial Oxidations of Aromatic Compounds

295

Chlorodiene diol 1 was protected as the acetonide and epoxidized with the expected and stereochemistry. The necessary syn relationship of nitrogen/oxygen functionality at C4-C5 was attained by opening with chloride followed by an inversion with NaN3. Ozonolysis gave, on reductive work-up, the azido mannose lactone 114, which on hydrogenation furnished mannojirimycin (115). Each of these compounds was converted to the known open-chain oxalyl amide 116, which was cyclized according to Hashimoto's procedure to the bis-acetonide of kifunensine and thence to the title alkaloid, known for its glycosidase inhibitory properties (Figure 27).86 We have recently completed a model study designed to test the possibility of synthesizing morphine (120) from the styrene-derived diol.22 It involves the DielsAlder reaction of diene 117 under thermal and transition-metal-catalyzed conditions. Tricyclic ether 118 was obtained in good yield and with the proper absolute stereochemistry. The secondary methyl group serves as a model for the incipient formation of the ethylamino bridge in 120, which is envisioned to come from ether 119 (see Figure 28). Carbohydrates and Cyclitols In 1989 we published the first synthesis of a carbohydrate (erythrose) from chlorobenzene.57 Following the reasoning made in the introductory section on the total control over the design of topology as well as topography, a claim could be made that any carbohydrate system is accessible from the achiral chlorobenzene unit. In other words, a total replacement would be at hand for the tedious manipulation connected with carbohydrate-based transformations.87 The first step toward reinforcing the credibility of this claim was the connection of the carbohydrate and aromatic domains through a common intermediate, erythruronolactone (86), which

9

Figure 28. Morphine model study.

120

TOMAS HUDLICKY and JOSEPHINE W. REED

296 sugar domain

aromatic domain

iio^v^h)„

CI

X

121 L-arabinose

55

HO 123a L-erythrose

II 123b D-erythrose

HO—'

124

125

Figure 29. Tetrose and pentose synthesis.

can be manufacturedfromarabinose or gulonolactone, orfromchlorocyclohexadienediol(la). 58 Both enantiomers of erythrose were synthesized from 86 by controlling the reductive work-up of ozonolysis (Figure 29). Conversion of 86 to acid 124,58 itself a useful chiral synthon, provided access to L-ribonolactone (125)88 via osmylation and in situ lactonization. Several years later, in 1993, the diol derived from 55 by osmylation was converted to mannosolactone (127) by adjusting the conditions of reductive work-up (Figure 30).59 Thus representative members of four-, five-, and six-carbon carbohydrates have all been madefroma single source, chlorobenzene.

55

OsQ

HO

Figure 30. Mannose synthesis.

DH

_„

Microbial Oxidations of Aromatic Compounds

297

OH

0

^J.OH

oxidation oxidation

HO,

reduction iwhirfinn

HO^ " V ^ ^OH

OH

cleavage cyclization

S ^ ^ O ^ ^„OH O HO^^V^^OH

OH

OH

Figure 31, Redox and hydration relationship of benzene, sugars and cyclitols

The diastereomeric or regiosiomeric constitution of sugars should follow from the defined placement of atoms around the periphery of the initial cyclohexadiene diol. In fact a connection between diene diols derived from monocyclic aromatic compounds and both sugars and cyclitols is made apparent by considering the above schematic (Figure 31). An inositol is simply a triply hydrated and triply oxidized benzene ring. A hexose is a product of cyclization of a cleaved inositol in which one of the two aldehydes is reduced. Keeping this identity in mind we turned to the synthesis of conduritols, inositols, and conduramines in the area of carbocyclic ci

55

CI

CI

HOT OH

6H

60

33

r

OH

&

56

OH

OH

128 conduritol E

conduritol F

OH

^v^OH

^s^OH

^N^*OH

^>v^*OH

OH

OH

i

130 conduritol C

Figure 32. Conduritol synthesis.

OH

131 conduritol A

TOMAS HUDLICKY and JOSEPHINE W. REED

298

ci

5 5

CI

CI

^ HO'


5 9

OH

OH

Me

"VVv

60

OH

Vvv

MeC 6H

,%

OH

OH HO.

62

OH

Js^^OH

McCv^^^OH

MeO^^y^OH

HO''

OH

>^^OH OH 32a

32b

Figure 33. Pinitol synthesis.

sugars. These syntheses required only a simple analysis of the stereochemistry in thefinalproducts and the use of epoxidation, osmylation, or singlet oxygen addition to set up the required stereocenters (Figure 32). The ultimate application of this technology was expressed in the fully enantiodivergent synthesis of (+) and (-)-pinitol45 (Figure 33). The cycloaddition route to enone 56, which was formed by cc-elimination of the chlorohydrin generated by the reduction of endoperoxide 132, then provided the background to expand this

&x CI

I

132

0

OH

CI

|| -

~

*

&

&

NH2

133

C—I

.As NH2

35

36

Microbial Oxidations of Aromatic Compounds

299

technique to the synthesis of conduramines. The corresponding reduction of oxazines such as 35 was found to be easily controlled by adjustments in conditions to give either the amino ketone 133 or amino alcohol 36.54'55 By nucleophilic opening of epoxide 59 (Figure 34) we were able to synthesize the azido alcohol isomers 134, 135, 136, and 138, which possess most of the configurations required for conduramines. Additional methods of nitrogen introduction relied on the opening of epoxide 59 with derivatives of ammonia to access conduramine derivatives 137 and 139. Fluoroconduritol 140 was attained by opening the epoxide with BF3-Et20.

on

CI

OCX 55

CI

NH2

36

CI

CI

X OH

or 134

135

59

CI

RUN

HO'

OH

138

136

CI >OH

HO'

F^V^OH OH

140

Figure 34. Conduramine and fluoroconduritol synthesis via epoxide opening.

300

TOMAS HUDLICKY and JOSEPHINE W. REED

OH 134

141

139 OH

(X

HO' -v- V ^

H^'V^O^

HO^N^^OH

OH

OH

OH

60

142

143

•

i

>

This method, especially the manipulations involving regio- and stereochemical switches via aziridines, is almost exhaustive as it addresses all eight possible structures for the azido alcohol unit located at C4-C5. The most recent task, in addition to the investigation of the general chemistry of aziridines of type 141, was the general approach to inositols, or hexahydroxycyclohexanes. Several of the nine total isomers are commercially available and one, D-cfa>0-inositol, has gained prominence for its potential in treatment of type II diabetes. As D-c/iiro-inositol became the major focus of this part of the program, adaptation of the synthesis of (+)-pinitol yielded the desired compound in five steps.8990 Seeking a more environmentally acceptable procedure, we prepared quite fortuitously the chloro epoxide 144 by substituting KMnCU for OsCU (our initial expectation was an equivalent yield of diol 60).89 Chloro epoxide 144 was transformed to three of the nine inositols and also to the rare D-c/wr<0-3-inosose (145).89 The synthesis of D-c/wro-inositols was accomplished in four chemical operations; all but one performed in aqueous medium. As a bonus, the chloro epoxide was also converted to erythruronolactone (86), with two equivalents of aqueous IC>4~, thereby providing for an easier synthesis of this synthon which is now commercially available (Eastman Fine Chemicals) (Figure 35).91 Other Classes of Compounds

The diene diols are amenable to a host of other reactions some as yet unexplored. Examples of cycloaddition chemistry beyond the typical Diels-Alder processes include the dimers of chlorocyclohexadiene diol62 and styrene diol,63 the latter depicted in Figure 36. The cycloaddition of chlorocyclohexadienediol with tropone is shown in Figure 37.59,92 Reaction of chloroepoxide 144 with ammonia gave aromatic pyrazine dimers (Figure 38).59'93 It is in this area that we expect major breakthroughs and easy access to poly cyclic compounds. It is clear that potential exists for multiple cycloaddi-

CI

CI

CI

HO'

HO'

55

HO'' > ^ N o H OH 145 D-c/wro-inosose

HO*

60

OH

142

86

OH

OH

OH

HO*. ^

HO''^^N)H

HO''

146 a//oinositol

OH

144

•00<

"OVJI^OH

OH

OH

^OH

> < \ ) H

HO.

^ s ^ ^OH

HO'' >>^^ >^OH ( HO'

OH

OH

143

D-c7i/rr;-inositol

147 neo-\no$\to\

Figure 35. Inositol synthesis.

kOH

r

OH

150

Figure 36. Dimers of the cyclohexadienediol derived from styrene. 301

302

TOMAS HUDLICKY and JOSEPHINE W. REED

R = H,C(CH 3 ) 2

157

Figure 37. Cycloaddition of chlorocyclohexadienediol with tropone.

HO'

144

OH

NH,

Figure 38.

tion-basedstrategy as well as the synthesis of compounds that may play a role in molecular recognition. Such topics are briefly addressed in the concluding section of this chapter. D. Future Prospects

It should be evident that the complexity of applications of diene diols in synthesis is increasing. All the obvious reaction schemes have been pursued by us and others. What then lies in the future as far as our program is concerned? One area of research that can be envisioned is that of higher order cycloaddition chemistry combined with tandem sigmatropic processes. The idea of controlled oligomerization of more complex diols would also seem attractive in the field of chiral materials. The richest rewards will probably come in the increase of the number of substrates amenable to oxidation and adjustments in the strains of organisms that would biooxidize more complex and more highly substituted compounds.

Microbial Oxidations of Aromatic Compounds

303

As the pool of metabolites expands so will the new applications and targetoriented endeavors. The area of molecular recognition, for example, could benefit from the availability of novel structures that may become accessible via manipulation of cyclohexadiene diols. One expects to see even further increase in the next few years in the number of reports and investigations in the area of cyclohexadiene cis-diols. A new area in which biocatalysis will play a major role is that of environmentally benign synthesis. Biocatalytic methods are ideally suited for this strategy, as they significantly shorten synthetic routes and therefore reduce the total output of waste connected to the preparation of a chiral intermediate. When a method such as the biooxidation of chlorinated aromatics can further be linked to the disposal issue of undesired compounds, the benefit is twofold. Future endeavors will no doubt see the connection of these two issues. At the time of this writing, the group, composed of 18 co-workers, is busy investigating projects in morphine alkaloid synthesis, approaches to taxol, carbocyclic sugar design, and isolation and utility of new metabolites. Exciting new results motivate all of us to report on new applications in this field of research.

IV. CONCLUSIONS An attempt was made to describe chronologically the events that led to many concise synthetic schemes using the cyclohexadiene cw-diols. Table 2 lists the natural product targets made to date in our research group, and shows along with the structure, the overall number of chemical steps. Without exception, these syntheses are the shortest available for a given target, thus demonstrating adequately the claims made throughout this review. We look forward to reporting on further examples of this fascinating technology in the near future.

Table 2. Naturally Occurring Compounds Synthesized from Aromatic Compounds by the Hudlicky Group, 1988-1993 Starting Material

Number of Steps Reference

Product

~6

02H

PGE20C

41

304

TOMAS HUDLICKY and JOSEPHINE W. REED Table 2. (conti nued) Starting Material

Product

Number of Steps Reference

Cl

S^

V,

15

79

14

83

(-)-specionin UCPh *OH

Ph-

KC

(-)-zeylena OH

Cl

3

57,58a

4

57,58a

5

95,45a

L-erythrose acetonide

H(

D-erythrose acetonide ci

HO"

L-ribonolactone acetonide OH

Cl

6C *OH

OH

(-)-dihydroconduritol C

HO'

CC (')H

(-)-conduritol E

95

Microbial Oxidations of Aromatic Compounds

305

Table 2. (continued) Number of Steps Reference

Product

Starting Material

HO^V^OH

5

95

OH

(-)-conduritol F OH

&

:

45a

OH

(-)-conduritol C OH

6z

54

NH 2

(+)-conduramine Al CI

o kOH

54 ^^X^OH HO

OH

mannojirimycin lactam ,*-OH

HO

---CO

10

58

10

58

(-)-trihydroxyheliotridane

Hq

H

r-OH

HO--<

(+)-trihydroxyheliotridane

306

TOMAS HUDLICKY and JOSEPHINE W. REED Table 2.

(continued)

Starting Material

Product

Number of Steps Reference

OH

55

(+)-lycoricidine OH Me()

45

Vr^\r-*C)H

110'' ^ V ^ O H Oil (+)-pinitol CI

OH

45

MeO^Y^^0" OH

(-)-pinitol OH

4

59,89

HO**' > ^ N ) H OH

(+)-D-c/wro-inositol OH

OH

vr^Y^OH

90

HO-'^Y^^0" OH

a/Zo-inositol

V-NH / V S I I OH

OH

(+)-kifunensine

8

78

Microbial Oxidations of Aromatic Compounds

307

ACKNOWLEDGMENTS None of the results described in the Sections IH.B and III.C of this chapter would have materialized were it not for the effort of the co-workers whose names are associated in more than 30 publications we have produced since 1988. Most notably Dr. Larry Kwart of Genencor International is to be credited for his persuasive reasoning and insistence that we seriously look at cw-diols as synthetic intermediates and for his ability to train all of us in fermentation techniques. Dr. Gregg Whited of Genencor International deserves many thanks for scientific, logistical, and financial support of our diol ventures during the past three years. Finally Professor David Gibson of the University of Iowa is especially acknowledged for his continuing advice, gifts of organisms, and most of all for his past role as mentor to both Dr. Kwart and Dr. Whited.

NOTE ADDED IN PROOF The following papers describing synthetic ventures from ds-dihydrodiols have been published or are in press as of October 1, 1994: Banwell, M. G.; Collis, M. P.; Mackay, M. R; Richards, S. L.; "ds-Dihydrocatechols as Precursors to Highly Oxygenated Troponoids." J. Chem. Soc, Perkin Trans. 1 1993, 1913. Boyd, D. R.; Sharma N. D.; Barr, S. A. "Chemoenzymatic Synthesis of the 2,3and 3,4-ds'-Dihydrodiol Rnantiomers of Monosubstituted Benzenes." J. Am. Chem. Soc. 1994,116, 1147. Boyd, D. R.; Sharma, H. D.; Agarwal, R.; Kerley, N. A.; McMordie, A. S.; Smith, A.; Dalton, H.; Blacker, J.; Sheldrake, G. N. "A New Synthetic Route to Non-K and Bay Region Arene Oxide Metabolites from cw-Diols." J. Chem. Soc, Chem. Commun. 1994, 59, 2910. Carless, H. A.; Busia, K.; Oak, O. Z. "Microbial Oxidation of Benzene as a Route to Inositol Stereoisomers and (±)-Quebrachitol.,, Synlett 1993, 9, 672-4. Carless, H. A.; Busia, K.; Dove, Y; Malik, S. S. "Syntheses of Conduritol D Derivatives from Aromatic Compounds." J. Chem. Soc, Perkin Trans. 1 1993, 27, 2505. Hudlicky, T.; Tian, X; Konigsberger, K.; Rouden, J. "Oxa- and Azabicyclo[4.1.0]heptenes as New Synthons for C-Disaccharide and Alkaloid Synthesis. Reactivity Trends with Carbon Nucleophiles." J. Org. Chem. 1994, 59,4037. Hudlicky T.; McKibben, B. P. "New Cycloaddition Chemistry of l-Chloro-5,6dj-isopropylidenedioxycyclohexa-l,3-diene Derived from the Oxidation of Halogenobenzenes of Pseudomonas putida 39/D." J. Chem. Soc, Perkin Trans 1 1994,485.

308

TOMAS HUDLICKY and JOSEPHINE W. REED

Hudlicky, T.; Thorpe, A. J. "Glycoconjugate Coupling Strategy: Synthesis of a L-c/nro-Inositol-gtf/tf-Quercitol Conjugae and the Synthesis of (+)proto-Quercitol." Synlett 1994, in press. Hudlicky, T.; Fearnley, S. P.; Olivo, H. R; Parker, D. P.; Whited, G. M ; Downie, J. C ; Dudding, T. "Oxidation of 2-Methoxynaphthalene by Toluene, Naphthalene and Biphenyl Dioxygenases: Structure and Absolute Stereochemistry of Metabolites." J. Bioorg. Med. Chem. 1994, in press. Johnson, C. R.; Adams, J. P.; Bis, S. S.; De Jong, R. L.; Golebiowski, A.; Medich, J. R.; Penning, T. D.; Senanayake, C. H.; Chrisantha, H.; Steensma, D. H.; Van Zandt, M. C. "Applications of Enzymes in the Synthesis of Bioactive Polyols." Indian J. Chem. Sect. B 1993,32B, 140. Hudlicky, T; Fan, R.; Luna, H.; Olivo, H.; Price, J. "Enzymatic Hydroxylation of Arene and Symmetry Considerations in Efficient Synthetic Design of Oxygenated Natural Products." Indian J. Chem. Sect. B. 1993,32B, 154. Johnson, C. R.; Golebiowski, A.; Steensma, D. H.; Scialdone, M. A. "Enantioand Diastereoselective Transformations of Cycloheptatriene to Sugars and Related Products." J. Org. Chem. 1993, 58,7185. Ribbons, D. W.; Sutherland, A. G. "(+)-Muconolactone from Arene Biotransformation in Pseudomonas putida: Production, Absolute Configuration and Enantiomeric Purity." Tetrahedron 1994,50, 3587. Sutherland, J. K.; Whitehead, R. C ; Gareth, M. D. 'The Synthesis of 6-Substituted Shikimic Acids." J. Chem. Soc, Chem. Commun. 1993,464. Vandewalle, M ; Pingli, L. "Cyclohexane Polyols: Enantioselective Synthesis of (+)-Fortamine and of Pseudosugars." Tetrahedron 1994, 50, 7061. Vandewalle, M.; Pingli, L."Enantioselective Synthesis of Pseudosugars of the Alio-, Gulo-, Manno- and Talo- Series." Synlett 1994, 228.

REFERENCES AND NOTES 1. (a) Drueckhammer, D. G.; Hennen, W. J.; Pederson R. L.; Barbas, C. F, III; Gautheron, C. M.; Krach, T; Wong, C.-H. Synthesis 1991,499; (b) Klibanov, A. M. Ace. Chem. Res. 1990,23,114; (c) Pratt, A. J. Chem. Brit. 1989,25,282; (d) Turner, N. J. Nat. Prod. Rep. 1989,625; (e) Yamada, H.; Shimizu, S. Angew. Chem., Int. Ed. Engl. 1988,27,622; (f) Roberts, S. M. Chem. Ind. 1988, 384; (g) Toone, E. J.; Simon, E. S.; Bednarski, M. D.; Whitesides, G. M. Tetrahedron 1989,45, 5365; (h) Servi, S. Synthesis 1990,1; (i) Csuk, R.; Glanzer, B. I. Chem. Rev. 1991, 91, 49; (j) Microbial Reagents in Organic Synthesis; Servi, S., Ed.; NATO ASI Series C 381; Kluwer Academic: Dordrecht, The Netherlands, 1992. 2. Jones, J. B. In Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1985; Vol. 5, p. 309.

Microbial Oxidations of Aromatic Compounds

309

3. Sih, C. J.; Wu, S.-H. In Topics in Stereochemistry; Eliel, E. L.; Wilen, S. H., Eds.; John Wiley: New York, 1989; Vol. 19, p. 63. 4. For a discussion of the history of fermentations see: Nicolk, G. B. In Microbial Technology-, Peppier, H. J.; Perlman, D., Eds.; Academic Press: New York, 1979; Vol. 2, p. 155. 5. For a recent discussion of importance of chiral drugs see: Layman, P. L. Chem. Eng. News 1993, 71,14, 17. 6. Gibson, D. T.; Koch, J. R.; Kallio, R. E. Biochemistry 1968, 7, 2653. 7. Gibson, D. T.; Hensley, M ; Yoshioka, H.; Mabry, J. J. Biochemistry 1970, 9, 1626. 8. (a) Gibson, D. T; Zylstra, G. J.; Chauhan, S. In Pseudomonas: Biotransformations, Pathenogenesis, and Evolving Biochemistry, Silver, S.; Chakrabarty, A. M ; Iglewski, B.; Kaplan, S., Eds.; Am. Soc. for Microbiol., 1990; Chapter 13, p. 121; (b) Zylstra, G. J.; Gibson, D. T. In Genetic Engineering', Setlow, J. A., Ed.; Pergamon: New York, 1991; Vol. 13, p. 183; (c) Gibson, D. T. Crit. Rev. Microbiol. 1971,1, 199; (d) Gibson, D. T. Toxilogical and Environment. Chem. 1982, 5, 237. 9. Gibson, D. T.; Subramanian, V. In Microbial Degradation of Organic Compounds; Gibson. D. T.. Ed.; Microbiology Series, Vol. 13; Marcel Dekker: New York, 1984; Chapter 7. 10. For a discussion of bacterial metabolism of aromatic compounds see: (a) Bayly, R. C ; Barbour, M. G. In Microbial Degradation of Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; Chapter 8; (b) Trudgill, P. W. In Microbial Degradation of Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; Chapter 9; (c) Ensley, B. D., Jr. In Microbial Degradation of Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; Chapter 10; (d) Reineke, W. In Microbial Degradation of Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; Chapter 11; (e) Safe, S. H. In Microbial Degradation of Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; Chapter 12; (f) Ribbons, D. W.; Keyser, P.; Eaton, R. W.; Anderson, B. N.; Kunz, D. A.; Taylor, B. F. In Microbial Degradation of Organic Compounds; Gibson, D. T., Ed.; Marcel Dekker: New York, 1984; Chapter 13. 11. (a) Sato, T.; Fukuyama, T.; Suzuki, T.; Yoshikawa, H. J. Biochem. 1963, 53, 23; (b) Jerina, D. M.; Daly, J. W.; Witkop, B.; Zaltzman-Nirenberg, P.; Udenfriend, S. Arch. Biochem. Biophys. 1968,128,176. 12. Ley, S. V; Sternfeld, R; Taylor, S. M. Tetrahedron Lett. 1987, 28, 225. 13. Diol reviews: (a) Carless, H. A. J. Tetrahedron: Asymmetry 1992, 3, 795; (b) Brown, S. M.; Hudlicky, T. In Organic Synthesis: Theory and Applications; Hudlicky, T, Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p. 113; (b) Widdowson, D. A.; Ribbons, D. A.; Thomas, S. D. Janssen Chim. Acta 1990, 8, 3. 14. Ribbons, D. W.; Williams, J. O. Advances in Nat. Prod. Chem., in preparation. 15. Stormer, K. Zentralbl. Bakteriol. Parasitenk. lnfek. 1908,20, 282. 16. Sohngen, N. L. Centr. Bakteriol, Parasitenk. Abt. II1913, 37, 595. 17. Weiland, T; Griss, G.; Haccius, B. Arch. Microbiol. 1958, 28, 383. 18. Haccius, B.; Helfrich, O. Arch. Microbiol. 1958, 28, 394. 19. (a) Thakker, D. R.; Yagi, H.; Levin, W; Wood, A. W; Conney, A. H.; Jerina, D. M. In Bioactivation of Foreign Compounds; Anders, M. W, Ed.; Academic Press: New York, 1985; p. 177; (b) Chada, A.; Sayer, J. M.; Yeh, H. J. C ; Yagi, H.; Cheh, A. M.; Pannell, L. K.; Jerina, D. M. /. Am. Chem. Soc. 1989, 111, 5456. 20. Zylstra, G. J.; Gibson, D. T. J. Biol. Chem. 1989,264,14940. 21. Gibson, D. T. Science 1968,161,1093. 22. For laboratory-scale production of diols, see: Hudlicky, T; Boros, C. H.; Boros, E. E. Synthesis 1992,174. 23. (a) Gibson, D. T; Roberts, R. L.; Wells, M. G; Kobal, V. M. Biochem. Biophys. Res. Commun. 1973,50,211; (b) Kiyohara, H.; Sugiyama, M.; Mondello, F. J.; Gibson, D. T; Yano, K. Biochem. Biophys. Res. Commun. 1983, HI, 939.

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TOMAS HUDLICKY and JOSEPHINE W. REED

24. (a) Ensley, B. D.; Gibson, D. T. J. Bacter. 1983, 155, 505; (b) Ensley, B. D.; Ratzkin, B. J.; Osslund, T. D.; Simon, M. J.; Wackett, L. P.; Gibson, D. T. Science 1983, 222, 167; (c) Ensley, B. D.; Gibson, D. T.; Laborde, A. L. J. Bacter 1982,149,948. 25. (a) McMordie, R. A. S. Ph.D. Thesis, The Queen's University of Belfast, 1989; (b) Stabile, M. M.S. Thesis, Virginia Polytechnic Institute and State University, 1993. 26. (a) Hudlicky, T.; Boros, E. E.; Boros, C. H. Synlett 1992, 391; Tetrahedron: Asymmetry 1993, 4,1365; (b) Konigsburger, K.; Hudlicky, T. Unpublished results. 27. Hudlicky, T.; Stabile, M ; Whited, G. M. Unpublished observations. 28. Deluca, M ; Hudlicky, T. Tetrahedron Lett. 1990, 31,13. 29. Boyd, D. R.; Sharma, N. D.; Boyle, R.; Malone, J. R; Chima, J.; Dalton, H. Tetrahedron: Asymmetry 1993,4, 1307. 30. Boyd, D. P.; Sharma, N. D.; Dority, M. R. J.; Hand, M. V.; McMordie, R. A. S.; Malone, J. R.; Porter, H. P.; Dalton, H.; Chima, J.; Sheldrake, G. N. J. Chem. Soc, Perkin Trans. 11993,1065. 31. Engesser, K. H.; Auling, G.; Busse, J.; Knackmuss, H. J. Arch. Microbiol. 1990,153, 193. 32. Boyd, D. R.; Sharma, N. D.; Stevenson, P. J.; Chima, J.; Gray, D. J.; Dalton, H. Tetrahedron Lett. 1991,32, 3887. 33. (a) Boyd, D. R.; Sharma, N. D.; Boyle, R.; McMurray, T. T; Evans, T. A.; Malone, J. R; Dalton, H.; Chima, J.; Sheldrake, G. N. J. Chem. Soc, Chem. Commun. 1993, 49; (b) Boyd, D. R.; Sharma, N. D.; Boyle, R.; McMordie, R. A. S.; Chima, J.; Dalton, H. Tetrahedron Lett. 1992, 33, 1241. 34. Geary, P. J.; Pryce, R. J.; Roberts, S. M.; Ryback, G.; Winders, J. A. J. Chem. Soc, Chem. Commun. 1990, 204. 35. Knackmuss, H. J.; Beckmann, W.; Otting, W. Angew. Chem. Int. Ed. Eng. 1976,15, 549. 36. Cerniglia, C. E.; Morgan, J. C ; Gibson, D. T. Biochem. J. 1979,180, 175. 37. Eaton, R. W.; Ribbons, D. W. J. Bacteriol. 1982,151, 48. 38. Reineke, W.; Otting, W.; Knackmuss, H. J. Tetrahedron 1978, 34,1707. 39. (a) Kobal, V. M.; Gibson, D. T; Davis, R. E.; Garza, A. J. Am. Chem. Soc. 1973, 95, 4420; (b) Ziffer, H.; Jerina, D. M.; Gibson, D. T; Kobal. V. M. J. Am. Chem. Soc 1973, 95, 4048; (c) Jerina, D. M.; Daly, J. W.; Jeffrey, A. M.; Gibson, D. T. Arch. Biochem. Biophys. 1971,142,394. 40. Boyd, D. R.; Dorrity, M. R. J.; Hand, M. V.; Malone, J. R; Sharma, N. D.; Dalton, H.; Gray, D. J.; Sheldrake, G. N. J. Am. Chem. Soc. 1991,113, 666. 41. Hudlicky, T; Luna, H.; Barbieri, G.; Kwart, L. D. /. Am. Chem. Soc. 1988,110, 4735. 42. Commercial availability of cw-diols derived from aromatic substrates; (a) Genencor International, Inc.; (b) ICI Bioproducts; (c) Janssen Chimica; (d) Aldrich Chemical Company. 43. (a) Ribbons, D. W.; Cass, A. E. G.; Rossiter, J. T.; Taylor, S. J. C ; Woodland, M. P. /. Fluorine Chem. 1987, 37, 299; (b) Rossiter, J. T; Williams, S. R.: Cass, A. E. G.; Ribbons, D. W. Tetrahedron Lett. 1987, 28, 5173; (c) Engesser, K. H.; Rubio, M. A.; Ribbons, D. W Arch. Microbiol. 1988,149,198. 44. Carless, H. A. J.; Oak, O. Z. / Chem Soc, Chem. Commun. 1991, 61. 45. (a) Hudlicky, T.; Rulin, R; Tsunoda, T.; Luna, H.; Andersen, C ; Price, J. Isr. J. Chem. 1991,31, 229; (b) Hudlicky, T; Rulin, P.; Tsunoda, T.; Luna, H.; Price, J. D. J. Am. Chem. Soc. 1990,112, 9439. 46. Hudlicky, T; Luna, H.; Olivo, H. P.: Andersen, C ; Nugent, T; Price, J. D. J. Chem. Soc, Perkin Trans. 11991, 2907. 47. Ley, S. V.; Sternfeld, P. Tetrahedron Lett. 1989, 30, 3463. 48. Johnson, C. R.; Pie, P. A.; Adams, J. P. J. Chem. Soc, Chem. Commun. 1991,1006. 49. (a) Carless, H. A. J.; Busia, K. Carbohydr. Res. 1992,234,207; (b) Carless, H. A. J. Tetrahedron Lett. 1992, 6379. 50. Hudlicky, T; Rouden. J.; Luna, H. J. Org. Chem. 1993, 58, 985. The structure of azide i was originally reported as ii, incorrectly assigned in reference 46 above. See Corrigendum, J. Chem. Soc. Perkin Trans. 11993, 535.

Microbial Oxidations of Aromatic Compounds

311

HO'

51. (a) Schurrle, K.; Beier, B.; Piepersberg, W. J. Chem. Soc Perkin Trans 1 1991, 2407; (b) Dumortier, L.; Liu, P.; Dobbelaere, S.; van der Eycken, J.; Vanderwalle, M. Synlett 1992, 241; (c) Johnson, C. R.; Pie, P. A.; Su, L.; Heeg, M. S.; Adam, J. P. Synlett 1992, 388; (d) Braun, H., Burger, W.; Kresze, G.; Schmidtchen, F. P.; Vaerman, J. L.; Viehe, H. G. Tetrahedron: Asymmetry 1990, 1,403; 52. For a review of nitrosyl cycloadditions, see: Boger, D. L.; Weineb, S. N. In Hetero Diels-Alder Methodology in Organic Synthesis; Academic Press: New York, 1987. 53. For applications of the nitrosyl cycloaddition in the synthesis of natural products, see: (a) Keck, G. E.; Nickell, D. G. J. Am. Chem. Soc. 1980,102,3632; (b) Keck, G. E. Tetrahedron Lett. 1978, 4767; (c) Burkholder, T. P.; Fuchs, P. L. J. Am. Chem. Soc. 1988, 110, 2431; (d) Iida, H.; Watanabe, Y; Kibayashi,C. J. Am. Chem. Soc. 1985,107,5535; (e) Kresze,G.;Dittel, W.Liebigs Ann. Chem. 1981, 610; (f) Braun, H.; Burger, W.; Kresze, G.; Schmidtchen, F. P.; Vaerman, J. L.; Viehe, H. G. Tetrahedron: Asymmetry 1990,1, 403; (g) Shishido, Y; Kybayashi, C. J. Org. Chem. 1992, 57, 2876'. 54. Hudlicky, T.; Olivo, H. F. Tetrahedron Lett. 1991, 32, 6077. 55. Hudlicky, T.; Olivo, H. F. J. Am. Chem. Soc. 1992,114, 9694. 56. Cotterill, I. C.; Roberts, S. M.; Williams, J. O. J. Chem. Soc, Chem. Commun. 1988,1628. 57. Hudlicky, T.; Luna, H.; Price, J. D.; Rulin, F. Tetrahedron Lett. 1989,30,4053. 58. (a) Hudlicky, T.; Price, J. D.; Rulin, F. J. Org. Chem. 1990,55,4683; (b) Hudlicky, T.; Seoane, G.; Price, J. D.; Gadamasetti. K. (in part) Synlett 1990, 443. 59. (a) Hudlicky, T.; Mandel, M ; Rouden, J.; Lee, R. S.; Bachmann, B.; Dudding, T.; Yost, K.; Merola, J. S. J. Chem. Soc, Perkin Trans. 11994,1553; (b) Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994, 116, 5099; (c) Hudlicky, T.; Olivo, H. R; McKibben, B. J. Am. Chem. Soc. 1994,116, 5108. 60. (a) Banwell, M. G.; Collis, M. P. J. Chem Soc. Chem. Commun. 1991, 1343; (b) Banwell, M. G.; Corbett, M ; Mackay, M. F ; Richards, S. L. /. Chem Soc, Perkin Trans. 11992,1329. 61. (a) Downing, W.; Latouche, R.; Pittol, C. A.; Pryce, R. J.; Roberts, S. M ; Ryback, G.; Williams, J. O. /. Chem. Soc, Perkin Trans. 1 1990, 2613; (b) Mahon, M. F ; Molloy, K.; Pittol, C. A.; Pryce, R. J.; Roberts, S. M ; Ryback, G.; Sik, V; William, J. O.; Winders, J. A. J. Chem. Soc, Perkin Trans. 1 1991,1255. 62. (a) Hudlicky, T.; Boros, E. E.; Olivo, H. F ; Merola, J. S. J. Org. Chem. 1992,57,1026; (b) Pittol, C.A.; Pryce, R. J.; Ryback, G.; Sik, V; Williams, J. O. J. Chem. Soc, Perkin Trans. 1 1989, 1160; (c) Ley, S. V; Redgrave, A. J.; Taylor, S. C.; Ahmed, S.; Ribbons, D. W. Synlett 1991,741. 63. Hudlicky, T.; Boros, C. H. Tetrahedron Lett. 1993,34, 2557. 64. Carless, H. A. J.; Oak, O. Z. Tetrahedron Lett. 1989,30,1719. 65. (a) Boyd, D. R.; Hand, M. V; Sharma, N. D.; Chima, J.; Dalton, H.; Sheldrake, G. N. /. Chem. Soc, Chem. Commun. 1991, 1630; (b) Ley, S. V; Redgrave, A. J.; Taylor, S. C.; Ahmed, S.; Ribbons, D. W. Synlett 1991,741; (c) Hudlicky, T; Boros, E. E. Tetrahedron: Asymmetry 1992, 3, 217. 66. Stephenson, G. R.; Howard, P. U.; Taylor, S. C. J. Chem. Soc, Chem. Commun. 1991,127. 67. Conticello, V. P.; Gin, D. L.; Grubbs, R. H. J. Am. Chem. Soc 1992,114, 9708. 68. Johnson, C. R.; Adams, J. P.; Collins, M. A. J. Chem. Soc, Perkin Trans. 1 1993, 1.

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69. Hudlicky, T.; Rulin, R; Lovelace, T. C ; Reed, J. W. In Studies in Natural Product Chemistry; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1989; Vol. 3, p. 1. 70. (a) Wenkert, E.; Hudlicky, T. J. Org. Chem. 1988, 53, 1953; (b) Wenkert, E. Ace. Chem. Res. 1968, 7, 78; (c) Wenkert, E. Ace. Chem. Res. 1980, 73, 27. 71. Stevens, R. V. In The Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley: New York, 1977; Vol. 3, p. 439. 72. (a) Review: Oppolzer, W; Snieckus, V; Angew. Chem., Int. Ed. Engl. 1978, 77, 476; (b) Khusimone synthesis: Oppolzer, W; Pitteloud, R. J. Am. Chem. Soc. 1982,104,6478. 73. Hudlicky, T.; Fleming, A.; Radesca, L. J. Am. Chem. Soc. 1989, 777,6691. 74. Hudlicky, T.; Natchus, M. G. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p. 1. 75. Bertz, S. H. /. Chem. Soc, Chem. Commun. 1984, 218. 76. (a) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p. 27; (b) Bertz, S. H.; Sommer, T. J. In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; JAI Press: Greenwich, CT, 1993; Vol. 2, p. 67. 77. For definitions of topology and topography in synthetic contexts see: Rigby, L.; Rami, B. C ; Kwart, L. D.; Short, R. P.; Hudlicky, T.; Frazier, J. O. Synthesis 1986,716. 78. Rouden, J.; Hudlicky, T. /. Chem. Soc, Perkin Trans. 11993, 1095. 79. Hudlicky, T; Natchus, M. G. /. Org. Chem. 1992,57,4740. 80. Hudlicky, T.; Natchus, M. G„ Nugent, T. Synth. Commun. 1992,22,151. 81. (a) Borcherding, D. R.; Scholtz. S. A.; Borchardt, R. T. J. Org. Chem. 1987,52,5457; (b) Wolfe, M. S.; Anderson. B. L.; Borcherding, D. R.; Borchardt, R. T. J. Org. Chem. 1990,55,4712. 82. Johnson, C. R.; Penning, T. D. J. Am. Chem. Soc. 1986,108, 5655; ibid. 1988,110, 4726. 83. Hudlicky, T; Seoane, G.; Pettus, T. J. Org. Chem. 1989,54,4239. 84. Hudlicky, T.; Seoane, G.; Seoane, A.; Frazier, J. O.; Kwart, L. D.; Tiedje, M. H.; Beal, C. J. Am. Chem. Soc. 1986,108, 3755. 85. Chida, N.; Ohtsuka, M ; Ogawa, S. Tetrahedron Lett. 1991, 32,4525. 86. (a) Kayakiri, H.; Kasahara, C ; Oku, T.; Hashimoto, M. Tetrahedron Lett. 1990, 37, 225; (b) Kayakiri, H.; Kasahara, C; Nakamura, K.; Oku, T; Hashimoto, M. Chem. Pharm. Bull. 1991, 39, 1392. 87. Hanessian, S. Total Synthesis of Natural Products: The 'Chiron'Approach; Pergamon: Oxford, 1983. 88. Hudlicky, T.; Price, J. D. Synlett 1990,159. 89. Mandel, M.; Hudlicky, T.; Kwart, L. D.; Whited, G. M. J. Org. Chem. 1993,58, 2331. 90. Mandel, M.; Hudlicky, T. /. Chem Soc, Perkin Trans. 11993, 741. 91. Mandel, M.; Hudlicky, T; Kwart, L. D.; Whited, G. M. Coll. Czech. Chem. Commun. 1993,58, 2517. 92. Hudlicky, T; Tian, X., unpublished observations. 93. Mandel, M.; Hudlicky, T., unpublished observations. 94. Hudlicky, T.; Price, J. D.; Luna, H.; Andersen, C. Synlett 1990, 309. 95. (a) Hudlicky, T.; Price, J. D.; Olivo, H. F. Synlett 1991, 645; (b) Corrigendum, Synlett 1992, 1008. The sign of optical rotation and the name of the conduritol E is incorrecdy stated as (+). The correct name is (-)-conduritol E, and the rotation is -330° as reported in a later full paper; see: /. Chem. Soc, Perkin Trans. 11991, 2907.

INDEX ACC (1-aminocyclopropane-lcarboxylic acids), asymmetric synthesis, 66-72 Acetaldehyde, 191 1 -Acyl-3-hydroxy-/J-lactams, Taxol/ Taxotere synthesis and, 133135 Acyl silanes, DIP-Chloride and, 193194 S-Adenosylmethionine (SAM), 115 Aldehyde/Lewis acid, complexation states, 9-10, 19 Aldol reactions asymmetric, 136-138 condensation, 78-79 Alkaloids, 292-295 Alkanones, 166 cw-Alkenes, 159 f/ww-Alkenes, 157, 159 Alkenones, 166 Alkoxyaldehyde-ene reaction, 15-16 a-Alkyl-a-amino acids, asymmetric synthesis, 115-129 Alkylations asymmetric double, of j3-lactam esters, 123-124

asymmetric single, of /J-lactam esters, 123-124 typel, 116-118,128-129 type 2, 118-119 Alkyl halides, 124-125 Alkylmonoisopinocampheylhloroboranes, 199 Alkynones, 166-167 Allylboration, asymmetric, 173-180 applications, 180-183 chiral auxiliaries, 177-178 j3-Allyldiisopinocampheylborane, 174-175 Alpine-Borane, 185-186, 194 applications, 188-189, 196 poor ketone reduction and, 186-188 Alpine-hydride, 185 pri- Amines, 165 sec- Amines, 165 Amino acid j8-carboxy aspartic acid, 56-57 Amino acids a. See a-Amino acids, asymmetric synthesis non-protein, 115-135. See ako specific non-protein amino acids

313

314

a-Amino acids, asymmetric synthesis, 45-47, 106 cyclopropanations and, 70, 72 electrophilic glycinates and, 51-66 enantiomerically pure /Macatam intermediates, 96-101 glycine enolates and, 72-84 methods, 46-47 from N-CBz lactones, 53 N-f-BOC protected, 51, 53, 68, 75 optically active glycinates and, 4851 Amino alcohols, 48 Amino conduritols, 278, 292 Aminocyclitol, 278 1 - Aminocyclopropane-1 -carboxylic acids (ACQ, asymmetric synthesis, 66-72 Amino sugar synthesis, 289 Antifeedants, synthesis of, 218, 223226 Anti-Markovnikov addition, 150 Aplysiatoxins, 197 Aralkyl ketone, reduction by DIPChloride, 189-191 Arenes bacterial oxidation, 274 eukaryotic biooxidation, 274, 275 Artemesia alcohol, 176 Asymmetric double alkylation, of /?lactam esters, 123-124 Asymmetric single alkylation of /Mactam esters, 123-124 reaction temperature and, 125 Asymmetric synthesis of a-amino acids. See a-Amino acids, asymmetric synthesis via chiral organoboranes, 147 general, 160 j8-Lactam Synthon Method, 95 Avenaciolide, 12-13

INDEX

Aza sugars synthesis, 289 topologial control of synthesis, 294 Azidoketene cycloadditions, 97, 109115 Baccatin III, 133 Bacterial metabolism, 274 Benzene, 297 JV-Benzylcinnamaldimine, 130 Bicyclic diazolidinones, 141 Binaphthol, 189 BINOL ligand, 24-27 BINOL-titanium complex, 25-27, 3839 Birch reduction, modified, 106 Bishomolllylic ether system, 19-20 Bis-/3-lactams, 99 Borinate, 162 Borinate esters applications, 163-168 asymmetric synthesis, 162-163 Boron, 149 Boronate esters, applications, 163-168 Boron enolate reactions, 79 Boronic esters, asymmetric synthesis, 161-162 j8-Bourbenene, 160 Brassinosteroids, 7, 9, 15-16 exo-Brevicomin enantiomers, 239, 242 2-Butanone, 192 r-Butylpotassium, 179 Capsorubin, 153, 155 Carbo-cyclization, 33 Carbohydrates, 295-300. See also specific carbohydrates synthesis, 278-279 synthesis design, 277-288 topological relationship with cyclitols, 286-287

Index

Carbonyl-ene reactions asymmetric catalysis, 21-23 asymmetric desymmetrization, 2732 catalytic, 28-29 kinetic optical resolution and double asymmetric induction, 30-32 internal asymmetric induction, 713 olefinic stereoselection, 6-7 positive nonlinear effect, 23-27 regioselection, 4-6 relative asymmetric induction, 1319 remote asymmetric induction, 1921 transition-state model, 2-3, 3-4 Carene, 160 Catechols, 274 a-Chiral acetylenes, 168 a-Chiral acids, 165 a-Chiral aldehydes, 164-165 a-Chiral amines, 165 Chiral /J-amino alcohols, 16 Chiral auxiliary, 149 Chiral building blocks, 96 Chiral enolate-imine cyclocondensations, 132 Chiral ester enolate-imine cyclocondensation, asymmetric synthesis and, 126-129 /J-Chiral esters, 168-169 Chiral imines, 104-105 Chiral ketenes, asymmetric cycloaddition, 104-106 a-Chiral ketones, 165-166 /3-Chiral ketones, 168-169 Chiral /{-lactams, asymmetric aldol reaction and, 136-138 /3-Chiral nitriles, 168-169 a-Chiral olefins, 167-168

315

/J-Chlorodiiso-2-ethylapopinocampheylborane (Eap2BCl), 202-203 /J-Chlorodiisopinocampheylborane (DIP-chloride). See DIPChloride Claisen sigmatropic shifts, cyclic, 32 Clavalanine, 54, 55 Conduramines, 280, 294, 305 Conduritols, 277, 280, 297, 304, 305 Corey-lactone intermediate, 153 Crotylboration, asymmetric, 173-180 applications, 180-183 chiral auxiliaries, 177-178 J?-(JE)-Crotyldiisopinocampheylborane, 178-179 (Z)-Crotyldiisopinocampheylborane, 178-179 Crotylpotassium, 179 Cryptone, 160 Curtin-Hammett principle, 16, 18 Cyclitols, 277-278, 295-300 redox-hydration relationship, 297 topological relationship with carbohydrates, 287 Cycloadditions, 278, 279 of azidoketene to iminoazetidine, 109-115 of azidoketene to imino-/?lactams, 109-115 of chiral ketenes, 104-106, 122-123 of chlorocyclohexadienediol with tropone, 302 ketene-imine, mechanism of, 107115 Cyclohexadiene cw-diols history of, 274-276 literature survey, 276-280 metabolites, 276 Cyclohexadiene diols, 282-283 design principles, 286-289 Cyclopropanations, 68, 72 Cyclopropane amino acids, 70

316

DAP (diaminoopimelic acid), 79, 81 DCC (dicyclohexylcarbodimide), 98 a,/3-Dehydrolactones, 66 Desymmetrization asymmetric, in carbonyl-ene reactions, 27-32 catalytic, in carbonyl-ene reactions, 28-29 of meso compounds, 282 a,/J-Diamino acids, asymmetric synthesis, 129-131 N-2,6-Diamino-6-hydroxymethylpimelic acid, 81 N-(2,6-Diamino-6-hydroxymethylpimelyl)-L-alanine, 81 Diaminoopimelic acid (DAP), 79, 81 Diastereofacial selection, 15, 19 in ene cyclizations, 33-35 Diastereoselection extraannular, 36 intraannular, 36 olefinic, 37 Diborane, 149 Dichloromethyllitlhium, 169 Dicyclohexylcarbodimide (DCC), 98 Diethanolamine, 191 Dihydroactinidiolide enantiomers, 248, 250-252 Dihydroconduritol C, 304 Diisopinocamphelborane (Ipc2BH), 152-153 applications, 153-155 asymmetric reduction, 184 Diisopinocampheylhaloboranes, 198 meyo-Diols, lipase resolution, 280 2,5-Dimethylborolane, 160 3,3-Dimethyl-2-butanone, 192 3,3-Dimethymethylallyldiisopinocampheylborane, 176 DIP-Chloride acyl silanes and, 193-194 applications, 194-197

INDEX

aralkyl ketone reduction, 189-191 a-hindered ketones and, 192-193 mechanism of reduction, 191-192 modified reagents, 197-200 olefinic ketones and, 194 perfluoroalkyl ketones and, 193 Dipeptide synthons, asymmetric synthesis, 104-106 1,3-Dipolar cycloadditions, asymmetric, 84-89 Disparlure enantiomers, 248-249, 253-255 Eap2BCl (/3-chlorodiiso-2ethylapopinocampheylborane), 202-203 Eapine-Borane, 200-201 Eapine-Hydride, 201-202 Enantiodivergent synthesis of pinitols, 285 symmetry-based design of, 281-286 of trihydroxyheliotridanes, 293 Enantiomeric cyclohexanes, 284 Enantiomeric excesses, 204-205 Enantioselective synthesis, 267 methods, 214 microbial oxidations in, 272-273 of pheromones. See Pheromones purpose in insect chemistry, 212214 Ene cyclizations, 32-33 asymmetric catalysis, 38-39 asymmetric desymmetrization, 40 diastereofacial selection, 33-35 extraannular diastereoselection, 36 intraannular diastereoselection, 36 olefinic diastereoselection, 37 Ene reactions, 2 of carbonyl enophiles. See Carbonyl-ene reactions Enkephalin, analog, 100 Enolate alkylations, of oxazinones, 75-76, 84

Index

Enolate dialkylations, of oxazinones, 77 Enolates, kinetic vs. thermodynamic, 119-122 Enolboration, asymmetric, 183 meso-Epoxides, asymmetric cleavage, 203 Erythrose acetonide, 304 Extraannular diastereoselection, in ene cyclizations, 36 Fluoroconduritol, 299 Fluoxetine (Prozac), 194 Geraniol, Sharpless epoxidation, nonlinear effect, 23-24 Germacrene-D, 160 German cockroach pheromone, 249, 257-261 Glycinates electrophilic, 51-66 optically active, preparation of, 48-51 Glycine enolates, 72-84 Glyoxylate-ene reaction, diastereofacial selective, 29, 30 Heterocyclitols, 287 Heterosugars, 287 Hexose, 287 a-Hindered ketones, DIP-Chloride and, 192-193 (+)-Hirsutic acid, 155 HMPA, 72, 76 Homoallylic alcohols, 173 Homologation asymmetric, 169-173 three-carbon, 172 Hydroboration, asymmetric, 149150,152-160, 203-204 agents, 160 diisopinocamphelborane and, 152156

317

mechanism, 156 of monoisopinocampheylborane, 156-159 of olefins, 156 of 2-substituted-l-alkenes, alternatives, 169-172 Hydrogenolysis, 97, 100 a-Hydroxy acids, asymmetric synthesis, enantiomerically pure /J-lacatam intermediates, 96101 (3/?,45)3-Hydroxy-4-phenylazetidien-2-one, 133-134 Iminoazetidine, cycloaddition of azidoketene, asymmetric, 109115 Imino-j3-lactams, cycloaddition of azidoketene, asymmetric, 107,109-115 3-Imino-j3-lactams, type 1 alkylation, 128-129 Inositols, 278, 300, 301, 306 Intraannular diastereoselection, in ene cyclizations, 36 Ionophore antibiotics, 173-174 IPC2BH. See Diisopinocamphelborane (Ipc2BH) IpcBH2. See Monoisopinocampheylborane (IpcBHk) Ipsdienol, 179 Ipsdienol enantiomers, 243, 247 Ipsenol, 179 Ipsenol enantiomers, 243, 246 Isoperiplanone-A, 238-239 jS-Isopinocampheyl-9borabicyclo[3.3. Unonane. See Alpine-Borane Isopinocampheyldihaloboranes, 198 B-2'-Isoprenyldiisopinocampheylborane, 179-180

318

Japonilure, 249, 256 Joganin, 153, 154 Juvenile hormones, 214-218 JH I enantiomers, 218, 221-222 JH I synthesis, 214-215 JH III enantiomers, 215-220 Kifunesine, 294, 306 /J-Lactam esters, asymmetric alkylation, 121 /3-Lactams asymmetric synthesis, 126-128 first generation, 97-98 ketene-immine cycloadditions, asymmetric, 107-115 as peptide synthesis intermediates, 96-106 second generation, 104 Bis-j8-Lactams, 115 stereoselective synthesis, 107-109 jS-Lactam Synthon Method, 96 second generation, 142 Lardolure enantiomers, 229, 234-237 Latent syimmetry, 283 Least motion principle, 114 Lewis acid-promoted reactions, 4 Limonene, 160 Lineatin enantiomers, 227-228, 230233 Lipase resolution, of meso-diols, 280 Lithium aluminum hydride, 189 reduction, 129 Lithium chiral ester enolate-imine cyclocondensation, 133 Lithium enolate, 122 Lone pair-lone pair interactions, 113 Longifolene, 160 /J-LSM, second generation, 115 Lycoricidine, 293, 294, 306 Macrolide antibiotics, 173-174 Mannojirimycin lacatam, 305

INDEX

Mannose, 296 Matteson homologation procedure, 164, 170, 172 2-Methyl-l-alkenes, 159 /J-Methylallyldiisopinocampheylborane, 175-176 3-Methyl-2-butanone, 192 (S)-a-Methyl-dopa, 116 3-Methyl-/J-lactam, 130 (iS)-a-Methylphenylalanine, 116 (5)-a-Methyl-phenylalanyl-(/?)-aallylalanine, 126 O-Methyl pisiferic acid, synthesis of, 225-227 (Z)-3-Methyoxyallyldiisopinocampheylborane, 176-177 Mevinic acid, 189 Microbial oxidations, of aromatic compounds, 271-312. See also Cyclohexadiene cisdiols Mintsulfide, 160 Model-MM2-Rotochem program, 109,110,121 Monoisopinocampheylborane, asymmetric hydroboration, 156-159 Monoisopinocampheylborane (IpcBH2) applications, 159-160 asymmetric reduction, 184 Morphine, 295 Nisoxetine, 194 Norstatine, asymmetric synthesis, 131-133 Olean enantiomers, 261-265 Olefination reactions, stereoselectivity, 70 Olefmic diastereoselection, in ene cyclizations, 37

Index

Olefinic ketones, DIP-Chloride and, 194 (£)-01efins, 167 (Z)-01efins, 167 cw-Olefins, 157 Olefins, asymmetric hydroboration, 159 Oligopeptides, asymmetric synthesis, enantiomerically pure /?lacatam intermediates, 96101 Oligopeptide synthons, 99 Optically active compounds, 149 Organoboranes, 149-151, 172-173 asymmetric hydroboration and, 152-160 chiral, 149 substitution with retention, 151 Oxazinones enolate alkylations of, 75-76, 84 enolate dialkylations of, 77 3-Oxazolidinyl-)3-lactams, 138-141 PAF-antagonists, 197 PAM (peptidyl a-amidating monooxygenase), 54 Pentose, 287, 296 Peptides building blocks of, 98 C3-labeled optically pure, 104 regioselective labeling, 101-104 stereoselective labeling, 101-104 synthesis, entiomerically pure /}lactam intermediates of, 96106 Peptidyl a-amidating monooxygenase (PAM), 54 Perfluoroalkyl ketones, 193 Perhydroazulene terpene synthons, 291 Periplanone-A, 229, 238-239 enantiomers, 239-241 Periplanone-B, 160

319 (-)-Pestalotin, 189 PGE2a, 290-291, 303 Phenylalanylglycinate equivalent, asymmetric alkylations, 122126 (i?)-Phenylalanyl-(S)-amethylphenylalanine, 118 Pheromones, 212-214. See also specific pheromones synthesis to clarify stereochemistry-bioactivity relationships, 239-266 synthesis to solve structural problems, 227-239 Pinanediol, 169 a-Pinene, 149, 203-204 Pinitols, 306 synthesis, 297 Polygodial enantiomers, synthesis of, 218, 223-224 Poly-/Mactams, 99 Polymers, 279 Prelog-Djerassi lactone, 189 Prochiral ketones, reduction, 203 Proenantiotopic differentiation, 282 Prostaglandins, 290-291, 303 Prostaglandin synthesis, 153 Prostanoid synthon, 290 Prozac (fluoxetine), 194 Pseudomonic acid, 189 Pyrrolizidine alkaloid, 292 Reaction site differentiation, 283 Reduction, asymmetric, 183-184 of diisopinocamphelborane (Ipc2BH), 184 of monoisopinocampheylborane (IpcBH2), 184 Reflexivity, 284 Ribonolactone acetonide, 304 SAR (structure-activity relationship), 133

INDEX

320

Sequential asymmetric triple alkylation, 125-126 Shikimic acid esters, 280 3-Silyloxy-j8-lactams, 131 Specionin, 290, 304 Spiro /J-lactams, 136 frww-Stilbene, asymmetric dihydroxylation, 48, 50 Structure-activity relationship (SAR), 133 Styrene, 301 4-Styryl-/J-lactam, 139 2-Substituted-l-alkenes, asymmetric hydroboration alternatives, 169-172 Sugars. See also Specific sugars redox-hydration relationship, 297 Sulcatol enantiomers, 239, 243-245 Syn selectivity, 11-12, 16 Taxol, 96 antitumor activity, 133 cytotoxicity, 133 synthesis, l-acyl-3-hydroxy-/Jlactams and, 133-135 Taxotfere, 96 synthesis, l-acyl-3-hydroxy-/3lactams and, 133-135 Terpenes, 149, 290-292

N, N, N, 'AP-Tetramethylethylenediamine (TMEDA), 157 Tetrose, 287, 296 Three-carbon homologation, 172 TIPSO (triisopropylsilyloxy), 132 TMEDA (A^Ar/AP-tetramethylethylenediamine), 157 Toluene dioxygenase, 275 Tomoxetine, 194 Topography, 286 Topology, 286-287 Transition-metal-mediated transformations, 280 Trifluoroborane-etherate, 152 Trihydroxyheliotridane, 305 Trihydroxyheliotridanes, enantiodivergent synthesis, 293 Triisopropylsilyloxy (TIPSO), 132 Trisubstituted-alkenes, 157, 159 Trogodermal enantiomers, 227, 228 Tsetse fly pheromone, 261, 266 Tylonolide, 155 Type 1 chiral a-lactam enolate, 116 Vinylsilanes, 5-6 Zeaxanthins, 153-154 Zeylena, 291, 304

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Edited by Dennis R Curran, Department of Chemistry, University of Pittsburgh REVIEWS: "It is the intention of this volume to begin a serial coverage of the broad areas of cycloaddition chemistry. Cycloaddition reactions are among the most powerful reactions available to the organic chemist. The ability to simultaneously form and break several bonds, with a wide variety of atomic substitution patterns, and often with a high degree of stereocontrol, has made cycloaddition reactions the subject of intense study. The productive interplay between theory and experiment has resulted in sophisticated models which often allow one to predict reactivity, regioselectivity, and stereoselectivity for given cycloaddition partners."

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