Syntheses of Natural Products and Biologically Active Compounds by Means of Enantioselective Deprotonation Strategy

Toshio Honda Faculty of PharmaceuticalSciences, Hoshi University,

Received April 30, 2002

Abstract : Enantioselective deprotonation reactions of prochiral 4, 4-disubstituted cyclohexanone, 3-substituted cyclobutanones and 3, 5-dioxygenated cyclohexanones with a chiral lithium amide bases in the presence of silylating agents, were carried out to give the corresponding silyl enol ethers. The silyl enol ether obtained from 4-methyl-4-tolylcyclohexanone was converted to (+)-a-cuparenone. On the other hand , the silyl enol ethers derived from 3-substituted cyclobutanones were utilized in the synthesis of naturally occurring (-)-methylenolactocine and several kinds of lignan lactones, and also in the synthesis of medicinally important compound, (R)-( - )-r olipr am . Moreover, the silyl enol ethers prepared from prochiral 3, 5-dioxygenated cyclohexanones were employed as the starting materials in the synthesis of biologically important compounds, such as HMG-CoA reductase inhibitor and antiobesity agent , tetrahydrolipstatin, with the opposite mode of asymmetric induction even by using the same chiral amide base. Finally, a synthetic procedure for enantiomerically enriched 5-hydroxycyclohex-2-enone was established by elimination of the alkox- ide group in the chiral silyl enol ether, which was further transformed into an inositol phosphatase inhibitor.

1. Introduction The development of the enantioselective deprotonation of meso or prochiral compounds having a a-plane using chiral lithium amide bases has opened an efficient and simple route for the synthesis of a wide variety of chiral organic compounds including natural products. In 1980, Whitesell reported an enantioselective ring-opening reaction of prochiral cyclohexene oxide by employing the chiral lithium amide to provide the corresponding allylic alcohol with 31% enan- tiomeric excess (ee).1 This reaction, thereafter, was further investigated by Asami, where the ee was finally increased to 92% by using lithium (S)-2-(pyrrolidinylmethyl)pyrrolidine as the chiral base as depicted in Figure 1.7

Figure 1. Enantioselective rearrangement of meso-epoxide.

On the other hand, application of an enantioselective deprotonation to prochiral carbonyl compounds was developed by Koga in 1986,3 and by Simpkins in 1990,4 indepen- dently, where the chiral enolates, generated from 4-substituted cyclohexanones and chiral lithium amide bases, were Figure 2. Enantioselective deprotonation of 4-substituted cyclo- trapped with silylating agents to give the corresponding silyl hexanones. enol ethers in relatively high ee. Obviously, the enantioselectivity depends on the conformational rigidity of the starting widely been applied to the synthesis of optically active com- materials, and the reaction mechanism for the selectivity was pounds, in recent years, where a variety of chiral lithium rationalized by assuming the transition state as shown in Fig- amides have also been developed. In this paper, we would like ure 2 by Koga.3 to introduce our own work on the synthesis of natural prod- Since enantioselective deprotonation has been proved to be ucts and biologically active compounds by application of an a highly promising and useful synthetic strategy for introduc- enantioselective deprotonation strategy. ing a chiral center to prochiral compounds,5 this reaction has

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were decarboxylated to furnish the known cyclopentanone 7 2. Application to 4,4-disubstituted cyclohexanone: {[a]D + 10.3 (CHC13), lit.,7 [a]D + 13.3 (CHC13)}. Since this Synthesis of (+)-a-cuparenone6 compound has already been transformed into Although an enantioselective deprotonation of 4-substitut- (+)-a-cuparenone,7 this synthesis constitutes its formal syn- ed cyclohexanones with chiral lithium amides was well estab- thesis. lished to date as mentioned above, an application of this methodology to 4, 4-disubsutituted cyclohexanone aimed at Scheme 1. Enantioselective synthesis of (+)-a-cuparenone the construction of a chiral quaternary carbon center seemed to be lacking prior to our study. Thus, we investigated a pos- sibility of chiral induction for 4-methy1-4-phenylcyclohex- anone with several kinds of chiral lithium amide bases, since a benzylic quaternary carbon center is often observed in a variety of natural products. The results obtained are summarized in Table 1.

Table 1. Enantioselective deprotonation to 4, 4-disubstituted cyclohexanone

3. Application to 3-substituted and ,3, 3-disubstituted cyclobutanones8 The asymmetric inductions for five- and six-membered prochiral cycloalkanones by applying the enantioselective deprotonation strategy have been well established and are widely utilized in the synthesis of optically active natural products. However, no systematic investigation on an asymmetric induction for four-membered cycloalkanones with chiral lithium amide bases seems to have been described. Therefore, we attempted an enantioselective deprotonation reaction of 3-substituted and 3, 3-disubstituted cyclobutanones, and the results obtained are summarized in Tables 2 and 3. Usually, the chiral enolates, derived from five- and six-membered cycloalkanones, are trapped in situ with trimethylsilyl chloride to give the corresponding trimethylsilyl enol ethers; however, triethylsilyl chloride has to be employed for the preparation of the silyl enol ether of cyclobutanone, Although the observed enantioselectivities were inferior to probably because of its instability. As can be seen in the those of 4-monosubstituted cyclohexanones, these results Tables 2 and 3, lithium (S,S)-a,d-dimethyldibenzylamide would provide alternative routes for the construction of a chi- (B) as the chiral base gave the highest enantioselectivity (92% ral benzylic quaternary carbon center in relatively short steps. ee) in the asymmetric induction for 3-phenylcyclobutanone. Using this strategy, the chiral synthesis of (+)-a-cuparenone On the other hand, lithium (R)-2-(4-methylpiperazin-l- was investigated as shown in Scheme 1. y1)-N-neopenty1-1-phenylethylamide (A) was the best chiral Enantioselective deprotonation of the cyclohexanone 1 amide in the asymmetric induction for 3, 3-disubstituted with lithium (S, S)-a, d-dimethyldibenzylamide in THE at cyclobutanones. Since it would be considered that the silyl -1 00 °C in the presence of trimethylsilyl chloride afforded enol ethers could be converted into the substituted y-butyro- the silyl enol ether 2 in 94% yield with 70% ee, which on lactones, often observed in nature and also are biologically oxidative bond cleavage reaction with molybdenyl acetylacet- significant, by oxidative bond cleavage, we planned to synthe- onate and tent-butyl hydroperoxide in dry benzene gave the size the y-lactonic natural products by application of this diacid 3. After esterification of the acid, the resulting diester strategy. 4 was subjected to the Dieckmann condensation to provide 3.1 Synthesis of (-)-methylenolactocine9 the cyclization products 5 and 6, which, without separation, (-)-Methylenolactocine,1° isolated from the culture filtrate

Vol.60 No.11 2002 ( 75 ) 1105 Table 2. Enantioselective deprotonation strategy to 3, 3-disubstitut- not unfortunately be observed in this aldol reaction; however, ed cyclobutanone acetylation of the mixture, followed by treatment of the acetates with DBU gave the a, P-unsaturated ketones 11 and 12, in 47% and 23% yields, respectively. Catalytic hydrogenation of the E-enone 11 afforded the cis- 13 and trans-isomers 14 in a ratio of ca. 2:1, whereas the reduction of the Z-enone 12 furnished 13 and 14 in a ratio of ca. 1:2. Although these isomers could not be separated at this stage, the cis-isomer 13 could easily be isomerized to the trans-isomer 14, in a ratio of 1:20, by treatment with sodium hydride in THF. The stereoselective introduction of a suitable alkyl group at the desired position was thus achieved. Baeyer-Vil- liger oxidation of the ketones 13 and 14 (1:20, v/v) proceeded regioselectively to provide the lactone 15 together with its diastereomer 16 in 86% and 4 % yields, respectively. Finally, oxidation of the phenyl group in 15 with ruthenium tetroxide under the Sharpless condition afforded the carboxylic acid 17 [a]p -50.5 (CHC13), lit.," [a]i) -54 (CHC13)}, which has already been converted into (-)-methylenolactocine by methylenation.11 Thus, we were able to establish a novel synthetic path to 3, 4-disubstituted y-lactone, starting from prochiral 3-substituted cyclobutanone by means of the enantioselective deprotonation strategy. (Scheme 2)

Scheme 2. Enantioselective synthesis of (-)-methylenolactocine

Table 3. Enantioselective deprotonation strategy to 3-monosubstituted cyclobutanone

of Penicilliurn sp., is a highly functionalized and isomeriza- tion-prone antitumor antibiotic having a 4-pentyl-y-butyrolactone structure as a basic skeleton. By application of the enantioselective deprotonation strategy for 3-phenylcyclobutanone 8 developed above, we achieved the chiral synthesis of (-)-methylenolactocine, where the stereoselective introduction of a pentyl group at the 2-position was recognized as the crucial step. Although difficulties were initially encoun- tered in the direct introduction of a pentyl group at the 2-position of the enol ether 9, aldol reaction with valeralde- hyde in the presence of TBAF gave the four possible diastere- omers as an inseparable mixture 10 in 75% yield. The expected stereoselectivity giving a trans isomer predominantly could

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3.2 Synthesis of lignan lactones, (-)-hinokinin, (-)- Scheme 3. Enantioselective synthesis of a, /3-dibenzyllignan lactones deoxypodorhizone,(-)-isohibalactone and (-)-savinin12 As described above, we have established a procedure for chiral synthesis of 3-substituted y-butyrolactones by utilizing the enantioselectivedeprotonation strategy,in which cyclobutanone having a phenyl group at the 3-position was employed as the starting material. As an extension of this work, we are interested in the chiral synthesis of lignan lactones, since these compounds are known to exhibit interest- ing antileukaemicactivity. Based on the consideration of our earlier work, an enantioselective deprotonation of the cyclobutanone 18 was carried out by using the chiral base, lithium (S,S)-a, d-dimethyldibenzylamide, at 100 °C, and the resulting enolate was trapped by triethylsilylchloride to provide the silyl enol ether 19 in 77% yield with 80% ee. The relatively poor asymmetric induction observed here, com- pared with the case of 3-phenylcyclobutanone, is obviously due to the introduction of a sterically less hindered alkyl group, a methyleneunit, at the 3-position, and similar results were also observed in the enantioselective deprotonation of 4-substituted cyclohexanones.13Since we had established a chiral synthetic procedure for the f3-alkyl- y-butyrolactone ring system with reasonable optical purity," this strategy was applied to the synthesis of naturally occurring a, P-dibenzyllignan lactones and a-benzylidene-/3-benzyllignan lactones as depicted in Schemes 3 and 4. The stereoselective alkyla- tion of the y-butyrolactone 20 with 3,4-methylenedioxyben- zyl bromide in the presence of LDA afforded (-)-hinokinin Scheme 4. Enantioselective synthesis of a-benzylidene-J3-benzyllig- 21, {[a]D-28 (CHC13),lit.,14 [a]D-35.1 (CHC13)}.(-)-Deoxy- nan lactones podorhizone 22, l[a]D-19.4 (CHC13), lit.,15 [a]r, 25.2 (CHC13)},was also synthesized by using 3,4,5-trimethoxy- benzyl bromide as an alkylating agent. Moreover, the reaction of the y-butyrolactone 20 with 3,4-methylenedioxyben- zaldehyde in the presence of LDA gave the alcohols 23 as a mixture of the threo- and erythro-isomers,in the ratio of ca. 1:1, which, after conversion into the corresponding mesylates 24 in the usual manner, were treated with DBU in acetoni- trile to furnish (-)-isohibalactone 25, {[(AD 110.4 (CHC13), lit.,16[oc]D+ 86 (CHC13)}as a major product together with (-)-savinin 26, {[a]D-67.3 (CHC13), lit.,17 [a]D-82 (CHC13)} in 63 and 17 % yields, respectively. Although (-)-isohibalactone is not a naturally occurring lignan lactone, its antipodal form, gadain, was isolated from Jatropha gossypifolia,16and this synthesis provides access to a chiral synthesis of gadain by using ent-20, a readily accessiblestart- ing material. Finally, the major product, (-)-isohibalactone, was isomerized to (-)-savinin by treatment with tributyltin hydride in the presence of AIBN in refluxing benzene. 3.3 Synthesis of phosphodiesteraseinhibitor, (R)-( )- rolipram18 Further application of this strategy to a biologically active compound, antidepressant rolipram, was successfully achieved as shown in Scheme 5. Rolipram having a y-lactam ring system, is known to be a selective,prototypical inhibitor of the calcium-independent, low Km cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) dimethyldibenzylamide at 100 t in the presence of tri- designated PDE IV,19and its pharmacological activity ethylsilyl chloride gave the silyl enol ether 28, which, on depends on the absolute configuration; the more effective ozonolysis, followed by reductive work-up provided the y enantiomer to be (R)-( )-form.2°Again, an enantioselective -1 actone 29. Although direct transformation of a lactone to a deprotonation of the cyclobutanone 27, readily accessible lactam ring by ammonolysis was not successful, the lactone from isovanilin in four steps, with lithium (R, - was converted to the azide 31 in three steps via the alcohol

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30. Finally, reduction of the azide 31 with magnesium turn- could also be prepared from a much cheaper starting materi- ing in methanol furnished (-)-rolipram with >95% ee, al, a mixture of cis, trans- and cis, cis-1, 3, 5-trihydroxycylo- gab 30.2 (MeOH), lit.,20MD-31.0 (Me0H)} . hexane, by using the same procedure as above. Enantioselec- tive deprotonation of the ketone 33 with lithium (S, S')-a, Scheme 5. Enantioselective synthesis of (R)-( )-rolipram d-dimethyldibenzylamide at 78 °C in the presence of trimethylsilyl chloride gave the silyl enol ether 34, which, on ozonolysis, followed by treatment with triphenylphosphine afforded the aldehyde 35. First, we attempted esterification of the acid prior to reduction of the formyl group and a partial epimerization of the hydroxy group at the 5-position was observed. Therefore, the aldehyde 35 was treated with sodium borohydride, and the alcohol 36 obtained was esterified with iodomethane in the presence of potassium carbonate to give the ester 37. The ee of the product 37, however, was found to be only 70.2%. When this enantioselective deprotonation was carried out at 100 t, the ee was increased to 73.8%. Although the stereocontrolled construction of a 1,3-syn dihydroxy system was thus achieved by employing an enantioselective deprotonation of a cis-3, 5-dihydroxycyclohex- anone derivative and the structure of the hydroxy groups could be assumed based on consideration of the previous results, the determination of its absolute configuration still remained obscure. As a means to determining the absolute 4. Application to 3, 5-disubstituted cyclohexanones configuration of the stereogenic centers on 37 unambiguous- 4.1 Synthesis of the lactone moiety of HMG-CoA ly, we attempted the conversion of 37 into a compactin ana- reductase inhibitor21 logue. Swern oxidation of 37, followed by Wittig reaction of The recent discovery of compactin,22 mevinolin23 and their the resulting aldehyde with benzyltriphenylphosphonium relatives provided impetus to the design of general strategies chloride and n-butyllithium furnished the olefin 38 as a mix- for the synthesis of those HMG-CoA reductase inhibitors ture of EIZ isomers, in a ratio of 1/4. Finally, deprotection of due to their significant biological activity. The important syn- the benzyl ethers under the catalytic hydrogenation reaction thetic feature of such compounds is the stereocontrolled con- conditions using palladium hydroxide as a catalyst, followed struction of the stereogenic centers bearing two hydroxy by lactonization of the resulting hydroxy-ester with p-tolue- groups for the (3R, 5R)-3, 5-dihydroxy-6-alkanoic acid 1, nesulfonic acid afforded the desired (+)-(4R, 6R)-4- 5-lactone system, which are essential for activity. hydroxy-6-(2-phenylethyl)tetrahydro-2H-pyran-2-one 39. Since the sign of rotation of our synthetic product 39, {[a]D+ 64.6 (CHC13) (after one recrystallization); [a]D+ 69.5 (CHC13) (after two recrystallization)} corresponds to that of the literature flit.,24 [a]D+ 71 (CHC13); lit.,25 [a]D+ 67.2 (CHC13)}, its absolute stereochemistry can now be assigned as 4R and 6R. 4.2 Synthesis of an antiobesity agent, (-)-tetrahydro- lipstatin26 (-)-Tetrahydrolipstatin,27 a member of the lipstatin family of P-lactonic microbial agents, acts as a potent inhibitor of Figure 3. HMG-CoA reductase inhibitors. pancreatic lipases, and is used clinically as an antiobesity drug (trade name Xenical® marketed by Roche) to block the Consequently, a number of enantioselective or enantiospe- digestion of dietary fat in overweight patients.28 cific syntheses of natural products, including the synthesis of Due to its attractive pharmacological properties and struc- the lactone moiety, have appeared to date. In order to synthe- tural novelty, this lipase inhibitor has been the subject of size a 3, 5-dihydroxy-6-alkanoic acid system, construction of extensive synthetic efforts to date. In analyzing the structure a 1, 3-syn-dihydroxy system with the correct stereochemistry of tetrahydrolipstatin for retrosynthetic disconnection, we in an optically active form would be required. We, therefore, focused our attention on the construction of a 1,3-syn-dihy- decided to apply the enantioselective deprotonation strategy droxy system with an antipodal form of the key intermediate to a prochiral 3, 5-dioxygenated cyclohexanone, since this for the synthesis of HMG-CoA reductase inhibitor, in an strategy seemed to be one of the most reliable methods to optically active form. Although we decided to adopt the introduce chirality to prochiral compounds. Thus, the com- same synthetic strategy and the same starting material as mercially available prochiral cis, cis-1,3, 5-trihydroxycylohex- above to synthesize the desired 1, 3-syn-dihydroxy system for ane 32 was converted into 3, 5-dibenzyloxycyclohexanone tetrahydrolipstatin, the ee of the product from the enantiose- 33,26 in which the two bulky dibenzyloxy groups should lective deprotonation of 3, 5-dibenzyloxycyclohexanone was locate in equatorial orientation, in four steps including silyla- only 74% even at 100 °C. We thought that the observed low tion, benzylation, desilylation, and oxidation. The ketone 33 enantioselectivity probably arose from the conformational

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Scheme 6. Synthesis of the lactone moiety of HMG-CoA reductase inhibitor

Figure 5. Enantioselective deprotonation of prochiral cyclohexanones.

with the chiral column CHIRALCEL 0J. It is noteworthy that the enantioselective deprotonation of 40 afforded the hydroxy-ester with >95% ee when this reaction was carried out, even at 78 r . In order to complete the synthesis of tetrahydrolipstatin, the alcohol 42 was converted to the known lactone 44 as follows. Swern oxidation of 42, followed by Wittig reaction of the resulting aldehyde gave the olefin 43. Catalytic hydrogenation of the olefin and deprotection of the benzylideneacetal in 43 over palladium hydroxide simulta- neously brought about a lactone formation to furnish the 8- lactone 44. Since the sign of rotation of our synthetic compound corresponds to those of the antipodal forms of the structurally related 3-lactonic compounds, the absolute stereochemistry of 44 can now be unambiguously assigned as depicted in Scheme 7. The lactone was already transformed to (-)-tetrahydrolipstatin by Ghosh; therefore, this synthesis also constitutes its formal synthesis.29

Scheme 7. Synthesis of (-)-tetrahydrolipstatin

Figure 4. Lipstatin family of P-lactonic microbial agents. change of the starting material, where, in part, the 7r--7r stack- ing interaction of the two aromatic rings resulted in the two benzyloxy-substituents moving to the axial orientation as depicted in Figure 5. Therefore, we chose a conformationally rigid starting material, 3, 5-O-benzylidenecyclohexanone 40, where the two oxy- genated substituents located in axial orientation leading to the opposite mode of the chiral induction to the case of 3, 5-dibenzyloxycyclohexanone. The starting material was prepared from 1, 3, 5-trihydroxycylohexane 32 in 3 steps as shown in Scheme 7. Enantioselective deprotonation of 40 with lithium (S,S)-a, d-dimethyldibenzylamide at 100 t in the presence of trimethysilyl chloride gave the silyl enol ether 41, which was further converted into the hydroxy-ester 42 by using the same procedures as described above. The ee of 42 was determined to be 99.9% based on HPLC analysis

Vol.60 No.11 2002 ( 79 ) 1109 As can be seen in Table 4, partial desilylation of the silyl 5. Synthesis of enantiomerically enriched 5-hydroxycyclo- enol ether to the ketone might occur prior to elimination of hex-2-enone: application to the synthesis of inositol the alkoxy group during this conversion. Although the mech- phosphatase inhibitor30 anistic details for this elimination are still obscure at present, Synthesis of chiral cyclohex-2-enone derivatives has been the absolute stereochemistry of the synthesized of continuing interest in organic chemistry, since these com- 5-cyclohex-2-enone was unambiguously determined by its pounds have often been employed as convenient building conversion to the corresponding tert-butyldimethylsilyl ether blocks for the preparation of a variety of biologically impor- 46, whose sign of optical rotation was equal to the sign of the tant compounds including natural products. As described reported literature value.31 The silyl ether 46 was further above, we have established the synthesis of a 1, 3-syn-dihy- transformed to the key intermediate 51 for an inositol phos- droxy system by using an enantioselective deprotonation, phatase inhibitor as follows. (Scheme 8) Epoxidation of 46 where meso-3, 5-dioxygenated cyclohexanones were employed with alkaline hydrogen peroxide gave the epoxide 47, stereo- as starting materials. In these reactions, it would be reason- selectively, which, on reduction with NaBH4 gave a diastere- able to assume that careful desilylation of the chiral silyl enol omixture of alcohols 48 and 49, in a ratio of ca. 1:2. ether prior to ozonolysis in those reaction sequences, would Although the desired alcohol 48 was obtained as the minor give the desired 5-hydroxycyclohex-2-enone 45 with reason- product unfortunately, which, on desilylation with TBAF, fol- able ee by elimination of the 3-alkoxy group as shown in Fig- lowed by dibenzylation of the diol 50 afforded the key inter- ure 6. mediate 51 for an inositol phosphatase inhibitor.32 In this synthesis, however, low stereoselectivity in the reduction of 47 was observed; we therefore investigated an alternative route to 50. We thought that a presence of hydroxy group instead of the bulky silyl ether in 47 might take place a reduction with the desired stereochemistry due to a steric reason and also by participation of hydroxy group with NaBH4. Although attempted desilylation of 47 under various reaction conditions failed, treatment of 47 with iodine in Me0H,33 followed by hydrolysis of the ketal group in 52 gave 53, fortu- Figure 6. Synthesis of 5-hydroxycyclohex-2-enone. nately. Reduction of 53 with NaBH4 afforded the desired diol Thus, we searched for the optimal conditions for the elimi- 50 as the major product as expected, although the overall nation reaction using the bicyclic silyl enol ether 41 as the starting material as follows. We first screened the effective- Scheme 8. Synthesis of inositol phosphatase inhibitor ness of the fluoride ion species for this elimination. When the silyl enol ether was treated with HF-Py, only the starting prochiral ketone was isolated. Other fluoride species, such as CsF and KF gave unsatisfactory results in terms of yields and enantioselectivity. Among the various fluoride species investigated, TBAF seemed to be the most effective reagent, and the results obtained are summarized in Table 4.

Table 4. Synthesis of 5-hydroxycyclohex-2-enone

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yield of this conversion was not high enough. Thus, we could Trends Pharm. Sci. 1990, 11, 150. 20) Baures, P. W; Eggleston, D. S.; Erhard, K. F.; Cieslinski, L. B.; develop a novel synthetic procedure for enantiomerically Torphy, T. J.; Christensen, S. B. J. Med. Chem. 1993, 36, 3274. enriched 5-hydroxycyclohex-2-enone and its utilization in 21) Honda, T.; Ono, S.; Mizutani, H.; Hallinan, K. 0. Tetrahedron: the synthesis of a biologically active compound. Asymmetry 1997, 8, 181. 22) Endo, A.; Kuroda, M.; Tsujita, Y. J. Antibiot. 1976, 29, 1346; 6. Conclusion Brown, A. G.; Smale, T. C.; King, T. J.; Hasenkamp, R.; Thompson, R. H. J. Chem. Soc., Perkin Trans. 1 1976, 1165. Thus, we introduced our own work on the synthesis of nat- 23) Endo, A. J. Antibiot. 1979, 32, 852; Alberts, A. W; Chen, J.; ural products and biologically active compounds by applica- Kuron, G.; Hunt, V.; Huff, J.; Hoffman, C.; Rothrock, J.; Lopez, M.; Joshua, H.; Harris, E.; Patchett, A.; Monaghan, R.; tion of an enantioselective deprotonation to prochiral com- Currie, S.; Stapley, E.; Albers-Schonberg, G.; Hensens, O.; Hir- pounds. This strategy has been recognized as a powerful syn- shfield, J.; Hoogsteen, K.; Liesch, J.; Springer, J. Proc. Natl. thetic tool to introduce a stereogenic center to prochiral com- Acad. Sci. USA 1980, 77, 3957. 24) Solladie, G.; Bauder, C.; Rossi, L. J. Org. Chem. 1995, 60, 7774. pounds, and has already been applied to the synthesis of a 25) Rychnovsky, S. D.; Griesgraber, G.; Zeller, S.; Skalitzky, D. J. J. wide variety of natural products by many other groups. This Org. Chem. 1991, 56, 5161. methodology would be further utilized for the synthesis of 26) Honda, T.; Endo, K.; Ono, S. Chem. Pharm. Bull. 2000, 48, various types of chiral compounds. 1545. 27) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld, H. J. Antibiot. 1987, 40, 1081; Hochuli, E.; Kupfer, E.; Maurer, References R.; Meister, W; Mercadal, Y; Schmidt, K. J. Antibiot. 1987, 40, 1) Whitesell, J. K.; Felman, S. W. J. Org. Chem. 1980, 45, 755. 1086. 2) Asami, M. Chem. Lett. 1984, 829; Asami, M. J. Synth. Org. 28) Zhi, J.; Melia, A. T.; Guerciolini, R.; Chung, J.; Kinberg, J.; Chem., Jpn. 1996, 54, 188; Asami, M.; Ogawa, M.; Inoue, S. Hauptman, J. B.; Patel, I. H. Clin. Pharm. Ther. 1994, 56, 82. Tetrahedron Lett. 1999, 40, 1563; Asami, M.; Sato, S.; Honda, 29) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743. K.; Inoue, S. Heterocycles 2000, 52, 1029; Asami, M.; Seki, A. 30) Honda, T.; Endo, K. J. Chem. Soc., Perkin Trans. 1 2001, 2915. Chem. Lett. 2002, 160. 31) Hareau, G. P. -J.; Koiwa, M.; Hikichi, S.; Sato, F. J. Am. Chem. 3) Koga, K. J. Synth. Org. Chem., Jpn. 1990, 48, 463; Koga, K. Soc. 1999, 121, 3640; Hareau, G.; Koiwa, M.; Hanazawa, T.; Pure and Appl. Chem. 1994, 66, 1487; Koga, K.; Shindo, M. J. Sato, F. Tetrahedron Lett. 1999, 40, 7493; Hareau, G. P. J.; Synth. Org. Chem., Jpn. 1995, 53, 1021. Koiwa, M.; Sato, F. Tetrahedron Lett. 2000, 41, 2385; Koiwa, 4) Simpkins, N. S. Chem. Soc. Rev. 1990, 19, 335; Cox, P. J.; Simp- M.; Hareau, G. P. J.; Sato, F. TetrahedronLett. 2000, 41, 2389. kins, N. S. Tetrahedron: Asymmetry 1991, 2, 1; Simpkins, N. S. 32) Schulz, J.; Wilkie, J.; Lightfoot, P.; Rutherford, T.; Gani, D. J. Pure and Appl. Chem. 1996, 68, 691. Chem. Soc., Chem. Commun. 1995, 2353; Schulz, J.; Beaton, M. 5) Other reviews for chiral amide chemistry: see Hodgson, D. M.; W; Gani, D. J. Chem. Soc., Perkin Trans. 1 2000, 943. Gibbs, A. R.; Lee, G. P. Tetrahedron1996, 52, 14361; O'Brien, P. 33) Vaino, A. R.; Szarek, W. A. Chem. Commun. 1996, 2351; Lip- J. Chem. Soc., Perkin Trans. 1 1998, 1439; O'Brien, P. J. Chem. shutz, B. H.; Keith, J. TetrahedronLett. 1998, 29, 2495. Soc., Perkin Trans. 1 2001, 95. 6) Honda, T.; Kimura, N.; Tsubuki, M. Tetrahedron: Asymmetry 1993, 4, 21. PROFILE 7) Asaoka, M.; Takenouchi, K.; Takei, H. Tetrahedron Lett. 1988, 29, 325. 8) Honda, T.; Kimura, N.; Tsubuki, M. Tetrahedron: Asymmetry Toshio Honda is Professor of organic 1993, 4, 1475. chemistry at Hoshi University. He 9) Honda, T.; Kimura, N. J. Chem. Soc., Chem. Commun. 1994, 77. received his Ph. D. degree from Tohoku 10) Park, B. K.; Nakagawa, M.; Hirota, A.; Nakayama, M. J. University in 1975 under the direction Antibiot. 1988, 41, 751. of Prof. T. Kametani. He started his 11) de Azevedo, M. B. M.; Murta, M. M.; Greene, A. E. J. Org. academic career in 1972, right after he Chem. 1992, 57, 4567. retired his Ph. D. course, as a research 12) Honda, T.; Kimura, N.; Sato, S.; Kato, D.; Tominaga, H. J. associate at the Faculty of Pharmaceuti- Chem. Soc., Perkin Trans. 1 1994, 1043. cal Sciences, Tohoku University, and 13) Aoki, K.; Nakajima, M.; Tomioka, K.; Koga, K. Chem. Pharm. spent a postdoctoral year (1976-1978) Bull. 1993, 41, 994. at the University of British Columbia. 14) Tomioka, K.; Koga, K. TetrahedronLett. 1979, 20, 3315. He became Lecturer at Tohoku Univer- 15) Tomioka, K.; Mizuguchi, H.; Koga, K. Chem. Pharm. Bull. sity in 1980 and moved to Hoshi Uni- 1982, 30, 4304; Tomioka, K.; lshiguro, T.; litaka, Y.; Koga, K. vcrsity in 1981. Since 1992, he has been Tetrahedron 1984, 40, 1303. a full professor at the same university. In 16) Banerji, J.; Das, B.; Chatterjee, A.; Shoolery, J. N. Phytochem- 1989, Professor Honda received The istry 1984, 23, 2323. Pharmaceutical Society of Japan Award 17) Batterbee, J. E.; Burden, R. S.; Crombie, L.; Whiting, D. A. J. for Young Scientists. His research inter- Chem. Soc., (C) 1969, 2470. ests include the total synthesis of natural 18) Honda, T.; Ishikawa, F.; Kanai, K.; Sato, S.; Kato, D.; Tomina- products, development of new synthetic strategy, and structure determination of ga, H. Heterocycles 1996, 42, 109. 19) Davis, C. W. Biochim. Biophys. Acta 1984, 797, 354; Nemoz, G.; natural products. He is also working in Moueqqit, M.; Prigent, A. -F.; Pacheco, H.; Eur. J. Biochem. the field of medicinal chemistry. 1989, 184, 511; Reeves, M. L.; Leigh, B. K.; England, P. J. Biochem. J. 1987, 241, 535; Beavo, J. A.; Reifsnyder, D. H.

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