Stereoselective Reactions. XXXIV.<SUP>1)</SUP> Enantioselective Deprotonation of Prochiral 4-Substituted Cyclohexanones Using Chiral Bidentate Lithium Amides Having a Bulky Group Instead of a Phenyl Group on the Chiral Carbon

Abstract

Lithium dialkylamides such as lithium diisopropylamide (LDA) are widely used in organic synthesis as strong bases with low nucleophilicity.2) We have previously reported enantioselective deprotonation 3) of prochiral 4-substituted cyclohexanones (1) using chiral lithium amides in the presence of excess trimethylsilyl chloride (TMSCl) (Corey's internal quench method 4) ) to isolate the corresponding lithium enolates (2) as trimethylsilyl enol ethers (3). 5) Among various chiral lithium amides examined, chiral bidentate lithium amides ((R)-5a, (R)-5b) having a phenyl group on the chiral carbon, a neopentyl or trifluoroethyl group on the amide nitrogen, and a piperidino group as an internal ligation site for the lithium give the products ((R)-3) in high ee's. 5b,c,i,l) By Xray and NMR studies, it is shown that these chiral lithium amides ((R)-5a, (R)-5b) exist almost entirely as a chelated monomeric form ((R)-6) having a chiral amide nitrogen in tetrahydrofuran (THF) or dimethoxyethane (DME), and in THF, DME, ether, or toluene in the presence of 2 eq of hexamethylphosphoric triamide (HMPA). 5b,c,i,l) In this structure, the substituent (a neopentyl or trifluoroethyl group) on the amide nitrogen and the phenyl group on the chiral carbon are trans, presumably due to the steric repulsion between them. It is therefore reasonable to assume that bidentate chiral lithium amides ((R)-12a, b-(R)-15a, b, (S)-16a, b) having a bulkier substituent instead of a phenyl group on the chiral carbon would be more effective as chiral bases for enantioselective deprotonation. Based on this consideration, we prepared chiral bidentate amines ((R)-7a, b-(R)-10a, b, (S)-11a, b) for the preparation of their corresponding lithium amides.1) The present paper describes the results of deprotonation reactions of 4-substituted cyclohexanones (1a-d) by these chiral bidentate lithium amides.The reactions of 1a-d were carried out under the fixed conditions, using 1.2 eq of lithium amide and 5 eq of TMSCl in the presence of 1.2 eq of HMPA in THF at Ϫ78°C for 30 min.6) The results using chiral lithium amides ((R)-5a, (R)-11a-(R)-15a, and (S)-16a) having a neopentyl group on the amide nitrogen are summarized in Table 1. It is shown that, except one case (run 20), chiral lithium amides having R-configuration give the products rich in R-enantiomer, while that having S-configuration gives the products rich in S-enantiomer. It is also shown that the enantioselectivities of the reactions are dependent on the bulkiness of both the substituent on the chiral carbon of the chiral lithium amides and the sub- * To whom correspondence should be addressed. e-mail: kkoga@ms.aist-nara.ac. Narashinodai, Funabashi-shi, Chiba 274-8555, Japan, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., b 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan, and Research and Education Center for Materials Science, Nara Institute of Science and Technology, c Takayama-cho, Ikomashi, Nara 630-0101, Japan. Received January 5, 2001; accepted February 1, 20...

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