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Synthesis of (Z)-Alkene and (E)-Fluoroalkene-Containing Diketopiperazine Mimetics Utilizing Organocopper-Mediated Reduction−Alkylation and Diastereoselectivity Examination Using DFT Calculations

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journal contribution
posted on 26.05.2006, 00:00 by Ayumu Niida, Makiko Mizumoto, Tetsuo Narumi, Eriko Inokuchi, Shinya Oishi, Hiroaki Ohno, Akira Otaka, Kazuo Kitaura, Nobutaka Fujii
We have carefully examined the organocopper-mediated reduction−alkylation of γ-acetoxy or γ,γ-difluoro-α,β-unsaturated-δ-lactams for the synthesis of (Z)-alkene- or (E)-fluoroalkene-containing diketopiperazine mimetics. Reduction of acetates 2, 12, 14, and difluorolactam 18 with higher-order cuprate reagents (Me3CuLi2·LiI·3LiBr), followed by trapping the resulting metal dienolate with an electrophile in a one-pot procedure gave α-alkylated-β,γ-unsaturated-δ-lactams in good yields. Because of side-chain steric repulsion, we found that alkylation using relatively large electrophiles such as BnBr gave mostly 3,6-trans isomers by kinetic trapping of metal enolates. On the other hand, MeI-mediated alkylations predominantly provided the unexpected 3,6-cis isomers despite the presence of a bulky benzyl side chain. Based on density functional theory calculations, we concluded that formation of the 3,6-cis isomers was due to the occurrence of oxa-π-allyllithium complexes 29 and 31.