Synthesis of (<i>Z</i>)-Alkene and (<i>E</i>)-Fluoroalkene-Containing Diketopiperazine Mimetics Utilizing Organocopper-Mediated Reduction−Alkylation and Diastereoselectivity Examination Using DFT Calculations NiidaAyumu MizumotoMakiko NarumiTetsuo InokuchiEriko OishiShinya OhnoHiroaki OtakaAkira KitauraKazuo FujiiNobutaka 2006 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 (<i>Z</i>)-alkene- or (<i>E</i>)-fluoroalkene-containing diketopiperazine mimetics. Reduction of acetates <b>2</b>, <b>12</b>, <b>14</b>, and difluorolactam <b>18</b> with higher-order cuprate reagents (Me<sub>3</sub>CuLi<sub>2</sub>·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 <b>29</b> and <b>31</b>.