title: Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utilizing organocopper-mediated reduction-alkylation and diastereoselectivity examination using DFT calculations.
abstract: We have carefully examined the organocopper-mediated reduction-alkylation of gamma-acetoxy or gamma,gamma-difluoro-alpha,beta-unsaturated-delta-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 x LiI x 3 LiBr), followed by trapping the resulting metal dienolate with an electrophile in a one-pot procedure gave alpha-alkylated-beta,gamma-unsaturated-delta-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-pi-allyllithium complexes 29 and 31.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Niida
authors.forename: Makiko
authors.initials: M
authors.lastname: Mizumoto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Narumi
authors.forename: Eriko
authors.initials: E
authors.lastname: Inokuchi
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Ohno
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kitaura
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D054659:Diketopiperazines; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*
chemical_list: D000475:Alkenes; D054659:Diketopiperazines; D010879:Piperazines; D003300:Copper