Synthesis of (Z)-alkene and (E)-fluoroalkene-containing diketopiperazine mimetics utilizing organocopper-mediated reduction-alkylation and diastereoselectivity examination using DFT calculations.
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.
Niida
Ayumu
A
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Mizumoto
Makiko
M
Narumi
Tetsuo
T
Inokuchi
Eriko
E
Oishi
Shinya
S
Ohno
Hiroaki
H
Otaka
Akira
A
Kitaura
Kazuo
K
Fujii
Nobutaka
N
D000475:Alkenes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D054659:Diketopiperazines; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry*
D000475:Alkenes; D054659:Diketopiperazines; D010879:Piperazines; D003300:Copper