Collective synthesis of acetylenic pharmaceuticals via enantioselective Nickel/Lewis acid-catalyzed propargylic alkylation

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. Here, we describe an enantioselective nickel/Lewis acid-catalyzed asymmetric propargylic substitution reaction from simple achiral materials under mild condition. The introduction of a Lewis acid cocatalyst is crucial to the efficiency of the transformation. Notably, we investigate this asymmetric propargylic substitution reaction for the development of a range of structurally diverse natural products. The power of this strategy is highlighted by the collective synthesis of seven biologically active compounds: (−)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (−)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (−)-Citralis Nitrile.

Synthesis of TNF inhibitor, flurbiprofen and an i-Pr analogue in enantioenriched forms by copper-catalyzed propargylic substitution with Grignard reagents

The copper-catalyzed substitution reaction of 5-(TBDPS-oxy)-1-(TMS)pent-1-yn-3-yl phosphate with [3-(cyclopentyloxy)-4-methoxyphenyl]MgBr, followed by several transformations, afforded the tumor necrosis factor inhibitor possessing a Ph-acetylene moiety. The inhibitor was also synthesized from 5-(TBDPS-oxy)-1-(Ph)pent-1-yn-3-yl...