Asymmetric Synthesis of a Potent hNK-1 Receptor Antagonist

Abstract

The hNK-1 antagonist candidate 3 is synthetically one of most challenging antagonist candidates at Merck, having six chiral centers. The ether bond was formed via π-allyl palladium chemistry with the zinc alkoxide of the chiral alcohol and chiral 2-cyclopenten-1-ol, prepared via enzymatic reduction of the corresponding ketone, to set two chiral centers. 4-Fluorophenyl group was introduced to the cyclopentene ring via 1,4-addition in a stereospecific manner. The δ-lactam having the quaternary chiral amine function was embedded onto the cyclopentane ring using Seebach’s chiral oxazolidinone. In this article, scalable synthesis of 3 is described in a chronological order.