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

Xihao Chang,Chang Guo,Jiayin Zhang,Lingzi Peng

doi:10.1038/s41467-020-20644-9

Abstract

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.

Highlights

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry
Various powerful catalysts based on transition metals have been disclosed for the asymmetric propargylic substitution (APS) reactions of terminal propargylic carbonates via themetal intermediate[16,17,18], offering a convenient way to install a synthetically versatile alkyne unit onto target molecules[19,20,21]
In light of the synthetic value of the reaction products, we embarked on the study to address the synthetic challenge and accomplish the enantioselective collective synthesis

Summary

Introduction

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. A Enantioselective collective synthesis of (−)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (−)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (−)-Citralis Nitrile. We hypothesized that strategies through the judicious introduction of a Lewis acid co-catalyst to enhance the nucleophilicity of malonates would permit efficient APS reactions (Fig. 1c)[43,44].

Results

Conclusion