Enantioselective Access to Trifluoromethylated Spirocyclopropyl Heterocycles

Abstract

ABSTRACT Chiral spirocyclopropyl heterocycles have emerged as privileged three‐dimensional structural motifs in medicinal chemistry. Nevertheless, efficient catalytic enantioselective assembly of such compounds still faces considerable synthetic difficulties. Herein, we describe a rhodium‐mediated asymmetric [2+1] cyclopropanation reaction using methylene azacycles and fluoroalkyl triftosylhydrazones as reaction partners, which offers a concise synthetic route toward enantioenriched trifluoromethylated spirocyclopropyl heterocyclic derivatives. This synthetic transformation tolerates various substrates and functional groups, and achieves remarkable stereochemical control. Multiple spirocyclic skeletons can be efficiently constructed with favorable yields and prominent diastereo‐ and enantioselectivity, with the highest e.e. value recorded at 99%. The acquired spirocyclopropyl oxazolidinone derivatives can be further derivatized via internal reactive moieties, which allows their integration into bioactive molecular frameworks. By combining fluoroalkyl carbenes with asymmetric spirocyclopropanation, the present work develops a general catalytic system to synthesize elusive fluoroalkyl‐bearing chiral spirocyclopropyl heterocycles.