Catalytic enantioselective synthesis of alkylidenecyclopropanes

Abstract

Abstract The enantioselective construction of small-ring carbocycles provides organic chemists with an enduring challenge1. Despite their commercial importance, enantioselective synthetic routes towards alkylidenecyclopropanes, a class of small-ring carbocycles, remain underdeveloped2,3. Alkylidenecyclopropanes can be converted into cyclopropanes, a common feature in drug molecules (for example, Nirmatrelvir 1)4, as well as both naturally occurring and synthetic agrochemicals (for example, permethrin 2)5,6. Here we describe the facile synthesis of highly enantioenriched alkylidenecyclopropanes through the use of a bifunctional iminophosphorane catalysed, stereo-controlled, strain-relieving deconjugation. Small modifications to the basic catalyst system were used to broaden the scope of the reaction to substrates containing ester, amide, phosphine oxide and ketone functionalities. Through the design of a suitable substrate and retuning of the catalyst’s iminophosphorane moiety, the transformation was effectively applied to the synthesis of a single stereoisomer of the commonplace insecticide permethrin as well as a range of cyclopropane-based insecticide cores. State-of-the-art computational studies were performed to provide detailed insights into the mechanistic pathway and origin of both diastereoselectivities and enantioselectivities.