Efficient approaches to the stereoselective synthesis of cyclopropyl alcohols

Cyclopropanes occur in a diverse array of natural products, including pheromones, steroids, terpenes, fatty acid metabolites, and amino acids, and compounds that contain cyclopropanes exhibit interesting and important pharmacological properties. These valuable synthetic intermediates can be functionalized, or their rings can be opened, and the synthetic utility and unique biological activity of cyclopropanes have inspired many investigations into their preparation. One of the most powerful methods to generate cyclopropanes is the Simmons-Smith cyclopropanation. Since the original studies in the late 1950s reported that IZnCH(2)I could transform alkenes into cyclopropanes, researchers have introduced various modifications of the original procedure. Significantly, Furukawa demonstrated that diethylzinc and CH(2)I(2) react to generate carbenoids, and Shi described more reactive zinc carbenoids that contain electron-withdrawing groups on zinc (XZnCHI(2)). Despite these advances, the development of catalytic asymmetric Simmons-Smith reactions remains challenging. Although researchers have achieved catalytic asymmetric cyclopropanation of allylic alcohols, these reactions have had limited success. One attractive approach to the synthesis of cyclopropanes involves tandem reactions, where researchers carry out sequential synthetic transformations without the isolation or purification of intermediates. Such a synthetic strategy minimizes difficulties in the handling and purification of reactive intermediates and maximizes yields and the generation of molecular complexity. This Account summarizes our recent effort in the one-pot enantio- and diastereoselective synthesis of cyclopropyl alcohols. In one approach, an asymmetric alkyl addition to α,β-unsaturated aldehydes or asymmetric vinylation of aliphatic or aromatic aldehydes generates allylic zinc alkoxide intermediates. Directed diastereoselective cyclopropanation of the resulting alkoxide intermediates using in situ generated zinc carbenoids provides cyclopropyl or halocyclopropyl alcohols with high enantio-, diastereo-, and chemoselectivity. Other strategies employ bimetallic reagents such as 1-alkenyl-1,1-heterobimetallics or CH(2)(ZnI)(2) and provide access to di- and trisubstituted cyclopropyl alcohols. These methods enable facile access to skeletally diverse chiral cyclopropyl alcohols in high yields and stereoselectivities without the isolation or purification of the intermediates.