Hexafluoroisopropanol for the Selective Deactivation of Poisonous Nucleophiles Enabling Catalytic Asymmetric Cyclopropanation of Complex Molecules
Jack C. Sharland, David I. Dunstan, Dyuti Majumdar, Jinhai Gao, Kian L. Tan, Hasnain A. Malik, Huw M. L. Davies
Abstract
In the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), nucleophilic and reactive reagents are prevented from interacting with a rhodium carbene, allowing asymmetric cyclopropanation to occur with high yield and stereoselectivity on a variety of compounds. A high-throughput screen was conducted on cyclopropanation with a complementary catalytic system in the presence of 90 different poisonous nucleophiles and varying amounts of HFIP (10 equiv, used as reaction solvent). The scope of both the aryl/heteroaryl diazoacetate and the olefin was expanded, and the study culminated in the enantioselective functionalization of complex molecules including API and natural products.