In the presence of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), nucleophilic and reactive reagents including heterocycles, amides, alcohols, and amines are prevented from interacting with a rhodium carbene, allowing asymmetric cyclopropanation to occur with high yield and stereoselectivity (up to &gt;99% ee) on a variety of compounds. In this study, 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 complementary methods also feature a newly developed dirhodium tetracarboxylate as one of the optimal catalysts for the reaction in 0-10 equiv HFIP. The scope of both the aryl/heteroaryl diazoacetate and the olefin was expanded and the study culminates in the enantioselective functionalization of complex molecules featuring various reactive and nucleophilic functionality that is classically incompatible with dirhodium catalyzed asymmetric cyclopropanation. These complex molecules included relevant medicinal compounds including the immunosuppressant FK506, the hepatitis-C therapeutic Asunaprevir, and the procaspase-3-activator PAC-1, as well as natural products like (<i>S)-</i>Cinchonidine.

Hexafluoroisopropanol for the selective deactivation of poisonous nucleophiles enabling catalytic asymmetric cyclopropanation of complex molecules

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