Optimization of enantioselective halocyclizations via BAM catalysis, and investigation of aryl triflamides as achiral modifiers in organocatalysis

Abstract

As a means to prepare enantioenriched small molecules, chiral hydrogen bond catalysts have been developed. These organocatalysts are the latest broad class of reagents for enantioselective reaction development, but they have already impacted the advancement of new therapeutics. The BisAmidine (BAM) organocatalyst system combines chiral neutral bis(amidine) ligands with a strong Brønsted acid to create a bifunctional (acid-base) catalyst. Using BAM catalysis, an enantioselective iodocarbamation reaction was developed that captures CO2 using mild conditions with high reactivity to prepare cyclic carbamates. An additional halocyclization reaction was developed to prepare enantioenriched ε-lactones using PIDA/I2 as a dual oxidant system. Prior to this work, halocyclizations were limited to the preparation of δ- and γ-lactones. Additionally, BAM catalysis was employed to effect the asymmetric addition of azide to nitroalkenes. While initial studies were essentially non-selective, aryl triflamides served as an unusual design point in catalyst optimization. This project uniquely illustrated the power of these achiral modifiers in organocatalysis: a ligand system which had originally been evaluated as a failure was restored through the application of aryl triflamides.