UC Santa Barbara

Many bioactive compounds contain cyclic moieties and stereogenic centers. While there are many preexisting cyclization reactions and ways to install stereocenters, new methods are constantly being developed. The Michael-initiated ring closure (MIRC) is a useful method to construct cyclic compounds in a diastereoselective fashion. We envisioned inducing enantioselectivity by utilizing chiral lithium amides as a noncovalent chiral auxiliary. We herein report a stereoselective MIRC reaction to construct 1,2-(trans)-disubstituted cycloalkanes between arylacetic acids and α,β-unsaturated esters. This method yields ring sizes varying from cyclopropane to cycloheptane with high diastereoselectivity (>20:1 dr) and enantioselectivity (up to 99% ee). We have also demonstrated the versatility of this method by showcasing the use of various aryl substituents and α-substitutents for the substrate acid as well as the use of different α,β-unsaturated esters and sulfone. In addition, we illustrated the utility of this method by applying it in the synthesis of a selective diacylglycerol acyltransferase (DGAT-1) inhibitor, A-922500, which could be further used to study its effects on obesity and insulin resistance.