Thermodynamic Understanding of an Aza-Michael Reaction Enables Five-Step Synthesis of the Potent Integrin Inhibitor MK-0429.

Abstract

We describe a general strategy for the aza-Michael addition of nucleophilic heterocycles into β-substituted acrylates using potassium tert-butoxide as catalyst. Demonstrating that the reaction is under thermodynamic control underpins optimization efforts and enables rapid exploration of the substrate scope, with yields ranging from 55% to 94%. We further leverage these lessons in a significantly shortened synthesis of MK-0429, a potent pan-integrin inhibitor previously taken into human clinical trials for the treatment of prostate cancer and osteoporosis.