A Mild Rhodium‐Catalyzed Asymmetric 1,4‐Conjugate Addition of Organoboranes to α‐Substituted Heterocyclic Acrylates for Use in Pharmaceutical Products

Abstract Cyclic acrylates are an under‐explored class of electrophile for conjugate addition reactions with aromatic boronic acids. In order to supply a range of saturated heterocycles for medicinal chemistry hit optimization, plate‐based parallel screening enabled the discovery of a rhodium‐catalyzed 1,4‐conjugate addition using Hayashi ligand. Scope exploration included variation in the cyclic acrylate ring size (pyrrolidine, piperidine, azepane), the choice of N ‐protection group (CBz, Boc, and other carbamates) and the range of boronic acid nucleophiles, amongst other parameters. The influence of these parameters on yield and enantioselectivity is described. The step was then established into a 3‐step sequence consisting of: asymmetric conjugate addition; base‐mediated epimerization to the trans diastereoisomer; and borohydride reduction of the ester to the alcohol building block. Multi‐gram deliveries of complex sp3 ‐rich enantio‐ and diastereo‐meric building blocks could thereby be established.