Asymmetric Synthesis of Antithrombotic Agents M58163 and M58169: Dynamic Kinetic Resolution in Amide Formation Catalyzed by La‐Linked BINOL Complex

Abstract

The first asymmetric syntheses of antithrombotic agents M58163 and M58169 are reported. Dynamic kinetic resolution is observed in the amide formation step.

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…Saitoh, Mikami, and co-workers completed the asymmetric total syntheses of M58163 ( 303 ) and M58169 ( 304 ), both of which display antithrombotic activity (Scheme ). Access to their imidazopyrazinone core ( 301 ) was achieved using a lanthanum-catalyzed asymmetric cascade cyclization proceeding through racemic aminal 302 . , Mechanistic studies revealed that the aminal is formed reversibly, with enantioselection occurring during the La-catalyzed amide bond-forming step. A survey of various lanthanide metal complexes revealed that the La-linked BINOL complex 294 (Figure ) gave the best yield and selectivity.…”

Dynamic Kinetic Resolution for the Catalytic Asymmetric Total Synthesis of Antithrombotic Agents M58163 and M58169

“…We report here the full account of the dynamic kinetic resolution in the amide formation step following formation of a cyclic N,N-acetal leading to the tricyclic key intermediate of M58163 and M58169 (Scheme 2). [10] Results and Discussion Enantioselective Cyclic N,N-Acetal Formation First, the chiral Brønsted acids and salen-manganese complex, by which the cyclic N,O-acetal had been obtained enantioselectively, [4] were examined. The results are summarized in Table 1.…”