The identification and evolution of a series of IRAK4 inhibitors will be presented. During the course of lead optimization efforts, the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic aminal protected α,β-unsaturated lactams derived from pyroglutaminol was found to be determined by the structure of the cyclic aminal group. The properties and remarkably different reactivities of these bicyclic α,β-unsaturated lactams were studied further. The results of these investigations and their application to the multi- kilogram synthesis of the IRAK4 inhibitor clinical candidate PF-06650833 will be discussed.

Discovery of a novel diastereoselective cuprate conjugate addition reaction and its application to the multi-kilogram synthesis of a clinical candidate

253rd National Meeting (2017)

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