Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib via Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition

An efficient and elegant enantioselective synthesis of the key chiral pyrrolidine fragment of Upadacitinib (ABT-494) has been described. Oppolzer's chiral sultam-directed asymmetric 1,3-dipolar cycloaddition was employed as a convenient tool to obtain the desired level of concomitant diastereoselectivity and enantioselectivity in the construction of the 3,4-syn substituted pyrrolidine moiety. The synthesis process was demonstrated as a proof of study on a lab scale and was refined during scale-up to allow for easy disengagement of the chiral auxiliary and its subsequent reuse.