Highly substituted pyrrolidines have a ubiquitous presence among natural products and bioactive pharmaceuticals, which has led to an ongoing need for development of selective methods for their preparation. Herein we describe the identification and optimization of a surprisingly general method to synthesize tetrasubstituted pyrrolidines with up to &gt;20:1 diastereoselectivity and 99% enantioselectivity via asymmetric [3+2] cycloaddition between azomethine ylides and nitroalkenes. Subsequent downstream transformations of the cycloadducts are described that enabled access to versatile intermediates of significant impact to medicinal chemistry programs, and kg-scale campaigns successfully incorporated the methodology into the scale up of C2-corrector compound ABBV-3221 for AbbVie’s cystic fibrosis program.

Asymmetric synthesis of densely functionalized pyrrolidines via copper-catalyzed [3+2] cycloaddition: Scope, optimization, and application to the scale up of ABBV-3221

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