Asymmetric Synthesis of Noncanonical Prolines via a TrpB-IRED Enzymatic Cascade

Noncanonical amino acids (ncAAs) are valuable building blocks for novel therapeutics. Prolines are particularly useful because their cyclic cores can limit the conformational flexibility of a larger molecular framework, allowing such scaffolds to be further tuned to enhance engagement with their biological targets. Herein, we describe a convergent approach to synthesizing noncanonical prolines from readily available starting materials mediated by a tryptophan synthase β-subunit (TrpB)-imine reductase (IRED) cascade. In the first step, the TrpB catalyzes ketone substrate activation and C–C bond formation with an L-serine- or L-threonine (L-Thr)-derived amino acrylate intermediate. In the second step, the IRED reduces the cyclic imine intermediate, in some cases simultaneously setting two stereocenters via a dynamic kinetic resolution. With this one-pot, sequential cascade, we demonstrate the synthesis of mono-, bi-, and tricyclic prolines bearing as many as four chiral centers, including three examples possessing a remote desymmetrized stereocenter and one example possessing an L-Thr-derived, fully functionalized pyrrolidine ring. Furthermore, we show that D-prolines are accessible from L-amino acid starting materials, which has not been observed in tryptophan synthase catalysis previously. This cascade is a scalable, operation-ally simple method to synthesize new prolines, and is poised to expand the development of novel therapeutics featuring structurally complex ncAAs.