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

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Abstract
Noncanonical amino acids (ncAAs) are valuable building blocks for therapeutic design. 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 C−C bond formation between a ketone substrate and an l-serine- or l-threonine (l-Thr)-derived amino acrylate intermediate. In the second step, the IRED reduces the resulting cyclic imine, 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 that contain a remote desymmetrized stereocenter and one example featuring an l-Thr-derived, fully functionalized pyrrolidine ring. Furthermore, we show that a d-proline is formed from l-amino acid starting materials, which has not been observed in closed-shell tryptophan synthase catalysis previously. This cascade is a scalable, operationally simple method to synthesize new prolines, and is poised to expand the development of therapeutics featuring structurally complex ncAAs.
Funding Information
  • Merck

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