Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction

Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high‐pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding. Evolution for synthetic efficiency: Target‐driven evolution optimizes enzymes for synthetically desired transformations under conditions that challenge and surpass known limitations of enzyme performance. A biocatalyst that was engineered for stereoselective, dynamic kinetic reduction in a high‐pH environment has enabled an efficient synthesis of vibegron, a potent β3‐adrenergic agonist for the treatment of overactive bladder syndrome.