Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction. Issue 23 (3rd May 2018)

• Record Type: Journal Article
• Authors: Xu, Feng; Kosjek, Birgit; Cabirol, Fabien L.; Chen, Haibin; Desmond, Richard; Park, Jeonghan; Gohel, Anupam P.; Collier, Steven J.; Smith, Derek J.; Liu, Zhuqing; Janey, Jacob M.; Chung, John Y. L.; Alvizo, Oscar
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 23(2018)
• Page Start: 6863
• Page End: 6867
• Publication Date: 2018-05-03
• Subjects: biocatalysis -- directed evolution -- enzymes -- ketoreductases -- total synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201802791
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : 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.