James Kempson, Rulin Zhao, Joseph Pawluczyk, Bei Wang, Huiping Zhang, Xiaoping Hou, Martin P Allen, Dauh-Rurng Wu, Peng Li, Shiuhang Yip, Aaron Smith, Sarah C Traeger, Stella Huang, Jingfang Cutrone, Subha Mukherjee, Chris Sfouggatakis, Michael Poss, Paul M Scola, Nicholas A Meanwell, Percy H Carter, Arvind Mathur
We describe an optimization and scale-up of the 45-membered macrocyclic thioether peptide BMS-986189 utilizing solid-phase peptide synthesis (SPPS). Improvements to linear peptide isolation, macrocyclization, and peptide purification were demonstrated to increase the throughput and purification of material on scale and enabled the synthesis and purification of >60 g of target peptide. Taken together, not only these improvements resulted in a 28-fold yield increase from the original SPPS approach, but also the generality of this newly developed SPPS purification sequence has found application in the synthesis and purification of other macrocyclic thioether peptides...
April 23, 2024: Journal of Organic Chemistry