Asymmetric Copper-Catalyzed Conjugate Addition with Trimethylboroxine Enables Direct Synthesis of Frespaciguat
Andrew J. Neel, Gregorio J. Estrada, Feng Xu, Cecilia Bottechia, Longrui Chen, Yining Ji, John Y. L. Chung, Michael J. Di Maso, Cyndi Q. He, Artis Klapars, Jongrock Kong, François Lévesque, Tao Liang, Zhijian Liu, Xiaoshen Ma, Kevin M. Maloney, Jamie M. McCabe Dunn, Karthik Narsimhan, Jennifer Victoriano Obligacion, Douglas A. L. Otte, Nastaran Salehi Marzijarani, Stephan M. Rummelt, Heather Wang, Lu Wang, Mark Weisel, Matthew S. WinstonAbstract
Herein we disclose a concise synthesis of inhaled soluble guanylate cyclase (isGC) stimulator Frespaciguat (MK-5475) that relies exclusively on complexity-increasing transformations from commodity chemicals. Key transformations include a solvent-free photochemical reaction that converts two gaseous reactants into a liquid product in high yield; a direct ester-to-amidine conversion using HMDS, water, and triflic acid; and a rare example of enantioselective methylation via copper-catalyzed asymmetric conjugate addition (ACA) to install a quaternary center using trimethylboroxine as a nucleophile. Given the general challenge of asymmetric methyl installation, we further demonstrate the utility of this methodology beyond the present setting and suggest its strategic value in synthetic planning where nonracemic, quaternary methyl-containing stereocenters are required.