Asymmetric Copper-Catalyzed Conjugate Addition with Trimethylboroxine Enables Direct Synthesis of Frespaciguat
Abstract 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.
Authors
- François Lévesque (ORCID: https://orcid.org/0000-0001-9529-4993)
- Karthik Narsimhan (ORCID: https://orcid.org/0000-0003-4111-0487)
- Feng Xu (ORCID: https://orcid.org/0000-0003-1949-324X)
- Cyndi Qixin He (ORCID: https://orcid.org/0000-0002-3143-6435)
- Douglas A. L. Otte (ORCID: https://orcid.org/0000-0002-4700-2842)
- Cecilia Bottecchia (ORCID: https://orcid.org/0000-0003-3355-1805)
- Xiaoshen Ma (ORCID: https://orcid.org/0000-0002-0713-2896)
- John Y. L. Chung (ORCID: https://orcid.org/0000-0001-6094-5549)
- Matthew S. Winston (ORCID: https://orcid.org/0000-0002-0228-4911)
- Yining Ji (ORCID: https://orcid.org/0000-0002-9650-6844)
- Artis Klapars (ORCID: https://orcid.org/0000-0002-6244-5502)
- Tao Liang (ORCID: https://orcid.org/0000-0003-1646-9666)
- Michael J. Di Maso (ORCID: https://orcid.org/0000-0003-1262-6126)
- Andrew J. Neel (ORCID: https://orcid.org/0000-0003-2872-5292)
- Heather Wang (ORCID: https://orcid.org/0000-0002-4001-236X)
- Gregorio Estrada
- Jongrock Kong (ORCID: https://orcid.org/0000-0003-1509-687X)
- Mark Weisel (ORCID: https://orcid.org/0000-0001-7260-7010)
- Nastaran Salehi Marzijarani (ORCID: https://orcid.org/0000-0001-8940-4674)
- Jamie M. McCabe Dunn (ORCID: https://orcid.org/0000-0003-1103-8859)
- Longrui Chen (ORCID: https://orcid.org/0009-0002-7125-3956)
- Stephan M. Rummelt (ORCID: https://orcid.org/0000-0003-3996-0271)
- Kevin M. Maloney (ORCID: https://orcid.org/0000-0003-1422-5422)
- Jennifer Victoriano Obligacion (ORCID: https://orcid.org/0000-0001-9308-0932)
- Lu Wang (ORCID: https://orcid.org/0000-0003-2032-8874)
- Zhijian Liu
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2026-10-19
- DOI
- https://doi.org/10.1021/jacs.6c17539
- Primary Topic
- Asymmetric Synthesis and Catalysis
- Type
- article
- Field-Weighted Citation Impact
- 0.00