Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir

• DOI: 10.1021/acs.oprd.4c00527
• Publication Date: 2025-02-26T16:51:51Z
• Authors: Aline Nunes De Souza; Nagaraju Sakkani; Daryl Guthrie; Rajkumar Lalji Sa...; John M. Saathoff; Samuel R. Hochste...; Justina M. Burns; Saeed Ahmad; G. Michael Laidlaw; B. Frank Gupton; Douglas A. Klumpp; Limei Jin

(1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one is used in the asymmetric synthesis of lenacapavir. Herein, we report an enantioselective this important chiral intermediate from inexpensive commodity (R)-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I2-promoted hydroxylation, and Albright–Goldman oxidation. sequence affords (1R,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one overall 25% isolated yield as enantiomerically pure compound. The entire process has been successfully demonstrated on hundred-gram scale.