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Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important
Aline Nunes De Souza1, Nagaraju Sakkani1, Daryl Guthrie1
1Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia, 23284-3068, United States.
Abstract:
(1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one is used in the asymmetric synthesis of lenacapavir. Herein, we report an enantioselective synthesis of this important chiral intermediate from the inexpensive commodity (R)-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I2-promoted hydroxylation, and an Albright-Goldman oxidation. This sequence affords (1R,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one in an overall 25% isolated yield as an enantiomerically pure compound. The entire process has been successfully demonstrated on a hundred-gram scale.
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