Nunes De Souza Aline, Sakkani Nagaraju, Guthrie Daryl, Sahani Rajkumar Lalji, Saathoff John M, Hochstetler Samuel R, Burns Justina M, Ahmad Saeed, Laidlaw G Michael, Gupton B Frank, Klumpp Douglas A, Jin Limei
Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia, 23284-3068, United States.
Org Process Res Dev. 2025 Feb 26;29(3):846-855. doi: 10.1021/acs.oprd.4c00527. eCollection 2025 Mar 21.
(1,5)-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 ()-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I-promoted hydroxylation, and an Albright-Goldman oxidation. This sequence affords (1,5)-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.
(1,5)-2,2-二甲氧基双环[3.1.0]己烷-3-酮用于来那卡韦的不对称合成。在此，我们报道了一种从廉价的商品（）-环氧氯丙烷对这种重要手性中间体进行对映选择性合成的方法。该合成方法包括6步，其中有4步串联的双环酮合成、碘促进的羟基化反应以及奥尔布赖特-戈德曼氧化反应。该反应序列以对映体纯化合物的形式，以25%的总分离产率得到(1,5)-2,2-二甲氧基双环[3.1.0]己烷-3-酮。整个过程已在百克规模上成功得到验证。
