(1,5)-2,2-二甲氧基双环[3.1.0]己烷-3-酮的可扩展合成路线的开发：来那卡韦合成中的重要中间体
Development of a Scalable Synthetic Route to (1,5)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir.
作者信息
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
机构信息
Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia, 23284-3068, United States.
出版信息
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。
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