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Synthesis of Fused Oxepane HIV Integrase Inhibitor MK-1376
Synthesis ( IF 2.2 ) Pub Date : 2020-03-16 , DOI: 10.1055/s-0040-1707994 Peter E. Maligres 1 , Zhiguo Jake Song , Neil A. Strotman , Jinquin Yin , Tao Pei , Hallena R. Strotman , Tetsuji Itoh , Edward C. Sherer , Guy R. Humphrey
Synthesis ( IF 2.2 ) Pub Date : 2020-03-16 , DOI: 10.1055/s-0040-1707994 Peter E. Maligres 1 , Zhiguo Jake Song , Neil A. Strotman , Jinquin Yin , Tao Pei , Hallena R. Strotman , Tetsuji Itoh , Edward C. Sherer , Guy R. Humphrey
Affiliation
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Controlling the absolute and relative stereochemistry of a seven-membered oxepane in the formation of HIV integrase inhibitor MK-1376 was accomplished through a strategy involving the use of asymmetric allylation and stereoconvergent, substrate-directed installation of an amine fragment. Surprising reactivity was demonstrated during the asymmetric allylation in which the allyl-pyrimidone product was formed reversibly. The stereoconvergent amine addition was accomplished through an elimination/addition sequence involving a quinone methide reactive intermediate, and nucleophilic trapping of the reactive quinone methide intermediate with methylamine. This novel approach delivered MK-1376, offering 100-fold greater productivity and 50-fold less waste than the initial synthetic chemistry route.
中文翻译：
熔融氧杂环丁烷HIV整合酶抑制剂MK-1376的合成
控制HIV整合酶抑制剂MK-1376形成过程中七元氧杂环丁烷的绝对和相对立体化学是通过一种策略实现的，该策略涉及使用不对称的烯丙基化和胺基化合物的立体收敛，底物定向安装。在不对称烯丙基化过程中显示出惊人的反应性，其中烯丙基嘧啶酮产物可逆地形成。立体会聚胺的添加是通过涉及醌甲基化物反应性中间体的消除/加成序列，以及反应性醌甲基化物中间体与甲胺的亲核捕集来完成的。这种新颖的方法交付了MK-1376，与最初的合成化学路线相比，生产率提高了100倍，浪费减少了50倍。
更新日期：2020-03-16
中文翻译：
熔融氧杂环丁烷HIV整合酶抑制剂MK-1376的合成
控制HIV整合酶抑制剂MK-1376形成过程中七元氧杂环丁烷的绝对和相对立体化学是通过一种策略实现的，该策略涉及使用不对称的烯丙基化和胺基化合物的立体收敛，底物定向安装。在不对称烯丙基化过程中显示出惊人的反应性，其中烯丙基嘧啶酮产物可逆地形成。立体会聚胺的添加是通过涉及醌甲基化物反应性中间体的消除/加成序列，以及反应性醌甲基化物中间体与甲胺的亲核捕集来完成的。这种新颖的方法交付了MK-1376，与最初的合成化学路线相比，生产率提高了100倍，浪费减少了50倍。
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