TY - JOUR AU - Maligres, Peter E.; Song, Zhiguo Jake; Strotman, Neil A.; Yin, Jinquin; Pei, Tao; Strotman, Hallena R.; Itoh, Tetsuji; Sherer, Edward C.; Humphrey, Guy R. TI - Synthesis of Fused Oxepane HIV Integrase Inhibitor MK-1376 SN - 0039-7881 SN - 1437-210X PY - 2020 JO - Synthesis JF - Synthesis LA - EN VL - 52 IS - 22 SP - 3378 EP - 3388 ET - 2020/03/16 DA - 2020/10/21 KW - HIV integrase inhibitor KW - oxepane KW - pyrimidine KW - π-allyl cyclization KW - quinone methide AB - 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. PB - © Georg Thieme Verlag DO - 10.1055/s-0040-1707994 UR - http://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-0040-1707994 ER -