Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir
Highly diastereo- and enantioselective catalytic synthesis of the bis-tetrahydrofuran alcohol of Brecanavir and Darunavir
复制标题
DOI：
10.1016/j.tetasy.2008.07.037
复制
发表时间：
2008-09-08
影响因子：
--
通讯作者：
Xie, Shiping
中科院分区：
文献类型：
--
作者：
Black, David M.;Davis, Roman;Xie, Shiping
利用（苄氧基）乙醛和甲硅烷基烯酮缩醛的Evans Mukaiyama羟醛缩合反应，实现了几种HIV蛋白酶抑制剂（包括布瑞那韦和达芦那韦）的双四氢呋喃（bis-THF）醇的高效高非对映体和对映体选择性合成。将来自催化羟醛缩合反应的内酯醇中间体还原成内缩醛。钯催化的氢解除去了苄基保护并促进了原位环化，以98：2的非对映异构体比率和97：3的对映异构体比率形成双-THF醇的差向异构体。醇差向异构体通过氧化成酮，然后高度选择性地还原成双-THF醇，在两个步骤中容易地转化为目标。(C)2008爱思唯尔有限公司保留所有权利。
An efficient highly diastereo- and enantioselective synthesis of the bis-tetrahydrofuran (bis-THF) alcohol of several HIV protease inhibitors, including Brecanavir and Darunavir, has been achieved utilizing an Evans Mukaiyama aldol reaction of (benzyloxy)acetaldehyde and a silyl ketene acetal. The lactone alcohol intermediate from the catalytic aldol reaction was reduced to a lactol. Palladium catalyzed hydrogenolysis removed the benzyl protection and promoted an in situ cyclization to form the epimer of the bis-THF alcohol in a 98:2 diastereomeric ratio and 97:3 enantiomeric ratio. The alcohol epimer was readily converted to the target in two steps by oxidation to a ketone followed by highly selective reduction to the bis-THF alcohol. (C) 2008 Elsevier Ltd. All rights reserved.