Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization
Total Synthesis of Resiniferatoxin Enabled by Radical-Mediated Three-Component Coupling and 7-endo Cyclization
复制标题
DOI：
10.1021/jacs.7b10177
复制
发表时间：
2017-11-15
影响因子：
15
通讯作者：
Inoue, Masayuki
中科院分区：
文献类型：
--
作者：
Hashimoto, Satoshi;Katoh, Shun-ichiro;Inoue, Masayuki
树脂毒素（1）属于瑞香烷型二萜类化合物家族，对TRPV 1有强烈的激动作用，TRPV 1是伤害性温度和化学刺激的转换器。1的密集氧化的反式稠合的5/7/6-三碳环（ABC-环）对化学合成提出了令人生畏的挑战。在这里，我们报告了一种新的自由基为基础的战略，从三个组件组装1：A-环9，烯丙基锡烷18 b，和C-环17 b的发展。由d-核糖衍生物19制备的6元17 b被设计为具有笼状原酸酯结构，其中a-烷氧基硒化物作为自由基前体。在用18 b、9和V-40处理17 b时，从17 b产生有效反应性的α-烷氧基桥头自由基，然后依次与9和18 b偶联，得到16 b。该第一自由基反应在A环和C环之间形成受阻的C9，10-键，并以立体选择性方式延伸A环上的C4-链。16 b衍生为15后，在n-Bu_3 SnH和V-40存在下，利用C环上的黄原酸酯作为自由基前体，烯丙基二硫代碳酸酯作为终止剂，使剩余的7元B环化。因此，第二自由基反应不仅能够进行7-内环化，而且能够构建C8-立构中心和C6-外链烯烃。通过一系列高度优化的化学选择性反应，将Triclycoprotein 14加工成靶向1。本发明的1的全合成展示了自由基反应用于连接碳环内的受阻键而不破坏预先存在的官能团的优点，从而为多步靶向合成提供了新的策略设计。
Resiniferatoxin (1) belongs to a daphnane diterpenoid family and has strong agonistic effects on TRPV1, a transducer of noxious temperature and chemical stimuli. The densely oxygenated trans-fused 5/7/6-tricarbocycle (ABC-ring) of 1 presents a daunting challenge for chemical synthesis. Here we report the development of a novel radical-based strategy for assembling 1 from three components: A-ring 9, allyl stannane 18b, and C-ring 17b. The 6-membered 17b, prepared from d-ribose derivative 19, was designed to possess the caged orthoester structure with a-alkoxy selenide as a radical precursor. Upon treatment of 17b with 18b, 9, and V-40, the potently reactive a-alkoxy bridgehead radical was generated from 17b and then sequentially coupled with 9 and 18b to yield 16b. This first radical reaction formed the hindered C9,10-linkage between the A and C-rings and extended the C4-chain on the A-ring in a stereoselective fashion. After derivatization of 16b into 15, the remaining 7-membered B-ring was cyclized in the presence of n-Bu3SnH and V-40 by utilizing the xanthate on the C-ring as the radical precursor and the allylic dithiocarbonate as the terminator. The second radical reaction thus enabled not only the 7-endo cyclization but also construction of the C8-stereocenter and the C6-exo olefin. Tricycle 14 was elaborated into the targeted 1 by a series of highly optimized chemoselective reactions. The present total synthesis of 1 demonstrates the advantages of radical reactions for linking hindered bonds within carbocycles without damaging preexisting functionalities, thereby offering a new strategic design for multistep target-oriented synthesis.