Enantioselective synthesis of stephacidin B
Enantioselective synthesis of stephacidin B
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DOI：
10.1021/ja0510616
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发表时间：
2005-04-20
影响因子：
15
通讯作者：
Myers, AG
中科院分区：
文献类型：
--
作者：
Herzon, SB;Myers, AG
我们描述了一种对映选择性合成抗增殖生物碱 Stephacidin B (1) 的路线，该路线经过 18 个步骤，从 4,4-(亚乙基二氧基)-2,2-二甲基环己酮 (3) 得到 4.0% 的产率。合成序列的关键特征包括在合成路线早期使用 Corey−Bakshi−Shibata (CBS) 还原引入不对称性、在立体选择性烯醇烷基化中使用新型亲电子试剂 N-(叔丁氧基羰基)-5-(异丙基磺酰氧基甲基)-2,3-二氢吡咯、在溶剂中将氰化氢非对映选择性 Strecker 型加成到 N-Boc 烯胺底物上六氟异丙醇，中性条件下铂催化的腈水解，酰氨基自由基中间体环化形成千金藤素B的二酮哌嗪核心，并在路线的最后阶段实施收敛程序引入关键的3-亚烷基-3H-吲哚1-氧化物官能团以制备结构2，先前提出是真菌代谢物avrainvillamide（17个步骤， 4.2% 产率）。我们观察到合成的 (−)-2 在三乙胺存在下二聚形成 (+)-千金藤酸 B (>95%)。我们还获得了证据表明2可以在温和条件下形成1，并且2可以通过共轭加成与亲核试剂（例如甲醇）发生反应。
We describe an enantioselective synthetic route to the antiproliferative alkaloid stephacidin B (1) proceeding in 18 steps and 4.0% yield from 4,4-(ethylenedioxy)-2,2-dimethylcyclohexanone (3). Key features of the synthetic sequence include the use of the Corey−Bakshi−Shibata (CBS) reduction to introduce asymmetry early in the synthetic route, use of the novel electrophileN-(tert-butoxycarbonyl)-5-(isopropylsulfonyloxymethyl)-2,3-dihydropyrrole in a stereoselective enolate alkylation, a diastereoselective Strecker-type addition of hydrogen cyanide to anN-Boc enamine substrate in the solvent hexafluoroisopropanol, platinum-catalyzed nitrile hydrolysis under neutral conditions, cyclization of an acylamino radical intermediate to form the diketopiperazine core of stephacidin B, and implementation of a convergent procedure for introduction of the key 3-alkylidene-3H-indole 1-oxide functional group in the final stage of the route to prepare the structure2, previously proposed to be the fungal metabolite avrainvillamide (17 steps, 4.2% yield). We observed that synthetic (−)-2dimerized in the presence of triethylamine to form (+)-stephacidin B (>95%). We also obtained evidence that2can form1under mild conditions, and that2reacts with nucleophiles, such as methanol, by conjugate addition.