An efficient approach to Aspidosperma alkaloids via [4+2] cycloadditions of aminosiloxydienes:: Stereocontrolled total synthesis of (±)-tabersonine.: Gram-scale catalytic asymmetric syntheses of (+)-tabersonine and (+)-16-methoxytabersonine.: Asymmetric syntheses of (+)-aspidospermidine and (-)-quebrachamine
An efficient approach to Aspidosperma alkaloids via [4+2] cycloadditions of aminosiloxydienes:: Stereocontrolled total synthesis of (±)-tabersonine.: Gram-scale catalytic asymmetric syntheses of (+)-tabersonine and (+)-16-methoxytabersonine.: Asymmetric syntheses of (+)-aspidospermidine and (-)-quebrachamine
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DOI：
10.1021/ja017863s
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发表时间：
2002-05-01
影响因子：
15
通讯作者：
Rawal, VH
中科院分区：
文献类型：
--
作者：
Kozmin, SA;Iwama, T;Rawal, VH
描述了一种简明的、高度立体控制的吲哚生物碱Aspidosperma家族的策略，该策略很容易适应这些化合物的不对称合成。(+/-)-tabersonine(RAC-1)的全合成证明了这一策略，通过12步序列进行。2-乙基丙烯醛与1-氨基-3-硅氧基二烯的高度区域和立体选择性的[4+2]环加成反应为该反应提供了基础。六氢喹啉DE环体系的初始加合物的后续精制是通过闭环烯烃歧化反应有效地完成的。报道了一种新型的烯醇硅基醚与(邻硝基苯基)氟化苯碘的邻硝基苯基化反应，以实现对吲哚结构的高效、区域选择性的引入。通过分子内吲哚烷基化反应和区域选择性的C-甲氧基化反应，最终将四环乙烷高产率转化为五环目标RAC-1。我们的方法在战略上不同于以前的路线，并包含访问吲哚生物碱的Aspidosperma家族的许多其他成员所需的内置灵活性。通过不对称合成阿司匹林生物碱：(+)-阿司匹林、(-)-奎贝拉明、(-)-脱氢奎铃胺、(+)-塔伯松碱和(+)-16-甲氧基塔伯松碱，说明了该合成策略的多功能性。其中，(+)-tabersonine和(+)-16-甲氧基tabersonine的合成数量大于1-g，并以对映体富集型形式(类似于95%ee)合成。关键的不对称引入步骤是催化的对映选择性Diels-Alder反应，该反应在高达95%ee的条件下生成环加合物。值得注意的是，合成序列很容易执行，在12步合成路线中只需要四次提纯。
Described is a concise, highly stereocontrolled strategy to the Aspidosperma family of indole alkaloids, one that is readily adapted to the asymmetric synthesis of these compounds. The strategy is demonstrated by the total synthesis of (+/-)-tabersonine (rac-1), proceeding through a 12-step sequence. The basis for this approach was provided by a highly regio- and stereoselective [4 + 2] cycloaddition of 2-ethylacrolein with 1-amino-3-siloxydiene developed in our laboratory. Subsequent elaboration of the initial adduct into the hexahydroquinoline DE ring system was accomplished efficiently by a ring-closing olefin metathesis reaction. A novel ortho nitrophenylation of an enol silyl ether with (o-nitrophenyl)phenyliodonium fluoride was developed to achieve an efficient, regioselective introduction of the requisite indole moiety. The final high-yielding conversion of the ABIDE tetracycle into pentacyclic target rac-1 relied on intramolecular indole alkylation and regioselective C-carbomethoxylation. Our approach differs strategically from previous routes and contains built-in flexibility necessary to access many other members of the Aspidosperma family of indole alkaloids. The versatility of the synthetic strategy was illustrated through the asymmetric syntheses of the following Aspidosperma alkaloids: (+)-aspidospermidine, (-)-quebrachamine, (-)-dehydroquebrachamine, (+)-tabersonine, and (+)-16-methoxytabersonine. Of these, (+)-tabersonine and (+)-16-methoxytabersonine were synthesized in greater than 1-g quantities and in enantiomerically enriched form (similar to95% ee). The pivotal asymmetry-introducing step was a catalyzed enantioselective Diels-Alder reaction, which proceeded to afford the cycloadducts in up to 95% ee. Significantly, the synthetic sequence was easy to execute and required only four purifications over the 12-step synthetic route.