Total synthesis of (±)-nominine, a heptacyclic hetisine-type aconite alkaloid
Total synthesis of (±)-nominine, a heptacyclic hetisine-type aconite alkaloid
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DOI：
10.1002/anie.200460332
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发表时间：
2004-01-01
影响因子：
16.6
通讯作者：
Natsume, M
中科院分区：
文献类型：
--
作者：
Muratake, H;Natsume, M
4647 Angew.国际化学版2004，43，4646-4649 www. angewandte。org 2004 Wiley-VCH Verlag GmbH & Co. KGaA，魏因海姆，甲苯回流，得到所需的亚甲基双环[2.2. 2]辛烷衍生物18（57%）、甲锡烷基环丙烷衍生物19（31%）和亚甲基双环[3.2. 1]辛烷衍生物20（8%），在用硅胶将乙烯基锡烷产物脱锡后。[12]简单加热17、Bu 3SnH和AIBN在甲苯中的混合物，得到19作为主要产物。因此，在自由基中间体21和22之间似乎存在平衡，其中前者在热力学上是有利的（方案4）。Toyota等人报道的类似自由基环化反应主要得到双环[2.2. 2]辛烷或双环[3.2. 1]辛烷，这取决于底物的取代基;没有形成甲锡烷基环丙烷衍生物。[13]然而，在我们的情况下，所需的化合物18和甲锡烷基环丙烷19作为主要产物形成，并且双环[3.2. 1]辛烷衍生物20是次要产物，这可能是由于分子的扭曲性质。通过Lemieux氧化生成相应的环戊酮衍生物（IR：n= 1730 cm-1）来确认20的结构。接着，18通过甲磺酸酯23转化为溴化物24（方案5）。化合物24在二氯甲烷中用叔丁基OH水溶液和SeO 2 [14]在环境温度下进行烯丙基氧化，得到烯酮25（77%）、醇15α-26（14%）和痕量的烯醛27。15α-羟基产物26在C15处具有与天然产物相反的构型，用MnO 2定量氧化为25。在CeCl 3存在下用NaBH 4还原烯酮25，仅得到所需的15β-羟基化合物29。26和29的结构根据Kawazoe等人报道的规则得到了证实。（方案6）。[15]因此，在它们的1H NMR谱中，由于顺式15-羟基的影响，26的7α-H和29的7β-H的信号向低场移动。此外，在羟基的乙酰化后，所得化合物28和30中相应氢原子的信号根据规则（d= 2.38- 2.38）向高场移动。
4647 Angew. Chem. Int. Ed. 2004, 43, 4646–4649 www. angewandte. org 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim toluene at reflux to secure the desired methylenebicyclo [2.2. 2] octane derivative 18 (57%), the stannyl cyclopropane derivative 19 (31%), and the methylenebicyclo [3.2. 1] octane derivative 20 (8%) after destannylation of the vinyl stannane products with silica gel.[12] Simple heating of a mixture of 17, Bu3SnH, and AIBN in toluene afforded 19 as the major product. Thus, there appears to be an equilibrium between the radical intermediates 21 and 22, with the former favored thermodynamically (Scheme 4). Similar radical cyclization reactions reported by Toyota et al. afforded mainly bicyclo [2.2. 2] octanes or bicyclo [3.2. 1] octanes, depending on the substituents of the substrates; no stannyl cyclopropane derivatives were formed.[13] However, in our case the desired compound 18 and the stannyl cyclopropane 19 were formed as the main products, and the bicyclo [3.2. 1] octane derivative 20 was a minor product, probably as a result of the distorted nature of the molecule. The structure of 20 was confirmed by generation of the corresponding cyclopentanone derivative (IR: n= 1730 cmÀ1) by the Lemieux oxidation. Next, 18 was transformed into the bromide 24 via the mesylate 23 (Scheme 5). Compound 24 underwent allylic oxidation with aqueous tert-BuOOH and SeO2[14] in CH2Cl2 at ambient temperature to afford the enone 25 (77%), the alcohol 15α-26 (14%), and a trace amount of the enal 27. The 15α-hydroxy product 26, with the opposite configuration at C15 to the natural product, was oxidized quantitatively to 25 with MnO2. The enone 25 was reduced with NaBH4 in the presence of CeCl3 to afford the desired 15β-hydroxy compound 29 exclusively. The structures of 26 and 29 were confirmed on the basis of the rule reported by Kawazoe et al.(Scheme 6).[15] Thus, in their 1H NMR spectra, the signals for 7α-H of 26 and 7β-H of 29 were shifted downfield owing to the influence of the syn 15-hydroxy group. Furthermore, upon acetylation of the hydroxy group, the signal for the corresponding hydrogen atom in the resulting compounds 28 and 30 was shifted upfield in accordance with the rule (d= 2.38–