A biomimetic approach to the Strychnos alkaloids. A novel, concise synthesis of (+/-)-akuammicine and a route to (+/-)-strychnine
A biomimetic approach to the Strychnos alkaloids. A novel, concise synthesis of (+/-)-akuammicine and a route to (+/-)-strychnine
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DOI：
10.1021/ja962577f
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发表时间：
1996-10-09
影响因子：
15
通讯作者：
Mortimore, M
中科院分区：
文献类型：
--
作者：
Martin, SF;Clark, CW;Mortimore, M
士的宁(1)1和苦参碱(2)2是吲哚生物碱中士的宁(1)1和阿瓜米星(2)2的代表性成员，自近50年前其结构被阐明以来，一直是合成研究的目标。3-9伍德沃德40多年前对1的全合成可以说标志着现代合成有机化学的起源。4今天，伍德沃德的方法仍然是如何利用独创性和仔细的规划来设计短而有效的复杂目标合成的例证。除了保护基团外，引入中间体的每个碳原子都保留在最终产品中，因此，该策略代表了有机合成中原子经济性的第一个例子。10在伍德沃德的开创性成就之后，士的宁直到1992年才再次屈服于完全合成，马格努斯、5斯托克、6奥弗曼、7奎恩、8和拉瓦尔进行了优雅的合成。9由Overman，11 Kuehne，12和Bonjoch和Bosch记录了阿夸米星(2)的三次合成。13在这里，我们报告了一种新的仿生策略的实施，以方便地全合成阿库阿米星(2)和氧化类似物，这是一种潜在的马钱子碱(1)的正式合成法。综合计划设计中的关键要素的灵感来自于拟议的将具有鸡冠花骨架的吲哚生物碱分别转化为马钱子科生物碱2和1的生物遗传转化(方案1)。14我们最近报道了杂环生物碱和冠花环生物碱家族的吲哚类生物碱的一般条目，其特征是Venylogy Mannich反应，然后是分子内杂化Diels-Alder反应，以组装这些生物碱的五环分子骨架。15例如，以色胺为原料，经两步反应制得6，与1-(三甲基硅氧基)丁二烯在巴豆酰氯(7a)存在下反应，得到8a，加热后环合得到五环加合物9a，总收率为6的70%(方案2)。要将方案1中提到的逆合成分析应用于阿奎米星(2)的简明合成，首先需要将9a转化为去甲酰基吉西西嗪(12a)，这是合成鸡冠花生物碱的著名中间体。在此情况下，9a的烯醇醚部分的水合反应和中间产物内酯的氧化反应得到了内酯10a，产率为79%。当10a暴露在甲醇钠中时，β消除得到一种酸，该酸在原位酯化得到11a，产率为79%。以91%的产率从色胺经8步选择性还原得到12A。以类似的反应顺序以类似的总收率制备含氧类似物12b。有了关键的中间体12a，b，我们研究了模仿角叉菜中间体生物遗传重组成为马钱子家族五环骨架的可行性。在SnCl4存在下，用叔丁基次氯酸盐处理12a，得到一种不是分离的、而是直接用六甲基二硅氮化锂处理的表观氯吲哚13a的混合物，从该混合物中以30-35%的产率分离(()-阿库阿米星(2))(方案3)。所得产物经TLC、~1H、~(13)C核磁共振谱测定，与正品完全一致。含氧类似物12b经过类似的转化，以大约25%-30%的产率得到16。
Strychnine (1) 1 and akuammicine (2) 2 are representative members of the Strychnos family of indole alkaloids and have been targets of synthetic investigations since the elucidation of their structures nearly 50 years ago. 3-9 The total synthesis of 1 by Woodward more than 40 years ago arguably marked the genesis of modern synthetic organic chemistry. 4 Today, the Woodward approach still exemplifies how ingenuity and careful planning may be exploited in the design of short and efficient syntheses of complex targets. With the exception of protecting groups, each carbon atom introduced into an intermediate was retained in the final product, therefore, the strategy represents the first example of atom economy in organic synthesis. 10 Subsequent to the seminal achievement of Woodward, strychnine did not succumb again to total synthesis until 1992 with the elegant syntheses by Magnus, 5 Stork, 6 Overman, 7 Kuehne, 8 and Rawal. 9 Three total syntheses of akuammicine (2) have been recorded by Overman, 11 Kuehne, 12 and Bonjoch and Bosch. 13 Herein we report the implementation of a novel biomimetic strategy to a facile total synthesis of akuammicine (2) and an oxygenated analogue that is a potential intermediate in a formal synthesis of strychnine (1). The critical element in the design of the synthetic plan was inspired by a transformation in the proposed biogenetic conversion of indole alkaloids possessing the corynantheoid skeleton, which may be represented by 4 and 5, into alkaloids of the Strychnos family such as 2 and 1, respectively (Scheme 1). 14 We recently reported a general entry to indole alkaloids of the heteroyohimboid and corynantheoid families that featured a vinylogous Mannich reaction followed by an intramolecular hetero-Diels-Alder reaction to assemble the pentacyclic molecular framework of these alkaloids. 15 For example, reaction of 6, which was prepared in two steps from tryptamine, with 1-((trimethylsilyl) oxy) butadiene in the presence of crotonyl chloride (7a) gave 8a that underwent cyclization upon heating to give the pentacyclic adduct 9a in 70% overall yield from 6 (Scheme 2).To apply the retrosynthetic analysis adumbrated in Scheme 1 to a concise synthesis of akuammicine (2), it was first necessary to convert 9a into deformylgeissoschizine (12a), which is a well-known intermediate in the syntheses of corynantheoid alkaloids. In the event, hydration of the enol ether moiety of 9a followed by oxidation16 of the intermediate lactol gave the lactone 10a in 79% yield. When 10a was exposed to sodium methoxide, β-elimination ensued to give an acid that was esterified in situ to give 11a in 79% yield. Selective reduction of the amide moiety of 11a proceeded in 91% yield to furnish 12a in only eight steps from tryptamine. A similar sequence of reactions was performed to prepare the oxygenated analogue 12b in comparable overall yield. With the key intermediates 12a, b in hand, we examined the feasibility of mimicking the biogenetic reorganization of a corynantheoid intermediate into the pentacyclic skeleton of the Strychnos family. Treatment of 12a with tert-butylhypochlorite in the presence of SnCl4 gave a mixture of epimeric chloroindolenines 13a that were not isolated but rather treated directly with lithium hexamethyldisilazide to give a mixture from which (()-akuammicine (2) was isolated in 30-35% yield (Scheme 3). The synthetic 2 thus obtained was identical (TLC, 1H and 13C NMR) with an authentic sample. 17 The oxygenated analogue 12b underwent a similar conversion to give 16 in about 25-30% yield.