Chemical Synthesis of Aspidosperma Alkaloids Inspired by the Reverse of the Biosynthesis of the Rhazinilam Family of Natural Products
Chemical Synthesis of Aspidosperma Alkaloids Inspired by the Reverse of the Biosynthesis of the Rhazinilam Family of Natural Products
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DOI：
10.1002/anie.201204151
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发表时间：
2012-01-01
影响因子：
16.6
通讯作者：
Gaunt, Matthew J.
中科院分区：
文献类型：
--
作者：
McMurray, Lindsay;Beck, Elizabeth M.;Gaunt, Matthew J.
吡咯和吡咯烷杂环化合物是天然产物中普遍存在的结构特征。自然界的生物合成机制通常从饱和吡咯烷合成这些分子中的吡咯官能团，作为其代谢降解途径的一部分。[1]有趣的是，取代吡咯的化学合成通常比相应的吡咯烷更简单;吡咯烷的饱和烃框架相对不活泼，[2]通常需要额外的官能团来安装特定的取代基，因此与芳香族同系物相比，这些化合物的合成变得困难。因此，将高度取代的吡咯转化为结构上复杂的吡咯烷成为全合成的有吸引力和潜在的强大策略（图1A）。[3，4]在本文中，我们报告了通过还原性跨环级联策略实现这一理想，该策略将含吡咯的芳香族代谢物rhazinilam（1a）直接转化为aspidospermidine（2），aspidospermidine是一种更复杂的含吡咯烷的天然产物，具有大量Terestrin-吲哚生物碱所共有的核心分子结构（图1B）。[5]该策略通过触发级联反应来利用取代的吡咯环的反应性，该级联反应导致戏剧性的结构重排;含吡咯的代谢物转化为含吡咯烷的天然产物。实施该合成的关键是使用金属催化的C13 H键官能化[6]来选择性地并顺序地在吡咯环周围引入所需的取代基，[7]从而允许快速组装拉唑尼仑的核心框架。[8，9]这种简洁的吡咯官能化策略与产生复杂性的级联的结合提供了一种强大的合成过程，能够将平面杂芳烃转化为结构复杂的生物碱天然产物。[10]此外，这种方法可以
Pyrrole and pyrroldine heterocycles are ubiquitous structural features in natural products. Nature’s biosynthetic machinery often synthesizes the pyrrole functionality in these molecules from a saturated pyrrolidine as part of its metabolic degradation pathway.[1] Interestingly, the chemical synthesis of substituted pyrroles is usually more straightforward in comparison to that of the corresponding pyrrolidines; the saturated hydrocarbon framework of pyrrolidine is relatively unreactive,[2] usually requiring the presence of additional functional groups to install a particular substituent, thus rendering the synthesis of such compounds difficult in comparison to their aromatic congeners. Therefore, the transformation of a highly substituted pyrrole into an architecturally complex pyrrolidine becomes an attractive and potentially powerful strategy for total synthesis (Figure 1 A).[3, 4]Herein, we report the realization of this ideal through a reductive transannular cascade strategy that transforms the pyrrole-containing aromatic metabolite, rhazinilam (1a), directly into aspidospermidine (2), a more complex pyrrolidine-containing natural product possessing a core molecular architecture that is common to a large number of terpene–indole alkaloids (Figure1B).[5] This strategy exploits the reactivity of the substituted pyrrole ring by triggering a cascade reaction that results in a dramatic structural rearrangement; pyrrole-containing metabolites are transformed into pyrrolidine-containing natural products. Key to the implementation of this synthesis is the use of metalcatalyzed CÀH bond functionalization [6] to introduce the desired substituents selectively and sequentially around the pyrrole ring,[7] thereby allowing rapid assembly of the core framework of rhazinilam.[8, 9] The confluence of this concise pyrrole functionalization tactic with the complexity-generating cascade delivers a powerful synthetic process capable of converting planar heteroarenes into architecturally complex alkaloid natural products.[10] Moreover, this approach could