Concise total synthesis of (-)-calycanthine, (+)-chimonanthine, and (+)-folicanthine
Concise total synthesis of (-)-calycanthine, (+)-chimonanthine, and (+)-folicanthine
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DOI：
10.1002/anie.200700705
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Schmidt, Michael A.
中科院分区：
文献类型：
--
作者：
Movassaghi, Mohammad;Schmidt, Michael A.
六氢吡咯并吲哚生物碱构成了一大类天然化合物，其形式上衍生自色氨酸。[1]存在一系列令人着迷的二聚和低聚衍生物，其中一个大的子集在六氢吡咯并吲哚子结构的C3 a和C3 a '处含有邻位季立体中心（方案1）。这些生物碱的诱人结构与其生物活性相结合，导致了对其全合成的极大兴趣。该领域的重要贡献已经建立了羟吲哚和色胺的生物合成启发的氧化二聚[2]，用于获得外消旋和内消旋形式的衍生物。[3]Overman及其同事报道了利用二烷基化或双Heck环化在这些靶标中建立季立体中心的优雅的对映选择性合成。[4]本文中，我们描述了一种简洁的对映选择性合成（+）-chimonanthine（1），（+）-folicanthine（2），（+）-calycanthine（3）通过收敛还原二聚化策略，同时确保相邻的四级立体中心。我们对（+）-蜡梅黄碱（1）的逆合成分析如方案2所示。作为二聚六氢吡咯并吲哚生物碱的合成计划的一部分，我们寻求一种有效的和收敛的策略，引入两个四元立体中心具有完全的立体选择性。迄今为止在这些生物碱的合成中尚未探索的强断开将涉及对映体富集的三环自由基6或相关衍生物的同偶联，以提供关键的C3 a-C3 a '键（方案2）。[5]我们预期在三环6的C8 a-位置处的立体化学在成键事件中施加高水平的非对映选择性并确保（+）-1中的邻位季立体中心。三环溴化物7被预测为6的多用途前体，并且设想基于由Hino、Crich和Danishefsky的研究组关于在C3对位官能化的六氢吡咯并吲哚生物碱的合成的优雅报告来制备。[1d用纯磷酸处理可商购的Nα-甲氧基羰基-L-色氨酸甲酯（8，方案2），然后进行N磺酰化，得到所需的三环六氢吡咯并吲哚（+）-9（> 99%de，> 99%ee）（方案3）。[1d甲基酯水解，然后在三环（+）-9的C2-位[8]脱羧，得到所需的六氢-
Hexahydropyrroloindole alkaloids constitute a large class of natural compounds that are formally derived from tryptophan.[1] A fascinating array of dimeric and oligomeric derivatives exist, a large subset of which contain vicinal quaternary stereocenters at C3a and C3a’of the hexahydropyrroloindole substructure (Scheme 1). The alluring structure of these alkaloids combined with their biological activity has led to significant interest in their total syntheses. Important contributions in this area have established a biosynthetically inspired oxidative dimerization [2] of oxindoles and tryptamines for accessing derivatives in racemic and meso form.[3] Overman and co-workers have reported elegant enantioselective syntheses that take advantage of dialkylation or double Heck cyclizations to establish the quaternary stereocenters in these targets.[4] Herein we describe a concise enantioselective synthesis of (+)-chimonanthine (1),(+)-folicanthine (2), and (À)-calycanthine (3) by a convergent reductive dimerization strategy to simultaneously secure the vicinal quaternary stereocenters. Our retrosynthetic analysis of (+)-chimonanthine (1) is illustrated in Scheme 2. As part of a program directed toward the synthesis of dimeric hexahydropyrroloindole alkaloids we sought an efficient and convergent strategy for the introduction of the two quaternary stereocenters with complete stereoselectivity. A powerful disconnection that has heretofore been unexplored in the synthesis of these alkaloids would involve the homocoupling of the enantiomerically enriched tricyclic free radical 6, or a related derivative, to provide the crucial C3aÀC3a’bond (Scheme 2).[5] We expected the stereochemistry at the C8a-position of the tricycle 6 to impose a high level of diastereoselectivity in the bond-forming event and secure the vicinal quaternary stereocenters in (+)-1. Tricyclic bromide 7 was predicted to serve as a versatile precursor to 6, and was envisioned to be prepared based on the elegant reports on the synthesis of hexahydropyrroloindole alkaloids functionalized at the C3aposition by the research groups of Hino, Crich, and Danishefsky.[1d, 6]Treatment of the commercially available Nα-methoxycarbonyl-L-tryptophan methyl ester (8, Scheme2) with neat phosphoric acid followed by N sulfonylation provided the desired tricyclic hexahydropyrroloindole (+)-9 (> 99% de,> 99% ee) on multigram scale (Scheme 3).[1d, 7] Hydrolysis of the methyl ester followed by decarboxylation at the C2-position [8] of tricycle (+)-9 afforded the desired hexahydro-