Total Synthesis of (+)-Haplophytine
Total Synthesis of (+)-Haplophytine
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DOI：
10.1002/anie.200904588
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发表时间：
2009-01-01
影响因子：
16.6
通讯作者：
Chen, David Y-K.
中科院分区：
文献类型：
--
作者：
Nicolaou, K. C.;Dalby, Stephen M.;Chen, David Y-K.
尽管近年来在全合成领域取得了许多令人印象深刻的成就，[1]许多天然产物已经被证明顽固地抵抗其进步。[2]其中之一是haplophytine（1，方案1a），它只是最近才屈服于合成以下的优雅工作福山，德山和同事。[3]1952年，Snyder及其同事首次分离出Haplophytine，并将其鉴定为野生花卉Haplophyton cimicidum的主要生物活性成分，[4]几个世纪以来，阿兹特克人和随后的中美洲定居者因其杀虫特性而受到重视。一种异二聚体吲哚生物碱，haplophytine具有特别复杂的十个环，六个立体中心（其中五个是四元的）和一个高度密集的碳环碳键连接分子的两个不同的一半。四环左侧结构域具有独特的桥连酮结构，而右侧结构域由天然存在的盾籽植物生物碱，aspidophytine组成（2，方案1 B）。[4，5]在Cava，Yates和Zacharias的小组进行了广泛的化学降解，光谱和X射线晶体学研究[6]，其中包括二氢溴酸盐衍生物3的鉴定（方案1a）之后，在其分离后约21年才完全了解了haplophytine的分子结构。如图所示，该化合物是通过左侧结构域独特的酸介导的骨架重排形成的，涉及胺CÁN键的1，2-位移。然而，在碱性条件下，该过程可以逆转，例如通过互补的半频哪醇型机制返回haplophytine。作为定向全合成haplophytine的程序的一部分，我们先前已经证明了这种重排作为构建左侧结构域片段4的方法的适用性（方案1 B）。[7]Fukuyama及其同事独立报道了类似的方法。[8]同时，我们对aspidophytine [5 f]的方法是专门设计的，以补充4，以促进haplophytine的全合成（1）。在这里，我们希望报告我们自己的不对称全合成这个历史性的合成目标，这项工作的高潮。
Despite the many impressive accomplishments in the field of total synthesis in recent years,[1] a number of natural products have proven stubbornly resistant to its advances.[2] Among them is haplophytine (1, Scheme 1a), which has only very recently succumbed to synthesis following the elegant work of Fukuyama, Tokuyama and co-workers.[3] Haplophytine was first isolated by Snyder and co-workers in 1952, and identified as the principle bioactive component of the wild flower Haplophyton cimicidum,[4] valued for centuries by the Aztecs and subsequent settlers of Central America for its insecticidal properties. A heterodimeric indole alkaloid, haplophytine features a particularly complex polycyclic array of ten rings, six stereocenters (five of which are quaternary) and a highly congested carbonÀcarbon bond adjoining the two distinct halves of the molecule. The tetracyclic left-hand domain features a unique bridged ketone structure, while the righthand domain consists of the naturally occurring aspidosperma alkaloid, aspidophytine (2, Scheme 1 b).[4, 5] A complete appreciation of haplophytine s molecular structure was only reached some 21 years subsequent to its isolation, following extensive chemical degradation, spectroscopic, and X-ray crystallographic studies from the groups of Cava, Yates, and Zacharias,[6] which included identification of the dihydrobromide derivative 3 (Scheme 1 a). As depicted, this compound is formed through a unique acid-mediated skeletal rearrangement of the left-hand domain involving the 1, 2-shift of an aminal CÀN bond. Under basic conditions, however, this process can be reversed such as to return haplophytine through a complementary semi-pinacol type mechanism. As part of a program directed toward the total synthesis of haplophytine, we have previously demonstrated the suitability of this rearrangement as a means to construct the left-hand domain fragment 4 (Scheme 1 b).[7] A similar approach has been reported independently by Fukuyama and co-workers.[8] Our approach to aspidophytine,[5f] meanwhile, was specifically designed to complement that for 4, in order to facilitate the total synthesis of haplophytine (1). Herein we wish to report the culmination of this work with our own asymmetric total synthesis of this historic synthetic target.