An Iterative Approach to Biologically Important Fused Polycyclic Ethers via Acyl Radical Cyclizations
An Iterative Approach to Biologically Important Fused Polycyclic Ethers via Acyl Radical Cyclizations
复制标题
通过酰基自由基环化制备具有重要生物学意义的稠合多环醚的迭代方法
DOI：
10.1021/jo9605861
复制
发表时间：
1996
影响因子：
3.6
通讯作者：
L. Garber
中科院分区：
文献类型：
--
作者：
P. Evans;and Jamie D. Roseman;L. Garber
含有稠合多环醚的天然产物由于其固有的结构复杂性而成为难以克服的合成目标。[1]人们已经为这类化合物开发了各种优雅的方法，并越来越强调迭代策略。2最近由Yasumoto及其同事从毒性冈比亚盘菌培养基中分离出的gamberic acids AD特别有趣。它们具有独特的梯形多环分子结构，由九个连续的聚醚环和一个孤立的四氢呋喃环组成。此外，它们的抗真菌活性超过阿替霉素B 3个数量级以上，使它们具有显著的治疗意义。这些药剂所表现出的生物活性归因于所有四种gamberic酸的共生组合，提供了关于作用机制的有趣问题。3在本文中，我们描述了一个迭代的酰基自由基环化策略，用于合成这个极其重要的分子的关键左手（BC片段）3（n）2）和右手（IJ片段）3（n）1）组分。4-6我们的逆合成分析设想分子被断开成两个复杂的四环单元，即BCDE和GHIJ亚基，每个亚基都应该通过方案1中概述的策略来获得。方案2总结了为合成四氢吡喃-3-酮和氧杂卓-3-酮系统而设计的初始序列。6用丙炔酸甲酯和三丁基膦处理仲醇4a 7和4 b8得到碳酸乙烯酯，9用琼斯试剂直接氧化得到相应的羧酸5a和5 b，总收率分别为82%和81%。10然后使用Crich方案将羧酸5a和5 b转化为酰基硒化物6a和6 b，产率为86%和85%。在室温下，在空气存在下，用三（三甲基甲硅烷基）硅烷和三乙基硼烷处理酰基硒化物6a和6 b，得到环状醚7a/8a和7 b/8b，产率分别为94%和90%，为5.7：1和g 19：1的立体异构体混合物，如前所述。6通过NOE研究确认立体化学归属，并且使用催化量的二氮杂双环[5.4][5.5][5.6][5.5][ 0]十一碳-7-烯（DBU）在乙苯中的反应，产率95%。
Fused polycyclic ether containing natural products present formidable synthetic targets owing to their inherent structural complexity. 1 A variety of elegant approaches have been developed for this class of compounds with an increasing emphasis on iterative strategies. 2 The gamberic acids AD, recently isolated by Yasumoto and co-workers from a culture medium of Gambierdiscus toxicus, are particularly interesting. They have a unique ladder-like polycyclic molecular framework, consisting of nine contiguous trans-fused polyether rings with an isolated tetrahydrofuran ring. Furthermore, they have antifungal activity exceeding that of amphotericin B by more than 3 orders of magnitude, making them of significant therapeutic interest. The biological activity exhibited by these agents has been attributed to the symbiotic combination of all four gamberic acids, providing an intriguing question with regard to the mechanism of action. 3 In this paper, we describe an iterative acyl radical cyclization strategy for the synthesis of the key left hand (BC segment) 3 (n) 2) and right hand (IJ segment) 3 (n) 1) components of this extremely important molecule. 4-6 Our retrosynthetic analysis envisioned the molecule being disconnected into two complex tetracyclic units, namely the BCDE and GHIJ subunits, each of which should be accessible via the strategy outlined in Scheme 1.Scheme 2 summarizes the initial sequence devised for the synthesis of the tetrahydropyran-3-one and oxepin-3-one systems. 6 Treatment of the secondary alcohols 4a7 and 4b8 with methyl propiolate and tributylphosphine furnished the vinylogous carbonates, 9 which were oxidized directly with Jones reagent to the corresponding carboxylic acids 5a and 5b in 82% and 81% overall yield, respectively. 10 The carboxylic acids 5a and 5b were then converted to the acyl selenides 6a and 6b in 86% and 85% yield, using the Crich protocol. 11 Treatment of the acyl selenides 6a and 6b with tris (trimethylsilyl) silane and triethylborane at room temperature, in the presence of air, furnished the cyclic ethers 7a/8a and 7b/8b in 94% and 90% yield as 5.7: 1 and g19: 1 mixture of stereoisomers, respectively, as previously reported. 6 The stereochemical assignments were confirmed by NOE studies, and the mixture of tetrahydropyran-3-ones 7a/8a equilibrated to the thermodynamically more stable cis-diastereoisomer 7a (16-19: 1) using a catalytic amount of diazabicyclo [5.4. 0] undec-7-ene (DBU) in refluxing benzene in 95% yield.