Enantioselective total synthesis of batzelladine F: Structural revision and stereochemical definition
Enantioselective total synthesis of batzelladine F: Structural revision and stereochemical definition
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DOI：
10.1021/ja017067m
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发表时间：
2001-10-31
影响因子：
15
通讯作者：
Overman, LE
中科院分区：
文献类型：
--
作者：
Cohen, F;Overman, LE
1997年，Patil和同事报道了从牙买加红色海绵中分离出batzelladines FI，当时被错误地鉴定为Batzella sp. 1,2。这些生物碱每个含有两个三环胍，并被发现诱导蛋白酪氨酸激酶p56lck从CD4分离。据推测，破坏这种相互作用可用于治疗自身免疫性疾病。我们对batzelladine F(1)的兴趣是2倍。首先，我们对制备抑制特定蛋白质-蛋白质相互作用的化合物感兴趣，其次，我们试图完全定义batzelladine F的立体化学，其中大部分在这项工作开始时尚不清楚。巴齐拉定F右三环部分（C20 ~ C29）的相对构型与合成后确定的巴齐拉定D的相对构型进行了对比1。左三环部分最初被认为在C4和C7的角氢之间有反关系。根据Snider和Murphy的模型研究，这种相对构型随后被修正为syn。5没有关于两种三环胍的相对构型的相关信息，也没有指定C18的构型。因此，有八种化合物（四对对映体）符合修改后的batzelladine F结构的现有数据。直到我们合成了每种结构的一个对映体，才清楚提出的batzelladine F的连性也是不正确的。在这里，我们报告了我们对巴齐拉定f正确结构1的对映选择性全合成。我们的合成策略概述在方案1中。我们设想右三环胍是由五环双胍演变而来的。这种中间体可能是β-酮酯和胍类半胺之间高度收敛的比奇内利缩合反应的产物；含壬基侧链的类似物4的合成，我们以前已经报道过。4b三氮杂萘3被认为是由β-酮酯6和胍半胺5之间的聚合、同步选择性系链Biginelli缩合产生的，然后是脱羧和还原。从羟基丁酸7,10开始合成，以58%的总收率转化为二胺8（方案2）。我们早前制备了一种类似的含有壬基链的二胺作为巴齐拉定b的前体。用新型胍基化试剂9将二胺8转化为受保护胍10。11,12氢解除去10的Cbz基团，所得产物的缩醛用醋酸水溶液裂解，得到胍半胺5。该中间体与β-酮酯6在我们先前优化的合成立体选择条件下缩合，得到三氮杂苊
In 1997, Patil and co-workers reported the isolation of batzelladines FI from a red Jamaican sponge incorrectly identified at the time as Batzella sp. 1, 2 These alkaloids each contain two tricyclic guanidines and were found to induce dissociation of protein tyrosine kinase p56lck from CD4. It was postulated that disruption of this interaction could be used to treat autoimmune disorders. Our interest in batzelladine F (1) was 2-fold. First, we were interested in preparing compounds that inhibit specific protein-protein interactions, and second, we sought to define totally the stereochemistry of batzelladine F, much of which was unclear at the outset of this work. The relative configuration of the right-hand tricyclic portion of batzelladine F (C20 through C29) was assigned1 by comparison of its 13C NMR spectrum to that of batzelladine D, 3 the configuration of which had been established by synthesis. 4 The lefthand tricyclic moiety was originally proposed to have an anti relationship between the angular hydrogens at C4 and C7. This relative configuration was subsequently revised to syn based on model studies by Snider and Murphy. 5 There was no information that related the relative configurations of the two tricyclic guanidines nor specified the configuration at C18. Thus, there were eight compounds (four pairs of enantiomers) that fit the available data for the revised structure of batzelladine F. It did not become clear until we had synthesized one enantiomer of each structure that the proposed connectivity of batzelladine F was also incorrect. 6 Herein, we report our enantioselective total synthesis of the correct structure 1 of batzelladine F. Our synthesis strategy is outlined in Scheme 1. 7 We envisaged the right-hand tricyclic guanidine as evolving from pentacyclic bisguanidine 2. This intermediate would be the product of a highly convergent tethered Biginelli condensation8 between β-keto ester 3 and guanidine hemi-aminal 4; a synthesis of an analogue of 4 bearing a nonyl side chain had been described by us earlier. 4b Triazaacenaphthalene 3 was seen as arising from a convergent, syn selective tethered Biginelli condensation between β-keto ester 6 and guanidine hemi-aminal 5, 9 followed by decarboxylation and reduction.The synthesis began with hydroxybutyrate 7, 10 which was converted to diamine 8 in 58% overall yield (Scheme 2). A similar diamine bearing a nonyl chain had been prepared by us earlier as a precursor to batzelladine B. 9 Diamine 8 was converted to protected guanidine 10 with novel guanylating reagent 9. 11, 12 The Cbz group of 10 was removed by hydrogenolysis and the acetal of the resulting product was cleaved with aqueous acetic acid to provide guanidine hemi-aminal 5. This intermediate was condensed with β-keto ester 6, under conditions we had optimized earlier for syn stereoselection, 9 to provide triazaacenaphthalene