Total synthesis of (+)-azaspiracid-1.: part II:: Synthesis of the EFGHI sulfone and completion of the synthesis
Total synthesis of (+)-azaspiracid-1.: part II:: Synthesis of the EFGHI sulfone and completion of the synthesis
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DOI：
10.1002/anie.200701520
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Favor, David A.
中科院分区：
文献类型：
--
作者：
Evans, David A.;Dunn, Travis B.;Favor, David A.
如方案1中所概述，将衍生自3的异头砜阴离子添加至如由醛2表示的C20-亲电试剂，可以提供对目标的高度收敛的方法。由于azaspiracid-1（1）的所有9个环在该最终片段偶联之前形成，因此偶联步骤后所需的操作次数将是最少的。这种异头砜阴离子加成有相当多的先例，无论是在衍生自碳水化合物的异头砜阴离子的原始研究[2，3]中，还是随后在全合成中的高级片段偶联[4-6]中，尽管关键的砜阴离子3与亲电试剂如醛2的加成将代表迄今为止最复杂的异头砜阴离子加成。五环砜3的HI螺缩醛胺部分的构象分析（图1）表明，基于异头稳定性和空间效应分析，该合成子以其有利构型存在。因此，将许多缩酮化事件并入3的组装体中，其中预期分子在平衡条件下自发形成所需的四环FGHI体系。与构建体中间体4的片段偶联（方案1）将涉及FG环片段6的C27-甲基酮与E环醛5的硼介导加成，而衍生自7的C35-甲基酮的烯醇硅烷与6的醛的螯合物控制的Mukaiyama羟醛加成[7]预计将在C34处建立立构中心。通过观察，在E环和I环的氮杂螺酸结构中嵌入了两个构型相同的顺式1，3-二甲基二酮。我们被吸引到构建这两个亚基的可能性，从共同的
As outlined in Scheme 1, the addition of an anomeric sulfone anion derived from 3 to a C20-electrophile, as represented by aldehyde 2, could provide a highly convergent approach to the target. Since all nine rings of azaspiracid-1 (1) are formed prior to this final fragment coupling, the number of manipulations required after the coupling step would be minimal. Such anomeric sulfone anion additions have considerable precedent, both in the original investigations of anomeric sulfone anions derived from carbohydrates [2, 3] and subsequently in advanced fragment couplings in total synthesis,[4–6] although the crucial sulfone anion addition of 3 to electrophiles such as aldehyde 2 would represent the most complex anomeric sulfone anion addition to date. Conformational analysis of the HI spiroaminal portion of pentacyclic sulfone 3 (Figure1) suggests, on the basis of anomeric stabilization and an analysis of steric effects, that this synthon exists in its favored configuration. Therefore, a number of ketalization events were incorporated into the assembly of 3, in which the molecule is anticipated to spontaneously form the desired tetracyclic FGHI system under equilibrating conditions. The fragment couplings to construct intermediate 4 (Scheme 1) would involve a boronmediated addition of the C27-methyl ketone of the FG ring fragment 6 to the E ring aldehyde 5, while a chelatecontrolled Mukaiyama aldol addition [7] of the enolsilane derived from the C35-methyl ketone of 7 to the aldehyde of 6 was anticipated to establish the stereocenter at C34. By inspection, two syn 1, 3-dimethyl synthons of the same configuration are embedded in the azaspiracid structure in the E and the I rings. We were attracted to the possibility of constructing both of these subunits from the common