A surprising mechanistic "switch" in Lewis acid activation: a bifunctional, asymmetric approach to alpha-hydroxy acid derivatives.
A surprising mechanistic "switch" in Lewis acid activation: a bifunctional, asymmetric approach to alpha-hydroxy acid derivatives.
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DOI：
10.1021/ja806818a
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发表时间：
2008-12-17
影响因子：
15
通讯作者：
Lectka T
中科院分区：
文献类型：
--
作者：
Abraham CJ;Paull DH;Bekele T;Scerba MT;Dudding T;Lectka T
我们报道了一种特殊的双功能、有序的杂化Diels-Alder/开环反应的详细的合成和机理研究。在该反应中，手性金属络合的烯醇酸酯与邻苯二酚反应，以极高的产率合成了高度对映富集型的α羟基化的羰基衍生物。许多Lewis酸与金鸡纳生物碱衍生物一起进行了筛选；令人惊讶的是，反式-(Ph3p)2PdCl2被发现在产率和反应速度方面获得了最显著的提高。通过分子模拟、红外光谱、紫外光谱和核磁共振光谱研究了一系列的Lewis酸结合基序。我们的观察证明了一个基本的机械“开关”--即形成串联的Lewis碱/Lewis酸激活的金属烯酸，而不是金属配位的苯醌物种(如在邻苯二酚衍生物的其他反应中观察到的)。该方法被应用于多种药物靶标的合成，每个靶标都具有较高的产率和对映体选择性。
We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential hetero-Diels–Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with o-quinones to afford highly enantioenriched, α-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph3P)2PdCl2 was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV and NMR spectroscopy. Our observations document a fundamental mechanistic “switch” – namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metal-coordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.
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