Catalytic enantioselective aldol-type reaction of beta-ketosters with acetals.
Catalytic enantioselective aldol-type reaction of beta-ketosters with acetals.
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DOI：
10.1002/anie.200705344
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发表时间：
2008-05
影响因子：
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通讯作者：
N. Umebayashi;Y. Hamashima;D. Hashizume;M. Sodeoka
中科院分区：
文献类型：
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作者：
N. Umebayashi;Y. Hamashima;D. Hashizume;M. Sodeoka
光学活性β-氧羰基化合物是有机合成化学中有用的中间体，人们在催化不对称羟醛反应的发展上付出了巨大的努力。利用手性路易斯酸和手性仲胺开发了出色的方法，其中酮及其甲硅烷基衍生物与醛以高度对映选择性的方式反应。相比之下，易于烯醇化的1,3-二羰基化合物，例如β-酮酯和丙二酸酯很少被用作亲核试剂，可能是因为此类化合物的金属烯醇化物的亲核性不足，尽管另一种可能的解释是产物不稳定并且容易发生逆醛醇反应（方案1）。由于这些普遍的困难，利用π-烯丙基钯化学、羟醛反应和氧-迈克尔反应合成光学活性β-羟基丙二酸酯的例子很少。对于1,3-二羰基化合物的催化羟甲基化反应，我们最近报道了使用多聚甲醛作为C1单元的β-酮酯的催化不对称羟甲基化反应。然而，与反应性较低的醛的反应很困难（见下文），我们在文献中没有发现先例。此前，我们证明手性钯烯醇化物是通过手性钯-双膦配合物1与β-酮酯反应形成的，并伴随着质子酸的形成（方案1）。我们设想该质子可能会激活O,O-缩醛，生成氧鎓中间体，从而使与β-酮酯的醇醛型反应顺利进行。由于该产物是 O-保护的，我们预计不需要的逆羟醛反应将被抑制。 O,O-缩醛作为醛的合成等价物的使用已在路易斯酸介导或催化的与甲硅烷基烯醇化物的醇醛型反应中得到了广泛研究。这些反应的一般原理是手性诱导很难实现，因为手性路易斯酸与前手性亲电子试剂的相互作用很弱（方案 2）。据我们所知，尚未报道此类反应的不对称版本。在这里，我们公开了使用手性 Pd 和 Pt 配合物催化 O,O-缩醛的不对称羟醛型反应的第一个例子，其中前手性 β-酮酯的手性金属烯醇化物是关键中间体。
Optically active β-oxycarbonyl compounds are useful intermediates in synthetic organic chemistry, and great efforts have been devoted to the development of catalytic asymmetric aldol reactions. Excellent methods have been developed with chiral Lewis acids and chiral secondary amines, in which ketones and their silyl derivatives react with aldehydes in a highly enantioselective manner. In contrast, readily enolizable 1,3-dicarbonyl compounds, such as β-keto esters and malonates have rarely been used as nucleophiles, probably because of insufficient nucleophilicity of the metal enolates of such compounds, although a plausible alternative explanation is that the products are unstable and readily undergo retro-aldol reaction (Scheme 1). Because of these general difficulties, there are only a few examples of the synthesis of optically active β-oxymalonates using π-allyl Pd chemistry, aldol reaction, and oxy-Michael reaction. As for catalytic aldol reactions of 1,3-dicarbonyl compounds, we recently reported a catalytic asymmetric hydroxymethylation of β-keto esters using paraformaldehyde as a C1 unit. However, reactions with less reactive aldehydes were difficult (vide infra), and we found no precedents in the literature. Previously, we showed that chiral Pd enolates were formed by the reaction of chiral Pd-bisphosphine complexes 1 with β-keto esters, being accompanied with the formation of a protic acid (Scheme 1). We envisaged that this proton might activate O,O-acetals to give an oxonium intermediate, so that aldol-type reactions with β-keto esters would proceed smoothly. Since the product is O-protected, we expected that the undesired retro-aldol reaction would be suppressed. The use of O,O-acetals as a synthetic equivalent of aldehydes has been extensively investigated in Lewis acid-mediated or catalyzed aldol-type reactions with silyl enolates. A general principle of these reactions is that chiral induction is hard to achieve, since the chiral Lewis acid interacts only weakly with the prochiral electrophile (Scheme 2). To our knowledge, no asymmetric version of such reactions has been reported. Here, we disclose the first example of a catalytic asymmetric aldol-type reaction of O,O-acetals using chiral Pd and Pt complexes, in which the chiral metal enolates of prochiral β-keto esters are the key intermediates.