An efficient titanium catalyst for enantioselective cyanation of aldehydes: cooperative catalysis.
An efficient titanium catalyst for enantioselective cyanation of aldehydes: cooperative catalysis.
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DOI：
10.1002/anie.201002127
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发表时间：
2010-09
影响因子：
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通讯作者：
Zhipeng Zhang;Zheng Wang;Ruzhou Zhang;K. Ding
中科院分区：
文献类型：
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作者：
Zhipeng Zhang;Zheng Wang;Ruzhou Zhang;K. Ding
氰醇含有腈和醇，并且可以容易地操作以产生大范围的生物学上重要的化合物，包括α-羟基酸和酯、α-羟基醛和酮、α-氨基酸和β-氨基醇，其已被广泛用作工业上有价值的产品如药物、农用化学品、调味剂和香料的组分。[1-3]氰化物与羰基化合物加成生成氰醇是有机化学中最基本的碳-碳键形成反应之一。[4]自从第一次报道了杏仁提取物催化氰化氢对苯甲醛的对映选择性加成[5]以来，已经开发了许多用于合成对映体富集的氰醇的酶促方法。[6，7]然而，就催化剂的效率、成本和适应性而言，这仍然是一个巨大的挑战。或者，已报道使用人工手性刘易斯酸、碱或混合双官能刘易斯酸/碱催化剂催化对映选择性合成光学活性氰醇衍生物得到非常高的对映选择性。[4，8-13]大多数报道的方法在制备规模上的应用有限，因为实际的催化剂必须能够使反应快速，能够放大，并且在产物形成中具有选择性。[14]剩下的挑战包括催化剂的低活性和高成本，或必须使用昂贵的氰化物源。在这里，我们报告了一种高效的方法，用于不对称合成高度对映体富集的天然或非天然氰醇衍生物，使用一个优雅的催化剂设计控制的关键氰化步骤。在用于光学活性氰醇衍生物的对映选择性合成的各种人工手性催化剂中，[2-4，8-13]钛配合物[15，16]由于其低成本和容易获得而非常有前途。这一领域的一个非常重要的成就是发现了催化活性的二聚钛络合物[{（salen）Ti（μ-O）} 2]（2;方案1a），其在三甲基甲硅烷基氰化物（TMSCN）与醛的加成中具有高效率（在0.1摩尔%的催化剂负载下具有50-92%的对映选择性）。[17动力学研究揭示了1.3-1.8的催化剂级数，表明不止一个金属中心参与催化;认为两个salen-Ti= O单元同时活化醛和氰基亲核试剂。[19]然而，发现钛络合物的单体（1）和二聚体物质（2）在溶液中以浓度依赖性平衡存在。[20]我们设想，这种平衡可能降低活性二聚体物质（2）的浓度，因此对催化是有害的。因此，两个金属salen单元的适当连接可以克服催化活性二聚体解离的问题，这将导致促进亲核试剂和亲电试剂两者的协同活化的分子内双链催化剂的优势。2的分子内类似物的设计中的关键问题是如何能够适当地桥接两个金属salen单元以使催化中有利的协同作用最大化（4;方案1 B）。[21]基于上述工作假设，我们设计并合成了一系列由不同长度和空间取向的间隔基桥联的双（salen）配体（3a-f，方案1b），以考察桥联间隔基对协同催化性能的影响。钛配合物4a-f通过相应配体3a-f与2当量的Ti（OiPr）4在CH 2Cl 2中的反应制备，并且...
Cyanohydrins contain a nitrile and an alcohol, and can be readily manipulated to produce a large range of biologically important compounds including α-hydroxy acids and esters, α-hydroxy aldehydes and ketones, α-amino acids, and βamino alcohols, which have been widely used as the components of industrially valuable products such as pharmaceuticals, agrochemicals, flavorings, and fragrances.[1–3] The addition of cyanide to a carbonyl compound to form a cyanohydrin is one of the most fundamental carbon–carbon bondforming reactions in organic chemistry.[4] Since the first report of the enantioselective addition of hydrogen cyanide to benzaldehyde catalyzed by an extract of almonds,[5] numerous enzymatic methods for the synthesis of enantioenriched cyanohydrins have been developed.[6, 7] However, it is still a great challenge in terms of the efficiency, cost, and adaptability of the catalysis. Alternatively, catalytic enantioselective synthesis of optically active cyanohydrin derivatives using either an artificial chiral Lewis acid, base, or a hybrid bifunctional Lewis acid/base catalyst has been reported to give very high enantioselectivity.[4, 8–13] Most of the reported methods have seen limited applications on preparative scales since the practical catalysts must enable reactions to be rapid, capable of being scaled up, and selective in the product formation.[14] The remaining challenges include low activity and high cost of the catalysts, or the requisite use of expensive cyanide sources. Herein we report an efficient method for asymmetric syntheses of highly enantioenriched natural or nonnatural cyanohydrin derivatives using an elegantly designed catalyst to control the key cyanation step. Among various artificial chiral catalysts discovered for enantioselective synthesis of optically active cyanohydrin derivatives,[2–4, 8–13] titanium complexes [15, 16] are very promising because of their low cost and ready availability. A very important achievement in this area was the discovery of a catalytically active dimeric titanium complex [{(salen) Ti (μ-O)} 2](2; Scheme 1a) in the addition of trimethylsilyl cyanide (TMSCN) to aldehydes with high efficiency (at 0.1 mol% of catalyst loading with 50–92% enantioselectivity).[17, 18] A kinetic study disclosed a catalyst order of 1.3–1.8, indicating that more than one metal center is involved in the catalysis; the two salen–Ti= O units are thought to simultaneously activate the aldehyde and cyano nucleophile.[19] However, the monomeric (1) and dimeric species (2) of the titanium complexes were found to exist as a concentration-dependent equilibrium in solution.[20] We envisaged that such an equilibrium may reduce the concentration of active dimeric species (2) and accordingly is detrimental to the catalysis. Therefore, appropriate linking of two metallosalen units may overcome the problem of dissociation of the catalytically active dimer, which would result in the predominance of an intramolecular bimetallic catalyst that promotes the cooperative activation of both the nucleophile and electrophile. A key issue in the design of intramolecular analogues of 2 is how one can bridge two metallosalen units properly so as to maximize cooperative actions favored in the catalysis (4; Scheme 1 b).[21] On the basis of the working hypothesis mentioned above, we therefore designed and synthesized a variety of bis (salen) ligands (3a–f, Scheme 1b) bridged by spacers with diverse length and spatial orientations to investigate the impact of bridging spacers on the cooperative catalytic performance. The titanium complexes 4a–f were prepared by the reaction of the respective ligands 3a–f with 2 equivalents of Ti (OiPr) 4 in CH2Cl2 and …