Metal-Free, Organocatalytic Asymmetric Transfer Hydrogenation of ?,?-Unsaturated Aldehydes
Metal-Free, Organocatalytic Asymmetric Transfer Hydrogenation of ?,?-Unsaturated Aldehydes
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DOI：
10.1002/ange.200462432
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发表时间：
2005
影响因子：
--
通讯作者：
J. Yang;M. H. Fonseca;N. Vignola;B. List
中科院分区：
文献类型：
--
作者：
J. Yang;M. H. Fonseca;N. Vignola;B. List
不对称催化氢化用于制药和精细化学品的大规模工业生产，也用于所有生物体。虽然化学氢化需要金属催化剂或使用化学计量的金属氢化物，[1]生物体通常依赖于有机辅因子，如烟酰胺腺嘌呤二核苷酸（NADH）与金属酶的组合。[2]到目前为止，无金属催化不对称氢化反应在化学合成中是未知的，在自然界中似乎是罕见的。[3]在这里，我们表明，一个小的有机分子有效地催化高对映选择性仿生转移氢化的α，β-不饱和醛使用合成的二氢吡啶辅因子。在工业上，金属催化氢化是最常用的催化不对称方法。从反应产物中完全除去金属杂质虽然困难，但由于毒性问题，在药物中间体的生产中通常需要。[4]有机催化是一个快速发展的研究领域，其优点之一是普遍缺乏金属。[5]我们最近开发了α，β-不饱和醛1与Hantzsch酯2的胺催化的非不对称转移氢化[Eq.①]。[6]该反应是烯烃完全无金属转移氢化的第一个例子。[7]我们还可以证明，该反应的对映选择性亚胺催化在原则上是可能的。碘催化是近年来发展起来的一种有机催化方法，可用于羰基的共轭加成和环加成反应。[8]我们现在已经完成了广泛的筛选几个合成和市售的Hantzsch二氢吡啶和手性铵盐催化剂，并在这里报告一个有效的对映选择性的变体，我们的转移氢化。
Asymmetric catalytic hydrogenations are used in the largescale industrial production of pharmaceuticals and fine chemicals and also by all living organisms. While chemical hydrogenations require metal catalysts or the use of stoichiometric amounts of metal hydrides,[1] living organisms typically rely on organic cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with metalloenzymes.[2] Until now, metal-free catalytic asymmetric hydrogenations have been unknown in chemical synthesis and seem to be rare in nature.[3] Here we show that a small organic molecule effectively catalyzes a highly enantioselective biomimetic transfer hydrogenation of α, β-unsaturated aldehydes using a synthetic dihydropyridine cofactor. Industrially, metal-catalyzed hydrogenations are the most often used catalytic asymmetric processes. The complete removal of metal impurities from the reaction product, though difficult, is generally required in the production of pharmaceutical intermediates because of toxicity concerns.[4] Organocatalysis is a rapidly growing area of research, and one of its advantages is the general lack of metals.[5] We have recently developed an amine-catalyzed nonasymmetric transfer hydrogenation of α, β-unsaturated aldehydes 1 with Hantzsch ester 2 [Eq.(1)].[6]This reaction is the first example of a completely metalfree transfer hydrogenation of olefins.[7] We could also show that enantioselective iminium catalysis of the reaction is in principle possible. Iminium catalysis has recently been introduced as a powerful organocatalytic method for carbonyl transformations such as conjugate additions and cycloadditions.[8] We have now completed an extensive screening of several synthetic and commercially available Hantzsch dihydropyridines and chiral ammonium salt catalysts and report here on an efficient enantioselective variant of our transfer hydrogenation.