Mass spectrometric screening of chiral catalysts by monitoring the back reaction of quasienantionneric products:: Palladium-catalyzed allylic substitution
Mass spectrometric screening of chiral catalysts by monitoring the back reaction of quasienantionneric products:: Palladium-catalyzed allylic substitution
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DOI：
10.1002/anie.200705081
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Pfaltz, Andreas
中科院分区：
文献类型：
--
作者：
Mueller, Constanze A.;Pfaltz, Andreas
手性催化剂的对映选择性通常通过测量反应产物的对映体过量来确定。然而，从产物分析获得的ee值不一定反映催化剂的固有对映选择性。产生外消旋产物、催化活性杂质或手性配体从金属催化剂解离的竞争性非催化背景反应可导致低对映体纯度，即使催化剂本身是高度选择性的。我们最近报道了一种利用准对映体底物和电喷雾质谱（ESI-MS）作为分析工具测定手性催化剂的本征对映体选择性的方法。[1-3]与以前开发的对映体选择性反应的筛选方法（也使用准对映体底物）相比，[4，5]我们的方法依赖于催化中间体的定量，而不是产物的分析。作为第一个应用，我们研究了外消旋烯丙基酯的动力学拆分，通过使用钯催化的烯丙基取代反应（方案1）。[6]通过以两种质量标记的准对映体底物（S）-4a和（R）-4b的1：1混合物开始，催化剂的选择性因子s= ka/kb可以由质谱法测定的相应烯丙基中间体5a/5 b的比率推导出（方案2）。由于ESI-MS允许在大量过量的中性化合物存在下选择性检测带电物质，因此即使在通常用于制备催化反应的条件下在低催化剂负载下也可以观察到阳离子中间体如5a和5 b。该方法快速可靠，不需要对反应混合物进行后处理，并且与基于产物分析的方法相比，允许同时筛选催化剂混合物（如果催化剂具有不同的分子量）。大量催化剂的筛选表明，在动力学拆分步骤中催化剂的选择性与亲核加成到烯丙基中间体2的对映选择性无关。正是该步骤决定了从外消旋烯丙基酯1到光学活性取代产物3的整个反应的对映选择性（方案1）。许多在反应中表现出高对映选择性的催化剂在烯丙基酯的动力学拆分中效率不高。在这里，我们报告我们的筛选方法，它允许在亲核加成步骤中的对映选择性的测定，因此，可以用于评估的整体烯丙基取代过程的手性催化剂的固有的对映选择性的扩展。而不是筛选的正向反应，我们监测的quasienantiomeric产品，导致相应的质量标记的烯丙基钯配合物的逆反应。根据微观可逆性原理，
The enantioselectivity of a chiral catalyst is usually determined by measuring the enantiomeric excess of the reaction product. However, the ee value obtained from analysis of the product does not necessarily reflect the intrinsic enantioselectivity of the catalyst. A competing noncatalytic background reaction which produces a racemic product, catalytically active impurities, or dissociation of a chiral ligand from a metal catalyst can lead to low enantiomeric purity even though the catalyst itself is highly selective. We recently reported a method for determining the intrinsic enantioselectivity of chiral catalysts by using quasienantiomeric substrates and electrospray ionization mass spectrometry (ESI-MS) as the analytical tool.[1–3] In contrast to previously developed screening methods for enantioselective reactions which also make use of quasienantiomeric substrates,[4, 5] our method relies on the quantification of catalytic intermediates rather than analysis of the product. As a first application, we studied the kinetic resolution of racemic allyl esters by using a palladium-catalyzed allylic substitution reaction (Scheme 1).[6] By starting with a 1: 1 mixture of two mass-labeled, quasienantiomeric substrates (S)-4a and (R)-4b, the selectivity factor s= ka/kb of a catalyst can be deduced from the ratio of the corresponding allyl intermediates 5a/5b as determined by mass spectrometry (Scheme2). As ESI-MS allows the selective detection of charged species in the presence of a large excess of neutral compounds, cationic intermediates such as 5a and 5b can be observed even at low catalyst loadings under conditions normally used for preparative catalytic reactions. The method is fast and reliable, does not require workup of the reaction mixture, and in contrast to methods based on product analysis allows the simultaneous screening of catalyst mixtures (if the catalysts have different molecular masses). The screening of a large number of catalysts showed that the selectivity of a catalyst in the kinetic resolution step did not correlate with the enantioselectivity of the nucleophilic addition to the allyl intermediate 2. It is this step that determines the enantioselectivity of the overall reaction leading from the racemic allyl ester 1 to the optically active substitution product 3 (Scheme 1). Many catalysts that gave high enantioselectivity in the overall reaction were inefficient in the kinetic resolution of allyl esters. Herein we report an extension of our screening method which allows the determination of the enantioselectivity in the nucleophilic addition step and can, therefore, be used to evaluate the intrinsic enantioselectivity of chiral catalysts for the overall allylic substitution process. Instead of screening the forward reaction, we monitored the back reaction of quasienantiomeric products that leads to the corresponding mass-labeled allyl–palladium complexes. According to the principle of microscopic reversibility, the transition states of