Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
Nat Commun. 2019 Jul 30;10(1):3402. doi: 10.1038/s41467-019-11345-z.
Conjugate addition of organometallics to carbonyl based Michael acceptors is a widely used method that allows the building of new carbon-carbon (C-C) bonds and the introduction of chirality in a single step. However, conjugate additions to the simplest Michael acceptors, namely unprotected, unsaturated carboxylic acids, are considered to be prohibited by the fact that acid-base reactions overpower any other type of reactivity, including nucleophilic addition. Here we describe a transient protecting group strategy that allows efficient catalytic asymmetric additions of organomagnesium reagents to unprotected α,β-unsaturated carboxylic acids. This unorthodox pathway is achieved by preventing the formation of unreactive carboxylate salts by means of a reactive intermediate, allowing modifications of the carbon chain to proceed unhindered, while the stereochemistry is controlled with a chiral copper catalyst. A wide variety of β-chiral carboxylic acids, obtained with excellent enantioselectivities and yields, can be further transformed into valuable molecules through for instance catalytic decarboxylative cross-coupling reactions.
有机金属试剂与羰基化合物的共轭加成是一种广泛应用的方法，可在一步反应中构建新的碳-碳（C-C）键并引入手性。然而，对于最简单的迈克尔受体，即未保护的不饱和羧酸，共轭加成被认为是被禁止的，因为酸碱反应会压倒任何其他类型的反应性，包括亲核加成。在这里，我们描述了一种瞬态保护基策略，该策略允许未保护的α，β-不饱和羧酸的高效催化不对称有机镁试剂加成。这种非传统途径是通过使用反应性中间体来防止形成无反应性的羧酸盐来实现的，从而允许不受阻碍地进行碳链修饰，同时通过手性铜催化剂控制立体化学。通过例如催化脱羧交叉偶联反应，可以进一步将通过该方法获得的各种β-手性羧酸转化为有价值的分子，这些羧酸具有优异的对映选择性和产率。
