Abstract
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.
Highlights
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
One of the simplest ways to generate target carboxylic acids would exist of taking simple, readily available variants, and modifying the carbon chain by, for example, introducing functional groups, forming additional carbon–carbon bonds, and introducing chirality. This implies conjugate addition of organometallics, a highly important and widely used method, that allows the introduction of carbon–carbon (C–C) bonds and chirality in a single step[4,5,6,7]. Applying this method to unprotected α,βunsaturated carboxylic acids is inhibited by a fundamental problem, namely that upon mixing with common organometallics the acidity of the carboxylic acids and the basicity of the organometallics invariably leads to deprotonation and the formation of carboxylate salts, as the organometallic functions primarily as a base instead of as a nucleophile (Fig. 1a)
We realized that the fundamental issue of the acid–base reactions leading to the formation of unreactive carboxylate salts could be circumvented by in situ formation of a reactive intermediate B from or instead of the carboxylate salt A (Fig. 2a)
Summary
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. Even though the first effort to do this, in a non-enantioselective manner, dates back to 19538, and despite many further attempts[9,10,11,12,13], to our knowledge no examples of direct applications of unsaturated carboxylic acids in either catalytic or stoichiometric enantioselective reactions with hard organometallics, nor with organoboron or organosilicon reagents, are known This is unfortunate, given that carboxylic acids are not just the main precursors of various carbonyl compounds and common components of biologically active compounds but, perhaps even more importantly, because of their potential for application in decarboxylative coupling reactions that have witnessed tremendous progress in recent years and would allow access to a variety of β-chiral functionalized molecules in a simple manner (Fig. 1b)[14,15,16,17,18,19]. Making this possible via additions of organometallics directly to unprotected α,β-unsaturated carboxylic acids would present a unique and important step forward in organic synthesis, but requires circumventing the fundamental issue of the acid–base reactions hindering the desired carbon–carbon bondforming process
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