Abstract
The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated α-substituted acrylate esters catalyzed by a bifunctional iminophosphorane organocatalyst under mild conditions is described. The strong Brønsted basicity of the iminophosphorane moiety of the catalyst provides the necessary activation of the alkyl thiol pro-nucleophile, while the two tert-leucine residues flanking a central thiourea hydrogen-bond donor facilitate high enantiofacial selectivity in the protonation of the transient enolate intermediate. The reaction is broad in scope with respect to the alkyl thiol, the ester moiety, and the α-substituent of the α,β-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivities (up to 96% ee), and is amenable to decagram scale-up using catalyst loadings as low as 0.05 mol %.
Highlights
An effective approach to overcoming low inherent reagent electrophilicity in Brønsted base catalyzed addition reactions of pronucleophiles is to raise the Brønsted basicity of the catalyst.[7]
We recently developed a new family of modular bifunctional iminophosphorane (BIMP) superbase organocatalysts for the first general enantioselective organocatalytic nitro-Mannich reaction to unactivated ketimines;[8] a reaction where an organosuperbase was essential for reactivity.[9]
We postulated that the poor reactivity of unactivated methacrylate esters toward nucleophilic addition may be overcome using our BIMP organosuperbase family (Scheme 1)
Summary
An effective approach to overcoming low inherent reagent electrophilicity in Brønsted base catalyzed addition reactions of pronucleophiles is to raise the Brønsted basicity of the catalyst.[7]. One class of Michael acceptor, α,βunsaturated esters substituted with alkyl or aryl groups at either the α- or β-position, has remained a persistent challenge in enantioselective organocatalysis due to their low inherent electrophilicity[4] and low propensity for catalyst activation.
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