Intramolecular hydrogen bonding guides a cationic amphiphilic organocatalyst to highly stereoselective aldol reactions in water

Abstract

A novel amphiphilic acylguanidine organocatalyst using intramolecular hydrogen bonding as a key structural motif is efficient for asymmetric aldol reactions of ketones in water at neutral pH.

Green Asymmetric Organocatalysis

“…A neutral solution with pH 7 was the most suitable for hydrogen bonds between the guanidine catalyst and substrates. Desired product 13 a was synthesized in 96 % yield, dr 28:1, and 96 % ee ( anti ; Scheme a) …”

A copper-templated, bifunctional organocatalyst: a strongly cooperative dynamic system for the aldol reaction

“…[11][12] The following recent example also shows the potential of metal-bound organocatalytic ligands: Mirkin et al have demonstrated how Pt complexes bearing amino-squaramide P,S-ligands can be allosterically regulated by HCl in the nonasymmetric Michael addition of nitroethane to nitrostyrene. 19 In the context of our program aimed at understanding and developing water-tolerant organocatalysts [20][21][22][23][24] and dynamic systems able to recognize organic molecules in aqueous environment, [25][26] we have recently developed a metaltemplated, dynamic approach wherein ligands and metal salts were simply mixed together to generate efficient organocatalytic asymmetric systems. Catalysis was carried out solely through the ligands, which upon binding to the metal center generate a new bifunctional, efficient catalyst in the asymmetric aldol reaction (Scheme 1).…”

An efficient dynamic asymmetric catalytic system within a zinc-templated network

“…We recently approached this issue through a simple methodology combining our developments in dynamic systems [12][13][14][15][16][17][18][19] and organocatalysis. [20][21][22][23] In our approach, the rapidly exchanging metalÀpyridine ligand bonds furnished the catalytic network. The dynamic system thus generated contained sufficient amounts of a catalytically (kinetically) competent self-assembled species leading to high reaction rate acceleration and subsequent high enantioselectivity in the direct aldol reaction.…”

“…was crucial to ensure the activity of the catalytic system, as we have always encountered during the development of organocatalytic Michael and aldol reactions. [20][21][22][23][24][25][26][27] Moreover, our methodology involves the catalyst pre-formation in solution for 1 hour at room temperature before the reaction temperature is set and substrates are added. Otherwise, an induction period is observed before the catalytic activity can be detected (see ESI ‡ for details).…”

“…This is not strange since we and others already showed some time ago the important electronic effects that hamper the reactivity of electron rich aldehydes in this reaction. 23,[34][35][36] In turn, cyclopentanone and acetone yielded the aldol products in high yields but modest stereoselectivities (entries 8 and 9).…”