Chiral Aminophosphines as Catalysts for Enantioselective Double-Michael Indoline Syntheses

Abstract

The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient acetylenes is an efficient process for the synthesis of many nitrogen-containing heterocycles. Because the resulting heterocycles contain at least one stereogenic center, this double-Michael reaction would be even more useful if an asymmetric variant of the reaction were to be developed. Aminophosphines can also facilitate the double-Michael reaction and chiral amines are more readily available in Nature and synthetically; therefore, in this study we prepared several new chiral aminophosphines. When employed in the asymmetric double-Michael reaction between ortho-tosylamidophenyl malonate and 3-butyn-2-one, the chiral aminophosphines produced indolines in excellent yields with moderate asymmetric induction.

Effect of Anchimeric Assistance in the Reaction of Triphenylphosphine with α,β‐Unsaturated Carboxylic Acids

“…A rate increase due to neighboring group participation is known as anchimeric assistance or synartetic acceleration. This is a general chemical phenomenon covering reactions of various mechanisms and is also typical for enzymatic reactions, effecting a complementary reduction of their energy barriers . A well‐known example of anchimeric assistance in nucleophilic substitution reactions is the hydrolysis of yperite (also known as mustard gas), in which a lone electron pair of the heteroatom in the β‐position relative to the leaving group attached to the α‐carbon atom generates a three‐membered ring that extremely facilitates the reaction (Scheme ).…”

Phosphine Organocatalysis

“…Khong and Kwon synthesized several proline-derived chiral phosphines as potential catalysts for an asymmetric double-Michael reaction (Scheme 441). 515 Nevertheless, they observed low enantioselectivities, with the chiral phosphine P80 being one of the better catalysts.…”

Chiral phosphines in nucleophilic organocatalysis

“…To develop its asymmetric variant, Kwon and co-workers examined several common and commercially available chiral bisphosphines, as well as a series of newly prepared chiral aminophosphines [96]. Unfortunately, these phosphines displayed no or very poor enantioselectivity.…”

“…The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient alkynes provides an efficient approach for the synthesis of biologically significant nitrogen-containing heterocycles. To develop its asymmetric variant, Kwon and co-workers examined several common and commercially available chiral bisphosphines, as well as a series of newly prepared chiral aminophosphines [ 96 ]. Unfortunately, these phosphines displayed no or very poor enantioselectivity.…”