Enantioselective concomitant creation of vicinal quaternary stereogenic centers via cyclization of alkynols triggered addition of azlactones

An asymmetric cyclization of alkynols triggered addition of azlactones catalyzed by a combined catalyst system consisting of a chiral gold phosphate and a phosphoric acid produces conformationally restricted amino acid precursors bearing vicinal quaternary stereogenic centers in high levels of stereoselectivity. 2011 Elsevier Ltd. All rights reserved. The enantioselective construction of quaternary stereogenic centers has long been holding great importance, but accepted as a challenging task in organic synthesis. As a result, great efforts have been made in this field, leading to elegant advances on the enantioselective formation of the single quaternary stereogenic carbon and of adjacent quaternary and tertiary stereogenic centers. Unarguably, the concomitant creation of the vicinal quaternary stereogenic centers in highly enantioselective manner is an even more formidable challenge owing to the huge steric repulsion between the two tetrasubstituted carbons. So far, very few successful methods have been available to forge the skeletons of this type, including intramolecular double Heck reaction, aldol reaction, [3+2] cycloaddition, and others. All these reactions involve substrates with pre-quaternary carbon centers where the reactions take place (Eq. 1). Herein, we propose an alternative strategy, which consists of a conversion of a linear functionality, carbon– carbon triple-bond, to an electrophile with a pre-quaternary carbon center able to subsequently undergo an addition reaction, to enantioselectively afford vicinal quaternary stereogenic centers (Eq. 2). As proof-of-principle, we will present a highly enantioselective intramolecular cyclization of alkynols triggered addition reaction of azlactones catalyzed by a combined catalyst system of a gold complex and a chiral Brønsted acid. ll rights reserved. X + Y X Chiral Cat pre-quaternary carbon centers: X = C (Heck and 3+2), O (aldol, alkylation) Y = Proton or leaving group Previous Strategy for Concomitant Creation of Vicinal Quaternary Stereogenic Centers