Site-selective and Stereoselective Syntheses Controlled by the Electron-withdrawing Properties of Cationic Heterocycles

This article describes our stereoselective and site-selective chemical methods for exploiting cationic heterocycles as electron-withdrawing groups (EWGs). We envisioned that the phosphoramide N-H proton of a pyridyl phosphoramide 3 would be activated by the cationic pyridinium moiety that is formed upon protonation. The resulting imide-like N-H proton and the acidic pyridinium proton of the pyridinium phosphoramide 3-HX cooperate together, making 3-HX a highly acidic dual Bronsted acid. The catalytic ability of 3-HX was demonstrated in the development of the first asymmetric Diels-Alder reaction between 1-amide dienes and maleimides. Focusing on the activation of N-bromosuccinimide (NBS) because of its structural similarity to maleimides, the enantioselective bromolactonization of trisubstituted olefinic acids was accomplished utilizing pyridyl phosphoramide 3f as a Bronsted base catalyst bearing an acidic N-H proton. Lastly, our strategy for the site-selective acylation of polyol compounds is described. In our system, a pyridine aldoxime ester 10, used as a mild acylating reagent, was activated by a catalytic amount of Lewis acid via the inductive effect of the cationic pyridinium moiety. The resulting metal complex preferentially attracted the alcohol with a Lewis basic site, thereby facilitating selective acylation via a template effect. This metal-template-driven strategy allowed for the site-selective acylation of diverse alpha-hydroxyamides, including unprotected N-glycolyl aminosugars.