Synthesis of Enantiopure 3-Substituted Pyrroline N-Oxides by Highly Regioselective Oxidation of the Parent Hydroxylamines: A Mechanistic Rationale

The syntheses of four new, differently O-substituted 3-hydroxypyrroline N-oxides and the first 3-amino analogue have been performed by the use of a strategy involving double nucleophilic displacement of the corresponding dimesylates by hydroxylamine and oxidation of the resulting 1-hydroxypyrrolidines. The regioselectivity data of the oxidation reactions nicely confirm the mechanistic hypothesis, which explains the dependence on the electronic nature of the substituent. The trend of the regioselectivity ratio has useful predictive value. Practical complete regioselection has been obtained by substitution with a benzoyloxy functionality. The O-allyl-substituted nitrone is not stable in the reaction conditions, undergoing immediately an intramolecular cycloaddition reaction with complete stereocontrol and inversion of regio- and stereoselectivity with respect to the intermolecular case.