Brønsted acid promoted additions of diazoalkanes to imines: the interplay of mechanism and stereochemical outcome as a tool to discover and develop a new syn glycolate Mannich reaction

Abstract

The 1,2-amino alcohol is a prevalent motif in natural products with biological activity. Many synthetic methods exist for the synthesis of 1,2-amino alcohols. Yet few are capable of setting both stereocenters in a single step under metal free conditions. Brønsted acids of varying strength have received considerable attention in recent years for the metal free catalysis of a variety of reactions. The Brønsted acid catalyzed diastereoselective aza-Darzens reaction demonstrated that azomethines could be selectively activated toward diazoalkanes using Brønsted acids and with significant stereocontrol. The development of a new Brønsted acid catalyzed, diastereoselective glycolate Mannich reaction for the synthesis of syn-α-oxy-β-amino ester derivatives is described in this dissertation. The products are obtained in good yield through a highly diastereoselective addition. Studies were performed to determine the optimal acid, imine, solvent, and temperature for the reaction. A variety of imines were found to be efficient substrates for the reaction. The design and synthesis of a novel α-diazoimide was a key development of this study. The inspiration for the α-diazoimide was a result of our studies on the mechanism of the addition of diazoalkanes to imines in the presence of triflic acid. These results are informative in light of concurrent studies on the transformation of triazolines to either cis-aziridines or anti-oxazolidindione products in the presence of triflic acid. A clearer picture of the mechanisms of these two reactions has emerged as a result of the analysis of the stereochemical outcome of both reactions. The evidence also supports a closed transition state that avoids formation of a discrete alkyl diazonium intermediate. These findings extend the utility of diazo alkanes as carbene equivalents using non-redox catalysis.