Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds

Abstract

The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.

A One-Pot Cascade Strategy toward Organocatalytic Enantioselective Construction of Fused Benzimidazoles

“…In contrast to the racemic condensation of ortho -diaminobenzene with dialdehyde/formyl-tethered cyclohexadienone under the influence of formic acid/TFA, currently, there remains a lack of comprehensive reports detailing the organocatalytic synthesis of enantioenriched fused benzimidazoles through amination/aza-Michael addition reactions (Scheme Ac) . Reviewing relevant literature on such a methodology, we found that the Liqin Qiu group documented a chiral phosphoric acid-catalyzed cascade reaction in 2014, where the cascade sequence involves imine formation–nucleophilic addition followed by lactamization (Scheme B)…”