Stereoselective 1,2‒ and 1,4‒Additions Enabled by Asymmetric Organocatalysis

Abstract

I. Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters. Enantio- and diastereoselective conjugate addition reactions between nitroethane or nitropropane and enone diesters are described. A bifunctional triaryliminophosphorane catalyzed the addition reaction with consistently excellent stereoselectivities and yields across a wide range of substrates. Using the geminal diester functional handle present in the adducts, local desymmetrization via diastereotopic group discrimination was demonstrated and a polyfunctionalized lactam with three contiguous stereocenters was synthesized. II. Asymmetric Organocatalytic Sulfa-Michael Addition to Enone Diesters. An asymmetric sulfa-Michael addition of alkyl thiols to enone diesters is reported. The reaction is catalyzed by a bifunctional triaryliminophosphorane-thiourea organocatalyst and provides a range of α-sulfaketones in high yields and enantioselectivities. Leveraging the gem-diester functional handle via a subsequent diastereotopic group discrimination generates functionalized lactones with three contiguous stereocenters. III. Efforts Towards the Reduction of α-Imino Esters via Dynamic Kinetic Resolution. Efforts toward the enantioconvergent trichlorosilane-mediated reduction of β-substituted α-imino esters are described. Chiral Lewis base catalysis enables the synthesis of N-aryl unnatural amino esters with β-alkyl or β-halo substitution in moderate yields and stereoselectivities. Reactions of β-alkyl α-imino esters provided suffered from poor diastereoselectivity, whereas decomposition and product instability plagued the β-halo analogs. Additional complicating factors associated with dynamic kinetic resolution and imine chemistry are broadly discussed and noted in this work. IV. Organocatalytic Iso-Pictet-Spengler Reaction for the Enantioconvergent Synthesis of Tetrahydro-γ-Carbolines. Progress towards an enantioconvergent iso-Pictet-Spengler reaction using thiourea/Brønsted acid co-catalysis is reported. Preliminary control studies demonstrated a significant difference in reactivity between α-substituted β-formyl amides and esters, with the latter proving amenable for asymmetric reaction development. Optimized conditions provide unprotected tetrahydro-γ-carbolines with two contiguous stereocenters, including an exocyclic stereogenic center and orthogonal ester functional handle. Finally, promising efforts to expand the substrate scope to include α- and β-keto esters are disclosed.Doctor of Philosoph