• Asymmetric Synthesis of Nitrogen Containing Bioactive Compounds via the Utilization of Enantiopure p-Toluenesulfinimines

      Davis, Franklin A.; Andrade, Rodrigo B.; Dalton, David R., 1936-; Cannon, Kevin C. (Temple University. Libraries, 2013)
      The research objective of this thesis research was to develop new methods for the asymmetric synthesis of amine derivatives using p-toluenesulfinimines. Enantiopure sulfinimines are versatile chiral building blocks for the asymmetric synthesis of alkaloids. Sulfinimines were prepared by the condensation of (S)- or (R)-p-toluenesulfinamide with aldehydes and ketones in good to excellent yields, which were prepared from the commercially available Anderson reagent. The first research project was the development of a new method for the preparation of enantiopure anti-anti- α-lkyl β-amino ketones and was accomplished by the stereoselective α-alkylation of enolates of sulfinimine derived β-amino esters. The anti- α-lkyl β-amino esters were transformed to their corresponding Weinreb amides by reacting with lithium dimethyl hydroxyl amine without epimerization. Reactions of the Weinreb amides with Grignard and organolithium reagents afforded the corresponding anti- α-lkyl β-amino ketones in modest yields and high optical purity. The modest yields are the results of competition between addition and reduction of the Weinreb amide. anti- α-lkyl β-amino ketones are important chiral building blocks for the asymmetric synthesis of nitrogen-containing biologically active molecules, such as pyrrolidines, piperidines and other alkaloids. To further illustrate the utility of sulfinimine -derived enantiopure N-sulfinyl anti- α-lkyl β-amino ketones, they was applied to the asymmetric synthesis of the unknown anti-C5, C6 derivative of 2,3,4,6-tetrasubsituted indolizidine 221-T. The key step in the synthesis was the stereoselective construction of the piperidine ring of the 5,6,8-tri-substituted indolizidine and was realized via the use of an acid-catalyzed intramolecular Mannich cyclization. The indolizidine was readily transformed in to the key intermediate 7-hydroxyl-2,3,4,6-tetrasubsituted indolizidine in high stereoselectivity and yield. Changing the sequence of chemical operation steps avoided the production of the side product β-pyrrole ketone. Reduction of the intermediate piperdinone, followed by ring-closing metathesis and reductive catalytic hydrogenation afford the bicyclic indolizidine with overall 76% yield of 3 steps. The C-2 branched cocaine analogs are thought to have varied bioactivities and potent therapeutical uses compared to other positions of substituted cocaine analogs. However, reports on the synthesis of such analogs are few. The first example of preparation of a cocaine analog having a dimethylphosphonate group at the C-2 position was reported. The key step in forming the required isoxazolidine intermediate, which controls the required cis stereochemistry at C-2 and C-3, was a novel microwave induce stereoselective [3+2] intramolecular cycloaddition of an α,β-unsaturated pyrrolidine nitrone. The use of the microwave irradiation techniques significantly reduce the time required for isoxazolidine formation from 96 hours to five hours.