A large majority of new chiral pharmaceuticals are marketed as single enantiomers; however, limitations in methods for single enantiomer organic synthesis hinder drug development, particularly for nitrogen-containing small molecules. Meso-aziridine desymmetrization is an efficient process for producing chiral, nitrogen-containing small molecules. Cationic diphosphine-palladium (II) Lewis acids have seen rapid development in recent years for various bond constructions. What is not known are enantioselective aziridine desymmetrization reactions catalyzed by diphosphine-palladium (II) complexes. The long-term goal is to discover novel catalytic methods for biologically-active small molecule synthesis. The overall objective of the proposed research, which is the next step toward attainment of the long-term goal, is to develop enantioselective, palladium (II)-catalyzed rearrangements and carbon-carbon bond forming reactions. This is driven by a central hypothesis that cationic palladium complexes possess dual reactivity for the production of diverse nitrogen-containing small molecules by enantioselective aziridine desymmetrization. The rationale that underlies the proposed research is completion of this project will define new reactivity for diphosphine-palladium (II) catalysts in novel enantioselective small molecule synthesis. Directed by strong preliminary data, the research plan includes objectively testing the central hypothesis and, thereby, attaining the objective of this application by pursuing the following two specific aims: 1 Develop palladium (II)-catalyzed, enantioselective rearrangements for unique bond constructions, and 2) Obtain access to single enantiomer secondary amine derivatives by carbon-carbon bond formation.
Each aim will operate with a working hypothesis that diphosphine-palladium (II) complexes possess novel reactivity for biologically-active substrate synthesis by enantioselective rearrangements and aziridine ring opening with carbon nucleophiles, making this approach innovative. The expected outcomes of our specific aims are as follows: first, developing new enantioselective reactions catalyzed by palladium (II) Lewis acids; second, synthesis of enantioenriched heterocycles for testing by the NIH Molecular Libraries Small Molecule Repository and NCI Developmental Therapeutics Program; third, production of a structurally diverse collection of chiral, neurologically-active small molecules fo submission to the NIMH Psychoactive Drug Screening Program. These outcomes will have a significant positive impact by establishing N-acylaziridines as linchpin intermediates for chiral, bio-active small molecule synthesis. New pathways will be opened to produce previously unknown pharmaceuticals for the enhancement of human health.
The proposed research is relevant to public health because the investigation of new chemical reactions leads to improvement in the medications available to treat human illness. Specifically, chiral nitrogen-containing organic starting materials will be synthesized in an economical fashion. The project is in line with part of the NIH's mission because new pathways will be opened to produce previously unavailable pharmaceuticals for the enhancement of human health.
| Punk, Molly; Merkley, Charlotte; Kennedy, Katlyn et al. (2016) Palladium-Catalyzed, Enantioselective Heine Reaction. ACS Catal 6:4694-4698 |
| Kidd, Jesse; Maiden, Kristen; Morgan, Jeremy B (2016) Synthesis of ?-substituted tryptamines by regioselective ring opening of aziridines. Tetrahedron 72:3802-3807 |
