A large majority of new synthetic, 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. Ring opening of aziridines and azetidines by nucleophiles are efficient processes for producing chiral, nitrogen-containing small molecules. Palladium (II) catalysis has seen continued development in recent years for various bond constructions. What is not known are palladium-catalyzed, enantioselective desymmetrization of aziridines and synthesis of enantioenriched azetidines by carbon?carbon bond formation. 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 carbon?carbon bond forming reactions. This is driven by a central hypothesis that palladium complexes possess sufficient reactivity for the production of diverse nitrogen-containing small molecules by enantioselective functionalization of strained heterocycles. The rationale that underlies the proposed research is completion of this project will define new reactivity for 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 catalytic, enantioselective carbon?carbon bond constructions for the synthesis of chiral nitrogen synthons, and 2) Obtain access to single enantiomer amine derivatives by azetidine synthesis and ring opening.
Each aim will operate with a working hypothesis that palladium (II) complexes possess novel reactivity for biologically-active substrate synthesis by enantioselective aziridine ring opening with carbon nucleophiles and azetidine synthesis by C?H functionalization, making this approach innovative. The expected outcomes of our specific aims are as follows: first, developing new enantioselective reactions catalyzed by palladium (II) complexes; second, synthesis of enantioenriched nitrogen heterocycles for testing by the NIMH Psychoactive Drug Screening Program, Community for Open Antimicrobial Drug Discovery and NCI Developmental Therapeutics Program; third, provide advanced, individual research opportunities for undergraduate students with applications in the biomedical field. These outcomes will have a significant positive impact as unique single enantiomer small molecules will become available for pharmaceutical 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. 1
| 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 |
