The overarching goal of this proposal is the development of new reactions, and the reagents that control them, to generate enantioenriched organic compounds. These products are valuable precursors to more elaborate small molecules that are medicinal agents and/or more complex biologically active natural products. The proposed methods specifically target the concise synthesis of secondary amines, tertiary amines, and vicinal diamines as single stereoisomers. These methods are based on the development of bis (amidine) reagents that form chiral proton complexes (a polar ionic hydrogen bond) when a strong acid is added, or when used with acidic substrates. Exploration of a new variant is also described, which contains a single amidine in close proximity to a hydrogen bond donor (polar covalent hydrogen bond) when projected from the same chiral scaffold. These studies continue the successful application of bifunctional organocatalysts to the stereocontrolled creation of structural and functional motifs that, while common, are otherwise difficult to prepare using conventional alternatives. These studies also explore an entirely new mode of activation that involves chiral Bronsted acid mediated halogen- alkene reactions. A range of innovative multicomponent coupling reactions will be developed using chiral proton catalysis as the means to control enantioselection. These studies have the potential to impact small molecule synthesis, and ultimately the development of therapeutic agents. Moreover, the methods enable the metal-free production of functionally dense, single enantiomer (and diastereomer) organic compounds.
The development of small molecule organocatalysts based on Bronsted acid catalysis, particularly those that enable the streamlined synthesis of complex small molecule therapeutics is an activity that ultimately promises low-cost medicines.
|Tsukanov, Sergey V; Johnson, Martin D; May, Scott A et al. (2016) Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous BrÃ¸nsted Acid-Base Catalyst with Recycle. Org Process Res Dev 20:215-226|
|Grace, Christy R; Ban, David; Min, Jaeki et al. (2016) Monitoring Ligand-Induced Protein Ordering in Drug Discovery. J Mol Biol 428:1290-303|
|Vara, Brandon A; Struble, Thomas J; Wang, Weiwei et al. (2015) Enantioselective small molecule synthesis by carbon dioxide fixation using a dual BrÃ¸nsted acid/base organocatalyst. J Am Chem Soc 137:7302-5|
|Sprague, Daniel J; Nugent, Benjamin M; Yoder, Ryan A et al. (2015) Adaptation of a small-molecule hydrogen-bond donor catalyst to an enantioselective hetero-Diels-Alder reaction hypothesized for brevianamide biosynthesis. Org Lett 17:880-3|
|Liu, Yan; Hawkins, Oriana E; Vilgelm, Anna E et al. (2015) Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models. Clin Cancer Res 21:5338-48|
|Schwieter, Kenneth E; Johnston, Jeffrey N (2015) Enantioselective Addition of Bromonitromethane to Aliphatic N-Boc Aldimines Using a Homogeneous Bifunctional Chiral Organocatalyst. ACS Catal 5:6559-6562|
|Vilgelm, Anna E; Pawlikowski, Jeff S; Liu, Yan et al. (2015) Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells. Cancer Res 75:181-93|
|Toda, Yasunori; Pink, Maren; Johnston, Jeffrey N (2014) BrÃ¸nsted acid catalyzed phosphoramidic acid additions to alkenes: diastereo- and enantioselective halogenative cyclizations for the synthesis of C- and P-chiral phosphoramidates. J Am Chem Soc 136:14734-7|
|Makley, Dawn M; Johnston, Jeffrey N (2014) Silyl imine electrophiles in enantioselective catalysis: a Rosetta Stone for peptide homologation, enabling diverse N-protected aryl glycines from aldehydes in three steps. Org Lett 16:3146-9|
|Vara, Brandon A; Mayasundari, Anand; Tellis, John C et al. (2014) Organocatalytic, diastereo- and enantioselective synthesis of nonsymmetric cis-stilbene diamines: a platform for the preparation of single-enantiomer cis-imidazolines for protein-protein inhibition. J Org Chem 79:6913-38|
Showing the most recent 10 out of 24 publications