The overarching goal of this proposal is the development of new methods 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 1-amino acids, 1,2-diamino acids, 1-aminophosphonic acids and chiral secondary amines. These methods are based on the development of chiral proton catalysts as new chiral, non-racemic reagents for enantioselective synthesis. The complexes are readily prepared organocatalysts, and are often bench stable solids. They are metal free, and therefore may be referred to as organic catalysts. These studies have the potential to impact the synthesis of both small molecule and "biologic" therapeutic agents. Moreover, the methods enable the metal-free production of functionally dense, single enantiomer (and diastereomer) organic compounds.

Public Health Relevance

This proposal describes the development of chiral small molecule organocatalysts and the corresponding enantioselective reactions. In a single step, chiral nonracemic secondary amines and their derivatives (1-amino acids, 1-aminophosphonates, 1,2- diamino acids) are produced in stereochemically enriched form. These chemical commodities are common subunits of biologically active natural products, biologics, and small molecule therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084333-04
Application #
8267696
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2009-05-01
Project End
2013-12-30
Budget Start
2012-05-01
Budget End
2013-12-30
Support Year
4
Fiscal Year
2012
Total Cost
$253,478
Indirect Cost
$77,060
Name
Vanderbilt University Medical Center
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
Toda, Yasunori; Pink, Maren; Johnston, Jeffrey N (2014) Brønsted 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
Davis, Tyler A; Vilgelm, Anna E; Richmond, Ann et al. (2013) Preparation of (-)-Nutlin-3 using enantioselective organocatalysis at decagram scale. J Org Chem 78:10605-16
Dobish, Mark C; Johnston, Jeffrey N (2012) Achiral counterion control of enantioselectivity in a Bronsted acid-catalyzed iodolactonization. J Am Chem Soc 134:6068-71
Davis, Tyler A; Danneman, Michael W; Johnston, Jeffrey N (2012) Chiral proton catalysis of secondary nitroalkane additions to azomethine: synthesis of a potent GlyT1 inhibitor. Chem Commun (Camb) 48:5578-80
Shackleford, Jessica P; Shen, Bo; Johnston, Jeffrey N (2012) Discovery of competing anaerobic and aerobic pathways in umpolung amide synthesis allows for site-selective amide 18O-labeling. Proc Natl Acad Sci U S A 109:44-6
Johnston, Jeffrey N (2011) A chiral N-phosphinyl phosphoramide: another offspring for the sage phosphoric acid progenitor. Angew Chem Int Ed Engl 50:2890-1
Tomasiak, Thomas M; Archuleta, Tara L; Andrell, Juni et al. (2011) Geometric restraint drives on- and off-pathway catalysis by the Escherichia coli menaquinol:fumarate reductase. J Biol Chem 286:3047-56

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