Nitrogen containing molecules are ubiquitous among compounds possessing significant biological activity due to their polarization, basicity, hydrogen-bonding ability and other physiological properties. This proposal describes a program in synthetic organic methodology aimed at developing rapid, stereoselective syntheses of complex nitrogen heterocycles using readily available precursors. The key to our approach is efficiency: we require rapid access to the starting material followed by high selectivity in the assembly of the components enabling two to three step syntheses of target molecules from readily available precursors. As part of this goal, we envision allowing the rapid assembly of complex biologically active heterocycles such as secu'amamine A, a compound related to the securinine/norsecurinine family of alkaloids that display antitumor, antimalarial, antibacterial, and CNS activity, the potent immunosuppressive FR901483, the important neurophysiological tools hydrohistrionicotoxin and perhydrohistrionicotoxin, and halichlorine, shown to selectively inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1). The specific goals of this research are as follows: 1) develop the catalytic enantioselective alkenyl isocyanate and alkyne [2+2+2] cycloaddition; 2) expand the scope of alkene partners to include di-, tri- and tetra-substituted partners;3) explore the nature and substitution patterns on the tether leading to diastereoselective reactions; 4) pursue the rapid total synthesis of a variety of alkaloids using isocyanate [2+2+2] cycloadditions; 5) investigate the use of new pi systems in [2+2+2] cycloadditions using our alkenyl isocyanate/alkyne coupling as a platform. The long-term impact of this science is to enable chemists to rapidly assemble alkaloidal structures with high efficiency. Project Narrative One of the most significant barriers to health-related research involving small molecules is the rapid assembly of therapeutic agents. This proposal seeks to develop new methods to synthesize alkaloidal frameworks using easily accessible precursors with high efficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080442-02
Application #
7499540
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Schwab, John M
Project Start
2007-09-21
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$235,923
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Conway Jr, John H; Rovis, Tomislav (2018) Regiodivergent Iridium(III)-Catalyzed Diamination of Alkenyl Amides with Secondary Amines: Complementary Access to ?- or ?-Lactams. J Am Chem Soc 140:135-138
Piou, Tiffany; Rovis, Tomislav (2018) Electronic and Steric Tuning of a Prototypical Piano Stool Complex: Rh(III) Catalysis for C-H Functionalization. Acc Chem Res 51:170-180
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Piou, Tiffany; Romanov-Michailidis, Fedor; Ashley, Melissa A et al. (2018) Stereodivergent Rhodium(III)-Catalyzed cis-Cyclopropanation Enabled by Multivariate Optimization. J Am Chem Soc 140:9587-9593
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Piou, Tiffany; Romanov-Michailidis, Fedor; Romanova-Michaelides, Maria et al. (2017) Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C-H Activation Reactions: An Experimental and Computational Study. J Am Chem Soc 139:1296-1310
Chu, John C K; Rovis, Tomislav (2016) Amide-directed photoredox-catalysed C-C bond formation at unactivated sp3 C-H bonds. Nature 539:272-275
Davis, Tyler A; Wang, Chuanqi; Rovis, Tomislav (2015) Rhodium(III)-Catalyzed C-H Activation: An Oxidative Intramolecular Heck-Type Reaction Directed by a Carboxylic Acid. Synlett 26:1520-1524
Chu, John C K; Dalton, Derek M; Rovis, Tomislav (2015) Zn-catalyzed enantio- and diastereoselective formal [4 + 2] cycloaddition involving two electron-deficient partners: asymmetric synthesis of piperidines from 1-azadienes and nitro-alkenes. J Am Chem Soc 137:4445-52

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