Modern drug discovery mandates the rapid and modular assembly of increasingly complex substances. Medicinally relevant molecules overwhelmingly bear nitrogen functionality with 179 of the top 200 brand name drugs containing at least one N-atom. Increasingly, the nitrogen atom is not merely a functional substituent, such as a pendant amine or linking amide, but is present in the form of a heterocycle, often bearing stereocenters. The development of methods to access these heterocycles from easily accessible precursors is an attractive goal. The resultant heterocycles will facilitate the pace of drug discovery, with the common motifs visible in biologically active agents ranging from antibiotics, antidepressants as well as agonists and antagonists of protein-protein interactions such as Hsp40-Hsp70. The specific goals of this research are as follows: 1) develop temporary tethering strategies for [2+2+2] cycloadditions;2) Investigate the oxidative coupling of amides and alkene/alkyne ? systems to assemble piperidines by a catalyzed/oxidative protocol;3) Exploit readily available aza-dienes in metal-catalyzed [4+2] reactions;and 4) Implement isocyanate cycloadditions to involve allenes and vinyl cyclopropanes. The long-term impact of this science is to enable chemists to rapidly assemble complex structures with high efficiency.

Public Health Relevance

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 complex 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 #
2R01GM080442-05
Application #
8106054
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2007-09-21
Project End
2015-08-31
Budget Start
2011-09-15
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$253,306
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
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
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Romanov-Michailidis, Fedor; Sedillo, Kassandra F; Neely, Jamie M et al. (2015) Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C-H Activation. J Am Chem Soc 137:8892-5
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
Hyster, Todd K; Dalton, Derek M; Rovis, Tomislav (2015) Ligand Design for Rh(III)-Catalyzed C-H Activation: An Unsymmetrical Cyclopentadienyl Enables a Regioselective Synthesis of Dihydroisoquinolones. Chem Sci 6:254-258

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