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 #
5R01GM080442-07
Application #
8540435
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
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$270,514
Indirect Cost
$83,986
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; Rovis, Tomislav (2014) Rh(III)-catalyzed cyclopropanation initiated by C-H activation: ligand development enables a diastereoselective [2 + 1] annulation of N-enoxyphthalimides and alkenes. J Am Chem Soc 136:11292-5
Oberg, Kevin M; Martin, Timothy J; Oinen, Mark Emil et al. (2014) Enantioselective Rhodium-Catalyzed [2+2+2] Cycloaddition of Pentenyl Isocyanate and 4-Ethynylanisole: Preparation and Use of Taddolpyrrolidine Phosphoramidite. Organic Synth 91:150-161
Neely, Jamie M; Rovis, Tomislav (2014) Rh(III)-catalyzed decarboxylative coupling of acrylic acids with unsaturated oxime esters: carboxylic acids serve as traceless activators. J Am Chem Soc 136:2735-8
Martin, Timothy J; Rovis, Tomislav (2013) A catalytic asymmetric synthesis of polysubstituted piperidines using a rhodium(I)-catalyzed [2+2+2] cycloaddition employing a cleavable tether. Angew Chem Int Ed Engl 52:5368-71
Dalton, Derek M; Rovis, Tomislav (2013) Catalytic, asymmetric indolizidinone aza-quaternary stereocenter synthesis: expedient synthesis of the cylindricine alkaloid core. Org Lett 15:2346-9
Neely, Jamie M; Rovis, Tomislav (2013) Rh(III)-catalyzed regioselective synthesis of pyridines from alkenes and ?,?-unsaturated oxime esters. J Am Chem Soc 135:66-9
Davis, Tyler A; Hyster, Todd K; Rovis, Tomislav (2013) Rhodium(III)-catalyzed intramolecular hydroarylation, amidoarylation, and Heck-type reaction: three distinct pathways determined by an amide directing group. Angew Chem Int Ed Engl 52:14181-5
Hyster, Todd K; Ruhl, Kyle E; Rovis, Tomislav (2013) A coupling of benzamides and donor/acceptor diazo compounds to form ?-lactams via Rh(III)-catalyzed C-H activation. J Am Chem Soc 135:5364-7
Du, Ya; Hyster, Todd K; Rovis, Tomislav (2011) Rhodium(III)-catalyzed oxidative carbonylation of benzamides with carbon monoxide. Chem Commun (Camb) 47:12074-6
Hyster, Todd K; Rovis, Tomislav (2011) Pyridine synthesis from oximes and alkynes via rhodium(III) catalysis: Cp* and Cp(t) provide complementary selectivity. Chem Commun (Camb) 47:11846-8

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