The development of novel expeditious and efficient methodologies toward the synthesis of biologically significant heterocyclic compounds is planned. The proposed project consists of four major sections. The first section is devoted to the investigation and development of novel cycloisomerization approaches toward monocyclic and fused furans, pyrroles, and thiophenes, and to the development of cascade migration/cyclization methodologies en route to highly substituted heterocycles. The second section is directed toward investigation of the scope of the recently discovered transannulation reaction as a highly attractive modular approach to a variety of diverse heteroaromatic scaffolds. The third section covers transition metal- and Lewis acid-catalyzed C-H functionalization of aromatic and heterocyclic building blocks employing a recently proposed Si-tether motif. The fourth section is aimed at development of new synthetic approaches for the rapid construction of naturally occurring and unnatural heterocyclic molecules of biological importance using methodologies developed in our laboratories. Synthetic targets for the proposed research include various diversely substituted indolizines not easily available by existing techniques, potential selective group V sPLA2 inhibitors;lamellarin D and its analogs;novel lamellarin-campthothecin hybrid pentacyclic scaffolds, potential topoisomerase I inhibitors, and tetra- and pentacyclic heterocyclic skeletons, potential QR2 and aromatase inhibitors. The synthetic part of the proposed work toward selected targets is essential as it may lead to discovery of potent anti-inflammatory and anticancer agents. The methodological part of this proposal toward general and efficient methods for construction and functionalization of diverse fused heterocycles has even broader impact, as upon development, it would dramatically broaden the arsenal of libraries of biologically important molecules available for medicinal chemists and biologists, and will most certainly impact drug discovery research and related health-oriented sciences.

Public Health Relevance

The synthetic part of the proposed work will be focused on the synthesis of diversely substituted indolizines not easily available by existing techniques, potential selective group V sPLA2 inhibitors;lamellarin D and its analogs;novel lamellarin-campthothecin hybrid pentacyclic scaffolds, potential topoisomerase I inhibitors, and tetra- and pentacyclic heterocyclic skeletons, potential QR2 and aromatase inhibitors. This work is essential as it may lead to discovery of potent anti-inflammatory and anticancer agents. The methodological part of this proposal toward general and efficient methods for construction and functionalization of diverse fused heterocycles has even broader impact, as upon development, it would dramatically broaden the arsenal of libraries of biologically important molecules available for medicinal chemists and biologists, and will most certainly impact drug discovery research and related health-oriented sciences.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064444-09
Application #
8300928
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2002-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$303,863
Indirect Cost
$103,388
Name
University of Illinois at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Ghavtadze, Nugzar; Melkonyan, Ferdinand S; Gulevich, Anton V et al. (2014) Conversion of 1-alkenes into 1,4-diols through an auxiliary-mediated formal homoallylic C-H oxidation. Nat Chem 6:122-5
Shiroodi, Roohollah Kazem; Koleda, Olesja; Gevorgyan, Vladimir (2014) 1,2-boryl migration empowers regiodivergent synthesis of borylated furans. J Am Chem Soc 136:13146-9
Shi, Yi; Gulevich, Anton V; Gevorgyan, Vladimir (2014) Rhodium-catalyzed NH insertion of pyridyl carbenes derived from pyridotriazoles: a general and efficient approach to 2-picolylamines and imidazo[1,5-a]pyridines. Angew Chem Int Ed Engl 53:14191-5
Kazem Shiroodi, Roohollah; Soltani, Mohammad; Gevorgyan, Vladimir (2014) Gold-catalyzed 1,3-transposition of ynones. J Am Chem Soc 136:9882-5
Kuznetsov, Alexey; Gulevich, Anton V; Wink, Donald J et al. (2014) A new reactivity mode for the diazo group: diastereoselective 1,3-aminoalkylation reaction of ?-amino-?-diazoesters to give triazolines. Angew Chem Int Ed Engl 53:9021-5
Gulevich, Anton V; Gevorgyan, Vladimir (2013) Versatile reactivity of rhodium-iminocarbenes derived from N-sulfonyl triazoles. Angew Chem Int Ed Engl 52:1371-3
Gulevich, Anton V; Dudnik, Alexander S; Chernyak, Natalia et al. (2013) Transition metal-mediated synthesis of monocyclic aromatic heterocycles. Chem Rev 113:3084-213
Wang, Yang; Gulevich, Anton V; Gevorgyan, Vladimir (2013) General and practical carboxyl-group-directed remote C-H oxygenation reactions of arenes. Chemistry 19:15836-40
Kuznetsov, Alexey; Makarov, Anton; Rubtsov, Aleksandr E et al. (2013) Brönsted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans. J Org Chem 78:12144-53
Shi, Yi; Gevorgyan, Vladimir (2013) Intramolecular transannulation of alkynyl triazoles via alkyne-carbene metathesis step: access to fused pyrroles. Org Lett 15:5394-6

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