Nitrogen heterocycles constitute an important substructure in pharmaceuticals and natural products that improve the quality of life and health of humans. The development of new methods that access these compounds from simple, readily available starting materials remains a current challenge of organic synthesis. The functionalization of C H bonds by metal reagents, including nitrenoids, holds great promise as it reduces the functional group manipulation inherent in many N-heterocycle syntheses. Since azides are readily available, the prospect of transition metal nitrenoid generation from them is highly appealing. Our initial results demonstrate that vinyl- and aryl azides are valuable precursors for the transition metal-catalyzed synthesis of indoles, pyrroles, and carbazoles. Herein, we describe new methods that build upon our initial results to permit access to pharmacologically important heterocyclic scaffolds and natural products. From a fundamental point of view, our methods will establish new reactivity for transition metal complexes, while from a synthetic standpoint, they will enable rapid access to N-heterocycles from readily available starting materials via C H amination or nitrogen atom transfer reactions. In the first specific aim, we strive to fully investigate the scope and limitations this transformation through the examination of substrates with (1) alternative electron-withdrawing 1-substituents;(2) heteroaromatic or vinyl 2-substituents;(3) aliphatic 2-substituents;(4) dearomatization of electron rich aryl groups. These methods will enable access to a range of N-heterocycles, including sulfonylindoles, azaindoles, dihydropyrroles, and spirocycles. Within specific aim #2, we seek to expand the scope and methodology of transition metal- catalyzed aryl azide or o-anthranil decomposition to enable the rapid synthesis of heteroaromatic carbazoles, indoles, functionalized azepines, and aziridines. In the third specific aim, we showcase our methods in syntheses that rapidly generate multiple drug resistance (MDR) reversal agents, N-acetylardeemin, KT-5720, and coronaridine. We will collaborate with the Beck laboratory to test the activity of these compounds as well as any synthetic intermediates towards sensitizing MDR resistant cancer cell lines to chemotherapeutic agents.

Public Health Relevance

The ubiquitous nature of N-heterocycles in natural products and pharmaceutical agents continues to inspire organic chemists to design new methods that facilitate access to them. Herein, we describe new methods that involve transition metal catalysts azides, which permit access to pharmacologically important heterocyclic scaffolds and natural products. We also showcase our new methods in succinct syntheses of multiple drug resistance (MDR) reversal agents.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Illinois at Chicago
Schools of Arts and Sciences
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Zhou, Fei; Driver, Tom G (2014) Efficient synthesis of 3H-indoles enabled by the lead-mediated ?-arylation of ?-ketoesters or ?-lactams using aryl azides. Org Lett 16:2916-9
Jana, Navendu; Nguyen, Quyen; Driver, Tom G (2014) Development of a Suzuki cross-coupling reaction between 2-azidoarylboronic pinacolate esters and vinyl triflates to enable the synthesis of [2,3]-fused indole heterocycles. J Org Chem 79:2781-91
Kong, Chen; Jana, Navendu; Driver, Tom G (2013) Rh2(II)-catalyzed selective aminomethylene migration from styryl azides. Org Lett 15:824-7
Nguyen, Quyen; Nguyen, Tuyen; Driver, Tom G (2013) Iron(II) bromide-catalyzed intramolecular C-H bond amination [1,2]-shift tandem reactions of aryl azides. J Am Chem Soc 135:620-3
Pumphrey, Ashley L; Dong, Huijun; Driver, Tom G (2012) Rh(II)2-catalyzed synthesis of ýý-, ýý-, or ýý-carbolines from aryl azides. Angew Chem Int Ed Engl 51:5920-3
Nguyen, Quyen; Sun, Ke; Driver, Tom G (2012) Rh2(II)-catalyzed intramolecular aliphatic C-H bond amination reactions using aryl azides as the N-atom source. J Am Chem Soc 134:7262-5
Sun, Ke; Liu, Sheng; Bec, Patryk M et al. (2011) Rhodium-catalyzed synthesis of 2,3-disubstituted indoles from ?,?-disubstituted stryryl azides. Angew Chem Int Ed Engl 50:1702-6
Dong, Huijun; Latka, Regina T; Driver, Tom G (2011) Ruthenium-catalyzed ýý-carbolinium ion formation from aryl azides; synthesis of dimebolin. Org Lett 13:2726-9
Stokes, Benjamin J; Liu, Sheng; Driver, Tom G (2011) Rh2(II)-catalyzed nitro-group migration reactions: selective synthesis of 3-nitroindoles from ?-nitro styryl azides. J Am Chem Soc 133:4702-5
Driver, Tom G (2010) Recent advances in transition metal-catalyzed N-atom transfer reactions of azides. Org Biomol Chem 8:3831-46

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