The indole heterocycle is ubiquitous amongst bioactive molecules and drug substances. More than 10,000 biologically active indole derivatives have been discovered to date, of which over two hundred are currently marketed as pharmaceuticals or undergoing clinical trials. Despite the development of an impressive array of strategies to synthesize functionalized indoles, methods to selectively substitute the indole benzenoid ring are limited. A new technology that allows for the simultaneous introduction of multiple functional groups on the indole benzenoid ring and the assembly of sterically congested bond systems would be of tremendous value, and would ultimately enable the synthesis of a host of biologically- relevant indole-containing complex molecules that are not accessible by conventional means. Thus, the long-term goal of the proposed research is to develop new tactics for the synthesis of highly functionalized small molecules that possess the privileged indole motif. Our approach, and the focus of this proposal, involves the synthesis and study of highly reactive aryne derivatives of indoles, or """"""""indolynes"""""""". These species would function as electrophiles, which lies in contrast to the well-known nucleophilic character of the indole heterocycle. We anticipate that this rare indole 'umpolung'will provide unconventional strategies for the synthesis of functionalized indole-containing natural products, including a number of intriguing targets that possess multiple benzenoid substituents or sterically congested frameworks. If the goals of this proposal are achieved, new chemical methods for preparing biologically active molecules will be developed. Ultimately, this contribution will facilitate the discovery of new medicinal agents for treating human illnesses.

Public Health Relevance

If the goals of this proposal are achieved, new chemical methods for preparing biologically active molecules will be developed. Ultimately, this contribution will facilitate the discovery of new medicinal agents for treating human illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM090007-04
Application #
8518377
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2010-09-30
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$338,992
Indirect Cost
$106,172
Name
University of California Los Angeles
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Shah, Tejas K; Medina, Jose M; Garg, Neil K (2016) Expanding the Strained Alkyne Toolbox: Generation and Utility of Oxygen-Containing Strained Alkynes. J Am Chem Soc 138:4948-54
Barber, Joyann S; Styduhar, Evan D; Pham, Hung V et al. (2016) Nitrone Cycloadditions of 1,2-Cyclohexadiene. J Am Chem Soc 138:2512-5
Picazo, Elias; Houk, K N; Garg, Neil K (2015) Computational predictions of substituted benzyne and indolyne regioselectivities. Tetrahedron Lett 56:3511-3514
McMahon, Travis C; Medina, Jose M; Yang, Yun-Fang et al. (2015) Generation and regioselective trapping of a 3,4-piperidyne for the synthesis of functionalized heterocycles. J Am Chem Soc 137:4082-5
Nathel, Noah F Fine; Shah, Tejas K; Bronner, Sarah M et al. (2014) Total syntheses of indolactam alkaloids (-)-indolactam V, (-)-pendolmycin, (-)-lyngbyatoxin A, and (-)-teleocidin A-2. Chem Sci 5:2184-2190
Medina, Jose M; McMahon, Travis C; Jiménez-Osés, Gonzalo et al. (2014) Cycloadditions of cyclohexynes and cyclopentyne. J Am Chem Soc 136:14706-9
Goetz, Adam E; Silberstein, Amanda L; Corsello, Michael A et al. (2014) Concise enantiospecific total synthesis of tubingensin A. J Am Chem Soc 136:3036-9
Medina, Jose M; Mackey, Joel L; Garg, Neil K et al. (2014) The role of aryne distortions, steric effects, and charges in regioselectivities of aryne reactions. J Am Chem Soc 136:15798-805
Smith, Joel M; Moreno, Jesus; Boal, Ben W et al. (2014) Total synthesis of the akuammiline alkaloid picrinine. J Am Chem Soc 136:4504-7
Weires, Nicholas A; Styduhar, Evan D; Baker, Emma L et al. (2014) Total synthesis of (-)-N-methylwelwitindolinone B isothiocyanate via a chlorinative oxabicycle ring-opening strategy. J Am Chem Soc 136:14710-3

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