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.
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.
| Barber, Joyann S; Yamano, Michael M; Ramirez, Melissa et al. (2018) Diels-Alder cycloadditions of strained azacyclic allenes. Nat Chem 10:953-960 |
| 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 |
| Fine Nathel, Noah F; Morrill, Lucas A; Mayr, Herbert et al. (2016) Quantification of the Electrophilicity of Benzyne and Related Intermediates. J Am Chem Soc 138:10402-5 |
| 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 |
| 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 |
| 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 |
| Medina, Jose M; McMahon, Travis C; Jiménez-Osés, Gonzalo et al. (2014) Cycloadditions of cyclohexynes and cyclopentyne. J Am Chem Soc 136:14706-9 |
Showing the most recent 10 out of 18 publications
