The overarching theme of this proposal is the application of new photoredox catalysis methods to the preparation of biologically active compounds. These methodologies provide strategy-level advantages in their respective syntheses due to broad functional group compatibility and mild reaction conditions. Importantly they will also enable syntheses in an environmentally conscious fashion. New methods using visible light, a non-toxic 'reagent'that does not generate chemical waste, are attractive strategies for chemical synthesis. Since most organic molecules do not productively absorb visible light, photosensitive catalysts, widely studied for their photophysical properties, have been successfully employed for numerous new chemical methods which will be applied in the synthesis of biologically active natural compounds. The compounds prepared as part of this proposal will be evaluated for their biological activity by the Inglese Laboratory at the NIH Chemical Genomics Center (NCGC) using their high throughput screening capabilities. Leads which arise from these screening activities will be followed up in collaboration with the medicinal chemistry group at NCGC. The initial targeted libraries will be prepared at BU, with follow-up scaffold development, where appropriate, using scaffolds prepared in the Principal Investigator's lab for modification at NCGC. In addition, the Liu Group (University of Colorado) will evaluate the effect of the developed compounds on cell-cycle regulation.
The aims of the proposed research projects are to: 1) Synthesize the bisindole alkaloid natural products gliocladin C, deoxyleptosin D, deoxybionectin A and plectosphaeroic acid A, achieve the synthesis of heterodimeric bis(pyrroloindoline) alkaloids asperdimin and WIN 64745, undertake the syntheses of a series of indolizidine alkaloids using photoredox- mediated, stereocontrolled radical cyclization onto pyrroles, and achieve the synthesis of actinophyllic acid using a photoredox-catalyzed fragment coupling strategy. 2) Develop new methods for the ?-C-H functionalization of amines using photoredox catalysis and appyl these methods to the syntheses of the alkaloid natural products crispine A, harmicine, tangutorine and undulifoline.

Public Health Relevance

The fundamentally new chemical reactions in photoredox catalysis being proposed will enable the synthesis of biologically active natural products implicated in cancer, infection, and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM096129-04
Application #
8750909
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2013-09-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$187,226
Indirect Cost
$52,834
Name
University of Michigan Ann Arbor
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Staveness, Daryl; Bosque, Irene; Stephenson, Corey R J (2016) Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer. Acc Chem Res 49:2295-2306
Kärkäs, Markus D; Porco Jr, John A; Stephenson, Corey R J (2016) Photochemical Approaches to Complex Chemotypes: Applications in Natural Product Synthesis. Chem Rev 116:9683-747
Lofstrand, Verner A; Matsuura, Bryan S; Furst, Laura et al. (2016) Formation and Trapping of Azafulvene Intermediates Derived from Manganese-Mediated Oxidative Malonate Coupling. Tetrahedron 72:3775-3780
Matsuura, Bryan S; Keylor, Mitchell H; Li, Bo et al. (2015) A scalable biomimetic synthesis of resveratrol dimers and systematic evaluation of their antioxidant activities. Angew Chem Int Ed Engl 54:3754-7
Beatty, Joel W; Stephenson, Corey R J (2015) Amine Functionalization via Oxidative Photoredox Catalysis: Methodology Development and Complex Molecule Synthesis. Acc Chem Res 48:1474-84
Keylor, Mitchell H; Matsuura, Bryan S; Stephenson, Corey R J (2015) Chemistry and Biology of Resveratrol-Derived Natural Products. Chem Rev 115:8976-9027
Douglas, James J; Albright, Haley; Sevrin, Martin J et al. (2015) A Visible-Light-Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro-Substituted Spirocyclic ORL-1 Antagonist. Angew Chem Int Ed Engl 54:14898-902
Beatty, Joel W; Douglas, James J; Cole, Kevin P et al. (2015) A scalable and operationally simple radical trifluoromethylation. Nat Commun 6:7919
Beatty, Joel W; Stephenson, Corey R J (2014) Synthesis of (-)-pseudotabersonine, (-)-pseudovincadifformine, and (+)-coronaridine enabled by photoredox catalysis in flow. J Am Chem Soc 136:10270-3
Garlets, Zachary J; Nguyen, John D; Stephenson, Corey R J (2014) The Development of Visible-Light Photoredox Catalysis in Flow. Isr J Chem 54:351-360

Showing the most recent 10 out of 18 publications