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.
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.
|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|
|Douglas, James J; Cole, Kevin P; Stephenson, Corey R J (2014) Photoredox catalysis in a complex pharmaceutical setting: toward the preparation of JAK2 inhibitor LY2784544. J Org Chem 79:11631-43|
|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|
|Bergonzini, Giulia; Schindler, Corinna S; Wallentin, Carl-Johan et al. (2014) Photoredox Activation and Anion Binding Catalysis in the Dual Catalytic Enantioselective Synthesis of *-Amino Esters. Chem Sci 5:|
|Sebren, Leanne J; Devery 3rd, James J; Stephenson, Corey R J (2014) Catalytic Radical Domino Reactions in Organic Synthesis. ACS Catal 4:703-716|
|Dai, Chunhui; Meschini, Francesco; Narayanam, Jagan M R et al. (2012) Friedel-Crafts amidoalkylation via thermolysis and oxidative photocatalysis. J Org Chem 77:4425-31|
|Freeman, David B; Furst, Laura; Condie, Allison G et al. (2012) Functionally diverse nucleophilic trapping of iminium intermediates generated utilizing visible light. Org Lett 14:94-7|
|Matsuura, Bryan S; Condie, Allison G; McBee, Ian A et al. (2011) Intercepting Wacker intermediates with arenes: C-H functionalization and dearomatization. Org Lett 13:6320-3|
|Furst, Laura; Narayanam, Jagan M R; Stephenson, Corey R J (2011) Total synthesis of (+)-gliocladinýýýC enabled by visible-light photoredox catalysis. Angew Chem Int Ed Engl 50:9655-9|