The objective of this research proposal is to invent new catalytic synthetic methods or strategies that allow access to structural and stereochemical motifs, which, although common among anti-viral, anti-cancer, anti-bacterial and anti-inflammatory medicinal agents, cannot be readily accessed using conventional methods. In this endeavor, we target processes that are readily applied within the related discipline of photoredox catalysis and therefore will have a direct and immediate impact on the accessibility of new carbon-carbon bonds frequently found in molecular scaffolds that have established biological importance. Our intent is to develop operationally trivial synthetic methods of broad utility and function that will ultimately provide new chemical tools for the diverse range of biomedical researchers that utilize molecule construction. As a consequence, this core research will prove valuable within the therapeutic realm. Despite the identification of photoredox catalysis as an important chemical strategy over the past ten years, the vast potential of these simple and widely available catalysts is largely unexplored. However, many of these photoredox active catalysts can engage in single electron transfer reactions upon treatment with only visible light, indicating that their incorporation into mainstream utilization offers savings in cost, time, energy and operation complexity. This proposal outlines the development of an innovative and general strategy for photoredox catalysis that enables readily accessible complexes, activated by only a simple and inexpensive household light source, to function as catalysts for a wide range of transformations. When coupled with well-established organocatalysis protocols, this strategy provides an effective and robust catalyst system that can effect high levels of asymmetric induction across a broad spectrum of chemical processes. During the tenure of this granting period, the value of this new chemical strategy will be demonstrated in the context of the first examples of enantioselective photoredox mediated ?-aldehyde (1) alkylations, (2) trifluoromethylations, (3) perfluoroalkylations, (4) benzylations, and (5) aminations, as well as photoredox mediated (6) aryl trifluoromethylations and (7) C-H bond arylations. Although each of these transformations yield important structural scaffolds, the enantioselective installation of trifluoromethyl substituents offers a milestone in pharmaceutical synthesis, where this functionality is frequently exploited. Lignans represent a unique family of structurally complex non-symmetrical phenylpropanoid dimers that exhibit remarkable biological properties across a broad spectrum of pharmacological screens (anti-viral, anti-tumor and anti-mitotic activity). This proposal outlines an innovative application of the photoredox organocatalysis activation strategy towards the rapid construction of lignan architectures. Having demonstrated the utility of these photoredox mediated transformations, the scope of this catalytic methodology will be applied to the highly expeditious one-pot synthesis of (-)-yatein. This new methodology will be further employed as a template for subsequent complex target syntheses endeavors.

Public Health Relevance

The objective of this research is to establish a synthetic protocol whereby a simple and inexpensive household light source will initiate the catalytic formation of structural motifs that are integral components in many medicinal agents, but that are not currently accessible using known chemical methods.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM093213-03
Application #
8220903
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$291,921
Indirect Cost
$98,871
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Johnston, Craig P; Smith, Russell T; Allmendinger, Simon et al. (2016) Metallaphotoredox-catalysed sp(3)-sp(3) cross-coupling of carboxylic acids with alkyl halides. Nature 536:322-5
Zuo, Zhiwei; Cong, Huan; Li, Wei et al. (2016) Enantioselective Decarboxylative Arylation of α-Amino Acids via the Merger of Photoredox and Nickel Catalysis. J Am Chem Soc 138:1832-5
Chu, Lingling; Lipshultz, Jeffrey M; MacMillan, David W C (2015) Merging Photoredox and Nickel Catalysis: The Direct Synthesis of Ketones by the Decarboxylative Arylation of α-Oxo Acids. Angew Chem Int Ed Engl 54:7929-33
Terrett, Jack A; Cuthbertson, James D; Shurtleff, Valerie W et al. (2015) Switching on elusive organometallic mechanisms with photoredox catalysis. Nature 524:330-4
Welin, Eric R; Warkentin, Alexander A; Conrad, Jay C et al. (2015) Enantioselective α-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β-Cyanoaldehydes. Angew Chem Int Ed Engl 54:9668-72
Ventre, Sandrine; Petronijevic, Filip R; MacMillan, David W C (2015) Decarboxylative Fluorination of Aliphatic Carboxylic Acids via Photoredox Catalysis. J Am Chem Soc 137:5654-7
Terrett, Jack A; Clift, Michael D; MacMillan, David W C (2014) Direct β-alkylation of aldehydes via photoredox organocatalysis. J Am Chem Soc 136:6858-61
Zuo, Zhiwei; MacMillan, David W C (2014) Decarboxylative arylation of α-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J Am Chem Soc 136:5257-60
Prier, Christopher K; MacMillan, David W C (2014) Amine α-heteroarylation via photoredox catalysis: a homolytic aromatic substitution pathway. Chem Sci 5:4173-4178
Cecere, Giuseppe; König, Christian M; Alleva, Jennifer L et al. (2013) Enantioselective direct α-amination of aldehydes via a photoredox mechanism: a strategy for asymmetric amine fragment coupling. J Am Chem Soc 135:11521-4

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