Over the past five years, visible light-mediated photoredox catalysis has emerged as a versatile new activation platform in organic synthesis. Ruthenium or iridium-based polypyridyl photoredox catalysts absorb light in the visible range to generate stable, long-lived excited states that may act as either single-electron oxidants or reductants. Due to their unique reactivity profile, photoredox catalysts have the capacity to enable challenging bond constructions that are not accessible under standard approaches. In a seminal 2008 disclosure, our lab described the asymmetric ?-alkylation of aldehydes via the synergistic merger of photoredox catalysis and chiral amine organocatalysis;this powerful dual-catalysis strategy features the simultaneous generation of catalytic quantities of both reactive intermediates. Subsequent reports, from our group and others, have further established the remarkable complexity-building capabilities of photoredox catalysis, particularly when merged with organocatalysis. In this research proposal, we outline new directions for our photoredox-based research program. Each of the four aims proposed herein envisions a novel reactivity platform featuring a transient, photoredox-generated active species that may be productively harnessed for the synthesis of a menu of high-value functional motifs.
In Aim 1, we propose to develop direct, one-carbon expanded variants of the Mannich, Michael, and aldol reactions via a novel 5? electron intermediate species that is transiently generated from ketone or aldehyde precursors through synergistic organocatalysis and photoredox catalysis.
Aim 2 leverages an amino radical species - generated in situ via photoredox catalysis - en route to valuable amine-containing scaffolds, including vicinal diamines and allylic amines.
Aim 3 envisions the direct arylation of labile allylic and benzylic C-H bonds through synergistic thiol-based organocatalysis and photoredox catalysis, as a means by which to gain rapid access to diaryl methanes and vinyl-aryl methanes. Finally, in Aim 4, we propose to accomplish the photoredox-catalyzed decarboxylative functionalization of ? amino acids en route to valuable benzylic amine and alkyl amine motifs. In a key expansion of this project, we will explore opportunities for the development of an asymmetric variant for the synthesis of ?-amino aldehydes via merged photoredox and chiral amine-based organocatalysis.

Public Health Relevance

The research proposed in this funding cycle will allow the development of new chemical reactions that will benefit society as a whole. In particular these new chemical reactions will allow more rapid access to medicinal agents via industrial and academic research. These studies will allow the production of molecules of value to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM093213-05
Application #
8774802
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-04-01
Project End
2018-05-31
Budget Start
2014-09-15
Budget End
2015-05-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Princeton
State
NJ
Country
United States
Zip Code
08543
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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