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)
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
Project End
Budget Start
Budget End
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
Terrett, Jack A; Clift, Michael D; MacMillan, David W C (2014) Direct ?-alkylation of aldehydes via photoredox organocatalysis. J Am Chem Soc 136:6858-61
Zuo, Zhiwei; MacMillan, David W C (2014) Decarboxylative arylation of ?-amino acids via photoredox catalysis: a one-step conversion of biomass to drug pharmacophore. J Am Chem Soc 136:5257-60
Cecere, Giuseppe; Konig, Christian M; Alleva, Jennifer L et al. (2013) Enantioselective direct *-amination of aldehydes via a photoredox mechanism: a strategy for asymmetric amine fragment coupling. J Am Chem Soc 135:11521-4
Simonovich, Scott P; Van Humbeck, Jeffrey F; Macmillan, David W C (2012) A general approach to the enantioselective ?-oxidation of aldehydes via synergistic catalysis. Chem Sci 3:58-61
Nagib, David A; MacMillan, David W C (2011) Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis. Nature 480:224-8
McNally, Andrew; Prier, Christopher K; MacMillan, David W C (2011) Discovery of an ýý-amino C-H arylation reaction using the strategy of accelerated serendipity. Science 334:1114-7
Mastracchio, Anthony; Warkentin, Alexander A; Walji, Abbas M et al. (2010) Direct and enantioselective {alpha}-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis. Proc Natl Acad Sci U S A 107:20648-51
Rendler, Sebastian; Macmillan, David W C (2010) Enantioselective polyene cyclization via organo-SOMO catalysis. J Am Chem Soc 132:5027-9
Jui, Nathan T; Lee, Esther C Y; MacMillan, David W C (2010) Enantioselective organo-SOMO cascade cycloadditions: a rapid approach to molecular complexity from simple aldehydes and olefins. J Am Chem Soc 132:10015-7
Van Humbeck, Jeffrey F; Simonovich, Scott P; Knowles, Robert R et al. (2010) Concerning the mechanism of the FeCl3-catalyzed alpha-oxyamination of aldehydes: evidence for a non-SOMO activation pathway. J Am Chem Soc 132:10012-4

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