We wish to develop a new paradigm for the selective oxidation of complex molecules. Our approach is based on the unified development of the now-validated approach of "aspartic acid catalysis." More generally, we have documented previously unknown catalytic cycles for olefin epoxidation and the Baeyer-Villiger oxidation, wherein a carboxylic acid functions as a catalytic moiety. We are particularly eager to explore this unique catalytic strategy for these two venerable processes, which engage an intermediate peracid moiety for mechanistically distinct functions: in epoxidation, the peracid functions as an electrophile;in the Baeyer-Villiger oxidation, the peracid functions as a nucleophile. Our specific goals include development of ever-more active and selective catalysts for each process. We intend to push the frontiers for epoxidations wherein venerable catalysts fail, including applications to problems in remote, isolated olefin functionalization. We will also explore selective epoxidations of highly substituted, electron-rich arenes, such as indoles, that are relevant to natural product synthesis. We will expand the catalysts'diversity through the synthesis of libraries that will be applied to the regioselective epoxidation of polyene-containing natural products. These same catalysts will also be applied to enantioselective Baeyer-Villiger oxidations, a class of catalytic reactions that are truly under- developed from the standpoint of enantioselective catalysis. These studies will also lead to explorations of site-selective Baeyer-Villiger oxidations performed on natural products containing multiple carbonyl sites. All the while, this work will be conducted in an environment where mechanistic studies will be performed to enhance our understanding of the selective reactions we discover. So too, collaborations are in place so that the impact of our studies will expand beyond our own laboratory, assisting colleagues engaged in complex molecule total synthesis, and in the biological evaluation of the new natural product analogs we obtain.

Public Health Relevance

We wish to develop a new paradigm for the selective oxidation of complex molecules. Success in this endeavor will enable efficient synthesis of complex, biologically active molecules. A particular emphasis will be on natural product diversification, which is a long-standing problem in the field of medicinal chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM096403-03
Application #
8374418
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Lees, Robert G
Project Start
2010-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$286,860
Indirect Cost
$93,860
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Romney, David K; Colvin, Sean M; Miller, Scott J (2014) Catalyst control over regio- and enantioselectivity in Baeyer-Villiger oxidations of functionalized ketones. J Am Chem Soc 136:14019-22
Mercado-Marin, Eduardo V; Garcia-Reynaga, Pablo; Romminger, Stelamar et al. (2014) Total synthesis and isolation of citrinalin and cyclopiamine congeners. Nature 509:318-24
Abascal, Nadia C; Lichtor, Phillip A; Giuliano, Michael W et al. (2014) Function-Oriented Investigations of a Peptide-Based Catalyst that Mediates Enantioselective Allylic Alcohol Epoxidation. Chem Sci 5:4504-4511
Lichtor, Phillip A; Miller, Scott J (2014) Experimental lineage and functional analysis of a remotely directed peptide epoxidation catalyst. J Am Chem Soc 136:5301-8
Romney, David K; Miller, Scott J (2012) A peptide-embedded trifluoromethyl ketone catalyst for enantioselective epoxidation. Org Lett 14:1138-41
Kolundzic, Filip; Noshi, Mohammad N; Tjandra, Meiliana et al. (2011) Chemoselective and enantioselective oxidation of indoles employing aspartyl peptide catalysts. J Am Chem Soc 133:9104-11
Lichtor, Phillip A; Miller, Scott J (2011) One-bead-one-catalyst approach to aspartic acid-based oxidation catalyst discovery. ACS Comb Sci 13:321-6
Li, Yang; Miller, Scott J (2011) Chemoenzymatic synthesis of each enantiomer of orthogonally protected 4,4-difluoroglutamic acid: a candidate monomer for chiral Bronsted acid peptide-based catalysts. J Org Chem 76:9785-91