We wish to develop a new paradigm for the selective oxidation of complex molecules. Our approach will extend the development of the now-validated paradigm of aspartic acid catalysis. We will also develop additional catalysis paradigms based on catalytic ketones and metal complexes. All of the catalytic centers to be developed will be incorporated into peptides. The peptide-based scaffolds will provide the molecular environment that will be responsible for selectivity. Enantioselective reactions, as well as those that deal wih regio-, chemo- and site-selectivity will be explored. This project began with previously unknown catalytic cycles for olefin epoxidation and the Baeyer-Villiger oxidation, wherein a carboxylic acid functions as a catalytic moiety. We are now poised to explore this unique catalytic strategy for these two venerable processes, each of which engages an intermediate peracid moiety for a mechanistically distinct function: 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 involving remote olefin functionalization when several alkenes are present. We will also examine these catalysts for site- and enantioselective oxidations of conjugated polyenes, so commonly found in complex natural products. We will also continue our studies of selective epoxidations of highly substituted, electron-rich arenes, such as indoles, furans and pyrroles; the products of these reactions will be relevant to natural product synthesis, as well as for the synthesis of natural product analogs. We plan to expand greatly our study of 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 ketone sites. This work will enable an aggressive set of applications involving the catalyst-dependent diversification of biologically active natural products. 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 and plans are in place so that the impact of our studies will extend beyond our own laboratory, assisting colleagues engaged in complex molecule synthesis, and in the biological evaluation of the new natural product analogs we obtain.

Public Health Relevance

We wish to continue our development of 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 new 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 #
5R01GM096403-07
Application #
9208777
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2010-12-01
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
7
Fiscal Year
2017
Total Cost
$276,949
Indirect Cost
$91,549
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Shugrue, Christopher R; Featherston, Aaron L; Lackner, Rachel M et al. (2018) Divergent Stereoselectivity in Phosphothreonine (pThr)-Catalyzed Reductive Aminations of 3-Amidocyclohexanones. J Org Chem 83:4491-4504
Storch, Golo; Kim, Byoungmoo; Mercado, Brandon Q et al. (2018) A Stereodynamic Redox-Interconversion Network of Vicinal Tertiary and Quaternary Carbon Stereocenters in Hydroquinone-Quinone Hybrid Dihydrobenzofurans. Angew Chem Int Ed Engl 57:15107-15111
Ryss, Jonathan M; Turek, Amanda K; Miller, Scott J (2018) Disulfide-Bridged Peptides That Mediate Enantioselective Cycloadditions through Thiyl Radical Catalysis. Org Lett 20:1621-1625
Cusso, Olaf; Giuliano, Michael W; Ribas, Xavi et al. (2017) A Bottom Up Approach Towards Artificial Oxygenases by Combining Iron Coordination Complexes and Peptides. Chem Sci 8:3660-3667
Shugrue, Christopher R; Miller, Scott J (2017) Applications of Nonenzymatic Catalysts to the Alteration of Natural Products. Chem Rev 117:11894-11951
Kim, Byoungmoo; Storch, Golo; Banerjee, Gourab et al. (2017) Stereodynamic Quinone-Hydroquinone Molecules That Enantiomerize at sp3-Carbon via Redox-Interconversion. J Am Chem Soc 139:15239-15244
Metrano, Anthony J; Abascal, Nadia C; Mercado, Brandon Q et al. (2017) Diversity of Secondary Structure in Catalytic Peptides with ?-Turn-Biased Sequences. J Am Chem Soc 139:492-516
Abascal, Nadia C; Miller, Scott J (2016) Solution Structures and Molecular Associations of a Peptide-Based Catalyst for the Stereoselective Baeyer-Villiger Oxidation. Org Lett 18:4646-9
Featherston, Aaron L; Miller, Scott J (2016) Synthesis and evaluation of phenylalanine-derived trifluoromethyl ketones for peptide-based oxidation catalysis. Bioorg Med Chem 24:4871-4874
Alford, Joshua S; Abascal, Nadia C; Shugrue, Christopher R et al. (2016) Aspartyl Oxidation Catalysts That Dial In Functional Group Selectivity, along with Regio- and Stereoselectivity. ACS Cent Sci 2:733-739

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