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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BCMB-B (02))
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Lees, Robert G
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Yale University
Schools of Arts and Sciences
New Haven
United States
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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
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
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

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