We wish to develop a new paradigm for the selective functionalization of complex molecules. Our approach is predicated on the development of fundamental reactions of functional groups that are ubiquitous in bioactive agents. The main emphasis of this proposal is the development of simple-to-make catalyst libraries that target functionalization of hydroxyl groups, amines and arene C-H bonds. Thus, the workhorse reactions we wish to develop are hydroxyl group transfer reactions (acylation, phosphorylation, sulfonylation and thiocarbonylation), amine group transfer reactions, and electrophilic aromatic substitutions. Each of these processes has been developed to varying degrees in our laboratory, and we now wish to study them at appropriate levels of commitment to render them truly applicable in complex molecular arenas. Selective polyol derivatization reactions have value in and of themselves for natural product analog generation. Moreover, the reactions we will study may be used as a springboard for additional, value-added transformations (e.g., displacement reactions, deoxygenations, inter alia). Catalytic, site-selective amine functionalization within polyamines is virtually unknown, and we have initiated first steps for the development of these processes with a generalizable catalyst platform. So too of site-selective C-H bond functionalization in complex polycyclic arene-containing natural products. Our study of each of these fundamental chemical reactions begins with examination of enantioselective reactions. These processes are important to the field of asymmetric catalysis. Development of enantioselective reactions in the proposed reaction types affords generally unprecedented access to building blocks in single enantiomer form. But, the significance for our overall goals may be even greater as these studies define catalysis principles, and catalyst scaffolds that may then be applied to the site-selective modification of complex, bioactive natural products. These studies enable systematic and fundamental research in the less well-studied arena of regioselective catalysis. In the end, we will apply the new catalyst libraries to the selective derivatization of important and fascinating biological agents, including apoptolidin, neomycin, vancomycin and teicoplanin. In each case, collaborations are in place so that the impact of our studies will extend beyond our own laboratory, assisting colleagues engaged in biological studies of the natural products we will diversify.
We wish to develop new paradigms for the selective synthesis of complex natural product scaffolds. Progress in this field will enable efficient syntheses 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.
|Key, Hanna M; Miller, Scott J (2017) Site- and Stereoselective Chemical Editing of Thiostrepton by Rh-Catalyzed Conjugate Arylation: New Analogues and Collateral Enantioselective Synthesis of Amino Acids. J Am Chem Soc 139:15460-15466|
|Shugrue, Christopher R; Miller, Scott J (2017) Applications of Nonenzymatic Catalysts to the Alteration of Natural Products. Chem Rev 117:11894-11951|
|Hurtley, Anna E; Stone, Elizabeth A; Metrano, Anthony J et al. (2017) Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst. J Org Chem 82:11326-11336|
|Chinn, Alex J; Kim, Byoungmoo; Kwon, Yongseok et al. (2017) Enantioselective Intermolecular C-O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst. J Am Chem Soc 139:18107-18114|
|Wadzinski, Tyler J; Gea, Katherine D; Miller, Scott J (2016) A stepwise dechlorination/cross-coupling strategy to diversify the vancomycin 'in-chloride'. Bioorg Med Chem Lett 26:1025-1028|
|Metrano, A J; Abascal, N C; Mercado, B Q et al. (2016) Structural studies of ?-turn-containing peptide catalysts for atroposelective quinazolinone bromination. Chem Commun (Camb) 52:4816-9|
|Pelletier, Guillaume; Zwicker, Aaron; Allen, C Liana et al. (2016) Aqueous Glycosylation of Unprotected Sucrose Employing Glycosyl Fluorides in the Presence of Calcium Ion and Trimethylamine. J Am Chem Soc 138:3175-82|
|Kim, Byoungmoo; Chinn, Alex J; Fandrick, Daniel R et al. (2016) Distal Stereocontrol Using Guanidinylated Peptides as Multifunctional Ligands: Desymmetrization of Diarylmethanes via Ullman Cross-Coupling. J Am Chem Soc 138:7939-45|
|Xiong, Hai; Reynolds, Noah M; Fan, Chenguang et al. (2016) Dual Genetic Encoding of Acetyl-lysine and Non-deacetylatable Thioacetyl-lysine Mediated by Flexizyme. Angew Chem Int Ed Engl 55:4083-6|
|Xiong, Hai; Reynolds, Noah M; Fan, Chenguang et al. (2016) [Dual genetic encoding of acetyl-lysine and non-deacetylatablethioacetyl-lysine mediated by flexizyme]. Angew Chem Weinheim Bergstr Ger 128:4151-4154|
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