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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM068649-11
Application #
8265600
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (03))
Program Officer
Lees, Robert G
Project Start
2003-08-01
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
11
Fiscal Year
2012
Total Cost
$322,060
Indirect Cost
$107,060
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Han, Sunkyu; Le, Binh V; Hajare, Holly S et al. (2014) X-ray crystal structure of teicoplanin A?-2 bound to a catalytic peptide sequence via the carrier protein strategy. J Org Chem 79:8550-6
Chandler, Brent D; Burkhardt, Anne L; Foley, Klaudia et al. (2014) A fully synthetic and biochemically validated phosphatidyl inositol-3-phosphate hapten via asymmetric synthesis and native chemical ligation. J Am Chem Soc 136:412-8
Barrett, Kimberly T; Metrano, Anthony J; Rablen, Paul R et al. (2014) Spontaneous transfer of chirality in an atropisomerically enriched two-axis system. Nature 509:71-5
Barrett, Kimberly T; Miller, Scott J (2013) Enantioselective synthesis of atropisomeric benzamides through peptide-catalyzed bromination. J Am Chem Soc 135:2963-6
Pathak, Tejas P; Miller, Scott J (2013) Chemical tailoring of teicoplanin with site-selective reactions. J Am Chem Soc 135:8415-22
Han, Sunkyu; Miller, Scott J (2013) Asymmetric catalysis at a distance: catalytic, site-selective phosphorylation of teicoplanin. J Am Chem Soc 135:12414-21
Yoganathan, Sabesan; Miller, Scott J (2013) N-Methylimidazole-catalyzed synthesis of carbamates from hydroxamic acids via the Lossen rearrangement. Org Lett 15:602-5
Jordan, Peter A; Miller, Scott J (2012) An approach to the site-selective deoxygenation of hydroxy groups based on catalytic phosphoramidite transfer. Angew Chem Int Ed Engl 51:2907-11
Gustafson, Jeffrey L; Lim, Daniel; Barrett, Kimberly T et al. (2011) Synthesis of atropisomerically defined, highly substituted biaryl scaffolds through catalytic enantioselective bromination and regioselective cross-coupling. Angew Chem Int Ed Engl 50:5125-9