Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction technology reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, the synthesis activity is a critical discipline which continues to have an important impact upon the fields of both medicine and biology. The present grant will continue to address the development of new stereoselective reactions which are relevant to the synthesis of antibiotic and antineoplastic agents derived from amino acid constituents The methodological studies dealing with new reaction discovery will emphasize the development of chiral metal catalysts for the catalyzed aldol and imino-aldol reactions of glycine enolates and the catalyzed variant of the Strecker reaction. These advances should culminate in practical routes to the asymmetric synthesis of hydroxy-alpha-amino acids and alpha,beta-diamino acids as well as alpha-amino nitriles. In closely related studies, we will utilize chiral metal catalysts to promote the enol insertion of metal nitrenoids as a method for the asymmetric synthesis of alpha-amino acids through enol amination. These reactions will be incorporated into projects whose focus is the synthesis of amino acid-derived natural products. Some of the synthesis objectives will include the development of an asymmetric synthesis of the cephalosporin, carbacephalosporin, and oxacephalosporin antibiotics through catalytic asymmetric synthesis methods. We will also determine the structure and develop an asymmetric synthesis of the hexapeptide complestatin, the most potent inhibitor of the human complement system. We will also address the structure determination and synthesis of diphthamide, the most complex amino acid yet isolated. This histidine-derived amino acid is an essential constituent in elongation factor-2, the protein responsible for translation during protein synthesis. The diphthamide moiety is intimately involved, in some as yet undefined way, in the function of this protein. Collaborative studies will be pursued to more closely define the role of diphthamide in protein synthesis.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Medicinal Chemistry Study Section (MCHA)
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Harvard University
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Bonazzi, Simone; Cheng, Bichu; Wzorek, Joseph S et al. (2013) Total synthesis of (-)-nakadomarin A. J Am Chem Soc 135:9338-41
Wzorek, Joseph S; Knopfel, Thomas F; Sapountzis, Ioannis et al. (2012) A macrocyclic approach to tetracycline natural products. Investigation of transannular alkylations and Michael additions. Org Lett 14:5840-3
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Evans, David A; Fandrick, Keith R; Song, Hyun-Ji et al. (2007) Enantioselective Friedel-Crafts alkylations catalyzed by bis(oxazolinyl)pyridine-scandium(III) triflate complexes. J Am Chem Soc 129:10029-41
Evans, David A; Adams, Drew J (2007) Total synthesis of (+)-galbulimima alkaloid 13 and (+)-himgaline. J Am Chem Soc 129:1048-9
Evans, David A; Dunn, Travis B; Kvaerno, Lisbet et al. (2007) Total synthesis of (+)-azaspiracid-1. Part II: synthesis of the EFGHI sulfone and completion of the synthesis. Angew Chem Int Ed Engl 46:4698-703
Evans, David A; Mito, Shizue; Seidel, Daniel (2007) Scope and mechanism of enantioselective Michael additions of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by nickel(II)-diamine complexes. J Am Chem Soc 129:11583-92
Evans, David A; Kvaerno, Lisbet; Mulder, Jason A et al. (2007) Total synthesis of (+)-azaspiracid-1. Part I: Synthesis of the fully elaborated ABCD aldehyde. Angew Chem Int Ed Engl 46:4693-7

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