Abstract

? 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 that 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 antinepolastic agents derived from amino acid constituents. The methodological studies dealing with new reaction discovery will emphasize the development of chiral metal catalysts for the synthesis of complex amino acids. These advances should culminate in practical routes to the asymmetric synthesis of beta-hydroxy-alpha-amino acids and alpha, beta-diamino acids. Synthesis targets associated with this project will include the antiviral cyclic heptapeptide cyclomarin A, the marine toxin, azaspiracid 1, and the cytotoxic hexacyclic alkaloid daphnicyclidin A. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033328-20
Application #
6737581
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
1983-08-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
20
Fiscal Year
2004
Total Cost
$383,050
Indirect Cost

  Institution

Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138

  Publications

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
Evans, David A; Adams, Drew J; Kwan, Eugene E (2012) Progress toward the syntheses of (+)-GB 13, (+)-himgaline, and himandridine. new insights into intramolecular imine/enamine aldol cyclizations. J Am Chem Soc 134:8162-70
Marcoux, David; Bindschädler, Pascal; Speed, Alexander W H et al. (2011) Effect of counterion structure on rates and diastereoselectivities in ?,?-unsaturated iminium-ion Diels-Alder reactions. Org Lett 13:3758-61
Evans, David A; Welch, Dennie S; Speed, Alexander W H et al. (2009) An aldol-based synthesis of (+)-peloruside a, a potent microtubule stabilizing agent. J Am Chem Soc 131:3840-1
Evans, David A; Kvaerno, Lisbet; Dunn, Travis B et al. (2008) Total synthesis of (+)-azaspiracid-1. An exhibition of the intricacies of complex molecule synthesis. J Am Chem Soc 130:16295-309
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
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

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