Abstract

The overriding objectives of this proposal are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. The principal classes of structures which will be the focal point for both new reaction methodology and the subject of synthesis activities are largely derived from amino acids. Targets for total synthesis will include the Beta-lactam antibiotics thienamycin, northienamycin, PS-5 and related carbapenems. Two fundamentally different general approaches to the asymmetric synthesis of the Beta-lactam nucleus will be investigated. Other targets for total synthesis will include the powerful antineoplastic agents, saframycin, macbecin, herbimycin, bouvardin, deoxybouvardin, and patellamides A-C. Related targets for total synthesis will include the complex peptide antibiotics of the vancomycin class. Specific objectives within this family include vancomycin, teicoplanin, and restocetin. The major thrust in new reaction methodology which will accompany these target-oriented projects will be the development of new approaches to the asymmetric synthesis of Alpha-amino acids. Within the context of this objective, a number of complementary concepts are outlined. For example, amino acid syntheses based upon the development of chiral glycine enolate synthons, chiral electrophilic aminating agents, and chiral metal nitrenoids are presented.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033328-08
Application #
3282910
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1983-08-01
Project End
1991-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
8
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Harvard University
Department
Type
Schools of Arts and Sciences
DUNS #
071723621
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

Showing the most recent 10 out of 37 publications