The applicant will study the total synthesis of several potent, naturally occurring antifungal agents including (1) the nikkomycins and neopolyoxins which are nucleoside dipeptide chitin synthetase inhibitors produced by Streptomyces tendae or cacaoi var asoensis; (2) jaspamide which is a marine peptide polyketide macrocycle produced by a sponge of the genus Jaspis; (3) papulacandin A which is a 1,3-beta-D-glucan synthase inhibitor elaborated by Papularia sphaerosperma; (4) trichoviridin which is an epoxy isonitrile derivative produced by a Trichoderma species. It is the intention of this study to clarify the mode of action of these active compounds and thereby design more active analogs and to develop novel organic transformations of general synthetic importance. Specifically the applicant shall seek to develop (1) the use of isoxazoline intermediates in stereospecific gamma- hydroxy-alpha- amino acid construction; (2) the homologation of ribose aldehydes in the stereochemically controlled synthesis of nucleoside amino acids; (3) the elaboration of macrocyclic seco acids units via the diastereoselective alkylation of N-propanoyl alanine trianions; (4) macrocyclization via N-acyl-2-azetidinones and transacylation; (5) the regioselective manipulation of D-lactose using 4-azido-2,2- dimethylbutanoyl chloride and aryl titanium chelates (6) the construction of alpha,beta-epoxy isonitriles via the corresponding isocyanates or isothiocyanates and deoxygenation or desulfurization or via chromium carbene chemistry.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022252-05
Application #
3133147
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1985-09-30
Project End
1990-08-31
Budget Start
1989-09-01
Budget End
1990-08-31
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
Schools of Arts and Sciences
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60208
Barrett, A G; Doubleday, W W; Gross, T et al. (2000) Total synthesis of antifungal natural products. Ernst Schering Res Found Workshop :149-81