The goal of this research is to develop and test new strategems and methodologies for the synthesis of naturally occurring macrolide antibiotics. Synthetic pathways to five macrolides will be investigated, each of which seeks to elaborate, in a stereo- controlled fashion, the complete molecular architecture of these complex structures. The planned route to avermectin B1a, a broad-spectrum anthelmintic with promising indications for treatment of human parasitic infections, makes use of an intramolecular Julia olefin synthesis for closing the macrocycle. Novel methodology, including translactonization of an interesting bridged gamma-lactone intermediate, is employed for linking the three subunits of avermectin aglycone. Latrunculin A, a potent fish toxin isolated from a marine sponge and possessing activity similar to but more specific than cytochalasin D, is to be assembled from three subunits and a final lactonization-ketalization protocol. The preparation of a key subunit of latrunculin A involves a tandem dianion-Wittig reaction that produces the Z,E-diene moiety stereo- specifically. Synthesis of another marine macrolide, geodiamolide A, possessing antifungal activity, is projected from a novel tripeptide containing m-iodo-N-methyl-D-tyrosine and a nonenoic acid segment. Formation of the depsipeptide is envisioned by means of an Eschenmoser-Claisen rearrangement. Synthesis of cathedulin K-19, a constituent of the natural stimulant and narcotic """"""""khat"""""""", necessitates synthesis of its principal structural subunit euonyminol, with subsequent connection of cathic acid and a second dicarboxylic acid to complete the bis macrodiolide. A route to euonyminol based on a Diels-Alder cycloaddition to a quinone, followed by sequential oxidation steps, is proposed. The final target, rutamycin B, is an antifungal agent for which a lactonization strategy invoking conjugate carboxylate addition, followed by spiroketalization, is proposed. A plan for construction of the nine stereogenic centers in the C(1)-C(16) segment of rutamycin is suggested that begins with cycloaddition of an oxoallyl cation to a chiral furan.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
9R01GM050574-20
Application #
2188504
Study Section
Medicinal Chemistry Study Section (MCHA)
Project Start
1993-12-01
Project End
1997-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
20
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Oregon State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
053599908
City
Corvallis
State
OR
Country
United States
Zip Code
97339
White, James D; Li, Yang; Kim, Jungchul et al. (2015) Cyclobutane Synthesis and Fragmentation. A Cascade Route to the Lycopodium Alkaloid (-)-Huperzine A. J Org Chem 80:11806-17
Avery, Mitchell A; Choudhry, Satish C; Dhingra, Om Prakash et al. (2014) Total synthesis of macrodiolide ionophores aplasmomycin A and boromycin via double ring contraction. Org Biomol Chem 12:9116-32
Kuntiyong, Punlop; Lee, Tae Hee; Kranemann, Christian L et al. (2012) Total synthesis of the marine toxin phorboxazole A using palladium(II)-mediated intramolecular alkoxycarbonylation for tetrahydropyran synthesis. Org Biomol Chem 10:7884-99
White, James D; Jeffrey, Scott C (2009) Synthesis of the northern sector (C8-C19) of rapamycin via Chan rearrangement and oxidation of an alpha-acyloxyacetate. Tetrahedron 35:6642-6647
White, James D; Kuntiyong, Punlop; Lee, Tae Hee (2006) Total synthesis of phorboxazole a. 1. Preparation of four subunits. Org Lett 8:6039-42
White, James D; Smits, Helmars; Hamel, Ernest (2006) Synthesis of cryptothilone 1, the first cryptophycin-epothilone hybrid. Org Lett 8:3947-50
White, James D; Lee, Tae Hee; Kuntiyong, Punlop (2006) Total synthesis of phorboxazole A. 2. Assembly of subunits and completion of the synthesis. Org Lett 8:6043-6
Blakemore, Paul R; Browder, Cindy C; Hong, Jian et al. (2005) Total synthesis of polycavernoside A, a lethal toxin of the red alga Polycavernosa tsudai. J Org Chem 70:5449-60
White, James D; Smits, Helmars (2005) Application of the Dotz reaction to construction of a major portion of the ansa macrocycle (-)-kendomycin. Org Lett 7:235-8
White, James D; Xu, Qing; Lee, Chang-Sun et al. (2004) Total synthesis and biological evaluation of +-kalkitoxin, a cytotoxic metabolite of the cyanobacterium Lyngbya majuscula. Org Biomol Chem 2:2092-102

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