This grant application describes a research program, which demonstrates a novel strategy for the efficient chemical synthesis of oligosaccharide structures bearing anticancer, cardiotonic, and antimicrobial activity. The research described effectively couples stereoselective methods for glycoside formation from glycals with a novel method for the synthesis of carbohydrate glycals via a novel alkynol cycloisomerization transformation discovered in the Principal Investigator's laboratories. This unique approach has many advantages over classical synthetic methods when applied to the construction of oligosaccharides bearing unusual or unnatural stereochemical and substitution patterns, as well as the highly deoxygenated carbohydrate oligosaccharides present in many compounds exhibiting anticancer and other therapeutic properties.
Specific aims of this research plan include: (1) development of new reagents and catalysts for endo -selective cycloisomerization of alkynyl alcohols; (2) synthesis of the trisaccharide moiety of cardiotonic steroids; (3) parallel synthesis methodology for preparing libraries of glycoconjugate analogs of compounds exhibiting anticancer and other biological activities; and (4) synthesis of glycoside linkages exhibited in the antimicrobial saccharomicin heptadecasaccharides, leading to a total synthesis of saccharomicin A.
|Balthaser, Bradley R; McDonald, Frank E (2009) Brønsted acid-promoted glycosylations of disaccharide glycal substructures of the saccharomicins. Org Lett 11:4850-3|
|Fei, ZhongBo; McDonald, Frank E (2007) Stereo- and regioselective glycosylations to the bis-C-arylglycoside of kidamycin. Org Lett 9:3547-50|
|Koo, Bonsuk; McDonald, Frank E (2007) Fischer carbene catalysis of alkynol cycloisomerization: application to the synthesis of the altromycin B disaccharide. Org Lett 9:1737-40|
|Koo, Bonsuk; McDonald, Frank E (2005) Synthesis of the branched C-glycoside substructure of altromycin B. Org Lett 7:3621-4|
|Fei, ZhongBo; McDonald, Frank E (2005) Synthesis of the aglycones of altromycins and kidamycin from a common intermediate. Org Lett 7:3617-20|
|Nowroozi-Isfahani, Taraneh; Musaev, Djamaladdin G; McDonald, Frank E et al. (2005) Density Functional Study of Mo-Carbonyl-Catalyzed Alkynol Cycloisomerization: Comparison with W-Catalyzed Reaction. Organometallics 24:2921-2929|