PROJECT SUMMARY The work in this proposal builds on our expertise in catalytic stereoselective glycosylations to result in efficient synthetic methodologies for construction of the challenging glycosidic bonds. We recently discovered that readily available phenanthrolines, rigid and planar organic compound with two pyridine rings fused to a benzene ring, effectively act as nucleophilic catalysts to promote stereoselective 1,2- cis glycosylation reactions of alcohol nucleophiles with both pyranosyl and furanosyl bromide donors. The phenanthroline catalytic system provides efficient access to a myriad of 1,2-cis pyranosides and furanosides bearing the C2-oxygen, -azido and -fluoro functional groups under mild and operationally simple conditions. The phenanthroline-catalyzed methodologies represent long standing synthetic challenges for highly desirable glycosylations to generate biologically important oligosaccharides and glycopeptides to advance an understanding of their biological functions. In this R35 grant, we continue uncovering the simplicity and versatility of phenanthroline catalysts to provide a new principle for the stereoselective construction of the challenging α-2-deoxy glycosides. Precisely tailored phenanthroline catalysts can activate both the alcohol nucleophile and the glycosyl halide electrophile simultaneously. We will also investigate the dual activation mechanism of the phenanthroline catalysts to control site- selective coupling of polyol nucleophiles and chemoselective coupling of the hydroxyl of serine residue in the presence of the thiol of cysteine-containing peptides. Further, we will apply the phenanthroline catalyst platform to the synthesis of heparan sulfate-like oligosaccharides as inhibitors of heparanase, which is a druggable target for anticancer therapy. We will also develop the library of heparan sulfate mimetics with all of the possible O- and N-sulfation motifs from readily available aminoglycosides to advance an understanding of the role of sulfated glycosaminoglycans in many biological systems. In particular, we will investigate these structurally well-defined heparan sulfate mimetics as the potential binders of clinically important fibroblast growth factors.