Synthesis of glycosamino acids and antisense nucleosides, I: Progress in radical-based total synthesis and FGI approaches

ORGN 500

M.-E. Duban, R.E. Glowinski, and F.M. Rivas. Laboratory for the Design of Bioactive Molecules, Dept. Chemistry and Physics, Chicago State University, DH Williams Science Center 295C, 9501 S ML King Drive, Chicago, IL 60628-1598

Glycosamino acids (GAAs) of interest in traditional and antisense drug discovery ultimately require cost-effective syntheses. Here we report progress toward efficient, general routes to 5- and/or 3-substituted ribofuranosides (eg, glycosamino thionoester 1, a precursor aimed at a neutral, oligoamide antisense agent with adequate potency and ADME), and review their context in academic/industrial GAA syntheses and antisense therapeutic design. In the total synthesis approach we adopt a “base on last” strategy to avoid multiple parallel nucleoside syntheses, preparing 2 (eg, by enantioselective alkyne addition to N-protected glycinal, etc) en route to a Stork-Just radical ring closure. In the FGI approach, we modify stereoselective Chu-Tam allylation to allow use of various sp2-hybridized acceptors with the radical derived from 3, thus providing efficient entree into 3′-C-functionalized nucleosides (and reduced reliance on tin). This work is supported by grants S06 GM08043 and R25 GM59218 from the NIH, NIGMS.

Total Synthesis, Asymmetric Reactions and Syntheses, Bioorganic 9:00 AM-11:00 AM, Wednesday, March 31, 2004 Anaheim Convention Center -- Hall C, Poster Division of Organic Chemistry The 227th ACS National Meeting, Anaheim, CA, March 28-April 1, 2004