The goals of the proposed research are the development, mechanistic description, and application of new methodology for the synthesis of 2-amino sugars, crucial molecular components and precursors in biological systems, including structural polymers, enzyme inhibitors, and cell-surface glycoproteins. The synthetic approach uses glycal 3-carbamates as starting materials and proceeds through a tandem alkene amidation- glycosylation sequence-amidoglycosylation-to introduce nitrogen at C2 of the sugar framework and to establish an anomeric linkage to a nucleophilic reaction partner, the glycosyl acceptor. Iodosobenzene carries out this overall oxidation, in a process best catalyzed by dirhodium(II) carboxylates and apparently involving a rhodium-complexed acyl nitrene intermediate. The amidation step is intramolecular, forging the C2-N bond on the more hindered glycal face, and, ideally, glycosylation should occur stereospecifically, anti to the newly incorporated nitrogen substituent. While certain glycal 3-carbamates react with efficiency and high anomeric stereoselectivity, other substrates with potentially high synthetic value provide substantial amounts of C3-oxidized dihydropyranone byproducts and low stereocontrol in the glycosylation step. Using the mechanistic hypotheses that (1) both amidoglycosylation and C3 oxidation occur via a common metallanitrene intermediate and (2) stereoselective glycosylation requires neighboring-group participation from the C2 nitrogen, probably by way of a glycosyl aziridine, this application outlines how controlling the conformation of the glycal 3-carbamate framework will enable both high chemo- and stereoselectivity in the amidoglycosylation reactions. Other proposed investigations will further illuminate mechanistic details of the reactions, providing crucial information for improving and increasing the utility and scope of amidoglycosylation for the preparation of amino sugars. With input from both the method development and mechanistic study components of the proposed project, this application outlines the completion of a synthesis of the disaccharide portion of the potent chitinase inhibitor allosamidin. Iterative application of the amidoglycosylation technology will enable streamlined preparation of an allosamidin disaccharide module readily amenable for analogue synthesis. To be conducted at Barnard College, an undergraduate liberal arts college for women, the project will provide students with numerous opportunities in organic chemical synthesis, helping to attract and propel them into careers in chemistry and other health-related professions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15GM081889-03S1
Application #
7629238
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Schwab, John M
Project Start
2001-03-01
Project End
2010-09-30
Budget Start
2007-04-01
Budget End
2010-09-30
Support Year
3
Fiscal Year
2008
Total Cost
$9,445
Indirect Cost
Name
Barnard College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
068119601
City
New York
State
NY
Country
United States
Zip Code
10027
Hurlocker, Brisa; Abascal, Nadia C; Repka, Lindsay M et al. (2011) Dihydropyranone formation by ipso C-H activation in a glucal 3-carbamate-derived rhodium acyl nitrenoid. J Org Chem 76:2240-4
Gupta, Ritu; Sogi, Kimberly M; Bernard, Sarah E et al. (2009) Protecting group and solvent control of stereo- and chemoselectivity in glucal 3-carbamate amidoglycosylation. Org Lett 11:1527-30