Glycosyl Iodides:
A Powerful Tool for the Stereoselective Synthesis of Glycosides

Suvarn Kulkarni, Matt Schombs, Ryan Davis and Mark Witschi

α-O-Galactosyl ceramides (GalCer) have been shown to display antitumor properties and immuno-stimulatory activity resulting in natural killer T (NKT) cell activation and subsequent cytokine secretion. Our group has developed a three-step, one-pot synthesis of GalCer analogs utilizing galactosyl iodides to install the key a glycosidic linkage.¹

Lipid Raft Formation

A crucial step in viral or bacterial entry into cell, viz. HIV, lyme disease, cholera, Alzheimer's and prion related diseases is the interaction of lipid rafts with pathogenic proteins. The proposed chemical technology aims to understand the correlation between pathogen attachment and immune signaling at the molecular level by studying the effect of introducing bacterial glycolipids on lipid raft constructs.

Lipid Raft Formation with β-GalCer

Synthesis of the C-analog of BbGL2

Two major glycolipids have been isolated from Borrelia burgdorferi, the etiological agent of Lyme disease, which is a multisystemic disorder that affects skin, nervous system, heart and joints. The first synthesis of a C-analog of BbGL2 is accomplished using Grignard reaction of the in situ generated β-galactosyl iodide and concomitant olefin cross metathesis reaction of C-vinyl galactoside.²

Synthesis of Glucuronic-Acid Linked Ceramides

Recent literature has shown a carboxyl functionality at the C-6 position of the sugar moiety, present in the bacterial glycolipid GSL-1, results in significant cytokine production. It has been postulated this effect may be a result of increased NKT cell binding due to increased H-bonding.

Mechanistic Studies Using Kinetic Isotope Effect

The stereoselective synthesis of β-O-mannopyranosides is one of the most difficult linkages to achieve due to steric repulsion of the C2 axial group, anchimeric assistance, and the anomeric effect. The ability to modify reaction conditions and the glycosyl iodide can control the stereo-outcome of glycosidation products.

By incorporating a benzylidene protecting group and using low temperature, destabilization of the oxonium cation can be achieved leading to exclusive β-D-mannopyranoside products. Kinetic studies will be done to examine the transition state.

Computed geometry for the proposed transition state of trimethylene oxide and α-mannosyl iodide.

Acknowledgments
This work was supported by National Science Foundation CHE-0196482, NSF 0518010, NSF CRIF program (CHE-9808 183), NSF Grant OSTI 97-24412, California HIV/AIDS Research Program and NIH Grants RR11973 and GM075093 provided funding for the NMR spectrometers used on this project.

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