A Cyclopropyl Glycoside Donor for

Synthesis of Lipid A Disaccharide

Hannah Curran, Dr. Robert Giuliano
Villanova University, Department of Chemistry, Villanova, PA 19085
Lipid A is the innermost of the three regions of the lipopolysaccharide molecule that is responsible for the toxicity of gram-
negative bacteria. It is also responsible for adjuvant activity toward protein and carbohydrate antigens. Although its toxic effects
can be harmful, it is also believed to be a major component of stimulating the immune system in response to Gram-negative
infections; it presents itself as an area of interest for potential use in antibiotics.

Lipid A Disaccharide: Donor Molecule

The core structure of lipid A consists of two β-linked glucosamines with attached acyl chains. Our approach to the
synthesis of the lipid A disaccharide is based on the coupling of a cyclopropyl glycoside donor and a diol acceptor. Past
obstacles of our pathway included the failure of the glycosides to couple due to the inability of the glycoside acceptor to
withstand the reaction conditions. If the coupling is successful, it will contribute to existing methodologies for the
synthesis of Lipid A.

Retrosynthetic Analysis

A cyclopropyl glycoside will serve as a donor in the formation of a protected Lipid A disaccharide.
This should react selectively with the primary OH group on the acceptor molecule.
Glucosamine hydrochloride was reacted with phathalic anhydride and sodium, then with
acetic anhydride and pyridine to form the phthalimido group, and to acylate the –OH groups.
HBr was then used to create cis/trans Br group to be reacted with allyl alcohol to produce
primarily the β allyl glycoside. This was then isomerized with [Ir(cod)(PMePh2)2]PF6 . NMR
indicates that the product was formed in low yield.

JEFFREY

Crystal structure of the β allyl

glycoside.

Conclusion
Cyclopropyl glycoside was successfully synthesized from an allyl glycoside in a
model study. An allyl glycoside with the nitrogen containing group was also
synthesized. Continuing research will attempt to cyclopropanate the nitrogen
containing allyl glycoside. Glycosidation of both cyclopropyl glycosides, the model
study and the proposed Lipid A donor, will also be attempted.

Acknowledgements:
Villanova University Summer Undergraduate Research Department,
Villanova University Chemistry Department
References: Johnson D.A., Keegan D.S., Sowell C.G., Livesay
M.T., Johnson C.L., Taubner L.M., Harris A., Myers K.R., Thompson J.D., Gustafson G.L. 3-O-Desacyl
Dr. Nicholas Piro, Villanova University, Chemistry Department
monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J. Med. Chem.
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