Synthesis of difluorinated galactose-UDP

for studies against tuberculosis

Quí-Hiển Nguyễn, Dr. Julien Malassis, Prof. Bruno Linclau*

*School of Chemistry, University of Southampton, Southampton, SO17 1BJ

Introduction

• M.tuberculosis cell wall uses the furanose form of

galactose, converted from galactopyranose-UDP

in an enzymatic process:

• Design of inhibitors based on galactose can lead

to novel therapeutic approach to cure TB.

Edvard Munch’s The Sick

Child, 1896, depicting the

artist’s sister dying of

tuberculosis.1

(Photo in public domain)

• Tuberculosis is still one of the most feared

diseases to human.

• WHO estimated 1.5 million people died of TB in

2014.

• Drug-resistant TB strains are major concerns

nowadays.

References (1) E. Munch, Det syke barn, 1896,

https://commons.wikimedia.org/wiki/File:Munch_Det_Syke_Barn_1896.jpg,

(2) I. N’Go, S. Golten, A. Ardá, J. Cañada, J. Jiménez-Barbero, B. Linclau, and S. P. Vincent,

Chem. Eur. J., 2014, 20, 106 – 112.

(3) K. E. van Straaten, J. R. A. Kuttiyatveetil, C. M. Sevrain, S. A. Villaume, J. Jiménez-

Barbero, B. Linclau, S. P. Vincent, D. A. R. Sanders, J. Am. Chem. Soc., 2015, 137, 1230

– 1244.

(4) C. Dalvit, C. Invernizzi and A. Vulpetti, Chem. Eur. J., 2014, 20, 11058 -11068.

(5) T. S. Ramussen and H. H. Jensen, Org. Biomol. Chem., 2010, 8, 433–441.

(6) L. Mtashobya, L. Quiquempoix and B. Linclau, J. Fluorine Chem., 2015, 171, 92-96.

Previous studies and aims of this project

• Both show to be good inhibitors to UGM.

• Crystal structures have revealed similar binding

modes to that of normal Galp-UDP.3

Our group has been using fluorinated sugars as an

approach to design inhibitors that have higher

affinity to UGM than galactose-UDP.

Previously, we have synthesised and assayed 2,3-

tetrafluorinated Galp and Galf-UDP.2

F4-Galp-UDP F4-Galf-UDP

This project aims to synthesise the 2,3-difluorinated

Galp-UDP and Galf-UDP to continue the search for

potent UGM inhibitors.

• Use this system to study the effect of fluorination

motifs on binding of carbohydrates to proteins

(probed by electron density on fluorine atoms).4

F4-Galp-UDP F4-Galf-UDP

Synthesis of difluorinated galactose-UDP • Preparation of Černý epoxide from levoglucosan.5

• Fluorine substituents introduced to C2-C3 subsequently.6

Galp UDP Galf

• C4 inversion by SN2 reaction led to galactose configuration.

• 1,6-ether bridge deprotected by acetolysis, followed by

hydrolysis to give free F2-Galp.

• Acetal protection of F2-Galp gave access to both protected F2-

Galp and F2-Galf (α-anomer for acetal-F2-Galp proven by X-ray)

• Anomeric phosphorylation, deprotection steps and final UMP

coupling to reach target molecules.

Crystal structure of

acetal-F2-Galp

Conclusion • Synthetic access to the phosphorylated sugars is

possible, ready for UMP-coupling for final targets.

• Spectral characterisation for furanose is in

progress.

• Optimisation for the final steps is underway.