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 F 4 -Galp-UDP F 4 -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 F 4 -Galp-UDP F 4 -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 S N 2 reaction led to galactose configuration. • 1,6-ether bridge deprotected by acetolysis, followed by hydrolysis to give free F 2 -Galp. • Acetal protection of F 2 -Galp gave access to both protected F 2 - Galp and F 2 -Galf (α-anomer for acetal-F 2 -Galp proven by X-ray) • Anomeric phosphorylation, deprotection steps and final UMP coupling to reach target molecules. Crystal structure of acetal-F 2 -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.