3,4-Dideoxy-3,3,4,4-tetrafluoro-and 4-OH 1 Epimeric 3-Deoxy-3,3-difluoro--GalCer 2 Analogues: Synthesis and Biological Evaluation 3 on Human iNKT Cells Stimulation. 4

20 iNKT cells recognize CD1d/-galactosylceramide (-GalCer) complexes via their invariant 21 TCR receptor and stimulate the immune response. Many -GalCer analogues have been 22 investigated to interrogate this interaction. Following our previous work related to the 23 modification of the hydrogen bond network between -GalCer and CD1d, we have now 24 focused our attention on the synthesis of 3-deoxy-3,3-difluoro-and 3,4-dideoxy-3,3,4,4-25 tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In 26 2 each case, deoxygenation at the indicated positions was accompanied by difluoro introduction 1 in order to evaluate the resulting electronic effect on the stability of the ternary 2 CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-3 difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish 4 their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. 5 The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen 6 bond properties. 7 8