A divergent approach to the synthesis of iGb3 sugar and lipid analogues via a lactosyl 2-azido-sphingosine intermediate

Isoglobotrihexosylceramide (iGb3, 1) is an immunomodulatory glycolipid that binds to CD1d and is presented to the T-cell receptor (TCR) of invariant natural killer T (iNKT) cells. To investigate how modifications to the lipid tail or terminal sugar residue of iGb3 influence iNKT cell activity, we developed an efficient and divergent synthetic route that provided access to both sugar and lipid iGb3 analogues which utilised a lactosyl 2-azido-sphingosine derivative as a common intermediate. In this way, iGb3 (1) and the unprecedented analogues 6′′′-deoxy-iGb3-sphingosine 2, 6′′′-deoxy-iGb3-sphinganine 3, C12 N-acyl iGb3 4 and C20:2 N-acyl iGb3 5 were prepared so that key structure–activity relationships can be explored.