Efficient divergent synthesis of new immunostimulant 4″-modified α-galactosylceramide analogues

A synthesis strategy for the swift generation of 4"-modified alpha-galactosylceramide (alpha-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure activity relationships (SAR) of this understudied glycolipid part. The strategy relies on a late-stage reductive ring-opening of a p-methoxybenzylidene (PMP) acetal to regioselectively liberate the 4"-OH position. The expediency of this methodology is demonstrated by the synthesis of a small yet diverse set of analogues, which were tested for their ability to stimulate invariant natural killer T cells (iNKT) in vitro and in vivo. The introduction of a p-chlorobenzyl ether yielded an analogue with promising immunostimulating properties, paving the way for further SAR studies