Efficient Divergent Synthesis of New Immunostimulant 4″-Modified α-Galactosylceramide Analogues

Abstract

A synthesis strategy for the swift generation of 4″-modified α-galactosylceramide (α-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 <i>p</i>-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 (<i>i</i>NKT) <i>in vitro</i> and <i>in vivo</i>. The introduction of a <i>p</i>-chlorobenzyl ether yielded an analogue with promising immunostimulating properties, paving the way for further SAR studies.