New synthesis of glycolipid immunostimulants RC-529 and CRX-524

Abstract An efficient and scalable synthesis of the potent vaccine adjuvant RC-529 ( 3 ) and TLR4 agonist CRX-524 ( 4 ) is described in eight steps from 1,3,4,6-tetra- O -acetyl-2-amino-2-benzyloxycarbonyl-2-deoxy-β- d -glucopyranose ( 10c ) in ca. 25% overall yield. The synthesis features the strategic use of the N -Cbz group for β-glycosylation and the selective N,N,O-triacylation of common advanced intermediate 15 with ( R )-3-tetradecanoyloxy or decanoyloxytetradecanoic acid ( 8 , 9 ) late in the synthesis. A new method for preparing and enhancing the enantiopurity of ( R )-3-hydroxytetradecanoic acid ( 6 ), a key component of 3 and 4 as well as bacterial lipid A, is also described.