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

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-beta-D-glucopyranose (10c) in ca. 25% overall yield. The synthesis features the strategic use of the N-Cbz group for P-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. (c) 2006 Elsevier Ltd. All rights reserved.