New synthesis of glycolipid immunostimulants RC-529 and CRX-524 |
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Authors: | Hélène G Bazin |
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Institution: | GlaxoSmithKline Biologicals, 553 Old Corvallis Road, Hamilton, MT 59840, USA |
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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. |
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Keywords: | Lipid A mimetics Glycolipids Immunostimulants TLR4 agonist Vaccine adjuvant AGP |
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