Rembold H, Schmidt R R
Fakultät für Chemie, Universität Konstanz, Germany.
Carbohydr Res. 1993 Aug 17;246:137-59. doi: 10.1016/0008-6215(93)84029-6.
The synthesis of the lipopolysaccharide fragment O-(4,5,7,8-tetra-O-acetyl-3-deoxy-N-methyl-alpha-D-manno-2- octulopyranosylonamide)-(2-->6)-O-(2-deoxy-2-[(3R)-3- dodecanoyloxytetradecanamido]-4-O- phosphono-3-O-tetradecanoyl-beta-D-glucopyranosyl)-(1-->6)-1-O-acetyl-2- deoxy-2 - [(3R)-3-dodecanoyloxytetradecanamido]-3-O-tetradecanoyl-alpha-D- glucopyranose (35 alpha) is performed via anomeric O-alkylation. With this objective, the 2-azido-3-O-benzyl-2-deoxy-6-O-trifluoromethanesulfonyl-beta-D-glu copyranosides 5, 7, and 19 alpha, beta were synthesized from D-glucal and employed as alkylating agents. Reaction of 5 with the O-cyclohexylidene-protected Kdo-derivative 10 afforded the desired alpha-linked disaccharide, tert-butyldimethylsilyl 4-O-allyl-2-azido-3-O-benzyl-2-deoxy-6- O-(4,5:7,8-di-O-cyclohexylidene-3-deoxy-N-methyl-alpha-D-manno-2- octulopyranosylonamide)-beta-D-glucopyranoside (11); even better yields of the structurally related disaccharide 12 were obtained with the 4-O-unprotected 7 as alkylating agent. 1-O-Desilylation of 12 furnished the lactol 20, which could be alkylated at the anomeric position with 1-O-allyl protected alkylating agents 19 alpha and 19 beta, both of which furnished exclusively the desired beta-(1-->6)-linked trisaccharides allyl O-(4,5:7,8-di-O-cyclohexylidene-3- deoxy-N-methyl-alpha-D-manno-2-octulopyranosylonamide)-(2-->6)-O-( 2-azido-3- O-benzyl-2-deoxy-beta-D-glucopyranosyl)-(1-->6)-2-azido-3, 4-di-O-benzyl-2-deoxy-alpha- (21 alpha) and -beta-D-glucopyranoside (21 beta), respectively. Phosphorylation with diphenyl phosphorochloridate, replacement of the O-cyclohexylidene protective group by O-triethylsilyl (TES) protective groups, removal of the 1-O-allyl group, azido group reduction, subsequent N-acylation, and then O-acetylation provided the key 1-O-acetyl protected intermediate 30 alpha. Removal of the O-TES groups, subsequent O-acetylation, and hydrogenolytic O-debenzylation furnished O-[4,5:7,8-tetra-O-acetyl-3-deoxy-N-methyl-alpha-D-manno-2- octulopyranosylonamide]-(2-->6)-O-(2-deoxy-4-O-diphenoxyphospho ryl-2-[(3R)- 3-dodecanoyloxytetradecanamido]-beta-D-glucopyranosyl)-(1-->6)-1-O -acetyl-2- deoxy-2[(3R)-dodecanoyloxytetradecanamido]-alpha-D-glucopyranose (33 alpha), which underwent the required selective O-tetradecanoylation at the 3-O- and 3'-O-position, thus furnishing, after hydrogenolytic O-dephenylation of the diphenoxyphosphoryl group, the target molecule 35 alpha.
脂多糖片段O-(4,5,7,8-四-O-乙酰基-3-脱氧-N-甲基-α-D-甘露糖-2-辛吡喃糖酰胺)-(2→6)-O-(2-脱氧-2-[(3R)-3-十二烷酰氧基十四烷酰胺]-4-O-膦酰基-3-O-十四烷酰基-β-D-吡喃葡萄糖基)-(1→6)-1-O-乙酰基-2-脱氧-2-[(3R)-3-十二烷酰氧基十四烷酰胺]-3-O-十四烷酰基-α-D-吡喃葡萄糖(35α)的合成是通过异头O-烷基化进行的。为此，由D-葡糖醛合成了2-叠氮基-3-O-苄基-2-脱氧-6-O-三氟甲磺酰基-β-D-吡喃葡萄糖苷5、7和19α、β，并用作烷基化剂。5与O-环己叉基保护的Kdo衍生物10反应得到所需的α-连接二糖，叔丁基二甲基甲硅烷基4-O-烯丙基-2-叠氮基-3-O-苄基-2-脱氧-6-O-(4,5:7,8-二-O-环己叉基-3-脱氧-N-甲基-α-D-甘露糖-2-辛吡喃糖酰胺)-β-D-吡喃葡萄糖苷(11)；以4-O-未保护的7作为烷基化剂时，得到结构相关的二糖12的产率更高。12的1-O-去甲硅烷基化得到内酯20，其可以用1-O-烯丙基保护的烷基化剂19α和19β在异头位置进行烷基化，二者分别仅得到所需的β-(1→6)-连接的三糖烯丙基O-(4,5:7,8-二-O-环己叉基-3-脱氧-N-甲基-α-D-甘露糖-2-辛吡喃糖酰胺)-(2→6)-O-(2-叠氮基-3-O-苄基-2-脱氧-β-D-吡喃葡萄糖基)-(1→6)-2-叠氮基-3,4-二-O-苄基-2-脱氧-α-(21α)和-β-D-吡喃葡萄糖苷(21β)。用二苯基磷酰氯进行磷酸化，用O-三乙基甲硅烷基(TES)保护基取代O-环己叉基保护基，除去1-O-烯丙基，还原叠氮基，随后进行N-酰化，然后进行O-乙酰化，得到关键的1-O-乙酰基保护的中间体30α。除去O-TES基团，随后进行O-乙酰化，并通过氢解进行O-脱苄基化，得到O-[4,5:7,8-四-O-乙酰基-3-脱氧-N-甲基-α-D-甘露糖-2-辛吡喃糖酰胺]-(2→6)-O-(2-脱氧-4-O-二苯氧基磷酰基-2-[(3R)-3-十二烷酰氧基十四烷酰胺]-β-D-吡喃葡萄糖基)-(1→6)-1-O-乙酰基-2-脱氧-2[(3R)-十二烷酰氧基十四烷酰胺]-α-D-吡喃葡萄糖(33α)，其在3-O-和3'-O-位置进行所需的选择性O-十四烷酰化，因此在二苯氧基磷酰基进行氢解O-脱苯基化后，得到目标分子35α。
