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【结 构 式】 
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【分子编号】59080 【品名】(4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol 【CA登记号】 |
【 分 子 式 】C15H29N3O5Si 【 分 子 量 】359.49798 【元素组成】C 50.12% H 8.13% N 11.69% O 22.25% Si 7.81% |
合成路线1
该中间体在本合成路线中的序号：(XI)Peracetylation of (I) to yield (II), followed by treatment with thiophenol and boron trifluoride, afforded the mannopyranoside (III). After methanolysis of the acetate esters of (III) in the presence of NaOMe, the resultant tetrahydroxy derivative (IV) was protected as the bis-acetonide (V) by treatment with 2,2-dimethoxypropane and 10-camphorsulfonic acid. The phenylsulfanyl group of (V) was reductively removed by means of lithium and a catalytic amount of naphthalene, yielding the dihydropyran derivative (VI). The free hydroxyl group of (VI) was then esterified with Ac2O in pyridine to give (VII). Addition of sodium azide to dihydropyran (VII) in the presence of cerium ammonium nitrate furnished the azido nitrate (VIII). The nitrate ester of (VIII) was then selectively cleaved by means of sodium nitrite, giving alcohol (IX), which was further protected by silylation with tert-butyldimethylsilyl chloride and imidazole to provide silyl ether (X). Subsequent alcoholysis of the acetate ester group of (X) in the presence of NaOMe provided the key intermediate (XI).
| 【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 43107 | (3S,4S,5S,6R)-6-(hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrol | 3458-28-4 | C6H12O6 | 详情 | 详情 |
| (II) | 54319 | [(2R,3R,4S,5S,6R)-3,4,5,6-tetrakis(acetyloxy)tetrahydro-2H-pyran-2-yl]methyl acetate | n/a | C16H22O11 | 详情 | 详情 |
| (III) | 59072 | (2R,3S,4S,5S)-3,5-bis(acetyloxy)-2-[(acetyloxy)methyl]-6-(phenylsulfanyl)tetrahydro-2H-pyran-4-yl acetate | C20H24O9S | 详情 | 详情 | |
| (IV) | 59073 | (2R,3S,4S,5S)-2-(hydroxymethyl)-6-(phenylsulfanyl)tetrahydro-2H-pyran-3,4,5-triol | C12H16O5S | 详情 | 详情 | |
| (V) | 59074 | (3aS,4S,5aR,9aS,9bR)-2,2,8,8-tetramethyl-4-(phenylsulfanyl)hexahydro[1,3]dioxolo[4',5':4,5]pyrano[3,2-d][1,3]dioxine; (3aS,4S,5aR,9aS,9bR)-2,2,8,8-tetramethylhexahydro[1,3]dioxolo[4',5':4,5]pyrano[3,2-d][1,3]dioxin-4-yl phenyl sulfide | C18H24O5S | 详情 | 详情 | |
| (VI) | 59075 | (4aR,8R,8aS)-2,2-dimethyl-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxin-8-ol | C9H14O4 | 详情 | 详情 | |
| (VII) | 59076 | (4aR,8R,8aR)-2,2-dimethyl-4,4a,8,8a-tetrahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C11H16O5 | 详情 | 详情 | |
| (VIII) | 59077 | (4aR,7R,8R,8aR)-7-azido-2,2-dimethyl-6-(nitrooxy)hexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C11H16N4O8 | 详情 | 详情 | |
| (IX) | 59078 | (4aR,7R,8R,8aR)-7-azido-6-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C11H17N3O6 | 详情 | 详情 | |
| (X) | 59079 | (4aR,6S,7R,8R,8aR)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl acetate | C17H31N3O6Si | 详情 | 详情 | |
| (XI) | 59080 | (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | C15H29N3O5Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Reformatskii condensation of the organozinc reagent derived from methyl bromoacetate (XIII) with n-heptyl cyanide (XII) gave rise to the keto ester adduct (XIV). Catalytic hydrogenation of (XIV) in the presence of the chiral catalyst generated from dichloro(cycloocta-1,5-diene)ruthenium and (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl furnished the (R)-hydroxyester (XV) in high enantiomeric excess. Ester group reduction in (XV) by means of LiAlH4 afforded diol (XVI), which was further converted to the primary tosylate (XVII) with p-toluenesulfonyl chloride in pyridine. Then, alkylation of the intermediate alcohol (XI) with tosylate (XVII) under Williamson's ether synthesis conditions provided the common precursor (XVIII).
| 【1】 Christ, W.J.; Kawata, T.; Hawkins, L.D.; Kobayashi, S.; Asano, O.; Rossignol, D.P. (Eisai Co., Ltd.); Anti-endotoxin cpds.. EP 0536969; JP 1993194470; US 5530113 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 59080 | (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | C15H29N3O5Si | 详情 | 详情 | |
| (XII) | 59081 | octanenitrile | 124-12-9 | C8H15N | 详情 | 详情 |
| (XIII) | 12309 | methyl 2-bromoacetate; methyl bromoacetate | 96-32-2 | C3H5BrO2 | 详情 | 详情 |
| (XIV) | 59082 | methyl 3-oxodecanoate | C11H20O3 | 详情 | 详情 | |
| (XV) | 59083 | methyl (3R)-3-hydroxydecanoate | C11H22O3 | 详情 | 详情 | |
| (XVI) | 59084 | (3R)-1,3-decanediol | C10H22O2 | 详情 | 详情 | |
| (XVII) | 49121 | (3R)-3-hydroxydecyl 4-methylbenzenesulfonate | C17H28O4S | 详情 | 详情 | |
| (XVIII) | 59085 | (3R)-1-[((4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)oxy]-3-decanol | C25H49N3O6Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLIV)Hydroxy acid (II) was converted to methyl ether (XLI) by treatment with trimethylsilyl diazomethane. Reduction of acid (XLI) to alcohol (XLII) was accomplished by treatment with DIBAL in cold dichloromethane. Alcohol (XLII) was transformed to alkyl iodide (XLIII) via tosylation to (V), followed by displacement of tosylate (V) with NaI in acetone. Alkylation of the known azido sugar (XLIV) with the alkyl iodide (XLIII) in the presence of Ag2O provided ether (XLV). Then, acidic acetonide (XLV) hydrolysis led to diol (XLVI). Selective alkylation of the primary hydroxyl group of (XLVI) using iodomethane in the presence of Ag2O, followed by reprotection of some desilylated product, furnished the methyl ether (XLVII). The secondary hydroxyl group of (XLVII) was then converted to phosphate ester (XLVIII) employing the same phosphitylation/oxidation sequence as above.
| 【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 64140 | (3R)-3-hydroxydecanoic acid | C10H20O3 | 详情 | 详情 | |
| (V) | 64141 | (3R)-3-methoxydecyl 4-methylbenzenesulfonate | C18H30O4S | 详情 | 详情 | |
| (XLI) | 64173 | (3R)-3-methoxydecanoic acid | C11H22O3 | 详情 | 详情 | |
| (XLII) | 64174 | (3R)-3-methoxy-1-decanol | C11H24O2 | 详情 | 详情 | |
| (XLIII) | 64175 | (3R)-1-iodo-3-methoxydecane; (1R)-1-(2-iodoethyl)octyl methyl ether | C11H23IO | 详情 | 详情 | |
| (XLIV) | 59080 | (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | C15H29N3O5Si | 详情 | 详情 | |
| (XLV) | 64176 | [((4aR,6S,7R,8R,8aS)-7-azido-8-{[(3R)-3-methoxydecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl)oxy](tert-butyl)dimethylsilane; (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-methoxydecyl ether | C26H51N3O6Si | 详情 | 详情 | |
| (XLVI) | 64177 | (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)-4-{[(3R)-3-methoxydecyl]oxy}tetrahydro-2H-pyran-3-ol | C23H47N3O6Si | 详情 | 详情 | |
| (XLVII) | 64178 | (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)tetrahydro-2H-pyran-3-ol | C24H49N3O6Si | 详情 | 详情 | |
| (XLVIII) | 64179 | diallyl (2R,3S,4R,5R,6S)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)tetrahydro-2H-pyran-3-yl phosphate | C30H58N3O9PSi | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XLIV)Alkylation of azido sugar (XLIV) with 1-iododecane (LI) in the presence of Ag2O provided decyl ether (LII). Then, selective acetonide hydrolysis in (LII) to (LIII), followed by silylation with tert-butyldimethylsilyl chloride provided the bis-silyl ether (LIV). Alcohol (LIV) was then protected as the allyl carbonate (LV) by treatment with phosgene, followed by allyl alcohol. The primary silyl ether group of (LV) was selectively removed by treatment with HF giving the monosaccharide (LVI), which was coupled with imidate (XXXIV) yielding disaccharide (LVII).
| 【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIV) | 64166 | (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl 2,2,2-trichloroethanimidoate | C29H47Cl6N2O11P | 详情 | 详情 | |
| (XLIV) | 59080 | (4aR,6S,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | C15H29N3O5Si | 详情 | 详情 | |
| (LI) | 64182 | 1-iododecane | C10H21I | 详情 | 详情 | |
| (LII) | 64183 | {[(4aR,7R,8R,8aS)-7-azido-8-(decyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}(tert-butyl)dimethylsilane; (4aR,7R,8R,8aS)-7-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-yl decyl ether | C25H49N3O5Si | 详情 | 详情 | |
| (LIII) | 64184 | (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol | C22H45N3O5Si | 详情 | 详情 | |
| (LIV) | 64185 | (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)tetrahydro-2H-pyran-3-ol | C28H59N3O5Si2 | 详情 | 详情 | |
| (LV) | 64186 | allyl (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)tetrahydro-2H-pyran-3-yl carbonate | C32H63N3O7Si2 | 详情 | 详情 | |
| (LVI) | 64187 | allyl (2R,3S,4R,5R)-5-azido-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-yl carbonate | C26H49N3O7Si | 详情 | 详情 | |
| (LVII) | 64188 | allyl (2R,3S,4R,5R)-5-azido-2-{[((2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-2-yl)oxy]methyl}-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)tetrahydro-2H-pyran-3-yl carbonate | C53H94Cl3N4O17PSi | 详情 | 详情 |