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【结 构 式】 
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【分子编号】62626 【品名】(3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine 【CA登记号】 |
【 分 子 式 】C18H25NO4 【 分 子 量 】319.40084 【元素组成】C 67.69% H 7.89% N 4.39% O 20.04% |
合成路线1
该中间体在本合成路线中的序号：(XII)The reaction of benzyl alpha-D-mannopyranoside (I) with Tbdms-Cl and imidazole gives the silyl ether (II), which is treated with 2,2-dimethoxypropane (III) and CSA in dichloromethane to yield the acetonide (IV). The oxidation of the free OH group of (IV) with PCC in dichloromethane affords the ketone (V), which is reduced with NaBH4 to provide benzyl 6-O-(tert-butyldimethylsilyl)-2,3-O-isopropylidene-alpha-D-talopyranoside (VI) with inverted configuration at C4. The reaction of (VI) with Tf2O and pyridine gives the triflate (VII), which is treated with NaN3 in DMF to yield the 4-azido derivative (VIII) with a new inversion of configuration at C4. The reaction of (VIII) with TBAF, followed by oxidation with PCC afforded the carbaldehyde (IX), which is condensed with the phosphorane (X) to provide the unsaturated azidoaldehyde (XI). The treatment of (XI) with H2 over Pd/C in methanol produces the reduction of the double bond, the reduction of the azide group to amine, and subsequent reductive cyclization of the resulting aminoaldehyde to give the perhydropyranopyridine derivative (XII). Further reductive debenzylation of (XII) with H2 over Pd/C in AcOH produces the formation of a lactol in equilibrium with the open chain aminoaldehyde (XIII), which undergoes a reductive amination to form the acetonide of swainsonine (XIV). Finally, this acetonide is decomposed by reaction with TFA to afford the target swainsonine.
| 【1】 Bashyal, B.P.; et al.; Synthesis of the alpha-mannosidase inhibitors swainsonine [(1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine and 1,4-dideoxy-1,4-imino-D-mannitol from mannose. Tetrahedron 1987, 43, 13, 3083. |
| 【2】 Fleet, G.W.J.; et al.; Enantiospecific synthesis of swainsonine (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizine, from D-mannose. Tetrahedron Lett 1984, 25, 17, 1853. |
| 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) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62618 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)tetrahydro-2H-pyran-3,4,5-triol | C29H36O6Si | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62619 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (V) | 62620 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C32H38O6Si | 详情 | 详情 | |
| (VI) | 62621 | (3aS,4S,6R,7S,7aS)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C32H40O6Si | 详情 | 详情 | |
| (VII) | 62622 | (3aS,4S,6R,7S,7aR)-4-(benzyloxy)-6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trifluoromethanesulfonate | C33H39F3O8SSi | 详情 | 详情 | |
| (VIII) | 62623 | [(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl tert-butyl(diphenyl)silyl ether; {[(3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methoxy}(tert-butyl)diphenylsilane | C32H39N3O5Si | 详情 | 详情 | |
| (IX) | 62624 | (3aS,4S,6S,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-carbaldehyde | C16H19N3O5 | 详情 | 详情 | |
| (X) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (XI) | 62625 | (E)-3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]-2-propenal | C18H21N3O5 | 详情 | 详情 | |
| (XII) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 | |
| (XIII) | 62627 | (4S,5S)-5-[(2R,3R)-3-hydroxypiperidinyl]-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C11H19NO4 | 详情 | 详情 | |
| (XIV) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)The reaction of benzyl-alpha-D-mannoside (I) with Ts-Cl in pyridine gives the 6-O-tosylate (II), which is treated with 2,2-dimethoxypropane (III), trimethyl orthoacetate and naphthalenesulfonic acid to yield the acetonide (IV). The silylation of the remaining OH group of (IV) with Tms-Cl and TEA in THF affords the silyl ether (V), which is condensed with allylmagnesium bromide (VI) in ethyl ether to provide the olefinic compound (VII). The desilylation of (VII) by means of TBAF in THF gives the secondary alcohol (VIII); which is oxidized by means of (COCl)2, DMSO and TEA in dichloromethane to yield the ketone derivative (IX). The oxidation of the terminal double bond of (IX) by means of RuO2 and NaIO4 in CCl4/acetonitrile affords the carboxylic acid (X), which is methylated with diazomethane to provide the corresponding methyl ester (XI). Alternatively the propionic ester (XI) can also be obtained by the following sequence: The condensation of the silyl ether (V) with the sodium salt of diethyl malonate (XII) in refluxing toluene gives the malonyl derivative (XIII), which is treated with NaCl at 145 C, yielding the lactone (XIV). The methanolysis of (XIV) with KOH in methanol affords the hydroxyester (XV), which is finally oxidized with PCC in dichloromethane to provide the target ketoester (XI), already reported. The reduction of the carbonyl group of (XI) by means of NaBH4 in ethanol gives the hydroxyester (XVI), which is treated with triflic anhydride and pyridine to yield the corresponding triflate (XVII). The reaction of (XVII) with sodium azide in DMF affords the azido derivative (XVIII), which is reduced with H2 over Pd/C to provide the expected amino derivative (XIX). The cyclization of (XIX) in refluxing toluene gives the lactam (XX), which is finally reduced to the target perhydro-pyrano[3,2-b]pyridine (XXI) intermediate.
| 【1】 Bermejo Gonzalez, F.; et al.; Efficient preparation of a valuable intermediate in the synthesis of (-)-swainsonine. Bull Chem Soc Jpn 1992, 65, 2, 567. |
| 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) | 62617 | (2S,3S,4S,5S,6R)-2-(benzyloxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol | C13H18O6 | 详情 | 详情 | |
| (II) | 62659 | [(2R,3S,4S,5S,6S)-6-(benzyloxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl]methyl 4-methylbenzenesulfonate | C20H24O8S | 详情 | 详情 | |
| (III) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (IV) | 62660 | [(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]methyl 4-methylbenzenesulfonate | C23H28O8S | 详情 | 详情 | |
| (V) | 62661 | {(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl 4-methylbenzenesulfonate | C26H36O8SSi | 详情 | 详情 | |
| (VI) | 61128 | C4H8 | 详情 | 详情 | ||
| (VII) | 62662 | (3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl trimethylsilyl ether; {[(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl]oxy}(trimethyl)silane | C22H34O5Si | 详情 | 详情 | |
| (VIII) | 62663 | (3aS,4S,6R,7R,7aS)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C19H26O5 | 详情 | 详情 | |
| (IX) | 62664 | (3aS,4S,6R,7aR)-4-(benzyloxy)-6-(3-butenyl)-2,2-dimethyldihydro-4H-[1,3]dioxolo[4,5-c]pyran-7(6H)-one | C19H24O5 | 详情 | 详情 | |
| (X) | 62665 | 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoic acid | C18H22O7 | 详情 | 详情 | |
| (XI) | 62667 | methyl 3-[(3aS,4S,6R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-oxotetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H24O7 | 详情 | 详情 | |
| (XII) | 16336 | [2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]sodium | C7H11NaO4 | 详情 | 详情 | |
| (XIII) | 62666 | diethyl 2-({(3aS,4S,6R,7R,7aR)-4-(benzyloxy)-2,2-dimethyl-7-[(trimethylsilyl)oxy]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl}methyl)malonate | C26H40O9Si | 详情 | 详情 | |
| (XIV) | 62669 | (3aS,4S,5aR,9aR,9bR)-4-(benzyloxy)-2,2-dimethylhexahydro[1,3]dioxolo[4,5-d]pyrano[3,2-b]pyran-8(4H)-one | C18H22O6 | 详情 | 详情 | |
| (XV) | 62668 | methyl 3-[(3aS,4S,6R,7R,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H26O7 | 详情 | 详情 | |
| (XVI) | 62670 | methyl 3-[(3aS,4S,6R,7S,7aS)-4-(benzyloxy)-7-hydroxy-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H26O7 | 详情 | 详情 | |
| (XVII) | 62671 | methyl 3-((3aS,4S,6R,7S,7aR)-4-(benzyloxy)-2,2-dimethyl-7-{[(trifluoromethyl)sulfonyl]oxy}tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl)propanoate | C20H25F3O9S | 详情 | 详情 | |
| (XVIII) | 62672 | methyl 3-[(3aS,4S,6R,7R,7aS)-7-azido-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H25N3O6 | 详情 | 详情 | |
| (XIX) | 62673 | methyl 3-[(3aS,4S,6R,7R,7aS)-7-amino-4-(benzyloxy)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6-yl]propanoate | C19H27NO6 | 详情 | 详情 | |
| (XX) | 62674 | (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethylhexahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-8(5aH)-one | C18H23NO5 | 详情 | 详情 | |
| (XXI) | 62626 | (3aS,4S,5aR,9aR,9bS)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridin-4-yl benzyl ether; (3aS,4S,5aR,9aR,9bS)-4-(benzyloxy)-2,2-dimethyloctahydro-4H-[1,3]dioxolo[4',5':4,5]pyrano[3,2-b]pyridine | C18H25NO4 | 详情 | 详情 |