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【结 构 式】 
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【分子编号】62648 【品名】(5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone 【CA登记号】 |
【 分 子 式 】C18H25NO5 【 分 子 量 】335.40024 【元素组成】C 64.46% H 7.51% N 4.18% O 23.85% |
合成路线1
该中间体在本合成路线中的序号：(XXIV)The oxidation of 5-(trimethylsilyl)-4-pentyn-1-ol (I) with oxalyl chloride in dichloromethane gives the corresponding aldehyde (II),which is condensed with furan (III) by means of BuLi in THF, yielding 1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol (IV). The optical resolution of (IV) by means of diisopropyl-L-tartrate affords the (R)-isomer (V), which is treated with NBS and sodium acetate in THF to provide the dihydropyranone derivative (VI). The reaction of (VI) with ethyl vinyl ether (VII) by means of PPTS gives the 1-ethoxyethyl ether as a diastereomeric mixture that is separated by column chromatography affording the desired isomer (VIII). The reduction of the carbonyl group of (VIII) by means of LAH in ethyl ether provides alcohol (IX) along with minor amounts of its diastereomer that is separated by column chromatography. The dihydroxylation of (IX) by means of OsO4 in ethyl ether proceeded diastereoselectively giving triol (X), which is treated with 2,2-dimethoxypropane (XI) and PPTS in acetone to yield the acetonide (XII). The reaction of (XII) with thiocarbonyl diimidazole (TCDI) in dichloroethane affords intermediate (XIII), which is submitted to a radical cyclization by means of Bu3SnH and AIBN in benzene to provide the exomethylene derivative (XIV). The oxidation of the vinylsilane (XIV) by means of NaIO4 and OsO4 in t-butanol/pyridine gives the ketone (XV), which is submitted to a Birch reduction with Na in liquid ammonia to yield alcohol (XVI) along with some of its diastereomer that is separated by chromatography. The reaction (XVI) with benzyl bromide and NaH in THF affords the benzyl ether (XVII), which is treated with HCl in THF to provide the lactol (XVIII). The reduction of (XVIII) with NaBH4 in methanol/dichloromethane gives the diol (XIX), which is selectively monosilylated with Tbdms-Cl, yielding the primary silyl ether (XX). The oxidation of the secondary OH group of (XX) by means of TPAP in dichloromethane affords the cyclopentanone (XXI), which is treated with hydroxylamine and pyridine in methanol to provide the corresponding oxime (XXII). The oxime (XXII) was subjected to a Beckmann rearrangement by means of SOCl2 to give the lactam (XXIII), which is finally desilylated by means of TBAF in THF to yield the primary alcohol (XXIV).
| 【1】 Honda, T.; et al.; Enantioselective synthesis of indolizidine alkaloids: Formal synthesis of (-)-swainsonine and of (+)-pumiliotoxin 251D. J Chem Soc - Perkins Trans I 1994, 15, 2091. |
| 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) | 62628 | 5-(trimethylsilyl)-4-pentyn-1-ol | C8H16OSi | 详情 | 详情 | |
| (II) | 62115 | 5-(trimethylsilyl)-4-pentynal | C8H14OSi | 详情 | 详情 | |
| (III) | 22372 | Furan | 110-00-9 | C4H4O | 详情 | 详情 |
| (IV) | 62629 | 1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol | C12H18O2Si | 详情 | 详情 | |
| (V) | 62630 | (1R)-1-(2-furyl)-5-(trimethylsilyl)-4-pentyn-1-ol | C12H18O2Si | 详情 | 详情 | |
| (VI) | 62631 | (2R)-6-hydroxy-2-[4-(trimethylsilyl)-3-butynyl]-2H-pyran-3(6H)-one | C12H18O3Si | 详情 | 详情 | |
| (VII) | 62632 | 1-propoxyethylene; propyl vinyl ether | C5H10O | 详情 | 详情 | |
| (VIII) | 62633 | (2R,6R)-6-(1-propoxyethoxy)-2-[4-(trimethylsilyl)-3-butynyl]-2H-pyran-3(6H)-one | C17H28O4Si | 详情 | 详情 | |
| (IX) | 62634 | (2R,3S,6R)-6-(1-propoxyethoxy)-2-[4-(trimethylsilyl)-3-butynyl]-3,6-dihydro-2H-pyran-3-ol | C17H30O4Si | 详情 | 详情 | |
| (X) | 62635 | (2R,3S,4S,5S,6R)-2-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-2H-pyran-3,4,5-triol | C17H32O6Si | 详情 | 详情 | |
| (XI) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (XII) | 62636 | (3aS,4R,6R,7R,7aS)-2,2-dimethyl-4-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-ol | C20H36O6Si | 详情 | 详情 | |
| (XIII) | 62637 | O-{(3aS,4R,6R,7R,7aR)-2,2-dimethyl-4-(1-propoxyethoxy)-6-[4-(trimethylsilyl)-3-butynyl]tetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-7-yl} 1H-imidazole-1-carbothioate | C24H38N2O6SSi | 详情 | 详情 | |
| (XIV) | 62638 | (3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-8-[(E)-(trimethylsilyl)methylidene]hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4(4H)-yl 1-propoxyethyl ether; {[(3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-4-(1-propoxyethoxy)hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8(4H)-ylidene]methyl}(trimethyl)silane | C20H36O5Si | 详情 | 详情 | |
| (XV) | 62639 | (3aS,4R,5aR,8aS,8bS)-2,2-dimethyl-4-(1-propoxyethoxy)hexahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8(4H)-one | C16H26O6 | 详情 | 详情 | |
| (XVI) | 62640 | (3aS,4R,5aR,8R,8aS,8bS)-2-ethyl-2-methyl-4-(1-propoxyethoxy)octahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-8-ol | C17H30O6 | 详情 | 详情 | |
| (XVII) | 62641 | (3aS,4R,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyloctahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4-yl 1-propoxyethyl ether; (3aS,4R,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyl-4-(1-propoxyethoxy)octahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran | C23H34O6 | 详情 | 详情 | |
| (XVIII) | 62642 | (3aS,4S,5aR,8R,8aS,8bS)-8-(benzyloxy)-2,2-dimethyloctahydrocyclopenta[b][1,3]dioxolo[4,5-d]pyran-4-ol | C18H24O5 | 详情 | 详情 | |
| (XIX) | 62643 | (1R,2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanol | C18H26O5 | 详情 | 详情 | |
| (XX) | 62644 | (1R,2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanol | C24H40O5Si | 详情 | 详情 | |
| (XXI) | 62645 | (2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanone | C24H38O5Si | 详情 | 详情 | |
| (XXII) | 62646 | (2R,3R)-3-(benzyloxy)-2-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]cyclopentanone oxime | C24H39NO5Si | 详情 | 详情 | |
| (XXIII) | 62647 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C24H39NO5Si | 详情 | 详情 | |
| (XXIV) | 62648 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C18H25NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIV)The reaction of (XXIV) with Ms-Cl and TEA in dichloromethane gives the mesylate (XXV), which is cyclized by means of K2CO3 in hot dioxane to yield the perhydroindolizinone (XXVI). The reductive debenzylation of (XXVI) with H2 over Pd/C in ethanol affords the hydroxy-perhydroindolizinone (XXVII), which is finally reduced with BH3/Me2S in THF to provide the target swainsonine acetonide (XXVIII) intermediate.
| 【1】 Honda, T.; et al.; Enantioselective synthesis of indolizidine alkaloids: Formal synthesis of (-)-swainsonine and of (+)-pumiliotoxin 251D. J Chem Soc - Perkins Trans I 1994, 15, 2091. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 62648 | (5R,6R)-5-(benzyloxy)-6-[(4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-piperidinone | C18H25NO5 | 详情 | 详情 | |
| (XXV) | 62649 | {(4R,5S)-5-[(2R,3R)-3-(benzyloxy)-6-oxopiperidinyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl methanesulfonate | C19H27NO7S | 详情 | 详情 | |
| (XXVI) | 62650 | (3aR,9R,9aR,9bS)-9-(benzyloxy)-2,2-dimethylhexahydro[1,3]dioxolo[4,5-a]indolizin-6(4H)-one | C18H23NO4 | 详情 | 详情 | |
| (XXVII) | 62651 | (3aR,9R,9aR,9bS)-9-hydroxy-2,2-dimethylhexahydro[1,3]dioxolo[4,5-a]indolizin-6(4H)-one | C11H17NO4 | 详情 | 详情 | |
| (XXVIII) | 62616 | (3aR,9R,9aR,9bS)-2,2-dimethyloctahydro[1,3]dioxolo[4,5-a]indolizin-9-ol | C11H19NO3 | 详情 | 详情 |