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【结 构 式】 
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【分子编号】11503 【品名】(5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone 【CA登记号】 |
【 分 子 式 】C14H16O3 【 分 子 量 】232.27924 【元素组成】C 72.39% H 6.94% O 20.66% |
合成路线1
该中间体在本合成路线中的序号：(IV)A new total synthesis of FK-506 is described: This synthesis has been performed by previous construction of two building fragments (XXIV) and (LI), which later were coupled and cyclized. (Schemes 1-3): 1) (1R*S*,3R,5S,6R,7S,9R)-6-(tert-butyldimethylsilyloxy)-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1-methyldecyl diphenyl phosphine oxide (XXIV). The Sharpless asymetric epoxidation of 1,4-pentadien-3-ol (I) with (-)-diisopropyltartrate and tert-butylhydroperoxide gives the epoxy alcohol (II) with high optical purity, which is benzylated in the usual way to (III). The reaction of (III) with lithioacetonitrile and then HCl yields lactone (IV), which is methylated with lithium diisopropylamide and methyl iodide to lactone (V) as major isomer (separated by chromatography on SiO2). The reduction of (V) with LiAlH4 affords the diol (VI), which is converted into the bis(tert-butyl carbonate) (VII) with 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (BOC-N). The reaction of (VII) with Br2 and K2CO3 in dichloromethane gives the bromocarbonate (VIII), which by selective saponification of the cyclic carbonate with NaOCH3 in methanol yields the epoxy alcohol (IX). Methylation of (IX) with NaH and methyl iodide affords the methyl ether (X), which is converted into the butyrolactone (XI) with lithioacetonitrile as before. The protection of the OH group of (XI) with TBS-Cl gives the silyl ether (XII), which by trans-selective methylation with lithium diisopropylamide and methyl iodide yields lactone (XIII). The reduction of (XIII) with LiAlH4 affords diol (XIV) as major isomer (separated by column chromatography). The selective esterification of the primary OH group of (XIV) with pivaloyl chloride gives the hydroxy ester (XV), which is methylated with NaH and methyl iodide as usual to the methoxy derivative (XVI). Debenzylation of (XVI) by hydrogenolysis with H2 over Pd/C yields the hydroxy ester (XVII), which is silylated with TBS-SO3CF3 to the fully protected compound (XVIII).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 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) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 11501 | (1R)-1-[(2S)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 11502 | (2S)-2-[(1R)-1-(Benzyloxy)-2-propenyl]oxirane; benzyl (1R)-1-[(2S)Oxiranyl]-2-propenyl ether | C12H14O2 | 详情 | 详情 | |
| (IV) | 11503 | (5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone | C14H16O3 | 详情 | 详情 | |
| (V) | 11504 | (3R,5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]-3-methyldihydro-2(3H)-furanone | C15H18O3 | 详情 | 详情 | |
| (VI) | 11505 | (2R,4S,5R)-5-(Benzyloxy)-2-methyl-6-heptene-1,4-diol | C15H22O3 | 详情 | 详情 | |
| (VII) | 11506 | (2R,4S,5R)-5-(benzyloxy)-4-[(tert-butoxycarbonyl)oxy]-2-methyl-6-heptenyl tert-butyl carbonate | C25H38O7 | 详情 | 详情 | |
| (VIII) | 11507 | (2R)-3-[(4S,5S)-5-(benzyloxy)-6-(bromomethyl)-2-oxo-1,3-dioxan-4-yl]-2-methylpropyl tert-butyl carbonate | C21H29BrO7 | 详情 | 详情 | |
| (IX) | 11508 | (2R,4S,5S)-5-(benzyloxy)-4-hydroxy-2-methyl-5-[(2S)oxiranyl]pentyl tert-butyl carbonate | C20H30O6 | 详情 | 详情 | |
| (X) | 11509 | (2R,4S,5S)-5-(benzyloxy)-4-methoxy-2-methyl-5-[(2S)oxiranyl]pentyl tert-butyl carbonate | C21H32O6 | 详情 | 详情 | |
| (XI) | 11510 | (5S)-5-[(1S,2S,4R)-1-(Benzyloxy)-5-hydroxy-2-methoxy-4-methylpentyl]dihydro-2(3H)-furanone | C18H26O5 | 详情 | 详情 | |
| (XII) | 11511 | (5S)-5-((1S,2S,4R)-1,5-Bis[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-4-methylpentyl)dihydro-2(3H)-furanone | C23H48O5Si2 | 详情 | 详情 | |
| (XIII) | 11512 | (3R,5S)-5-((1S,2S,4R)-1-(Benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-methoxy-4-methylpentyl)-3-methyldihydro-2(3H)-furanone | C25H42O5Si | 详情 | 详情 | |
| (XIV) | 11513 | (2R,4S,5R,6S,8R)-5-(Benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-6-methoxy-2,8-dimethyl-1,4-nonanediol | C25H46O5Si | 详情 | 详情 | |
| (XV) | 11514 | (2R,4S,5R,6S,8R)-5-(benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-4-hydroxy-6-methoxy-2,8-dimethylnonyl pivalate | C30H54O6Si | 详情 | 详情 | |
| (XVI) | 11515 | (2R,4S,5R,6S,8R)-5-(benzyloxy)-9-[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C31H56O6Si | 详情 | 详情 | |
| (XVII) | 11516 | (2R,4S,5R,6S,8R)-9-[[tert-butyl(dimethyl)silyl]oxy]-5-hydroxy-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C24H50O6Si | 详情 | 详情 | |
| (XVIII) | 11517 | (2R,4S,5R,6S,8R)-5,9-bis[[tert-butyl(dimethyl)silyl]oxy]-4,6-dimethoxy-2,8-dimethylnonyl pivalate | C30H64O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The total synthesis of (+)-resiniferatoxin started with the asymmetric Sharpless epoxidation of 1,4-pentadien-3-ol (I) to afford the epoxy-alcohol (II), which was further protected as the benzyl ether (III). Epoxide ring opening in (III) with the lithium acetylide (IV) in the presence of BF3 at -78 ºC yielded the acetylenic alcohol (V), which was subsequently cyclized to lactone (VI) under acidic conditions. Methylation of the lithium enolate of lactone (VI) gave rise to the trans- lactone (VII) as the major diastereoisomer. Addition of the lithiated derivative of O-(tert-butyldimethylsilyl)furfuryl alcohol (VIII) to the lactone (VII) produced the furyl ketone (IX). After protection of the hydroxyl group of (IX) as the corresponding acetate ester (X), reduction of its ketone function with NaBH4 furnished alcohol (XI). Oxidation of the furan nucleus of (XI) with m-CPBA produced the intermediate diketone (XII) which spontaneously cyclized to the pyranone (XIII). Acetylation of the hydroxyl group of (XIII) gave the (acetyloxy)pyranone (XIV).
| 【1】 Boger, D.L.; Searcey, M.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of (+)-resiniferatoxin. Chemtracts - Org Chem 1998, 11, 9, 647. |
| 【2】 Wender, P.A.; et al.; The first synthesis of a daphnane diterpene: The enantiocontrolled total synthesis of resiniferatoxin. J Am Chem Soc 1997, 119, 52, 12976. |
| 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) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 11501 | (1R)-1-[(2S)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 11502 | (2S)-2-[(1R)-1-(Benzyloxy)-2-propenyl]oxirane; benzyl (1R)-1-[(2S)Oxiranyl]-2-propenyl ether | C12H14O2 | 详情 | 详情 | |
| (IV) | 55241 | (2-ethoxyethynyl)lithium | C4H5LiO | 详情 | 详情 | |
| (V) | 55242 | (3R,4S)-3-(benzyloxy)-7-ethoxy-1-hepten-6-yn-4-ol | C16H20O3 | 详情 | 详情 | |
| (VI) | 11503 | (5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]dihydro-2(3H)-furanone | C14H16O3 | 详情 | 详情 | |
| (VII) | 11504 | (3R,5S)-5-[(1R)-1-(Benzyloxy)-2-propenyl]-3-methyldihydro-2(3H)-furanone | C15H18O3 | 详情 | 详情 | |
| (VIII) | 55243 | tert-butyl(2-furylmethoxy)dimethylsilane; tert-butyl(dimethyl)silyl 2-furylmethyl ether | C11H20O2Si | 详情 | 详情 | |
| (IX) | 55244 | (2R,4S,5R)-5-(benzyloxy)-1-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-4-hydroxy-2-methyl-6-hepten-1-one | C26H38O5Si | 详情 | 详情 | |
| (X) | 55245 | (1S,2R)-2-(benzyloxy)-1-{(2R)-3-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-2-methyl-3-oxopropyl}-3-butenyl acetate | C28H40O6Si | 详情 | 详情 | |
| (XI) | 55246 | (1S,2R)-2-(benzyloxy)-1-{(2R)-3-[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-furyl]-3-hydroxy-2-methylpropyl}-3-butenyl acetate | C28H42O6Si | 详情 | 详情 | |
| (XII) | 55247 | (1S,3R,6Z)-1-[(1R)-1-(benzyloxy)-2-propenyl]-9-{[tert-butyl(dimethyl)silyl]oxy}-4-hydroxy-3-methyl-5,8-dioxo-6-nonenyl acetate | C28H42O7Si | 详情 | 详情 | |
| (XIII) | 55248 | (1S,2R)-2-(benzyloxy)-1-{(2R)-2-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-hydroxy-3-oxo-3,6-dihydro-2H-pyran-2-yl]propyl}-3-butenyl acetate | C28H42O7Si | 详情 | 详情 | |
| (XIV) | 55249 | 6-[(1R,3S,4R)-3-(acetyloxy)-4-(benzyloxy)-1-methyl-5-hexenyl]-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-oxo-5,6-dihydro-2H-pyran-2-yl acetate | C30H44O8Si | 详情 | 详情 |