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【结 构 式】 
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【药物名称】Himbacine 【化学名称】(+)-(3S,3aR,4S,4aS,8aR,9aS)-4-[(E)-2-[1,6(S)-Dimethylpiperidin-2(R)-yl]vinyl]-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one 【CA登记号】6879-74-9 【 分 子 式 】C22H35NO2 【 分 子 量 】345.52975 |
【开发单位】University of Sydney (Originator) 【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, PHARMACOLOGICAL TOOLS, Muscarinic M2 Antagonists |
合成路线1
The ozonolysis of cylcoheptene (I) with O3 in dichloromethane, followed by a treatment with methanol and p-toluenesulfonic acid gives 7,7-dimethoxyheptanal (II), which is condensed with methoxycarbonyl-methylenetriphenylphosphorane (III) in methanol yielding methyl 9,9-dimethoxy-2-nonenoate (IV). The condensation of (IV) with 2(S)-(tetrahydropyranyloxy)propanal (V) by means of LDA in THF/HMPA affords the beta-hydroxyester (VI), which is cyclized by means of p-toluenesulfonic acid and mesyl chloride affording the furanone (VII). The hydrolysis of the acetal group of (VII) with Amberlyst 15 gives the aldehyde (VIII), which is condensed with the phosphorane (IX) yielding the unsaturated thioester (X). The cyclization of (XV) by means of Et2AlCl in toluene affords the tricyclic thioester (XI), which is reduced with RaNi in ethanol/ethyl ether affording the carbinol (XII). The reaction of (XII) with tosyl chloride and thiophenol provides the pheylsulfanyl derivative (XIII), which is reduced at the lactone group with iBu2AlH in ethyl ether giving the lactol (XIV). The methylation of the lactol (XIV) with BF3/Et2O and methanol yields the cyclic ketal (XV), which is finally oxidized with meta-chloroperbenzoic acid (MCPBA) in dichloromethane to afford the desired tricyclic sulfone intermediate (XVI).
| 【1】 Hart, D.J.and Wu, W.-L.; Total syntheses of (+)-Himbacine and (-)-Himbeline. J Am Chem Soc 1995, 117, 9369. |
| 【2】 Wu, W.-L.; Hart, D.J.; Li, J.; Applications of Organosulfur Chemistry to Organic Synthesis: Total Synthesis of (+)-Himbeline and (-)-Himbacine. J Org Chem 1997, 62, 5023. |
| 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) | 33179 | 1-cycloheptene | 628-92-2 | C7H12 | 详情 | 详情 |
| (II) | 33180 | 7,7-dimethoxyheptanal | C9H18O3 | 详情 | 详情 | |
| (III) | 14689 | Methyl (triphenylphosphoranylidene)acetate; (methoxycarbonylmethylene)triphenylphosphorane；Methyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate | 2605-67-6 | C21H19O2P | 详情 | 详情 |
| (IV) | 33181 | methyl (E)-9,9-dimethoxy-2-nonenoate | C12H22O4 | 详情 | 详情 | |
| (V) | 33182 | (2R)-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propanal | C9H16O3 | 详情 | 详情 | |
| (VI) | 33183 | methyl (E)-2-[(2R)-1-hydroxy-2-methyl-3-(tetrahydro-2H-pyran-2-yloxy)propyl]-9,9-dimethoxy-3-nonenoate | C21H38O7 | 详情 | 详情 | |
| (VII) | 33184 | (5S)-3-[(E)-7,7-dimethoxy-1-heptenyl]-5-methyl-2(5H)-furanone | C14H22O4 | 详情 | 详情 | |
| (VIII) | 33185 | (E)-7-[(5S)-5-methyl-2-oxo-2,5-dihydro-3-furanyl]-6-heptenal | C12H16O3 | 详情 | 详情 | |
| (IX) | 33186 | S-ethyl 2-(triphenylphosphoranylidene)ethanethioate | C22H21OPS | 详情 | 详情 | |
| (X) | 33187 | S-ethyl (2E,8E)-9-[(5S)-5-methyl-2-oxo-2,5-dihydro-3-furanyl]-2,8-nonadienethioate | C16H22O3S | 详情 | 详情 | |
| (XI) | 33188 | S-ethyl (3S,3aR,4R,4aS,8aS)-3-methyl-1-oxo-1,3,3a,4,4a,5,6,7,8,8a-decahydronaphtho[2,3-c]furan-4-carbothioate | C16H22O3S | 详情 | 详情 | |
| (XII) | 33189 | (3S,3aR,4R,4aS,8aR,9aS)-4-(hydroxymethyl)-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one | C14H22O3 | 详情 | 详情 | |
| (XIII) | 33190 | (3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]decahydronaphtho[2,3-c]furan-1(3H)-one | C20H26O2S | 详情 | 详情 | |
| (XIV) | 33191 | (1S,3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan-1-ol | C20H28O2S | 详情 | 详情 | |
| (XV) | 33192 | (1S,3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan-1-yl methyl ether; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan | C21H30O2S | 详情 | 详情 | |
| (XVI) | 33193 | [(1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl phenyl sulfone; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfonyl)methyl]dodecahydronaphtho[2,3-c]furan | C21H30O4S | 详情 | 详情 |
合成路线2
The reduction of piperidine-2(R)-carboxylic acid (XVII) with BH3/Me2S and BF3/Et2O in THF gives the carbinol (XVIII), which is treated with Boc2O and NaOH in THF yielding the carbamate (XIX). The silylation of the carbinol group of (XIX) with TBDMS-Cl and imidazole in DMF affords the silyl ether (XX), which is methylated with BuLi and methyl iodide providing the 2-methyl derivative (XXI). The desilylation of (XXI) with TBAF in THF affords the free carbinol (XXII), which is oxidized to the corresponding aldehyde (XXIII) with RuO4NPr4. The condensation of aldehyde (XXII) with the tricyclic sulfone intermediate (XVI) by means of BuLi in DME and sodium amalgam in methanol yields the vinylpiperidine intermediate (XVII), which is oxidized at the lactol group with Jones reagent (CrO3, H2SO4) giving the tricyclic lactone (XVIII). The deprotection of the piperidine ring of (XVIII) with TFA in dichloromethane yields the intermediate (XIX), which is finally methylated with formaldehyde and sodium cyanoborohydride in acetonitrile/water.
| 【1】 Wu, W.-L.; Hart, D.J.; Li, J.; Applications of Organosulfur Chemistry to Organic Synthesis: Total Synthesis of (+)-Himbeline and (-)-Himbacine. J Org Chem 1997, 62, 5023. |
| 【2】 Hart, D.J.and Wu, W.-L.; Total syntheses of (+)-Himbacine and (-)-Himbeline. J Am Chem Soc 1995, 117, 9369. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 33193 | [(1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl phenyl sulfone; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfonyl)methyl]dodecahydronaphtho[2,3-c]furan | C21H30O4S | 详情 | 详情 | |
| (XVII) | 26751 | (2R)-2-piperidinecarboxylic acid | C6H11NO2 | 详情 | 详情 | |
| (XVII) | 33198 | tert-butyl (2R,6S)-2-[(E)-2-[(1S,3S,3aR,4S,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]ethenyl]-6-methyl-1-piperidinecarboxylate | C27H45NO4 | 详情 | 详情 | |
| (XVIII) | 26746 | (2R)-piperidinylmethanol | C6H13NO | 详情 | 详情 | |
| (XVIII) | 33199 | tert-butyl (2R,6S)-2-[(E)-2-[(3S,3aR,4S,4aS,8aR,9aS)-3-methyl-1-oxododecahydronaphtho[2,3-c]furan-4-yl]ethenyl]-6-methyl-1-piperidinecarboxylate | C26H41NO4 | 详情 | 详情 | |
| (XIX) | 26747 | tert-butyl (2R)-2-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (XIX) | 33200 | (3S,3aR,4S,4aS,8aR,9aS)-3-methyl-4-[(E)-2-[(2R,6S)-6-methylpiperidinyl]ethenyl]decahydronaphtho[2,3-c]furan-1(3H)-one | C21H33NO2 | 详情 | 详情 | |
| (XX) | 33194 | tert-butyl (2R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-piperidinecarboxylate | C17H35NO3Si | 详情 | 详情 | |
| (XXI) | 33195 | tert-butyl (2R,6S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-6-methyl-1-piperidinecarboxylate | C18H37NO3Si | 详情 | 详情 | |
| (XXII) | 33196 | tert-butyl (2R,6S)-2-(hydroxymethyl)-6-methyl-1-piperidinecarboxylate | C12H23NO3 | 详情 | 详情 | |
| (XXIII) | 33197 | tert-butyl (2R,6S)-2-formyl-6-methyl-1-piperidinecarboxylate | C12H21NO3 | 详情 | 详情 |
合成路线3
The tricyclic sulfone intermediate (XVI) has also been obtained as follows: The Diels-Alder condensation between 4,5,6,7-tetrahydroisobenzofuran (XX) and 5(R)-methylfuran-2(5H)-one (XXI) catalyzed by LiClO4 in ethyl ether gives the unsaturated tricyclic epoxyketone (XXII), which is hydrogenated with H2 over Pd/C in ethanol yielding the corresponding saturated epoxylactone (XXIII). Opening of the epoxide ring of (XXIII) by means of lithium hexamethyldisylazane (LiHMDS) in THF affords the hydroxyketone (XXIV), which is isomerized to (XXV) by means of DBU in hot toluene. The hydrogenation of the double bond of (XXV) with H2 over PtO2 in ethanol gives the saturated hydroxylactone (XXVI) with the correct stereochemical configuration. The reduction of the lactone group of (XXVI) with DIBAL, followed by methylation with BF3/Et2O and methanol affords the cyclic hemiketal (XXVII), which is oxidized at the secondary hydroxyl group with Dess-Martin oxidant to give the tricyclic ketone (XXVIII). The reaction of (XXVIII) with methyltriphenylphosphonium iodide and sodium hexamethyldisilazane (NaHMDS) in ethyl ether yields the corresponding methylene derivative (XXIX), which is hydroxylated with BH3/THF and H2O2/NaOH to provide the expected hydroxymethyl derivative (XXX). The reaction of (XXX) with Ms-Cl and triethylamine in dichloromethane gives the mesylate (XXXI), which is condensed with thiophenol and potassium tert-butoxide in DMSO to yield the previously described phenylsulfanyl intermediate (XV), which is finally oxidized with MCPBA as before to the target tricyclic sulfone intermediate (XVI).
| 【1】 Takadoi, M.; et al.; A novel total synthesis of (+)-himbacine, a potent antagonist of the muscarinic receptor of M-2 subtype. Tetrahedron Lett 1999, 40, 17, 3399. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 33192 | (1S,3S,3aS,4R,4aS,8aR,9aS)-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan-1-yl methyl ether; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfanyl)methyl]dodecahydronaphtho[2,3-c]furan | C21H30O2S | 详情 | 详情 | |
| (XVI) | 33193 | [(1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl phenyl sulfone; (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyl-4-[(phenylsulfonyl)methyl]dodecahydronaphtho[2,3-c]furan | C21H30O4S | 详情 | 详情 | |
| (XX) | 33201 | 4,5,6,7-tetrahydro-2-benzofuran | C8H10O | 详情 | 详情 | |
| (XXI) | 33202 | (5S)-5-methyl-2(5H)-furanone | C5H6O2 | 详情 | 详情 | |
| (XXII) | 33203 | (1R,8S,9R,12S,13S)-12-methyl-11,14-dioxatetracyclo[6.5.1.0(2,7).0(9,13)]tetradec-2(7)-en-10-one | C13H16O3 | 详情 | 详情 | |
| (XXIII) | 33204 | (1S,2S,7R,8R,9R,12S,13S)-12-methyl-11,14-dioxatetracyclo[6.5.1.0(2,7).0(9,13)]tetradecan-10-one | C13H18O3 | 详情 | 详情 | |
| (XXIV) | 33205 | (3S,3aS,4R,4aS,8aS)-4-hydroxy-3-methyl-3a,4,4a,5,6,7,8,8a-octahydronaphtho[2,3-c]furan-1(3H)-one | C13H18O3 | 详情 | 详情 | |
| (XXV) | 33206 | (3S,3aS,4R,4aS,9aS)-4-hydroxy-3-methyl-3a,4,4a,5,6,7,8,9a-octahydronaphtho[2,3-c]furan-1(3H)-one | C13H18O3 | 详情 | 详情 | |
| (XXVI) | 33207 | (3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-3-methyldecahydronaphtho[2,3-c]furan-1(3H)-one | C13H20O3 | 详情 | 详情 | |
| (XXVII) | 33208 | (1S,3S,3aS,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-ol | C14H24O3 | 详情 | 详情 | |
| (XXVIII) | 33209 | (1S,3S,3aR,4aS,8aR,9aS)-1-methoxy-3-methyldecahydronaphtho[2,3-c]furan-4(1H)-one | C14H22O3 | 详情 | 详情 | |
| (XXIX) | 33210 | (1S,3S,3aS,4aS,8aR,9aS)-1-methoxy-3-methyl-4-methylenedodecahydronaphtho[2,3-c]furan; (1S,3S,3aS,4aS,8aR,9aS)-3-methyl-4-methylenedodecahydronaphtho[2,3-c]furan-1-yl methyl ether | C15H24O2 | 详情 | 详情 | |
| (XXX) | 33211 | [(1S,3S,3aR,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methanol | C15H26O3 | 详情 | 详情 | |
| (XXXI) | 33212 | [(1S,3S,3aR,4R,4aS,8aR,9aS)-1-methoxy-3-methyldodecahydronaphtho[2,3-c]furan-4-yl]methyl methanesulfonate | C16H28O5S | 详情 | 详情 |