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【结 构 式】 
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【分子编号】13768 【品名】methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate 【CA登记号】 |
【 分 子 式 】C27H48O5Si 【 分 子 量 】480.76062 【元素组成】C 67.45% H 10.06% O 16.64% Si 5.84% |
合成路线1
该中间体在本合成路线中的序号：(XLV)4) The protection of the bicyclic lactone (XXVIII) with dihydropyran and PPTS in THF gives the bistetrahydropyranyl ether (XXIX), which is reduced with DIBAL in THF to the lactol (XXX). The reaction of (XXX) with bromomagnesium acetylide in THF yields (XXXI), which is selectively benzoylated with benzoyl chloride and pyridine affording the monobenzoyl ester (XXXII). The silylation of the secondary hydroxy group of (XXXII) with TBDMS-Cl and imidazole in THF gives the fully protected compound (XXXIII), which is treated with KOH in methanol in order to eliminate the benzoyl group, yielding the hydroxymethyl derivative (XXXIV). The reaction of (XXXIV) with mesyl chloride and triethylamine in dichloromethane affords the mesylate (XXXV), which is cyclized by means of NaI, AIBN and tributyltin hydride in hot glyme giving the bicyclo[3.3.0]octane (XXXVI). The desilylation of (XXXVI) with TBAF and triethylamine in THF yields compound (XXXVII) with a secondary hydroxy group, which is acetylated with acetic anhydride to the acetate (XXXVIII). The condensation of (XXXVIII) with the copper derivative (XXXIX) affords the silylated pentanol derivative (XL), which is deprotected with TBAF and triethylamine in THF to the free pentanol derivative (XLI). The oxidation of (XLI) with SO3/Pyr in DMSO gives the corresponding aldehyde (XLII), which is further oxidized with Ag2O and NaOH in ethanol, and esterified with diazomethane yielding the methyl ester (XLIII). The deprotection of (XLIII) with PPTS in methanol, followed by selective silylation of the primary alcohol with TBDMS-Cl affords the monosilylated compound (XLIV), which is treated with dihydropyran and PPTS in order to protect the secondary hydroxy group yielding (XLV). The desilylation of (XLV) with TBAF, followed by oxidation of the primary alcohol with SO3/Pyr gives the corresponding aldehyde (XLVI), which is condensed with the previously described phosphonate (XV) by means of NaH in glyme affording the ketonic prostacycline (XLVII). Finally, this compound is deprotected with PPTS in methanol and reduced with diisobutylaluminum 2,6-di-tert-butylphenolate giving a mixture of diastereomers that is separated by column chromatography.
| 【1】 Hemmerle, H.; Gais, H.-J.; Flexible synthesen optisch aktiver isocarbacycline. Angew Chem 1989, 101, 362-5. |
| 【2】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 51602 | 1-Propyne | C3H4 | 详情 | 详情 | ||
| (XV) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (XXVIII) | 13751 | (3aR,4S,5R,6aS)-5-Hydroxy-4-(hydroxymethyl)hexahydro-1H-cyclopenta[c]furan-1-one | C8H12O4 | 详情 | 详情 | |
| (XXIX) | 13752 | (3aR,4S,5R,6aS)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-1H-cyclopenta[c]furan-1-one | C20H32O6 | 详情 | 详情 | |
| (XXX) | 13753 | (1S,3aR,4R,5R,6aS)-4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-1H-cyclopenta[c]furan-1-ol | C20H34O6 | 详情 | 详情 | |
| (XXXI) | 13754 | (1R)-1-[(1S,2R,3R,4R)-2-(Hydroxymethyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-2-propyn-1-ol | C22H36O6 | 详情 | 详情 | |
| (XXXII) | 13755 | [(1R,2S,3R,5S)-5-[(1R)-1-hydroxy-2-propynyl]-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methyl benzoate | C29H40O7 | 详情 | 详情 | |
| (XXXIII) | 13756 | [(1R,2S,3R,5S)-5-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methyl benzoate | C35H54O7Si | 详情 | 详情 | |
| (XXXIV) | 13757 | [(1R,2R,3R,5S)-5-((1R)-1-[[tert-Butyl(dimethyl)silyl]oxy]-2-propynyl)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methanol | C28H50O6Si | 详情 | 详情 | |
| (XXXV) | 13758 | [(1R,2S,3R,5S)-5-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]-2-propynyl)-2-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methyl methanesulfonate | C29H52O8SSi | 详情 | 详情 | |
| (XXXVI) | 13759 | [(1R,2R,3aS,4R,6aR)-4-[[tert-Butyl(dimethyl)silyl]oxy]-5-methylene-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]octahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,3aR,4R,5R,6aS)-2-Methylene-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenyl]oxy)(tert-butyl)dimethylsilane | C28H50O5Si | 详情 | 详情 | |
| (XXXVII) | 13760 | (1R,3aR,4R,5R,6aS)-2-Methylene-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenol | C22H36O5 | 详情 | 详情 | |
| (XXXVIII) | 13761 | (1R,3aR,4R,5R,6aS)-2-methylene-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenyl acetate | C24H38O6 | 详情 | 详情 | |
| (XXXIX) | 13762 | Bis[4-(tert-butyldimethylsilyloxy)butyl] coppermagnesium chloride | C21H48O2Si2 | 详情 | 详情 | |
| (XL) | 13763 | [(2R,3R,3aS,6aS)-5-(5-[[tert-Butyl(dimethyl)silyl]oxy]pentyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1,2,3,3a,4,6a-hexahydro-2-pentalenyl]methyl tetrahydro-2H-pyran-2-yl ether | C32H58O5Si | 详情 | 详情 | |
| (XLI) | 13764 | 5-[(3aS,5R,6R,6aS)-6-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-1-pentanol | C26H44O5 | 详情 | 详情 | |
| (XLII) | 13765 | 5-[(3aS,5R,6R,6aS)-6-[2-(Tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanal | C26H42O5 | 详情 | 详情 | |
| (XLIII) | 13766 | methyl 5-[(3aS,5R,6R,6aS)-6-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C27H44O6 | 详情 | 详情 | |
| (XLIV) | 13767 | methyl 5-[(3aS,5R,6S,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C21H38O4Si | 详情 | 详情 | |
| (XLV) | 13768 | methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C27H48O5Si | 详情 | 详情 | |
| (XLVI) | 13769 | methyl 5-[(3aS,5R,6R,6aS)-6-formyl-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C21H32O5 | 详情 | 详情 | |
| (XLVII) | 13770 | methyl 5-[(3aS,5R,6S,6aS)-6-[(E)-3-oxo-1-octenyl]-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C28H44O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLV)5) The unsaturated pentanoic acid methyl ester derivative (XLV) obtained in scheme 16133803a can also be obtained as follows: The reaction of lactol (II) with methyltriphenylphosphonium bromide and t-BuOK in THF, followed by oxidation with PCC in dichloromethane gives the allyl ketone (XLVIII), which is methylenated with Zn/CH2Br2/TiCl4 to yield compound (XLIX). The reaction of (XLIX) with disiamylborane (DSB) and H2O2 hydroxylates the two double bonds, affording compound (L) with two primary hydroxy groups, which are oxidized with oxalyl chloride to the corresponding (LI) with two aldehyde groups. This compound cyclizes to the bicyclic hydroxyaldehyde (LII), which is dehydrated with dibenzylammonium trifluoroacetate to the unsaturated bicyclic aldehyde (LIII). The condensation of (LIII) with 3-carboxypropyltriphenylphosphonium bromide (LIV) by means of t-BuOK in THF followed by methylation with diazomethane gives the bicyclic dienoic ester (LV), which is then selectively reduced to the previously described intermediate (XLV).
| 【1】 Sodeoka, M.; Shibasaki, M.; The highly potent carbon analog of prostacyclin. Chem Lett 1984, 4, 4, 579-82. |
| 【2】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【3】 Shibasaki, M.; Mase, T.; Sodeoka, M.; Ogawa, Y. (Sagami Chemical Research Center); Bicyclo[3.3.0]octane deriv. and preparation thereof. EP 0134153 . |
| 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) | 13714 | Methyl 5-chloro-2-hydroxybenzoate; Methyl 5-chlorosalicylate | 4068-78-4 | C8H7ClO3 | 详情 | 详情 |
| (II) | 13725 | (3aR,4S,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C20H38O5Si | 详情 | 详情 | |
| (XLV) | 13768 | methyl 5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C27H48O5Si | 详情 | 详情 | |
| (XLVIII) | 13771 | (2R,3S,4R)-2-Allyl-3-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentanone | C21H38O4Si | 详情 | 详情 | |
| (XLIX) | 13772 | [(1R,2R,3R)-3-Allyl-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylenecyclopentyl]methyl tetrahydro-2H-pyran-2-yl ether; ([(1R,2R,5R)-2-Allyl-3-methylene-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]methoxy)(tert-butyl)dimethylsilane | C22H40O3Si | 详情 | 详情 | |
| (L) | 13773 | 3-[(1S,2R,3R,5S)-2-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-(hydroxymethyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-1-propanol | C22H44O5Si | 详情 | 详情 | |
| (LI) | 13774 | (1S,2R,3R,4R)-3-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2-(3-oxopropyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentanecarbaldehyde | C22H40O5Si | 详情 | 详情 | |
| (LII) | 13775 | (1R,3aR,4R,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-1-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-2-pentalenecarbaldehyde | C22H40O5Si | 详情 | 详情 | |
| (LIII) | 13776 | (3aS,5R,6R,6aS)-6-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenecarbaldehyde | C22H38O4Si | 详情 | 详情 | |
| (LIV) | 13777 | (3-Carboxypropyl)phosphonium bromide | C4H10BrO2P | 详情 | 详情 | |
| (LV) | 13778 | methyl (Z)-5-[(3aS,5R,6R,6aS)-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]-4-pentenoate | C27H46O5Si | 详情 | 详情 |