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【结 构 式】 
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【分子编号】13738 【品名】dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate 【CA登记号】36969-89-8 |
【 分 子 式 】C9H19O4P 【 分 子 量 】222.221222 【元素组成】C 48.64% H 8.62% O 28.8% P 13.94% |
合成路线1
该中间体在本合成路线中的序号：(IX)The ketalization of cis-bicyclo[3.3.0]octane-3,7-dione (I) with ethylene glycol (A) and p-toluenesulfonic acid gives the diethyleneketal (II), which by controlled hydrolysis with acetic acid-THF-water is converted into the monoketal (III). Carboxylation of (III) with diethyl carbonate by means of NaH yields the ketoester (IV), which is reduced with sodium borohydride in ethanol to afford the hydroxyester (V). Protection of (V) with dimethyl-tert-butylsilyl chloride gives the silylether (VI), which is reduced with diisobutylaluminum hydride to the alcohol (VII). Oxidation of (VII) with pyridinium chlorochromate affords the aIdehyde (VIII), which by a Wittig reaction with the sodium salt of dimethyl 2-oxoheptylphosphonate (IX) is converted into the enone (X). The reduction of (X) with zinc borohydride yields the protected alcohol (XI), which is deprotected to the corresponding dihydroxyketone (XII) by treatment with acetic acid-THF-water. Finally, this compound is submitted to a Wittig reaction with the sodium salt of 4-carboxybutyltriphenylphosphorane (XIII) in DMS.
| 【1】 Shibasaki, M.; Ikegami, S.; Ueda, J.; New synthetic routes to 9(O)-methanopostacyclin. A highly stable and biologically potent analog of prostacyclin. Tetrahedron Lett 1979, 5, 433-436. |
| 【2】 Magolda, R.L.; Barnette, W.E.; Nicolaou, K.C.; Seitz, S.; Sipio, W.J.; Total synthesis of carboprostacyclin, a stable and biologically active analog of prostacyclin (PGI2). J Chem Soc Chem Commun 1978, 23, 1067-68. |
| 【3】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (I) | 37496 | tetrahydro-2,5(1H,3H)-pentalenedione | C8H10O2 | 详情 | 详情 | |
| (II) | 37497 | C12H18O4 | 详情 | 详情 | ||
| (III) | 11311 | Perhydropentalene-2,5-dione mono ethyleneketal | C10H14O3 | 详情 | 详情 | |
| (IV) | 37498 | C13H18O5 | 详情 | 详情 | ||
| (V) | 37499 | C13H20O5 | 详情 | 详情 | ||
| (VI) | 37500 | C19H34O5Si | 详情 | 详情 | ||
| (VII) | 37501 | C17H32O4Si | 详情 | 详情 | ||
| (VIII) | 11315 | (3'aS,4'R,5'R,6'aR)-5'-(tert-Butyldimethylsilyloxy)perhydrospiro[1,3-dioxolane-2,2'-pentalen]-4'-ylcarbaldehyde | C17H30O4Si | 详情 | 详情 | |
| (IX) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (X) | 37502 | C24H42O4Si | 详情 | 详情 | ||
| (XI) | 37503 | C24H44O4Si | 详情 | 详情 | ||
| (XII) | 37504 | (3aS,4S,5R,6aR)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenone | C16H26O3 | 详情 | 详情 | |
| (XIII) | 37505 | 5-(triphenylphosphoranylidene)pentanoic acid | C23H23O2P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of 5-norbornen-2,3-dicarboxylic anhydride (XXXVII) with hot H2SO4 gives the lactone (XXXVIII), which is reduced with diborane in THF yielding the hydroxylactone (XXXIX). The mesylation of (XXXIX) as usual gives the ester (XL), which by reaction with NaCN in DMSO is converted into the cyanolactone (XLI). The reduction of the lactone ring with LiBH4 in diglyme affords the dihydroxynitrile (XLII), which by benzoylation and oxidation with Jones reagent yields the benzoylated cyanoketone (XLIII). The oxidation of (XLIII) with peracetic acid gives the benzoylated cyanolactone (XLIV), which by methanolysis with H2SO4 and methanol is converted into the cyanoester (XLV). The protection of the free alcohol of (XLV) with dihydropyran and debenzoylation of the resulting product affords the hydroxymethyl cyanoester (XLVI), which by oxidation with pyridinium chlorochromate is converted into the aldehyde (XLVII). The Wittig reaction of (XLVII) with the phosphonate (IX) yields the ketonic cyanoester (XLVIII), which is reduced with NaBH4 to the corresponding alcohol (XLIX). The reaction of (II) with dihydropyran affords the corresponding bis(tetrahydropyranyl) derivative (L).
| 【1】 Sugie, A.; Katsube, J.; Shimomura, H.; Yamamoto, H.; Synthetic studies on cyclopentane derivatives. Part 10. Stereocontrolled approaches to 9(O)-methanoprostacyclin. Tetrahedron Lett 1979, 28, 2607-10. |
| 【2】 Castaner, J.; Hillier, K.; Carbacyclin. Drugs Fut 1981, 6, 12, 753. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IL) | 37544 | methyl 2-[(1R,2S,3S,4R)-3-[(E,3S)-3-hydroxy-1-octenyl]-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C24H39NO5 | 详情 | 详情 | |
| (IX) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (XXXVII) | 11171 | (1R,2R,6S,7S)-4-Oxatricyclo[5.2.1.0(2,6)]dec-8-ene-3,5-dione | C9H8O3 | 详情 | 详情 | |
| (XXXVIII) | 37533 | (3R,6R,9S)-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonane-9-carboxylic acid | C9H10O4 | 详情 | 详情 | |
| (XXXIX) | 37534 | (3R,6S,9S)-9-(hydroxymethyl)-4-oxatricyclo[4.2.1.0(3,7)]nonan-5-one | C9H12O3 | 详情 | 详情 | |
| (XL) | 37535 | (3R,6S,9S)-9-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-4-oxatricyclo[4.2.1.0(3,7)]nonan-5-one | C12H18O3S | 详情 | 详情 | |
| (XLI) | 37536 | 2-[(3R,6S,9S)-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]non-9-yl]acetonitrile | C10H11NO2 | 详情 | 详情 | |
| (XLII) | 37537 | 2-[(2S,3S,5R)-5-hydroxy-3-(hydroxymethyl)bicyclo[2.2.1]hept-2-yl]acetonitrile | C10H15NO2 | 详情 | 详情 | |
| (XLIII) | 37538 | [(2S,3S)-3-(cyanomethyl)-6-oxobicyclo[2.2.1]hept-2-yl]methyl benzoate | C17H17NO3 | 详情 | 详情 | |
| (XLIV) | 37539 | [(6S,7R)-6-(cyanomethyl)-3-oxo-2-oxabicyclo[3.2.1]oct-7-yl]methyl benzoate | C17H17NO4 | 详情 | 详情 | |
| (XLV) | 37540 | [(1S,2S,3R,5R)-2-(cyanomethyl)-5-hydroxy-3-(2-methoxy-2-oxoethyl)cyclopentyl]methyl benzoate | C18H21NO5 | 详情 | 详情 | |
| (XLVI) | 37541 | methyl 2-[(1R,2S,3R,4R)-3-(hydroxymethyl)-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C17H27NO5 | 详情 | 详情 | |
| (XLVII) | 37542 | methyl 2-[(1R,2S,3R,4R)-3-formyl-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C17H25NO5 | 详情 | 详情 | |
| (XLVIII) | 37543 | methyl 2-[(1R,2S,3S,4R)-2-(2-nitriloethyl)-3-[(E)-3-oxo-1-octenyl]-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]acetate | C24H37NO5 | 详情 | 详情 | |
| (L) | 37545 | methyl 2-((1R,2S,3S,4R)-2-(2-nitriloethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-3-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]cyclopentyl)acetate | C30H49NO6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XV)1) The reduction of the Corey lactone (I) with diisobutylaluminum hydride (DIBAL) in hexane/toluene gives the lactol (II), which is condensed with 4-carboxybutyltriphenylphosphonium bromide (III) by means of t-BuOK in THF yielding the pentenoic ester (IV). The oxidation of the free hydroxy group of (IV) with pyridinium chlorochromate (PCC) in dichloromethane affords the cyclopentanone (V), which is methylenated with Zn/CH2Br2/TiCl4 in dichloromethane giving compound (VI). The THP ether group of (VI) was selectively eliminated with dimethylaluminum chloride in dichloromethane and protected again with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF yielding the disilylated compound (VII). The hydrolytic cleavage of the exocyclic double bond of (VII) with 9-borabicyclo[3.3.1]nonane (9-BBN) in THF affords compound (VIII), which is oxidized with Collins reagent (CrO3/Pyr) to the corresponding aldehyde (IX). The cyclization of (IX) by heating at 180 C in toluene in a sealed tube gives the bicyclo[3.3.0]octane (X), still with the double bond in the pentenoic side chain, which is reduced with H2 over Pd/C in methanol yielding the saturated compound (XI). The dehydration of (XI) by mesylation with mesyl chloride and reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in refluxing methanol affords the bicyclo[3.3.0]-2-octene (XII), which is selectively deprotected with pyridinium para-toluenesulfonate (PPTS) in ethanol giving the hydroxymethyl derivative (XIII). The oxidation of (XIII) with SO3/Pyr in DMSO yields the corresponding aldehyde (XIV), which is condensed with dimethyl 2-oxoheptylphosphonate (XV) in THF giving the oxidized isocarbacyclin derivative (XVI). The reduction of the keto group of (XVI) with NaBH4 in methanol yields the corresponding secondary alcohol (XVII) as a mixture of diastereomers. Finally, this compound is deprotected with tetrabutylammonium fluoride (TBAF) in THF and submitted to column chromatography over silicagel in ether/hexane in order to isolate the pure enantiomer.
| 【1】 Graul, A.; Leeson, P.; Castaner, J.; Clinprost. Drugs Fut 1997, 22, 6, 608. |
| 【2】 Ogawa, Y.; Shibasaki, M.; The intramolecular thermal ene reaction route to (+)-9(O)-methano-DELTA6(9alpha)-PGI1. Tetrahedron Lett 1984, 25, 10, 1067-1070. |
| 【3】 Sodeoka, M.; Ogawa, Y.; Mase, T.; Shibasaki, M.; Efficient synthesis of isocarbacyclins. Chem Pharm Bull 1989, 37, 3, 586-598. |
| 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) | 13724 | (3aR,4S,5R,6aS)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]hexahydro-2H-cyclopenta[b]furan-2-one | C20H36O5Si | 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 | |
| (III) | 13726 | p-[4-(Methoxycarbonyl)butyl]triphenylphosphonium bromide | C24H27BrO2P | 详情 | 详情 | |
| (IV) | 13727 | methyl (Z)-7-[(1R,2S,3R,5S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-hydroxy-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C26H48O6Si | 详情 | 详情 | |
| (V) | 13728 | methyl (Z)-7-[(1R,2S,3R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C26H46O6Si | 详情 | 详情 | |
| (VI) | 13729 | methyl (Z)-7-[(1R,2R,3R)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-methylene-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C27H48O5Si | 详情 | 详情 | |
| (VII) | 13730 | methyl (Z)-7-[(1R,2S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-methylenecyclopentyl]-5-heptenoate | C27H52O4Si2 | 详情 | 详情 | |
| (VIII) | 13731 | methyl (Z)-7-[(1S,2S,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-(hydroxymethyl)cyclopentyl]-5-heptenoate | C27H54O5Si2 | 详情 | 详情 | |
| (IX) | 13732 | methyl (Z)-7-[(1R,2S,3R,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-5-formylcyclopentyl]-5-heptenoate | C27H52O5Si2 | 详情 | 详情 | |
| (X) | 13733 | methyl (E)-5-[(1S,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-hydroxyoctahydro-2-pentalenyl]-4-pentenoate | C27H52O5Si2 | 详情 | 详情 | |
| (XI) | 13734 | methyl 5-[(1S,3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-hydroxyoctahydro-2-pentalenyl]pentanoate | C27H54O5Si2 | 详情 | 详情 | |
| (XII) | 13735 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C27H52O4Si2 | 详情 | 详情 | |
| (XIII) | 13736 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-(hydroxymethyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C21H38O4Si | 详情 | 详情 | |
| (XIV) | 13737 | methyl 5-((3aS,5R,6R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-formyl-1,3a,4,5,6,6a-hexahydro-2-pentalenyl)pentanoate | C21H36O4Si | 详情 | 详情 | |
| (XV) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (XVI) | 13739 | (3aS,5S,6S,6aS)-5-[5-(tert-Butyldimethylsilyloxy)-6-(3-oxo-1(E)-heptenyl)-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoic acid methyl ester | C27H46O4Si | 详情 | 详情 | |
| (XVII) | 13740 | methyl 5-[(3aS,5R,6S,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-hydroxy-1-octenyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl]pentanoate | C28H50O4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XV)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5
该中间体在本合成路线中的序号：(XV)7) The regio- and stereoselective carboxylation of the tricyclic ketone (LXVI) with dimethyl carbonate by means of t-BuOK in THF gives the keto ester (LXVII), which by treatment with acetic acid/H2SO4 is converted into the acetoxy keto ester (LXVIII). The reduction of (LXVIII) with NaBH4 in methanol followed by reaction with dihydropyran/PPTS yields the tetrahydropyranyl ether (LXIX), which is deacetylated with K2CO3 in methanol, and the resulting alcohol is protected again with TBDPS-Cl and imidazole in DMF to afford the protected dihydroxy ester (LXX). The reduction of (LXX) with DIBAL, followed by oxidation with CrO3/Pyr gives the aldehyde (LXXI), which is condensed with dimethyl 2-oxoheptylphosphonate (XV) by means of NaH in THF yielding the bicyclic enone (LXXII). Selective elimination of the THP group, followed by reduction of the keto group with DIBAL in toluene and flash column chromatography affords the diol (LXXIII) as a pure enantiomer. Protection of the two hydroxy groups with dihydropyran/PPTS, followed by desilylation with TBAF in THF gives the bicyclic alcohol (LXXIV), which is oxidized with CrO3/Pyr in DMF to the corresponding ketone (LXXV). The condensation of (LXXV) with 4-formylbutyric acid methyl ester (LXXVI) by means of lithium diisopropylamide in THF yields the oxocarbacycline derivative (LXXVII). The reductoisomerization of the enone (LXXVII) with NaBH4/CeCl4 in methanol affords the hydroxylated isocarbacycline derivative (LXXVIII), which is treated with phenoxythionocarbonyl chloride and DMAP to give the thiocarbonate (LXXIX) [intermediate for the elimination of the hydroxy group of (LXXVIII)]. The reductive cleavage of (LXXIX) with Bu3SnH/AIBN in refluxing benzene yields the bitetrahydropyranyl derivative of clinprost (LXXX), which is finally deprotected with acetic acid/THF/water.
| 【1】 Park, H.; Lee, Y.S.; Shim, S.C.; Bull Korean Chem Soc 1993, 14, 86-91. |
| 【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 |
|---|---|---|---|---|---|---|
| (XV) | 13738 | dimethyl 2-oxoheptylphosphonate; Dimethyl (2-oxoheptyl)phosphonate | 36969-89-8 | C9H19O4P | 详情 | 详情 |
| (LXVI) | 13789 | (2bR,4aR,4bS)Hexahydrocyclopropa[cd]pentalen-2(1H)-one | C8H10O | 详情 | 详情 | |
| (LXVII) | 13790 | methyl (1R,2bR,4aS,4bR)-2-oxooctahydrocyclopropa[cd]pentalene-1-carboxylate | C10H12O3 | 详情 | 详情 | |
| (LXVIII) | 13791 | methyl (1R,3aS,4S,6aS)-4-(acetoxy)-2-oxooctahydro-1-pentalenecarboxylate | C12H16O5 | 详情 | 详情 | |
| (LXIX) | 13792 | methyl (1R,2R,3aS,4S,6aS)-4-(acetoxy)-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenecarboxylate | C18H28O6 | 详情 | 详情 | |
| (LXX) | 13793 | methyl (1R,2R,3aS,4S,6aS)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenecarboxylate | C22H40O5Si | 详情 | 详情 | |
| (LXXI) | 13794 | (1R,2R,3aS,4S,6aS)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenecarbaldehyde | C21H38O4Si | 详情 | 详情 | |
| (LXXII) | 13796 | (E)-1-[(1S,2R,3aS,4S,6aR)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydro-1-pentalenyl]-1-octen-3-one | C28H50O4Si | 详情 | 详情 | |
| (LXXIII) | 13797 | (1R,2R,3aS,4S,6aR)-4-[[tert-Butyl(dimethyl)silyl]oxy]-1-[(E,3S)-3-hydroxy-1-octenyl]octahydro-2-pentalenol | C22H42O3Si | 详情 | 详情 | |
| (LXXIV) | 13798 | (1S,3aR,4R,5R,6aS)-5-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]octahydro-1-pentalenol | C28H48O5 | 详情 | 详情 | |
| (LXXV) | 13799 | (3aR,4R,5R,6aS)-5-[(Tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-1(2H)-pentalenone | C28H46O5 | 详情 | 详情 | |
| (LXXVI) | 13800 | methyl 5-oxopentanoate | C6H10O3 | 详情 | 详情 | |
| (LXXVII) | 13801 | methyl 5-[(3aR,4R,5R,6aS)-1-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenylidene]pentanoate | C34H54O7 | 详情 | 详情 | |
| (LXXVIII) | 13802 | methyl 5-((3aS,5R,6S,6aS)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl)-5-hydroxypentanoate | C34H56O7 | 详情 | 详情 | |
| (LXXIX) | 13803 | methyl 5-((3aS,5R,6S,6aS)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl)-5-[(phenoxycarbonyl)sulfanyl]pentanoate | C41H60O8S | 详情 | 详情 | |
| (LXXX) | 13804 | methyl 5-((3aS,5R,6S,6aS)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-6-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-1,3a,4,5,6,6a-hexahydro-2-pentalenyl)pentanoate | C34H56O6 | 详情 | 详情 |