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【结 构 式】 
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【分子编号】37504 【品名】(3aS,4S,5R,6aR)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenone 【CA登记号】 |
【 分 子 式 】C16H26O3 【 分 子 量 】266.38064 【元素组成】C 72.14% H 9.84% O 18.02% |
合成路线1
该中间体在本合成路线中的序号：(XII)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：(XII)Reduction of (XXXIV) with LiAlH4, followed by oxidation with Collins reagent affords the bis(tetrahydropyranyl)ketone (XXXV) (which can also be obtained by reaction of dihydroxyketone (XII) with dihydropyran). The Wittig reaction of (XXXV) with phosphorane (XIII) gives the protected carbacyclin (XXXVI), which is finally deprotected in the usual way.
| 【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】 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. |
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXXIV) | 37530 | (1aS,1bS,2S,3R,4aR)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]octahydropentaleno[1,2-b]oxirene; (2S,3E)-4-[(1aS,1bS,2S,3R,4aR)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]octahydropentaleno[1,2-b]oxiren-2-yl]-2-pentyl-3-butenyl tetrahydro-2H-pyran-2-yl ether | C28H46O5 | 详情 | 详情 | |
| (XXXV) | 37531 | (3aS,4S,5R,6aR)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenone | C28H46O5 | 详情 | 详情 | |
| (XXXVI) | 37532 | 5-[(3aS,4S,5R,6aR)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenylidene]pentanoic acid | C33H54O6 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)Compound (L) is hydrolyzed with KOH and methylated with diazomethane to yield the diester (LI). The Dieckmann cyclization of (LI) by means of potassium tert-butoxide in THF yields the bicyclic ketoester (LII), which is decarboxylated by treatment with LiI in pyridine yielding the previously obtained bis tetrahydropyranylketone (XXXV). This compound can be deprotected to the dihydroxyketone (XII) with aqueous acetic acid.
| 【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 |
|---|---|---|---|---|---|---|
| (XII) | 37504 | (3aS,4S,5R,6aR)-5-hydroxy-4-[(E,3S)-3-hydroxy-1-octenyl]hexahydro-2(1H)-pentalenone | C16H26O3 | 详情 | 详情 | |
| (XXXV) | 37531 | (3aS,4S,5R,6aR)-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]hexahydro-2(1H)-pentalenone | C28H46O5 | 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 | |
| (LI) | 37546 | methyl 2-((1R,2S,3S,4R)-2-(2-methoxy-2-oxoethyl)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-3-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]cyclopentyl)acetate | C31H52O8 | 详情 | 详情 | |
| (LII) | 37547 | methyl (1R,3aR,4R,5R,6aS)-2-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-4-[(E,3S)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]octahydro-1-pentalenecarboxylate | C30H48O7 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XII)The reaction of 7-oxotricyclo[4.2.0.0(2.4)]octane-3-endo-carboxaldehyde neopentylglycol acetal (LIII) with dimethylsulfonium methylide (G) gives the spiroepoxide (LIV), which by isomerization with LiI in THF yields the tricyclononanone (LV). The reduction of (LV) with NaBH4 in ethanol, followed by acetylation with acetic anhydride in pyridine affords the tricyclic acetate (LVI), which is treated with formic acid to eliminate the acetalic residue and form the free aldehyde (LVII). The Wittig reaction of (LVII) with triphenylhexylidenephosphorane (LVIII) affords the tricyclic acetate (LIX), which is hydrolyzed with base and oxidized with Jones reagent to yield the tricyclic ketone (LX). The oxidation of the double bond of (LX) with 0sO4 gives the diol (LXI), which submitted successively to: triethyl orthopropionate (H) in pyridine, to anhydrous formic acid, to aqueous methanolic K2CO3 and to sodium metaperiodate, is converted into the previously obtained dihydroxyketone (XII). This compound can be used in the preceding syntheses or protected with dimethyltert-butylsilyl chloride to afford the bis(silyl) ether (LXII), which by reaction with the sulfoximine (LXIII), and then with AlHg is converted into the protected trialcohol (LXIV).
| 【1】 Morton, D.R.Jr.; DE 2904655 . |
| 【2】 Brokaw, F.C.; Morton, D.R.Jr.; Total synthesis of 6a-carboprostaglandin I2 and related isomers. J Org Chem 1979, 44, 16, 2880-87. |
| 【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 |
|---|---|---|---|---|---|---|
| (G) | 16180 | Dimethyl(methylene)-lambda(4)-sulfane; Dimethylsulfonium-methylide | C3H8S | 详情 | 详情 | |
| (H) | 37557 | 1-ethoxypropyl ethyl ether; 1,1-diethoxypropane | 4744-08-5 | C7H16O2 | 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 | |
| (LIII) | 37548 | (1R,2S,4S,6S)-3-(5,5-dimethyl-1,3-dioxan-2-yl)tricyclo[4.2.0.0(2,4)]octan-7-one | C14H20O3 | 详情 | 详情 | |
| (LIV) | 37549 | C15H22O3 | 详情 | 详情 | ||
| (LV) | 37550 | (1aR,1bS,4aR,5aS)-1-(5,5-dimethyl-1,3-dioxan-2-yl)octahydro-3H-cyclopropa[a]pentalen-3-one | C15H22O3 | 详情 | 详情 | |
| (LVI) | 37551 | (1aR,1bS,4aR,5aS)-1-(5,5-dimethyl-1,3-dioxan-2-yl)octahydro-1H-cyclopropa[a]pentalen-3-yl acetate | C17H26O4 | 详情 | 详情 | |
| (LVII) | 37552 | (1aR,1bS,4aR,5aS)-1-formyloctahydro-1H-cyclopropa[a]pentalen-3-yl acetate | C12H16O3 | 详情 | 详情 | |
| (LVIII) | 37553 | hexylidene(triphenyl)phosphorane | C24H27P | 详情 | 详情 | |
| (LIX) | 37554 | (1aS,1bS,4aR,5aS)-1-[(E)-1-heptenyl]octahydro-1H-cyclopropa[a]pentalen-3-yl acetate | C18H28O2 | 详情 | 详情 | |
| (LX) | 37555 | (1aS,1bS,4aR,5aS)-1-[(E)-1-heptenyl]octahydro-3H-cyclopropa[a]pentalen-3-one | C16H24O | 详情 | 详情 | |
| (LXI) | 37556 | (1aR,1bS,4aR,5aS)-1-[(1R,2S)-1,2-dihydroxyheptyl]octahydro-3H-cyclopropa[a]pentalen-3-one | C16H26O3 | 详情 | 详情 | |
| (LXII) | 37558 | (3aS,4S,5R,6aR)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)hexahydro-2(1H)-pentalenone | C28H54O3Si2 | 详情 | 详情 | |
| (LXIII) | 37559 | bromo[1-[methyl(phenyl)sulfonimidoyl]-6-(tetrahydro-2H-pyran-2-yloxy)hexyl]magnesium | C18H28BrMgNO3S | 详情 | 详情 | |
| (LXIV) | 37560 | [((1S,2E)-3-[(1S,2R,3aS,6aS)-2-[[tert-butyl(dimethyl)silyl]oxy]-5-[(E)-6-(tetrahydro-2H-pyran-2-yloxy)hexylidene]octahydro-1-pentalenyl]-1-pentyl-2-propenyl)oxy](tert-butyl)dimethylsilane; 6-[(3aS,4S,5R,6aS)-5-[[tert-butyl(dimethyl)silyl]oxy]-4-((E,3S)-3-[[tert-butyl(dimethyl)silyl]oxy]-1-octenyl)hexahydro-2(1H)-pentalenylidene]hexyl tetrahydro-2H-pyran-2-yl ether | C39H74O4Si2 | 详情 | 详情 |