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【结 构 式】 
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【分子编号】11584 【品名】methyl (1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate 【CA登记号】 |
【 分 子 式 】C8H12O3 【 分 子 量 】156.18148 【元素组成】C 61.52% H 7.74% O 30.73% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The Diels-Alder reaction of butadiene (VIII) with acrylic acid (IX) gives cyclohexene-4-carboxylic acid (X), which by treatment with I2 and KI in water followed by a treatment with 1,5-diazabicyclo[4.3.0]non-5-ene (XI) in benzene is converted to 3-hydroxycyclohexene-5-carboxylic acid lactone (XII). The opening of (XII) with NaOMe in MeOH yields methyl 3-hydroxycyclohexene-5-carboxylate (XIII) as a mixture of isomers, which by treatment with phenylacetyl chloride (A) affords the corresponding phenylacetate (XIV), which by optical resolution and successive racemization of the residue with mercuric trifluoroacetate yields the active methyl 3-hydroxycyclohexene-5-carboxylate (XIIIa). The treatment of (XIIIa) with biphenylyl-4-carbonyl chloride gives the corresponding ester (XV), which is submitted to hydroxylation with OsO4-sodium chlorate yielding the glycol (XVI). Ring opening of (XVI) with sodium periodate in THF-water affords the dialdehyde (XVII), which is cyclized by treatment with pyrrolidine acetate (B) in benzene giving 5-methoxycarbonyl-3-(biphenylylcarbonyloxy)cyclopentene-1-carboxaldehyde (XVIII). The conjugate addition of (XVIII) with the vinyl cuprate (XIX) in HMPT-THF-ether at -78 C gives rise to 2-[3-(1-ethoxyethoxy)-1-octen-1-yl]-3-(4-biphenylylcarbonyloxy)-5-methyloxycarbonylcyclopentane-1-carboxaldehyde (XX), which is converted into the corresponding ethylene ketal (XXI) in the usual way (C).
| 【1】 Trost, B.M.; et al.; An enantioconvergent approach to prostanoids. J Chem Soc Chem Commun 1978, 10, 436-438. |
| 【2】 Castaner, J.; Owen, R.T.; U-46619. Drugs Fut 1980, 5, 9, 453. |
| 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) | 28439 | [1,1'-biphenyl]-4-carbonyl chloride | 14002-51-8 | C13H9ClO | 详情 | 详情 |
| (B) | 39152 | C6H12NO2 | 详情 | 详情 | ||
| (VIII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (IX) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (X) | 39146 | 3-cyclohexene-1-carboxylic acid；Cyclohex-3-ene-1-carboxylic acid | 4771-80-6 | C7H10O2 | 详情 | 详情 |
| (XI) | 39147 | 2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine | 3001-72-7 | C7H12N2 | 详情 | 详情 |
| (XII) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XIII) | 11584 | methyl (1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate | C8H12O3 | 详情 | 详情 | |
| (XIV) | 39148 | methyl (1R,5R)-5-[(2-phenylacetyl)oxy]-3-cyclohexene-1-carboxylate | C16H18O4 | 详情 | 详情 | |
| (XV) | 39149 | (1R,5R)-5-(methoxycarbonyl)-2-cyclohexen-1-yl [1,1'-biphenyl]-4-carboxylate | C21H20O4 | 详情 | 详情 | |
| (XVI) | 39150 | (1R,2R,3R,5R)-2,3-dihydroxy-5-(methoxycarbonyl)cyclohexyl [1,1'-biphenyl]-4-carboxylate | C21H22O6 | 详情 | 详情 | |
| (XVII) | 39151 | (1R,3S)-1-formyl-3-(methoxycarbonyl)-5-oxopentyl [1,1'-biphenyl]-4-carboxylate | C21H20O6 | 详情 | 详情 | |
| (XVIII) | 39153 | (1R,4S)-3-formyl-4-(methoxycarbonyl)-2-cyclopenten-1-yl [1,1'-biphenyl]-4-carboxylate | C21H18O5 | 详情 | 详情 | |
| (XIX) | 39154 | C17H30CuO2 | 详情 | 详情 | ||
| (XX) | 39155 | (1R,2R,3R,4S)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-3-formyl-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C33H42O7 | 详情 | 详情 | |
| (XXI) | 39157 | (1R,2R,3R,4S)-3-(1,3-dioxolan-2-yl)-2-[(E,3S)-3-(1-ethoxyethoxy)-1-octenyl]-4-(methoxycarbonyl)cyclopentyl [1,1'-biphenyl]-4-carboxylate | C35H46O8 | 详情 | 详情 | |
| (C) | 39156 | 2,2-dimethyl-1,3-dioxolane | 2916-31-6 | C5H10O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVII)The starting compounds (I) and (II) are obtained as follows: Aldehyde (I): The esterification of (R,R)-dihydrobenzoin (IX) with acryloyl chloride (X) by means of triethylamine in dichloromethane gives the corresponding diester (XI), which by bis-cyclization with butadiene (XII) by means of TiCl4 in dichloromethane yields the bis(3-cyclohexenecarboxylic acid) ester (XIII). The hydrolysis of (XIII) with LiOH in methanol affords (R)-3-cyclohexenecarboxylic acid (XIV), which by reaction with I2, KI and NaHCO3 is converted to the iodolactone (XV). The reaction of (XV) with 1,5-diazabicyclo[5.4.0]-5-undecene (DBU) in refluxing THF affords the unsaturated lactone (XVI), which by treatment with NaHCO3 in anhydrous methanol yields (1R,3R)-3-hydroxy-4-cyclohexenecarboxylic acid methyl ester (XVII). The methylation of (XVII) with methyl trifluoromethanesulfonate and 2,6-di-tert-butyl-4-methylpyridine (DBMP) in dichloromethane gives the 3-methoxy ester (XVIII), which is selectively hydroxylated with BH3, H2O2 and NaOH to (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylic acid methyl ester (XIX). The protection of (XIX) with triisopropylsilyl (TIPS) trifluoromethanesulfonate (XX) and triethylamine in dichloromethane affords the protected ester (XXI), which is reduced with dibutylaluminum hydride (DIBAL) in hexane to the corresponding aldehyde (XXII). Finally, this compound is condensed with the N-tert-butylimine of 2-(triethylsilyl)propanol (XXIII) by means of butyllithium in THF to afford the desired aldehyde (I).
| 【1】 Marshall, J.A.; Xie, S.P.; Synthesis of a C22-34 subunit of the immunosuppressant FK-506. J Org Chem 1995, 60, 22, 7230. |
| 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) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (IX) | 11576 | (1S,2S)-1,2-Diphenyl-1,2-ethanediol; (S,S)-(-)-1,2-Diphenyl-1,2-ethanediol | 2325-10-2 | C14H14O2 | 详情 | 详情 |
| (X) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XI) | 11578 | (1R,2R)-2-(Acryloyloxy)-1,2-diphenylethyl acrylate | C20H18O4 | 详情 | 详情 | |
| (XII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (XIII) | 11580 | (1R,2R)-2-[[(1R)-3-cyclohexen-1-ylcarbonyl]oxy]-1,2-diphenylethyl (1R)-3-cyclohexene-1-carboxylate | C28H30O4 | 详情 | 详情 | |
| (XIV) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (XV) | 11582 | (1R,4R,5R)-4-Iodo-6-oxabicyclo[3.2.1]octan-7-one | C7H9IO2 | 详情 | 详情 | |
| (XVI) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XVII) | 11584 | methyl (1R,5R)-5-hydroxy-3-cyclohexene-1-carboxylate | C8H12O3 | 详情 | 详情 | |
| (XVIII) | 11585 | methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate | C9H14O3 | 详情 | 详情 | |
| (XIX) | 11586 | methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylate | C9H16O4 | 详情 | 详情 | |
| (XX) | 11587 | triisopropylsilyl trifluoromethanesulfonate | 80522-42-5 | C10H21F3O3SSi | 详情 | 详情 |
| (XXI) | 11588 | methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate | C18H36O4Si | 详情 | 详情 | |
| (XXII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XXIII) | 11590 | N-(tert-Butyl)-N-[(E)-2-(triethylsilyl)propylidene]amine; 2-Methyl-N-[(E)-2-(triethylsilyl)propylidene]-2-propanamine | C13H29NSi | 详情 | 详情 |