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【结 构 式】 
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【分子编号】11581 【品名】(1R)-3-Cyclohexene-1-carboxylic acid 【CA登记号】 |
【 分 子 式 】C7H10O2 【 分 子 量 】126.1552 【元素组成】C 66.65% H 7.99% O 25.36% |
合成路线1
该中间体在本合成路线中的序号：(XIV)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 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)The condensation of sultam (XXII) with propenoyl chloride (XXIII) by means of TEA in dichloromethane gives the acryloyl sultam (XXIV), which is submitted to a Diels Alder cyclization with butadiene (XXV) by means of EtAlCl2 in dichloromethane to yield the chiral cyclohexenylcarbonyl derivative (XXVI). The hydrolysis of (XXVI) with LiOH in THF affords 3-cyclohexene-1(R)-carboxylic acid (XXVII), which is treated with I2, KI, NaHCO3 and DBU to provide the bicyclic lactone (XXVIII). The reduction of (XXVIII) with LiAlH4 in THF gives the chiral diol (XXIX), which is treated with diphenyl disulfide and tributylphosphine to yield the phenyl thioether (XXX). The methylation of the OH group of (XXX) with methyl iodide and KOH in DMSO afford the methoxy derivative (XXXI). The oxidation of (XXXI) with oxone in THF/methanol provides the sulfone (XXXII), which is submitted to hydroboration with BH3/Me2S and tBu-OOH in THF to give the chiral 4-hydroxy-3-methoxycyclohexylmethyl sulfone (XXXIII). The reaction of (XXXIII) with Tbdps-Cl and imidazole in DMF yields the silyl ether (XXXIV), which is condensed with the intermediate butyraldehyde (X) by means of BuLi in THF to afford the chiral pentanol derivative (XXXV). The oxidation of (XXXV) with TFAA and DMSO in dichloromethane provides the corresponding ketone (XXXVI), which is desulfonated by means of aluminum amalgam in refluxing THF/water to give the ketone (XXXVII). The reaction of (XXXVII) with Tf2N-Ph and KHMDS in THF yields the triflate enol ester (XXXVIII), which is methylated with Me-Li and CuI in THF to afford the unsaturated dithiane derivative (XXXIX). The reaction of (XXXIX) with NaH and Tips-OTf in HMPA provides the triisopropylsilyl ether (XL) (1) (Scheme 12407109c). The condensation of (XL) with the intermediate 14-iodo-10-tetradecenal dimethylacetal (XXI) by means of BuLi in THF/HMPA gives the adduct (XLI), which is desulfurized by means of NCS and AgNO3 in acetone/THF/water to yield the ketonic product (XLII). The cleavage of the 4-methoxybenzyl group of (XLII) by means of DDQ in dichloromethane affords the beta-hydroxyketone (XLIII). The reduction of the ketonic group of (XLIII) with LiAlH4 and LiI in ethyl ether provides the dihydroxy compound (XLIV), which is selectively monoprotected with Tips-OTf and 2,6-lutidine in dichloromethane to give the intermediate (XLV).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 57335 | (2S,3S)-3-(1,3-dithian-2-yl)-2-[(4-methoxybenzyl)oxy]butanal | C16H22O3S2 | 详情 | 详情 | |
| (XXII) | 24401 | 1,7,7-Trimethylbicyclo[2,2,1]heptane-1',2-sultam; (1S)-(-)-2,10-Camphorsultam | C10H17NO2S | 详情 | 详情 | |
| (XXIII) | 11577 | Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride | 814-68-6 | C3H3ClO | 详情 | 详情 |
| (XXIV) | 57357 | 4-acryloyl-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (XXV) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (XXVI) | 57358 | 4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (XXVII) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (XXVIII) | 11583 | (1R,5R)-6-Oxabicyclo[3.2.1]oct-3-en-7-one | C7H8O2 | 详情 | 详情 | |
| (XXIX) | 57345 | (1R,5R)-5-(hydroxymethyl)-2-cyclohexen-1-ol | C7H12O2 | 详情 | 详情 | |
| (XXX) | 57346 | (1R,5R)-5-[(phenylsulfanyl)methyl]-2-cyclohexen-1-ol | C13H16OS | 详情 | 详情 | |
| (XXXI) | 57347 | 1-({[(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl}sulfanyl)benzene; methyl (1R,5R)-5-[(phenylsulfanyl)methyl]-2-cyclohexen-1-yl ether | C14H18OS | 详情 | 详情 | |
| (XXXII) | 57348 | {[(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl}(dioxo)phenyl-lambda~6~-sulfane; [(1R,5R)-5-methoxy-3-cyclohexen-1-yl]methyl phenyl sulfone | C14H18O3S | 详情 | 详情 | |
| (XXXIII) | 57349 | (1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexanol | C14H20O4S | 详情 | 详情 | |
| (XXXIV) | 57350 | ((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)methyl phenyl sulfone; tert-butyl({(1R,2R,4R)-2-methoxy-4-[(phenylsulfonyl)methyl]cyclohexyl}oxy)diphenylsilane | C30H38O4SSi | 详情 | 详情 | |
| (XXXV) | 57351 | (1S,3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-1-(phenylsulfonyl)-2-pentanol | C46H60O7S3Si | 详情 | 详情 | |
| (XXXVI) | 57352 | (1S,3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-1-(phenylsulfonyl)-2-pentanone | C46H58O7S3Si | 详情 | 详情 | |
| (XXXVII) | 57353 | (3S,4S)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-pentanone | C40H54O5S2Si | 详情 | 详情 | |
| (XXXVIII) | 57354 | (Z)-2-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1S,2S)-2-(1,3-dithian-2-yl)-1-[(4-methoxybenzyl)oxy]propyl}ethenyl trifluoromethanesulfonate | C41H53F3O7S3Si | 详情 | 详情 | |
| (XXXIX) | 57355 | tert-butyl(diphenyl)silyl (1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl ether; tert-butyl[((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy]diphenylsilane | C41H56O4S2Si | 详情 | 详情 | |
| (XL) | 57356 | [((1R,2R,4R)-4-{(E,3S,4S)-4-(1,3-dithian-2-yl)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-pentenyl}-2-methoxycyclohexyl)oxy](triisopropyl)silane; (1S,2E)-1-[(1S)-1-(1,3-dithian-2-yl)ethyl]-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl 4-methoxybenzyl ether | C34H58O4S2Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)The reaction of the labeled acylated (+)-bornane-10,2-sultam (IV) with triethyl phosphite gives the phosphonate (V), which is treated with paraformaldehyde, galvinoxyl and K2CO3 yielding the acrylate derivative (VI). The cyclization of (VI) with butadiene (VII) by means of diethylaluminum chloride and galvinoxyl (as radical scavenger) affords the cyclohexene-carboxamide derivative (VIII), which is hydrolyzed with LiOH in THF/water giving the (1R)-3-cyclohexenecarboxylic acid (IX). The oxidation of (IX) with m-chloroperbenzoic acid and triethylamine in CCl4 yielded regioselectively the hydroxylactone (X), which is finally hydrolyzed with HCl to the labeled intermediate (I).
| 【1】 Moenius, T.; et al.; C-14 labelling of NVP RAD001 - A new rapamycin derivative. J Label Compd Radiopharm 1999, 42, 1, 29. |
| 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) | 32019 | (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid | C7H12O4 | 详情 | 详情 | |
| (I) | 45302 | (1R,3R,4R)-3,4-dihydroxycyclohexanecarboxylic acid | C7H12O4 | 详情 | 详情 | |
| (IV) | 32020 | (1S,5S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C12H18BrNO3S | 详情 | 详情 | |
| (IV) | 45305 | (1S,5S)-4-(2-bromoacetyl)-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C12H18BrNO3S | 详情 | 详情 | |
| (V) | 32021 | diethyl 2-[(1S,5S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-oxoethylphosphonate | C16H28NO6PS | 详情 | 详情 | |
| (V) | 45306 | diethyl 2-[(1S,5S)-10,10-dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-oxoethylphosphonate | C16H28NO6PS | 详情 | 详情 | |
| (VI) | 32022 | (1S,5S)-4-acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (VI) | 45307 | (1S,5S)-4-acryloyl-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C13H19NO3S | 详情 | 详情 | |
| (VII) | 11579 | 1,3-Butadiene; Butadiene | 106-99-0 | C4H6 | 详情 | 详情 |
| (VIII) | 32023 | (1S,5S)-4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (VIII) | 45308 | (1S,5S)-4-[(1R)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C17H25NO3S | 详情 | 详情 | |
| (IX) | 11581 | (1R)-3-Cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (IX) | 45309 | (1R)-3-cyclohexene-1-carboxylic acid | C7H10O2 | 详情 | 详情 | |
| (X) | 11528 | (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 | |
| (X) | 45310 | (1R,4R,5R)-4-hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 |