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【结 构 式】 
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【分子编号】11585 【品名】methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate 【CA登记号】 |
【 分 子 式 】C9H14O3 【 分 子 量 】170.20836 【元素组成】C 63.51% H 8.29% O 28.2% |
合成路线1
该中间体在本合成路线中的序号：(XXXIX)2) (2R,3S,5S(2'S,4'R))-5-(2-(iodomethyl)tetrahydrofuran-4-yl)-5-(4-methoxy benzyloxy)-2-methyl-3-(triisopropylsilyloxy)pentanal (XXXII). The regioselective reduction of methyl 5-(4-methoxybenzyloxy)-3-oxopentanoate (XXI) with H2 over Ru2Cl4((S)-BINAP)2(C2H5)3N in methanol gives the 3(S)-hydroxy derivative (XXII), which is condensed with ally bromide (XXIII) by means of lithium diisopropylamide THF-HMPA to yield the ally derivative (XXIV). The reduction of (XXIV) with LiAlH4 in THF affords the diol (XXV), which is cyclized to the ketal (XXVI) by means of DDQ in dichloromethane. The reaction of (XXVI) first with N-iodosuccinimide (NIS) and then with diisobutylaluminum hydride affords (3S(2'S,4'R))-3-(2-iodomethyl)tetrahydrofuran-4-yl)-3-(4-methoxybenzyl)-1-propanol (XXVII), which is oxidized to the corresponding aldehyde (XXVIII) by means of oxalyl chloride in dichloromethane. The condensation of (XXVIII) with 2(E)-butenyltriphenylstannane (XXIX) by means of boron trifluoride ethearate in dichloromethane gives the alcohol (XXX), which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding the fully protected diol (XXXI). Finally, the double bond of (XXXI) is oxidized with ozone in methanol - dichloromethane yielding the second building fragment (XXXII).
| 【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 11461 | methyl 6-(4-methoxyphenyl)-3-oxohexanoate | C14H18O4 | 详情 | 详情 | |
| (XXII) | 11462 | methyl (3S)-3-hydroxy-6-(4-methoxyphenyl)hexanoate | C14H20O4 | 详情 | 详情 | |
| (XXIII) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXIV) | 11464 | methyl (2S)-2-[(1S)-1-hydroxy-4-(4-methoxyphenyl)butyl]-4-pentenoate | C17H24O4 | 详情 | 详情 | |
| (XXV) | 11465 | (2R,3S)-2-Allyl-5-[(4-methoxybenzyl)oxy]-1,3-pentanediol | C16H24O4 | 详情 | 详情 | |
| (XXVI) | 11466 | (2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol | C16H22O4 | 详情 | 详情 | |
| (XXVII) | 11467 | (3S)-3-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-4-(4-methoxyphenyl)-1-butanol | C16H23IO3 | 详情 | 详情 | |
| (XXVIII) | 11468 | (3S)-3-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-4-(4-methoxyphenyl)butanal | C16H21IO3 | 详情 | 详情 | |
| (XXIX) | 11469 | (E)-2-Butenyl(triphenyl)stannane | C22H22Sn | 详情 | 详情 | |
| (XXX) | 11470 | (3S,4S,6S)-6-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-7-(4-methoxyphenyl)-3-methyl-1-hepten-4-ol | C20H29IO3 | 详情 | 详情 | |
| (XXXI) | 11481 | ([(1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl]oxy)(triisopropyl)silane; (1S,2S)-1-[(2S)-2-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-3-(4-methoxyphenyl)propyl]-2-methyl-3-butenyl triisopropylsilyl ether | C29H49IO3Si | 详情 | 详情 | |
| (XXXIII) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (XXXIV) | 11472 | (1S)-1-[(2R)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (XXXV) | 11473 | (2S)-2-[(1S)-1-(4-Methoxybenzyl)-2-propenyl]oxirane; Methyl 4-[(2S)-2-[(2S)oxiranyl]-3-butenyl]phenyl ether | C13H16O2 | 详情 | 详情 | |
| (XXXVI) | 11474 | (3S,4R)-7-Ethoxy-4-methoxy-3-(4-methoxybenzyl)-1-hepten-6-yne; 4-[(2S,3R)-6-Ethoxy-3-methoxy-2-vinyl-5-hexynyl]phenyl methyl ether | C18H24O3 | 详情 | 详情 | |
| (XXXVII) | 11475 | ethyl (4R,5S)-5-hydroxy-4-methoxy-6-heptenoate | C10H18O4 | 详情 | 详情 | |
| (XXXVIII) | 11476 | (5R,6S)-5-Methoxy-6-vinyltetrahydro-2H-pyran-2-one | C8H12O3 | 详情 | 详情 | |
| (XXXIX) | 11585 | methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate | C9H14O3 | 详情 | 详情 | |
| (XL) | 11586 | methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexanecarboxylate | C9H16O4 | 详情 | 详情 | |
| (XLI) | 11588 | methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate | C18H36O4Si | 详情 | 详情 | |
| (XLII) | 11480 | [(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methanol | C17H36O3Si | 详情 | 详情 | |
| (XLIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVIII)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3
该中间体在本合成路线中的序号：(XI)The intermediate chiral 2-bromovinyl cyclohexane (XVIII) has been obtained as follows: The asymmetric epoxidation of divinyl carbinol (I) by means of L-(+)-diisopropyl tartrate, Ti(O-iPr)4 and tBu-OOH gives the epoxy alcohol (II), which is protected with p-methoxybenzyl bromide and NaH in THF to yield the benzyl ether (III). The condensation of (III) with the lithium derivative of ethyl acetate (IV) by means of BF3/Et2O, followed by hydrolysis with LiOH affords the 6-heptenoic acid (V). The methylation of the OH group of (V) with methyl iodide and NaH provides the corresponding methoxy acid (VI), which is esterified with diazomethane to give the methyl ester (VII). The debenzylation of (VII) by means of DDQ in dichloromethane yields the hydroxyester (VIII), which is cyclized by means of Ts-OH in refluxing benzene to afford the chiral tetrahydropyranone (IX). The Claisen rearrangement of the lactone (IX) catalyzed by Tbdms-OTf in refluxing toluene provides the cyclohexane carboxylic acid (X), which is esterified with diazomethane to give the methyl ester (XI). The hydroboration of the double bond of (XI) with BH3/THF, followed by protection with Tips-OTf yield the silyl ether (XII). The reduction of the ester group of (XII) with LiAlH4 affords the carbinol (XIII), which is treated with the Swern oxidant to afford the carbaldehyde (XIV). The condensation of (XIV) with the diazophosphonate (XV) and tBuOK provides the ethynyl cyclohexane (XVI), which is methylated with methyl iodide and BuLi in THF to give the propynyl cyclohexane (XVII). Finally, this compound is brominated by means of NBS and Cp2ZrHCl to yield the target intermediate, the chiral 2-bromovinyl cyclohexane (XVIII).
| 【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
| 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) | 11471 | 1,4-Pentadien-3-ol | 922-65-6 | C5H8O | 详情 | 详情 |
| (II) | 11472 | (1S)-1-[(2R)Oxiranyl]-2-propen-1-ol | C5H8O2 | 详情 | 详情 | |
| (III) | 57251 | 4-methoxybenzyl (1S)-1-[(2R)oxiranyl]-2-propenyl ether; (2R)-2-{(1S)-1-[(4-methoxybenzyl)oxy]-2-propenyl}oxirane | C13H16O3 | 详情 | 详情 | |
| (IV) | 44205 | (2-ethoxy-2-oxoethyl)lithium | C4H7LiO2 | 详情 | 详情 | |
| (V) | 57252 | (4R,5S)-4-hydroxy-5-[(4-methoxybenzyl)oxy]-6-heptenoic acid | C15H20O5 | 详情 | 详情 | |
| (VI) | 57253 | (4R,5S)-4-methoxy-5-[(4-methoxybenzyl)oxy]-6-heptenoic acid | C16H22O5 | 详情 | 详情 | |
| (VII) | 57254 | methyl (4R,5S)-4-methoxy-5-[(4-methoxybenzyl)oxy]-6-heptenoate | C17H24O5 | 详情 | 详情 | |
| (VIII) | 57255 | methyl (4R,5S)-5-hydroxy-4-methoxy-6-heptenoate | C9H16O4 | 详情 | 详情 | |
| (IX) | 11476 | (5R,6S)-5-Methoxy-6-vinyltetrahydro-2H-pyran-2-one | C8H12O3 | 详情 | 详情 | |
| (X) | 57256 | (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylic acid | C8H12O3 | 详情 | 详情 | |
| (XI) | 11585 | methyl (1R,5R)-5-methoxy-3-cyclohexene-1-carboxylate | C9H14O3 | 详情 | 详情 | |
| (XII) | 11588 | methyl (1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarboxylate | C18H36O4Si | 详情 | 详情 | |
| (XIII) | 11480 | [(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methanol | C17H36O3Si | 详情 | 详情 | |
| (XIV) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XV) | 57257 | dimethyl diazomethylphosphonate | C3H7N2O3P | 详情 | 详情 | |
| (XVI) | 11483 | (1R,2R,4R)-4-Ethynyl-2-methoxycyclohexyl triisopropylsilyl ether; [[(1R,2R,4R)-4-Ethynyl-2-methoxycyclohexyl]oxy](triisopropyl)silane | C18H34O2Si | 详情 | 详情 | |
| (XVII) | 11484 | (1R,2R,4R)-2-Methoxy-4-(1-propynyl)cyclohexyl triisopropylsilyl ether; Triisopropyl[[(1R,2R,4R)-2-methoxy-4-(1-propynyl)cyclohexyl]oxy]silane | C19H36O2Si | 详情 | 详情 | |
| (XVIII) | 11485 | ([(1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(triisopropyl)silane; (1R,2R,4R)-4-[(E)-2-Bromo-1-propenyl]-2-methoxycyclohexyl triisopropylsilyl ether | C19H37BrO2Si | 详情 | 详情 |