|
【结 构 式】 
|
【分子编号】11485 【品名】([(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 【CA登记号】 |
【 分 子 式 】C19H37BrO2Si 【 分 子 量 】405.49108 【元素组成】C 56.28% H 9.2% Br 19.71% O 7.89% Si 6.93% |
合成路线1
该中间体在本合成路线中的序号：(XLVI)3) (1R,2R,4R)-4-(2(E)-Bromo-1-propenyl)-2-methoxy-1-(triisopropylsilyloxy)cyclohexane (XLVII).- The catalytic asymetric epoxidation of divinylcarbinol (XXXIII) with titanium isopropoxide and L-(+)-diisopropyl tartrate in dichloromethane gives (2R,3S)-1,2-epoxy-4-penten-3-ol (XXXIV), which is protected with PMB-Br and tetrabutylammonium bromide in dichloromethane yielding the benzyl derivative (XXXV). The condensation of (XXXV) with ethoxyacetylene (V) by means of boron trifluoride ethearate in THF affords the acetylenic ether (XXXVI), which is treated with ethanol and HgCl2 giving ethyl (4R,5S)-5-hydroxy-4-methoxyhept-6-enoate (XXXVII). The lactonization of (XXXVII) by means of p-toluenesulfonic acid in benzene yields the lactone (XXXVIII), which is submitted to a Claisen rearrangement by means of TBS trifluoromethanesulfonate and the resulting acid was methylated with diazomethane to afford methyl (1R,3R)-3-methoxy-4-cyclohexene-1-carboxylate (XXXIX). Hydroboration of (XXXIX) with BH3 and NaOH gives methyl (1R,3R,4R)-4-hydroxy-3-methoxycyclohexane-1-carboxylate (XL), which is protected with TIPS trifluoromethanesulfonate in dichloromethane yielding ester (XLI). The reduction of (XLI) with LiAlH4 in THF affords the hydroxymethyl derivative (XLII), which is oxidized to the corresponding aldehyde (XLIII) by means of oxalyl chloride in dichloromethane - DMSO. The reaction of (XLIII) with dimethyl diazomethylphosphonate and potassium tert-butoxide in THF gives (1R,2R,4R)-4-ethynyl-2-methoxy-1-(triisopropylsilyloxy)cyclohexane (XLIV), which is methylated with methyl iodide and butyllithium in THF to yield the corresponding propynyl derivative (XLV). Finally, this compound is treated with NBS in benzene affording the third building fragment (XLVI) (Scheme 2). 4) The first coupling reaction was the addition of vinyl bromide (XLVI) to aldehyde (XXXII). This was performed by reaction of (XLVI) with butyllithium and the resulting vinyllithium derivative was treated with aldehyde (XXXII) and catalytic amounts of MgBr giving the carbinol (XLVII), which was esterified with N-(tert-butoxycarbonyl)piperidine-2(S)-carboxylic acid (XLVIII) by means of DDC and 4-pyrrolidinopyridine, yielding the corresponding ester (XLIX). Treatment of (XLIX) with Zn dust and NH4Cl affords the 2-allyl substituted alcohol (L), which is oxidized with oxalyl chloride and DMSO in dichloromethane giving a fourth building block, the allyl substituted aldehyde (LI).
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXXII) | 11482 | (2R,3R,5S)-5-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-6-(4-methoxyphenyl)-2-methyl-3-[(triisopropylsilyl)oxy]hexanal | C28H47IO4Si | 详情 | 详情 | |
| (XLIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XLIV) | 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 | |
| (XLV) | 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 | |
| (XLVI) | 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 | |
| (XLVII) | 11486 | (E,3S,4S,5S,7S)-7-[(3S,5S)-5-(Iodomethyl)tetrahydro-3-furanyl]-8-(4-methoxyphenyl)-1-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-5-[(triisopropylsilyl)oxy]-1-octen-3-ol | C47H85IO6Si2 | 详情 | 详情 | |
| (XLVIII) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (XLIX) | 11488 | 1-(tert-butyl) 2-((1S,2E)-1-[(1S,2S,4S)-4-[(3S,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-5-(4-methoxyphenyl)-1-methyl-2-[(triisopropylsilyl)oxy]pentyl]-3-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C58H102INO9Si2 | 详情 | 详情 | |
| (L) | 11489 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-(hydroxymethyl)-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H103NO9Si2 | 详情 | 详情 | |
| (LI) | 11490 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-formyl-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H101NO9Si2 | 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 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 |
合成路线3
该中间体在本合成路线中的序号：(XVIII)The asymmetric reduction of 5-(4-methoxybenzyloxy)-3-oxopentanoic acid methyl ester (XXXIII) with H2 over a chiral Ru catalyst gives the chiral hydroxyester (XXXIV), which is alkylated by means of allyl bromide (XXXV) and LDA to yield the chiral 2-allyl-3-hydroxypentanoic ester (XXXVI). The reduction of (XXXVI) with LiAlH4, and then with DDQ affords the 1,3-dioxan-4-ylethanol (XXXVII), which is treated with NIS, NaHCO3 and reduced with DIBAL to afford the iodomethyl tetrahydrofuran (XXXVIII). The oxidation of the primary OH group of (XXXVIII) with oxalyl chloride provides the carbaldehyde (XXXIX), which is condensed with the propenylstannane (XL) by means of BF3/Et2O in dichloromethane to give the unsaturated alcohol (XLI). The protection of the OH group of (XLI) with TipsOTf yields the unsaturated silyl ether (XLII), which is ozonolyzed by means of O3, pyridine and Me2S to afford the carbaldehyde (XLIII). The condensation of (XLIII) with the chiral intermediate 2-bromovinyl cyclohexane (XVIII) by means of tBuLi and MgBr2 provides the alcohol (XLIV), which is esterified with 1-(tert-butoxycarbonyl)piperidine-2(S)-carboxylic acid (XLV) by means of DCC to give the expected ester (XLVI). The reaction of (XLVI) with Zn and NH4Cl yields the chiral alpha-allyl alcohol (XLVII), which is oxidized by means of oxalyl chloride to afford the corresponding carbaldehyde (XLVIII).
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXXIII) | 57260 | methyl 5-[(4-methoxybenzyl)oxy]-3-oxopentanoate | C14H18O5 | 详情 | 详情 | |
| (XXXIV) | 57261 | methyl (3S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]pentanoate | C14H20O5 | 详情 | 详情 | |
| (XXXV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XXXVI) | 57262 | methyl (2S)-2-{(1S)-1-hydroxy-3-[(4-methoxybenzyl)oxy]propyl}-4-pentenoate | C17H24O5 | 详情 | 详情 | |
| (XXXVII) | 11466 | (2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol | C16H22O4 | 详情 | 详情 | |
| (XXXVIII) | 57263 | (3S)-3-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-3-[(4-methoxybenzyl)oxy]-1-propanol | C16H23IO4 | 详情 | 详情 | |
| (XXXIX) | 57264 | (3S)-3-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-3-[(4-methoxybenzyl)oxy]propanal | C16H21IO4 | 详情 | 详情 | |
| (XL) | 11469 | (E)-2-Butenyl(triphenyl)stannane | C22H22Sn | 详情 | 详情 | |
| (XLI) | 57265 | (1S,3S,4S)-1-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-1-[(4-methoxybenzyl)oxy]-4-methyl-5-hexen-3-ol | C20H29IO4 | 详情 | 详情 | |
| (XLII) | 57266 | (1S,2S)-1-{(2S)-2-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-2-[(4-methoxybenzyl)oxy]ethyl}-2-methyl-3-butenyl triisopropylsilyl ether; [((1S,2S)-1-{(2S)-2-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-2-[(4-methoxybenzyl)oxy]ethyl}-2-methyl-3-butenyl)oxy](triisopropyl)silane | C29H49IO4Si | 详情 | 详情 | |
| (XLIII) | 57267 | (2R,3S,5S)-5-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-5-[(4-methoxybenzyl)oxy]-2-methyl-3-[(triisopropylsilyl)oxy]pentanal | C28H47IO5Si | 详情 | 详情 | |
| (XLIV) | 57268 | (E,3S,4S,5S,7S)-7-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-7-[(4-methoxybenzyl)oxy]-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4-dimethyl-5-[(triisopropylsilyl)oxy]-1-hepten-3-ol | C47H85IO7Si2 | 详情 | 详情 | |
| (XLV) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (XLVI) | 57269 | 1-(tert-butyl) 2-((1S,2E)-1-{(1S,2S,4S)-4-[(3R,5S)-5-(iodomethyl)tetrahydro-3-furanyl]-4-[(4-methoxybenzyl)oxy]-1-methyl-2-[(triisopropylsilyl)oxy]butyl}-3-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C58H102INO10Si2 | 详情 | 详情 | |
| (XLVII) | 57270 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6R)-6-(hydroxymethyl)-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H103NO10Si2 | 详情 | 详情 | |
| (XLVIII) | 57271 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H101NO10Si2 | 详情 | 详情 |