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【结 构 式】

【分子编号】11480

【品名】[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]methanol

【CA登记号】

【 分 子 式 】C17H36O3Si

【 分 子 量 】316.55654

【元素组成】C 64.5% H 11.46% O 15.16% Si 8.87%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XLII)

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:(XIII)

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
Extended Information