• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【分子编号】11466

【品名】(2R)-2-[(2S,4S)-2-(4-Methoxyphenyl)-1,3-dioxan-4-yl]-4-penten-1-ol

【CA登记号】

【 分 子 式 】C16H22O4

【 分 子 量 】278.34828

【元素组成】C 69.04% H 7.97% O 22.99%

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:(XXVI)

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:(XXXVII)

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
Extended Information