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【结 构 式】 
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【分子编号】11487 【品名】(2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C11H19NO4 【 分 子 量 】229.2762 【元素组成】C 57.63% H 8.35% N 6.11% O 27.91% |
合成路线1
该中间体在本合成路线中的序号：(XLVIII)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：(LV)3) Coupling and cyclization process.- The condensation of the diphenylphosphine derivative (XXIV) with aldehyde (LI) by means of butyllithium in THF gives the hydroxy phosphine derivative (LII), which is treated with potassium hexamethyldisylazane (KHMDS) to afford dithiane (LIII). Partial desilylation of (LIII) with THF - water - trifluoroacetic acid gives alcohol (LIV), which is condensed with N-tert-butoxycarbonylpiperidine-2(S)-carboxylic acid (LV) by means of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine in dichloromethane to yield the ester (LVI). Elimination of the dithiane ring of (LVI) with N-chlorosuccinimide and silver nitrate in anhydrous methanol affords the dimethyl acetal (LVII), which is hydrolyzed to the corresponding aldehyde (LVIII) with acetic acid. The condensation of (LVIII) with 4(S)-benzyl-3-[2-(4-methoxybenzyloxy)acetyl]oxazolidin-2-one (LIX) by means of dibutylboron trifluoromethylsulfonate in toluene gives the oxazolidone derivative (LX).
| 【1】 Jones, T.K.; Askin, D.; Mills, S.G.; Reamer, R.A.; Desmond, R.; Volante, R.P.; Tschaen, D.M.; Shinkai, I. (Merck & Co., Inc.); Process for synthesis of FK-506 and tricarbonyl intermediates. EP 0378318; JP 1990233643 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 11523 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl(diphenyl)phosphine oxide; [(3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl](oxo)diphenylphosphorane | C36H59O4PS2Si | 详情 | 详情 | |
| (LI) | 11550 | (2S,3S,5S,6S,7S,8E)-2-Allyl-3-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-6,8-dimethyl-7-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-8-nonenal | C51H104O6Si4 | 详情 | 详情 | |
| (LII) | 11553 | (1E,3S,4S,5S,7S,8R,9E,12S,14S,15R,16S,18R)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-18-(1,3-dithian-2-yl)-14,16-dimethoxy-1-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4,10,12-tetramethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol | C69H138O8S2Si4 | 详情 | 详情 | |
| (LIII) | 11552 | (5R,6S,8S,10E,12R,13S,15S,16S,17S)-12-Allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-5-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-19,19-diethyl-6-methoxy-17-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,2,3,3,8,10,16-heptamethyl-15-[(triisopropylsilyl)oxy]-4,18-dioxa-3,19-disila-10-henicosene; (1S,3S,4R,5E,8S,10S,11R,12S,14R)-4-Allyl-3,11-bis[[tert-butyl(dimethyl)silyl]oxy]-14-(1,3-dithian-2-yl)-10,12-dimethoxy-1-[(1S,2S,3E)-4-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1,3-dimethyl-2-[(triethylsilyl)oxy]-3-butenyl]-6,8-dimethyl-5-pentadecenyl triisopropylsilyl ether | C75H152O8S2Si5 | 详情 | 详情 | |
| (LIV) | 11551 | (5R,6S,8R,12R,13S,15S,16S,17S)-12-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-9-(diphenylphosphoryl)-5-[(1S,3R)-3-(1,3-dithian-2-yl)-1-methoxybutyl]-19,19-diethyl-6-methoxy-17-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methyl | C87H163O10PS2Si5 | 详情 | 详情 | |
| (LV) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (LVI) | 11555 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-16-(1,3-dithian-2-yl)-12,14-dimethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C80H155NO11S2Si4 | 详情 | 详情 | |
| (LVII) | 11556 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,14,17,17-tetramethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C79H155NO13Si4 | 详情 | 详情 | |
| (LVIII) | 11557 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C77H149NO12Si4 | 详情 | 详情 | |
| (LIX) | 11558 | (4S)-4-Benzyl-3-[3-(4-methoxyphenyl)propanoyl]-1,3-oxazolidin-2-one | C20H21NO4 | 详情 | 详情 | |
| (LX) | 11559 | 2-[(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R,17R)-6-allyl-19-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-5,13-bis[[tert-butyl(dimethyl)silyl]oxy]-17-hydroxy-12,14-dimethoxy-18-[(4-methoxybenzyl)oxy]-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C97H170N2O17Si4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XLV)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 |
合成路线4
该中间体在本合成路线中的序号：(VI)The intermediate (IX) has been obtained as follows: The reduction of the spiroenone (I) with Li(s-Bu)3BH gives the corresponding alcohol that is protected with Tbdms-Cl and imidazole to yield the silyl ether (II). The oxidation of the vinyl group of (II) with OsO4, NaIO4 and NMO affords the carbaldehyde (III), which is condensed with the vinyl bromide (IV) by means of t-BuLi to provide the alcohol (V). The esterification of the alcohol (V) with the chiral piperidine-2-carboxylic acid (VI) by means of DCC and DMAP gives the ester (VII), which is selectively monodesilylated by means of TBAF to yield the alcohol (VIII). Finally this alcohol is oxidized by means of Dess Martin periodinane (DMP) to afford the target spiroenone (IX).
| 【1】 Gleason, J.L.; The total synthesis of FK-506 and its spiroketal analogs. Diss Abstr Int B - Sci Eng 1994, 54, 12, Part 1, 6206. |
| 【2】 Ireland, R.E.; et al.; A total synthesis of FK-506. J Org Chem 1996, 61, 20, 6856. |
| 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) | 57299 | (4S,6R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-one | C14H20O4 | 详情 | 详情 | |
| (II) | 57300 | tert-butyl(dimethyl)silyl (4S,6R,9R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-yl ether; tert-butyl({(4S,6R,9R)-2,2-dimethyl-4-[(1S)-1-methyl-2-propenyl]-1,3,7-trioxaspiro[5.5]undec-10-en-9-yl}oxy)dimethylsilane | C20H36O4Si | 详情 | 详情 | |
| (III) | 57301 | (2R)-2-((4S,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)propanal | C19H34O5Si | 详情 | 详情 | |
| (IV) | 17368 | (1R,2R,5R)-5-[(E)-2-bromo-1-propenyl]-2-[[tert-butyl(diphenyl)silyl]oxy]cyclohexyl methyl ether; ([(1R,2R,4R)-4-[(E)-2-bromo-1-propenyl]-2-methoxycyclohexyl]oxy)(tert-butyl)diphenylsilane | C26H35BrO2Si | 详情 | 详情 | |
| (V) | 57302 | (E,3S,4S)-4-((4R,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)-1-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-1-penten-3-ol | C45H70O7Si2 | 详情 | 详情 | |
| (VI) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (VII) | 57303 | 1-(tert-butyl) 2-[(1S,2E)-1-[(1R)-1-((4R,6R,9R)-9-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl)ethyl]-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-2-methyl-2-propenyl] (2S)-1,2-piperid | C56H87NO10Si2 | 详情 | 详情 | |
| (VIII) | 57304 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R,9R)-9-hydroxy-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H73NO10Si | 详情 | 详情 | |
| (IX) | 57305 | 1-(tert-butyl) 2-((1S,2E)-3-((1R,3R,4R)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methoxycyclohexyl)-1-{(1R)-1-[(4R,6R)-2,2-dimethyl-9-oxo-1,3,7-trioxaspiro[5.5]undec-10-en-4-yl]ethyl}-2-methyl-2-propenyl) (2S)-1,2-piperidinedicarboxylate | C50H71NO10Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XXIV)Intermediate (II): Compound (II) is obtained starting from two new previously synthesized intermediates, the oxazolidinone (XX) (scheme 17565203d) and the aldehyde (XXI) (scheme 17565203e), which are condensed by means of dibutylboron trifluoromethanesulfonate in dichloromethane to give compound (XXII), which is reduced first with LiBH4, tosylated with tosyl chloride and reduced again with lithium triethylborohydride in THF to yield compound (XXIII). The esterification of (XXIII) with the piperidine-2-carboxylic acid (XXIV) by means of DIC in dichloromethane followed by iodination of the terminal vinyl group by means of OsO4-catalyzed diol formation - Pb(OAc)4 cleavage, followed by CrCl2-mediated iodo-olefination with triiodomethane in THF/dioxane, affords the iodovinyl ester (XXV). Finally, (XXV) is debenzylated with DDQ in CHCl3 and silylated with triethylsilyl trifluoromethanesulfonate in dichloromethane to afford intermediate (II) (see K.C. Nicolau et al., J Chem Soc Chem Commun 1993, 7: 619). (1,2)
| 【1】 Nicolaou, K.C.; Piscopio, A.D.; Bertinato, P.; Chakraborty, T.K.; Minowa, N.; Koide, K.; Total Synthesis of Rapamycin. Chemistry (Weinheim) 1995, 1, 5, 318. |
| 【2】 Nicolaou, K.C.; Chakraborty, T.K.; Piscopio, A.D.; Minowa, N.; Bertinato, P.; Total synthesis of rapamycin. J Am Chem Soc 1993, 115, 10, 4419. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 14990 | (1S,3S,4R,5E,7R,8R,9R,10R,12S,13E)-1-[(1R)-2-((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethyl]-14-iodo-8-methoxy-4,6,10,12-tetramethyl-3,9-bis(triethylsilyl)-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienyl (2S)-2-piperidinecarboxylate | C72H128INO6Si4 | 详情 | 详情 | |
| (XX) | 15008 | (4R,5S)-3-[3-((1S,3R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)propanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C36H45NO5Si | 详情 | 详情 | |
| (XXI) | 15009 | (3S,4R,5E,7R,8S,9R,10R,12S)-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienal | C44H70O7Si | 详情 | 详情 | |
| (XXII) | 15010 | (4R,5S)-3-[(2R,3S,5S,6R,7E,9R,10S,11R,12R,14S)-2-[((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)methyl]-3-hydroxy-10-methoxy-5,11-bis[(4-methoxybenzyl)oxy]-6,8,12,14-tetramethyl-9-[(triisopropylsilyl)oxy]-7,15-hexadecadienoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C80H115NO12Si2 | 详情 | 详情 | |
| (XXIII) | 15011 | (2R,3S,5S,6R,7E,9R,10S,11R,12R,14S)-1-((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-10-methoxy-5,11-bis[(4-methoxybenzyl)oxy]-2,6,8,12,14-pentamethyl-9-[(triisopropylsilyl)oxy]-7,15-hexadecadien-3-ol | C70H108O9Si2 | 详情 | 详情 | |
| (XXIV) | 11487 | (2S)-1-(tert-Butoxycarbonyl)hexahydro-2-pyridinecarboxylic acid | C11H19NO4 | 详情 | 详情 | |
| (XXV) | 15013 | 1-(tert-butyl) 2-[(1S,3S,4R,5E,7R,8S,9R,10R,12S,13E)-1-[(1R)-2-((1S,3R,4R)-4-[[tert-butyl(diphenyl)silyl]oxy]-3-methoxycyclohexyl)-1-methylethyl]-14-iodo-8-methoxy-3,9-bis[(4-methoxybenzyl)oxy]-4,6,10,12-tetramethyl-7-[(triisopropylsilyl)oxy]-5,13-tetradecadienyl] (2S)-1,2-piperidinedicarboxylate | C81H124INO12Si2 | 详情 | 详情 |