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【结 构 式】 
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【分子编号】11534 【品名】(E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal 【CA登记号】 |
【 分 子 式 】C20H38O3Si 【 分 子 量 】354.60542 【元素组成】C 67.74% H 10.8% O 13.54% Si 7.92% |
合成路线1
该中间体在本合成路线中的序号：(XXXV)2) [2S,3S,5S,6R,7S,8E,9(1'R,3'R,4'R)]-2-Allyl-3-(tert-butyldimethylsilylox y)-6,8-dimethyl-7-(triethylsilyloxy)-5-(triisopropylsilyloxy)-9-[3-meth oxy-4-(triisopropylsilyloxy)cyclohexyl]-8-nonenal (LI). Quinic acid (XXV) is converted into the lactone (XXVI) by known methods. Then this lactone is treated with thiocarbonyldiimidazole in refluxing dichloroethane yielding the bis(thiocarbonyl)lactone (XXVII), which by reaction with tributyltin hydride and AIBN in refluxing xylene is converted into the lactone (XXIX), either directly or through the intermediate thiocarbonyl-lactone (XXVIII). The silylation of (XXIX) with TIPS-SO3CF3 as usual affords the protected lactone (XXX). Opening of the lactone ring with methylchloroaluminum N-methoxy-N-methylamide gives the methoxyamide (XXXI), which is methylated with methyl trifluoromethylsulfonate to the methoxy-N-methoxyamide (XXXII). The reduction of (XXXII) with diisobutylaluminum hydride gives the aldehyde (XXXIII), which is condensed with 2-lithio-2-(triethylsilyl)propanal (XXXIV), yielding unsaturated aldehyde (XXXV). The condensation of (XXXV) with the boron enolate of oxazolidone (XXVI) affords the oxazolidone derivative (XXXVII), which is treated with methylchloroaluminum N-methoxy-N-methylamide to give the methoxyamide (XXXVIII). The silylation of (XXXVIII) with TES-SO3CF3 as usual yields the silylated amide (XXXIX), which is reduced with diisobutylaluminum hydride to the aldehyde (XL). The condensation of (XL) with chiral acetate (XLI) by means of lithium diisopropylamide in THF affords the hydroxy ester (XLII). Transesterification of (XLII) with NaOCH3 and methanol gives methyl ester (XLIII).
| 【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 |
|---|---|---|---|---|---|---|
| 63305 | di(1H-imidazol-2-yl)methanethione | C7H6N4S | 详情 | 详情 | ||
| 63306 | C3H9AlClNO | 详情 | 详情 | |||
| (XXV) | 11524 | D-Quinic acid; D-(-)-Chinic acid; D-(-)-Quinic acid; (3R,5R)-1,3,4,5-Tetrahydroxycyclohexanecarboxylic acid | 77-95-2 | C7H12O6 | 详情 | 详情 |
| (XXVI) | 11525 | (1S,3R,4R,5R)-1,3,4-Trihydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O5 | 详情 | 详情 | |
| (XXVII) | 11526 | O-[(1R,2S,6R)-9-oxo-4-thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undec-8-yl] 1H-imidazole-1-carbothioate | C12H10N2O5S2 | 详情 | 详情 | |
| (XXVIII) | 11527 | (1R,2S,6R,8S)-4-Thioxo-3,5,10-trioxatricyclo[6.2.1.0(2,6)]undecan-9-one | C8H8O4S | 详情 | 详情 | |
| (XXIX) | 11528 | (1R,4R,5R)-4-Hydroxy-6-oxabicyclo[3.2.1]octan-7-one | C7H10O3 | 详情 | 详情 | |
| (XXX) | 11529 | (1R,4R,5R)-4-[(Triisopropylsilyl)oxy]-6-oxabicyclo[3.2.1]octan-7-one | C16H30O3Si | 详情 | 详情 | |
| (XXXI) | 11530 | (1R,3R,4R)-3-Hydroxy-N-methoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide | C18H37NO4Si | 详情 | 详情 | |
| (XXXII) | 11531 | (1R,3R,4R)-N,3-Dimethoxy-N-methyl-4-[(triisopropylsilyl)oxy]cyclohexanecarboxamide | C19H39NO4Si | 详情 | 详情 | |
| (XXXIII) | 11532 | (1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexanecarbaldehyde | C17H34O3Si | 详情 | 详情 | |
| (XXXIV) | 11533 | [1-Methyl-1-[(4-methylphenyl)sulfonyl]-2-oxoethyl]lithium | C10H11LiO3S | 详情 | 详情 | |
| (XXXV) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (XXXVI) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (XXXVII) | 11536 | (4S)-3-((2S,3S,4E)-3-Hydroxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-4-pentenoyl)-4-isopropyl-1,3-oxazolidin-2-one | C29H53NO6Si | 详情 | 详情 | |
| (XXXVIII) | 11537 | (2S,3S,4E)-3-Hydroxy-N-methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-4-pentenamide | C25H49NO5Si | 详情 | 详情 | |
| (XXXIX) | 11538 | (2S,3S,4E)-N-Methoxy-5-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-N,2,4-trimethyl-3-[(triethylsilyl)oxy]-4-pentenamide | C31H63NO5Si2 | 详情 | 详情 | |
| (XL) | 11539 | (2S,3S,4E)-5-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2,4-dimethyl-3-[(triethylsilyl)oxy]-4-pentenal | C29H58O4Si2 | 详情 | 详情 | |
| (XLI) | 11540 | (1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate | 95061-47-5 | C22H20O3 | 详情 | 详情 |
| (XLII) | 11541 | (1S)-2-hydroxy-1,2,2-triphenylethyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C51H78O7Si2 | 详情 | 详情 | |
| (XLIII) | 11542 | methyl (3S,4R,5S,6E)-3-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-5-[(triethylsilyl)oxy]-6-heptenoate | C32H64O6Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The synthesis of the C22-C34 subunit (C12-C16 of the chemical name) of FK-506 has been reported: The condensation of the chiral aldehyde (I) with the (S)-allenyl stannane (II) by means of boron trifluoride ethearate in dichloromethane yields an epimeric mixture of the acetylenic alcohol (III), which by protection with p-methoxybenzyl (PMB) trichloroacetimidate, followed by chromatographic separation, gives the enantiomerically pure protected acetylenic diol (IV). The reduction of (IV) with bis(2-methoxyethoxy)aluminum hydride in THF affords the (E,E)-dienic alcohol (V), which is submitted to a Sharpless asymmetric epoxidation with (-)-diethyl tartrate [(-)-DETR], titanium tetraisopropoxide and tert-butyl hydroperoxide (TBHP) in dichloromethane, yielding the chiral epoxy alcohol (VI). The reduction of (VI) with bis(2-methoxyethoxy)aluminum hydride in THF affords the partially protected triol (VII), which is finally dehydrogenated with dichlorodicyanobenzoquinone (DDQ) in dichloromethane to give the chiral 1,3-dioxane (VIII), which is the desired intermediate.
| 【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 |
|---|---|---|---|---|---|---|
| 63307 | 1,1,1-trichloro-3-(4-methoxyphenyl)-2-propanimine | C10H10Cl3NO | 详情 | 详情 | ||
| (I) | 11534 | (E)-3-[(1R,3R,4R)-3-Methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-2-methyl-2-propenal | C20H38O3Si | 详情 | 详情 | |
| (II) | 11569 | 2-(tributylstannyl)-2,3-pentadienyl pivalate | C22H42O2Sn | 详情 | 详情 | |
| (III) | 11570 | (4R,6E)-5-hydroxy-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-6-hepten-2-ynyl pivalate | C30H54O5Si | 详情 | 详情 | |
| (IV) | 11571 | (4R,5S,6E)-5-[(4-methoxybenzyl)oxy]-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-6-hepten-2-ynyl pivalate | C38H62O6Si | 详情 | 详情 | |
| (V) | 11572 | (2E,4R,5S,6E)-5-[(4-Methoxybenzyl)oxy]-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-2,6-heptadien-1-ol | C33H56O5Si | 详情 | 详情 | |
| (VI) | 11573 | [(2R,3R)-3-((1S,2S,3E)-2-[(4-Methoxybenzyl)oxy]-4-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1,3-dimethyl-3-butenyl)oxiranyl]methanol | C33H56O6Si | 详情 | 详情 | |
| (VII) | 11574 | (3S,4R,5S,6E)-5-[(4-Methoxybenzyl)oxy]-7-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,6-dimethyl-6-heptene-1,3-diol | C33H58O6Si | 详情 | 详情 | |
| (VIII) | 11575 | 2-[(4S,5S,6S)-2-(4-Methoxyphenyl)-6-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-5-methyl-1,3-dioxan-4-yl]-1-ethanol | C33H56O6Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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 |