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【结 构 式】 
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【分子编号】11535 【品名】(4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one 【CA登记号】77877-19-1 |
【 分 子 式 】C9H15NO3 【 分 子 量 】185.22304 【元素组成】C 58.36% H 8.16% N 7.56% O 25.91% |
合成路线1
该中间体在本合成路线中的序号：(XXXVI)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)Boron-catalyzed condensation of propionyl oxazolidinone (I) with acrolein (II) stereoselectively provided the aldol product (III), and further methanolysis afforded beta-hydroxy ester (IV). A second aldol condensation of (IV) with methacrolein (V) furnished a difficultly separable mixture of diols (VI). Conversion of (VI) to the corresponding acetonides by treatment with 2-methoxypropene (VII) allowed chromatographical separation of the required major isomer (VIII). Hydrolysis of the acetonide, followed by ring-closing metathesis of diene (XI) in the presence of Grubbs catalyst gave rise to cyclopentene (XII). Selective silylation of the less hindered allylic hydroxyl of (XII) with tert-butyldimethylsilyl chloride yielding (XIII) and subsequent oxidation of the remaining alcohol group with MnO2 then provided ketone (XIV). Conjugate addition of lithium di-n-butylcuprate to the unsaturated ketone, followed by phenylselenylation of the intermediate enolate with PhSeBr yielded alpha-selenyl ketone (XV). Oxidative elimination of the phenylselenyl group gave a (1:1) mixture of the required unsaturated ketone (XVII) and its exomethylene isomer (XVI). Isomerization of (XVI) to the desired endo isomer (XVII) was carried out by treatment with RhCl3.
| 【1】 Sunazuka, T.; et al.; Total synthesis of (+)-madindoline A and (-)-madindoline B, potent, selective inhibitors of interleukin 6. Determination of the relative and absolute configurations. J Am Chem Soc 2000, 122, 9, 2122. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIa) | 36695 | methyl (2R,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (VIb) | 36696 | methyl (2S,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (VIc),(XI) | 36697 | methyl (2S,3S)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate | C11H18O4 | 详情 | 详情 | |
| (I) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 36693 | (4S)-3-[(2S,3R)-3-hydroxy-2-methyl-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one | C12H19NO4 | 详情 | 详情 | |
| (IV) | 36694 | methyl (2S,3R)-3-hydroxy-2-methyl-4-pentenoate | C7H12O3 | 详情 | 详情 | |
| (V) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (VII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VIII) | 36698 | methyl (4S,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (IX) | 36699 | methyl (4R,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (X) | 36700 | methyl (4R,5S,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate | C14H22O4 | 详情 | 详情 | |
| (XII) | 36701 | methyl (1S,2S,5R)-2,5-dihydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate | C9H14O4 | 详情 | 详情 | |
| (XIII) | 36702 | methyl (1R,2S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate | C15H28O4Si | 详情 | 详情 | |
| (XIV) | 36703 | methyl (1S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-cyclopentene-1-carboxylate | C15H26O4Si | 详情 | 详情 | |
| (XV) | 36704 | methyl (1S,5R)-4-butyl-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-(phenylselanyl)cyclopentanecarboxylate | C25H40O4SeSi | 详情 | 详情 | |
| (XVI) | 36705 | methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-methylene-5-oxocyclopentanecarboxylate | C19H34O4Si | 详情 | 详情 | |
| (XVII) | 36706 | methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1,4-dimethyl-5-oxo-3-cyclopentene-1-carboxylate | C19H34O4Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)The intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII) has been obtained as follows: The reaction of 4(S)-isopropyloxazolidin-2-one (XIX) with propionyl chloride (XX) by means of BuLi in THF gives 4(S)-isopropyl-3-propionyloxazolidin-2-one (XXI), which is condensed with benzyl bromide (XXII) by means of LHMDS in THF yielding 4(S)-isopropyl-3-(2(R)-methyl-3-phenylpropionyl)oxazolidin-2-one (XXIII). The oxidative cleavage of (XXIII) with H2O2 in THF/water affords 2(R)-methyl-3-phenylpropionic acid (XXIV), which is hydrogenated with H2 over alumina providing 3-cyclohexyl-2(R)-methylpropionic acid (XXV). Finally, this compound is treated with oxalyl chloride in DMF to afford the desired intermediate 3-cyclohexyl-2(R)-methylpropionyl chloride (XVIII).
| 【1】 Gauthier, J.-A.; Moss, N. (Bio-Mega, Inc.; Boehringer Ingelheim GmbH); Herpes ribonucleotide reductase inhibitors. EP 0837845; JP 1999508246; US 5672586; WO 9700855 . |
| 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) | 27157 | (2R)-3-cyclohexyl-2-methylpropanoyl chloride | C10H17ClO | 详情 | 详情 | |
| (XIX) | 12867 | (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone | 17016-83-0 | C6H11NO2 | 详情 | 详情 |
| (XX) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (XXI) | 11535 | (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one | 77877-19-1 | C9H15NO3 | 详情 | 详情 |
| (XXII) | 12912 | 1-(Bromomethyl)benzene; Alpha-bromotoluene | 100-39-0 | C7H7Br | 详情 | 详情 |
| (XXIII) | 27167 | (4S)-4-isopropyl-3-[(2R)-2-methyl-3-phenylpropanoyl]-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (XXIV) | 27168 | (2R)-2-methyl-3-phenylpropionic acid | C10H12O2 | 详情 | 详情 | |
| (XXV) | 27169 | (2R)-3-cyclohexyl-2-methylpropionic acid | C10H18O2 | 详情 | 详情 |