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【结 构 式】 
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【分子编号】17128 【品名】Methyl (2S)-3-hydroxy-2-methylpropanoate 【CA登记号】72657-23-9 |
【 分 子 式 】C5H10O3 【 分 子 量 】118.1326 【元素组成】C 50.84% H 8.53% O 40.63% |
合成路线1
该中间体在本合成路线中的序号：(I)The intermediate stannane derivative (XVI) has been obtained as follows: The esterification of propynoic acid (XII) with diphenyldiazomethane (XIII) in benzene gives the corresponding ester (XIV), which is then condensed with Me3Sn-Cu(CN)Li (XV) in THF/methanol to yield the desired intermediate (XVI). 3-Hydroxy-2(S)-methylpropionic acid methyl ester (I) is converted into the chiral tosylate (II) by conventional methods. The condensation of (II) with 4-pentenylmagnesium bromide (III) in THF gives the chiral tetrahydropyranyl ether (IV), which is condensed with the phosphonate (V) by means of KHMDS in THF/toluene yielding the chiral nonenoic ester (VI). The reduction of (VI) with DIBAL in the same solvent, followed by protection of the resulting alcohol with TBDPSCl and TEA in dichloromethane affords the protected diol (VII). The selective elimination of the THP protecting group, followed by reaction with TsCl and TEA in dichloromethane affords the tosylate (VIII), which is condensed with lithium acetylide (IX) in DMSO to provide the terminal acetylene (X). The deprotection of (X) with TBAF, followed by reaction with Me3Al, Cp2ZrCl2, and I2 in THF gives the omega iodoundecadienol (XI), which is condensed with the stannane derivative (XVI) by means of PdCl2 in DMF yielding the tetradecatrienoic diphenylmethyl ester (XVII). The chiral epoxidation of (XVII) with Ti(OiPr)4, BuOOH and (R,R)(+)-diisopropyl tartrate (DIPT) in dichloroethane affords the hydroxymethyl-oxirane (XVIII), which is oxidized with tetrapropylammonium perruthenate (TPAP) to provide the oxirane carbaldehyde (XIX).
| 【1】 Bates, R.W.; et al.; Total synthesis of the cholesterol biosynthesis inhibitor 1233A via a (Pi-allyl)tricarbonyliron lactone complex. J Chem Soc - Perkins Trans I 1999, 14, 1917. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 41854 | (2S)-2-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl 4-methylbenzenesulfonate | C17H26O5S | 详情 | 详情 | |
| (III) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (IV) | 41855 | (3R)-3-methyl-8-nonenyl tetrahydro-2H-pyran-2-yl ether; 2-[[(3R)-3-methyl-8-nonenyl]oxy]tetrahydro-2H-pyran | C15H28O2 | 详情 | 详情 | |
| (V) | 41856 | methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate | 88738-78-7 | C7H9F6O5P | 详情 | 详情 |
| (VI) | 41857 | methyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenoate | C17H30O4 | 详情 | 详情 | |
| (VII) | 41858 | tert-butyl[[(Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-10-(tetrahydro-2H-pyran-2-yloxy)-2-decenyl ether | C32H48O3Si | 详情 | 详情 | |
| (VIII) | 41859 | (2R,7Z)-9-[[tert-butyl(diphenyl)silyl]oxy]-2-methyl-7-nonenyl 4-methylbenzenesulfonate | C33H44O4SSi | 详情 | 详情 | |
| (IX) | 17461 | ethynyllithium | C2HLi | 详情 | 详情 | |
| (X) | 41860 | tert-butyl[[(Z,8R)-8-methyl-2-undecen-10-ynyl]oxy]diphenylsilane; tert-butyl(diphenyl)silyl (Z,8R)-8-methyl-2-undecen-10-ynyl ether | C28H38OSi | 详情 | 详情 | |
| (XI) | 41861 | (2Z,8R,10E)-11-iodo-8,10-dimethyl-2,10-undecadien-1-ol | C13H23IO | 详情 | 详情 | |
| (XII) | 10398 | 2-Ethoxy-4-iodo-1-(pentyloxy)benzene; 2-Ethoxy-4-iodophenyl pentyl ether | C13H19IO2 | 详情 | 详情 | |
| (XIII) | 40585 | 1-[diazo(phenyl)methyl]benzene | C13H10N2 | 详情 | 详情 | |
| (XIV) | 41862 | benzhydryl 2-butynoate | C17H14O2 | 详情 | 详情 | |
| (XVI) | 41863 | benzhydryl (E)-3-(trimethylstannyl)-2-butenoate | C20H24O2Sn | 详情 | 详情 | |
| (XVII) | 41864 | benzhydryl (2E,4E,7R,12Z)-14-hydroxy-3,5,7-trimethyl-2,4,12-tetradecatrienoate | C30H38O3 | 详情 | 详情 | |
| (XVIII) | 41865 | benzhydryl (2E,4E,7R)-11-[(2R,3S)-3-(hydroxymethyl)oxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H38O4 | 详情 | 详情 | |
| (XIX) | 41866 | benzhydryl (2E,4E,7R)-11-[(2R,3R)-3-formyloxiranyl]-3,5,7-trimethyl-2,4-undecadienoate | C30H36O4 | 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 intermediate (XV) has been obtained as follows: The reaction of methyl 3-hydroxy-2(S)-methylpropionate (I) with 4-methoxybenzyl trichloroacetimidate gives methyl 3-(4-methoxybenzyloxy)-2(S)-methylpropionate (II), which is reduced with LiAlH4, yielding the primary alcohol (III). The Swern oxidation of (III) affords the aldehyde (IV), which is condensed with the chiral imidazolidinone (V) to provide the adduct (VI). The transamidation of (VI) with N,O-dimethylhydroxylamine by means of Me3Al gives the methoxyamide (VII), which is debenzylated with DDQ to yield the diol (VIII). The reaction of (VIII) with 4-methoxybenzaldehyde diethylacetal (IX) and CSA affords the cyclic ketal (X), which is condensed with the propionyloxazolidinone (XI) by means of dibutylboron triflate to furnish the adduct (XII). The silylation of the OH group of (XII) with Tbdms-OTf gives the silyl ether (XIII), which is reduced at the amide group with LiBH4 to yield the primary alcohol (XIV). Finally, this compound is treated with I2 and PPH3 to afford the intermediate iodo derivative (XV).
| 【1】 Smith, A.B. III; et al.; Gram-scale synthesis of (+)-discodermolide. Org Lett 1999, 1, 11, 1823. |
| 【2】 Smith, A.B. III; et al.; Evolution of a gram-scale synthesis of (+)-discodermolide. J Am Chem Soc 2000, 122, 36, 8654. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42655 | (2R)-3-[(4-methoxybenzyl)oxy]-2-methyl-1-propanol | C12H18O3 | 详情 | 详情 | |
| (IV) | 42656 | (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanal | C12H16O3 | 详情 | 详情 | |
| (V) | 42657 | (4R,5S)-3-[(Z)-1-butoxy-1-propenyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C17H23NO3 | 详情 | 详情 | |
| (VI) | 42658 | (4R,5S)-3-[(2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoyl]-4-methyl-5-phenyl-1,3-oxazolidin-2-one | C25H31NO6 | 详情 | 详情 | |
| (VII) | 42659 | (2R,3S,4S)-3-hydroxy-N-methoxy-5-[(4-methoxybenzyl)oxy]-N,2,4-trimethylpentanamide | C17H27NO5 | 详情 | 详情 | |
| (VIII) | 42660 | (2R,3S,4S)-3,5-dihydroxy-N-methoxy-N,2,4-trimethylpentanamide | C9H19NO4 | 详情 | 详情 | |
| (IX) | 35670 | 1-(diethoxymethyl)-4-methoxybenzene; 4-(diethoxymethyl)phenyl methyl ether | C12H18O3 | 详情 | 详情 | |
| (X) | 42661 | (2R)-N-methoxy-2-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-N-methylpropanamide | C17H25NO5 | 详情 | 详情 | |
| (XI) | 10968 | (4R)-3-Acetyl-4-benzyl-1,3-oxazolidin-2-one; (R)-(-)-3-Acetyl-4-benzyl-2-oxazolidinone | 184363-65-3 | C12H13NO3 | 详情 | 详情 |
| (XII) | 42662 | (4R)-4-benzyl-3-[(2R,3S,4S)-3-hydroxy-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C28H35NO7 | 详情 | 详情 | |
| (XIII) | 42663 | (4R)-4-benzyl-3-[(2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methylpentanoyl]-1,3-oxazolidin-2-one | C34H49NO7Si | 详情 | 详情 | |
| (XIV) | 42664 | (2S,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]-2-methyl-1-pentanol | C24H42O5Si | 详情 | 详情 | |
| (XV) | 42665 | tert-butyl(dimethyl)silyl (1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl ether; tert-butyl[((1S,2R)-3-iodo-1-[(1R)-1-[(4S,5S)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2-methylpropyl)oxy]dimethylsilane | C24H41IO4Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Chiral 5-oxohexanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with benzyl trichloroacetimidate gives the benzyl ether (II), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (III). The reaction of (III) with (c-hexyl)2B-Cl ad TEA affords the boron enolate (IV), which is condensed with acetaldehyde to provide the intermediate boron aldolate (V). The reduction of (V) with LiBH4 and H2O2 in aqueous methanol gives the chiral diol (VI), which is silylated by means of Tbdms-OTf to yield the bis-silyl ether (VII). The selective deprotection of (VII) by means of CSA in methanol/dichloromethane affords the alcohol (VIII), which is debenzylated by means of H2 over Pd/C in ethanol to provide the diol (IX). The oxidation of (IX) with (COCl)2 and DMSO in dichloromethane gives the intermediate oxoaldehyde that is oxidized with NaClO2 to yield the 5-oxohexanoic acid (X). Finally, this compound is methylated with diazomethane in ethyl ether to afford the target, chiral 5-oxohexanoic ester intermediate (XI).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 62835 | methyl (2S)-3-(benzyloxy)-2-methylpropanoate | C12H16O3 | 详情 | 详情 | |
| (III) | 42633 | (2S)-1-(benzyloxy)-2-methyl-3-pentanone | C13H18O2 | 详情 | 详情 | |
| (IV) | 62836 | (E)-1-[(1S)-2-(benzyloxy)-1-methylethyl]-1-propenyl dicyclohexylborinate | C25H39BO2 | 详情 | 详情 | |
| (V) | 62837 | C27H43BO3 | 详情 | 详情 | ||
| (VI) | 42635 | (2S,3S,4R,5S)-6-(benzyloxy)-3,5-dimethyl-2,4-hexanediol | C15H24O3 | 详情 | 详情 | |
| (VII) | 42636 | benzyl (2S,3R,4S,5S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethylhexyl ether; (5R,6S,7S)-5-[(1S)-2-(benzyloxy)-1-methylethyl]-2,2,3,3,6,7,9,9,10,10-decamethyl-4,8-dioxa-3,9-disilaundecane | n/a | C27H52O3Si2 | 详情 | 详情 |
| (VIII) | 42637 | (2S,3S,4R,5S)-6-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3,5-dimethyl-2-hexanol | n/a | C21H38O3Si | 详情 | 详情 |
| (IX) | 42638 | (2S,3R,4S,5S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1,5-hexanediol | C14H32O3Si | 详情 | 详情 | |
| (X) | 42639 | (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoic acid | C14H28O4Si | 详情 | 详情 | |
| (XI) | 42640 | methyl (2R,3S,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-5-oxohexanoate | C15H30O4Si | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Synthesis of the target (+)-Discodermolide: The reaction of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with p-methoxybenzyl trichloroacetimidate gives the benzyl ether (XXVI), which is condensed with ethylmagnesium bromide in THF to yield the chiral ketone (XXVII). The reaction of (XXVII) with 2-methylpropenal (XXVIII) by means of (c-Hex)2B-Cl and TEA in ethyl ether affords the chiral hydroxyketone (XXIX), which is reduced with SmI2 and propanal to provide the beta-diol monoester (XXX). The methanolysis of (XXX) by means of K2CO3 furnishes the diol (XXXI), which can also be obtained directly by reduction of (XXIX) with Me4NBH(OAc)3 in acetonitrile/AcOH. The reaction of (XXXI) with the diethylacetal (XXXII) and PPTS in refluxing toluene gives the phenylselenoacetal (XXXIII), which is oxidized with NaIO4 and treated with DBU to achieve a Claisen rearrangement and yield the eight member lactone (XXXIV). The hydrolysis of (XXXIV) with KOH in refluxing aqueous methanol affords the hydroxyacid (XXXV), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP in dichloromethane to provide the phenyl ester (XXXVII). The reaction of (XXXVII) with Tbdms-OTf and lutidine gives the silylated ester (XXXVIII). Alternatively, the methanolysis of the lactone (XXXIV) with NaOMe in methanol gives the hydroxyester (XXXIX), which is treated with Tbdms-OTf as before to yield the silylated ester (XL). The hydrolysis of the ester (XL) with KOH in refluxing aqueous methanol affords the silylated hydroxyacid (XLI), which is esterified with 2,6-dimethylphenol (XXXVI) by means of DCC and DMAP to provide the already reported phenyl ester (XXXVIII).
| 【1】 Paterson, I.; Florence, G.J.; Gerlach, K.; Scott, J.P.; Sereinig, N.; A practical synthesis of (+)-discodermolide and analogues: Fragment union by complex aldol reactions. J Am Chem Soc 2001, 123, 39, 9535. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (XXVI) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (XXVII) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (XXVIII) | 11387 | 2-Methylacrylaldehyde; Methacrylaldehyde | 78-85-3 | C4H6O | 详情 | 详情 |
| (XXIX) | 42615 | (2S,4S,5R)-5-hydroxy-1-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-6-hepten-3-one | C18H26O4 | 详情 | 详情 | |
| (XXX) | 62842 | (1R)-1-{(1R,2S,3S)-2-hydroxy-4-[(4-methoxybenzyl)oxy]-1,3-dimethylbutyl}-2-methyl-2-propenyl butyrate | C22H34O5 | 详情 | 详情 | |
| (XXXI) | 62843 | (3R,4R,5S,6S)-7-[(4-methoxybenzyl)oxy]-2,4,6-trimethyl-1-heptene-3,5-diol | C18H28O4 | 详情 | 详情 | |
| (XXXII) | 62844 | 1-[(2,2-dipropoxyethyl)selanyl]benzene; 2-(phenylselanyl)-1-propoxyethyl propyl ether | C14H22O2Se | 详情 | 详情 | |
| (XXXIII) | 42618 | (4R,5S,6S)-4-isopropenyl-6-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxane; (2S)-2-[(4S,5S,6R)-6-isopropenyl-5-methyl-2-[(phenylselanyl)methyl]-1,3-dioxan-4-yl]propyl 4-methoxybenzyl ether | C26H34O4Se | 详情 | 详情 | |
| (XXXIV) | 42620 | (7S,8R)-8-[(1S)-2-[(4-methoxybenzyl)oxy]-1-methylethyl]-5,7-dimethyl-3,4,7,8-tetrahydro-2H-oxocin-2-one | C20H28O4 | 详情 | 详情 | |
| (XXXV) | 62845 | (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C20H30O5 | 详情 | 详情 | |
| (XXXVI) | 37388 | 2,6-dimethylphenol | 576-26-1 | C8H10O | 详情 | 详情 |
| (XXXVII) | 62847 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C28H38O5 | 详情 | 详情 | |
| (XXXVIII) | 42622 | 2,6-dimethylphenyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C34H52O5Si | 详情 | 详情 | |
| (XXXIX) | 62846 | methyl (Z,6S,7R,8S)-7-hydroxy-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C21H32O5 | 详情 | 详情 | |
| (XL) | 42621 | methyl (Z,6S,7R,8S)-7-[[tert-butyl(dimethyl)silyl]oxy]-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoate | C27H46O5Si | 详情 | 详情 | |
| (XLI) | 62848 | (Z,6S,7R,8S)-7-{[tert-butyl(dimethyl)silyl]oxy}-9-[(4-methoxybenzyl)oxy]-4,6,8-trimethyl-4-nonenoic acid | C26H44O5Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Synthesis of the chiral 5-oxopentanoic ester intermediate (XI): The reaction of 3-hydroxy-2(S)-methylpentanoic acid methyl ester (I) with 4-methoxybenzyl trichloroacetimidate gives the aryl ether (II), which is treated with ethylmagnesium bromide to yield the ketone (III). The condensation of (III) with formaldehyde by means of (c-Hex)2B-Cl and H2O2 affords the hydroxypentanone (IV), which is reduced by means of NaBH(OAc)3 in THF/AcOH to provide the diol (V). The regioselective oxidation of the primary alcohol of (V) with TEMPO and BAIB in dichloromethane gives the beta-hydroxyaldehyde (VI), which is further oxidized with NaClO2 yielding the carboxylic acid (VII). The esterification of (VII) by means of Me-I and K2CO3, or with TMS-CHN2 affords the methyl ester (VIII), which is treated with Tbdms-OTf and lutidine to provide the silyl ether (IX). The selective deprotection of (IX) by means of DDQ in dichloromethane furnishes the omega-hydroxyester (X), which is finally submitted to a Swern oxidation to yield the chiral 5-oxopentanoic ester intermediate (XI).
| 【1】 Paterson, I.; Delgado, O.; Florence, G.J.; Lyothier, I.; Scott, J.P.; Sereinig, N.; 1,6-asymmetric induction in boron-mediated aldol reactions: Application to a practical total synthesis of (+)-discodermolide. Org Lett 2003, 5, 1, 35. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42654 | methyl (2S)-3-[(4-methoxybenzyl)oxy]-2-methylpropanoate | C13H18O4 | 详情 | 详情 | |
| (III) | 42614 | (2S)-1-[(4-methoxybenzyl)oxy]-2-methyl-3-pentanone | C14H20O3 | 详情 | 详情 | |
| (IV) | 62852 | (2S,4S)-1-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-3-pentanone | C15H22O4 | 详情 | 详情 | |
| (V) | 62853 | (2S,3R,4S)-5-[(4-methoxybenzyl)oxy]-2,4-dimethyl-1,3-pentanediol | C15H24O4 | 详情 | 详情 | |
| (VI) | 62854 | (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanal | C15H22O4 | 详情 | 详情 | |
| (VII) | 62855 | (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoic acid | C15H22O5 | 详情 | 详情 | |
| (VIII) | 62856 | methyl (2R,3S,4S)-3-hydroxy-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate | C16H24O5 | 详情 | 详情 | |
| (IX) | 62857 | methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(4-methoxybenzyl)oxy]-2,4-dimethylpentanoate | C22H38O5Si | 详情 | 详情 | |
| (X) | 62858 | methyl (2R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxy-2,4-dimethylpentanoate | C14H30O4Si | 详情 | 详情 | |
| (XI) | 62859 | methyl (2R,3S,4R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2,4-dimethyl-5-oxopentanoate | C14H28O4Si | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VIII)The nitrile (III), a chiral key intermediate of this synthesis, can be obtained by two different synthetic routes as follows: Route-b: The starting material of this route is methyl (S)-3-hydroxy-2-methylpropionate (VIII), which contains one additional carbon between the hydroxyl group and the 2-position carbon of (R)-lactate, the starting material of route-a. The hydroxyl group of (VIII) is protected by triphenylmethyl group. Then, 2,4-difluorophenyl moiety is introduced to give the ketone (X). Direct conversion of the ketone (X) to the oxirane (XIV) by dimethylsulfoxonium methylide, the same condition for compound (IV) in route-a, does not proceed. The oxirane (XIV) having desired stereochemistry is obtained via oxidation reaction. The ketone (X) is converted to the exomethylene (XI) by Wittig reaction. The stereoselective oxidation of (XI) is achieved by means of osmium tetroxide in the presence of 4-methylmorpholine N-oxide to give the diol (XII) in 58% yield after separation of its epimer by column chromatography. After methanesulfonylation of the primary alcohol of (XII), a triazole moiety is introduced and the triphenylmethyl group is deprotected. Then, the primary hydroxyl group of (XVI) is oxidized under Swern oxidation condition to give the aldehyde (XVII), which is converted to the chiral nitrile intermediate (III) by means of heating with hydroxylamine-O-sulfonic acid.
| 【1】 Saji, I.; Tamoto, K.; Tanaka, Y.; Fujimoto, K.; Ohashi, N.; Stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl)-2-butanol (SM-8668). Bull Chem Soc Jpn 1994, 67, 1427-33. |
| 【2】 Konos, T.; Miyaoka, T.; Tajima, Y.; Oida, S.; Triazole antifungals. III. Stereocontrolled synthesis of an optically active triazolylmethyloxirane precursor to antifungal oxazolodine derivatives. Chem Pharm Bull 1991, 39, 9, 2241. |
| 【3】 Naito, T.; Hata, K.; Tsuruoka, A.; ER-30346. Drugs Fut 1996, 21, 1, 20. |
| 【4】 Tasaka, A.; Tamura, N.; Matsushita, Y.; Teranishi, K.; Hayashi, R.; Okonogi, K.; Itoh, K.; Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol and stereoisomers. Chem Pharm Bull 1993, 41, 6, 1035-42. |
| 【5】 Naito, T.; Hata, K.; Kaku, Y.; Tsuruoka, A.; Tsukada, I.; Yanagisawa, M.; Toyosawa, T.; Nara, K. (Eisai Co., Ltd.); Azole antifungal agents, process for the preparation thereof and intermediates. CA 2141731; EP 0667346; JP 1995223950; JP 1996020578; JP 1996053426; US 5648372; US 5789429; US 5792781 . |
| 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) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 | |
| (VIII) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (IX) | 17129 | Methyl (2S)-2-methyl-3-(trityloxy)propanoate | C24H24O3 | 详情 | 详情 | |
| (X) | 17130 | (2S)-1-(2,4-difluorophenyl)-2-methyl-3-(trityloxy)-1-propanone | C29H24F2O2 | 详情 | 详情 | |
| (XI) | 17131 | (2R)-3-(2,4-difluorophenyl)-2-methyl-3-butenyl trityl ether; 2,4-difluoro-1-[1-[(1R)-1-methyl-2-(trityloxy)ethyl]vinyl]benzene | C30H26F2O | 详情 | 详情 | |
| (XII) | 17132 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(trityloxy)-1,2-butanediol | C30H28F2O3 | 详情 | 详情 | |
| (XIII) | 17133 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-4-(trityloxy)-2-butanol | C33H34F2O3S | 详情 | 详情 | |
| (XIV) | 17134 | (2R)-2-(2,4-difluorophenyl)-2-[(1S)-1-methyl-2-(trityloxy)ethyl]oxirane; (2S)-2-[(2R)-2-(2,4-difluorophenyl)oxiranyl]propyl trityl ether | C30H26F2O2 | 详情 | 详情 | |
| (XV) | 17135 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-(trityloxy)-2-butanol | C32H29F2N3O2 | 详情 | 详情 | |
| (XVI) | 17136 | (2S,3R)-3-(2,4-difluorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol | C13H15F2N3O2 | 详情 | 详情 | |
| (XVII) | 17137 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanal | C13H13F2N3O2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The synthesis of (2S,3S)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1,2,4-triazol-1-yl)butyronitrile (XV), a key intermediate the synthesis of ER-30346 has been described: The tritylation of 3-hydroxy-2(S)-methylpropionic acid methyl ester (I) with trityl chloride in hot pyridine gives the trityl ether (II), which is hydrolyzed with LiOH in H2O/THF/methanol yielding the free acid (III). The esterification of (III) with 2-mercaptopyridine (IV) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane gives the thioester (V), which is treated with 2,4-difluorophenylmagnesium bromide (VI) in THF yielding the propiophenone (VII), which by treatment with methyltriphenylphosphonium bromide/NaH in THF is converted into the methylene derivative (VIII). The oxidation of (VIII) with OsO4 and N-methylmorpholine oxide in acetone affords, after column chromatography, the chiral diol (IX), which is monomesylated with mesyl chloride/triethylamine in dichlormethane giving the monoester (X). The reaction of (X) with 1,2,4-triazol (XI) and NaH in DMF yields (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1,2,4-triazol-1-yl)-4-(triphenylmethoxy)-2-butanol (XII), which is detritylated with p-toluenesulfonic acid in methanol affording the diol (XIII). The oxidation of (XIII) with oxalyl chloride/DMSO in dichloromethane gives the aldehyde (XIV), which is finally treated with hydroxylamine-O-sulfonic acid in water yielding the desired bytyronitrile intermediate (XV) already referenced.
| 【1】 Kaku, Y.; et al.; A novel route for chiral synthesis of the triazole antifungal ER-30346. Chem Pharm Bull 1998, 46, 7, 1125. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 17129 | Methyl (2S)-2-methyl-3-(trityloxy)propanoate | C24H24O3 | 详情 | 详情 | |
| (III) | 20259 | (2S)-2-methyl-3-(trityloxy)propionic acid | C23H22O3 | 详情 | 详情 | |
| (IV) | 20260 | 2-Mercaptopyiridine; 2-pyridinethiol; 2-pyridinylhydrosulfide | 2637-34-5 | C5H5NS | 详情 | 详情 |
| (V) | 20261 | S-(2-pyridinyl) (2S)-2-methyl-3-(trityloxy)propanethioate | C28H25NO2S | 详情 | 详情 | |
| (VI) | 20262 | bromo(2,4-difluorophenyl)magnesium | C6H3BrF2Mg | 详情 | 详情 | |
| (VII) | 17130 | (2S)-1-(2,4-difluorophenyl)-2-methyl-3-(trityloxy)-1-propanone | C29H24F2O2 | 详情 | 详情 | |
| (VIII) | 17131 | (2R)-3-(2,4-difluorophenyl)-2-methyl-3-butenyl trityl ether; 2,4-difluoro-1-[1-[(1R)-1-methyl-2-(trityloxy)ethyl]vinyl]benzene | C30H26F2O | 详情 | 详情 | |
| (IX) | 17132 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-4-(trityloxy)-1,2-butanediol | C30H28F2O3 | 详情 | 详情 | |
| (X) | 20266 | (2R,3S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methyl-4-(trityloxy)butyl methanesulfonate | C31H30F2O5S | 详情 | 详情 | |
| (XI) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (XII) | 17135 | (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)-4-(trityloxy)-2-butanol | C32H29F2N3O2 | 详情 | 详情 | |
| (XIII) | 17136 | (2S,3R)-3-(2,4-difluorophenyl)-2-methyl-4-(1H-1,2,4-triazol-1-yl)-1,3-butanediol | C13H15F2N3O2 | 详情 | 详情 | |
| (XIV) | 17137 | (2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanal | C13H13F2N3O2 | 详情 | 详情 | |
| (XV) | 17123 | (2S,3R)-3-(2,4-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butanenitrile | C13H12F2N4O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Protection of (S)-3-hydroxy-2-methylpropionic acid methyl ester (I) as the corresponding silyl ether, followed by reduction with DIBAL provides the aldehyde (II). Diastereoselective aldol condensation of (II) with the chiral N-propionyl oxazolidinone (III) in the presence of dibutylboron triflate leads to adduct (IV), which is then reduced with LiBH4 to give the diol (V). The diol (V) is protected as the cyclic ketal (VII) by treatment with anisaldehyde dimethylacetal (VI) in the presence of pyridinium p-toluenesulfonate (PPTS). Desilylation of (VII) using tetrabutylammonium fluoride yields the alcohol (VIII). Subsequent iodination of (VIII) with I2/PPh3, followed by displacement of alkyl iodide (IX) with PPh3 in refluxing benzene, furnishes the phosphonium salt (X).
| 【1】 Choy, N.; Shin, Y.; Nguyen, P.Q.; Curran, D.P.; Balachandran, R.; Madiraju, C.; Day, B.W.; Simplified discodermolide analogues: Synthesis and biological evaluation of 4-epi-7-dehydroxy-14,16-didemethyl-(+)-discodermolides as microtubule-stabilizing agents. J Med Chem 2003, 46, 14, 2846. |
| 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) | 17128 | Methyl (2S)-3-hydroxy-2-methylpropanoate | 72657-23-9 | C5H10O3 | 详情 | 详情 |
| (II) | 42624 | (2S)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-methylpropanal | C10H22O2Si | 详情 | 详情 | |
| (III) | 25713 | (4S)-4-benzyl-3-propionyl-1,3-oxazolidin-2-one | C13H15NO3 | 详情 | 详情 | |
| (IV) | 64732 | 3-(5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-hydroxy-2,4-dimethylpentanoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one | C23H37NO5Si | 详情 | 详情 | |
| (V) | 64733 | 5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2,4-dimethyl-1,3-pentanediol | C13H30O3Si | 详情 | 详情 | |
| (VI) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (VII) | 64734 | (1,1-dimethylethyl)(dimethyl)[(2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)oxy]silane; (1,1-dimethylethyl)(dimethyl)silyl 2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl ether | C21H36O4Si | 详情 | 详情 | |
| (VIII) | 64735 | 2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}-1-propanol | C15H22O4 | 详情 | 详情 | |
| (IX) | 64736 | 4-(2-iodo-1-methylethyl)-5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxane; 4-[4-(2-iodo-1-methylethyl)-5-methyl-1,3-dioxan-2-yl]phenyl methyl ether | C15H21IO3 | 详情 | 详情 | |
| (X) | 64737 | (2-{5-methyl-2-[4-(methyloxy)phenyl]-1,3-dioxan-4-yl}propyl)(triphenyl)phosphonium iodide | C33H36IO3P | 详情 | 详情 |