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【结 构 式】 
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【分子编号】39424 【品名】bromo(4-pentenyl)magnesium 【CA登记号】 |
【 分 子 式 】C5H9BrMg 【 分 子 量 】173.33546 【元素组成】C 34.65% H 5.23% Br 46.1% Mg 14.02% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(XXXIV)C17-C27 Fragment: The monotosylation of 2,2-dimethylpropane-1,3-diol (XXIX) with TsCl and pyridine in CH2Cl2 gives the monotosylate (XXX), which is condensed with thiophenol by means of NaH in hot DMF yielding the phenylsulfanyl derivative (XXXI). The oxidation of (XXXI) with MCPBA in dichloromethane affords the corresponding sulfone (XXXII), which is oxidized with oxalyl chloride in DMSO to give the aldehyde (XXXIII). The Grignard reaction of (XXXIII) with 4-pentenylmagnesium bromide (XXXIV) in ethyl ether/CH2Cl2 yields the secondary alcohol (XXXV), which is oxidized with oxalyl chloride in DMSO to the ketone (XXXVI). The dihydroxylation of the double bond of (XXXVI) with K2OsO4 in t-BuOH/H2O followed by oxidation with NaIO4 in t-BuOH/H2O/THF affords the keto aldehyde (XXXVII), which is condensed with the chiral butanone (XXXVIII) by means of (-)-diisopinocampheyl chloride ((-)-DIP-Cl) and Et3N in dichloromethane to give aldol (XXXIX). The SmI2 catalyzed Tishchenko reduction of (XXXIX) in the presence of 4-nitrobenzaldehyde yields the diastereomerically pure 4-nitrobenzoate (XL), which is silylated with TBDMS-OTf to afford the protected ketone (XLI). The hydrolysis of the 4-nitrobenzoate group of (XLI) with LiOH in THF/MeOH/H2O gives the alcohol (XLII), which is cyclized by means of camphorsulfonic acid (CSA) in refluxing benzene yielding the dihydropyran (XLIII), the desired C17-C27 fragment. The intermediate, the chiral butanone (XXXVIII) has been obtained as follows: The optical resolution of 3-methyl-4-phenyl-3-buten-2-ol (XLIV) with (+)-DIPT gives the (R)-isomer (XLV), which is protected with p-methoxybenzyl bromide and NaH yielding the benzyl ether (XLVI). Finally, (XLVI) is ozonolyzed with O3 in MeOH / CH2Cl2 dichloromethane to afford the desired intermediate (XXXVIII).
| 【1】 Lautens, M.; Prunet, J.A.; Carreira, E.M.; Carter, P.H.; Charette, A.B.; Evans, D.A.; Total synthesis of bryostatin 2. J Am Chem Soc 1999, 121, 33, 7540. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIX) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (XXX) | 39420 | 3-hydroxy-2,2-dimethylpropyl 4-methylbenzenesulfonate | C12H18O4S | 详情 | 详情 | |
| (XXXI) | 39421 | 2,2-dimethyl-3-(phenylsulfanyl)-1-propanol | C11H16OS | 详情 | 详情 | |
| (XXXII) | 39422 | 2,2-dimethyl-3-(phenylsulfonyl)-1-propanol | C11H16O3S | 详情 | 详情 | |
| (XXXIII) | 39423 | 2,2-dimethyl-3-(phenylsulfonyl)propanal | C11H14O3S | 详情 | 详情 | |
| (XXXIV) | 39424 | bromo(4-pentenyl)magnesium | C5H9BrMg | 详情 | 详情 | |
| (XXXV) | 39425 | 2,2-dimethyl-1-(phenylsulfonyl)-7-octen-3-ol | C16H24O3S | 详情 | 详情 | |
| (XXXVI) | 39426 | 2,2-dimethyl-1-(phenylsulfonyl)-7-octen-3-one | C16H22O3S | 详情 | 详情 | |
| (XXXVII) | 39427 | 6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptanal | C15H20O4S | 详情 | 详情 | |
| (XXXVIII) | 39428 | (3R)-3-[(4-methoxybenzyl)oxy]-2-butanone | C12H16O3 | 详情 | 详情 | |
| (XXXIX) | 39429 | (7S,10R)-7-hydroxy-10-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1-(phenylsulfonyl)-3,9-undecanedione | C27H36O7S | 详情 | 详情 | |
| (XL) | 39430 | (1S)-1-[(2R,3R)-2-hydroxy-3-[(4-methoxybenzyl)oxy]butyl]-6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptyl 4-nitrobenzoate | C34H41NO10S | 详情 | 详情 | |
| (XLI) | 39431 | (1S)-1-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-6,6-dimethyl-5-oxo-7-(phenylsulfonyl)heptyl 4-nitrobenzoate | C40H55NO10SSi | 详情 | 详情 | |
| (XLII) | 39432 | (7S,9R,10R)-9-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-10-[(4-methoxybenzyl)oxy]-2,2-dimethyl-1-(phenylsulfonyl)-3-undecanone | C33H52O7SSi | 详情 | 详情 | |
| (XLIII) | 39433 | tert-butyl([(1R,2R)-1-([(2S)-6-[1,1-dimethyl-2-(phenylsulfonyl)ethyl]-3,4-dihydro-2H-pyran-2-yl]methyl)-2-[(4-methoxybenzyl)oxy]propyl]oxy)dimethylsilane; 2-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-2-methylpropyl phenyl sulfone | C33H50O6SSi | 详情 | 详情 | |
| (XLIV) | 39434 | (E)-3-methyl-4-phenyl-3-buten-2-ol | C11H14O | 详情 | 详情 | |
| (XLV) | 39435 | (2R,3E)-3-methyl-4-phenyl-3-buten-2-ol | C11H14O | 详情 | 详情 | |
| (XLVI) | 39436 | (1R,2E)-1,2-dimethyl-3-phenyl-2-propenyl 4-methoxybenzyl ether; 1-([[(1R,2E)-1,2-dimethyl-3-phenyl-2-propenyl]oxy]methyl)-4-methoxybenzene | C19H22O2 | 详情 | 详情 |