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【结 构 式】 
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【分子编号】39433 【品名】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 【CA登记号】 |
【 分 子 式 】C33H50O6SSi 【 分 子 量 】602.9079 【元素组成】C 65.74% H 8.36% O 15.92% S 5.32% Si 4.66% |
合成路线1
该中间体在本合成路线中的序号：(XLIII)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 |
合成路线2
该中间体在本合成路线中的序号：(XLIII)Fragment coupling: Coupling of the C10-C16 fragment (XXVIII) with the C17-C27 fragment (XLIII) by means of BuLi, Ac2O and Mg in THF gives (XLVII), which is selectively deprotected with TBAF yielding the carbinol (XLVIII). The reaction of (XLVIII) with triflic anhydride and lutidine in CH2Cl2 affords the triflate (IL), which is coupled with the C1-C9 fragment (XVIII) by means of n-BuLi in THF giving the tricyclic intermediate (L). The opening of the lactol ring of (L) with triethylsilyl chloride and imidazole yields the silylated hydroxyketone (LI), which is treated first with tert-butoxycarbonyl anhydride and then with the lithium salt of benzyl alcohol in order to convert the phenylcarboxamide of (LI) into the benzyl ester (LII). The epoxidation of the dihydropyran double bond of (LII) with MCPBA followed by epoxide opening with MeOH and oxidation of the resulting alcohol with DMP in CH2Cl2 gives the oxoketal (LIII).
| 【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 |
|---|---|---|---|---|---|---|
| 40733 | lithium phenylmethanolate | C7H7LiO | 详情 | 详情 | ||
| (IL) | 39439 | [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methyl trifluoromethanesulfonate | C41H69F3O9SSi2 | 详情 | 详情 | |
| (XXVIII) | 39419 | (2R,4R,6S)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-([[tert-butyl(dimethyl)silyl]oxy]methyl)tetrahydro-2H-pyran-2-carbaldehyde | C19H40O4Si2 | 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 | |
| (XLVII) | 39437 | tert-butyl(dimethyl)silyl [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methyl ether; tert-butyl([(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methoxy)dimethylsilane | C46H84O7Si3 | 详情 | 详情 | |
| (XLVIII) | 39438 | [(2S,4S,6R)-4-[[tert-butyl(dimethyl)silyl]oxy]-6-[(E)-3-((2S)-2-[(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(4-methoxybenzyl)oxy]butyl]-3,4-dihydro-2H-pyran-6-yl)-3-methyl-1-butenyl]tetrahydro-2H-pyran-2-yl]methanol | C40H70O7Si2 | 详情 | 详情 | |
| (L) | 39440 | C71H115NO12Si3 | 详情 | 详情 | ||
| (LI) | 39441 | C77H129NO12Si4 | 详情 | 详情 | ||
| (LII) | 39442 | C78H130O13Si4 | 详情 | 详情 | ||
| (LIII) | 39443 | C79H132O15Si4 | 详情 | 详情 |