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【结 构 式】 
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【分子编号】43864 【品名】(1S,3S,5S,6R,10S,11S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-12-oxo-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-7,14-dien-7-yl trifluoromethanesulfonate 【CA登记号】 |
【 分 子 式 】C37H53F3O9SSi 【 分 子 量 】758.9691296 【元素组成】C 58.55% H 7.04% F 7.51% O 18.97% S 4.22% Si 3.7% |
合成路线1
该中间体在本合成路线中的序号：(XXXV)Hydrogenation of (XXI) with H2 over Pd/C in ethanol gives the triol (XXII), which is treated with benzaldehyde dimethyl acetal and camphorsulfonic acid (CSA) in dichloromethane yielding the cyclic ketal (XXIII). The cyclopropanation of (XXIII) with chloro(iodo)methane and Et2Zn in toluene affords compound (XXIV), which is oxidized with Dess-Martin periodinane (DMPI) in dichloromethane providing the ketonic compound (XXV). The deproctection of (XXV) with H2 over Pd(OH)2 in ethanol in order to remove the benzylidene ketal group, followed by reaction with triphosgene in order to form a cyclic carbonate and finally selective desilylation of the cyclic silyl ether with TBAF, furnishes diol (XXVI). The protection of the diol moiety of (XXVI) with benzaldehyde dimethylacetal, followed by cleavage of the cyclic carbonate with K2CO3 in methanol provides the diol (XXVII), which is submitted to cyclopropane ring-opening with SmI2 and TBAF in THF giving the enol (XXVIII). Enol-keto isomerization of (XXVIII) by treatment with NaOMe in methanol yields ketone (XXIX), which is treated with phenylboronic acid and pyridine to afford the cyclic phenylboronic ester (XXX). Silylation of the remaining hydroxy group of (XXX) with TBDMS-OTf gives the silyl ether (XXXI), which is then treated with H2O2 and NaHCO3 in water/ethyl acetate to remove the boron-protecting group and yielding diol (XXXII). The selective oxidation of diol (XXXII) with Dess-Martin periodinane in dichloromethane, followed by protection of the remaining OH group as a 2-methoxy-2-propyl (MOP) ether by reaction with 2-methoxypropene (XXXIII) and PPTS in THF gives diketone (XXXIV), which is enolized with PhNTf2 and KHMDS in THF yielding the enol triflate (XXXV).
| 【1】 Kashima, H.; Kusama, H.; Hara, R.; Morihira, K.; Nakamura, N.; Kuwajima, I.; Kawahara, S.; Nishimori, T.; Enantioselective total synthesis of (-)-Taxol. J Am Chem Soc 2000, 122, 16, 3811. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXI) | 43852 | (1S,5S,7R,10S,12S,16S)-12-(benzyloxy)-3,3-di(tert-butyl)-16-[[tert-butyl(dimethyl)silyl]oxy]-15,18,18-trimethyl-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6(11),14-diene-7,10-diol | C39H64O6Si2 | 详情 | 详情 | |
| (XXII) | 43853 | (1S,5S,7R,10S,12S,16S)-3,3-di(tert-butyl)-16-[[tert-butyl(dimethyl)silyl]oxy]-15,18,18-trimethyl-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6(11),14-diene-7,10,12-triol | C32H58O6Si2 | 详情 | 详情 | |
| (XXIII) | 43854 | (2S,6S,8S,12S,16S,19R)-4,4-di(tert-butyl)-8-[[tert-butyl(dimethyl)silyl]oxy]-9,21,21-trimethyl-14-phenyl-3,5,13,15-tetraoxa-4-silapentacyclo[10.7.1.1(6,10).0(2,6).0(16,20)]henicosa-1(20),9-dien-19-ol | C39H62O6Si2 | 详情 | 详情 | |
| (XXIV) | 43855 | (1R,2S,6S,8S,12S,14R,16S,19R,21R)-4,4-di(tert-butyl)-8-[[tert-butyl(dimethyl)silyl]oxy]-9,22,22-trimethyl-14-phenyl-3,5,13,15-tetraoxa-4-silahexacyclo[10.7.2.1(6,10).0(1,21).0(2,6).0(16,21)]docos-9-en-19-ol | C40H64O6Si2 | 详情 | 详情 | |
| (XXV) | 43856 | (1S,2S,6S,8S,12S,14R,16S,21R)-4,4-di(tert-butyl)-8-[[tert-butyl(dimethyl)silyl]oxy]-9,22,22-trimethyl-14-phenyl-3,5,13,15-tetraoxa-4-silahexacyclo[10.7.2.1(6,10).0(1,21).0(2,6).0(16,21)]docos-9-en-19-one | C40H62O6Si2 | 详情 | 详情 | |
| (XXVI) | 43857 | (1S,2S,3S,5S,9S,13S,18R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,3-dihydroxy-6,19,19-trimethyl-10,12-dioxapentacyclo[7.7.2.1(3,7).0(1,18).0(13,18)]nonadec-6-ene-11,16-dione | C26H40O7Si | 详情 | 详情 | |
| (XXVII) | 43858 | (1S,2S,4S,6S,8S,12S,13S,14S)-8-[[tert-butyl(dimethyl)silyl]oxy]-12,14-dihydroxy-9,19,19-trimethyl-4-phenyl-3,5-dioxapentacyclo[11.4.1.1(6,10).0(1,13).0(2,6)]nonadec-9-en-17-one | C32H46O6Si | 详情 | 详情 | |
| (XXVIII) | 43859 | (1S,3S,5S,10S,11S,12S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-11,15,18,18-tetramethyl-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,14-diene-7,10,12-triol | C32H48O6Si | 详情 | 详情 | |
| (XXIX) | 31998 | (1S,3S,5S,6R,10S,11S,12S,16S)-10,12,16-trihydroxy-11,15,18,18-tetramethyl-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-7-one | C26H34O6 | 详情 | 详情 | |
| (XXX) | 43860 | (1R,2S,4S,6S,8S,12S,16S,20R)-8-hydroxy-9,20,21,21-tetramethyl-4,14-diphenyl-3,5,13,15-tetraoxa-14-borapentacyclo[10.7.1.1(6,10).0(2,6).0(16,20)]henicos-9-en-19-one | C32H37BO6 | 详情 | 详情 | |
| (XXXI) | 43861 | (1R,2S,4S,6S,8S,12S,16S,20R)-8-[[tert-butyl(dimethyl)silyl]oxy]-9,20,21,21-tetramethyl-4,14-diphenyl-3,5,13,15-tetraoxa-14-borapentacyclo[10.7.1.1(6,10).0(2,6).0(16,20)]henicos-9-en-19-one | C38H51BO6Si | 详情 | 详情 | |
| (XXXII) | 43862 | (1S,3S,5S,6R,10S,11S,12S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-10,12-dihydroxy-11,15,18,18-tetramethyl-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-7-one | C32H48O6Si | 详情 | 详情 | |
| (XXXIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XXXIV) | 43863 | (1S,3S,5S,6R,10S,11S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-ene-7,12-dione | C36H54O7Si | 详情 | 详情 | |
| (XXXV) | 43864 | (1S,3S,5S,6R,10S,11S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-12-oxo-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-7,14-dien-7-yl trifluoromethanesulfonate | C37H53F3O9SSi | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXV)The introduction of a methylene group in (XXXV) by reaction with the Grignard reagent TMSCH2MgCl and Pd(PPh3)3 as catalyst in ethyl ether, affords the trimethylsilylmethyl compound (XXXVI), which is chlorinated with N-chlorosuccinimide (NCS) in methanol and treated with 2-methoxypropene (XXXIII) and PPTS to provide the chloro derivative (XXXVII). Regioselective hydroxylation of (XXXVII) is performed by enolization with LDA, followed by oxidation with MoO5/pyridine in HMPA and final acylation with Ac2O to give the alpha-acetoxy compound (XXXVIII). This acetate (XXXVIII) is isomerized to the corresponding beta-isomer (XXXIX) by heating with a base such as DBN. The dihydroxylation of the exo-methylene moiety of (XXXIX) with OsO4 and pyridine in ethyl ether yields the corresponding dihydroxy compound (XL), which is cyclized with DBU in refluxing toluene in order to form the oxetane ring of (XLI). The removal of the MOP group of (XLI) with PPTS, followed by reprotection with TES-Cl in DMF gives the triethylsilyl ether (XLII). Cleavage of the cyclic benzylidene ketal of (XLII) with H2 over Pd(OH)2, followed by reaction with triphosgene and pyridine yields the cyclic carbonate (XLIII), which is acetylated at the tertiary OH group of with acetic anhydride and DMAP to yield the acetoxy compound (XLIV). Reaction of (XLIV) with phenyl lithium in THF gives the benzoate (XLV), which is selectively desilylated with HF/pyridine and reprotected with 2,2,2-trichloroethyl chloroformate (Troc-Cl) yielding the intermediate (XLVI). Compound (XLVI) is again desilylated with tris(diethylamino)sulfoxonium difluorotrimethylsiliconate (TASF) affording the secondary alcohol (XLVII).
| 【1】 Kashima, H.; Kusama, H.; Hara, R.; Morihira, K.; Nakamura, N.; Kuwajima, I.; Kawahara, S.; Nishimori, T.; Enantioselective total synthesis of (-)-Taxol. J Am Chem Soc 2000, 122, 16, 3811. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XXXV) | 43864 | (1S,3S,5S,6R,10S,11S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-12-oxo-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-7,14-dien-7-yl trifluoromethanesulfonate | C37H53F3O9SSi | 详情 | 详情 | |
| (XXXVI) | 43865 | (1S,3S,5S,6S,10S,11S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-3-phenyl-7-[(trimethylsilyl)methyl]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-7,14-dien-12-one | C40H64O6Si2 | 详情 | 详情 | |
| (XXXVII) | 43866 | (1S,3S,5S,6S,8S,10S,11S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-8-chloro-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-7-methylene-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-12-one | C37H55ClO6Si | 详情 | 详情 | |
| (XXXVIII) | 43867 | (1S,3S,5S,6S,8S,10S,11S,13S,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-8-chloro-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-7-methylene-12-oxo-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C39H57ClO8Si | 详情 | 详情 | |
| (XXXIX) | 43868 | (1S,3S,5S,6S,8S,10S,11S,13R,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-8-chloro-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-7-methylene-12-oxo-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C39H57ClO8Si | 详情 | 详情 | |
| (XL) | 43869 | (1S,3S,5S,6R,7S,8S,10S,11S,13R,16S)-16-[[tert-butyl(dimethyl)silyl]oxy]-8-chloro-7-hydroxy-7-(hydroxymethyl)-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-12-oxo-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C39H59ClO10Si | 详情 | 详情 | |
| (XLI) | 43870 | (1S,3S,5S,6R,7S,10R,12S,13S,15R,18S)-18-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-12-(1-methoxy-1-methylethoxy)-13,17,20,20-tetramethyl-14-oxo-3-phenyl-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-15-yl acetate | C39H58O10Si | 详情 | 详情 | |
| (XLII) | 43871 | (1S,3S,5S,6R,7S,10R,12S,13S,15R,18S)-18-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-13,17,20,20-tetramethyl-14-oxo-3-phenyl-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-15-yl acetate | C41H64O9Si2 | 详情 | 详情 | |
| (XLIII) | 43872 | (1S,5S,6R,7S,10R,12S,13S,15R,18S)-18-[[tert-butyl(dimethyl)silyl]oxy]-7-hydroxy-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-15-yl acetate | C35H58O10Si2 | 详情 | 详情 | |
| (XLIV) | 43873 | (1S,5S,6R,10R,12S,13S,15R,18S)-15-(acetoxy)-18-[[tert-butyl(dimethyl)silyl]oxy]-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-7-yl acetate | C37H60O11Si2 | 详情 | 详情 | |
| (XLV) | 43874 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H66O11Si2 | 详情 | 详情 | |
| (XLVI) | 43875 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H53Cl3O13Si | 详情 | 详情 | |
| (XLVII) | 10448 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C34H39Cl3O13 | 详情 | 详情 |