|
【结 构 式】 
|
【分子编号】43853 【品名】(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 【CA登记号】 |
【 分 子 式 】C32H58O6Si2 【 分 子 量 】594.97992 【元素组成】C 64.6% H 9.83% O 16.13% Si 9.44% |
合成路线1
该中间体在本合成路线中的序号：(XXII)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：(XXII)Alternatively, condensation of the dienol silyl ether intermediate (XIV) with 2-bromobenzaldehyde dibenzyl acetal (L) by means of t-BuLi in the presence of t-BuMgCl in THF furnishes the expected addition compound (LI).Protection of the vicinal diol moiety of (LI) with trimethyl borate and pyridine in benzene gives the boronic ester (LII), which is cyclized by means of SnCl4 in dichloromethane to yield the tricarbocyclic compound (LIII). Hydrolysis of the boronic ester of (LIII) with pinacol and DMAP in benzene affords the vicinal diol (LIV), which is reduced at the keto group with DIBAL in dichloromethane and silylated at the resulting alcohol with TBDMS-OTf in the same solvent to give the fully protected intermediate (LV). Elimination of the phenylthio group of (LV) by means of Bu3SnH and AIBN in refluxing benzene yields the tricyclic compound (LVI), which is debenzylated with H2 over Pd/C and treated with Swern oxidant to provide ketone (LVII). Selective hydrogenation of (LVII) with potassium in liquid ammonia in the presence of 2,2,4-trimethyl-3-isopropyl-3-pentanol furnishes the dihydro intermediate (LVIII), which is selectively desilylated with TBAF in THF to yield the vicinal diol (LIX). Silylation of diol (LIX) with t-Bu2SiHCl and BuLi in THF affords the cyclic silyl ether (LX), which is reduced at the carbonyl group with NaBH4 and CeCl3 in methanol giving the secondary alcohol (LXI). Finally, this compound is dihydroxylated by oxidation with O2, light and rose bengal as photoinductor to furnish the triol (XXII), already reported.
| 【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 |
|---|---|---|---|---|---|---|
| (XIV) | 27204 | (1S)-1-hydroxy-4,6,6-trimethyl-5-[(E)-(phenylsulfanyl)methylidene]-3-[(triisopropylsilyl)oxy]-3-cyclohexene-1-carbaldehyde | C26H40O3SSi | 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 | |
| (L) | 43877 | 1-[bis(benzyloxy)methyl]-2-bromobenzene; benzyl (benzyloxy)(2-bromophenyl)methyl ether | C21H19BrO2 | 详情 | 详情 | |
| (LI) | 43878 | (1S)-1-[(S)-[2-[bis(benzyloxy)methyl]phenyl](hydroxy)methyl]-4,6,6-trimethyl-5-[(Z)-(phenylsulfanyl)methylidene]-3-[(triisopropylsilyl)oxy]-3-cyclohexen-1-ol | C47H60O5SSi | 详情 | 详情 | |
| (LII) | 43879 | ([(4S,5S)-4-[2-[bis(benzyloxy)methyl]phenyl]-2,8,10,10-tetramethyl-9-[(Z)-(phenylsulfanyl)methylidene]-1,3-dioxa-2-boraspiro[4.5]dec-7-en-7-yl]oxy)(triisopropyl)silane; benzyl (benzyloxy)(2-[(4S,5S)-2,8,10,10-tetramethyl-9-[(Z)-(phenylsulfanyl)methylidene]-7-[(triisopropylsilyl)oxy]-1,3-dioxa-2-boraspiro[4.5]dec-7-en-4-yl]phenyl)methyl ether | C48H61BO5SSi | 详情 | 详情 | |
| (LIII) | 43880 | (1S,5S,12R,13R)-12-(benzyloxy)-3,15,18,18-tetramethyl-13-(phenylsulfanyl)-2,4-dioxa-3-boratetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,8,10,14-tetraen-16-one | C32H33BO4S | 详情 | 详情 | |
| (LIV) | 43881 | (1S,2S,9R,10R)-9-(benzyloxy)-1,2-dihydroxy-12,15,15-trimethyl-10-(phenylsulfanyl)tricyclo[9.3.1.0(3,8)]pentadeca-3,5,7,11-tetraen-13-one | C31H32O4S | 详情 | 详情 | |
| (LV) | 43882 | (1S,2S,9R,10R,13S)-9-(benzyloxy)-2,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,15,15-trimethyl-10-(phenylsulfanyl)tricyclo[9.3.1.0(3,8)]pentadeca-3,5,7,11-tetraen-1-ol | C43H62O4SSi2 | 详情 | 详情 | |
| (LVI) | 43883 | (1S,2S,9S,13S)-9-(benzyloxy)-2,13-bis[[tert-butyl(dimethyl)silyl]oxy]-12,15,15-trimethyltricyclo[9.3.1.0(3,8)]pentadeca-3,5,7,11-tetraen-1-ol | C37H58O4Si2 | 详情 | 详情 | |
| (LVII) | 43884 | (1S,2S,13S)-2,13-bis[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-12,15,15-trimethyltricyclo[9.3.1.0(3,8)]pentadeca-3,5,7,11-tetraen-9-one | C30H50O4Si2 | 详情 | 详情 | |
| (LVIII) | 43885 | (1S,2S,13S)-2,13-bis[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-12,15,15-trimethyltricyclo[9.3.1.0(3,8)]pentadeca-3,7,11-trien-9-one | C30H52O4Si2 | 详情 | 详情 | |
| (LIX) | 43886 | (1S,2S,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-1,2-dihydroxy-12,15,15-trimethyltricyclo[9.3.1.0(3,8)]pentadeca-3,7,11-trien-9-one | C24H38O4Si | 详情 | 详情 | |
| (LX) | 43887 | (1S,5S,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-6,10,14-trien-12-one | C32H54O4Si2 | 详情 | 详情 | |
| (LXI) | 43888 | (1S,5S,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-6,10,14-trien-12-ol | C32H56O4Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The reaction of the propargyl tetrahydropyranyl ether (I) with TBDMS-Cl and BuLi in THF gives the silylated acetylene (II), which is treated with Br2 and PPh3 to yield the silylated propargyl bromide (III). The reaction of (III) with the pyranopyridone (IV) by means of NaH and LiBr in DMF/DME affords the alkylated pyranopyridone (V), which is cyclized with 4-acetoxyphenyl isocyanide (VI) by means of hexamethyldistannane in refluxing benzene to provide the silylated acetoxycamptothecin (VII). Finally, this compound is deacetylated with K2CO3 in methanol.
| 【1】 Bom, D.; et al.; The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 2000, 43, 21, 3970. |
| 【2】 Bom, D.; Curran, D.P.; Josien, H. (University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. EP 1017399; JP 2001513567; US 6150343; WO 9909996 . |
| 【3】 Bom, D.; Curran, D.P.; Josien, H.; Burke, T.G. (University of Pittsburgh); Camptothecin analogs and methods of preparation thereof. WO 0035924 . |
| 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) | 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 | |
| (II) | 49254 | 4,5-dichloro-2-iodoaniline; tert-butyl(dimethyl)[3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl]silane | C14H26O2Si | 详情 | 详情 | |
| (III) | 35102 | (3-bromo-1-propynyl)(tert-butyl)dimethylsilane | C9H17BrSi | 详情 | 详情 | |
| (IV) | 49255 | (4S)-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C10H10INO4 | 详情 | 详情 | |
| (V) | 49256 | (4S)-7-[3-[tert-butyl(dimethyl)silyl]-2-propynyl]-4-ethyl-4-hydroxy-6-iodo-1H-pyrano[3,4-c]pyridine-3,8(4H,7H)-dione | C19H26INO4Si | 详情 | 详情 | |
| (VI) | 49257 | C9H7NO2 | 详情 | 详情 | ||
| (VII) | 49258 | (4S)-11-[tert-butyl(dimethyl)silyl]-4-ethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl acetate | C28H32N2O6Si | 详情 | 详情 |