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【结 构 式】 
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【分子编号】43852 【品名】(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 【CA登记号】 |
【 分 子 式 】C39H64O6Si2 【 分 子 量 】685.10456 【元素组成】C 68.37% H 9.42% O 14.01% Si 8.2% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The condensation of the acetylenic tetrahydropyranyl ether (I) with propionaldehyde (II) by means of BuLi in THF gives 6-(tetrahydropyranyloxy)-4-hexyn-3-ol (III), which by reduction with H2 over Lindlar catalyst in hexane yields compound (IV). The Swern oxidation of (IV) with oxalyl chloride in dichloromethane affords enone (V), which is condensed with the lithium enolate (VI) in THF to afford the addition keto ester (VII). Cyclization of (VII) by means of potassium tert-butoxide, followed by acylation with pivaloyl chloride gives the cyclohexenone (VIII). Elimination of the tetrahydropyranyl protecting group of (VIII) with TsOH in methanol yields the carbinol (IX), which is oxidized with oxalyl chloride and TEA in dichloromethane to afford the carbaldehyde (X). The enolization of the aldehyde group of (X) with TIPSOTf, DBU and DMAP in dichloromethane provides exclusively the (E)-enol ether (XI), which is submitted to a Sharpless' asymetric dihydroxylation using DHQ-PHN as a chiral ligand to give the chiral alpha-hydroxy aldehyde (XII). Elimination of the pivaloyl group of (XII) with N,N'-dimethylethylenediamine and potassium methoxide in refluxing benzene, followed by reprotection with TIPSCl in THF provides aldehyde (XIII). The reaction of the ketonic group of (XIII) with PhSCH(Li)TMS in THF affords the dienol silyl ether (XIV), which by condensation with 2-bromo-4,5-dihydrobenzaldehyde dibenzyl acetal (XV) by means of t-BuLi in the presence of t-BuMgCl furnishes the expected addition compound (XVI) as a single isomer. Protection of the vicinal diol of (XVI) with trimethyl borate and pyridine in benzene gives the boronic ester (XVII), which is cyclized by means of (i-PrO)2TiCl2 in dichloromethane to yield the polycyclic compound (XVIII). The hydrolysis of the boronic ester of (XVIII) with pinacol and DMAP in benzene, followed by silylation with t-Bu2SiHCl and BuLi in THF affords the cyclic silyl ether (XIX). Reduction of the ketonic group of (XIX) with DIBAL in dichloromethane, followed by silylation with TBDMS-OTf affords the silyl ether (XX), which is dihydroxylated by oxidation with O2 and light using TPP as catalyst, and desulfurized by treatment with Bu3SnH and AIBN in refluxing benzene to provide diol (XXI).
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 43835 | 2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-(2-propynyloxy)tetrahydro-2H-pyran | 6089-04-9 | C8H12O2 | 详情 | 详情 |
| (II) | 15966 | propionaldehyde | 123-38-6 | C3H6O | 详情 | 详情 |
| (III) | 43836 | 6-(tetrahydro-2H-pyran-2-yloxy)-4-hexyn-3-ol | C11H18O3 | 详情 | 详情 | |
| (IV) | 43837 | (Z)-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexen-3-ol | C11H20O3 | 详情 | 详情 | |
| (V) | 43838 | (Z)-6-(tetrahydro-2H-pyran-2-yloxy)-4-hexen-3-one | C11H18O3 | 详情 | 详情 | |
| (VI) | 43839 | lithium 1-ethoxy-2-methyl-1-propen-1-olate | C6H11LiO2 | 详情 | 详情 | |
| (VII) | 43840 | ethyl 2,2-dimethyl-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]heptanoate | C17H30O5 | 详情 | 详情 | |
| (VIII) | 43841 | 2,4,4-trimethyl-3-oxo-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-cyclohexen-1-yl pivalate | C20H32O5 | 详情 | 详情 | |
| (IX) | 43842 | 5-(hydroxymethyl)-2,4,4-trimethyl-3-oxo-1-cyclohexen-1-yl pivalate | C15H24O4 | 详情 | 详情 | |
| (X) | 43843 | 5-formyl-2,4,4-trimethyl-3-oxo-1-cyclohexen-1-yl pivalate | C15H22O4 | 详情 | 详情 | |
| (XI) | 43844 | 2,4,4-trimethyl-3-oxo-5-[(E)-[(triisopropylsilyl)oxy]methylidene]-1-cyclohexen-1-yl pivalate | C24H42O4Si | 详情 | 详情 | |
| (XII) | 43845 | (5S)-5-formyl-5-hydroxy-2,4,4-trimethyl-3-oxo-1-cyclohexen-1-yl pivalate | C15H22O5 | 详情 | 详情 | |
| (XIII) | 43846 | (1S)-1-hydroxy-4,6,6-trimethyl-5-oxo-3-[(triisopropylsilyl)oxy]-3-cyclohexene-1-carbaldehyde | C19H34O4Si | 详情 | 详情 | |
| (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 | |
| (XV) | 43847 | benzyl (benzyloxy)(6-bromo-1,5-cyclohexadien-1-yl)methyl ether; 1-[[(benzyloxy)(6-bromo-1,5-cyclohexadien-1-yl)methoxy]methyl]benzene | C21H21BrO2 | 详情 | 详情 | |
| (XVI) | 43848 | (1S)-1-[(S)-[6-[bis(benzyloxy)methyl]-1,5-cyclohexadien-1-yl](hydroxy)methyl]-4,6,6-trimethyl-5-[(Z)-(phenylsulfanyl)methylidene]-3-[(triisopropylsilyl)oxy]-3-cyclohexen-1-ol | C47H62O5SSi | 详情 | 详情 | |
| (XVII) | 31990 | ([(4S,5S)-4-[6-[bis(benzyloxy)methyl]-1,5-cyclohexadien-1-yl]-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)(6-[(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]-1,5-cyclohexadien-1-yl)methyl ether | C48H63BO5SSi | 详情 | 详情 | |
| (XVIII) | 43849 | (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-6,10,14-trien-16-one | C32H35BO4S | 详情 | 详情 | |
| (XIX) | 43850 | (1S,5S,12R,13R)-12-(benzyloxy)-3,3-di(tert-butyl)-15,18,18-trimethyl-13-(phenylsulfanyl)-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,10,14-trien-16-one | C39H50O4SSi | 详情 | 详情 | |
| (XX) | 43851 | (1S,5S,12R,13R,16S)-12-(benzyloxy)-3,3-di(tert-butyl)-16-[[tert-butyl(dimethyl)silyl]oxy]-15,18,18-trimethyl-13-(phenylsulfanyl)-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,10,14-triene; benzyl (1S,5S,12R,13R,16S)-3,3-di(tert-butyl)-16-[[tert-butyl(dimethyl)silyl]oxy]-15,18,18-trimethyl-13-(phenylsulfanyl)-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,10,14-trien-12-yl ether | C45H66O4SSi2 | 详情 | 详情 | |
| (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 |
合成路线2
该中间体在本合成路线中的序号：(XXI)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 |