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【结 构 式】 
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【分子编号】31998 【品名】(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 【CA登记号】 |
【 分 子 式 】C26H34O6 【 分 子 量 】442.55236 【元素组成】C 70.56% H 7.74% O 21.69% |
合成路线1
该中间体在本合成路线中的序号：(XI)The condensation of the chiral aldehyde (I) with the phenyllithium compound (II) in the presence of magnesium ion gives, after protection of the resulting vicinal diol as a boronate, the cyclization precursor (III). The cyclization of (III) by means of TiCl2 in dichloromethane yields the tricarbocyclic compound (IV), which is silylated at the vicinal diol with butyllithium and di-tert-butylsilyl chloride in THF, reduced with DIBAL in dichloromethane and silylated with TBS-OTf to afford intermediate (V). Singlet oxygen oxygenation of the diene moiety of (V), followed by a treatment with tributyl tin hydride produced the peroxide bonds cleavage and removal of the phenylsulfanyl group; and elimination of the benzyl protecting group by hydrogenation, followed by reprotection of the vicinal diol with benzaldehyde dimethylacetal gave a mixture of two diastereoisomers (VI). This mixture was treated with diethylzinc/chloroiodomethane, only the beta-isomer underwent the cyclopropanation, followed by Dess-Martin periodinane (DMP), affording the ketone (VII). Elimination of the benzylidene group of (VII), followed by reaction with triphosgene, and desilylation with TBAF provided the cyclic carbonate (VIII). The reprotection of the free hydroxy groups of (VIII) with benzaldehyde dimethylacetal, followed by hydrolysis of the cyclic carbonate group affords intermediate (IX). This compound was treated with samarium iodide and TBAF to induce the cleavage of the cyclopropane ring resulting in a mixture of enol (X) and ketone (XI). The enol was treated with NaOMe to complete the ketonization to (XI). The vicinal diol of (XI) was initially protected as a boronate with phenylboronic acid and the remaining hydroxy group was silylated with TBS-OTf. After removal the boron-protecting group, selective Dess Martin oxidation and protection of the remaining hydroxy group with 2-methoxypropene, the dione (XII) was obtained. The reaction of (XII) with KHMDS and PhNTf2 yielded the corresponding enol, which was reacted with trimethylsilyl magnesium chloride in ether to give the allylsilane (XIII). The reaction of (XIII) with N-chlorosuccinimide (NCS) and 2-methoxypropene yielded the chlorinated compound (XIV), which was treated successively with LDA to generate the enol, oxidized with MoO5, and acetylated with acetic anhydride to provide the acetoxy derivative (XV). The oxidation of the exocyclic double bond of (XV) with OsO4 and pyridine gave the corresponding diol, which by treatment with DBU in refluxing toluene and silylation with TES-Cl yielded the oxetane derivative (XVI).
| 【1】 Morihira, K.; et al.; Enantioselective total synthesis of Taxol. J Am Chem Soc 1998, 120, 49, 12980. |
| 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) | 27204 | (1S)-1-hydroxy-4,6,6-trimethyl-5-[(E)-(phenylsulfanyl)methylidene]-3-[(triisopropylsilyl)oxy]-3-cyclohexene-1-carbaldehyde | C26H40O3SSi | 详情 | 详情 | |
| (II) | 31989 | [6-[bis(benzyloxy)methyl]-1,5-cyclohexadien-1-yl]lithium | C21H21LiO2 | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 31991 | (1S,2S,9R,10R)-9-(benzyloxy)-1,2-dihydroxy-12,15,15-trimethyl-10-(phenylsulfanyl)tricyclo[9.3.1.0(3,8)]pentadeca-3,7,11-trien-13-one | C31H34O4S | 详情 | 详情 | |
| (V) | 31992 | (1S,5S,12R,13R,16S)-12-(benzyloxy)-3,3-di(tert-butyl)-15,18,18-trimethyl-13-(phenylsulfanyl)-16-[(tributylsilyl)oxy]-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)-15,18,18-trimethyl-13-(phenylsulfanyl)-16-[(tributylsilyl)oxy]-2,4-dioxa-3-silatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,10,14-trien-12-yl ether | C51H78O4SSi2 | 详情 | 详情 | |
| (VI) | 31993 | (2S,6S,8S,12S,16S,19R)-4,4-di(tert-butyl)-9,21,21-trimethyl-14-phenyl-8-[(tributylsilyl)oxy]-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 | C45H74O6Si2 | 详情 | 详情 | |
| (VII) | 31994 | (1S,2S,6S,8S,12S,14R,16S,21R)-4,4-di(tert-butyl)-9,22,22-trimethyl-14-phenyl-8-[(tributylsilyl)oxy]-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 | C46H74O6Si2 | 详情 | 详情 | |
| (VIII) | 31995 | (1S,2S,3S,5S,9S,13S,18R)-2,3-dihydroxy-6,19,19-trimethyl-5-[(tributylsilyl)oxy]-10,12-dioxapentacyclo[7.7.2.1(3,7).0(1,18).0(13,18)]nonadec-6-ene-11,16-dione | C32H52O7Si | 详情 | 详情 | |
| (IX) | 31996 | (1S,2S,4S,6S,8S,12S,13S,14S)-12,14-dihydroxy-9,19,19-trimethyl-4-phenyl-8-[(tributylsilyl)oxy]-3,5-dioxapentacyclo[11.4.1.1(6,10).0(1,13).0(2,6)]nonadec-9-en-17-one | C38H58O6Si | 详情 | 详情 | |
| (X) | 31997 | (1S,3S,5S,10S,11S,12S,16S)-11,15,18,18-tetramethyl-3-phenyl-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-6,14-diene-7,10,12,16-tetrol | C26H34O6 | 详情 | 详情 | |
| (XI) | 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 | |
| (XII) | 31999 | (1S,3S,5S,6R,10S,11S,16S)-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-3-phenyl-16-[(tributylsilyl)oxy]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-ene-7,12-dione | C42H66O7Si | 详情 | 详情 | |
| (XIII) | 32000 | (1S,3S,5S,6S,10S,11S,16S)-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-3-phenyl-16-[(tributylsilyl)oxy]-7-[(trimethylsilyl)methyl]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadeca-7,14-dien-12-one | C46H76O6Si2 | 详情 | 详情 | |
| (XIV) | 32001 | (1S,3S,5S,6S,8S,10S,11S,16S)-8-chloro-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-7-methylene-3-phenyl-16-[(tributylsilyl)oxy]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-12-one | C43H67ClO6Si | 详情 | 详情 | |
| (XV) | 32002 | (1S,3S,5S,6S,8S,10S,11S,13R,16S)-8-chloro-10-(1-methoxy-1-methylethoxy)-11,15,18,18-tetramethyl-7-methylene-12-oxo-3-phenyl-16-[(tributylsilyl)oxy]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate | C45H69ClO8Si | 详情 | 详情 | |
| (XVI) | 32003 | (1S,3S,5S,6R,7S,10R,12S,13S,15R,18S)-7-hydroxy-13,17,20,20-tetramethyl-14-oxo-3-phenyl-18-[(tributylsilyl)oxy]-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 | C47H76O9Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)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 |