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【结 构 式】 
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【分子编号】31990 【品名】([(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 【CA登记号】 |
【 分 子 式 】C48H63BO5SSi 【 分 子 量 】790.98772 【元素组成】C 72.89% H 8.03% B 1.37% O 10.11% S 4.05% Si 3.55% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(XVII)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 |