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【结 构 式】

【分子编号】17354

【品名】isopropenyl methyl ether; 2-methoxy-1-propene

【CA登记号】116-11-0

【 分 子 式 】C4H8O

【 分 子 量 】72.10692

【元素组成】C 66.63% H 11.18% O 22.19%
与该中间体有关的原料药合成路线共 23 条
合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20合成路线21合成路线22合成路线23

合成路线1

该中间体在本合成路线中的序号：(XIII)

The enantioselective condensation of 3-(trimethylsilyl)propynal (V) with allylmagnesium bromide (VI) by means of (+)-Ipc2B-OMe as chiral catalyst gives hex-5-en-1-yn-3(R)-ol (VII), which is silylated with Tbdps-Cl and imidazole to yield the silyl ether (VIII). The oxidation of the terminal double bond of (VII) by means of OsO4 and NaIO4 affords the aldehyde (IX), which is submitted to a Wittig condensation with the phosphorane (X) in benzene to provide the unsaturated ester (XI). The enantioselective dihydroxylation of the double bond of (XI) with AD-mix-beta in tert-butanol/water gives the dihydroxyester (XII), which is protected with 2-methoxypropene (XIII) and PPTS to yield the isopropylidene ketal (XIV). The bromination of the triple bond of (XIV), followed by selective hydrogenation, affords the cis-bromovinyl compound (XV), whose ester group is reduced with LiAlH4 in THF to provide the primary alcohol (XVI). The oxidation of (XVI) with (COCl)2 and TEA in DMSO gives the carbaldehyde (XVII), which is submitted to a Wittig condensation with the phosphorane (XVIII) in hot dichloromethane to yield the diunsaturated aldehyde (XIX). The enantioselective condensation of aldehyde (XIX) with allylmagnesium bromide catalyzed by (+)Ipc2-B-OMe affords the chiral alcohol (XX), which is esterified with acryloyl chloride (XXI) and DIEA in dichloromethane to provide the ester (XXII). Compound (XXII) is submitted to a ring-closing metathesis catalyzed by a Rh catalyst (Grubbs's catalyst), yielding the dihydropyran derivative (XXIII), which is submitted to cleavage of the acetonide group by means of Montmorillonite K 10 to afford the diol (XXIV). The condensation of the bromovinyl group of (XXIV) with the intermediate boronic ester (IV) by means of Pd(PPh3)4 and Ag2O gives compound (XXV) with the complete backbone of the target fostriecin. The selective monosilylation of (XXV) with Tbdps-OTf gives the intermediate (XXVI).

参考文献 中间体
合成目标
【1】 Falck, J.R.; Reddy, Y.K.; Asymmetric total synthesis of (+)-fostriecin. Org Lett 2002, 4, 6, 969.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(IV) 55458 tert-butyl(diphenyl){[(2E,4Z)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-pentadienyl]oxy}silane; tert-butyl(diphenyl)silyl (2E,4Z)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-pentadienyl ether C27H37BO3Si 详情 详情
(V) 20043 3-(trimethylsilyl)-2-propynal C6H10OSi 详情 详情
(VI) 10386 Allyl(bromo)magnesium 1730-25-2 C3H5BrMg 详情 详情
(VII) 55459 (3R)-5-hexen-1-yn-3-ol C6H8O 详情 详情
(VIII) 55460 tert-butyl(diphenyl)silyl (1R)-1-ethynyl-3-butenyl ether; tert-butyl{[(1R)-1-ethynyl-3-butenyl]oxy}diphenylsilane C22H26OSi 详情 详情
(IX) 55461 (3R)-3-{[tert-butyl(diphenyl)silyl]oxy}-4-pentynal C21H24O2Si 详情 详情
(X) 37071 ethyl 2-(triphenylphosphoranylidene)propanoate 5717-37-3 C23H23O2P 详情 详情
(XI) 55462 ethyl (E,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-2-methyl-2-hepten-6-ynoate C26H32O3Si 详情 详情
(XII) 55463 ethyl (2S,3R,5R)-5-{[tert-butyl(diphenyl)silyl]oxy}-2,3-dihydroxy-2-methyl-6-heptynoate C26H34O5Si 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 55464 ethyl (4S,5R)-5-((2R)-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butynyl)-2,2,4-trimethyl-1,3-dioxolane-4-carboxylate C29H38O5Si 详情 详情
(XV) 55465 ethyl (4S,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolane-4-carboxylate C29H39BrO5Si 详情 详情
(XVI) 55466 [(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]methanol C27H37BrO4Si 详情 详情
(XVII) 55467 (4S,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolane-4-carbaldehyde C27H35BrO4Si 详情 详情
(XVIII) 55468 2-(triphenylphosphoranylidene)acetaldehyde C20H17OP 详情 详情
(XIX) 55469 (E)-3-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]-2-propenal C29H37BrO4Si 详情 详情
(XX) 55470 (1E,3R)-1-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]-1,5-hexadien-3-ol C32H43BrO4Si 详情 详情
(XXI) 11577 Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride 814-68-6 C3H3ClO 详情 详情
(XXII) 55471 (1R)-1-{(E)-2-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-3-butenyl acrylate C35H45BrO5Si 详情 详情
(XXIII) 55472 (6R)-6-{(E)-2-[(4R,5R)-5-((2R,3Z)-4-bromo-2-{[tert-butyl(diphenyl)silyl]oxy}-3-butenyl)-2,2,4-trimethyl-1,3-dioxolan-4-yl]ethenyl}-5,6-dihydro-2H-pyran-2-one C33H41BrO5Si 详情 详情
(XXIV) 55473 (6R)-6-((1E,3R,4R,6R,7Z)-8-bromo-6-{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-3-methyl-1,7-octadienyl)-5,6-dihydro-2H-pyran-2-one C30H37BrO5Si 详情 详情
(XXV) 55474 (6R)-6-((1E,3R,4R,6R,7Z,9Z,11E)-6,13-bis{[tert-butyl(diphenyl)silyl]oxy}-3,4-dihydroxy-3-methyl-1,7,9,11-tridecatetraenyl)-5,6-dihydro-2H-pyran-2-one C51H62O6Si2 详情 详情
(XXVI) 55475 (6R)-6-((1E,3R,4R,6R,7Z,9Z,11E)-3,6,13-tris{[tert-butyl(diphenyl)silyl]oxy}-4-hydroxy-3-methyl-1,7,9,11-tridecatetraenyl)-5,6-dihydro-2H-pyran-2-one C67H80O6Si3 详情 详情

合成路线2

该中间体在本合成路线中的序号：

The condensation of verbenone (I) with 1-bromo-3-methyl-2-butene (II) by means of t-BuOK in DME, followed by ozonolysis of the aliphatic double bond gives acetaldehyde (III), which is isomerized with UV light in methanol to the chrysanthenone derivative (IV). The condensation of (IV) with ethyl propynoate (V) by means of LDA in THF, followed by silylation with TMSCl affords the silylated 4-hydroxy-2-pentynoate (VI), which is cyclized by means of Me2CuLi in ethyl ether giving the methanonaphthalene derivative (VII). The oxidation of the secondary OH group of (VII) with Dess Martin periodinane (DMP) yields the ketoester (VIII), which is hydroxylated with Davis' oxaziridine to the ketonic dihydroxyester (IX). The reduction of the ester group of (IX) with LiAlH4 in ethyl ether affords the tetrahydroxy compound (X), which is protected by silylation with TBDMS-Cl and imidazole and ketalization with PPTS and 2-methoxypropene providing the silylated acetonide (XI). The rearrangement of (XI) by means of MCPBA, followed by silylation with Tips-OTf gives (XII) with the A-B-bicycle of Taxol. The hydroxylation of (XII) with t-BuOK and oxygen, followed by reduction of its ketonic group with NaBH4 yields the trihydroxy compound (XIII), which is stereoselectively reduced with H2 and Crabtree catalyst, silylated with TMSCl and treated with triphosgene to afford the cyclic carbonate (XIV). The oxidation of (XIV) with pyridinium chlorochromate (PCC) in dichloromethane gives the carbaldehyde (XV), which is condensed with methoxymethyl(triphenyl)phosphorane to yield the acetaldehyde derivative (XVI). The selective silylation of (XVI) with Tes-Cl, followed by oxidation of the remaining secondary OH group with Dess Martin periodinane (DMP) and methylenation acetaldehyde CH2 group with Me2N-CH2-I affords the substituted propenoic aldehyde (XVII).

参考文献 中间体
合成目标
【1】 Wender, P.A.; et al.; The pinene path to taxanes. 5. Stereocontrolled synthesis of a versatile taxane precursor. J Am Chem Soc 1997, 119, 11, 2755.
【2】 Wender, P.A.; et al.; The pinene path to taxanes. 6. Concise stereocontrolled synthesis of Taxol. J Am Chem Soc 1997, 119, 11, 2757.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
40589 methyl (triphenylphosphoranylidene)methyl ether; (methoxymethylene)(triphenyl)phosphorane C20H19OP 详情 详情
40590 iodo-N,N-dimethylmethanamine; N-(iodomethyl)-N,N-dimethylamine C3H8IN 详情 详情
(I) 35330 4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one 1196-01-6 C10H14O 详情 详情
(II) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(III) 35331 2-(2,6,6-trimethyl-4-oxobicyclo[3.1.1]hept-2-en-3-yl)acetaldehyde C12H16O2 详情 详情
(IV) 35332 2-(2,6,6-trimethyl-7-oxobicyclo[3.1.1]hept-2-en-1-yl)acetaldehyde C12H16O2 详情 详情
(V) 35333 ethyl propiolate 623-47-2 C5H6O2 详情 详情
(VI) 35334 ethyl 5-(2,6,6-trimethyl-7-oxobicyclo[3.1.1]hept-2-en-1-yl)-4-[(trimethylsilyl)oxy]-2-pentynoate C20H30O4Si 详情 详情
(VII) 35335 ethyl (6R)-3,6-dihydroxy-4,10,11,11-tetramethyltricyclo[5.3.1.0(1,6)]undeca-4,9-diene-5-carboxylate C18H26O4 详情 详情
(VIII) 35336 ethyl (6R)-6-hydroxy-4,10,11,11-tetramethyl-3-oxotricyclo[5.3.1.0(1,6)]undeca-4,9-diene-5-carboxylate C18H24O4 详情 详情
(IX) 35337 ethyl (2S,6R)-2,6-dihydroxy-4,10,11,11-tetramethyl-3-oxotricyclo[5.3.1.0(1,6)]undeca-4,9-diene-5-carboxylate C18H24O5 详情 详情
(X) 35338 (2S,3S,6S)-5-(hydroxymethyl)-4,10,11,11-tetramethyltricyclo[5.3.1.0(1,6)]undeca-4,9-diene-2,3,6-triol C16H24O4 详情 详情
(XI) 35339 (2S,6S,9S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-3,5-dioxatetracyclo[8.3.1.0(1,9).0(2,6)]tetradeca-7,12-dien-9-ol C25H42O4Si 详情 详情
(XII) 35340 (2S,6S,12S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-12-[(triisopropylsilyl)oxy]-3,5-dioxatricyclo[8.3.1.0(2,6)]tetradeca-1(13),7-dien-9-one C34H62O5Si2 详情 详情
(XIII) 35341 (2S,6S,9S,10S,12S)-8-(hydroxymethyl)-4,4,7,13,14,14-hexamethyl-12-[(triisopropylsilyl)oxy]-3,5-dioxatricyclo[8.3.1.0(2,6)]tetradeca-1(13),7-diene-9,10-diol C28H50O6Si 详情 详情
(XIV) 35342 (1S,5S,6S,7S,8S,12S,15S)-7,10,10,14,17,17-hexamethyl-15-[(triisopropylsilyl)oxy]-6-[[(trimethylsilyl)oxy]methyl]-2,4,9,11-tetraoxatetracyclo[11.3.1.0(1,5).0(8,12)]heptadec-13-en-3-one C32H58O7Si2 详情 详情
(XV) 35343 (1S,5S,6R,7S,8S,12S,15S)-7,10,10,14,17,17-hexamethyl-3-oxo-15-[(triisopropylsilyl)oxy]-2,4,9,11-tetraoxatetracyclo[11.3.1.0(1,5).0(8,12)]heptadec-13-ene-6-carbaldehyde C29H48O7Si 详情 详情
(XVI) 35344 2-[(1S,5S,6R,7S,8S,9S,12S)-8,9-dihydroxy-7,11,14,14-tetramethyl-3-oxo-12-[(triisopropylsilyl)oxy]-2,4-dioxatricyclo[8.3.1.0(1,5)]tetradec-10-en-6-yl]acetaldehyde C27H46O7Si 详情 详情
(XVII) 35345 2-[(1S,5S,6S,7S,8S,12S)-7,11,14,14-tetramethyl-3,9-dioxo-8-[(triethylsilyl)oxy]-12-[(triisopropylsilyl)oxy]-2,4-dioxatricyclo[8.3.1.0(1,5)]tetradec-10-en-6-yl]acrylaldehyde C34H58O7Si2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XXXIII)

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).

参考文献 中间体
合成目标
【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4

该中间体在本合成路线中的序号：(XXXIII)

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).

参考文献 中间体
合成目标
【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

合成路线5

该中间体在本合成路线中的序号：(V)

The reaction of (2R,3S)-phenylisoserine (I) with 2-propynyl chloroformate (II) in aq. NaHCO3 gives the N-acylated compound (III), which is treated with diazomethane in ethyl ether (CDI and methanol) to yield the corresponding methyl ester (IV). The reaction of (IV) with 2-methoxypropene (V) and pyridinium p-toluenesulfonate in toluene affords the oxazolidine (VI), which is treated with LiOH in water to provide the oxazolidine-5-carboxylic acid (VII). The esterification of 7-O-(trichloroethoxycarbonyl)baccatin (VIII) with acid (VII) by means of DCC in toluene gives the corresponding ester (IX), which is treated with ammonium tetrathiomolybdate to cleave the oxazolidine ring and yield the 3-amino-2-hydroxypropionyl ester (X). The reaction of (X) with benzoyl chloride (XI) and NaHCO3 in ethyl acetate affords the expected benzamido derivative (XII), which is finally deprotected by means of Zn and AcOH to afford the target paclitaxel.

参考文献 中间体
合成目标
【1】 Sharma, A.P.; Sarkar, S. (Dabur India Ltd.); Method of preparation of paclitaxel (Taxol) using 3-(alk-2-ynyloxy)carbonyl-5-oxazolidine carboxylic acid. WO 0266448 .
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) 54908 (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoic acid 136561-53-0 C9H11NO3 详情 详情
(II) 55690 Propargyl chloroformate C4H3ClO2 详情 详情
(III) 55691 (2R,3S)-2-hydroxy-3-phenyl-3-{[(2-propynyloxy)carbonyl]amino}propanoic acid C13H13NO5 详情 详情
(IV) 55692 methyl (2R,3S)-2-hydroxy-3-phenyl-3-{[(2-propynyloxy)carbonyl]amino}propanoate C14H15NO5 详情 详情
(V) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VI) 55693 5-methyl 3-(2-propynyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate C17H19NO5 详情 详情
(VII) 55694 (4S,5R)-2,2-dimethyl-4-phenyl-3-[(2-propynyloxy)carbonyl]-1,3-oxazolidine-5-carboxylic acid C16H17NO5 详情 详情
(VIII) 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
(IX) 55695 5-((1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-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-15-yl) 3-(2-propynyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate C50H54Cl3NO17 详情 详情
(X) 10554 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]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 C43H48Cl3NO15 详情 详情
(XI) 10463 Benzoyl chloride 98-88-4 C7H5ClO 详情 详情
(XII) 55696 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,4-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 C48H50Cl3NO15 详情 详情

合成路线6

该中间体在本合成路线中的序号：

The synthesis of a key intermediate for a new total synthesis of forskolin has been reported: The methylation of 3-hydroxy-2-methyl-2-cyclohexenone (I) with dimethyl sulfate and potassium carbonate in refluxing acetone gives the methoxy compound (II), which is dimethylated by successive treatments with lithium diisopropylamide (LDA) and methyl iodide yielding 3-methoxy-2,6,6-trimethyl-2-cyclohexenone (III). The reaction of (III) with vinylmagnesium bromide in THF affords 2,4,4-trimethyl-3-vinyl-2-cyclohexenone (IV), which is reduced with LiAlH4 in ethyl ether to the cyclohexenol (V). The esterification of (V) with 2-butynoic acid (VI) by means of dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) in dichloromethane gives the ester (VII), which is cyclized in refluxing decane to the dienic lactone (VIII). The reduction of (VIII) with LiAlH4 in ethyl ether yields the diol (IX), which is selectively epoxidized with tert-butyl hydroperoxide and VO(acac)2 as catalyst to the monoepoxide (X). The ketalization of (X) with benzaldehyde dimethyl ketal and POCl3 or p-toluenesulfonic acid gives the benzylidene ketal (XI). The cleavage of the ketal ring of (XI) either with LiBF4/BH3.THF or with LiBH4/BF3.Et2O yields the benzyl ether (XII), which is selectively silylated with tert-butyldimethylsilyl chloride (TBDMS-Cl) in DMF to the mono-silyl ether (XIII). The oxidation of the secondary alcohol of (XIII) with CrO3-pyridine in dichloromethane affords the corresponding ketone (XIV), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol giving the dihydroxyketone (XV). The protection of (XV) with 2-methoxypropene and POCl3 in CCl4 yields the acetonide (XVI), which is dehydrogenated by successive treatments first with LDA and phenylselanyl chloride and then with H2O2 in dichloromethane/pyridine to afford the enone (XVII). The cis-configuration of enone (XVII) was isomerized to the trans-isomer by treatment with basic alumina in refluxing toluene yielding compound (XVIII) used as the starting intermediate in a total synthesis of forskolin (Delpech, B. et al. Tetrahedron Lett 1996, 37(7): 1019).

参考文献 中间体
合成目标
【1】 Calvo, D.; Lett, R.; Delpech, B.; Total synthesis of forskolin. 1. Tetrahedron Lett 1996, 37, 7, 1015.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(I) 10933 3-Hydroxy-2-methyl-2-cyclohexen-1-one C7H10O2 详情 详情
(II) 10934 3-Methoxy-2-methyl-2-cyclohexen-1-one C8H12O2 详情 详情
(III) 10935 3-Methoxy-2,6,6-trimethyl-2-cyclohexen-1-one C10H16O2 详情 详情
(IV) 10936 2,4,4-Trimethyl-3-vinyl-2-cyclohexen-1-one C11H16O 详情 详情
(V) 10937 2,4,4-Trimethyl-3-vinyl-2-cyclohexen-1-ol C11H18O 详情 详情
(VI) 10938 2-Butynoic acid 590-93-2 C4H4O2 详情 详情
(VII) 10939 2,4,4-trimethyl-3-vinyl-2-cyclohexen-1-yl 2-butynoate C15H20O2 详情 详情
(VIII) 10940 (8aS,8bS)-3,6,6,8b-Tetramethyl-4,6,7,8,8a,8b-hexahydro-2H-naphtho[1,8-bc]furan-2-one C15H20O2 详情 详情
(IX) 10941 (1S,8aS)-8-(Hydroxymethyl)-4,4,7,8a-tetramethyl-1,2,3,4,6,8a-hexahydro-1-naphthalenol C15H24O2 详情 详情
(X) 10942 (1aR,7S,7aR,7bR)-7b-(Hydroxymethyl)-1a,4,4,7a-tetramethyl-1a,2,4,5,6,7,7a,7b-octahydronaphtho[1,2-b]oxiren-7-ol C15H24O3 详情 详情
(XI) 10943 (1aR,5aS,8bR,10aR)-8,8,8b,10a-Tetramethyl-4-phenyl-5a,7,8,8b,10,10a-hexahydro-6H-oxireno[2',3':7,8]naphtho[1,8-de][1,3]dioxepine C22H28O3 详情 详情
(XII) 10944 (1R,2R,4R,4aR,8S,8aR)-8-(Benzyloxy)-1-(hydroxymethyl)-2,5,5,8a-tetramethyldecahydro-1,4-naphthalenediol C22H34O4 详情 详情
(XIII) 10945 (1R,2R,4R,4aR,8S,8aR)-8-(Benzyloxy)-1-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,5,5,8a-tetramethyldecahydro-1,4-naphthalenediol C28H48O4Si 详情 详情
(XIV) 10946 (3R,4R,4aR,5S,8aR)-5-(Benzyloxy)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-3,4a,8,8-tetramethyloctahydro-1(2H)-naphthalenone C28H46O4Si 详情 详情
(XV) 10947 (3R,4R,4aR,5S,8aR)-4-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-4,5-dihydroxy-3,4a,8,8-tetramethyloctahydro-1(2H)-naphthalenone C21H40O4Si 详情 详情
(XVI) 10948 (3aR,4R,6aR,9aS,9bR)-3a-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2,4,7,7,9b-hexamethyloctahydronaphtho[1,8-de][1,3]dioxin-6(3aH)-one C24H44O4Si 详情 详情
(XVII) 10949 (3aR,6aR,9aS,9bR)-3a-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2,4,7,7,9b-hexamethyl-6a,7,8,9,9a,9b-hexahydronaphtho[1,8-de][1,3]dioxin-6(3aH)-one C24H42O4Si 详情 详情
(XVIII) 10950 (3aR,6aS,9aS,9bR)-3a-([[tert-Butyl(dimethyl)silyl]oxy]methyl)-2,2,4,7,7,9b-hexamethyl-6a,7,8,9,9a,9b-hexahydronaphtho[1,8-de][1,3]dioxin-6(3aH)-one C24H42O4Si 详情 详情

合成路线7

该中间体在本合成路线中的序号：(II)

synthesis of (3S,4S)-3-hexyl-4-[2(S)-hydroxytridecyl]oxetan-2-one (VI), a key intermediate in the synthesis of orlistat has been reported: Reaction of methyl 3(S)-hydroxytetradecanoate (I) with 2-methoxypropene (II) by means of pyridinium p-toluenesulfonate gives the protected ester (III), which is reduced with DIBAL to the aldehyde (IV). Finally, aldehyde (IV) is condensed with the lithium amide-enolate (V) generated from 1-octanoylbenzotriazole and LiHMDS, resulting in a 4:1 mixture of diastereomeric oxetanones (VI) and (VII) separated by flash chromatography.

参考文献 中间体
合成目标
【1】 Wedler, C.; et al.; Synthesis of enantiomerically pure beta-lactones by the tandem aldol - Lactonization. A highly efficient access to (3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridencyl]oxetan-2-one, the key intermediate for the enzyme inhibitors tetrahydrolipstatin and tetrahydroes. J Org Chem 1999, 64, 14, 5301.
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) 41729 methyl (3S)-3-hydroxytridecanoate C14H28O3 详情 详情
(II) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(III) 41730 methyl (3S)-3-(1-methoxy-1-methylethoxy)tridecanoate C18H36O4 详情 详情
(IV) 41731 (3S)-3-(1-methoxy-1-methylethoxy)tridecanal C17H34O3 详情 详情
(V) 41732 lithium (E)-1-(1H-1,2,3-benzotriazol-1-yl)-1-octen-1-olate C14H18LiN3O 详情 详情
(VI) 41733 (3S,4S)-3-hexyl-4-[(2S)-2-hydroxydodecyl]-2-oxetanone C21H40O3 详情 详情
(VII) 41734 (3R,4R)-3-hexyl-4-[(2S)-2-hydroxydodecyl]-2-oxetanone C21H40O3 详情 详情

合成路线8

该中间体在本合成路线中的序号：(XII)

The synthesis of the C16-C34 fragment of tacrolimus (FK-506), the key intermediate on the total synthesis of tacrolimus has been described: 1) The reaction of (Z)-2-butene (I) with (­)-beta-methoxydiisopinocamphenylborane (IPCB-OCH3; II) by means of potassium tert-butoxide and butyllithium in THF gives the butenyl borane (III), which is condensed with 2-benzyl-acetaldehyde (IV) by means of BF3 ethearate in ether to yield the monobenzylated diol (V). The silylation of (V) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole affords the fully protected olefine (VI), which is oxidized with OsO4 and N-methylmorpholine N-oxide (NMO) in acetone/water/benzene to give a diastereomeric mixture of the diols (VII) and (VIII) separated by column chromatography. The epoxidation of (VII) with NaH and tosyl imidazole in THF afforded epoxide (IX), which was condensed with the protected furfuryl alcohol (X) by means of butyllithium and BF3 ethearate in THF giving the diol (XI). The oxidation of (XI) with m-chloroperbenzoic acid (MCPBA) with simultaneous trapping of the intermediate with 2-methoxypropene (XII) afforded the spiroenone (XIII), which was condensed with alkyne (XIV) by means of trimethylaluminum and a zircornium complex yielding the expected spiroketone (XV). 2) The alkyne intermediate (XIV) has been obtained by condensation of the chiral tosylate (XXVII) with lithium acetylide giving the chiral pentynol ether (XVIII). (XVIII) then was deprotected with p-toluenesulfonic acid and silylated with TBDMS-Cl. 3) The undesired diol (VIII) can also be converted into the epoxide (IX) by reaction with benzoyl chloride and dimethylaminopyridine (DMAP) to give the expected benzoate, which was subsequently treated with methanesulfonyl chloride and DMAP, and finally epoxidized with sodium methoxide in methanol. 4) The diol (VII) can be selectively obtained by reaction of methyl 5-O-benzyl-beta-D-ribofuranoside (XXIV) with methylmagnesium chloride and copper bromide giving methyl 5-O-benzyl-3-deoxy-3-C-methyl-beta-D-xylofuranoside (XXV). (XXV) was treated with ethanethiol and TBDMS-Cl in the presence of imidazole and a catalytic amount of DMAP affording the dithioacetal (XXVI). Finally, this compound is treated with HgCl2 and CaCO3, and reduced with NaBH4 in THF/methanol to afford the desired diol (VII). 5) The intermediate vinyl bromide (XXIII) has been obtained according to a previously reported method (Ragan, J.A. et al. J Org Chem 1989, 54(18): 4267) .

参考文献 中间体
合成目标
【1】 Liu, L.B.; Roper, T.D.; Ireland, R.E.; Total synthesis of FK-506. 1. Construction of the C16-C34 fragment. Tetrahedron 1997, 53, 39, 13221.
【2】 Liu, L.B.; Roper, T.D.; Gleason, J.L.; Ireland, R.E.; Total synthesis of FK-506. 2. Completion of the synthesis. Tetrahedron 1997, 53, 39, 13257.
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) 17343 2-Butene-cis; (Z)-2-butene 590-18-1 C4H8 详情 详情
(II) 63308 methyl 2,7,7-trimethylbicyclo[4.1.0]hept-3-yl(5,7,7-trimethylbicyclo[4.1.0]hept-3-yl)borinate C21H37BO 详情 详情
(III) 17345 2-butenyl(2,7,7-trimethylbicyclo[4.1.0]hept-3-yl)(5,7,7-trimethylbicyclo[4.1.0]hept-3-yl)borane C24H41B 详情 详情
(IV) 17346 Benzyloxyacetaldehyde; 2-(Benzyloxy)acetaldehyde 60656-87-3 C9H10O2 详情 详情
(V) 17347 (2S,3R)-1-(benzyloxy)-3-methyl-4-penten-2-ol C13H18O2 详情 详情
(VI) 17348 benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-4-pentenyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-methyl-3-butenyl]oxy)(tert-butyl)dimethylsilane C19H32O2Si 详情 详情
(VII) 17349 (2S,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1,2-pentanediol C19H34O4Si 详情 详情
(VIII) 17350 (2R,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyl-1,2-pentanediol C19H34O4Si 详情 详情
(IX) 17351 benzyl (2S,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-[(2R)oxiranyl]butyl ether; ([(1S,2R)-1-[(benzyloxy)methyl]-2-[(2R)oxiranyl]propyl]oxy)(tert-butyl)dimethylsilane C19H32O3Si 详情 详情
(X) 17352 2-[(1-methoxy-1-methylethoxy)methyl]furan; 1-(2-furylmethoxy)-1-methylethyl methyl ether C9H14O3 详情 详情
(XI) 17353 (2S,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-[5-(hydroxymethyl)-2-furyl]-3-methyl-2-pentanol C24H38O5Si 详情 详情
(XII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIII) 17355 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-9-one C27H42O6Si 详情 详情
(XIV) 17356 tert-butyl(dimethyl)[[(2S)-2-methyl-4-pentynyl]oxy]silane; tert-butyl(dimethyl)silyl (2S)-2-methyl-4-pentynyl ether C12H24OSi 详情 详情
(XV) 17357 4-((1R,2S)-3-(benzyloxy)-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methylpropyl)-11-((E,4S)-5-[[tert-butyl(dimethyl)silyl]oxy]-2,4-dimethyl-1-pentenyl)-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undecan-9-one C40H70O7Si2 详情 详情
(XVII) 17358 (2R)-3-methoxy-2-methylpropyl 4-methylbenzenesulfonate C12H18O4S 详情 详情
(XVIII) 17359 (4S)-5-methoxy-4-methyl-1-pentyne; methyl (2S)-2-methyl-4-pentynyl ether C7H12O 详情 详情
(XXIV) 17360 (1S,2R,4R,5R)-2-[(benzyloxy)methyl]-4-methoxy-3,6-dioxabicyclo[3.1.0]hexane; benzyl [(1S,2R,4R,5R)-4-methoxy-3,6-dioxabicyclo[3.1.0]hex-2-yl]methyl ether C13H16O4 详情 详情
(XXV) 17361 (2R,3R,4R,5S)-5-[(benzyloxy)methyl]-2-methoxy-4-methyltetrahydro-3-furanol C14H20O4 详情 详情
(XXVI) 17362 (2R,3R,4S)-5-(benzyloxy)-4-[[tert-butyl(dimethyl)silyl]oxy]-1,1-bis(ethylsulfanyl)-3-methyl-2-pentanol C23H42O3S2Si 详情 详情

合成路线9

该中间体在本合成路线中的序号：(II)

The reaction of 3-chloropropanol (I) with 2-methoxypropene (II) by means of PPTS gives the mixed ketal (III), which is condensed with diethyl malonate (IV) by means of sodium ethoxide in hot ethanol, affording the adduct (V). The reduction of (V) with NaH and Red-Al in refluxing toluene provides the allyl alcohol derivative (VI), which is submitted to an asymmetric epoxidation to give the epoxide (VII). The reaction of (VII) with octadecyl bromide (VIII) by means of NaH and tetrabutylammonium iodide (TBAI) yields the corresponding ether (IX), which by reaction with PPTS in HOAc is converted to the tetrahydrofuran-2-methanol derivative (X). Finally, this compound is condensed with POCl3, TEA, choline mesylate (XI) and DMAP in dichloromethane/pyridine to afford the target compound.

参考文献 中间体
合成目标
【1】 Lohmeyer, M.; Bittman, R.; Antitumor ether lipids and alkylphosphocholines. Drugs Fut 1994, 19, 11, 1021.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
41308 2-hydroxy-N,N,N-trimethyl-1-ethanaminium methanesulfonate C6H17NO4S 详情 详情
(I) 19490 3-chloro-1-propanol 627-30-5 C3H7ClO 详情 详情
(II) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(III) 41304 1-(3-chloropropoxy)-1-methylethyl methyl ether; 1-chloro-3-(1-methoxy-1-methylethoxy)propane C7H15ClO2 详情 详情
(IV) 16829 Diethyl malonate 105-53-3 C7H12O4 详情 详情
(V) 41309 diethyl 2-[3-(1-methoxy-1-methylethoxy)propyl]malonate C14H26O6 详情 详情
(VI) 41305 2-[3-(1-methoxy-1-methylethoxy)propyl]-2-propen-1-ol C10H20O3 详情 详情
(VII) 28797 1-bromooctadecane 112-89-0 C18H37Br 详情 详情
(VIII) 41306 [(2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]oxiranyl]methyl octadecyl ether; (2S)-2-[3-(1-methoxy-1-methylethoxy)propyl]-2-[(octadecyloxy)methyl]oxirane C28H56O4 详情 详情
(IX) 41307 [(2S)-2-[(octadecyloxy)methyl]tetrahydro-2-furanyl]methanol C24H48O3 详情 详情

合成路线10

该中间体在本合成路线中的序号：

1) The reaction of cis-(1S,2R)-indanediol (I) with acetonitrile and concentrated H2SO4 gives cis-(1S,2R)-1-aminoindan-2-ol (II), which is cyclocondensed with 3-phenylpropionyl chloride (III), isopropenyl methyl ether and triethylamine to yield the acetonide amide (IV). The condensation of amide (IV) with (S)-(+)-glycidyl p-toluenesulfonate (V) in the presence of lithium hexamethyldisylazide (LHS) affords the chiral epoxide (VI), which is condensed with 4-(tert-butoxycarbonyl)-N-tert-butylpiperazine-2(S)-carboxamide (VII) in refluxing isopropyl acetate and deprotected with aqueous HCl to give the dihydroxy-diamide (VIII). Finally, this compound is condensed with 3-(chloromethyl)pyridine (IX) by means of triethylamine in DMF. 2) The amide (IV) can also be alkylated with allyl bromide and butyllithium to the pentenyl amide (X), which is diastereoselectively converted to the chiral iodohydrine (XI) by means of N-iodosuccinimide (NIS). Finally, this compound is cyclized in basic medium, yielding the epoxide (VI), already obtained.

参考文献 中间体
合成目标
【1】 Maligres, P.E.; Upadhyay, V.; Rossen, K.; Cianciosi, S.J.; Purick, R.M.; Eng, K.K.; Reamer, R.A.; Askin, D.; Volante, R.P.; Reider, P.J.; Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate. Tetrahedron Lett 1995, 36, 13, 2195-8.
【2】 Mealy, N.; Castaner, J.; Indinavir Sulfate. Drugs Fut 1996, 21, 6, 600.
【3】 Askin, D.; Volante, R.P.; Eng, K.K. (Merck & Co., Inc.); Process for making HIV protease inhibitors. WO 9502584 .
【4】 Verhoeven, T.R.; Roberts, E.F.; Senanayake, C.H.; Ryan, K.M. (Merck & Co., Inc.); Regiospecific processes to make cis-1-amino-2-alkanol from diol or halohydrin. US 5449830 .
【5】 Askin, D.; Eng, K.K.; Rossen, K.; Purick, R.M.; Wells, K.M.; Volante, R.P.; Reider, P.J.; Highly diastereoselective reaction of a chiral, non-racemic amide enolate with (S)-glycidyl tosylate. Synthesis of the orally active HIV-1 protease inhibitor L-735,524. Tetrahedron Lett 1994, 35, 5, 673-6.
【6】 Dorsey, B.D.; Levin, R.B.; McDaniel, S.L.; et al.; L-735,524: The design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994, 37, 21, 3443-51.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(I) 16238 (1S,2R)-2,3-dihydro-1H-indene-1,2-diol 67528-22-7 C9H10O2 详情 详情
(II) 16239 (1S,2R)-1-amino-2,3-dihydro-1H-inden-2-ol; Cis-(1S)-1-amino-2,3-dihydro-1H-inden-2-ol 126456-43-7 C9H11NO 详情 详情
(III) 16240 3-phenylpropanoyl chloride; Hydrocinnamoylchloride 645-45-4 C9H9ClO 详情 详情
(IV) 16241 1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-phenyl-1-propanone C21H23NO2 详情 详情
(V) 16242 (2R)oxiranylmethyl 4-methylbenzenesulfonate; (2R)-(-)-Glycidyl tosylate 113826-06-5 C10H12O4S 详情 详情
(VI) 16243 (2R)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-3-[(2S)oxiranyl]-1-propanone C24H27NO3 详情 详情
(VII) 16244 tert-butyl (3S)-3-[(tert-butylamino)carbonyl]tetrahydro-1(2H)-pyrazinecarboxylate 150323-35-6 C14H27N3O3 详情 详情
(VIII) 16245 (2S)-1-((2S,4R)-4-benzyl-2-hydroxy-5-[[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino]-5-oxopentyl)-N-(tert-butyl)-2-piperazinecarboxamide C30H42N4O4 详情 详情
(IX) 15793 3-(Chloromethyl)pyridine 3099-31-8 C6H6ClN 详情 详情
(X) 16247 (2S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-penten-1-one C24H27NO2 详情 详情
(XI) 16248 (2R,4S)-1-[(3aS,8aR)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-2-benzyl-4-hydroxy-5-iodo-1-pentanone C24H28INO3 详情 详情

合成路线11

该中间体在本合成路线中的序号：(VIII)

C1-C6 fragment.- The reaction of 3-methyl-2-butenylmagnesium chloride (I) with propanal (II) gives racemic 4,4-dimethyl-5-hexen-3-ol (III), which was submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme yielding the (R) enantiomer (IV). The esterification of (IV) with bromoacetyl bromide (V) and dimethylaniline yields the corresponding ester (VI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to afford chiral tetrahydropyran-2-one (VII). The reduction of (VII) with Red-Al, followed by cyclization with 2-methoxypropene (VIII) and PPTS yields the acetonide (IX), which is finally oxidized with N-methylmorpholine-N-oxide and PPTS in dichloromethane giving the target intermediate (X).

参考文献 中间体
合成目标
【1】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.
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) 27170 chloro(3-methyl-2-butenyl)magnesium C5H9ClMg 详情 详情
(II) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(III) 27171 4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(IV) 27172 (3R)-4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(V) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(VI) 27173 (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate C10H17BrO2 详情 详情
(VII) 27174 (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one C10H18O2 详情 详情
(VIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(IX) 27175 (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol C12H24O3 详情 详情
(X) 27176 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone C12H22O3 详情 详情

合成路线12

该中间体在本合成路线中的序号：(XIII)

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, TsOH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and TsOH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线13

该中间体在本合成路线中的序号：(XIII)

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线14

该中间体在本合成路线中的序号：(VII)

Boron-catalyzed condensation of propionyl oxazolidinone (I) with acrolein (II) stereoselectively provided the aldol product (III), and further methanolysis afforded beta-hydroxy ester (IV). A second aldol condensation of (IV) with methacrolein (V) furnished a difficultly separable mixture of diols (VI). Conversion of (VI) to the corresponding acetonides by treatment with 2-methoxypropene (VII) allowed chromatographical separation of the required major isomer (VIII). Hydrolysis of the acetonide, followed by ring-closing metathesis of diene (XI) in the presence of Grubbs catalyst gave rise to cyclopentene (XII). Selective silylation of the less hindered allylic hydroxyl of (XII) with tert-butyldimethylsilyl chloride yielding (XIII) and subsequent oxidation of the remaining alcohol group with MnO2 then provided ketone (XIV). Conjugate addition of lithium di-n-butylcuprate to the unsaturated ketone, followed by phenylselenylation of the intermediate enolate with PhSeBr yielded alpha-selenyl ketone (XV). Oxidative elimination of the phenylselenyl group gave a (1:1) mixture of the required unsaturated ketone (XVII) and its exomethylene isomer (XVI). Isomerization of (XVI) to the desired endo isomer (XVII) was carried out by treatment with RhCl3.

参考文献 中间体
合成目标
【1】 Sunazuka, T.; et al.; Total synthesis of (+)-madindoline A and (-)-madindoline B, potent, selective inhibitors of interleukin 6. Determination of the relative and absolute configurations. J Am Chem Soc 2000, 122, 9, 2122.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIa) 36695 methyl (2R,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate C11H18O4 详情 详情
(VIb) 36696 methyl (2S,3R)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate C11H18O4 详情 详情
(VIc),(XI) 36697 methyl (2S,3S)-3-hydroxy-2-[(1R)-1-hydroxy-2-propenyl]-2,4-dimethyl-4-pentenoate C11H18O4 详情 详情
(I) 11535 (4S)-4-Isopropyl-3-propionyl-1,3-oxazolidin-2-one 77877-19-1 C9H15NO3 详情 详情
(II) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(III) 36693 (4S)-3-[(2S,3R)-3-hydroxy-2-methyl-4-pentenoyl]-4-isopropyl-1,3-oxazolidin-2-one C12H19NO4 详情 详情
(IV) 36694 methyl (2S,3R)-3-hydroxy-2-methyl-4-pentenoate C7H12O3 详情 详情
(V) 11387 2-Methylacrylaldehyde; Methacrylaldehyde 78-85-3 C4H6O 详情 详情
(VII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VIII) 36698 methyl (4S,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate C14H22O4 详情 详情
(IX) 36699 methyl (4R,5R,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate C14H22O4 详情 详情
(X) 36700 methyl (4R,5S,6R)-4-isopropenyl-2,2,5-trimethyl-6-vinyl-1,3-dioxane-5-carboxylate C14H22O4 详情 详情
(XII) 36701 methyl (1S,2S,5R)-2,5-dihydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate C9H14O4 详情 详情
(XIII) 36702 methyl (1R,2S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-2-hydroxy-1,3-dimethyl-3-cyclopentene-1-carboxylate C15H28O4Si 详情 详情
(XIV) 36703 methyl (1S,5R)-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-cyclopentene-1-carboxylate C15H26O4Si 详情 详情
(XV) 36704 methyl (1S,5R)-4-butyl-5-[[tert-butyl(dimethyl)silyl]oxy]-1,3-dimethyl-2-oxo-3-(phenylselanyl)cyclopentanecarboxylate C25H40O4SeSi 详情 详情
(XVI) 36705 methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-methylene-5-oxocyclopentanecarboxylate C19H34O4Si 详情 详情
(XVII) 36706 methyl (1S,2R)-3-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1,4-dimethyl-5-oxo-3-cyclopentene-1-carboxylate C19H34O4Si 详情 详情

合成路线15

该中间体在本合成路线中的序号：(XIII)

The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and MeLi in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and Raney-Ni in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情

合成路线16

该中间体在本合成路线中的序号：(VI)

Preparation of the precursor alcohol (XI) is outlined in Scheme 1. Reduction of 2-bromo-5-methoxybenzoic acid (I) with borane-dimethylsulfide complex gave benzylic alcohol (II). After conversion of (II) to the corresponding mesylate, treatment with NaBr provided bromide (III). (1R,2S)-Aminoindanol (IV) was acylated with propionyl chloride to afford amide (V), which was converted to acetonide (VII) with 2-methoxypropene (VI) using pyridinium tosylate as the acid catalyst. Acetonide (VII) was then alkylated with bromide (III) in the presence of lithium hexamethyldisilazide at -35 C to give the chiral intermediate (VIII). Hydrolysis of acetonide at 10 C, followed by amide hydrolysis under reflux furnished a mixture of acid (IX) and methyl ester (X). This mixture was then reduced with LiAlH4 to provide the chiral alcohol (XI).

参考文献 中间体
合成目标
【1】 Frey, L.F.; Devine, P.N.; Tschaen, D.M.; Dolling, U.H.; Tillyer, R.D.; Kato, Y. (Banyu Pharmaceutical Co., Ltd.; Merck & Co., Inc.); Stereoselective deoxygenation reaction. EP 0923557; JP 1999514676; WO 9806700 .
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) 17819 2-bromo-5-methoxybenzoic acid 22921-68-2 C8H7BrO3 详情 详情
(II) 27551 (2-bromo-5-methoxyphenyl)methanol C8H9BrO2 详情 详情
(III) 27552 1-bromo-2-(bromomethyl)-4-methoxybenzene C8H8Br2O 详情 详情
(IV) 27559 (1R,2S)-1-amino-2,3-dihydro-1H-inden-2-ol C9H11NO 详情 详情
(V) 27553 N-[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]propanamide C12H15NO2 详情 详情
(VI) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VII) 27554 1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-1-propanone C15H19NO2 详情 详情
(VIII) 27555 (2S)-1-[(3aR,8aS)-2,2-dimethyl-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanone C23H26BrNO3 详情 详情
(IX) 27556 (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropionic acid C11H13BrO3 详情 详情
(X) 27557 methyl (2S)-3-(2-bromo-5-methoxyphenyl)-2-methylpropanoate C12H15BrO3 详情 详情
(XI) 27558 (2S)-3-(2-bromo-5-methoxyphenyl)-2-methyl-1-propanol C11H15BrO2 详情 详情

合成路线17

该中间体在本合成路线中的序号：(XIII)

The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).

参考文献 中间体
合成目标
【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622.
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) 19373 dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester 108-59-8 C5H8O4 详情 详情
(II) 31608 2,3-dichloro-1-propene 78-88-6 C3H4Cl2 详情 详情
(III) 31609 dimethyl 2-(2-chloro-2-propenyl)malonate C8H11ClO4 详情 详情
(IV) 17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(V) 31610 1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate C14H21ClO6 详情 详情
(VI) 31611 4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate C12H19ClO4 详情 详情
(VII) 31612 (2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid C11H17ClO4 详情 详情
(VIII) 29543 (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol C14H29NO2 详情 详情
(IX) 31613 tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate C25H44ClNO5 详情 详情
(X) 31614 (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid C21H36ClNO5 详情 详情
(XI) 29540 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide C17H27N3O 详情 详情
(XII) 31615 (2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C38H61ClN4O5 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 31616 (2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65ClN4O5 详情 详情
(XV) 31617 (2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide C41H65BrN4O6 详情 详情

合成路线18

该中间体在本合成路线中的序号：(II)

Protection of 2-bromoethanol (I) upon treatment with 2-methoxypropene (II) gave a mixture of ketals (III) and (IV). This mixture was used for N-alkylation of 5-bromoindole (V) in the presence of KOH to afford, after ketal hydrolysis, 1-(2-hydroxyethyl)-5-bromoindole (VI) (1). Alternatively, compound (VI) was obtained by alkylation of 5-bromoindole (V) with ethylene oxide (VII) in the presence of NaOH in DMSO (2). The hydroxyl group of (VI) was then protected as the silyl ether (VII) by treatment with tert-butyldimethylsilyl chloride. Subsequent lithium-halogen exchange in (VIII) with tert-butyllithium, followed by reaction with bismuth trichloride provided the triindolyl bismuthane (IX) (1, 2). This was oxidized with either benzoyl peroxide (1) or peracetic acid (2) to produce the corresponding di(acyloxy) pentavalent bismuthanes (X).

参考文献 中间体
合成目标
【1】 Brands, K.M.J.; et al.; Mild aryl ether formation in the semisynthesis of the novel macrolide immunosuppressant L-732,531. J Org Chem 1998, 63, 19, 6721.
【2】 Sinclair, P.J.; Goulet, M.; Wong, F.; Parsons, W.H.; Goulet, J.; Wyvratt, M.J. (Merck & Co., Inc.); O-Heteroaryl, O-alkylheteroaryl, O-alkenylheteroaryl and O-alkynylheteroaryl macrolides. EP 0532088; JP 1994116274; US 5252732; WO 9305058 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(Xa) 26858 2-[5-(bis(acetoxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether C52H78BiN3O7Si3 详情 详情
(Xb) 26859 2-[5-(bis(benzoyloxy)[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]]-lambda(5)-bismuthanyl)-1H-indol-1-yl]ethyl tert-butyl(dimethyl)silyl ether C62H82BiN3O7Si3 详情 详情
(I) 10059 Ethylene bromohydrin; 2-Bromo-1-ethanol 540-51-2 C2H5BrO 详情 详情
(II) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(III) 26853 2-(2-bromoethoxy)-2-methoxypropane C6H13BrO2 详情 详情
(IV) 26854 1-(2-bromoethoxy)-1-methylethyl 2-bromoethyl ether C7H14Br2O2 详情 详情
(V) 13309 5-Bromo-1H-indole; 5-Bromoindole 10075-50-0 C8H6BrN 详情 详情
(VI) 26855 2-(5-bromo-1H-indol-1-yl)-1-ethanol C10H10BrNO 详情 详情
(VII) 10393 Oxirane; Ethylene oxide 75-21-8 C2H4O 详情 详情
(VIII) 26856 2-(5-bromo-1H-indol-1-yl)ethyl tert-butyl(dimethyl)silyl ether C16H24BrNOSi 详情 详情
(IX) 26857 2-(5-[bis[1-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-1H-indol-5-yl]bismuthino]-1H-indol-1-yl)ethyl tert-butyl(dimethyl)silyl ether C48H72BiN3O3Si3 详情 详情

合成路线19

该中间体在本合成路线中的序号：(XXIII)

The reaction of 3-methyl-2-butenylmagnesium bromide (XVI) with propanal (XVII) gives racemic hexenol (XVIII), which is submitted to enzymatic resolution with ChiroCLEC-PC dry enzyme, yielding the R-enantiomer (XIX). The esterification of (XIX) with bromoacetyl bromide (XX) and dimethylaniline (DMA) affords the corresponding ester (XXI), which is oxidized with O3 and trimethyl phosphite and cyclized with SmI2 in THF to provide the chiral tetrahydropyranone (XXII). The reduction of (XXII) with Red-Al, followed by cyclization with 2-methoxypropene (XXIII) and PPTS, gives the acetonide (XXIV), which is oxidized with PPTS and NMO to provide the protected dihydroxyketone (XXV). The condensation of the ketone (XXV) with 2(S)-methyl-6-heptenal (XXVI) by means of LDA in THF gives the hydroxyundecenone (XXVII), which is treated with pyridinium p-toluenesulfonate (PPTS) in methanol to cleave the 1,3-dioxane ring and yield the trihydroxy compound (XXVIII). The silylation of (XXVIII) with Tbdms-OTf and lutidine in dichloromethane affords the fully silylated compound (XXIX), which is selectively monodesilylated with CSA to provide the primary alcohol (XXX). Finally, this alcohol is oxidized by means of pyridinium dichromate (PDC) in DMF to furnish the target tridecenoic acid intermediate (XII).

参考文献 中间体
合成目标
【1】 Schinzer, D.; et al.; Total synthesis of (-)-epothilone A. Angew Chem. Int Ed Engl 1997, 36, 5, 523.
【2】 Taylor, R.E.; et al.; A formal total synthesis of epothiolone A: Enantioselective preparation of the C1-C6 and C7-C12 fragments. J Org Chem 1998, 63, 25, 9580.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XVI) 27170 chloro(3-methyl-2-butenyl)magnesium C5H9ClMg 详情 详情
(XVII) 15966 propionaldehyde 123-38-6 C3H6O 详情 详情
(XVIII) 27171 4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(XIX) 27172 (3R)-4,4-dimethyl-5-hexen-3-ol C8H16O 详情 详情
(XX) 14005 2-Bromoacetyl bromide; Bromoacetyl bromide 598-21-0 C2H2Br2O 详情 详情
(XXI) 27173 (1R)-1-ethyl-2,2-dimethyl-3-butenyl 2-bromoacetate C10H17BrO2 详情 详情
(XXII) 27174 (4S,6R)-6-ethyl-4,5,5-trimethyltetrahydro-2H-pyran-2-one C10H18O2 详情 详情
(XXIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XXIV) 27175 (3R)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanol C12H24O3 详情 详情
(XXV) 27176 2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methyl-3-pentanone C12H22O3 详情 详情
(XXVI) 27185 (2S)-2-methyl-6-heptenal C8H14O 详情 详情
(XXVII) 44434 (4R,5S,6S)-2-[(4S)-2,2-dimethyl-1,3-dioxan-4-yl]-5-hydroxy-2,4,6-trimethyl-10-undecen-3-one C20H36O4 详情 详情
(XXVIII) 44435 (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8-tetramethyl-12-tridecen-5-one C17H32O4 详情 详情
(XXIX) 44436 (5S,6R,9S)-9-[[tert-butyl(dimethyl)silyl]oxy]-2,2,3,3,6,8,8,13,13,14,14-undecamethyl-5-[(1S)-1-methyl-5-hexenyl]-4,12-dioxa-3,13-disilapentadecan-7-one C35H74O4Si3 详情 详情
(XXX) 44437 (5S,8R,9S)-5-(2-hydroxyethyl)-2,2,3,3,6,6,8,11,11,12,12-undecamethyl-9-[(1S)-1-methyl-5-hexenyl]-4,10-dioxa-3,11-disilatridecan-7-one C29H60O4Si2 详情 详情
(XXX) 44438 (3S,6R,7S,8S)-3,7-bis[[tert-butyl(dimethyl)silyl]oxy]-4,4,6,8-tetramethyl-5-oxo-12-tridecenoic acid C29H58O5Si2 详情 详情

合成路线20

该中间体在本合成路线中的序号：(VII)

Condensation of protected ketone (I) with 2-benzyloxy-1-trimethylsilyloxyphenoxyethane (II) by means of Sn(OTf)2 and chiral amine (III) in propionitrile affords aldolic reaction product (IV), which is then dehydroxylated by treatment with thiocarbonyl diimidazole (A) in THF followed by reduction with Bu3SnH in refluxing toluene to provide the protected hydroxyester (V). Reduction of the ester group of (V) with DIBAL in CH2Cl2 followed by Swern oxidation with (COCl)2, DMSO and Et3N in dichloromethane yields aldehyde (VI), which is then condensed with 2-methoxypropene (VII) and 2-methoxyaniline (VIII) in the presence of yterbium triflate (Yb(OTf)3) in THF/H2O to furnish a mixture of diastereoisomers from which anti-(IX) is separated. Derivative anti-(IX) is treated with HF in THF for TBS removal and cyclization is induced by reaction with PPh3 and CBr4 in CH2Cl2, affording piperidine (X). Next, treatment of (X) with cerium ammonium nitrate (CAN) in acetonitrile/H2O allows N-protecting group removal, giving piperidine derivative (XI). Alternatively, (XI) can be obtained as follows: Treatment of aldehyde (VI) with 2-methoxyaniline (VIII) and PMB-protected 2-methoxypropene (XII) in the presence of scandium trisdodecylsulfate (STDS) in THF/H2O yields a mixture of diastereoisomers from which anti-(XIII) is separated. Derivative anti-(XIII) is then converted into (XI) by following the same procedure as for the conversion of anti-(IX) into (XI). Derivative (XI) is then subjected to: (i) N-protection by means of Boc2O; (ii) treatment with lithium hexamethyl disilazide (LHMDS) followed by trimethylsilyl chloride (TMSCl); (iii) oxidation of the silylenol ether by means of MCPBA; and (iv) bromination with PPh3 and CBr4. After all these steps bromo derivative (XIV) is obtained. Finally, coupling of (XIV) with 4-hydroxyquinazoline (XV) using KOH followed by Boc removal by treatment with refluxing HCl furnishes the target compound.

参考文献 中间体
合成目标
【1】 Wataya, Y.; Ueno, M.; Suzuki, R.; Kim, H.-S.; Kobayashi, S.; Ishitani, H.; Catalytic asymmetric synthesis of antimalarial alkaloids febrifubine and isofebrifugine and their biological actvity. J Org Chem 1999, 64, 18, 6833.
【2】 Kobayashi, S.; Kim, H.-S.; Wataya, Y. (Japan Science and Technology Corp.); Febrifugine and isofebrifugine and processes for the preparation of both. EP 1076057; WO 0052005 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 11990 Di(1H-imidazol-1-yl)methanethione; 1,1'-Thiocarbonyldiimidazole 6160-65-2 C7H6N4S 详情 详情
(I) 44768 4-[[tert-butyl(dimethyl)silyl]oxy]-2-butanone C10H22O2Si 详情 详情
(II) 44769 benzyl (Z)-2-phenoxy-2-[(trimethylsilyl)oxy]ethenyl ether; [[(Z)-2-(benzyloxy)-1-phenoxyethenyl]oxy](trimethyl)silane C18H22O3Si 详情 详情
(III) 44770 N-[[(2S)-1-methylpyrrolidinyl]methyl]-N-(1-naphthyl)amine; N-[[(2S)-1-methylpyrrolidinyl]methyl]-1-naphthalenamine 82160-07-4 C16H20N2 详情 详情
(IV) 44771 phenyl (2S,3R)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxypentanoate C24H34O5Si 详情 详情
(V) 44773 phenyl (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanoate C24H34O4Si 详情 详情
(VI) 44774 (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanal C18H30O3Si 详情 详情
(VII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VIII) 25193 2-methoxyphenylamine; 2-methoxyaniline 517-28-2 C7H9NO 详情 详情
(IX) 44777 　 C27H42NO4Si 详情 详情
(X) 44778 1-[(2R,3S)-3-(benzyloxy)-1-(2-methoxyphenyl)piperidinyl]acetone C22H27NO3 详情 详情
(XI) 44779 1-[(2R,3S)-3-(benzyloxy)piperidinyl]acetone C15H21NO2 详情 详情
(XII) 44780 1-methoxy-4-(3-methoxy-3-butenyl)benzene; 4-(3-methoxy-3-butenyl)phenyl methyl ether C12H16O2 详情 详情
(XIII) 44781 　 C35H50NO5Si 详情 详情
(XIV) 44782 tert-butyl (2R,3S)-3-(benzyloxy)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate C20H28BrNO4 详情 详情
(XV) 44783 4-quinazolinol C8H6N2O 详情 详情

合成路线21

该中间体在本合成路线中的序号：(IX)

The enantioselective condensation of the silylated 4-hydroxy-2-butanone (I) with the silylated enol ester (II) by means of Sn(OTf)2 and the chiral pyrrolidine (III) gives the chiral benzylated trihydroxyester (IV), which is partially dehydroxylated with thiocarbonyl diimidazole (TCDI) and tributyltin hydride in refluxing toluene to yield the protected dihydroxy ester (V). The reduction of (V) with DIBAL in dichloromethane affords the corresponding alcohol (VI), which is oxidized with oxalyl chloride and TEA in DMSO/dichloromethane to provide the aldehyde (VII). The condensation of (VII) with the enol ether (IX) and 2-methoxyaniline (VIII) by means of Yb(OTf)3 in THF/water gives the beta aminoketone (X), which is cyclized by means of HF, PPh3, CBr4 and cerium ammonium nitrate (CAN) in acetonitrile/water to yield the chiral piperidine (XI). The bromination of (XI) with Br2 and HBr in HOAc affords the bromo derivative (XII), which is treated with Boc2O to provide the N-protected piperidine (XIII). The condensation of (XIII) with quinazolin-4(3H)-one (XIV) by means of KOH gives the adduct (XV), which is finally deprotected and cyclized by treatment with refluxing 6N HCl to afford the target isofebrifugine.

参考文献 中间体
合成目标
【1】 Wataya, Y.; Ueno, M.; Suzuki, R.; Kim, H.-S.; Kobayashi, S.; Ishitani, H.; Catalytic asymmetric synthesis of antimalarial alkaloids febrifubine and isofebrifugine and their biological actvity. J Org Chem 1999, 64, 18, 6833.
【2】 Kobayashi, S.; Kim, H.-S.; Wataya, Y. (Japan Science and Technology Corp.); Febrifugine and isofebrifugine and processes for the preparation of both. EP 1076057; WO 0052005 .
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) 44768 4-[[tert-butyl(dimethyl)silyl]oxy]-2-butanone C10H22O2Si 详情 详情
(II) 44769 benzyl (Z)-2-phenoxy-2-[(trimethylsilyl)oxy]ethenyl ether; [[(Z)-2-(benzyloxy)-1-phenoxyethenyl]oxy](trimethyl)silane C18H22O3Si 详情 详情
(III) 51268 N-(1-naphthyl)-N-[(2S)pyrrolidinylmethyl]amine; N-[(2S)pyrrolidinylmethyl]-1-naphthalenamine C15H18N2 详情 详情
(IV) 44771 phenyl (2S,3R)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]-3-hydroxypentanoate C24H34O5Si 详情 详情
(V) 44773 phenyl (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanoate C24H34O4Si 详情 详情
(VI) 41269 2-(2-fluoro-4'-hydroxy[1,1'-biphenyl]-4-yl)acetic acid C14H11FO3 详情 详情
(VII) 44774 (2S)-2-(benzyloxy)-5-[[tert-butyl(dimethyl)silyl]oxy]pentanal C18H30O3Si 详情 详情
(VIII) 25193 2-methoxyphenylamine; 2-methoxyaniline 517-28-2 C7H9NO 详情 详情
(IX) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(X) 41270 8-(acetamido)-2,3-dihydro-1,4-benzodioxine-5-carboxylic acid C11H11NO5 详情 详情
(XI) 51271 1-[(2S,3S)-3-(benzyloxy)piperidinyl]acetone C15H21NO2 详情 详情
(XII) 51272 1-[(2S,3S)-3-(benzyloxy)piperidinyl]-3-bromoacetone C15H20BrNO2 详情 详情
(XIII) 51273 tert-butyl (2S,3S)-3-(benzyloxy)-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate C20H28BrNO4 详情 详情
(XIV) 14634 4(3H)-quinazolinone C8H6N2O 详情 详情
(XV) 51274 tert-butyl (2S,3S)-3-(benzyloxy)-2-[2-oxo-3-[4-oxo-3(4H)-quinazolinyl]propyl]-1-piperidinecarboxylate C28H33N3O5 详情 详情

合成路线22

该中间体在本合成路线中的序号：(VI)

The condensation of 2,4,6-trimethylaniline (I) with adipoin (II) in hot toluene, followed by reaction of the resulting intermediate (III) with malononitrile (IV), gave rise to the tetrahydroindole (V). Subsequent condensation of amino nitrile (V) with 2-methoxypropene (VI) produced the tetrahydropyrido[2,3-b]indole system (VII), which was dehydrogenated to (VIII) by means of Pd/C in boiling decalin. Acylation of (VIII) with isobutyryl chloride (IX) afforded amide (X), which was reduced to amine (XI) employing borane-dimethyl sulfide complex. Further acylation with chloroacetyl chloride (XII), and then reduction of the resulting chloroacetamide (XIII) with borane-dimethyl sulfide, provided the chloroethyl amine (XIV). This was finally treated with dimethylamine in hot N-methylpyrrolidinone in a steel bomb to furnish the desired dimethylamino compound.

参考文献 中间体
合成目标
【1】 Darrow, J.W.; Maynard, G.D.; Horvath, R.F. (Neurogen Corp.); Aminoalkyl substd. 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivs.. EP 1068207; US 6147085; WO 9951600 .
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) 28804 2,4,6-trimethylaniline 88-05-1 C9H13N 详情 详情
(II) 44979 2-hydroxycyclohexanone 533-60-8 C6H10O2 详情 详情
(III) 44980 2-(mesitylamino)-1-cyclohexen-1-ol C15H21NO 详情 详情
(IV) 12061 Malononitrile 109-77-3 C3H2N2 详情 详情
(V) 44981 2-amino-1-mesityl-4,5,6,7-tetrahydro-1H-indole-3-carbonitrile C18H21N3 详情 详情
(VI) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(VII) 44982 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-4-amine C21H25N3 详情 详情
(VIII) 44983 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-ylamine; 9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine C21H21N3 详情 详情
(IX) 14932 isobutyryl chloride; 2-methylpropanoyl chloride 79-30-1 C4H7ClO 详情 详情
(X) 44984 N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)-2-methylpropanamide C25H27N3O 详情 详情
(XI) 44985 N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine C25H29N3 详情 详情
(XII) 11296 2-Chloroacetyl chloride; Chloroacetic chloride 79-04-9 C2H2Cl2O 详情 详情
(XIII) 44986 2-chloro-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)acetamide C27H30ClN3O 详情 详情
(XIV) 44987 N-(2-chloroethyl)-N-isobutyl-9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-amine; N-(2-chloroethyl)-N-isobutyl-N-(9-mesityl-2-methyl-9H-pyrido[2,3-b]indol-4-yl)amine C27H32ClN3 详情 详情

合成路线23

该中间体在本合成路线中的序号：(XIII)

Synthesis of undecenoic ester intermediate (XXI): The reaction of 2,2-dimethylpropane-1,3-diol (I) with benzaldehyde, Ts-OH and DIBAL gives the monobenzyl ether (II), which is oxidized with SO3/pyridine in dichloromethane, yielding the propionaldehyde (III). The condensation of (III) with butanone (IV) by means of LDA and TFAA affords the heptenone (V), which is epoxidated with H2O2 and NaOH in aq. methanol to provide the racemic epoxide (rac)-(VI). The reaction of ketone (VI) with O-methylhydroxylamine and NaOAc in methanol gives the corresponding oxime (rac)-(VII), which is treated with CuCN and Me-Li in ethyl ether to yield the beta-hydroxy oxime (rac)-(VIII). The treatment of (VIII) with H2 and RaNi in acetone/THF affords the corresponding beta-hydroxy ketone (rac)-(IX), which is allylated with allyl bromide (X) and LHMDS in the presence of 1,3-dimethylperhydropyrimidin-2-one to give the beta-hydroxynonen-5-one (rac)-(XI). The reduction of (XI) with Me4NBH(OAc)3 and HOAc in acetonitrile yields the diol (rac)-(XII), which is protected with 2-methoxypropene (XIII) and Ts-OH, affording the 1,3-dioxane (rac)-(XIV). The reaction of (XIV) with Li in liquid ammonia, tert-butanol and THF provides the debenzylated primary alcohol (rac)-(XV), which is oxidized with tetrapropylammonium perrhuthenate in dichloromethane, giving the corresponding aldehyde (rac)-(XVI).

参考文献 中间体
合成目标
【1】 Sawada, D.; et al.; Enantioselective total synthesis of epothilones A and B using multifunctional asymmetric catalysis. J Am Chem Soc 2000, 122, 43, 10521.
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) 12641 Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol 126-30-7 C5H12O2 详情 详情
(II) 44529 3-(benzyloxy)-2,2-dimethyl-1-propanol C12H18O2 详情 详情
(III) 44504 3-(benzyloxy)-2,2-dimethylpropanal C12H16O2 详情 详情
(IV) 33891 Methyl ethyl ketone; 2-Butanone 78-93-3 C4H8O 详情 详情
(V) 44505 (E)-7-(benzyloxy)-6,6-dimethyl-4-hepten-3-one C16H22O2 详情 详情
(VI) 44506 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone C16H22O3 详情 详情
(VII) 44507 1-[3-[2-(benzyloxy)-1,1-dimethylethyl]-2-oxiranyl]-1-propanone O-methyloxime C17H25NO3 详情 详情
(VIII) 44508 (4R,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone O-methyloxime C18H29NO3 详情 详情
(IX) 44509 (4S,5R)-7-(benzyloxy)-5-hydroxy-4,6,6-trimethyl-3-heptanone C17H26O3 详情 详情
(X) 11463 3-Bromo-1-propene; 3-Bromopropene；allyl bromide 106-95-6 C3H5Br 详情 详情
(XI) 44510 (4S,6S,7R)-9-(benzyloxy)-7-hydroxy-4,6,8,8-tetramethyl-1-nonen-5-one C20H30O3 详情 详情
(XII) 44511 (3R,4R,5S,6S)-1-(benzyloxy)-2,2,4,6-tetramethyl-8-nonene-3,5-diol C20H32O3 详情 详情
(XIII) 17354 isopropenyl methyl ether; 2-methoxy-1-propene 116-11-0 C4H8O 详情 详情
(XIV) 44512 benzyl 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propyl ether; (4R,5S,6S)-4-[2-(benzyloxy)-1,1-dimethylethyl]-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxane C23H36O3 详情 详情
(XV) 44513 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]-1-propanol C16H30O3 详情 详情
(XVI) 44514 2-methyl-2-[(4R,5S,6S)-2,2,5-trimethyl-6-[(1S)-1-methyl-3-butenyl]-1,3-dioxan-4-yl]propanal C16H28O3 详情 详情
Extended Information