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【结 构 式】 
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【分子编号】34374 【品名】(2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid 【CA登记号】 |
【 分 子 式 】C21H32O3Si 【 分 子 量 】360.56878 【元素组成】C 69.95% H 8.95% O 13.31% Si 7.79% |
合成路线1
该中间体在本合成路线中的序号：(X)The intermediate epoxyamide (XVIII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensa-tion of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide.
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The intermediate epoxyamide (XVII) has been obtained as follows: The cyclization of 2-methylacetoacetic acid ethyl ester (I) by means of potassium tert-butoxide gives 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one (I), which is enantiomerically reduced with Mortierella isabellina ATCC 42613 yielding (S,S)-4-hydroxy-3-methyltetrahydropyran-2-one (III). The silylation of (III) by means of TBDMS-Cl, imidazole and DMAP affords the silyl ether (IV), which is reduced with DIBAL to the corresponding lactol and condensed with benzyldiphenylphosphine oxide (V) to give (3S,4R)-3-(tert-butyldimethylsilyloxy)-4-methyl-6-phenyl-5-hexen-1-ol (VI). The oxidation of (VI) with oxalyl chloride in dichloromethane/DMSO yields the corresponding aldehyde (VII), which is submitted to a Wittig condensation with trimethyl phosphonoacetate (VIII) by means of 1,1,3,3-tetramethylguanidine (TMG) to afford the octadienoic ester (IX). The hydrolysis of (IX) with KOH in dioxane gives the corresponding acid (X), which is esterified with N-hydroxysuccinimide (XI) and EDC to give the activated ester (XII). The epoxidation of (XII) with oxone or MCPBA, followed by HPLC chromatography separation of the resulting mixture of epoxides, gives the (2E,5S,6S,7R,8R)-5-(tert-butyldimethylsilyloxy)-7,8-epoxy-6-methyl-8-phenyl-2-octenoic acid N-succinimidinyl ester (XIII). The condensation of activated ester (XIII) with amino acid (XIV) yields the corresponding amide (XV), which is desilylated with TBAF in DMF to afford the hydroxyacid (XVI). Finally, compound (XVI) is treated with DMSO and NaHCO3 and tert-butyl bromide to provide the desired intermediate the epoxyamide (XVII).
| 【1】 Zmijewski, M.J.J.; Zhang, T.Y.; Aikins, J.A.; Briggs, B.S. (Eli Lilly and Company; University of Hawaii; Wayne State University); Stereoselective process for producing antineoplastic agents. WO 0023429 . |
| 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) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
| (II) | 36494 | 4-hydroxy-3-methyl-5,6-dihydro-2H-pyran-2-one | C6H8O3 | 详情 | 详情 | |
| (III) | 36495 | (3S,4S)-4-hydroxy-3-methyltetrahydro-2H-pyran-2-one | C6H10O3 | 详情 | 详情 | |
| (IV) | 36496 | (3S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-3-methyltetrahydro-2H-pyran-2-one | C12H24O3Si | 详情 | 详情 | |
| (V) | 36497 | benzyl(diphenyl)phosphine oxide; benzyl(oxo)diphenylphosphorane | 2959-74-2 | C19H17OP | 详情 | 详情 |
| (VI) | 36498 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexen-1-ol | C19H32O2Si | 详情 | 详情 | |
| (VII) | 36499 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-6-phenyl-5-hexenal | C19H30O2Si | 详情 | 详情 | |
| (VIII) | 13272 | Methyl 2-(dimethoxyphosphoryl)acetate; Trimethyl phosphoroacetate | 5927-18-4 | C5H11O5P | 详情 | 详情 |
| (IX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (X) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XI) | 10264 | 1-Hydroxydihydro-1H-pyrrole-2,5-dione; N-Hydroxysuccinimide; 1-Hydroxy-2,5-pyrrolidinedione | 6066-82-6 | C4H5NO3 | 详情 | 详情 |
| (XII) | 36500 | 1-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)oxy]-2,5-pyrrolidinedione | C25H35NO5Si | 详情 | 详情 | |
| (XIII) | 36501 | 1-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]oxy)-2,5-pyrrolidinedione | C25H35NO6Si | 详情 | 详情 | |
| (XIV) | 36502 | (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propionic acid | C10H12ClNO3 | 详情 | 详情 | |
| (XV) | 36503 | (2R)-2-([(E,5S,6R)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C31H42ClNO6Si | 详情 | 详情 | |
| (XVI) | 36504 | N,N,N-tributyl-1-butanaminium (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C41H63ClN2O6 | 详情 | 详情 | |
| (XVII) | 36505 | (methylsulfanyl)methyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-([(E,5S,6S)-5-hydroxy-6-[(2R,3S)-3-phenyloxiranyl]-2-heptenoyl]amino)propanoate | C27H32ClNO6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXI)Synthesis of 261501: The optical resolution of trans-3-penten-2-ol (IX) with porcine pancreatic lipase (PPL) and trifluoroethyl laurate in ethyl ether gives the (S)-trans-isomer (X), which is condensed with propargyl alcohol (XI) by means of tetrabutylammonium hyrogensulfate and NaOH in water, yielding the corresponding ether (XII). Rearrangement of (XII) by means of BuLi in THF affords (3R,4R,5E)-4-methylhept-5-en-1-yn-3-ol (XIII), which is silylated with Tbdms-Cl and imidazole to afford the corresponding silyl ether (XIV). The reaction of (XIV) with BH3 in THF provides the aldehyde (XV), which is condensed with phosphonate (XVI) by means of tetramethylguanidine (TMG) in THF to give the nonadienoic ester (XVII). Ozonolysis of (XVII), followed by reaction with Zn/HOAc yields the aldehyde (XVIII), which is condensed with benzyltriphenylphosphonium chloride (XIX) by means of BuLi in THF to afford the 8-phenyloctadienoic ester (XX). The hydrolysis of (XX) with LiOH in acetone/water furnishes the corresponding free acid (XXI), which is condensed with 3-chloro-4-methoxy-L-phenylalanine trichloroethyl ester (XXII) by means of pentafluorodiphenylphosphinate (FDPP) and DIEA in DMF to give the corresponding amide (XXIII). The desilylation of (XXIII) with aqueous HF in acetonitrile affords the hydroxyamide (XXIV), which is esterified with the intermediate 2(S)-[3-(tert-butoxycarbonylamino)-2,2-dimethylpropionyloxy]-4-methylpentanoic acid (VIII) by means of DCC and DMAP in dichloromethane gives the corresponding ester (XXV).
| 【1】 WO 9640184 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (IX) | 42786 | (E)-3-penten-2-ol | C5H10O | 详情 | 详情 | |
| (X) | 42787 | (2S,3E)-3-penten-2-ol | C5H10O | 详情 | 详情 | |
| (XI) | 16664 | Propargyl Alcohol; 2-propyn-1-ol | 107-19-7 | C3H4O | 详情 | 详情 |
| (XII) | 42788 | (1S,2E)-1-methyl-2-butenyl 2-propynyl ether; (E,4S)-4-(2-propynyloxy)-2-pentene | C8H12O | 详情 | 详情 | |
| (XIII) | 42789 | (3R,4R,5E)-4-methyl-5-hepten-1-yn-3-ol | C8H12O | 详情 | 详情 | |
| (XIV) | 42790 | tert-butyl(dimethyl)silyl (1R,2R,3E)-1-ethynyl-2-methyl-3-pentenyl ether; tert-butyl[[(1R,2R,3E)-1-ethynyl-2-methyl-3-pentenyl]oxy]dimethylsilane | C14H26OSi | 详情 | 详情 | |
| (XV) | 42791 | (3S,4R,5E)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methyl-5-heptenal | C14H28O2Si | 详情 | 详情 | |
| (XVI) | 27698 | methyl 2-(diethoxyphosphoryl)acetate | 1067-74-9 | C7H15O5P | 详情 | 详情 |
| (XVII) | 42792 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-2,7-nonadienoate | C17H32O3Si | 详情 | 详情 | |
| (XVIII) | 42793 | methyl (E,5S,6S)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-7-oxo-2-heptenoate | C15H28O4Si | 详情 | 详情 | |
| (XIX) | 42794 | Benzyl(triphenyl)phosphonium chloride | 1449-46-3 | C25H22ClP | 详情 | 详情 |
| (XX) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (XXI) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (XXII) | 42795 | 2,2,2-trichloroethyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl)propanoate | C12H13Cl4NO3 | 详情 | 详情 | |
| (XXIII) | 42796 | 2,2,2-trichloroethyl (2R)-2-[((2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoyl)amino]-3-(3-chloro-4-methoxyphenyl)propanoate | C33H43Cl4NO5Si | 详情 | 详情 | |
| (XXIV) | 18905 | 2,2,2-trichloroethyl (2R)-3-(3-chloro-4-methoxyphenyl)-2-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]amino]propanoate | C27H29Cl4NO5 | 详情 | 详情 | |
| (XXV) | 18906 | 2,2,2-trichloroethyl (10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oate | C43H56Cl4N2O10 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VII)The known methyl ester (VI was hydrolyzed to carboxylic acid (VII) with LiOH in aqueous acetone. After conversion of (VII) to the corresponding succinimidyl ester with N-hydroxysuccinimide and EDC, fluoride-mediated desilylation under acidic conditions furnished alcohol (VIII). Subsequent esterification of (VIII) with the protected amino acid (IX) using EDC and a catalytic amount of DMAP provided intermediate (X). Then, chemoselective coupling of (X) with amino acid (V) was achieved in the presence of N,O-bis(trimethylsilyl)acetamide (BSA) in hot DMF to afford the acyclic precursor (XI). After removal of the Boc group of (XI) with trifluoroacetic acid, the resulting amino acid (XII) was converted to the cyclic depsipeptide (XIII) by macrolactonization under high dilution conditions in the presence of pentafluorophenyl diphenylphosphinate. The aryl amine of (XIII) was protected as the Fmoc derivative (XIV).
| 【1】 Schultz, R.M.; Andis, S.L.; Ray, J. E.; Patel, V.F.; Kennedy, J.H.; Novel cryptophycin antitumor agents: Synthesis and cytotoxicity of fragment "B" analogues. J Med Chem 1999, 42, 14, 2588. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40597 | 9-[[(chlorocarbonyl)oxy]methyl]-9H-fluorene | 28920-43-6 | C15H11ClO2 | 详情 | 详情 | |
| (V) | 34372 | (2R)-2-amino-3-(4-amino-3-chlorophenyl)propionic acid | C9H11ClN2O2 | 详情 | 详情 | |
| (VI) | 34373 | methyl (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoate | C22H34O3Si | 详情 | 详情 | |
| (VII) | 34374 | (2E,5S,6R,7E)-5-[[tert-butyl(dimethyl)silyl]oxy]-6-methyl-8-phenyl-2,7-octadienoic acid | C21H32O3Si | 详情 | 详情 | |
| (VIII) | 34375 | 1-[[(2E,5S,6R,7E)-5-hydroxy-6-methyl-8-phenyl-2,7-octadienoyl]oxy]-2,5-pyrrolidinedione | C19H21NO5 | 详情 | 详情 | |
| (IX) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (X) | 34376 | (1S,3E)-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-5-oxo-3-pentenyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate | C35H48N2O10 | 详情 | 详情 | |
| (XI) | 34377 | (10S,13S,15E,19R)-19-(4-amino-3-chlorobenzyl)-10-isobutyl-2,2,7,7-tetramethyl-13-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-4,8,11,17-tetraoxo-3,9,12-trioxa-5,18-diaza-15-icosen-20-oic acid | C40H54ClN3O9 | 详情 | 详情 | |
| (XII) | 34378 | (2R)-3-(4-amino-3-chlorophenyl)-2-[[(2E,5S,6R,7E)-5-([(2S)-2-[(3-amino-2,2-dimethylpropanoyl)oxy]-4-methylpentanoyl]oxy)-6-methyl-8-phenyl-2,7-octadienoyl]amino]propionic acid | C35H46ClN3O7 | 详情 | 详情 | |
| (XIII) | 34379 | (3S,10R,16S)-10-(4-amino-3-chlorobenzyl)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C35H44ClN3O6 | 详情 | 详情 | |
| (XIV) | 34380 | 9H-fluoren-9-ylmethyl 2-chloro-4-([(3S,10R,16S)-3-isobutyl-6,6-dimethyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-2,5,9,12-tetraoxo-1,4-dioxa-8,11-diaza-13-cyclohexadecen-10-yl]methyl)phenylcarbamate | C50H54ClN3O8 | 详情 | 详情 |