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【结 构 式】 
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【分子编号】18905 【品名】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 【CA登记号】 |
【 分 子 式 】C27H29Cl4NO5 【 分 子 量 】589.3418 【元素组成】C 55.03% H 4.96% Cl 24.06% N 2.38% O 13.57% |
合成路线1
该中间体在本合成路线中的序号：(VIII)Title compound can be prepared either by bacterial fermentation or by chemical synthesis. Thus, the compund was isolated from cultures of Nostoc sp. GSV 224, growing in the presence of 2,2-dimethyl-b-alanine. After lyophilization and extraction with CH3CN-CH2Cl2, the extract was subjected to several chromatographic purifications to provide the pure compound. Alternatively, 2,2-dimethyl-b-alanine tert-butyl ester (I) was deprotected with trifluoroacetic acid, and the resulting carboxylic acid (II) was treated with di tert-butyl oxalate (III) in the presence of NaOH to afford carbamate (IV). Subsequent coupling with allyl (S)-2-hydroxy-4-methylpentanoate (V) using DCC and DMAP gave ester (VI). The allyl ester was then cleaved by treatment with Pd(Ph3P)4 and morpholine in THF at r.t., and the resulting acid (VII) was coupled with compound (VIII) in the presence of DCC and DMAP to afford (IX). After deprotection of the trichloroethyl ester group by treatment with Zn in AcOH and subsequent cleavage of the N-Boc group with trifluoroacetic acid, the resulting amino acid compound (XI) was cyclized using pentafluorophenyl diphenyl phosphinate (FDPP) to furnish (XII). Finally, epoxidation with meta-chloroperbenzoic acid provided a mixture of diastereomeric epoxides that were separated by reverse phase HPLC.
| 【1】 Shih, C.; Gossett, L.S.; Gruber, J.M.; Grossman, C.S.; Andis, S.L.; Schultz, R.M.; Worzalla, J.F.; Corbett, T.H.; Metz, J.T.; Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region. Bioorg Med Chem Lett 1999, 9, 1, 69. |
| 【2】 Moore, R.E.; Patel, V.F.; Ray, J.E.; Toth, J.E. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0850057; JP 2000501067; WO 9707798; WO 9708334 . |
| 【3】 Shih, C. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0869786; JP 2000502351; WO 9723211 . |
| 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) | 18898 | tert-butyl 3-amino-2,2-dimethylpropanoate | C9H19NO2 | 详情 | 详情 | |
| (II) | 18899 | 2,2-dimethyl-beta-alanine | C5H11NO2 | 详情 | 详情 | |
| (III) | 18900 | tert-butyl 2-(tert-butoxy)-2-oxoacetate | C10H18O4 | 详情 | 详情 | |
| (IV) | 18901 | N-(tert-butoxycarbonyl)-2,2-dimethyl-beta-alanine | C10H19NO4 | 详情 | 详情 | |
| (V) | 18902 | allyl (2S)-2-hydroxy-4-methylpentanoate | C9H16O3 | 详情 | 详情 | |
| (VI) | 18903 | allyl (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoate | C19H33NO6 | 详情 | 详情 | |
| (VII) | 18904 | (2S)-2-([3-[(tert-butoxycarbonyl)amino]-2,2-dimethylpropanoyl]oxy)-4-methylpentanoic acid | C16H29NO6 | 详情 | 详情 | |
| (VIII) | 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 | |
| (IX) | 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 | |
| (X) | 18907 | (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-oic acid | C41H55ClN2O10 | 详情 | 详情 | |
| (XI) | 18908 | (2R)-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]-3-(3-chloro-4-methoxyphenyl)propionic acid | C36H47ClN2O8 | 详情 | 详情 | |
| (XII) | 18909 | (3S,10R,16S)-10-(3-chloro-4-methoxybenzyl)-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 | C36H45ClN2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Condensation of (R)-3-(tert-butoxycarbonylamino)butyric acid (II) with hydroxyester (I) using DCC and DMAP provided compound (III). Removal of the allyl group of (III) ester was then effected by treatment with Pd(PPh3)4 and N-methylmorpholine (NMM) to afford acid (IV). Subsequent coupling of (IV) with alcohol (V) in the presence of DCC and DMAP yielded the corresponding ester (VI). After deprotection of the trichloroethyl ester with Zn in AcOH, and subsequent deprotection of the N-tert--butoxycarbonyl group with trifluoroacetic acid, the resulting amino acid compound (VIII) was cyclized by treatment with FDPP in the presence of diisopropylethylamine to provide lactam (IX). Finally, epoxidation of the styrene olefin with m-chloroperbenzoic acid in CH2Cl2 furnished a mixture of diastereoisomeric epoxides, from which the title compound was isolated by reverse-phase HPLC.
| 【1】 Shih, C.; Gossett, L.S.; Gruber, J.M.; Grossman, C.S.; Andis, S.L.; Schultz, R.M.; Worzalla, J.F.; Corbett, T.H.; Metz, J.T.; Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region. Bioorg Med Chem Lett 1999, 9, 1, 69. |
| 【2】 Moore, R.E.; Patel, V.F.; Ray, J.E.; Toth, J.E. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0850057; JP 2000501067; WO 9707798; WO 9708334 . |
| 【3】 Shih, C. (Eli Lilly and Company; University of Hawaii; Wayne State University); Pharmaceutical cpds.. EP 0869786; JP 2000502351; WO 9723211 . |
| 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) | 18902 | allyl (2S)-2-hydroxy-4-methylpentanoate | C9H16O3 | 详情 | 详情 | |
| (II) | 19889 | (3R)-3-[(tert-butoxycarbonyl)amino]butyric acid | C9H17NO4 | 详情 | 详情 | |
| (III) | 19890 | allyl (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoate | C18H31NO6 | 详情 | 详情 | |
| (IV) | 19891 | (2S)-2-([(3R)-3-[(tert-butoxycarbonyl)amino]butanoyl]oxy)-4-methylpentanoic acid | C15H27NO6 | 详情 | 详情 | |
| (V) | 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 | |
| (VI) | 19893 | 2,2,2-trichloroethyl (6R,10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,6-trimethyl-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 | C42H54Cl4N2O10 | 详情 | 详情 | |
| (VII) | 19894 | (6R,10S,13S,15E,19R)-19-(3-chloro-4-methoxybenzyl)-10-isobutyl-2,2,6-trimethyl-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 | C40H53ClN2O10 | 详情 | 详情 | |
| (VIII) | 19895 | (2R)-2-([(2E,5S,6R,7E)-5-[((2S)-2-[[(3R)-3-aminobutanoyl]oxy]-4-methylpentanoyl)oxy]-6-methyl-8-phenyl-2,7-octadienoyl]amino)-3-(3-chloro-4-methoxyphenyl)propionic acid | C35H45ClN2O8 | 详情 | 详情 | |
| (IX) | 19896 | (3S,7R,10R,16S)-10-(3-chloro-4-methoxybenzyl)-3-isobutyl-7-methyl-16-[(1R,2E)-1-methyl-3-phenyl-2-propenyl]-1,4-dioxa-8,11-diaza-13-cyclohexadecene-2,5,9,12-tetrone | C35H43ClN2O7 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIV)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：(I)The epoxidation of the octadienamide intermediate (I) (scheme no. 26150102b, intermediate (XXIV)) by means of ketone (II), Oxone, Bu4N HSO4 and Na2-EDTA in acetonitrile/water gives the epoxide (III), which is condensed with the pentanoic acid (IV) by means of DCC and DMAP in dichloromethane to yield the ester (V). Finally, this compound is deprotected and submitted to macrocyclization by means of piperidine in DMF to afford the target Cryptophycin 52.
| 【1】 Hoard, D.W.; et al.; Synthesis of cryptophycin 52 using the shi epoxidation. Org Lett 2002, 4, 10, 1813. |
| 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) | 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 | |
| (II) | 58313 | C12H18O6 | 详情 | 详情 | ||
| (III) | 58514 | N-(5-chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)benzamide | C16H10ClF6NO2 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 58515 | N-(5-chloro-2-methoxyphenyl)-3,5-bis(trifluoromethyl)benzenecarbohydrazonamide | C16H12ClF6N3O | 详情 | 详情 |