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【结 构 式】 
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【分子编号】50788 【品名】(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid 【CA登记号】 |
【 分 子 式 】C12H23NO4 【 分 子 量 】245.31896 【元素组成】C 58.75% H 9.45% N 5.71% O 26.09% |
合成路线1
该中间体在本合成路线中的序号：(XI)Protection of the carboxyl group of Boc-L-threonine (I) with [2-(chloromethoxy)ethyl]trimethylsilane (SEM-Cl) (II) by means of Li2CO3 affords protected threonine (III). Separately, Z-L-tyrosine (IV) is treated with dimethyl sulfate and KOH in THF with tetrabutylammonium hydrogen sulfate as a catalyst to furnish N,O-dimethyl-L-tyrosine (V), which is then converted into secondary amine (VI) by coupling with protected threonine (III) either by means of 2,4,6-trichlorobenzoyl chloride in THF and DMAP in benzene or with isopropenyl chloroformate, Et3N and DMAP, followed by elimination of the carbobenzyloxy group by hydrogenation over Pd/C. Coupling of Z-L-leucine (IX) to L-proline methyl ester (X) by means of DCC, HOBt and NMM in CH2Cl2, followed by hydrolysis with LiOH, affords Z-leucylproline (VII), which is then coupled to amine (VI) by means of BOPCl and Et3N in CH2Cl2, and then subjected to deprotection with hydrofluoric acid in acetonitrile affording intermediate (VIII).
| 【1】 Hamada, Y.; Shioiri, T.; Anti-tumor active cyclic peptide derived from marine organism: Synthesis, conformation and bioactivity. Kagaku Zokan 1990, 118, 31. |
| 【2】 Harris, B.D.; et al.; Synthetic studies of didemnins. II. Approaches to statine diastereomers. Tetrahedron Lett 1987, 28, 25, 2837. |
| 【3】 Hamada, Y.; et al.; Efficient total synthesis of didemnins A and B. J Am Chem Soc 1989, 111, 2, 669. |
| 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) | 50775 | (2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | C11H21NO4 | 详情 | 详情 | |
| (II) | 44205 | (2-ethoxy-2-oxoethyl)lithium | C4H7LiO2 | 详情 | 详情 | |
| (III) | 50776 | ethyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate | C15H27NO5 | 详情 | 详情 | |
| (IV) | 50777 | tert-butyl (1R,2S)-1-formyl-2-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (V) | 50778 | ethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate | C15H29NO5 | 详情 | 详情 | |
| (VI) | 50779 | 2,2,2-trichloro-1-ethanol | C2H3Cl3O | 详情 | 详情 | |
| (VII) | 50780 | 2,2,2-trichloroethyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate | C15H26Cl3NO5 | 详情 | 详情 | |
| (VIII) | 50781 | 2,2,2-trichloroethyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate | C10H18Cl3NO3 | 详情 | 详情 | |
| (IX) | 50782 | (2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid | C16H23NO5 | 详情 | 详情 | |
| (X) | 50783 | 2,2,2-trichloroethyl (3S,4R,5S)-4-[[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino]-3-hydroxy-5-methylheptanoate | C21H31Cl3N2O5 | 详情 | 详情 | |
| (XI) | 50788 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | C12H23NO4 | 详情 | 详情 | |
| (XII) | 31819 | (2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid | 16937-99-8 | C11H21NO4 | 详情 | 详情 |
| (XIII) | 50787 | 2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C39H66Cl3N3O8Si | 详情 | 详情 | |
| (XIV) | 50784 | 2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C32H60Cl3N3O8Si | 详情 | 详情 | |
| (XV) | 50747 | (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid | C19H21NO5 | 详情 | 详情 | |
| (XVI) | 39328 | (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid | C17H17NO5 | 详情 | 详情 | |
| (XVII) | 50785 | 2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oate | C46H71Cl3N4O10Si | 详情 | 详情 | |
| (XVIII) | 50786 | (5S,8R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-5-(4-methoxybenzyl)-4,8-dimethyl-9-[[(2R)-4-methyl-2-(methylamino)pentanoyl]amino]-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic acid | C44H70N4O10Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)Removal of the N-Boc protecting group of (XXIV) by means of HCl in dioxane generated the macrocyclic amine (XXV). The protected aminoacid (XXVII) was prepared by treatment of D-leucine (XXVI) with Boc2O, followed by N-methylation under phase-transfer conditions. Coupling of N-Boc-N-methyl-D-leucine (XXVII) with amine (XXV) provided amide (XXVIII). Then, acidic Boc group cleavage in (XXVIII) furnished didemnin A (XXIX)
| 【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
| 【2】 Giralt Lledo, E.; Albericio Palomera, F.; Lloyd-Williams, P.; Gonzalez Valcarcel, I.; Jou Prat, G.; Gomez Gonzalez, A.; Manzanares Secades, I. (PharmaMar, SA); Process for the preparation of didemnine A. ES 2102322 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXIV) | 62539 | tert-butyl (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-ylc | C47H73N5O13 | 详情 | 详情 | |
| (XXV) | 50768 | (3S,6R,7S,10R,11S,15S,17S,20S,25aS)-7-amino-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]tetradecahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosine-1,4,8,13,16,18,21(17H)-heptone | C42H65N5O11 | 详情 | 详情 | |
| (XXVI) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (XXVII) | 50788 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | C12H23NO4 | 详情 | 详情 | |
| (XXVIII) | 62540 | tert-butyl (1R)-1-[({(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotric | C54H86N6O14 | 详情 | 详情 | |
| (XXIX) | 50796 | (2R)-N-[(3S,6R,7S,10R,11S,15S,17S,20S,25aS)-11-hydroxy-20-isobutyl-15-isopropyl-3-(4-methoxybenzyl)-2,6,17-trimethyl-10-[(1S)-1-methylpropyl]-1,4,8,13,16,18,21-heptaoxodocosahydro-15H-pyrrolo[2,1-f][1,15,4,7,10,20]dioxatetraazacyclotricosin-7-yl]-4-methyl-2-(methylamino)pentanamide | C49H78N6O12 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXVII)For the synthesis of the other peptidic moiety (L), removal of the N-Boc group from the isostatine derivative (XLI) by means of trifluoroacetic acid gave amino ester (XLII), which was coupled with N-Boc-L-threonine benzyl ether (III) to afford dipeptide (XLIII). Boc group removal in (XLIII) with HCl provided peptide (XLIV), which was coupled with N-Boc-N-methyl-D-leucine (XXVII) to yield tripeptide (XLV). Saponification of the methyl ester group of (XLV) with NaOH provided acid (XLVI). Sequential protection of the alcohol hydroxyl of (XLVI) as the tert-butyldimethylsilyl ether, and esterification of the carboxyl group with trichloroethanol led to the fully protected tripeptide (XLVII). The benzyl ether group of (XLVII) was then removed by catalytic hydrogenolysis to furnish alcohol (XLVIII)
| 【1】 Jou, G.; Gonzalez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E.; Total synthesis of dehydrodidemnin B. Use of uronium and phosphonium salt coupling reagents in peptide synthesis in solution. J Org Chem 1997, 62, 2, 354. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 50782 | (2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid | C16H23NO5 | 详情 | 详情 | |
| (XXVII) | 50788 | (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoic acid | C12H23NO4 | 详情 | 详情 | |
| (XLI) | 62534 | methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate | C14H27NO5 | 详情 | 详情 | |
| (XLII) | 62550 | methyl (3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoate | C9H19NO3 | 详情 | 详情 | |
| (XLIII) | 62551 | methyl (3S,4R,5S)-4-({(2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butanoyl}amino)-3-hydroxy-5-methylheptanoate | C25H40N2O7 | 详情 | 详情 | |
| (XLIV) | 62552 | methyl (3S,4R,5S)-4-{[(2S,3R)-2-amino-3-(benzyloxy)butanoyl]amino}-3-hydroxy-5-methylheptanoate | C20H32N2O5 | 详情 | 详情 | |
| (XLV) | 62553 | methyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-hydroxy-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C32H53N3O8 | 详情 | 详情 | |
| (XLVI) | 62554 | (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-hydroxy-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oic acid | C31H51N3O8 | 详情 | 详情 | |
| (XLVII) | 50787 | 2,2,2-trichloroethyl (6R,9S,12R,13S)-9-[(1R)-1-(benzyloxy)ethyl]-13-[[tert-butyl(dimethyl)silyl]oxy]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C39H66Cl3N3O8Si | 详情 | 详情 | |
| (XLVIII) | 50784 | 2,2,2-trichloroethyl (6R,9S,12R,13S)-13-[[tert-butyl(dimethyl)silyl]oxy]-9-[(1R)-1-hydroxyethyl]-6-isobutyl-2,2,5-trimethyl-12-[(1S)-1-methylpropyl]-4,7,10-trioxo-3-oxa-5,8,11-triazapentadecan-15-oate | C32H60Cl3N3O8Si | 详情 | 详情 |