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【结 构 式】

【药物名称】Dehydrodidemnin B, Aplidine, DDB, Aplidin

【化学名称】(3S,6S,8S,12S,13R,16S,17R,20S,23S)-16-[N-(1,2-Dioxopropyl)-L-prolyl-D-(N-methyl)leucylamino]-12-hydroxy-3-isobutyl-8-isopropyl-20-(4-methoxybenzyl)-6,17,21-trimethyl-13-[1(S)-methylpropyl]-9,18-dioxa-1,4,14,21-tetraaza[21.3.0]hexacosane-2,5,7,10,15,19,22-heptaone
　　　　　　N-[1-(1,2-Dioxopropyl)-L-prolyl]didemnin A

【CA登记号】137219-37-5

【 分 子 式 】C57H87N7O15

【 分 子 量 】1110.36684

【开发单位】PharmaMar (Orphan Drug), PharmaMar (Originator)

【药理作用】Colorectal Cancer Therapy, Head and Neck Cancer Therapy, Leukemia Therapy, Lung Cancer Therapy, Lymphoma Therapy, Melanoma Therapy, Non-Hodgkin's Lymphoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Renal Cancer Therapy, Small Cell Lung Cancer Therapy, Solid Tumors Therapy, Apoptosis Inducers, Vascular Endothelial Growth Factor (VEGF) Inhibitors, VEGFR-1 (Flt-1) Inhibitors
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1

The modified tyrosine building block (II) was prepared by alkylation of N-Cbz-L-tyrosine (I) at both the phenolic OH and the NH groups employing dimethyl sulfate under phase-transfer conditions. N-Boc-L-Threonine benzyl ether (III) was converted to the corresponding (triethylsilyl)ethoxymethyl ester, and the O-benzyl group was subsequently removed by catalytic hydrogenolysis to afford (IV). Coupling between the tyrosine (II) and threonine (IV) derivatives using DCC and DMAP gave rise to the protected didepsipeptide (V). The SEM protecting group was then cleaved by means of HF in acetonitrile, yielding intermediate (VI)

参考文献 中间体
【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
(I) 39328 (2S)-2-[[(benzyloxy)carbonyl]amino]-3-(4-hydroxyphenyl)propionic acid C17H17NO5 详情 详情
(II) 50747 (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C19H21NO5 详情 详情
(III) 50782 (2S,3R)-3-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]butyric acid C16H23NO5 详情 详情
(IV) 50746 [2-(trimethylsilyl)ethoxy]methyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate C15H31NO6Si 详情 详情
(V) 62532 [2-(trimethylsilyl)ethoxy]methyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate C34H50N2O10Si 详情 详情
(VI) 52709 (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid C28H36N2O9 详情 详情

合成路线2

Activation of N-Boc-D-allo-isoleucine (VII) with carbonyl diimidazole, followed by condensation with the lithium enolate of methyl acetate provided keto ester (VIII). Keto group reduction in (VIII) by means of KBH4 led to the isostatine derivative (IX), which was further hydrolyzed to acid (X) with NaOH in aqueous dioxane. Silylation of hydroxy acid (X) at both the alcohol and carboxyl groups employing tert-butyldimethylsilyl chloride and imidazole, followed by selective desilylation of the carboxyl group with NaOH afforded the protected amino hydroxy acid (XI)

参考文献 中间体
【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
(VII) 50775 (2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid C11H21NO4 详情 详情
(VIII) 62533 methyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate C14H25NO5 详情 详情
(IX) 62534 methyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate C14H27NO5 详情 详情
(X) 52722 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoic acid C13H25NO5 详情 详情
(XI) 50802 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid C19H39NO5Si 详情 详情

合成路线3

The protected dipeptide (XIV) was prepared by coupling between L-proline benzyl ester (XII) and N-Boc-L-leucine (XIII) in the presence of DCC and HOBt. Acidic Boc group cleavage in (XIV) then gave amine (XV). The unstable keto acid (XVII) was obtained by hydrogenolysis of the epimeric benzyl esters (XVI), and subsequently coupled to the dipeptide ester (XV) by means of HBTU to afford the keto amide (XVIII) as a diastereomeric mixture. Desilylation of (XVIII) with tetrabutylammonium fluoride furnished the deprotected alcohol (XIX), which was further esterified with the protected isostatine (XI) leading to depsipeptide (XX). Then, removal of the O-silyl and N-Boc protecting groups of (XX) under acidic conditions provided intermediate (XXI)

参考文献 中间体
【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
(XI) 50793 benzyl (2S)-1-((2S)-2-[[(2S,4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino]-4-methylpentanoyl)-2-pyrrolidinecarboxylate C26H38N2O6 详情 详情
(XII) 20930 benzyl (2S)-2-pyrrolidinecarboxylate 16652-71-4 C12H15NO2 详情 详情
(XIII) 23663 (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine C11H21NO4 详情 详情
(XIV) 52728 benzyl (2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C23H34N2O5 详情 详情
(XV) 50792 benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate C18H26N2O3 详情 详情
(XVI) 52727 benzyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoate C21H34O4Si 详情 详情
(XVII) 50791 (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid C14H28O4Si 详情 详情
(XVIII) 52729 benzyl (2S)-1-{(2S)-2-[((2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C32H52N2O6Si 详情 详情
(XX) 62535 benzyl (2S)-1-{(2S,7S,11S,12R)-11-{[tert-butyl(dimethyl)silyl]oxy}-2-isobutyl-7-isopropyl-5,16,16-trimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14-tetraoxo-8,15-dioxa-3,13-diazaheptadec-1-anoyl}-2-pyrrolidinecarboxylate C45H75N3O10Si 详情 详情
(XXI) 62536 benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C34H53N3O8 详情 详情

合成路线4

Coupling between segments (VI) and (XXI) by means of HBTU gave rise to the depsipeptide (XXII). Simultaneous deprotection of the C- and N-terminal functions of (XXII) by hydrogenolysis led to the linear precursor (XXIII), which was then cyclized to (XXIV) in the presence of HATU and HOAt

参考文献 中间体
【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
(VI) 52709 (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid C28H36N2O9 详情 详情
(XXI) 62536 benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C34H53N3O8 详情 详情
(XXII) 62537 benzyl (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18,21-hexaoxo-23-phenyl-8,17,22-trioxa-3,13,20-triazatricos-1-anoyl C62H87N5O16 详情 详情
(XXIII) 62538 (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16-dimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18-pentaoxo-8,17-dioxa-3,13,20-triazahenicos-1-anoyl}-2-pyrrolidinecarboxylic C47H75N5O14 详情 详情
(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

合成路线5

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)

参考文献 中间体
【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6

Keto amide (XXXI) was obtained by acylation of L-proline benzyl ester (XII) with pyruvic acid (XXX). Subsequent hydrogenolysis of the benzyl ester group provided pyruvyl proline (XXXII). The target dehydrodidemnin B was then prepared by coupling of didemnin A (XXIX), from either natural or synthetic sources, with pyruvyl proline (XXXII)

参考文献 中间体
【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】 Rinehart, K.L.; Lithgow-Bertelloni, A.M. (PharmaMar, SA); Dehydrodidemnin B. WO 9104985 .
【3】 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
(XII) 20930 benzyl (2S)-2-pyrrolidinecarboxylate 16652-71-4 C12H15NO2 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
(XXX) 24066 2-oxopropionic acid 127-17-3 C3H4O3 详情 详情
(XXXI) 62541 benzyl (2S)-1-pyruvoyl-2-pyrrolidinecarboxylate C15H17NO4 详情 详情
(XXXII) 62542 (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid C8H11NO4 详情 详情

合成路线7

In a related semisynthetic strategy, didemnin A (XXIX) was first acylated by N-Boc-L-proline (XXXIII) yielding amide (XXXIV), which was further deprotected by treatment with HCl in EtOAc. The resultant prolyl didemnin A (XXXV) was then coupled with pyruvic acid (XXX) to furnish the title compound

参考文献 中间体
【1】 Rinehart, K.L.; Katauskas, A.J. (University of Illinois); Semi-synthetic studies toward didemnin analogues. EP 0973518; JP 2001503746; WO 9817275 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(XXX) 24060 3-chloro-N-(3-methoxyphenethyl)-N-methyl-1-propanamine C13H20ClNO 详情 详情
(XXXII) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(XXXIV) 62543 tert-butyl (2S)-2-{[{(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]dioxatetraaz C59H93N7O15 详情 详情
(XXXV) 62544 (2S)-N-{(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]dioxatetraazacyclotricosi C54H85N7O13 详情 详情

合成路线8

In an alternative synthesis, the previously reported trichloroethyl ester (XXXVI) was deprotected by treatment with zinc dust in the presence of ammonium acetate yielding acid (XXXVII). This was then coupled to proline trichloroethyl ester (XXXVIII), prepared from N-Boc-L-proline (XXXIII), to furnish amide (XXXIX). Subsequent hydrogenolysis of the O-benzyl group of (XXXIX) provided intermediate (XL)

参考文献 中间体
【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
(XXXIII) 16734 (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid C10H17NO4 详情 详情
(XXXVI) 62545 2,2,2-trichloroethyl (2S)-2-{[(4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoate C23H32Cl3NO5 详情 详情
(XXXVII) 62546 (2S)-2-{[(4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoic acid C21H31NO5 详情 详情
(XXXVIII) 62547 2,2,2-trichloroethyl (2S)-2-pyrrolidinecarboxylate C7H10Cl3NO2 详情 详情
(XXXIX) 62548 2,2,2-trichloroethyl (2S)-1-((2S)-2-{[(4S)-4-(benzyloxy)-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C28H39Cl3N2O6 详情 详情
(XL) 62549 2,2,2-trichloroethyl (2S)-1-((2S)-2-{[(4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C21H33Cl3N2O6 详情 详情

合成路线9

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)

参考文献 中间体
【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

合成路线10

Esterification of the peptide alcohol (XLVIII) with the modified tyrosine derivative (II) afforded depsipeptide (XLIX). After reductive cleavage of the trichloroethyl ester of (XLIX), using zinc dust and ammonium acetate, the resultant carboxylic acid (L) was coupled to the alcohol segment (XL) in the presence of DIC and DMAP·CF3COOH to furnish the linear precursor depsipeptide (LI)

参考文献 中间体
【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
(II) 50747 (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C19H21NO5 详情 详情
(XL) 62549 2,2,2-trichloroethyl (2S)-1-((2S)-2-{[(4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C21H33Cl3N2O6 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
(XLIX) 62555 2,2,2-trichloroethyl (5S,8R,9S,12R,13S)-9-({(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl}amino)-13-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)-4,8-dimethyl-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diaz C51H79Cl3N4O12Si 详情 详情
(L) 62556 (5S,8R,9S,12R,13S)-9-({(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl}amino)-13-{[tert-butyl(dimethyl)silyl]oxy}-5-(4-methoxybenzyl)-4,8-dimethyl-12-[(1S)-1-methylpropyl]-3,6,10-trioxo-1-phenyl-2,7-dioxa-4,11-diazapentadecan-15-oic ac C49H78N4O12Si 详情 详情
(LI) 62557 2,2,2-trichloroethyl (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-({(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl}amino)-11-{[tert-butyl(dimethyl)silyl]oxy}-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-12-[(1S)-1-methylpro C70H109Cl3N6O17Si 详情 详情

合成路线11

Sequential deprotection of the trichloroethyl ester and the N-benzyloxycarbonyl groups of (LI) led to (LII) and the linear aminoacid (LIII), which underwent macrocyclization to the N-Boc didemnin A (XXVIII) upon treatment with HATU and HOAt. The title compound was then obtained by acidic Boc group deprotection, followed by coupling with pyruvyl proline as outlined in Schemes 23437701e and 23437701f

参考文献 中间体
【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
(XXVIII) 62560 　 C60H100N6O14Si 详情 详情
(LI) 62557 2,2,2-trichloroethyl (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-({(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl}amino)-11-{[tert-butyl(dimethyl)silyl]oxy}-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-12-[(1S)-1-methylpro C70H109Cl3N6O17Si 详情 详情
(LII) 62558 (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-({(2R)-2-[(tert-butoxycarbonyl)(methyl)amino]-4-methylpentanoyl}amino)-11-{[tert-butyl(dimethyl)silyl]oxy}-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16,20-trimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18,21-h C68H108N6O17Si 详情 详情
(LIII) 62559 (2S)-1-{(2S,7S,11S,12R,15S,18R)-11-{[tert-butyl(dimethyl)silyl]oxy}-2,18-diisobutyl-7-isopropyl-15-((1R)-1-{[(2S)-3-(4-methoxyphenyl)-2-(methylamino)propanoyl]oxy}ethyl)-5,19,22,22-tetramethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,17,20-hexaoxo-8,21-dio C60H102N6O15Si 详情 详情

合成路线12

A modification of the previous synthetic methods was further reported. The protected isostatine (XI) was prepared by a related procedure utilizing benzyl ester protected intermediates instead of the methyl ester analogues. After activation of N-Boc-D-allo-isoleucine (VII) with carbonyl diimidazole, condensation with the lithium enolate of benzyl acetate yielded keto ester (LIV). Reduction of the keto group of (LIV), followed by silylation of the resultant alcohol (LV) and benzyl group hydrogenolysis led to the amino hydroxy acid derivative (XI)

参考文献 中间体
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 50775 (2R,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid C11H21NO4 详情 详情
(XI) 50802 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid C19H39NO5Si 详情 详情
(LIV) 62561 benzyl (4R,5S)-4-[(tert-butoxycarbonyl)amino]-5-methyl-3-oxoheptanoate C20H29NO5 详情 详情
(LV) 62562 benzyl (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-methylheptanoate C20H31NO5 详情 详情

合成路线13

Similarly, (S)-2-hydroxy-3-methylbutyric acid (LV) was protected as the silyl ether (LVI) and then condensed with benzyl acetate, via activation with CDI, to afford keto ester (LVII). Subsequent methylation of (LVII) using iodomethane and NaH provided (XVI) as a diastereomeric mixture. The unstable keto acid (XVII), obtained in situ by catalytic hydrogenolysis of (XVI), was then coupled to the dipeptide ester (XV) to afford, after desilylation, the hydroxy keto amide (XIX). Esterification of alcohol (XIX) with the isostatine derivative (XI) as in Scheme 3, followed by acidic cleavage of the O-silyl and N-Boc protecting groups led to depsipeptide (XXI)

参考文献 中间体
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 50802 (3S,4R,5S)-4-[(tert-butoxycarbonyl)amino]-3-[[tert-butyl(dimethyl)silyl]oxy]-5-methylheptanoic acid C19H39NO5Si 详情 详情
(XV) 50792 benzyl (2S)-1-[(2S)-2-amino-4-methylpentanoyl]-2-pyrrolidinecarboxylate C18H26N2O3 详情 详情
(XVI) 62563 benzyl (4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2,5-dimethyl-3-oxohexanoate C21H34O4Si 详情 详情
(XVII) 50791 (2S,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2,5-dimethyl-3-oxohexanoic acid C14H28O4Si 详情 详情
(XIX) 62564 benzyl (2S)-1-((2S)-2-{[(4S)-4-hydroxy-2,5-dimethyl-3-oxohexanoyl]amino}-4-methylpentanoyl)-2-pyrrolidinecarboxylate C26H38N2O6 详情 详情
(XXI) 62536 benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C34H53N3O8 详情 详情
(LV) 37829 (2S)-2-hydroxy-3-methylbutyric acid C5H10O3 详情 详情
(LVI) 52726 (2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-methylbutanoic acid C11H24O3Si 详情 详情
(LVII) 50790 benzyl (4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-5-methyl-3-oxohexanoate C20H32O4Si 详情 详情

合成路线14

N-Boc-L-Threonine (LVI) was protected as the corresponding phenacyl ester (LVII) by treatment with 2-bromoacetophenone and Et3N. Esterification of (LVII) with the modified tyrosine building block (II) yielded the protected didepsipeptide (LVIII). Removal of the phenacyl ester group of (LVIII) under reductive conditions provided the carboxylic acid (VI). Coupling of acid (VI) with the depsipeptide segment (XXI), followed by deprotection by hydrogenolysis furnished the linear precursor (XXIII). Macrocyclization of (XXIII) using HATU and subsequent acidic Boc group cleavage led to the macrocyclic amine (XXV)

参考文献 中间体
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10315 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone 70-11-1 C8H7BrO 详情 详情
(II) 50747 (2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propionic acid C19H21NO5 详情 详情
(VI) 52709 (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoic acid C28H36N2O9 详情 详情
(XXI) 62536 benzyl (2S)-1-{(2S)-2-[((4S)-4-{[(3S,4R,5S)-4-amino-3-hydroxy-5-methylheptanoyl]oxy}-2,5-dimethyl-3-oxohexanoyl)amino]-4-methylpentanoyl}-2-pyrrolidinecarboxylate C34H53N3O8 详情 详情
(XXIII) 62538 (2S)-1-{(2S,7S,11S,12R,15S,16R,19S)-15-[(tert-butoxycarbonyl)amino]-11-hydroxy-2-isobutyl-7-isopropyl-19-(4-methoxybenzyl)-5,16-dimethyl-12-[(1S)-1-methylpropyl]-4,6,9,14,18-pentaoxo-8,17-dioxa-3,13,20-triazahenicos-1-anoyl}-2-pyrrolidinecarboxylic C47H75N5O14 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
(LVI) 50745 N-BOC-L-threonine; Boc-Threonine; N-tert-Butoxycarbonyl-L-threonine; N-(tert-Butoxycarbonyl)-L-threonine; BOC-L-Threonine 2592-18-9 C9H17NO5 详情 详情
(LVII) 62565 2-oxo-2-phenylethyl (2S,3R)-2-[(tert-butoxycarbonyl)amino]-3-hydroxybutanoate C17H23NO6 详情 详情
(LVIII) 62566 2-oxo-2-phenylethyl (2S,3R)-3-{[(2S)-2-[[(benzyloxy)carbonyl](methyl)amino]-3-(4-methoxyphenyl)propanoyl]oxy}-2-[(tert-butoxycarbonyl)amino]butanoate C36H42N2O10 详情 详情

合成路线15

N-Benzyloxycarbonyl-N-methyl-D-leucine (LX) was prepared by methylation of the N-protected D-leucine (LIX) with iodomethane in the presence of NaH. Acylation of macrocyclic amine (XXV) with the N-protected aminoacid (LX) furnished the N-carbobenzoxy didemnin A (LXI). The title compound was then obtained by hydrogenolysis of the N-carbobenzoxy group of (LXI), followed by acylation with pyruvyl proline (XXXII) by means of diisopropyl carbodiimide

参考文献 中间体
【1】 Edge, A. (Diacrin, Inc.); Method for improving graft acceptance in a recipient by administration of a cytokine profile altering agent. WO 0051630 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(XXXII) 62542 (2S)-1-pyruvoyl-2-pyrrolidinecarboxylic acid C8H11NO4 详情 详情
(LIX) 22838 (2S)-2-[[(benzyloxy)carbonyl]amino]-4-methylpentanoic acid C14H19NO4 详情 详情
(LXI) 50810 benzyl (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]dioxatetraazacyclotricosin C57H84N6O14 详情 详情
Extended Information