WO2008151306A1 - Synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne - Google Patents
Synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne Download PDFInfo
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- WO2008151306A1 WO2008151306A1 PCT/US2008/065991 US2008065991W WO2008151306A1 WO 2008151306 A1 WO2008151306 A1 WO 2008151306A1 US 2008065991 W US2008065991 W US 2008065991W WO 2008151306 A1 WO2008151306 A1 WO 2008151306A1
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- WIPO (PCT)
- Prior art keywords
- compound
- mmol
- etoac
- nmr
- hexane
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 62
- 108010002156 Depsipeptides Proteins 0.000 title claims abstract description 27
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 10
- 230000000118 anti-neoplastic effect Effects 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title abstract description 17
- 238000003786 synthesis reaction Methods 0.000 title abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 41
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 52
- 150000002148 esters Chemical class 0.000 claims description 32
- 235000019439 ethyl acetate Nutrition 0.000 claims description 30
- -1 and (b) is H2 Chemical compound 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 230000003197 catalytic effect Effects 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- 230000008878 coupling Effects 0.000 claims description 10
- 238000010168 coupling process Methods 0.000 claims description 10
- 238000005859 coupling reaction Methods 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000012634 fragment Substances 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical group [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 6
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 1
- HJNZTHHOZWMVPB-WCSXKIRISA-N respirantin Chemical compound C[C@H]1OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)CC)OC(=O)[C@H](C)OC(=O)[C@H]1NC(=O)C1=CC=CC(NC=O)=C1O HJNZTHHOZWMVPB-WCSXKIRISA-N 0.000 abstract description 27
- HJNZTHHOZWMVPB-UHFFFAOYSA-N Respirantin Natural products CC1OC(=O)C(CC(C)C)OC(=O)C(C)(C)C(=O)C(CC(C)C)NC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C1NC(=O)C1=CC=CC(NC=O)=C1O HJNZTHHOZWMVPB-UHFFFAOYSA-N 0.000 abstract description 18
- 108010036959 respirantin Proteins 0.000 abstract description 18
- NHGPGFIEZTYBBN-UHFFFAOYSA-N kitastatin 1 Natural products CC1OC(=O)C(CC(C)C)OC(=O)C(C)(C)C(=O)C(CC(C)C)NC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C1NC(=O)C1=CC=CC(N)=C1O NHGPGFIEZTYBBN-UHFFFAOYSA-N 0.000 abstract description 14
- 206010028980 Neoplasm Diseases 0.000 abstract description 13
- 201000011510 cancer Diseases 0.000 abstract description 13
- NHGPGFIEZTYBBN-GTBKNNTQSA-N 3-amino-n-[(2s,5s,8s,13s,16r,17s)-5-butan-2-yl-2,10,10,16-tetramethyl-8,13-bis(2-methylpropyl)-3,6,9,11,14,18-hexaoxo-1,4,12,15-tetraoxa-7-azacyclooctadec-17-yl]-2-hydroxybenzamide Chemical compound C[C@H]1OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H](C(C)CC)OC(=O)[C@H](C)OC(=O)[C@H]1NC(=O)C1=CC=CC(N)=C1O NHGPGFIEZTYBBN-GTBKNNTQSA-N 0.000 abstract description 6
- 230000010261 cell growth Effects 0.000 abstract description 6
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- CQIUKKVOEOPUDV-IYSWYEEDSA-N antimycin Chemical compound OC1=C(C(O)=O)C(=O)C(C)=C2[C@H](C)[C@@H](C)OC=C21 CQIUKKVOEOPUDV-IYSWYEEDSA-N 0.000 abstract description 2
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 31
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 25
- 239000012230 colorless oil Substances 0.000 description 25
- 239000000377 silicon dioxide Substances 0.000 description 24
- 229910052681 coesite Inorganic materials 0.000 description 23
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- 229910052905 tridymite Inorganic materials 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
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- 239000011780 sodium chloride Substances 0.000 description 19
- 150000001408 amides Chemical class 0.000 description 17
- NHGPGFIEZTYBBN-FBIIVLIJSA-N kitastatin 1 Chemical compound C[C@H]1OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)C(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)OC(=O)[C@H](C)OC(=O)[C@H]1NC(=O)C1=CC=CC(N)=C1O NHGPGFIEZTYBBN-FBIIVLIJSA-N 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- YEKPNMQQSPHKBP-UHFFFAOYSA-N 2-methyl-6-nitrobenzoic anhydride Chemical compound CC1=CC=CC([N+]([O-])=O)=C1C(=O)OC(=O)C1=C(C)C=CC=C1[N+]([O-])=O YEKPNMQQSPHKBP-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 11
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 238000003776 cleavage reaction Methods 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
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- 230000007017 scission Effects 0.000 description 7
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- 239000005711 Benzoic acid Substances 0.000 description 4
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- KJOZJSGOIJQCGA-UHFFFAOYSA-N dichloromethane;2,2,2-trifluoroacetic acid Chemical compound ClCCl.OC(=O)C(F)(F)F KJOZJSGOIJQCGA-UHFFFAOYSA-N 0.000 description 4
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- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 2
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- LOQGWPAHLXFXOG-UHFFFAOYSA-N 3-formamido-2-phenylmethoxybenzoic acid Chemical compound OC(=O)C1=CC=CC(NC=O)=C1OCC1=CC=CC=C1 LOQGWPAHLXFXOG-UHFFFAOYSA-N 0.000 description 1
- ICPMZKSUCHXWRC-UHFFFAOYSA-N 3-o-benzyl 1-o-methyl 2-[1-(2-hydroxy-4-methylpentanoyl)oxyethyl]propanedioate Chemical compound CC(C)CC(O)C(=O)OC(C)C(C(=O)OC)C(=O)OCC1=CC=CC=C1 ICPMZKSUCHXWRC-UHFFFAOYSA-N 0.000 description 1
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- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 241000656145 Thyrsites atun Species 0.000 description 1
- DLNWZIVYKQXLTN-UMJYHBPBSA-N [(1r,8s)-4-oxido-2,3,5,6,7,8-hexahydro-1h-pyrrolizin-4-ium-1-yl]methyl (2s)-2-hydroxy-2-[(1s)-1-hydroxyethyl]-3-methylbutanoate Chemical compound C1CC[C@H]2[C@H](COC(=O)[C@@](O)([C@H](C)O)C(C)C)CC[N+]21[O-] DLNWZIVYKQXLTN-UMJYHBPBSA-N 0.000 description 1
- OOVLEMKVLXPJSG-UHFFFAOYSA-N [4-methoxy-4-oxo-3-(phenylmethoxycarbonylamino)butan-2-yl] 2-[tert-butyl(dimethyl)silyl]oxy-4-methylpentanoate Chemical compound CC(C)(C)[Si](C)(C)OC(CC(C)C)C(=O)OC(C)C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 OOVLEMKVLXPJSG-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
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- 150000008043 acidic salts Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
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- 230000001093 anti-cancer Effects 0.000 description 1
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- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
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- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 1
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- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
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- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
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- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- DORDKUBCRPNETF-UHFFFAOYSA-N jatropham Natural products CC1=CC(O)NC1=O DORDKUBCRPNETF-UHFFFAOYSA-N 0.000 description 1
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- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- DUFJJWZFBLUSPI-UHFFFAOYSA-N methyl 2,2,6-trimethyl-4-[(2-methylpropan-2-yl)oxycarbonylamino]-3-oxoheptanoate Chemical compound COC(=O)C(C)(C)C(=O)C(CC(C)C)NC(=O)OC(C)(C)C DUFJJWZFBLUSPI-UHFFFAOYSA-N 0.000 description 1
- XAFGELWRFWBATE-UHFFFAOYSA-N methyl 2-(2-hydroxypropanoyloxy)-3-methylpentanoate Chemical compound CCC(C)C(C(=O)OC)OC(=O)C(C)O XAFGELWRFWBATE-UHFFFAOYSA-N 0.000 description 1
- YDWFJIQGJXJAML-UHFFFAOYSA-N methyl 2-[2-[tert-butyl(dimethyl)silyl]oxypropanoyloxy]-3-methylpentanoate Chemical compound CCC(C)C(C(=O)OC)OC(=O)C(C)O[Si](C)(C)C(C)(C)C YDWFJIQGJXJAML-UHFFFAOYSA-N 0.000 description 1
- ZUVSSCGMRZANCC-UHFFFAOYSA-N methyl 2-[5-(2-methoxy-2-oxoethyl)-3,6-bis(2-methylpropyl)pyrazin-2-yl]acetate Chemical compound COC(=O)CC1=NC(CC(C)C)=C(CC(=O)OC)N=C1CC(C)C ZUVSSCGMRZANCC-UHFFFAOYSA-N 0.000 description 1
- HFPPOXICJNWLHC-UHFFFAOYSA-N methyl 3-formamido-2-phenylmethoxybenzoate Chemical compound COC(=O)C1=CC=CC(NC=O)=C1OCC1=CC=CC=C1 HFPPOXICJNWLHC-UHFFFAOYSA-N 0.000 description 1
- PWBCUVINZIBLMK-UHFFFAOYSA-N methyl 4-[[2-[2-[3-(2-hydroxy-4-methylpentanoyl)oxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoyl]amino]-6-methyl-3-oxoheptanoate Chemical compound COC(=O)CC(=O)C(CC(C)C)NC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C(C(C)OC(=O)C(O)CC(C)C)NC(=O)OCC1=CC=CC=C1 PWBCUVINZIBLMK-UHFFFAOYSA-N 0.000 description 1
- PSHPPROXYOJADK-UHFFFAOYSA-N methyl 4-[[2-[2-[3-[2-[tert-butyl(diphenyl)silyl]oxy-4-methylpentanoyl]oxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoyl]amino]-6-methyl-3-oxoheptanoate Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)(C=1C=CC=CC=1)OC(CC(C)C)C(=O)OC(C)C(C(=O)OC(C)C(=O)OC(C(C)CC)C(=O)NC(CC(C)C)C(=O)CC(=O)OC)NC(=O)OCC1=CC=CC=C1 PSHPPROXYOJADK-UHFFFAOYSA-N 0.000 description 1
- NSKZUPSOMYZFBG-UHFFFAOYSA-N methyl 4-[[2-[2-[3-[2-[tert-butyl(methyl)silyl]oxy-4-methylpentanoyl]oxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoyl]amino]-6-methyl-3-oxoheptanoate Chemical compound CCC(C)C(OC(=O)C(C)OC(=O)C(NC(=O)OCc1ccccc1)C(C)OC(=O)C(CC(C)C)O[SiH](C)C(C)(C)C)C(=O)NC(CC(C)C)C(=O)CC(=O)OC NSKZUPSOMYZFBG-UHFFFAOYSA-N 0.000 description 1
- UTXIPKJQKUJCRN-UHFFFAOYSA-N methyl 4-[[2-[2-[3-hydroxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoyl]amino]-6-methyl-3-oxoheptanoate Chemical compound COC(=O)CC(=O)C(CC(C)C)NC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C(C(C)O)NC(=O)OCC1=CC=CC=C1 UTXIPKJQKUJCRN-UHFFFAOYSA-N 0.000 description 1
- YYDLQEWOOQIGQO-UHFFFAOYSA-N methyl 4-[[2-[2-[tert-butyl(dimethyl)silyl]oxypropanoyloxy]-3-methylpentanoyl]amino]-6-methyl-3-oxoheptanoate Chemical compound CC(C)(C)[Si](C)(C)OC(C)C(=O)OC(C(C)CC)C(=O)NC(CC(C)C)C(=O)CC(=O)OC YYDLQEWOOQIGQO-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- DOQJUNNMZNNQAD-UHFFFAOYSA-N pyrrolidine-2,4-dione Chemical compound O=C1CNC(=O)C1 DOQJUNNMZNNQAD-UHFFFAOYSA-N 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical class [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- RMNSVCGPWVJHAB-UHFFFAOYSA-N tert-butyl 2-(2-hydroxypropanoyloxy)-3-methylpentanoate Chemical compound CC(O)C(=O)OC(C(C)CC)C(=O)OC(C)(C)C RMNSVCGPWVJHAB-UHFFFAOYSA-N 0.000 description 1
- OREJLSHGCYMKHO-UHFFFAOYSA-N tert-butyl 2-[2-[3-[2-[tert-butyl(dimethyl)silyl]oxy-4-methylpentanoyl]oxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoate Chemical compound CC(C)(C)OC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C(C(C)OC(=O)C(CC(C)C)O[Si](C)(C)C(C)(C)C)NC(=O)OCC1=CC=CC=C1 OREJLSHGCYMKHO-UHFFFAOYSA-N 0.000 description 1
- CCPCYQLRKVKSPF-UHFFFAOYSA-N tert-butyl 2-[2-[3-[2-[tert-butyl(diphenyl)silyl]oxy-4-methylpentanoyl]oxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoate Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)(C=1C=CC=CC=1)OC(CC(C)C)C(=O)OC(C)C(C(=O)OC(C)C(=O)OC(C(C)CC)C(=O)OC(C)(C)C)NC(=O)OCC1=CC=CC=C1 CCPCYQLRKVKSPF-UHFFFAOYSA-N 0.000 description 1
- ULNZTIQRJKHSOH-UHFFFAOYSA-N tert-butyl 2-[2-[3-[tert-butyl(dimethyl)silyl]oxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoate Chemical compound CC(C)(C)OC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C(C(C)O[Si](C)(C)C(C)(C)C)NC(=O)OCC1=CC=CC=C1 ULNZTIQRJKHSOH-UHFFFAOYSA-N 0.000 description 1
- LPKIREREZJJPPH-UHFFFAOYSA-N tert-butyl 2-[2-[3-hydroxy-2-(phenylmethoxycarbonylamino)butanoyl]oxypropanoyloxy]-3-methylpentanoate Chemical compound CC(C)(C)OC(=O)C(C(C)CC)OC(=O)C(C)OC(=O)C(C(C)O)NC(=O)OCC1=CC=CC=C1 LPKIREREZJJPPH-UHFFFAOYSA-N 0.000 description 1
- TXFCTNAJRVIEOP-UHFFFAOYSA-N tert-butyl 2-[2-[tert-butyl(dimethyl)silyl]oxypropanoyloxy]-3-methylpentanoate Chemical compound CC(C)(C)OC(=O)C(C(C)CC)OC(=O)C(C)O[Si](C)(C)C(C)(C)C TXFCTNAJRVIEOP-UHFFFAOYSA-N 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
- C07D273/01—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 having one nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
- C07C69/675—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids of saturated hydroxy-carboxylic acids
- C07C69/68—Lactic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the present invention is directed to effective methods of synthesizing cyclodepsipeptide compounds having antineoplastic and/or antimicrobial activity.
- the methods are directed to synthesis of kitastatin 1 (1a), respirantin (1b) or a valeryl modification (Ic).
- the present invention is further directed to important intermediates used in the disclosed methods.
- FDA United States Food, Drug and Cosmetic Administration
- kitastatin 1 (1a) respirantin (1b) or a valeryl modification (Ic) in sufficient quantities to meet the public demand. It is toward the fulfillment of that need that the present invention is directed.
- the present invention is directed to methods of synthesis of potentially useful cyclodepsipeptide compounds having antineoplastic and/or antimicrobial activity.
- the methods of synthesis are directed to production of three exceptional cancer cell growth inhibitory cyclodepsipeptides from the bacteria Kitasatospora spp. found on the Beaufort Sea coast of the Alaska North Slope 1a , including newly discovered kitastatin 1 (1a) ( Figure 1), and two other cyclodepsipeptides, namely respirantin (1b) and a valeryl modification (1c). 1b
- One preferred method of preparing a cyclodepsipeptide comprises coupling a compound having the structure
- R is H or CHO
- R 1 is CH 2 CH(CH 3 ) 2 or CH(CH 3 ) 2 ;
- X is CHO or Cbz.
- the intermediate compound having the structure is prepared according to the following scheme:
- the ⁇ -keto ester alcohol intermediate compound having the structure of: is preferably prepared by coupling a compound having the structure and the fragment having the structure
- the preferred method of synthesizing a cyclodepsipeptide compound having antineoplastic and/or antimicrobial activity comprises the steps set forth in the following scheme:
- R is R is H or CHO; and X is CHO or Cbz.
- the present invention is further directed to the important intermediates used in the synthesis of these cyclodepsipeptide having antineoplastic and/or antimicrobial activity.
- the intermediate are selected from the group consisting of:
- the intermediate compound is in a substantially pure form.
- the invention further encompasses methods of preparing the intermediates.
- Preferred methods of preparing intermediates include for example, coupling the compounds below:
- Another example includes selective carboxyl deprotection by treatment of a £-butyl ester compound having the following structure:
- the catalytic salt is CuSO 4 and the reaction is carried out in refluxing toluene.
- FIG. 1 shows cyclodepsipeptides, specifically, kitastatin (1a), respirantin (1b) and valeryl modification (1c); (+)-Antimycin A 3b (2).
- salts of the compounds of the invention may be formed, for example, by reacting the compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Formation salts is well within the ability of one skilled in the art. Examples of specific salts of the compound of the invention are provided herein, but are not intended to be limiting.
- Preferred compounds synthesized by the methods disclosed herein inhibit the growth of cancer cells and/or parasitic microbial growth.
- the compounds synthesized can be used to inhibit cancer cell growth and microbial activity.
- kitastatin 1 (1a) and respirantin (1b) macrocycle reveals that these compounds are composed of common amino acids, or ⁇ -hydroxycarboxylic acids derived from them, along with the ⁇ -ketoester unit.
- Ia and 1b Since the absolute stereochemistry of Ia and 1b was undetermined at the onset of this study, our initial target Ib was selected by assuming the most common S-configuration for the constituent amino acids and their presumed ⁇ -hydroxy derivatives. Fortunately, that proved to be the correct choice among the 256 possible optical isomers.
- a retrosynthetic analysis of the ultimately successful route to respirantin (1b) is presented in Scheme 1. Antimycin syntheses 2 techniques were used for appending the protected benzoic acid 3 to amino substituted macrocycles.
- aReagents and conditions (a) K 2 CO 3 , MeI, DMSO, 23°C, 48 h, 65%. (b) KOH, aq CH 3 OH,
- aReagents and conditions (a) (i) Oxalyl chloride, catalytic DMF, DCM, 0-23°C, 2h. (ii) 19, pyridine, 23°C, 16 h, 75%. (b) LiI, pyridine, H0°C, 40 h, 89%. (c) (i) 7, 1:1 TFA-DCM, 0.5 h. (ii) PyBroP, DIPEA, DCM, product from (i), 4 h, 65%. (d) BF 3 .Et 2 O, DCM, 0.5 h, 87% for 23, 83% for 27-28. (e) 25, MNBA, DMAP, TEA, DCM, 23°C, 16 h, 77%.
- the diester 20 was obtained via reaction of the acid chloride derived from silyl ester 18 under neutral conditions 11,12 with alcohol 19. 5 Selective hydrolytic cleavage of methyl ester 20 could not be achieved as extensive cleavage of the internal ester linkage occurred.
- the desired carboxylic acid 21 was obtained via nucleophilic alkyl cleavage with LiI in pyridine. 13 Formation of the amide linkage leading to amide 22 proved to be problematic. Reaction of carboxylic acid 21 with the amine derived from TFA deprotection of Boc protected 7 under a variety of peptide coupling procedures (BOP 14 , PyBroP 15 , DEPC 16 ) afforded at best low yields of amide 22 along with the pyrazine 24.
- aReagents and conditions (a) TBAF, THF, 0°C, 1 h, 85%. (b) 25, MNBA, DMAP, TEA, DCM, 23°C, 16 h, 75%. (c) BF 3 -Et 2 O, DCM, 23°C, 1.5 h, 92%.
- aReagents and conditions (a) (i) Oxalyl chloride, catalytic DMF, DCM, 0-23°C, 2h. (ii) 33, pyridine, 23°C, 16 h, 55%. (b) BF 3 -Et 2 O, DCM, 23°C, 1 h, 51%. (c) K 2 CO 3 , aqueous CH 3 OH or TBAF.
- aReagents and conditions (a) (i) Oxalyl chloride, catalytic DMF, DCM, 0-23°C, 2h. (ii) 37, pyridine, 23°C, 16 h, 81%. (b) TBAF, THF, 23°C, 1 h, 100%. (c) 25, MNBA, DMAP, TEA, DCM, 23°C, 16 h, 87%. (d) TBAF, THF, 23°C, 1 h, 100%. (e) (i) TBDPSCl or TBDMSCl, imidazole, DMF, 23°C, 16 h.
- amide 45 was inert to BF 3 .Et 2 O at ambient temperature, as well as several other acidic reagents, and TBAF caused the expected elimination of the leucic acid residue. Consequently, we chose to proceed with a MNBA promoted coupling of alcohol 9 with carboxylic acid 41 to provide ester 43. To achieve good results with this esterfication, it was necessary to use freshly prepared acid 41. Apparently the acidity of 41 is sufficient to cause decomposition to the corresponding ⁇ -hydroxyacid. As anticipated, cleavage of the t- butyl ester in the presence of the TBDMS group proved to be problematic.
- aReagents and conditions (a) MeI, K 2 CO 3 , DMSO, 23°C, 3 h, 28%. (b) H 2 , Pd/C, EtOAc, 23°C, 2 h, 73%. (c) 3, EDCI, HOBt, NMM, DMF, 23°C, 11 h, 61%. (d) H 2 , Pd/C, EtOAc,
- aReagents and conditions (a) CbzNHS, DMF, 100°C, 6 h. (b) (i) BzIBr, K 2 CO 3 , DMF, 120°C, 3 h. (ii) LiOH, aq THF/CH 3 OH, 23°C, 18 h. (c) 4, EDCI, HOBt, NMM, DMF, 23°C, 11 h. (d) H2, Pd/C, EtOAc, 23°C, 2 h.
- Kitastatin 1 (1a), respirantin (1b), and the valeryl analog Ic were evaluated as inhibitors of cancer cell growth versus the murine P388 leukemia cell line 30 and a panel of human cancer cell lines. 31 The data are reported in Table 1. Table 1. Comparison of the Cancer Cell Growth Inhibition (GI 50 , ⁇ g/ml) of Kitastatin 1 (1a), Respirantin (1b), and the Valeryl Analog Ic against a Panel of Murine (P388, Lymphocytic Leukemia) and Human Cancer Cell Lines.
- pancreatic cancer is one of the most deadly types and is notoriously refractory to current modes of treatment.
- Solvents were redistilled prior to use. Reagents were used as received. MNBA was obtained from TCI America. Thin layer chromatography (tic) was carried out with Analtech 250 ⁇ thick silica gel GHLF plates and visualized with H 2 SO 4 , phosphomolybdic acid, iodine, or UV. Organic extracts were dried over anhydrous NaSO 4 and evaporated under reduced pressure using a rotary evaporator. The crude products were separated by flash column chromatography on flash (230-400 mesh ASTM) silica from E. Merck.
- Silyl ether 18 (3.23 g, 10.16 mmol) was dissolved in CH 2 Cl 2 (10 mL) containing DMF (280 ⁇ L, 0.26 g, 3.62 mmol) under N 2 and cooled to 0°C.
- Oxalyl chloride (5.6 mL of 2M solution in CH 2 Cl 2 , 11.2 mmol) was added dropwise over 5 min. The solution was stirred at 0°C for 1.5 h and at ambient temperature for 0.5 h. The solvent was evaporated. To the residue was added dropwise a solution of alcohol 19 (1.27 g, 8.71 mmol) in pyridine (5 mL).
- Methyl (3,6-diisobutyl-5-methoxycarbonylmethyl-pyrazin-2-yl)acetate (24).
- Ketone 7 (0.28g, 0.97 mmol) was placed in 1:1 TFA-DCM (4.0 mL) under N 2 and stirred at ambient for 45 min. The solvent was evaporated and the residue coevaporated with toluene (2 x 10 mL). The residue was dissolved in DCM (3.0 mL) and cooled to 0°C.
- TEA (0.41 mL, 293.3 mg, 2.91 mmol) was added dropwise and the solution stirred at 0°C for 4 h.
- reaction mixture was diluted with EtOAc (50 mL), washed with 5% citric acid (2 x 10 mL), H 2 O (10 mL), 6% NaHCO 3 (2 x 10 mL), H 2 O (10 mL), 5 M NaCl (10 mL), dried and evaporated.
- Methyl 4-(2- ⁇ 2-[2-benyloxycarbonylamino-3-(t-butyldimethylsilyloxy) butyryloxy]propionyloxy ⁇ -3-methylpentanoylamino)6-methyl-3-oxoheptanoate (26).
- Carboxylic acid 25 (0.26g, 0.72 mmol)
- alcohol 23 241.2 mg, 0.65 mmol
- MNBA (0.25g, 0.73 mmol)
- DMAP (20.0 mg, 0.16 mmol) and TEA (0.30 mL, 0.22 g, 2.13 mmol) were placed in DCM (3.5 mL) under N 2 and stirred at ambient for 16 h.
- reaction mixture was diluted with EtOAc (50 mL), washed with H 2 O (10 mL), 6% NaHCO 3 (2 x 10 mL), H 2 O (10 mL), 5% citric acid (2 x 10 mL), H 2 O (10 mL), 5 M NaCl (10 mL), dried, and evaporated.
- Methyl 2-hydroxy 3-formylaminobenzoate 50.
- Benzoic acid derivative 49 (1.37 g, 7.57 mmol) and NaHCO 3 (1.40 g, 16.65 mmol) were placed in DMF (20 mL) under N 2 .
- MeI (5.37 g, 2.36 mL, 37.85 mmol) in DMF (20 mL) was added and the mixture stirred at ambient temperature for 15 h.
- Methyl 2-benzyloxy-3-formylaminobenzoate (51). To methyl ester 50 (1.01 g, 5.20 mmol) and benzyl bromide (1.44 g, 1 mL, 8.42 mmol) in DMF (20 mL under N 2 ) was added K 2 CO 3 (1.44 g, 10.40 mmol) and the mixture stirred at 60°C for 15 h. The mixture was diluted with EtOAc (100 mL), washed with H 2 O (2 x 20 mL), 5 M NaCl (10 mL), dried, solvent evaporated and the residue coevaporated with toluene (20 mL).
- Benzoic acid 3 (14.0 mg, 0.051 mmol), 1-hydroxybenzotriazole (7.0 mg, 0.051 mmol), EDCI (7.4 mg, 0.038 mmol), and N-methylmorpholine (20 ⁇ L, 0.18 mmol) were added successively to a solution of amine 4 (15.0 mg, 0.026 mmol) in DMF (1.5 mL) under N 2 .
- the reaction mixture was stirred at ambient temperature for H h, the reaction was terminated by addition of saturated NaHSO 4 (20 mL), and extracted with EtOAc (30 mL).
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Abstract
La présente invention concerne des procédés efficaces de synthèse de composés cyclodepsipeptide ayant une activité antinéoplasique et/ou antimicrobienne. Les synthèses totales des cyclodepsipeptides cycliques à dix-huit chaînons kitastatine (1a) et respirantine (1b) sont apprises. Une étape importante de la synthèse est une transestérification intramoléculaire de l'alcool cétoester 6 pour permettre le macrocycle protégé 5. Les produits de synthèse se sont avérés être identiques aux produits naturels et la stéréochimie absolue de 6 des 7 centres asymétriques de cyclodepsipeptide 1b a été établie de manière univoque. La kitatastine (1a) et la respirantine (1b) se sont avérées être des inhibiteurs remarquables de la croissance de cellules cancérigènes et sont liées à la famille antimycine d'antibiotiques.
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Cited By (2)
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US11174291B2 (en) | 2015-02-13 | 2021-11-16 | Arizona Board Of Regents On Behalf Of Arizona State University | Silstatin compounds |
US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
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Publication number | Priority date | Publication date | Assignee | Title |
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US11629167B2 (en) | 2017-11-09 | 2023-04-18 | Arizona Board Of Regents On Behalf Of Arizona State University | Betulastatin compounds |
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