AU716610B2 - Method for producing epothilones, and intermediate products obtained during the production process - Google Patents
Method for producing epothilones, and intermediate products obtained during the production process Download PDFInfo
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- AU716610B2 AU716610B2 AU21493/97A AU2149397A AU716610B2 AU 716610 B2 AU716610 B2 AU 716610B2 AU 21493/97 A AU21493/97 A AU 21493/97A AU 2149397 A AU2149397 A AU 2149397A AU 716610 B2 AU716610 B2 AU 716610B2
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- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title description 13
- 229930013356 epothilone Natural products 0.000 title description 9
- 238000004519 manufacturing process Methods 0.000 title description 7
- 239000013067 intermediate product Substances 0.000 title description 3
- -1 p-methoxybenzyl Chemical group 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- OORUMIIDKDTTNO-QMMMGPOBSA-N (2s)-2-methylhept-6-enal Chemical compound O=C[C@@H](C)CCCC=C OORUMIIDKDTTNO-QMMMGPOBSA-N 0.000 claims description 4
- SRLDRAQKTUVOIC-VIFPVBQESA-N (2s)-2,6-dimethylhept-6-enal Chemical compound O=C[C@@H](C)CCCC(C)=C SRLDRAQKTUVOIC-VIFPVBQESA-N 0.000 claims description 3
- QGPKAFNRXHKSMT-UHFFFAOYSA-N 2-(2,2-dimethyl-1,3-dioxan-4-yl)-2-methylpentan-3-one Chemical compound CCC(=O)C(C)(C)C1CCOC(C)(C)O1 QGPKAFNRXHKSMT-UHFFFAOYSA-N 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- NABMPOXTCLBNMV-JUVOFCAFSA-N (4s,6s)-2-(2,2-dimethyl-1,3-dioxan-4-yl)-5-hydroxy-2,4,6-trimethylundecan-3-one Chemical compound CCCCC[C@H](C)C(O)[C@H](C)C(=O)C(C)(C)C1CCOC(C)(C)O1 NABMPOXTCLBNMV-JUVOFCAFSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 80
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 52
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 28
- 229920006395 saturated elastomer Polymers 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 15
- 238000004440 column chromatography Methods 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 150000001299 aldehydes Chemical class 0.000 description 8
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 229920002554 vinyl polymer Polymers 0.000 description 6
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 5
- 230000032050 esterification Effects 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 239000012259 ether extract Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000000707 stereoselective effect Effects 0.000 description 5
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000005575 aldol reaction Methods 0.000 description 4
- 238000005865 alkene metathesis reaction Methods 0.000 description 4
- 238000005828 desilylation reaction Methods 0.000 description 4
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000006735 epoxidation reaction Methods 0.000 description 4
- DLLJVQNYBYOKGS-UHFFFAOYSA-N ethoxyethane;pentane Chemical compound CCCCC.CCOCC DLLJVQNYBYOKGS-UHFFFAOYSA-N 0.000 description 4
- 239000012634 fragment Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 4
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IYFMRXJBXNNNDL-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxyhexanoic acid Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC(O)=O IYFMRXJBXNNNDL-UHFFFAOYSA-N 0.000 description 3
- QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 3
- FZRNGYOBZVZULF-UHFFFAOYSA-N CCC(CC)(P(O)(O)=O)C1=CSC(C)=N1 Chemical compound CCC(CC)(P(O)(O)=O)C1=CSC(C)=N1 FZRNGYOBZVZULF-UHFFFAOYSA-N 0.000 description 3
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 238000007514 turning Methods 0.000 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical class N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- YBUPWRYTXGAWJX-RXMQYKEDSA-N (4s)-4-propan-2-yl-1,3-oxazolidin-2-one Chemical compound CC(C)[C@H]1COC(=O)N1 YBUPWRYTXGAWJX-RXMQYKEDSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
- PHMRPWPDDRGGGF-UHFFFAOYSA-N 2-bromoprop-1-ene Chemical compound CC(Br)=C PHMRPWPDDRGGGF-UHFFFAOYSA-N 0.000 description 2
- NETUFVYVNJNFMU-UHFFFAOYSA-N 3-[tert-butyl(dimethyl)silyl]oxypropan-1-ol Chemical compound CC(C)(C)[Si](C)(C)OCCCO NETUFVYVNJNFMU-UHFFFAOYSA-N 0.000 description 2
- AQBBZYVPKBIILN-UHFFFAOYSA-N 4-(chloromethyl)-2-methyl-1,3-thiazole Chemical compound CC1=NC(CCl)=CS1 AQBBZYVPKBIILN-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- DIMLZGVFOXGJIW-UHFFFAOYSA-N 6-[tert-butyl(dimethyl)silyl]oxyhexanoyl chloride Chemical compound CC(C)(C)[Si](C)(C)OCCCCCC(Cl)=O DIMLZGVFOXGJIW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC=CCC1C(C)=CC1=CSC(C)=N1 BEFZAMRWPCMWFJ-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- SCHJIKPVOOCORF-UHFFFAOYSA-M sodium;6-hydroxyhexanoate Chemical compound [Na+].OCCCCCC([O-])=O SCHJIKPVOOCORF-UHFFFAOYSA-M 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- XBRMHTMQENGRNB-RYTGYZLSSA-N (1r,5s,6s,7r,9r,10s,14s,16s)-6,10-dihydroxy-5,7,9-trimethyl-14-[(e)-1-(2-methyl-1,3-thiazol-4-yl)prop-1-en-2-yl]-13,17-dioxabicyclo[14.1.0]heptadecane-8,12-dione Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)[C@H](C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 XBRMHTMQENGRNB-RYTGYZLSSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- DAAXYQZSKBPJOX-FQEVSTJZSA-N (2S)-2-amino-3-[4-[5-[3-(4-hydroxyphenyl)-4-methoxyphenyl]-1,2,4-oxadiazol-3-yl]phenyl]propanoic acid Chemical compound COC1=C(C=C(C=C1)C2=NC(=NO2)C3=CC=C(C=C3)C[C@@H](C(=O)O)N)C4=CC=C(C=C4)O DAAXYQZSKBPJOX-FQEVSTJZSA-N 0.000 description 1
- GUIBQTSZYLPXBH-VIFPVBQESA-N (2s)-2,6-dimethylhept-6-en-1-ol Chemical compound OC[C@@H](C)CCCC(C)=C GUIBQTSZYLPXBH-VIFPVBQESA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- UVGLIWCAMUOQPL-QMMMGPOBSA-N (2s)-2-methylhept-6-en-1-ol Chemical compound OC[C@@H](C)CCCC=C UVGLIWCAMUOQPL-QMMMGPOBSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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Description
-1- Method for producing epothilones, and intermediate products obtained during the production process The invention relates to a method for producing epothilones, and intermediate products obtained during the production process.
Epothilones 1 (DE 41 38 042 C2) represent a new class of tubulin-stabilising natural substances having a taxol-like action. In particular, their cytotoxic action with respect to medicament-resistant tumour cell lines is of enormous importance for potential application in the treatment of cancer Hofle, N. Bedorf, H. Steinmetz, D. Schomburg, K. Gerth, H. Reichenbach Angew. Chem. 1996, 108, 1671; Angew. Chem. Int. Ed. Engl. 1996, 1567; D. Schinzer "Epothilones New Promising Microtubule-stabilizing Natural Products with Taxol-like Biological Activity", Eur. Chem. Chron. 1996, 1, 7; D.M. Bollag, P.A. McQueney, J. Zhu, O. Hensens, L. Koupal, J. Liesch, M. Goetz, E. Lazarides, C.M. Woods, Cancer Res. 1995, 55, 2325]. Further interesting publications, some only after the priority applications of this Application, are: Acc. Chem. Res. 28, 446 (1995) generally about olefin metathesis, WO 93/10121 and J. Antibiot. 49, 560 (1996) with the isolation of epothilone A and B from natural sources, J. Org. Chem. 38, 2136 (1973) on the synthesis of substituted aldehydes and ketones, Helv. Chim. Acta 4, 1253 (1983) about certain 1,3from Streptomyces spp., Chem. Ber. 100, 720 (1967) about cyclohexanone derivatives, and the intermediate publications Angew. Chem. Int. Ed. 2801 (1996), J. Am. Chem. Soc. 119, 2733 (1997), Tetrahedron Lett. 38, 2061 (1997), Angew. Chem. Int. Ed. 36, 166 (1997), Lieb. Ann. Chem. 2135 (1996), J. Org. Chem. 61, 7998 (1996), J. Org. Chem. 61, 8000 (1996), Angew. Chem. Int. Ed. 35, 2399 (1996) and WO 97/19086.
Epothilones 1 R H, B: R Me) have recently been isolated from Myxobacteria and are obtainable via fermentation. As a result of the very interesting biological properties, the synthesis of epothilones is of the greatest importance. The invention relates to the total synthesis of epothilone A and B 1.
S
N
I f/ olefin metathesis, epoxidation 4 OH
R
N OH 3 aldol reaction esterification O 0 OH O 2 Scheme 1. Retrosynthetic analysis, Schinzer, A. Limberg, O.M. Bbhm, Chem. Eur. J. 1996, 2, 1477].
Epothilones 1 are obtainable in a convergent reaction procedure from the three building blocks 2, 3 and 4. As the retrosynthesis in Scheme 1 shows, building blocks 2 and 3 are linked in a stereoselective aldol reaction. An esterification with fragment 4 yields the almost completely functionalised fragment 17, which is cyclised in a ring-closure metathesis to form deoxy-epothilone A 19. A concluding epoxidation finally yields 1. The key step in the synthesis is the stereoselective aldol reaction of fragments 2 and 3 (obtainable from the commercially available heptenoic acid). Under kinetically controlled reaction conditions in the presence of LDA, exclusively the desired compound 5 having the four correctly positioned centres of asymmetry is obtained in a yield of 70 Here, evidently as a result of a double stereodifferentiation there takes place a chiral overriding of the preferred Cram selectivity of the aldehyde 3, since both reaction partners are used in optically active form.
The invention therefore relates to a method for producing epitholone A or B of the general formula 1
N
0 OH O wherein R hydrogen or a methyl group wherein a thiazolealkyldiene-alcohol derivative of formula 4 Sj
OH
is esterified with a carboxylic acid of general formula 9a
HO
OB O OB 0 OB O OB wherein B benzyl, tetrahydropyranyl and/or a silyl protecting group(s).and R hydrogen or methyl, the resulting ester has the ring closed by means of an olefin metathesis in the presence of a noble metal catalyst, if appropriate the hydroxyl-protecting groups are cleaved, the newly formed double bond is epoxidised and if appropriate the hydroxyl-protecting groups are cleaved.
As silyl protecting groups B there are generally suitable all different trialkyl- or diaryl-alkylsilyl protecting groups, especially the tert-butyl-dimethyl-, trimethyl-silyl and diphenyl-tertbutyl-silyl groups.
-4- The derivatives 4a and 9a are esterified, preferably by the use of DCCI/DMAP, and the resulting ester with the two terminal alkene groups has the ring closed by olefin metathesis, preferably by the use of RuCI 2 (=CHPh)(PCy 3 2 (Grubbs catalyst) Org. Chem. 1996, 61, 3942-3943; Tetrahedron 1996, 52, 7251-7264; J. Am. Chem. Soc., 1995, 117, 12364-12365; J. Am. Chem. Soc., 1995, 117, 2943-2944 and Tetrahedron Lett.; 1994, 35, 3191-3194, J. Am. Chem. Soc., 1996, 118, 6634-6640 and J. Am. Chem. Soc., 1995, 118, 100-110.
The epoxidation of the newly formed double bond is effected preferably by means of peracid, e.g. perchloric acid, or peroxide, e.g. cumene hydroperoxide or dimethyldioxirane.
The invention also includes deoxy-epothilones according to general formula 19a
R
S
N OB O 19a O OB 0wherein B benzyl, p-methoxybenzyl, tetrahydropyranyl and/or a silyl protecting group and S R hydrogen or methyl, S (2-(2,2-dimethyl-[13]dioxan-4-yl)-2-methyl-pentan-3-one) 2, (S)-2-methyl-6-heptenal 3 :0 3
H
o in its optically active form and (S)-2,6-dimethyl-6-heptenal 3a S3a
H
in its optically active form and compounds of general formula 9a
HO
OB
P
I
V
GB
wherein B benzyl, tetrahydropyranyl and/or a silyl protecting group R hydrogen or methyl, and B may have different meanings within the molecule, and compounds of general formula 4a
N
4~:wherein B hydrogen, benzyl, p-methoxybenzyl, tetraliydropyranyl or a silyl protecting group *and (4S,6S)-2-(2 ,2-dimethyl4l 2
O
0 3 a N b O 0 o OH TBSO OTBS O OTBS 7 OH OH 0 OH 6 OH OTBS O OTBS 8 0
HO
0 OTBS O OTBS 9 Scheme 2. a) LDA, THF, -780C, 70%; b) pyridinium p-toluenesulfonate (PPTS), MeOH, RT, 36 h, 88 c) 12 eq. tert-BuMe 2 SiOTf (Tf=trifluoromethanesulfonate), 6 eq. 2,6-lutidine,
CH
2
CI
2 -78°C, 96 d) 0.2 eq. CSA (camphorsulfonic acid), MeOH, CH2C1 2 0°C, 5 h, 82 e) 11 eq. pyridinium dichromate (PDC), DMF, RT, 36 h, 79 The cleavage of the acetonide 5 to form the triol 6 takes place smoothly in the presence of pyridinium p-toluenesulfonate (PPTS). A subsequent trisilylation with TBSOTf and lutidine as auxiliary base yields the desired compound 7. In order to facilitate the oxidation to the acid 9 it is necessary to remove the primary silyl group selectively. This takes place smoothly in the presence of camphorsulfonic acid (CSA) and generates compound 8.
A concluding oxidation with pyridinium dichromate (PDC) produces fragment 9, which is the C1-C12 sub-unit of 1.
-7- TBSO OH a rl TBSO OTBS b TBSO OTBS 12
C
N OTBS
OTBS
d
OH
OTBS
14
S
16
OTBS
e
N
OTBS
f
>N
OH
4 0 Scheme 3. a) TBSCI, imidazole, DMF, RT, 10 h, 98 b) 03, PPh 3 0H 2
CI
2 -78 0 C, 70 c) 1.5 eq. diethyl-(2-methylthiazol-4-yI)methanephosphonate, nBuLi, THE, -78'C RT, d) HF, MeCN, a few splinters of glass, 0 0 C, 87 e) Dess-Martin periodinane, 0H 2 01 2 RT, 1 h, 78 f) 1.85 eq. PPh 3 MeBr/NaNH 2 THE, RT, 20 min., 83 g) 2.5 eq. tetrabutylammonium fluoride (TBAF), molecular sieve 4 A, THE, -780C RT, 99 The (8)-alcohol 10 obtainable via a Sharpless resolution Schinzer, A. Limberg, O.M.
Bohm, Chem. Eur. J. 1996, 2, 1477] was first silylated with TBSCI, then ozonised to the methylketone 12 and reacted in a stereoselective Horner-Wadsworth-Emmons reaction to -8form the tricyclic olefin 13. A selective desilylation with HF in acetonitrile yields compound 14. The desilylation to 14 functions only in the presence of a few splinters of glass; the reaction is evidently catalysed by H 2 SiF 6 Dess-Martin oxidation, followed by a Wittig olefination generates compound 16 which, in a concluding desilylation with TBAF in THF, yields segment 4. The esterification of building blocks 9 and 4 in the presence of DCC and 4-DMAP produces compound 17, which is isolated in stereochemically homogeneous form.
-9- HO N N O 0 OTBSO OTBS
O
4 9 a I OTBS 0 OTBSO0 17
S
N"J OTBS 0 O OTBSO0 18
S
N 1
OH
0 O OH 0 Epothilone C: 19 N .0 0 O OH 0 Epothilone A: 1 Scheme 4. a) 1 .3 eq. dicyclohexylcarbodiimide (DCC), 0.2 eq. 4-dimethylaminopyridine (4-DMAP), CH 2
CI
2 RT, 12 h, 80 b) C1 2 [RuCHPhl(PCY 3 2
CH
2
CI
2 RT, 12 h, 94 E 1 c) HF, MeON, Et 2 O, RT, 12 h, 65 d) dimethyldioxirane, CH 2
CI
2 -350C, 2 h, 48 Ring closure metathesis with CI2[RuCHPh](PCy 3 2 in CH 2
CI
2 yields 18 in the form of a diastereoisomeric mixture E 1 1) in a yield of 94 The total synthesis is concluded by the desilylation with HF in acetonitrile/ether to form 19 and a regio- and stereo-selective epoxidation with dimethyldioxirane to form 1. The main product of this reaction is (-)-epothilone A, which is chromatographically and spectroscopically identical to an authentic sample.
All in all, a strictly convergent synthesis has been described, which allows many options for analogues, which is significant in view of the biological activity. The entire synthesis can be carried out using a type of protecting group (TBS) that is linked or removed in selective reactions. The stereoselective aldol reaction is high and constitutes a further impressive example of the chiral overriding of the aldehyde selectivity with a chiral enolate. The ring closure metathesis to form 18 takes place with an isolated yield of 94 but yields a 1 1 mixture of the Z- and E-isomers. The biologically significantly more active epothilone B 1 (R Me) can be obtained by the same preparation route.
11 Preparation of 2 0 OH OH NaH, TIIF
TBDMSCI
92% OH OTBOMS 441 Me 2 CO, H.
CUSO 4 81%
CICOCOCI,
DMSO, Et 3
N
80%
X>:
O OTBOMS u) BI PC 2 2. NaOH, H 202 42%, 92% ee
OH
~-~OTDMS
43 NaIO 4 OSO 4 76% O~x) EtMgBr, Et 20 80% OH TPAP, NMO 86% O X -12- Working procedures for the synthesis of segment 2 (2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-one) Schinzer, A. Limberg, O.M. Bohm, Chem. Eur. J. 1996, 2, 1477].
The 3-[(tert-butyldimethylsilyl)oxy]propanal 42 is prepared starting from propane-1,3-diol by first monosilylating in accordance with a method of P.G. McDougal, J.G. Rico, Y. Oh, B.D.
Condon, J. Org. Chem. 1986, 51, 3388-3390, to form 3-[(tert-butyldimethylsilyl)oxy]-1propanol 41 which is then oxidised with DMSO/oxalyl chloride to form the aldehyde 42 Jenmalm, W. Berts, Y. Li, K. Luthmann, I. Csoregh, U. Hacksell, J. Org. Chem. 1994, 59, 1139-1148).
Preparation of 1-[(tert-butyldimethylsilyl)oxy]-4,4-dimethyl-hex-5-en-3-ol 43 Brown, P.K. Jadhav, Tetrahedron Lett. 1984, 25, 1215-1218; P.K. Jadhav, K.S. Bhat and P. Thirumalai, H.C. Brown, J. Org. Chem. 1986, 51, 432-439).
500 mg (7.34 mmol, 1 equiv.) of 3-methyl-1,2-butadiene are slowly added dropwise to a suspension, cooled to -250C, of Ipc 2 BH (7.34 mmol, prepared from -pinene [99%, 97% ee] H.C. Brown, M.C. Desai, P.K. Jadhav, J. Org. Chem. 1982, 47, 5065-5069; H.C.
Brown, B. Singaram, J. Org. Chem. 1984, 49, 945-947) in 2.6 ml of THF and the reaction mixture is stirred at -25oC for 6 hours. The THF is then pumped off at RT (14 mm Hg/- 1 hour), (0.5 mm/2 hours) and the residue is dissolved in 10.5 ml of diethyl ether. The solution is cooled to -78°C and 1.382 g (7.34 mmol, 1 equiv.) of aldehyde 42 are added dropwise thereto. The reaction mixture is stirred at -78 0 C for 12 hours and then heated to RT. 10.7 ml of 3N NaOH solution and then 4.4 ml of 30% H 2 0 2 solution are added and the reaction mixture is heated under reflux for 2 hours. The organic phase is separated off, washed with 15 ml of H 2 0 and 15 ml of saturated NaCI solution, dried over MgSO 4 and concentrated. The residue is purified by column chromatography with pentane:ether 2:1, and 800 mg (3.098 mmol) of the alcohol 43 are obtained, corresponding to a yield of 42%.
The determination of the enantiomeric excess was effected by gas chromatographic analysis of the diastereoisomeric compounds which are obtained on esterification of the alcohol with (1R)-(-)-camphanic acid chloride and gave an ee value of 92%.
General data: C 14
H
30 0 2 Si, formula weight 258.47 g/mol 13 C-NMR (100 MHz, CDCI 3 145.69 112.27 78.52 63.29 41.19 33.39 25.89 22.85 22.43 18.17 -5.52 (q) -13- Preparation of 4-(1,1 -dimethyl-allyl)-2,2-dimethyl-[1,3]dioxane 44 278 mg (1.076 mmol) of the alcohol 43 are dissolved in 13 ml of acetone, and 200 mg (2.51 mmol, 2.3 equiv.) of anhydrous CuSO 4 are added. Then 40 drops of a solution of 0.1 ml of glacial acetic acid in 1 ml of CH 2
CI
2 are added dropwise and stirring is carried out at RT for 12 hours. If starting material can still be detected by thin-layer chromatography, further acid solution is added until the reaction is complete. For working up, the reaction mixture is poured into saturated NaHCO 3 solution and the aqueous phase is extracted with DE. The combined organic phases are dried over MgSO 4 and concentrated using a rotary evaporator. The residue is purified by column chromatography with pentane:ether 2:1.
161 mg (0.87 mmol) of the acetonide 44 are obtained, corresponding to a yield of 81%.
General data: C 11
H
20 0 2 formula weight 184.28 g/mol 13 C-NMR (100 MHz, CDC13): 145.10 111.88 98.19 75.32 60.10 39.97 29.80 25.88 22.86 22.45 19.11 (q) Preparation of 2-(2,2-dimethyl-[1,3]dioxan-4-yl)-2-methyl-propionaldehyde 286 mg (1.55 mmol) of the acetonide 44 are dissolved in 18 ml of THF, and 14 ml of aqueous phosphate buffer pH 7 are added. 400 pl (0.
0 3 1 mmol, 0.02 equiv.) of Os0 4 solution in tert-butanol) are added dropwise to the reaction mixture, which is stirred vigorously. After 10 minutes, 996 mg (4.656 mmol, 3 equiv.) of NalO 4 are added in portions over a period of 20 minutes. The mixture is stirred vigorously at RT and after 24 hours and after 48 hours a further 332 mg (each 1.55 mmol, 2x1.0 equiv.) of NalO 4 are added. After hours the phases are separated; the aqueous phase is extracted with ether and the combined organic phases are dried over MgSO 4 and concentrated. The residue is purified by column chromatography with pentane:DE 1:1. 221 mg (1.19 mmol) of the aldehyde are obtained, corresponding to a yield of 76%.
General data: CloH 18 0 3 formula weight 186.25 g/mol 1 C-NMR (100 MHz, CDCI 3 206.09 98.43 72.94 59.75 48.84 29.57 25.57 18.96 18.62 16.46 (q) Preparation of 2-(2,2-dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-ol 46 At 0°C, 528 p (1.58 mmol, 1.1 equiv.) of a 3M solution of EtMgBr in ether are added to a solution of 268 mg (1.44 mmol) of the aldehyde 45 in 4 ml of diethyl ether. The mixture is stirred at 0°C for 2 hours, heated to RT and stirred for a further one hour. For working up, saturated aqueous NH 4 CI solution is added and then water is added until the precipitate -14dissolves. The aqueous phase is extracted with ether, and the combined organic phases are dried over MgSO 4 and concentrated. The residue is purified by column chromatography with pentane:ether 1:1. 251 mg (1.16 mmol) of the alcohol 46 are obtained, corresponding to a yield of General data: C 12
H
24 0 3 formula weight 216.31 g/mol 13 C-NMR (100 MHz, CsD 6 98.41 79.95 76.65 60.10 40.60 Diastereoisomer 1: 30.04 25.73 24.64 20.03 19.25 15.99 11.67 (q) 13 C-NMR (100 MHz, C 6 De): 98.57 78.85 76.46 60.08 39.93 Diastereoisomer 2: 30.02 25.41 25.08 20.85 20.30 18.90 11.95 (q) Preparation of 2-(2,2-dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan- 3 -one 2: W.P. Griffith, S.V. Ley, G.P. Whitcombe, A.D. White, J. Chem. Soc., Chem. Commun. 1987, 1625-1627 mg (0.32 mmol) of the alcohol 46 are dissolved in 5 ml of CH 2
CI
2 and 6 4A molecular sieve beads and 66 mg (0.48 mmol, 1.5 equiv.) of 4-methylmorpholine N-oxide (NMO) are added. After stirring for 10 minutes, 6 mg of tetrapropylammonium perruthenoate (VII) (TPAP) (0.016 mmol, 0.05 equiv.) are added and stirring is carried out at RT for 4 hours.
The reaction mixture is then concentrated using a rotary evaporator and purified directly by column chromatography with pentane:ether 1:1. 60 mg (0.28 mmol) of the ethyl ketone 2 are obtained, corresponding to a yield of 86%.
General data: C 12
H
22 0 3 formula weight 214.30 g/mol 13 C-NMR (100 MHz, C 6 De): 213.23 98.42 74.18 59.82 50.44 31.70 30.03 25.55 20.97 19.35 19.04 8.16 (q) Synthesis of 2-methyl-6-heptenal 3 and 3a
R
R 3 R=H I 3a R=Me 0 The preparation is effected following the method of the synthesis of 6-tert-butyldimethylsilyloxy-2-methyl-hexanal 50 Schinzer, A. Limberg, O.M. B6hm, Chem. Eur. J. 1996, 2, 1477].
Synthesis of segment 4: 0 0 NaOH, EtOH 81% 0 HO ONa
TBDMSCI.
imidazole, DMF 86% 0 TBDMSO S.
TBDMS
MeOH. THF
K
2 00 3 90% 0 TBOM SO
OH-
S001 2. benzene 92% 0
TBDMSO
0
LN
,,-BuLi 0 0 II
OTBDMS
1--ly NaHMDS; Mel 82%
OTBDMS
LA.H, Et 2 0 84% HO O B M
CICOCOCI,
DMSO, Et 3
N
87%
OTBDMS
0 Working procedures for the preparation of segment 3: The sodium 6-hydroxyhexanoate is prepared from o-caprolactone in accordance with a procedure of Wulff, KrOger and R~hle, Chem. Ben. 1971, 104, 1387-1 399.
-16- Preparation of 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid silyl ester A mixture of 2.00 g (12.97 mmol) of sodium 6-hydroxyhexanoate, 25 ml of DMF, 5.87 g (38.93 mmol, 3 equiv.) of TBDMSCI and 5.3 g (77.85 mmol, 6 equiv.) of imidazole is stirred at RT for 48 hours. The reaction mixture is flash-filtered and then purified by column chromatography with pentane:DE 4:1. 3.99 g (11.1 mmol) of the bis-silylated compound 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid silyl ester are obtained, corresponding to a yield of General data: C 18
H
40 03Si 2 formula weight 360.69 g/mol "C-NMR (100 MHz, CDC13): 174.17 63.00 36.02 32.53 25.95 25.55 25.40 24.91 18.33 17.57 -4.83 -5.32 (q) Preparation of 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid in accordance with D.R. Morton, J.L. Thompson, J. Org. Chem. 1978, 43, 2102-2106.
A solution of 4.4 g (31.8 mmol, 3.5 equiv.) of K 2 C0 3 in 44 ml of H 2 0 is added to a solution of 3.25 g (9.02 mmol) of the bis-silylated compound 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid silyl ester in 130 ml of methanol and 44 ml of THF and stirring is carried out at RT for 1 hour. The volume of the reaction solution is then reduced to a quarter in vacuo. Dilution is carried out with 130 ml of saturated NaCI solution and the pH is adjusted to 4-5 with 1M
KHSO
4 solution. Extraction is carried out with diethyl ether. The combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. 2.01 g (8.17 mmol) of 6-[(tert-butyldimethylsilyl)oxy]-hexanoic acid are obtained, corresponding to a yield of General data: C 1 2
H
2 6 03Si, formula weight 246.42 g/mol 1 3 C-NMR (100 MHz, CDCl3): 180.09 62.90 34.05 32.37 25.93 25.31 24.46 18.32 -5.33 (q) Preparation of 6-[(tert-butyldimethylsilyl)oxy]-hexanoyl chloride J. Tanaka, Bull. Chem. Jpn. 1992, 65, 2851-2853 362 mg (3.04 mmol, 1.5 equiv.) of SOCI 2 are added to a solution of 0.5 g (2.03 mmol) of 6- [(tert-butyldimethylsilyl)oxy]-hexanoic acid in 4 ml of benzene and the mixture is heated under reflux for 2 hours. The mixture is allowed to cool and the solvent is distilled off using a rotary evaporator. In order to remove excess SOC12 from the reaction mixture, benzene is again added to the residue and distillation is again carried out. 494 mg (1.865 mmol, 92%) -17of the 6-[(tert-butyldimethylsilyl)oxy]-hexanoyl chloride are obtained. This crude product is reacted further without being purified or characterised.
*(S)-4-lsopropyl-3-propenoyl-oxazolidin-2-one 0 0 Prepared following the method of: D.A. Evans, K.T. Chapman, J. Bisha J. Am. Chem. Soc.
1988, 110, 1238; A. Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185.
6.88 ml of a 1.6M solution of n-BuLi in hexane (11.0 mmol) are slowly added at -780C to a solution of 1.299 g (10.0 mmol) of (S)-4-isopropyl-oxazolidin-2-one in 15 ml of absolute THF.
The solution is stirred at -78°C for 30 minutes, 1.22 ml (15.0 mmol) of acrylic acid chloride are added dropwise thereto and the mixture is heated to room temperature and hydrolysis is carried out with 50 ml of saturated NH 4 CI solution. Extraction is carried out three times using ml of Et 2 0 each time. After drying over MgSO 4 the solvent is removed. Purification by flash chromatography with pentane/Et 2 0 (10:1) yields 1.63 g (8.9 mmol, 89 of (S)-4-Isopropyl-3-(6-methylhept-6-enoyl)-oxazolidin-2-one 21a
O_
S0 21a Prepared following the method of: A. Studer, T. Hintermann, D. Seebach Helv. Chim. Acta 1995, 78, 1185 47 mg (1.9 mmol) of Mg turnings are stirred at room temperature (or with occasional heating) in 1.5 ml of absolute THF with 283 mg (1.9 mmol) of 4-bromo-2-methyl-1-butene until all the magnesium has dissolved. To this Grignard solution there is added at a suspension of 197 mg (1.00 mmol) of CuBr-Me 2 S in 1.5 ml of absolute THF. Stirring is carried out at that temperature for 30 minutes; 117 mg (0.64 mmol) of 20 in 2 ml of absolute THF are added and the mixture is stirred at -10 0 C for 16 hours and hydrolysis is carried out with 10 ml of saturated NH 4 CI solution. Extraction is carried out three times using 20 ml of Et 2 0 each time. After drying over MgSO 4 the solvent is removed. Purification by flash chromatography with pentane/Et20 (15:1) yields 128 mg (0.51 mmol, 79 of 21a.
-18- Hept-6-enoyl chloride 5.11 g (40.26 mmol, 2 eq.) of oxalyl chloride are added to a solution of 2.58 g (20.13 mmol) of hept-6-enoic acid in 10 ml of CH2C1 2 then stirred at RT for 1 hour and at 40°C for 1 hour.
The mixture is allowed to cool and the solvent is distilled off at 5 mbar. 2.95 g (20.13 mmol, 100 of the acid chloride are obtained. This crude product is reacted without further purification.
General data: C 7
H
1 1 CIO, formula weight 146.62 g/mol (S)-3-Hept-6-enoyl-4-isopropyl-oxazolidin-2-one 21 O N 21 A. Gonzalez, Synth. Comm. 1991, 21, 1353-1360 A solution of 2.08 g (16.10 mmol, 1 eq.) of (4S)-4-isopropyl-oxazolidin-2-one in 15 ml of THF is cooled to -780C and 11.6 ml (18.52 mmol, 1.15 eq.) of a 1.6M solution of n-BuLi solution in hexane are added dropwise thereto. Then at -780C a solution of 2.95 g (20.13 mmol, 1.25 eq.) of hept-6-enoyl chloride in 10 ml of THF is added dropwise. The reaction solution is heated to RT and poured into saturated NaCI solution. The aqueous phase is extracted with ether, the combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. The residue is purified by column chromatography with PE DE 3 1. 3.55 g (14.82 mmol, 92 of the oxazolidinone 21 are obtained in the form of a colourless oil.
General data: C 13
H
21
NO
3 formula weight 239.31 g/mol -19- (4S,2'S)-4-Isopropyl-3-(2-methyl-hept-6-enoyl)-oxazolidin-2-one 22 analogous to preparation 25 and (4S,2'S)-4-isopropyl-3-(2,6-dimethyl-hept-6-enoyl)-oxazolidin-2-one 22a 0 N 22 R=H v v22a R=Me 0 0 D.A. Evans, A.E. Weber J. Am. Chem. Soc. 1986, 108, 6757-6761 9.02 ml (9.02 mmol, 1.15 equiv.) of a 1M solution of NaHMDS in THF are cooled to -78°C, and a solution, cooled to 0°C, of 1.88 g (7.84 mmol) of oxazolidinone 21 in 8 ml of THF is added dropwise thereto. Stirring is carried out at -780C for 1 hour; 5.57 g (39.22 mmol, equiv.) of Mel dissolved in 2 ml of THF are added and stirring is carried out at -78 0 C for 4 hours. The reaction mixture is then quenched with saturated NH 4 CI solution, extracted with diethyl ether, dried over MgSO 4 and concentrated. The residue is purified by column chromatography with PE DE 4 1. 1.51 g (5.96 mmol, 76 of the methylated compound 22 are obtained.
General data: C 14
H
23
NO
3 formula weight 253.34 g/mol Compound 22a is prepared analogously. 1.56 g (5.84 mmol, 73 of 22a are obtained from 2.03 g (8.0 mmol) of 21a.
(S)-2-Methyl-hept-6-en-1-ol 23 and (S)-2,6-dimethylhept-6-en-1-ol 23a
R
s23 R=H OH 23a R=Me D.A. Evans, A.E. Weber J. Am. Chem. Soc. 1986, 108, 6757-6761 5.83 ml (5.83 mmol, 2 eq.) of a 1M suspension of LAH in diethyl ether are slowly added to a solution, cooled to 0°C, of 738 mg (2.91 mmol) of the methylated compound 22 in 10 ml of diethyl ether. The reaction mixture is quenched by the addition of 221 ml of water, 221 ml of aqueous NaOH solution and 663 ml of water. Flash filtration is then carried out over Celite with diethyl ether and purification is carried out by column chromatography with pentane DE 3 1. 299 mg (2.33 mmol, 80 of the alcohol 23 are obtained in the form of a colourless liquid.
General data: C 8
H
16 0, formula weight 128.21 g/mol Compound 23a is prepared analogously. 331 mg (2.32 mmol, 83 of 23a are obtained from 748 mg (2.80 mmol) of 22a.
(S)-2-Methyl-hept-6-enal 3 and (S)-2,6-dimethylhept-6-enal 3a
R
A 3 R=H 3a R=Me 0 1.269 g (2.99 mmol, 1.3 eq.) of Dess-Martin periodinane (1,1,1-triacetoxy-1,1-dihydro-1,2benziodoxol-3(1H)-one) are added to a solution of 295 mg of alcohol 23 (2.30 mmol) in 5 ml of CH 2
CI
2 and stirring is carried out at RT for 25 minutes. For working-up, one volume equivalent of phosphate buffer pH 7 is added. The aqueous phase is extracted with CH 2
CI
2 the combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. The residue is purified by column chromatography with pentane DE 10 1.
224 mg (1.77 mmol, 77 of the aldehyde are obtained in the form of a colourless liquid.
General data: C 8
H
14 0, formula weight 126.20 g/mol Compound 3a is prepared analogously. 199 mg (1.42 mmol, 71 of 3a are obtained from 284 mg (2.00 mmol) of 23a.
21 Preparation of 4:
S
4 OH TBSO OHi a TBSO OTBS b r'a1 TBSO OTBS 12
C
OTBS
N
OTBS
d p.- OH N OTBS 14
N
16
OTBS
e ~0
N
OTBS
f
OH
4 Synthesis of segment 4: 3-(Tert-butyldimethylsilyl)oxy]-propanal Synthesis by monosilylation of 1,3-propanediol and subsequent Swern oxidation of the resulting 3-[(tert-butyldimethylsilyl)oxy]-1 -propanol.
General data: C 9
H
20
O
2 Si; formula weight 188.36; CAS No. [89922-82-71 13 0C-NMR (100 MHz, CDC 3 d=202.05 57.42 46.58 25.82 18.23 -5.43 (q) I Tert-butyldimethylsi IyI)oxy]-3-hyd roxy-4-methyl-4-pentene 0.2 ml of 2-bromopropene is added under N 2 to 443 mg of Mg turnings (18.2 mmol) and 1 .5 ml of absolute THIF so that the reaction starts. With occasional cooling, a solution of -22- 1.7 ml of 2-bromopropene (22 mmol in total) in 6 ml of absolute THF is slowly added dropwise until all the Mg turnings have dissolved. While the mixture is still warm, a solution of 2.862 g of 1 (15.2 mmol) in 6 ml of absolute THF is added dropwise. Stirring is carried out at RT for 6 hours. 25 ml of saturated NH 4 CI solution are then added to the reaction solution and stirring is carried out for 10 minutes. The mixture is poured into 30 ml of saturated NH 4
CI
solution and extracted twice with ether. The combined organic phases are washed once with saturated NH 4 CI solution and once with saturated NaCI solution. Drying over MgSO 4 concentration in vacuo and purification by flash chromatography (ether:pentane 1:6) are carried out. 2.749 g of 2 (11.9 mmol; 79% of theory) are obtained in the form of a colourless oil.
General data: C 12
H
26 0 2 Si; formula weight 230.43 13 C-NMR (100 MHz, CDCI 3 d=147.10 110.39 75.21 62.17 36.79 25.89 18.41 -5.49 -5.53 (q) (S)-1,3-Di-[(tert-butyldimethylsilyloxy)]-l-methyl-4-pentene 11 TBSO OTBS 11 946 mg (6.28 mmol, 1.3 eq.) of tert-butyldimethylchlorosilane are added to a solution of 1.173 g (4.83 mmol) of (S)-l-[(tert-butyldimethylsilyloxy)]-4-methyl-4-penten-3-ol 10 and 855 mg (12.56 mmol, 2.6 eq.) of imidazole in 15.0 ml of absolute DMF. The mixture is stirred at room temperature for 16 hours. 50 ml of an aqueous 1M KHSO 4 solution are added and extraction is carried out four times using 50 ml of Et 2 0 each time. The combined ether extracts are dried over MgSO 4 After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with pentane/- Et 2 0 As an alternative to that aqueous working-up, the reaction mixture can be chromatographed directly. In accordance with both variants of working-up, 1.643 g (4.73 mmol, 98 of 11 are obtained.
-23- (S)-3,5-Di-[(tert-butyldimethylsilyloxy)]-pentan-2-one 12 TBSO OTBS 12 Ozone in 02 is passed at -780C through a solution of 1.610 g (4.67 mmol) of 11 in 200 ml of absolute dichloromethane (dry ice/acetone cooling bath). When starting compound 11 can no longer be detected in the solution by thin-layer chromatography, 3.89 g (14.83 mmol) of triphenylphosphine are added and the cooling bath is removed. The reaction mixture is heated slowly to room temperature and the solvent is distilled off in vacuo. Flash chromatography of the residue through a column of silica gel with pentane/Et20 (50:1) yields 1.135 g (3.27 mmol, 70 of 12.
Diethyl-(2-methylthiazol-4-yl)-methanephosphonate 'k P(OEt)2 Preparation is effected starting from 4-chloromethyl-2-methylthiazole, which is known in the literature, analogously to the procedure for 4-bromomethyl-2-methylthiazole. From 7.381 g mmol) of 4-chloromethyl-2-methylthiazole there are obtained 9.971 g (40 mmol, 80 of diethyl-(2-methylthiazol-4-yl)-methanephosphonate.
(S,4E)-4-[3,5-Di-(tert-butyldimethylsilyloxy)-2-methyl-pent-1-enyl]-2-methylthiazole 13
S
OTBS
13 2.94 ml of n-BuLi (1.6M solution in hexane) are added dropwise at -780C to a solution of 1.170 g (4.70 mmol) of diethyl-(2-methylthiazol-4-yl)-methanephosphonate in 15 ml of absolute THF. The mixture is stirred at -78°C for 45 minutes and then a solution of 1.135 g (3.27 mmol) of 12 in 10 ml of absolute THF is slowly added dropwise thereto; the mixture is heated to room temperature and stirred at room temperature for a further 12 hours. 100 ml of saturated NH 4 CI solution are added to the reaction mixture and extraction is carried out -24four times using 80 ml of Et20 each time. The combined ether extracts are washed with saturated NaCI solution and dried over MgSO 4 After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with pentane/dichloromethane 1.090 g (2.47 mmol, 75 of 13 are obtained.
Tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-en-1-ol 14 N% OH 14
OTBS
0.45 ml of hydrofluoric acid (40 is added dropwise at -200C to a solution of 442 mg mmol) of 13 in 40 ml of acetonitrile. After the addition of a few splinters of glass or 0.045 ml of hexafluorosilicic acid (30 stirring is carried out at 0°C until starting compound 13 can no longer be detected in the solution by thin-layer chromatography. 50 ml of saturated NaHCO 3 solution are added to the reaction mixture and extraction is carried out four times using 80 ml of Et 2 0 each time. The combined ether extracts are dried over MgSO 4 After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with Et 2 0. 284 mg (0.87 mmol, 87 of 14 are obtained.
(S,4E)-3-(Tert-butyldimethylsilyloxy)-4-methyl-5-(2-methylthiazol-4-yl)-pent-4-ena
OTBS
A solution of 284 mg (0.87 mmol) of 14 in 5.0 ml of absolute CH 2
CI
2 is added to a suspension of 478 mg (1.127 mmol, 1.3 eq.) of Dess-Martin periodinane (1,1,1-triacetoxy- 1,1-dihydro-1,2-benziodoxol-3(1H)-one) in 5.6 ml of absolute CH 2
CI
2 and stirring is carried out at room temperature for 60 minutes. After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with pentane/Et 2 0 222 mg (0.68 mmol, 78 of 15 are obtained.
Tert-butyldimethylsilyloxy)-2-methyl-hexa-1,5-dienyl]-2-methyl-thiazole 16 16
OTBS
440 mg (1.06 mmol, 1.85 eq.) of a mixture of equimolar amounts of sodium amide and methyltriphenylphosphonium bromide are stirred at room temperature for 30 minutes in ml of absolute THF. A solution of 185 mg (0.57 mmol) of 15 in 5.0 ml of absolute THF is added and stirring is continued for a further 20 minutes; 20 ml of saturated NaHCO 3 solution are added and extraction is carried out four times using 30 ml of Et 2 0 each time. The combined ether extracts are dried over MgSO 4 After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with 151 mg (0.47 mmol, 83 of 16 are obtained.
2-Methyl- -(2-methyl-thiazol-4-yl)-hexa-1,5-dien-3-ol 4 4 OH 1.18 ml (1.18 mmol, 2.5 eq.) of a 1M TBAF solution in THF are stirred at room temperature for 20 minutes in 10 ml of absolute THF with activated molecular sieve 4A in order to bind residual water of the TBAF solution. There is then added dropwise to the resulting anhydrous TBAF solution, at -780C, a solution of 151 mg (0.47 mmol) of 16. The mixture is slowly heated to room temperature, with stirring, and hydrolysed with 50 ml of saturated
NH
4 CI solution when starting compound 16 can no longer be detected in the solution by thinlayer chromatography. Extraction is carried out three times using 50 ml of Et20 each time.
After drying over MgSO 4 the solvent is removed. Purification by flash chromatography with pentane/Et 2 0 (20:1) yields 97 mg (0.465 mmol, 99 of 4.
The preparation of compounds of general formula 4a
N
4a
OB
-26- (B represents benzyl, p-methoxybenzyl, tetrahydropyranyl or a silyl protecting group; e.g.
trialkyl- or diaryl-alkyl-silyl protecting groups, especially tert-butyl-dimethyl-, trimethylsilyl and diphenyl-tert-butyl-silyl groups) is effected from S 4
OH
by the use of conventional protecting group techniques of etherification, see also Schinzer, A. Limberg, O.M. Bohm, Chem. Eur. J. 1996, 2, 1477).
Preparation of 5 and compounds of general formula 9a (4'S,4R,5S,6S)-2-(2,2-dimethyl-[1,3]dioxan-4-yl)-5-hydroxy-2,4,6-trimethyl-undec-10-en- 3-one 5 and (4'S,4R,5S,6S)-2-(2,2-dimethyl-[1,3]dioxan-4-yl)-5-hydroxy-2,4,6,10-tetramethyl-undec- 10-en-3-one analogously to Scheme 2.
R=H
0 O 5a R=Me O O O OH C.H. Heathcock, C.T. Buse, W.A. Kleschick, M.C. Pirrung, J.E. Sohn, J. Lampe J. Org. Chem. 1980, 45, 1066.
943 microlitres (1.509 mmol, 0.98 eq.) of a 1.6M solution of n-BuLi in hexane are added dropwise at 0°C to a solution of 153 mg (1.509 mmol, 0.98 eq.) in 1.5 ml of THF and the mixture is stirred for 30 minutes before being cooled to -78oC. 330 mg (1.540 mmol, 1 eq.) of (S)-2-(2,2-dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-one 2 dissolved in 1 ml of THF are then slowly added dropwise. The solution is stirred at -780C for 1 hour. 194 mg (1.540 mmol, 1 eq.) of (S)-2-methyl-hept-6-enal 3 are then added dropwise and stirring is carried out at -780C for 45 minutes. The reaction solution is quenched by the addition of saturated NH 4 CI solution and heated to RT. The aqueous phase is extracted with ether; the -27combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. The residue is purified by column chromatography with pentane diethyl ether 3 1. 369 mg (1.084 mmol, 70 of the aldol product 5 are obtained in the form of a colourless oil.
General data: C 20
H
36 0 4 formula weight 340.50 g/mol Compound 5a is prepared analogously. 386 mg (1.09 mmol, 64 of 5a are obtained from 238 mg (1.70 mmol) of 3a.
(3S,6R,7S,8S)-1,3,7-Trihydroxy-4,4,6,8-tetramethyl-tridec-12-en-5-one 6 and (3S,6R,7S,8S)-1,3,7-trihydroxy-4,4,6,8,12-pentamethyl-tridec-12-en-5-one 6a 6 R=H OH OH O OH 6a R=Me L.A. Paquette, D.R. Sauer, D.G. Cleary, M.A. Kinsella, C.M. Blackwell, L.G. Anderson J. Am. Chem. Soc. 1992, 114, 7375-7387. 95 mg (0.378 mmol, 1.3 eq.) of PPTS are added to a solution of 100 mg (0.294 mmol) of the aldol product 5 in 14 ml of MeOH and the mixture is stirred at RT for 36 hours and then quenched by the addition of 33 drops of saturated NaHCO 3 solution. The mixture is concentrated using a rotary evaporator and the residue is taken up in ether. Washing is carried out with saturated NaCI solution and the aqueous phase is extracted with ether. The combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. The residue is purified by column O chromatography with diethyl ether. 78 mg (0.260 mmol, 88 of the triol 6 are obtained in the form of a colourless oil.
General data: C 17
H
32 0 4 formula weight 300.44 g/mol Compound 6a is prepared analogously. 77 mg (0.246 mmol, 91 of 6a are obtained from 96 mg (0.270 mmol) of -28- (3S,6R,7S,8S)-1,3,7-Tri-(tert-butyldimethylsilyloxy)-4,4,6,8-tetramethyl-tridec-1 one I and (3S,6R,7S,8S)-1,3,7-tri-(tert-butyldimethylsilyloxy)-4,4,6,8,12-pentamethyltridec-12-en-5-one 7a 7 R=H OTBS I O OTBS 7a R=Me
OTBS
Yuanwei Chen, Pierre Vogel, J. Org. Chem. 1994, 59, 2487-2496 963 mg (8.99 mmol, 12 eq.) of 2,6-lutidine and 1188 mg (4.49 mmol, 6 eq.) of tert-butyldimethylsilyltrifluoromethanesulfonate are slowly added dropwise to a solution, cooled to -780C, of 225 mg (0.749 mmol) of the triol 6 in 13 ml of CH 2
CI
2 The mixture is stirred at -780C for 30 minutes and at OoC for 3 hours and quenched with saturated NaHCO 3 solution.
The aqueous phase is extracted with CH 2
CI
2 The combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. The residue is purified by column chromatography with pentane diethyl ether 30: 1. 462 mg (0.719 mmol, 96 of the trisilylated product 7 are obtained in the form of a colourless oil.
General data: C 35
H
74 0 4 Si 3 formula weight 643.22 g/mol Compound 7a is prepared analogously. 423 mg (0.644 mmol, 99 of 7a are obtained from 204 mg (0.650 mmol) of 6a.
(3S,6R,7S,8S)-3,7-Di-(tert-butyldimethylsilyloxy)-1 -hydroxy-4,4,6,8-tetramethyl-tridec- 12-en-5-one 8 and (3S,6R,7S,8S)-3,7-di-(tert-butyldimethylsilyloxy)-1 -hydroxy- 4,4,6,8,12-penta-methyl-tridec-12-en-5-one 8a 8 R=H OH 6TBS 8a R=Me
OTBS
K.C. Nicolaou, K.R. Reddy, G. Skokotas, F. Sato, Xiao J. Am. Chem. Soc. 1992, 114, 7935. A solution of 156 mg (0.243 mmol) of the trisilylated compound 7 in 6.5 ml of MeOH and 6.5 ml of CH 2 01 2 is cooled to OoC and 11 mg of camphorsulfonic acid (0.0485 mmol, 0.2 eq.) are added. After being stirred for 5 hours at 00C, the mixture is quenched by the addition of saturated NaHCO 3 solution. The aqueous phase is extracted with CH 2 C1 2 The combined organic phases are dried over MgSO 4 and the solvent is distilled using a rotary evaporator. The residue is purified by column chromatography with pentane diethyl ether -29- =3 1. 105 mg (0.199 mmol, 82 of the alcohol 8 are obtained in the form of a colourless oil.
General data: C 29
H
60 04Si 2 formula weight 528.96 g/mol Compound 8a is prepared analogously. 101 mg (0.186 mmol, 80 of 8a are obtained from 152 mg (0.232 mmol) of 7a.
3
S,
6
R,
7
S,
8
S)-
3 7 -Di-(tert-butyldimethylsilyloxy)-4,4,6,8-tetramethyl-5-oxo-tridec-12enoic acid 9 and (3S,6R,7S,8S)-3,7-di-(tert-butyldimethylsilyloxy)-4,4,6,8,12-pentamethyl-5-oxo-tridec-12-enoic-acid 9a HO 9 R= 9 R=H o o 6TBS 9a R=Me
OTBS
E.J. Corey, G. Schmidt, Tetrahedron Lett. 1979, 399-402 2371 mg (6.30 mmol, 11 eq.) of PDC dissolved in 3 ml of DMF are added dropwise at 0°C to a solution of 303 mg (0.573 mmol) of alcohol 8 in 6 ml of DMF. The mixture is stirred at RT for 36 hours and then poured into 50 ml of saturated NaCI solution, diluted with water and extracted with CH 2
CI
2 The combined organic phases are dried over MgSO 4 and the solvent is distilled off using a rotary evaporator. The residue is purified by column chromatography with pentane diethyl ether 2 1. 247 mg (0.455 mmol, 79 of the acid 9 are obtained in the form of a colourless oil.
General data: C 29
H
58 ssSi 2 formula weight 542.94 g/mol S Compound 9a is prepared analogously. 273 mg (0.490 mmol, 83 of 9a are obtained from 320 mg (0.590 mmol) of 8a.
30 (3 S,6R, 7S, 8S)-3,7-D i-tert-b utyld imethyls ilyl oxy-4,4,6,8-tetram ethyl -5-oxo-tridec-1 2enoic acid (1 S)-1 -methyl-2-(2-methyl-thiazol-4-yI)-vinyl]-but-3-eny ester 17 and *(3S,6R,7S8S).37.d..terj.butyidmethysjiyoxy.446,8,2-pentamethyl-5-oxo-tridec-1 2enoic acid (1 S)-1 -m ethyl -2 -(2-methyl -th iazoI-4-yI) -vinyl] -b ut-3-enyI ester 1 7a
\R
.,OTBS
17 R=H 0OTBSJ 17a R=Me Esterification according to B. Neises, W. Steglich Angew. Chem. 1978, 90, 556.
72 mg (0.348 mmol, 1.3 eq.) of dicyclohexylcarbodiimide are added at 000 to a solution of 145 mg (0.268 mmol) of acid 9, 56 mg (0.268 mmol) of alcohol 4 and 6.5 mg (0.0536 mmol, 0.2 eq.) of DMAP in 1.5 ml of absolute 0H 2
CI
2 Stirring is carried out at 000 for 10 minutes and at room temperature for 12 hours. After removal of the solvent and flash chromatography of the residue with pentane/Et 2 O 157 mg (0.214 mmol, 80 of the ester 17 are obtained.
Ester 17a is prepared analogously. 166 mg (0.222 mmol, 74 of 17a are obtained from 167 mg (0.30 mmol) of 9a and the equimolar amount of 4.
(4S,7R,8S,9S,1 GS,1 3Z)-4,8-Di-tert-butyldimethylsilyloxy-5,5,7,9-tetramethyl-I methyl-2-(2-methyl-thiazol-4-yI)-vinyl]-1 -oxa-cyclohexadec-1 3-ene-2,6-dione 18 and *(4S7R8S,9S,16S,1 3Z)-4,8-di-tert-butyldimethylsilyloxy-5,5,7,9,1 3-pentamethy-1 I -methyl-2-(2-methyl-thiazol-4-y)-vinyl]-1 -oxa-cyclohexadec-1 3-ene-2,6-dione 1 8a
R
.ODTBS
0 18 R=H 0 0TB8D 18a R=Me An Ar-saturated solution of 49.3 mg (0.067 1 mmol) of the ester 17 in 33.5 ml of absolute 0H 2 C1 2 (corresponding to a substrate concentration of 0.002M) is stirred for 16 hours under an argon atmosphere with 3.3 mg (6 mol Of 01 2 [Ru=CHPh](PCy 3 2 (Cy =cyclohexyl).
After removal of the solvent and flash chromatography of the residue with pentane/Et 2
O
-31 44 mg (0.0630 mmol, 94 of compound 18 are obtained in the form of a 1:1 mixture with its E-isomer.
*49.0 mg (0.068 mmol, 68 of a mixture of 18a and its E-isomer are obtained analogously from 74.8 mg (0.100 mmol) of 17a.
(4S,7R,8S,9S,16S,1Z)-4,8-Dihydroxy-5,5,7,9-tetramethyl-16-[(E)-1-methyl-2-(2-methylthiazol-4-yl)-vinyl]-1-oxa-cyclohexadec-13-ene-2,6-dione 19 ("Epothilone and *(4S,7R,8S,9S,16S,13Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2methyl-thiazol-4-yl)-vinyl]-1-oxa-cyclohexadec-13-ene-2,6-dione 19a (Epothilone D")
R
,0H 19 R=H O 19a R=Me 0 OH O 0.27 ml of hydrofluoric acid (40 is added dropwise at 0°C to a solution of 35.3 mg (0.05 mmol) of 18 (Z:E mixture 1:1) in 2.4 ml of acetonitrile/Et20 After the addition of a few splinters of glass or 0.027 ml of hexafluorosilicic acid (30 stirring is carried out at room temperature for 17 hours. 10 ml of saturated NaHCO 3 solution are added to the reaction mixture and extraction is carried out three times using 20 ml of Et20 each time. The combined ether extracts are dried over MgSO 4 After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with Et 2 O. 16.5 mg (0.0325 mmol, 65 of 19 are obtained in the form of al.1 Z:E mixture.
*20.7 mg (0.042 mmol, 70 of 19a (in the form of a Z:E mixture) are obtained analogously from 43.2 mg (0.06 mmol) of 18a.
Epothilone A 1 and *epothilone B la
Q.
R
O-OH
1 R=H 0 OH O la R=Me 0.36 ml (0.035 mmol, 1.2 eq.) of a freshly prepared solution of dimethyldioxirane in acetone is added dropwise, with stirring, at -35oC to a solution of 14.3 mg (0.03 mmol) of 19 (1:1 Z:E -32mixture) in 2.5 ml of CH2C1 2 The mixture is stirred at -35°C for 2 hours, then 5 ml of a 10 aqueous solution of iron(ll) sulfate are added and extraction is carried out three times using ml of CH 2
CI
2 each time. After the solvent has been distilled off in vacuo, the residue is subjected to flash chromatography through a column of silica gel with Et20. 7.1 mg (0.0144 mmol, 48 of epothilone A are obtained.
*6.2 mg (0.0123 mmol, 41 of epothilone B are obtained analogously from 14.8 mg (0.03 mmol) of 19a.
The invention relates also to stereoisomers of the compounds according to the claims, as they are customarily obtained during the synthesis.
Claims (6)
- 2. A deoxy-epothilone according to general formula 19a o o ooo a. a. a. a.* a a a a a.* a. a o• wherein and B benzyl, p-methoxybenzyl, tetrahydropyranyl and/or a silyl protecting group R hydrogen or methyl.
- 3. 2-(2,2-Dimethyl-[1,3]dioxan-4-yl)-2-methyl-pentan-3-one 2
- 4. (S)-2-Methyl-6-heptenal 3 H in its optically active form. (S)-2,6-Dimethyl-6-heptenal 3a OY 3a H in its optically active form.
- 6. A compound of general formula 9a R HO 0 OB O OB 9a wherein B benzyl, tetrahydropyranyl and/or a silyl protecting group R hydrogen or methyl, and B may have different meanings within the molecule.
- 7. A compound of the general formula 4a 4a OB wherein S. B hydrogen, benzyl, p-methoxybenzyl, tetrahydropyranyl or a silyl protecting group.
- 8. (4S,6S)-2-(2,2-dimethyl-[1,3] dioxan-4-yl)-5-hydroxy-2,4,6-trimethyl- undecan-3-one DATED this 30th day of November, 1999 Novartis Aktiengesellschaft By DAVIES COLLISON CAVE ytent Attorneys for the Applicant
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19636343 | 1996-08-30 | ||
DE19636343A DE19636343C1 (en) | 1996-08-30 | 1996-08-30 | New (di:methyl)-dioxanyl-methyl-pentanone and related compounds |
DE19645362 | 1996-10-28 | ||
DE19645361A DE19645361A1 (en) | 1996-08-30 | 1996-10-28 | Production of epothilone compounds with taxol-like activity |
DE19645361 | 1996-10-28 | ||
DE19645362A DE19645362A1 (en) | 1996-10-28 | 1996-10-28 | Production of epothilone compounds with taxol-like activity |
PCT/DE1997/000111 WO1998008849A1 (en) | 1996-08-30 | 1997-01-15 | Method for producing epothilones, and intermediate products obtained during the production process |
Publications (2)
Publication Number | Publication Date |
---|---|
AU2149397A AU2149397A (en) | 1998-03-19 |
AU716610B2 true AU716610B2 (en) | 2000-03-02 |
Family
ID=27216622
Family Applications (1)
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AU21493/97A Ceased AU716610B2 (en) | 1996-08-30 | 1997-01-15 | Method for producing epothilones, and intermediate products obtained during the production process |
Country Status (5)
Country | Link |
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EP (1) | EP0923583A1 (en) |
JP (1) | JP2001500851A (en) |
AU (1) | AU716610B2 (en) |
NZ (1) | NZ334821A (en) |
WO (1) | WO1998008849A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US7846952B2 (en) | 1996-11-18 | 2010-12-07 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Epothilones C, D, E, and F, preparation and compositions |
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DE4138042C2 (en) * | 1991-11-19 | 1993-10-14 | Biotechnolog Forschung Gmbh | Epothilones, their production processes and agents containing these compounds |
ES2178093T5 (en) * | 1995-11-17 | 2009-02-16 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | EPOTILON DERIVATIVES AND ITS PREPARATION. |
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1997
- 1997-01-15 AU AU21493/97A patent/AU716610B2/en not_active Ceased
- 1997-01-15 NZ NZ334821A patent/NZ334821A/en not_active IP Right Cessation
- 1997-01-15 JP JP10511141A patent/JP2001500851A/en active Pending
- 1997-01-15 EP EP97914077A patent/EP0923583A1/en not_active Withdrawn
- 1997-01-15 WO PCT/DE1997/000111 patent/WO1998008849A1/en not_active Application Discontinuation
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Title |
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CHEMICAL PHYSICS LETTERS 1981 VOL. 77(1) PAGES 131-134 * |
JOURNAL OF ORGANIC CHEMISTRY 1973 V.38(12) PAGES 2136-2143 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US7846952B2 (en) | 1996-11-18 | 2010-12-07 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Epothilones C, D, E, and F, preparation and compositions |
US8076490B2 (en) | 1996-11-18 | 2011-12-13 | Helmholtz-Zentrum Fuer Infektionsforschung Gmbh | Epothilones C, D, E, and F, preparation and compositions |
Also Published As
Publication number | Publication date |
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NZ334821A (en) | 2000-12-22 |
AU2149397A (en) | 1998-03-19 |
WO1998008849A1 (en) | 1998-03-05 |
EP0923583A1 (en) | 1999-06-23 |
JP2001500851A (en) | 2001-01-23 |
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