WO1999034793A1 - Pyronin antibacterials, process and novel intermediates thereto - Google Patents
Pyronin antibacterials, process and novel intermediates thereto Download PDFInfo
- Publication number
- WO1999034793A1 WO1999034793A1 PCT/US1999/000303 US9900303W WO9934793A1 WO 1999034793 A1 WO1999034793 A1 WO 1999034793A1 US 9900303 W US9900303 W US 9900303W WO 9934793 A1 WO9934793 A1 WO 9934793A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pyrone
- mmol
- solution
- reaction
- added
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 73
- 230000008569 process Effects 0.000 title claims abstract description 64
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 9
- INCIMLINXXICKS-UHFFFAOYSA-M pyronin Y Chemical compound [Cl-].C1=CC(=[N+](C)C)C=C2OC3=CC(N(C)C)=CC=C3C=C21 INCIMLINXXICKS-UHFFFAOYSA-M 0.000 title abstract description 7
- 239000000543 intermediate Substances 0.000 title description 51
- 230000000844 anti-bacterial effect Effects 0.000 title description 6
- 239000000203 mixture Substances 0.000 claims abstract description 35
- -1 pyrone ketone Chemical class 0.000 claims description 135
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 claims description 103
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 87
- 150000001299 aldehydes Chemical class 0.000 claims description 69
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 51
- 239000002253 acid Substances 0.000 claims description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 49
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical group [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 38
- 239000003153 chemical reaction reagent Substances 0.000 claims description 36
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 21
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000002524 organometallic group Chemical group 0.000 claims description 13
- 230000001590 oxidative effect Effects 0.000 claims description 13
- 150000003973 alkyl amines Chemical class 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical group C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 10
- 150000004679 hydroxides Chemical class 0.000 claims description 9
- 238000006969 Curtius rearrangement reaction Methods 0.000 claims description 8
- 229930040373 Paraformaldehyde Natural products 0.000 claims description 8
- 125000005265 dialkylamine group Chemical group 0.000 claims description 8
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 229920002866 paraformaldehyde Polymers 0.000 claims description 8
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 7
- QMBQEXOLIRBNPN-UHFFFAOYSA-L zirconocene dichloride Chemical group [Cl-].[Cl-].[Zr+4].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 QMBQEXOLIRBNPN-UHFFFAOYSA-L 0.000 claims description 7
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical group [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 6
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- IDASTKMEQGPVRR-UHFFFAOYSA-N cyclopenta-1,3-diene;zirconium(2+) Chemical compound [Zr+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 IDASTKMEQGPVRR-UHFFFAOYSA-N 0.000 claims description 4
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 claims description 4
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 claims description 4
- LPSKDVINWQNWFE-UHFFFAOYSA-M tetrapropylazanium;hydroxide Chemical compound [OH-].CCC[N+](CCC)(CCC)CCC LPSKDVINWQNWFE-UHFFFAOYSA-M 0.000 claims description 4
- LCKIEQZJEYYRIY-UHFFFAOYSA-N Titanium ion Chemical compound [Ti+4] LCKIEQZJEYYRIY-UHFFFAOYSA-N 0.000 claims description 3
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 3
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 2
- DRTZAIDVOGUYSP-UHFFFAOYSA-N pyridin-1-ium;chloride;hydrochloride Chemical compound Cl.Cl.C1=CC=NC=C1 DRTZAIDVOGUYSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 4
- 238000002360 preparation method Methods 0.000 abstract description 35
- 150000001875 compounds Chemical class 0.000 abstract description 19
- 239000003242 anti bacterial agent Substances 0.000 abstract description 9
- 229930189675 Corallopyronin Natural products 0.000 abstract description 8
- 229940126573 antibacterial therapeutic Drugs 0.000 abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 167
- 239000000243 solution Substances 0.000 description 152
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 148
- 238000006243 chemical reaction Methods 0.000 description 108
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 83
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 80
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 79
- 239000012044 organic layer Substances 0.000 description 65
- 238000005481 NMR spectroscopy Methods 0.000 description 61
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 60
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 59
- 238000003756 stirring Methods 0.000 description 53
- 229910001868 water Inorganic materials 0.000 description 52
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 42
- 239000003921 oil Substances 0.000 description 42
- 235000019198 oils Nutrition 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 36
- UQFNCSLGZUJVQP-JNZIYJEQSA-N chembl2204381 Chemical compound CCC\C(C)=C\C=C(/C)C(=O)C1=C(O)C=C([C@H](C)CC\C=C\NC(=O)OC)OC1=O UQFNCSLGZUJVQP-JNZIYJEQSA-N 0.000 description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 32
- UQFNCSLGZUJVQP-UHFFFAOYSA-N Myxopyronine A Natural products CCCC(C)=CC=C(C)C(=O)c1c(O)cc(oc1=O)C(C)CCC=CNC(=O)OC UQFNCSLGZUJVQP-UHFFFAOYSA-N 0.000 description 32
- 229910000104 sodium hydride Inorganic materials 0.000 description 30
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 28
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 230000015572 biosynthetic process Effects 0.000 description 27
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 239000000047 product Substances 0.000 description 25
- 229920006395 saturated elastomer Polymers 0.000 description 25
- 150000002148 esters Chemical class 0.000 description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 229910052786 argon Inorganic materials 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 238000011010 flushing procedure Methods 0.000 description 20
- 239000010410 layer Substances 0.000 description 20
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
- 229910052681 coesite Inorganic materials 0.000 description 19
- 229910052906 cristobalite Inorganic materials 0.000 description 19
- 229910052682 stishovite Inorganic materials 0.000 description 19
- 229910052905 tridymite Inorganic materials 0.000 description 19
- 238000000746 purification Methods 0.000 description 18
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 18
- 229960001225 rifampicin Drugs 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 230000037361 pathway Effects 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 16
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 15
- 230000029936 alkylation Effects 0.000 description 15
- 238000005804 alkylation reaction Methods 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 230000000269 nucleophilic effect Effects 0.000 description 15
- 239000003960 organic solvent Substances 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 15
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 14
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 14
- SPQDIDVJAZFBRL-WXFBSNOUSA-N Myxopyronin B Chemical compound CCCC\C(C)=C\C=C(/C)C(=O)C1=C(O)C=C([C@H](C)CC\C=C\NC(=O)OC)OC1=O SPQDIDVJAZFBRL-WXFBSNOUSA-N 0.000 description 13
- SPQDIDVJAZFBRL-UHFFFAOYSA-N Myxopyronine B Natural products CCCCC(=CC=C(/C)C(=O)C1=C(O)C=C(OC1=O)C(C)CCC=CNC(=O)OC)C SPQDIDVJAZFBRL-UHFFFAOYSA-N 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- 239000007789 gas Substances 0.000 description 12
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 12
- 230000003647 oxidation Effects 0.000 description 12
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 230000010933 acylation Effects 0.000 description 11
- 238000005917 acylation reaction Methods 0.000 description 11
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 11
- 238000000338 in vitro Methods 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 10
- 241000588724 Escherichia coli Species 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical group Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 9
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 8
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- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 6
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
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- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
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- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 1
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- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
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- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 229910000065 phosphene Inorganic materials 0.000 description 1
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- TZLVRPLSVNESQC-UHFFFAOYSA-N potassium azide Chemical compound [K+].[N-]=[N+]=[N-] TZLVRPLSVNESQC-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- FMNMEQSRDWIBFO-UHFFFAOYSA-N propanoyl phosphate Chemical compound CCC(=O)OP(O)(O)=O FMNMEQSRDWIBFO-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- KVTPRMVXYZKLIG-NCAOFHFGSA-N streptolydigin Chemical compound N1([C@H](C(C(=C(\O)/C=C/C(/C)=C/[C@@H](C)[C@@H]2[C@H]([C@@H]3O[C@]([C@@]4(OC4)C=C3)(C)O2)C)/C1=O)=O)[C@H](C)C(=O)NC)[C@@H]1CC[C@H](O)[C@H](C)O1 KVTPRMVXYZKLIG-NCAOFHFGSA-N 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000005758 transcription activity Effects 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/298—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with manganese derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/21—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/64—Acyl halides
- C07C57/66—Acyl halides with only carbon-to-carbon double bonds as unsaturation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
- C07D309/38—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms one oxygen atom in position 2 or 4, e.g. pyrones
-
- 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
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- 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 in the field of pyronin antibiotics.
- the present invention relates to processes for the preparation of myxopyronins and corallopyronins, compounds useful as antibacterial therapeutics.
- the present invention also provides novel compositions of matter which are useful as intermediates for preparing the pyronin antibiotics.
- Myxopyronins and corallopyronins are 2-pyrone-containing antibiotics which present a significant opportunity in antibacterial therapy. They constitute a synthetically accessible, unexploited series of low molecular weight bacterial RNA polymerase (RNAP) inhibitors with favorable properties: selectivity vs. human RNAP, cell penetration (minimal inhibitory concentrations (MICs) at concentrations comparable to in vitro bacterial RNAP IC 50 s), and potency against rifampicin-resistant S. aureus equal to that against a rifampicin-susceptible strain.
- MICs minimum inhibitory concentrations
- rifampicin-resistant S. aureus equal to that against a rifampicin-susceptible strain.
- Corallopyronin A/B and myxopyronin A/B are natural products isolated from gliding bacteria
- the pyronins have good intrinsic activity in antibacterial assays against both E. coli and S. aureus RNA polymerase. This activity is specific with respect to human or SP6 polymerases. MIC data (see Table I) show that these compounds, like rifampicin, are not absorbed well by E. coli but that they have intrinsic activity against both gram positive and gram negative bacteria.
- 2H-Pyran-2,6(3H)-dione derivatives are reported to be active at reasonable doses in a passive cutaneous anaphylaxis model in rats when administered by either the intravenous or oral route.
- the present invention provides novel intermediates useful in the synthesis of myxopyronins A and B and derivatives thereof.
- the present invention provides processes for synthesizing myxopyronins A and B and derivatives thereof as well as corallopyronins.
- the myxopyronins of the invention are useful against gram negative and positive bacteria. Summary of the Invention
- One object of the present invention is to provide processes for the preparation of myxopyronins and corallopyronins, compounds useful as antibacterial therapeutics.
- the present invention provides myxopyronins A and B.
- Another object of the present invention is to provide various compositions of matter useful as intermediates in the preparation of the antibiotic myxopyronin.
- a further object of the present invention is to provide methods of preparing such intermediates.
- FIG. 1(a) shows the structures of corallopyronin A/B and myxopyronin A/B.
- Fig. 1(b) illustrates coumarin derivatives which inhibit HIV protease in enzymatic assays and cell culture. Skulnick, H. I., et al., J. Med. Chem., 1995, 38, 4968.
- Fig. 2 illustrates a retrosynthetic analysis for the preparation of myxopyronin A.
- Fig. 3 illustrates the synthesis of compound 1 in accord with the present invention. (The natural products have been illustrated with the natural occurring (Reconfiguration, however all materials in this paper were synthesized in racemic form.)
- Fig. 4 illustrates alkylation of the 7-position of compound 3 for the preparation of compound 10.
- Fig. 5 illustrates the synthesis of compound 6 in accord with the present invention.
- Fig. 6 illustrates the synthesis of compound 10 in accord with the present invention.
- Fig. 7 illustrates an alternative synthesis of compound 10 in accord with the present invention.
- Fig. 8 illustrates the synthesis of compound 18 in accord with the present invention.
- Fig. 9 illustrates the attempted acylation of pyrone 10 with acyl chloride 19.
- Fig. 10 illustrates an alternative retrosynthetic analysis for the preparation of myxopyronin A.
- Fig. 11 illustrates the acylation of pyrone 10 with propionyl chloride and subsequent elaboration to myxopyronin A.
- Fig. 12 shows a retrosynthetic analysis of myxopyronin A.
- Fig. 12(a) shows the preparation of allyl aldehyde 14.
- Fig. 12(b) shows the preparation of acylated pyrone 5.
- Fig. 12(c) shows the preparation of iodide 8b.
- Fig. 13(a) provides a synthetic route to acyl pyrone intermediate 15.
- Fig. 13(b) illustrates the condensation reaction of intermediates 14 and 15 and subsequent elaboration to myxopyronin A.
- Fig. 14 shows the preparation of allyl aldehyde 14.
- Fig. 15 provides a synthetic route to intermediate pyrone 10.
- Fig. 16 illustrates a retrosynthetic analysis of myxopyronin A and B.
- Fig. 17 provides a synthetic route to compound 15a.
- Fig. 18 shows a method for preparing ⁇ , ⁇ -unsaturated aldehydes useful as intermediates in the synthesis of myxopyronins.
- Fig. 19 shows a synthetic route to myxopyronin A and B starting from intermediate 15a.
- Fig. 20(a) provides a graphical representation of the inhibitory effect as a function of concentration of a mixture of isolated natural myxopyronins A and B, compared with synthetic racemic myxopyronin A and rifampicin, in an in vitro transcription assay using E. coli RNA polymerase.
- Fig. 20(b) provides a graphical representation of the inhibitory effect as a function of concentration of synthetic myxopyronins A and B in an in vitro transcription assay using E. coli RNA polymerase.
- the present invention provides a convergent synthetic route to prepare myxopyronin compounds, including myxopyronins A and B ( Figure 1).
- the invention provides two variant pathways based on alternative approaches to install the side chain at the pyrone 3-position.
- a Wadsworth-Emmons reaction is performed with triethyl phosphonoacetate in THF in the presence of NaH.
- Ester 16 (see Figure 3) is sequentially reduced with DIBAL and oxidized with DDQ to produce aldehyde 14.
- a Wadsworth-Emmons reaction is used to condense aldehyde 14 and triethyl 2-phosphonopropionate in THF in the presence of NaH.
- the resulting product is sequentially reduced with DIBAL and oxidized with DDQ to produce aldehyde 1. This constitutes the 3-position side chain precursor.
- the pyrone portion is constructed as follows. Ethyl propionylacetate is hydrolyzed with aqueous NaOH.
- pyrone 5 Two equivalents of the resulting acid are condensed with an equivalent of carbonyldiimidazole to produce pyrone 5 (see Figure 5).
- the 3-propionyl group is hydrolyzed using concentrated H 2 SO 4 at elevated temperature to afford pyrone 6, which is then alkylated with 3-bromopropionaldehyde dimethylacetal using n-BuLi and THF/HMPT as a solvent to give 7.
- the 4-position hydroxyl is converted to SEM ether 8 using SEM-C1 and diisopropylamine in CH 2 C1 2 .
- the dimethylacetal is removed under acidic conditions and the resulting aldehyde is alkylated under Wadsworth-Emmons conditions with triethylphosphonoacetate in THF in the presence of NaH to produce the unsaturated ester 9.
- the SEM ether is cleaved using TBAF and DMPU to give key intermediate 10.
- Intermediate 10 can be synthesized by an alternate pathway. Pyrone 6 is deprotonated with n-BuLi and then alkylated with allyl bromide in THF/HMPT. The 4-position hydroxyl is converted to SEM ether 11 by treatment with SEM-C1 and diisopropylamine in CH 2 C1 2 .
- the allyl group is hydroborated using a borane reagent and the subsequent borate is removed oxidatively to give the alcohol.
- the resulting alcohol is oxidized under standard Swern conditions to give aldehyde 12.
- Aldehyde 12 was alkylated with triethylphosphonoacetate in THF in the presence of
- the second route takes advantage of the convenient availability of intermediates 10 and 14 by processes disclosed below.
- Pyrone 10 is acylated with propionyl chloride in TFA at elevated temperature to afford intermediate 15 ( Figure 11).
- a base-catalyzed aldol between compounds 14 and 15 using LDA in THF forms an intermediate that is sequentially treated with mesyl chloride and triethylamine in CH 2 C1 2 followed by DBU to afford compound 17, which is also an intermediate in pathway A.
- Myxopyronin A results after a Curtius sequence.
- the present invention provides a process of preparing a myxopyronin having the structure:
- step (b) oxidizing the adduct formed in step (a) under suitable conditions to form a pyrone ketone having the structure:
- step (b) (i) saponifying the pyrone ketone formed in step (b) under suitable conditions to form a pyrone acid;
- step (ii) acylating the pyrone acid formed in step (c)(i) under suitable conditions to form a pyrone anhydride
- step (iii) treating the pyrone anhydride formed in step (c)(ii) with an azide salt to form a pyrone acyl azide;
- step (iv) heating the pyrone acyl azide formed in step (c)(iii) in methanol under suitable conditions to form myxopyronin A.
- the 1,2-addition step (a) recited above is performed using an acid catalyst, such as trifluoroacetic acid (TFA), hydrochloric acid, sulfuric acid, or p- toluenesulfonic acid, preferably in the presence of a dehydrating agent, such as molecular sieves, more preferably using 4 A molecular sieves, in an inert organic solvent, such as dichloromethane or p-dioxane.
- Alcohol oxidation step (b) is carried out using various oxidants, such as 2,3-dichloro- 5,6-dicyano-l,4-benzoquinone (DDQ), manganese dioxide or chromium chlorochr ornate.
- Saponifying step (c)(i) is carried out using a hydroxide base, such as LiOH, NaOH, KOH or CsOH, in a solvent mixture comprising water and at least one organic co-solvent, such as methanol, ethanol, or tetrahydrofuran (THF).
- a hydroxide base such as LiOH, NaOH, KOH or CsOH
- a solvent mixture comprising water and at least one organic co-solvent, such as methanol, ethanol, or tetrahydrofuran (THF).
- a preferred solvent composition is methanol/THF/ water in the proportion 2:2:1.
- step (c)(ii) is effected using an alkyl or aryl chloroformate, including, but not limited to, methyl chloroformate, ethyl chloroformate, isopropyl and phenyl chloroformate, in the presence of a base, such as DIPEA, in an inert organic solvent, preferably miscible with water, preferably, acetone.
- a base such as DIPEA
- an inert organic solvent preferably miscible with water, preferably, acetone.
- the resulting product may be purified, or used directly in the subsequent step.
- Step (c)(iii) is carried out using an azide salt, such as lithium azide, sodium azide, or tetraalkylammonium azide, preferably in the presence of water.
- Rearrangement step (c)(iv) entails heating the acid azide formed in step (c)(iii) in a solvent mixture, containing an alcohol, such as ethanol, methanol, or phenol, preferably, methanol, and an inert solvent such as benzene or toluene, at elevated temperatures, preferably, at the reflux temperature of the solvent mixture.
- an alcohol such as ethanol, methanol, or phenol, preferably, methanol
- an inert solvent such as benzene or toluene
- the present invention also provides a process of preparing a myxopyronin having the structure: which comprises:
- ketone adduct having the structure:
- step (b) (i) condensing the ketone adduct formed in step (a) under suitable conditions with an aldehyde having the structure:
- a pyrone aldol (ii) mesylating the pyrone aldol formed in step (b)(i) under suitable conditions to form a pyrone aldol mesylate; and (iii) reacting the pyrone aldol mesylate under suitable basic conditions to form a pyrone ketone having the structure:
- step (c) saponifying the pyrone ketone formed in step (b)(iii) under suitable conditions to form a pyrone acid; (ii) acylating the pyrone acid formed in step (c)(i) under suitable conditions to form a pyrone anhydride; and
- step (iii) treating the pyrone anhydride formed in step (c)(ii) with an azide salt to form a pyrone acyl azide, and (iv) heating the pyrone acyl azide formed in step (c)(iii) under suitable conditions to form the myxopyronin.
- Acylation step (a) may be effected using an acid catalyst, such as TFA, hydrochloric acid, or p-toluenesulfonic acid, preferably in the presence of a dehydrating agent, such as molecular sieves, preferably using 4A molecular sieves, in an inert organic solvent, such as dichloromethane.
- Condensation step (b)(i) is performed using a strong, non-nucleophilic base, such as LDA, potassium t-butoxide, or sodium hydride, preferably, LDA, in an inert organic solvent, such as THF.
- Mesylation step (b)(ii) is carried out using an acylating agent, such as mesyl chloride, p- tosyl chloride, acetic anhydride, preferably, mesyl chloride, in the presence of a non-nucleophilic organic base, such as DIPEA or triethylamine.
- Elimination step (b)(iii) may be performed using a variety of reagents effective to cause elimination, preferably, a strong non-nucleophilic base such as DBU.
- a strong non-nucleophilic base such as DBU.
- the Curtius rearrangement is effected as described above.
- the present invention also provides a process of preparing an unsaturated aldehyde having the structure:
- step (b) (i) reducing the unsaturated ester formed in step (a) under suitable conditions to form an unsaturated alcohol; and (ii) oxidizing the unsaturated alcohol under conditions suitable to form a monounsaturated aldehyde having the structure:
- step (c) (i) condensing triethyl phosphonopropionate with the monounsaturated aldehyde formed in step (b)(ii) under suitable conditions to form a diene ester;
- step (ii) reducing the diene ester formed in step (c)(i) under suitable conditions to form a diene alcohol
- the condensation step preferably of the Wadsworth-Emmons type, is favorably performed in the presence of a non-nucleophilic base, such as LDA or sodium hydride, in an inert polar, aprotic organic solvent, such as THF.
- a non-nucleophilic base such as LDA or sodium hydride
- the ester reduction step (b)(i) may be carried out using any of a variety of reducing agents, such as diisobutylaluminum hydride (DIBAL) in an inert aprotic organic solvent, such as THF.
- Oxidation step (b)(ii) may be effected using any of a range of mild oxidants, preferably, DDQ, in an inert organic solvent, such as dichloromethane.
- the subsequent condensation step (c)(i) may be performed in the presence of a non-nucleophilic base, such as sodium hydride, in an inert organic solvent, preferably, THF.
- Reduction step (c)(ii) may be carried out using various reducing agents, preferably, diisobutylaluminum hydride (DIBAL) in an aprotic organic solvent, such as THF.
- DIBAL diisobutylaluminum hydride
- oxidation step (c)(iii) may be effected using a variety of oxidants, such as DDQ, in dichloromethane.
- the present invention provides a process of preparing the unsaturated ester having the structure:
- step (a) which comprises (a) condensing ethyl butyryl acetate with diethyl phosphorochloridate under suitable conditions to form an enol phosphonate; and (b) alkylating the enol phosphonate formed in step (a) with an organometallic reagent under suitable conditions to form the unsaturated ester.
- condensing step (a) is performed using a non-nucleophilic base, including, but not limited to, potassium t-butoxide, sodium hydride, LDA, and lithium diethylamide, preferably, sodium hydride, in an inert aprotic organic solvent, such as THF or diethyl ether.
- a non-nucleophilic base including, but not limited to, potassium t-butoxide, sodium hydride, LDA, and lithium diethylamide, preferably, sodium hydride, in an inert aprotic organic solvent, such as THF or diethyl ether.
- Alkylation step (b) is effected using an organometallic reagent, such as lithium dimethyl cuprate, methyl lithium, methyl magnesium bromide or chloride, preferably, lithium dimethyl cuprate, in an inert aprotic solvent, preferably, diethyl ether, at a temperature ranging from about -100°C to about 0°C, more preferably, from about -90°C to about -50°C, most preferably, at -78°C.
- an organometallic reagent such as lithium dimethyl cuprate, methyl lithium, methyl magnesium bromide or chloride, preferably, lithium dimethyl cuprate
- an inert aprotic solvent preferably, diethyl ether
- the present invention provides a process of preparing a pyrone ester having the structure: which comprises:
- step (b) hydrolyzing the acyl pyrone formed in step (a) under suitable conditions to form a pyrone having the structure:
- step (c) alkylating the pyrone formed in step (b) under suitable conditions to form a pyrone acetal having the structure:
- step (d) etherifying the pyrone acetal formed in step (c) under suitable conditions to form an ether pyrone acetal having the structure:
- step (a) Hydrolysis in step (a) recited above is carried out using a hydroxide base, such as LiOH, NaOH, or KOH, preferably NaOH, followed by acidification with a variety of acids, including, but not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and TFA, preferably, hydrochloric acid.
- Dimerization in step (a) is effected using a condensing agent, such as carbonyl diimidazole, or an equivalent reagent known in the art.
- Hydrolysis step (b) is performed using a strong acid such as hydrochloric acid, hydrobromic, trifluoroacetic or sulfuric acid, preferably 90% sulfuric acid, at elevated temperature, in the range from about 65°C to about 160 °C, preferably between about 100°C and about 140 °C, more preferably, at 130°C.
- Alkylation step (c) with fluor-, Clair- or bromopropionaldehyde dimethyl acetal is carried out using a strong base such as n-butyl lithium, t-butyl lithium, sec-butyl lithium or phenyl lithium, in an inert polar aprotic solvent, such as THF in the presence or absence of a co-solvent, such as HMPT.
- a strong acid such as hydrochloric acid, hydrobromic, trifluoroacetic or sulfuric acid, preferably 90% sulfuric acid
- Etherification step (d) is effected using a strong non-nucleophilic base such DIPEA or triethylamine in an inert organic solvent, such as dichloromethane.
- Acetal cleavage step (e)(i) is carried out using a strong acid, such as sulfuric acid or p-tonic acid, in a solvent mixture preferably comprising THF and water in a ratio of 10:1.
- Condensation step (e)(ii) employs a strong non-nucleophilic base, such as sodium hydride, in a solvent mixture favorably comprising toluene and DMF.
- Deprotection step (f) utilizes an organic fluoride salt, preferably tetrabutylammonium fluoride.
- the present invention further provides a process of preparing a pyrone ester having the structure:
- step (ii) etherifying the pyrone formed in step (i) under suitable conditions to form protected pyrone having the structure:
- step (b) (i) hydroborating the protected pyrone formed in step (a)(ii) under suitable basic conditions; and (ii) oxidizing under suitable conditions to form a pyrone aldehyde having the structure:
- step (c) condensing the pyrone aldehyde formed in step (b)(ii) with triethyl phosphonoacetate under suitable conditions to form a protected pyrone ester having the structure: and (d) cleaving the protected pyrone ester under suitable conditions to form the pyrone ester.
- allylation step (a)(i) is effected using allyl chloride, bromide or fluoride as the halide and a strong base, such as sodium hydride or n-butyl lithium, in a polar aprotic solvent mixture favorably made up of THF and HMPT.
- Protection step (a)(ii) is carried out using a strong non-nucleophilic base, such as DIPEA or triethylamine, in an inert organic solvent, such as dichloromethane.
- Hydroboration (b)(i) is performed with a borane complex, such as BH 3 - SMe 2 , followed by treatment with hydrogen peroxide and inorganic base, such as NaOH.
- Oxidation (b)(ii) preferably utilizes standard Swern conditions.
- Condensation step (c) is performed using a strong non-nucleophilic base such as sodium hydride.
- Deprotection step (d) is effected using a strong acid such as sulfuric acid in the presence of a protic solvent, such as ethanol, and a miscible aprotic organic solvent, such as THF.
- the Wadsworth-Emmons reaction is applied in the pathway leading to both 1 and 9, and tolerates the use of aprotic, anhydrous solvents. While both toluene and THF have been used effectively, higher yields are obtained with THF.
- the preferred base is NaH although other anhydrous bases are also effective. Other reactions generating carbon-carbon double bonds could be equivalently used.
- Intermediate ester 16 may alternatively be prepared by an addition reaction involving lithium dimethyl cuprate, or an equivalent organometallic reagent. The reductions of the two esters on the pathway to 1 are both performed with DIBAL, although a number of hydride reagents could have been used.
- Any aprotic, anhydrous solvent would be permissible as long as its melting point is below -78°C.
- the reaction proceeds rapidly at -78°C, but may optionally be carried out at temperatures up to -40 °C without untoward consequences.
- the oxidations on the pathway to 1 have been efficiently performed both under Swern conditions and with DDQ, or any reagent proficient in the oxidation of allylic alcohols or primary alcohols, including, but not limited to, manganese oxide, pyridinium chlorochromate, and pyridinium dichromate.
- the pathway using DDQ is more effective with unsaturated alcohols.
- the oxidation reaction is preferably performed using a variety of aprotic, anhydrous solvents.
- ethyl propionylacetate is hydroyzed with aqueous NaOH.
- the reaction may be carried out using any hydroxylic base.
- the dimerization of the acid to produce pyrone 5 is preferably effected in aprotic, anhydrous solvents.
- Other carbonyldiimidazole equivalents e.g., phosphene
- the hydroysis of the propionyl groups to yield 6 occurs in strong acids, including, but not limited to, hydrochloric acid, phosphoric acid, nitric acid.
- the alkylation of 6 with either 3-bromopropionaldehyde dimethyl acetal or allyl bromide is preferably performed in the presence of hexamethylphosphoric triamide
- the SEM ether is a preferred protecting group.
- various amine bases may be used, including, but not limited to, diisopropylethylamine (DIPEA), triethylamine, DBU (l,8-diazbicyclo[5.4.0]undec-7-ene), and pyridine.
- DIPEA diisopropylethylamine
- DBU l,8-diazbicyclo[5.4.0]undec-7-ene
- pyridine pyridine
- the reaction may be performed in various polar aprotic solvents, including, but not limited to, chloroform, carbon tetrachloride and dimethyl formamide (DMF).
- the removal of the dimethyl acetal using dilute H 2 S0 4 in THF/H 2 0 may be carried out with mild acids which do not cleave the SEM group.
- H 2 0 is used as a co- solvent rather than an alcohol
- the SEM group is not affected.
- the removal of the SEM group in intermediate 9 to produce compound 10 is effected using either TBAF/DMPU or dilute H 2 S0 4 in THF/EtOH, acidic conditions being the more effective.
- the hydroboration of intermediate 11 is carried out with a number of borane reagents, e.g., BH 3 THF or borane-dimethyl sulfide complex (Figure 7). Yields are limited by the reactivity of the pyrone under these conditions.
- the aldol reaction between compounds 1 and 10 is best performed using TFA in CH 2 C1 2 .
- the acylation of compound 10 with propionyl chloride to produce intermediate 15 proceeds efficiently in the presence of TFA at elevated temperature.
- Lithium diisopropylamide (LDA) is an efficient base for the aldol reaction of between compounds 14 and 15 yielding intermediate 17.
- a variety of other bases are also useful for the purpose, including, but not limited to, hydroxide bases, lithium- containing bases and alkoxides.
- the present invention provides a process of preparing a myxopyronin having the structure:
- step (b)(i) mesylating the pyrone aldol formed in step (a) under suitable conditions to form a pyrone aldol mesylate; and (ii) reacting the pyrone aldol mesylate formed in step (b)(i) under suitable basic conditions to form a pyrone diene having the structure:
- step (c) saponifying the pyrone diene formed in step (b)(ii) under suitable conditions to form a pyrone acid; (d) converting the pyrone acid formed in step (c) under suitable conditions to a pyrone acyl azide; and (e) solvolyzing the pyrone acyl azide formed in step (d) with methanol under suitable conditions to form the myxopyronin.
- the present invention provides a process as disclosed above wherein the acyl pyrone in step (a) is treated with the unsaturated aldehyde in the presence of a Lewis acid catalyst.
- the present invention provides a process wherein the acid catalyst is titanium tetrachloride/triethylamine combination.
- the present invention provides a process as disclosed above wherein the pyrone aldol in step (b)(i) is mesylated with methanesulfonyl (mesyl) chloride in the presence of triethylamine.
- the present invention provides a process as disclosed above wherein the pyrone aldol mesylate in step (b)(ii) is reacted with DBU. In another embodiment, the present invention provides a process as above wherein the pyrone diene in step (c) is saponified with lithium hydroxide. In yet another embodiment, the present invention provides a process as above wherein the pyrone acid in step (d) is converted using diphenylphosphoryl azide in the presence of triethylamine.
- step (a) may be effected at subambient temperatures, preferably at -78 °C.
- Mesylation step (b)(i) is carried out preferably using mesyl chloride but an equivalent reaction sequence would result using another acylating agent, such as p-tosyl chloride, acetic anhydride.
- Step (b)(i) occurs efficiently in the presence of a non-nucleophilic organic base, such as DIPEA or triethylamine.
- Elimination step (b)(ii) may be performed using a reagent effective to cause elimination, preferably, a strong non-nucleophilic base such as DBU.
- Saponifying step (c) is effected using a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide under aqueous or mixed aqueous/dipolar solvent conditions.
- Converting step (d) is carried out by heating the pyrone acid with diphenylphosphoryl azide, or an equivalent reagent, in the present of a strong non-nucleophilic base, such as triethylamine or diethylisopropylamine, in a noninteracting organic solvent, such as benzene, toluene or xylene, at a temperature above room temperature, preferably at the reflux temperature of the solvent.
- Solvolyzing step (e) is effected by heating the pyrone acyl azide in methanol at a temperature above room temperature, preferably at the reflux temperature of methanol.
- the present invention provides a process of preparing an acyl pyrone having the structure:
- the present invention provides a process as shown above wherein the pyrone diol in step (a) is oxidized with a Dess- Martin periodinate. In another embodiment, the present invention provides a process as above wherein the condensing step is effected with sodium hydride.
- Oxidizing step (a) is carried out using any oxidant known in the art suited to the purpose, including chromium oxide, pyridinium chlorochromate, dicyclo- hexylcarbodiimide/dimethylsulf oxide, aluminum oxide/acetone, lead tetra acetate, etc.
- a preferred oxidant is the Dess-Martin periodinate.
- Condensing step (b) is effected in the presence of a strong non-nucleophilic base, such as sodium hydride or potassium t-butoxide, in an inert organic solvent such as benzene, toluene, or xylene, typically at ambient temperatures.
- the present invention provides a process of preparing a pyrone diol having the structure:
- step (ii) alkylating the anion formed in step (a)(i) with a siloxyalkyl halide having the structure:
- the present invention provides a process as disclosed wherein the acyl pyrone in step (a)(i) is deprotonated using lithium diisopropylamide or lithium diethylamide.
- the present invention provides a process as above wherein the alkylated pyrone in step (b) is deprotected with a weak acid.
- the invention provides a process wherein the weak acid is acetic acid.
- Deprotonating step (a)(i) is carried out using a strong non-nucleophilic base, such as LDA, lithium diethylamide, potassium t-butoxide, sodium amide, sodium hydride, etc., in a non- interacting organic dipolar solvent or solvent mixture, such as tetrahydrofuran (THF) and/or hexamethylphosphoramide (HMPA), at subambient temperatures, preferably at -78 °C.
- a strong non-nucleophilic base such as LDA, lithium diethylamide, potassium t-butoxide, sodium amide, sodium hydride, etc.
- a non- interacting organic dipolar solvent or solvent mixture such as tetrahydrofuran (THF) and/or hexamethylphosphoramide (HMPA)
- THF tetrahydrofuran
- HMPA hexamethylphosphoramide
- the deprotonated dianion is used directly in the alkylation step
- the present invention provides a process of preparing a myxopyronin having the structure:
- R is C,. 9 alkyl, and wherein R, is C,. 9 alkoxy; which comprises: (a) condensing an aldehyde having the structure:
- step (b) (i) saponifying the pyrone ketone formed in step (a) under suitable conditions to form a pyrone acid; and (ii) treating the pyrone acid under suitable Curtius conditions to form the myxopyronin.
- the subject invention provides a process as above wherein the pyrone is condensed with the aldehyde in the presence of a titanium( ⁇ V) reagent.
- the pyrone ketone is saponified in the presence of a hydroxide salt.
- the hydroxide salt is LiOH, NaOH, KOH, ammonium hydroxide, tetramethylammonium hydroxide, tetraethyl- ammonium hydroxide, tetra-n-propylammonium hydroxide or tetra-n-butylammoni m hydroxide.
- the present invention provides a process as above wherein the Curtius conditions comprise:
- step (b) treating the pyrone anhydride formed in step (a) with an azide salt to form a pyrone acyl azide;
- step (c) heating the pyrone acyl azide formed in step (b) with an alcohol R,OH under conditions suitable to form the myxopyronin.
- the process is carried out using methanol as the alcohol R,OH.
- the pyrone is treated with alkyl haloformate, and subsequently with an azide salt.
- the alkylhaloformate may favorably be methyl or ethyl chloroformate, and the azide salt may be LiN 3 or NaN 3 .
- R may be methyl or ethyl.
- the present invention also provides a process of preparing an unsaturated aldehyde having the structure: wherein R is C,_ 9 alkyl; which comprises: (a) treating an acetylene having the structure:
- the process may be effected wherein the first organometallic reagent comprises a zirconocene dihalide in the presence of a trialkylalane.
- the zirconocene dihalide is zirconocene dichloride and the trialane is trimethylaluminum.
- the process may be effected wherein the second organometallic reagent is an alkyllithium reagent.
- the allylic alcohol is oxidized with any of a variety of oxidants suited for the purpose, for example, pyridinium chlorochromate, pyridine dichloride, manganese dioxide, a
- the first organometallic reagent is typically prepared from a metallocene dihalide and a trialkylaluminum reagent, using an organic-miscible solvent such as dichloromethane or dichloroethane, at subambient temperatures, preferably at -5°C to 5°C, more preferably at 0°C.
- the addition of the acetylenic reagent may be effected at a temperature between -20 °C and 30°C, preferably at 15 °C to 25 °C, more preferably at room temperature.
- step (b) Prior to step (b), solvents are evaporated and the residue is extracted with a hydrocarbon solvent, such as n- pentane, n-hexanes or heptane.
- a hydrocarbon solvent such as n- pentane, n-hexanes or heptane.
- This extract is then treated with the second organometallic reagent, for example, an alkyl lithium such as n-butyl lithium, typically at subambient temperatures, preferably at 0°C.
- Condensing step (c) may be carried out by transferring the solution of the second intermediate to a suspension of paraformaldehyde in a non-aqueous dipolar solvent such as THF, at a temperature ranging from 0°C to 35 °C, but preferably at room temperature.
- the present invention further provides a process of preparing a myxopyronin having the structure:
- R is C,_ 9 alkyl, and wherein Rj is NH 2 , alkylamine, dialkylamine, or optionally substituted phenylamine; which comprises:
- the pyrone ketone is saponified in the presence of a hydroxide salt.
- the hydroxide salt may be LiOH, NaOH, KOH, ammonium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydrox-ide, tetra-n-propylammonium hydroxide or tetra-n-butyl-ammonium hydroxide.
- the process is favorably carried out wherein the Curtius conditions comprise:
- step (b) treating the pyrone anhydride formed in step (a) with an azide salt to form a pyrone acyl azide;
- step (c) treating the pyrone acyl azide formed in step (b) with an ammonia, alkylamine, dialkylamine or optionally substituted phenylamine under conditions suitable to form the myxopyronin.
- the alkylamine is methylamine.
- the pyrone is treated with an alkyl haloformate, and subsequently with an azide salt.
- the alkylhaloformate is favorably methyl or ethyl chloroformate
- the azide salt is LiN 3 or NaN 3 .
- the process may be carried out wherein R is methyl or ethyl.
- the pyrone ketone is dissolved in a nonaqueous dipolar solvent such as THF and treated with a hydroxide salt such as lithium hydroxide, sodium hydroxide, or potassium hydroxide, preferably lithium hydroxide, at a temperature ranging from 0°C to 45 °C, and preferably at room temperature.
- the azide salt may be any suitable azide salt, such as trimethyammonium azide, lithium azide, sodium azide or potassium azide, which is dissolved water with or without a miscible non-reactive cosolvent prior to addition to the product of step (a), favorably at subambient temperatures, preferably at 0°C.
- Treating step (c) is carried out in a non-reactive dipolar solvent such as THF at a temperature determined by the ammonia or amine component reacted, and may range from -78°C to 120°C.
- R is C,_ 9 alkyl, and wherein R, is H, C,. 9 alkyl, benzyl, optionally substituted phenyl, OH, C,. 9 alkoxy, NH 2 , alkylamine, dialkylamine, or optionally substituted phenylamine.
- R is H, C,. 9 alkyl, benzyl, optionally substituted phenyl, OH, C,. 9 alkoxy, NH 2 , alkylamine, dialkylamine, or optionally substituted phenylamine.
- R is C,. 9 alkyl, and wherein R ⁇ is H, C,. 9 alkyl, benzyl, optionally substituted phenyl, OH, C,. 9 alkoxy, NH 2 , alkylamine, dialkylamine, or optionally substituted phenylamine; and wherein when R is methyl or ethyl, R* is not methoxy.
- the present invention further provides the following compositions of matter, having the structures set forth below. These compounds are useful as intermediates in the synthesis of myxopyronins and corallopyronins according to the present invention:
- the processes of the present invention encompass the use of various alternate protecting groups known in the art.
- ethyl ester 16 may be equivalently replaced with a methyl, propyl, isobutyl, phenyl or benzyl ester, wherein the triethylphosphonoacetate or triethylphosphonopropionate may be replaced with the corresponding alternate ester.
- the ethyl ester may be equivalently replaced with, for example, a methyl, propyl, isobutyl, phenyl, or benzyl ester, wherein the triethylphosphonoacetate used in the conversion from 8 to 9 may be replaced with the corresponding alternate ester.
- the bromopropionaldehyde dimethyl acetal may be equivalently replaced with, for example, an ethyl, propyl, butyl, ethylene, or propylene acetal
- SEM-C1 may be equivalently replaced with another protecting group, for example, methoxymethyl, methyl-thiomethyl, trimethylsilyl, t-butyldimethylsilyl, or tetrahydropyranyl .
- Titanium tetrachloride (TiCl 4 ) was freshly distilled from copper powder under reduced pressure before each use.
- the aqueous and organic layers were separated.
- the organic layer was washed with 300 mL of saturated NaHC0 3 .
- the organic layer was dried with filtered and evaporated on a rotary evaporator. This yielded the 35.4 g of the enol phosphonate which was used without further purification.
- the enol phosphonate was dissolved in 120 mL of diethyl ether and added to the first flask containing LiMe 2 Cu over the course of 20 minutes with the solution was being cooled to -78°C.
- the solution was stirred for 2.5 hours while being cooled at -78°C.
- the solution was poured into 300 mL of saturated NH 4 C1.
- the aqueous and organic layers were separated.
- DIBAL reduction of the ethyl ester A flame-dried flask under flushing argon containing 4.9 g (31.4 mmol, 1 eq) of the ethyl ester dissolved in 100 mL of freshly distilled THF was cooled to -78°C with a dry ice/acetone bath. 78.5 mL (78.5 mmol, 2.5 eq) of a 1.0M solution of DIBAL was dripped into the solution by syringe over the course of 10 minutes. The solution was left to stir for 1 hour. Fifty milliliters of methanol were poured into the solution to quench the excess DIBAL. The solution was diluted with 200 mL of H 2 0.
- the syringe was washed with 10 mL of CH 2 C1 2 and this solution added to the reaction. The solution was allowed to stir for 30 minutes. The reaction was stopped by the addition of 3.81 mL (27.3 mmol, 2.6 eq) of triethylamine and stirring for 5 minutes before allowing the solution to warm to room temperature.
- the solution was diluted with 20 mL of H 2 0 and the aqueous and organic layers separated. The aqueous layer was extracted with CH 2 C1 2 (2x10 mL). The combined organic layers were extracted with brine solution, dried with Na ⁇ O ⁇ filtered and evaporated on a rotary evaporator. The residue was placed on a Si0 2 column and eluted with 2:1 toluene/ethyl acetate. This yielded 0.45 g
- DIBAL reduction of the ethyl ester A flame-dried flask under flushing argon containing 1.86 g (9.5 mmol, 1 eq) of the ethyl ester dissolved in 40 mL of freshly distilled THF was cooled to -78°C with a dry ice/ acetone bath. 23.7 mL (23.7 mmol, 2.5 eq) of a 1.0M solution of DIBAL was dripped into the solution by syringe over the course of 5 minutes. The solution was left to stir for 2 hours. An additional 5 mL of DIBAL was added. One hour later, 20 mL of methanol was poured into the solution to quench the excess DIBAL.
- the solution was diluted with 50 mL of H 2 0. Fifty milliliters of Et 2 0 were added to the solution followed by 25 mL of 5% HCl. The whole solution was poured into a separatory funnel and the aqueous and organic layers separated. The aqueous layer was extracted with EtjO (2x20 mL). The combined organic layers were dried with Na ⁇ O ⁇ filtered and evaporated on a rotary evaporator. The residue was placed on a Si0 2 column and eluted with 3:1 hexane/ethyl acetate. This yielded 1.32 g (91 %) of a clear oil.
- IR (Film, KBr): v max 3436 m (b), 2966 s, 2931 s, 2872 m, 1731 s, 1713 s, 1613 s, 1548 s (b), 1443 m, 1384 m, 1255 m.
- the reaction was cooled to 0°C (ice water bath), ice was added to quench the reaction, and then saturated NH 4 C1 (100 mL) was added. The ice bath was removed and the reaction was further acidified with 3 M HCl until the reaction turned to a clear yellow (homogeneous) solution. At this time, the reaction pH was 2 * 3.
- the organic layer was separated, and the aqueous layer was extracted with ether (2x150 mL). The organic extracts were combined and washed with a saturated solution NaHC0 3 (200 mL), then dried with Na 2 S0 4 , filtered and concentrated under reduced pressure to provide crude allylic alcohol 13a.
- the mixture was allowed to warm to 0°C for 30 min and then recooled to -78 °C.
- the resulting solution was treated with a solution of pyrone 5 (1.47 g, 7.5 mmol) in 10 mL of THF, and stirred for 1.0 h at -78°C.
- the derived dianion was treated with iodide 8b (2.5 g, 8.25 mmol) in 10 mL THF, followed by the addition of HMPA (4.0 mL, 23.2 mmol).
- the reaction mixture was allowed to stir for 30 min at -78 °C, before being diluted with saturated NH 4 C1 aqueous solution (50 mL).
- v max 2978 s, 2942 s, 1731 s (b), 1637 s, 1631 s, 1554 s, 1443 s, 1272 m, 1178 m, 1043 m.
- IR (Film, KBr): v max 2966 m, 2931 m, 2872 m, 1748 s, 1736 s, 1719 s, 1701 s, 1560 s, 1542 s, 1454 s.
- EXAMPLE 7 Preparation of Compound 15a 3-(l-Propionyl)-4-hydroxy-6-ethyl-2-pyrone (5).
- Ethyl propionate (5.0 g, 35 mmol) was dissolved in 30 mL of 1.5 M solution NaOH and stirred at RT for 30 h. The reaction mixture was cooled to 0 °C, and 3 M HCl was slowly added until the mixture reached a pH of about 1; then solid KCl was added to saturate the solution.
- the derived dianion was treated with iodide 8c (2.5 gm, 8.25 mmol) in 10 mL THF, followed by the addition of HMPA (4.0 mL, 23.2 mmol).
- HMPA 4.0 mL, 23.2 mmol
- the reaction mixture was allowed to stir for 30 min at -78 °C, before being diluted with saturated NH 4 C1 aqueous solution (50 mL).
- the organic layer was separated, and the aqueous layer was extracted with ether (2 x 50 mL). The organic layers were combined and dried (MgSO 4 ), filtered, and concentrated in vacuo.
- the resulting solution (homogeneous, brown-yellow color) was cannulated to a suspension of paraformaldehyde (6.0 g, 200 mmol) in THF (lOOmL) under a N 2 atmosphere.
- This orange-yellow mixture was allowed to stir at RT for 20 h before it was cooled to 0 °C (ice water bath). Ice was added to dilute the reaction, and then saturated NH 4 C1 (100 mL) was added. The ice bath was removed and the reaction was acidified with 3 M HCl until the reaction mixture turned clear yellow (and became homogeneous). At this time, the reaction pH was measured at 2-3. The organic layer was separated, and the aqueous layer was extracted with ether (2 x 150 mL).
- MIC Microdilution Minimal Inhibitory Concentration
- MMC Minimum Bactericidal Concentration
- the minimal inhibitory concentration is defined as the lowest concentration of antimicrobial agent that completely inhibits growth of the organism in the microliter plate.
- the MIC is reported as a range between the concentration at which no growth is observed and the concentration of the dilution which immediately followed. Selected inhibitors from the RNA polymerase screen described above were tested for their ability to inhibit bacterial growth in a broth microdilution assay as follows.
- Mueller-Hinton broth containing 20-25 mg/L Ca2+ and 10- 12.5 mg/L Mg2+ (Difco #0757-07-8) is recommended as the medium (pH 7.2 and 7.4 at room temperature) of choice by the NCCLS for rapidly growing or facultative organisms and it demonstrates good batch-to-batch reproducibility for susceptibility testing; is low in sulfonamide, trimethoprim, and tetracycline inhibitors; and yields satisfactory growth of most pathogens.
- Dilution of antimicrobial agents is performed in a sterile, covered 96- well microliter plate with flat bottom wells (Costar #9017), and each well contains 100 ⁇ L of both +/- antimicrobial agent.
- the final concentrations of the small molecule antimicrobial agents are 100, 50, 25, 12.5, 6.25, 3.12,
- the overnight culture of a single colony is diluted in sterile Mueller-Hinton broth so that, after inoculation, each well contains approximately 5 x 105 CFU/mL.
- 50 mL of the adjusted inoculum suspension is added to the microliter plate.
- Each well is diluted with an equal volume of the antimicrobial agent/control substance diluted with sterile Mueller-Hinton broth.
- the inoculated microliter plate is incubated at 35 °C for 16-20 hours.
- the turbidity of each well is determined by measuring the absorbance at 595 nm on the BioRad Model 3550-UV microplate reader.
- the rows containing broth only (no cells) serve as a control, and the rows containing the titration of 1 % DMSO serve as a control for 100% growth.
- the average of the broth only controls is subtracted from the average of each duplicate. This value is subsequently normalized to the average of the DMSO controls.
- the minimum bactericidal concentration is defined as the concentration of antimicrobial agent from which no colonies grow on petri plates or in the medium.
- MBC is arbitrarily defined as the concentration at which a 1000-fold reduction in colony forming units is observed with respect to the original inoculum (survival of 0.1 %).
- the broth dilution method consists of inoculating the wells from an MIC microliter plate using a 96-well inoculation grid into a fresh microliter plate containing 100 ⁇ L Mueller-Hinton broth per well. The MBC plates are incubated at 37 °C for 16-20 hrs and the MBC values are determined. The MIC data suggest that these compounds, like rifampicin, do not penetrate E.
- Ester 1 is available from 2-pentanone through Wadsworth-Emmons chemistry (Wadsworth, W., Emmons, W., Org. Synth. , 1965, 45, 44) and commercially available triethylphosphonates (Figure 3).
- the anion of triethyl phosphonacetate is created by stirring with NaH in THF, and is condensed with 2-pentanone to create unsaturated ester 16.
- the ester 16 is reduced with DIBAL to the alcohol and then oxidized to the aldehyde 14 with DDQ.
- Compound 1 is produced by going through another cycle of Wadsworth-Emmons chemistry, DIBAL reduction and DDQ oxidation.
- Intermediate 13 can also be made using lithium dimethyl cuprate chemistry (Sum and Weiler, Can. J. Chem. , 1979, 57, 1431), which procedure produces 13 in a higher E/Z ratio.
- the other half of the molecule containing the 6-substituted pyrone is dissected in the following manner. This scheme requires a pyrone functionalized at the 6-position (Douglas, J., Money, T., Can. J. Chem., 1968, 46, 695) and commercially available reagents shown in Figure 2.
- the three necessary segments can be joined by an additional Wadsworth-Emmons olefination and a simple alkylation.
- the terminal methyl carbamate can then be introduced by the use of a modified Curtius rearrangement. Overman, L., Taylor, G., Petty, C, Jessup, P., J. Org. Chem. , 1978, 43,
- the first pathway is based on the known alkylation of the commercially available compound 3 at the 7-postion using n-BuLi and an alkyl halide.
- a model pyrone containing an ethyl group was alkylated at the 7-position in a similar manner by constructing the 6-position side chain after the desired methyl group (C-8) was already in place at C-7.
- Figure 8 schematically demonstrates the completion of the myxopyronin A synthesis from key intermediate 10.
- Aldol condensation with 1 to produce 13 is followed by oxidation with any reagent effective for oxidizing alcohols at allylic or benzylic positions, including DDQ, Mn0 2 , K 2 CrO 7 , etc., to afford ketone 17.
- Conversion of the ethyl ester to the acid is effected by saponification with LiOH.
- installation of the vinyl carbamate is effected by modified Curtius conditions.
- the present invention provides an alternate pathway for the total synthesis of myxopyronin A. Formation of the bond between C-3 and C-15 has proven to be a difficult synthetic step.
- the routes may be modified by those of ordinary skill in the art to provide derivatives from the isocyanate intermediate other than carbamates.
- reaction with ammonia or an alkylamine would lead to a substituted urea analog. Satchell, Chem. Soc. Rev., 1975, 4, 231.
- hydrolysis generates a primary amine myxopyronin analog.
- Figure 13(b) schematically demonstrates the completion of the myxopyronin A synthesis from key intermediate 15.
- Alkyl iodide 8c was prepared from 1,3-propane diol by a two step reaction sequence: (i) selective protection with TBSC1 (1.0 equiv), NaH (1.0 equiv), 98% yield; (ii) I 2 PPh 3 imidazole, 96% yield; satisfactory spectroscopic data ('H and 13 C-NMR, IR, CIMS and CIHRMS) were obtained for all new compounds.) Oxidation of the primary hydroxyl with freshly prepared Dess-Martin reagent (2.0 equiv, 0°C, 2 h) gave aldehyde 5c. (Dess, D.B.; Martin, J.C. J. Org. Chem.
- Titanium (IV) Promoted Aldol Condensation and Completion of the Syntheses.
- the introduction of the upperside chains of myxopyronin A and B was carried out utilizing a Ti(IV) tetrachloride promoted aldol condensation between the ethyl ketone of 15a and aldehydes 14b and 14c ( Figure 19).
- the titanium enolate was generated at -78 °C by treatment of ethyl ketone 15a with TiCl 4 (4.0 equiv) and DIPEA (4.8 equiv).
- the derived enolate was condensed with freshly prepared aldehyde 14b/c at -78 °C for 48-56 h to directly afford after in situ dehydration the respective (E, E)- dienones 17c and 17d.
- both side chains installed onto the o -pyrone core, completion of the individual syntheses required the conversion of the ⁇ , ⁇ -unsaturated methyl ester to the methylcarbamate. This was initiated by a LiOH (10 equiv, THF/H 2 O 4:1, 15h) promoted hydrolysis of the methylesters which afforded the free carboxylic acids 17c and 17d in quantitative yield.
- the vinyl carbamate was introduced by a modified Curtius rearrangement (Overman, L., et al, J. Org. Chem. 1978, 43, 2164-2167) employing ethylchloroformate and NaN 3 . This sequence completed the assembly of the lower side and achieved the synthesis of ( ⁇ )-myxopyronin A and B.
- (+)-Myxopyronin A & B The biological activities of the myxypyronins were evaluated with an in vitro transcription assay using E. coli RNA polymerase ( Figure 20a,b).
- the myxopyronins A/B were isolated as a mixture of natural products containing a 9:1 ratio of A and B.
- the synthetic ( ⁇ )-myxopyronin A ( Figure 20a) is equally potent as the natural product mixtures.
- a known transcription inhibitor, rifampicin was included in the assay.
- the synthetic myxypyronin A and B were tested against E. coli RNA polymerase separately and myxopyrorin B is shown to be a more potent molecule than A ( Figure 20b).
- Table II summarizes in vitro IC 50 and MIC values obtained from the cell-based evaluation of the myxopyronins using both gram-positive and gram-negative bacteria. The data show that myxopyronins have in vivo cell-based activities against rifampicin-resistant bacteria. In complement to the in vitro transcription activities, myxopyronin B is also shown to have up to 30 fold more potent cell-based activities than A (Table II).
- the present invention therefore provides a highly convergent synthetic pathways to myxopyronin A and B, as well as analogs and derivatives thereof. Biological evaluation of these agents against RNA polymerase for a variety of bacteria including mammalian culture cells demonstrates their considerable utility as antibacterial agents.
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WO2000015626A1 (en) * | 1998-09-16 | 2000-03-23 | Anadys Pharmaceuticals, Inc. | Process for the preparation of intermediates for pyronin antibacterials |
EP2520293A1 (en) * | 2011-05-05 | 2012-11-07 | Rheinische Friedrich-Wilhelms-Universität Bonn | Compounds for use in the treatment of filariasis |
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AU2003249194A1 (en) * | 2002-07-11 | 2004-02-02 | The Ohio State University Research Foundation | In vitro transcription assay for t box antitermination system |
WO2012033846A1 (en) | 2010-09-09 | 2012-03-15 | Rutgers, The State University Of New Jersey | Arylpropionyl-triketone antibacterial agents |
US9133155B2 (en) * | 2010-09-17 | 2015-09-15 | Rutgers, The State University Of New Jersey | Antibacterial agents: high-potency myxopyronin derivatives |
WO2013103969A1 (en) | 2012-01-05 | 2013-07-11 | Rutgers, The State University Of New Jersey | Antibacterial agents: phloroglucinol derivatives |
US9187446B2 (en) * | 2012-03-22 | 2015-11-17 | Rutgers, The State University Of New Jersey | Antibacterial agents: sidechainfluorinated myxopyronin derivatives |
EP2861570B1 (en) | 2012-06-19 | 2018-07-18 | Rutgers, The State University of New Jersey | Antibacterial agents: aryl myxopyronin derivatives |
US10450292B2 (en) | 2015-12-10 | 2019-10-22 | Rutgers, The State University of New Jersesy | Inhibitors of bacterial RNA polymerase: arylpropanoyl, arylpropenoyl, and arylcyclopropanecarboxyl phloroglucinols |
US11685723B2 (en) | 2018-02-13 | 2023-06-27 | Rutgers, The State University Of New Jersey | Antibacterial agents: O-alkyl-deuterated pyronins |
US11572337B2 (en) | 2018-03-06 | 2023-02-07 | Rutgers, The State University Of New Jersey | Antibacterial agents: arylalkylcarboxamido phloroglucinols |
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Non-Patent Citations (2)
Title |
---|
HU T., ET AL.: "TOTAL SYNTHESIS AND PRELIMINARY ANTIBACTERIAL EVALUATION OF THE RNA POLYMERASE INHIBITORS (PLUS OR MINUS)-MYXOPYRONIN A AND B.", THE JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 63., no. 07., 1 March 1998 (1998-03-01), US, pages 2401 - 2406., XP002920662, ISSN: 0022-3263, DOI: 10.1021/jo9721610 * |
KOHL W., ET AL.: "DIE BIOSYNTHESE DES ANTIBIOTIKUMS MYXOPYRONIN A AUS MYXOCOCCUS FULVUS STAMM MX F50.", LIEBIGS ANNALEN DER CHEMIE., VERLAG CHEMIE GMBH. WEINHEIM., DE, 1 January 1985 (1985-01-01), DE, pages 1080 - 1093., XP002920663, ISSN: 0170-2041 * |
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WO2000015626A1 (en) * | 1998-09-16 | 2000-03-23 | Anadys Pharmaceuticals, Inc. | Process for the preparation of intermediates for pyronin antibacterials |
US6191288B1 (en) | 1998-09-16 | 2001-02-20 | Anadys Pharmaceuticals, Inc. | Pyronin antibacterials, process and novel intermediates thereto |
EP2520293A1 (en) * | 2011-05-05 | 2012-11-07 | Rheinische Friedrich-Wilhelms-Universität Bonn | Compounds for use in the treatment of filariasis |
WO2012150340A1 (en) * | 2011-05-05 | 2012-11-08 | Rheinische Friedrich-Wilhelms Universität Bonn | Compounds for use in the treatment of filariasis |
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