CA2369043A1 - Novel ligands for chiral catalysis - Google Patents
Novel ligands for chiral catalysis Download PDFInfo
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- CA2369043A1 CA2369043A1 CA002369043A CA2369043A CA2369043A1 CA 2369043 A1 CA2369043 A1 CA 2369043A1 CA 002369043 A CA002369043 A CA 002369043A CA 2369043 A CA2369043 A CA 2369043A CA 2369043 A1 CA2369043 A1 CA 2369043A1
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- 239000003446 ligand Substances 0.000 title claims abstract description 20
- 238000006555 catalytic reaction Methods 0.000 title claims description 12
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 17
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 150000001412 amines Chemical class 0.000 claims abstract description 12
- 125000001033 ether group Chemical group 0.000 claims abstract description 12
- 125000001475 halogen functional group Chemical group 0.000 claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 239000002184 metal Substances 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 6
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims abstract description 5
- 125000000524 functional group Chemical group 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 5
- 229910052785 arsenic Inorganic materials 0.000 claims abstract description 3
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 3
- 125000004001 thioalkyl group Chemical group 0.000 claims abstract description 3
- 125000005000 thioaryl group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 150000004696 coordination complex Chemical class 0.000 claims description 11
- 125000005843 halogen group Chemical group 0.000 claims description 5
- DUPSXQCQECCSIE-YTTGMZPUSA-N diphenyl-[2-[(4s)-2-trityl-4,5-dihydro-1,3-oxazol-4-yl]ethyl]phosphane Chemical compound C([C@@H]1N=C(OC1)C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 DUPSXQCQECCSIE-YTTGMZPUSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910052723 transition metal Inorganic materials 0.000 claims description 3
- 150000003624 transition metals Chemical class 0.000 claims description 3
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 2
- 239000004952 Polyamide Substances 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 229910052737 gold Inorganic materials 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 239000004584 polyacrylic acid Substances 0.000 claims description 2
- 229920002239 polyacrylonitrile Polymers 0.000 claims description 2
- 229920002647 polyamide Polymers 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 230000003019 stabilising effect Effects 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 6
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 abstract description 4
- NHFAABIHBNXKDT-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;phosphane Chemical compound P.C1CN=CO1 NHFAABIHBNXKDT-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002894 organic compounds Chemical class 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229910052727 yttrium Inorganic materials 0.000 abstract description 2
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 30
- 101150041968 CDC13 gene Proteins 0.000 description 20
- 238000005481 NMR spectroscopy Methods 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- AJOXZAAREAYBQR-RGMNGODLSA-N diethyl (2s)-2-aminobutanedioate;hydrochloride Chemical compound Cl.CCOC(=O)C[C@H](N)C(=O)OCC AJOXZAAREAYBQR-RGMNGODLSA-N 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 230000003595 spectral effect Effects 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- -1 DIOP Chemical compound 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QKZWXPLBVCKXNQ-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)CCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WERYXYBDKMZEQL-UHFFFAOYSA-N 1,4-butanediol Substances OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- GYKMEKRMASHMIH-VSJLXWSYSA-N [(3r,4r)-1-benzyl-4-diphenylphosphanylpyrrolidin-3-yl]-diphenylphosphane Chemical compound C=1C=CC=CC=1P([C@H]1[C@@H](CN(C1)CC=1C=CC=CC=1)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 GYKMEKRMASHMIH-VSJLXWSYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- MIBQYWIOHFTKHD-UHFFFAOYSA-N adamantane-1-carbonyl chloride Chemical compound C1C(C2)CC3CC2CC1(C(=O)Cl)C3 MIBQYWIOHFTKHD-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 238000005937 allylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- FWXAUDSWDBGCMN-ZEQRLZLVSA-N chiraphos Chemical compound C=1C=CC=CC=1P([C@@H](C)[C@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-ZEQRLZLVSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- CQBWPUJYGMSGDU-UHFFFAOYSA-N ethyl benzenecarboximidate Chemical group CCOC(=N)C1=CC=CC=C1 CQBWPUJYGMSGDU-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000004820 halides Chemical group 0.000 description 1
- 238000007037 hydroformylation reaction Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- BFMKBYZEJOQYIM-UCGGBYDDSA-N tert-butyl (2s,4s)-4-diphenylphosphanyl-2-(diphenylphosphanylmethyl)pyrrolidine-1-carboxylate Chemical compound C([C@@H]1C[C@@H](CN1C(=O)OC(C)(C)C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 BFMKBYZEJOQYIM-UCGGBYDDSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Novel phosphine oxazoline ligands of formula (I) wherein m is 1, 2, 3 or 4; n, p, q, r are independently zero or 1 provided that at least one of n, p, q and r is 1; X is O, S, Se, CH2, NH; Y is N, P, As, S; R is H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; ferrocenyl; a thioalkyl group; a thioaryl group; or R is derived from a hydrocarbyl group attached to a functional group of an organic compound or a polymer capable of giving rise to the grouping -N-C-X- in the ring structure of (I); R1 to R13 are independently selected from H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; with the proviso that when m is 1, one of n, p, q and r is 1 the remaining three being zero, X is O, Y is P, R1 and R2 are both H, R3 to R11 if present are H, and R12 and R13 are both phenyl, then R is not CH3, C(CH3)3, CHPh2, CPh3, adamantyl, C6H3(t-Bu)2, ferrocenyl, CF3, Ph, C6H4OMe, C6H4Me, C6H4NO2 or C6F5, a process for the preparation thereof, metal complexes containing such ligands and the use of such complexes, or combinations of ligand with metal salts or complexes, as catalysts for asymmetric syntheses.
Description
NOVEL LIGANDS FOR CHIRAL CATALYSIS
The present invention relates to novel optically active phosphine oxazoline ligands, a process for the preparation thereof, metal complexes containing such novel ligands and the use of such complexes, or combinations of ligand with metal salts or complexes, as catalysts for asymmetric syntheses.
The development of novel catalytic systems exhibiting unique reactivity and high enantioselectivity is of great importance in science and technology. The activity of many pharmaceuticals, agrochemicals, fragrances and food additives are associated with a specific enantiomer. Thus, the ability to produce enantiomerically pure compounds is ~ 5 essential. Many approaches have been explored to acquire such enantiomerically pure compounds, ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Asymmetric catalysis has been found to be one of the most efficient, if not the most efficient method of producing enantiomerically pure compounds since a small amount of a chiral catalyst can be used to produce a large quantity of a chiral compound.
One class of ligands which have played a significant role in the development of chiral catalysts are asymmetric phosphine ligands. Although over 1000 chiral diphosphine ligands have been prepared since the application of the DIPAMP
ligand in the production of L-Dopa, only a few of these have the efficiency and selectivity of commercial applications. Some of the most well known phosphine ligands used include BINAP, BPPM, DEGPHOS, DIOP, Chiraphos, Skewphos, Duphos and BPE all of which acronyms are described by annotated references in e.g. WO 97/47633 and are incorporated herein by reference. However, these ligands have their disadvantages and 3o are not ideal for all applications.
There is still, therefore, the need to develop novel chiral catalysts which are highly enantiomerically selective and carry out the required reaction giving a high yield.
Accordingly. the present invention provides a phosphine oxazoline ligand of formula (I) R~2 4 R; R8 R9 R ~ R
Y~Rt3 I
. -~R7 R~~, I
p r X
~N R
R
wherein mis1,2,3or4;
n, p, q, r are independently zero or I provided that at least one of n, p, q and r is 1;
X is O, S, Se, CH2, NH;
Y is N, P, As, S;
R is H; a straight - chain alkyl group, branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; ferrocenyl; a thioalkyl group; a thioaryl group;
or R is ~ 5 derived from a hydrocarbyl group attached to a functional group of an organic compound or a polymer capable of giving rise to the grouping -N-C-X- in the ring structure of (I);
R' to R'3 are independently selected from H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups;
an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups;
with the proviso that when m is 1, one of n, p, q and r is 1 the remaining three being zero, X is O, Y is P, R~ and R'' are both H, R3 to Rl ~ if present are H, and R'2 and R13 are both phenyl, then R is not CH3, C(CH3)3, CHPhz, CPh3, adamantyl, C6H3(t-Bu)2, ferrocenyl, CF3, Ph, CbH40Me, C6H4Me, C6H4N0~ or C6F5 By the term "alkyl'" we mean a straight. branched or cyclo alkyl group having any number of carbon atoms, for example from 1 to 14 carbon atoms. such as from I to carbon atoms. The cyclo alkyl groups may have one or more rings in its structure e.g.
adamantyl which has a fused tricyclic ring structure.
By the term "aryl'" we mean an aromatic monovalent hydrocarbyl group which include inter alia aryl, alkaryl and aralkyl groups. for example phenyl, benzyl, naphthyl, etc.
to Suitably, m is 1 or 2; preferably 1.
Suitably, at least two of n, p, q and r are 1. the remaining two may be zero or I ;
preferably, two of n, p, q and r are 1, the remaining two are zero.
Suitably, X is O, S, CHz or NH; preferably O.
Suitably, Y is P, N or S; preferably P.
In the above structure, R may be derived from a hydrocarbyl group attached to a 2o functional group of an organic compound or a polymer capable of giving rise to the grouping -N-C-X- in the ring structure of (I). Thus, R may be an alkyl group of a polyacrylic acid, polymethacrylic acid, a polyacrylonitrile or a polyamide, all of which are polymers carrying a function group capable of giving rise to the grouping -N-C-X- in the ring structure of (I).
A first embodiment of the invention provides a compound of formula (IA) Rz Ra Rs R~
R~z Y~ IA
X ~ N i' R
wherein m, X, Y. R. and R' to R' and R' ~ and R' ~ are as hereinbefore defined. provided that when m is 1. X is O. Y is P. R', R'. R'. R~' and R' are H, and R'~ and R'3 are both phenyl. then R is not CH;. C(CH3);. CHPh~. CPh;. adamanty-l. C~H3(t-Bu)~.
ferrocenyl.
CF3. Ph, C6H:~OMe. C~H.~Me. C6H~N0~ or CbF;.
A second embodiment of the invention provides a compound of formula (IB) IB
Ri3 R
wherein m, X, Y, R and R' to R' and R' ~ and R' 3 are as hereinbefore defined.
A third embodiment of the invention provides a compound of formula (IC) Rz Ra Rs Rs R9 R~
/R,z IC
X 3 ~ 'Y
N R6 R~ R»
R
to wherein m, X. Y, R and R' to R9 and R'' and R'3 are as hereinbefore defined.
A fourth embodiment of the invention provides a compound of formula (ID) RZ R4 R; Rs R9 Ii2 R~
ID
YwR~3 X ~ N~3R6 R~ R~ R> >
R
i 5 wherein m, X, Y. R and R' to R' 3 are as hereinbefore defined.
A particularly preferred embodiment of the invention provides a compound of R~ R~ R~ R,, R' Y~
X
the following structure:
O
N /P~Rn R~3 R
wherein R is a C~_.~ alkyl group optionally substituted by one or more groups selected from phenyl and halo; where said substituent group is phenyl it may be optionally further substituted by one to five substituents selected from the group consisting of halo, C»
5 alkyl, C,_4 alkoxy or nitro; ferrocenyl or adamantyl; and R''' and R'3 each of which may be a phenyl or cyclohexyl group.
Particularly preferred compounds include those of the following formulae:
,,, ,,,,,,,, O
' N ph~P~Ph ' N ph~P~Ph Ph t-Bu to (l la) (l lc) (S)-2-Phenyl-4-[(diphenyl- (S)-2-tert Butyl-4-[(diphenyl-phosphino)ethyl]oxazoline phosphino)ethyl]oxazoline O~ '''''''~ 0 Ph~P~Ph ~ N ph~P~Ph t-a (lld) (llb) (S)-2-(3,5-ditertiarybutylphenyl)-4- (S)-2-Adamantyl-4-[(diphenyl-[(diphenylphosphino)ethyl]oxazoline phosphino)ethyl]oxazoline 2o and (S)-2-Triphenylmethyl-4-[(diphenylphosphino)ethyl]oxazoline (1 le) Compounds of formula (I) are novel and accordingly a further aspect of the present invention provides a process for the preparation of a compound of formula (I).
Compounds of formula (I) may be prepared by the reaction of a compound of formula (II) s 4 R; R8 R9 R 1 R.. I
r Y~R> > .BH3 II
p ~3 X ~R~7 Rlqy 1 Pro R~~
R~
wherein m, n, p, q, r, X. Y and R~ to R'3 are as hereinbefore defined; R~'~
and RAs are alkyl groups which may be the same or different and Pro is a nitrogen protecting group, for example a butoxy carbonyl group (hereafter "BOC"), with a compound of formula (III) H.H+.Hal-III
R OR'6 wherein R is as hereinbefore defined. R'6 is an alkyl group, for example ethyl, and Hal is ~ 5 a halide group, for example chloride. The reaction is carried out by the addition of for example gaseous HCI, in the presence of an alcohol, such as methanol to the compound of formula (II), followed by the addition of a compound of formula (III) in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane.
20 Compounds of formula (III) are known in the literature (Meyers, A.L;
Schmidt, W; McKennon, M.J., Synthesis, 1993, 250-262).
Compounds of formula (II) may be prepared by the reaction of a compound of formula (IV) R 1 R2 4 R; R8 R9 L
p '~ IV
1(1R11 Pro R»
R~s wherein m, n. p, q, r, X, R~ to R~s and Pro are as hereinbefore defined, and L
is a leaving group, such as e.g tosylate, iodide, triflate or bromide, with a compound of formula s LiYR~2R~3, wherein Y, R~'' and R'3 are as hereinbefore defined. The reaction is carried out in the presence of an organic solvent, such as THF, and with the addition of BH3.
Compounds of formula (IV) may be prepared from the corresponding alcohol of formula (V) 4 Rs R8 R9 OH
p '~ V
N R6 ~~ R1aR11 Pro Ria to R~s wherein m, n, p, q, r, X, R' to R'' and Pro are as hereinbefore defined. The reaction is carried out with a suitable compound to give the desired leaving group, L. For example if the leaving group is tosyl, the reaction is carried out with, e.g. tosyl chloride, in the 15 presence of a base such as e.g. triethylamine, and a suitable solvent, such as e.g. dichloromethane. A catalytic amount of 4-dimethylaminopyridine (DMAP) may also be added.
Compounds of formula (V) are known in the literature (Ksander, G.M.; de 2o Jesus, R.; Yuan, A.; Ghai, R.D.: Trapani, A.; McMartin, C.; Bohacek. R., J.
Med. Chem.
1997, 40, 495-505).
Compounds of formulae (II) and (IV) are also novel and accordingly form a further aspect of the invention.
A yet further aspect of the present invention provides a metal complex containing a ligand of formula (I) comprising a metal and optionally other ligands capable of stabilising the complex, e.g. chloride, acetate etc. Suitably. the metal is a transition metal; for example, the metal may be selected from the group consisting of Ni, Pd, Rh, Ir, Cu, Ag, Au and Zn.
to A metal complex of the present invention may be of use in any chemical reaction requiring an asymmetric catalyst. Examples of such reactions include but are not limited to Heck type reactions, Suzuki type reactions, allylation reactions.
cross-coupling reactions, hydrogenations, hydroformylations and isomerisation reactions.
Therefore, a still further aspect of the invention provides a metal complex of the invention for use in asymmetric catalytic reactions. Alternatively, the invention provides the use of a metal complex of the invention in asymmetric catalytic reactions. Alternatively, there is provided a method for performing an asymmetric catalytic reaction, said method comprising the use of a metal complex of the invention.
2o The metal complex of the invention may be formed in situ from a ligand of formula (I) and a suitable precursor complex or salt of a metal, which is preferably a transition metal as recited above. Therefore, a further aspect of the invention provides for the use of a ligand of formula (I) in combination with a metal complex or salt in asymmetric catalysis.
The invention will now be described by way of example only.
(51-N-tert-butoxvcarbonyl-aspartic acid diethyl ester (3).
Absolute ethanol (420 ml) was cooled in ice and acetyl chloride (71.4 ml, 1.03 mol) was added dropwise to generate HC1 in situ. After the addition, the reaction was stirred for additional 30 minutes. L-Aspartic acid (33.278, 0.25 mol) was added in one portion and the solution heated slowly after dissolution to reflux. Refluxing was continued until the reaction was complete as monitored by thin layer chromatography (TLC). The reaction mixture was then cooled to 25°C and the solvent was removed under reduced pressure. Further drying under vacuum gave crude diethyl L-aspartate hydrochloride (2) as a viscous oil which crystallised on standing to a white solid, yield:
60 g (100%). This material was used without further purification. Spectral data for this sample were consistent with those given in the literature'. '3C NMR (75 MHz, d6-DMSO) 169.1, 168.2, 70.0, 60.9, 48.5, 34.2, 14.9 and 13.9.
1o A sample of the diethyl L-aspartate hydrochloride (2) (57.5 g, 0.273 mol) was dissolved in water (59 ml) and dioxane (149 ml) then cooled to 0°C.
Triethylamine (74 ml, 0.53 mol), then di-tert-butyl dicarbonate (74.99 g, 0.34 mol) were added with stirring. The reaction mixture was then heated at 50°C overnight after which TLC (ethyl acetate-ethanol 1:1 ) indicated complete consumption of the starting material.
The solvent was removed in vacuum, aqueous citric acid (150 ml, 10 %, w/v) added to adjust the pH to 2-3. Diethyl ether (300 ml) was added and the organic phase was separated.
The aqueous phase was extracted with ether (4 x 250 ml), the combined ether extracts washed with brine (100 ml), dried over NazS04, concentrated under vacuum to give (3) (78.8 g, 99 %) as light yellow oil, which can be used without further purification.
2o Spectral data for this sample were consistent with those given in the literature2~ 'H NMR
(300 MHz, CDC13) 5.48 (1 H), 4.49 (m, 1 H), 4.12 (m, 4H), 2.90 (dd, J = 16.8 Hz, J =
4.6 Hz), 2.76 (d, J = 4.88 Hz, 1 H), 1.46 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); '3C NMR (75 MHz, CDC13) 170.9, 170.8, 155.4, 79.8, 61.6, 60.9, 49.9, 36.7, 28.2, 14.0 and 13.9.
(,S~-2-(tert-Butoxycarbonylamino)-1,4-butanediol (4).
A stirred solution of (S~-N-ten-butoxycarbonyl diethyl L-aspartate (3) (47.41 g, 0.16 mol) in absolute ethanol (770 ml) was cooled in ice, then sodium borohydride (60.8 g, 1.6 mol) was added in 10 g portions. The cooling bath was removed when the reaction 3o subsided, and the reaction mixture was heated slowly to reflux for 1 h;
after this time TLC (EtOAc-EtOH 3:1 ) analysis indicated complete consumption of the starting material. The reaction mixture was cooled to 25°C, and the lumps formed were broken-up to give a slurry that was poured into brine (450 ml). The mixture was filtered, the filtrate concentrated in vacuum to ca. 100 ml, and was extracted with ether (6 x 300 ml).
The insoluble solid material was extracted by stirring in ether (4 x 1 L) for 2 h.
5 The combined ether extracts were dried over MgS04, filtered and concentrated to give (4) as a colourless oil (24.4 g, 73%), which crystallised on standing.
Spectral data for this sample were consistent with those given in the literature2. 'H NMR (200 MHz, d6-DMSO) 6.45 (d, J = 8.4 Hz, 1 H), 4.57 (t, J = 5.6 Hz, 1 H), 4.35 (t, J = 5.1 Hz. 1 H), 3.40 (m, 4H), 3.23 (m, 1 H), 1.62 (m, 1 H), 1.40 (m, 1 H), 1.36 (s, 9H); ~ 3C NMR
(50 MHz, d6-to DMSO) 155.5, 77.4, 63.5, 58.0, 49.6, 34.4, 28.3.
(S~-N-tert -butoxycarbonyl-4-(2-hydroxy)ethyl-2,2-dimethyloxazolidine (5).
2,2-Dimethoxypropane (87 ml, 0.707 mol) and p-toluenesulphonic acid monohydrate (1.33 g, 7mmol) were added to a stirred solution of the diol (4) (14.39 g, 70 mmol) in dichloromethane (319 ml) at 25°C. The reaction was monitored by TLC (ethyl acetate-hexanes 2:1 ) until complete (36 h). The reaction mixture was then washed with aqueous NaHC03 (5%, 2 x 50 ml), brine (50 ml), dried (MgS04) and concentrated to form a colourless oil, which crystallised upon standing. The ratio of the desired five-membered ring product (5) to the undesired six-membered ring product (6) was 6.4:3.6.
Recrystallisation from heptane gave (5) as colourless needles (8.2 g, 48%).
Spectral data for this sample were consistent with those given in the literature3. 'H NMR
(200 MHz, CDCl3) 4.17 (m, 1 H), 3.97 (m, 1 H), 3.86-3.42 (m, 3H), 3.33 (br, 1 H), 1.76 (m, 2H), 1.5 (s, 3H), 1.46 (s, 9H); 13C NMR (50 MHz, , CDCl3) 153.9, 93.6, 80.9, 68.2, 58.6, 53.9, 37.7, 27.7, 26.3, 24.3.
(S~-N-tert-butoxvcarbonyl-2,2-dimethyl-4-hvdroxvmethyl-1,3-oxazine (6).
A sample of pure (6) was isolated via flash chromatography using ethyl acetate/hexanes (3:1 v/v) as eluant. ~H NMR (200 MHz, CDC13) 3.37-3.77 (m, SH), 1.62 (m, 2H), 1.35 (s, 9H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (50 MHz, , CDCl3) 155.0, 101.2, 79.1, 63.8, 57.9, 48.5, 35.7, 28.3, 24.7, 24.6.
~S~-2-(tert-Butoxvcarbonvl-4-(4-toluenesulfonvloxvethvl)-2,2-dimethvloxazolidine Dry, freshly crystallised p-toluenesulphonyl chloride (1.86 g, 9.8 mmol) and 4-dimethylaminopyridine ( 10 mg, 0.082 mmol) were added to a solution of alcohol (5) (2.00 g, 8.15 mmol) and triethylamine (2.6 ml, 18.75 mmol) in dichloromethane (20 ml) at 5°C with stirring. The resulting solution was protected from moisture and kept at 5°C
until all the starting material (5) had reacted (33 h, TLC). A colourless solid, presumably triethylamine hydrochloride, crystallised out of the reaction, and was filtered away.
The filtrate was diluted with dichloromethane to a volume of 90 ml, and washed with water (2 x 20 ml), brine (20 ml), dried over Na2S04, and concentrated to give the crude tosylate (7) as white solid. This material was purified by dissolving in ether (ca. 330 ml), filtering through celite 545 on a wad of cotton wool to give 2.95 g (90 %) of (7).
'H NMR (200 MHz, CDC13) 7.78 (m, 2H), 7.35 (d, 2H), 4.09 (m, 2H), 4.09 (m, 2H), 3.90 (m, 2H), 3.73 (m, 1 H), 2.95 (m, 2H), 1.51 (s, 6H), 1.44 (s, 9H).
(S~-N-tert-butoxycarbonyl-4-ethylenediphenylphosphinoborane-2,2-dimethyloxazolidine (8).
n-Butyl lithium in hexanes (1.6 M, 17.1 ml, 27.4 mmol)was added to a solution of diphenylphosphine (4.52g, 24.3 mmol) and THF (100 ml) at 0°C. The orange-red 2o solution was stirred at 0°C for 30 minutes. A solution of tosylate (7) (8.44 g, 21.1 mmol) in THF (60 ml) was then added dropwise to the solution of the diphenylphosphide anion at 0°C. The reaction mixture was stirred for another 30 minutes. Borane-THF complex (1 M, 26 ml, 26 mmol) was added to the solution at 0°C and this was then stirred for an additional 20 minutes. The solvent was removed, and the remaining material was dissolved in ethyl acetate (600 ml) and washed with 1 M HCl~aq~ (100 ml), sat.
NaHC03 (100 ml), brine (100 ml), dried over Na2S04, and filtered. The solvent was removed under reduced pressure. The residue was then purified by column chromatography on silica gel using ethyl acetate/hexane eluant (3:7 v/v) to give 8.1 g (18.9 mmol, 90%) of a colourless oil, which crystallised upon standing at 25°C. m.p. 95.0-96.5°C; Rf 0.81 (ethyl acetate/hexane, 1:1 v/v). This was the protected phosphine (8). 'H-NMR
(CDC13, 300 MHz): 7.63 (m, 4H), 7.43 (m, 6H), 3.92 (m, 2H), 3.67 (m, 1H), 2.17 (m, 2H), 1.83 (m, 2H), 1.60 (s, 3H), 1.54 (s, 9H), 1.34 (s, 3H); '3C-NMR (CDC13, 7~ MHz):
151.9.
131.9-132.1, 131.2, 128.9, 128.8, 94Ø 19.9, 67Ø 57.4, 28.3. 26.7, 22.9.
22.3, 21.8; 3'P-NMR (CDC13, 121 MHz): 16.76 (br).
(S~-2-Phenyl-4-[(diphenvlphosphino)ethylloxazoline (lla).
The protected phosphine (8) (500 mg, 1.17 mmol) was dissolved in 8 ml of methanol and cooled to 0°C. Gaseous HCl was bubbled through the reaction for 5-10 minutes. The methanol was removed under vacuum and the residue was dissolved in 8 ml of 1,2-dichloroethane. Triethylamine (1.5 ml, 9.3 mmol) and benzimidic acid ethyl 1o ester hydrochloride4 (230 mg, 1.24 mmol) were added, and the reaction was refluxed for 6 h. The solvent was removed giving colourless oil, and the crude product was purified by column chromatography on silica gel using ethyl acetate/hexane eluant (2:8 v/v) to afford oxazoline (lla) (210 mg, 0.58 mmol, 50% yield) as a colourless solid.
m.p. 52.5-54°C; Rf 0.76 (ethyl acetate/hexane, 3:7 v/v). 'H-NMR (CDC13, 300 MHz):
7.93 (d, J
= 7 Hz), 7.29-7.49 (m, 13H), 4.34-4.49 (m, 4H), 4.00 (dd, J = 7.5 Hz, J = 7.5 Hz), 2.24-2.34 (m, 2H), 2.07-2.15 (m, 2H), 1.67-1.85 (m, 4H); 13C-NMR (CDCl3, 75 MHz):
163.7, 138.6, 138.3, 132.8, 132.6, 128.6, 128.5-128.2, 127.7, 72.2, 67.5 (d, J= 13.5 Hz), 32.1 (d, J = 16.5 Hz), 24.1 (d, J = I 1.5 Hz); 3' P-NMR (CDC13, 121 MHz): -15.8 I HRMS
(M+ + 1 ) m/z Calcd. for C23Hz3NOP: 360.15170. Found 360. I 5147.
General Procedure for Preparation of Oxazolines (1lb-e).
(~f)-2-Adamantyl-4-[(diphenylphosphino)ethylloxazoline (llb).
The protected phosphine (8) (500 mg, 1.17 mmol) was dissolved in 8 ml of methanol and cooled to 0°C. Gaseous HCl was bubbled through the reaction for 5-10 minutes, and the methanol was removed under vacuum. The residue was dissolved in 8 ml of 1,2-dichloroethane and triethylamine (0.44 ml, 4.lmmol), catalytic 4-dimethylaminopyridine (2 mg), then adamantanecarbonyl chloride (256 mg, 1.28 mmol) were added and reaction was stirred for 12 h. Subsequently, borane-THF (1 M, 2 ml, 2 mmol) was added to the reaction mixture at 0°C, and this was stirred for 10 minutes.
The reaction mixture was diluted with 1 S ml of dichloromethane and washed with HCl,aq~
(0.5 M, 10 ml x 2) and brine (10 ml), dried over Na2S0.~, filtered and concentrated.
1,4-Diazobicyclo[2.2.2]octane (656 mg, 5.85 mmol) and THF (8 ml) were added to this material. The reaction mixture was cooled to 0°C and methanesulphonyl chloride (86Y1, 1.28 mmol) was added. The reaction was stirred at 25°C for 4 h then heated to 50 °C for another 4 h. The resulting slurry was filtered and concentrated at reduced pressure, and the residue was flash chromatographed using ethyl acetate/hexane eluant (2:8 v/v) to give 370 mg (0.89 mmol, 75%) of the product (llb) as an oil. Rf 0.76 (ethyl acetate/hexane, 3:7 v/v)~H-NMR (CDC13, 300 MHz): 7.43-7.48 (m, 4H), 7.34-7.41 (m, 6H), 4.14-4.23 (m, 2H), 3.81 (m, 1H), 2.18-2.24 (m, 1H), 2.03-2.08 (m, 3H), 1.90 (m. 3H), 1.64-1.83 (m, 12H); '3C-NMR (CDC13, .75 MHz): 173.5, 138.6, 138.2. 132.9. 132.7. 132.4, 128.6-128.3, 71.5, 66.4 (d, J = 13.5 Hz), 39.6, 36.5, 35.1, 32.1(d, J = 16.5 Hz), 28.1, 23.6 (d, J = 11.5 Hz); 3'P-NMR (CDC13, 121 MHz): -15.81. HRMS (M+ + 1) m/z Calcd. for C2~H33NOP: 418.22998. Found 418.22583.
(S~-2-tert-Butyl-4-1(diuhenylphosphino)ethvlloxazoline (llc).
This compound was prepared via the same method used for compound (llb), but beginning with 500 mg of (8), 117 mg (0.34 mmol, 30%) of the oxazoline (llc) was produced as colourless oil. Rf 0.68 (ethyl acetate/hexane, 3:7 v/v). 1H-NMR
(CDC13, 300 MHz): 7.78 (s, 2H), 7.38-7.56 (m, 5H), 7.26-7.34 (m, 6H), 4.33-4.47 (m, 2H), 3.97 (t, J= 7 Hz, 1 H), 2.14-2.27 (m, 1 H), 2.04-2.12 (m, 1 H), 1.70-1.84 (m, 1 H), 1.65-1.70 (m, 1H), 1.33 (s, 18H); '3C-NMR (CDC13, 75 MHz): 174.0, 138.6, 138.2, 132.7, 132.4, 132.1, 128.6-128.3, 72.0, 66.6 (d, J = 13.5 Hz), 33.2, 32.1 (d, J = 16.5 Hz), 27.8, 23.6 (d, J= 11.5 Hz); 3'P-NMR (CDC13, 121 MHz): -15.37. HRMS (M+ + 1) mlz Calcd. for C21HZ~NOP 340.18303. Found 340.18281.
(S1-2-(3,5-Di-tert -butylphenyl)-4-1(diphenylphosphino)ethylloxazoline (l ld).
This compound was prepared via the same method used to prepare (llb).
Beginning with 500 mg of (8), 227 mg (0.48 mmol, 41%) of the oxazoline (lld) was produced as colourless oil. Rf 0.77 (ethyl acetate/hexane, 3:7 v/v). ~ H-NMR
(CDC13, 300 MHz): 7.38-7.44 (m, 4H), 7.27-7.37 (m, 6H), 4.21 (m, 1H), 4.12 (m, 1H), 3.80 (dd, J = 6.3 Hz, J = 7.8 Hz), 2.14 (m, 1H), 2.01 (m, 1H), 1.60 (m, 2H), 1.57 (s, 9H); ~3C-NMR (CDC13, 75 MHz): 164.4, 150.9, 138.5. 138.3, 132.9, 132.8. 132.6. 128.7-128.4, 127.0, 125.6. 122.5. 72Ø 67.5 (d. J = 13.5 Hz), 34.9, 32.1 (d, J = 16.5 Hz), 31.4. 24.0 (d, J = 12.0 Hz); 3' P-NMR (CDCl3. 121 MHz): -15.20. HRMS (M+ + 1 ) min Calcd. for C3,H39NOP 472.27693. Found 472.27524 (S1-2-Triphenvlmethvl-4-[(dinhenvlphosphino)ethvlloxazoline (lle).
This compound was prepared via the same method for compound (llb).
Beginning with 500 mg of (8), 191 mg (0.36 mmol, 31%) of the oxazoline (lle) was produced as colourless oil. Rf~ 0.71 (ethyl acetate/hexane, 3:7 v/v). ~H-NMR
(CDC13, 300 MHz): 7.25-7.50 (m. 25H), 4.35 (m, 2H0, 4.02 (m. 1H), 2.21 (m, 1H), 2.10 (m, 1H), 1.77 (m, 2H); '3C-NMR (CDC13, 75 MHz): 169.6, 143.4, 138.4, 138.2. 132.9, 132.6, 132.4, 130.1-126.5, 71.9, 66.8(d, J= 13.5 Hz), 61.4, 31.8 (d, J = 16.5 Hz), 23.7 (d, J = I 1.5 Hz); 3 ~ P-NMR (CDC13, 121 MHz): -15.51.
References:
1. (a) Williams, R.M.; Im, M-N., J. Am. Chem. Soc. 1991, 113, 9276-9286.
(b) Williams, R.M.; Sinclair, P.J.; Zhai, D.; Chen, D., J. Am. Chem. Soc.
1988, 110, 1547-1557.
2. Deaimoni, G.; Dusi, G.; Quadrelli, P.; Righetti, P.. Tetrahedron, 1995, 51, 4144.
3. Ksander, G.M.; de Jesus, R.; Yuan, A.; Ghai, R.D.; Trapani, A.; McMartin, C.;
Bohacek, R., J. Med. Chem. 1997, 40, 495-505.
4. Meyers, A.L; Schmidt, W; McKennon, M.J., Synthesis, 1993, 250-262.
The present invention relates to novel optically active phosphine oxazoline ligands, a process for the preparation thereof, metal complexes containing such novel ligands and the use of such complexes, or combinations of ligand with metal salts or complexes, as catalysts for asymmetric syntheses.
The development of novel catalytic systems exhibiting unique reactivity and high enantioselectivity is of great importance in science and technology. The activity of many pharmaceuticals, agrochemicals, fragrances and food additives are associated with a specific enantiomer. Thus, the ability to produce enantiomerically pure compounds is ~ 5 essential. Many approaches have been explored to acquire such enantiomerically pure compounds, ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Asymmetric catalysis has been found to be one of the most efficient, if not the most efficient method of producing enantiomerically pure compounds since a small amount of a chiral catalyst can be used to produce a large quantity of a chiral compound.
One class of ligands which have played a significant role in the development of chiral catalysts are asymmetric phosphine ligands. Although over 1000 chiral diphosphine ligands have been prepared since the application of the DIPAMP
ligand in the production of L-Dopa, only a few of these have the efficiency and selectivity of commercial applications. Some of the most well known phosphine ligands used include BINAP, BPPM, DEGPHOS, DIOP, Chiraphos, Skewphos, Duphos and BPE all of which acronyms are described by annotated references in e.g. WO 97/47633 and are incorporated herein by reference. However, these ligands have their disadvantages and 3o are not ideal for all applications.
There is still, therefore, the need to develop novel chiral catalysts which are highly enantiomerically selective and carry out the required reaction giving a high yield.
Accordingly. the present invention provides a phosphine oxazoline ligand of formula (I) R~2 4 R; R8 R9 R ~ R
Y~Rt3 I
. -~R7 R~~, I
p r X
~N R
R
wherein mis1,2,3or4;
n, p, q, r are independently zero or I provided that at least one of n, p, q and r is 1;
X is O, S, Se, CH2, NH;
Y is N, P, As, S;
R is H; a straight - chain alkyl group, branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; ferrocenyl; a thioalkyl group; a thioaryl group;
or R is ~ 5 derived from a hydrocarbyl group attached to a functional group of an organic compound or a polymer capable of giving rise to the grouping -N-C-X- in the ring structure of (I);
R' to R'3 are independently selected from H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups;
an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups;
with the proviso that when m is 1, one of n, p, q and r is 1 the remaining three being zero, X is O, Y is P, R~ and R'' are both H, R3 to Rl ~ if present are H, and R'2 and R13 are both phenyl, then R is not CH3, C(CH3)3, CHPhz, CPh3, adamantyl, C6H3(t-Bu)2, ferrocenyl, CF3, Ph, CbH40Me, C6H4Me, C6H4N0~ or C6F5 By the term "alkyl'" we mean a straight. branched or cyclo alkyl group having any number of carbon atoms, for example from 1 to 14 carbon atoms. such as from I to carbon atoms. The cyclo alkyl groups may have one or more rings in its structure e.g.
adamantyl which has a fused tricyclic ring structure.
By the term "aryl'" we mean an aromatic monovalent hydrocarbyl group which include inter alia aryl, alkaryl and aralkyl groups. for example phenyl, benzyl, naphthyl, etc.
to Suitably, m is 1 or 2; preferably 1.
Suitably, at least two of n, p, q and r are 1. the remaining two may be zero or I ;
preferably, two of n, p, q and r are 1, the remaining two are zero.
Suitably, X is O, S, CHz or NH; preferably O.
Suitably, Y is P, N or S; preferably P.
In the above structure, R may be derived from a hydrocarbyl group attached to a 2o functional group of an organic compound or a polymer capable of giving rise to the grouping -N-C-X- in the ring structure of (I). Thus, R may be an alkyl group of a polyacrylic acid, polymethacrylic acid, a polyacrylonitrile or a polyamide, all of which are polymers carrying a function group capable of giving rise to the grouping -N-C-X- in the ring structure of (I).
A first embodiment of the invention provides a compound of formula (IA) Rz Ra Rs R~
R~z Y~ IA
X ~ N i' R
wherein m, X, Y. R. and R' to R' and R' ~ and R' ~ are as hereinbefore defined. provided that when m is 1. X is O. Y is P. R', R'. R'. R~' and R' are H, and R'~ and R'3 are both phenyl. then R is not CH;. C(CH3);. CHPh~. CPh;. adamanty-l. C~H3(t-Bu)~.
ferrocenyl.
CF3. Ph, C6H:~OMe. C~H.~Me. C6H~N0~ or CbF;.
A second embodiment of the invention provides a compound of formula (IB) IB
Ri3 R
wherein m, X, Y, R and R' to R' and R' ~ and R' 3 are as hereinbefore defined.
A third embodiment of the invention provides a compound of formula (IC) Rz Ra Rs Rs R9 R~
/R,z IC
X 3 ~ 'Y
N R6 R~ R»
R
to wherein m, X. Y, R and R' to R9 and R'' and R'3 are as hereinbefore defined.
A fourth embodiment of the invention provides a compound of formula (ID) RZ R4 R; Rs R9 Ii2 R~
ID
YwR~3 X ~ N~3R6 R~ R~ R> >
R
i 5 wherein m, X, Y. R and R' to R' 3 are as hereinbefore defined.
A particularly preferred embodiment of the invention provides a compound of R~ R~ R~ R,, R' Y~
X
the following structure:
O
N /P~Rn R~3 R
wherein R is a C~_.~ alkyl group optionally substituted by one or more groups selected from phenyl and halo; where said substituent group is phenyl it may be optionally further substituted by one to five substituents selected from the group consisting of halo, C»
5 alkyl, C,_4 alkoxy or nitro; ferrocenyl or adamantyl; and R''' and R'3 each of which may be a phenyl or cyclohexyl group.
Particularly preferred compounds include those of the following formulae:
,,, ,,,,,,,, O
' N ph~P~Ph ' N ph~P~Ph Ph t-Bu to (l la) (l lc) (S)-2-Phenyl-4-[(diphenyl- (S)-2-tert Butyl-4-[(diphenyl-phosphino)ethyl]oxazoline phosphino)ethyl]oxazoline O~ '''''''~ 0 Ph~P~Ph ~ N ph~P~Ph t-a (lld) (llb) (S)-2-(3,5-ditertiarybutylphenyl)-4- (S)-2-Adamantyl-4-[(diphenyl-[(diphenylphosphino)ethyl]oxazoline phosphino)ethyl]oxazoline 2o and (S)-2-Triphenylmethyl-4-[(diphenylphosphino)ethyl]oxazoline (1 le) Compounds of formula (I) are novel and accordingly a further aspect of the present invention provides a process for the preparation of a compound of formula (I).
Compounds of formula (I) may be prepared by the reaction of a compound of formula (II) s 4 R; R8 R9 R 1 R.. I
r Y~R> > .BH3 II
p ~3 X ~R~7 Rlqy 1 Pro R~~
R~
wherein m, n, p, q, r, X. Y and R~ to R'3 are as hereinbefore defined; R~'~
and RAs are alkyl groups which may be the same or different and Pro is a nitrogen protecting group, for example a butoxy carbonyl group (hereafter "BOC"), with a compound of formula (III) H.H+.Hal-III
R OR'6 wherein R is as hereinbefore defined. R'6 is an alkyl group, for example ethyl, and Hal is ~ 5 a halide group, for example chloride. The reaction is carried out by the addition of for example gaseous HCI, in the presence of an alcohol, such as methanol to the compound of formula (II), followed by the addition of a compound of formula (III) in the presence of a base, for example triethylamine, in a suitable solvent such as dichloromethane.
20 Compounds of formula (III) are known in the literature (Meyers, A.L;
Schmidt, W; McKennon, M.J., Synthesis, 1993, 250-262).
Compounds of formula (II) may be prepared by the reaction of a compound of formula (IV) R 1 R2 4 R; R8 R9 L
p '~ IV
1(1R11 Pro R»
R~s wherein m, n. p, q, r, X, R~ to R~s and Pro are as hereinbefore defined, and L
is a leaving group, such as e.g tosylate, iodide, triflate or bromide, with a compound of formula s LiYR~2R~3, wherein Y, R~'' and R'3 are as hereinbefore defined. The reaction is carried out in the presence of an organic solvent, such as THF, and with the addition of BH3.
Compounds of formula (IV) may be prepared from the corresponding alcohol of formula (V) 4 Rs R8 R9 OH
p '~ V
N R6 ~~ R1aR11 Pro Ria to R~s wherein m, n, p, q, r, X, R' to R'' and Pro are as hereinbefore defined. The reaction is carried out with a suitable compound to give the desired leaving group, L. For example if the leaving group is tosyl, the reaction is carried out with, e.g. tosyl chloride, in the 15 presence of a base such as e.g. triethylamine, and a suitable solvent, such as e.g. dichloromethane. A catalytic amount of 4-dimethylaminopyridine (DMAP) may also be added.
Compounds of formula (V) are known in the literature (Ksander, G.M.; de 2o Jesus, R.; Yuan, A.; Ghai, R.D.: Trapani, A.; McMartin, C.; Bohacek. R., J.
Med. Chem.
1997, 40, 495-505).
Compounds of formulae (II) and (IV) are also novel and accordingly form a further aspect of the invention.
A yet further aspect of the present invention provides a metal complex containing a ligand of formula (I) comprising a metal and optionally other ligands capable of stabilising the complex, e.g. chloride, acetate etc. Suitably. the metal is a transition metal; for example, the metal may be selected from the group consisting of Ni, Pd, Rh, Ir, Cu, Ag, Au and Zn.
to A metal complex of the present invention may be of use in any chemical reaction requiring an asymmetric catalyst. Examples of such reactions include but are not limited to Heck type reactions, Suzuki type reactions, allylation reactions.
cross-coupling reactions, hydrogenations, hydroformylations and isomerisation reactions.
Therefore, a still further aspect of the invention provides a metal complex of the invention for use in asymmetric catalytic reactions. Alternatively, the invention provides the use of a metal complex of the invention in asymmetric catalytic reactions. Alternatively, there is provided a method for performing an asymmetric catalytic reaction, said method comprising the use of a metal complex of the invention.
2o The metal complex of the invention may be formed in situ from a ligand of formula (I) and a suitable precursor complex or salt of a metal, which is preferably a transition metal as recited above. Therefore, a further aspect of the invention provides for the use of a ligand of formula (I) in combination with a metal complex or salt in asymmetric catalysis.
The invention will now be described by way of example only.
(51-N-tert-butoxvcarbonyl-aspartic acid diethyl ester (3).
Absolute ethanol (420 ml) was cooled in ice and acetyl chloride (71.4 ml, 1.03 mol) was added dropwise to generate HC1 in situ. After the addition, the reaction was stirred for additional 30 minutes. L-Aspartic acid (33.278, 0.25 mol) was added in one portion and the solution heated slowly after dissolution to reflux. Refluxing was continued until the reaction was complete as monitored by thin layer chromatography (TLC). The reaction mixture was then cooled to 25°C and the solvent was removed under reduced pressure. Further drying under vacuum gave crude diethyl L-aspartate hydrochloride (2) as a viscous oil which crystallised on standing to a white solid, yield:
60 g (100%). This material was used without further purification. Spectral data for this sample were consistent with those given in the literature'. '3C NMR (75 MHz, d6-DMSO) 169.1, 168.2, 70.0, 60.9, 48.5, 34.2, 14.9 and 13.9.
1o A sample of the diethyl L-aspartate hydrochloride (2) (57.5 g, 0.273 mol) was dissolved in water (59 ml) and dioxane (149 ml) then cooled to 0°C.
Triethylamine (74 ml, 0.53 mol), then di-tert-butyl dicarbonate (74.99 g, 0.34 mol) were added with stirring. The reaction mixture was then heated at 50°C overnight after which TLC (ethyl acetate-ethanol 1:1 ) indicated complete consumption of the starting material.
The solvent was removed in vacuum, aqueous citric acid (150 ml, 10 %, w/v) added to adjust the pH to 2-3. Diethyl ether (300 ml) was added and the organic phase was separated.
The aqueous phase was extracted with ether (4 x 250 ml), the combined ether extracts washed with brine (100 ml), dried over NazS04, concentrated under vacuum to give (3) (78.8 g, 99 %) as light yellow oil, which can be used without further purification.
2o Spectral data for this sample were consistent with those given in the literature2~ 'H NMR
(300 MHz, CDC13) 5.48 (1 H), 4.49 (m, 1 H), 4.12 (m, 4H), 2.90 (dd, J = 16.8 Hz, J =
4.6 Hz), 2.76 (d, J = 4.88 Hz, 1 H), 1.46 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); '3C NMR (75 MHz, CDC13) 170.9, 170.8, 155.4, 79.8, 61.6, 60.9, 49.9, 36.7, 28.2, 14.0 and 13.9.
(,S~-2-(tert-Butoxycarbonylamino)-1,4-butanediol (4).
A stirred solution of (S~-N-ten-butoxycarbonyl diethyl L-aspartate (3) (47.41 g, 0.16 mol) in absolute ethanol (770 ml) was cooled in ice, then sodium borohydride (60.8 g, 1.6 mol) was added in 10 g portions. The cooling bath was removed when the reaction 3o subsided, and the reaction mixture was heated slowly to reflux for 1 h;
after this time TLC (EtOAc-EtOH 3:1 ) analysis indicated complete consumption of the starting material. The reaction mixture was cooled to 25°C, and the lumps formed were broken-up to give a slurry that was poured into brine (450 ml). The mixture was filtered, the filtrate concentrated in vacuum to ca. 100 ml, and was extracted with ether (6 x 300 ml).
The insoluble solid material was extracted by stirring in ether (4 x 1 L) for 2 h.
5 The combined ether extracts were dried over MgS04, filtered and concentrated to give (4) as a colourless oil (24.4 g, 73%), which crystallised on standing.
Spectral data for this sample were consistent with those given in the literature2. 'H NMR (200 MHz, d6-DMSO) 6.45 (d, J = 8.4 Hz, 1 H), 4.57 (t, J = 5.6 Hz, 1 H), 4.35 (t, J = 5.1 Hz. 1 H), 3.40 (m, 4H), 3.23 (m, 1 H), 1.62 (m, 1 H), 1.40 (m, 1 H), 1.36 (s, 9H); ~ 3C NMR
(50 MHz, d6-to DMSO) 155.5, 77.4, 63.5, 58.0, 49.6, 34.4, 28.3.
(S~-N-tert -butoxycarbonyl-4-(2-hydroxy)ethyl-2,2-dimethyloxazolidine (5).
2,2-Dimethoxypropane (87 ml, 0.707 mol) and p-toluenesulphonic acid monohydrate (1.33 g, 7mmol) were added to a stirred solution of the diol (4) (14.39 g, 70 mmol) in dichloromethane (319 ml) at 25°C. The reaction was monitored by TLC (ethyl acetate-hexanes 2:1 ) until complete (36 h). The reaction mixture was then washed with aqueous NaHC03 (5%, 2 x 50 ml), brine (50 ml), dried (MgS04) and concentrated to form a colourless oil, which crystallised upon standing. The ratio of the desired five-membered ring product (5) to the undesired six-membered ring product (6) was 6.4:3.6.
Recrystallisation from heptane gave (5) as colourless needles (8.2 g, 48%).
Spectral data for this sample were consistent with those given in the literature3. 'H NMR
(200 MHz, CDCl3) 4.17 (m, 1 H), 3.97 (m, 1 H), 3.86-3.42 (m, 3H), 3.33 (br, 1 H), 1.76 (m, 2H), 1.5 (s, 3H), 1.46 (s, 9H); 13C NMR (50 MHz, , CDCl3) 153.9, 93.6, 80.9, 68.2, 58.6, 53.9, 37.7, 27.7, 26.3, 24.3.
(S~-N-tert-butoxvcarbonyl-2,2-dimethyl-4-hvdroxvmethyl-1,3-oxazine (6).
A sample of pure (6) was isolated via flash chromatography using ethyl acetate/hexanes (3:1 v/v) as eluant. ~H NMR (200 MHz, CDC13) 3.37-3.77 (m, SH), 1.62 (m, 2H), 1.35 (s, 9H), 1.24 (s, 3H), 1.22 (s, 3H); 13C NMR (50 MHz, , CDCl3) 155.0, 101.2, 79.1, 63.8, 57.9, 48.5, 35.7, 28.3, 24.7, 24.6.
~S~-2-(tert-Butoxvcarbonvl-4-(4-toluenesulfonvloxvethvl)-2,2-dimethvloxazolidine Dry, freshly crystallised p-toluenesulphonyl chloride (1.86 g, 9.8 mmol) and 4-dimethylaminopyridine ( 10 mg, 0.082 mmol) were added to a solution of alcohol (5) (2.00 g, 8.15 mmol) and triethylamine (2.6 ml, 18.75 mmol) in dichloromethane (20 ml) at 5°C with stirring. The resulting solution was protected from moisture and kept at 5°C
until all the starting material (5) had reacted (33 h, TLC). A colourless solid, presumably triethylamine hydrochloride, crystallised out of the reaction, and was filtered away.
The filtrate was diluted with dichloromethane to a volume of 90 ml, and washed with water (2 x 20 ml), brine (20 ml), dried over Na2S04, and concentrated to give the crude tosylate (7) as white solid. This material was purified by dissolving in ether (ca. 330 ml), filtering through celite 545 on a wad of cotton wool to give 2.95 g (90 %) of (7).
'H NMR (200 MHz, CDC13) 7.78 (m, 2H), 7.35 (d, 2H), 4.09 (m, 2H), 4.09 (m, 2H), 3.90 (m, 2H), 3.73 (m, 1 H), 2.95 (m, 2H), 1.51 (s, 6H), 1.44 (s, 9H).
(S~-N-tert-butoxycarbonyl-4-ethylenediphenylphosphinoborane-2,2-dimethyloxazolidine (8).
n-Butyl lithium in hexanes (1.6 M, 17.1 ml, 27.4 mmol)was added to a solution of diphenylphosphine (4.52g, 24.3 mmol) and THF (100 ml) at 0°C. The orange-red 2o solution was stirred at 0°C for 30 minutes. A solution of tosylate (7) (8.44 g, 21.1 mmol) in THF (60 ml) was then added dropwise to the solution of the diphenylphosphide anion at 0°C. The reaction mixture was stirred for another 30 minutes. Borane-THF complex (1 M, 26 ml, 26 mmol) was added to the solution at 0°C and this was then stirred for an additional 20 minutes. The solvent was removed, and the remaining material was dissolved in ethyl acetate (600 ml) and washed with 1 M HCl~aq~ (100 ml), sat.
NaHC03 (100 ml), brine (100 ml), dried over Na2S04, and filtered. The solvent was removed under reduced pressure. The residue was then purified by column chromatography on silica gel using ethyl acetate/hexane eluant (3:7 v/v) to give 8.1 g (18.9 mmol, 90%) of a colourless oil, which crystallised upon standing at 25°C. m.p. 95.0-96.5°C; Rf 0.81 (ethyl acetate/hexane, 1:1 v/v). This was the protected phosphine (8). 'H-NMR
(CDC13, 300 MHz): 7.63 (m, 4H), 7.43 (m, 6H), 3.92 (m, 2H), 3.67 (m, 1H), 2.17 (m, 2H), 1.83 (m, 2H), 1.60 (s, 3H), 1.54 (s, 9H), 1.34 (s, 3H); '3C-NMR (CDC13, 7~ MHz):
151.9.
131.9-132.1, 131.2, 128.9, 128.8, 94Ø 19.9, 67Ø 57.4, 28.3. 26.7, 22.9.
22.3, 21.8; 3'P-NMR (CDC13, 121 MHz): 16.76 (br).
(S~-2-Phenyl-4-[(diphenvlphosphino)ethylloxazoline (lla).
The protected phosphine (8) (500 mg, 1.17 mmol) was dissolved in 8 ml of methanol and cooled to 0°C. Gaseous HCl was bubbled through the reaction for 5-10 minutes. The methanol was removed under vacuum and the residue was dissolved in 8 ml of 1,2-dichloroethane. Triethylamine (1.5 ml, 9.3 mmol) and benzimidic acid ethyl 1o ester hydrochloride4 (230 mg, 1.24 mmol) were added, and the reaction was refluxed for 6 h. The solvent was removed giving colourless oil, and the crude product was purified by column chromatography on silica gel using ethyl acetate/hexane eluant (2:8 v/v) to afford oxazoline (lla) (210 mg, 0.58 mmol, 50% yield) as a colourless solid.
m.p. 52.5-54°C; Rf 0.76 (ethyl acetate/hexane, 3:7 v/v). 'H-NMR (CDC13, 300 MHz):
7.93 (d, J
= 7 Hz), 7.29-7.49 (m, 13H), 4.34-4.49 (m, 4H), 4.00 (dd, J = 7.5 Hz, J = 7.5 Hz), 2.24-2.34 (m, 2H), 2.07-2.15 (m, 2H), 1.67-1.85 (m, 4H); 13C-NMR (CDCl3, 75 MHz):
163.7, 138.6, 138.3, 132.8, 132.6, 128.6, 128.5-128.2, 127.7, 72.2, 67.5 (d, J= 13.5 Hz), 32.1 (d, J = 16.5 Hz), 24.1 (d, J = I 1.5 Hz); 3' P-NMR (CDC13, 121 MHz): -15.8 I HRMS
(M+ + 1 ) m/z Calcd. for C23Hz3NOP: 360.15170. Found 360. I 5147.
General Procedure for Preparation of Oxazolines (1lb-e).
(~f)-2-Adamantyl-4-[(diphenylphosphino)ethylloxazoline (llb).
The protected phosphine (8) (500 mg, 1.17 mmol) was dissolved in 8 ml of methanol and cooled to 0°C. Gaseous HCl was bubbled through the reaction for 5-10 minutes, and the methanol was removed under vacuum. The residue was dissolved in 8 ml of 1,2-dichloroethane and triethylamine (0.44 ml, 4.lmmol), catalytic 4-dimethylaminopyridine (2 mg), then adamantanecarbonyl chloride (256 mg, 1.28 mmol) were added and reaction was stirred for 12 h. Subsequently, borane-THF (1 M, 2 ml, 2 mmol) was added to the reaction mixture at 0°C, and this was stirred for 10 minutes.
The reaction mixture was diluted with 1 S ml of dichloromethane and washed with HCl,aq~
(0.5 M, 10 ml x 2) and brine (10 ml), dried over Na2S0.~, filtered and concentrated.
1,4-Diazobicyclo[2.2.2]octane (656 mg, 5.85 mmol) and THF (8 ml) were added to this material. The reaction mixture was cooled to 0°C and methanesulphonyl chloride (86Y1, 1.28 mmol) was added. The reaction was stirred at 25°C for 4 h then heated to 50 °C for another 4 h. The resulting slurry was filtered and concentrated at reduced pressure, and the residue was flash chromatographed using ethyl acetate/hexane eluant (2:8 v/v) to give 370 mg (0.89 mmol, 75%) of the product (llb) as an oil. Rf 0.76 (ethyl acetate/hexane, 3:7 v/v)~H-NMR (CDC13, 300 MHz): 7.43-7.48 (m, 4H), 7.34-7.41 (m, 6H), 4.14-4.23 (m, 2H), 3.81 (m, 1H), 2.18-2.24 (m, 1H), 2.03-2.08 (m, 3H), 1.90 (m. 3H), 1.64-1.83 (m, 12H); '3C-NMR (CDC13, .75 MHz): 173.5, 138.6, 138.2. 132.9. 132.7. 132.4, 128.6-128.3, 71.5, 66.4 (d, J = 13.5 Hz), 39.6, 36.5, 35.1, 32.1(d, J = 16.5 Hz), 28.1, 23.6 (d, J = 11.5 Hz); 3'P-NMR (CDC13, 121 MHz): -15.81. HRMS (M+ + 1) m/z Calcd. for C2~H33NOP: 418.22998. Found 418.22583.
(S~-2-tert-Butyl-4-1(diuhenylphosphino)ethvlloxazoline (llc).
This compound was prepared via the same method used for compound (llb), but beginning with 500 mg of (8), 117 mg (0.34 mmol, 30%) of the oxazoline (llc) was produced as colourless oil. Rf 0.68 (ethyl acetate/hexane, 3:7 v/v). 1H-NMR
(CDC13, 300 MHz): 7.78 (s, 2H), 7.38-7.56 (m, 5H), 7.26-7.34 (m, 6H), 4.33-4.47 (m, 2H), 3.97 (t, J= 7 Hz, 1 H), 2.14-2.27 (m, 1 H), 2.04-2.12 (m, 1 H), 1.70-1.84 (m, 1 H), 1.65-1.70 (m, 1H), 1.33 (s, 18H); '3C-NMR (CDC13, 75 MHz): 174.0, 138.6, 138.2, 132.7, 132.4, 132.1, 128.6-128.3, 72.0, 66.6 (d, J = 13.5 Hz), 33.2, 32.1 (d, J = 16.5 Hz), 27.8, 23.6 (d, J= 11.5 Hz); 3'P-NMR (CDC13, 121 MHz): -15.37. HRMS (M+ + 1) mlz Calcd. for C21HZ~NOP 340.18303. Found 340.18281.
(S1-2-(3,5-Di-tert -butylphenyl)-4-1(diphenylphosphino)ethylloxazoline (l ld).
This compound was prepared via the same method used to prepare (llb).
Beginning with 500 mg of (8), 227 mg (0.48 mmol, 41%) of the oxazoline (lld) was produced as colourless oil. Rf 0.77 (ethyl acetate/hexane, 3:7 v/v). ~ H-NMR
(CDC13, 300 MHz): 7.38-7.44 (m, 4H), 7.27-7.37 (m, 6H), 4.21 (m, 1H), 4.12 (m, 1H), 3.80 (dd, J = 6.3 Hz, J = 7.8 Hz), 2.14 (m, 1H), 2.01 (m, 1H), 1.60 (m, 2H), 1.57 (s, 9H); ~3C-NMR (CDC13, 75 MHz): 164.4, 150.9, 138.5. 138.3, 132.9, 132.8. 132.6. 128.7-128.4, 127.0, 125.6. 122.5. 72Ø 67.5 (d. J = 13.5 Hz), 34.9, 32.1 (d, J = 16.5 Hz), 31.4. 24.0 (d, J = 12.0 Hz); 3' P-NMR (CDCl3. 121 MHz): -15.20. HRMS (M+ + 1 ) min Calcd. for C3,H39NOP 472.27693. Found 472.27524 (S1-2-Triphenvlmethvl-4-[(dinhenvlphosphino)ethvlloxazoline (lle).
This compound was prepared via the same method for compound (llb).
Beginning with 500 mg of (8), 191 mg (0.36 mmol, 31%) of the oxazoline (lle) was produced as colourless oil. Rf~ 0.71 (ethyl acetate/hexane, 3:7 v/v). ~H-NMR
(CDC13, 300 MHz): 7.25-7.50 (m. 25H), 4.35 (m, 2H0, 4.02 (m. 1H), 2.21 (m, 1H), 2.10 (m, 1H), 1.77 (m, 2H); '3C-NMR (CDC13, 75 MHz): 169.6, 143.4, 138.4, 138.2. 132.9, 132.6, 132.4, 130.1-126.5, 71.9, 66.8(d, J= 13.5 Hz), 61.4, 31.8 (d, J = 16.5 Hz), 23.7 (d, J = I 1.5 Hz); 3 ~ P-NMR (CDC13, 121 MHz): -15.51.
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1988, 110, 1547-1557.
2. Deaimoni, G.; Dusi, G.; Quadrelli, P.; Righetti, P.. Tetrahedron, 1995, 51, 4144.
3. Ksander, G.M.; de Jesus, R.; Yuan, A.; Ghai, R.D.; Trapani, A.; McMartin, C.;
Bohacek, R., J. Med. Chem. 1997, 40, 495-505.
4. Meyers, A.L; Schmidt, W; McKennon, M.J., Synthesis, 1993, 250-262.
Claims (22)
1. A compound of formula (I) wherein m is 1, 2, 3 or 4;
n, p, q, r are independently zero or 1 provided that at least two of n, p, q and r are 1;
X is O; S, Se, CH2, NH;
Y is N, P, As, S;
R is H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group opdonally substituted by one or mere groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; ferrocenyl; a thioalkyl group; a thioaryl group;
or R is a polymeric structure wherein the functional groups of the polymer are capable of reacting to produce the N-C-X- grouping in the ring structure of (I);and R1 to R13 are independently selected from H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group opdonally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups.
n, p, q, r are independently zero or 1 provided that at least two of n, p, q and r are 1;
X is O; S, Se, CH2, NH;
Y is N, P, As, S;
R is H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group opdonally substituted by one or mere groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; ferrocenyl; a thioalkyl group; a thioaryl group;
or R is a polymeric structure wherein the functional groups of the polymer are capable of reacting to produce the N-C-X- grouping in the ring structure of (I);and R1 to R13 are independently selected from H; a straight-chain alkyl group, a branched-chain alkyl group or a cyclo alkyl group opdonally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups; an aryl group optionally substituted by one or more groups independently selected from alkyl, aryl, halo, alkoxy, amine, phosphine and ether groups.
2. A compound according to claim 1, wherein m is 1 or 2.
3. A compound according to claims 1 or 2, wherein X is O, S, CH2 or NH.
4. A compound according to claim 3 wherein X is O.
5. A compound according to any one of claims 1 to 4 wherein Y is P, N or S.
6. A compound according to claim 5 wherein Y is P.
7. A compound according to any one of the preceding claims wherein the group R
is a polymeric structure wherein the functional groups of the polymer are capable of reacting to product the -N-C-X- grouping in the ring structure of (I), said polymeric structure being selected from the group polyacrylic acid, polymethacrylic acid, polyacrylonitrile and polyamide.
is a polymeric structure wherein the functional groups of the polymer are capable of reacting to product the -N-C-X- grouping in the ring structure of (I), said polymeric structure being selected from the group polyacrylic acid, polymethacrylic acid, polyacrylonitrile and polyamide.
8. A compound according to claim 1 which is a compound of formula (IB) wherein m, X, Y, R1 and R7 to R12 and R13 and R13 are as defined in claim 1.
9. A compound according to claim 1 which is a compound of formula (IC) wherein m, X, Y, R and R1 to R9 and R12 and R13 are as defined in claim 1.
10. A compound according to claim 1 which is a compound of formula (ID) wherein m, X, Y, R and R1 to R13 are as defined in claim 1.
11. A compound according to claim 1 which is a compound of structure wherein R is a C1-4 alkyl group optionally substituted. by one or more groups selected from phenyl and halo; where said substituent group is phenyl it may be optionally further substituted by one to five substituents selected from the group consisting of halo, C1-4 alkyl, C1-4 alkoxy or vitro; ferrocenyl or adamantyl; end R12 and R13 each of which may be a phenyl or a cyolohexyl group.
12. A, compound according to claim 1 which is a compound selected from the group consisting of:
and (S)-2-Triphenylmethyl-4-[(diphenylphosphino)ethyl]oxazoline (11e)
and (S)-2-Triphenylmethyl-4-[(diphenylphosphino)ethyl]oxazoline (11e)
13. A process for the preparation of a compound of formula (1) according to claim 1, said process comprising the reaction of a compound of formula (II) wherein m, n, p, q, r, X, Y and R1 to R13 arc as defined in claim 1; R14 and R15 are alkyl groups which may be the same of different and Pro is a nitrogen protecting group, with a compound of formula (III) wherein R is as defined in claim 1, R16 is an alkyl group, and Hal is a halide group.
14. A metal complex containing a compound according to any one of the claims 1 to 12 comprising a metal and optionally other ligands capable of stabilising the complex.
15. A complex according to claim 14 wherein the metal is a transition metal.
16. A complex according to claim 15 wherein the metal is selected from the group consisting of Ni, Pd, Rh, Ir, Cu, Ag, Au and Zn.
17. A metal complex according to any one of claims 14 to 16 for use in asymmetric catalytic reactions.
18. The use of a metal complex according to any one of claims 14 to 16 in asymmetric catalytic reactions.
19. The use of a compound according to any one of claims 1 to 12 in combination with known metal complexes or salts in asymmetric catalysis.
20. A method for performing as asymmetric catalytic reaction, composing the use of a metal complex according to any one of claims 14 to 16.
21. An intermediate of formula (II) wherein in, n, p, q, r, X, Y and R1 to R13 are as defined in claim 1; R14 and R15 are alkyl groups which may be the same of different and Pro is a nitrogen protecting group.
22. An intermediate of formula (IV) wherein m, n, p, q, r, X, R1 to R15 are as defined in claim 1, Pro is a nitrogen protecting group, and L is a suitable having group.
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GBGB9907895.8A GB9907895D0 (en) | 1999-04-08 | 1999-04-08 | Novel ligands for chiral catalysis |
GB9907895.8 | 1999-04-08 | ||
PCT/GB2000/000758 WO2000061589A1 (en) | 1999-04-08 | 2000-03-03 | Novel ligands for chiral catalysis |
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EP (1) | EP1165574A1 (en) |
JP (1) | JP2002541262A (en) |
CN (1) | CN1353718A (en) |
AU (1) | AU2925300A (en) |
CA (1) | CA2369043A1 (en) |
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WO (1) | WO2000061589A1 (en) |
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DE60110516T2 (en) | 2000-09-21 | 2005-10-13 | Solvias Ag | Phosphinite oxazolines and metal complexes |
CN1314673C (en) * | 2002-07-02 | 2007-05-09 | 中国科学院上海有机化学研究所 | Multidentate oxazoline ligand having chirality and its compounding product with main group metal or transition metal, synthesis method and its use |
CN102744106B (en) * | 2012-07-27 | 2014-08-06 | 山东师范大学 | Palladium catalyst for catalyzing Suzuki coupling reaction, synthesis method, application and ligand |
CN106588987B (en) * | 2016-11-30 | 2019-09-24 | 上海师范大学 | A kind of chirality oxazoline class NNP type ligand and its synthetic method and application |
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JPH0761992B2 (en) * | 1987-02-06 | 1995-07-05 | 武田薬品工業株式会社 | Substituted amine derivative |
US4902684A (en) * | 1988-06-20 | 1990-02-20 | E. R. Squibb & Sons, Inc. | Benzazepine and benzothiazepine derivatives |
US4963671A (en) * | 1989-11-20 | 1990-10-16 | E. R. Squibb & Sons, Inc. | Process for resolving chiral intermediates used in making calcium channel blockers |
JPH08503195A (en) * | 1992-11-05 | 1996-04-09 | ドンペー ファルマツエウティチイ エッセ.ペー.アー. | Tartronic acids, their acetalic ethers and O-esters |
DE4243030A1 (en) * | 1992-12-18 | 1994-06-23 | Basf Ag | New cyclic imine derivs useful as ligands |
GB9612884D0 (en) * | 1996-06-20 | 1996-08-21 | Smithkline Beecham Plc | Novel compounds |
AU7473398A (en) * | 1997-05-07 | 1998-11-27 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
-
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- 2000-03-03 CN CN 00808503 patent/CN1353718A/en active Pending
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AU2925300A (en) | 2000-11-14 |
GB9907895D0 (en) | 1999-06-02 |
EP1165574A1 (en) | 2002-01-02 |
CN1353718A (en) | 2002-06-12 |
WO2000061589A1 (en) | 2000-10-19 |
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