WO2009030626A1 - New phosphine-phosphite ligands - Google Patents
New phosphine-phosphite ligands Download PDFInfo
- Publication number
- WO2009030626A1 WO2009030626A1 PCT/EP2008/061264 EP2008061264W WO2009030626A1 WO 2009030626 A1 WO2009030626 A1 WO 2009030626A1 EP 2008061264 W EP2008061264 W EP 2008061264W WO 2009030626 A1 WO2009030626 A1 WO 2009030626A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- alkyl
- independently selected
- optionally substituted
- ring system
- Prior art date
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- 239000003446 ligand Substances 0.000 title abstract description 27
- ZOGYOOUMDVKYLM-UHFFFAOYSA-N phosphane phosphorous acid Chemical compound P.OP(O)O ZOGYOOUMDVKYLM-UHFFFAOYSA-N 0.000 title abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 26
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims abstract description 21
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 85
- 150000001875 compounds Chemical class 0.000 claims description 64
- -1 nitro, hydroxyl Chemical group 0.000 claims description 64
- 125000004122 cyclic group Chemical group 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 239000010948 rhodium Substances 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 125000004429 atom Chemical group 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- PKAUJJPTOIWMDM-UHFFFAOYSA-N 3h-dioxaphosphepine Chemical compound C=1C=CPOOC=1 PKAUJJPTOIWMDM-UHFFFAOYSA-N 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 229920006395 saturated elastomer Polymers 0.000 claims description 13
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 11
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 claims description 9
- 229910052703 rhodium Inorganic materials 0.000 claims description 9
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 9
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 7
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical group OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 150000001993 dienes Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 150000003283 rhodium Chemical class 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 4
- 125000002971 oxazolyl group Chemical group 0.000 claims description 4
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 150000001252 acrylic acid derivatives Chemical class 0.000 claims description 3
- 150000001805 chlorine compounds Chemical group 0.000 claims description 3
- 150000002081 enamines Chemical class 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- NASRDENTZCCAPN-UHFFFAOYSA-N OC([Na])=O Chemical compound OC([Na])=O NASRDENTZCCAPN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004437 phosphorous atom Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000000243 solution Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical class PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- DQTRYXANLKJLPK-UHFFFAOYSA-N chlorophosphonous acid Chemical compound OP(O)Cl DQTRYXANLKJLPK-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 0 *CC(C**)O*(O*)ON Chemical compound *CC(C**)O*(O*)ON 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- ZNINJKVULVRHHX-UHFFFAOYSA-N B.OP Chemical class B.OP ZNINJKVULVRHHX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000004593 Epoxy Substances 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- USKHBABPFFAKJD-FLIBITNWSA-N methyl (z)-2-acetamido-3-phenylprop-2-enoate Chemical compound COC(=O)C(\NC(C)=O)=C\C1=CC=CC=C1 USKHBABPFFAKJD-FLIBITNWSA-N 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 238000005598 Sharpless reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
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- 150000001295 alanines Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
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- 150000001413 amino acids Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 1
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- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- BWJRMVLPCQPWGR-UHFFFAOYSA-N boron;phosphane Chemical compound [B].P BWJRMVLPCQPWGR-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000005356 chiral GC Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000006001 difluoroethyl group Chemical group 0.000 description 1
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- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 125000005816 fluoropropyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- FCLYZQXPJKJTDR-UHFFFAOYSA-N potassium;diphenylphosphanide Chemical compound C=1C=CC=CC=1P([K])C1=CC=CC=C1 FCLYZQXPJKJTDR-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
Definitions
- the present invention relates to a re-usable and highly stable catalyst which exhibits high reactivity, stability and enantioselectivity for asymmetric hydrogenation of functional ized olefins. More specifically, the present invention relates to a catalyst which comprises a metal complex of an stereoisomerically enriched ligand. This invention also relates to the ligand, a preparation process thereof, as well as the preparation process of the catalyst complex and their use for asymmetric hydrogenation reactions.
- Asymmetric catalysis is the most efficient method for generating products having high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in the generation of the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals.
- the asymmetric catalysts employed can be enzymatic or synthetic in nature.
- asymmetric hydrogenation reactions are used in a wide variety of chemical processes, in particular in the manufacture of pharmaceutical intermediates.
- a high reaction rate and enantioselectivity are attainable by appropriate molecular architecture of the catalysts and suitable selection of reaction conditions.
- Highly enantioselective hydrogenation was achieved mostly with substrates that have a functionality close to the unsaturated moiety and by use of Rh(I) or Ru(II) complexes that have a chiral diphosphine ligand.
- One of the problems associated with asymmetric hydrogenation reactions in general, is to maximize the enantiomeric excess of the desired asymmetrically hydrogenated product over its unwanted enantiomer.
- a suitable combination of a metal species and chiral organic ligand is the key factor to prepare high-performance catalysts for asymmetric hydrogenation. Modulation of the electronic and steric properties of the different modules of a catalyst, allows improving the enantioselectivity in asymmetric reactions (Rajanbabu et al. Advances in Catalytic Processes, 1997, 2 (Asymmetric Catalysis), 1 -41 ; Vidal-Ferran et al. J. Org. Chem. 1997 4970). The disadvantage of most of the currently known ligands is that only limited substitution opportunities are available for varying their electronic and steric properties.
- the new catalysts of the invention are rhodium complexes of phosphine-phosphite ligands.
- the catalysts of the invention show a high purity and a high enantioselectivity for the asymmetric hydrogenation of unsaturated hydrocarbon compounds. Furthermore, the catalysts of the invention are stable, and maintain its activity during a long time.
- the new ligands of the invention have great substitution opportunities available for varying their electronic and steric properties.
- the invention provides an stereoisomehcally pure compound of formula I, or a salt thereof, or a N-oxide thereof, or a solvate thereof,
- the wavy line means any of the two possible configurations of the attached stereogenic atom
- R-I, R2, R3, R 4 , R5 and R 6 are independently selected from the group consisting of hydrogen, linear or branched (C-i-C-i 2 )alkyl optionally substituted, (C 2 -C- ⁇ 2 )alkenyl optionally substituted, (C 2 -C- ⁇ 2 )alkynyl optionally substituted, and a radical derived from one of the known ring systems with 1 -4 rings, wherein each one of the rings forming said ring system has 3-7 members, each member independently selected from P, C, N, O, S, CH, CH 2 , NH, is saturated, partially unsaturated or aromatic, and is partially/totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; optionally, Ri and R 2 taken together with the atoms to which they are attached, and/or R 3 and R 4 taken together with the phosphorus atom to which they are attached, form one of the known ring systems with 1 -7
- R 7 and R 8 are independently selected from the group consisting of H and (Ci-Ci 2 )alkyl;
- R 9 is selected from the group consisting of H, (Ci-C- ⁇ 2 )alkyl, sodium and potassium.
- alkyl, alkenyl and alkynyl can be substituted by one or more substituents selected from the one mentioned above. Generally, if present, the number of substituents is between 1 and 6.
- the invention provides a catalyst, comprising a rhodium complex of a compound according to the first aspect of the invention as ligand.
- the catalyst of the invention is obtainable by reaction of a compound according to the first aspect of the invention and a rhodium salt or a rhodium precursor-complex selected from the group consisting of RhA 3 , RhBC 2 , L 3 [RhD 4 ], and [RhE 2 ]F; wherein
- A is chloride, bromide, iodide, acetate, nitrate, methanesulfonate, triflate, sulfonate, p-toluensulfonate, or acetyl-acetonate
- B is chloride, bromide, acetate, methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenylborate;
- C is a linear or branched (C 2 -d 2 )alkene or (C 4 -d 2 )alkadiene;
- L is lithium, sodium, potassium, ammonium, tetra((Ci-C 6 )alkyl)ammonium
- D is chloride or bromide
- E is a (C 4 -C- ⁇ 2 )alkadiene
- F is methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenyl borate.
- the invention provides a method for preparing the catalyst which comprises: reacting in a appropriate solvent a rhodium salt or a rhodium precursor- complex selected from the group consisting of RhA 3 , RhBC 2 , L 3 [RhD 4 ], and [RhE 2 ]F, as defined above, with a compound according to the first aspect of the invention.
- the invention provides the use of the compound as defined in the second aspect of the invention, as catalyst for the asymmetric hydrogenation reaction of unsaturated hydrocarbon compounds.
- the invention provides a process for the asymmetric hydrogenation of unsaturated hydrocarbon compounds, which comprises contacting an unsaturated hydrocarbon compound with the catalyst of the invention and hydrogen under appropriate conditions of hydrogenation.
- the present invention relates to a compound of formula I,
- the compounds of formula I are useful as ligands for the preparation of catalyst for the asymmetric hydrogenation of unsaturated hydrocarbon compounds.
- R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, and an optionally substituted radical selected from linear or branched (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, naphtyl, oxazolyl, benzofuranyl, dibenzofuranyl, furanyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl; being the substituents
- R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, (Ci-C 4 )alkyl-tri-(d-C 6 )alkyl-siloxyl, phenyl, naphtyl, propynyl, triazolylmethyl, phenylmethyl, phenylethyl, diphenylmethyl, and trityl.
- the compounds of formula I are those wherein R 3 and R 4 are independently selected from the group consisting of tert-butyl, phenyl, propynyl, triazolylmethyl, phenylmethyl, phenylethyl and trityl.
- the compounds of formula I are those wherein R 5 and R 6 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trityl, triazolylmethyl, propynyl, diphenylmethyl, phenylmethyl, phenyl and propyl-triethyl-siloxyl.
- R 3 and R 4 are simultaneously selected from tert-butyl and phenyl, and R 5 and R 6 are independently selected from the group consisting of methyl, trityl, triazolylmethyl, propynyl and phenyl.
- R 1 and R 2 are independently selected from the group consisting of an optionally substituted radical selected from a linear or branched (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, naphtyl, oxazolyl, benzofuranyl, dibenzofuranyl, furanyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and indolyl; or R 1 and R 2 taken together with the atoms to
- R 1 and R 2 are independently selected from the group consisting of an optionally substituted radical selected from phenyl, trityl, naphtyl, tert-butyl, propynyl, and triazolylmethyl; or R 1 and R 2 taken together with the atoms to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,
- C, N, O, S, CH, CH 2 , NH is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; being R 1 and R 2 optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, hydroxyl, hydroxy protecting-groups, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, (CrC 6 )alkylazolyl, tri-(CrC6)alkyl-siloxyl, (C r C 4 )alkoxy, -COR 7 , -COOR 9 , -OC(O)R 7 , -R 7 PO(OR 7 ) 2 , -S-R 7 , -SO-R 7 , -SO 2 -R 9 , and -SO 3 R 9 .
- R 1 and R 2 taken together with the atoms to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P, C, N, O, S, CH, CH 2 , NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents.
- R 1 and R 2 taken together with the atoms to which they are attached, form a ring system selected from the group consisting of:
- a and B are independently selected from the group consisting of one of the known ring systems with 1 -3 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,
- C, N, O, S, CH, CH 2 , NH is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; and the dotted line represents the presence or absence of a double bond.
- the molecule may have free or restricted rotation.
- Preferred examples of compounds with L 4 ring systems are those of formula L 4 -I and L 4 -2:
- preferred compounds of the invention are those selected from the group consisting of the racemic mixture of the two possible stereoisomers around the biarylic moiety, the substantially pure L 4 -P stereoisomer, the substantially pure L 4 -M stereoisomer, and mixtures thereof.
- the present invention also encompasses other possible rings system with free or restricted rotation, not only those represented above (L 4 -I and L 4 -2).
- L 4 -I and L 4 -2 The above mentioned examples are provided by way of illustration, and are not intended to be limiting of the present invention.
- the catalyst of the present invention has at least two optical centers and to thus form stereoisomers. All optical isomers are part of the present invention and are thus encompassed by the scope of the claims.
- the wavy line means any of the two possible configurations of the attached stereogenic atom.
- the compounds of the invention can be prepared in various ways. They can be prepared by using the methods described below, together with methods known in the field of organic chemical synthesis, or by the variations that might be made thereto by an expert in the subject. Preferred methods include, but are not limited to, those described below.
- the reactions are carried out in the solvents appropriate for the reagents and materials used and suited for the transformations carried out. Moreover, in some of the procedures described below it may be desirable or necessary to protect the reagent functional groups present in the compounds or intermediates of this invention with conventional protecting groups.
- Various protecting groups and procedures for introducing them and removing them are described in Greene and Wuts (Protective Groups in Organic Synthesis, Wiley and Sons, 1999).
- the inversion of the configuration at the hydroxyl carbon can be carried out by a Mitsunobu inversion (e.g. PPh3, DEAD, Ar-COOH) followed by a reduction (e.g. DIBAL-H) (Mitsunobu Synthesis 1981 , 1 -28; and Vidal-Ferran et al. J. Org. Chem. 1997, 4970-4982).
- the molecule may have free or restricted rotation.
- the epoxy intermediates can be obtained by an asymmetric Sharpless reaction, c.f. Sharpless et al. J. Am. Chem. Soc. 1987, 5765-5780; Vidal- Ferran et al. J. Org. Chem. 1997, 4970.
- chloro-phosphite intermediates are known in the art, and may be obtained as described in J. MoI. Cat. A 2000, 164, 125-130 and J. Organomet. Chem. 1996, 520, 45-58; those not known can be prepared anagously from the appropriate starting materials.
- KPR 3 R 4 intermediates are known in the art, and may be obtained as described in Power et al. Inorg. Chem. 1987, 1941 -1946; Mintz et al. J. Org. Chem 1988, 4417-4419; Bakos et al. Tetrahedron Asymm. 2004; 1673-1676;
- the catalyst of the invention which is useful for the asymmetric hydrogenation of unsaturated hydrocarbon compounds, comprises a rhodium complex of a compound according to the first aspect of the invention as ligand.
- the catalyst of the invention is obtainable by reaction of a compound according to the first aspect of the invention and a rhodium salt or a rhodium precursor-complex selected from the group consisting of RhA 3 , RhBC 2 , L 3 [RhD 4 ], and [RhE 2 ]F; wherein A, B, C, L, D, E and F are as defined above.
- the invention provides a catalyst which is selected from the group consisting of: [Rh(X)HaI] 2 ; [Rh(COd)X]Y; and
- Hal is selected from the group consisting of chloride, bromide and iodide
- X is a compound as defined in the first aspect of the invention; (cod) is 1 ,5-cyclooctadiene; (nbd) is norbornadiene; and
- Y is selected from the group consisting of metanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, and tetraphenylborate.
- the catalyst of the invention is useful for the asymmetric hydrogenation reactions of unsaturated hydrocarbon compounds.
- the catalysts of the present invention are useful in the asymmetric hydrogenation of functionalized olefins, particularly enamides, acrylic acid derivatives, enamines, alkenyl esters, alkenyl ethers, ⁇ , ⁇ - and ⁇ , ⁇ - unsaturated carboxylic acids, ⁇ , ⁇ -unsaturated esters, ⁇ , ⁇ -unsaturated amides, ⁇ , ⁇ -unsaturated aldehydes, ⁇ , ⁇ -unsaturated ketones, allylic and homoallylic alcohols.
- functionalized olefins particularly enamides, acrylic acid derivatives, enamines, alkenyl esters, alkenyl ethers, ⁇ , ⁇ - and ⁇ , ⁇ - unsaturated carboxylic acids, ⁇ , ⁇ -unsaturated esters, ⁇ , ⁇ -unsaturated amides, ⁇ , ⁇ -unsaturated aldehydes, ⁇ , ⁇ -unsaturated ketones, allylic and
- unsaturated hydrocarbon compound is an acrylic acid derivative or an enamine derivative.
- the unsaturated hydrocarbon compound has the formula II:
- R-io, R-I-I, R-I2 and Ri 3 are independently selected from the group consisting of hydrogen, linear or branched (C- ⁇ -C- ⁇ 2 )alkyl optionally substituted, (C 2 -C- ⁇ 2 )alkenyl optionally substituted, (C 2 -d 2 )alkynyl optionally substituted, COORi 4 , NRi 4 Ri5, and phenyl optionally substituted; the substituents being a radical independently selected from the group consisting of: halogen, nitro, hydroxyl, cyano, amino, (Ci-Ci 2 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (d-C 6 )alkylazolyl, (d-C 4 )alkoxy, -CORi 4 , -COOR 14 , -OC(O)R 14 , -C(O)NR 14 R 15 , -
- R 9 , R 10 , R 11 and R 12 is a COOR 14 or NR 14 R 15 radical.
- the unsaturated hydrocarbon is selected from the group consisting of:
- the hydrogenation is carried out at a temperature between -60 0 C and 100 0 C. Preferably between -40 0 C and room temperature.
- the catalyst of the invention may be properly used in the preparation of enantiomerically enriched aminoacids.
- the catalyst of the present invention may be used in the preparation of enantiomerically enriched alanines which could be protected, e.g. with a Cbz, Boc or Fmoc protecting group.
- the catalyst of the invention may be properly used in the preparation of Fmoc derivatives by hydrogenation in an easy way instead of the known prior art methods.
- the catalysts of the invention show high conversion and enantioselectivity in the asymmetric hydrogenation of unsaturated hydrocarbon compounds. (conversion > 99%, enantioselectivity 80-99%).
- pharmaceutically acceptable salt used herein encompasses any salt formed from organic and inorganic acids, such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1 ,5-naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic, tartaric acids and the like.
- organic and inorganic acids such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, male
- protecting group refers to a chemical moiety or group which protects or prevents an active moiety or group from participating with or interfering with one or more chemical synthetic steps and its removal restores the moiety to its original active state.
- protecting group refers to those groups intended to protect against undesirable reactions during synthetic procedures. Such protecting groups are well known to those skilled in the art. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry” (Wiley, 2nd ed. 1991 ), McOmie et al. "Protective Groups in Organic Chemistry” (Plenam Press, New York, 1973), and Harrison et al, “Compendium of Synthetic Organic Methods", VoIs.
- Protecting groups can be removed with inter alia acid, base, fluoride ions, hydrogenation, metals such as zinc as well as by numerous other methods which are well known in the art.
- One of ordinary skill in the art can readily choose an appropriate protecting group to facilitate synthetic reactions according to methodological aspects of the present invention without engaging in undue experimentation.
- stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
- enantiomers refers to two stereoisomers of a compound which are non supehmposable mirror images of one another.
- diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
- a “stereoselective process” is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product.
- An “enantioselective process” is one which favors production of one of the two possible enantiomers of a reaction product.
- the "enantiomerically pure” means a compound with enough enantiomeric excess for its preparation to industrial scale, which depends on each particular case as it would be decided by the person skilled in the art. For most purposes, a enantiomeric excess higher than 95% is enough.
- enantiomerically pure is meant to indicate the ee of the catalyst, such ee is preferably higher than 99%.
- solvent is used to describe a medium typically, but not necessarily inert in which a reaction takes place using the organocatalyst according to the present invention.
- Solvents may include polar and non-polar solvents, including, for example, H 2 O, pyridine, triethanolamine, tetrahydrofuran (THF), 1 ,4-dioxane, dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), dichloromethane (DCM), nitromethane, chloroform, methanol, ethanol, isopropanol, N-methylpyrrolidone (NMP), ethylacetate, benzene, hexane, heptane, toluene, acetonitrile, etc. and mixtures thereof.
- NMP N-methylpyrrolidone
- asymmetric reactions catalyzed by the catalyst of the invention takes place using DCM, THF, hexane
- an (d-C 6 )alkyl group is taken to mean a lineal or branched alkyl group which contains up to 6 atoms of carbon. Thus it includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, and hexyl.
- an (Ci-C 6 )alkoxy group refers to a saturated branched or linear hydrocarbon chain with 1 to 6 hydrocarbon atoms (i.e.
- (Ci-C 6 )alkoxy includes, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy group.
- An (C 2 -C 6 )alkenyl group includes, for example, a vinyl, allyl, propenyl and 1 -butenyl, 2-butenyl and 3-butenyl group.
- a (d-C 6 )haloalkyl group means an (d-C 6 )alkyl group substituted by one or more atoms of halogen, the same or different. It thus includes, for example, chloromethyl, fluoromethyl, thfluoromethyl, chloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, chloropropyl, etc.
- a (Ci-C 6 )haloalkoxy group means an (d-C 6 )alkoxy group substituted by one or more atoms of halogen, the same or different.
- chloromethoxy includes, for example, chloromethoxy, fluoromethoxy, thfluoromethoxy, chloroethoxy, fluoroethoxy, difluoroethoxy, thfluoroethoxy, fluoropropoxy, chloropropoxy, etc.
- halogen is meant to include fluorine, chlorine, bromine and iodine.
- aryl alone or in combination with other groups, means a radical derived from one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 3-7 members, each member independently selected from C, N, O, S 1 CH 1 CH 2 1 NH, is partially unsaturated or aromatic, and is partially/totally fused; being each ring forming part of the ring system optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, hydroxyl, (d-C 6 )alkyl, (C 2 -C 6 )alkenyl, (d-C 6 )haloalkyl, (d-C 6 )haloalkoxy, and amino.
- Example 1 General procedure for the synthesis of the intermediate hydroxy phosphine-borane complexes.
- aqueous phase was extracted three times with AcOEt and the combined organic phases were washed twice with brine, dried over MgSO 4 , filtered, and concentrated under reduced pressure.
- the resulting residue was purified by flash chromatography using Hexane/AcOEt as eluent to give the corresponding hydroxyl phosphine-borane complexes.
- Toluene was removed under vacuum (oil pump) to give the desired hydroxy-phosphine ligand as a white solid in quantitative yield.
- a solution of appropriate chlorophosphite (1.51 mmol) and NEt 3 (2.74 mmol) in toluene (24.0 ml_) was added dropwise a solution of the corresponding hydroxy-phosphine ligand (1.37 mmol) in toluene (16.0 ml_).
- the mixture was stirred for 16 h at room temperature.
- the reaction mixture was filtered via cannula on celite under argon atmosphere and the filtrate was evaporated under vaccum (oil pump).
- Example 10 Asymmetric hydrogenation of (Z)-methyl-2-acetamido-3- phenylacrylate.
- Example 11 Asymmetric hydrogenation of different unsaturated hydrocarbon compounds with chiral ligand 2 and [Rh(nbd) 2 ]BF 4 at -40 0 C
- Example 12 Asymmetric hydrogenation of different unsaturated hydrocarbon compounds with chiral ligand 6 and [Rh(nbd) 2 ]BF 4 at room temperature.
- Table 3 summarizes the results obtained. Table 3. Asymmetric hydrogenation with chiral ligand 6 and [Rh(nbd) 2 ]BF 4 at room temperature
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Abstract
The invention relates to new phosphine-phosphite ligands for the preparation of a catalyst for the asymmetric hydrogenation of unsaturated hydrocarbon compounds, methods for their preparation and use thereof.
Description
New phosphine-phosphite liqands.
FIELD OF THE INVENTION
The present invention relates to a re-usable and highly stable catalyst which exhibits high reactivity, stability and enantioselectivity for asymmetric hydrogenation of functional ized olefins. More specifically, the present invention relates to a catalyst which comprises a metal complex of an stereoisomerically enriched ligand. This invention also relates to the ligand, a preparation process thereof, as well as the preparation process of the catalyst complex and their use for asymmetric hydrogenation reactions.
BACKGROUND ART
Asymmetric catalysis is the most efficient method for generating products having high enantiomeric purity, as the asymmetry of the catalyst is multiplied many times over in the generation of the chiral product. These chiral products have found numerous applications as building blocks for single enantiomer pharmaceuticals as well as in some agrochemicals. The asymmetric catalysts employed can be enzymatic or synthetic in nature.
Particularly, asymmetric hydrogenation reactions are used in a wide variety of chemical processes, in particular in the manufacture of pharmaceutical intermediates.
A high reaction rate and enantioselectivity are attainable by appropriate molecular architecture of the catalysts and suitable selection of reaction conditions. Highly enantioselective hydrogenation was achieved mostly with substrates that have a functionality close to the unsaturated moiety and by use of Rh(I) or Ru(II) complexes that have a chiral diphosphine ligand.
One of the problems associated with asymmetric hydrogenation reactions in general, is to maximize the enantiomeric excess of the desired asymmetrically hydrogenated product over its unwanted enantiomer.
A suitable combination of a metal species and chiral organic ligand is the key factor to prepare high-performance catalysts for asymmetric hydrogenation.
Modulation of the electronic and steric properties of the different modules of a catalyst, allows improving the enantioselectivity in asymmetric reactions (Rajanbabu et al. Advances in Catalytic Processes, 1997, 2 (Asymmetric Catalysis), 1 -41 ; Vidal-Ferran et al. J. Org. Chem. 1997 4970). The disadvantage of most of the currently known ligands is that only limited substitution opportunities are available for varying their electronic and steric properties.
In spite of the known prior art for asymmetric hydrogenation of functionalized olefins, there still is a need to find a catalyst that ensures high enantioselectivity for a wide range of substrates.
Thus, there is a need to develop catalysts which, particularly when used in asymmetric hydrogenations, give not only a high enantioselectivity but also high conversions and mild to moderate reaction conditions.
SUMMARY OF THE INVENTION
Inventors have found new ligands for the preparation of catalysts for asymmetric reactions, particularly for asymmetric hydrogenation reactions of unsaturated hydrocarbons.
The new catalysts of the invention are rhodium complexes of phosphine-phosphite ligands. The catalysts of the invention show a high purity and a high enantioselectivity for the asymmetric hydrogenation of unsaturated hydrocarbon compounds. Furthermore, the catalysts of the invention are stable, and maintain its activity during a long time. The new ligands of the invention have great substitution opportunities available for varying their electronic and steric properties.
According to a first aspect, the invention provides an stereoisomehcally pure compound of formula I, or a salt thereof, or a N-oxide thereof, or a solvate thereof,
R-I, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, linear or branched (C-i-C-i2)alkyl optionally substituted, (C2-C-ι2)alkenyl optionally substituted, (C2-C-ι2)alkynyl optionally substituted, and a radical derived from one of the known ring systems with 1 -4 rings, wherein each one of the rings forming said ring system has 3-7 members, each member independently selected from P, C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially/totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; optionally, Ri and R2 taken together with the atoms to which they are attached, and/or R3 and R4 taken together with the phosphorus atom to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P, C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; the substituents being a radical independently selected from the group consisting of: halogen, nitro, hydroxyl, protected hydroxyl, cyano, amino, (Ci-Ci2)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)alkylazolyl,
tri-(Ci-C6)alkyl-siloxyl, (d-C4)alkoxy, -COR7, -COOR9, -OC(O)R7, -C(O)NR7R8, -R7NHR8, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, -SO3R9, -NHSO2-R9, -SO2-NR7R8, -NR7R8;
R7 and R8 are independently selected from the group consisting of H and (Ci-Ci2)alkyl;
R9 is selected from the group consisting of H, (Ci-C-ι2)alkyl, sodium and potassium.
The alkyl, alkenyl and alkynyl can be substituted by one or more substituents selected from the one mentioned above. Generally, if present, the number of substituents is between 1 and 6.
In a second aspect, the invention provides a catalyst, comprising a rhodium complex of a compound according to the first aspect of the invention as ligand.
The catalyst of the invention is obtainable by reaction of a compound according to the first aspect of the invention and a rhodium salt or a rhodium precursor-complex selected from the group consisting of RhA3, RhBC2, L3[RhD4], and [RhE2]F; wherein
A is chloride, bromide, iodide, acetate, nitrate, methanesulfonate, triflate, sulfonate, p-toluensulfonate, or acetyl-acetonate; B is chloride, bromide, acetate, methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenylborate;
C is a linear or branched (C2-d2)alkene or (C4-d2)alkadiene;
L is lithium, sodium, potassium, ammonium, tetra((Ci-C6)alkyl)ammonium;
D is chloride or bromide; E is a (C4-C-ι2)alkadiene;
F is methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenyl borate.
In a further aspect, the invention provides a method for preparing the catalyst which comprises: reacting in a appropriate solvent a rhodium salt or a rhodium precursor-
complex selected from the group consisting of RhA3, RhBC2, L3[RhD4], and [RhE2]F, as defined above, with a compound according to the first aspect of the invention.
According to another aspect, the invention provides the use of the compound as defined in the second aspect of the invention, as catalyst for the asymmetric hydrogenation reaction of unsaturated hydrocarbon compounds.
In another aspect, the invention provides a process for the asymmetric hydrogenation of unsaturated hydrocarbon compounds, which comprises contacting an unsaturated hydrocarbon compound with the catalyst of the invention and hydrogen under appropriate conditions of hydrogenation.
DETAILED DESCRIPTION OF THE INVENTION:
As it is said above, the present invention relates to a compound of formula I,
and pharmaceutically acceptable salts, N-oxides or solvates thereof, wherein R-I, R2, R3 , R4, R5 and R6 are as mentioned above.
The compounds of formula I are useful as ligands for the preparation of catalyst for the asymmetric hydrogenation of unsaturated hydrocarbon compounds.
According to an embodiment of the invention, it relates to a compound of formula I, wherein R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, and an optionally substituted radical selected
from linear or branched (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, naphtyl, oxazolyl, benzofuranyl, dibenzofuranyl, furanyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl; being the substituents selected from the group consisting of: halogen, nitro, hydroxyl, cyano, amino, (d-C6)alkyl, (d-C6)alkylazolyl, tri-(Ci-C6)alkyl-siloxyl, (d-C4)alkoxy, -COR7, -COOR9, -OC(O)R7, -C(O)NR7R8, -R7NHR8, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, -SO3R9, -NHSO2-R9, -SO2-NR7R8, -NR7R8.
Preferably R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, (Ci-C4)alkyl-tri-(d-C6)alkyl-siloxyl, phenyl, naphtyl, propynyl, triazolylmethyl, phenylmethyl, phenylethyl, diphenylmethyl, and trityl.
In another preferred embodiment of the invention, the compounds of formula I are those wherein R3 and R4 are independently selected from the group consisting of tert-butyl, phenyl, propynyl, triazolylmethyl, phenylmethyl, phenylethyl and trityl. In a yet more preferred embodiment of the invention, the compounds of formula I are those wherein R5 and R6 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trityl, triazolylmethyl, propynyl, diphenylmethyl, phenylmethyl, phenyl and propyl-triethyl-siloxyl. Particularly preferred, are those wherein R3 and R4 are simultaneously selected from tert-butyl and phenyl, and R5 and R6 are independently selected from the group consisting of methyl, trityl, triazolylmethyl, propynyl and phenyl.
According to another embodiment of the invention, it provides a compound of formula I, wherein R1 and R2 are independently selected from the group consisting of an optionally substituted radical selected from a linear or branched (Ci-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, naphtyl, oxazolyl, benzofuranyl, dibenzofuranyl, furanyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and indolyl; or R1 and R2 taken together with the atoms to which they are attached,
form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P, C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; being the substitutents selected from the group consisting of: halogen, nitro, hydroxyl, hydroxy protecting-groups, cyano, amino, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkylazolyl, tri-(Ci-C6)alkyl-siloxyl, (d-C4)alkoxy, -COR7, -COOR9, -OC(O)R7, -C(O)NR7R8, -R7NHR8, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, -SO3R9, -NHSO2-R9, -SO2-NR7R8, -NR7R8.
In a preferred embodiment of the invention, R1 and R2 are independently selected from the group consisting of an optionally substituted radical selected from phenyl, trityl, naphtyl, tert-butyl, propynyl, and triazolylmethyl; or R1 and R2 taken together with the atoms to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; being R1 and R2 optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, hydroxyl, hydroxy protecting-groups, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl, (CrC6)alkylazolyl, tri-(CrC6)alkyl-siloxyl, (CrC4)alkoxy, -COR7, -COOR9, -OC(O)R7, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, and -SO3R9.
In a more preferred embodiment, R1 and R2 taken together with the atoms to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents.
Particularly preferred are those compounds wherein R1 and R2 taken together with the atoms to which they are attached, form a ring system selected from the group consisting of:
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; and the dotted line represents the presence or absence of a double bond.
When R1 and R2 taken together with the atoms to which they are attached form a L4 ring system, the molecule may have free or restricted rotation.
Preferred examples of compounds with L4 ring systems are those of formula L4-I and L4-2:
When the compound has a L4 ring system with restricted rotation (e.g. L4-2) around the biarylic moiety, two possible stereoisomers (P and M) may occur:
Accordingly, preferred compounds of the invention are those selected from the group consisting of the racemic mixture of the two possible stereoisomers around the biarylic moiety, the substantially pure L4-P stereoisomer, the substantially pure L4-M stereoisomer, and mixtures thereof.
Obviously, the present invention also encompasses other possible rings system with free or restricted rotation, not only those represented above (L4-I and L4-2). The above mentioned examples are provided by way of illustration, and are not intended to be limiting of the present invention.
It is clear to a person skilled in the art that the catalyst of the present invention has at least two optical centers and to thus form stereoisomers. All optical isomers are part of the present invention and are thus encompassed by the scope of the claims. As defined above, in the formula I, the wavy line means any of the two possible configurations of the attached stereogenic atom.
In the molecular structures herein, the use of bold and dashed lines to denote particular configuration of groups follows the IUPAC convention. A bond indicated by a broken line indicates that the group in question is below the general plane of the molecule as drawn, and a bond indicated by a bold line indicates that the group at the position in question is above the general plane of the molecule as drawn.
Therefore, in view of the two optical centers and the wavy lines showed in formula I, at least four stereoisomers are possible \-anti, \-syn, ent-\-anti or ent-\-syn:
Specific compounds of formula I are selected from the group consisting of:
2-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2-yloxy)-1 ,3,2- dioxaphospholane (1);
6-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2- yloxy)dibenzo[c/,/][1 ,3,2]dioxaphosphepine (2);
6-((1 R,2S)-1 -(diphenylphosphino)-i -phenyl-3-(tritryloxy)propen-2- yloxy)dibenzo[c/,/][1 ,3,2]dioxaphosphepine (3);
6-((1 S,2R)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2-yloxy)-
2,4,8,10-tetramethyldibenzo[c/,/][1 ,3,2]dioxaphosphepine (4);
(11 bM)-4-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropan-2- yloxy)dinaphtho[2,1 -c/:1 \2'-/][1 ,3,2]dioxaphosphepine (5); (11 bP)-4-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropan-2- yloxy)dinaphtho[2,1 -c/:1 ',2'-/][1 ,3,2]dioxaphosphepine (6);
The compounds of the invention can be prepared in various ways. They can be prepared by using the methods described below, together with methods known in the field of organic chemical synthesis, or by the variations that might be made thereto by an expert in the subject. Preferred methods include, but are not limited to, those described below. The reactions are carried out in the solvents appropriate for the reagents and materials used and suited for the transformations carried out. Moreover, in some of the procedures described below it may be desirable or necessary to protect the reagent functional groups present in the compounds or intermediates of this invention with conventional protecting groups. Various protecting groups and
procedures for introducing them and removing them are described in Greene and Wuts (Protective Groups in Organic Synthesis, Wiley and Sons, 1999).
The following reaction Schemes illustrate the preparation of the compounds of the present invention.
Scheme 1. Synthesis of compounds l-anti
Compounds of formula ent-l-anti are prepared starting from the appropriate epoxy-ether enantiomer.
Scheme 2. Synthesis of compounds l-syn:
The inversion of the configuration at the hydroxyl carbon can be carried out by a Mitsunobu inversion (e.g. PPh3, DEAD, Ar-COOH) followed by a reduction (e.g. DIBAL-H) (Mitsunobu Synthesis 1981 , 1 -28; and Vidal-Ferran et al. J. Org. Chem. 1997, 4970-4982).
Compounds of formula ent-l-syn are prepared starting from the appropriate epoxy-ether enantiomer.
Those compounds wherein R1 and R2 taken together with the atoms to which they are attached, form a ring system selected from the group consisting of L1, L2, L3 or L4
may be obtained starting from the appropriate chloro-phosphite:
As indicated above, when R1 and R2 taken together with the atoms to which they are attached form a L4 ring system, the molecule may have free or restricted rotation.
The preparation process for those compounds of formula I wherein R1 and R2 taken together with the atoms to which they are attached form a L4-I ring system, i.e. the biarylic moiety has free rotation, is illustrated in scheme 3.
Scheme 3. Preparation process of compounds l-anti with a biarylic moiety with free rotation.
Compounds of formula ent-l-anti with a biarylic moiety with free rotation are prepared starting from the appropiate hydroxyphosphine stereoisomer.
The epoxy intermediates can be obtained by an asymmetric Sharpless reaction, c.f. Sharpless et al. J. Am. Chem. Soc. 1987, 5765-5780; Vidal- Ferran et al. J. Org. Chem. 1997, 4970.
The chloro-phosphite intermediates are known in the art, and may be obtained as described in J. MoI. Cat. A 2000, 164, 125-130 and J. Organomet. Chem. 1996, 520, 45-58; those not known can be prepared anagously from the appropriate starting materials.
The KPR3R4 intermediates are known in the art, and may be obtained as described in Power et al. Inorg. Chem. 1987, 1941 -1946; Mintz et al. J. Org. Chem 1988, 4417-4419; Bakos et al. Tetrahedron Asymm. 2004; 1673-1676;
Dorta et al. Chem. Eur. J. 2004, 267-278; Ashby et al. J. Org. Chem. 1988, 5832-5837; Berthold et al. Inorg. Chem. 2003, 3623; those not known can be prepared anagously from the appropriate starting materials.
Analogously, compounds l-syn with a biarylic moiety with free rotation may be obtained following the preparation process illustrated in the scheme 4:
Scheme 4. Preparation process of compounds l-syn with a biarylic moiety with free rotation.
Compounds of formula ent-l-syn with a biarylic moiety with free rotation, are prepared starting from the appropiate hydroxyphosphine stereoisomer.
Compounds l-syn-P, ent-l-syn-P, l-syn-M, ent-l-syn-M, l-anti-P, ent-l-anti-P, l-anti-M and ent-l-anti-M, i.e. with a biarylic moiety with restricted rotation may be obtained starting from the appropriate hydroxyphosphine and the appropriate chloro-phosphite.
As said above, the catalyst of the invention, which is useful for the asymmetric hydrogenation of unsaturated hydrocarbon compounds, comprises a rhodium complex of a compound according to the first aspect of the invention as ligand.
The catalyst of the invention is obtainable by reaction of a compound according to the first aspect of the invention and a rhodium salt or a rhodium precursor-complex selected from the group consisting of RhA3, RhBC2, L3[RhD4], and [RhE2]F; wherein A, B, C, L, D, E and F are as defined above.
In a preferred embodiment, the invention provides a catalyst which is selected from the group consisting of: [Rh(X)HaI]2;
[Rh(COd)X]Y; and
[Rh(nbd)X]Y wherein
Hal is selected from the group consisting of chloride, bromide and iodide X is a compound as defined in the first aspect of the invention; (cod) is 1 ,5-cyclooctadiene; (nbd) is norbornadiene; and
Y is selected from the group consisting of metanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, and tetraphenylborate.
As said above, the catalyst of the invention is useful for the asymmetric hydrogenation reactions of unsaturated hydrocarbon compounds.
The catalysts of the present invention are useful in the asymmetric hydrogenation of functionalized olefins, particularly enamides, acrylic acid derivatives, enamines, alkenyl esters, alkenyl ethers, α,β- and β,γ- unsaturated carboxylic acids, α,β-unsaturated esters, α,β-unsaturated amides, α,β-unsaturated aldehydes, α,β-unsaturated ketones, allylic and homoallylic alcohols.
In a preferred embodiment of the invention, unsaturated hydrocarbon compound is an acrylic acid derivative or an enamine derivative. Preferably, the unsaturated hydrocarbon compound has the formula II:
wherein:
R-io, R-I-I, R-I2 and Ri3 are independently selected from the group consisting of hydrogen, linear or branched (C-ι-C-ι2)alkyl optionally substituted, (C2-C-ι2)alkenyl optionally substituted, (C2-d2)alkynyl optionally substituted, COORi4, NRi4Ri5, and phenyl optionally substituted; the substituents being a radical independently selected from the group consisting of: halogen, nitro, hydroxyl, cyano, amino, (Ci-Ci2)alkyl,
(C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)alkylazolyl, (d-C4)alkoxy, -CORi4, -COOR14, -OC(O)R14, -C(O)NR14R15, -R14NHR15, -R14PO(OR15)2, -S-R14, -SO-R14, -SO2-R14, -SO3R14, -NHSO2-R14, -SO2-NR14R15, and -NR14R15; R14 and R15 are independently selected from the group consisting of H, alkyl(C-ι-C12), CH3COO-, protected amino, protected hydroxyl, protected carboxy, sodium and potassium;
and wherein at least one of R9, R10, R11 and R12 is a COOR14 or NR14R15 radical.
In a more preferred embodiment, the unsaturated hydrocarbon is selected from the group consisting of:
The catalyst of the invention may be properly used in the preparation of enantiomerically enriched aminoacids. Thus for example, the catalyst of the present invention may be used in the preparation of enantiomerically enriched alanines which could be protected, e.g. with a Cbz, Boc or Fmoc protecting group. Particularly, the catalyst of the invention may be properly used in the preparation of Fmoc derivatives by hydrogenation in an easy way instead of the known prior art methods.
The catalysts of the invention show high conversion and enantioselectivity in the asymmetric hydrogenation of unsaturated hydrocarbon compounds. (conversion > 99%, enantioselectivity 80-99%).
DEFINITIONS
As used herein, the following terms are used to describe the present invention. The definitions provided below, within context, may be used exclusively, or may be used to supplement definitions which are generally known to those of ordinary skill in the art.
The term "pharmaceutically acceptable salt" used herein encompasses any salt formed from organic and inorganic acids, such as hydrobromic, hydrochloric, phosphoric, nitric, sulfuric, acetic, adipic, aspartic, benzenesulfonic, benzoic, citric, ethanesulfonic, formic, fumaric, glutamic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, 1 ,5-naphthalendisulfonic, oxalic, pivalic, propionic, p-toluenesulfonic, succinic, tartaric acids and the like.
The term "protecting group" refers to a chemical moiety or group which protects or prevents an active moiety or group from participating with or interfering with one or more chemical synthetic steps and its removal restores the moiety to its original active state. The term protecting group as used herein refers to those groups intended to protect against undesirable reactions during synthetic procedures. Such protecting groups are well known
to those skilled in the art. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2nd ed. 1991 ), McOmie et al. "Protective Groups in Organic Chemistry" (Plenam Press, New York, 1973), and Harrison et al, "Compendium of Synthetic Organic Methods", VoIs. 1 -8 (John Wiley and Sons, 1971 -1996). Protecting groups can be removed with inter alia acid, base, fluoride ions, hydrogenation, metals such as zinc as well as by numerous other methods which are well known in the art. One of ordinary skill in the art can readily choose an appropriate protecting group to facilitate synthetic reactions according to methodological aspects of the present invention without engaging in undue experimentation.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space. In particular, the term "enantiomers" refers to two stereoisomers of a compound which are non supehmposable mirror images of one another. The term "diastereomers", on the other hand, refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
Furthermore, a "stereoselective process" is one which produces a particular stereoisomer of a reaction product in preference to other possible stereoisomers of that product. An "enantioselective process" is one which favors production of one of the two possible enantiomers of a reaction product.
In the context of this invention, the "enantiomerically pure" means a compound with enough enantiomeric excess for its preparation to industrial scale, which depends on each particular case as it would be decided by the person skilled in the art. For most purposes, a enantiomeric excess higher than 95% is enough. When the term enantiomerically pure is meant to indicate the ee of the catalyst, such ee is preferably higher than 99%.
The term "solvent" is used to describe a medium typically, but not necessarily inert in which a reaction takes place using the organocatalyst according to the present invention. Solvents may include polar and non-polar solvents, including, for example, H2O, pyridine, triethanolamine, tetrahydrofuran (THF), 1 ,4-dioxane, dimethylacetamide (DMA), dimethylformamide (DMF),
dimethylsulfoxide (DMSO), dichloromethane (DCM), nitromethane, chloroform, methanol, ethanol, isopropanol, N-methylpyrrolidone (NMP), ethylacetate, benzene, hexane, heptane, toluene, acetonitrile, etc. and mixtures thereof. Preferably, asymmetric reactions catalyzed by the catalyst of the invention takes place using DCM, THF, hexane, heptane, toluene or mixtures thereof as solvent.
The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
In the definitions of this invention, an (d-C6)alkyl group, as a group or as part of a group, is taken to mean a lineal or branched alkyl group which contains up to 6 atoms of carbon. Thus it includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, and hexyl. Likewise, an (Ci-C6)alkoxy group as used herein refers to a saturated branched or linear hydrocarbon chain with 1 to 6 hydrocarbon atoms (i.e. (d-C6)alkyl groups as defined above) linked to an oxygen, thus (d-C6)alkyl-O. Preferably (Ci-C6)alkoxy includes, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy group. An (C2-C6)alkenyl group includes, for example, a vinyl, allyl, propenyl and 1 -butenyl, 2-butenyl and 3-butenyl group. A (d-C6)haloalkyl group means an (d-C6)alkyl group substituted by one or more atoms of halogen, the same or different. It thus includes, for example, chloromethyl, fluoromethyl, thfluoromethyl, chloroethyl, fluoroethyl, difluoroethyl, trifluoroethyl, fluoropropyl, chloropropyl, etc. A (Ci-C6)haloalkoxy group means an (d-C6)alkoxy group substituted by one or more atoms of halogen, the same or different. Thus it includes, for example, chloromethoxy, fluoromethoxy, thfluoromethoxy, chloroethoxy, fluoroethoxy, difluoroethoxy, thfluoroethoxy, fluoropropoxy, chloropropoxy, etc.
The term "halogen" is meant to include fluorine, chlorine, bromine and iodine.
The term "aryl", alone or in combination with other groups, means a radical derived from one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 3-7 members, each member independently selected from C, N, O,
S1 CH1 CH2 1 NH, is partially unsaturated or aromatic, and is partially/totally fused; being each ring forming part of the ring system optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, cyano, hydroxyl, (d-C6)alkyl, (C2-C6)alkenyl, (d-C6)haloalkyl, (d-C6)haloalkoxy, and amino.
Throughout the description and claims the word "comprise" and variations of the word, such as "comprising", are not intended to exclude other technical features, additives, components, or steps.
Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention.
DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS
Example 1. General procedure for the synthesis of the intermediate hydroxy phosphine-borane complexes.
In a general procedure, to a flame-dried flask under Ar atmosphere was added (via cannula) a solution of optically pure epoxy ethers (1 mmol) in dry
THF from solvent purification system (SPS). The solution was cooled at -30 0C and a solution of KPPh2 in THF (0.98 mmol) was added via syringe. The mixture was stirred for 1 h at this temperature and then it was slowly allowed to reach room temperature and stirred for the adequate reaction time. After this, the mixture was cooled at -10 0C and BH3-DMS complex (2.94 mmol) was added dropwise. The reaction mixture was stirred for 1 h at this temperature and then it was allowed to reach room temperature and stirred during the adequate reaction time. Finally, the reaction mixture was quenched with distilled water, and the two phases (organic and aqueous) were separated. The aqueous phase was extracted three times with AcOEt and the combined organic phases were washed twice with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by
flash chromatography using Hexane/AcOEt as eluent to give the corresponding hydroxyl phosphine-borane complexes.
Example 2. General Procedure for the synthesis of the ligands.
In a general procedure, the phosphine-borane ligand (1.37 mmol) and diazabyciclo[2.2.2]octane (3.01 mmol) were charged in a flame-dried schlenk flask. The system was purged with three vacuum-argon cycles. Toluene (5.0 ml_) from SPS system was syringed to the schlenk flask. The reaction mixture was warmed at 60 0C and stirred for 2h. The mixture was then cooled to room temperature and purified on a silica pad (2 cm) under argon atmosphere and eluted with 25.0 ml_ of toluene from SPS system. Toluene was removed under vacuum (oil pump) to give the desired hydroxy-phosphine ligand as a white solid in quantitative yield. After this, over another flame-dried schlenk flask containing a solution of appropriate chlorophosphite (1.51 mmol) and NEt3 (2.74 mmol) in toluene (24.0 ml_) was added dropwise a solution of the corresponding hydroxy-phosphine ligand (1.37 mmol) in toluene (16.0 ml_). The mixture was stirred for 16 h at room temperature. The reaction mixture was filtered via cannula on celite under argon atmosphere and the filtrate was evaporated under vaccum (oil pump). The resulting residue was dissolved in diethyl ether (30.0 ml_) from SPS system and the solution was filtered through a short pad of neutral alumina (4.5 ml_), previously dried under vacuum. Solvent evaporation under vacuum (oil pump) produced the desired phosphine-phosphite ligand.
Following the general procedures of examples 1 and 2, compounds of examples 3-10 were prepared starting from the appropriate reactants
Example 3. 2-((1R,2S)-1-(diphenylphosphino)-3-methoxy-1- phenylpropen-2-yloxy)-1,3,2-dioxaphospholane (l-anti, 1).
1H-NMR (400MHz, CDCI3) δ 7.76-7.72 (m, 2H), 7.45-7.33 (m, 5H), 7.22-7.06 (m, 8H), 4.31 -4.22 (m, 2H), 4.08-3.88 (m, 3H), 3.79 (dd, 2JH-P= 5.2 Hz, 3JH-H= 2.8 Hz, 1 H), 3.18 (s, 3H), 3.10 (dd, 2JH-H= 9.6 Hz, 3JH-H= 6.4 Hz, 1 H), 3.03 (dd, 2JH-H= 9.6 Hz, 3JH-H= 6.8 Hz, 1 H); 13C(1HJ-NMR (100MHz, CDCI3) δ 137.04 (d, Jc-P= 10.6 Hz, C), 137.03 (d, JC-P= 13.7 Hz, C), 136.41 (d, JC-P= 16.6 Hz, C), 134.86 (d, Jc-P= 21.4 Hz, CH), 133.22 (d, JC-P= 18.6 Hz, CH), 131.12 (d, JC-P=
8.6 Hz, CH), 129.77 (CH), 128.86 (d, JC-P= 7.8 Hz, CH), 128.29 (CH), 128.01 (CH), 127.94 (d, JC-P= 6.8 Hz, CH), 126.82 (d, J0-P= 1 .4 Hz, CH), 74.23 (dd, 3Jc-P= 4.2 Hz, 3Jc-P= 2.2 Hz, CH2), 71 .70 (dd, 2Jc-P= 2Jc-P= 13.2 Hz, CH), 63.99 (d, 2Jc-P= 8.3 Hz, CH2), 63.78 (d, 2Jc-P= 8.6 Hz, CH2), 58.86 (CH3), 47.57 (dd, 1Jc-P= 13.2 Hz, 3Jc-P= 4.4 Hz, CH); 31P(1HJ-NMR (162MHz, CDCI3) δ 138.84 (d, 4JP-P= 12.0 Hz), -7.03 (d, 4JP.P= 12.0 Hz); [α]D 28 589= -146.1 (c O.99, THF); MS HR-ESI [found 441 .1396; C24H27O4P2 (M-H+) requires 441 .1385]. (Colorless oil, yield 69%)
Example 4.
6-((1/?,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2- yloxy)dibenzo[rf,/][1 ,3,2]dioxaphosphepine (l-anti, 2).
1H-NMR (500MHz, CDCI3) 5 7.81 -7.77 (m, 2H), 7.54-7.09 (m, 20H), 7.00-6.98 (m, 1 H), 4.50 (m, 1 H), 3.80 (dd, 2JH-P= 4.5 Hz, 3JH-H= 3.5 Hz, 1 H), 3.25 (dd, 2JH-
H= 9.6 Hz, 3JH-H= 5.2 Hz, 1 H), 3.22 (s, 3H), 3.07 (dd, 2JH-H= 9.6 Hz, 3JH-H= 7.0
Hz, 1 H); 13C(1HJ-NMR (125MHz, CDCI3) δ 150.08 (d, JC-P= 5.5 Hz, C), 149.57
(d, Jc-P= 4.8 Hz, C), 137.04 (d, JC-P= 15.8 Hz, C), 136.94 (d, JC-P= 1 1 .2 Hz, C),
136.03 (d, Jc-P= 17.4 Hz, C), 135.02 (d, JC-P= 21 .6 Hz, CH), 133.18 (d, JC-P= 18.6 Hz, CH), 131 .79 (d, JC-P= 2.9 Hz, C), 131 .37 (d, JC-P= 2.9 Hz, C), 131 .07
(d, Jc-P= 8.1 Hz, CH), 129.89 (d, JC-P= 17.0 Hz, CH), 129.82 (CH), 128.97
(CH), 128.95 (d, JC-P= 10.1 Hz, CH), 128.32 (CH), 128.15 (CH), 128.00 (d, J0.
P= 6.5 Hz, CH), 126.88 (CH), 125.04 (CH), 122.93 (d, JC-P= 3.6 Hz, CH),
122.29 (CH), 74.54 (bs, CH2), 74.42 (dd, 2Jc-P= 16.6 Hz, 2JC-P= 12.3 Hz, CH), 58.88 (CH3), 48.09 (dd, 1Jc-P= 14.8 Hz, 3JC-P= 6.1 Hz, CH); 31P(1HJ-NMR
(202MHz, CDCI3) δ 155.25 (d, 4JP.P= 7.5 Hz), -5.22 (d, 4JP.P= 7.5 Hz); M.p.
138.0-143.3 0C; [α]D 25 589= -135.2 (c θ.98, THF); MS HR-ESI [found 587.1533;
C34H30O4P2Na (M-Na+) requires 587.1517].
(White solid, yield 66%).
Example 5.
6-((1/?,2S)-1 -(diphenylphosphino)-1 -phenyl-3-(tritryloxy)propen-2- yloxy)dibenzo[d,/][1 ,3,2]dioxaphosphepine {l-anti, 3).
1H-NMR (500MHz, CDCI3) δ 7.69-7.66 (m, 2H), 7.46-7.03 (m, 35H), 6.71 (d, 3JH-H= 8.0 Hz, 1 H), 4.75 (m, 1 H), 3.82 (dd, 2JH-P= 3JH-H= 4.8 Hz, 1 H), 3.06 (dd, 2JH-H= 9.6 Hz, 3JH-H= 5.5 Hz, 1 H), 3.00 (dd, 2JH-H= 9.6 Hz, 3JH-H= 7.8 Hz, 1 H);
13C(1HJ-NMR (125MHz, CDCI3) δ 149.88 (d, JC-P= 5.5 Hz, C), 149.51 (d, JC-P= 4.4 Hz, C), 143.89 (C), 136.84 (d, JC-P= 8.4 Hz, C), 136.67 (d, JC-P= 14.6 Hz, C), 136.25 (d, Jc-P= 16.4 Hz, C), 134.73 (d, JC-P= 21.4 Hz, CH), 133.46 (d, J0. P= 19.1 Hz, CH), 131.65 (d, JC-P= 3.0 Hz, C), 131.25 (d, JC-P= 2.6 Hz, C), 130.82 (d, Jc-P= 7.2 Hz, CH), 129.75 (CH), 129.72 (d, JC-P= 8.4 Hz, CH),
128.88 (CH), 128.86 (d, JC-P= 4.6 Hz, CH), 128.38 (CH), 128.33 (CH), 128.02 (CH), 127.91 (CH), 127.89 (d, JC-P= 7.1 Hz, CH), 127.08 (CH), 126.64 (bs, CH), 124.92 (d, JC-P= 2.0 Hz, CH), 122.79 (d, JC-P= 2.6 Hz, CH), 122.35 (CH), 87.54 (C), 75.87 (dd, 2Jc-P= 2Jc-P= 19.0 Hz, CH), 65.96 (bd, 3Jc-P= 4.4 Hz, CH2), 48.36 (dd, 1Jc-P= 15.8 Hz, 3JC-P= 4.8 Hz, CH); 31P(1HJ-NMR (202MHz, CDCI3) δ 155.41 (d, 4JP.P= 11.9 Hz), -5.99 (d, 4JP.P= 11.9 Hz); M.p. 97.3-102.7 or 26
C; [CC]D 589= -125.6 (c θ.50, THF); MS HR-ESI [found 793.2599; C52H43O4P2 (M-H+) requires 793.2637]. (White solid, yield 64%)
Example 6.
6-((1 S,2/?)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2-yloxy)-
2,4,8,10-tetramethyldibenzo[d,/][1,3,2]dioxaphosphepine (ent-l-anti, 4).
1H-NMR (400MHz, CDCI3) δ 7.74-7.70 (m, 2H), 7.40-6.97 (m, 17H), 4.56 (m, 1 H), 3.85 (dd, 2JH-P= 3JH-H= 4.8 Hz, 1 H), 3.17-3.15 (m, 5H), 2.44 (bs, 3H), 2.35 (bs, 6H), 2.08 (bs, 3H); 13C(1HJ-NMR (100MHz, CDCI3) δ 146.03 (d, JC-P= 6.4 Hz, C), 145.92 (d, JC-P= 5.3 Hz, C), 137.01 (C), 136.84 (C), 136.76 (d, JC-P= 10.5 Hz, C), 136.44 (d, JC-P= 17.5 Hz, C), 134.74 (d, JC-P= 21.4 Hz, CH), 133.74 (d, Jc-P= 18.4 Hz, C), 133.38 (d, JC-P= 19.1 Hz, CH), 131.61 (d, JC-P=
3.5 Hz, C), 131.33 (d, JC-P= 2.9 Hz, C), 131.22 (d, JC-P= 8.1 Hz, CH), 130.96 (d, Jc-P= 10.0 Hz, CH), 130.55 (d,
1.1 Hz, C), 130.13 (C), 129.67 (CH), 128.85 (d, Jc-P= 7.7 Hz, CH), 128.30 (CH), 128.03 (CH), 128.02 (d, JC-P= 10.3 Hz, CH), 127.91 (d, JC-P= 6.8 Hz, CH), 126.78 (CH), 74.04 (dd, 3Jc-P= 3Jc-P= 3.2 Hz, CH2), 73.55 (dd, 2Jc-P= 2Jc-P= 13.2 Hz, CH), 58.75 (CH3), 47.76 (dd,
1Jc-P= 14.6 Hz, 3Jc-P= 5.0 Hz, CH), 20.98 (bs, 2 CH3), 17.36 (d, 4Jc-P= 4.3 Hz, CH3), 16.73 (CH3); 31P(1HJ-NMR (162MHz, CDCI3) δ 151.14 (d, 4JP.P= 17.6 Hz), -7.35 (d, 4JP-P= 17.6 Hz); M.p. 70.7-74.6 0C; [α]D 26 589= +96.0 (c 1.00, THF); MS HR-ESI [found 621.2299; C38H39O4P2 (M-H+) requires 621.2324]. (White solid, yield 48%)
Example 7.
(11bM)-4-((1/?,2S)-1-(diphenylphosphino)-3-methoxy-1-phenylpropan-2- yloxy)dinaphtho[2,1-d:1',2'-/][1,3,2]dioxaphosphepine (l-anti-M, 5).
1H-NMR (500MHz, CDCI3) 58.09-8.05 (m. 2H), 7.99-7.98 (m, 1 H), 7.92-7.90 (m, 2H), 7.84-7.81 (m, 2H), 7.46-7.00 (m, 20H), 4.44 (m, 1 H), 3.75 (dd, 2JH-P= 4.5 Hz, 3JH-H= 3.5 Hz, 1 H), 3.22 (dd, 2JH-H= 9.8 Hz, 3JH-H= 4.5 Hz, 1 H), 3.21 (s, 3H), 2.91 (dd, 2JH-H= 9.8 Hz, 3JH-H= 7.8 Hz, 1 H); 13C(1HJ-NMR (125MHz, CDCI3) δ 148.84 (d, JC-P= 4.4 Hz, C), 147.91 (d, JC-P= 2.5 Hz, C), 137.16 (d, Jc-P= 15.6 Hz, C), 136.95 (d, JC-P= 11.2 Hz, C), 136.00 (d, JC-P= 17.5 Hz, C), 135.09 (d, Jc-P= 21.8 Hz, CH), 133.09 (d, JC-P= 18.4 Hz, CH), 132.90 (d, JC-P= 36.5 Hz, C), 131.53 (d, JC-P= 16.6 Hz, C), 130.93 (d, JC-P= 8.1 Hz, CH), 130.11 (d, Jc-P= 6.9 Hz, CH), 129.56 (CH), 129.05 (d, JC-P= 7.6 Hz, CH), 128.43 (CH), 128.33 (CH), 128.20 (CH), 128.07 (d, JC-P= 6.2 Hz, CH), 127.23 (d, JC-P= 7.5 Hz, CH), 126.93 (CH), 126.17 (d, JC-P= 33.0 Hz, CH), 124.95 (d, JC-P= 25.5 Hz, CH), 124.62 (d, JC-P= 5.1 Hz, CH), 123.40 (d, JC-P= 7.6 Hz, CH), 123.14 (d, Jc-P= 1.9 Hz, C), 122.09 (CH), 75.01 (dd, 2Jc-P= 17.3 Hz, 2JC-P= 12.3 Hz, CH), 74.67 (bd, 2Jc-P= 12.3 Hz, CH2), 58.88 (CH3), 48.24 (dd, 1Jc-P= 15.1 Hz, 3Jc-P= 6.6 Hz, CH); 31P(1HJ-NMR (202MHz, CDCI3) δ 156.63 (bs), -4.54 (bs); M.p. 147.6-151.1 0C; [α]D 26 589= -395.2 (c 0.60, THF); MS HR-ESI [found 665.2028; C42H35O4P2 (M-H+) requires 665.2011].
(White solid, yield 71 %)
Example 8.
(11bP)-4-((1/?,2S)-1-(diphenylphosphino)-3-methoxy-1-phenylpropan-2- yloxy)dinaphtho[2,1-d:1',2'-/][1,3,2]dioxaphosphepine {l-anti-P, 6).
1H-NMR (500MHz, CDCI3) 57.99-7.92 (m, 3H), 7.82-7.75 (m, 3H), 7.54-7.41 (m, 8H), 7.30-7.04 (m, 13H), 4.52 (m, 1 H), 3.78 (dd, 2JH-P= 3JH-H= 4.2 Hz, 1 H), 3.30 (dd, 2JH-H= 10.0 Hz, 3JH-H= 5.0 Hz, 1 H), 3.28 (s, 3H), 3.23 (dd, 2JH-H= 10.0 Hz, 3JH-H= 7.2 Hz, 1 H); 13C(1HJ-NMR (125MHz, CDCI3) δ 148.22 (d, JC-P= 4.5
Hz, C), 147.97 (d, JC-P= 1.6 Hz, C), 136.84 (d,
11 -1 Hz, C), 136.66 (d, JC- P= 15.4 Hz, C), 135.96 (d, JC-P= 17.5 Hz, C), 134.95 (d, JC-P= 21.6 Hz, CH), 133.30 (d, Jc-P= 19.1 Hz, CH), 132.94 (d, JC-P= 29.6 Hz, C), 131.44 (d, JC-P= 46.1 Hz, C), 130.07 (d, JC-P= 31.8 Hz, CH), 129.52 (CH), 128.88 (d, JC-P= 7.8 Hz, CH), 128.48 (CH), 128.35 (d, JC-P= 6.6 Hz, CH), 128.12 (CH), 127.95 (d, Jc-P= 6.9 Hz, CH), 127.25 (d, JC-P= 6.1 Hz, CH), 126.87 (d, JC-P= 1.4 Hz, CH), 126.18 (d, Jc-P= 19.1 Hz, CH), 124.95 (d, JC-P= 20.1 Hz, CH), 124.69 (d, JC-P=
5.2 Hz, C), 123.34 (d, J0-P= 1 .8 Hz, C), 122.36 (CH), 122.26 (CH), 74.85- 74.62 (m, CH2 and CH), 58.91 (CH3), 48.03 (dd, 1Jc-P= 14.8 Hz, 3JC-P= 5.9 Hz, CH); 31P(1HJ-NMR (202MHz, CDCI3) δ 156.20 (d, 4JP-P= 1 1 .4 Hz), -5.49 (bs, d, 4JP-P= 1 1 .4 Hz); M.p. 103.4-108.7 0C; [α]D 26 589= +161 .9 (c O.50, THF); MS HR- ESI [found 665.2020; C42H35O4P2 (M-H+) requires 665.201 1 ]. (White solid, yield 50%)
Example 9. General procedure for the asymmetric hydrogenation reactions.
In a typical run, in the glove-box, a 0.20 M solution of chiral ligand (0.01 1 mmol), Rh precursor (0.01 mmol) and the substrate (1 mmol) was prepared in the desired solvent. The reaction mixture was syringed in one autoclave. The autoclave was purged three times with hydrogen gas (10 bar). Finally, the autoclave was pressurized under hydrogen pressure (usually 20 bar) and the reaction mixture was stirred at desired temperature during the adequate reaction time. After this, the autoclave was depressurized and the conversion and enantiomeric excess was determined, without further purification, by 1H- NMR spectrum and chiral HPLC or GC.
Example 10. Asymmetric hydrogenation of (Z)-methyl-2-acetamido-3- phenylacrylate.
Following the general procedure of example 11 , the title compound was hydrogenated in presence of the catalyst of the invention which comprises the phosphine-phosphite ligands of the invention and [Rh(NBD)2]BF4 as Rhodium precursor. Table 1 summarizes the results obtained.
Table 1. Asymmetric hydrogenation of (Z)-methyl-2-acetamido-3- phenylacrylate with phosphine-phosphite ligands and [Rh(nbd)2]BF4
Ligand T (0C) pH2 (bar) Solvent Conv.(%) i ee (%)
1 rt 20 THF >99 78 (R)
2 -40 20 THF >99 98 (R)
3 -40 20 THF >99 92 (R)
4 rt 20 DCM >99 47 (S)
6 rt 20 THF >99 99 (R)
5 rt 20 THF >99 86 (S) rt : room temperature
Example 11. Asymmetric hydrogenation of different unsaturated hydrocarbon compounds with chiral ligand 2 and [Rh(nbd)2]BF4 at -40 0C
The following compounds (a-n) were hydrogenated in presence of a catalyst of the invention (ligand 2 and [Rh(nbd)2]BF4) at -40 0C.
CO2Me CO2Me CO2H
Ph Ph
NHAc Y NHAc NHA Y CO2H c NHAc (a) (b) (C) (d)
e
Table 2. Asymmetric hydrogenation with chiral ligand 2 and [Rh(nbd)2]BF4 at -40 0C
Entry Substrate pH2 (bar) Solvent Conv. (%) ee (%)
1 a 20 THF >99 98 (R)
2 b 20 THF >99 96 (R)
3 C 20 THF >99 94 (R)
4 d 20 THF >99 89 (R)
5 e 20 THF >99 98 (R)
6 f 20 THF >99 97 (R)
7 g 20 THF >99 97 (R)
8 h 20 THF >99 98 (R)
9 i 20 THF >99 98 (R)
10 j 20 THF >99 98 (R)
11 k 20 THF >99 90 (R)
12 I 20 DCM >99 80 (R)
14 m 40 THF >99 97 (R)
15 n 20 THF >99 97 (R)
Example 12. Asymmetric hydrogenation of different unsaturated hydrocarbon compounds with chiral ligand 6 and [Rh(nbd)2]BF4 at room temperature.
The following compounds were hydrogenated in presence of a catalyst of the invention (ligand 6 and [Rh(nbd)2]BF4) at room temperature.
Table 3 summarizes the results obtained.
Table 3. Asymmetric hydrogenation with chiral ligand 6 and [Rh(nbd)2]BF4 at room temperature
Entry Substrate pH2 (bar) Solvent Conv. (%) ee (%)
1 a 20 THF >99 99(R)
2 b 20 THF >99 99(R)
3 C 20 THF >99 99(R)
4 d 20 THF >99 99(R)
5 e 20 THF >99 99(R)
6 f 20 THF >99 99(R)
7 g 20 THF >99 99(R)
8 h 20 THF >99 99(R)
9 i 20 THF >99 99(R)
10 j 20 THF >99 98 (R)
11 k 20 THF >99 96 (R)
12 I 20 DCM >99 99(R)
14 m 40 THF >99 98 (R)
15 n 20 THF >99 98 (R)
Claims
1. An stereoisomerically pure compound of formula I, or a salt thereof, or a N- oxide thereof, or a solvate thereof,
R-I, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, linear or branched (C-ι-C-ι2)alkyl optionally substituted, (C2-C-ι2)alkenyl optionally substituted, (C2-C-ι2)alkynyl optionally substituted, and a radical derived from one of the known ring systems with 1 -4 rings, wherein each one of the rings forming said ring system has 3-7 members, each member independently selected from P,
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially/totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; optionally, Ri and R2 taken together with the atoms to which they are attached, and/or R3 and R4 taken together with the phosphorus atom to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; the substituents being a radical independently selected from the group consisting of: halogen, nitro, hydroxyl, protected hydroxyl, cyano, amino, (Ci-Ci2)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (d-C6)alkylazolyl, tri-(Ci-C6)alkyl-siloxyl, (d-C4)alkoxy, -COR7, -COOR9, -OC(O)R7,
-C(O)NR7R8, -R7NHR8, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, -SO3R9, -NHSO2-R9, -SO2-NR7R8, -NR7R8,
R7 and R8 are independently selected from the group consisting of H and (Ci-Ci2)alkyl; R9 is selected from the group consisting of H, (Ci-C-ι2)alkyl, sodium and potassium.
2. The compound according to claim 1 , wherein R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, and an optionally substituted radical selected from linear or branched (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, naphtyl, oxazolyl, benzofuranyl, dibenzofuranyl, furanyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl; being the substituents selected from the group consisting of: halogen, nitro, hydroxyl, cyano, amino, (d-C6)alkyl, (d-C6)alkylazolyl, tri-(Ci-C6)alkyl-siloxyl, (d-C4)alkoxy, -COR7, -COOR9, -OC(O)R7, -C(O)NR7R8, -R7NHR8, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, -SO3R9, -NHSO2-R9, -SO2-NR7R8, -NR7R8.
3. The compound according to claim 2, wherein
R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, (Ci-C4)alkyl-tri-(Ci- C6)alkyl-siloxyl, phenyl, naphtyl, propynyl, triazolylmethyl, phenylmethyl, phenylethyl, diphenylmethyl and trityl.
4. The compound according to claim 3, wherein R3 and R4 are independently selected from the group consisting of tert-butyl, phenyl, propynyl, triazolylmethyl, phenylmethyl, phenylethyl and trityl.
5. The compound according to claim 3, wherein R5 and R6 are independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, trityl, triazolyl methyl, propynyl, phenyl, diphenylmethyl, phenylmethyl and propyl-triethyl-siloxyl.
6. The compound according to any of claims 1 to 5, wherein R1 and R2 are
5 independently selected from the group consisting of an optionally substituted radical selected from linear or branched (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, naphtyl, oxazolyl, benzofuranyl, dibenzofuranyl, furanyl, pyridazinyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl,0 benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl; or R1 and R2 taken together with the atoms to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,5 C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; 0 being the substitutents selected from the group consisting of: halogen, nitro, hydroxyl, hydroxy protecting-groups, cyano, amino, (d-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (Ci-C6)alkylazolyl, tri -(Ci -C6)a I ky I -s i loxy I , (Ci-C4)alkoxy, -COR7, -COOR9, -OC(O)R7, -C(O)NR7R8, -R7NHR8, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, -SO3R9, -NHSO2-R9, -SO2-NR7R8, 5 -NR7R8.
7. The compound according to claim 6, wherein R1 and R2 are independently selected from the group consisting of phenyl, trityl, naphtyl, tert-butyl, propynyl, and triazolylmethyl; or R1 and R2 taken together with the O atoms to which they are attached, form one of the known ring systems with
1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P, C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and 5 is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; being R1 and R2 optionally substituted by at least one radical selected from the group consisting of: halogen, nitro, hydroxyl, hydroxy protecting- groups, cyano, amino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, (Ci-C6)alkylazolyl, tri-(Ci-C6)alkyl-siloxyl, (d-C4)alkoxy, -COR7, -COOR9, -OC(O)R7, -R7PO(OR7)2, -S-R7, -SO-R7, -SO2-R9, and -SO3R9.
8. The compound according to claim 7, wherein R1 and R2 taken together with the atoms to which they are attached, form one of the known ring systems with 1 -7 rings, wherein each one of the rings forming said ring system has 5-7 members, each member independently selected from P,
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents.
9. The compound according to claim 8, wherein R1 and R2 taken together with the atoms to which they are attached, form a ring system selected from the group consisting of:
C, N, O, S, CH, CH2, NH, is saturated, partially unsaturated or aromatic, and is partially or totally fused, being each ring forming part of the ring system optionally substituted with 1 to 3 substituents; and the dotted line represents the presence or absence of a double bond.
10. The compound according to claim 9, wherein R1 and R2 taken together with the atoms to which they are attached form a L4 ring system with free or restricted rotation.
11. The compound according to claim 10, wherein L4 is selected from the group consisting of:
12. The compound according to claim 11 , wherein the compound is selected from the group consisting of the racemic mixture of the two possible stereoisomers around the biarylic moiety, the substantially pure L4-P stereoisomer, the substantially pure L4-M stereoisomer, and mixtures thereof:
13. The compound of formula I according to any of claims 1 to 12, having one of the following formulae: \-anti, \-syn, ent-\-anti or ent-\-syn:
14. The compound according to any of claims 1 to 13, which is selected from the group consisting of:
2-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2-yloxy)-1 ,3,2- dioxaphospholane;
6-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2- yloxy)dibenzo[c/,/][1 ,3,2]dioxaphosphepine; 6-((1 R,2S)-1 -(diphenylphosphino)-i -phenyl-3-(tritryloxy)propen-2- yloxy)dibenzo[c/,/][1 ,3,2]dioxaphosphepine;
6-((1 S,2R)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropen-2-yloxy)- 2,4,8,10-tetramethyldibenzo[c/,/][1 ,3,2]dioxaphosphepine; (11 bM)-4-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropan-2- yloxy)dinaphtho[2,1 -c/:1 ',2'-/][1 ,3,2]dioxaphosphepine;
(11 bP)-4-((1 R,2S)-1 -(diphenylphosphino)-3-methoxy-1 -phenylpropan-2- yloxy)dinaphtho[2,1 -c/:1 ',2'-/][1 ,3,2]dioxaphosphepine;
15. A catalyst comprising a rhodium complex of a compound as defined in any of claims 1 to 14.
16. A catalyst obtainable by reaction of the compound as defined in any of claims 1 to 14 and a rhodium salt or a rhodium precursor-complex selected from the group consisting of RhA3, RhBC2, L3[RhD4], and [RhE2]F; wherein A is chloride, bromide, iodide, acetate, nitrate, methanesulfonate, triflate, sulfonate, p-toluensulfonate, or acetyl-acetonate;
B is chloride, bromide, acetate, methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenylborate; C is a linear or branched (C2-C-ι2)alkene or (C4-d2)alkadiene; L is lithium, sodium, potassium, ammonium, tetra((Ci-C6)alkyl)ammonium; D is chloride or bromide; E is a (C4-Ci2)alkadiene;
F is methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenylborate.
17. The catalyst according to claim 16, which has one of the following general formulae
[Rh(X)HaI]2, [Rh(COd)X]Y, or [Rh(nbd)X]Y wherein
Hal is selected from the group consisting of chloride, bromide and iodide X is a compound as defined in any of claims 1 to 14; (cod) is 1 ,5-cyclooctadiene; (nbd) is norbornadiene; and Y is selected from the group consisting of methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, and tetraphenylborate.
18. A method for preparing the catalyst of claim 16 which comprises a) reacting in a appropriate solvent a rhodium salt or a rhodium precursor- complex selected from the group consisting of RhA3, RhBC2, L3[RhD4], and [RhE2]F, as defined in claim 16, with a compound as defined in any of claims 1 to 14; wherein
A is chloride, bromide, iodide, acetate, nitrate, methanesulfonate, triflate, sulfonate, p-toluensulfonate, or acetyl-acetonate; B is chloride, bromide, acetate, methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenylborate;
C is a linear or branched (C2-C-ι2)alkene or (C4-d2)alkadiene;
L is lithium, sodium, potassium, ammonium, tetra((Ci-C6)alkyl)ammonium; D is chloride or bromide;
E is a (C4-Ci2)alkadiene;
F is methanesulfonate, triflate, tetrafluoroborate, hexafluorophosphate, perchlorate, hexafluoroantimoniate, tetra(bis-3,5-trifluoromethylphenyl)borate, or tetraphenyl borate.
19. Use of the compound as defined in any of claims 15 to 18, as catalyst for the asymmetric hydrogenation reaction of unsaturated hydrocarbon compounds.
20. Use according to claim 19, wherein the unsaturated hydrocarbon compound is an acrylic acid derivative or an enamine derivative.
21. Use according to any of claim 19 to 20, wherein the unsaturated hydrocarbon compound has the formula II:
wherein:
R-io, R-I-I, R-I2 and Ri3 are independently selected from the group consisting of hydrogen, hydroxyl, fluoride, chloride, bromide, iodide, NO2, linear or branched (Ci-C-ι2)alkyl optionally substituted, (C2-d2)alkenyl optionally substituted, (C2-d2)alkynyl optionally substituted, COORi4, NRi4Ri5, and phenyl optionally substituted; the substituents being a radical independently selected from the group consisting of: fluoride, bromide, chloride, iodide, nitro, hydroxyl, cyano, amino, (CrCi2)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (CrC6)alkylazolyl,
(Ci-C4)alkoxy, -CORi4, -COORi4, -OC(O)Ri4, -C(O)NRi4Ri5, -Ri4NHRi5,
-Ri4PO(ORi5)2, -S-Ri4, -SO-Ri4, -SO2-Ri4, -SO3Ri4, -NHSO2-Ri4, -SO2- 
Ri4 and Ri5 are independently selected from the group consisting of H and alkyl(Ci-Ci2), CH3COO-, protected amino, protected hydroxyl, protected carboxy, sodium and potassium; and wherein at least one of Ri0, Rn, Ri2 and Ri3 is a COORi4 or NRi4Ri5 radical.
22. Use according to any of claims 19 to 21 , wherein the unsaturated hydrocarbon is selected from the group consisting of:
CO2Me CO2Me CO2H CO2H
Ph Ph
NHAc NHAc NHAc NHAc
Me ^,NHAc
COpMe WC°; CO2Me
Ph Ph Ph
NHBoc CO2Me NHFmoc
23. A process for the asymmetric hydrogenation of unsaturated hydrocarbon compounds, which comprises contacting an unsaturated hydrocarbon compound with the catalyst as defined in any of claims 15 to 18, and hydrogen under appropriate conditions of hydrogenation.
24. The process according to claim 23, wherein the hydrogenation is carried out in presence of a solvent selected from the group consisting of dichloromethane, tetrahydrofurane, hexane, heptane, toluene or mixtures thereof.
25. The process according to any of claims 23 to 24, wherein the hydrogenation is carried out at a temperature between -60 0C and 100 0C.
26. The process according to claim 25, wherein the hydrogenation is carried out at a temperature between -40 0C and room temperature.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2392875A1 (en) * | 2011-06-01 | 2012-12-14 | Consejo Superior De Investigaciones Científicas (Csic) | Hydrogenation catalysts enantioselectiva based on phosphines-chiral phosphites linked to polystyrene resins. (Machine-translation by Google Translate, not legally binding) |
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2008
- 2008-08-28 WO PCT/EP2008/061264 patent/WO2009030626A1/en active Application Filing
Non-Patent Citations (4)
| Title |
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| BERGAMINI ET AL: "Template Synthesis of Chiral Vicinal Diphosphinites as Their PtII and PdII Complexes", EUR. J. INORG. CHEM., 2003, pages 918 - 925, XP002460551 * |
| DEERENBERG, SIRIK ET AL: "Chiral Phosphine-Phosphite Ligands in the Highly Enantioselective Rhodium-Catalyzed Asymmetric Hydrogenation", JOURNAL OF ORGANIC CHEMISTRY , 66(23), 7626-7631 CODEN: JOCEAH; ISSN: 0022-3263, 2001, XP002460550 * |
| SCHERER, JOHANNES ET AL: "Chiral tripodal ligands bearing a phosphite donor group: synthesis and coordination chemistry", CHEMISCHE BERICHTE , 129(6), 697-713 CODEN: CHBEAM; ISSN: 0009-2940, 1996, XP002460549 * |
| VARGAS ET AL: "Asymmetric hydrogenation of imines catalyzed by iridium complexes with phosphine?phosphite ligands: importance of backbone flexibility", TETRAHEDRON LETT., vol. 46, 2005, pages 2049 - 2052, XP004768403 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2392875A1 (en) * | 2011-06-01 | 2012-12-14 | Consejo Superior De Investigaciones Científicas (Csic) | Hydrogenation catalysts enantioselectiva based on phosphines-chiral phosphites linked to polystyrene resins. (Machine-translation by Google Translate, not legally binding) |
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