WO2011056737A1 - Novel chiral phosphorus ligands - Google Patents
Novel chiral phosphorus ligands Download PDFInfo
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- WO2011056737A1 WO2011056737A1 PCT/US2010/054912 US2010054912W WO2011056737A1 WO 2011056737 A1 WO2011056737 A1 WO 2011056737A1 US 2010054912 W US2010054912 W US 2010054912W WO 2011056737 A1 WO2011056737 A1 WO 2011056737A1
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- Prior art keywords
- formula
- membered
- alkyl
- compound
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- 239000003446 ligand Substances 0.000 title abstract description 35
- 229910052698 phosphorus Inorganic materials 0.000 title abstract description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title abstract description 9
- 239000011574 phosphorus Substances 0.000 title abstract description 9
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 84
- -1 -(Q-C^alkyl Chemical group 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- IYGMJRCUQOOENU-UHFFFAOYSA-N oxaphosphole Chemical compound C1=COP=C1 IYGMJRCUQOOENU-UHFFFAOYSA-N 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 33
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 31
- 150000004696 coordination complex Chemical class 0.000 claims description 30
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 150000001993 dienes Chemical class 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- 150000003624 transition metals Chemical class 0.000 claims description 6
- 150000001336 alkenes Chemical class 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 4
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 abstract description 9
- 239000002184 metal Substances 0.000 abstract description 9
- 239000003054 catalyst Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 39
- 238000002360 preparation method Methods 0.000 description 38
- 239000010948 rhodium Substances 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000004679 31P NMR spectroscopy Methods 0.000 description 25
- 239000010410 layer Substances 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 235000019439 ethyl acetate Nutrition 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 239000012267 brine Substances 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 125000002619 bicyclic group Chemical group 0.000 description 6
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 6
- CAVTUIDTRDJLGP-DOOQXGAZSA-N (2r,3r)-3-tert-butyl-2-[(2r,3r)-3-tert-butyl-2h-1,3-benzoxaphosphol-2-yl]-2h-1,3-benzoxaphosphole Chemical compound O1C2=CC=CC=C2[P@@](C(C)(C)C)[C@@H]1[C@H]1[P@](C(C)(C)C)C2=CC=CC=C2O1 CAVTUIDTRDJLGP-DOOQXGAZSA-N 0.000 description 5
- CAVTUIDTRDJLGP-HKDRDPIHSA-N (2s,3s)-3-tert-butyl-2-[(2s,3s)-3-tert-butyl-2h-1,3-benzoxaphosphol-2-yl]-2h-1,3-benzoxaphosphole Chemical compound O1C2=CC=CC=C2[P@](C(C)(C)C)[C@H]1[C@@H]1[P@@](C(C)(C)C)C2=CC=CC=C2O1 CAVTUIDTRDJLGP-HKDRDPIHSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 5
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- LDIOUQIXNSSOGU-UHFFFAOYSA-N 8-(3-pentylamino)-2-methyl-3-(2-chloro-4-methoxyphenyl)-6,7-dihydro-5h-cyclopenta[d]pyrazolo[1,5-a]pyrimidine Chemical compound CC1=NN2C(NC(CC)CC)=C3CCCC3=NC2=C1C1=CC=C(OC)C=C1Cl LDIOUQIXNSSOGU-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 229910052703 rhodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- ZDHXKXAHOVTTAH-UHFFFAOYSA-N trichlorosilane Chemical compound Cl[SiH](Cl)Cl ZDHXKXAHOVTTAH-UHFFFAOYSA-N 0.000 description 4
- 239000005052 trichlorosilane Substances 0.000 description 4
- HPJGEESDHAUUQR-SKGSPYGFSA-N (2s)-2-[[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-1-[(2s)-5-(diaminomethylideneamino)-2-[[(2s)-2-[[(2s)-3-naphthalen-2-yl-2-(3-pyridin-3-ylpropanoylamino)propanoyl]amino]-3-phenylpropanoyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]buta Chemical compound NC(=O)C[C@@H](C(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=C2C=CC=CC2=CC=1)NC(=O)CCC=1C=NC=CC=1)CC1=CC=CC=C1 HPJGEESDHAUUQR-SKGSPYGFSA-N 0.000 description 3
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical group C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- KAFZOLYKKCWUBI-HPMAGDRPSA-N (2s)-2-[[(2s)-2-[[(2s)-1-[(2s)-3-amino-2-[[(2s)-2-[[(2s)-2-(3-cyclohexylpropanoylamino)-4-methylpentanoyl]amino]-5-methylhexanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]butanediamide Chemical compound N([C@@H](CC(C)C)C(=O)N[C@@H](CCC(C)C)C(=O)N[C@@H](CN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CC(N)=O)C(N)=O)C(=O)CCC1CCCCC1 KAFZOLYKKCWUBI-HPMAGDRPSA-N 0.000 description 2
- KVPCVNGTJXEQKH-OBMDHMNCSA-N (2s,3s)-3-tert-butyl-2-[(2s,3s)-3-tert-butyl-4-methoxy-2h-1,3-benzoxaphosphol-2-yl]-4-methoxy-2h-1,3-benzoxaphosphole Chemical compound O1C2=CC=CC(OC)=C2[P@](C(C)(C)C)[C@H]1[C@H]1OC(C=CC=C2OC)=C2[P@@]1C(C)(C)C KVPCVNGTJXEQKH-OBMDHMNCSA-N 0.000 description 2
- KIUPCUCGVCGPPA-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) carbonochloridate Chemical compound CC(C)C1CCC(C)CC1OC(Cl)=O KIUPCUCGVCGPPA-UHFFFAOYSA-N 0.000 description 2
- DPZNOMCNRMUKPS-UHFFFAOYSA-N 1,3-Dimethoxybenzene Chemical compound COC1=CC=CC(OC)=C1 DPZNOMCNRMUKPS-UHFFFAOYSA-N 0.000 description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- KLIDCXVFHGNTTM-UHFFFAOYSA-N 2,6-dimethoxyphenol Chemical group COC1=CC=CC(OC)=C1O KLIDCXVFHGNTTM-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- QUMCIHKVKQYNPA-RUZDIDTESA-N C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC Chemical compound C1(CCCCC1)CN1[C@@H](C=2N(C=3C=NC(=NC1=3)NC1=C(C=C(C(=O)NC3CCN(CC3)C)C=C1)OC)C(=NN=2)C)CC QUMCIHKVKQYNPA-RUZDIDTESA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229910021592 Copper(II) chloride Inorganic materials 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical compound CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N but-2-ene Chemical compound CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- CDPKWOKGVUHZFR-UHFFFAOYSA-N dichloro(methyl)phosphane Chemical compound CP(Cl)Cl CDPKWOKGVUHZFR-UHFFFAOYSA-N 0.000 description 2
- LWNLXVXSCCLRRZ-UHFFFAOYSA-N dichlorophosphane Chemical compound ClPCl LWNLXVXSCCLRRZ-UHFFFAOYSA-N 0.000 description 2
- ZWWQRMFIZFPUAA-UHFFFAOYSA-N dimethyl 2-methylidenebutanedioate Chemical compound COC(=O)CC(=C)C(=O)OC ZWWQRMFIZFPUAA-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- KKSOKTQAWHCIMG-UHFFFAOYSA-N tert-butyl 4-bromo-2-methylbenzoate Chemical compound CC1=CC(Br)=CC=C1C(=O)OC(C)(C)C KKSOKTQAWHCIMG-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 239000012485 toluene extract Substances 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- SJNUZTRUIDRSJK-KNCCTNLNSA-N (1s,2r)-1-tert-butyl-2-[(1s,2r)-1-tert-butylphospholan-2-yl]phospholane Chemical compound CC(C)(C)[P@]1CCC[C@@H]1[C@@H]1[P@@](C(C)(C)C)CCC1 SJNUZTRUIDRSJK-KNCCTNLNSA-N 0.000 description 1
- BXSSCSKCOFKPOK-ARGVQFGUSA-N (2s)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-n-[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-[[(2s)-1-amino-1-oxohexan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1h-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3- Chemical compound C([C@@H](C(=O)N[C@@H](CCCC)C(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C(C)C)C1=CC=CC=C1 BXSSCSKCOFKPOK-ARGVQFGUSA-N 0.000 description 1
- WNLRJVGYKJCADM-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) hydrogen carbonate Chemical compound CC(C)C1CCC(C)CC1OC(O)=O WNLRJVGYKJCADM-UHFFFAOYSA-N 0.000 description 1
- UXKLQDCALAWFIU-VKNDCNMPSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-tetradecoxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCCCC)C1=CC=CC=C1 UXKLQDCALAWFIU-VKNDCNMPSA-N 0.000 description 1
- VGNCBRNRHXEODV-XXVHXNRLSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-6-dodecoxy-4,7-dihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@H](O)[C@H](C(O2)(C(O)=O)C(O)(C(O1)C(O)=O)C(O)=O)OCCCCCCCCCCCC)C1=CC=CC=C1 VGNCBRNRHXEODV-XXVHXNRLSA-N 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 1
- AEBWATHAIVJLTA-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydropentalene Chemical compound C1CCC2CCCC21 AEBWATHAIVJLTA-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- QTYUSOHYEPOHLV-FNORWQNLSA-N 1,3-Octadiene Chemical compound CCCC\C=C\C=C QTYUSOHYEPOHLV-FNORWQNLSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- MWVBVDJUFFMLAR-UHFFFAOYSA-N 3-acetamidoprop-2-enoic acid Chemical class CC(=O)NC=CC(O)=O MWVBVDJUFFMLAR-UHFFFAOYSA-N 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000005508 decahydronaphthalenyl group Chemical group 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 125000005046 dihydronaphthyl group Chemical group 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- XNMQEEKYCVKGBD-UHFFFAOYSA-N dimethylacetylene Natural products CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- QKZWXPLBVCKXNQ-ROJLCIKYSA-N dipamp Chemical compound COC1=CC=CC=C1[P@@](C=1C=CC=CC=1)CC[P@@](C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-ROJLCIKYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 125000005298 iminyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- SYTLRIRYZMOMIO-UHFFFAOYSA-N lithium;1,3-dimethoxybenzene-2-ide Chemical compound [Li+].COC1=CC=CC(OC)=[C-]1 SYTLRIRYZMOMIO-UHFFFAOYSA-N 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- YSMZEMQBSONIMJ-UHFFFAOYSA-M magnesium;2-methanidylpropane;chloride Chemical compound [Mg+2].[Cl-].CC(C)[CH2-] YSMZEMQBSONIMJ-UHFFFAOYSA-M 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- BGXZIBSLBRKDTP-UHFFFAOYSA-N methyl 9-(4-chloroanilino)-[1,3]thiazolo[5,4-f]quinazoline-2-carboximidate Chemical compound C12=C3SC(C(=N)OC)=NC3=CC=C2N=CN=C1NC1=CC=C(Cl)C=C1 BGXZIBSLBRKDTP-UHFFFAOYSA-N 0.000 description 1
- 125000001620 monocyclic carbocycle group Chemical group 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 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
- C07F9/6568—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 atoms as the only ring hetero atoms
- C07F9/65685—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 atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
-
- 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
-
- 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
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
Definitions
- the present invention relates to a series of novel chiral phosphorus ligands and their metal complexes as catalysts for applications in asymmetric hydro genation. More particularly, the present invention relates to the transition metal complexes of these novel phosphine ligands and their use as catalysts in asymmetric hydro genation.
- Asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines has become one of most efficient methods for constructing chiral compounds. It also accounts for the major asymmetric catalytic transformation at commercial scales. Development of efficient chiral phosphorus ligands is essential for the success of asymmetric hydrogenation.
- Known chiral phosphorus ligands in this field include Knowles' DIP AMP [Knowles, W. S. Acc. Chem. Res. 1983, 16, 106], Kagan's DIOP [Kagan et al, J. Am. Chem. Soc. 1972, 94, 6429], Noyori' s BINAP [Noyori, R. Chem. Soc. Rev. 1989, 18, 187], Burk's Duphos and BPE [Burk, M. J. et al,
- FIG. 1 shows an x-ray crystal structure of Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 (the H atoms are omitted), where each of the letters on the atoms (C, O, P, Rh, B, and F) refer to carbon, oxygen, phosphorus, rhodium, boron and fluorine, respectively.
- nbd norbornadiene
- TfO " trifluoromethanesulfonate or triflate
- the present invention relates to novel phosphine ligands, novel metal complexes containing the novel phosphine ligands of the invention, and methods of using the novel metal complexes to carry out asymmetric hydrogenations as described below.
- the present invention relates to a compound of formula (la), (lb), or a mixture thereof ("the phosphine ligand of the invention”):
- X is O, S, or -NR 5 ;
- R 1 is -(Ci-C 6 )alkyl, -CF 3 , -(C3-C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 - C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -Cio)aryl and -(5 to 11- membered)heteroaryl of said R 1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, and -CF 3 ;
- R 2 is H, -0(Ci-C 6 )alkyl, -(C 1 -C 6 )alkyl, -(C 3 -Ci 0 )carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, -NR 5 R 6 , or -SR 5 ; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C 6 - C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C 1 -C 6 )alkyl, -(C 1 -C 6 )al
- R 3 is -PR 7 R 8 , -CH 2 PR 7 R 8 , -CH 2 OPR 7 R 8 , or a group of formula (A) or (B):
- R 4 is H, -(CrC 6 )alkyl, -(C 3 -C 6 )cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, (5- to 6-membered)heteroaryl, or -SiR 5 3 ; wherein said -(Ci-C 6 )alkyl of said R 4 is optionally substituted with 1 to 3 substituents independently selected from -0(C - C 6 )alkyl, -(C 3 -C 6 )cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl; and wherein said -(C 3 -C 6 )cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, and (5- to 6- membered)heteroaryl of said R 4 is optionally substituted with 1 to 3 substituents independently selected from
- R 5 and R 6 are each independently H, -(CrC 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, or -(5 to l l-membered)heteroaryl; wherein each -(Ci-C 6 )alkyl, -CF 3 , -(C3-C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R 5 and R 6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(C 1 -C 6 )alkyl, -(C
- R 7' and R 8° are each independently -(Ci-C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl,
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the embodiment described immediately above, wherein X is O.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein X is S
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein X is NR 5 .
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to any of the preceding embodiments, wherein R 1 is -(Q- C 6 )alkyl selected from -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , or
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 1 is -(C 3 -C 1 o)carbocyclyl selected from cyclopentyl, cyclohexyl, and 1-adamantyl.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 1 is -(C 6 -C 1 o)aryl selected from phenyl, ortho-tolyl, para-tolyl, 3,5-dimethylphenyl, 3,5-di-i- butylphenyl, 3,5-di-CF 3 -phenyl, ortho-CF 3 -phenyl, ortho-anisyl, and naphthyl.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according any of the preceding embodiments, wherein R is H, -CH 3 or -OCH 3 .
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above wherein R is phenyl.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according any of the preceding embodiments, wherein R 4 is -H.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 4 is -(C 1 -C 6 )alkyl optionally substituted with 1 to 3 substituents independently selected from -OCH 3 , -(C 3 -C 6 )cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the embodiment described immediately above, wherein R 4 is -CH 2 (chiral oxazoline) or -CH 2 (o/ /iosubstituted pyridine).
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R 4 is a -(5- to 6-membered)heteroaryl selected from ori/iosubstituted pyridine, oxazoline, and chiral oxazoline.
- the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to any of the preceding embodiments, wherein R 3 is -PR 7 R 8 or a group of formula (A) ("the bis-phosphine ligand of the invention")
- the invention relates to a bis-phosphine ligand of the invention, wherein R 1 is -C(CH 3 ) 3 ; R 2 is -H, -CH 3 , -OCH 3 , or phenyl; and R 3 is -PR 7 R 8 .
- the invention relates to a bis-phosphine ligand of the invention, wherein R 7 and R 8 are each independently H, -(Ci-C 6 )alkyl, or -(C 3 -C 6 )cycloalkyl.
- the invention relates to a bis-phosphine ligand of the invention, wherein R 7 and R 8 are each -C(CH 3 ) 3 .
- the invention relates to a bis-phosphine ligand of the invention, wherein, X is S.
- the invention relates to a bis-phosphine ligand of the invention, wherein, X is O.
- the invention relates to a bis-phosphine ligand of the invention, wherein, X is NR 5 .
- the invention relates to a bis-phosphine ligand of the invention, wherein X is O, R 1 is -C(CH 3 ) 3 ; R 2 is -H, -CH 3 , -OCH 3 , or phenyl; and R 3 is -PR 7 R 8 .
- the invention relates to a bis-phosphine ligand of the invention, wherein R 3 is a group of formula (A) or (B).
- the invention relates to a bis-phosphine ligand of the invention, according to the embodiment described immediately above, wherein R 1 is -C(CH 3 ) 3 ; and R 2 is -H, -CH 3 , -OCH 3 , or phenyl.
- the invention relates to a bis-phosphine ligand of the invention, wherein X is O; R 1 is -C(CH 3 ) 3 ; and R2 is -H, -CH 3 , -OCH 3 , or phenyl; and R 3 is a group of formula of formula (A) or (B)..
- the invention relates to a bis-phosphine ligand of the invention having the formula (Ila) or (lib)
- R 1 is -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 )(CH 3 ) 2 , cyclohexyl, 1-adamantyl, phenyl, ortho- tolyl, 3,5-xylyl, ortho-anisyl, or ferrocenyl ; and
- R 2 is H, -OCH 3 , -CH 3 , -CF 3 , phenyl, or -N(CH 3 ) 2 .
- the invention relates to a bis-phosphine ligand of the invention having the formula (Ilia) or (Illb):
- R 1 is -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 )(CH 3 ) 2 , cyclohexyl, or 1-adamantyl;
- R is H, -OCH 3 , -CH 3 , -CF 3 , phenyl, or -N(CH 3 ) 2 ; and R 7 and R 8 are each -C(CH 3 ) 3 .
- the invention relates to a phosphine ligand of the invention selected from:
- the invention relates to complexes formed between a transition metal and the phosphine ligands of the invention. Accordingly, in one embodiment, the invention relates to a metal complex of formula (IVa), (IVb), (Va) or (Vb) ("the metal complexes of the invention"):
- M is a transition metal selected from Co, Ni, Pd, Pt, Cu, Ag, Au, Ru, Fe, Rh and Ir;
- a " is a counter anion;
- n is the oxidation state of the transition metal M;
- L 1 and L2 are each olefins, or L 1 and L2 together represent a diolefin;
- X is O, S, or -NR 5 ;
- R 1 is -(Ci-C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 - C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl and -(5 to 11- membered)heteroaryl of said R 1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, and -CF 3 ;
- R is H, -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, -(C 3 -Ci 0 )carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, -NR 5 R 6 , or -SR 5 ; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C 6 - C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C 1 -C 6 )alkyl, -(C 1 -C 6 )alkyl
- each -(C 1 -C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, and -(5 to l l-membered)heteroaryl of said R 5 and R 6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(Ci-C 6 )alkyl, -(Ci-C 6 )alkyl, and -CF 3 ; and
- R 7' and R 8° are each independently -(C 1 -C 6 )alkyl, -CF 3 , -(C 3 -C 1 o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C 6 -C 1 o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C 3 -C 1 o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, yl and -(5 to 1 l-membered)heteroaryl of said R 7 and R 8
- -(C 6 -C 1 o)ar are each optionally independently substituted with 1 to 3 substituents independently selected from -0(C - C 6 )alkyl, -(C 1 -C 6 )alkyl, and -CF 3 .
- the invention relates to a metal complex of the invention wherein M is Rh and n is i.
- the invention relates to a metal complex of the invention according to any of the two embodiments described immediately above, wherein A " is BF 4 " , SbF 6 " , TfO ,B(C 6 H 5 ) 4 “ , B[3,5-(CF 3 ) 2 C 6 H 3 ] 4 -, or PF 6 " .
- the invention relates to a metal complex of the invention according to any of the three embodiments described immediately above, wherein M is Rh, A " is BF 4 " , and n is i.
- the invention relates to a metal complex of the invention according to any of the four embodiments described immediately above, wherein R 1 is -C(CH 3 ) 3 , and R 2 is -H, -CH 3 , -OCH 3 , or phenyl.
- the invention relates to a metal complex of the invention wherein
- L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
- the invention relates to a metal complex of the invention, wherein the metal complex is of formula (IVa).
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 ⁇ ; and n is 1.
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
- the invention relates to a metal complex of the invention, wherein the metal complex is of formula (Va).
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 " ; and n is 1.
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
- the invention relates to a metal complex of the invention, wherein the metal complex is of formula (IVb).
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 " ; and n is 1.
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
- the invention relates to a metal of the invention, wherein the metal complex is of formula (Vb).
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A " is BF 4 ⁇ ; and n is 1.
- the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
- the invention relates to a metal complex of the invention selected from:
- the invention relates to a process for the asymmetric hydrogenation of a compound having a carbon-carbon or carbon-heteroatom double bond ("the asymmetric hydrogenation process of the invention"), the process comprising allowing said compound having a carbon-carbon or carbon-heteroatom double bond to react with hydrogen in the presence of a catalytic amount of the metal complex of the invention described in any of the embodiments above.
- carbon- heteroatom double bonds include those formed between carbon and nitrogen, oxygen, or sulfur.
- carbon-heteroatom double bond is formed between carbon and nitrogen or carbon and oxygen.
- the invention relates to the asymmetric hydrogenation process of the invention in the embodiment described immediately above, wherein L 1 and L 2 together represent norbornadiene.
- the invention relates to the asymmetric hydrogenation process of the invention in the broadest embodiment described above, wherein L 1 and L 2 together represent octadiene.
- the invention relates to the asymmetric hydrogenation process of the invention in any of the embodiments described above, wherein M is Rh, A " is BF 4 ⁇ , and n is i.
- the invention relates to the asymmetric hydrogenation process of the invention in any of the embodiments described above, wherein R 1 is -C(CH 3 ) 3 ; R 2 is - H, -CH 3 , -OCH 3 , or phenyl; and R 7 and R 8 are each -C(CH 3 ) 3 .
- compounds of the invention refers to the phosphine ligands of the invention (including bis-phosphine ligands of the invention) and the metal complexes of the invention.
- isotopically-labelled form of a compound of the present invention is identical to said compound of the invention but for the fact that one or more atoms of said compound of the invention have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature.
- isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon,
- a compound of the present invention which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the present invention.
- the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. All such isomeric forms of these compounds are expressly included in the present invention.
- Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
- Some of the compounds of the invention can exist in more than one tautomeric form.
- the invention includes methods using all such tautomers.
- C 1-6 alkoxy or "0(Ci- 6)alkyl” is a (C 1-6 )alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy.
- All alkyl, alkenyl, and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows: The term “alkyl” refers to both branched and unbranched alkyl groups.
- alk or “alkyl” prefix refers to analogs according to the above definition of “alkyl”.
- terms such as “alkoxy”, “alkythio” refer to alkyl groups linked to a second group via an oxygen or sulfur atom.
- one or more carbon atoms can be optionally replaced by heteroatoms such as O, S or N. It shall be understood that if N is not substituted then it is NH. It shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain.
- Such groups can be substituted as herein above described by groups such as oxo to result in definitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
- nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
- nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
- a -S-C 1-6 alkyl radical unless otherwise specified, shall be understood to include -S(0)-C 1-6 alkyl and
- (C3_ 1 o)carbocycle refers to a nonaromatic 3 to 10-membered (but preferably, 3 to 6-membered) monocyclic carbocyclic radical or a nonaromatic 6 to 10-membered fused bicyclic, bridged bicyclic, or spirocyclic carbocyclic radical.
- the C3.10 carbocycle may be either saturated or partially unsaturated, and the carbocycle may be attached by any atom of the cycle which results in the creation of a stable structure.
- Non-limiting examples of 3 to 10-membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, and cyclohexanone.
- Non-limiting examples of 6 to 10-membered fused bicyclic carbocyclic radicals include bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decanyl (decahydronaphthalenyl).
- Non-limiting examples of 6 to 10-membered bridged bicyclic carbocyclic radicals include bicyclo [2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl.
- Non-limiting examples of 6 to 10-membered spirocyclic carbocyclic radicals include but are not limited to spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl.
- the term "(C 6-1 o)aryl" refers to aromatic hydrocarbon rings containing from six to ten carbon ring atoms.
- C 6-10 aryl includes monocyclic rings and bicyclic rings where at least one of the rings is aromatic.
- Non-limiting examples of C 6 -io aryls include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl.
- (5 to l l-membered)heterocycle refers to a stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical.
- the 5 to 11-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur.
- the heterocycle may be either saturated or partially unsaturated.
- Non-limiting examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l,l-dioxo-l 6 -thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl.
- Non-limiting examples of nonaromatic 6 to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl.
- Non-limiting examples of nonaromatic 6 to 11-membered bridged bicyclic radicals include 2- azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl.
- Non-limiting examples of nonaromatic 6 to 11-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza- spiro[3,4]octanyl.
- (5 to l l-membered)heteroaryl refers to an aromatic 5 to 6-membered monocyclic heteroaryl or an aromatic 7 to 11-membered heteroaryl bicyclic ring where at least one of the rings is aromatic, wherein the heteroaryl ring contains 1-4 heteroatoms such as N, O and S.
- Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl.
- Non-limiting examples of 7 to 11-membered heteroaryl bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl and benzothiazolyl.
- heteroatom as used herein shall be understood to mean atoms other than carbon such as O, N, and S.
- halogen as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine.
- alkyl a non-limiting example would be -CH 2 CHF 2 , -CF 3 etc.
- olefin refers to an unsaturated hydrocarbon containing carbon atoms linked by a double bond (i.e., an alkene) such as, for example, ethylene, propene, 1-butene, 2-butene, styrene, norbornadiene, or cyclooctadiene.
- alkene such as, for example, ethylene, propene, 1-butene, 2-butene, styrene, norbornadiene, or cyclooctadiene.
- diolefin refers an unsaturated hydrocarbon containing two pairs of carbon atoms linked by double bonds, e.g., norbornadiene, or cyclooctadiene.
- the invention also provides processes for making compounds of formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb.
- R 1 , R 2 , R 3 , R 4 R 7 , R 8 , L 1 , L 2 , A, M and n in the formulas below shall have the meaning of R 2 , R 3 , R 4 R 7 , R 8 , L 1 , L 2 , A, M and n in formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb of the invention described herein above.
- reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.
- TLC thin layer chromatography
- intermediates and products may be purified by chromatography on silica gel and/or by recrystallization.
- dichlorophosphine of formula VII in a suitable solvent, in the presence of an alkyl magnesium chloride and hydrogen peroxide provides a phosphine oxide of formula VIII.
- Demethylation of the methoxy groups of compound IX by a reagent such as boron tribromide (BBr 3 ) followed by cyclization provides the corresponding cyclized intermediate of formula X.
- Resolution of the intermediate X using a resolving agent such as (+) menthyl chloroformate provides the corresponding ( R ) isomer of formula XIa.
- the hydroxyl group of compound XIa may be modified to other groups, such as methoxy, aryl etc., under standard reaction conditions known in the literature, to provide a compound of formula Xlla.
- Reaction of the compound of formula Xlla, in a suitable solvent, in the presence of suitable base and copper chloride provides the corresponding bisphosphine oxide of formula XHIa.
- Reduction of the bisphosphine oxide XHIa provides a compound of formula la or Ila.
- resolution of the intermediate X using a resolving agent such as (-) menthyl chloroformate provides the corresponding ( S ) isomer Xlb which may be converted to compounds of formula lb or lib using the above Scheme.
- Compounds of formula Ilia and Illb may be prepared as illustrated in Scheme 2.
- reaction of a compound of formula Xllb, obtained via Scheme 1, with a phosphorus chloride of formula XIV, in the presence of a suitable base and hydrogen peroxide provides a bisphosphine oxide of formula XVb.
- Reduction of the bisphosphine oxide XVb as in Scheme 1, provides a compound of formula Illb.
- a compound of formula Xlla may be converted to a compound of formula Ilia using the method depicted in Scheme 2.
- reaction of a compound of formula Ila with a transition metal salt [ ⁇ ( ⁇ 2 )] ⁇ + nA ⁇ provides a compound of formula IVa.
- reaction of a compound of formula Illb with a transition metal salt [ ⁇ ( ⁇ 2 )] ⁇ + nA " provides a compound of formula Vb.
- dichlorophosphine of formula VII in a suitable solvent, in the presence of an alkyl magnesium chloride and hydrogen peroxide provides a phosphine oxide of formula XVII.
- X O, S or NR 5 , PG 1 1 and PG 2" are suitable protecting groups such as methyl, benzyl, methoxymethyl etc. Iodination of the phosphine oxide XVII, in a suitable solvent, in the presence of a suitable base, provides the iodinated intermediate of formula XVIII.
- Example 1 Preparation of ieri-butyl(2,6-dimethoxyphenyl)(methyl)phosphine oxide (1).
- dichloromethylphosphine (6.61 g, 57 mmol, 1.0 equiv.) in THF (50 mL) was added dropwise 1.0 M iBuMgCl (57 mL, 57 mmol, 1.0 equiv.) over 1 h while controlling the reaction temperature ⁇ - 10°C.
- the mixture was stirred at -10 to 0°C for 1 h and then warmed to 25°C over 1 h and stirred at 25°C for at least 1 h.
- the dichloromethane layer was washed with brine (300 mL), dried over magnesium sulfate, and purified by column chromatography (eluents: EtOAc to EtOAc/MeOH 4/1; monitored at 290 nm) to provide 1 as a thick oil (9.5 g, 37 mmol, 65 %).
- Example 2 Preparation of ieri-butyl(2,6-dimethoxyphenyl)(iodomethyl)phosphine (2). To a solution of 1 (7.4 g, 28.9 mmol, 1 equiv.) and TMEDA (6.50 mL, 43 mmol, 1.5 equiv.) in THF (40 mL) at -78°C was added 2.5 M BuLi in hexanes (13.9 mL, 35 mmol, 1.2 equiv.) over 10 min. The resulting mixture was stirred at -78°C for 1 h.
- Example 3 Preparation of racemic 3-ieri-butyl-2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3).
- BBr 3 2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3).
- BBr 3 2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3).
- BBr 3 21.2 g, 64.8 mmol, 4 equiv.
- MeOH 200 mL
- MeOH 200 mL X3
- the CH 2 C1 2 layer was separated, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluents: hexanes to EtOAc) to provide the triflate product (65 mg, 0.18 mmol, 82%) as white solid.
- Example 6 Preparation of (2 l S , ,2' l S , ,3R,3'R)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole bisoxide (7a). To a solution of 6a (155 mg, 0.737 mmol, 1 equiv) in THF (4 mL) at -78°C was added LDA (0.49 mL, 1.8 M in
- dichloromethane solution was washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:THF 3: 1 to 2: 1) to provide 7a (93 mg, 0.22 mmol, 60%) as white solid.
- Example 7 Preparation of (2 l S , ,2' l S , ,3 l S , ,3' l S , )-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole bisoxide (8a).
- 8a To a solution of 7a (70 mg, 0.17 mmol, 1 equiv), triethylamine (169 mg, 1.7 mmol, 10 equiv) in toluene (10 mL) at 25°C was added trichlorosilane (114 mg, 0.84 mmol, 5 equiv).
- the mixture was heated to 80°C and stirred under nitrogen for 12 h. To the mixture at 0°C was added degassed 30% NaOH (10 mL) over 5 min. The resulting mixture was stirred at 60°C for about 1 h until the two layers became clear.
- the toluene layer was separated under N 2 and the aqueous layer was further extracted with toluene twice (5 mL X 2). The combined toluene was dried over Na 2 S0 4 , concentrated under N 2 , and purified by passing through a neutral alumina plug (eluent: hexanes/ether 1/1) to provide 8a (60 mg, 0.155 mmol, 93 %) as white solid.
- Example 10 Preparation of ((2 l S , ,2' l S , ,3R,3'R)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7b).
- 6b 150 mg, 0.624 mmol
- THF 5 mL
- LDA 0.416 mL, 0.749 mmol, 1.2 equiv
- Example 11 (25,2'5,35,3 , 5)-3,3 , -di-ieri-butyl-4,4 , -dimethoxy-2,2 , ,3,3 , -tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole (8b).
- 7b 100 mg, 0.209 mmol
- triethylamine 422 mg, 4.18 mmol, 20 equiv
- the combined toluene solution was dried over sodium sulfate, concentrated under N 2 , and purified by passing through a neutral alumina plug (eluent: hexanes/ether 5/1) to provide 8b (70 mg, 0.157 mmol, 75%) as a white solid.
- Example 13 Preparation of (R)-3-tert-butyl-4-phenyl-2,3- dihydrobenzo[d][l,3]oxaphosphole.
- phenylboronic acid (1.02 g, 8.37 mmol, 1.5 equiv)
- Pd 2 dba 3 153 mg, 0.17 mmol, 3 mol%)
- PCy 3 (0.31 g, 1.12 mmol, 20 mol
- potassium fluoride (1.30 g, 23.3 mmol, 4.0 equiv) was charged degassed dioxane (30 mL).
- Example 14 Preparation of (25,2'5,3R,3'R)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7c).
- Compound 7c was prepared as a white solid (43%) under similar conditions to those described for compound 7b in Example 10 except that compound 6c was used instead of compound 6b.
- Example 15 Preparation of (25,2'5,35,3 , 5)-3,3 , -di-ieri-butyl-4,4 , -diphenyl-2,2 , ,3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole ((2S,2'S,3S,3'S)-Ph-BIBOP) (8c).
- Example 16 Preparation of Rh[(25,2'5,35,3'5)-Ph-BIBOP(nbd)]BF 4 (9c).
- Examples 17-20 describe the preparation of Rh[(2S,2'S,3S,3'S)-Me-BIBOP(nbd)]BF 4 (9d) as depicted in below:
- Example 17 Preparation of (R)-3-tert-butyl-4-methyl-2,3- dihydrobenzo[JJ[l,3]oxaphosphole (6d).
- (R)-3 chiral triflate 0.5 g, 1.4 mmol
- trimethylboroxine 0.21 g, 1.7 mmol, 1.2 equiv
- Pd 2 dba 3 38 mg, 0.042 mmol, 3 mol%)
- PCy 3 0.078 g, 0.28 mmol, 20 mol
- potassium fluoride (0.33 g, 5.6 mmol, 4.0 equiv) was charged degassed dioxane (10 mL).
- Example 18 Preparation of (25,2'5,3R,3'R)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7d).
- Compound 7d was prepared as a white solid (74%) under similar conditions to those described for compound 7b in Example 10 except that compound 6d was used instead of compound 6b.
- Example 19 Preparation of (25,2'5,35,3 , 5)-3,3 , -di-ieri-butyl-4,4 , -dimethyl-2,2 , ,3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole ((2S,2'S,3S,3'S)-Me-BIBOP, 8d).
- Example 20 Preparation of Rh[(2S,2'S,3S,3'S)-Me-BIBOP(nbd)]BF 4 (9d).
- Metal complex 9d was prepared as a yellow-red solid (85%) under similar conditions to those described in Example 12 for compound 9b except that compound 8d was used instead of compound 8b.
- Example 22 Preparation of (2 l S',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-4-methoxy- 2,3-dihydrobenzo[d][l,3]oxaphosphole (10b).
- 10a (0.12 g, 0.30 mmol) in toluene (10 mL) at 25°C under nitrogen was added triethylamine (0.61 g, 5.99 mmol, 20 equiv) and trichlorosilane (0.41 g, 2.99 mmol).
- the mixture was heated to 120°C for 12 h.
- Example 23 Preparation of Rh[(2 l S',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-4- methoxy-2,3-dihydrobenzo[JJ[l,3]oxaphosphole (nbd)]BF 4 (10c).
- Rh(NBD) 2 BF 4 46 mg, 0.122 mmol
- 10b 50 mg, 0.136 mmol, 1.1 equiv
- the mixture was stirred at 25°C for 0.5 h, and then concentrated to about 1 mL.
- Example 24 Preparation of (2 l S',3 l S , )-3-tert-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole bisoxide (11a).
- Example 25 Preparation of (2 l S',3R)-3-tert-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole (lib).
- Example 26 Preparation of Rh[(2 l S',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole (nbd)]BF 4 (11c).
- Rh(NBD) 2 BF 4 (0.27 g, 0.718 mmol) in THF (2 mL)
- lib 0.27 g, 0.798 mmol, 1.1 equiv
- ((S)-3) was then reacted with the same reagents and in the same as described in Examples 6 and 7 to provide the bis-phosphine ligand (2R,2'R,3R,3'R)-3,3'- di-tert-butyl-2,2',3,3'-tetrahydro-2,2'-bibenzo[ ⁇ i][l,3]oxaphosphole bisoxide.
- the bis- phoshine ligand was then reacted with Rh(bbd) 2 BF 4 in a manner similar to that described in Example 8 to provide the title compound.
- Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 (the H atoms are omitted) is shown in FIG. 1.
- Example 28 describes the use of the exemplary rhodium complex
- Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 from Example 27 for hydrogenation of cc- arylenamides, cc-dehydroamino acid derivatives, -(acetylamino)acrylates, and dimethyl itaconate
- Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF 4 is efficient for the enantioselective hydrogenation of cc-arylenamides, cc-dehydro amino acid derivatives, ⁇ - (acetylamino)acrylates, and dimethyl itaconate.
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Abstract
The invention relates to a series of novel chiral phosphorus ligands of formulae (Ia) and (Ib): wherein R, 1 - rR> 4 and X are as defined herein. The invention also relates to chiral metal complexes prepared with these chiral phosphorus ligands. The chiral metal complexes are useful as catalysts for carrying out asymmetric hydro genation.
Description
NOVEL CHIRAL PHOSPHORUS LIGANDS
FIELD OF THE INVENTION
The present invention relates to a series of novel chiral phosphorus ligands and their metal complexes as catalysts for applications in asymmetric hydro genation. More particularly, the present invention relates to the transition metal complexes of these novel phosphine ligands and their use as catalysts in asymmetric hydro genation.
BACKGROUND OF THE INVENTION
The increasing demand to produce enantiomerically pure pharmaceuticals,
agrochemicals, flavors, and other fine chemicals has advanced the field of asymmetric catalytic technologies. Development of efficient asymmetric metal-catalyzed
transformations has played a central role for the advancement of asymmetric catalysis (Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds., Comprehensive Asymmetric Catalysis, Springer, Berlin, 1999; Ojima, I., Ed, Catalytic Asymmetric Synthesis, VCH, New York, 1993; and Noyori, R. Asymmetric Catalysis In Organic Synthesis, John Wiley & Sons, Inc, New York, 1994). Among most successful transformations are asymmetric hydrogenation, asymmetric epoxidation and dihydroxylations, which were awarded Nobel Prizes in 2001 for their efficiency, simplicity, and practicality. Chiral ligand design has become and will continue to be of great importance for developing new efficient asymmetric metal-catalyzed reactions.
Asymmetric hydrogenation utilizing molecular hydrogen to reduce prochiral olefins, ketones, and imines has become one of most efficient methods for constructing chiral compounds. It also accounts for the major asymmetric catalytic transformation at commercial scales. Development of efficient chiral phosphorus ligands is essential for the success of asymmetric hydrogenation. Known chiral phosphorus ligands in this field include Knowles' DIP AMP [Knowles, W. S. Acc. Chem. Res. 1983, 16, 106], Kagan's DIOP [Kagan et al, J. Am. Chem. Soc. 1972, 94, 6429], Noyori' s BINAP [Noyori, R.
Chem. Soc. Rev. 1989, 18, 187], Burk's Duphos and BPE [Burk, M. J. et al,
Organometallics 1990, 9, 2653; Burk, M. J. et a\, Angew. Chem., Int. Ed. Engl. 1990, 29, 1462], Imamoto's BisP* [ Imamoto, T. et al, J. Am. Chem. Soc. 1997, 119, 1799], Zhang's PennPhos [Zhang, X. et a\, Angew. Chem. Int. Ed. Engl. 1999, 38, 516] and TangPhos [US2004/0229846 and Zhang, X. et al, Angew. Chem. Int. Ed. 2002, 41, 1613.], Pfizer' s trichickenfootphos [WO2005/087370 and Hoge, G. et al, J. Am. Chem. Soc. 2004, 126, 5966].
Although tremendous progress has been made in the field of asymmetric hydrogenation and many efficient chiral ligands have been developed, the design of new efficient ligands continues to be important since there is no universal ligand for hydrogenation of various kinds of prochiral substrates.
BRIEF SUMMARY OF THE INVENTION
We have developed a series of novel and efficient chiral phosphorus ligands that have shown excellent reactivity and enantio selectivity in asymmetric hydrogenation. High enantio selectivity has been achieved in asymmetric hydrogenation of alpha- arylenamides, alpha-dehydroamino acid derivatives, and beta-dehydroamino acid derivatives.
BRIEF DESCRmON OF THE DRAWINGS
FIG. 1 shows an x-ray crystal structure of Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF4 (the H atoms are omitted), where each of the letters on the atoms (C, O, P, Rh, B, and F) refer to carbon, oxygen, phosphorus, rhodium, boron and fluorine, respectively.
DETAILED DESCRIPTION OF THE INVENTION
Abbreviations:
DCM = dichloromethane
DMF = dimethylformamide
EtOH = ethanol
EtOAC = ethyl acetate
MeOH = methanol
MTB = methyl tert-butyl ether
nbd = norbornadiene
PCy = tri(cyclohexyl)phosphine
THF = tetrahydrofuran
TfO" = trifluoromethanesulfonate or triflate
In its broadest embodiments, the present invention relates to novel phosphine ligands, novel metal complexes containing the novel phosphine ligands of the invention, and methods of using the novel metal complexes to carry out asymmetric hydrogenations as described below.
The Phosphine Ligands of the Invention
As noted above, in one embodiment, the present invention relates to a compound of formula (la), (lb), or a mixture thereof ("the phosphine ligand of the invention"):
(la) (lb) wherein:
X is O, S, or -NR5 ;
R1 is -(Ci-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C3- C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-Cio)aryl and -(5 to 11-
membered)heteroaryl of said R1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C6)alkyl, -(Ci-C6)alkyl, and -CF3;
R2 is H, -0(Ci-C6)alkyl, -(C1-C6)alkyl, -(C3-Ci0)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, -NR5R6, or -SR5; wherein said -(C3-C1o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C6- C1o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C1-C6)alkyl, -(C1-C6)alkyl, and -CF3;
R3 is -PR7R8, -CH2PR7R8, -CH2OPR7R8, or a group of formula (A) or (B):
wherein X, R 1 and R 2 of the group of formula (A) or (B) are as defined above, and wherein the group of formula (A) only joins to the compound of formula (la), and the group of formula (B) only joins to the compound of formula (lb);
R4 is H, -(CrC6)alkyl, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, (5- to 6-membered)heteroaryl, or -SiR5 3; wherein said -(Ci-C6)alkyl of said R4 is optionally substituted with 1 to 3 substituents independently selected from -0(C - C6)alkyl, -(C3-C6)cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl; and wherein said -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, and (5- to 6- membered)heteroaryl of said R4 is optionally substituted with 1 to 3 substituents independently selected from -0(C1-C6)alkyl, -(Ci-C6)alkyl, and -CF3;
R5 and R6 are each independently H, -(CrC6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl, or -(5 to l l-membered)heteroaryl;
wherein each -(Ci-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, and -(5 to l l-membered)heteroaryl of said R5 and R6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(C1-C6)alkyl, -(C1-C6)alkyl, and -CF3; and
R 7' and R 8° are each independently -(Ci-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl,
-(C6-C R 7 and R 8
1o)aryl and -(5 to 1 l-membered)heteroaryl of said are each optionally independently substituted with 1 to 3 substituents independently selected from -0(Cr C6)alkyl, -(Ci-C6)alkyl, and -CF3.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the embodiment described immediately above, wherein X is O.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein X is S
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein X is NR5.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to any of the preceding embodiments, wherein R1 is -(Q- C6)alkyl selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH2CH3)3, or
-C(CH2CH3)(CH3)2.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R1 is -(C3-C1o)carbocyclyl selected from cyclopentyl, cyclohexyl, and 1-adamantyl.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R1 is -(C6-C1o)aryl selected from phenyl, ortho-tolyl, para-tolyl, 3,5-dimethylphenyl, 3,5-di-i- butylphenyl, 3,5-di-CF3-phenyl, ortho-CF3-phenyl, ortho-anisyl, and naphthyl.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according any of the preceding embodiments, wherein R is H, -CH3 or -OCH3.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above wherein R is phenyl.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according any of the preceding embodiments, wherein R4 is -H.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R4 is -(C1-C6)alkyl optionally substituted with 1 to 3 substituents independently selected from -OCH3, -(C3-C6)cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the embodiment described immediately above, wherein R4 is -CH2(chiral oxazoline) or -CH2(o/ /iosubstituted pyridine).
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to the broadest embodiment described above, wherein R4 is a -(5- to 6-membered)heteroaryl selected from ori/iosubstituted pyridine, oxazoline, and chiral oxazoline.
In another embodiment, the invention relates to a compound of formula (la), (lb), or a mixture thereof, according to any of the preceding embodiments, wherein R 3 is -PR 7 R 8 or a group of formula (A) ("the bis-phosphine ligand of the invention")
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein R1 is -C(CH3)3; R2 is -H, -CH3, -OCH3, or phenyl; and R3 is -PR7R8.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein R 7 and R 8 are each independently H, -(Ci-C6)alkyl, or -(C3-C6)cycloalkyl.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein R 7 and R 8 are each -C(CH3)3.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein, X is S.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein, X is O.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein, X is NR5.
In another embodiment the invention relates to a bis-phosphine ligand of the invention, wherein X is O, R1 is -C(CH3)3; R2 is -H, -CH3, -OCH3, or phenyl; and R3 is -PR7R8.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein R3 is a group of formula (A) or (B).
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, according to the embodiment described immediately above, wherein R1 is -C(CH3)3; and R2 is -H, -CH3, -OCH3, or phenyl.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention, wherein X is O; R 1 is -C(CH3)3; and R2 is -H, -CH3, -OCH3, or phenyl; and R 3 is a group of formula of formula (A) or (B)..
In another embodiment, the invention relates to a bis-phosphine ligand of the invention having the formula (Ila) or (lib)
(lib) wherein:
R1 is -CH(CH3)2, -C(CH3)3, -C(CH2CH3)(CH3)2, cyclohexyl, 1-adamantyl, phenyl, ortho- tolyl, 3,5-xylyl, ortho-anisyl, or ferrocenyl ; and
R2 is H, -OCH3, -CH3, -CF3, phenyl, or -N(CH3)2.
In another embodiment, the invention relates to a bis-phosphine ligand of the invention having the formula (Ilia) or (Illb):
(Ilia) (IHb) wherein
R1 is -CH(CH3)2, -C(CH3)3, -C(CH2CH3)(CH3)2, cyclohexyl, or 1-adamantyl;
R is H, -OCH3, -CH3, -CF3, phenyl, or -N(CH3)2; and
R7 and R8 are each -C(CH3)3.
In one embodiment, the invention relates to a phosphine ligand of the invention selected from:
(2lS,,2'lS,,3lS',3'lS,)-3,3'-di-ieri-butyl-2,2',3,3'-tetrahydro-2,2'-bibenzo[(i][l,3]oxaphosphole, (25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole,
(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole,
(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole,
(2lS',3R)-3-ieri-butyl-2-(di-ieri-butylphosphino-4-methoxy)-2,3- dihydrobenzo[JJ [1,3] oxaphosphole, and
(2lS',3R)-3-ieri-butyl-2-(di-ieri-butylphosphino)-2,3-dihydrobenzo[(i][l,3]oxaphosphole. The Metal Complexes of the Invention
As noted above, the invention relates to complexes formed between a transition metal and the phosphine ligands of the invention. Accordingly, in one embodiment, the invention relates to a metal complex of formula (IVa), (IVb), (Va) or (Vb) ("the metal complexes of the invention"):
(Va) (Vb)
wherein
M is a transition metal selected from Co, Ni, Pd, Pt, Cu, Ag, Au, Ru, Fe, Rh and Ir; A" is a counter anion; n is the oxidation state of the transition metal M;
L 1 and L2 are each olefins, or L 1 and L2 together represent a diolefin; X is O, S, or -NR5 ;
R1 is -(Ci-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C3- C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl and -(5 to 11- membered)heteroaryl of said R1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C6)alkyl, -(Ci-C6)alkyl, and -CF3;
R is H, -0(Ci-C6)alkyl, -(Ci-C6)alkyl, -(C3-Ci0)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, -NR5R6, or -SR5; wherein said -(C3-C1o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C6- C1o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C1-C6)alkyl, -(C1-C6)alkyl, and -CF3;
R5 and R6 are each independently H, -(Ci-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl, or -(5 to l l-membered)heteroaryl;
wherein each -(C1-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, and -(5 to l l-membered)heteroaryl of said R5 and R6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(Ci-C6)alkyl, -(Ci-C6)alkyl, and -CF3; and
R 7' and R 8° are each independently -(C1-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, yl and -(5 to 1 l-membered)heteroaryl of said R 7 and R 8
-(C6-C1o)ar are each optionally independently substituted with 1 to 3 substituents independently selected from -0(C - C6)alkyl, -(C1-C6)alkyl, and -CF3.
In another embodiment, the invention relates to a metal complex of the invention wherein M is Rh and n is i.
In another embodiment, the invention relates to a metal complex of the invention according to any of the two embodiments described immediately above, wherein A" is BF4 ", SbF6 " , TfO ,B(C6H5)4 ", B[3,5-(CF3)2C6H3]4-, or PF6 ".
In another embodiment, the invention relates to a metal complex of the invention according to any of the three embodiments described immediately above, wherein M is Rh, A" is BF4 ", and n is i.
In another embodiment, the invention relates to a metal complex of the invention according to any of the four embodiments described immediately above, wherein R1 is -C(CH3)3, and R2 is -H, -CH3, -OCH3, or phenyl.
In another embodiment, the invention relates to a metal complex of the invention wherein
L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
In another embodiment, the invention relates to a metal complex of the invention, wherein the metal complex is of formula (IVa).
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A" is BF4 ~; and n is 1.
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
In another embodiment, the invention relates to a metal complex of the invention, wherein the metal complex is of formula (Va).
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A" is BF4 "; and n is 1.
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
In another embodiment, the invention relates to a metal complex of the invention, wherein the metal complex is of formula (IVb).
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A" is BF4 "; and n is 1.
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
In another embodiment, the invention relates to a metal of the invention, wherein the metal complex is of formula (Vb).
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein M is Rh, A" is BF4 ~; and n is 1.
In another embodiment, the invention relates to a metal complex of the invention according to the embodiment immediately above, wherein L 1 and L 2 together represent a diolefin selected from norbornadiene and cyclooctadiene.
In one embodiment, the invention relates to a metal complex of the invention selected from:
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(2S,3R)-3-ieri-butyl-2-(di-ieri-butylphosphino)-4-methoxy-2,3- dihydrobenzo[JJ [ 1 ,3]oxaphosphole(nbd)]BF4 and
Rh[(2S,3R)-3-ieri-butyl-2-(di-ieri-butylphosphino)-2,3-dihydrobenzo[JJ[l,3]- oxaphosphole(nbd)]BF4
Asymmetric Hydro genation
In one embodiment, the invention relates to a process for the asymmetric hydrogenation of a compound having a carbon-carbon or carbon-heteroatom double bond ("the asymmetric hydrogenation process of the invention"), the process comprising allowing said compound having a carbon-carbon or carbon-heteroatom double bond to react with
hydrogen in the presence of a catalytic amount of the metal complex of the invention described in any of the embodiments above. Non-limiting examples of carbon- heteroatom double bonds include those formed between carbon and nitrogen, oxygen, or sulfur. In a preferred embodiment, carbon-heteroatom double bond is formed between carbon and nitrogen or carbon and oxygen.
In another embodiment , the invention relates to the asymmetric hydrogenation process of the invention in the embodiment described immediately above, wherein L 1 and L 2 together represent norbornadiene.
In another embodiment , the invention relates to the asymmetric hydrogenation process of the invention in the broadest embodiment described above, wherein L 1 and L 2 together represent octadiene.
In another embodiment, the invention relates to the asymmetric hydrogenation process of the invention in any of the embodiments described above, wherein M is Rh, A" is BF4 ~, and n is i.
In another embodiment, the invention relates to the asymmetric hydrogenation process of the invention in any of the embodiments described above, wherein R 1 is -C(CH3)3; R 2 is - H, -CH3, -OCH3, or phenyl; and R7 and R8 are each -C(CH3)3.
Unless stated otherwise, the term "compounds of the invention" refers to the phosphine ligands of the invention (including bis-phosphine ligands of the invention) and the metal complexes of the invention.
For all compounds of the invention disclosed hereinabove in this application, in the event the nomenclature is in conflict with the structure, it shall be understood that the compound is defined by the structure.
Compounds of the invention also include their isotopically-labelled forms. An
isotopically-labelled form of a compound of the present invention is identical to said compound of the invention but for the fact that one or more atoms of said compound of the invention have been replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of said atom which is usually found in nature. Examples of isotopes which are readily available commercially and which can be incorporated into an active agent of a combination of the present invention in accordance with well established procedures, include isotopes of hydrogen, carbon,
2 3 13 14 15 18 17 nitrogen, oxygen, phosphorous, fluorine and chlorine, e.g., H, H, C, C, N, O, O,
31 32 35 18 36
P, P, S, F, and CI, respectively. A compound of the present invention which contains one or more of the above-mentioned isotopes and/or other isotopes of other atoms is contemplated to be within the scope of the present invention.
The invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Isomers shall be defined as being enantiomers and diastereomers. All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
Some of the compounds of the invention can exist in more than one tautomeric form. The invention includes methods using all such tautomers.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, "C1-6 alkoxy" or "0(Ci- 6)alkyl" is a (C1-6 )alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl, and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
The term "alkyl" refers to both branched and unbranched alkyl groups. It should be understood that any combination term using an "alk" or "alkyl" prefix refers to analogs according to the above definition of "alkyl". For example, terms such as "alkoxy", "alkythio" refer to alkyl groups linked to a second group via an oxygen or sulfur atom. "Alkanoyl" refers to an alkyl group linked to a carbonyl group (C=0).
In all alkyl groups or carbon chains, one or more carbon atoms can be optionally replaced by heteroatoms such as O, S or N. It shall be understood that if N is not substituted then it is NH. It shall also be understood that the heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain. Such groups can be substituted as herein above described by groups such as oxo to result in definitions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
As used herein, "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen. For example, for a -S-C1-6 alkyl radical, unless otherwise specified, shall be understood to include -S(0)-C1-6 alkyl and
-S(0)2-d_6 alkyl.
The term "(C3_1o)carbocycle" refers to a nonaromatic 3 to 10-membered (but preferably, 3 to 6-membered) monocyclic carbocyclic radical or a nonaromatic 6 to 10-membered fused bicyclic, bridged bicyclic, or spirocyclic carbocyclic radical. The C3.10 carbocycle may be either saturated or partially unsaturated, and the carbocycle may be attached by any atom of the cycle which results in the creation of a stable structure. Non-limiting examples of 3 to 10-membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, and cyclohexanone. Non-limiting examples of 6 to 10-membered fused bicyclic carbocyclic radicals include bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decanyl (decahydronaphthalenyl). Non-limiting examples of 6 to 10-membered bridged bicyclic carbocyclic radicals include bicyclo [2.2.2]heptanyl, bicyclo[2.2.2]octanyl, and bicyclo[3.2.1]octanyl. Non-limiting examples of 6 to 10-membered spirocyclic carbocyclic radicals include but are not limited to spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl.
The term "(C6-1o)aryl" refers to aromatic hydrocarbon rings containing from six to ten carbon ring atoms. The term C6-10 aryl includes monocyclic rings and bicyclic rings where at least one of the rings is aromatic. Non-limiting examples of C6-io aryls include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptanyl and benzocycloheptenyl.
The term "(5 to l l-membered)heterocycle" refers to a stable nonaromatic 4-8 membered monocyclic heterocyclic radical or a stable nonaromatic 6 to 11-membered fused bicyclic, bridged bicyclic or spirocyclic heterocyclic radical. The 5 to 11-membered heterocycle consists of carbon atoms and one or more, preferably from one to four heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle may be either saturated or partially unsaturated. Non-limiting examples of nonaromatic 4-8 membered monocyclic heterocyclic radicals include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, l,l-dioxo-l 6-thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of nonaromatic 6 to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothiophenyl. Non-limiting examples of nonaromatic 6 to 11-membered bridged bicyclic radicals include 2- azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of nonaromatic 6 to 11-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza- spiro[3,4]octanyl.
The term "(5 to l l-membered)heteroaryl" refers to an aromatic 5 to 6-membered monocyclic heteroaryl or an aromatic 7 to 11-membered heteroaryl bicyclic ring where at least one of the rings is aromatic, wherein the heteroaryl ring contains 1-4 heteroatoms such as N, O and S. Non-limiting examples of 5 to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7 to 11-membered heteroaryl
bicyclic heteroaryl rings include benzimidazolyl, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl and benzothiazolyl.
It will be understood that one to three carbon ring moieties in the each of the (C3- 1o)carbocyclic rings, the (5 to l l-membered)heterocyclic rings, the nonaromatic portion of the bicyclic aryl rings, and the nonaromatic portion of the bicyclic heteroaryl rings can independently be replaced with a carbonyl, thiocarbonyl, or iminyl moiety, i.e., -C(=0)-,
8 8
-C(=S)- and -C(=NR )-, respectively, where R is as defined above.
The term "heteroatom" as used herein shall be understood to mean atoms other than carbon such as O, N, and S.
The term "halogen" as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine. The definitions "halogenated", "partially or fully halogenated"; partially or fully fluorinated; "substituted by one or more halogen atoms", includes for example, mono, di or tri halo derivatives on one or more carbon atoms. For alkyl, a non-limiting example would be -CH2CHF2, -CF3 etc.
Each alkyl, carbocycle, heterocycle or heteroaryl, or the analogs thereof, described herein shall be understood to be optionally partially or fully halogenated.
The term "olefin" as used herein refers to an unsaturated hydrocarbon containing carbon atoms linked by a double bond (i.e., an alkene) such as, for example, ethylene, propene, 1-butene, 2-butene, styrene, norbornadiene, or cyclooctadiene. The term "diolefin" refers an unsaturated hydrocarbon containing two pairs of carbon atoms linked by double bonds, e.g., norbornadiene, or cyclooctadiene.
The compounds of the invention may be made using the general synthetic methods described below, which also constitute part of the invention.
GENERAL SYNTHETIC METHODS
The invention also provides processes for making compounds of formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb. In all methods, unless specified otherwise, R1, R2, R3 , R4 R7, R8, L1, L2, A, M and n in the formulas below shall have the meaning of
R2, R3 , R4 R7, R8, L1, L2, A, M and n in formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb of the invention described herein above.
Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC), if desired, and intermediates and products may be purified by chromatography on silica gel and/or by recrystallization. The examples which follow are illustrative and, as recognized by one skilled in the art, particular reagents or conditions could be modified as needed for individual compounds without undue experimentation.
Starting materials and reagents are either commercially available or may be prepared by one skilled in the art using methods described in the chemical literature. Initial products of formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb may be modified further by methods known in the art to produce additional compounds of formula la, lb, Ila, lib, Ilia, Illb, IVa, IVb, Va and Vb.
Compounds of formula la, lb, Ila and lib wherein X is O, may be prepared as shown in Scheme 1.
Scheme 1
As illustrated in Scheme 1, reaction of dimethoxy phenyllithium VI with a
dichlorophosphine of formula VII, in a suitable solvent, in the presence of an alkyl magnesium chloride and hydrogen peroxide provides a phosphine oxide of formula VIII. lodination of the phosphine oxide VIII, in a suitable solvent, in the presence of a suitable base, provides the iodinated intermediate of formula IX. Demethylation of the methoxy groups of compound IX by a reagent such as boron tribromide (BBr3) followed by cyclization, provides the corresponding cyclized intermediate of formula X. Resolution of the intermediate X using a resolving agent such as (+) menthyl chloroformate provides the corresponding ( R ) isomer of formula XIa. The hydroxyl group of compound XIa may be modified to other groups, such as methoxy, aryl etc., under standard reaction conditions known in the literature, to provide a compound of formula Xlla. Reaction of the compound of formula Xlla, in a suitable solvent, in the presence of suitable base and copper chloride provides the corresponding bisphosphine oxide of formula XHIa.
Reduction of the bisphosphine oxide XHIa provides a compound of formula la or Ila. Alternately, resolution of the intermediate X using a resolving agent such as (-) menthyl chloroformate provides the corresponding ( S ) isomer Xlb which may be converted to compounds of formula lb or lib using the above Scheme.
Compounds of formula Ilia and Illb may be prepared as illustrated in Scheme 2.
Scheme 2
Illb
As illustrated in Scheme 2, reaction of a compound of formula Xllb, obtained via Scheme 1, with a phosphorus chloride of formula XIV, in the presence of a suitable base and hydrogen peroxide, provides a bisphosphine oxide of formula XVb. Reduction of the bisphosphine oxide XVb as in Scheme 1, provides a compound of formula Illb.
Alternately, A compound of formula Xlla may be converted to a compound of formula Ilia using the method depicted in Scheme 2.
Compounds of formula IVa and IVb may be prepared according to Scheme 3
Scheme 3
As illustrated in Scheme 3, reaction of a compound of formula Ila with a transition metal salt [Μ(Ι^2)]η+ nA~, in a suitable solvent, provides a compound of formula IVa.
Similarly, starting with a compound of formula lib provides the corresponding compound of formula IVb.
Compounds of formula Va and Vb may be prepared according to Scheme 4
Scheme 4
As illustrated in Scheme 4, reaction of a compound of formula Illb with a transition metal salt [Μ(Ι^2)]η+ nA", in a suitable solvent, provides a compound of formula Vb.
Similarly, starting with a compound of formula Ilia provides the corresponding compound of formula Va.
Compounds of formula la and lb may also be prepared as shown in Scheme 5.
Scheme 5
As illustrated in Scheme 5, reaction of .a compound of formula XVI with a
dichlorophosphine of formula VII, in a suitable solvent, in the presence of an alkyl magnesium chloride and hydrogen peroxide provides a phosphine oxide of formula XVII.
X = O, S or NR 5 , PG 11 and PG 2" are suitable protecting groups such as methyl, benzyl, methoxymethyl etc. Iodination of the phosphine oxide XVII, in a suitable solvent, in the presence of a suitable base, provides the iodinated intermediate of formula XVIII.
Deprotection of compound XVIII followed by cyclization, provides the corresponding cyclized intermediate of formula XIX. Further deprotection of compound XIX followed by the resolution of the intermediate hydroxyl compound using a resolving agent such as (+) menthyl chloroformate, provides the corresponding ( R ) isomer of formula XXa. The hydroxyl group of compound XXa may be modified to other groups, such as methoxy, aryl etc., under standard reaction conditions known in the literature to provide a compound of formula XXIa. Compound XXIa maybe converted to a compound of formula la by the method shown in Scheme 1.
Alternately, resolution of the intermediate using a resolving agent such as (-) menthyl chloroformate provides the corresponding ( S ) isomer XXIb which may be converted to compounds of formula lb by the method described in Scheme 1.
All of the compounds of the invention may prepared by the methods described above and in the Examples section below.
EXAMPLES
Examples 1-4
Examples 1-4 describe the preparation of (R)-3-tert-butyl-2,3- dihydrobenzo[JJ[l,3]oxaphosphol-4-ol oxide ((R)-3) as depicted below: fBuMgCI
(R)-3
Example 1 Preparation of ieri-butyl(2,6-dimethoxyphenyl)(methyl)phosphine oxide (1). To a solution of dichloromethylphosphine (6.61 g, 57 mmol, 1.0 equiv.) in THF (50 mL) was added dropwise 1.0 M iBuMgCl (57 mL, 57 mmol, 1.0 equiv.) over 1 h while controlling the reaction temperature < - 10°C. The mixture was stirred at -10 to 0°C for 1 h and then warmed to 25°C over 1 h and stirred at 25°C for at least 1 h. To a solution of 1,3-dimethoxybenzene (9.37 g, 68 mmol, 1.2 equiv. )in THF (50 mL) in a separated flask was added 1.6 M BuLi (42.4 mL, 68 mmol, 1.2 equiv.) over 1 h while controlling the temperature < 0°C. The mixture was further stirred at 0°C for 0.5 h. To the
aforementioned mixture of dichloromethylphosphine and TiuMgCl was added dropwise the mixture of in situ generated 2,6-dimethoxyphenyllithium made above over 0.5 h while controlling the reaction temperature < 25°C. The resulting mixture was further stirred at 25°C for 1 h. To the mixture was added dropwise 30% H202 over 10 min at 0°C
and the mixture was further stirred at 25 °C for 0.5 h, and then quenched with addition of 2 N HC1 ( 300 mL) and dichloromethane (300 mL). The dichloromethane layer was washed with brine (300 mL), dried over magnesium sulfate, and purified by column chromatography (eluents: EtOAc to EtOAc/MeOH 4/1; monitored at 290 nm) to provide 1 as a thick oil (9.5 g, 37 mmol, 65 %). 1: 1HNMR (400 MHz, CDC13): δ= 7.41 (m, 1H), 6.60 (dd, / = 8.4, 3.8 Hz, 2H), 3.84 (s, 6H), 1.83 (d, / = 13.2 Hz, 3H), 1.18 (d, / = 15.4 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 51.4; 13CNMR (100 MHz, CDC13): S= 163.1 (d, / = 1.0 Hz), 133.7 (d, / = 1.0 Hz), 107.3 (d, / = 82 Hz), 104.5 (d, / = 6 Hz), 55.65, 34.6 (d, J = 72 Hz), 24.4 (d, / = 1.6 Hz), 15.8 (d, / = 69 Hz); ESI-MS: m/z 257 [M +H]+.
Example 2: Preparation of ieri-butyl(2,6-dimethoxyphenyl)(iodomethyl)phosphine (2). To a solution of 1 (7.4 g, 28.9 mmol, 1 equiv.) and TMEDA (6.50 mL, 43 mmol, 1.5 equiv.) in THF (40 mL) at -78°C was added 2.5 M BuLi in hexanes (13.9 mL, 35 mmol, 1.2 equiv.) over 10 min. The resulting mixture was stirred at -78°C for 1 h. To the mixture at -78°C was added iodine (11.0 g, 43 mmol, 1.5 equiv.) in THF (20 mL) while controlling the temperature <-70°C. After the addition, the mixture was further stirred at - 78°C for 0.5 h and then warmed to 25°C over 1 h. To the mixture was added 10%
NaHS03 solution (100 mL) and dichloromethane (100 mL).The dichloromethane layer was washed with brine (100 mL), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluents: EtOAc to EtOAc/MeOH 10/1; monitored at 290 nm) to provide 2 as a thick oil (8.8 g, 23.0 mmol, 80 %). 1HNMR (400 MHz, CDC13): δ= 7.40 (t, / = 8.4 Hz, 1H), 6.56 (dd, / = 8.4, 4.0 Hz, 2H), 3.80 (s, 6H), 3.79 (m, 1H), 3.34 (dd, / = 11.2, 8.3 Hz, 1H), 1.18 (d, / = 15.6 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 50.4; 13CNMR (100 MHz, CDC13): S= 163.2, 134.2, 104.9 (d, / = 63 Hz), 104.3 (d, / = 6 Hz), 55.9, 35.3 (d, 7 = 71 Hz), 25.0, -1.8 (d, / = 59 Hz); ESI-MS: m/z 383 [M +H]+.
Example 3: Preparation of racemic 3-ieri-butyl-2,3-dihydrobenzo[d][l,3]oxaphosphol oxide -4-ol (3). To a mixture of 2 (8.1 g, 21.2 mmol) in 1,2-dichloroethane (100 mL) at 0°C was added BBr3 (21.2 g, 64.8 mmol, 4 equiv.). The mixture was warmed to 60°C over 0.5 h and stirred at ~ 60°C for 2 h. To the mixture was carefully added MeOH (200
mL) while cooling and then concentrated. MeOH (200 mL X3) was further added and evaporated for three times to provide a residue as thick oil. To the residue was further added K2C03 (14.6 g, 105 mmol, 5 equiv.) and DMF (100 mL). The mixture was stirred at 60°C for 2 h and then cooled to 0°C. Water (200 mL) was added followed by cone. HC1 to adjust the pH of the mixture to ~3. To the mixture was added dichloromethane (200 mL). The dichloromethane layer was separated and the aqueous layer was further washed twice with dichloromethane (50 mL X2). The combined dichloromethane layer was washed with brine (100 mL), dried over sodium sulfate, and purified by column chromatography (eluent: EtOAc/MeOH 4: 1, monitored at 290 nm) to provide 3 as a white solid (4.3 g, 19.1 mmol, 90% yield). 1HNMR (400 MHz, CD3OD): δ = 7.33 (t, / = 8.2 Hz, 1H), 6.45 (m, 2H), 4.72 (dd, / = 14.3, 3.3 Hz, 1H), 4.30 (dd, / = 14.3, 10.7 Hz, 1H), 1.28 (d, / = 16.6 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 68.6; 13CNMR (100 MHz, CD3OD): δ = 168.5 (d, / = 17.2 Hz), 161.4 (d, J = 2.2 Hz), 138.3, 109.0 (d, / = 6.1 Hz), 105.5 (d, J = 5.4 Hz), 101.7 (d, / = 94.3 Hz), 67.0 (d, / = 61 Hz), 34.5 (d, / = 74 Hz), 24.9; ESI-MS: m/z 227 [M +H]+.
Example 4: Preparation of (R)-3-tert-butyl-2,3-dihydrobenzo[JJ[l,3]oxaphosphol-4-ol oxide ((R)-3). To a mixture of racemic 3 (3.1 g, 13.7 mmol) and triethylamine (2.77 g, 27.4 mmol, 2 equiv) in methylene chloride (40 mL) was added (+)-menthyl
chloroformate (3.6 g, 16.4 mmol, 1.2 equiv) at 0°C over 5 min. The mixture was allowed to warm to 25°C over 0.5 h and stirred at 25°C for 2 h, then quenched by addition of water (100 mL). The methylene chloride layer was washed with brine, dried over Na2S04, and purified by column chromatography (eluent: hexane/EtOAc to EtOAc, monitored at -290 nm) to give a mixture of (+)-menthyl carbonate diastereomers (5.6 g, 13.7 mmol, 100%). The mixture was further treated with benzene (15 mL) and heated to reflux to form a clean solution. Crystallization by cooling down to 25°C and filtration provided optically pure diastereomer in 42% yield (>99% de). 1HNMR (400 MHz, CDC13): S= 7.46 (t, / = 8.2 Hz, 1H), 7.01 (m, 1H), 6.79 (m, 1H), 4.57 (m, 2H), 4.42 (dd, / = 13.9, 10.7 Hz, 1H), 2.20 (m, 1H), 1.98 (m, 1H), 1.69 (m, 2H), 1.49 (m, 2H), 1.23 (dd, / = 16.4, 1.9 Hz, 9H), 1.95-1.21 (m, 2H), 0.90 (td, / = 8.9, 1.9 Hz, 6H), 0.86 (m, 1H), 0.78 (d, / = 6.9 Hz, 3H); 13PNMR (162 MHz, CDC13): δ= 62.78; 13CNMR (100 MHz,
CDC13): 5 = 166.0 (d, 7 = 16 Hz), 152.2 (d, / = 23 Hz), 135.9, 114.5 (d, J = 5 Hz), 111.0 (d, / = 5 Hz), 106.8 (d, / = 88 Hz), 80.1, 66.1 (d, / = 60 Hz), 46.8, 40.3, 34.0, 33.7 (d, / = 73 Hz), 31.4, 25.9, 24.2, 23.1, 21.9, 20.7, 16.0; ESI-MS: m/z 409 [M +H]+. Note: Chiral HPLC conditions for separation of diastereomers: Chiralcel OD-H, n- heptane/isopropanol 95/5, 25°C.
To a solution of the aforementioned solid (0.4 g, 0.98 mmol) in EtOH (8 mL) was added at 25°C a solution of KOH (0.41 lg, 7.34 mmol, 20 equiv.) in water (2 mL). The mixture was stirred at 25°C for 2 h. LC showed complete conversion of SM. To the mixture at 0°C was added cone. HC1 to control the pH ~ 4 followed by dichloromethane (20 mL). The dichloromethane layer was washed with brine, dried over sodium sulfate, and purified by column chromatography (silica gel, eluent: EtOAc/MeOH 4: 1, monitored at -290 nm) to provide ((RJ-3) as white solid (200 mg, 0.88 mmol, 90% yield). Chiral separation: chrialpak AD-H, heptane/isopropanol (95:5), 2 ml/min, isocratic, 9.60 min (enantiomer), 16.60 min (this configuration).
Examples 5-8
Examples 5-8 describe the preparation of preparation of Preparation of
Rh[(2S,2'S,3S,3'S)-BIBOP(nbd)]BF4 (9a) as depicted below:
(R)-3 6a 7a
8a 9a
(2S,2'S,3S,3'S)-BIBOP
Example 5: Preparation of (R)-3-tert-butyl-2,3-dihydrobenzo[<i][l,3]oxaphosphole (6a). To a solution of (R)-3, 50 mg, 0.221 mmol) and triethylamine (89 mg, 0.88 mmol, 4 equiv) in CH2C12 (2 mL) at 0°C was added Tf2NPh (96 mg, 0.27 mmol, 1.2 equiv) over 1 min. The mixture was stirred at 25°C for 2 h and then quenched with addition of water (2 mL). The CH2C12 layer was separated, dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluents: hexanes to EtOAc) to provide the triflate product (65 mg, 0.18 mmol, 82%) as white solid. 1HNMR (500 MHz, CD2C12): δ = 7.58 (t, / = 8.3 Hz, 1H), 7.03 (dd, / = 8.2, 3.5 Hz, 1H), 7.00 (dd, / = 8.5, 2.4 Hz, 1H), 4.67 (dd, / = 14.2, 2.1 Hz, 1H), 4.46 (dd, / = 14.1, 11.1 Hz, 1H), 1.21 (d, / = 16.8 Hz, 9H); 31PNMR (202 MHz, CD2C12): S= 75.6; 13CNMR (125 MHz, CD2C12): S= 167.1 (d, / = 16.8 Hz), 150.0, 137.1, 120.3, 117.8, 114.7 (d, / = 4.4 Hz), 114.2 (d, J = 4.3 Hz), 66.9 (d, / = 59.3 Hz), 34.7 (d, / = 72.0 Hz), 24.2; ESI-MS: m/z 359 [M +H]+.
To a solution of the triflate (300 mg, 0.836 mmol, 1.0 equiv) in EtOAc (4 mL) was added triethylamine (1 mL) and 20% Pd(OH)2/C (100 mg, wet). The mixture was stirred at 25°C under 100 psi H2 for 12 h, then filtered over Celite, and concentrated. The residue was re-dissolved in dichloromethane (4 mL), washed with water (5 mL), concentrated, and purified by silica gel column chromatography (eluent: EtOAc to EtOAc/MeOH 2: 1) to provide 6a (155 mg, 0.737 mmol, 88%) as a white solid. 1HNMR (400 MHz, CDC13): δ= 7.62 (m, 1H), 7.47 (m,lH), 7.06 (m, 1H), 6.96 (m, 1H), 4.57 (m, 1H), 4.40 (m, 1H), 1.21 (dd, / = 16.0, 3.8 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 63.2; 13CNMR (100 MHz, CDC13): S= 165.0, 134.9 (d, / = 1.7 Hz), 129.3 (d, / = 6.5 Hz), 122.0 (d, / = 9.2 Hz), 113.9 (d, / = 5.5 Hz), 112.9, 65.0 (d, / = 59.0 Hz), 33.2 (d, / = 71.3 Hz), 23.6; ESI- MS: m/z 211 [M +H]+.
Example 6: Preparation of (2lS,,2'lS,,3R,3'R)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole bisoxide (7a). To a solution of 6a (155 mg, 0.737 mmol, 1 equiv) in THF (4 mL) at -78°C was added LDA (0.49 mL, 1.8 M in
heptane/THF/chlorobenzene, 0.884 mmol, 1.2 equiv). The mixture was stirred at -78°C for 1 h before addition of anhydrous CuCl2 (0.299 g, 2.21 mmol, 3 equiv) in one portion. The resulting mixture was kept at -78°C for 1 h before it was warmed to 25°C over 1 h.
To the mixture was added 10% NH4OH (10 mL) and dichloromethane (10 mL). The aqueous layer was further extracted with dichloromethane (10 mL X 2). The combined dichloromethane solution was washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (DCM:THF 3: 1 to 2: 1) to provide 7a (93 mg, 0.22 mmol, 60%) as white solid. 1HNMR (400 MHz, CDC13): δ= 7.63 (m, 2H), 7.33 (t, / = 8.4 Hz, 2H), 7.05 (dt, / = 7.4, 2.0 Hz, 2H), 6.47 (dd, / = 8.3, 3.0 Hz, 2H), 5.22 (t, / = 3.5 Hz, 2H), 1.23 (d, / = 16.0 Hz, 18H); 31PNMR (162 MHz, CDCI3): S= 61.8 Hz; 13CNMR (100 MHz, CDC13): S= 163.9 (m), 134.6, 129.1 (t, / = 3.3 Hz), 122.0 (t, / = 4.7 Hz), 113.5 (t, / = 2.7 Hz), 113.5 (d, J = 94.8 Hz), 72.4 (dd, / = 64.8,
9.0 Hz), 33.5 (dd, / = 37.9, 5.4 Hz), 23.3. ESI-MS: m/z 419 [M +H]+.
Example 7: Preparation of (2lS,,2'lS,,3lS,,3'lS,)-3,3'-di-tert-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole bisoxide (8a). To a solution of 7a (70 mg, 0.17 mmol, 1 equiv), triethylamine (169 mg, 1.7 mmol, 10 equiv) in toluene (10 mL) at 25°C was added trichlorosilane (114 mg, 0.84 mmol, 5 equiv). The mixture was heated to 80°C and stirred under nitrogen for 12 h. To the mixture at 0°C was added degassed 30% NaOH (10 mL) over 5 min. The resulting mixture was stirred at 60°C for about 1 h until the two layers became clear. The toluene layer was separated under N2 and the aqueous layer was further extracted with toluene twice (5 mL X 2). The combined toluene was dried over Na2S04, concentrated under N2, and purified by passing through a neutral alumina plug (eluent: hexanes/ether 1/1) to provide 8a (60 mg, 0.155 mmol, 93 %) as white solid. 1HNMR (400 MHz, CD2C12): δ= 7.43 (m, 2H), 7.26 (m, 2H), 7.94 (m, 2H), 6.83 (d, / = 8.2 Hz, 2H), 5.01 (t, / = 3.2 Hz, 2H), 0.95 (d, / = 12.8 Hz, 18H); 31PNMR (162 MHz, CD2C12): S= -1.5; 13CNMR (100 MHz, CD2C12): S= 163.9, 131.6 (t, / = 10.4 Hz), 131.5, 122.6 (t, / = 5.1 Hz), 121.4 (t, J = 3.2 Hz), 111.6, 85.8 (dd, / = 70.5, 64.3 Hz), 31.0 (t, / =
9.1 Hz), 26.9 (t, 7 = 7.5 Hz).
Example 8: Preparation of Rh[(2S,2'S,3S,3'S)-BIBOP(nbd)]BF4 (9a)
To a mixture of Rh(nbd)2BF4 (40.1 mg, 0.11 mmol, 0.9 equiv) in THF (0.5 mL) at 0°C was added a solution of 8a (46 mg, 0.12 mmol, 1.0 equiv) in THF (0.5 mL). The mixture was stirred at 25 °C for 0.5 h, then concentrated to about 0.5 mL. Ether (10 mL) was
added, the mixture was stirred at 25°C for 10 min, and filtered under N2 to provide 9a (70 mg, 0.104 mmol, 88 %) as a red solid. 1HNMR (400 MHz, CD2C12): δ= 7.62 (t, / = 6.3 Hz, 2H), 7.54 (t, J = 1.4 Hz, 2H), 7.24 (td, / = 7.5, 1.7 Hz, 2H), 7.04 (d, / = 8.2 Hz, 2H), 5.97 (m, 4H), 5.41 (dd, / = 22.9, 1.2 Hz, 2H), 4.25 (br s, 2H), 1.93 (br s, 2H), 0.99 (d, / = 16.1 Hz, 18H); 31PNMR (162 MHz, CD2C12): S= 85.8 (dd, / = 152.6, 6.5 Hz); 13CNMR (100 MHz, CD2C12): S= 161.1 (d, / = 3.0 Hz), 134.8, 130.7 (t, / = 4.7 Hz), 124.2 (t, / = 4.2 Hz), 114.8 (m), 113.8, 92.2 (m), 87.6 (td, 7 =22.4, 3.3 Hz ), 86.6 (dd, / = 10.3, 5.7 Hz), 73.0 (m), 56.7 (d, / = 1.5 Hz), 35.9 (m), 26.5 (t, / = 2.5 Hz).
Examples 9-12
Examples 9-12 describe the preparation of preparation of R [(2S,2'S,3S,3'S)-MeO- BIBOP(nbd)]BF4 (9b) as depicted below:
8b 9b
(2S,2'S,3S,3'S)-MeO-BIBOP Example 9: Preparation of (R)-3-ieri-butyl-4-methoxy-2,3- dihydrobenzo[JJ[l,3]oxaphosphole oxide (6b). To a suspension of 3 (170 mg, 0.752 mmol) and potassium carbonate (0.519 g, 3.76 mmol, 5 equiv) in DMF (5 mL) at 25°C was added Mel (0.32 g, 2.26 mmol, 3 equiv). The mixture was stirred at 25°C for 12 h, then quenched with water (5 mL) and Me-THF (20 mL). The water layer was washed with Me-THF (10 mL). The combined Me-THF was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography (eluent:
EtOAc/MeOH 4/1) to provide 6b (150 mg, 0.625 mmol, 83%) as white solid. 1HNMR (400 MHz, CDC13): S= 7.38 (t, / = 8.2 Hz, 1H), 6.52 (dd, / = 8.3, 3.0 Hz, 1H), 6.46 (dd, / = 8.2, 4.2 Hz, 1H), 4.50 (dd, / = 13.9, 2.3 Hz, 1H), 4.38 (dd, / = 13.9, 10.4 Hz, 1H), 3.87 (s, 3H), 1.26 (d, / = 16.4 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 64.5; 13CNMR (100 MHz, CDCI3): δ= 166.6 (d, 7 =17.0 Hz), 161.3, 136.5, 106.4 (d, / = 5.0 Hz), 103.1 (d, / = 6.0 Hz), 102.5 (d, / = 92.0 Hz), 66.0 (d, / = 59.0 Hz), 55.6, 33.6 (d, / = 73.0 Hz), 24.5; ESI-MS: m/z 241 [M +H]+.
Example 10: Preparation of ((2lS,,2'lS,,3R,3'R)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7b). To a solution of 6b (150 mg, 0.624 mmol) in THF (5 mL) at -78°C was added 1.8 M LDA (0.416 mL, 0.749 mmol, 1.2 equiv) over 5 min. The mixture was stirred at -78°C for 1 h before the addition of anhydrous CuCl2 (253 mg, 1.87 mmol, 3 equiv) in one portion. The resulting mixture was stirred at -78°C for 1 h before it was warmed to 25°C over 1 h. To the mixture was added 10% NH4OH (10 mL) and dichloromethane (10 mL). The aqueous layer was further extracted with dichloromethane (5 mL). The combined dichloromethane solution was washed with brine (10 mL), dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (eluent: EtOAc to EtOAc/MeOH 3/2) to provide 7b (100 mg, 0.21 mmol, 67%) as a white solid. 1HNMR (400 MHz, CD2C12): δ= Ί .32 (t, / = 8.2 Hz, 1H), 6.53 (dd, / = 8.2, 3.9 Hz, 1H), 6.19 (dd, / = 8.3, 2.6 Hz, 1H), 5.14 (m, 1H), 3.92 (s, 3H), 1.25 (d, / = 16.2 Hz, 9H); 31PNMR (162 MHz, CD2C12): S= 60.9; 13CNMR (100 MHz, CD2C12): =166.3 (t, / = 7.9 Hz), 161.7, 136.8, 106.5 (t, / = 2.6 Hz), 104.1 (t, 7 = 2.8 Hz), 102.7 (dd, / = 96.9, 4.9 Hz), 73.31 (m), 56.2, 34.5 (m), 24.5; ESI-MS: m/z 479 [M +H]+.
Example 11 : (25,2'5,35,3,5)-3,3,-di-ieri-butyl-4,4,-dimethoxy-2,2,,3,3,-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole (8b). To a solution of 7b (100 mg, 0.209 mmol) and triethylamine (422 mg, 4.18 mmol, 20 equiv) in toluene (10 mL) was added
trichlorosilane (283 mg, 2.09 mmol, 10 equiv). The mixture was heated to 80°C for 12 h, then cooled to 0°C and quenched with addition of degassed 30% NaOH solution (5 mL) over 5 min. The mixture was further stirred at 60°C for about 1 h until the two layers
became clear. The toluene layer was separated under N2 and the aqueous layer was further extracted with toluene twice (5 mL X 2). The combined toluene solution was dried over sodium sulfate, concentrated under N2, and purified by passing through a neutral alumina plug (eluent: hexanes/ether 5/1) to provide 8b (70 mg, 0.157 mmol, 75%) as a white solid. 1HNMR (500 MHz, CD2C12): δ= 7.22 (t, / = 8.2 Hz, 2H), 6.50 (d, / = 8.2 Hz, 2H), 6.48 (m, 2H), 4.93 (t, / = 3.0 Hz, 2H), 3.83 (s, 6H), 0.98 (d, / = 12.7 Hz, 18H); 31PNMR (202 MHz, CD2C12): S= -5.3; 13CNMR (125 MHz, CD2C12): S= 165.4, 162.3 (t, / = 6.2 Hz), 132.8, 110.0 (t, / = 5.9 Hz), 104.9, 103.3, 86.3 (m), 55.9, 32.6 (m), 27.7 (t, 7 = 7.3 Hz).
Example 12: Preparation of Rh[(25,2'5,35,3'5)-MeO-BIBOP(nbd)]BF4 (9b)
To a mixture of Rh(NBD)2BF4 (37.7 mg, 0.10 mmol, 0.9 equiv) in THF (0.1 mL) at 0°C was added a solution of 8b (50 mg, 0.11 mmol, 1.0 equiv) in THF (0.5 mL). The mixture was stirred at 25 °C for 0.5 h before ether (10 mL) was added. After stirred at 25 °C for 10 min, the mixture was filtered under N2 to provide 9b (60 mg, 0.082 mmol, 73%) as a red solid. 1HNMR (400 MHz, CD2C12): δ= 7.49 (t, / = 8.2 Hz, 2H), 6.74 (dd, J = 1.6, 3.4 Hz, 2H), 6.66 (d, / = 8.0 Hz, 2H), 6.31 (br s, 2H), 6.07 (br s, 2H), 5.36 (m, 2H), 4.24 (br s, 2H), 4.04 (s, 6H), 1.96 (br s, 2H), 1.04 (d, / = 16.0 Hz, 18H); 31PNMR (162 MHz, CD2C12): S= 84.0 (dd, / = 155.2, 4.9 Hz); ESI-MS: m/z 557 [M-BF4 "]+; 13CNMR (100 MHz, CD2C12): S= 162.1 ', 161.3 (t, / = 3.0 Hz), 136.1, 106.5, 105.4 (t, / = 2.0 Hz), 103.7 (m), 91.7 (dd, / = 11.2, 5.0 Hz), 89.3 (dd, / = 10.2, 4.6 Hz), 88.9 (td, 7 =23.3, 3.2 Hz), 72.6 (m), 56.4, 56.1, 37.3, 27.0 (t, / = 2.7 Hz).
Examples 13-16
Examples 13-16 describe the preparation of preparation ofR [(2S,2'S,3S,3'S)- BIBOP(nbd)]BF4 (9c) as depicted below:
8c 9c
(2S,2'S,3S,3'S)-Ph-BIBOP
Example 13: Preparation of (R)-3-tert-butyl-4-phenyl-2,3- dihydrobenzo[d][l,3]oxaphosphole. To a mixture of (R)-3 chiral triflate (2.0 g, 5.58 mmol) (prepared as described in Example 5), phenylboronic acid (1.02 g, 8.37 mmol, 1.5 equiv), Pd2dba3 (153 mg, 0.17 mmol, 3 mol%), PCy3 (0.31 g, 1.12 mmol, 20 mol ), and potassium fluoride (1.30 g, 23.3 mmol, 4.0 equiv) was charged degassed dioxane (30 mL). The mixture was stirred at 100°C under nitrogen for 24 h and then concentrated to remove most of dioxane. To the residue was added with dichloromethane (50 mL) and water (50 mL) and the mixture was filtered over a celite pad. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column
chromatography (eluent: hexane to EtOAc) to provide 6c as a white crystalline solid (1.5 g, 5.24 mmol, 94%). 1HNMR (400 MHz, CDC13): δ= 7.76 (m, 2H), 7.35-7.53 (m, 4H), 7.05 (dd, 7 = 7.5, 3.6 Hz, 1H), 6.91 (dd, / = 8.3, 3.2 Hz, 1H), 4.56 (dd, / = 13.9, 1.1 Hz, 1H), 4.44 (dd, 7 = 13.8, 10.5 Hz, 1H), 0.78 (d, J = 16.1 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 65.1; 13CNMR (100 MHz, CDC13): S= 165.7 (d, / = 19.0 Hz), 146.7 (d, / = 6.0 Hz), 140.6 (d, J = 2.0 Hz), 134.8 (d, J = 2.0 Hz), 129.6, 128.5, 128.3, 123.5 (d, / = 8.0 Hz), 112.6 (d, / = 6.0 Hz), 112.4 (d, / = 88.0 Hz), 65.3 (d, / = 62.0 Hz), 33.8 (d, / = 70 Hz), 33.9; ESI-MS: m/z 287 [M +H]+.
Example 14: Preparation of (25,2'5,3R,3'R)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7c). Compound 7c was prepared
as a white solid (43%) under similar conditions to those described for compound 7b in Example 10 except that compound 6c was used instead of compound 6b. 1HNMR (400 MHz, CDC13): δ= 7.85 (d, 7 = 10.9 Hz, 4H), 7.47 (t, 7 = 7.2 Hz, 4H), 7.38 (dd, 7 = 15.6, 8.0 Hz, 4H), 7.08 (dd, 7 = 7.4, 2.6 Hz, 2H), 6.58 (dd, 7 = 8.2, 2.3 Hz, 2H), 5.30 (m, 2H), 0.84 (d, 7 = 15.9 Hz, 18H); 31PNMR (162 MHz, CDC13): S= 62.9; 13CNMR (100 MHz, CDCI3): δ= 164.9(t, 7 = 9.0 Hz), 146.2 (t, 7 = 3.0 Hz), 140.4, 134.6, 129.8, 128.5, 128.3, 123.3 (t, 7 = 4.0 Hz), 112.3 (t, 7 = 3.0 Hz), 112.2 (dd, 7 = 94.0, 4.7 Hz), 71.8 (m), 34.2 (m), 23.6; ESI-MS: m/z 571 [M +H]+.
Example 15: Preparation of (25,2'5,35,3,5)-3,3,-di-ieri-butyl-4,4,-diphenyl-2,2,,3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole ((2S,2'S,3S,3'S)-Ph-BIBOP) (8c).
Compound 8c was prepared as a white solid (84%) under similar conditions to those described for compound 8b in Example 11 except that compound 7c was used instead of compound 7b. 1HNMR (400 MHz, CD2C12): δ= 7.71 (d, 7 = 7.2 Hz, 4H), 7.41 (t, 7 = 7.0 Hz, 4H), 7 '.25-7.36 (m, 4H), 6.99 (d, 7 = 7.6, 2H), 6.79 (d, 7 = 8.2 Hz, 2H), 5.07 (t, 7 =
3.2 Hz, 2H), 0.70 (d, 7 = 12.3 Hz, 18H); 31PNMR (162 MHz, CD2C12): δ= -3.3; 13CNMR (100 MHz, CD2C12): δ= 164.6, 146.3, 143.1, 131.8, 129.7 (t, 7 = 2.0 Hz), 128.9, 128.0, 122.6, 110.5, 86.2 (d, 7 = 4.0 Hz), 32.8 (t, 7 = 10.0 Hz), 27.2 (t, 7 = 7.0 Hz).
Example 16: Preparation of Rh[(25,2'5,35,3'5)-Ph-BIBOP(nbd)]BF4 (9c). Metal complex 9c was prepared as yellow-red solid (85%) under similar conditions to those described in Example 12 for compound 9b except that except that compound 8d was used instead of compound 8b: 1HNMR (500 MHz, CD2C12): δ= 7.68 (t, J = 1.4 Hz, 4H), 7.59 (dd, 7 = 13.5, 6.4 Hz, 4H), 7.54 (d, 7 = 7.8 Hz, 4H), 7.19 (d, 7 = 8.3 Hz, 2H), 6.99 (d, 7 =
7.3 Hz, 2H), 5.61 (s, 2H), 5.09 (s, 2H), 3.79 (s, 2H), 3.65 (s, 2H), 1.51 (s, 2H), 0.86 (d, 7 = 15.6 Hz, 18H); 31PNMR (202 MHz, CD2C12): δ= 46.8 (d, 27 κω>= 154 Hz); 13CNMR (125 MHz, CD2C12): δ= 162.2, 147.9, 142.6, 134.8, 130.1, 139.7, 129.4, 126.7 (d, 7 = 2.5 Hz), 113.8, 94.1, 86.9 (t, 7 = 26.8 Hz), 83.4, 71.9, 56.8, 36.9, 26.3.
Examples 17-20
Examples 17-20 describe the preparation of Rh[(2S,2'S,3S,3'S)-Me-BIBOP(nbd)]BF4 (9d) as depicted in below:
8d
(2S,2'S,3S,3'S)-Me-BIBOP
Example 17: Preparation of (R)-3-tert-butyl-4-methyl-2,3- dihydrobenzo[JJ[l,3]oxaphosphole (6d). To a mixture of (R)-3 chiral triflate (0.5 g, 1.4 mmol) (prepared as described in Example 5), trimethylboroxine (0.21 g, 1.7 mmol, 1.2 equiv), Pd2dba3 (38 mg, 0.042 mmol, 3 mol%), PCy3 (0.078 g, 0.28 mmol, 20 mol ), and potassium fluoride (0.33 g, 5.6 mmol, 4.0 equiv) was charged degassed dioxane (10 mL). The mixture was stirred at 100°C under nitrogen for 24 h and then concentrated to remove most of dioxane. To the residue was added dichloromethane (15 mL) and water (15 mL) and the mixture was filtered over a celite pad. The organic layer was separated, washed with brine, concentrated, and purified by silica gel column chromatography (eluent: hexane to EtOAc) to provide 6d as a white crystalline solid (0.2 g, 0.89 mmol, 64%). 1HNMR (500 MHz, CDC13): δ= 7.32 (t, J = 7.9 Hz, 1H), 6.83 (dd, / = 7.4, 3.4 Hz, 1H), 6.72 (dd, / = 8.3, 3.4 Hz, 1H), 4.56 (d, / = 13.7 Hz, 1H), 4.33 (dd, J = 13.7, 10.4 Hz, 1H), 2.57 (s, 3H), 1.22 (d, / = 15.9 Hz, 9H); 31PNMR (202 MHz, CDC13): S= 65.2;
13CNMR (125 MHz, CDC13): S= 165.1 (d, / = 20.0 Hz), 142.0 (d, / = 7.5 Hz),134.7 (d, / = 2.5 Hz), 123.8 (d, / = 8.8 Hz), 112.5 (d, / = 91.3 Hz), 111.0 (d, / = 5.0 Hz), 65.4 (d, / =
60.0 Hz), 34.2 (d, / = 70.0 Hz), 24.2 (d, / = 1.4 Hz), 20.7 (d, / = 2.8 Hz); ESI-MS: m/z 225 [M +H]+.
Example 18: Preparation of (25,2'5,3R,3'R)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole bisoxide (7d). Compound 7d was prepared as a white solid (74%) under similar conditions to those described for compound 7b in Example 10 except that compound 6d was used instead of compound 6b. 1HNMR (500 MHz, CDC13): δ= 7.10 (t, J = 7.9 Hz, 2H), 6.76 (dd, / = 7.4, 2.4 Hz, 2H), 6.10 (dd, / = 8.2, 2.4 Hz, 2H), 5.14 (m, 2H), 2.56 (s, 6H), 1.20 (d, / = 15.7 Hz, 18H); 31PNMR (202 MHz, CDCI3): S= 63.2; 13CNMR (125 MHz, CDC13): S= 164.1 (t, / = 8.8 Hz), 141.3 (t, J = 2.5 Hz),134.1, 123.6 (t, / = 3.8 Hz), 112.3 (d, / = 93.8 Hz), 110.7 (t, / = 2.5 Hz), 72.6 (m), 34.4 (m), 23.9, 20.5 (t, / = 1.3 Hz); ESI-MS: m/z 447 [M +H]+.
Example 19: Preparation of (25,2'5,35,3,5)-3,3,-di-ieri-butyl-4,4,-dimethyl-2,2,,3,3'- tetrahydro-2,2'-bibenzo[JJ[l,3]oxaphosphole ((2S,2'S,3S,3'S)-Me-BIBOP, 8d).
Compound 8d was prepared as a white solid (86%) under similar conditions to those described for compound 8b in Example 11 except that compound 7d was used instead of compound 7b. HNMR (500 MHz, CD2C12): δ= 7 '.13 (t, J = 7.8 Hz, 2H), 6.78 (d, / = 7.3 Hz, 2H), 6.61 (d, / = 8.0 Hz, 2H), 4.89 (t, J = 2.5 Hz, 2H), 2.48 (s, 6H), 0.98 (d, / = 12.4 Hz, 18H); 31PNMR (202 MHz, CD2C12): S= -6.2; 13CNMR (125 MHz, CD2C12): S= 164.1, 142.2 (t, / = 8.8 Hz), 131.4, 122.9 (t, / = 1.9 Hz), 122.3 (m), 108.9 (t, / = 0.9 Hz), 85.9 (m), 33.1 (m), 27.8 (t, J = 6.3 Hz), 23.3 (t, / = 3.8 Hz).
Example 20: Preparation of Rh[(2S,2'S,3S,3'S)-Me-BIBOP(nbd)]BF4 (9d). Metal complex 9d was prepared as a yellow-red solid (85%) under similar conditions to those described in Example 12 for compound 9b except that compound 8d was used instead of compound 8b. 1HNMR (500 MHz, CD2C12): δ= 7.42 (t, / = 7.8 Hz, 2H), 7.03 (dd, / = 7.1, 2.2 Hz, 2H), 6.91 (d, / = 8.2 Hz, 2H), 5.96 (s, 2H), 5.93 (s, 2H), 5.21 (d, / = 8.7 Hz, 2H), 4.29 (s, 2H), 2.69 (s, 6H), 1.98 (s, 2H), 0.96 (d, / = 15.6 Hz, 18H); (202 MHz, CD2C12): = 71.6 (d, 2/ RhP= 152 Hz); 13CNMR (125 MHz, CD2C12): S= 162.3, 141.6 (t, / = 5.0 Hz), 134.9 (d, / = 6.3 Hz), 115.5 (d, / = 32.5 Hz), 111.7 (t, / = 1.8 Hz), 89.9 (m),
88.7 (m), 73.4 (m), 55.9 (d, / = 1.4 Hz), 37.6 (m), 27.2 (d, / = 2.5 Hz), 25.2 (d, / = 4.6 Hz).
Examples 21-23
Examples 21-23 describe the preparation of Rh[(2lS',3R)-3-ieri-butyl-2-(di-tert- butylphosphino)-4-methoxy-2,3-dihydrobenzo[(i][l,3]oxaphosphole (nbd)]BF4 (10c) as depicted below:
HSiCI3
TEA, toluene
10a
10b 10c
Example 21: Preparation of (2lS',3lS,)-3-ieri-butyl-2-(di-tert-butylphosphino)-4-methoxy- 2,3-dihydrobenzo[d][l,3]oxaphosphole bisoxide (10a). To a solution of
4-methoxy-2,3-dihydrobenzo[d][l,3]oxaphosphole oxide (100 mg, 0.42 mmol) prepared using procedure described in Example 4, in THF (3 mL) at -78°C was added LDA (0.24 mL, 1.8 mol/L, 0.46 mmol, 1.1 equiv). The mixture was stirred at -78°C for 1 h before iBu2PCl (90 mg, 0.50 mmol, 1.2 equiv) was added. The resulting mixture was further stirred at -78°C for 1 h then allowed to warm to 25°C over 1 h. To the mixture at 0°C was added 30% H202 solution (94 mg, 0.83 mmol, 2.0 equiv). The resulting mixture was stirred at 25 °C for 1 h then quenched with water (5 mL) and dichloromethane (5 mL). The dichloromethane layer was dried and purified by column chromatography (eluent:
EtOAc to EtOAc/MeOH 3/2) to provide 10a as a thick oil (120 mg, 0.30 mmol, 72 %). 1HNMR (400 MHz, CD2C12): δ= 7.45 (t, / = 8.2 Hz, 1H), 6.57 (m, 2H), 4.90 (dd, / = 9.0, 3.5 Hz, 1H), 3.90 (s, 3H), 1.41 (d, / = 13.5 Hz, 9H), 1.32 (d, J = 1.3 Hz, 9H), 1.28 (d, J = 9 A Hz, 9H); 31PNMR (162 MHz, CDC13): S= 61.7 (d, 3/ PP = 9.8 Hz), 60.9 (d, 3/ PP = 9.8 Hz); 13CNMR (100 MHz, CD2C12): S= 171.1, 164.8 (dd, / = 14.4, 5.8 Hz), 161.6 (d, J = 23 Hz), 136.7, 106.3 (d, / = 5.2 Hz), 104.1 (d, / = 5.6 Hz), 71.3 (dd, / = 52.4, 43.0 Hz), 56.0, 37.9 (dd, / = 55.7, 3.3 Hz), 37.0 (d, / = 57.0 Hz), 35.0 (d, / = 76.5 Hz), 27.7, 26.5, 25.9; ESI-MS: m/z 401 [M +H]+.
Example 22: Preparation of (2lS',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-4-methoxy- 2,3-dihydrobenzo[d][l,3]oxaphosphole (10b). To a solution of 10a (0.12 g, 0.30 mmol) in toluene (10 mL) at 25°C under nitrogen was added triethylamine (0.61 g, 5.99 mmol, 20 equiv) and trichlorosilane (0.41 g, 2.99 mmol). The mixture was heated to 120°C for 12 h. To the mixture at 0°C was added degassed 30% NaOH (10 mL) over 5 min. The resulting mixture was stirred at 60°C for about 1 h until the two layers became clear. The toluene layer was separated under N2 and the aqueous layer was further extracted with toluene twice (5 mL X 2). The combined toluene extracts was dried over Na2S04, concentrated under N2, and purified by passing through a neutral alumina plug (eluent: hexanes/ether 5: 1) to provide 10b (0.1 g, 0.27 mmol, 90 %) as white solid. 31PNMR (162 MHz, CD2C12): δ= 52.0 (d, 3/ PP = 145.8 Hz), 9.4 (d, 3/ PP = 146.7 Hz)
Example 23: Preparation of Rh[(2lS',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-4- methoxy-2,3-dihydrobenzo[JJ[l,3]oxaphosphole (nbd)]BF4 (10c). To a suspension of Rh(NBD)2BF4 (46 mg, 0.122 mmol) in THF (0.5 mL) was added a solution of 10b (50 mg, 0.136 mmol, 1.1 equiv) in THF (0.5 mL). The mixture was stirred at 25°C for 0.5 h, and then concentrated to about 1 mL. Degassed ether (10 mL) was added, the mixture was stirred at 25°C for 10 min, and filtered under N2 to provide 10c (60 mg, 0.092 mmol, 68%) as a yellow solid. 1HNMR (400 MHz, CD2C12): δ= 7.49 (t, / = 8.2 Hz, 1H), 6.71 (dd, / = 8.3, 4.6 Hz, 1H), 6.64 (m, 2H), 6.10 (m, 1H), 5.97 (m, 1H), 5.83 (m, 1H), 5.74 (m, 1H), 4.27 (m, 2H), 3.98 (s, 3H), 1.77 (m, 2H), 1.50 (d, / = 14.0 Hz, 9H), 1.18 (d, / =
14.8 Hz, 9H), 1.10 (d, J = 16.7 Hz, 9H); 31PNMR (162 MHz, CD2C12): S= 27.3 (dd, / = 131.3, 39.2 Hz), 4.6 (dd, / = 144.8, 39.2 Hz).
Examples 24-26
Examples 24-26 describe the preparation of Rh[(2lS',3R)-3-ieri-butyl-2-(di-tert- butylphosphino)-2,3-dihydrobenzo[d][l,3]oxaphosphole (nbd)]BF4 (11c) as depicted below:
11 b 11c
Example 24: Preparation of (2lS',3lS,)-3-tert-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole bisoxide (11a). To a solution of (lS')-3-tert-butyl-2,3- dihydrobenzo[d][l,3]oxaphosphole (0.5 g, 2.38 mmol) in THF (6 mL) was added LDA (1.45 mL, 1.8 M, 2.62 mol, 1.1 equiv) at -78°C. The mixture was stirred at -78°C for 1 h before addition of chloro di-ie/ -butylphosphine (0.473 g, 2.62 mmol, 1.1 equiv) at -78°C The resulting mixture was stirred at -78°C for 15 min then warmed to 25°C over lh. 30% H202 (0.54 g, 4.76 mmol, 2 equiv) was added and the mixture was further stirred at 25°C for 1 h. 10% NaHSC"3 (10 mL) was added and the mixture was concentrated to remove most THF. DCM (20 mL) was added and the DCM layer was separated, dried over sodium sulfate and purified by column chromatography (eluent: EtOAc:MeOH = 60:40)
to provide 11a as a white solid (0.85 g, 2.30 mmol, 95%): 1HNMR (400 MHz, CDC13): δ = 7.70 (dt, 7 = 7.3, 1.0 Hz, 1H), 7.50 (t, 7 = 7.4 Hz, 1H), 7.12 (dt, / = 7.4, 2.7 Hz, 1H), 6.99 (dd, / = 8.4, 3.2 Hz, 1H), 4.94 (dd, / = 10.1, 3.8 Hz, 1H), 1.44 (d, / = 13.5 Hz, 9H), 1.36 (d, / = 14.6 Hz, 9H), 1.34 (d, / = 16.1 Hz, 9H); 31PNMR (162 MHz, CDC13): S= 60.9 (d, 3/ pp = 9.4 Hz), 60.0 (d, 3/ PP = 9.3 Hz); 13CNMR (100 MHz, CDC13): =162.9, 134.7 (d, J = 1.7 Hz), 129.8 (d, / = 6.6 Hz), 122.7 (d, / = 9.1 Hz), 114.9 (m), 113.6 (d, / = 5.4 Hz), 70.8 (dd, / = 51.8, 43.4 Hz), 37.6 (dd, / = 55.8, 3.3 Hz), 36.7 (d, / = 56.9 Hz), 34.6 (d, / = 74.6 Hz), 27.3, 26.4, 25.1; ESI-MS: m/z 371 [M +H]+.
Example 25: Preparation of (2lS',3R)-3-tert-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole (lib). To a solution of 11a (0.64 g, 1.73 mmol) in toluene (10 mL) at 25°C under nitrogen was added triethylamine (1.75 g, 17.3 mmol, 10 equiv) and trichlorosilane (1.40 g, 10.4 mmol, 6 equiv). The mixture was heated to 110°C for 3 d. To the mixture at 0°C was added degassed 30% NaOH (20 mL) over 5 min. The resulting mixture was stirred at 60°C for about 1 h until the two layers became clear. The toluene layer was separated under N2 and the aqueous layer was further extracted with toluene twice (10 mL X 2). The combined toluene extracts was dried over Na2S04, concentrated under N2, and purified by passing through a neutral alumina plug (eluent: hexanes/ether 5: 1) to provide lib (0.5 g.1.48 mmol, 85 %) as a white solid. 1HNMR (400 MHz, CD2C12): δ= 7.39 (m, 1H), 7.23 (t, J = 7.3 Hz, 1H), 6.88 (m, 1H), 6.78 (d, / = 8.2 Hz, 1H), 5.57 (t, 7 = 5.3 Hz, 1H), 1.34 (d, / = 11.0 Hz, 9H), 1.15 (d, / = 11.1 Hz, 9H), 0.93 (d, / = 12.2 Hz, 9H); 31PNMR (162 MHz, CD2C12): S= 52.0 (d, 3/ PP = 146.1 Hz), 12.2 (d, 3/ PP = 146.4 Hz).
Example 26: Preparation of Rh[(2lS',3R)-3-ieri-butyl-2-(di-tert-butylphosphino)-2,3- dihydrobenzo[d][l,3]oxaphosphole (nbd)]BF4 (11c). To a suspension of Rh(NBD)2BF4 (0.27 g, 0.718 mmol) in THF (2 mL) was added a solution of lib (0.27 g, 0.798 mmol, 1.1 equiv) in THF (2 mL). The mixture was stirred at 25 °C for 0.5 h, then concentrated to about 2 mL. Degassed ether (20 mL) was added, the mixture was stirred at 25 °C for 10 min, and filtered under N2 to provide 11c (0.40 g, 0.645 mmol, 90%) as a yellow solid. 1HNMR (400 MHz, CD2C12): δ= 7.61 (m, 1H), 7.56 (m, 1H), 7.23 (dt, / = 6.6, 3.0 Hz,
1H), 6.71 (dd, / = 6.1, 3.6 Hz, 1H), 5.97 (m, 1H), 5.88 (m, 2H), 5.78 (m,lH), 4.30 (m, 1H), 4.28 (m, 1H), 1.78 (m, 2H), 1.52 (d, / = 14.1 Hz, 9H), 1.18 (d, / = 14.9 Hz, 9H), 1.03 (d, / = 16.6 Hz, 9H); 31PNMR (162 MHz, CD2C12): S= 25.5 (dd, / = 131.3, 40.0 Hz), 5.4 (dd, / = 130.0, 41.1 Hz).
Example 27: Preparation of Rh[(2R,2'R,3R,3'R)-BIBOP(nbd)]BF4.
The title compound was prepared in a manner similar to that described for the preparation of compound 9a in Examples 5-8 except that of (lS')-3-tert-butyl-2,3- dihydrobenzo[JJ[l,3]oxaphosphol-4-ol oxide ((S)-3), was used in instead of (R)-3 (see Example 5). ((S)-3) was then reacted with the same reagents and in the same as described in Examples 6 and 7 to provide the bis-phosphine ligand (2R,2'R,3R,3'R)-3,3'- di-tert-butyl-2,2',3,3'-tetrahydro-2,2'-bibenzo[<i][l,3]oxaphosphole bisoxide. The bis- phoshine ligand was then reacted with Rh(bbd)2BF4 in a manner similar to that described in Example 8 to provide the title compound.
An x-ray crystal structure of Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF4 (the H atoms are omitted) is shown in FIG. 1.
Example 28
Example 28 describes the use of the exemplary rhodium complex
Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF4 (from Example 27) for hydrogenation of cc- arylenamides, cc-dehydroamino acid derivatives, -(acetylamino)acrylates, and dimethyl itaconate
Entry Ar R ee [%]
4 /?-CF3-Ph Me >99
5 m-Me-Ph Me >99
6 3-thiophenyl Me >99
Entry Ar R R' ee [%]
1 Ph tBu Me 99
2 H Me Me >99
3 Ph Me Me 97
4 p-F-P Me Me 97
6 m-Br-Ph Me Me 98
7 o-Cl-Ph Me Me 97
8 2-thionyl Me Me 99
9 2-naphthyl Me Me 96
10 Ph N-morpholine Me 98
11 Ph Me H 98
Entry R R' R" ee [%] Config
1 H NHAc Me 99 R
2 H Me NHAc 99 R
3 CH2COOMe H H 94 S
The results of the study show that the exemplary metal complex of the invention Rh[(nbd)((2R,2'R,3R,3'R)-BIBOP)]BF4 is efficient for the enantioselective hydrogenation of cc-arylenamides, cc-dehydro amino acid derivatives, β- (acetylamino)acrylates, and dimethyl itaconate.
BLANK UPON FILING
Claims
1. A compound of formula (la), (lb), or a mixture thereof:
(la) (lb) wherein:
X is O, S, or -NR5 ;
R1 is -(Ci-C6)alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C3- C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-Cio)aryl and -(5 to 11- membered)heteroaryl of said R1 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C6)alkyl, -(Ci-C6)alkyl, and -CF3;
R2 is H, -0(Ci-C6)alkyl, -(Ci-C6)alkyl, -(C3-Ci0)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, -NR5R6, or -SR5; wherein said -(C3-C1o)carbocyclyl, -(5- to 1 l-membered)heterocarbocyclyl, -(C6- C1o)aryl, and -(5 to l l-membered)heteroaryl of said R is optionally substituted with 1 to 3 substituents independently selected from -0(C1-C6)alkyl, -(Q-C^alkyl, and -CF3;
R3 is -PR7R8, -CH2PR7R8, -CH2OPR7R8, or a group of formula (A) or (B):
wherein X, R 1 and R 2 of the group of formula (A) or (B) are as defined above, and wherein the group of formula (A) only joins to the compound of formula (la), and the group of formula (B) only joins to the compound of formula (lb);
R4 is H, -(C1-C6)alkyl, -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, (5- to 6-membered)heteroaryl, or -SiR5 3; wherein said -(Q-C^aLkyl of said R4 is optionally substituted with 1 to 3 substituents independently selected from -0(Cr C6)alkyl, -(C3-C6)cycloalkyl, phenyl, and -(5- to 6-membered)heteroaryl; and wherein said -(C3-C6)cycloalkyl, -(3- to 6-membered)heterocycloalkyl, phenyl, and (5- to 6- membered)heteroaryl of said R4 is optionally substituted with 1 to 3 substituents independently selected from -0(Ci-C6)alkyl, -(CrC^alkyl, and -CF3;
R5 and R6 are each independently H, -(Q-C^alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -(C6-C1o)aryl, or -(5 to l l-membered)heteroaryl;
wherein each -(CrC^alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, and -(5 to l l-membered)heteroaryl of said R5 and R6 is optionally independently substituted with 1 to 3 substituents independently selected from halo, -0(C1-C6)alkyl, -(Q-C^alkyl, and -CF3; and
R 7' and R 8° are each independently -(CrC^alkyl, -CF3, -(C3-C1o)carbocyclyl, -(5- to 11- membered)heterocarbocyclyl, -(C6-C1o)aryl, -(5 to l l-membered)heteroaryl, or ferrocenyl; wherein said -(C3-C1o)carbocyclyl, -(5- to l l-membered)heterocarbocyclyl, -C ered)heteroaryl of said R 7 and R 8
-(C6 1o)aryl and -(5 to 1 l-memb are each optionally independently substituted with 1 to 3 substituents independently selected from -0(Cr C6)alkyl, -(Ci-C6)alkyl, and -CF3.
2. The compound of claim 1 of formula (la), (lb), or a mixture thereof, wherein X is O.
3. The compound of formula (la), (lb), or a mixture thereof, according to any of the preceding claims, wherein R1 is -(Ci-C6)alkyl selected from -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -C(CH2CH3)3, or -C(CH2CH3)(CH3)2.
4. The compound of formula (la), (lb), or a mixture thereof, according to any of the preceding claims, wherein R is H, -CH3 or -OCH3.
5. The compound of formula (la), (lb), or a mixture thereof, according to any of the preceding claims, wherein R4 is -H.
6. The compound of formula (la), (lb), or a mixture thereof, according to any of the preceding claims, R3 is -PR7R8 or a group of formula (A).
7. The compound of formula (la), (lb), or a mixture thereof, according to claim 1, wherein R1 is -C(CH3)3; R2 is -H, -CH3, -OCH3, or phenyl; and R3 is -PR7R8.
8. The compound of formula (la), (lb), or a mixture thereof, according to claim 1 or
7, wherein R 7 and R 8 are each -C(CH3)3 and X is O.
9. The compound of formula (la), according to any one of claims 1 to 6, wherein R1 is -C(CH3)3; R2 is -H, -CH3, -OCH3, or phenyl; and R3 is a group of formula (A).
(lib)
wherein
R1 is -CH(CH3)2, -C(CH3)3, -C(CH2CH3)(CH3)2, cyclohexyl, 1-adamantyl, phenyl, ortho- tolyl, 3,5-xylyl, ortho-anisyl, or ferrocenyl ; and
R2 is H, -OCH3, -CH3, -CF3, phenyl, or -N(CH3)2.
10. The compound according to claim 1 having the formula (Ilia), (Illb), or a mixture thereof:
(Ilia) (Hlb) wherein
R1 is -CH(CH3)2, -C(CH3)3, -C(CH2CH3)(CH3)2, cyclohexyl, or 1-adamantyl; R2 is H, -OCH3, -CH3, -CF3, phenyl, or -N(CH3)2; and R7 and R8 are each -C(CH3)3.
11. The compound according to claim 1 selected from:
(2lS,,2'lS,,3lS',3'lS,)-3,3'-di-ieri-butyl-2,2',3,3'-tetrahydro-2,2'-bibenzo[(i][l,3]oxaphosphole, (25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole, (25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole,
(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole,
(2lS',3R)-3-ieri-butyl-2-(di-ieri-butylphosphino-4-methoxy)-2,3- dihydrobenzo[JJ [1,3] oxaphosphole, and
(2lS',3R)-3-ieri-butyl-2-(di-ieri-butylphosphino)-2,3-dihydrobenzo[(i][l,3]oxaphosphole.
A metal complex of formula (IVa), (IVb), (Va) or (Vb)
(Va) (Vb)
wherein
M is a transition metal selected from Co, Ni, Pd, Pt, Cu, Ag, Au, Ru, Fe, Rh and Ir; A" is a counter anion; n is the oxidation state of the transition metal M;
L 1 and L2 are each olefins, or L 1 and L2 together represent a diolefin; and
1 2 7 8
X, R\ ir, R', anci R° are as defined in claim 1.
13. The metal complex of claim 12, wherein M is Rh, A" is BF4 ~, and n is 1.
14. The metal complex of claim 12 selected from:
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ[l,3]oxaphosphole(nbd)]BF4j
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethoxy-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-diphenyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(25,2'5,35,3'5)-3,3'-di-ieri-butyl-4,4'-dimethyl-2,2',3,3'-tetrahydro-2,2'- bibenzo[JJ [ 1 ,3] oxaphosphole(nbd)]BF4>
Rh[(2lS',JR)-3-ieri-butyl-2-(di-ieri-butylphosphino)-4-methoxy-2,3- dihydrobenzo[JJ [ 1 ,3]oxaphosphole(nbd)]BF4 and
Rh[(2lS',JR)-3-ieri-butyl-2-(di-ieri-butylphosphino)-2,3-dihydrobenzo[(i][l,3]- oxaphosphole(nbd)]BF4
15. A method of carrying out an asymmetric hydrogenation of a compound having a carbon-carbon or carbon-heteroatom double bond, the method comprising allowing said compound having a carbon-carbon or carbon-heteroatom double bond to react with hydrogen in the presence of a catalytic amount of the metal complex of any one of claims 12 to 14.
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CN112574234A (en) * | 2019-09-27 | 2021-03-30 | 江苏恒瑞医药股份有限公司 | Preparation method of ecteinascidin derivative |
CN111647020A (en) * | 2020-04-09 | 2020-09-11 | 宁波赜军医药科技有限公司 | Synthesis method of phosphine oxide bidentate ligand |
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JP5750449B2 (en) | 2015-07-22 |
US20120277455A1 (en) | 2012-11-01 |
EP2496589A1 (en) | 2012-09-12 |
EP2496589B1 (en) | 2014-03-05 |
JP2013510154A (en) | 2013-03-21 |
US8552212B2 (en) | 2013-10-08 |
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