EP1105400A1 - Asymmetrische katalysis mit hilfe von chiralen phospholanen - Google Patents
Asymmetrische katalysis mit hilfe von chiralen phospholanenInfo
- Publication number
- EP1105400A1 EP1105400A1 EP99941237A EP99941237A EP1105400A1 EP 1105400 A1 EP1105400 A1 EP 1105400A1 EP 99941237 A EP99941237 A EP 99941237A EP 99941237 A EP99941237 A EP 99941237A EP 1105400 A1 EP1105400 A1 EP 1105400A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- aryl
- substituted
- divalent
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000004850 phospholanes Chemical class 0.000 title description 13
- 238000006555 catalytic reaction Methods 0.000 title description 4
- 239000003446 ligand Substances 0.000 claims abstract description 46
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- -1 diphenylphosphino groups Chemical group 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 229910052796 boron Inorganic materials 0.000 claims description 17
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229920000642 polymer Polymers 0.000 claims description 16
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 239000010948 rhodium Substances 0.000 claims description 13
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims description 12
- 150000002009 diols Chemical class 0.000 claims description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 150000003573 thiols Chemical group 0.000 claims description 8
- 229910052723 transition metal Inorganic materials 0.000 claims description 8
- 150000003624 transition metals Chemical class 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 7
- 229920002554 vinyl polymer Polymers 0.000 claims description 7
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 5
- 150000003983 crown ethers Chemical class 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006845 Michael addition reaction Methods 0.000 claims description 4
- 238000006579 Tsuji-Trost allylation reaction Methods 0.000 claims description 4
- 238000005865 alkene metathesis reaction Methods 0.000 claims description 4
- 150000001336 alkenes Chemical class 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 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 4
- 238000005888 cyclopropanation reaction Methods 0.000 claims description 4
- 125000005610 enamide group Chemical group 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
- 238000007871 hydride transfer reaction Methods 0.000 claims description 4
- 238000006197 hydroboration reaction Methods 0.000 claims description 4
- 238000007037 hydroformylation reaction Methods 0.000 claims description 4
- 238000006459 hydrosilylation reaction Methods 0.000 claims description 4
- 238000006267 hydrovinylation reaction Methods 0.000 claims description 4
- 150000002466 imines Chemical class 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 4
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 150000003460 sulfonic acids Chemical class 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- 238000006352 cycloaddition reaction Methods 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N acetic acid;palladium Chemical compound [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 claims description 2
- DHCWLIOIJZJFJE-UHFFFAOYSA-L dichlororuthenium Chemical compound Cl[Ru]Cl DHCWLIOIJZJFJE-UHFFFAOYSA-L 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Chemical group 0.000 claims description 2
- 229910052705 radium Inorganic materials 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 229910000077 silane Inorganic materials 0.000 claims description 2
- 239000010703 silicon Chemical group 0.000 claims description 2
- 229910052710 silicon Chemical group 0.000 claims description 2
- 150000001735 carboxylic acids Chemical group 0.000 claims 4
- 150000002431 hydrogen Chemical group 0.000 claims 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 abstract description 14
- 235000010355 mannitol Nutrition 0.000 abstract description 7
- GWLJTAJEHRYMCA-UHFFFAOYSA-N phospholane Chemical group C1CCPC1 GWLJTAJEHRYMCA-UHFFFAOYSA-N 0.000 abstract description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 3
- 229930014626 natural product Natural products 0.000 abstract description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 abstract description 2
- 235000002906 tartaric acid Nutrition 0.000 abstract description 2
- 239000011975 tartaric acid Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 238000003786 synthesis reaction Methods 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 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 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- KGHIFMQWNYFRHG-UHFFFAOYSA-N 1-hydroxyphospholane Chemical class OP1CCCC1 KGHIFMQWNYFRHG-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004679 31P NMR spectroscopy Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000005712 Baylis-Hillman reaction Methods 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 4
- 239000007832 Na2SO4 Substances 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 150000000190 1,4-diols Chemical class 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000011914 asymmetric synthesis Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 150000003003 phosphines Chemical class 0.000 description 3
- RYIOLWQRQXDECZ-UHFFFAOYSA-N phosphinous acid Chemical compound PO RYIOLWQRQXDECZ-UHFFFAOYSA-N 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LPYLNJHERBLCRN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;hexafluorophosphate Chemical compound [Rh].F[P-](F)(F)(F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LPYLNJHERBLCRN-QMDOQEJBSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- JAHNSTQSQJOJLO-UHFFFAOYSA-N 2-(3-fluorophenyl)-1h-imidazole Chemical class FC1=CC=CC(C=2NC=CN=2)=C1 JAHNSTQSQJOJLO-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001733 carboxylic acid esters Chemical group 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012038 nucleophile 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
- RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/04—Nickel compounds
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/165—Polymer immobilised coordination complexes, e.g. organometallic complexes
- B01J31/1658—Polymer immobilised coordination complexes, e.g. organometallic complexes immobilised by covalent linkages, i.e. pendant complexes with optional linking groups, e.g. on Wang or Merrifield resins
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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- B01J31/2433—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising P as ring member with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
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- B01J31/2466—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring comprising aliphatic or saturated rings
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- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
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- B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
- B01J31/2461—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring
- B01J31/2471—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom
- B01J31/2476—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as ring members in the condensed ring system or in a further ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/49—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide
- C07C45/50—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
- C07C45/505—Asymmetric hydroformylation
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- 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
-
- 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
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Definitions
- This invention relates to chiral phospholanes derived from natural products, and asymmetric catalysis using these phospholanes.
- the ligands DuPhosTM and BPE have been used effectively for certain asymmetric hydrogenation reactions. See U.S. Patent Nos. 5,329,015; 5,202,493; and 5,329,015; Burk, M.J., J. Am. Chem. Soc. (1991) 113, 8518; Burk, M.J., J. Am. Chem. Soc. (1993) 115, 10125; Burk, M.J., J. Am. Chem. Soc. (1996) 118, 5142. These ligands, however, are not effective for some other asymmetric reactions. Moreover, synthesis of these ligands can be difficult, involving a tedious Kolbe reaction. Also, several liquid DuPhosTM BPE ligands are air-sensitive and therefore difficult to handle.
- One aspect of the invention is a ligand of formula A, , B, B', C, C, D, or D', or the corresponding enantiomer:
- Another aspect of the invention is a compound of the formula E:
- Another aspect of the invention is a catalyst including one of the compounds A-E above, wherein the compound is in the form of a complex with a transition metal.
- Another aspect of the invention is a process for preparing a compound of formula B, by reacting a compound of formula B x with a phosphine:
- Another aspect of the invention is a process that includes subjecting a substrate to an asymmetric reaction in the presence of one of the above-described ligands, wherein said asymmetric reaction is a hydrogenation, hydride transfer, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels- Alder, Aldol, Heck, [m + n] cycloaddition, or Michael addition reaction.
- said asymmetric reaction is a hydrogenation, hydride transfer, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels- Alder, Aldol, Heck, [m + n] cycloaddition, or Michael addition reaction.
- one advantage of the invention is in providing chiral ligands that can be made in large scale from inexpensive natural products such as D-mannitol or tartaric acids.
- Another advantage is in providing new chiral ligands A'-D' in FIG. 3, in which the relative configuration of the four stereogenic centers around the phospholane differs from A-D.
- Yet another advantage is in providing chiral ligands that are solid and/or more air-stable due to added functional groups, and are more easily handled compared to air-sensitive liquids such as DuPhosTM/BPE ligands. Yet another advantage is in providing chiral ligands that have functional groups on the phospholanes that can be key stereochemistry-defining groups, such as a hemilabile anchor, a hydrogen bonding source, or a cation binding site through a crown ether. Yet another advantage is in providing chiral ligands that have additional functional groups on the phospholanes with water-soluble properties and a convenient site to link a polymer support.
- Yet another advantage of the invention is in providing catalysts for a variety of asymmetric reactions such as hydrogenation, hydride transfer reaction, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels- Alder reaction, Aldol reaction, Heck reaction, Baylis-Hillman reaction and Michael addition can be explored based on these innovative ligand systems.
- asymmetric reactions such as hydrogenation, hydride transfer reaction, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels- Alder reaction, Aldol reaction, Heck reaction, Baylis-Hillman reaction and Michael addition can be explored based on these innovative ligand systems.
- Yet another advantage of the invention is in providing a variety of methods to make both enantiomers of chiral phosphines.
- D-mannitol other chiral pool materials such as D and L-tartaric acids can also be used as suitable starting materials for ligand synthesis.
- D and L-tartaric acids can also be used as suitable starting materials for ligand synthesis. Only one phospholane enantiomer can be conveniently obtained using D-mannitol as the starting material while both phospholane enantiomers can be easily obtained when using D and L-tartaric acids for the ligand synthesis.
- FIG. 1 shows new chiral ligands A, A B, B', C, C, D, and D' of the invention.
- FIGs. 2A-2F shows the structure of ligand examples LI to L32.
- FIGs. 3A-3C illustrate syntheses of ligands LI to L32.
- FIGs. 4A-4C show syntheses of some chiral 1,4-diols.
- % ee enantiomeric excess, (%S - %R)/(%S + %R) or (%R - %S)/(%S + %R) acac: acetylacetonate
- Bn benzyl COD: 1,5-cyclooctadiene
- HMPA hexamethylphosphoramide
- the chiral ligands of the present invention may contain alkyl and aryl groups.
- alkyl is meant any straight, branched, or cyclic alkyl group.
- the number of carbons in the alkyl group is not particularly limited.
- alkyl refers to Cl- C20, more preferably C1-C8, even more preferably C1-C4 alkyl groups.
- alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and isomers of heptyl, octyl, and nonyl.
- Alkyl groups may be substituted without particular restriction, provided that the substituents do not have an adverse effect on the asymmetric reaction, and are inert to the reaction conditions or are thereby converted in a desirable manner.
- substituents include, but are not limited to, aryl, heterocyclo, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, nitro, amido, and carboxylic ester groups, and any suitable combination thereof.
- aryl any aromatic or heteroaromatic ring, including such rings fused to other aliphatic, aromatic or heteroaromatic rings.
- aromatic rings include, but are not limited to, phenyl, naphthyl, anthryl, fluorenyl, indenyl, and phenanthryl.
- Heteroaromatic rings may contain one or more heteroatoms, preferably one or more atoms of nitrogen, oxygen, or sulfur.
- heteroaromatic rings include, but are not limited to, pyrrole, pyridine, quinoline, isoquinoline, indole, furan, and thiophene.
- Aryl groups may be substituted without particular restriction, provided that the substituents do not have an adverse effect on the asymmetric reaction, and are inert to the reaction conditions or are thereby converted in a desirable manner.
- substituents include, but are not limited to alkyl, aryl, heterocyclo, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino, nitro, amido, and carboxylic ester groups, and any suitable combination thereof.
- the optical purity of the ligand is preferably at least about 85% ee, more preferably at least about 90% ee, more preferably at least about 95% ee, even more preferably at least about 98% ee, and even more preferably about 100% ee.
- a chiral ligand can exist as two enantiomers of opposite configuration.
- a person skilled in the art will recognize that for any given asymmetric reaction, each enantiomer will produce products of opposite configuration from the other, but with the same conversion and optical purity.
- ligand and product structures are shown for one enantiomer for convenience.
- the disclosure also applies to the corresponding enantiomers of opposite configuration, and a person skilled in the art can select the appropriate enantiomer to achieve the desired product configuration.
- FIG. 1 shows several classes of chiral phospholanes (A, B, C, D, and A', B', C ⁇ D').
- A, B, C, D, and A', B', C ⁇ D' is in the inversion of two chiral centers in the middle of the rings.
- enantiomers are also included, which can be made through different chiral pools.
- a and A' are chiral bidentate phospholanes with four chiral centers.
- B and B' are chiral bidentate phospholanes with four chiral centers and linked by a ring in the middle of five membered rings.
- C, D, C, D' are monophospholanes.
- Ligand LI (A) has a benzyl protecting group on the two center hydroxyl groups while ligand L3 has a hydroxyl group.
- Ligand L2 belongs to class B' with a cyclic ketyl in the center.
- Ligands LI -LI 3 contain bridging groups such as CH 2 CH 2 , benzene, ferrocene, biaryl, binaphthyl groups.
- Ligands LI 4- L17 are linked to a polymer backbone.
- Ligands L18-L21 have water soluble groups. In ligands L22-L25, an 18-crown-6 group was introduced.
- Ligands L26-L27 are monophospholanes containing a variety of groups.
- Ligands L30 - L32 have additional groups as substituents of aryls; some will lead to hemilabile ligands.
- One embodiment of the invention is a compound of formula A, A', B, B', C, C, D, or D', or the corresponding enantiomer:
- R and R 2 are aryl, alkyl, alkyl aryl, or aryl alkyl, which may be substituted with carboxylic acid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino, or chiral oxazolino groups;
- R 1 can be H, alkyl, silane, aryl, a water soluble unit, or a linked polymer chain or inorganic support;
- the ring component 0 O represents a protected diol, a crown ether linkage, -O-alkyl-O- wherein the alkyl group is linked to a polymer, or -O-(CH 2 CH 2 - O) n - wherein the methylene groups are optionally substituted by C1-C8 alkyl; and
- i Bridge may be:
- n is an integer ranging from 1 to 8; -(CH 2 ) n X(CH 2 ) m - wherein n and m are each integers, the same or different, ranging from 1 to 8, and X is O, S, NR 4 , PR 4 , AsR 4 , SbR 4 , divalent aryl, divalent fused aryl, divalent 5-membered ring heterocyclic group, or divalent fused heterocyclic group, wherein R 4 is hydrogen, aryl, alkyl, substituted aryl or substituted alkyl groups; or
- 1,2-divalent phenyl, 2,2'-divalent 1,1'biphenyl or 2,2'-divalent 1,2'binapthyl or ferrocene each of which may be substituted with aryl, C1-C8 alkyl, F, Cl, Br, I, COOR 5 , SO 3 R 5 , PO 3 R 5 2 , OR 5 , SR ⁇ NR 5 2 , PR 5 2 , AsR 5 2 , or SbR 5 2 , wherein: the substitution on 1 ,2-divalent phenyl, the ferrocene or biaryl bridge can be independently halogen, alkyl, alkoxyl, aryl, aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acids; and
- R 5 is hydrogen, C1-C8 alkyl, C1-C8 fluoroalkyl, or C1-C8 perfluoroalkyl, aryl; substituted aryl; arylalkyl; ring-substituted arylalkyl; or -CR 3 2 (CR 3 2 ) q X(CR 3 2 ) p R 1 wherein q and p are integers, the same or different, ranging from 1 to 8; R 3 is an aryl, alkyl, substituted aryl and substituted alkyl group; and R 1 and X are as defined above.
- the counterion for water soluble units bearing a charge include, but are not limited to, metals such as alkali and alkaline earth metals, and halogens and Otf.
- the polymer may be any polymer or copolymer, preferably polystyrene or a copolymer of styrene and a substituted vinyl monomer, polyacrylate, PEG or MeO-PEG, or dendritic polymers of polyesters or polyenamides.
- the preceding also applies to the ring component O ⁇ O as -O-alkyl-O- wherein the alkyl group is linked to a polymer.
- R 1 is a linked inorganic support
- examples of inorganic supports include, but are not limited to, silica or zeolites.
- the ring component O ⁇ O is a protected diol
- a person of skill in the art will recognize that any number of the diol protecting group may be used, e.g., those described in Greene and Wuts, Protective Groups in Organic Synthesis, 1991, John Wiley & Sons, and MacOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press, the entire contents of which are incorporated herein by reference.
- a suitable diol protecting group may be deprotected under conditions that do not significantly degrade the rest of the molecule. Examples of diol protecting groups include, but are not limited to acetals and ketals.
- the invention is a compound of formula A or A', or the corresponding enantiomer.
- R is methyl, ethyl, or benzyl
- R' is hydrogen or benzyl
- is -(CH 2 ) n - where n is an integer ranging from 1 to 3, 1,2-divalent phenyl; 2,2'-divalent 1,1'biphenyl, 2,2'-divalent 1,2'binapthyl, or ferrocene, each of which may be substituted with alkyl having 1-3 carbon atoms; or OR 5 , wherein R 5 is methyl or ethyl.
- Examples of the compound of formula A or A' include, but are not limited to LI, L3-L5, L7-L8, L10-L12, and L18-L21, and the corresponding enantiomers, and the compound of formula 2 below and its enantiomer.
- the invention is a compound of formula B or B', or the corresponding enantiomer.
- R is C1-C4 alkyl, unsubstituted or substituted by phenyl or
- R 5 is C1-C2 alkyl
- the ring component 0 ⁇ 0 is -O-CR a R b -O-
- R is hydrogen or C1-C4 alkyl and R b is an alkyl or aryl linker attached to a polymer.
- Examples of the compound of formula B or B' include, but are not limited to L2, L6, L9, L13, L14-L17, and L22-L25, and the corresponding enantiomers, and the compound of formula 3 below and its enantiomer:
- the invention is a compound of formula C, D, C, or D', or the corresponding enantiomer.
- R is methyl, ethyl, or benzyl;
- R' is hydrogen or benzyl;
- R 2 is o-X-phenyl wherein X is a carboxylic acid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino, or chiral oxazolino group; and the ring component 0 ⁇ 0 is -O-CR a R b -O-, wherein R a and R b are independently hydrogen or
- Examples of the compound of formula B or B' include, but are not limited to structures L26-L32, and the corresponding enantiomers, and the compound of formula 1 below and its enantiomer:
- Another embodiment of the invention is a compound of formula E or the corresponding enantiomer.
- R and R 9 are aryl, C1-C8 alkyl, C1-C8 alkyl aryl, or aryl C1-C8 alkyl, which may be substituted with carboxylic acid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino, or chiral oxazolino groups; and
- R is C1-C4 alkyl and R 9 is C1-C4 alkyl or phenyl.
- Another embodiment of the invention is a catalyst including any of the compounds described in the embodiments above, wherein the compound is in the form of a complex with a transition metal.
- any transition metal may be used.
- the transition metal is a Group VIII transition metal. More preferably, the transition metal is rhodium, iridium, ruthenium, nickel, or palladium.
- the compound is in the form of a complex with Pd 2 (DBA) 3 , Pd(OAc) 2 ; [Rh(COD)Cl] 2 , [Rh(COD) 2 ]X, Rh(acac)(CO) 2 ; RuCl 2 (COD), Ru(COD)(methylallyl) 2 , Ru(Ar)Cl 2 , wherein Ar is an aryl group, unsubstituted or substituted with an alkyl group; [Ir(COD)Cl] 2 , [Ir(COD) 2 ]X; or Ni(allyl)X; wherein X is a counterion.
- the counterion X may generally be any suitable anion for use in asymmetric synthesis.
- suitable counterions include, but are not limited to, halogen ions (including Cl ⁇ , Br ⁇ , and I ⁇ ), BF 4 - ClO 4 ⁇ SbF 6 ⁇ , CF 3 SO 3 - BAr 4 ⁇ (wherein Ar is aryl), and Otf- (trifluoromethanesulfonate).
- X is BF 4 , ClO 4 , SbF 6 , or CF 3 SO 3 .
- the catalyst comprises Ru(RCOO) 2 (diphosphine), RuX 2 (diphosphine), Ru(methylallyl) 2 (diphosphine), or Ru(aryl group)X 2 (diphosphine), and X is halogen.
- Another embodiment of the invention is a process including subjecting a substrate to an asymmetric reaction in the presence of a catalyst comprising a chiral ligand according to claim 1 , wherein said asymmetric reaction is a hydrogenation, hydride transfer, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels- Alder, Aldol, Heck, [m + n] cycloaddition, or Michael addition reaction.
- the process includes asymmetric hydrogenation of a ketone, imine, enamide, or olefin.
- Another embodiment of the invention is a process for preparing a compound of formula B, comprising reacting a compound of formula B x with a phosphine:
- the phosphine is H 2 PH Bridge ⁇ )-PH 2 ;
- R is aryl, alkyl, alkyl aryl, or aryl alkyl, which may be substituted with carboxylic acid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino, or chiral oxazolino groups;
- the ring component 0 ⁇ 0 represents a protected diol, a crown ether linkage, or -O-CH 2 CH 2 ) n -O- wherein n is an integer ranging from 1 to 8 and the methylene groups are optionally substituted by alkyl or linked to a polymer;
- I Bridge may be:
- n is an integer ranging from 1 to 8.
- n, m are each integers, the same or different, ranging from 1 to 8; or
- 1,2-divalent phenyl, 2,2'-divalent 1,1 'biphenyl or 2,2'-divalent 1,2'binapthyl or ferrocene each of which may be substituted with aryl or substituted aryl, or alkyl having 1-8 carbon atoms, heteroatom groups such as F, Cl, Br, I, COOR 5 , SO 3 R 5 , PO 3 R 5 2 , OR 5 , SR 5 , NR 5 2 , PR 5 2 , AsR 5 2 , or SbR 5 2 , wherein: the substitution on 1,2-divalent phenyl, the ferrocene or biaryl bridge can be independently halogen, alkyl, alkoxyl, aryl, aryloxy, nitro, amino, vinyl, substituted vinyl, akkynyl, or sulfonic acids; and R 5 is hydrogen, C1-C8 alkyl, C1-C8 fluoroalkyl, or C1-C8
- R is C1-C4 alkyl; the ring component 0 ⁇ 0 represents a protected diol; and I Bridge [ is unsubstituted or substituted 1,2-divalent phenyl. More prefarbly,
- R is methyl or ethyl
- the ring component O O is -O-C(CH 3 ) 2 -O-
- Bridge is unsubstituted 1 ,2-divalent phenyl.
- FIGs. 3A-3C show several pathways for the synthesis of compounds shown in FIGs. 2A-2F.
- the chiral 1,4-diols used in the synthesis of ligands L1-L32 can be derived from D-mannitol and related compounds. A number of these diols have been reported in the literature.
- the procedure for the synthesis of LI (A), L3(A) and L8 (A') is outlined in FIGs. 3A-3B; key intermediates L35 and L35' have been reported in the literature (Poitout, L.; Tetrahedron Letter (1994) 35, 3293).
- the epoxide opening step from L35 to L37 in FIG. 3A has also been reported (Nugel, S. et al J. Med.
- 18-crown-6 or water soluble groups can be linked to form compounds such as L19 (A) or L25 (B), as shown in FIGs. 2D and 2E, respectively.
- FIGs. 4A-4C outline some useful synthetic procedures, which was recently disclosed in the literature. Instead of using D-mannitol as the starting material, which can only lead to one enantiomer of the chiral phosphine, preparation of chiral diols from either D or L-tartaric ester can result in formation of either of two enantiomers. Using these reported procedures (Nugel, S. et al. J. Med. Chem. (1996) 39, 2136; Colobert, F. J. Org. Chem. (1998) 63, 8918; and Iwasaki, S. Tetrahedron Lett. (1996) 37, 885), several chiral 1,4-diols can be obtained, as shown in FIGs. 4A-4C.
- hydroxyl phosphine ligands 1, 2, and 3 were synthesized successfully in high yield using similar procedures. They are white solids.
- the synthetic route is exemplified below.
- Compound 10 is a nice colorless crystal and can be recrystallized from ethyl ether and methanol.
- Compound 2 was used directly after removal of the reaction solvent without any purification.
- An advantage of this route is that there is no need to run column chromatography for purification.
- Compound 14 is a colorless crystal and can be recrystallized from ethyl ether and methanol.
- the cyclic sulfate 15 was also made from the corresponding alcohol, which was synthesized in the same procedure to make 12.
- Ligand 16 can be made in a similar manner using the same procedure as for the synthesis of 2 and 3.
- Compound 18 was prepared by stirring 1 and phenylboronic acid in methylene chloride. After removal of the solvent, it was used directly in asymmetric reaction.
- Compound 21 was prepared from known cyclic sulfate 20. Several chiral monophospho lanes from D-mannitol (e.g., 19, 21) are made and many methods cleave the protecting groups to give hydroxyl phospholane 1. The iso-propylene group in 19 was smoothly removed by an acid catalyzed hydrolysis. However, the borane adduct of 21 was just selectively debenzylated when BC1 3 or BF 3 .Et 2 O was used as the reagent to give the derivatives bearing one hydroxyl and one benzyl ether group. Hydrogenation of 21 using Pd/C catalyst does not give the desired hydroxyl phospholane product 1.
- the corresponding phosphine oxide of 21 also gave selectively debenzylated products under mild hydrogenation conditions (10 % Pd(OH) 2 /C).
- the hydrogenation reaction done under high temperature (50 °C) and H 2 pressure (40 atm) not only cleaved the benzyl ether but also reduced the phenyl group to a cyclohexyl group.
- n-BuLi 1.6 M solution in n-hexane, 2.5 mL, 4.0 mmol
- the color of the reaction mixture changed from orange yellow to red, and then decolorized to colorless.
- the residue was dissolved in 40 mL of ethyl ether, and 30 mL of brine was added. The aqueous layer was then washed with 3 x 30 mL ethyl ether. The combined organic layers were dried over Na 2 SO 4 and concentrated to afford a colorless oil.
- This oil can be further purified by a short silica gel column eluted with hexane/ether (9:1), "H NMR (CDC1 3 ): ⁇ 7.72-7.27 (m, 5H, aromatic), 4.60-4.32 (m, 2H), 2.70-2.51 (m, 2H), 1.52 (s, 6H), 1.38-1.32 (m, 3H), 0.70-0.52(m, 3H). 31 P NMR (CDC13): ⁇ 50.2 ppm.
- Phosphine 19 obtained above was dissolved in 50 mL methanol and 2 mL of water. To this solution, 0.05 mL of methanesulfonic acid was added and the resulting mixture was refluxing for 10 h. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of methylene chloride. 30 mL of aq NaHCO 3 was added and the two layers were separated. The aqueous layer was washed with 3 x 40 mL of methylene chloride. The combined organic layers were dried over Na 2 SO 4 and concentrated to give a white solid, compound 1.
- n-BuLi 1.6 M n-hexane solution, 1.25 mL, 2.0 mmol
- n-BuLi 1.6 M solution in n-hexane, 11.0 mL, 17.5 mmol
- the reaction mixture was stirred for additional 20 h at room temperature.
- the residue was dissolved in 50 mL of ethyl ether, and 50 mL of brine was added.
- the aqueous layer was then washed with 3 x 40 mL ethyl ether.
- the combined organic layers were dried over Na 2 SO 4 and concentrated to afford a colorless crystal. This crystal was further recrystallized from ether/methanol.
- Phosphine 10 obtained above was disolved in 100 mL of methanol and 2 mL of water. 0.1 mL of methanesufonic acid was added and the resulting mixturing was refluxing for 10 h. After removal of the solvent the residue was passed through a short plug of silica gel eluted with ethyl acetate/methanol (95:5) to give compound 2 as a white solid.
- Phosphine 14 was prepared using the similar procedure for 10 and recrystallized from ethyl ether/methanol as a colorless crystal.
- EXAMPLE 8 General Procedure for the Baylis-Hillman Reaction The mixture of 4-pyridinecarbonaldehyde (1 mmol) and 1 mL of methyl acrylate was degassed three times by a freeze-thaw method, and then the resulting solution was transferred into another Schlenk tube containing 10% catalyst. The solution was stirred at room temperature for some time and the methyl acrylate was removed under vaccm. The residue was purified by a flash chromatograph eluted with hexanes/ethyl acetate (1 :2). The enantiomeric excess was measured by capillary GC.
- NHAc H 2 (3 atm), CH 3 OH, rt, 12 h NHAc
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US9747398P | 1998-08-21 | 1998-08-21 | |
US97473P | 1998-08-21 | ||
US377065 | 1999-08-19 | ||
US09/377,065 US6337406B1 (en) | 1998-08-21 | 1999-08-19 | Asymmetric catalysis based on chiral phospholanes and hydroxyl phospholanes |
PCT/US1999/018932 WO2000011008A1 (en) | 1998-08-21 | 1999-08-20 | Asymmetric catalysis based on chiral phospholanes |
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ES2236134T3 (es) | 2000-12-13 | 2005-07-16 | Warner-Lambert Company Llc | Ligandos bisfosfolanos p-quirales y sus complejos con metales de transicion. |
MXPA02001147A (es) | 2001-03-19 | 2004-04-21 | Warner Lambert Co | Sintesis de ligandos bisfosina no-c2-simetricos como catalizadores para la hidrogenacion asimetrica. |
JP4226847B2 (ja) | 2001-07-24 | 2009-02-18 | 高砂香料工業株式会社 | ホスフィン−ホスホラン化合物と遷移金属とを含有する遷移金属錯体の存在下、α,β−不飽和アミド誘導体から光学活性アミド類を製造する方法。 |
US6660876B2 (en) * | 2001-11-26 | 2003-12-09 | E. I. Du Pont De Nemours And Company | Phosphorus-containing compositions and their use in hydrocyanation, isomerization and hydroformylation reactions |
JP4005800B2 (ja) | 2001-12-10 | 2007-11-14 | 高砂香料工業株式会社 | 新規不斉ホスフィン配位子 |
JP4005801B2 (ja) | 2001-12-10 | 2007-11-14 | 高砂香料工業株式会社 | 新規なホスフィン配位子 |
CN100349907C (zh) * | 2003-05-09 | 2007-11-21 | 索尔维亚斯股份公司 | 膦烷盐及其在对映选择性氢化中的用途 |
JP4970249B2 (ja) * | 2005-03-29 | 2012-07-04 | Meiji Seikaファルマ株式会社 | L−2−アミノ−4−(ヒドロキシメチルホスフィニル)−ブタン酸の製造法 |
EP1874711A2 (de) * | 2005-04-22 | 2008-01-09 | Dow Gloval Technologies Inc. | Asymmetrisches hydroformylierungsverfahren |
TW200728315A (en) | 2005-12-06 | 2007-08-01 | Nippon Chemical Ind | Phosphorus transition-metal complex, method of producing the same, and anticancer agent forming the same |
CN113603691B (zh) * | 2021-08-12 | 2022-08-26 | 连云港冠昕医药科技有限公司 | L-5-甲基四氢叶酸钙的制备工艺 |
CN114085251B (zh) * | 2021-11-02 | 2024-01-19 | 中国人民解放军空军军医大学 | 一类手性二茂铁-螺环骨架双膦配体及其制备方法 |
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US5202493A (en) * | 1991-04-26 | 1993-04-13 | E. I. Du Pont De Nemours And Company | Chiral tridentate bis(phospholane) ligands |
DE19725796A1 (de) * | 1997-06-18 | 1998-12-24 | Basf Ag | Herstellung optisch aktiver Phospholane, deren Metallkomplexe und Anwendung in der asymmetrischen Synthese |
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