WO2016047388A1 - アルコール類の製造方法 - Google Patents
アルコール類の製造方法 Download PDFInfo
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- WO2016047388A1 WO2016047388A1 PCT/JP2015/074733 JP2015074733W WO2016047388A1 WO 2016047388 A1 WO2016047388 A1 WO 2016047388A1 JP 2015074733 W JP2015074733 W JP 2015074733W WO 2016047388 A1 WO2016047388 A1 WO 2016047388A1
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- Prior art keywords
- group
- substituent
- alkyl group
- general formula
- carbon atoms
- Prior art date
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- 238000000034 method Methods 0.000 title abstract description 33
- 150000001298 alcohols Chemical class 0.000 title description 2
- -1 boric acid enol ester Chemical class 0.000 claims abstract description 158
- 239000004327 boric acid Substances 0.000 claims abstract description 27
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 21
- 239000005749 Copper compound Substances 0.000 claims abstract description 15
- 150000001880 copper compounds Chemical class 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 67
- 125000004432 carbon atom Chemical group C* 0.000 claims description 51
- 125000001424 substituent group Chemical group 0.000 claims description 47
- 239000003054 catalyst Substances 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 23
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 14
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 238000006317 isomerization reaction Methods 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 229910052741 iridium Inorganic materials 0.000 claims description 5
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 150000002466 imines Chemical class 0.000 abstract description 8
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 42
- 239000000243 solution Substances 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- 150000001299 aldehydes Chemical class 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
- 125000003118 aryl group Chemical group 0.000 description 20
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000005575 aldol reaction Methods 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical group [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 13
- 239000000758 substrate Substances 0.000 description 13
- 150000002430 hydrocarbons Chemical group 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 11
- 125000003277 amino group Chemical group 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- ZNORAFJUESSLTM-UHFFFAOYSA-N [4-[5-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1P(C=1C(=C2OCOC2=CC=1)C=1C(=CC=C2OCOC2=1)P(C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C=1C=C(C(OC)=C(C=1)C(C)(C)C)C(C)(C)C)C1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 ZNORAFJUESSLTM-UHFFFAOYSA-N 0.000 description 9
- TYIFJJCPKPPNPM-UHFFFAOYSA-N copper(1+);1,3,5-trimethylbenzene-6-ide Chemical compound [Cu+].CC1=CC(C)=[C-]C(C)=C1 TYIFJJCPKPPNPM-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 125000001931 aliphatic group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 150000002009 diols Chemical class 0.000 description 5
- 239000012039 electrophile Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- MUHONFFTSOCMDH-JXNOXZOESA-N (1z,5z)-cycloocta-1,5-diene;iridium;methyl(diphenyl)phosphane;hexafluorophosphate Chemical compound [Ir].F[P-](F)(F)(F)(F)F.C\1C\C=C/CC\C=C/1.C=1C=CC=CC=1P(C)C1=CC=CC=C1.C=1C=CC=CC=1P(C)C1=CC=CC=C1 MUHONFFTSOCMDH-JXNOXZOESA-N 0.000 description 4
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 4
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 4
- 125000004104 aryloxy group Chemical group 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- NWVVVBRKAWDGAB-UHFFFAOYSA-N p-methoxyphenol Chemical compound COC1=CC=C(O)C=C1 NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 125000005916 2-methylpentyl group Chemical group 0.000 description 3
- 125000005917 3-methylpentyl group Chemical group 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 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 3
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KYADSONIGQJMAV-JQWIXIFHSA-N (2r,3s)-3-hydroxy-2-methyl-5-phenylpentanal Chemical compound O=C[C@H](C)[C@@H](O)CCC1=CC=CC=C1 KYADSONIGQJMAV-JQWIXIFHSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 2
- MNZAKDODWSQONA-UHFFFAOYSA-N 1-dibutylphosphorylbutane Chemical compound CCCCP(=O)(CCCC)CCCC MNZAKDODWSQONA-UHFFFAOYSA-N 0.000 description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 2
- 0 CC(C(C*Cc1ccccc1)O)C=O Chemical compound CC(C(C*Cc1ccccc1)O)C=O 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 2
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000012038 nucleophile Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- 125000005924 2-methylpentyloxy group Chemical group 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000005975 2-phenylethyloxy group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000001331 3-methylbutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000005925 3-methylpentyloxy group Chemical group 0.000 description 1
- 125000005977 3-phenylpropyloxy group Chemical group 0.000 description 1
- NGPJMZBMZXQOTD-UHFFFAOYSA-N 4-[4-(dimethylamino)-2-diphenylphosphanyl-6-methylphenyl]-3-diphenylphosphanyl-n,n,5-trimethylaniline Chemical group C=1C(N(C)C)=CC(C)=C(C=2C(=CC(=CC=2C)N(C)C)P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1P(C=1C=CC=CC=1)C1=CC=CC=C1 NGPJMZBMZXQOTD-UHFFFAOYSA-N 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000439 4-methylpentoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003836 4-phenylbutoxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 241000790917 Dioxys <bee> Species 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
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000002879 Lewis base Substances 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
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- QXJARVSGJXWJQR-UHFFFAOYSA-N [2-(6-diphenylphosphanyl-3-methoxy-2,4-dimethylphenyl)-4-methoxy-3,5-dimethylphenyl]-diphenylphosphane Chemical group CC=1C(OC)=C(C)C=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1C1=C(C)C(OC)=C(C)C=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QXJARVSGJXWJQR-UHFFFAOYSA-N 0.000 description 1
- QASBYAVLBAKYIJ-UHFFFAOYSA-N [2-[2-bis(2-methylphenyl)phosphanyl-6-methylphenyl]-3-methylphenyl]-bis(2-methylphenyl)phosphane Chemical group CC1=CC=CC=C1P(C=1C(=C(C)C=CC=1)C=1C(=CC=CC=1C)P(C=1C(=CC=CC=1)C)C=1C(=CC=CC=1)C)C1=CC=CC=C1C QASBYAVLBAKYIJ-UHFFFAOYSA-N 0.000 description 1
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- OKIAVLQZZLXXGX-UHFFFAOYSA-N [2-[6-diphenylphosphanyl-3-methyl-2,4-bis(trifluoromethyl)phenyl]-4-methyl-3,5-bis(trifluoromethyl)phenyl]-diphenylphosphane Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)C=1C=C(C(F)(F)F)C(C)=C(C(F)(F)F)C=1C1=C(C(F)(F)F)C(C)=C(C(F)(F)F)C=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 OKIAVLQZZLXXGX-UHFFFAOYSA-N 0.000 description 1
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- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
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- 125000004429 atom Chemical group 0.000 description 1
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- 125000006267 biphenyl group Chemical group 0.000 description 1
- AZEBUSRDBBMQGF-UHFFFAOYSA-N bis(3,5-ditert-butyl-4-methoxyphenyl)phosphane Chemical compound C1=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=C1PC1=CC(C(C)(C)C)=C(OC)C(C(C)(C)C)=C1 AZEBUSRDBBMQGF-UHFFFAOYSA-N 0.000 description 1
- ICFJFBGAFIUVKS-UHFFFAOYSA-N bis(3,5-ditert-butylphenyl)phosphane Chemical compound CC(C)(C)C1=CC(C(C)(C)C)=CC(PC=2C=C(C=C(C=2)C(C)(C)C)C(C)(C)C)=C1 ICFJFBGAFIUVKS-UHFFFAOYSA-N 0.000 description 1
- FWKICRREDMVWRF-UHFFFAOYSA-N bis(4-methoxyphenyl)phosphane Chemical compound C1=CC(OC)=CC=C1PC1=CC=C(OC)C=C1 FWKICRREDMVWRF-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GMGLYSIINJPYLI-UHFFFAOYSA-N butan-2-one;propan-2-one Chemical compound CC(C)=O.CCC(C)=O GMGLYSIINJPYLI-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 125000005390 cinnolyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- WILFNLHOTDCRAO-UHFFFAOYSA-N copper(1+);2-methylpropan-2-olate Chemical compound [Cu+].CC(C)(C)[O-] WILFNLHOTDCRAO-UHFFFAOYSA-N 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 description 1
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
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- 125000000753 cycloalkyl group Chemical group 0.000 description 1
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- HDULBKVLSJEMGN-UHFFFAOYSA-N dicyclohexylphosphane Chemical compound C1CCCCC1PC1CCCCC1 HDULBKVLSJEMGN-UHFFFAOYSA-N 0.000 description 1
- WLLHDCZHPMDDPJ-UHFFFAOYSA-N dicyclopentyl-[1-(2-dicyclopentylphosphanyl-5,6,7,8-tetrahydronaphthalen-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl]phosphane Chemical group C1CCCC1P(C=1C(=C2CCCCC2=CC=1)C=1C(=CC=C2CCCCC2=1)P(C1CCCC1)C1CCCC1)C1CCCC1 WLLHDCZHPMDDPJ-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
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- 150000007527 lewis bases Chemical class 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000006606 n-butoxy group Chemical group 0.000 description 1
- 125000003935 n-pentoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- ATYBXHSAIOKLMG-UHFFFAOYSA-N oxepin Chemical compound O1C=CC=CC=C1 ATYBXHSAIOKLMG-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 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
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000005542 phthalazyl group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl 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
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004665 trialkylsilyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0267—Phosphines or phosphonium compounds, i.e. phosphorus bonded to at least one carbon atom, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, the other atoms bonded to phosphorus being either carbon or hydrogen
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- 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
- B01J31/22—Organic complexes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- 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
- B01J31/24—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
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
- B01J31/2414—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings
-
- 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
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/02—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen
- C07C47/19—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/02—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen
- C07C47/19—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing hydroxy groups
- C07C47/192—Saturated compounds having —CHO groups bound to acyclic carbon atoms or to hydrogen containing hydroxy groups containing rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
- C07C47/27—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/20—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms
- C07C47/26—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups
- C07C47/273—Unsaturated compounds having —CHO groups bound to acyclic carbon atoms containing hydroxy groups containing halogen
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
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- C—CHEMISTRY; METALLURGY
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- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/36—Amides thereof
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
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Definitions
- the present invention relates to a method for producing an optically active compound using boric acid enol esters using a copper compound and an optically active bidentate phosphine compound as catalyst components.
- the asymmetric aldol reaction is a useful method for synthesizing optically active ⁇ -hydroxycarbonyl compounds.
- optically active ⁇ -hydroxyaldehydes are particularly important as intermediates for pharmaceuticals, agricultural chemicals, fragrances and the like.
- optically active ⁇ -hydroxy carboxylic acid derivatives must be obtained to obtain optically active ⁇ -hydroxy aldehydes. It required a multi-step conversion process.
- an asymmetric aldol reaction using an aldehyde-derived enolate or an enolate equivalent such as enamine is desirable.
- an asymmetric aldol reaction using an aldehyde-derived enolate or an enolate equivalent such as enamine is desirable.
- there is a technology that realizes control to make one aldehyde into an enolate or enolate equivalent and the other aldehyde as an electrophile. is necessary.
- Only a few organic catalysts are known as asymmetric catalysts known so far for synthesizing optically active ⁇ -hydroxyaldehydes by cross-asymmetric aldol reaction between different aldehydes.
- Non-patent Documents 1 and 2 a technique using a proline catalyst by McMillan et al.
- Non-patent Documents 1 and 2 Barbus et al.
- Non-patent Document 3 Barbus et al.
- Non-patent Document 4 Cordova et al.
- an imidazolidinone catalyst by McMillan et al. Technology
- Non-patent document 5 Hayashi et al.
- Non-patent document 6 Non-patent document 6
- Beckman et al. Non-patent document 7
- a prolinol catalyst Maruoka et al.
- a technique using a histidine catalyst by Marwald et al.
- Non-patent Document 11 a technique using a diamine catalyst by Luo et al.
- a technique for freely realizing a combination of an electrophile aldehyde and a nucleophilic aldehyde in a cross-asymmetric aldol reaction Danish et al.
- Using an enol silyl ether derived from an aldehyde using an optically active Lewis base organic catalyst Techniques (Non-Patent Documents 13, 14, and 15) are known.
- the conventional technology has realized high enantioselectivity and wide substrate versatility, and it has been difficult to control chemical selectivity regardless of the substrate used.
- the conventional technology using an organic catalyst in order to achieve chemical selectivity that depends only on the steric and electronic factors of aldehydes or imines, there is a great limitation on the combination of electrophiles and nucleophiles. It was. Specifically, the substrate versatility was poor, for example, it was impossible to use a linear aldehyde such as sterically small propanal as an electrophile.
- the technique using enol silyl ether as an aldehyde enolate equivalent has problems such as moderate enantioselectivity and poor substrate versatility.
- the inventors of the present invention obtained a boric acid enol ester obtained by isomerizing an allyl boric acid ester that can be easily obtained at low cost, a copper compound and an optically active compound. It has been found that optically active hydroxyaldehydes can be obtained with high enantioselectivity and diastereoselectivity by reacting with aldehydes in the presence of a bidentate phosphine compound. The produced aldehyde can be led to a polyol by repeating the same reaction, and by using imine instead of aldehyde, it is found that aminohydroxyaldehyde can be obtained, and the present invention is completed. It came.
- the present invention provides the following general formula (2) in the presence of a copper compound and an optically active bidentate phosphine compound.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R 3 and R 4 represent an alkyl group having 1 to 4 carbon atoms, or R 3 and R 4 represent an alkyl group. (It may form an optionally substituted methylene chain.)
- R 1 represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.
- Z represents an oxygen atom or NX (X may have a substituent) Represents a good thiophosphinoyl group.
- R 1 represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- Y represents a hydroxyl group or NX (X represents a thiophosphinoyl group which may have a substituent.)
- N represents 0 or 1.
- * represents an asymmetric carbon atom.
- optically active optically active hydroxyaldehydes or aminohydroxyaldehydes can be produced with high yield and high enantioselectivity and diastereoselectivity.
- the method of the present invention can also use a sterically small linear aldehyde such as propanal as an electrophile, and an electrophilic aliphatic aldehyde, aromatic aldehyde, araliphatic aldehyde, Not only can many aldehyde compounds such as heterocyclic aldehydes and their derivatives be used as substrates, but also imine compounds (—CH ⁇ N—R) derived from these aldehyde compounds can be used as substrates. It is excellent in substrate versatility.
- the produced aldehyde can be led to a polyol by repeating the same reaction.
- boric acid enol esters used as carbonyl enolate equivalents such as aldehyde enolate equivalents in the method of the present invention can be obtained easily and inexpensively by isomerizing allyl borate esters. .
- the method of the present invention relates to an asymmetric aldol reaction using a boric acid enol ester as a carbonyl enolate equivalent, such as an aldehyde enolate equivalent, performed in the presence of an optically active bidentate phosphine compound. More specifically, the method of the present invention relates to an asymmetric aldol reaction in which a boric acid enol ester is reacted with an aldehyde or an imine thereof in the presence of a copper compound and an optically active bidentate phosphine compound.
- the method of the present invention is not limited to an asymmetric aldol reaction between an aldehyde compound and an aldehyde compound, but a boric acid enol ester as a nucleophile is carbonylated in the presence of a copper compound and an optically active bidentate phosphine compound. It should be understood that this is a method for producing a product by a nucleophilic reaction by reacting an electrophilic substrate having a group or an imino group.
- R 1 CH Z
- R 1 represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.
- Z represents an oxygen atom or NX (X may have a substituent) Represents a good thiophosphinoyl group.
- an imine compound thereof represented by the following general formula (2):
- R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R 3 and R 4 represent an alkyl group having 1 to 4 carbon atoms, or R 3 and R 4 are substituted with an alkyl group. May form a methylene chain which may be Is reacted with a boric acid enol ester represented by the following general formula (3):
- R 1 represents a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- Y represents a hydroxyl group or NX (X represents a thiophosphinoyl group which may have a substituent.)
- N represents 0 or 1.
- * represents an asymmetric carbon atom.
- optically active bidentate phosphine compound is an optically active bidentate phosphine compound having axial asymmetry.
- optically active bidentate phosphine compound is represented by the following general formula (4):
- R 5 , R 6 , R 7 and R 8 are each independently phenyl optionally substituted with a substituent selected from the group consisting of an alkyl group, an alkoxy group, and a halogen atom.
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 may be the same or different and have a hydrogen atom or a substituent.
- An alkyl group, an alkoxy group, an acyloxy group, a halogen atom, a haloalkyl group, or a dialkylamino group that may be present, or R 10 and R 11 , and R 12 and R 13 may have a substituent.
- a methylene chain and an alkylenedioxy group may be formed, provided that R 11 and R 12 are not hydrogen atoms.
- the boric acid enol ester represented by the general formula (2) is produced by an isomerization reaction of the following scheme using an iridium catalyst, any one of (1) to (8) above The method according to claim 1.
- R 2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R 3 and R 4 represent an alkyl group having 1 to 4 carbon atoms or substituted with an alkyl group with R 3 and R 4. May form a methylene chain which may be
- the hydrocarbon group represented by R 1 is a monovalent group consisting of a carbon atom and a hydrogen atom, such as an alkyl group, an alkenyl group, An alkynyl group, an aryl group, an aralkyl group, etc. are mentioned.
- the alkyl group as one of the hydrocarbon groups represented by R 1 may be linear, branched or cyclic. Examples of these alkyl groups include alkyl groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms.
- alkyl groups may have a substituent, and examples of the substituent include a hydrocarbon group, an aliphatic heterocyclic group, an aromatic heterocyclic group, an alkoxy group, an alkylenedioxy group, an aryloxy group, Examples thereof include an aralkyloxy group, a heteroaryloxy group, a substituted amino group, and a halogen atom.
- hydrocarbon group substituted for the alkyl group examples include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group.
- the alkyl group may be linear, branched or cyclic, and examples thereof include an alkyl group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms.
- Examples include 2-methylpentan-3-yl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.
- the alkenyl group may be linear or branched, and examples thereof include alkenyl groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. , Propenyl group, 1-butenyl group, pentenyl group, hexenyl group and the like.
- the alkynyl group may be linear or branched, for example, an alkynyl group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, specifically an ethynyl group.
- aryl group examples include aryl groups having 6 to 14 carbon atoms, and specific examples include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and a biphenyl group.
- aralkyl group examples include a group in which at least one hydrogen atom of the alkyl group is substituted with the aryl group.
- an aralkyl group having 7 to 12 carbon atoms is preferable.
- examples thereof include an ethyl group, a 1-phenylpropyl group, and a 3-naphthylpropyl group.
- Examples of the aliphatic heterocyclic group to be substituted with an alkyl group include 2 to 14 carbon atoms and at least one hetero atom, preferably 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom, and a sulfur atom. And a 5- to 8-membered, preferably 5- or 6-membered monocyclic aliphatic heterocyclic group, polycyclic or condensed aliphatic heterocyclic group.
- Specific examples of the aliphatic heterocyclic group include 2-oxopyrrolidino group, piperidino group, piperazinyl group, morpholino group, tetrahydrofuryl group, tetrahydropyranyl group, tetrahydrothienyl group and the like.
- the aromatic heterocyclic group substituted for the alkyl group has, for example, 2 to 15 carbon atoms and includes at least one, preferably 1 to 3, hetero atoms such as nitrogen atom, oxygen atom and sulfur atom as hetero atoms.
- pyrazyl group pyridazyl group
- pyrazolyl group imidazolyl group, oxazolyl group, thiazolyl group, benzofuryl group, benzothienyl group, quinolyl group, isoquinolyl group, quinoxalyl group, phthalazyl group, quinazolyl group, naphthyridyl group, cinnolyl group, benzimidazolyl group Benzoxazolyl group, benzothiazolyl group and the like.
- the alkoxy group substituted for the alkyl group may be linear, branched or cyclic, and examples thereof include an alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, an n-propoxy group, Isopropoxy group, n-butoxy group, 2-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, 2-methylbutoxy group, 3-methylbutoxy group, 2,2-dimethylpropyloxy group, n -Hexyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 5-methylpentyloxy group, cyclohexyloxy group and the like.
- alkylenedioxy group substituted for the alkyl group examples include an alkylenedioxy group having 1 to 3 carbon atoms, and specifically include a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, and an isopropylidenedioxy group. Groups and the like.
- Examples of the aryloxy group substituted on the alkyl group include an aryloxy group having 6 to 14 carbon atoms, and specifically include a phenyloxy group, a naphthyloxy group, an anthryloxy group, and the like.
- Examples of the aralkyloxy group substituted for the alkyl group include an aralkyloxy group having 7 to 12 carbon atoms, and specifically include a benzyloxy group, a 2-phenylethoxy group, a 1-phenylpropoxy group, and a 2-phenylpropoxy group.
- 3-phenylpropoxy group 1-phenylbutoxy group, 2-phenylbutoxy group, 3-phenylbutoxy group, 4-phenylbutoxy group, 1-phenylpentyloxy group, 2-phenylpentyloxy group, 3-phenylpentyloxy group Group, 4-phenylpentyloxy group, 5-phenylpentyloxy group, 1-phenylhexyloxy group, 2-phenylhexyloxy group, 3-phenylhexyloxy group, 4-phenylhexyloxy group, 5-phenylhexyloxy group , 6-phenylhexyloxy group, etc. That.
- the heteroaryloxy group substituted for the alkyl group includes, for example, at least one hetero atom, preferably 1 to 3 hetero atoms such as nitrogen atom, oxygen atom, sulfur atom and the like having 2 to 14 carbon atoms. Specific examples thereof include 2-pyridyloxy group, 2-pyrazyloxy group, 2-pyrimidyloxy group, 2-quinolyloxy group, and the like.
- Examples of the substituted amino group substituted for the alkyl group include an amino group in which one or two hydrogen atoms of the amino group are substituted with a substituent such as an alkyl group, an aryl group, or an aralkyl group.
- an amino group substituted with an alkyl group that is, an alkyl group-substituted amino group include an N-methylamino group, an N, N-dimethylamino group, an N, N-diethylamino group, an N, N-diisopropylamino group, Examples thereof include mono- or dialkylamino groups such as N-cyclohexylamino group.
- an amino group substituted with an aryl group that is, an aryl group-substituted amino group
- an amino group substituted with an aryl group that is, an aryl group-substituted amino group
- N-phenylamino group N, N-diphenylamino group, N-naphthylamino group, and N-naphthyl-N-phenylamino group.
- Mono- or diarylamino groups such as
- amino group substituted with an aralkyl group that is, an aralkyl group-substituted amino group
- mono- or diaralkylamino groups such as N-benzylamino group and N, N-dibenzylamino group.
- halogen atom substituted for the alkyl group examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
- the hydrocarbon group, aliphatic heterocyclic group, aromatic heterocyclic group, alkoxy group, alkylenedioxy group, aryloxy group, aralkyloxy group, heteroaryloxy group or substituted amino group are the above And may be further substituted with a group selected from the group of substituents mentioned in the above.
- one of the hydrocarbon groups represented by R 1 may be a linear or branched linear or branched group having 2 to 20 carbon atoms, preferably examples include alkenyl groups having 2 to 10 carbon atoms.
- alkenyl groups include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-cyclopentenyl group, 3-cyclopentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-cyclohexenyl group and 3- A cyclohexenyl group etc. are mentioned.
- alkenyl groups may have a substituent, and examples of the substituent include an alkyl group, a halogen atom, an aryl group, and a heterocyclic group. Specific examples thereof include those described above. .
- one of the hydrocarbon groups represented by R 1 includes a linear or branched alkynyl group, specifically, an ethynyl group.
- alkynyl groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a heterocyclic group, a trialkylsilyl group, and the like. Specific examples include those described above.
- one of the hydrocarbon groups represented by R 1 includes an aryl group, and specifically includes the aryl group as described above.
- aryl groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, and a heterocyclic group, and specific examples include those described above.
- the heterocyclic group represented by R 1 includes an aliphatic or aromatic heterocyclic group, and specifically includes the heterocyclic group as described above.
- These heterocyclic groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a heterocyclic group and the like, and specific examples thereof include those described above.
- the general formula —P (S) Q 1 Q 2 (wherein Q 1 and Q 2 are Each independently an alkyl group having 1 to 10 carbon atoms, or an optionally substituted substituent selected from the group consisting of an alkyl group, a haloalkyl group, an alkoxy group, a halogen atom, and an alkylenedioxy group To 12 monocyclic, polycyclic, or condensed cyclic aryl groups). Examples of the alkyl group and aryl group herein include those described above.
- examples of the alkyl group having 1 to 6 carbon atoms represented by R 2 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, n -Butyl group, 2-butyl group, isobutyl group, tert-butyl group, n-pentyl group, 2-pentyl group, tert-pentyl group, 2-methylbutyl group, 3-methylbutyl group, 2,2-dimethylpropyl group, Examples include n-hexyl group, 2-hexyl group, 3-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2-methylpentan-3-yl group, and the like.
- the alkyl group represented by R 3 and R 4 is preferably an alkyl group having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group. 2-butyl group, isobutyl group, tert-butyl group and the like.
- Examples of the methylene chain formed by R 3 and R 4 include a methylene group, an ethylene group, and a trimethylene group.
- the alkyl group substituted for these methylene chains is preferably an alkyl group having 1 to 6 carbon atoms. Examples thereof include a methyl group and an ethyl group.
- the compound represented by the general formula (1) and the boric acid enol ester represented by the general formula (2) used as raw materials can be prepared by using a commercially available product as it is or by a known method. You may use what you did.
- Known preparation methods include, for example, a method of isomerizing a double bond using an iridium catalyst as described in the literature (Chem. Commun. 1998, 1337 and Organometallics, 1999, 18, 413, etc.). It is done.
- CuAr represents an aryl group
- CuR represents an alkyl group
- CuX represents a halogen group
- CuOR represents an alkoxy group and a phenoxy group
- CuO 2 CR O 2 CR represents a group obtained by removing a hydrogen atom from carboxylic acid
- CuAr represents an aryl group
- Examples of the alkyl group and aryl group herein include those described above.
- Ar and R herein may have a substituent, and examples of the substituent include an alkyl group, an alkoxy group, and a halogen group.
- the copper compound examples include mesityl copper, copper fluoride, copper iodide, tert-butoxy copper, and copper acetate.
- Mesityl copper is preferable.
- a copper compound or its precursor, and the compound which reacts with the said copper compound or its precursor can be made to coexist in a reaction system, and it can also be set as a new copper compound in a reaction system.
- bidentate phosphine compound used in the present invention As a bidentate phosphine compound used in the present invention. Those having an axial asymmetric structure are preferred, and one of them is the following general formula (4) having an axial asymmetric structure.
- R 5 , R 6 , R 7 and R 8 are each independently phenyl optionally substituted with a substituent selected from the group consisting of an alkyl group, an alkoxy group, and a halogen atom.
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and R 16 may be the same or different and have a hydrogen atom or a substituent.
- Methylene which may represent an alkyl group, an alkoxy group, an acyloxy group, a halogen atom, a haloalkyl group and a dialkylamino group, or may have a substituent at R 10 and R 11 , and R 12 and R 13 A chain or an alkylenedioxy group may be formed, provided that R 11 and R 12 are not a hydrogen atom.)
- the compound represented by these is mentioned.
- Examples of the alkyl group as a substituent for R 5 , R 6 , R 7 and R 8 include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group and a tert-butyl group.
- Examples of the alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as a methoxy group and a tert-butoxy group, and examples of the halogen atom include a chlorine atom, a bromine atom, a fluorine atom, and the like. Atoms and the like, and these substituents may be substituted on the phenyl ring or cycloalkyl ring.
- R 5 , R 6 , R 7 and R 8 include phenyl group, p-tolyl group, m-tolyl group, o-tolyl group, 3,5-xylyl group, 3,5-di-tert- Butylphenyl group, p-tert-butylphenyl group, p-methoxyphenyl group, 3,5-di-tert-butyl-4-methoxyphenyl group, p-chlorophenyl group, m-fluorophenyl group, cyclopentyl group and cyclohexyl group Etc.
- Examples of the alkyl group in R 9 to R 16 include linear or branched alkyl groups having 1 to 6 carbon atoms such as a methyl group and a tert-butyl group.
- Examples of the alkoxy group include: Examples thereof include a linear or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group and a tert-butoxy group.
- Examples of the acyloxy group include an acetoxy group, a propanoyloxy group, a trifluoroacetoxy group, and a benzoyloxy group.
- Examples of the halogen atom include a chlorine atom, a bromine atom, and a fluorine atom.
- haloalkyl group examples include a haloalkyl group having 1 to 4 carbon atoms such as a trifluoromethyl group, and a dialkylamino group.
- the group examples include a dimethylamino group and a diethylamino group.
- Examples of the methylene chain and alkylenedioxy group which may have a substituent formed by R 10 and R 11 and R 12 and R 13 include a methylene chain having 1 to 4 carbon atoms, a methylene dioxy group and ethylene.
- a dioxy group is preferable, and specific examples of the methylene chain include a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group.
- examples of the substituent substituted on the methylene chain and the alkylenedioxy group include an alkyl group and a halogen atom, and specific examples thereof include the above-described alkyl group having 1 to 4 carbon atoms and a fluorine atom. .
- optically active phosphine represented by the general formula (4) include, but are not limited to, for example, 2,2′-bis (diphenylphosphino) -5,5 ′, 6, 6 ′, 7,7 ′, 8,8′-octahydro-1,1′-binaphthyl, 2,2′-bis (di-p-tolylphosphino) -5,5 ′, 6,6 ′, 7,7 ′ , 8,8′-octahydro-1,1′-binaphthyl, 2,2′-bis (di-m-tolylphosphino) -5,5 ′, 6,6 ′, 7,7 ′, 8,8′-octahydro -1,1'-binaphthyl, 2,2'-bis (di-3,5-xylylphosphino) -5,5 ', 6,6', 7,7 ', 8,8'-octahydro-1 1′
- the boric acid enol ester represented by the general formula (2) preferably the general formula (2), wherein the double bond of the boric acid ester is isomerized ( 2)
- a boric acid enol ester represented by 2) is added to a solution containing a copper compound as a catalyst component and an optically active bidentate phosphine, and a compound represented by the general formula (1) is added to the solution.
- the optically active compound represented by the general formula (3) which is the target product, can be produced.
- a catalyst component may be added to the reaction substrate.
- the boric acid enol ester of the general formula (2) added to the reaction system can be used as a solution which has been isolated after the isomerization reaction or without being isolated. It is preferable to use one.
- the amount of the boric acid enol ester represented by the general formula (2) is 1 to 5 times, preferably 1.1 to 2 times the amount of the compound represented by the general formula (1). It is sufficient to use a mole, more preferably 1.1 times to 1.5 times mole.
- the iridium catalyst used in preparing the boric acid enol ester represented by the general formula (2) by isomerization of the boric acid ester represented by the general formula (2 ′) includes (1,5 -Cyclooctadiene) bis (methyldiphenylphosphine) iridium (I) hexafluorophosphate or bis (1,5-cyclooctadiene) iridium (I) hexafluorophosphate mixed with trialkylphosphine in the reaction solution
- tributylphosphine 1,5-cyclooctadiene
- the amount of the iridium catalyst used is 0.0001 to 0.5 times mol, preferably 0.001 to 0.05, moles of the boric acid ester represented by the general formula (2 ′) as the isomerization substrate. Double moles can be used.
- the isomerization reaction may be carried out in the presence of hydrogen gas in the reaction system.
- the copper compound and optically active bidentate phosphine used as catalyst components are used in an amount of 0.01 mol% to 50 mol%, preferably 1 mol% to 30 mol%, based on the compound represented by the general formula (1). Preferably, 3 mol% to 10 mol% is sufficient.
- the reaction solvent is not particularly limited as long as it does not participate in the reaction.
- amides such as N, N-dimethylformamide, N, N-diethylformamide, N, N-dimethylacetamide; dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane and o-dichlorobenzene; aliphatic hydrocarbons such as pentane, hexane, heptane, octane, decane and cyclohexane; aromatic hydrocarbons such as toluene and xylene; isopropanol, alcohols such as tert-butanol; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dimethoxyethane, ethylene glycol diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane
- the yield of the method of the present invention may be improved by using an additive.
- the additive used include triethylamine, triphenylphosphine oxide, tributylphosphine oxide, hexamethyltriphosphate amide and the like.
- the reaction temperature varies depending on the substrate used, but is usually in the range of ⁇ 80 ° C. to 100 ° C., preferably in the range of ⁇ 60 ° C. to 80 ° C., more preferably in the range of ⁇ 80 ° C. to 80 ° C., and ⁇ 80 ° C. to 20 ° C. Can be done.
- the reaction time varies depending on the substrate used, but is usually 10 minutes to 100 hours, preferably 0.5 hours to 80 hours.
- This reaction can be converted into an optically active polyol by repeatedly reacting the boric acid enol ester represented by the general formula (2). That is, after the above reaction is carried out, the reaction system is generally added in a range of 1 to 5 times mol, preferably 1.1 to 2 times mol, more preferably 1.1 to 1.5 times mol.
- boric acid enol esters represented by the formula (2) By adding boric acid enol esters represented by the formula (2) and continuing the reaction, it can be converted into an optically active polyol.
- X in the compound represented by the general formula (5) is preferably a thiophosphinyl group, particularly preferably a diphenylthiophosphinyl group (Ph 2 P ( ⁇ S)).
- the form of the reaction is not particularly limited, and it may be a batch method or a flow method.
- the objective optically active hydroxyaldehyde or aminohydroxyaldehyde can be obtained by singly or in combination with operations such as crystallization, distillation or various chromatography.
- the obtained product can also be reduced to a corresponding diol by reducing with a hydrogenating agent such as sodium borohydride.
- Example 2 Synthesis of hydroxy aldehydes Mesityl copper (0.9 mg, 0.005 mmol), (R) -DTBM-segphos (6.0 mg, 0.005 mmol), THF 0.5 mL, IPA 7.7 ⁇ L was added to a dry reaction vessel, Cooled to -78 ° C. To this, a 0.3 M solution of borate enolate (0.5 mL, 0.15 mmol) and hydrocinnamaldehyde (13.2 ⁇ L, 0.1 mmol) were sequentially added, followed by stirring at ⁇ 60 ° C. for 24 hours to obtain hydroxyaldehydes. Subsequently, the diol was induced in the same manner as in Example 1. The isolation yield was 93%, the diastereo ratio was 26: 1 (syn: anti), and the enantioselectivity was 94% ee (syn).
- Table 2 shows the results of the same operations as in Example 2 except that both boron enolate and aldehyde substrates were changed.
- catalyst solution A mesityl copper (0.9 mg, 0.005 mmol), (S) -DTBM-segphos (6.0 mg, 0.00505 mmol), isopropanol (0.39 ⁇ L, 0.005 mmol), and THF 0.25 mL were added to a dry reaction glass container. (Hereinafter referred to as catalyst solution A) was prepared.
- catalyst solution A ⁇ (0.25 mL, 0.005 mmol) and 0.4 M borate enolate solution (0.25 mL, 0.1 mmol) to the reaction solution, stir at -60 ⁇ ⁇ °C for 24 hours, then further catalyst solution A (0.25 mL, 0.005 mmol) ), 0.4 ⁇ M borate enolate solution (0.25 mL, 0.1 mmol) was added and stirred for 24 hours at -60 °C, finally catalyst solution A (0.25 mL, 0.005 mmol), borate enolate 0.4 M solution (0.25 mL, 0.1 mmol), and the mixture was stirred at ⁇ 60 ° C. for 42 hours.
- Diastereoselectivity was> 20: 1 (amino diol was obtained with the ratio of the main diastereomer to all other diastereomers).
- Table 3 shows the results of the same operations as in Example 16.
- the compound produced by the method of the present invention is useful as an intermediate for pharmaceuticals, agricultural chemicals, fragrances and the like, for example, and the method of the present invention provides an industrially useful production method.
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Abstract
Description
で表されるホウ酸エノールエステル類と、下記一般式(1)
R1CH=Z (1)
(式中、R1は置換基を有してもよい炭化水素基又は置換基を有してもよい複素環基を表す。Zは酸素原子又はNX(Xは置換基を有していてもよいチオホスフィノイル基を表す。)を表す。)
で表される化合物とを反応させることを特徴とする、下記一般式(3)
で表される化合物の製造方法に関する。
また、本発明の方法は、立体的に小さなプロパナールのような直鎖アルデヒドを求電子剤とすることも可能であり、求電子性を有する脂肪族アルデヒド、芳香族アルデヒド、芳香脂肪族アルデヒド、複素環式アルデヒドなどの多くのアルデヒド化合物やその誘導体を基質とすることができるだけでなく、これらのアルデヒド化合物から誘導されるイミン体(-CH=N-R)の化合物をも基質とすることができ、基質汎用性にも優れている。
さらに、本発明の方法によれば、生成したアルデヒドは、同様の反応を繰り返し行うことにより、ポリオールへと導くことができる。
また、本発明の方法におけるアルデヒドエノラート等価体などのカルボニルエノラート等価体として用いられるホウ酸エノールエステルは、アリルホウ酸エステルを異性化させることで安価で、かつ容易に得ることができ入手が容易である。
本発明の方法は、アルデヒド化合物とアルデヒド化合物による不斉アルドール反応に限定されるものではなく、求核剤としてのホウ酸エノールエステルを、銅化合物及び光学活性二座ホスフィン化合物の存在下に、カルボニル基やイミノ基などを有する求電子基質とを反応させて、求核反応による生成物を製造する方法であると解されるべきものである。
(1)下記一般式(1)
R1CH=Z (1)
(式中、R1は置換基を有してもよい炭化水素基又は置換基を有してもよい複素環基を表す。Zは酸素原子又はNX(Xは置換基を有していてもよいチオホスフィノイル基を表す。)を表す。)
で表されるアルデヒド化合物又はそのイミン体化合物を、下記一般式(2)
で表されるホウ酸エノールエステル類とを、銅化合物及び光学活性二座ホスフィン化合物の存在下で反応させて、下記一般式(3)
で表される化合物を製造する方法。
(2)反応が、さらに添加剤の存在下で行われる、前記(1)に記載の方法。
(3)添加剤が、トリエチルアミン、トリフェニルホスフィンオキサイド、トリブチルホスフィンオキサイド、及びヘキサメチルトリリン酸アミドからなる群から選ばれる化合物である、前記(2)に記載の方法。
(4)一般式(3)におけるnが、0である前記(1)から(3)のいずれか1項に記載の方法。
(5)一般式(3)におけるnが、1である前記(1)から(3)のいずれか1項に記載の方法。
(6)前記(1)から(3)のいずれか1項に記載の方法で製造された反応成績体に、さらに一般式(2)で表されるホウ酸エノールエステル類を反応させることを特徴とする前記(5)に記載の製造方法。
(7)光学活性二座ホスフィン化合物が、軸不斉を有する光学活性二座ホスフィン化合物である、前記(1)から(6)のいずれか1項に記載の方法。
(8)光学活性二座ホスフィン化合物が、下記一般式(4)
で示されるホスフィン化合物である、前記(1)から(7)のいずれか1項に記載の方法。
(9)一般式(2)で表されるホウ酸エノールエステル類が、イリジウム触媒を用いた下記スキームの異性化反応により製造されることを特徴とする、前記(1)から(8)のいずれか1項に記載の方法。
本発明の製造法における一般式(1)で示されるアルデヒド化合物において、R1で表される炭化水素基は炭素原子及び水素原子からなる一価の基であり、例えば、アルキル基、アルケニル基、アルキニル基、アリール基、アラルキル基等が挙げられる。
一般式(1)で表される化合物において、R1で表される炭化水素基の一つとしてのアルキル基は直鎖状でも、分岐状でも或いは環状でもよい。これらアルキル基としては例えば炭素数1~15、好ましくは炭素数1~10、より好ましくは炭素数1~6のアルキル基が挙げられ、具体的にはメチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、2-ブチル基、イソブチル基、tert-ブチル基、n-ペンチル基、2-ペンチル基、tert-ペンチル基、2-メチルブチル基、3-メチルブチル基、2,2-ジメチルプロピル基、n-ヘキシル基、2-ヘキシル基、3-ヘキシル基、2-メチルペンチル基、3-メチルペンチル基、4-メチルペンチル基、2-メチルペンタン-3-イル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。
一般式(1)で表される化合物において、NX基のXで表されるチオホスフィノイル基としては、一般式-P(S)Q1Q2(式中、Q1及びQ2は、それぞれ独立して、炭素数1~10のアルキル基、又はアルキル基、ハロアルキル基、アルコキシ基、ハロゲン原子、及びアルキレンジオキシ基からなる群から選ばれる置換基で置換されていてもよい炭素数6~12の単環式、多環式、又は縮合環式のアリール基を表す。)で表される基が挙げられる。ここにおけるアルキル基やアリール基などは、前記したようなものが挙げられる。
また、R3とR4とで形成するメチレン鎖としては、メチレン基、エチレン基、トリメチレン基等が挙げられ、これらメチレン鎖に置換するアルキル基としては、炭素数1~6のアルキル基が好ましく、例えばメチル基、エチル基等が挙げられる。
具体的な銅化合物としては、メシチル銅、フッ化銅、ヨウ化銅、tert-ブトキシ銅、酢酸銅等が挙げられ、メシチル銅が好ましい。また、反応系に銅化合物又はその前駆体と当該銅化合物又はその前駆体と反応する化合物を共存させて、反応系中で新たな銅化合物とすることもできる。
で表される化合物が挙げられる。
この際に反応系に加えられる一般式(2)のホウ酸エノールエステル類は、異性化反応を行なった後に単離されたもの、又は単離せずに溶液として用いることができるが、溶液状態のものを使用することが好ましい。
また異性化反応は水素ガスを反応系内に存在させて行なってもよい。
一般式(5)で示される化合物におけるXとしては、チオホスフィニル基が好ましく、特にジフェニルチオホスフィニル基(Ph2P(=S))が好ましい。
反応終了後は、結晶化、蒸留又は各種クロマトグラフィー等の操作を単独又は組み合わせることにより目的の光学活性ヒドロキシアルデヒド類またはアミノヒドロキシアルデヒド類を得ることができる。
また、得られた生成物を水素化ホウ素ナトリウムなどの水素化剤で還元することにより、対応するジオールとすることもできる。
(1)ホウ酸エノラートの調製
(2)アルドール反応
保持時間はsyn体: 63.9 (minor), 77.2 (major) およびanti体: 46.8 min, 49.0 min。
乾燥した反応容器にメシチル銅 (0.9 mg, 0.005 mmol)、(R)-DTBM-segphos (6.0 mg, 0.005 mmol)、THF 0.5 mL、IPA 7.7 μLを加え、-78 ℃に冷却した。ここに、ホウ酸エノラートの0.3 M溶液 (0.5 mL, 0.15 mmol)、ヒドロシンナムアルデヒド (13.2 μL, 0.1 mmol)を順に加え、-60 ℃にて24時間撹拌してヒドロキシアルデヒド類を得た。
続いて、実施例1と同様にジオールへと誘導した。単離収率93%、ジアステレオ比26:1(syn:anti)、エナンチオ選択性94%ee(syn)であった。
(1)ホウ酸エノラートの調製
実施例1と同様にジオールへと誘導して収率等を測定したところ、単離収率87%、ジアステレオ比8:1(syn:anti)、エナンチオ選択性87%ee(syn)であった。
(1)ホウ酸エノラートの調製
Claims (4)
- 銅化合物及び光学活性二座ホスフィン化合物の存在下、下記一般式(2)
で表されるホウ酸エノールエステル類と、下記一般式(1)
R1CH=Z (1)
(式中、R1は置換基を有してもよい炭化水素基又は置換基を有してもよい複素環基を表す。Zは酸素原子又はNX(Xは置換基を有していてもよいチオホスフィノイル基を表す。)を表す。)
で表される化合物とを反応させることを特徴とする、下記一般式(3)
で表される化合物の製造方法。 - 請求項1に記載の製造方法で製造された反応成績体に、さらに一般式(2)で表されるホウ酸エノールエステル類を反応させることを特徴とする、請求項1に記載の製造方法。
- 光学活性二座ホスフィン化合物が下記一般式(4)
で示されるホスフィン化合物である請求項1~3のいずれか1項に記載の製造方法。
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