JPWO2011052388A1 - Iodobenzene derivative and method for producing optically active spirolactone compound using the same - Google Patents
Iodobenzene derivative and method for producing optically active spirolactone compound using the same Download PDFInfo
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- JPWO2011052388A1 JPWO2011052388A1 JP2011538342A JP2011538342A JPWO2011052388A1 JP WO2011052388 A1 JPWO2011052388 A1 JP WO2011052388A1 JP 2011538342 A JP2011538342 A JP 2011538342A JP 2011538342 A JP2011538342 A JP 2011538342A JP WO2011052388 A1 JPWO2011052388 A1 JP WO2011052388A1
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- derivative
- iodobenzene
- compound
- iodobenzene derivative
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- -1 spirolactone compound Chemical class 0.000 title claims abstract description 77
- 229960002256 spironolactone Drugs 0.000 title claims abstract description 34
- 150000008424 iodobenzenes Chemical class 0.000 title claims description 100
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- 150000002497 iodine compounds Chemical class 0.000 claims abstract description 17
- 150000002989 phenols Chemical class 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 15
- SCKXCAADGDQQCS-UHFFFAOYSA-N Performic acid Chemical compound OOC=O SCKXCAADGDQQCS-UHFFFAOYSA-N 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000006575 electron-withdrawing group Chemical group 0.000 claims description 5
- 150000002596 lactones Chemical group 0.000 claims description 5
- 230000001590 oxidative effect Effects 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000004971 nitroalkyl group Chemical group 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical class C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 63
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 abstract description 9
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 abstract description 8
- BNJXHRMYHDWZKL-UHFFFAOYSA-N 2-iodobenzene-1,3-diol Chemical compound OC1=CC=CC(O)=C1I BNJXHRMYHDWZKL-UHFFFAOYSA-N 0.000 abstract description 7
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002243 precursor Substances 0.000 abstract description 6
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- 239000004310 lactic acid Substances 0.000 abstract description 4
- 235000014655 lactic acid Nutrition 0.000 abstract description 4
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical class IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 abstract description 3
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 239000012018 catalyst precursor Substances 0.000 description 22
- 238000003786 synthesis reaction Methods 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000758 substrate Substances 0.000 description 12
- 238000001308 synthesis method Methods 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 230000003595 spectral effect Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- 238000001228 spectrum Methods 0.000 description 7
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 4
- NPGXXEAJMZJFSK-UHFFFAOYSA-N 3-(1-hydroxynaphthalen-2-yl)propanoic acid Chemical compound C1=CC=CC2=C(O)C(CCC(=O)O)=CC=C21 NPGXXEAJMZJFSK-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- SNHMUERNLJLMHN-IDEBNGHGSA-N iodobenzene Chemical group I[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 SNHMUERNLJLMHN-IDEBNGHGSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 2
- OPELWUSJOIBVJS-UHFFFAOYSA-N 3,3'-spirobi[1,2-dihydroindene] Chemical group C12=CC=CC=C2CCC11C2=CC=CC=C2CC1 OPELWUSJOIBVJS-UHFFFAOYSA-N 0.000 description 2
- CJBDUOMQLFKVQC-UHFFFAOYSA-N 3-(2-hydroxyphenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=CC=C1O CJBDUOMQLFKVQC-UHFFFAOYSA-N 0.000 description 2
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 2
- MBLFVBCXHMTGFQ-UHFFFAOYSA-N 4,4'-diiodo-3,3'-spirobi[1,2-dihydroindene] Chemical group C1CC2=CC=CC(I)=C2C21CCC1=C2C(I)=CC=C1 MBLFVBCXHMTGFQ-UHFFFAOYSA-N 0.000 description 2
- OUNQUWORSXHSJN-UHFFFAOYSA-N 4-bromonaphthalen-1-ol Chemical compound C1=CC=C2C(O)=CC=C(Br)C2=C1 OUNQUWORSXHSJN-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- DBVQHXIXAVASKV-UHFFFAOYSA-N C1(=C(C(=CC(=C1)C)C)N(C(CC)=O)ON(C(CC)=O)C1=C(C=C(C=C1C)C)C)C Chemical compound C1(=C(C(=CC(=C1)C)C)N(C(CC)=O)ON(C(CC)=O)C1=C(C=C(C=C1C)C)C)C DBVQHXIXAVASKV-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YEJJUJNTWYKFLS-UHFFFAOYSA-N 1-pyrrolidin-1-ylpropan-1-one Chemical compound CCC(=O)N1CCCC1 YEJJUJNTWYKFLS-UHFFFAOYSA-N 0.000 description 1
- KWVPRPSXBZNOHS-UHFFFAOYSA-N 2,4,6-Trimethylaniline Chemical group CC1=CC(C)=C(N)C(C)=C1 KWVPRPSXBZNOHS-UHFFFAOYSA-N 0.000 description 1
- GBBQZSGRWMPLLF-UHFFFAOYSA-N 2,4,6-trimethyl-n-phenylaniline Chemical compound CC1=CC(C)=CC(C)=C1NC1=CC=CC=C1 GBBQZSGRWMPLLF-UHFFFAOYSA-N 0.000 description 1
- 125000005810 2,5-xylyl group Chemical group [H]C1=C([H])C(=C(*)C([H])=C1C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RTZQIVNJKIGDGJ-UHFFFAOYSA-N 2-iodo-5-methylbenzene-1,3-diol Chemical compound CC1=CC(O)=C(I)C(O)=C1 RTZQIVNJKIGDGJ-UHFFFAOYSA-N 0.000 description 1
- YBRDFCQKQVTQKX-UHFFFAOYSA-N 3,3'-spirobi[1,2-dihydroindene]-4,4'-diol Chemical compound C1CC2=CC=CC(O)=C2C21CCC1=C2C(O)=CC=C1 YBRDFCQKQVTQKX-UHFFFAOYSA-N 0.000 description 1
- CDIDGWDGQGVCIB-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)aniline Chemical compound NC1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CDIDGWDGQGVCIB-UHFFFAOYSA-N 0.000 description 1
- MJKNHXCPGXUEDO-UHFFFAOYSA-N 3,5-ditert-butylaniline Chemical compound CC(C)(C)C1=CC(N)=CC(C(C)(C)C)=C1 MJKNHXCPGXUEDO-UHFFFAOYSA-N 0.000 description 1
- FOSIWKADJDNVMJ-UHFFFAOYSA-N 3-(2-carboxyethoxy)propanoic acid Chemical compound OC(=O)CCOCCC(O)=O FOSIWKADJDNVMJ-UHFFFAOYSA-N 0.000 description 1
- CIFJEVFPQXGYQT-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1.COC1=CC=CC(C=O)=C1 CIFJEVFPQXGYQT-UHFFFAOYSA-N 0.000 description 1
- GUUPKXREMJGASF-UHFFFAOYSA-N 4-(1,3-benzothiazol-2-ylmethyl)aniline Chemical compound C1=CC(N)=CC=C1CC1=NC2=CC=CC=C2S1 GUUPKXREMJGASF-UHFFFAOYSA-N 0.000 description 1
- ZCVQIPROFDGUST-UHFFFAOYSA-N 4-(1-hydroxynaphthalen-2-yl)butanoic acid Chemical compound C1=CC=CC2=C(O)C(CCCC(=O)O)=CC=C21 ZCVQIPROFDGUST-UHFFFAOYSA-N 0.000 description 1
- CTIJRJWOAGTXJC-UHFFFAOYSA-N 4-(2-hydroxyphenyl)butanoic acid Chemical compound OC(=O)CCCC1=CC=CC=C1O CTIJRJWOAGTXJC-UHFFFAOYSA-N 0.000 description 1
- APRRQJCCBSJQOQ-UHFFFAOYSA-N 4-amino-5-hydroxynaphthalene-2,7-disulfonic acid Chemical compound OS(=O)(=O)C1=CC(O)=C2C(N)=CC(S(O)(=O)=O)=CC2=C1 APRRQJCCBSJQOQ-UHFFFAOYSA-N 0.000 description 1
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 1
- QFRLQXLWTCTUND-UHFFFAOYSA-N 5-fluoro-2-iodobenzene-1,3-diol Chemical compound OC1=CC(F)=CC(O)=C1I QFRLQXLWTCTUND-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- MWFYAXBLRRXWDS-UHFFFAOYSA-N C(C)(C)(C)C=1C=C(C=C(C1)C(C)(C)C)N(C(CC)=O)ON(C(CC)=O)C1=CC(=CC(=C1)C(C)(C)C)C(C)(C)C Chemical compound C(C)(C)(C)C=1C=C(C=C(C1)C(C)(C)C)N(C(CC)=O)ON(C(CC)=O)C1=CC(=CC(=C1)C(C)(C)C)C(C)(C)C MWFYAXBLRRXWDS-UHFFFAOYSA-N 0.000 description 1
- QKQLVSJIOXLRHJ-UHFFFAOYSA-N C(C)(C)(C)N(C(CC)=O)ON(C(CC)=O)C(C)(C)C Chemical compound C(C)(C)(C)N(C(CC)=O)ON(C(CC)=O)C(C)(C)C QKQLVSJIOXLRHJ-UHFFFAOYSA-N 0.000 description 1
- VYCDSEVVNZTXSN-UHFFFAOYSA-N C(CC)(=O)N1ON(C(CC)=O)O1 Chemical compound C(CC)(=O)N1ON(C(CC)=O)O1 VYCDSEVVNZTXSN-UHFFFAOYSA-N 0.000 description 1
- GNVPBUOGNCUWIF-UHFFFAOYSA-N C1(=C(C(=CC(=C1)C)C)N(C(CC(C)C)=O)ON(C(CC(C)C)=O)C1=C(C=C(C=C1C)C)C)C Chemical compound C1(=C(C(=CC(=C1)C)C)N(C(CC(C)C)=O)ON(C(CC(C)C)=O)C1=C(C=C(C=C1C)C)C)C GNVPBUOGNCUWIF-UHFFFAOYSA-N 0.000 description 1
- PTICHBBIGWZURI-UHFFFAOYSA-N C1(=CC=CC=C1)N(C(CC)=O)ON(C(CC)=O)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)N(C(CC)=O)ON(C(CC)=O)C1=CC=CC=C1 PTICHBBIGWZURI-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- OUPSHYIVJKXWCF-UHFFFAOYSA-N N-[3,5-bis(trifluoromethyl)phenyl]-N-[N-propanoyl-3,5-bis(trifluoromethyl)anilino]oxypropanamide Chemical compound FC(C=1C=C(C=C(C1)C(F)(F)F)N(C(CC)=O)ON(C(CC)=O)C1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)(F)F OUPSHYIVJKXWCF-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000004069 aziridinyl group Chemical group 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000001867 hydroperoxy group Chemical group [*]OO[H] 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
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 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
- YSGBMDFJWFIEDF-YFKPBYRVSA-N methyl (2s)-2-hydroxy-3-methylbutanoate Chemical compound COC(=O)[C@@H](O)C(C)C YSGBMDFJWFIEDF-YFKPBYRVSA-N 0.000 description 1
- JIRGTCBOQAJBHY-UHFFFAOYSA-N n,n-diphenylpropanamide Chemical compound C=1C=CC=CC=1N(C(=O)CC)C1=CC=CC=C1 JIRGTCBOQAJBHY-UHFFFAOYSA-N 0.000 description 1
- AQBZEZFDJWSZLE-UHFFFAOYSA-N n-(2,4,6-trimethylphenyl)propanamide Chemical compound CCC(=O)NC1=C(C)C=C(C)C=C1C AQBZEZFDJWSZLE-UHFFFAOYSA-N 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002825 nitriles Chemical class 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
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
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- 125000003386 piperidinyl group Chemical group 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- RXYRTWKMCKYKAI-UHFFFAOYSA-N propanoyloxy propaneperoxoate Chemical compound CCC(=O)OOOC(=O)CC RXYRTWKMCKYKAI-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 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
- 239000012363 selectfluor Substances 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
- C07C235/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
- C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Abstract
２，６−ジヒドロキシヨードベンゼンから乳酸をキラル源に用いて柔軟な超原子価ヨウ素化合物の前駆体（ヨードベンゼン誘導体）を３ステップで合成し、その前駆体を触媒量用いて化学量論量のｍ−ＣＰＢＡ存在下で超原子価ヨウ素化合物を反応系内（insitu）で調製し、ナフトール系化合物Ｓ１のスピロラクトン化反応を行った。そうしたところ、高い鏡像体過剰率で対応するスピロラクトン化合物Ｐ１が得られた。【化１】A flexible hypervalent iodine compound precursor (iodobenzene derivative) is synthesized from 2,6-dihydroxyiodobenzene using lactic acid as a chiral source in three steps, and the precursor is used in a catalytic amount with a stoichiometric amount. A hypervalent iodine compound was prepared in situ in the presence of m-CPBA, and a spirolactonization reaction of the naphthol compound S1 was performed. As a result, the corresponding spirolactone compound P1 was obtained with a high enantiomeric excess. [Chemical 1]
Description
本発明は、ヨードベンゼン誘導体及びそれを用いた光学活性スピロラクトン化合物の製法に関する。
The present invention relates to an iodobenzene derivative and a method for producing an optically active spirolactone compound using the same.
超原子価ヨウ素化合物の科学は、１世紀以上の歴史を持つにもかかわらず、キラルなヨードベンゼン誘導体を用いる不斉酸化反応は最近になってやっと報告されるようになってきた。最近の例として、北らの酸化的不斉スピロ環形成反応（特許文献１，非特許文献１）がある。北らは、下記式に示すように、３−（１−ヒドロキシ−２−ナフチル）プロピオン酸を反応基質とし、剛直なキラルスピロビインダン骨格を持つ超原子価ヨウ素化合物を化学量論量用いて酸化的不斉スピロ環形成反応を行い、対応するスピロラクトン化合物を最高８６％ｅｅで得ている。また、この触媒の前駆体である７，７’−ジヨード−１，１’−スピロビインダン骨格を持つ化合物を触媒量用いてｍ−ＣＰＢＡ、酢酸の存在下で同様の反応を行い、対応するスピロラクトン化合物を最高６９％ｅｅで得ている。 Although the science of hypervalent iodine compounds has a history of more than a century, asymmetric oxidation reactions using chiral iodobenzene derivatives have only recently been reported. A recent example is Kita et al.'S oxidative asymmetric spiro ring formation reaction (Patent Document 1, Non-Patent Document 1). Kita et al., Using a stoichiometric amount of a hypervalent iodine compound having a rigid chiral spirobiindane skeleton using 3- (1-hydroxy-2-naphthyl) propionic acid as a reaction substrate as shown in the following formula: Oxidative asymmetric spiro ring formation reaction is carried out, and the corresponding spirolactone compound is obtained at a maximum of 86% ee. In addition, a similar reaction is carried out in the presence of m-CPBA and acetic acid using a catalytic amount of a compound having a 7,7′-diiodo-1,1′-spirobiindane skeleton, which is a precursor of this catalyst, and the corresponding spirolactone The compound is obtained at up to 69% ee.
しかしながら、７，７’−ジヨード−１，１’−スピロビインダンは、市販されている３−メトキシベンズアルデヒド（ｍ−アニスアルデヒド）から６ステップで７，７’−ジヒドロキシ−１，１’−スピロビインダンとし、これを光学分割したあと更に４ステップで得られるものであるため、容易に入手することができないうえ光学分割に高価な反応剤が必要になるという問題があった。 However, 7,7′-diiodo-1,1′-spirobiindane is converted to 7,7′-dihydroxy-1,1′-spirobiindane in 6 steps from commercially available 3-methoxybenzaldehyde (m-anisaldehyde), Since this is obtained in four steps after optical resolution, there is a problem that it cannot be easily obtained and an expensive reagent is required for optical resolution.
本発明はこのような課題を解決するためになされたものであり、入手容易で安価な触媒前駆体を用いて光学活性スピロラクトン化合物を高エナンチオ選択的に製造することを主目的とする。 The present invention has been made to solve such problems, and has as its main object to produce an optically active spirolactone compound with high enantioselectivity using an easily available and inexpensive catalyst precursor.
上述した目的を達成するために、本発明者らは、２，６−ジヒドロキシヨードベンゼンから乳酸をキラル源に用いて柔軟な超原子価ヨウ素化合物の前駆体を３ステップで合成し、その前駆体を触媒量用いて化学量論量のｍ−ＣＰＢＡ存在下で超原子価ヨウ素化合物を反応系内（in situ）で調製し、３−（１−ヒドロキシ−２−ナフチル）プロピオン酸のスピロラクトン化反応を試みたところ、高い鏡像体過剰率で光学活性スピロラクトン化合物が得られることを見いだし、本発明を完成するに至った。 In order to achieve the object described above, the present inventors synthesized a flexible hypervalent iodine compound precursor from 2,6-dihydroxyiodobenzene using lactic acid as a chiral source in three steps, and the precursor. A hypervalent iodine compound was prepared in the reaction system in the presence of a stoichiometric amount of m-CPBA using a catalytic amount and spirolactonization of 3- (1-hydroxy-2-naphthyl) propionic acid When the reaction was attempted, it was found that an optically active spirolactone compound was obtained with a high enantiomeric excess, and the present invention was completed.
即ち、本発明のヨードベンゼン誘導体は、下記式（１）で表されるものである。式（１）中、Ｒ1，Ｒ2は互いに独立して水素原子、アルキル基、シクロアルキル基若しくはアリール基であるか又は互いに結合して環を形成し、Ｒ3はアルキル基、シクロアルキル基又はアリール基であり、Ｚは水素原子、電子吸引基又は電子供与基であり、＊の付いた２つの不斉中心炭素の立体配置は共にＲであるか共にＳである。That is, the iodobenzene derivative of the present invention is represented by the following formula (1). In the formula (1), R 1 and R 2 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, or bonded to each other to form a ring, and R 3 is an alkyl group or a cycloalkyl group Or an aryl group, Z is a hydrogen atom, an electron-withdrawing group or an electron-donating group, and the configurations of the two asymmetric central carbons marked with * are both R or S.
本発明の光学活性スピロラクトン化合物の製法は、ＯＨ基が結合した炭素の隣りの炭素に−（ＣＨ2）nＣＯＯＨ（ｎは２又は３）が結合したフェノール誘導体と、触媒前駆体である上述したヨードベンゼン誘導体と、その触媒前駆体を酸化して超原子価ヨウ素化合物へ変換可能な過カルボン酸とを混合して反応させることにより、フェノール誘導体のＯＨ基がオキソ基（＝Ｏ）に変換されて脱芳香化すると共にラクトン環がスピロ結合した光学活性スピロラクトン化合物を得るものである。The method for producing the optically active spirolactone compound of the present invention is the above-described catalyst precursor, a phenol derivative in which — (CH 2 ) n COOH (n is 2 or 3) is bonded to carbon adjacent to the carbon to which the OH group is bonded. The OH group of the phenol derivative is converted to an oxo group (= O) by mixing and reacting the iodobenzene derivative with a percarboxylic acid that can be converted to a hypervalent iodine compound by oxidizing the catalyst precursor. Thus, an optically active spirolactone compound having a lactone ring spiro-bonded while dearomatizing is obtained.
本発明のヨードベンゼン誘導体は、２，６−ジヒドロキシヨードベンゼン又はその誘導体から乳酸をキラル源に用いて短いステップ（３ステップ）で合成することができるため、安価に大量生産することができ、経済性が高い。このヨードベンゼン誘導体は、ＯＨ基が結合した炭素の隣りの炭素に−（ＣＨ2）nＣＯＯＨ（ｎは２又は３）が結合したフェノール誘導体のエナンチオ選択的な脱芳香化型酸化を促進する触媒（超原子価ヨウ素化合物）の前駆体として利用することができる。更に、構造上、触媒前駆体を柔軟に設計できるため、例えば反応基質ごとに種々の触媒前駆体を用いてスクリーニングを行い、その反応基質に合った触媒前駆体を容易に見つけることができる。更にまた、取り扱いが困難な超原子価ヨウ素化合物を予め単離する必要がないため、工業的見地からも優れている。Since the iodobenzene derivative of the present invention can be synthesized from 2,6-dihydroxyiodobenzene or its derivative using lactic acid as a chiral source in a short step (three steps), it can be mass-produced at low cost and economically. High nature. This iodobenzene derivative is a catalyst that promotes enantioselective dearomatic oxidation of a phenol derivative in which — (CH 2 ) n COOH (n is 2 or 3) is bonded to the carbon adjacent to the carbon to which the OH group is bonded. It can be used as a precursor of (hypervalent iodine compound). Furthermore, since the catalyst precursor can be designed flexibly in terms of structure, for example, screening can be performed using various catalyst precursors for each reaction substrate, and a catalyst precursor suitable for the reaction substrate can be easily found. Furthermore, since it is not necessary to previously isolate a hypervalent iodine compound that is difficult to handle, it is excellent from an industrial point of view.
本発明の光学活性スピロラクトン化合物の製法によれば、上述したヨードベンゼン誘導体を触媒前駆体として用いることにより、光学活性スピロラクトン化合物を高エナンチオ選択的に製造することができる。なお、上述したヨードベンゼン誘導体が触媒前駆体として機能するときの反応は、次のように進行すると考えられる。すなわち、このヨードベンゼン誘導体と過カルボン酸と反応基質とを混合すると、ヨードベンゼン誘導体は過カルボン酸によって酸化されて触媒（超原子価ヨウ素化合物）になり、その触媒が上述したナフタレン誘導体を酸化すると同時に脱芳香化させて対応するスピロラクトン化合物に変換すると共に、自らは還元されて再び触媒前駆体つまりヨードベンゼン誘導体に戻る。
According to the method for producing an optically active spirolactone compound of the present invention, an optically active spirolactone compound can be produced with high enantioselectivity by using the above-mentioned iodobenzene derivative as a catalyst precursor. In addition, it is thought that reaction when the iodobenzene derivative mentioned above functions as a catalyst precursor advances as follows. That is, when this iodobenzene derivative, percarboxylic acid and reaction substrate are mixed, the iodobenzene derivative is oxidized by the percarboxylic acid to become a catalyst (hypervalent iodine compound), and when the catalyst oxidizes the above-described naphthalene derivative. At the same time, it is dearomatized and converted into the corresponding spirolactone compound, and it is reduced and returns to the catalyst precursor, that is, the iodobenzene derivative.
本発明のヨードベンゼン誘導体は、上記式（１）で表されるものである。上記式（１）中、Ｒ1，Ｒ2は互いに独立して水素原子、アルキル基、シクロアルキル基若しくはアリール基であるか又は互いに結合して環を形成し、Ｒ3はアルキル基、シクロアルキル基又はアリール基であり、Ｚは水素原子、電子吸引基又は電子供与基であり、＊の付いた２つの不斉中心炭素の立体配置は共にＲであるか共にＳである。The iodobenzene derivative of the present invention is represented by the above formula (1). In the above formula (1), R 1 and R 2 are each independently a hydrogen atom, an alkyl group, a cycloalkyl group or an aryl group, or bonded to each other to form a ring, and R 3 is an alkyl group, cycloalkyl Z is a hydrogen atom, an electron-withdrawing group or an electron-donating group, and the configurations of the two asymmetric central carbons marked with * are both R or S.
ここで、アルキル基としては、特に限定するものではないが、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基などの分岐を有していてもよい炭素数１〜４のアルキル基が挙げられる。シクロアルキル基としては、特に限定するものではないが、例えば、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、シクロヘプチル基などの炭素数３〜７のシクロアルキル基が挙げられる。アリール基としては、特に限定するものではないが、フェニル基、ナフチル基及びそれらの少なくとも１つの水素原子が置換基で置換されたものなどが挙げられる。置換基としては、ハロゲン原子、アルキル基、シクロアルキル基、ペルフルオロアルキル基などが挙げられる。ここで、アルキル基、シクロアルキル基としては既に例示したものが挙げられ、ペルフルオロアルキル基としては、トリフルオロメチル基やペンタフルオロエチル基などが挙げられる。こうしたアリール基の具体例としては、フェニル基、ｏ−トリル基，ｍ−トリル基、ｐ−トリル基、２，３−キシリル基、２，４−キシリル基、２，５−キシリル基、２，６−キシリル基、３，４−キシリル基、３，５−キシリル基、２，４，６−トリメチルフェニル基（メシチル基）、２，３，４−トリメチルフェニル基、２，３，５−トリメチルフェニル基、２，３，６−トリメチルフェニル基、３，４，５−トリメチルフェニル基、２，３−ビス（トリフルオロメチル）フェニル基、２，４−ビス（トリフルオロメチル）フェニル基、２，５−ビス（トリフルオロメチル）フェニル基、２，６−ビス（トリフルオロメチル）フェニル基、３，４−ビス（トリフルオロメチル）フェニル基、３，５−ビス（トリフルオロメチル）フェニル基、２，３−ジ−ｔｅｒｔ−ブチルフェニル基、２，４−ジ−ｔｅｒｔ−ブチルフェニル基、２，５−ジ−ｔｅｒｔ−ブチルフェニル基、２，６−ジ−ｔｅｒｔ−ブチルフェニル基、３，４−ジ−ｔｅｒｔ−ブチルフェニル基、３，５−ジ−ｔｅｒｔ−ブチルフェニル基などが挙げられる。電子吸引基としては、塩素原子、臭素原子、シアノ基、ニトロ基などが挙げられ、電子供与基としては、アルキル基、アルコキシ基などが挙げられる。アルキル基としては既に例示したものが挙げられ、アルコキシ基としては、特に限定するものではないが、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、イソブトキシ基、ｓｅｃ−ブトキシ基、ｔｅｒｔ−ブトキシ基などの分岐を有していてもよい炭素数１〜４のアルコキシ基が挙げられる。また、Ｒ1，Ｒ2が互いに結合して環を形成する場合、形成される環は含窒素複素環となる。このような含窒素複素環としては、例えばアジリジン環、ピロリジン環、ピペリジン環などが挙げられる。Here, the alkyl group is not particularly limited. For example, it has a branch such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. And an alkyl group having 1 to 4 carbon atoms which may be used. Although it does not specifically limit as a cycloalkyl group, For example, C3-C7 cycloalkyl groups, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, are mentioned. Examples of the aryl group include, but are not limited to, a phenyl group, a naphthyl group, and those in which at least one hydrogen atom thereof is substituted with a substituent. Examples of the substituent include a halogen atom, an alkyl group, a cycloalkyl group, and a perfluoroalkyl group. Here, examples of the alkyl group and cycloalkyl group include those already exemplified, and examples of the perfluoroalkyl group include a trifluoromethyl group and a pentafluoroethyl group. Specific examples of such aryl groups include phenyl, o-tolyl, m-tolyl, p-tolyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2, 6-xylyl group, 3,4-xylyl group, 3,5-xylyl group, 2,4,6-trimethylphenyl group (mesityl group), 2,3,4-trimethylphenyl group, 2,3,5-trimethyl Phenyl group, 2,3,6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 2,3-bis (trifluoromethyl) phenyl group, 2,4-bis (trifluoromethyl) phenyl group, 2 , 5-bis (trifluoromethyl) phenyl group, 2,6-bis (trifluoromethyl) phenyl group, 3,4-bis (trifluoromethyl) phenyl group, 3,5-bis (trifluoromethyl) phenyl 2,3-di-tert-butylphenyl group, 2,4-di-tert-butylphenyl group, 2,5-di-tert-butylphenyl group, 2,6-di-tert-butylphenyl group, 3 , 4-di-tert-butylphenyl group, 3,5-di-tert-butylphenyl group, and the like. Examples of the electron withdrawing group include a chlorine atom, a bromine atom, a cyano group, and a nitro group. Examples of the electron donating group include an alkyl group and an alkoxy group. Alkyl groups include those already exemplified, and alkoxy groups are not particularly limited, but include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert -The C1-C4 alkoxy group which may have branches, such as a butoxy group, is mentioned. Further, when R 1 and R 2 are bonded to each other to form a ring, the formed ring is a nitrogen-containing heterocycle. Examples of such a nitrogen-containing heterocycle include an aziridine ring, a pyrrolidine ring, and a piperidine ring.
本発明のヨードベンゼン誘導体は、ＯＨ基が結合した炭素の隣りの炭素に−（ＣＨ2）nＣＯＯＨ（ｎは２又は３）が結合したフェノール誘導体のエナンチオ選択的な脱芳香化型酸化を促進する触媒（超原子価ヨウ素化合物）の前駆体として利用することができるが、その場合、式（１）のＲ1は水素原子、Ｒ2はアリール基であることが好ましい。こうすれば、フェノール誘導体から光学活性スピロラクトン化合物をより高い鏡像体過剰率で製造することができる。また、式（１）のＲ3はメチル基であることが好ましい。Ｒ3をイソプロピル基のような嵩高いアルキル基としてもよいが、光学活性スピロラクトン化合物の鏡像体過剰率はメチル基と比べてほとんど差がないため、構造がシンプルなメチル基とすることが好ましい。更に、式（１）のＺは水素原子、フッ素原子、塩素原子、臭素原子、アルキル基、アルコキシ基、ニトロ基及びシアノ基からなる群より選ばれたものであることが好ましい。このＺはヨードベンゼンのパラ位に結合しているが、ヨードベンゼンのメタ位の水素原子を他の官能基又は原子に置換することは良好な結果が得られなくなるおそれがあるため好ましくない。反応基質であるフェノール誘導体の構造に応じて触媒前駆体である本発明のヨードベンゼン誘導体の構造の最適化を図る場合、式（１）のヨードベンゼンのＲ1、Ｒ2が異なるものやＲ3が異なるものを種々合成し、それらを用いて反応基質から光学活性スピロラクトン化合物を製造したときに最適な結果が得られるものを選別すればよい。The iodobenzene derivative of the present invention promotes enantioselective dearomatic oxidation of a phenol derivative in which — (CH 2 ) n COOH (n is 2 or 3) is bonded to the carbon adjacent to the carbon to which the OH group is bonded. In this case, R 1 in the formula (1) is preferably a hydrogen atom and R 2 is preferably an aryl group. In this way, an optically active spirolactone compound can be produced from a phenol derivative with a higher enantiomeric excess. Further, R 3 in the formula (1) is preferably a methyl group. R 3 may be a bulky alkyl group such as an isopropyl group, but the enantiomeric excess of the optically active spirolactone compound is almost the same as that of the methyl group, so that the structure is preferably a simple methyl group. . Further, Z in formula (1) is preferably selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an alkoxy group, a nitro group, and a cyano group. This Z is bonded to the para position of iodobenzene, but it is not preferable to substitute the hydrogen atom at the meta position of iodobenzene with another functional group or atom because good results may not be obtained. When optimizing the structure of the iodobenzene derivative of the present invention, which is a catalyst precursor, according to the structure of the phenol derivative, which is a reaction substrate, the compounds in which R 1 and R 2 of the iodobenzene of the formula (1) are different or R 3 Various compounds having different values may be synthesized, and those that can be used to produce an optically active spirolactone compound from a reaction substrate may be selected.
本発明の光学活性スピロラクトン化合物の製法は、ＯＨ基が結合した炭素の隣りの炭素に−（ＣＨ2）nＣＯＯＨ（ｎは２又は３）が結合したフェノール誘導体と、触媒前駆体である式（１）のヨードベンゼン誘導体と、触媒前駆体を酸化して超原子価ヨウ素化合物へ変換可能な過カルボン酸とを混合して反応させることにより、フェノール誘導体のＯＨ基がオキソ基（＝Ｏ）に変換されて脱芳香化すると共にラクトン環がスピロ結合した光学活性スピロラクトン化合物を得るものである。The process for producing the optically active spirolactone compound of the present invention comprises a phenol derivative in which — (CH 2 ) n COOH (n is 2 or 3) is bonded to a carbon adjacent to a carbon to which an OH group is bonded, and a formula that is a catalyst precursor. By mixing and reacting the iodobenzene derivative of (1) and a percarboxylic acid that can be converted into a hypervalent iodine compound by oxidizing the catalyst precursor, the OH group of the phenol derivative becomes an oxo group (= O). To obtain an optically active spirolactone compound in which the lactone ring is spiro-bonded.
この製法に用いられるフェノール誘導体としては、例えば、３−（２−ヒドロキシフェニル）プロピオン酸や４−（２−ヒドロキシフェニル）ブタン酸などのフェノール系化合物、３−（１−ヒドロキシ−２−ナフチル）プロピオン酸や４−（１−ヒドロキシ−２−ナフチル）ブタン酸などのナフトール系化合物が挙げられる。フェノール系化合物の２−ヒドロキシフェニルは３〜５位の少なくとも一つに置換基を有していてもよく、ナフトール系化合物の１−ヒドロキシ−２−ナフチルは３位及び４位の少なくとも一つに置換基を有していてもよい。置換基としては、例えばメチル基、エチル基、プロピル基、イソプロピル基などのアルキル基；メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基などのアルコキシ基；ベンジル基などの芳香族アルキル基；ベンジルオキシメチルなどのエーテル結合を持つアルキル基などが挙げられる。このうち、反応性を考慮すると、フェノール系化合物よりもナフトール系化合物の方が好ましい。また、反応生成物であるスピロラクトン化合物の安定性を考慮すると、六員環ラクトンよりも五員環ラクトンの方が安定なことからｎは２の方が好ましい。 Examples of the phenol derivative used in this production method include phenolic compounds such as 3- (2-hydroxyphenyl) propionic acid and 4- (2-hydroxyphenyl) butanoic acid, and 3- (1-hydroxy-2-naphthyl). Examples thereof include naphtholic compounds such as propionic acid and 4- (1-hydroxy-2-naphthyl) butanoic acid. The 2-hydroxyphenyl of the phenolic compound may have a substituent in at least one of the 3-5 positions, and the 1-hydroxy-2-naphthyl of the naphthol compound is in at least one of the 3-position and 4-position. It may have a substituent. Examples of the substituent include an alkyl group such as a methyl group, an ethyl group, a propyl group, and an isopropyl group; an alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group; an aromatic alkyl group such as a benzyl group; Examples thereof include an alkyl group having an ether bond such as methyl. Among these, in consideration of reactivity, a naphthol compound is more preferable than a phenol compound. In consideration of the stability of the spirolactone compound as a reaction product, n is preferably 2 because a 5-membered lactone is more stable than a 6-membered lactone.
この製法に用いられるヨードベンゼン誘導体としては、上述した式（１）の化合物を使用する。 As the iodobenzene derivative used in this production method, the compound of the above formula (1) is used.
この製法に用いられる過カルボン酸としては、例えば、過酢酸、過安息香酸、ｍ−クロロ過安息香酸（ｍ−ＣＰＢＡ）などが挙げられるが、このうち取り扱いやすさの点から過安息香酸、ｍ−ＣＰＢＡが好ましい。また、過カルボン酸は、カルボン酸のヒドロキシ基をヒドロペルオキシ基に置き換えた過酸であり、カルボン酸に過酸化水素などの過酸化物を反応させると発生することから、過カルボン酸を反応系内に入れる代わりに、カルボン酸と過酸化物とを組み合わせて反応系内に入れてその場で過カルボン酸が生成されるようにしてもよい。 Examples of the percarboxylic acid used in this production method include peracetic acid, perbenzoic acid, and m-chloroperbenzoic acid (m-CPBA). Among these, perbenzoic acid, m -CPBA is preferred. Percarboxylic acid is a peracid obtained by replacing the hydroxy group of a carboxylic acid with a hydroperoxy group, and is generated when a peroxide such as hydrogen peroxide is reacted with the carboxylic acid. Instead of being put in, a combination of carboxylic acid and peroxide may be put in the reaction system so that the percarboxylic acid is generated in situ.
この製法の反応過程では、過カルボン酸は、上述したヨードベンゼン誘導体を酸化して超原子価ヨウ素化合物に変換すると共に自らは還元されてカルボン酸になる。一方、超原子価ヨウ素化合物は、フェノール誘導体をスピロラクトン化合物に変換すると共に自らは還元されてヨードベンゼン誘導体に戻る。このため、ヨードベンゼン誘導体は触媒量で足りるが、過カルボン酸は、フェノール誘導体に対して等モル以上必要になる。こうしたことから、ヨードベンゼン誘導体は、フェノール誘導体に対して０．５〜５０ｍｏｌ％使用することが好ましい。０．５ｍｏｌ％未満だと反応の進行が遅く反応時間が長時間になるため好ましくなく、５０ｍｏｌ％を超えても収率や鏡像体過剰率が大きく向上することはないため経済的見地から好ましくない。こうした反応性や経済性を両立させることを考慮すると１０〜３０ｍｏｌ％使用することがより好ましい。また、過カルボン酸の使用量は、フェノール誘導体に対して等モル使用すれば足りるが、反応をより円滑に進行させることを考慮すると１．１〜１．５倍モル使用することが好ましい。 In the reaction process of this production method, percarboxylic acid oxidizes the above iodobenzene derivative to convert it to a hypervalent iodine compound and reduces itself to carboxylic acid. On the other hand, a hypervalent iodine compound converts a phenol derivative into a spirolactone compound and is reduced itself to return to an iodobenzene derivative. For this reason, a catalytic amount is sufficient for the iodobenzene derivative, but the percarboxylic acid is required in an equimolar amount or more relative to the phenol derivative. For these reasons, it is preferable to use 0.5 to 50 mol% of the iodobenzene derivative with respect to the phenol derivative. If it is less than 0.5 mol%, the reaction progresses slowly and the reaction time becomes long, which is not preferable, and if it exceeds 50 mol%, the yield and the enantiomeric excess are not greatly improved, which is not preferable from an economic standpoint. . In consideration of achieving both such reactivity and economy, it is more preferable to use 10 to 30 mol%. Moreover, although the usage-amount of percarboxylic acid will suffice if it uses equimolar with respect to a phenol derivative, it is preferable to use 1.1-1.5 times mole considering that a reaction is advanced more smoothly.
この製法において、フェノール誘導体とヨードベンゼン誘導体と過カルボン酸とを混合して反応させる際、種々の反応溶媒を利用可能である。反応溶媒としては、例えば、塩化メチレン、クロロホルム、四塩化炭素、二塩化エチレンなどのハロゲン化アルカン；ベンゼン、トルエン、キシレン、塩化ベンゼンなどの芳香族炭化水素；ニトロメタンなどのニトロアルカン；アセトニトリル、プロピオニトリルなどのニトリル系溶媒；酢酸メチル、酢酸エチルなどのエステル系溶媒；２，２，２−トリフルオロエタノール、１，１，１，３，３，３−ヘキサフルオロ−２−プロパノールなどのフッ素系アルコールなどのほか、それらの混合物を使用することができる。このうち、収率及び鏡像体過剰率を考慮すると、ハロゲン化アルカン、ニトロアルカン又はそれらの混合物が好ましい。反応溶媒の使用量は、特に限定するものではないが、例えばフェノール誘導体の濃度が０．０１〜１Ｍ、好ましくは０．０２〜０．２Ｍとなるように設定する。 In this production method, various reaction solvents can be used when a phenol derivative, an iodobenzene derivative and a percarboxylic acid are mixed and reacted. Examples of the reaction solvent include halogenated alkanes such as methylene chloride, chloroform, carbon tetrachloride, and ethylene dichloride; aromatic hydrocarbons such as benzene, toluene, xylene, and benzene chloride; nitroalkanes such as nitromethane; acetonitrile, propio Nitrile solvents such as nitrile; ester solvents such as methyl acetate and ethyl acetate; fluorine systems such as 2,2,2-trifluoroethanol and 1,1,1,3,3,3-hexafluoro-2-propanol In addition to alcohol, a mixture thereof can be used. Among these, in consideration of the yield and the enantiomeric excess, halogenated alkanes, nitroalkanes or mixtures thereof are preferred. Although the usage-amount of the reaction solvent is not specifically limited, For example, it sets so that the density | concentration of a phenol derivative may be 0.01-1M, Preferably it is 0.02-0.2M.
この製法では、反応温度は、特に限定するものではないが、−２０〜５０℃が好ましく、０〜４０℃がより好ましい。−２０℃未満だと、反応速度が遅くなり過ぎるため好ましくなく、５０℃を超えると反応速度は向上するもののエナンチオ選択性が低下するおそれがあるため好ましくない。また、反応系の雰囲気は、窒素ガスやアルゴンガスなどの不活性雰囲気とする必要はなく、大気雰囲気でも支障なく反応が進行する。 In this production method, the reaction temperature is not particularly limited, but is preferably -20 to 50 ° C, more preferably 0 to 40 ° C. If it is less than −20 ° C., the reaction rate becomes too slow, which is not preferable. If it exceeds 50 ° C., the reaction rate is improved, but the enantioselectivity may be lowered, which is not preferable. The atmosphere in the reaction system does not need to be an inert atmosphere such as nitrogen gas or argon gas, and the reaction proceeds without any problem even in an air atmosphere.
なお、本発明は上述した実施形態に何ら限定されることはなく、本発明の技術的範囲に属する限り種々の態様で実施し得ることはいうまでもない。
It should be noted that the present invention is not limited to the above-described embodiment, and it goes without saying that the present invention can be implemented in various modes as long as it belongs to the technical scope of the present invention.
以下の実施例においては1Ｈ ＮＭＲスペクトルをＪＥＯＬ ＥＣＳ−４００（４００ＭＨｚ）スペクトロメータで、13Ｃ ＮＭＲスペクトルをＪＥＯＬ ＥＣＳ−４００（１００ＭＨｚ）スペクトロメータで測定した。反応生成物の光学純度は、高速液体クロマトグラフィー（ＨＰＬＣ）を、４．６ｍｍ×２５ｃｍ Ｄａｉｃｅｌ ＣＨＩＲＡＬＣＥＬ ＯＤ−ＨまたはＡＤ−Ｈを用いて、Ｓｈｉｍａｄｚｕ ＬＣ−１０装置で測定した。反応の進行は、薄層クロマトグラフィー（ＴＬＣ）で、Ｍｅｒｃｋ ｐｒｅｃｏａｔｅｄ ＴＬＣプレート（シリカゲル６０ ＧＦ２５４，０．２５ｍｍ）を用いてモニタリングした。In the following examples, 1 H NMR spectra were measured with a JEOL ECS-400 (400 MHz) spectrometer, and 13 C NMR spectra were measured with a JEOL ECS-400 (100 MHz) spectrometer. The optical purity of the reaction product was measured with a Shimadzu LC-10 apparatus using high performance liquid chromatography (HPLC) using 4.6 mm × 25 cm Daicel CHIRALCEL OD-H or AD-H. The progress of the reaction was monitored by thin layer chromatography (TLC) using Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm).
［１］ヨードベンゼン誘導体の合成
下記の反応式にしたがって下記表１に示すヨードベンゼン誘導体Ａ〜Ｍを合成した。このうちヨードベンゼン誘導体Ｃ〜Ｍが本発明の実施例に相当する。なお、２−ヨードレゾルシノール類は文献（Org. Syn., 2007, vol.84, p272）に記載された方法にしたがって合成した。[1] Synthesis of iodobenzene derivatives According to the following reaction formula, iodobenzene derivatives A to M shown in Table 1 below were synthesized. Of these, iodobenzene derivatives C to M correspond to examples of the present invention. In addition, 2-iodoresorcinol was synthesize | combined according to the method described in literature (Org. Syn., 2007, vol.84, p272).
・ヨードベンゼン誘導体Ａの合成
ヨードベンゼン誘導体Ａすなわち（２Ｒ，２’Ｒ）−ジエチル ２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ジプロパノエートを以下の手順により合成した。まず、２−ヨードレゾルシノール（２．３６ｇ，１０．０ｍｍｏｌ）をＴＨＦ（５０ｍＬ）に溶かし、ＰＰｈ3（６．５６ｇ，２５．０ｍｍｏｌ）と（−）−乳酸エチルエステル（２．８０ｍＬ，２５．０ｍｍｏｌ）を加えた。混合溶液を撹拌しながら０℃に冷やし、ジイソプロピル アゾジカルボキシレート（ＤＩＡＤ，約１．９Ｍトルエン溶液，１３．２ｍＬ，２５．０ｍｍｏｌ）をゆっくり滴下した。その後、反応液を室温に戻し、６時間撹拌した。反応終了後、反応液をエバボレータ−で濃縮し、得られた混合物をシリカゲルカラムクロマトグラフィーによって精製して（展開溶媒：ヘキサン−ＥｔＯＡｃ＝１５：１（ｖ／ｖ））、無色オイルのヨードベンゼン誘導体Ａを得た（３．９３ｇ，９．００ｍｍｏｌ，収率９０％）。ヨードベンゼン誘導体Ａのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative A Iodobenzene derivative A, ie (2R, 2′R) -diethyl 2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) dipropanoate, was synthesized by the following procedure. First, 2-iodoresorcinol (2.36 g, 10.0 mmol) was dissolved in THF (50 mL), PPh 3 (6.56 g, 25.0 mmol) and (−)-lactic acid ethyl ester (2.80 mL, 25.0 mmol). ) Was added. The mixed solution was cooled to 0 ° C. with stirring, and diisopropyl azodicarboxylate (DIAD, about 1.9 M toluene solution, 13.2 mL, 25.0 mmol) was slowly added dropwise. Then, the reaction liquid was returned to room temperature and stirred for 6 hours. After completion of the reaction, the reaction mixture was concentrated with an evaporator, and the resulting mixture was purified by silica gel column chromatography (developing solvent: hexane-EtOAc = 15: 1 (v / v)) to give an iodobenzene derivative as a colorless oil. A was obtained (3.93 g, 9.00 mmol, 90% yield). The spectral data of iodobenzene derivative A is as follows.
TLC,Rf=0.33(hexane-EtOAc=4:1);1H NMR(CDCl3,400MHz)δ1.24(t,J=7.2Hz,6H),1.70(d,J=6.8Hz,6H),4.18-4.24(m,4h),4.75(q,J=6.8Hz,2H),6.37(d,J=8.4Hz,2H),7.13(t,J=8.4Hz,1H).TLC, R f = 0.33 (hexane-EtOAc = 4: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.24 (t, J = 7.2 Hz, 6H), 1.70 (d, J = 6.8 Hz, 6H) 4.18-4.24 (m, 4h), 4.75 (q, J = 6.8Hz, 2H), 6.37 (d, J = 8.4Hz, 2H), 7.13 (t, J = 8.4Hz, 1H).
・ヨードベンゼン誘導体Ｂの合成
ヨードベンゼン誘導体Ｂすなわち（２Ｒ，２Ｒ’）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ジプロパン酸を以下の手順により合成した。まず、ヨードベンゼン誘導体Ａ（３．９３ｇ，９．００ｍｍｏｌ）をＴＨＦ（２５．０ｍＬ）とＭｅＯＨ（２５．０ｍＬ）に溶かし、２Ｎ ＮａＯＨ水溶液（２５．０ｍＬ）を加えて室温で終夜撹拌した。反応終了後、反応液に１Ｎ ＨＣｌを加えて酸性にした後、ＥｔＯＡｃで２回抽出した。有機層を無水ＭｇＳＯ4で乾燥させたあと、溶媒をエバボレータ−で除いて白色固体のヨードベンゼン誘導体Ｂを得た（３．４２ｇ，９．００ｍｍｏｌ，収率＞９９％）。ヨードベンゼン誘導体Ｂのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative B Iodobenzene derivative B, ie, (2R, 2R ′)-2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) dipropanoic acid, was synthesized by the following procedure. First, iodobenzene derivative A (3.93 g, 9.00 mmol) was dissolved in THF (25.0 mL) and MeOH (25.0 mL), 2N NaOH aqueous solution (25.0 mL) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was acidified with 1N HCl and extracted twice with EtOAc. After drying the organic layer with anhydrous MgSO 4 , the solvent was removed with an evaporator to obtain a white solid iodobenzene derivative B (3.42 g, 9.00 mmol, yield> 99%). The spectral data of iodobenzene derivative B is as follows.
TLC,Rf=0.15(hexane-EtOAc-CHCl3=1:2:1 with a few drops of AcOH);1H NMR(DMSO-d6,400MHz)δ1.54(d,J=6.8Hz,6H),4.84(q,J=6.8Hz,2H),6.42(d,J=8.0Hz,2H),7.21(t,J=8.0Hz,1H);13C NMR(DMSO-d6,100MHz)δ18.4(2C),72.8(2C),79.6,105.9(2C),129.7,157.8(2C),172.7(2C).TLC, R f = 0.15 (hexane-EtOAc-CHCl 3 = 1: 2: 1 with a few drops of AcOH); 1 H NMR (DMSO-d 6 , 400 MHz) δ1.54 (d, J = 6.8 Hz, 6H ), 4.84 (q, J = 6.8Hz, 2H), 6.42 (d, J = 8.0Hz, 2H), 7.21 (t, J = 8.0Hz, 1H); 13 C NMR (DMSO-d 6, 100MHz) δ18 .4 (2C), 72.8 (2C), 79.6, 105.9 (2C), 129.7, 157.8 (2C), 172.7 (2C).
・ヨードベンゼン誘導体Ｃの合成
ヨードベンゼン誘導体Ｃすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ジプロパンアミドを以下の手順により合成した。まず、ヨードベンゼン誘導体Ｂ（１９０ｍｇ，０．５０ｍｍｏｌ）とＳＯＣｌ2（４．０ｍＬ）との混合溶液を１時間加熱還流した。次に、その反応液にベンゼン（２ｍＬを２回）を加えて過剰の試薬と溶媒をエバボレータ−で除いた後、得られた黄色い液体をＣＨ2Ｃｌ2（５．０ｍＬ）に溶かした。反応液を−７８℃に冷やしながら過剰量のアンモニアガスを加え、その後ゆっくり室温に昇温させながら終夜撹拌した。反応終了後に、反応液に１Ｎ ＨＣｌ水溶液を加えて水層と有機層に分離した後、水層をＣＨＣｌ3で抽出した。有機層を無水ＭｇＳＯ4で乾燥させたあと、溶媒をエバボレータ−で除いた。得られた混合物をシリカゲルカラムクロマトグラフィーによって精製して（展開溶媒：ヘキサン−ＥｔＯＡｃ＝１：２（ｖ／ｖ））、白色固体のヨードベンゼン誘導体Ｃを得た（０．１５ｇ，０．４ｍｍｏｌ，収率７９％）。ヨードベンゼン誘導体Ｃのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative C Iodobenzene derivative C, ie, (2R, 2′R) -2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) dipropanamide was synthesized by the following procedure. . First, a mixed solution of iodobenzene derivative B (190 mg, 0.50 mmol) and SOCl 2 (4.0 mL) was heated to reflux for 1 hour. Next, benzene (2 mL was added twice) was added to the reaction solution, excess reagent and solvent were removed by an evaporator, and the resulting yellow liquid was dissolved in CH 2 Cl 2 (5.0 mL). An excess amount of ammonia gas was added while cooling the reaction solution to −78 ° C., and then the mixture was stirred overnight while slowly warming to room temperature. After completion of the reaction, 1N HCl aqueous solution was added to the reaction solution to separate it into an aqueous layer and an organic layer, and then the aqueous layer was extracted with CHCl 3 . After the organic layer was dried over anhydrous MgSO 4 , the solvent was removed with an evaporator. The resulting mixture was purified by silica gel column chromatography (developing solvent: hexane-EtOAc = 1: 2 (v / v)) to obtain iodobenzene derivative C as a white solid (0.15 g, 0.4 mmol, Yield 79%). The spectral data of iodobenzene derivative C is as follows.
TLC,Rf=0.13(hexane-EtOAc-CHCl3=1:2:1);1H NMR(DMSO-d6,400MHz)δ1.47(d,J=6.8Hz,6H),4.68(q,J=6.8Hz,2H),6.51(d,J=8.0Hz,2H),7.24(t,J=8.0Hz,1H),7.30(s,2H),7.42(s,2H);13C NMR(DMSO-d6,100MHz)δ18.6(2C),74.8(2C),80.6,106.7(2C),129.9,157.5(2C),172.9(2C).TLC, R f = 0.13 (hexane-EtOAc-CHCl 3 = 1: 2: 1); 1 H NMR (DMSO-d 6 , 400 MHz) δ 1.47 (d, J = 6.8 Hz, 6H), 4.68 (q, J = 6.8Hz, 2H), 6.51 (d, J = 8.0Hz, 2H), 7.24 (t, J = 8.0Hz, 1H), 7.30 (s, 2H), 7.42 (s, 2H); 13 C NMR ( DMSO-d 6, 100MHz) δ18.6 (2C), 74.8 (2C), 80.6,106.7 (2C), 129.9,157.5 (2C), 172.9 (2C).
・ヨードベンゼン誘導体Ｄの合成
ヨードベンゼン誘導体Ｄすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−ｔｅｒｔ−ブチルプロパンアミド）を以下の手順により合成した。まず、ヨードベンゼン誘導体Ｂ（１９０ｍｇ，０．５０ｍｍｏｌ）とＳＯＣｌ2（４．０ｍＬ）の混合溶液を１時間加熱還流した。次に、その反応液にベンゼン（２ｍＬを２回）を加えて過剰の試薬と溶媒をエバボレータ−で除いた後、得られた黄色い液体をＣＨ2Ｃｌ2（５．０ｍＬ）に溶かした。反応液を０℃に冷やし、ピリジン（０．５０ｍＬ）とｔｅｒｔ−ブチルアミン（０．３１ｍＬ，２ｍｍｏｌ）を加えてから室温で３時間撹拌した。反応終了後に、反応液に１Ｎ ＨＣｌ水溶液を加えて水層と有機層に分離した後、水層をＣＨＣｌ3で抽出した。有機層を無水ＭｇＳＯ4で乾燥させたあと、溶媒をエバボレータ−で除いた。得られた混合物をシリカゲルカラムクロマトグラフィーによって精製して（展開溶媒：ヘキサン−ＥｔＯＡｃ＝４：１（ｖ／ｖ））、白色固体のヨードベンゼン誘導体Ｄを得た（０．１９ｇ，０．３９ｍｍｏｌ，収率７８％）。ヨードベンゼン誘導体Ｄのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative D Iodobenzene derivative D, ie (2R, 2′R) -2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) bis (N-tert-butylpropanamide) Was synthesized by the following procedure. First, a mixed solution of iodobenzene derivative B (190 mg, 0.50 mmol) and SOCl 2 (4.0 mL) was heated to reflux for 1 hour. Next, benzene (2 mL was added twice) was added to the reaction solution, excess reagent and solvent were removed by an evaporator, and the resulting yellow liquid was dissolved in CH 2 Cl 2 (5.0 mL). The reaction solution was cooled to 0 ° C., pyridine (0.50 mL) and tert-butylamine (0.31 mL, 2 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 1N HCl aqueous solution was added to the reaction solution to separate it into an aqueous layer and an organic layer, and then the aqueous layer was extracted with CHCl 3 . After the organic layer was dried over anhydrous MgSO 4 , the solvent was removed with an evaporator. The resulting mixture was purified by silica gel column chromatography (developing solvent: hexane-EtOAc = 4: 1 (v / v)) to obtain iodobenzene derivative D as a white solid (0.19 g, 0.39 mmol, Yield 78%). The spectral data of iodobenzene derivative D is as follows.
TLC,Rf=0.37(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.40(s,18H),1.61(d,J=6.8Hz,6H),4.68(q,J=6.8Hz,2H),6.49(d,J=8.0Hz,2H),6.84(brs,2H),7.27(t,J=8.0Hz,1H);13C NMR(CDCl3,100MHz)δ18.2(2C),28.7(6C),51.1(2C),76.0(2C),80.3,106.5(2C),130.4,156.8(2C),170.1(2C).TLC, R f = 0.37 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.40 (s, 18 H), 1.61 (d, J = 6.8 Hz, 6H), 4.68 (q, J = 6.8Hz, 2H), 6.49 (d, J = 8.0Hz, 2H), 6.84 (brs, 2H), 7.27 (t, J = 8.0Hz, 1H); 13 C NMR (CDCl 3, 100MHz) δ18. 2 (2C), 28.7 (6C), 51.1 (2C), 76.0 (2C), 80.3, 106.5 (2C), 130.4, 156.8 (2C), 170.1 (2C).
なお、ヨードベンゼン誘導体Ａ〜Ｄを合成する反応式を以下にまとめた。 The reaction formulas for synthesizing iodobenzene derivatives A to D are summarized below.
・ヨードベンゼン誘導体Ｅの合成
ヨードベンゼン誘導体Dの合成方法のｔｅｒｔ−ブチルアミンの代わりにアニリンを用いることにより、白色固体のヨードベンゼン誘導体Ｅすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−フェニルプロパンアミド）を収率６９％で得た。ヨードベンゼン誘導体Ｅのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative E By using aniline instead of tert-butylamine in the synthesis method of iodobenzene derivative D, iodobenzene derivative E of white solid, that is, (2R, 2′R) -2,2 ′-(2 -Iodo-1,3-phenylene) bis (oxy) bis (N-phenylpropanamide) was obtained in a yield of 69%. The spectral data of iodobenzene derivative E is as follows.
TLC,Rf=0.37(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.75(d,J=6.4Hz,6H),4.96(q,J=6.4Hz,2H),6.60(d,J=8.4Hz,2H),7.16(t,J=8.0Hz,2H),7.33(t,J=8.4Hz,1H),7.37(t,J=8.0Hz,4H),7.66(d,J=8.0Hz,4H),8.79(brs,2H);13C NMR(CDCl3,100MHz)δ18.3(2C),76.1(2C),80.7,107.2(2C),119.8(4C),124.7(2C),129.1(4C),130.8,137.2(2C),156.7(2C),168.9(2C).TLC, R f = 0.37 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.75 (d, J = 6.4 Hz, 6H), 4.96 (q, J = 6.4 Hz, 2H) , 6.60 (d, J = 8.4Hz, 2H), 7.16 (t, J = 8.0Hz, 2H), 7.33 (t, J = 8.4Hz, 1H), 7.37 (t, J = 8.0Hz, 4H), 7.66 (d, J = 8.0Hz, 4H), 8.79 (brs, 2H); 13 C NMR (CDCl 3 , 100 MHz) δ18.3 (2C), 76.1 (2C), 80.7,107.2 (2C), 119.8 (4C) 124.7 (2C), 129.1 (4C), 130.8, 137.2 (2C), 156.7 (2C), 168.9 (2C).
・ヨードベンゼン誘導体Ｆの合成
ヨードベンゼン誘導体Dの合成方法のｔｅｒｔ−ブチルアミンの代わりに３，５−ジ−トリフルオロメチルアニリンを用いることにより、白色固体のヨードベンゼン誘導体Ｆすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−（３，５−ビス（トリフルオロメチル）フェニル）プロパンアミド）を収率８０％で得た。ヨードベンゼン誘導体Ｆのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative F By using 3,5-di-trifluoromethylaniline in place of tert-butylamine in the synthesis method of iodobenzene derivative D, white solid iodobenzene derivative F, that is, (2R, 2'R ) -2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) bis (N- (3,5-bis (trifluoromethyl) phenyl) propanamide) was obtained in a yield of 80%. . The spectrum data of iodobenzene derivative F are as follows.
TLC,Rf=0.57(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.77(d,J=6.8Hz,6H),5.00(q,J=6.8Hz,2H),6.64(d,J=8.4Hz,2H),7.38(t,J=8.4Hz,2H),7.67(s,2H),8.17(s,4H),9.06(brs,2H);13C NMR(CDCl3,100MHz)δ18.1(2C),76.1(2C),80.9,107.6(2C),118.1(2C),119.5(4C),123.0(d,JC-F=271Hz,4C),131.1,132.3(q,JC-F=33Hz,4C),138.6(2C),156.5(2C),169.5(2C);19F NMR(CDCl3,376MHz)δ-62.8.TLC, R f = 0.57 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.77 (d, J = 6.8 Hz, 6H), 5.00 (q, J = 6.8 Hz, 2H) , 6.64 (d, J = 8.4Hz, 2H), 7.38 (t, J = 8.4Hz, 2H), 7.67 (s, 2H), 8.17 (s, 4H), 9.06 (brs, 2H); 13 C NMR ( CDCl 3 , 100MHz) δ18.1 (2C), 76.1 (2C), 80.9,107.6 (2C), 118.1 (2C), 119.5 (4C), 123.0 (d, J CF = 271Hz, 4C), 131.1,132.3 ( q, J CF = 33Hz, 4C ), 138.6 (2C), 156.5 (2C), 169.5 (2C); 19 F NMR (CDCl 3, 376MHz) δ-62.8.
・ヨードベンゼン誘導体Gの合成
ヨードベンゼン誘導体Dの合成方法のｔｅｒｔ−ブチルアミンの代わりに３，５−ジ−ｔｅｒｔ−ブチルアニリンを用いることにより、白色固体のヨードベンゼン誘導体Ｇすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−（３，５−ジ−ｔｅｒｔ−ブチルフェニル）プロパンアミド）を収率６２％で得た。ヨードベンゼン誘導体Ｇのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative G By using 3,5-di-tert-butylaniline instead of tert-butylamine in the synthesis method of iodobenzene derivative D, white solid iodobenzene derivative G, that is, (2R, 2′R ) -2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) bis (N- (3,5-di-tert-butylphenyl) propanamide) was obtained in a yield of 62%. The spectral data of iodobenzene derivative G is as follows.
TLC,Rf=0.64(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.34(s,36H),1.75(d,J=6.8Hz,6H),4.93(q,J=6.8Hz,2H),6.62(d,J=8.4Hz,2H),7.19(s,2H),7.33(t,J=8.4Hz,2H),7.51(s,4H),8.79(brs,2H);13C NMR(CDCl3,100MHz)δ18.3(2C),31.3(12C),34.9(4C),76.4(2C),80.7,107.2(2C),114.4(4C),118.9(2C),130.8,136.6(2C),151.8(4C),156.9(2C),168.8(2C).TLC, R f = 0.64 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.34 (s, 36 H), 1.75 (d, J = 6.8 Hz, 6H), 4.93 (q, J = 6.8Hz, 2H), 6.62 (d, J = 8.4Hz, 2H), 7.19 (s, 2H), 7.33 (t, J = 8.4Hz, 2H), 7.51 (s, 4H), 8.79 (brs, 2H); 13 C NMR (CDCl 3, 100MHz) δ18.3 (2C), 31.3 (12C), 34.9 (4C), 76.4 (2C), 80.7,107.2 (2C), 114.4 (4C), 118.9 (2C) , 130.8, 136.6 (2C), 151.8 (4C), 156.9 (2C), 168.8 (2C).
・ヨードベンゼン誘導体Ｈの合成
ヨードベンゼン誘導体Dの合成方法のｔｅｒｔ−ブチルアミンの代わりにメシチルアニリンを用いることにより、白色固体のヨードベンゼン誘導体Ｈすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−メシチルプロパンアミド）を収率７０％で得た。ヨードベンゼン誘導体Ｈのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative H By using mesitylaniline in place of tert-butylamine in the synthesis method of iodobenzene derivative D, iodobenzene derivative H of white solid, that is, (2R, 2′R) -2,2′- (2-Iodo-1,3-phenylene) bis (oxy) bis (N-mesitylpropanamide) was obtained with a yield of 70%. The spectral data of iodobenzene derivative H is as follows.
TLC,Rf=0.42(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.77(d,J=6.8Hz,6H),2.15(s,12H),2.26(s,6H),5.00(q,J=6.8Hz,2H),6.64(d,J=8.4Hz,2H),6.86(s,4H),7.34(t,J=8.4Hz,1H),8.02(s,2H);13C NMR(CDCl3,400MHz)δ18.2(4C),18.7(2C),20.8(2C),76.0(2C),80.4,107.0(2C),128.9(4C),130.0(2C),130.6,135.0(4C),137.1(2C),156.9(2C),169.6(2C).TLC, R f = 0.42 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.77 (d, J = 6.8 Hz, 6H), 2.15 (s, 12H), 2.26 (s, 6H), 5.00 (q, J = 6.8Hz, 2H), 6.64 (d, J = 8.4Hz, 2H), 6.86 (s, 4H), 7.34 (t, J = 8.4Hz, 1H), 8.02 (s, 2H); 13 C NMR (CDCl 3, 400MHz) δ18.2 (4C), 18.7 (2C), 20.8 (2C), 76.0 (2C), 80.4,107.0 (2C), 128.9 (4C), 130.0 (2C) , 130.6, 135.0 (4C), 137.1 (2C), 156.9 (2C), 169.6 (2C).
・ヨードベンゼン誘導体Ｉの合成
ヨードベンゼン誘導体Dの合成方法のｔｅｒｔ−ブチルアミンの代わりにピロリジンを用いることにより、白色固体のヨードベンゼン誘導体Ｉすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（１−（ピロリジン−１−イル）プロパン−１−オンを収率＞９９％で得た。ヨードベンゼン誘導体Ｉのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative I By using pyrrolidine instead of tert-butylamine in the synthesis method of iodobenzene derivative D, iodobenzene derivative I of white solid, that is, (2R, 2′R) -2,2 ′-(2 -Iodo-1,3-phenylene) bis (oxy) bis (1- (pyrrolidin-1-yl) propan-1-one was obtained in a yield> 99% The spectral data of iodobenzene derivative I are as follows: .
TLC,Rf=0.19(hexane-EtOAc-CHCl3=1:2:1);1H NMR(CDCl3,400MHz)δ1.55-1.92(m,8H),1.68(d,J=6.8Hz,6H),3.31(dt,J=6.8,11.2Hz,2H),3.42-3.53(m,4H),3.72(dt,J=6.8,11.2Hz,2H),4.83(q,J=6.8Hz,2H),6.46(d,J=8.0Hz,2H),7.16(t,J=8.0Hz,2H).TLC, R f = 0.19 (hexane-EtOAc-CHCl 3 = 1: 2: 1); 1 H NMR (CDCl 3 , 400 MHz) δ1.55-1.92 (m, 8H), 1.68 (d, J = 6.8 Hz, 6H), 3.31 (dt, J = 6.8,11.2Hz, 2H), 3.42-3.53 (m, 4H), 3.72 (dt, J = 6.8,11.2Hz, 2H), 4.83 (q, J = 6.8Hz, 2H ), 6.46 (d, J = 8.0Hz, 2H), 7.16 (t, J = 8.0Hz, 2H).
・ヨードベンゼン誘導体Ｊの合成
ヨードベンゼン誘導体Dの合成方法のｔｅｒｔ−ブチルアミンの代わりにジフェニルアミンを用いることにより、白色固体のヨードベンゼン誘導体Ｊすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ，Ｎ−ジフェニルプロパンアミド）を収率７２％で得た。ヨードベンゼン誘導体Ｊのスペクトルデータは以下の通り。Synthesis of iodobenzene derivative J By using diphenylamine instead of tert-butylamine in the synthesis method of iodobenzene derivative D, iodobenzene derivative J of white solid, ie, (2R, 2′R) -2,2 ′-(2 -Iodo-1,3-phenylene) bis (oxy) bis (N, N-diphenylpropanamide) was obtained in a yield of 72%. The spectrum data of iodobenzene derivative J are as follows.
TLC,Rf=0.37(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.62(d,J=6.4Hz,6H),4.88(q,J=6.4Hz,2H),6.40(d,J=8.4Hz,2H),7.11(t,J=8.4Hz,2H),7.20-7.32(m,20H);13C NMR(CDCl3,100MHz)δ18.1(2C),73.6(2C),83.0,108.8(2C),126.1(m,8C),130.0(m,13C),141.0(m,2C),142.0(m,2C),158.0(2C),170.5(2C).TLC, R f = 0.37 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.62 (d, J = 6.4 Hz, 6H), 4.88 (q, J = 6.4 Hz, 2H) , 6.40 (d, J = 8.4Hz, 2H), 7.11 (t, J = 8.4Hz, 2H), 7.20-7.32 (m, 20H); 13 C NMR (CDCl 3 , 100 MHz) δ18.1 (2C), 73.6 (2C), 83.0, 108.8 (2C), 126.1 (m, 8C), 130.0 (m, 13C), 141.0 (m, 2C), 142.0 (m, 2C), 158.0 (2C), 170.5 (2C).
・ヨードベンゼン誘導体Ｋの合成
ヨードベンゼン誘導体Ａの合成方法の２−ヨードレゾルシノールの代わりに２−ヨード−５−メチルベンゼン−１，３−ジオールを使用し、ヨードベンゼン誘導体Ｈの合成方法に準じて、ヨードベンゼン誘導体Ｋすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−５−メチル−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−メシチルプロパンアミド）を茶色の固体として得た。ヨードベンゼン誘導体Ｋのスペクトルデータを以下の通り。Synthesis of iodobenzene derivative K According to the method for synthesizing iodobenzene derivative H, 2-iodo-5-methylbenzene-1,3-diol was used instead of 2-iodoresorcinol in the synthesis method of iodobenzene derivative A. Iodobenzene derivative K, ie, (2R, 2′R) -2,2 ′-(2-iodo-5-methyl-1,3-phenylene) bis (oxy) bis (N-mesitylpropanamide) Obtained as a solid. The spectrum data of iodobenzene derivative K are as follows.
TLC,Rf=0.42(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.77(d,J=6.8Hz,6H),2.14(s,12H),2.26(s,6H),2.35(s,3H),4.99(q,J=6.8Hz,2H),6.48(s,2H),6.90(s,4H),7.97(s,2H);13C NMR(CDCl3,400MHz)δ18.2(4C),18.8(2C),20.9(2C),21.8,76.0(2C),76.2,108.1(2C),129.0(4C),130.0(2C),135.0(4C),137.2(2C),141.4,156.6(2C),169.7(2C).TLC, R f = 0.42 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.77 (d, J = 6.8 Hz, 6H), 2.14 (s, 12H), 2.26 (s, 6H), 2.35 (s, 3H), 4.99 (q, J = 6.8Hz, 2H), 6.48 (s, 2H), 6.90 (s, 4H), 7.97 (s, 2H); 13 C NMR (CDCl 3 , 400MHz) δ 18.2 (4C), 18.8 (2C), 20.9 (2C), 21.8, 76.0 (2C), 76.2, 108.1 (2C), 129.0 (4C), 130.0 (2C), 135.0 (4C), 137.2 ( 2C), 141.4, 156.6 (2C), 169.7 (2C).
・ヨードベンゼン誘導体Ｌの合成
ヨードベンゼン誘導体Ａの合成方法の２−ヨードレゾルシノールの代わりに５−フルオロ−２−ヨードベンゼン−１，３−ジオールを使用し、ヨードベンゼン誘導体Ｈの合成方法に準じて、ヨードベンゼン誘導体Ｌすなわち（２Ｒ，２’Ｒ）−２，２’−（５−フルオロ−２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−メシチルプロパンアミド）を茶色の固体として得た。ヨードベンゼン誘導体Ｌのスペクトルデータを以下の通り。Synthesis of iodobenzene derivative L According to the synthesis method of iodobenzene derivative H, 5-fluoro-2-iodobenzene-1,3-diol was used instead of 2-iodoresorcinol in the synthesis method of iodobenzene derivative A. Iodobenzene derivative L, ie (2R, 2′R) -2,2 ′-(5-fluoro-2-iodo-1,3-phenylene) bis (oxy) bis (N-mesitylpropanamide) Obtained as a solid. The spectrum data of iodobenzene derivative L are as follows.
TLC,Rf=0.07(hexane-EtOAc-CHCl3=1:2:1);1H NMR(CDCl3,400MHz)δ1.77(d,J=6.8Hz,6H),2.16(s,12H),2.27(s,6H),4.95(q,J=6.8Hz,2H),6.44(d,JH-F=10.1Hz,2H),6.91(s,4H),7.94(s,2H);19FNMR(CDCl3,376MHz)δ-107.8.TLC, R f = 0.07 (hexane-EtOAc-CHCl 3 = 1: 2: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.77 (d, J = 6.8 Hz, 6H), 2.16 (s, 12H) , 2.27 (s, 6H), 4.95 (q, J = 6.8Hz, 2H), 6.44 (d, J HF = 10.1Hz, 2H), 6.91 (s, 4H), 7.94 (s, 2H); 19 FNMR ( (CDCl 3 , 376 MHz) δ-107.8.
・ヨードベンゼン誘導体Ｍの合成
ヨードベンゼン誘導体Ａの合成方法の（−）−乳酸エチルエステルの代わりに（Ｓ）−メチル ２−ヒドロキシ−３−メチルブタノエートを使用し、ヨードベンゼン誘導体Ｈの合成方法に準じて、ヨードベンゼン誘導体Ｍすなわち（２Ｒ，２’Ｒ）−２，２’−（２−ヨード−１，３−フェニレン）ビス（オキシ）ビス（Ｎ−メシチル−３−メチルブタンアミド）を黄色の固体として得た。ヨードベンゼン誘導体Ｍのスペクトルデータを以下の通り。Synthesis of iodobenzene derivative M Synthesis of iodobenzene derivative H using (S) -methyl 2-hydroxy-3-methylbutanoate instead of (-)-lactic acid ethyl ester in the synthesis method of iodobenzene derivative A According to the method, iodobenzene derivative M, ie (2R, 2′R) -2,2 ′-(2-iodo-1,3-phenylene) bis (oxy) bis (N-mesityl-3-methylbutanamide) Was obtained as a yellow solid. The spectrum data of iodobenzene derivative M are as follows.
TLC,Rf=0.48(hexane-EtOAc=1:1);1H NMR(CDCl3,400MHz)δ1.19(d,J=7.2Hz,6H),1.31(d,J=7.2Hz,6H),2.05(s,12H),2.24(s,6H),2.45-2.52(m,2H),4.73(q,J=6.8Hz,2H),6.62(d,J=8.4Hz,2H),6.86(s,4H),7.28(t,J=8.4Hz,1H),7.62(s,2H);13C NMR(CDCl3,400MHz)δ17.6(2C),18.5(4C),19.1(2C),20.8(2C),31.7(2C),79.3,84.4(2C),106.5(2C),129.0(4C),130.0(2C),130.6,134.8(4C),137.1(2C),157.6(2C),168.4(2C).TLC, R f = 0.48 (hexane-EtOAc = 1: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 1.19 (d, J = 7.2 Hz, 6H), 1.31 (d, J = 7.2 Hz, 6H) , 2.05 (s, 12H), 2.44 (s, 6H), 2.45-2.52 (m, 2H), 4.73 (q, J = 6.8Hz, 2H), 6.62 (d, J = 8.4Hz, 2H), 6.86 ( s, 4H), 7.28 (t, J = 8.4Hz, 1H), 7.62 (s, 2H); 13 C NMR (CDCl 3 , 400 MHz) δ17.6 (2C), 18.5 (4C), 19.1 (2C), 20.8 (2C), 31.7 (2C), 79.3, 84.4 (2C), 106.5 (2C), 129.0 (4C), 130.0 (2C), 130.6, 134.8 (4C), 137.1 (2C), 157.6 (2C), 168.4 (2C).
［２］光学活性スピロラクトン化合物の合成
［２−１］反応基質の合成
・ナフトール系化合物Ｓ１の合成
反応基質としてナフトール系化合物Ｓ１すなわち３−（１−ヒドロキシナフタレン−２−イル）プロパン酸を文献（J.Org.Chem.,1982,vol.47,p946;Angew.Chem.Int.Ed.,2008,vol.47,p3787）にしたがって合成した（下記式参照）。まず、１−ナフトール（４．３３ｇ，３０．０ｍｍｏｌ）のトルエン（１００ｍｌ）溶液にトリエチル オルソアクリレート（６．０ｍｌ，４８．０ｍｍｏｌ）とピバル酸（１．５３ｇ，１５．０ｍｍｏｌ）を加え、２４時間加熱還流した。反応終了後、反応液を室温に冷やし、その反応液に１Ｎ ＮａＯＨ水溶液を加えて水層と有機層に分離した後、水層をＥｔ2Ｏで２回抽出し、有機層を塩水で洗った。それぞれの有機層を合わせて無水Ｎａ2ＳＯ4で乾燥させた後、溶媒をエバボレータ−で除いた。得られた混合物をシリカゲルカラムクロマトグラフィーによって精製して（展開溶媒：ヘキサン−ＥｔＯＡｃ＝１５：１（ｖ／ｖ））、ピラン系中間体を無色液体として得た（８．１７ｇ，３０．０ｍｍｏｌ，収率＞９９％）。次に、ピラン系中間体（８．１７ｇ，３０．０ｍｍｏｌ）のＥｔ2Ｏ（８０ｍｌ）溶液に２Ｎ ＨＣｌ（４０ｍｌ）を加えて室温で終夜撹拌した。反応終了後、水層をＥｔＯＡｃで２回抽出し、有機層を塩水で洗った。それぞれの有機層を合わせて無水Ｎａ2ＳＯ4で乾燥させた後、溶媒をエバボレータ−で除いた。得られた混合物をＴＨＦ（３０ｍＬ）とＭｅＯＨ（３０ｍｌ）の混合溶媒に溶かし、２Ｎ ＮａＯＨ水溶液（４０ｍＬ）を加え、２４時間室温で撹拌した。反応終了後、反応液を室温に冷やし、その反応液に１Ｎ ＨＣｌ水溶液（５．０ｍＬ）を加えて水層と有機層に分離した後、水層をＥｔＯＡｃで２回抽出し、有機層を水で洗った。それぞれの有機層を合わせて無水ＭｇＳＯ4で乾燥させた後、溶媒をエバボレータ−で除いた。得られた混合物をシリカゲルカラムクロマトグラフィーによって精製して（展開溶媒：ヘキサン−ＥｔＯＡｃ＝４：１ ｔｏ １：２（ｖ／ｖ））、目的とするナフトール系化合物Ｓ１を白色固体として得た（４．０５ｇ，１８．７ｍｍｏｌ，収率６２％)。ナフトール系化合物Ｓ１のスペクトルデータは以下の通り。[2] Synthesis of optically active spirolactone compound [2-1] Synthesis of reaction substrate / synthesis of naphthol compound S1 Naphthol compound S1, that is, 3- (1-hydroxynaphthalen-2-yl) propanoic acid is used as a reaction substrate (J. Org. Chem., 1982, vol. 47, p946; Angew. Chem. Int. Ed., 2008, vol. 47, p3787) (see the following formula). First, triethyl orthoacrylate (6.0 ml, 48.0 mmol) and pivalic acid (1.53 g, 15.0 mmol) were added to a toluene (100 ml) solution of 1-naphthol (4.33 g, 30.0 mmol) for 24 hours. Heated to reflux. After completion of the reaction, the reaction solution was cooled to room temperature, 1N NaOH aqueous solution was added to the reaction solution to separate into an aqueous layer and an organic layer, the aqueous layer was extracted twice with Et 2 O, and the organic layer was washed with brine. . The organic layers were combined and dried over anhydrous Na 2 SO 4 , and then the solvent was removed with an evaporator. The obtained mixture was purified by silica gel column chromatography (developing solvent: hexane-EtOAc = 15: 1 (v / v)) to obtain a pyran intermediate as a colorless liquid (8.17 g, 30.0 mmol, Yield> 99%). Next, 2N HCl (40 ml) was added to a solution of pyran-based intermediate (8.17 g, 30.0 mmol) in Et 2 O (80 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the aqueous layer was extracted twice with EtOAc, and the organic layer was washed with brine. The organic layers were combined and dried over anhydrous Na 2 SO 4 , and then the solvent was removed with an evaporator. The obtained mixture was dissolved in a mixed solvent of THF (30 mL) and MeOH (30 ml), 2N NaOH aqueous solution (40 mL) was added, and the mixture was stirred for 24 hours at room temperature. After completion of the reaction, the reaction solution was cooled to room temperature, 1N HCl aqueous solution (5.0 mL) was added to the reaction solution to separate it into an aqueous layer and an organic layer, the aqueous layer was extracted twice with EtOAc, and the organic layer was washed with water. Washed with. The organic layers were combined and dried over anhydrous MgSO 4 , and then the solvent was removed with an evaporator. The resulting mixture was purified by silica gel column chromatography (developing solvent: hexane-EtOAc = 4: 1 to 1: 2 (v / v)) to obtain the desired naphthol compound S1 as a white solid (4 .05 g, 18.7 mmol, 62% yield). The spectrum data of the naphthol compound S1 are as follows.
TLC,Rf=0.27(hexane-EtOAc-CHCl3=1:2:1 with a few drops of AcOH);1H NMR(CDCl3,400MHz)δ2.86-2.89(m,2H),3.02-3.06(m,2H),7.17(d,J=8.4Hz,1H),7.39(d,J=8.4Hz,1H),7.40-7.47(m,2H),7.60-7.70(brs,1H),7.73-7.76(m,1H),8.24-8.27(m,1H).TLC, R f = 0.27 (hexane-EtOAc-CHCl 3 = 1: 2: 1 with a few drops of AcOH); 1 H NMR (CDCl 3 , 400 MHz) δ2.86-2.89 (m, 2H), 3.02-3.06 (m, 2H), 7.17 (d, J = 8.4Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 7.40-7.47 (m, 2H), 7.60-7.70 (brs, 1H), 7.73- 7.76 (m, 1H), 8.24-8.27 (m, 1H).
・ナフトール系化合物Ｓ２の合成
上述したナフトール系化合物Ｓ１の合成方法の１−ナフトールの代わりに４−ブロモ−１−ナフトールを用いて、ナフトール系化合物Ｓ２すなわち３−（４−ブロモ−１−ヒドロキシナフタレン−２−イル）プロパン酸を白色固体として収率８８％で得た。ナフトール系化合物Ｓ２のスペクトルデータは以下の通り。Synthesis of naphthol compound S2 Using 4-bromo-1-naphthol instead of 1-naphthol in the synthesis method of naphthol compound S1 described above, naphthol compound S2, that is, 3- (4-bromo-1-hydroxynaphthalene) 2-yl) propanoic acid was obtained as a white solid in 88% yield. The spectrum data of the naphthol compound S2 are as follows.
TLC,Rf=0.27(hexane-EtOAc-CHCl3=1:2:1 with a few drops of AcOH);1H NMR(CDCl3,400MHz)δ2.87-2.90(m,2H),3.00-3.03(m,2H),7.48(s,1H),7.51(dt,J=7.2,1.2Hz,1H),7.56(dt,J=7.2,1.2Hz,1H),7.60-8.08(brs,1H),8.09(d,J=7.2Hz,1H),8.31(d,J=7.2Hz,1H).TLC, R f = 0.27 (hexane-EtOAc-CHCl 3 = 1: 2: 1 with a few drops of AcOH); 1 H NMR (CDCl 3 , 400 MHz) δ 2.87-2.90 (m, 2H), 3.00-3.03 (m, 2H), 7.48 (s, 1H), 7.51 (dt, J = 7.2,1.2Hz, 1H), 7.56 (dt, J = 7.2,1.2Hz, 1H), 7.60-8.08 (brs, 1H), 8.09 (d, J = 7.2Hz, 1H), 8.31 (d, J = 7.2Hz, 1H).
［２−２］光学活性スピロラクトン化合物の合成
・実施例１〜１２，比較例１〜４
表２の実施例１〜１２、比較例１〜４に示すように、ナフトール系化合物Ｓ１と各種のヨードベンゼン誘導体とｍ−ＣＰＢＡとを反応させることにより、スピロラクトン化合物Ｐ１を得た。具体的には、ナフトール系化合物Ｓ１（０．１ｍｍｏｌ）と表２に記載のヨードベンゼン誘導体（０．０１５ｍｍｏｌ，１５ｍｏｌ％）とを塩化メチレン５ｍＬ（Ｓ１の濃度＝０．２Ｍ）に溶かし、反応液を表２の反応温度に調整した後、ｍ−ＣＰＢＡ（０．１３ｍｍｏｌ，１．３ｅｑｕｉｖ）を加えた。反応はＴＬＣでモニタリングした。各例の反応時間は表２に示したとおりである。反応終了後、Ｎａ2Ｓ2Ｏ3飽和水溶液、そしてＮａＨＣＯ3飽和水溶液をゆっくり加えて反応をクエンチした。水層をクロロホルムで２回抽出し、それぞれの有機層を合わせて無水ＭｇＳＯ4で乾燥させた。溶媒をエバポレーターで除いた後、シリカゲルカラムクロマトグラフィー（展開溶媒：ヘキサン−ＥｔＯＡｃ＝１０：１から４：１（ｖ／ｖ））によって対応するスピロラクトン化合物を分離した。表２にそのときの収率及び鏡像体過剰率を示す。なお、スピロラクトン化合物Ｐ１のスペクトルデータは以下の通り。このスピロラクトン化合物Ｐ１の不斉中心炭素の立体配置がＲ，Ｓのいずれであるかは未決定である。[2-2] Synthesis of optically active spirolactone compound Examples 1 to 12 and Comparative Examples 1 to 4
As shown in Examples 1 to 12 and Comparative Examples 1 to 4 in Table 2, the spirolactone compound P1 was obtained by reacting the naphthol compound S1, various iodobenzene derivatives, and m-CPBA. Specifically, the naphthol compound S1 (0.1 mmol) and the iodobenzene derivative (0.015 mmol, 15 mol%) shown in Table 2 were dissolved in 5 mL of methylene chloride (S1 concentration = 0.2 M), and the reaction solution was obtained. Was adjusted to the reaction temperature in Table 2, and then m-CPBA (0.13 mmol, 1.3 equiv) was added. The reaction was monitored by TLC. The reaction time in each example is as shown in Table 2. After completion of the reaction, a saturated aqueous solution of Na 2 S 2 O 3 and a saturated aqueous solution of NaHCO 3 were slowly added to quench the reaction. The aqueous layer was extracted twice with chloroform, and the organic layers were combined and dried over anhydrous MgSO 4 . After removing the solvent with an evaporator, the corresponding spirolactone compound was separated by silica gel column chromatography (developing solvent: hexane-EtOAc = 10: 1 to 4: 1 (v / v)). Table 2 shows the yield and enantiomeric excess. The spectral data of the spirolactone compound P1 is as follows. It is not yet determined whether the configuration of the asymmetric central carbon of the spirolactone compound P1 is R or S.
TLC,Rf=0.46(hexane-EtOAc-CHCl3=1:2:1);1H NMR(CDCl3,400MHz)δ2.18(ddd,J=20.8,13.6,11.2Hz,1H),2.49(ddd,J=13.6,9.6,1.6Hz,1H),2.60(ddd,J=17.6,9.6,1.6Hz,1H),2.92(ddd,J=20.8,17.6,11.2Hz,1H),6.21(d,J=10.4Hz,1H),6.66(d,J=10.4Hz,1H),7.26(d,J=8.0Hz,1H),7.41(t,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),8.02(d,J=8.0Hz,1H);HPLC(OD-H column),Hexane-i-PrOH=85:15 as eluent,1.0mL/min,tR1=17.8min,tR2=22.7min.TLC, R f = 0.46 (hexane-EtOAc-CHCl 3 = 1: 2: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 2.18 (ddd, J = 20.8, 13.6, 11.2 Hz, 1H), 2.49 ( ddd, J = 13.6,9.6,1.6Hz, 1H), 2.60 (ddd, J = 17.6,9.6,1.6Hz, 1H), 2.92 (ddd, J = 20.8,17.6,11.2Hz, 1H), 6.21 (d, J = 10.4Hz, 1H), 6.66 (d, J = 10.4Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 7.41 (t, J = 8.0Hz, 1H), 7.62 (t, J = 8.0Hz, 1H), 8.02 (d, J = 8.0Hz, 1H); HPLC (OD-H column), Hexane-i-PrOH = 85: 15 as eluent, 1.0mL / min, t R1 = 17.8min, t R2 = 22.7min.
表２に示すように、比較例１，２のようにヨードベンゼンのオルト位に結合した置換基の末端がエステルやカルボン酸の場合には、鏡像体過剰率が低かったが、実施例１〜１３のようにその置換基の末端がアミドの場合には、鏡像体過剰率が高かった。特に、実施例１〜８のうち置換基の末端がＮ−メシチルアミドである実施例６のとき、収率及び鏡像体過剰率において非常に良い結果を与えた。また、実施例６のヨードベンゼンに電子供与基（実施例９，１０）や電子吸引基（実施例１１）を付けたところ、いずれも反応活性は低下したが、鏡像体過剰率においては大きな差がなかった。実施例６の乳酸部位のメチルをイソプロピルに変えたところ（実施例１２）、収率及び鏡像体過剰率とも大きな差は見られなかった。更に、比較例３，４のようにＣ2対称性を持たないヨードベンゼン誘導体を触媒前駆体に用いたところ、鏡像体過剰率が大きく低下した。このことから、ヨードベンゼン誘導体はＣ2対称性を持つことが必要であることがわかった。なお、比較例３のヨードベンゼン誘導体は藤田らの文献（Tetrahedron Letters,2007,vol.48,p691）に開示されているものである。As shown in Table 2, when the terminal of the substituent bonded to the ortho position of iodobenzene was an ester or carboxylic acid as in Comparative Examples 1 and 2, the enantiomeric excess was low. When the terminal of the substituent was amide as in 13, the enantiomeric excess was high. In particular, Example 6 in which the terminal of the substituent is N-mesitylamide among Examples 1 to 8 gave very good results in yield and enantiomeric excess. Further, when an electron donating group (Examples 9 and 10) or an electron withdrawing group (Example 11) was added to the iodobenzene of Example 6, the reaction activity decreased in all cases, but there was a large difference in the enantiomeric excess. There was no. When the methyl at the lactic acid site in Example 6 was changed to isopropyl (Example 12), there was no significant difference in yield and enantiomeric excess. Furthermore, when an iodobenzene derivative having no C 2 symmetry as in Comparative Examples 3 and 4 was used as the catalyst precursor, the enantiomeric excess was greatly reduced. From this, it was found that the iodobenzene derivative needs to have C 2 symmetry. The iodobenzene derivative of Comparative Example 3 is disclosed in Fujita et al. (Tetrahedron Letters, 2007, vol. 48, p691).
・実施例１３〜１７
下記の表３の実施例１３〜１７では、実施例６の反応条件（反応基質濃度、温度、時間）を種々変更して、ナフトール系化合物Ｓ１からスピロラクトン化合物Ｐ１を得た。反応基質濃度を０．０２Ｍに設定した場合（実施例１３，１４）、実施例６に比べて反応性はわずかに低下したものの、鏡像体過剰率はむしろ向上した。この場合、反応時間を長くすることにより収率が改善された。また、反応基質濃度を０．０２Ｍに設定し反応温度を室温に上げた場合（実施例１５）、実施例６に比べて鏡像体過剰率は維持されたまま収率がやや改善され、反応温度を−２０℃に下げた場合（実施例１６）、実施例６に比べて反応時間を長くすることにより収率及び鏡像体過剰率とも改善された。また、反応基質濃度を０．０５Ｍ、反応温度を−２０℃に設定した場合も（実施例１７）、実施例６に比べて反応時間を長くすることにより収率及び鏡像体過剰率とも改善された。-Examples 13-17
In Examples 13 to 17 in Table 3 below, spirolactone compound P1 was obtained from naphthol compound S1 by variously changing the reaction conditions (reaction substrate concentration, temperature, time) of Example 6. When the reaction substrate concentration was set to 0.02 M (Examples 13 and 14), the reactivity was slightly decreased as compared with Example 6, but the enantiomeric excess was rather improved. In this case, the yield was improved by increasing the reaction time. Further, when the reaction substrate concentration was set to 0.02 M and the reaction temperature was raised to room temperature (Example 15), the yield was slightly improved while maintaining the enantiomeric excess as compared with Example 6, and the reaction temperature When the temperature was lowered to −20 ° C. (Example 16), the yield and the enantiomeric excess were improved by increasing the reaction time compared to Example 6. In addition, when the reaction substrate concentration was set to 0.05 M and the reaction temperature was set to −20 ° C. (Example 17), the yield and the enantiomeric excess were improved by increasing the reaction time compared to Example 6. It was.
・実施例１８〜２５
下記の表４の実施例１８〜２５では、実施例１３の反応条件において反応溶媒のみを変更して、スピロラクトン化合物Ｐ１を得た。実施例１８〜２２のようにクロロホルム、四塩化炭素、トルエン、アセトニトリル、酢酸エチルを反応溶媒として用いた場合には、塩化メチレンを反応溶媒として用いた実施例１３に比べて収率が低下したものの、鏡像体過剰率は遜色ない結果が得られた（７７−９０％ｅｅ）。実施例２３のようにフルオラス溶媒である２，２，２−トリフルオロエタノールを用いた場合には収率及び鏡像体過剰率とも良好であった。実施例２４のようにニトロメタンを反応溶媒として用いた場合には、反応の活性が最も高く、しかも鏡像体過剰率も非常に高い値となった。また、実施例２５のようにクロロホルムとニトロメタンとの混合溶媒を用いた場合にも、非常に良好な結果が得られた。なお、特許文献１や非特許文献１のようにキラルスピロビインダン骨格を持つ超原子価ヨウ素化合物を触媒前駆体に用いた場合、クロロホルム、四塩化炭素、塩化メチレンのような非極性溶媒中では良好な鏡像体過剰率が得られるものの、アセトニトリルなどの極性溶媒中では鏡像体過剰率が大幅に低下している（２０−０％ｅｅ）。これに対して、本発明のヨードベンゼン誘導体を触媒前駆体に用いた場合には、非極性溶媒でも極性溶媒でも高い鏡像体過剰率が得られる。Examples 18-25
In Examples 18 to 25 in Table 4 below, only the reaction solvent was changed under the reaction conditions of Example 13 to obtain spirolactone compound P1. When chloroform, carbon tetrachloride, toluene, acetonitrile, or ethyl acetate was used as the reaction solvent as in Examples 18 to 22, the yield decreased compared to Example 13 using methylene chloride as the reaction solvent. The enantiomeric excess was inferior (77-90% ee). When 2,2,2-trifluoroethanol, which is a fluorous solvent as in Example 23, was used, both the yield and the enantiomeric excess were good. When nitromethane was used as a reaction solvent as in Example 24, the reaction activity was the highest, and the enantiomeric excess was very high. In addition, when a mixed solvent of chloroform and nitromethane was used as in Example 25, very good results were obtained. When a hypervalent iodine compound having a chiral spirobiindane skeleton is used as a catalyst precursor as in Patent Document 1 and Non-Patent Document 1, in a nonpolar solvent such as chloroform, carbon tetrachloride, and methylene chloride Although a good enantiomeric excess is obtained, the enantiomeric excess is greatly reduced in a polar solvent such as acetonitrile (20-0% ee). On the other hand, when the iodobenzene derivative of the present invention is used as a catalyst precursor, a high enantiomeric excess can be obtained with either a nonpolar solvent or a polar solvent.
・実施例２６
上述した実施例では、ナフトール系化合物Ｓ１を出発原料として用いたが、実施例２６では、下記反応式に示すように、ナフトール系化合物Ｓ２すなわち３−（１−ヒドロキシ−５−ブロモナフタレン−２−イル）プロパン酸）を出発原料として、クロロホルムとニトロメタンとを２：１（ｖ／ｖ）で混合した溶媒中、触媒前駆体としてヨードベンゼン誘導体Ｈを用いて０℃で７時間反応させた。そうしたところ、対応するスピロラクトン化合物Ｐ２を白色固体として収率８０％、鏡像体過剰率８２％で得た。スピロラクトン化合物Ｐ２のスペクトルデータは以下の通り。Example 26
In the examples described above, naphthol compound S1 was used as a starting material. In Example 26, as shown in the following reaction formula, naphthol compound S2, that is, 3- (1-hydroxy-5-bromonaphthalene-2- The reaction was carried out at 0 ° C. for 7 hours using iodobenzene derivative H as a catalyst precursor in a solvent in which chloroform and nitromethane were mixed at a ratio of 2: 1 (v / v) starting from yl) propanoic acid). As a result, the corresponding spirolactone compound P2 was obtained as a white solid in a yield of 80% and an enantiomeric excess of 82%. Spectral data of spirolactone compound P2 is as follows.
TLC,Rf=0.51(hexane-EtOAc-CHCl3=1:2:1);1H NMR(CDCl3,400MHz)δ2.24(ddd,J=21.2,13.2,11.6Hz,1H),2.46(ddd,J=13.2,9.6,2.4Hz,1H),2.62(ddd,J=17.6,9.6,2.4Hz,1H),2.90(ddd,J=21.2,17.6,11.6Hz,1H),6.67(s,1H),7.49-7.53(m,1H),7.73-7.78(m,2H),8.05(d,J=7.2Hz,1H);HPLC(OD-H column),Hexane-i-PrOH=85:15 as eluent,1.0mL/min,tR1=18.4min,tR2=23.4min.TLC, R f = 0.51 (hexane-EtOAc-CHCl 3 = 1: 2: 1); 1 H NMR (CDCl 3 , 400 MHz) δ 2.24 (ddd, J = 21.2, 13.2, 11.6 Hz, 1H), 2.46 ( ddd, J = 13.2,9.6,2.4Hz, 1H), 2.62 (ddd, J = 17.6,9.6,2.4Hz, 1H), 2.90 (ddd, J = 21.2,17.6,11.6Hz, 1H), 6.67 (s, 1H), 7.49-7.53 (m, 1H), 7.73-7.78 (m, 2H), 8.05 (d, J = 7.2Hz, 1H); HPLC (OD-H column), Hexane-i-PrOH = 85: 15 as eluent, 1.0mL / min, t R1 = 18.4min, t R2 = 23.4min.
［２−３］反応機構
特許文献１（又は非特許文献１）に記載された方法にしたがって、触媒前駆体Ｈから三価の超原子価ヨウ素化合物（触媒Ｈ’）を調製した（下記式参照）。具体的には、触媒前駆体Ｈと酢酸とアセトニトリルとの混合物に、触媒前駆体Ｈの５倍モルのセレクトフルオール（Selectfluor，登録商標）を加えて、室温で攪拌して反応させ、目的とする触媒Ｈ’を得た。この触媒Ｈ’は、ヨウ素原子にＬ1，Ｌ2が結合しているが、これらは両方ともＯＡｃ、両方ともＦ、あるいは片方はＯＡｃでもう片方はＦのいずれかである。実施例６の触媒前駆体Ｈとｍ−ＣＰＢＡの代わりに、この触媒Ｈ’を化学量論量用いて反応を行ったところ、ナフトール系化合物Ｓ１からスピロラクトン化合物Ｐ１を収率７０％、鏡像体過剰率８５％ｅｅで得た。[2-3] Reaction mechanism A trivalent hypervalent iodine compound (catalyst H ′) was prepared from the catalyst precursor H according to the method described in Patent Document 1 (or Non-Patent Document 1) (see the following formula) ). Specifically, to a mixture of catalyst precursor H, acetic acid and acetonitrile, 5 times the mole of catalyst precursor H, Selectfluor (registered trademark), is added and stirred at room temperature for reaction. Catalyst H ′ was obtained. In this catalyst H ′, L 1 and L 2 are bonded to iodine atoms, both of which are OAc, both F, or one OOA and the other F. When a reaction was carried out using a stoichiometric amount of this catalyst H ′ instead of the catalyst precursor H and m-CPBA of Example 6, the yield of the spirolactone compound P1 from the naphthol compound S1 was 70%, and the enantiomer. Obtained with an excess of 85% ee.
この結果から、上述した各実施例のスピロ化合物Ｐ１の合成反応では、触媒前駆体がｍ−ＣＰＢＡによって系内で酸化されて三価の超原子価ヨウ素化合物である触媒が生成し、その触媒がナフトール系化合物Ｓ１を酸化すると同時に脱芳香化させて対応するスピロラクトン化合物に変換すると共に、自らは還元されて再び触媒前駆体つまりヨードベンゼン誘導体に戻ることが示唆される（下記式参照）。 From this result, in the synthesis reaction of the spiro compound P1 of each example described above, the catalyst precursor is oxidized in the system by m-CPBA to produce a catalyst that is a trivalent hypervalent iodine compound, and the catalyst is It is suggested that the naphthol-based compound S1 is oxidized and dearomatized at the same time to be converted into the corresponding spirolactone compound, and is itself reduced to return to the catalyst precursor, that is, the iodobenzene derivative again (see the following formula).
本出願は、2009年10月26日に出願した日本国特許出願第2009-245275号を優先権主張の基礎としており、引用によりその内容の全てが本明細書中に含まれる。
This application is based on Japanese Patent Application No. 2009-245275 filed on Oct. 26, 2009, the contents of which are incorporated herein by reference in their entirety.
本発明は、主に薬品化学産業に利用可能であり、例えば光学活性スピロラクトン骨格を有する天然物や医薬品、農薬、化粧品などを製造する際に利用することができる。 The present invention can be used mainly in the pharmaceutical and chemical industries, and can be used, for example, when producing natural products, pharmaceuticals, agricultural chemicals, cosmetics and the like having an optically active spirolactone skeleton.
Claims (7)
請求項１に記載のヨードベンゼン誘導体。In Formula (1), R 1 is a hydrogen atom and R 2 is an aryl group.
The iodobenzene derivative according to claim 1.
請求項１又は２に記載のヨードベンゼン誘導体。In Formula (1), R 3 is a methyl group.
The iodobenzene derivative according to claim 1 or 2.
請求項１〜３のいずれか１項に記載のヨードベンゼン誘導体。In the formula (1), Z is selected from the group consisting of a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an alkyl group, an alkoxy group, a nitro group, and a cyano group.
The iodobenzene derivative according to any one of claims 1 to 3.
光学活性スピロラクトン化合物の製法。5. The phenol derivative in which — (CH 2 ) n COOH (n is 2 or 3) is bonded to the carbon adjacent to the carbon to which the OH group is bonded, and an iodobenzene derivative. 5. The OH group of the phenol derivative is converted into an oxo group (= O) by mixing and reacting the iodobenzene derivative and a percarboxylic acid that can be converted into a hypervalent iodine compound by oxidizing the iodobenzene derivative. To obtain an optically active spirolactone compound having a lactone ring spiro-bonded and dearomatized.
A process for producing optically active spirolactone compounds.
請求項５に記載の光学活性スピロラクトン化合物の製法。The phenol derivative is a naphthol compound in which an OH group is bonded to the 1-position and-(CH 2 ) n COOH (n is 2 or 3) is bonded to the 2-position.
A process for producing the optically active spirolactone compound according to claim 5.
請求項５又は６に記載の光学活性スピロラクトン化合物の製法。When the phenol derivative, the iodobenzene derivative and the percarboxylic acid are mixed and reacted, a halogenated alkane, a nitroalkane or a mixture thereof is used as a reaction solvent.
The manufacturing method of the optically active spirolactone compound of Claim 5 or 6.
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