JP4618297B2 - Cyclic erythritol phosphate derivative and asymmetric synthesis method using the same - Google Patents
Cyclic erythritol phosphate derivative and asymmetric synthesis method using the same Download PDFInfo
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- JP4618297B2 JP4618297B2 JP2007505801A JP2007505801A JP4618297B2 JP 4618297 B2 JP4618297 B2 JP 4618297B2 JP 2007505801 A JP2007505801 A JP 2007505801A JP 2007505801 A JP2007505801 A JP 2007505801A JP 4618297 B2 JP4618297 B2 JP 4618297B2
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- -1 Cyclic erythritol phosphate derivative Chemical class 0.000 title claims description 104
- 238000011914 asymmetric synthesis Methods 0.000 title claims description 13
- 238000000034 method Methods 0.000 title claims description 12
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 title 1
- 239000004386 Erythritol Substances 0.000 title 1
- 229940009714 erythritol Drugs 0.000 title 1
- 235000019414 erythritol Nutrition 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 112
- 125000004432 carbon atom Chemical group C* 0.000 claims description 49
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 239000003054 catalyst Substances 0.000 claims description 35
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 150000002466 imines Chemical class 0.000 claims description 12
- 150000002085 enols Chemical class 0.000 claims description 7
- 238000006683 Mannich reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 description 90
- 230000015572 biosynthetic process Effects 0.000 description 85
- 238000006243 chemical reaction Methods 0.000 description 75
- 229910019142 PO4 Inorganic materials 0.000 description 50
- 239000010452 phosphate Substances 0.000 description 50
- 238000005160 1H NMR spectroscopy Methods 0.000 description 41
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000004809 thin layer chromatography Methods 0.000 description 15
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 14
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 13
- 239000002904 solvent Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 11
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 7
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000002597 Solanum melongena Nutrition 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000007281 aminoalkylation reaction Methods 0.000 description 6
- 150000001491 aromatic compounds Chemical class 0.000 description 6
- 238000006208 aza-Diels-Alder reaction Methods 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- GAAZWOUQHHMHAV-UHFFFAOYSA-N FC=1C=C(C=CC1)C1OC(C(O1)CO)CO Chemical compound FC=1C=C(C=CC1)C1OC(C(O1)CO)CO GAAZWOUQHHMHAV-UHFFFAOYSA-N 0.000 description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 229960001367 tartaric acid Drugs 0.000 description 5
- 239000011975 tartaric acid Substances 0.000 description 5
- 235000002906 tartaric acid Nutrition 0.000 description 5
- 150000003899 tartaric acid esters Chemical class 0.000 description 5
- QMGHHBHPDDAGGO-IIWOMYBWSA-N (2S,4R)-1-[(2S)-2-[[2-[3-[4-[3-[4-[[5-bromo-4-[3-[cyclobutanecarbonyl(methyl)amino]propylamino]pyrimidin-2-yl]amino]phenoxy]propoxy]butoxy]propoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide Chemical compound CN(CCCNC1=NC(NC2=CC=C(OCCCOCCCCOCCCOCC(=O)N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)NCC3=CC=C(C=C3)C3=C(C)N=CS3)C(C)(C)C)C=C2)=NC=C1Br)C(=O)C1CCC1 QMGHHBHPDDAGGO-IIWOMYBWSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000001309 chloro group Chemical group Cl* 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 125000006575 electron-withdrawing group Chemical group 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- NIXOIRLDFIPNLJ-UHFFFAOYSA-M magnesium;benzene;bromide Chemical compound [Mg+2].[Br-].C1=CC=[C-]C=C1 NIXOIRLDFIPNLJ-UHFFFAOYSA-M 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 3
- MNIPVWXWSPXERA-IDNZQHFXSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecanoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)CCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 MNIPVWXWSPXERA-IDNZQHFXSA-N 0.000 description 3
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 3
- ZMXYNJXDULEQCK-UHFFFAOYSA-N 2-amino-p-cresol Chemical compound CC1=CC=C(O)C(N)=C1 ZMXYNJXDULEQCK-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 229940126650 Compound 3f Drugs 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125796 compound 3d Drugs 0.000 description 3
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002009 diols Chemical class 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000005927 hydrophosphonylation reaction Methods 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
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- ALQIJXZCLUTTIY-UHFFFAOYSA-N 1-(2-methylphenyl)butan-1-one Chemical compound CCCC(=O)C1=CC=CC=C1C ALQIJXZCLUTTIY-UHFFFAOYSA-N 0.000 description 2
- LTVRSJBNXLZFGT-UHFFFAOYSA-N 2-silylethenone Chemical compound [SiH3]C=C=O LTVRSJBNXLZFGT-UHFFFAOYSA-N 0.000 description 2
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- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 2
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- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 2
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 2
- ISDBWOPVZKNQDW-UHFFFAOYSA-N 4-phenylbenzaldehyde Chemical compound C1=CC(C=O)=CC=C1C1=CC=CC=C1 ISDBWOPVZKNQDW-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 238000006366 phosphorylation reaction Methods 0.000 description 1
- PJGSXYOJTGTZAV-UHFFFAOYSA-N pinacolone Chemical compound CC(=O)C(C)(C)C PJGSXYOJTGTZAV-UHFFFAOYSA-N 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical class [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000001308 synthesis method 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940029273 trichloroacetaldehyde Drugs 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XKGLSKVNOSHTAD-UHFFFAOYSA-N valerophenone Chemical compound CCCCC(=O)C1=CC=CC=C1 XKGLSKVNOSHTAD-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
- B01J31/0255—Phosphorus containing compounds
- B01J31/0257—Phosphorus acids or phosphorus acid esters
- B01J31/0258—Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65744—Esters of oxyacids of phosphorus condensed with carbocyclic or heterocyclic rings or ring systems
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- General Health & Medical Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、新規環状リン酸化合物に関するものであり、当該環状リン酸化合物を触媒として用いる不斉合成法に関するものである。 The present invention relates to a novel cyclic phosphate compound, and to an asymmetric synthesis method using the cyclic phosphate compound as a catalyst.
キラルなビナフトール−リン酸誘導体の金属塩によりディールス−アルダー環化反応が知られている（例えば、特許文献１参照）。また、キラルな尿素誘導体を用いて不斉マンニッヒ型反応を行いキラルな化合物の合成を行っている（例えば、非特許文献１参照）。
酒石酸から誘導したキラルなジオール化合物を用いたヘテロディールスアルダー反応が報告されている（非特許文献２参照）。Diels-Alder cyclization reaction is known with a metal salt of a chiral binaphthol-phosphate derivative (see, for example, Patent Document 1). In addition, chiral compounds are synthesized by asymmetric Mannich-type reactions using chiral urea derivatives (see, for example, Non-Patent Document 1).
Heterodiels Alder reaction using a chiral diol compound derived from tartaric acid has been reported (see Non-Patent Document 2).
キラルなビナフトールリン酸誘導体を触媒として、ケテンシリルアセタールとイミンとを用いてβ−アミノエステルの合成が報告されている（非特許文献３）。 Synthesis of β-aminoesters using ketene silyl acetals and imines using a chiral binaphthol phosphate derivative as a catalyst has been reported (Non-patent Document 3).
新規環状リン酸化合物を提供することであり、当該環状リン酸化合物を触媒として用いる不斉合成法を提供することである。 It is to provide a novel cyclic phosphate compound, and to provide an asymmetric synthesis method using the cyclic phosphate compound as a catalyst.
上記の課題を解決するため本発明者は、種々の検討を行った結果、酒石酸から合成することにより、下記式（１）で表される新規な環状リン酸化合物を得られることを見出し、本発明を完成させたのである。また当該環状リン酸化合物が不斉合成の触媒として用いることが出来ることも見出し、本発明を完成させたのである。 As a result of various studies, the present inventor has found that a novel cyclic phosphate compound represented by the following formula (1) can be obtained by synthesis from tartaric acid. The invention was completed. The present inventors have also found that the cyclic phosphate compound can be used as a catalyst for asymmetric synthesis, and have completed the present invention.
式（１）において、Ｒ1およびＲ2は各々独立していてもよい水素原子、炭素数１〜６の分岐があっても良いアルキル基または置換基を有していても良いアリール基を示し、Ｒ3、Ｒ4、Ｒ5、およびＲ6は各々独立していてもよい置換基を有していても良いアリール基である。In Formula (1), R 1 and R 2 each independently represent a hydrogen atom, an alkyl group that may have 1 to 6 carbon atoms, or an aryl group that may have a substituent. , R 3 , R 4 , R 5 , and R 6 are each an optionally substituted aryl group.
本発明の一つの側面は、上記式（１）で表される化合物を触媒として用いる不斉合成方法である。
本発明の一つの側面は、上記式（１）で表される化合物を触媒として用いてイミン誘導体とエノール誘導体とからキラルなアミノ化合物を得る製造方法である。
本発明の一つの側面は、上記式（１）で表される化合物を触媒として用いる不斉マンニッヒ型反応である。
以下、本発明を詳細に説明する。
One aspect of the present invention is an asymmetric synthesis method using the compound represented by the above formula (1) as a catalyst.
One aspect of the present invention is a method for producing a chiral amino compound from an imine derivative and an enol derivative using the compound represented by the above formula (1) as a catalyst.
One aspect of the present invention is an asymmetric Mannich reaction using the compound represented by the above formula (1) as a catalyst.
Hereinafter, the present invention will be described in detail.
本発明の上記式（１）で表される環状リン酸化合物は、光学不斉を有するものを酒石酸から容易に合成することができる。また、当該環状リン酸化合物を不斉合成用の触媒として用いることにより、不斉部位を有する化合物を金属ルイス酸触媒を用いることなく合成することができる。 The cyclic phosphate compound represented by the above formula (1) of the present invention can be easily synthesized from tartaric acid having optical asymmetry. Further, by using the cyclic phosphate compound as a catalyst for asymmetric synthesis, a compound having an asymmetric moiety can be synthesized without using a metal Lewis acid catalyst.
本発明の式（1）で表される環状リン酸化合物は、Ｌ−酒石酸またはＤ−酒石酸等から容易に合成することができる。
下記スキーム１のように酒石酸のエステル体（化合物Ａ系）から本発明の環状リン酸化合物（化合物Ｅ系）を合成した。即ち、酒石酸のエステル体（化合物Ａ系）のジオールをパラホルムアルデヒド、アセトアルデヒド、ジメチルアセタールや３−ペンタノン等によりアセタール誘導体またはケタール誘導体（化合物Ｂ系、Ｒは水素原子炭素数１〜６の分岐を有していても良いアルキル基またはアリール基）を合成する。これをグリニヤール反応等によりアリール基を導入（化合物Ｃ系）し、ＰＣｌ3でリンを導入（化合物Ｄ系）した後、酸化して本発明の環状リン酸化合物（化合物Ｅ系）を合成した。The cyclic phosphate compound represented by the formula (1) of the present invention can be easily synthesized from L-tartaric acid or D-tartaric acid.
The cyclic phosphate compound (compound E system) of the present invention was synthesized from an ester of tartaric acid (compound A system) as shown in Scheme 1 below. That is, tartaric acid ester (compound A series) diol is acetal derivative or ketal derivative (compound B series, R is branched from 1 to 6 hydrogen atoms) by paraformaldehyde, acetaldehyde, dimethylacetal, 3-pentanone, etc. An alkyl group or an aryl group, which may be This was introduced with an aryl group by a Grignard reaction (compound C system), phosphorus was introduced with PCl 3 (compound D system), and then oxidized to synthesize a cyclic phosphate compound (compound E system) of the present invention.
○アセタール誘導体またはケタール誘導体の合成について
ジオール体の保護基として用いられているアセタール誘導体またはケタール誘導体を本発明の環状リン酸化合物の合成に用いることができる。例えば、酒石酸のエステル体（化合物Ａ系）のジオールをパラホルムアルデヒド、ジメトキシメタン、アセトアルデヒド、ジメトキシエタン、ジエトキシエタン、ジメチルアセタール、トリクロロアセトアルデヒド、３−ペンタノン、ジメトキシシクロヘキサン、フェニルアルデヒド、メトキシフェニルアルデヒド等により化合物Ｂ系（アセタール誘導体またはケタール誘導体）を合成することができる。O Synthesis of Acetal Derivative or Ketal Derivative An acetal derivative or ketal derivative used as a protecting group for a diol can be used for the synthesis of the cyclic phosphate compound of the present invention. For example, tartaric acid ester (compound A series) diol can be obtained by paraformaldehyde, dimethoxymethane, acetaldehyde, dimethoxyethane, diethoxyethane, dimethylacetal, trichloroacetaldehyde, 3-pentanone, dimethoxycyclohexane, phenylaldehyde, methoxyphenylaldehyde, etc. A compound B system (acetal derivative or ketal derivative) can be synthesized.
式（１）において、Ｒ1およびＲ2の炭素数１〜６の分岐があっても良いアルキル基とは、メチル基、エチル基、トリクロロメチル基等が例示できる。また、式（１）において、Ｒ1およびＲ2の置換基を有していても良いアリール基とは、フェニル基、ｐ−メトキシフェニル基、ジ−メトキシフェニル基、ナフチル基等が例示できる。In formula (1), examples of the alkyl group that may have 1 to 6 carbon atoms of R 1 and R 2 include a methyl group, an ethyl group, and a trichloromethyl group. In the formula (1), examples of the aryl group optionally having substituents R 1 and R 2 include a phenyl group, a p-methoxyphenyl group, a di-methoxyphenyl group, and a naphthyl group.
○アリール化について
化合物Ｂ系をグリニヤール反応によりアリール基（スキーム１ではＡｒと表示してあり、式（１）ではＲ3〜Ｒ6である。）を導入して、化合物Ｃ系を合成する。このグリニヤール反応は、一般的な条件のものを用いることができる。About Arylation Compound B system is synthesized by introducing an aryl group (labeled Ar in Scheme 1 and R 3 to R 6 in Formula (1)) by Grignard reaction. For this Grignard reaction, those having general conditions can be used.
式（１）において、Ｒ3〜Ｒ6としては、各々独立していてもよい置換基を有していても良いアリール基であり、具体的には置換基を有していても良いフェニル基、ナフチル基およびビフェニル基等が例示できる。これらアリール基に結合していてもよい置換基としては、フェニル基、ニトロ基、ハロゲン原子、モノハロゲノメチル基、ジハロゲノメチル基、トリハロゲノメチル基、ニトリル基、ホルミル基、−ＣＯＡ1（Ａ1は炭素数１〜６の分岐があっても良いアルキル基を示し）、−ＣＯＯＡ2（Ａ2は炭素数１〜６の分岐があっても良いアルキル基を示し）、炭素数１〜１０の分岐があってもよいアルキル基、炭素数２〜１０の分岐があってもよいアルケニル基、および炭素数１〜２０の分岐があってもよいアルコキシル基、炭素数２〜２０の分岐があってもよいアシル基等が例示できる。アリール基に結合する置換基の数としては４個以下である。In the formula (1), R 3 to R 6 are each an aryl group which may have a substituent which may be independent, specifically, a phenyl group which may have a substituent. And a naphthyl group and a biphenyl group. Examples of the substituent which may be bonded to these aryl groups include phenyl group, nitro group, halogen atom, monohalogenomethyl group, dihalogenomethyl group, trihalogenomethyl group, nitrile group, formyl group, —COA 1 (A 1 represents an alkyl group which may have 1 to 6 carbon atoms), —COOA 2 (A 2 represents an alkyl group which may have 1 to 6 carbon atoms), 1 to 10 carbon atoms There may be an alkyl group that may be branched, an alkenyl group that may be branched from 2 to 10 carbon atoms, an alkoxyl group that may be branched from 1 to 20 carbon atoms, and a branch from 2 to 20 carbon atoms. The acyl group etc. which may be sufficient can be illustrated. The number of substituents bonded to the aryl group is 4 or less.
ハロゲン原子としては、フッ素原子または塩素原子が好ましい。モノハロゲノメチル基のハロゲン原子としては、フッ素原子または塩素原子が好ましい。ジハロゲノメチル基のハロゲン原子としては、フッ素原子または塩素原子が好ましい。トリハロゲノメチル基のハロゲン原子としては、フッ素原子または塩素原子が好ましい。−ＣＯＡ1のＡ1としては、炭素数１〜６の分岐があっても良いアルキル基が好ましく、メチル基またはエチル基がより好ましい。−ＣＯＯＡ2のＡ2としては、炭素数１〜６の分岐があっても良いアルキル基が好ましく、メチル基またはエチル基がより好ましい。アルキル基としては、炭素数１〜１０の分岐があってもよいアルキル基が好ましく、メチル基またはエチル基がより好ましい。アルケニル基としては、炭素数２〜１０の分岐があってもよいアルケニル基が好ましく、炭素数３〜６の分岐があってもよいアルケニル基がより好ましく、炭素数３〜４の分岐があってもよいアルケニル基が更に好ましい。アルコキシル基としては、炭素数１〜２０の分岐があってもよいアルコキシル基が好ましく、炭素数１〜１０の分岐があってもよいアルコキシル基がより好ましく、炭素数１〜４の分岐があってもよいアルコキシル基が更に好ましい。アシル基としては、炭素数２〜２０の分岐があってもよいアシル基が好ましく、炭素数２〜１０の分岐があってもよいアシル基がより好ましく、炭素数２〜４の分岐があってもよいアシル基が更に好ましい。アリール基に結合する置換基の数としては４個以下であり、置換基の数としては２個以下が好ましい。
なお、以上述べてきたアリール基は、式（１）のＲ3〜Ｒ6のそれぞれ１個のものについて述べたものである。また、スキーム１において４つ結合しているＡｒ基は、同一であっても異なっていてもよく、好ましくは同一なものである。As the halogen atom, a fluorine atom or a chlorine atom is preferable. The halogen atom of the monohalogenomethyl group is preferably a fluorine atom or a chlorine atom. The halogen atom of the dihalogenomethyl group is preferably a fluorine atom or a chlorine atom. The halogen atom of the trihalogenomethyl group is preferably a fluorine atom or a chlorine atom. As A 1 of —COA 1 , an alkyl group which may have 1 to 6 carbon atoms is preferable, and a methyl group or an ethyl group is more preferable. As A 2 of —COOA 2 , an alkyl group which may have 1 to 6 carbon atoms may be preferable, and a methyl group or an ethyl group is more preferable. As the alkyl group, an alkyl group which may have 1 to 10 carbon atoms is preferable, and a methyl group or an ethyl group is more preferable. The alkenyl group is preferably an alkenyl group which may have 2 to 10 carbon atoms, more preferably an alkenyl group which may have 3 to 6 carbon atoms, and a branch having 3 to 4 carbon atoms. Even better alkenyl groups are more preferred. The alkoxyl group is preferably an alkoxyl group that may have 1 to 20 carbon atoms, more preferably an alkoxyl group that may have 1 to 10 carbon atoms, and has 1 to 4 carbon atoms. Even better alkoxyl groups are more preferred. The acyl group is preferably an acyl group that may have 2 to 20 carbon atoms, more preferably an acyl group that may have 2 to 10 carbon atoms, and a branch having 2 to 4 carbon atoms. More preferred are acyl groups. The number of substituents bonded to the aryl group is 4 or less, and the number of substituents is preferably 2 or less.
The aryl groups described above are those for each of R 3 to R 6 in formula (1). Further, the four Ar groups bonded in Scheme 1 may be the same or different, and are preferably the same.
○リン酸化
化合物Ｄ系は、化合物Ｃ系から例えば三塩化リンを用いて合成することができる。この合成は、一般的な条件を用いることができる。
本発明の化合物Ｄ系から環状リン酸化合物（化合物Ｅ系）へは、酸化することにより合成することができる。この酸化は、ヨウ素を用いる方法が例示できる。Phosphorylation The compound D system can be synthesized from the compound C system using, for example, phosphorus trichloride. General conditions can be used for this synthesis.
The compound D system of the present invention can be synthesized by oxidation to a cyclic phosphate compound (compound E system). This oxidation can be exemplified by a method using iodine.
本発明の式（１）で表される環状リン酸化合物は、Ｒ1が水素原子、メチル基等のものが好ましく、Ｒ2が水素原子、メチル基、フェニル基等のものが好ましく、Ｒ3がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基等のものが好ましく、Ｒ4がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基等のものが好ましく、Ｒ5がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基等のものが好ましく、Ｒ6がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基等のものが好ましい。In the cyclic phosphate compound represented by the formula (1) of the present invention, R 1 is preferably a hydrogen atom, a methyl group or the like, R 2 is preferably a hydrogen atom, a methyl group, a phenyl group or the like, and R 3 There phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, m- trifluoromethylphenyl group, p- trifluoromethylphenyl group, a 4-biphenyl group is preferably one or 2-naphthyl group, R 4 is Preferred are phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, 4-biphenyl group, 2-naphthyl group and the like, and R 5 is phenyl. Group, 3-fluorophenyl group, 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, 4-biphenyl group, A 2-naphthyl group or the like is preferable, and R 6 is a phenyl group, 3-fluorophenyl group, 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, 4-biphenyl group, 2 -A naphthyl group or the like is preferable.
○不斉反応への適用例
本発明の環状リン酸化合物は、マンニッヒ型反応、アザ ディールス−アルダー反応、アリル反応、ヒドロホスホリル化反応、ストレッカー型反応、および芳香族化合物のアミノアルキル化反応等の触媒として用いることができる。更に本発明の環状リン酸化合物は、不斉マンニッヒ型反応、不斉アザ ディールス−アルダー反応、不斉アリル反応、不斉ヒドロホスホニル化反応、不斉ストレッカー型反応、および芳香族化合物の不斉アミノアルキル化反応等の触媒として用いることができる。しかし、本発明の環状リン酸化合物を触媒として用いてキラルな化合物が得られるものであれば、これらの反応例に限られるものではない。
本発明の反応により得られる生成物の絶対配置は、本発明の環状リン酸化合物の絶対配置に依存する。即ち、Ｒ体の本発明の環状リン酸化合物を用いた場合、これに対応した不斉炭素を有する生成物を与え、そしてＳ体の本発明の環状リン酸化合物を用いた場合、これに対応した不斉炭素を有する生成物を与える。
なお、生成物の絶対配置については、Ｒ体の本発明の環状リン酸化合物の場合がＲ体を与えるということではなく、合成原料により生成物の絶対配置は異なる。
本発明の触媒を用いて合成反応を実施するとき、反応系内を脱水する目的で、必要に応じてモレキューラシーブ３Ａ、４Ａ、５Ａに代表されるＡ型ゼオライト、モレキュラシーブ１３Ｘ、Ｙ型、Ｌ型等様々なゼオライトを使用しても良い。Example of application to asymmetric reaction The cyclic phosphate compound of the present invention includes Mannich reaction, Azadirs-Alder reaction, allyl reaction, hydrophosphorylation reaction, Strecker reaction, aminoalkylation reaction of aromatic compounds, etc. It can be used as a catalyst. Furthermore, the cyclic phosphoric acid compound of the present invention includes an asymmetric Mannich type reaction, an asymmetric aza Diels-Alder reaction, an asymmetric allyl reaction, an asymmetric hydrophosphonylation reaction, an asymmetric Strecker type reaction, and an asymmetric amino acid of an aromatic compound. It can be used as a catalyst for an alkylation reaction or the like. However, the present invention is not limited to these reaction examples as long as a chiral compound can be obtained using the cyclic phosphate compound of the present invention as a catalyst.
The absolute configuration of the product obtained by the reaction of the present invention depends on the absolute configuration of the cyclic phosphate compound of the present invention. That is, when the R-form cyclic phosphate compound of the present invention is used, a product having an asymmetric carbon corresponding thereto is provided, and when the S-form cyclic phosphate compound of the present invention is used, this is handled. To give a product with asymmetric carbon.
In addition, regarding the absolute configuration of the product, the R configuration of the cyclic phosphate compound of the present invention does not give the R configuration, but the absolute configuration of the product varies depending on the synthesis raw material.
When carrying out the synthesis reaction using the catalyst of the present invention, for the purpose of dehydrating the reaction system, if necessary, A type zeolite represented by molecular sieves 3A, 4A, 5A, molecular sieves 13X, Y type, Various zeolites such as L-type may be used.
本発明の環状リン酸化合物を合成触媒として用いる場合は、電子求引性を有する基が結合しているアリール基が好ましく、更に電子求引性を有する基が結合しているフェニル基が好ましく、特にニトロ基、ハロゲン原子、モノハロゲノメチル基、ジハロゲノメチル基、トリハロゲノメチル基、ニトリル基、またはホルミル基が結合したフェニル基が好ましいものである。これらの電子求引性基は複数結合していてもよい。ニトロ基やトリフルオロメチル基等のような電子求引性を有するアリール基が結合していることが好ましい。なお、アリール基に結合する電子求引性基は、電子求引性を示す位置に結合していることが好ましい。
本発明の環状リン酸化合物は、酸触媒として用いることができるものであれば塩となっていてもよい。When the cyclic phosphate compound of the present invention is used as a synthesis catalyst, an aryl group to which an electron withdrawing group is bonded is preferable, and a phenyl group to which an electron withdrawing group is further bonded is preferable. In particular, a phenyl group to which a nitro group, a halogen atom, a monohalogenomethyl group, a dihalogenomethyl group, a trihalogenomethyl group, a nitrile group, or a formyl group is bonded is preferable. A plurality of these electron withdrawing groups may be bonded. It is preferable that an aryl group having an electron withdrawing property such as a nitro group or a trifluoromethyl group is bonded. In addition, it is preferable that the electron withdrawing group couple | bonded with an aryl group has couple | bonded with the position which shows electron withdrawing property.
The cyclic phosphate compound of the present invention may be a salt as long as it can be used as an acid catalyst.
○マンニッヒ型反応
本発明の環状リン酸化合物をマンニッヒ型反応の触媒として用いることができる。また、本発明の環状リン酸化合物を不斉マンニッヒ型反応の触媒として用いることもできる。この不斉マンニッヒ型反応としては、下記の式（２）で表されるエノール誘導体と下記式（３）で表されるイミン誘導体とから下記式（４）で表されるアミノ化合物を得るものが例示できる。Mannich type reaction The cyclic phosphate compound of the present invention can be used as a catalyst for the Mannich type reaction. Moreover, the cyclic phosphate compound of the present invention can also be used as a catalyst for an asymmetric Mannich type reaction. As this asymmetric Mannich type reaction, an amino compound represented by the following formula (4) is obtained from an enol derivative represented by the following formula (2) and an imine derivative represented by the following formula (3). It can be illustrated.
式（２）中のＲ5は、水素原子、炭素数１〜６個の分岐を有してもよいアルキル基、または炭素数１〜６個のアルキル基を有していてもよいアリール基を示し、Ｒ6は、水素原子または炭素数１〜６個の分岐を有してもよいアルキル基を示し、Ｒ7は、炭素数１〜６個の分岐を有してもよいアルキル基または炭素数１〜６個の分岐を有してもよいアルコキシ基を示し、Ｒ8は、それぞれ異なってもよい炭素数１〜６の分岐があってもよいアルキル基、フェニル基、または炭素数１〜６の分岐があってもよいアルキル基で１〜４置換されたフェニル基を表す。R 5 in Formula (2) represents a hydrogen atom, an alkyl group that may have a branch having 1 to 6 carbon atoms, or an aryl group that may have an alkyl group having 1 to 6 carbon atoms. R 6 represents a hydrogen atom or an alkyl group that may have 1 to 6 carbon atoms, and R 7 represents an alkyl group or carbon that may have 1 to 6 carbon atoms. An alkoxy group that may have 1 to 6 branches may be represented, and R 8 may be an alkyl group, a phenyl group, or a carbon group having 1 to 6 branches that may be different from each other. It represents a phenyl group substituted with 1 to 4 alkyl groups which may have 6 branches.
式（３）中のＲ9は水素原子、水酸基、ハロゲン原子、炭素数１〜６個の分岐を有してもよいアルキル基、または炭素数１〜６個の分岐を有してもよいアルコキシ基を示し、Ｒ10は水素原子、ハロゲン原子、炭素数１〜６個の分岐を有してもよいアルキル基、または炭素数１〜６個の分岐を有してもよいアルコキシ基を示す。R 9 in formula (3) is a hydrogen atom, a hydroxyl group, a halogen atom, an alkyl group that may have 1 to 6 carbon atoms, or an alkoxy that may have 1 to 6 carbon atoms. R 10 represents a hydrogen atom, a halogen atom, an alkyl group which may have a branch having 1 to 6 carbon atoms, or an alkoxy group which may have a branch having 1 to 6 carbon atoms.
式（４）中のＲ5〜Ｒ7は式（２）と同様なものであり、Ｒ9とＲ10は式（３）と同様なものである。R 5 to R 7 in the formula (4) are the same as those in the formula (2), and R 9 and R 10 are the same as those in the formula (3).
マンニッヒ型反応または不斉マンニッヒ型反応に適用するときの本発明の環状リン酸化合物の使用量については、あらゆる量比で使用可能であるが、余りにも過剰量の使用は経済的でなく、余りにも少量では合成反応が進行しない場合があり好ましくない。このことから、マンニッヒ型反応または不斉マンニッヒ型反応に本発明の環状リン酸化合物を適用するときの使用割合は、式（２）で表されるイミン誘導体に対して本発明の環状リン酸化合物が０．０１モル％以上であり、９０モル％以下である。このことから、本発明の環状リン酸化合物の使用割合は、０．０１〜９０モル％が好ましく、更に０．１〜６０モル％が好ましく、特に１〜５０モル％が好ましく、更に３〜３０モル％が特に好ましい。 As for the amount of the cyclic phosphate compound of the present invention when applied to the Mannich-type reaction or the asymmetric Mannich-type reaction, it can be used in any amount ratio, but the use of an excessive amount is not economical and too However, if the amount is too small, the synthesis reaction may not proceed. From this, when the cyclic phosphate compound of the present invention is applied to the Mannich type reaction or the asymmetric Mannich type reaction, the cyclic phosphate compound of the present invention is used with respect to the imine derivative represented by the formula (2). Is 0.01 mol% or more and 90 mol% or less. From this, the use ratio of the cyclic phosphate compound of the present invention is preferably 0.01 to 90 mol%, more preferably 0.1 to 60 mol%, particularly preferably 1 to 50 mol%, and further 3 to 30. Mole% is particularly preferred.
本発明の環状リン酸化合物を他の合成または不斉合成の触媒に適用するときの割合は、このマンニッヒ型反応または不斉マンニッヒ型反応に適用した割合を適用することができる。
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として用いるときに適用可能なイミン類としては、あらゆるイミン類が適用可能であり、具体的には、式（３）が挙げられる。
具体的にイミン類化合物としては、式（３）のＲ9が水酸基で、そしてＲ10が水素原子である化合物等が挙げられる。The ratio applied to the Mannich-type reaction or the asymmetric Mannich-type reaction can be applied as the ratio when the cyclic phosphate compound of the present invention is applied to another synthesis or asymmetric synthesis catalyst.
As imines applicable when the cyclic phosphate compound of the present invention is used as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction, all imines are applicable. Specifically, the formula (3) is Can be mentioned.
Specific examples of the imine compound include compounds in which R 9 in the formula (3) is a hydroxyl group and R 10 is a hydrogen atom.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として用いるときに適用可能なエノール類としては、あらゆるエノール類が適用可能であり、具体的には、式（２）が挙げられる。
式（２）のＲ5は、水素原子、炭素数１〜６個の分岐を有してもよいアルキル基、または炭素数１〜６個のアルキル基を有していてもよいアリール基であり、好ましくは炭素数１〜６個のアルキル基またはアリール基であり、更に好ましくはメチル基またはエチル基である。
式（２）のＲ6は、水素原子または炭素数１〜６個の分岐を有してもよいアルキル基であり、好ましくは炭素数１〜６個のアルキル基、更に好ましくはメチル基またはエチル基である。
式（２）のＲ7は、炭素数１〜６個の分岐を有してもよいアルコキシ基または炭素数１〜６個の分岐を有してもよいアルキル基であり、好ましくは炭素数１〜６個の分岐を有してもよいアルコキシ基であり、更に好ましくはメチル基、エチル基、またはプロピル基である。
式（２）のＲ8は、それぞれ異なってもよい炭素数１〜４個の分岐を有してもよいアルキル基またはフェニル基であり、好ましくはそれぞれ異なってもよい炭素数１〜４個の分岐を有してもよいアルキル基あり、更に好ましくは炭素数１〜３個の分岐を有してもよいアルキル基である。As enols applicable when the cyclic phosphate compound of the present invention is used as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction, all enols are applicable. Specifically, the formula (2) is Can be mentioned.
R 5 in formula (2) is a hydrogen atom, an alkyl group that may have 1 to 6 carbon atoms, or an aryl group that may have an alkyl group having 1 to 6 carbon atoms. , Preferably it is a C1-C6 alkyl group or an aryl group, More preferably, it is a methyl group or an ethyl group.
R 6 in the formula (2) is a hydrogen atom or an alkyl group which may have 1 to 6 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, more preferably a methyl group or ethyl group. It is a group.
R 7 in the formula (2) is an alkoxy group that may have 1 to 6 carbon atoms or an alkyl group that may have 1 to 6 carbon atoms, and preferably 1 carbon atom. An alkoxy group which may have -6 branches, and more preferably a methyl group, an ethyl group or a propyl group.
R 8 in the formula (2) is an alkyl group or a phenyl group which may have 1 to 4 carbon atoms which may be different from each other, and preferably 1 to 4 carbon atoms which may be different from each other. There is an alkyl group which may have a branch, and more preferably an alkyl group which may have a branch having 1 to 3 carbon atoms.
具体的にエノール類化合物として、式（２）のＲ5およびＲ6がメチル基でＲ7がメトキシ基でＲ8がメチル基のもの、Ｒ5およびＲ6がメチル基でＲ7がメトキシ基でＲ8がｔ−ブチル基とメチル基のもの、Ｒ5およびＲ6がメチル基でＲ7がｉ−プロポキシ基でＲ8がメチル基のもの、Ｒ5およびＲ6が水素原子でＲ7がメトキシ基でＲ8がメチル基のもの等が挙げられる。Specifically, as the enol compound, R 5 and R 6 in the formula (2) are methyl groups, R 7 is a methoxy group and R 8 is a methyl group, R 5 and R 6 are methyl groups, and R 7 is a methoxy group Wherein R 8 is a t-butyl group and a methyl group, R 5 and R 6 are methyl groups, R 7 is an i-propoxy group and R 8 is a methyl group, R 5 and R 6 are hydrogen atoms and R 7 Is a methoxy group and R 8 is a methyl group.
式（２）は、カルボン酸エステル、ケトン類、またはアルデヒド類と下記式（５）で例示できるシリルクロライド等とから得ることができる。
（Ｒ8）3ＳｉＣｌ （５）
式（５）中のＲ8は、式（２）のＲ8と同様なものである。
例えばシクロヘキサノンのシリルエノールエーテル体である１−シクロヘキセニルオキシ−［（（１−ナフチル）フェニル）メチル］ジメチルシランは、シクロヘキサノンを低温（例えば−７８℃）でリチウムジイソプロピルアミドにて処理してリチウムエノラートを発生させ、これを［（（１−ナフチル）フェニル）メチル］ジメチルシリルクロリドで捕捉すればよい。同様な方法により、アセトンやベンゾフェノン等の活性水素を有するケトンからも、対応するシリルエノールエーテルに誘導することができる。また、酢酸ベンジルのシリルケテンアセタール体は、酢酸ベンジルを低温（例えば−７８℃）でリチウムジイソプロピルアミドにて処理してリチウムエノラートを発生させ、これを［（（１−ナフチル）フェニル）メチル］ジメチルシリルクロリドで捕捉すればよい。同様に活性水素を有するカルボン酸エステルからも、対応するシリルケテンアセタールに誘導することができる。Formula (2) can be obtained from carboxylic acid esters, ketones, or aldehydes and silyl chloride, which can be exemplified by the following formula (5).
(R 8 ) 3 SiCl (5)
R 8 in the formula (5) are those similar to R 8 in formula (2).
For example, 1-cyclohexenyloxy-[((1-naphthyl) phenyl) methyl] dimethylsilane which is a silyl enol ether of cyclohexanone is obtained by treating cyclohexanone with lithium diisopropylamide at a low temperature (for example, −78 ° C.). May be generated and captured with [((1-naphthyl) phenyl) methyl] dimethylsilyl chloride. By a similar method, it is possible to derive the corresponding silyl enol ether from a ketone having active hydrogen such as acetone or benzophenone. The silyl ketene acetal form of benzyl acetate is produced by treating benzyl acetate with lithium diisopropylamide at a low temperature (for example, −78 ° C.) to generate lithium enolate, which is converted into [((1-naphthyl) phenyl) methyl] dimethyl. Capture with silyl chloride. Similarly, a corresponding silyl ketene acetal can be derived from a carboxylic acid ester having active hydrogen.
式（２）を得るために適用可能なケトン類としては、ほとんどのケトンが適用可能であり、アセトフェノン、（４−メチルフェニル）アセトフェノン、（３−メチルフェニル）アセトフェノン、（２−メチルフェニル）アセトフェノン、（４−エチルフェニル）アセトフェノン、（３−エチルフェニル）アセトフェノン、（２−エチルフェニル）アセトフェノン、（４−ｉ−プロピルフェニル）アセトフェノン、（３−ｉ−プロピルフェニル）アセトフェノン、（２−ｉ−プロピルフェニル）アセトフェノン、１−フェニルプロパン−１−オン、１−（４−メチルフェニル）プロパン−１−オン、１−（３−メチルフェニル）プロパン−１−オン、１−（２−メチルフェニル）プロパン−１−オン、１−フェニル−ブタン−１−オン、１−（４−メチルフェニル）−ブタン−１−オン、１−（３−メチルフェニル）−ブタン−１−オン、１−（２−メチルフェニル）−ブタン−１−オン、１−フェニル−２−メチルプロパン−１−オン、１−（４−フェニル）−２−メチルプロパン−１−オン、１−（３−フェニル）−２−メチルプロパン−１−オン、１−（２−フェニル）−２−メチルプロパン−１−オン、１−フェニル−ペンタン−１−オン、１−フェニル−ヘキサン−１−オン、１−フェニル−へプタン−１−オン、１−フェニル−オクタン−１−オン、１−フェニル−ノナン−１−オン、１−フェニル−デカン−１−オン、１−フェニル−ウンデカン−１−オン、１−フェニル−ドデカン−１−オン、１−フェニル−トリデカン−１−オン、１−フェニル−テトラデカン−１−オン、１−フェニル−ペンタデカン−１−オン、１−フェニル−ヘキサデカン−１−オン、メチル−ｔ−ブチルケトン、エチル グリオキシレート、エチル フェニルグリオキシレート、メチル フェニルグリオキシレート、エチル ｉ−プロピルグリオキシレート、エチル フェニルエテニルグリオキシレート、エチル シクロヘキシルグリオキシレート等が例示できる。 As ketones applicable to obtain the formula (2), most ketones are applicable, and acetophenone, (4-methylphenyl) acetophenone, (3-methylphenyl) acetophenone, (2-methylphenyl) acetophenone. , (4-ethylphenyl) acetophenone, (3-ethylphenyl) acetophenone, (2-ethylphenyl) acetophenone, (4-i-propylphenyl) acetophenone, (3-i-propylphenyl) acetophenone, (2-i- Propylphenyl) acetophenone, 1-phenylpropan-1-one, 1- (4-methylphenyl) propan-1-one, 1- (3-methylphenyl) propan-1-one, 1- (2-methylphenyl) Propan-1-one, 1-phenyl-butan-1-one, 1- ( -Methylphenyl) -butan-1-one, 1- (3-methylphenyl) -butan-1-one, 1- (2-methylphenyl) -butan-1-one, 1-phenyl-2-methylpropane- 1-one, 1- (4-phenyl) -2-methylpropan-1-one, 1- (3-phenyl) -2-methylpropan-1-one, 1- (2-phenyl) -2-methylpropane -1-one, 1-phenyl-pentan-1-one, 1-phenyl-hexane-1-one, 1-phenyl-heptan-1-one, 1-phenyl-octane-1-one, 1-phenyl- Nonan-1-one, 1-phenyl-decan-1-one, 1-phenyl-undecan-1-one, 1-phenyl-dodecan-1-one, 1-phenyl-tridecan-1-one, 1-phenyl- Tetradecane -One, 1-phenyl-pentadecan-1-one, 1-phenyl-hexadecan-1-one, methyl-t-butyl ketone, ethyl glyoxylate, ethyl phenylglyoxylate, methyl phenylglyoxylate, ethyl i-propyl Examples include glyoxylate, ethyl phenylethenyl glyoxylate, and ethyl cyclohexyl glyoxylate.
式（２）を得るために適用可能なアルデヒド類としては、ほとんどのアルデヒドが適用可能であり、ギ酸エチル、メトキシカルボニルアルデヒド、アセトアルデヒド、プロピオンアルデヒド、ブタナール、イソブタナール、ペンタナール、アクロレイン、クロトンアルデヒド、シクロへキシルアルデヒド、ベンズアルデヒド、４−メトキシベンズアルデヒド、４−メチルベンズアルデヒド、３，５−ジメチルベンズアルデヒド、４−フェニルベンズアルデヒド、４−クロロベンズアルデヒド、４−ニトロベンズアルデヒド、ナフチル−２−アルデヒド、２−フルフラール、桂皮アルデヒド、３−フェニルプロパナール、２−ベンジルオキシアセトアルデヒド等が例示でき、さらにアルデヒド類似化合物としてベンジルイミン、フェニルチオアミド等が例示できる。 Aldehydes that can be used to obtain the formula (2) are almost all aldehydes, such as ethyl formate, methoxycarbonylaldehyde, acetaldehyde, propionaldehyde, butanal, isobutanal, pentanal, acrolein, crotonaldehyde, cyclohexane. Xylaldehyde, benzaldehyde, 4-methoxybenzaldehyde, 4-methylbenzaldehyde, 3,5-dimethylbenzaldehyde, 4-phenylbenzaldehyde, 4-chlorobenzaldehyde, 4-nitrobenzaldehyde, naphthyl-2-aldehyde, 2-furfural, cinnamic aldehyde, Examples thereof include 3-phenylpropanal, 2-benzyloxyacetaldehyde, and aldehyde-like compounds such as benzylimine and phenylthioa De like.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として適用するに当たっては、式（３）で代表されるイミン類と式（２）で代表されるケトン類またはエノール類とを等モル量で反応させることが多いが、１モルのイミン類に対してケトン類またはエノール類を０．１〜１０モルで使用しても良く、好ましくは１〜５モルであり、更に好ましくは１〜４モルである。 In applying the cyclic phosphate compound of the present invention as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction, imines represented by formula (3) and ketones or enols represented by formula (2) The ketones or enols may be used in an amount of 0.1 to 10 mol, preferably 1 to 5 mol, more preferably 1 mol. Is 1 to 4 moles.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として適用するに当たっては、溶媒として反応に不活性な溶媒であれば、ほとんどのものが適用可能である。具体的には、四塩化炭素、クロロホルム、ジクロロメタン、１，２−ジクロロエタン、１，１，１−トリクロロエタン、および１，１，２−トリクロロエタン等のハロゲン化溶媒、ジエチルエーテルおよびテトラヒドロフラン等のエーテル系溶媒、トルエン、キシレン、エチルベンゼン、イソプロピルベンゼン、およびメシチレン等の芳香族系溶媒等が挙げられ、好ましくは芳香族系溶媒である。 In applying the cyclic phosphate compound of the present invention as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction, almost any solvent can be used as long as it is an inert solvent for the reaction. Specifically, halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,1-trichloroethane, and 1,1,2-trichloroethane, ether solvents such as diethyl ether and tetrahydrofuran , Aromatic solvents such as toluene, xylene, ethylbenzene, isopropylbenzene, and mesitylene, and the like. Preferred are aromatic solvents.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として適用するに当たっての反応温度としては、反応に用いる化合物により異なるが、通常、−１００℃〜５０℃の範囲で実施可能であり、−８０℃〜０℃が好ましく、更に−７８℃〜−４０℃が好ましい。 The reaction temperature for applying the cyclic phosphate compound of the present invention as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction varies depending on the compound used in the reaction, but can usually be carried out in the range of -100 ° C to 50 ° C. And is preferably −80 ° C. to 0 ° C., more preferably −78 ° C. to −40 ° C.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として適用するに当たって、反応に用いる式（２）と式（３）との濃度は、溶媒に溶解できれば特に限定はない。なお、溶解できないほど高濃度であっても、反応に支障がなければ本合成方法を適用することができる。通常は、溶媒に対し０．１質量％〜５０質量％の範囲である。 In applying the cyclic phosphate compound of the present invention as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction, the concentrations of the formulas (2) and (3) used in the reaction are not particularly limited as long as they can be dissolved in a solvent. Even if the concentration is so high that it cannot be dissolved, the present synthesis method can be applied as long as the reaction is not hindered. Usually, it is the range of 0.1 mass%-50 mass% with respect to a solvent.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として適用するに当たっての反応時間は、反応に用いる化合物の種類およびキラルなブレンステッド酸触媒の種類により異なるが、通常は１〜９６時間で行うことができる。 The reaction time for applying the cyclic phosphate compound of the present invention as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction varies depending on the type of compound used in the reaction and the type of chiral Bronsted acid catalyst. It can be performed in -96 hours.
本発明の環状リン酸化合物をマンニッヒ型反応または不斉マンニッヒ型反応の触媒として適用し合成した化合物は、一般的な精製方法を用いることができる。具体例としては、炭酸水素ナトリウム水溶液を適量反応液中に添加し、次い酢酸エチルエステルで抽出した後、無水硫酸ナトリウムで乾燥、ろ過、ろ液を濃縮することにより生成物を得る方法等である。この生成物の精製に当たっては、分取シリカゲル薄層クロマトグラフィー、カラムクロマトグラフィー、蒸留、または再結晶等の一般的な方法を用いることができる。 A general purification method can be used for the compound synthesized by applying the cyclic phosphate compound of the present invention as a catalyst for Mannich-type reaction or asymmetric Mannich-type reaction. As a specific example, a method of obtaining a product by adding an appropriate amount of aqueous sodium hydrogen carbonate solution to the reaction solution, followed by extraction with ethyl acetate, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate, etc. is there. For purification of the product, a general method such as preparative silica gel thin layer chromatography, column chromatography, distillation, or recrystallization can be used.
以上、マンニッヒ型反応または不斉マンニッヒ型反応に適用したものについて説明したが、先に述べたように、アザ ディールス−アルダー反応、アリル化反応、ヒドロホスホリル化反応、ストレッカー型反応、芳香族化合物のアミノアルキル化反応、不斉アザ ディールス−アルダー反応、不斉アリル化反応、不斉ヒドロホスホニル化反応、不斉ストレッカー型反応、および不斉芳香族化合物のアミノアルキル化反応等にも、本発明の環状リン酸化合物を触媒として用いることができる。 As described above, what has been applied to the Mannich type reaction or the asymmetric Mannich type reaction has been described. As described above, the Azadirs-Alder reaction, the allylation reaction, the hydrophosphorylation reaction, the Strecker reaction, the aromatic compound The present invention is also applicable to aminoalkylation reactions, asymmetric aza Diels-Alder reactions, asymmetric allylation reactions, asymmetric hydrophosphonylation reactions, asymmetric Strecker-type reactions, and aminoalkylation reactions of asymmetric aromatic compounds. The cyclic phosphate compound can be used as a catalyst.
本発明の環状リン酸化合物をこれら合成反応または不斉合成反応の触媒として適用するにあたり、各反応条件は、マンニッヒ型反応または不斉マンニッヒ型反応において記載した条件を準用することができる。即ち、各種合成反応または不斉合成反応における触媒量を考慮し、マンニッヒ型反応または不斉マンニッヒ型反応において記載した条件を適用すればよい。 In applying the cyclic phosphate compound of the present invention as a catalyst for these synthesis reactions or asymmetric synthesis reactions, the conditions described in the Mannich-type reaction or the asymmetric Mannich-type reaction can be applied mutatis mutandis. That is, the conditions described in the Mannich type reaction or the asymmetric Mannich type reaction may be applied in consideration of the amount of catalyst in various synthesis reactions or asymmetric synthesis reactions.
○アザ ディールス−アルダー反応
本発明の環状リン酸化合物を適用して行うアザ ディールス−アルダー反応または不斉アザ ディールス−アルダー反応としては、式（３）と下記式（６）とから下記式（７）を得るものが例示できる。
アザ ディールス−アルダー反応に用いる式（３）としては、マンニッヒ型反応に適用したものと同様なものを用いることが出来る。Aza Diels-Alder Reaction As an Aza Diels-Alder reaction or an asymmetric Aza Diels-Alder reaction performed by applying the cyclic phosphate compound of the present invention, the following formula (7) is obtained from Formula (3) and Formula (6) below. ) Can be exemplified.
As the formula (3) used for the Aza Diels-Alder reaction, the same one as applied to the Mannich type reaction can be used.
式（６）中のＲ8は式（２）のＲ8と同様なものを用いることができ、Ｒ11は炭素数１〜６個の分岐を有してもよいアルキル基を示す。好ましくはメチル基またはエチル基である。R 8 in the formula (6) can be similar to those in R 8 of formula (2), R 11 represents an alkyl group which may have 1-6 branched carbon atoms. A methyl group or an ethyl group is preferable.
式（７）中のＲ9とＲ10は式（３）と同様なものである。R 9 and R 10 in formula (7) are the same as in formula (3).
○不斉アリル反応
本発明の環状リン酸化合物を適用して行うアリル反応または不斉アリル反応としては、下記の式（８）と下記式（９）とから下記式（１０）を得るものが例示できる。
Ｒ12−ＣＨ＝Ｎ−Ｒ13 （８）
式（８）中のＲ12は炭素数１〜６個の分岐を有してもよいアルキル基または置換基を有するアリール基を示し、Ｒ13は水酸基等の置換基を有していてもよいアリール基を示す。
ＣＨ2＝ＣＨ−ＣＨ2−Ｂ１ （９）
式（９）中のＢ１は、トリアルキルスタニル基またはトリアルキルシリル基を示し、このアルキル基としては炭素数１〜６個の分岐を有していても良いものである。Asymmetric allyl reaction As an allyl reaction or asymmetric allyl reaction carried out by applying the cyclic phosphate compound of the present invention, a compound that obtains the following formula (10) from the following formula (8) and the following formula (9): It can be illustrated.
R 12 —CH═N—R 13 (8)
R 12 in formula (8) represents an alkyl group which may have 1 to 6 carbon atoms or an aryl group having a substituent, and R 13 may have a substituent such as a hydroxyl group. An aryl group is shown.
CH 2 = CH-CH 2 -B1 (9)
B1 in the formula (9) represents a trialkylstannyl group or a trialkylsilyl group, and this alkyl group may have 1 to 6 carbon atoms.
式（１０）中のＲ12とＲ13は式（８）と同様なものである。
式（８）中のＲ12は炭素数１〜６個の分岐を有してもよいアルキル基または置換基を有するアリール基を示し、好ましくはメチル基、エチル基、またはフェニル基等が例示でき、Ｒ13は水酸基等の置換基を有していてもよいアリール基を示し、好ましくはフェニル基や水酸基を有するフェニル基が例示でき、特に好ましくは２−ハイドロキシフェニル基である。
式（９）中のＢ１は、トリアルキルスタニル基またはトリアルキルシリル基を示し、このアルキル基としては炭素数１〜６個の分岐を有していても良いものであり、好ましくはメチル基またはエチル基である。
式（１０）中のＲ12とＲ13は式（８）と同様なものである。R 12 and R 13 in formula (10) are the same as in formula (8).
R 12 in the formula (8) represents an alkyl group which may have 1 to 6 carbon atoms or an aryl group having a substituent, preferably a methyl group, an ethyl group or a phenyl group. , R 13 represents an aryl group which may have a substituent such as a hydroxyl group, preferably a phenyl group or a phenyl group having a hydroxyl group, and particularly preferably a 2-hydroxyphenyl group.
B1 in Formula (9) represents a trialkylstannyl group or a trialkylsilyl group, and this alkyl group may have 1 to 6 carbon atoms, preferably a methyl group. Or it is an ethyl group.
R 12 and R 13 in formula (10) are the same as in formula (8).
○ヒドロホスホリル化反応
本発明の環状リン酸化合物を適用して行うヒドロホスホリル化反応または不斉ヒドロホスホニル化反応としては、式（８）と下記式（１１）とから式（１２）を得るものが例示できる。
（Ｒ14Ｏ）2ＰＯＨ （１１）
式（１１）中のＲ14は炭素数１〜６個の分岐を有してもよいアルキル基を示す。○ Hydrophosphorylation reaction As a hydrophosphorylation reaction or asymmetric hydrophosphonylation reaction carried out by applying the cyclic phosphate compound of the present invention, a compound that obtains the formula (12) from the formula (8) and the following formula (11) can be obtained. It can be illustrated.
(R 14 O) 2 POH (11)
R 14 in formula (11) represents an alkyl group which may have 1 to 6 carbon atoms.
式（１２）中のＲ12とＲ13は式（８）と同様なものであり、Ｒ14は式（１１）と同様のものである。
式（１１）中のＲ14は炭素数１〜６個の分岐を有してもよいアルキル基を示し、好ましくはメチル基またはエチル基である。
式（１２）中のＲ12とＲ13は式（８）と同様なものであり、Ｒ14は式（１２）と同様のものである。R 12 and R 13 in the formula (12) are the same as in the formula (8), and R 14 is the same as in the formula (11).
R 14 in formula (11) represents an alkyl group that may have 1 to 6 carbon atoms, and is preferably a methyl group or an ethyl group.
R 12 and R 13 in formula (12) are the same as in formula (8), and R 14 is the same as in formula (12).
○ストレッカー型反応
本発明の環状リン酸化合物を適用して行うストレッカー型反応または不斉ストレッカー型反応としては、式（８）と下記式（１３）とから式（１４）を得るものが例示できる。
Ｂ２−ＣＮ （１３）
式（１３）中のＢ２は、水素原子、トリアルキルスタニル基、またはトリアルキルシリル基を示し、このアルキル基としては炭素数１〜６個の分岐を有していても良いものである。Strecker-type reaction As a Strecker-type reaction or asymmetric Strecker-type reaction performed by applying the cyclic phosphate compound of the present invention, a formula (14) is obtained from the formula (8) and the following formula (13). Can be illustrated.
B2-CN (13)
B2 in Formula (13) represents a hydrogen atom, a trialkylstannyl group, or a trialkylsilyl group, and this alkyl group may have a branch having 1 to 6 carbon atoms.
式（１４）中のＲ12とＲ13は式（８）と同様なものである。
式（１３）中のＢ２は、水素原子、トリアルキルスタニル基、またはトリアルキルシリル基を示し、このアルキル基としては炭素数１〜６個の分岐を有していても良いものであり、好ましくはメチル基またはエチル基である。
式（１４）中のＲ12とＲ13は式（８）と同様なものである。R 12 and R 13 in the formula (14) are the same as those in the formula (8).
B2 in the formula (13) represents a hydrogen atom, a trialkylstannyl group, or a trialkylsilyl group, and this alkyl group may have 1 to 6 carbon atoms, A methyl group or an ethyl group is preferable.
R 12 and R 13 in the formula (14) are the same as those in the formula (8).
○芳香族化合物のアミノアルキル化反応
本発明の環状リン酸化合物を適用して行う芳香族化合物のアミノアルキル化反応または不斉アミノアルキル化反応としては、式（８）と下記式（１５）とから式（１６）を得るものが例示できる。Aminoalkylation reaction of aromatic compound As an aminoalkylation reaction or asymmetric aminoalkylation reaction of an aromatic compound performed by applying the cyclic phosphate compound of the present invention, the following formula (8) and the following formula (15) What can obtain | require Formula (16) from can be illustrated.
式（１５）中のＲ15は、複数結合していてもよく、複数結合しているときは、それぞれ異なっていてもよく、水酸基、ハロゲン原子、炭素数１〜６個の分岐を有してもよいアルキル基、または炭素数１〜６個の分岐を有してもよいアルコキシ基を示す。R 15 in formula (15) may be a plurality of bonds, and when a plurality of R 15 are bonded, they may be different from each other, and have a hydroxyl group, a halogen atom, or a branch having 1 to 6 carbon atoms. Or an alkyl group which may have a C1-C6 branch.
式（１６）中のＲ12とＲ13は式（８）と同様なものであり、Ｒ15は式（１５）と同様なものである。
式（１５）中のＲ15は、複数結合していてもよく、複数結合しているときは、それぞれ異なっていてもよく、水酸基、ハロゲン原子、炭素数１〜６個の分岐を有してもよいアルキル基、または炭素数１〜６個の分岐を有してもよいアルコキシ基を示す。そして、炭素数１〜６個の分岐を有してもよいアルキル基としては、メチル基、エチル基、またはプロピル基が好ましく、炭素数１〜６個の分岐を有してもよいアルコキシ基としては、メトキシ基、エトキシ基が好ましいものである。
式（１６）中のＲ12とＲ13は式（８）と同様なものであり、Ｒ15は式（１５）と同様なものである。R 12 and R 13 in formula (16) are the same as in formula (8), and R 15 is the same as in formula (15).
R 15 in formula (15) may be a plurality of bonds, and when a plurality of R 15 are bonded, they may be different from each other, and have a hydroxyl group, a halogen atom, or a branch having 1 to 6 carbon atoms. Or an alkyl group which may have a C1-C6 branch. And as an alkyl group which may have a C1-C6 branch, a methyl group, an ethyl group, or a propyl group is preferable, As an alkoxy group which may have a C1-C6 branch Is preferably a methoxy group or an ethoxy group.
R 12 and R 13 in formula (16) are the same as in formula (8), and R 15 is the same as in formula (15).
本発明の環状リン酸化合物を触媒として用いる合成反応に適用して、キラルな化合物を得ることができる。このとき、金属塩または金属錯体を用いないものであることから、環境への負荷が少ないものである。
本発明の環状リン酸化合物を適用して得られた化合物またはキラルな化合物は、香料、医薬、および農薬等に用いる化合物並びにそれらの合成中間体として有用なものである。A chiral compound can be obtained by applying it to a synthesis reaction using the cyclic phosphate compound of the present invention as a catalyst. At this time, since a metal salt or a metal complex is not used, the load on the environment is small.
A compound obtained by applying the cyclic phosphate compound of the present invention or a chiral compound is useful as a compound used for a fragrance, a medicine, an agrochemical or the like, and a synthetic intermediate thereof.
○実施態様
式（１）で表される環状リン酸化合物は、Ｒ1が水素原子またはメチル基であり、Ｒ2が水素原子、メチル基またはフェニル基であり、Ｒ3がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基であり、Ｒ4がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基であり、Ｒ5がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基であり、Ｒ6がフェニル基、３−フルオロフェニル基、４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、４−ビフェニル基、２−ナフチル基であるものが好ましい。
不斉合成用の触媒として用いられる式（１）で表される環状リン酸化合物は、Ｒ1が水素原子またはメチル基であり、Ｒ2が水素原子、メチル基またはフェニル基であり、Ｒ3が４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、または４−ビフェニル基であり、Ｒ4が４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、または４−ビフェニル基であり、Ｒ5が４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、または４−ビフェニル基であり、Ｒ6が４−フルオロフェニル基、ｍ−トリフルオロメチルフェニル基、ｐ−トリフルオロメチルフェニル基、または４−ビフェニル基であるものが好ましい。
式（１）で表される環状リン酸化合物は、Ｒ1とＲ2とが水素原子である場合、Ｒ3〜Ｒ6が全てフェニル基または４−メチルフェニル基であるものを除くことがある。Embodiment In the cyclic phosphate compound represented by the formula (1), R 1 is a hydrogen atom or a methyl group, R 2 is a hydrogen atom, a methyl group or a phenyl group, R 3 is a phenyl group, 3- A fluorophenyl group, a 4-fluorophenyl group, an m-trifluoromethylphenyl group, a p-trifluoromethylphenyl group, a 4-biphenyl group, and a 2-naphthyl group, and R 4 is a phenyl group, a 3-fluorophenyl group, 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, 4-biphenyl group, 2-naphthyl group, R 5 is phenyl group, 3-fluorophenyl group, 4-fluorophenyl Group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, 4-biphenyl group, 2-naphthyl group, and R 6 is phenyl group. , 3-fluorophenyl group, 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, 4-biphenyl group, and 2-naphthyl group are preferable.
In the cyclic phosphate compound represented by the formula (1) used as a catalyst for asymmetric synthesis, R 1 is a hydrogen atom or a methyl group, R 2 is a hydrogen atom, a methyl group or a phenyl group, and R 3 Is 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, or 4-biphenyl group, R 4 is 4-fluorophenyl group, m-trifluoromethylphenyl group, p- A trifluoromethylphenyl group or a 4-biphenyl group, R 5 is a 4-fluorophenyl group, an m-trifluoromethylphenyl group, a p-trifluoromethylphenyl group, or a 4-biphenyl group, and R 6 is What is 4-fluorophenyl group, m-trifluoromethylphenyl group, p-trifluoromethylphenyl group, or 4-biphenyl group Masui.
The cyclic phosphoric acid compound represented by the formula (1) may exclude those in which R 3 to R 6 are all phenyl groups or 4-methylphenyl groups when R 1 and R 2 are hydrogen atoms. .
＜実施例＞
以下実施例により本発明を具体的に説明するが、本発明はこれら実施例のみに限定されるものではない。Ｍはモル濃度（ｍｏｌ／リットル）を示す。合成操作は、反応系内を窒素ガス置換し、試薬や溶媒等は脱水して用いた。<Example>
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. M represents the molar concentration (mol / liter). In the synthesis operation, the inside of the reaction system was replaced with nitrogen gas, and reagents and solvents were dehydrated before use.
＜合成例１＞
○（４Ｒ，５Ｒ）−Ｄｉｅｔｈｙｌ １，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｃａｒｂｏｘｙｌａｔｅ（化合物Ｂ１）の合成
乾燥させた三口ナス型フラスコ（１００ｍｌ）に窒素雰囲気下、パラホルムアルデヒド（３２４．７ｍｍｏｌ）、塩化亜鉛（７３．３ｍｍｏｌ）、Ｌ−（＋）−酒石酸ジエチル（１２２．２ｍｍｏｌ）の順に加え１５０°Ｃで１時間撹拌した。その後、室温まで冷却させ、ジエチルエーテルで３回抽出した。抽出した有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。減圧蒸留（ｂ．ｐ．１４０−１６０℃，４００Ｐａ）し、（４Ｒ，５Ｒ）−ｄｉｅｔｈｙｌ １，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｃａｒｂｏｘｙｌａｔｅ（化合物Ｂ１、５９．６ｍｍｏｌ，収率４９％）を得た。
この化合物Ｂ１の1Ｈ−ＮＭＲのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝５．２６（ｓ，２Ｈ），４．７３（ｓ，２Ｈ），４．２９（ｑ，４Ｈ），１．３３（ｔ，６Ｈ）．<Synthesis Example 1>
Synthesis of (4R, 5R) -Diethyl 1,3-dioxolane-4,5-dicboxylate (Compound B1) Paraformaldehyde (324.7 mmol), zinc chloride in a dried three-necked eggplant-shaped flask (100 ml) under nitrogen atmosphere (73.3 mmol) and L-(+)-diethyl tartrate (122.2 mmol) were added in this order, and the mixture was stirred at 150 ° C. for 1 hour. Thereafter, the mixture was cooled to room temperature and extracted three times with diethyl ether. The extracted organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product. Distillation under reduced pressure (bp 140-160 ° C., 400 Pa) gave (4R, 5R) -diethyl 1,3-dioxolane-4,5-dicboxylate (compound B1, 59.6 mmol, yield 49%). .
The 1 H-NMR data of this compound B1 are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 5.26 (s, 2H), 4.73 (s, 2H), 4.29 (q, 4H), 1.33 (t, 6H).
＜合成例２＞
○（４Ｒ，５Ｒ）−Ｄｉｅｔｈｙｌ ２，２−ｄｉｍｅｔｈｙｌ−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｃａｒｂｏｘｙｌａｔｅ（化合物Ｂ２）の合成
Ｌ−（＋）−酒石酸ジエチルとアセトンとから常法に従って化合物Ｂ２を合成した。<Synthesis Example 2>
Synthesis of (4R, 5R) -Diethyl 2,2-dimethyl-1,3-dioxolane-4,5-dicboxylate (Compound B2) Compound B2 is synthesized from diethyl L-(+)-tartrate and acetone according to a conventional method. did.
＜合成例３＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａｐｈｅｎｙｌ−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃａ）の合成
乾燥させた三口ナス型フラスコ（２００ｍｌ）に窒素雰囲気下で化合物Ｂ１（９．１７ｍｍｏｌ）のＴＨＦ溶液１４ｍｌを加え０°Ｃで１０分間撹拌した。別途調製したＰｈＭｇＢｒ（４５．４ｍｍｏｌ）をここに滴下し、室温で１時間撹拌した後、更に２時間加熱還流した。ＴＬＣで化合物Ｂ１の消失を確認後、室温まで冷却させ、飽和塩化アンモニウム水溶液を加えて反応を停止させた。析出した結晶を１Ｎ塩酸で溶解させた後、ジエチルエーテルで３回抽出した。抽出した有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。カラムクロマトグラフィーで分離精製し、（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａｐｈｅｎｙｌ−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃａ，７．５２ｍｍｏｌ，収率８２％）を得た。
この化合物ＣａのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．６（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．５０−７．１８（ｍ，２０Ｈ），５．０８（ｓ，２Ｈ），４．７１（ｓ，２Ｈ），２．５９（ｓ，２Ｈ）．<Synthesis Example 3>
○ Synthesis of (4R, 5R) -α, α, α ′, α′-Tetraphenyl-1,3-dioxolane-4,5-dimethylanol (Compound Ca) In a nitrogen atmosphere in a dried three-necked eggplant type flask (200 ml) Then, 14 ml of THF solution of compound B1 (9.17 mmol) was added and stirred at 0 ° C. for 10 minutes. Separately prepared PhMgBr (45.4 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour, and further heated to reflux for 2 hours. After confirming disappearance of Compound B1 by TLC, the mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution was added to stop the reaction. The precipitated crystals were dissolved with 1N hydrochloric acid and extracted three times with diethyl ether. The extracted organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product. Separation and purification by column chromatography, (4R, 5R) -α, α, α ′, α′-tetraphenyl-1,3-dioxolane-4,5-dimethylanol (compound Ca, 7.52 mmol, yield 82%) Got.
The silica gel TLC and 1 H-NMR data of this compound Ca are described below.
Rf = 0.6 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.50-7.18 (m, 20H), 5.08 (s, 2H), 4.71 (s, 2H), 2.59 (s, 2H) ).
＜合成例４＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（３−ｆｌｕｏｒｏｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｂ）の合成
ＰｈＭｇＢｒの替わりに３−Ｆ−Ｃ6Ｈ4ＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｂを合成した。この化合物ＣｂのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．６（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．３６−６．８２（ｍ，１６Ｈ），４．９８（ｓ，２Ｈ），４．９５（ｓ，２Ｈ），２．７４（ｓ，２Ｈ）．<Synthesis Example 4>
Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (3-fluorophenyl) -1,3-dioxolane-4,5-dimethanol (Compound Cb) 3-F-C instead of PhMgBr Compound Cb was synthesized in the same manner as in Synthesis Example 3 except that 6 H 4 MgBr was used. The silica gel TLC and 1 H-NMR data of this compound Cb are shown below.
Rf = 0.6 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.36-6.82 (m, 16H), 4.98 (s, 2H), 4.95 (s, 2H), 2.74 (s, 2H) ).
＜合成例５＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｃ）の合成
ＰｈＭｇＢｒの替わりに４−Ｆ−Ｃ6Ｈ4ＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｃを合成した。この化合物ＣｃのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．５（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．４９（ｄｄ，４Ｈ），７．１９（ｄｄ，４Ｈ），７．０５（ｄｄ，４Ｈ），６．８５（ｄｄ，４Ｈ），４．９５（ｓ，２Ｈ），４．８２（ｓ，２Ｈ），２．６８（ｓ，２Ｈ）．<Synthesis Example 5>
Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (4-fluorophenyl) -1,3-dioxolane-4,5-dimethylanol (Compound Cc) 4-F-C instead of PhMgBr Compound Cc was synthesized in the same manner as in Synthesis Example 3 except that 6 H 4 MgBr was used. The silica gel TLC and 1 H-NMR data of this compound Cc are described below.
Rf = 0.5 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.49 (dd, 4H), 7.19 (dd, 4H), 7.05 (dd, 4H), 6.85 (dd, 4H), 4. 95 (s, 2H), 4.82 (s, 2H), 2.68 (s, 2H).
＜合成例６＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（３−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｄ）の合成
ＰｈＭｇＢｒの替わりに３−ＣＦ3Ｃ6Ｈ4ＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｄを合成した。この化合物ＣｄのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．５（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．８０−７．１８（ｍ，１６Ｈ），５．０２（ｓ，２Ｈ），４．８８（ｓ，２Ｈ），２．８３（ｓ，２Ｈ）．<Synthesis Example 6>
Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (3-trifluoromethylphenyl) -1,3-dioxolane-4,5-dimethylanol (Compound Cd) 3-CF 3 C instead of PhMgBr Compound Cd was synthesized in the same manner as in Synthesis Example 3 except that 6 H 4 MgBr was used. The silica gel TLC and 1 H-NMR data of this compound Cd are described below.
Rf = 0.5 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.80-7.18 (m, 16H), 5.02 (s, 2H), 4.88 (s, 2H), 2.83 (s, 2H) ).
＜合成例７＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｅ）の合成
乾燥させた三口ナス型フラスコ（１００ｍｌ）に窒素雰囲気下で化合物Ｂ１（６．８９ｍｍｏｌ）のＴＨＦ溶液５ｍｌを加え０°Ｃで１０分間撹拌した。別途調製したｐ−ＣＦ3Ｃ6Ｈ4ＭｇＢｒ（３４．４ｍｍｏｌ）を滴下し、室温で３０分間撹拌した後、３０分間加熱還流した。ＴＬＣで化合物Ｂ１の消失を確認後、室温まで冷却し、飽和塩化アンモニウム水溶液で反応を停止した。析出した結晶を１Ｎ塩酸で溶解させた後、ジエチルエーテルで３回抽出し、抽出した有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。カラムクロマトグラフィーで分離精製し、化合物Ｃｅ（３．８ｍｍｏｌ，収率５５％）を得た。この化合物ＣｅのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．５（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．６０−７．２２（ｍ，１６Ｈ），５．１２（ｓ，２Ｈ），５．０５（ｓ，２Ｈ），２．８１（ｓ，２Ｈ）．<Synthesis Example 7>
Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (4-trifluoromethylphenyl) -1,3-dioxolane-4,5-dimethylanol (Compound Ce) Dry three-necked eggplant type flask (100 ml) ) Was added with 5 ml of a solution of compound B1 (6.89 mmol) in THF under a nitrogen atmosphere and stirred at 0 ° C. for 10 minutes. Separately prepared p-CF 3 C 6 H 4 MgBr (34.4 mmol) was added dropwise, stirred at room temperature for 30 minutes, and then heated to reflux for 30 minutes. After confirming the disappearance of Compound B1 by TLC, the mixture was cooled to room temperature and quenched with a saturated aqueous ammonium chloride solution. The precipitated crystals were dissolved with 1N hydrochloric acid and extracted three times with diethyl ether. The extracted organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product. Separation and purification by column chromatography gave Compound Ce (3.8 mmol, yield 55%). The silica gel TLC and 1 H-NMR data of this compound Ce are described below.
Rf = 0.5 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.60-7.22 (m, 16H), 5.12 (s, 2H), 5.05 (s, 2H), 2.81 (s, 2H) ).
＜合成例８＞
○（４Ｒ，５Ｒ）−２，２−ｄｉｍｅｔｈｙｌ−α，α，α’，α’−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｆ）の合成
化合物Ｂ１の替わりに化合物Ｂ２を、ＰｈＭｇＢｒの替わりに４−ＣＦ3Ｃ6Ｈ4ＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｆを合成した。この化合物ＣｆのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．４（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．８６−７．３５（ｍ，１６Ｈ），４．５５（ｓ，２Ｈ），４．１３（ｓ，２Ｈ），１．１２（ｓ，６Ｈ）．<Synthesis Example 8>
Synthesis of (4R, 5R) -2,2-dimethyl-α, α, α ′, α′-tetra (4-trifluoromethylphenyl) -1,3-dioxolane-4,5-dimethylanol (Compound Cf) of Compound B1 Compound Cf was synthesized in the same manner as in Synthesis Example 3 except that compound B2 was used instead of 4-CF 3 C 6 H 4 MgBr instead of PhMgBr. The silica gel TLC and 1 H-NMR data of this compound Cf are shown below.
Rf = 0.4 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.86-7.35 (m, 16H), 4.55 (s, 2H), 4.13 (s, 2H), 1.12 (s, 6H) ).
＜合成例９＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（３−ｆｌｕｏｒｏ−４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｇ）の合成
ＰｈＭｇＢｒの替わりに３−Ｆ−４−ＣＦ3Ｃ6Ｈ3ＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｇを合成した。この化合物ＣｇのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．４（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．６４−６．８１（ｍ，１２Ｈ），５．１０（ｓ，２Ｈ），４．９８（ｓ，２Ｈ），３．０２（ｓ，２Ｈ）．<Synthesis Example 9>
Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (3-fluoro-4-trifluoromethyl) -1,3-dioxolane-4,5-dimethylanol (Compound Cg) 3 instead of PhMgBr except for using -F-4-CF 3 C 6 H 3 MgBr was synthesized compound Cg using the same method as in synthesis example 3. The silica gel TLC and 1 H-NMR data of this compound Cg are described below.
Rf = 0.4 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.64-6.81 (m, 12H), 5.10 (s, 2H), 4.98 (s, 2H), 3.02 (s, 2H) ).
＜合成例１０＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（４−ｂｉｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｈ）の合成
ＰｈＭｇＢｒの替わりに４−ｂｉｐｈｅｎｙｌＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｈを合成した。この化合物ＣｈのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．２（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．６８−７．２３（ｍ，３６Ｈ），５．３０（ｓ，２Ｈ），５．１３（ｓ，２Ｈ），２．８０（ｓ，２Ｈ）．<Synthesis Example 10>
○ Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (4-biphenyl) -1,3-dioxolane-4,5-dimethylanol (Compound Ch) 4-biphenylMgBr is used instead of PhMgBr Except for the above, compound Ch was synthesized in the same manner as in Synthesis Example 3. The silica gel TLC and 1 H-NMR data of this compound Ch are described below.
Rf = 0.2 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.68-7.23 (m, 36H), 5.30 (s, 2H), 5.13 (s, 2H), 2.80 (s, 2H) ).
＜合成例１１＞
○（４Ｒ，５Ｒ）−α，α，α’，α’−Ｔｅｔｒａ（２−ｎａｐｈｔｈｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｉ）の合成
ＰｈＭｇＢｒの替わりに２−ｎａｐｈｔｈｙｌＭｇＢｒを用いた以外は、合成例３と同様に操作して化合物Ｃｉを合成した。この化合物ＣｉのシリカゲルＴＬＣと1Ｈ−ＮＭＲのデータを下記に記載した。
Ｒｆ＝０．２（Ｈｅｘａｎｅ：Ｅｔ2Ｏ＝１：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝８．２０−６．７２（ｍ，２８Ｈ），５．５５（ｓ，２Ｈ），５．１８（ｓ，２Ｈ），２．９２（ｓ，２Ｈ）．<Synthesis Example 11>
○ Synthesis of (4R, 5R) -α, α, α ′, α′-Tetra (2-naphthyl) -1,3-dioxolane-4,5-dimethylanol (Compound Ci) Using 2-naphthylMgBr instead of PhMgBr Compound Ci was synthesized in the same manner as in Synthesis Example 3 except that. The silica gel TLC and 1 H-NMR data of this compound Ci are described below.
Rf = 0.2 (Hexane: Et 2 O = 1: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 8.20-6.72 (m, 28H), 5.55 (s, 2H), 5.18 (s, 2H), 2.92 (s, 2H) ).
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａｐｈｅｎｙｌ−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ａ）の合成
乾燥させた二口ナス型フラスコ（３０ｍｌ）に窒素雰囲気下、化合物Ｃａ（３ｍｍｏｌ）、ＴＨＦ（２５ｍｌ）、トリエチルアミン（９ｍｍｏｌ）の順に加え、０℃で１０分間撹拌した。ここに三塩化リン（６．６ｍｍｏｌ）のＴＨＦ溶液５ｍｌを滴下し、０℃で１時間撹拌した。その後、トリエチルアミン（４．５ｍｍｏｌ）、蒸留水（０．３ｍｌ）の順に滴下し、さらに３０分間撹拌した。この反応液を酢酸エチルエステルで３回抽出し、有機層を合わせ、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。
得られた粗生成物にピリジン６．８ｍｌ、蒸留水０．７５ｍｌ、ヨウ素（６．６ｍｍｏｌ）の順に加えて３０分間撹拌した。その後、飽和亜硫酸ナトリウム水溶液で反応を停止させ、ジクロロメタンで３回抽出した。これら有機層を合わせ、飽和亜硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。この粗生成物をメタノールに溶かし、１規定塩酸で沈澱させて下記式（１７）で表される化合物３ａ（２．３ｍｍｏｌ，収率７７％）を得た。この化合物３ａの1Ｈ−ＮＭＲと31Ｐ−ＮＭＲとのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．４９−７．２２（ｍ，２０Ｈ），５．０８（ｓ，２Ｈ），４．３６（ｓ，２Ｈ）
31Ｐ−ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ3）δ＝−６．８４．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetraphenyl-3,5,8,10-tetraoxa-4-phospho-bicyclo [5.3.0] decane (compound) Synthesis of 3a) Under a nitrogen atmosphere, a compound Ca (3 mmol), THF (25 ml) and triethylamine (9 mmol) were added in this order to a dried two-necked eggplant flask (30 ml), and the mixture was stirred at 0 ° C. for 10 minutes. 5 ml of a THF solution of phosphorus trichloride (6.6 mmol) was added dropwise thereto, and the mixture was stirred at 0 ° C. for 1 hour. Thereafter, triethylamine (4.5 mmol) and distilled water (0.3 ml) were added dropwise in this order, and the mixture was further stirred for 30 minutes. This reaction solution was extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product.
To the obtained crude product, 6.8 ml of pyridine, 0.75 ml of distilled water, and iodine (6.6 mmol) were added in this order, and the mixture was stirred for 30 minutes. Thereafter, the reaction was quenched with a saturated aqueous sodium sulfite solution, and extracted three times with dichloromethane. These organic layers were combined, washed with a saturated aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was dissolved in methanol and precipitated with 1N hydrochloric acid to obtain compound 3a represented by the following formula (17) (2.3 mmol, yield 77%). The 1 H-NMR and 31 P-NMR data of this compound 3a are described below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.49-7.22 (m, 20H), 5.08 (s, 2H), 4.36 (s, 2H)
31 P-NMR (121 MHz, CDCl 3 ) δ = −6.84.
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（３−ｆｌｕｏｒｏｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｂ）の合成
化合物Ｃａの替わりに化合物Ｃｂを用いた以外は実施例１と同様に操作し、化合物３ｂを得た。この化合物３ｂの1Ｈ−ＮＭＲと31Ｐ−ＮＭＲとのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．３４−６．９０（ｍ，１６Ｈ），４．９９（ｓ，２Ｈ），４．４２（ｓ，２Ｈ）
31Ｐ−ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ3）δ＝−７．４２．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (3-fluorphenyl) -3,5,8,10-tetraoxa-4-phospho-bicyclo [5.3. 0] Synthesis of Decane (Compound 3b) Compound 3b was obtained in the same manner as in Example 1 except that Compound Cb was used instead of Compound Ca. The 1 H-NMR and 31 P-NMR data of this compound 3b are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.34-6.90 (m, 16H), 4.99 (s, 2H), 4.42 (s, 2H)
31 P-NMR (121 MHz, CDCl 3 ) δ = −7.42.
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（４−ｆｌｕｏｒｏｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｃ）の合成
化合物Ｃａの替わりに化合物Ｃｃを用いた以外は実施例１と同様に操作し、化合物３ｃを得た。この化合物３ｃの1Ｈ−ＮＭＲのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．５０−６．９０（ｍ，１６Ｈ），４．９５（ｓ，２Ｈ），４．３８（ｓ，２Ｈ）．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (4-fluorophenyl) -3,5,8,10-tetraoxa-4-phosphopha-bicyclo [5.3. 0] Synthesis of Decane (Compound 3c) Compound 3c was obtained in the same manner as in Example 1 except that Compound Cc was used instead of Compound Ca. The 1 H-NMR data of this compound 3c are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.50-6.90 (m, 16H), 4.95 (s, 2H), 4.38 (s, 2H).
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（３−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｄ）の合成
化合物Ｃａの替わりに化合物Ｃｄを用いた以外は実施例１と同様に操作し、化合物３ｄを得た。この化合物３ｄの1Ｈ−ＮＭＲと31Ｐ−ＮＭＲとのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．８０−７．３５（ｍ，１６Ｈ），５．０８（ｓ，２Ｈ），４．４２（ｓ，２Ｈ）
31Ｐ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ3）δ＝−７．２７．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (3-trifluoromethyl) -3,5,8,10-tetraoxa-4-phosphopha-bicyclo [5.3. 0] Synthesis of Decane (Compound 3d) Compound 3d was obtained in the same manner as in Example 1 except that Compound Cd was used instead of Compound Ca. The 1 H-NMR and 31 P-NMR data of this compound 3d are described below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.80-7.35 (m, 16H), 5.08 (s, 2H), 4.42 (s, 2H)
31 P-NMR (100 MHz, CDCl 3 ) δ = −7.27.
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｅ）の合成
乾燥させた二口ナス型フラスコ（３０ｍｌ）に窒素雰囲気下、化合物Ｃｅ（１．５ｍｍｏｌ）、ＴＨＦ（９ｍｌ）、トリエチルアミン（４．５ｍｍｏｌ）の順に加え、０℃で１０分間撹拌した。その後、三塩化リン（３．３ｍｍｏｌ）のＴＨＦ溶液９ｍｌを滴下し、０℃で１時間撹拌した。その後、トリエチルアミン（１．５ｍｍｏｌ）、蒸留水（１．９ｍｍｏｌ）の順に滴下し、さらに３０分間撹拌した。この反応液を酢酸エチルエステルで３回抽出し、有機層を合わせて飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。
得られた粗生成物にピリジン３．６ｍｌ、蒸留水０．４ｍｌ、ヨウ素（３．８９ｍｍｏｌ）の順に加えて２０分間撹拌した。その後、飽和亜硫酸ナトリウム水溶液を用いて反応を停止させた後、ジクロロメタンで３回抽出し、有機層を合わせて飽和亜硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥後、無水硫酸ナトリウムをろ別し、溶媒を減圧下留去し、粗生成物を得た。この粗生成物をメタノールに溶かし、１Ｎ塩酸で沈澱させて下記式（１８）で表される化合物３ｅ（１．１８ｍｍｏｌ，収率７９％）を得た。この化合物３ｅの1Ｈ−ＮＭＲと31Ｐ−ＮＭＲとのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．７９−７．４８（ｍ，１６Ｈ），５．００（ｓ，２Ｈ），４．４２（ｓ，２Ｈ）
31Ｐ−ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ3）δ＝−７．３６．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (4-trifluoromethylphenyl) -3,5,8,10-tetraoxa-4-phospho-bicyclo [5.3. 0] Synthesis of Decane (Compound 3e) Compound Ce (1.5 mmol), THF (9 ml), and triethylamine (4.5 mmol) were added in this order to a dried two-necked eggplant-shaped flask (30 ml) in a nitrogen atmosphere at 0 ° C. For 10 minutes. Thereafter, 9 ml of a THF solution of phosphorus trichloride (3.3 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour. Thereafter, triethylamine (1.5 mmol) and distilled water (1.9 mmol) were added dropwise in this order, and the mixture was further stirred for 30 minutes. This reaction solution was extracted three times with ethyl acetate, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product.
To the obtained crude product, 3.6 ml of pyridine, 0.4 ml of distilled water, and iodine (3.89 mmol) were added in this order, followed by stirring for 20 minutes. Thereafter, the reaction was stopped using a saturated aqueous sodium sulfite solution, followed by extraction three times with dichloromethane. The organic layers were combined, washed with a saturated aqueous sodium sulfite solution and saturated brine, and dried over anhydrous sodium sulfate. After drying, anhydrous sodium sulfate was filtered off, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was dissolved in methanol and precipitated with 1N hydrochloric acid to obtain compound 3e (1.18 mmol, yield 79%) represented by the following formula (18). The 1 H-NMR and 31 P-NMR data of this compound 3e are described below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.79-7.48 (m, 16H), 5.00 (s, 2H), 4.42 (s, 2H)
31 P-NMR (121 MHz, CDCl 3 ) δ = −7.36.
○（１Ｒ，７Ｒ）−９，９−ｄｉｍｅｔｈｙｌ−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｆ）の合成
化合物Ｃｅの替わりに化合物Ｃｆを用いた以外は実施例５と同様に操作し、化合物３ｆを得た。この化合物３ｆの1Ｈ−ＮＭＲと31Ｐ−ＮＭＲとのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．６３−７．４９（ｍ，１６Ｈ），５．１３（ｓ，２Ｈ），０．７９（ｓ，６Ｈ）
31Ｐ−ＮＭＲ（１２１ＭＨｚ，ＣＤＣｌ3）δ＝−８．１４．(1R, 7R) -9,9-dimethyl-4-hydroxy-4-oxo-2,2,6,6-tetra (4-trifluoromethylphenyl) -3,5,8,10-tetraoxa-4-phospho- Synthesis of bicyclo [5.3.0] decane (Compound 3f) Compound 3f was obtained in the same manner as in Example 5 except that Compound Cf was used instead of Compound Ce. The 1 H-NMR and 31 P-NMR data of this compound 3f are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.63-7.49 (m, 16H), 5.13 (s, 2H), 0.79 (s, 6H)
31 P-NMR (121 MHz, CDCl 3 ) δ = −8.14.
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（３−ｆｌｕｏｒｏ−４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｇ）の合成
化合物Ｃｅの替わりに化合物Ｃｇを用いた以外は実施例５と同様に操作し、化合物３ｇを得た。この化合物３ｇの1Ｈ−ＮＭＲのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．５８−７．３６（ｍ，１２Ｈ），４．９４（ｓ，２Ｈ），４．５０（ｓ，２Ｈ）．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (3-fluoro-4-trifluoromethyl) -3,5,8,10-tetraoxa-4-phospho-cyclo [ 5.3.0] Synthesis of Decane (Compound 3g) The same operation as in Example 5 was carried out except that Compound Cg was used instead of Compound Ce to obtain Compound 3g. The 1 H-NMR data of 3 g of this compound are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.58-7.36 (m, 12H), 4.94 (s, 2H), 4.50 (s, 2H).
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（４−ｂｉｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｈ）の合成
化合物Ｃｅの替わりに化合物Ｃｈを用いた以外は実施例５と同様に操作し、化合物３ｈを得た。この化合物３ｈの1Ｈ−ＮＭＲのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．７９−７．２９（ｍ，３６Ｈ），５．２６（ｓ，２Ｈ），４．５０（ｓ，２Ｈ）．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (4-biphenyl) -3,5,8,10-tetraoxa-4-phospho-bicyclo [5.3. 0] Synthesis of Decane (Compound 3h) Compound 3h was obtained in the same manner as in Example 5 except that Compound Ch was used instead of Compound Ce. The 1 H-NMR data of this compound 3h are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.79-7.29 (m, 36H), 5.26 (s, 2H), 4.50 (s, 2H).
○（１Ｒ，７Ｒ）−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（２−ｎａｐｈｔｈｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｉ）の合成
化合物Ｃｅの替わりに化合物Ｃｉを用いた以外は実施例５と同様に操作し、化合物３ｉを得た。この化合物３ｉの1Ｈ−ＮＭＲのデータを下記に記載した。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝８．５１−６．９２（ｍ，２８Ｈ），５．６０（ｓ，２Ｈ），４．４３（ｓ，２Ｈ）．(1R, 7R) -4-hydroxy-4-oxo-2,2,6,6-tetra (2-naphthyl) -3,5,8,10-tetraoxa-4-phospho-bicyclo [5.3. 0] Synthesis of Decane (Compound 3i) Compound 3i was obtained in the same manner as in Example 5 except that Compound Ci was used instead of Compound Ce. The 1 H-NMR data of this compound 3i are shown below.
1 H-NMR (400 MHz, CDCl 3 ) δ = 8.51-6.92 (m, 28H), 5.60 (s, 2H), 4.43 (s, 2H).
＜合成例１２＞
○化合物１ａ（式（１９））の合成
ナスフラスコ（１００ｍｌ）にｏ−アミノフェノール（４９．１ｍｍｏｌ）を加えエタノールで溶かした。そこに室温で無水硫酸ナトリウムを加え、ベンズアルデヒド（４０．９ｍｍｏｌ）を滴下した。１時間撹拌した後、無水硫酸ナトリウムをろ過、濃縮し粗生成物を得た。得られた固体はエタノールを用いて再結晶法により精製し、下記式（１９）で表されるＮ−ｅｎｚｙｌｉｄｅｎｅ−２−ａｍｉｎｏｐｈｅｎｏｌ（化合物１ａ、２４．３ｍｍｏｌ，収率５９％）を得た。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝８．７１（ｓ，１Ｈ），７．９４−７．９２（ｍ，２Ｈ），７．５１−７．４７（ｍ，３Ｈ），７．３２−７．３０（ｍ，１Ｈ），７．２４（ｓ，１Ｈ），７．２２−７．１８（ｍ，１Ｈ），７．０３−７．０１（ｍ，１Ｈ），６．９３−６．８９（ｍ，１Ｈ）．<Synthesis Example 12>
Synthesis of Compound 1a (Formula (19)) o-Aminophenol (49.1 mmol) was added to an eggplant flask (100 ml) and dissolved in ethanol. Anhydrous sodium sulfate was added thereto at room temperature, and benzaldehyde (40.9 mmol) was added dropwise. After stirring for 1 hour, anhydrous sodium sulfate was filtered and concentrated to obtain a crude product. The obtained solid was purified by recrystallization using ethanol to obtain N-enylidene-2-aminophenol (compound 1a, 24.3 mmol, yield 59%) represented by the following formula (19).
1 H-NMR (400 MHz, CDCl 3 ) δ = 8.71 (s, 1H), 7.94-7.92 (m, 2H), 7.51-7.47 (m, 3H), 7.32 -7.30 (m, 1H), 7.24 (s, 1H), 7.22-7.18 (m, 1H), 7.03-7.01 (m, 1H), 6.93-6 .89 (m, 1H).
＜合成例１３＞
○化合物２ａ（式（２０））の合成
乾燥した三口（２００ｍｌ）ナスフラスコに窒素雰囲気下、ＴＨＦ（４５ｍｌ）、ジイソプロピルアミン（６６．３ｍｍｏｌ）を加え０℃で５分間撹拌後、ｎ−ブチルリチウム（６６．９ｍｍｏｌ）を１０分間かけて滴下した。−７８℃に冷却しイソ酪酸メチル（６５．４ｍｍｏｌ）を５分間かけて滴下した。３０分間撹拌後、−７８℃でトリメチルシリルクロリド（７０．９ｍｍｏｌ）を加えた。−７８℃で３０分間撹拌後、室温まで昇温し、減圧留去後、ジエチルエーテルを用いてセライトろ過（３回）した。減圧蒸留（ｂ．ｐ．７０−８０℃，１３０００ｐａ）を行いて精製し、下記式（２０）で表される１−Ｍｅｔｈｏｘｙ−２−ｍｅｔｈｙｌ−１−ｔｒｉｍｅｔｈｙｌｓｉｌｏｘｙｐｒｏｐｅｎｅ（化合物２ａ，３０．４ｍｍｏｌ，収率４７％）を得た。
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝３．５０（ｓ，３Ｈ），１．５７（ｓ，３Ｈ），１．５２（ｓ，３Ｈ），０．２１（ｓ，９Ｈ）。<Synthesis Example 13>
Synthesis of Compound 2a (Formula (20)) THF (45 ml) and diisopropylamine (66.3 mmol) were added to a dried three-necked (200 ml) eggplant flask under a nitrogen atmosphere and stirred at 0 ° C. for 5 minutes, and then n-butyllithium. (66.9 mmol) was added dropwise over 10 minutes. The mixture was cooled to −78 ° C. and methyl isobutyrate (65.4 mmol) was added dropwise over 5 minutes. After stirring for 30 minutes, trimethylsilyl chloride (70.9 mmol) was added at -78 ° C. After stirring at −78 ° C. for 30 minutes, the mixture was warmed to room temperature, evaporated under reduced pressure, and filtered through Celite (3 times) using diethyl ether. 1-Methoxy-2-methyl-1-trimethylsiloxane (compound 2a, 30.4 mmol, yield) represented by the following formula (20) is purified by distillation under reduced pressure (bp 70-80 ° C., 13000 pa). 47%).
1 H-NMR (400 MHz, CDCl 3 ) δ = 3.50 (s, 3H), 1.57 (s, 3H), 1.52 (s, 3H), 0.21 (s, 9H).
○化合物３ａ〜３ｉを触媒として用いた化合物４ａａの合成
乾燥した二口（１０ｍｌ）ナスフラスコに窒素雰囲気下、化合物１ａ（０．２ｍｍｏｌ）、化合物３ｅ（０．０１ｍｍｏｌ）、トルエン（１ｍｌ）の順に加え−７８℃で１０分間撹拌した。その後、化合物２ａ（０．３ｍｍｏｌ）を滴下した。数時間後ＴＬＣで化合物１ａのスポットの消失を確認後、飽和炭酸水素ナトリウム水溶液、飽和フッ化カリウム水溶液を滴下して反応を停止し、室温まで昇温して３０分間撹拌した。酢酸エチルエステルで３回抽出し、合わせた有機層を１規定塩酸、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。無水硫酸ナトリウムをろ別した後、溶媒を減圧下留去し、粗生成物を得た。薄層クロマトグラフィーで分離精製し、下記式（２１）で表されるマンニッヒ付加体４ａａを得た。光学純度の決定は高速液体クロマトグラフを用いて決定した。
［α］D 25 ０．２（ｃ １．０３，ＣＨＣｌ3）
ＴＬＣ：Ｒｆ＝０．３（Ｈｅｘａｎｅ：Ｅｔｈｙｌ ａｃｅｔａｔｅ＝４：１）
1Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ3）δ＝７．２９−７．１９（ｍ，５Ｈ），６．６９−６．４９（ｍ，３Ｈ），６．３９−６．３７（ｍ，１Ｈ），５．８０（ｂｒｓ，１Ｈ），４．９３（ｂｒｓ，１Ｈ），４．５７（ｓ，１Ｈ），３．６８（ｓ，３Ｈ），１．２４（ｓ，３Ｈ），１．２１（ｓ，３Ｈ）
13Ｃ−ＮＭＲ（１００ＭＨｚ，ＣＤＣｌ3）δ＝１７７．７，１４４．３，１３９．０，１３５．５，１２８．３，１２７．９，１２７．４，１２１．０，１１７．９，１１４．３，１１３．９，６４．６，５２．２，４７．４，２４．４，２０．０
ＨＰＬＣ：Ｄａｉｃｅｌ Ｃｈｉｒａｌｐａｋ ＡＤ−Ｈ，
Ｈｅｘａｎｅ／ｉ−ＰｒＯＨ＝９／１，
Ｆｌｏｗ ｒａｔｅ＝０．５ｍｌ／ｍｉｎ，ＵＶ＝２４４ｎｍ，
ｔＲ＝１８．０ｍｉｎ（３Ｒ），
ｔＲ＝３０．５ｍｉｎ（３Ｓ）．
化合物３ａ〜化合物３ｉについても同様の手順で行った。なお、反応条件は、表１に記載した。
これらの結果を表１に記載する。Synthesis of Compound 4aa Using Compounds 3a to 3i as Catalysts In a nitrogen atmosphere in a dry two-necked (10 ml) eggplant flask, compound 1a (0.2 mmol), compound 3e (0.01 mmol), and toluene (1 ml) in this order. The mixture was further stirred at −78 ° C. for 10 minutes. Thereafter, compound 2a (0.3 mmol) was added dropwise. Several hours later, the disappearance of the spot of compound 1a was confirmed by TLC, and then the reaction was stopped by adding dropwise a saturated sodium bicarbonate aqueous solution and a saturated potassium fluoride aqueous solution, and the mixture was warmed to room temperature and stirred for 30 minutes. The mixture was extracted three times with ethyl acetate, and the combined organic layer was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off, the solvent was distilled off under reduced pressure to obtain a crude product. Separation and purification by thin layer chromatography gave Mannich adduct 4aa represented by the following formula (21). The optical purity was determined using a high performance liquid chromatograph.
[Α] D 25 0.2 (c 1.03, CHCl 3 )
TLC: Rf = 0.3 (Hexane: Ethyl acetate = 4: 1)
1 H-NMR (400 MHz, CDCl 3 ) δ = 7.29-7.19 (m, 5H), 6.69-6.49 (m, 3H), 6.39-6.37 (m, 1H) , 5.80 (brs, 1H), 4.93 (brs, 1H), 4.57 (s, 1H), 3.68 (s, 3H), 1.24 (s, 3H), 1.21 ( s, 3H)
13 C-NMR (100 MHz, CDCl 3 ) δ = 177.7, 144.3, 139.0, 135.5, 128.3, 127.9, 127.4, 121.0, 117.9, 114. 3, 113.9, 64.6, 52.2, 47.4, 24.4, 20.0
HPLC: Daicel Chiralpak AD-H,
Hexane / i-PrOH = 9/1
Flow rate = 0.5 ml / min, UV = 244 nm,
tR = 18.0 min (3R),
tR = 30.5 min (3S).
The same procedure was performed for compound 3a to compound 3i. The reaction conditions are shown in Table 1.
These results are listed in Table 1.
○反応溶媒の検討
実施例１０においてｅｅ％が高かった化合物３ｅを用いて、反応溶媒の検討を行った。なお、下記表２に記載の反応条件以外は、実施例１０に記載と同様にして行った。
この結果を表２に記載する。○ Examination of reaction solvent The reaction solvent was examined using the compound 3e having a high ee% in Example 10. The reaction was performed in the same manner as described in Example 10 except for the reaction conditions described in Table 2 below.
The results are listed in Table 2.
＜合成例１４＞
ｏ−アミノフェノールの替わりに２−アミノ−４−メチルフェノールを用いた以外は合成例１３ど同様に操作し下記式（２２）で表される化合物１ｂを得た。<Synthesis Example 14>
A compound 1b represented by the following formula (22) was obtained in the same manner as in Synthesis Example 13 except that 2-amino-4-methylphenol was used instead of o-aminophenol.
＜合成例１５＞
ｏ−アミノフェノールの替わりに４−アミノ−フェノールを用いた以外は合成例１３と同様に操作し下記式（２３）で表される化合物１ｃを得た。<Synthesis Example 15>
A compound 1c represented by the following formula (23) was obtained in the same manner as in Synthesis Example 13 except that 4-amino-phenol was used instead of o-aminophenol.
○イミンの窒素に結合する置換基の効果
化合物１ａの替わりに化合物１ｂまたは化合物１ｃを用いて実施例１０、ｅｎｔｒｙ８と同様に合成を行った。この結果を表３に記載する。O Effect of substituent bonded to nitrogen of imine Synthesis was performed in the same manner as in Example 10 and entry 8 using Compound 1b or Compound 1c instead of Compound 1a. The results are listed in Table 3.
＜合成例１６＞
ベンズアルデヒドの替わりにｐ−ニトロベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（２４）で表される化合物１ａ２を得た。<Synthesis Example 16>
A compound 1a2 represented by the following formula (24) was obtained in the same manner as in Synthesis Example 13 except that p-nitrobenzaldehyde was used instead of benzaldehyde.
＜合成例１７＞
ベンズアルデヒドの替わりにｐ−クロロベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（２５）で表される化合物１ａ３を得た。<Synthesis Example 17>
A compound 1a3 represented by the following formula (25) was obtained in the same manner as in Synthesis Example 13 except that p-chlorobenzaldehyde was used instead of benzaldehyde.
＜合成例１８＞
ベンズアルデヒドの替わりにｐ−フルオロベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（２６）で表される化合物１ａ４を得た。<Synthesis Example 18>
A compound 1a4 represented by the following formula (26) was obtained in the same manner as in Synthesis Example 13 except that p-fluorobenzaldehyde was used instead of benzaldehyde.
＜合成例１９＞
ベンズアルデヒドの替わりにｐ−メチルベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（２７）で表される化合物１ａ５を得た。<Synthesis Example 19>
A compound 1a5 represented by the following formula (27) was obtained in the same manner as in Synthesis Example 13 except that p-methylbenzaldehyde was used instead of benzaldehyde.
＜合成例２０＞
ベンズアルデヒドの替わりにｐ−メトキシベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（２８）で表される化合物１ａ６を得た。<Synthesis Example 20>
A compound 1a6 represented by the following formula (28) was obtained in the same manner as in Synthesis Example 13 except that p-methoxybenzaldehyde was used instead of benzaldehyde.
＜合成例２１＞
ベンズアルデヒドの替わりに１−ナフチルアルデヒドを用いた以外は合成例１３と同様に操作し下記式（２９）で表される化合物１ａ７を得た。<Synthesis Example 21>
A compound 1a7 represented by the following formula (29) was obtained in the same manner as in Synthesis Example 13 except that 1-naphthylaldehyde was used instead of benzaldehyde.
＜合成例２２＞
ベンズアルデヒドの替わりに２−チオフェンカルボキシアルデヒドを用いた以外は合成例１３と同様に操作し下記式（３０）で表される化合物１ａ８を得た。<Synthesis Example 22>
Except having used 2-thiophene carboxaldehyde instead of benzaldehyde, it operated like the synthesis example 13, and obtained the compound 1a8 represented by following formula (30).
＜合成例２３＞
ベンズアルデヒドの替わりにtrans−シンナムアルデヒドを用いた以外は合成例１３と同様に操作し下記式（３１）で表される化合物１ａ９を得た。<Synthesis Example 23>
Compound 1a9 represented by the following formula (31) was obtained in the same manner as in Synthesis Example 13 except that trans-cinnamaldehyde was used instead of benzaldehyde.
＜合成例２４＞
ｏ−アミノフェノールの替わりに２−アミノ−４−メチルフェノールを用い、ベンズアルデヒドの替わりにｐ−フルオロベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（３２）で表される化合物１ｂ１を得た。<Synthesis Example 24>
Compound 1b1 represented by the following formula (32) is operated in the same manner as in Synthesis Example 13 except that 2-amino-4-methylphenol is used in place of o-aminophenol and p-fluorobenzaldehyde is used in place of benzaldehyde. Got.
＜合成例２５＞
ｏ−アミノフェノールの替わりに２−アミノ−４−メチルフェノールを用い、ベンズアルデヒドの替わりにｐ−メトキシベンズアルデヒドを用いた以外は合成例１３と同様に操作し下記式（３３）で表される化合物１ｂ２を得た。<Synthesis Example 25>
Compound 1b2 represented by the following formula (33) is operated in the same manner as in Synthesis Example 13 except that 2-amino-4-methylphenol is used instead of o-aminophenol and p-methoxybenzaldehyde is used instead of benzaldehyde. Got.
○イミン化合物の効果
表４に記載のイミン化合物を用いて実施例１０、ｅｎｔｒｙ８と同様に合成を行った。この結果を表４に記載する。Effect of imine compound Synthesis was carried out in the same manner as in Example 10 and entry 8 using the imine compounds listed in Table 4. The results are listed in Table 4.
○（１Ｒ，７Ｒ）−９−ｍｅｔｈｙｌ−９−ｐｈｅｎｙｌ−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｊ）の合成
合成例２においてアセトンの替わりに（１，１−ジメトキシエチル）ベンゼンを用いて酒石酸のケタール誘導体（化合物Ｂ３）を合成した。
合成例８において化合物Ｂ２の替わりに化合物Ｂ３を用いて（４Ｒ，５Ｒ）−２−ｍｅｔｈｙｌ−２−ｐｈｅｎｙｌ−α，α，α’，α’−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｊ）を合成した。
化合物Ｃｆの替わりに化合物Ｃｊを用いた以外は実施例６と同様に操作し下記式（３４）で表される化合物３ｊ（式（１）のＲ1＝フェニル基、Ｒ2＝メチル基、Ｒ3〜Ｒ6＝４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌのもの）を合成した。(1R, 7R) -9-methyl-9-phenyl-4-hydroxy-4-oxo-2,2,6,6-tetra (4-trifluoromethylphenyl) -3,5,8,10-tetraoxa-4- Synthesis of phospho-bicyclo [5.3.0] decane (Compound 3j) In Synthesis Example 2, a ketal derivative of tartaric acid (Compound B3) was synthesized using (1,1-dimethoxyethyl) benzene in place of acetone.
In Synthesis Example 8, (4R, 5R) -2-methyl-2-phenyl-α, α, α ′, α′-tetra (4-trifluoromethylphenyl) -1,3-dioxolane was used instead of compound B2 by using compound B3. -4,5-dimethanol (compound Cj) was synthesized.
The compound 3j represented by the following formula (34) (R 1 = phenyl group, R 2 = methyl group, R in formula (1)) is operated in the same manner as in Example 6 except that the compound Cj is used instead of the compound Cf. 3 to R 6 = 4-trifluoromethyl) were synthesized.
○（１Ｒ，７Ｒ）−９−ｐｈｅｎｙｌ−４−ｈｙｄｒｏｘｙ−４−ｏｘｏ−２，２，６，６−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−３，５，８，１０−ｔｅｔｒａｏｘａ−４−ｐｈｏｓｐｈａ−ｂｉｃｙｃｌｏ［５．３．０］ｄｅｃａｎｅ（化合物３ｋ）の合成
合成例２においてアセトンの替わりにベンズアルデヒドを用いて酒石酸のアセタール誘導体（化合物Ｂ４）を合成した。
合成例８において化合物Ｂ４の替わりに化合物Ｂ３を用いて（４Ｒ，５Ｒ）−２−ｐｈｅｎｙｌ−α，α，α’，α’−ｔｅｔｒａ（４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌ）−１，３−ｄｉｏｘｏｌａｎｅ−４，５−ｄｉｍｅｔｈａｎｏｌ（化合物Ｃｋ）を合成した。
化合物Ｃｆの替わりに化合物Ｃｋを用いた以外は実施例６と同様に操作し化合物３ｋ（式（１）のＲ1＝Ｐｈ、Ｒ2＝Ｈ、Ｒ3〜Ｒ6＝４−ｔｒｉｆｌｕｏｒｏｍｅｔｈｙｌｐｈｅｎｙｌのもの）を合成した。(1R, 7R) -9-phenyl-4-hydroxy-4-oxo-2,2,6,6-tetra (4-trifluoromethyl) -3,5,8,10-tetraoxa-4-phosphopha-bicyclo [ 5.3.0] Synthesis of Decane (Compound 3k) An acetal derivative of tartaric acid (Compound B4) was synthesized using benzaldehyde instead of acetone in Synthesis Example 2.
(4R, 5R) -2-phenyl-α, α, α ′, α′-tetra (4-trifluoromethylphenyl) -1,3-dioxolane-4,5 using Compound B3 instead of Compound B4 in Synthesis Example 8 -Dimethanol (compound Ck) was synthesized.
Compound 3k was prepared in the same manner as in Example 6 except that compound Ck was used instead of compound Cf (R 1 = Ph, R 2 = H, R 3 to R 6 = 4-trifluoromethylphenyl in formula (1)) Was synthesized.
本発明の環状リン酸化合物は、酒石酸から容易に光学不斉を有するもの提供することができる。また、当該環状リン酸化合物を不斉合成用の触媒として用いることにより、不斉部位を有する化合物を金属ルイス酸触媒を用いることなく合成することができる。このことから、本発明の環状リン酸化合物を用いることにより重金属を用いない不斉合成の手法を提供することができる。 The cyclic phosphoric acid compound of the present invention can be easily provided with optical asymmetry from tartaric acid. Further, by using the cyclic phosphate compound as a catalyst for asymmetric synthesis, a compound having an asymmetric moiety can be synthesized without using a metal Lewis acid catalyst. From this, by using the cyclic phosphate compound of the present invention, it is possible to provide a method for asymmetric synthesis without using heavy metals.
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| JP2007505801A Active JP4618297B2 (en) | 2005-02-25 | 2005-10-27 | Cyclic erythritol phosphate derivative and asymmetric synthesis method using the same |
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| JP (1) | JP4618297B2 (en) |
| WO (1) | WO2006092884A1 (en) |
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| JP4915696B2 (en) * | 2007-03-07 | 2012-04-11 | 独立行政法人科学技術振興機構 | Process for producing β-aminocarbonyl compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH11302236A (en) * | 1997-07-29 | 1999-11-02 | Sagami Chem Res Center | Production of optically active beta-aminoketones and optically active palladium binuclear complex and its production |
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| JPH11302236A (en) * | 1997-07-29 | 1999-11-02 | Sagami Chem Res Center | Production of optically active beta-aminoketones and optically active palladium binuclear complex and its production |
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| Publication number | Publication date |
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| WO2006092884A1 (en) | 2006-09-08 |
| JPWO2006092884A1 (en) | 2008-08-07 |
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