CN107400036B - A method of synthesis 1,2- dimethylene cyclobutane chipal compounds - Google Patents
A method of synthesis 1,2- dimethylene cyclobutane chipal compounds Download PDFInfo
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- CN107400036B CN107400036B CN201610335358.9A CN201610335358A CN107400036B CN 107400036 B CN107400036 B CN 107400036B CN 201610335358 A CN201610335358 A CN 201610335358A CN 107400036 B CN107400036 B CN 107400036B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 101
- 238000000034 method Methods 0.000 title claims abstract description 33
- QOFLWDYWJZBWHM-UHFFFAOYSA-N 1,2-dimethylidenecyclobutane Chemical compound C=C1CCC1=C QOFLWDYWJZBWHM-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 11
- 238000003786 synthesis reaction Methods 0.000 title abstract description 10
- -1 enamine compound Chemical class 0.000 claims abstract description 135
- 239000010948 rhodium Substances 0.000 claims abstract description 53
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 38
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 82
- 239000003446 ligand Substances 0.000 claims description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
- 239000000126 substance Substances 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 38
- 229910052799 carbon Inorganic materials 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 27
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 24
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
- 239000003208 petroleum Substances 0.000 claims description 23
- 238000004809 thin layer chromatography Methods 0.000 claims description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 20
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 20
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 150000002430 hydrocarbons Chemical class 0.000 claims description 14
- 239000004215 Carbon black (E152) Substances 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229930195733 hydrocarbon Natural products 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 238000006884 silylation reaction Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 241000790917 Dioxys <bee> Species 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 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 claims description 4
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006471 dimerization reaction Methods 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- SJYNFBVQFBRSIB-UHFFFAOYSA-N norbornadiene Chemical compound C1=CC2C=CC1C2 SJYNFBVQFBRSIB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- KWKXNDCHNDYVRT-UHFFFAOYSA-N dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1 KWKXNDCHNDYVRT-UHFFFAOYSA-N 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000012454 non-polar solvent Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- KDZMCHYOHSEAEJ-UHFFFAOYSA-N [Rh+].[Cl+].C1=CCCC=CCC1 Chemical class [Rh+].[Cl+].C1=CCCC=CCC1 KDZMCHYOHSEAEJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 210000000481 breast Anatomy 0.000 claims description 2
- IODAUHKLGWWCFT-UHFFFAOYSA-N carbonyl dichloride rhodium triphenylphosphane Chemical compound C(=O)(Cl)Cl.[Rh].C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC=C1 IODAUHKLGWWCFT-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 235000019441 ethanol Nutrition 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 150000002894 organic compounds Chemical class 0.000 claims description 2
- GNPXKHTZVDUNOY-UHFFFAOYSA-N oxomethylidenerhodium Chemical compound O=C=[Rh] GNPXKHTZVDUNOY-UHFFFAOYSA-N 0.000 claims description 2
- WQIQNKQYEUMPBM-UHFFFAOYSA-N pentamethylcyclopentadiene Chemical compound CC1C(C)=C(C)C(C)=C1C WQIQNKQYEUMPBM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 150000004032 porphyrins Chemical class 0.000 claims description 2
- 150000003283 rhodium Chemical class 0.000 claims description 2
- SXBHZLXNLHQSRD-UHFFFAOYSA-M rhodium(2+) 2,2,2-trifluoroacetate Chemical class [Rh+2].[O-]C(=O)C(F)(F)F SXBHZLXNLHQSRD-UHFFFAOYSA-M 0.000 claims description 2
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000006007 trichloroethoxy group Chemical group 0.000 claims description 2
- 229910052720 vanadium Inorganic materials 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims 1
- LWCCOKNDYFXUOG-UHFFFAOYSA-N cycloocta-1,5-dien-1-ol rhodium Chemical compound [Rh].OC1=CCCC=CCC1 LWCCOKNDYFXUOG-UHFFFAOYSA-N 0.000 claims 1
- HOXDXGRSZJEEKN-UHFFFAOYSA-N cycloocta-1,5-diene;rhodium Chemical compound [Rh].C1CC=CCCC=C1 HOXDXGRSZJEEKN-UHFFFAOYSA-N 0.000 claims 1
- 150000004816 dichlorobenzenes Chemical class 0.000 claims 1
- BDJAEZRIGNCQBZ-UHFFFAOYSA-N methyl-cyclobutane Natural products CC1CCC1 BDJAEZRIGNCQBZ-UHFFFAOYSA-N 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 3
- 238000004458 analytical method Methods 0.000 description 58
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 238000002360 preparation method Methods 0.000 description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 28
- 150000002081 enamines Chemical class 0.000 description 28
- 238000001514 detection method Methods 0.000 description 27
- 239000000203 mixture Substances 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 238000001819 mass spectrum Methods 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000004566 IR spectroscopy Methods 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 15
- 238000006467 substitution reaction Methods 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000007791 liquid phase Substances 0.000 description 14
- 239000002994 raw material Substances 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 8
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000007106 1,2-cycloaddition reaction Methods 0.000 description 4
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 4
- 150000001336 alkenes Chemical class 0.000 description 4
- 150000001491 aromatic compounds Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910052789 astatine Inorganic materials 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 150000001924 cycloalkanes Chemical class 0.000 description 2
- LDCRTTXIJACKKU-ARJAWSKDSA-N dimethyl maleate Chemical compound COC(=O)\C=C/C(=O)OC LDCRTTXIJACKKU-ARJAWSKDSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 description 1
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 1
- BUYVJWVYKPKZEX-DWVXZKBMSA-N (1z,5z)-cycloocta-1,5-diene;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].C\C(O)=C\C(C)=O.C\1C\C=C/CC\C=C/1 BUYVJWVYKPKZEX-DWVXZKBMSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 description 1
- 239000004912 1,5-cyclooctadiene Substances 0.000 description 1
- KAJRUHJCBCZULP-UHFFFAOYSA-N 1-cyclohepta-1,3-dien-1-ylcyclohepta-1,3-diene Chemical compound C1CCC=CC=C1C1=CC=CCCC1 KAJRUHJCBCZULP-UHFFFAOYSA-N 0.000 description 1
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- WTHKAJZQYNKTCJ-UHFFFAOYSA-N 4-methyl-N-(phenylmethyl)benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCC1=CC=CC=C1 WTHKAJZQYNKTCJ-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- NHKQVGVWARCKRT-ZPGRZCPFSA-N N-(1,3-benzodioxol-5-ylmethyl)-N-[(1S,2S)-2-[1,3-benzodioxol-5-ylmethyl-(4-methylphenyl)sulfonylamino]-3,4-dimethylidenecyclobutyl]-4-methylbenzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1=CC2=C(OCO2)C=C1)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1=CC2=C(OCO2)C=C1 NHKQVGVWARCKRT-ZPGRZCPFSA-N 0.000 description 1
- RYVNLFJYBGNBAC-WLTNIFSVSA-N N-(3,3-diphenylpropyl)-N-[(1S,2S)-2-[3,3-diphenylpropyl-(4-methylphenyl)sulfonylamino]-3,4-dimethylidenecyclobutyl]-4-methylbenzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC(C1=CC=CC=C1)C1=CC=CC=C1)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC(C1=CC=CC=C1)C1=CC=CC=C1 RYVNLFJYBGNBAC-WLTNIFSVSA-N 0.000 description 1
- NLZQQGNVNKHOTA-ZPGRZCPFSA-N N-[(1S,4S)-2,3-dimethylidene-4-[(4-methylphenyl)sulfonyl-(2-phenylethyl)amino]cyclobutyl]-4-methyl-N-(2-phenylethyl)benzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC1=CC=CC=C1)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC1=CC=CC=C1 NLZQQGNVNKHOTA-ZPGRZCPFSA-N 0.000 description 1
- ALYMPLSQBGKASY-ACHIHNKUSA-N N-[(1S,4S)-2,3-dimethylidene-4-[(4-methylphenyl)sulfonyl-(2-thiophen-2-ylethyl)amino]cyclobutyl]-4-methyl-N-(2-thiophen-2-ylethyl)benzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC=1SC=CC=1)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC=1SC=CC=1 ALYMPLSQBGKASY-ACHIHNKUSA-N 0.000 description 1
- QJTGADQHVLKQJK-COCZKOEFSA-N N-[(1S,4S)-2,3-dimethylidene-4-[(4-methylphenyl)sulfonyl-(naphthalen-1-ylmethyl)amino]cyclobutyl]-4-methyl-N-(naphthalen-1-ylmethyl)benzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1=CC=CC2=CC=CC=C12)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1=CC=CC2=CC=CC=C12 QJTGADQHVLKQJK-COCZKOEFSA-N 0.000 description 1
- XJTWWNJISRKFQM-FWYJNYDBSA-N N-[(1S,4S)-2,3-dimethylidene-4-[(4-methylphenyl)sulfonyl-(oxolan-2-ylmethyl)amino]cyclobutyl]-4-methyl-N-(oxolan-2-ylmethyl)benzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1OCCC1)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1OCCC1 XJTWWNJISRKFQM-FWYJNYDBSA-N 0.000 description 1
- WAURWHBNEBTKLI-YMDPOQPOSA-N N-[(1S,4S)-2,3-dimethylidene-4-[(4-methylphenyl)sulfonyl-[(Z)-octadec-9-enyl]amino]cyclobutyl]-4-methyl-N-[(Z)-octadec-9-enyl]benzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCCCCCCC\C=C/CCCCCCCC)N(S(=O)(=O)C1=CC=C(C=C1)C)CCCCCCCC\C=C/CCCCCCCC WAURWHBNEBTKLI-YMDPOQPOSA-N 0.000 description 1
- WUEUNQNCRTTXEL-ZPGRZCPFSA-N N-[(4-methoxyphenyl)methyl]-N-[(1S,2S)-2-[(4-methoxyphenyl)methyl-(4-methylphenyl)sulfonylamino]-3,4-dimethylidenecyclobutyl]-4-methylbenzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1=CC=C(C=C1)OC)N(S(=O)(=O)C1=CC=C(C=C1)C)CC1=CC=C(C=C1)OC WUEUNQNCRTTXEL-ZPGRZCPFSA-N 0.000 description 1
- ZBRWGDREQWFVIR-ZAQUEYBZSA-N N-[2-(1H-indol-3-yl)ethyl]-N-[(1S,2S)-2-[2-(1H-indol-3-yl)ethyl-(4-methylphenyl)sulfonylamino]-3,4-dimethylidenecyclobutyl]-4-methylbenzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC1=CNC2=CC=CC=C12)N(S(=O)(=O)C1=CC=C(C=C1)C)CCC1=CNC2=CC=CC=C12 ZBRWGDREQWFVIR-ZAQUEYBZSA-N 0.000 description 1
- SLNWNAVGUWDVJF-HEVIKAOCSA-N N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-N-[(1S,2S)-2-[2-[tert-butyl(dimethyl)silyl]oxyethyl-(4-methylphenyl)sulfonylamino]-3,4-dimethylidenecyclobutyl]-4-methylbenzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCO[Si](C)(C)C(C)(C)C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCO[Si](C)(C)C(C)(C)C SLNWNAVGUWDVJF-HEVIKAOCSA-N 0.000 description 1
- XSBAKNWCFUDOQJ-VXKWHMMOSA-N N-benzyl-N-[(1S,2S)-2-[benzyl(methylsulfonyl)amino]-3,4-dimethylidenecyclobutyl]methanesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C)CC1=CC=CC=C1)N(S(=O)(=O)C)CC1=CC=CC=C1 XSBAKNWCFUDOQJ-VXKWHMMOSA-N 0.000 description 1
- MYUXAQLFGQKGDD-NSOVKSMOSA-N N-butyl-N-[(1S,2S)-2-[butyl-(4-methylphenyl)sulfonylamino]-3,4-dimethylidenecyclobutyl]-4-methylbenzenesulfonamide Chemical compound C=C1[C@@H]([C@H](C1=C)N(S(=O)(=O)C1=CC=C(C=C1)C)CCCC)N(S(=O)(=O)C1=CC=C(C=C1)C)CCCC MYUXAQLFGQKGDD-NSOVKSMOSA-N 0.000 description 1
- AQPQIEOKYLDROR-UHFFFAOYSA-N [Rh+].OC1=CCCC=CCC1 Chemical compound [Rh+].OC1=CCCC=CCC1 AQPQIEOKYLDROR-UHFFFAOYSA-N 0.000 description 1
- IRTLGLYSFAKASM-UHFFFAOYSA-N acetic acid;propan-2-ol Chemical compound CC(C)O.CC(O)=O IRTLGLYSFAKASM-UHFFFAOYSA-N 0.000 description 1
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 239000010953 base metal Substances 0.000 description 1
- 230000037429 base substitution Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940116229 borneol Drugs 0.000 description 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical group ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- AFQSOHSPTULSFS-FGSKAQBVSA-N ethene;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical compound [Rh].C=C.C=C.C\C(O)=C\C(C)=O AFQSOHSPTULSFS-FGSKAQBVSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000001699 photocatalysis Effects 0.000 description 1
- RWRDJVNMSZYMDV-UHFFFAOYSA-L radium chloride Chemical class [Cl-].[Cl-].[Ra+2] RWRDJVNMSZYMDV-UHFFFAOYSA-L 0.000 description 1
- PZSJYEAHAINDJI-UHFFFAOYSA-N rhodium(3+) Chemical compound [Rh+3] PZSJYEAHAINDJI-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
Classifications
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- C07B53/00—Asymmetric syntheses
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
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- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/40—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing only non-condensed rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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- 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
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Abstract
This application discloses a kind of methods for synthesizing 1,2- dimethylene cyclobutane chipal compounds to synthesize 1,2- dimethylene cyclobutane chipal compounds by connection enamine compound in the presence of rhodium complex.This method can under mild reaction conditions, the synthesis 1 of high efficiency, high enantioselectivity and highly-solid selectively, 2- dimethylene cyclobutane chipal compounds.
Description
Technical field
This application involves a kind of methods for synthesizing 1,2- dimethylene cyclobutane chipal compounds, belong to natural products and medicine
Object field.
Background technique
Cyclobutane derivative compound has critical role in many natural products and drug molecule.And ring fourth is synthesized at present
The method of alkane mainly passes through alkene, alkynes, connection alkene and other unsaturated systems and synthesizes cyclobutane by [2+2] cycloaddition.Closely
Nian Lai has synthesized the method for cyclobutane making alkene or connection alkene that [2+2] cycloaddition occur with other unsaturated systems by heating
Largely studied, but such reaction has that selectivity is bad, reaction temperature is high (typically larger than 200 DEG C), when reaction
Between long (typically larger than 72h) the shortcomings that.
As the method for [2+2] cycloaddition synthesis cyclobutane makes progress in photocatalysis field, [the 2+ about metal catalytic
2] cycloaddition synthesis cyclobutane method gradually increase, wherein report about gold [Angew.Chem.Int.Ed.2009,48,
4532-4535；Org.Lett.2012,14,436-439.], palladium [J.Am.Chem.Soc.2000,122,11529-11530；
Angew.Chem.Int.Ed.2006,45,8009-8013.], nickel [J.Am.Chem.Soc.1985,107,3160-3172；
J.Am.Chem.Soc.1988,110,8494-8500；J.Am.Chem.Soc.1989,111,3761-3762；
J.Am.Chem.Soc.2000,122,10776-10780.], the metals such as copper [Org.Lett.2012,14,1366-1369.]
Catalysis reaction.The reaction of metal catalytic is remarkably improved regioselectivity and stereoselectivity.
Currently, not yet being had been reported that in the method that connection enamine [2+2] cycloaddition of rhodium catalysis prepares chiral cyclobutane.
Summary of the invention
The application's is designed to provide a kind of method for synthesizing 1,2- dimethylene cyclobutane chipal compounds.Match in rhodium
In the presence of body object, 1,2- dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound.This method can be mild
Reaction condition under, the synthesis 1 of high efficiency, high enantioselectivity and highly-solid selectively, 2- dimethylene cyclobutane chirality
Close object.
The method of synthesis 1, the 2- dimethylene cyclobutane chipal compounds, which is characterized in that in depositing for rhodium complex
Under, 1,2- dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound；
The rhodium complex is formed by the rhodium source containing rhodium element with ligand；The ligand is chiral ligand and/or non-hand
Property ligand；The chiral ligand and achiral ligand are selected from the organic compound containing P elements and/or nitrogen extremely
Few one kind；
The enamine compound is selected from least one of the compound with chemical structural formula shown in Formulas I:
The 1,2- dimethylene cyclobutane chipal compounds are the compounds with the chemical structural formula as shown in Formula II -1
And/or the compound with the chemical structural formula as shown in Formula II -2:
In Formulas I, Formula II -1 and Formula II -2, R1、R2Independently selected from hydrogen, carbon atom number no more than 18 aliphatic group, have
The group of structural formula shown in formula III, the group with structural formula shown in Formula V, has formula at the group with structural formula shown in Formula IV
The group of structural formula shown in VI or group with structural formula shown in Formula VII:
In formula III, R3Aliphatic group, carbon atom number selected from carbon atom number no more than 18 are no more than 18 substituted fatty hydrocarbon
Base, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, replaces heteroarylalkyl at aryl；
R4- A- formula IV
In formula IV, A is selected from the alkylene that carbon atom number is no more than 10；R4It is no more than 18 aliphatic hydrocarbon selected from carbon atom number
The substituted fatty hydrocarbon base of base, carbon atom number no more than 18, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substitution
Aralkyl, replaces heteroarylalkyl, silylation at heteroarylalkyl；
R5- O-B- Formula V
In Formula V, B is selected from the alkylene from carbon atom number no more than 10；R5It is no more than 18 aliphatic hydrocarbon selected from carbon atom number
The substituted fatty hydrocarbon base of base, carbon atom number no more than 18, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substitution
Aralkyl, replaces heteroarylalkyl, silylation at heteroarylalkyl；
In Formula IV, R6Aliphatic group, carbon atom number selected from carbon atom number no more than 18 are no more than 18 substituted fatty hydrocarbon
Base, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, replaces heteroarylalkyl, silicon at aryl
Alkyl；
In Formula VII, R7Aliphatic group, carbon atom number selected from carbon atom number no more than 18 are no more than 18 substituted fatty hydrocarbon
Base, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, replaces heteroarylalkyl, silicon at aryl
Alkyl.
Substituted fatty hydrocarbon base of the carbon atom number no more than 18 is substituted by least one hydrogen atom on aliphatic group
Base substitution is formed by group；Preferably, the substituent group on the substituted fatty hydrocarbon base is in nitro, amino, F, Cl, Br, I
At least one.
The substituted aryl is that at least one hydrogen atom is substituted with a substituent and is formed by group on the aromatic rings by aryl；
Preferably, the substituent group on the substituted aryl be selected from carbon atom number no more than 18 aliphatic group, nitro, amino, F, Cl,
At least one of Br, I.
The substituted heteroaryl is that at least one hydrogen atom is substituted with a substituent and is formed by the hetero-aromatic ring by heteroaryl
Group；Substituent group on the substituted heteroaryl be selected from aliphatic group of the carbon atom number no more than 18, nitro, amino, F, Cl,
At least one of Br, I.
As a kind of preferred scheme of the application, in Formulas I and Formula II, R1、R2Independently selected from carbon atom number no more than 18
Aliphatic group, acetyl group (being abbreviated as Ac), benzyl (being abbreviated as Bn), 1- menaphthyl, 4- methoxy-benzyl, tert-butyldimethyl silyl
Oxygen ethyl, 3,3- diphenyl propyl, 2- phenethyl, furfuryl, thienylethyl, indolylethyl, 1,3- benzo dioxy -5- first
Base, tertbutyloxycarbonyl (being abbreviated as Boc), benzoyl (being abbreviated as Bz), tablet held before the breast by officials methoxycarbonyl group (being abbreviated as Fmoc), tri-chloroethoxy base
Formoxyl (being abbreviated as Troc), p-nitrophenyl sulfonyl (are abbreviated as Methyl benzenesulfonyl base (being abbreviated as TS) or methyl sulphonyl
MS)。
As a kind of preferred scheme of the application, R1And R2In at least one be selected from the base with structural formula shown in formula III
Group.It is further preferred that R1And R2In at least one be p-nitrophenyl sulfonyl, to Methyl benzenesulfonyl base or methyl sulphonyl.
As a kind of preferred scheme of the application, R1And R2One of them is selected from the group with structural formula shown in formula III.
It is further preferred that R1And R2One of them is p-nitrophenyl sulfonyl, to Methyl benzenesulfonyl base or methyl sulphonyl.
Those skilled in the art can select suitable rhodium Base Metal organic compound as rhodium source according to actual needs.It is excellent
Selection of land, the rhodium source are selected from dimerization rhodium acetate [Rh (CH3COO)]2, triphenylphosphine rhodium carbonyl chloride Rh (PPh3) Cl (CO), dimerization
It closes hydroxyl (1,5- cyclo-octadiene) rhodium (I) [Rh (COD) OH]2, praseodynium rhodium (III) Rh (CH3COCHCOCH3)3, four carbonyls
Two rhodium of base dichloride [Rh (CO)2Cl]2, (1,5- cyclo-octadiene) chlorine rhodium (I) dimer [Rh (COD)2Cl]2, two rhodium of dichloride
(double down borneol diene) [Rh (NBD) Cl]2, acetylacetone,2,4-pentanedione bi-vinyl rhodium Rh (acac) (C2H4)2, (1,5- ring is pungent for acetylacetone,2,4-pentanedione
Diene) rhodium Rh (acac) (COD), trifluoroacetic acid rhodium (II) dimer Rh2(CF3COO)4, four or three [- (+)-N- is (to dodecyl
Benzene sulfonyl) porphyrin] two rhodium Rh2(R-DOSP)4, dichloro (pentamethylcyclopentadiene base) close rhodium dimer (Cp*RhCl2)2, triphen
Base phosphine hydrogenized carbonyl rhodium Rh (PPh3At least one of) H (CO).
As an implementation, the ligand is achiral ligand, selected from the chemical combination with structural formula shown in formula (1)
The compound of structural formula shown in the compound of structural formula shown in the compound of structural formula shown in object, formula (2), formula (3), formula (4), formula
(5) at least one of the compound of structural formula shown in the compound of structural formula shown in, formula (6):
In formula (1), R8Selected from hydrogen ,-CH3、—OCH3、—N(CH3)2、—OCH(CH3)2；R9Selected from hydrogen ,-OCH3、—N
(CH3)2、—OCH(CH3)2；R10Selected from cyclohexyl ,-C (CH3)3；
In formula (2), R11Selected from-OCH2CH3、—C(CH3)3, phenyl；
In formula (3), R12Selected from phenyl, cyclohexyl；N is 1 or 3；
In formula (4), R13Selected from phenyl ,-C (CH3)3；
In formula (5), R14Selected from hydrogen, phenyl ,-CH3；R15Selected from hydrogen ,-CH3、—C(CH3)3；
In formula (6), R16Selected from-CH3Or-COOH.
As an implementation, the ligand is chiral ligand, selected from structural formula shown in formula (7) compound,
The compound of structural formula shown in the compound of structural formula shown in the compound of structural formula shown in formula (8), formula (9), formula (10), formula
(11) compound of structural formula shown in the compound of structural formula shown in the compound of structural formula shown in, formula (12), formula (13), formula
(14) compound of structural formula shown in the compound of structural formula shown in the compound of structural formula shown in, formula (15), formula (16), formula
(17) compound of structural formula shown in the compound of structural formula shown in the compound of structural formula shown in, formula (18), formula (19), formula
(20) at least one of the compound of structural formula shown in:
In formula (7), R17Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,
5- 3,5-dimethylphenyl, p-nitrophenyl；R18Selected from methyl, phenyl, tert-butyl, isopropyl, cyclohexyl；
In formula (8), R19Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,
5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (9), R20Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,
5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (10), R21Selected from methyl, phenyl, trifluoromethy phenyl；R22Selected from methyl, phenyl, trifluoromethy benzene
Base, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (11), R23Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl,
3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (12), R24Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl,
3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (13), R25Selected from H, F；R26Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6-
Trimethylphenyl, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (18), R27Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl,
3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (19), R28Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl,
3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (20), R29Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl,
3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl.
When ligand is achiral ligand, 1, the 2- dimethylene cyclobutane chipal compounds are that have such as -1 institute of Formula II
Show the compound of chemical structural formula and mixing that compound mole ratio example with the chemical structural formula as shown in Formula II -2 is 1:1
Object；I.e. products therefrom is racemic product.
When ligand is chiral ligand, 1, the 2- dimethylene cyclobutane chipal compounds mainly have such as Formula II -1
The compound of shown chemical structural formula；I.e. products therefrom has optical activity.
Preferably, the achiral ligand is selected from the compound of structural formula shown in formula (4).
Preferably, the chiral ligand is selected from the compound of structural formula shown in formula (12).
As the application preferred embodiment, the method for synthesis 1, the 2- dimethylene cyclobutane chipal compounds,
It at least includes the following steps:
A) rhodium source, chirality and/or achiral ligand, connection enamine compound are added in organic solvent, in -78 DEG C to 120
It is stirred to react at DEG C 10 minutes to 120 hours；
B) after reaction, add water quenching to go out, through liquid separation, washing, drying, remove organic solvent, separation to get described 1,2-
Dimethylene cyclobutane chipal compounds.
The reaction equation of the synthesis 1,2- dimethylene cyclobutane chipal compounds method is as follows:
Preferably, reaction temperature is -20 DEG C to 100 DEG C in step a).It is further preferred that reaction temperature is in step a)
0 DEG C to 100 DEG C.It is further preferred that reaction temperature is 20 DEG C to 100 DEG C in step a).
Preferably, the reaction time is 10 minutes to 48 hours in step a).It is further preferred that the reaction time in step a)
It is 10 minutes to 10 hours.It is further preferred that the reaction time is 30 minutes to 8 hours in step a).
Preferably, the molar ratio of enamine compound and rhodium source and ligand is joined in step a) are as follows:
Join enamine compound: Rh: ligand=1:0.01~1:0.01~1；
In terms of the molal quantity of the molal quantity in rhodium source rhodium element contained in the rhodium source.
It is further preferred that joining the molar ratio of enamine compound and rhodium source and ligand in step a) are as follows:
Join enamine compound: Rh: ligand=1:0.01~0.15:0.05~0.50.
Those skilled in the art can according to actual needs, the additional amount selected from organic solvent.Preferably, organic solvent adds
Enter amount and join enamine compound ratio are as follows: in the organic solvent of 1L join enamine compound molal quantity be 0.05mol~
0.5mol。
Preferably, organic solvent described in step a) is selected from benzene, carbon tetrachloride, petroleum ether, tetrahydrofuran, dimethyl formyl
Amine, acetone, ether, methylene chloride, chloroform, toluene, dimethylbenzene, chlorobenzene, o-dichlorohenzene, hexamethylene, n-hexane, positive heptan
At least one of alkane, six ring of dioxane, acetonitrile, methanol, ethyl alcohol, pentane.
Preferably, step b) the isolated method selected from recrystallization, thin-layer chromatography, column chromatography, vacuum distillation in extremely
Few one kind.
Preferably, in the recrystallization, thin-layer chromatography and column chromatography method, used solvent is polar solvent and non-pole
The mixture of property solvent；Wherein, the volume ratio of polar solvent and nonpolar solvent is 1:0.1~500.It is further preferred that institute
It states in recrystallization, thin-layer chromatography and column chromatography method, used solvent is selected from methylene chloride-n-hexane mixture, isopropyl
Alcohol-petroleum ether mixture, the mixture of ethyl acetate-light petrol, the mixture of ethyl acetate-hexane, isopropanol-acetic acid
Any one in ethyl ester-petroleum ether mixture.It is further preferred that the recrystallization, thin-layer chromatography and column chromatography side
In method, used solvent is selected from the mixing of ethyl acetate/petroleum ether volume ratio=1:0.1~50 ethyl acetate-light petrol
Object, isopropanol/petroleum ether volume ratio=1:0.1~500 isopropanol-petroleum ether mixture.
In the application, " aliphatic group " is to be formed by base by losing any one hydrogen atom on aliphatic hydrocarbon compound molecule
Group.The aliphatic hydrocarbon compound does not contain aromatic rings or hetero-aromatic ring, including alkane compound, the olefinic compound containing C=C double bond
Object, the acetylene hydrocarbon compound containing three key of C ≡ C, the unsaturated hydrocarbon compound simultaneously containing three key of C=C double bond and C ≡ C.This Shen
Please in, " alkyl " is to be formed by group by losing any one hydrogen atom on alkane compound molecule.The alkane compound
Including linear paraffin, branched paraffin, cycloalkane, with the cycloalkane of branch.In the application, " aryl " is aromatic compound point
A hydrogen atom on aromatic rings is lost on son is formed by group；Benzene is formed by as lost any one hydrogen atom on phenyl ring
Base.In the application, " heteroaryl " is to contain the heteroatomic aromatic compound of O, N, S (abbreviation heteroaryl chemical combination in aromatic rings
Object) any one hydrogen atom on aromatic rings is lost on molecule is formed by group；As lost any one hydrogen atom on piperazine ring
Formed piperazinyl.In the application, " aralkyl " is the aromatic compound containing alkyl substituent, loses alkyl on molecule and takes
The upper any hydrogen atom of Dai Ji is formed by group；Benzyl is formed by as toluene loses a hydrogen atom on methyl." heteroaryl alkane
Base " is to lose alkyl containing the heteroatomic aromatic compound of O, N, S is contained in alkyl substituent and aromatic rings on molecule and take
Any one upper hydrogen atom of Dai Ji is formed by group；Such as 1,3- benzo dioxy -5- methyl.In the application, " alkylene " be by
Any two hydrogen atom is lost on hydrocarbon molecules is formed by group；As methyl loses the methylene of two hydrogen atoms formation
Two hydrogen atoms of contraposition are lost on base or phenyl ring is formed by group.In the chemical formula or structure of the application, " Ph " is phenyl
It writes a Chinese character in simplified form；"tBu " is writing a Chinese character in simplified form for tert-butyl；" ac " is writing a Chinese character in simplified form for acetyl group；" acac " is writing a Chinese character in simplified form for levulinic ketone group；" Cp " is ring
Pentadienyl is write a Chinese character in simplified form；" COD " is writing a Chinese character in simplified form for cyclo-octadiene base；" NBD " is the letter of bicycloheptadiene (alias: norbornadiene)
It writes；" DOSP " is (to dodecyl benzene sulfonyl) that porphyryl is write a Chinese character in simplified form.
The beneficial effect of the application includes but is not limited to:
(1) method provided herein, to join enamine compound as Material synthesis 1,2- dimethylene cyclobutane is chiral
Compound has the advantages that high-efficient, enantioselectivity is high and stereoselectivity is high.
(2) method provided herein uses rhodium complex as catalyst, and reaction condition is mild, easy to operate, produces
Object separating-purifying is easy, and product yield high, purity are good.
Specific embodiment
The application is described in detail below with reference to embodiment, but the application is not limited to these embodiments.
In embodiment, unless otherwise instructed, test condition is as follows:
Nuclear magnetic resoance spectrum1H-NMR and13C-NMR uses the III type spectroscope of 400AVANCE of Brooker company (Bruker)
(Spectrometer) it measures, 400MHz, the deuterated methane CDCl of trichlorine3.Product analysis is detected using thin-layered chromatography, and solvent is
The mixture (volume ratio ethyl acetate/petroleum ether=1/5) of ethyl acetate and petroleum ether.Infrared spectrum analysis (IR) is using Germany
The 27 type ftir analysis instrument of TENSOR of Brooker company.High resolution mass spectrum is analyzed HRMS and is flown using match is silent
The LTQ FT Ultra system mass spectrograph of your scientific & technical corporation (Thermo Fisher Scientific) of generation.Enantioselectivity
Excessive value analysis uses Shimadzu Corporation (Shimadzu) high-efficient liquid phase chromatogram HPLC LC-20AD, and chiral column uses Daicel company
(Daicel Chemical Industries, LTD) Chiralpak IA, IB, ID, IF column.Angle-of-rotation measuring uses Shanghai object
Light INESA SGW-1 automatic polarimeter.
In embodiment, the yield of 1,2- dimethylene cyclobutane chipal compounds is calculated by the following formula to obtain: yield
=(quality of 1,2- dimethylene cyclobutane chipal compounds)/(connection enamine compound molal quantity × 1,2- dimethylene ring fourth
The molal weight of alkane chipal compounds) × 100%.
In embodiment, bis- (1,5- cyclo-octadiene) radium chlorides are expressed as [Rh (COD) Cl]2。
The preparation of 1 product 1 of embodiment
Product 1: R in Formula II -1 and Formula II -21And R2Respectively benzyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula II -1
Corresponding product is denoted as product 1-1, and -1 corresponding product of Formula II is denoted as product 1-2.
The Chinese of product 1-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N- benzyls
Base -4- is to Methyl benzenesulfonyl base)；
The English name of product 1-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-benzyl-4-
methy lbenzenesulfonamide)
The structural formula of product 1-1 and 1-2 are respectively as follows:
The connection enamine raw material of use are as follows: R in Formulas I1And R2Respectively benzyl and the connection enamine to Methyl benzenesulfonyl base.Specifically
Preparation process is as follows:
In dry reaction tube, rhodium source, ligand, connection enamine, organic solvent are sequentially added, stirs one under reaction temperature
Section time, reaction terminate, and 1.5 times of organic solvent volume of water quenching is added and goes out, liquid separation retains organic layer.Organic layer is using organic molten
After the saturated salt solution that 2.5 times of agent volume washs 3 times respectively, anhydrous Na is used2SO4Dry, vacuum distillation removes organic solvent, warp
Column chromatographs (solvent: volume ratio ethyl acetate/petroleum ether=1/5) separation, and obtained solid is product 1.
Specifically the relationship of raw material, proportion, reaction condition, product yield and gained sample number into spectrum is as shown in table 1.
Table 1
Sample 1#- 1~sample 1#- 10 fusing point (mp): 135~137 DEG C.
Using thin-layer chromatography to sample 1#- 10 analyses: Rf=0.30 (ethyl acetate/petroleum ether=1/5, v/v).
Using nuclear magnetic resonance to sample 1#- 10 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.59 (d, J=8.0Hz, 4H), 7.27 (d, J=6.0Hz,
14H), 5.16 (s, 2H), 4.82 (s, 2H), 4.59 (d, J=15.6Hz, 2H), 4.08 (s, 2H), 3.97 (d, J=15.6Hz,
2H),2.43(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm): 143.5,142.3,137.2,137.0,
129.7,128.6,127.7,127.3,108.0,62.3,48.7,21.6。
Using infrared spectroscopy to sample 1#- 10 detections (KBr), in following wave number (cm-1) there is a diffraction maximum in position: 546,598,
660,698,740,771,813,1027.63,1090,1161,1344,1455,1494,1597,2924,3030。
Using high resolution mass spectrum HRMS (ESI+) to sample 1#- 10 analyses, as a result as follows:
With [C34H34N2O4S2+H]+Meter, calculated value: 599.2035；Test data: 599.2033.
Sample 1#- 1~sample 1#The analysis result of -9 thin-layer chromatography, nuclear magnetic resonance, infrared spectroscopy and high resolution mass spectrum
With sample 1#- 10 result is similar.Illustrate that technical solution provided herein is capable of the preparation 1 of highly selective high-purity,
2- dimethylene cyclobutane chipal compounds.
Using high-efficient liquid phase chromatogram HPLC to sample 1#- 7 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/
Min, λ=254nm, t (minor)=20.59min, t (major)=23.52min], ee=92%.
Using polarimeter to sample 1#- 7 analyses, it is as a result as follows: [α]D20=-8.6 (c=3.0, CHCl3).Sample 1#-8
~sample 1#- 10 detection data and sample 1#- 7 is almost the same；When illustrating using chiral ligand, products therefrom is mainly product
1-1.And sample 1#- 1~sample 1#- 6 do not have optical activity substantially, and when illustrate using achiral ligand, products therefrom is product 1-
1 and 1-2 molar ratio is the mixture of 1:1, is racemic product.
The preparation of 2 product 2 of embodiment
Product 2: R in Formula II -1 and Formula II -21And R2Respectively benzyl, methyl sulphonyl (being abbreviated as MS)；Formula II -1 is corresponding
Product is denoted as product 2-1, and -1 corresponding product of Formula II is denoted as product 2-2.
The Chinese of product 2-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N- benzyls
Base -4- methyl sulphonyl)
The English name of product 2-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-benzylmethane
sulfonamide)
The structural formula of product 2-1 and 2-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 2#- 1, yield 70%；Sample 2 is denoted as using chiral ligand products therefrom#- 2, yield 60%.
Sample 2#- 1 and sample 2#- 2 fusing point (mp): 170~174 DEG C.
Using thin-layer chromatography to sample 2#- 1 and sample 2#- 2 analyses: Rf=0.5 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 2#- 1 and sample 2#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.32 (s, 10H), 5.41 (s, 2H), 4.89 (d, J=
18.7Hz, 4H), 4.58 (d, J=15.5Hz, 2H), 4.14 (d, J=15.2Hz, 2H), 2.83 (s, 6H).13C NMR
(100MHz,CDCl3) chemical shift (ppm): 142.7,137.2,128.8,128.5,128.0,107.9,61.7,48.9,
40.5。
Using infrared spectroscopy to sample 2#- 1 and sample 2#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 518,699,757,792,961,1027,1150,1333,1456,1496,1681,2927,3 030.32.
Using high resolution mass spectrum HRMS (ESI+) to sample 2#- 1 and sample 2#- 2 analyses, as a result as follows:
With [C22H26N2O4S2+H]+Meter, calculated value: 447.1408；Test data: 447.1407.
Using high-efficient liquid phase chromatogram HPLC to sample 2#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/
Min, λ=254nm, t (major)=10.93min, t (minor)=13.01min], ee=92%.
Using polarimeter to sample 2#- 2 analyses, it is as a result as follows: [α]D20=-24.6 (c=1.0, CHCl3).Sample 2#-1
For the racemic mixture of product 2-1 and product 2-2；Sample 2#It is mainly product 2-1 in -2.
The preparation of 3 product 3 of embodiment
Product 3: R in Formula II -1 and Formula II -21And R2Respectively 4- methoxy-benzyl, Methyl benzenesulfonyl base (is abbreviated as
TS)；- 1 corresponding product of Formula II is denoted as product 3-1, and -1 corresponding product of Formula II is denoted as product 3-2.
The Chinese of product 3-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(4- methoxy-benzyl) -4- is to Methyl benzenesulfonyl base)
The English name of product 3-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(4-
methoxybenzyl)-4-methylbenzenesulfonamide)
The structural formula of product 3-1 and product 3-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 3#- 1, yield 76%；Sample 3 is denoted as using chiral ligand products therefrom#- 2, yield 79%.
Sample 3#- 1 and sample 3#- 2 fusing point (mp): 141~144 DEG C.
Using thin-layer chromatography to sample 3#- 1 and sample 3#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/v)
Using nuclear magnetic resonance to sample 3#- 1 and sample 3#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.58 (d, J=8.2Hz, 4H), 7.27 (d, J=8.0Hz,
4H), 7.19 (d, J=8.5Hz, 4H), 6.82 (d, J=8.6Hz, 4H), 5.16 (s, 2H), 4.78 (s, 2H), 4.54 (d, J=
15.2Hz, 2H), 4.06 (s, 2H), 3.92 (d, J=15.2Hz, 2H), 3.79 (s, 6H), 2.43 (s, 6H).13C NMR
(100MHz,CDCl3) chemical shift (ppm): 159.2,143.4,142.4,137.3,130.1,129.7,128.9,127.3,
113.9,107.9,62.2,55.3,48.1,21.5。
Using infrared spectroscopy to sample 3#- 1 and sample 3#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 535,663,751,814,881,915,1092,1164,1267,1315,1376,1455,15 11,1612,2926.
Using high resolution mass spectrum HRMS (ESI+) to sample 3#- 1 and sample 3#- 2 analyses, as a result as follows:
With [C36H38N2O6S2+H]+Meter, calculated value: 659.2248；Test data: 659.2244.
Using high-efficient liquid phase chromatogram HPLC to sample 3#- 2 analyses, as a result as follows:
[Daicel Chiralpak IB (0.46cm x 25cm), n-hexane/isopropanol=90/10, v=1.0mL/
Min, λ=254nm, t (minor)=24.85min, t (major)=35.41min], ee=99%.
Using polarimeter to sample 3#- 2 analyses, it is as a result as follows: [α]D20=-19.8 (c=3.4, CHCl3).Sample 3#-1
For the racemic mixture of product 3-1 and product 3-2；Sample 3#It is mainly product 3-1 in -2.
The preparation of 4 product 4 of embodiment
Product 4: R in Formula II -1 and Formula II -21And R2Respectively 1,3- benzo dioxy -5- methyl, to Methyl benzenesulfonyl base
(being abbreviated as TS)；- 1 corresponding product of Formula II is denoted as product 4-1, and -1 corresponding product of Formula II is denoted as product 4-2.
The Chinese of product 4-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(1,3- benzo dioxy -5- methyl) -4- is to Methyl benzenesulfonyl base)
The English name of product 4-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(benzo[d][1,
3]dioxol-5-ylmethyl)-4-methylbenzenesulfonamide)
The structural formula of product 4-1 and product 4-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 4#- 1, yield 86%；Sample 4 is denoted as using chiral ligand products therefrom#- 2, yield 95%.
Sample 4#- 1 and sample 4#- 2 fusing point (mp): 68~71 DEG C.
Using thin-layer chromatography to sample 4#- 1 and sample 4#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 4#- 1 and sample 4#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.61 (d, J=8.2Hz, 4H), 7.29 (d, J=8.0Hz,
4H), 6.83 (s, 2H), 6.70-6.65 (m, 4H), 5.93 (s, 4H), 5.20 (s, 2H), 4.83 (s, 2H), 4.52 (d, J=
15.2Hz, 2H), 4.11 (s, 2H), 3.92 (d, J=15.3Hz, 2H), 2.43 (s, 6H).13C NMR(100MHz,CDCl3) change
Displacement study (ppm): 148.0,147.3,143.5,142.2,137.3,130.7,129.7,127.3,121.9,10 9.3,
108.0,101.1,62.1,48.4,21.6。
Using infrared spectroscopy to sample 4#- 1 and sample 4#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 547,661,811,928,1038,1090,1161,1243,1334,1446,1489,1503,1597,2922.
Using high resolution mass spectrum HRMS (ESI+) to sample 4#- 1 and sample 4#- 2 analyses, as a result as follows:
With [C36H34N2O8S2+H]+Meter, calculated value: 687.1830；Test data: 687.1829.
Using high-efficient liquid phase chromatogram HPLC to sample 4#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/
Min, λ=254nm, t (minor)=37.03min, t (major)=47.42min], ee=90%
Using polarimeter to sample 4#- 2 analyses, it is as a result as follows: [α]D20=-21.7 (c=4.5, CHCl3).Sample 4#-1
For the racemic mixture of product 4-1 and product 4-2；Sample 4#It is mainly product 4-1 in -2.
The preparation of 5 product 5 of embodiment
Product 5: R in Formula II -1 and Formula II -21And R2Respectively 1- menaphthyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula
II-1 corresponding product is denoted as product 5-1, and -1 corresponding product of Formula II is denoted as product 5-2.
The Chinese of product 5-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(1- menaphthyl) -4- is to Methyl benzenesulfonyl base)
The English name of product 5-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N-
(naphthalen-1-ylmethyl)benzenesulfonamide)
The structural formula of product 5-1 and product 5-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 5#- 1, yield 71%；Sample 5 is denoted as using chiral ligand products therefrom#- 2, yield 84%.
Sample 5#- 1 and sample 5#- 2 fusing point (mp): 130~134 DEG C.
Using thin-layer chromatography to sample 5#- 1 and sample 5#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 5#- 1 and sample 5#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 8.17 (d, J=8.1Hz, 2H), 7.84 (d, J=7.5Hz,
2H), 7.78 (d, J=8.0Hz, 2H), 7.52-7.45 (m, 4H), 7.38-7.25 (m, 8H), 7.17 (d, J=8.0Hz, 4H),
5.11 (t, J=9.2Hz, 4H), 4.57 (s, 2H), 4.36 (d, J=15.4Hz, 2H), 3.77 (s, 2H), 2.39 (s, 6H).13C
NMR(100MHz,CDCl3) chemical shift (ppm): 143.4,142.3,136.7,133.7,131.5,131.5,129.6,
128.6,128.5,127.8,127.3,126.4,125.8,125.4,123.6,107.9,62.6,46.7,21.5。
Using infrared spectroscopy to sample 5#- 1 and sample 5#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 547,666,791,889,1037,1091,1161,1337,1510,1597,2922,3296.
Using high resolution mass spectrum HRMS (ESI+) to sample 5#- 1 and sample 5#- 2 analyses, as a result as follows:
With [C42H38N2O4S2+H]+Meter, calculated value: 699.2350；Test data: 699.2346.
Using high-efficient liquid phase chromatogram HPLC to sample 5#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/
Min, λ=254nm, t (major)=19.07min, t (minor)=32.05min], ee=78%
Using polarimeter to sample 5#- 2 analyses, it is as a result as follows: [α]D20=-28.2 (c=3.7, CHCl3).Sample 5#-1
For the racemic mixture of product 5-1 and product 5-2；Sample 5#It is mainly product 5-1 in -2.
The preparation of 6 product 6 of embodiment
Product 6: R in Formula II -1 and Formula II -21And R2Respectively phenethyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula
II-1 corresponding product is denoted as product 6-1, and -1 corresponding product of Formula II is denoted as product 6-2.
The Chinese of product 6-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N- benzene
Ethyl -4- is to Methyl benzenesulfonyl base)
The English name of product 6-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N-
phenethylbenzenesulfonamide)
The structural formula of product 6-1 and product 6-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 6#- 1, yield 89%；Sample 6 is denoted as using chiral ligand products therefrom#- 2, yield 58%.
Sample 6#- 1 and sample 6#- 2 fusing point (mp): 137~141 DEG C.
Using thin-layer chromatography to sample 6#- 1 and sample 6#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 6#- 1 and sample 6#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.84 (d, J=8.2Hz, 4H), 7.33 (t, J=7.5Hz,
8H), 7.26 (dd, J=13.2,8.8Hz, 6H), 5.21 (s, 2H), 5.13 (s, 2H), 4.32 (s, 2H), 3.49-3.41 (m,
2H),3.16-3.05(m,4H),3.01-2.92(m,2H),2.40(s,6H)。13C NMR(100MHz,CDCl3) chemical shift
(ppm): 143.9,142.7,138.7,137.0,129.9,128.8,128.6,127.4,126.6,10 8.1,61.7,46.4,
37.6,21.5。
Using infrared spectroscopy to sample 6#- 1 and sample 6#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak:
502,574,668,750,838,910,987,1040,1236,1309,1454,1597,2924,3029。
Using high resolution mass spectrum HRMS (ESI+) to sample 6#- 1 and sample 6#- 2 analyses, as a result as follows:
With [C36H38N2O4S2+H]+Meter, calculated value: 627.2346；Test data: 627.2346.
Using high-efficient liquid phase chromatogram HPLC to sample 6#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=95/5, v=1.0mL/min,
λ=254nm, t (major)=28.70min, t (minor)=40.80min], ee=99%.
Using polarimeter to sample 6#- 2 analyses, it is as a result as follows: [α]D20=-139.9 (c=0.7, CHCl3).Sample 6#-
1 is the racemic mixture of product 6-1 and product 6-2；Sample 6#It is mainly product 6-1 in -2.
The preparation of 7 product 7 of embodiment
Product 7: R in Formula II -1 and Formula II -21And R2Respectively 3,3- diphenyl propyl, Methyl benzenesulfonyl base (is abbreviated as
TS)；- 1 corresponding product of Formula II is denoted as product 7-1, and -1 corresponding product of Formula II is denoted as product 7-2.
The Chinese of product 7-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(3,3- diphenyl propyl) -4- is to Methyl benzenesulfonyl base)
The English name of product 7-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(3,3-
diphenylpropyl)-4-methylbenzenesulfonamide)
The structural formula of product 7-1 and product 7-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 7#- 1, yield 63%；Sample 7 is denoted as using chiral ligand products therefrom#- 2, yield 71%.
Sample 7#- 1 and sample 7#- 2 fusing point (mp): 169~170 DEG C.
Using thin-layer chromatography to sample 7#- 1 and sample 7#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 7#- 1 and sample 7#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.60 (d, J=8.1Hz, 4H), 7.28-7.17 (m,
24H), 5.07 (s, H), 4.87 (s, 2H), 4.21 (s, 2H), 3.80 (t, J=8.0Hz, 2H), 3.15-3.07 (m, 2H),
2.85-2.77(m,2H),2.57-2.43(m,4H),2.36(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm):
144.0,143.9,143.5,142.6,136.8,129.8,128.6,127.9,127.8,127.3,126.3,107.9,61.7,
49.3,43.7,36.3,21.5。
Using infrared spectroscopy to sample 7#- 1 and sample 7#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 546,585,664,764,814,909,1061,1092,1161,1208,1345,1451,14 93,1598,2925,3026.
Using high resolution mass spectrum HRMS (ESI+) to sample 7#- 1 and sample 7#- 2 analyses, as a result as follows:
With [C50H50N2O4S2+H]+Meter, calculated value: 807.3292；Test data: 807.3285.
Using high-efficient liquid phase chromatogram HPLC to sample 7#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/
Min, λ=254nm, t (minor)=11.65min, t (major)=14.71min], ee=97%.
Using polarimeter to sample 7#- 2 analyses, it is as a result as follows: [α]D20=-17.7 (c=5.6, CHCl3).Sample 7#-1
For the racemic mixture of product 7-1 and product 7-2；Sample 7#It is mainly product 7-1 in -2.
The preparation of 8 product 8 of embodiment
Product 8: R in Formula II -1 and Formula II -21And R2Respectively 3- indolylethyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；
- 1 corresponding product of Formula II is denoted as product 8-1, and -1 corresponding product of Formula II is denoted as product 8-2.
The Chinese of product 8-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(3- indolylethyl) -4- is to Methyl benzenesulfonyl base)
The English name of product 8-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(2-(1H-indol-
3-yl)ethyl)-4-methylbenzenesulfonamide)
The structural formula of product 8-1 and product 8-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 8#- 1, yield 88%；Sample 8 is denoted as using chiral ligand products therefrom#- 2, yield 86%.
Sample 8#- 1 and sample 8#- 2 fusing point (mp): 185~188 DEG C.
Using thin-layer chromatography to sample 8#- 1 and sample 8#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 8#- 1 and sample 8#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 8.06 (s, 2H), 7.85 (d, J=8.2Hz, 4H), 7.72
(d, J=7.7Hz, 2H), 7.36 (d, J=7.9Hz, 2H), 7.29 (d, J=8.1Hz, 4H), 7.21-7.13 (m, 4H), 7.05
(s,2H),5.20(s,4H),4.30(s,2H),3.62-3.54(m,2H),3.29-3.11(m,6H),2.37(s,6H)。13C
NMR(100MHz,CDCl3) chemical shift (ppm): 143.8,142.9,137.2,136.3,129.9,127.4,127.3,
122.2,122.1,119.5,119.0,112.9,111.2,108.1,62.1,45.8,27.4,21.5。
Using infrared spectroscopy to sample 8#- 1 and sample 8#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 424,546,661,751,815,906,988,1012,1088,1159,1205,1257,133 7,1457,1596,2852,
3402。
Using high resolution mass spectrum HRMS (ESI+) to sample 8#- 1 and sample 8#- 2 analyses, as a result as follows:
With [C40H40N4O4S2+H]+Meter, calculated value: 705.2564；Test data: 705.2566.
Using high-efficient liquid phase chromatogram HPLC to sample 8#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=70/30, v=1.0mL/
Min, λ=254nm, t (major)=12.70min, t (minor)=22.11min], ee=74%
Using polarimeter to sample 8#- 2 analyses, it is as a result as follows: [α]D20=-88.1 (c=1.0, CHCl3).Sample 8#-1
For the racemic mixture of product 8-1 and product 8-2；Sample 8#It is mainly product 8-1 in -2.
The preparation of 9 product 9 of embodiment
Product 9: R in Formula II -1 and Formula II -21And R2Respectively 2- thienylethyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；
- 1 corresponding product of Formula II is denoted as product 9-1, and -1 corresponding product of Formula II is denoted as product 9-2.
The Chinese of product 9-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(2- thienylethyl) -4- is to Methyl benzenesulfonyl base)
The English name of product 9-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N-(2-
(thiophen-2-yl)ethyl)benzenesulfonamide)
The structural formula of product 9-1 and product 9-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 9#- 1, yield 65%；Sample 9 is denoted as using chiral ligand products therefrom#- 2, yield 67%.
Sample 9#- 1 and sample 9#- 2 fusing point (mp): 191~195 DEG C.
Using thin-layer chromatography to sample 9#- 1 and sample 9#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 9#- 1 and sample 9#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.82 (d, J=8.4Hz, 4H), 7.34 (d, J=8.4Hz,
4H), 7.16 (d, J=4.3Hz, 2H), 6.96 (dd, J=5.2,3.6Hz, 2H), 6.88 (d, J=2.8Hz, 2H), 5.20 (s,
2H),5.01(s,2H),4.27(s,2H),3.56-3.48(m,2H),3.35-3.27(m,2H),3.20-3.10(m,4H),
2.42(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm): 143.9,142.5,140.7,136.8,130.0,
127.4,127.0,125.4,123.8,108.2,61.8,46.3,31.6,21.6。
Using infrared spectroscopy to sample 9#- 1 and sample 9#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 499,545,585,666,700,766,851,894,987,1053,1108,1229,1308,1344,1489,1596,
2937。
Using high resolution mass spectrum HRMS (ESI+) to sample 9#- 1 and sample 9#- 2 analyses, as a result as follows:
With [C32H34N2O4S4+H]+Meter, calculated value: 639.1477；Test data: 639.1474.
Using high-efficient liquid phase chromatogram HPLC to sample 9#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=99/1, v=1.0mL/min,
λ=254nm, t (major)=39.80min, t (minor)=47.92min], ee=99%
Using polarimeter to sample 9#- 2 analyses, it is as a result as follows: [α]D20=-29.3 (c=3.0, CHCl3).Sample 9#-1
For the racemic mixture of product 9-1 and product 9-2；Sample 9#It is mainly product 9-1 in -2.
The preparation of 10 product 10 of embodiment
Product 10: R in Formula II -1 and Formula II -21And R2Respectively 2- furfuryl, Methyl benzenesulfonyl base (is abbreviated as
TS)；- 1 corresponding product of Formula II is denoted as product 10-1, and -1 corresponding product of Formula II is denoted as product 10-2.
The Chinese of product 10-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(2- furfuryl) -4- is to Methyl benzenesulfonyl base)
The English name of product 10-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N-
((tetrahydrofuran-2-yl)methyl)benzenesulfonamide)
The structural formula of product 10-1 and product 10-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 10#- 1, yield 71%；Sample 10 is denoted as using chiral ligand products therefrom#- 2, yield 79%.
Sample 10#- 1 and sample 10#- 2 fusing point (mp): 72~75 DEG C.
Using thin-layer chromatography to sample 10#- 1 and sample 10#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 10#- 1 and sample 10#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.87-7.75 (m, 4H), 7.31 (d, J=7.3Hz, 4H),
5.47-5.19(m,4H),4.67(s,1H),4.24(s,1H),4.13-4.01(m,2H),3.90-3.80(m,2H),3.74-
3.64(m,2H),3.47-3.35(m,2H),3.30-3.22(m,2H),2.42(s,6H),2.01-1.78(m,6H),1.76-
1.70(m,1H),1.61-1.44(m,1H)。
13C NMR(100MHz,CDCl3) chemical shift (ppm): 144.3,143.6,143.3,143.2,143.1,
142.6,137.5,137.3,137.2,129.8,129.7,129.6,127.6,127.4,127.3,107.5,107.4,78.8,
78.7,77.9,67.9,67.8,62.5,62.4,61.4,49.3,49.0,29.5,29.1,25.4,25.3,21.5。
Using infrared spectroscopy to sample 10#- 1 and sample 10#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 547,660,706 766,815,1032,1089,1163,1346,1447,1494,1598,2871,2924.
Using high resolution mass spectrum HRMS (ESI+) to sample 10#- 1 and sample 10#- 2 analyses, as a result as follows: with
[C30H38N2O6S2+H]+Meter, calculated value: 587.2245；Test data: 587.2244.
Using high-efficient liquid phase chromatogram HPLC to sample 10#- 2 analyses, as a result as follows:
[Daicel Chiralpak IF (0.46cm x 25cm), n-hexane/isopropanol=90/10, v=1.0mL/
Min, λ=254nm, t (major)=59.68min, t (minor)=72.86min], ee=90%
Using polarimeter to sample 10#- 2 analyses, it is as a result as follows: [α]D20=-14.4 (c=3.0, CHCl3).Sample
10#- 1 is the racemic mixture of product 10-1 and product 10-2；Sample 10#It is mainly product 10-1 in -2.
The preparation of 11 product 11 of embodiment
Product 11: R in Formula II -1 and Formula II -21And R2Respectively normal-butyl, to Methyl benzenesulfonyl base (being abbreviated as TS)；Formula
II-1 corresponding product is denoted as product 11-1, and -1 corresponding product of Formula II is denoted as product 11-2.
The Chinese of product 11-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
Butyl -4- is to Methyl benzenesulfonyl base)
The English name of product 11-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-butyl-4-
methyl benzenesulfonamide)
The structural formula of product 11-1 and product 11-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 11#- 1, yield 66%；Sample 11 is denoted as using chiral ligand products therefrom#- 2, yield 67%.
Sample 11#- 1 and sample 11#- 2 fusing point (mp): 108~112 DEG C.
Using thin-layer chromatography to sample 11#- 1 and sample 11#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 11#- 1 and sample 11#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.78 (d, J=8.0Hz, 4H), 7.33 (d, J=8.0Hz,
4H),5.25(s,2H),5.01(s,2H),4.43(s,2H),3.25-3.17(m,2H),2.99-2.91(m,2H),2.43(s,
6H), 1.70-1.49 (m, 4H), 1.29-1.20 (m, 4H), 0.88 (t, J=7.3Hz, 6H).
13C NMR(100MHz,CDCl3) chemical shift (ppm): 143.5,143.1,137.3,129.8,127.4,
107.8,61.6,44.8,32.9,21.5,20.2,13.6。
Using infrared spectroscopy to sample 11#- 1 and sample 11#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 544,568,664,731,765,813,898,999,1029,1090,1139,1165,1221,1250,1345,2954.
Using high resolution mass spectrum HRMS (ESI+) to sample 11#- 1 and sample 11#- 2 analyses, as a result as follows: with
[C28H38N2O4S2+H]+Meter, calculated value: 531.2343；Test data: 531.2346.
Using high-efficient liquid phase chromatogram HPLC to sample 11#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=90/10, v=1.0mL/
Min, λ=254nm, t (minor)=19.29min, t (major)=26.54min], ee=82%
Using polarimeter to sample 11#- 2 analyses, it is as a result as follows: [α]D20=-21.5 (c=4.2, CHCl3).Sample
11#- 1 is the racemic mixture of product 11-1 and product 11-2；Sample 11#It is mainly product 11-1 in -2.
The preparation of 12 product 12 of embodiment
Product 12: R in Formula II -1 and Formula II -21And R2Respectively tert-butyl dimethyl silica ethyl (tert-butyl two therein
Methyl siloxy is abbreviated as OTBS), to Methyl benzenesulfonyl base (being abbreviated as TS)；- 1 corresponding product of Formula II is denoted as product 12-1, formula
II-1 corresponding product is denoted as product 12-2.
The Chinese of product 12-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
Tert-butyl dimethyl silica ethyl -4- is to Methyl benzenesulfonyl base)
The English name of product 12-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(N-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-4-methylbenzenesulfonamide)
The structural formula of product 12-1 and product 12-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 12#- 1, yield 84%；Sample 12 is denoted as using chiral ligand products therefrom#- 2, yield 93%.
Sample 12#- 1 and sample 12#- 2 fusing point (mp): 126~128 DEG C.
Using thin-layer chromatography to sample 12#- 1 and sample 12#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 12#- 1 and sample 12#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.69 (d, J=8.0Hz, 4H), 7.25 (d, J=8.0Hz,
4H),5.12(s,2H),4.89(s,2H),4.11(s,2H),3.82-3.70(m,4H),3.25-3.17(m,2H),2.99-
2.92(m,2H),2.35(s,6H),0.81(s,18H),-0.00(s,12H)。13C NMR(100MHz,CDCl3) chemical shift
(ppm): 143.7,142.6,136.9,129.8,127.3,108.0,62.7,62.2,46.0,25.9,21.5,18.3, -5.3.
Using infrared spectroscopy to sample 12#- 1 and sample 12#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 548,664,777,837,1089,1163,1255,1345,1471,1597,2929.
Using high resolution mass spectrum HRMS (ESI+) to sample 12#- 1 and sample 12#- 2 analyses, as a result as follows: with
[C36H58N2O6S2Si2+H]+Meter, calculated value: 735.3351；Test data: 735.3348.
Using high-efficient liquid phase chromatogram HPLC to sample 12#- 2 analyses, as a result as follows:
[Daicel Chiralpak IA (0.46cm x 25cm), n-hexane/isopropanol=99/1, v=1.0mL/min,
λ=254nm, t (minor)=23.67min, t (major)=33.71min], ee=96%
Using polarimeter to sample 12#- 2 analyses, it is as a result as follows: [α]D20=-9.3 (c=7.8, CHCl3).Sample 12#-
1 is the racemic mixture of product 12-1 and product 12-2；Sample 12#It is mainly product 12-1 in -2.
The preparation of 13 product 13 of embodiment
Product 13: R in Formula II -1 and Formula II -21And R2Respectively 9- octadecylene base, Methyl benzenesulfonyl base (is abbreviated as
TS)；- 1 corresponding product of Formula II is denoted as product 13-1, and -1 corresponding product of Formula II is denoted as product 13-2.
The Chinese of product 13-1 are as follows: N, N'- ((1S, 2S) -3,4- dimethylene cyclobutane -1,2- substitution) two (N-
(9- octadecylene base) -4- is to Methyl benzenesulfonyl base)
The English name of product 13-1 are as follows:
N,N'-((1S,2S)-3,4-dimethylenecyclobutane-1,2-diyl)bis(4-methyl-N-
((Z)-octadec-9-en-1-yl)benzenesulfonamide)
The structural formula of product 13-1 and product 13-2 are respectively as follows:
The preparation of sample 1#-1 in specific preparation process such as embodiment 1, the difference is that, the achirality and hand of use
Property ligand is respectively (n=1, the R of compound shown in formula (3)12=phenyl) and formula (7) shown in compound (R17And R18It is phenyl)；
The connection enamine raw material of use are as follows: R in Formulas I1And R2The respectively connection enamine of benzyl and methyl sulphonyl；Using achiral ligand institute
It obtains product and is denoted as sample 13#- 1, yield 76%；Sample 13 is denoted as using chiral ligand products therefrom#- 2, colorless oil, yield is
50%.
Using thin-layer chromatography to sample 13#- 1 and sample 13#- 2 analyses: Rf=0.3 (ethyl acetate/petroleum ether=1/5, v/
v)。
Using nuclear magnetic resonance to sample 13#- 1 and sample 13#- 2 detections, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.70 (d, J=8.0Hz, 4H), 7.25 (d, J=7.6Hz,
4H), 5.31 (d, J=14.6Hz, 4H), 5.18 (s, 2H), 4.94 (s, 2H), 4.36 (s, 2H), 3.16-3.09 (m, 2H),
2.91-2.83(m,2H),2.35(s,6H),1.94-1.89(m,8H),1.64-1.46(m,4H),1.18(s,44H),0.80
(d, J=6.8Hz, 6H).13C NMR(100MHz,CDCl3) chemical shift (ppm): 143.5,143.2,137.3,129.9,
129.8,129.7,127.6,107.8,61.6,45.1,32.6,31.9,30.9,29.8,29.7,29.5,29.3,29.2,
29.1,27.2,27.0,22.7,21.5,17.1。
Using infrared spectroscopy to sample 13#- 1 and sample 13#- 2 detections (KBr), in following wave number (cm-1) there is diffraction in position
Peak: 546,565,661,722,813,895,1090,1160,1346,1465,1598,2854,29 25.
Using high resolution mass spectrum HRMS (ESI+) to sample 13#- 1 and sample 13#- 2 analyses, as a result as follows: with
[C56H90N2O4S2+H]+Meter, calculated value: 919.6415；Test data: 919.6421.
Using high-efficient liquid phase chromatogram HPLC to sample 13#- 2 analyses, as a result as follows:
[Daicel Chiralpak ID (0.46cm x 25cm), n-hexane/isopropanol=99/1, v=1.0mL/min,
λ=254nm, t (major)=43.84min, t (minor)=65.22min], ee=84%
Using polarimeter to sample 13#- 2 analyses, it is as a result as follows: [α]D20=-13.7 (c=5.2, CHCl3).Sample
13#- 1 is the racemic mixture of product 13-1 and product 13-2；Sample 13#It is mainly product 13-1 in -2.
Embodiment 14
The cycloaddition reaction of gained 1,2- dimethylene cyclobutane chipal compounds and dimethyl maleate:
Sample 1 is sequentially added in a dry reaction tube#- 7 (120mg, 0.2mmol), dimethyl maleate
(170.5mg, 1.2mmol) and toluene (20mL) is reacted 7 hours at 110 DEG C, is quenched with water, then with water (50mL) and dichloro
Methane (50mL) extraction, stratification, organic phase are collected, and (3 × 50mL) is extracted with dichloromethane in water phase.Merge organic layer, does
It is dry, concentration, column chromatographic purifying (silica gel petrol ether/ethyl acetate: 2/1) to get arrive product (145.2mg, with sample 1#- 1 rubs
98%) that number meter, the yield of product are.
Product is detected using nuclear magnetic resonance, as a result as follows:
1H NMR(400MHz,CDCl3) chemical shift (ppm): 7.63 (d, J=8.0Hz, 4H), 7.31 (d, J=8.0Hz,
4H), 7.25 (t, J=3.0Hz, 6H), 7.16 (t, J=2.6Hz, 4H), 5.18 (s, 2H), 4.24 (s, 4H), 3.71 (s, 6H),
2.91(s,4H),2.47(s,6H)。13C NMR(100MHz,CDCl3) chemical shift (ppm): 167.1,143.9,137.5,
135.0,134.8,131.8,129.7,128.6,128.5,128.0,127.4,121.5,54.6,52.2,28.9,21.6。
Using infrared spectroscopy to sample 14#It detects (KBr), in following wave number (cm-1) there is a diffraction maximum in position: 549,643,
738,777,952,1091,1162,1307,1345,1453,1598,1650,1733,2919,2950,3034,3060。
Using high resolution mass spectrum HRMS (ESI+) to sample 14#Analysis, as a result as follows:
With [C40H40N2O8S2+H]+Meter, calculated value: 741.2299；Test data: 741.2300.
The above is only several embodiments of the application, not does any type of limitation to the application, although this Shen
Please disclosed as above with preferred embodiment, however not to limit the application, any person skilled in the art is not taking off
In the range of technical scheme, a little variation or modification are made using the technology contents of the disclosure above and is equal to
Case study on implementation is imitated, is belonged in technical proposal scope.
Claims (9)
1. a kind of method for synthesizing 1,2- dimethylene cyclobutane chipal compounds, which is characterized in that in the presence of rhodium complex
Under, 1,2- dimethylene cyclobutane chipal compounds are synthesized by connection enamine compound；
The rhodium complex is formed by the rhodium source containing rhodium element with ligand；The ligand is that chiral ligand and/or achirality are matched
Body；The chiral ligand and achiral ligand are selected from least one in the organic compound containing P elements and/or nitrogen
Kind；
The enamine compound is selected from least one of the compound with chemical structural formula shown in Formulas I:
The 1,2- dimethylene cyclobutane chipal compounds be with the chemical structural formula as shown in Formula II -1 compound and/or
Compound with the chemical structural formula as shown in Formula II -2:
In Formulas I, Formula II -1 and Formula II -2, R1、R2It is no more than 18 aliphatic group, with formula independently selected from hydrogen, carbon atom number
The group of structural formula shown in III, the group with structural formula shown in Formula V, has Formula IV at the group with structural formula shown in Formula IV
The group of shown structural formula or group with structural formula shown in Formula VII:
In formula III, R3The substituted fatty hydrocarbon base of aliphatic group, carbon atom number no more than 18, virtue selected from carbon atom number no more than 18
Base, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, replaces heteroarylalkyl at substituted aryl；
R4- A- formula IV
In formula IV, A is selected from the alkylene that carbon atom number is no more than 10；R4Aliphatic group, carbon selected from carbon atom number no more than 18 is former
Subnumber no more than 18 substituted fatty hydrocarbon base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,
Heteroarylalkyl replaces heteroarylalkyl, silylation；
R5- O-B- Formula V
In Formula V, B is selected from the alkylene that carbon atom number is no more than 10；R5Aliphatic group, carbon selected from carbon atom number no more than 18 is former
Subnumber no more than 18 substituted fatty hydrocarbon base, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl,
Heteroarylalkyl replaces heteroarylalkyl, silylation；
In Formula IV, R6The substituted fatty hydrocarbon base of aliphatic group, carbon atom number no more than 18, virtue selected from carbon atom number no more than 18
Base, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, replaces heteroarylalkyl, silylation at substituted aryl；
In Formula VII, R7The substituted fatty hydrocarbon base of aliphatic group, carbon atom number no more than 18, virtue selected from carbon atom number no more than 18
Base, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroarylalkyl, replaces heteroarylalkyl, silylation at substituted aryl；
The rhodium source be selected from dimerization rhodium acetate, triphenylphosphine rhodium carbonyl chloride, dimerization hydroxyl (1,5- cyclo-octadiene) rhodium (I),
Praseodynium rhodium (III), four carbonyl dichlorides, two rhodium, (1,5- cyclo-octadiene) chlorine rhodium (I) dimer, two rhodium of dichloride are (double
Norbornadiene), acetylacetone,2,4-pentanedione bi-vinyl rhodium, acetylacetone,2,4-pentanedione (1,5- cyclo-octadiene) rhodium, trifluoroacetic acid rhodium (II) dimer,
Four or three [- (+)-N- (to dodecyl benzene sulfonyl) porphyrin] two rhodiums, dichloro (pentamethylcyclopentadiene base) close rhodium dimer, triphen
At least one of base phosphine hydrogenized carbonyl rhodium；
The achiral ligand is selected from the compound of structural formula shown in the compound with structural formula shown in formula (1), formula (2), formula
(3) compound of structural formula shown in the compound of structural formula shown in the compound of structural formula shown in, formula (4), formula (5), formula (6) institute
Show at least one of the compound of structural formula:
In formula (1), R8Selected from hydrogen ,-CH3、—OCH3、—N(CH3)2、—OCH(CH3)2；R9Selected from hydrogen ,-OCH3、—N
(CH3)2、—OCH(CH3)2；R10Selected from cyclohexyl ,-C (CH3)3；
In formula (2), R11Selected from-OCH2CH3、—C(CH3)3, phenyl；
In formula (3), R12Selected from phenyl, cyclohexyl；N is 1 or 3；
In formula (4), R13Selected from phenyl ,-C (CH3)3；
In formula (5), R14Selected from hydrogen, phenyl ,-CH3；R15Selected from hydrogen ,-CH3、—C(CH3)3；
In formula (6), R16Selected from-CH3Or-COOH；
The chiral ligand is selected from the compound of structural formula shown in the compound with structural formula shown in formula (7), formula (8), formula (9)
The compound of structural formula shown in the compound of structural formula shown in the compound of shown structural formula, formula (10), formula (11), formula (12) institute
Show shown in the compound of structural formula shown in the compound of structural formula shown in the compound of structural formula, formula (13), formula (14), formula (15)
Knot shown in the compound of structural formula shown in the compound of structural formula shown in the compound of structural formula, formula (16), formula (17), formula (18)
At least one of the compound of structural formula shown in the compound of structural formula shown in the compound of structure formula, formula (19), formula (20):
In formula (7), R17Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5- bis-
Aminomethyl phenyl, p-nitrophenyl；R18Selected from methyl, phenyl, tert-butyl, isopropyl, cyclohexyl；
In formula (8), R19Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5- bis-
Aminomethyl phenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (9), R20Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5- bis-
Aminomethyl phenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (10), R21Selected from methyl, phenyl, trifluoromethy phenyl；R22Selected from methyl, phenyl, trifluoromethy phenyl, first
Phenyl, 2,4,6- trimethylphenyl, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (11), R23Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5-
3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (12), R24Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5-
3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (13), R25Selected from H, F；R26Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethyls
Phenyl, 3,5- 3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (18), R27Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyls, 3,5-
3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (19), R28Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5-
3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl；
In formula (20), R29Selected from methyl, phenyl, trifluoromethy phenyl, methoxyphenyl, 2,4,6- trimethylphenyl, 3,5-
3,5-dimethylphenyl, p-nitrophenyl, isopropyl, cyclohexyl.
2. the method according to claim 1, wherein in Formulas I and Formula II, R1、R2Not independently selected from carbon atom number
Aliphatic group, acetyl group, benzyl more than 18,4- methoxy-benzyl, 1- menaphthyl, tert-butyl dimethyl silica ethyl, 3,3-
Diphenyl propyl, 2- phenethyl, furfuryl, thienylethyl, indolylethyl, 1,3- benzo dioxy -5- methyl, tertiary butyloxycarbonyl
Base, benzoyl, tablet held before the breast by officials methoxycarbonyl group, tri-chloroethoxy base formoxyl, p-nitrophenyl sulfonyl, to Methyl benzenesulfonyl base or methyl sulphur
Acyl group.
3. the method according to claim 1, wherein R1And R2In at least one be selected from have formula III shown in structure
The group of formula.
4. the method according to claim 1, wherein at least including the following steps:
A) rhodium source, chirality and/or achiral ligand, connection enamine compound are added in organic solvent, at -78 DEG C to 120 DEG C
It is stirred to react 10 minutes to 120 hours；
B) after reaction, add water quenching to go out, through liquid separation, washing, drying, remove organic solvent, separation to get bis- Asia 1,2-
Methyl cyclobutane chipal compounds.
5. according to the method described in claim 4, it is characterized in that, reaction temperature is -20 DEG C to 100 DEG C in step a)；Reaction
Time is 10 minutes to 48 hours.
6. according to the method described in claim 4, it is characterized in that, connection enamine compound and rhodium source and ligand rub in step a)
That ratio are as follows:
Join enamine compound: Rh: ligand=1:0.01~1:0.01~1.
7. according to the method described in claim 4, it is characterized in that, connection enamine compound and rhodium source and ligand rub in step a)
That ratio are as follows:
Join enamine compound: Rh: ligand=1:0.01~0.15:0.05~0.50；
In terms of the molal quantity of the molal quantity in rhodium source rhodium element contained in the rhodium source.
8. according to the method described in claim 4, it is characterized in that, organic solvent described in step a) be selected from benzene, carbon tetrachloride,
Petroleum ether, tetrahydrofuran, dimethylformamide, acetone, ether, methylene chloride, chloroform, toluene, dimethylbenzene, chlorobenzene, neighbour
At least one of dichloro-benzenes, hexamethylene, n-hexane, normal heptane, six ring of dioxane, acetonitrile, methanol, ethyl alcohol, pentane.
9. according to the method described in claim 4, it is characterized in that, step b) the isolated method is selected from recrystallization, thin layer
At least one of chromatography, column chromatography, vacuum distillation；
In the recrystallization, thin-layer chromatography and column chromatography method, used solvent is the mixed of polar solvent and nonpolar solvent
Close object；Wherein, the volume ratio of polar solvent and nonpolar solvent is 1:0.1~500.
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| Controllable [2+2] Cycloadditions of 1,5-Bisallenyl-Substituted Compounds;Xuefeng Jiang等;《Angewandte Chemie, International Edition》;20061231;第45卷(第47期);第8009-8013页 * |
| Generation of Acyloxyketenes from Unstable Mesoionic 1,3-Dioxolium-4-olates and Their Reaction with Ketenophiles To Give [2+2] Cycloadducts;Masashi Hamaguchi等;《J.Org.Chem.》;20061231;第71卷;第5162-5170页 * |
| Intramolecular Cyclizations of Allenic Acylureas and ‐Amides;Latchezar S. Trifonov Alexander S. Orahovats;《Helvetica Chimica Acta》;19870204;第70卷;第262-270页 * |
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