CN117209375A - 一种含季碳中心的多取代手性己二酸化合物的制备方法 - Google Patents
一种含季碳中心的多取代手性己二酸化合物的制备方法 Download PDFInfo
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- CN117209375A CN117209375A CN202310640984.9A CN202310640984A CN117209375A CN 117209375 A CN117209375 A CN 117209375A CN 202310640984 A CN202310640984 A CN 202310640984A CN 117209375 A CN117209375 A CN 117209375A
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- China
- Prior art keywords
- chiral
- polysubstituted
- adipic acid
- quaternary carbon
- containing quaternary
- Prior art date
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- -1 adipic acid compound Chemical class 0.000 title claims abstract description 41
- WNLRTRBMVRJNCN-UHFFFAOYSA-N hexanedioic acid Natural products OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 239000001361 adipic acid Substances 0.000 title claims abstract description 31
- 235000011037 adipic acid Nutrition 0.000 title claims abstract description 30
- 229910052799 carbon Inorganic materials 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 239000000758 substrate Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000012298 atmosphere Substances 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 239000011734 sodium Substances 0.000 claims description 65
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 150000001279 adipic acids Chemical class 0.000 claims description 9
- 239000010949 copper Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 claims description 7
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 229910052802 copper Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 125000000217 alkyl group Chemical class 0.000 claims description 3
- JILPJDVXYVTZDQ-UHFFFAOYSA-N lithium methoxide Chemical compound [Li+].[O-]C JILPJDVXYVTZDQ-UHFFFAOYSA-N 0.000 claims description 3
- NRVSCUABVKRWEH-UHFFFAOYSA-N pentyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CCCCC)C1=CC=CC=C1 NRVSCUABVKRWEH-UHFFFAOYSA-N 0.000 claims description 3
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- RFKZUAOAYVHBOY-UHFFFAOYSA-M copper(1+);acetate Chemical compound [Cu+].CC([O-])=O RFKZUAOAYVHBOY-UHFFFAOYSA-M 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- WHOBZBLBTZHMGY-UHFFFAOYSA-N ditert-butyl(ethyl)phosphane Chemical compound CCP(C(C)(C)C)C(C)(C)C WHOBZBLBTZHMGY-UHFFFAOYSA-N 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 claims description 2
- CTYPJIUQROQJBG-UHFFFAOYSA-N 4-diphenylphosphanylpentan-2-yl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)CC(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 CTYPJIUQROQJBG-UHFFFAOYSA-N 0.000 claims 1
- 239000004327 boric acid Substances 0.000 claims 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical class C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 125000000524 functional group Chemical group 0.000 abstract description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 abstract description 6
- 238000006473 carboxylation reaction Methods 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 5
- 238000010276 construction Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 239000001569 carbon dioxide Substances 0.000 abstract description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 229910052723 transition metal Inorganic materials 0.000 abstract description 2
- 150000003624 transition metals Chemical class 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000000178 monomer Substances 0.000 abstract 1
- 229920000642 polymer Polymers 0.000 abstract 1
- YHGNXQAFNHCBTK-OWOJBTEDSA-N trans-3-hexenedioic acid Chemical compound OC(=O)C\C=C\CC(O)=O YHGNXQAFNHCBTK-OWOJBTEDSA-N 0.000 description 52
- 238000005481 NMR spectroscopy Methods 0.000 description 39
- 239000000047 product Substances 0.000 description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 12
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical group CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 235000010290 biphenyl Nutrition 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 4
- 229910000831 Steel Inorganic materials 0.000 description 4
- 239000004305 biphenyl Substances 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000001465 metallisation Methods 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 241000894007 species Species 0.000 description 4
- 239000010959 steel Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- 230000021523 carboxylation Effects 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 229930192474 thiophene Natural products 0.000 description 3
- UQRONKZLYKUEMO-UHFFFAOYSA-N 4-methyl-1-(2,4,6-trimethylphenyl)pent-4-en-2-one Chemical group CC(=C)CC(=O)Cc1c(C)cc(C)cc1C UQRONKZLYKUEMO-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 229910020366 ClO 4 Inorganic materials 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- CSHQDFGRFMLWRA-UHFFFAOYSA-N copper(1+);prop-1-ene Chemical compound [Cu+].[CH2-]C=C CSHQDFGRFMLWRA-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- IUGIICGLLMXGAP-UHFFFAOYSA-N diphenyl(1h-pyrrol-2-yl)phosphane Chemical compound C1=CNC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 IUGIICGLLMXGAP-UHFFFAOYSA-N 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- MRCAAFFMZODJBP-UHFFFAOYSA-N 1-fluoro-3-phenylbenzene Chemical compound FC1=CC=CC(C=2C=CC=CC=2)=C1 MRCAAFFMZODJBP-UHFFFAOYSA-N 0.000 description 1
- RHDYQUZYHZWTCI-UHFFFAOYSA-N 1-methoxy-4-phenylbenzene Chemical compound C1=CC(OC)=CC=C1C1=CC=CC=C1 RHDYQUZYHZWTCI-UHFFFAOYSA-N 0.000 description 1
- VACQQHZZCOZKJC-UHFFFAOYSA-N 2-fluoro-1-methoxy-4-phenylbenzene Chemical compound C1=C(F)C(OC)=CC=C1C1=CC=CC=C1 VACQQHZZCOZKJC-UHFFFAOYSA-N 0.000 description 1
- NWAGCUZYTLIMCJ-UHFFFAOYSA-N 2-fluoro-1-methyl-4-phenylbenzene Chemical compound C1=C(F)C(C)=CC=C1C1=CC=CC=C1 NWAGCUZYTLIMCJ-UHFFFAOYSA-N 0.000 description 1
- FQBRXXBMYKCMBZ-UHFFFAOYSA-N B(O)(O)O.CC(C)(CC(C)(O)C)O.CC(C)(CC(C)(O)C)O Chemical compound B(O)(O)O.CC(C)(CC(C)(O)C)O.CC(C)(CC(C)(O)C)O FQBRXXBMYKCMBZ-UHFFFAOYSA-N 0.000 description 1
- BDEIASRRCFZGBR-UHFFFAOYSA-N B(O)(O)O.CC(C)(CC(C)O)O.CC(C)(CC(C)O)O Chemical compound B(O)(O)O.CC(C)(CC(C)O)O.CC(C)(CC(C)O)O BDEIASRRCFZGBR-UHFFFAOYSA-N 0.000 description 1
- XUHDHOPBLIXFAI-UHFFFAOYSA-N B(O)(O)OCC(C)(COB(O)O)C Chemical compound B(O)(O)OCC(C)(COB(O)O)C XUHDHOPBLIXFAI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
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- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical group CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- FZQBLSFKFKIKJI-UHFFFAOYSA-N boron copper Chemical compound [B].[Cu] FZQBLSFKFKIKJI-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
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- HFDWIMBEIXDNQS-UHFFFAOYSA-L copper;diformate Chemical compound [Cu+2].[O-]C=O.[O-]C=O HFDWIMBEIXDNQS-UHFFFAOYSA-L 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
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- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- SAMCXPGNUAXAOO-UHFFFAOYSA-N diphenylphosphane;pentane Chemical compound CCCCC.C=1C=CC=CC=1PC1=CC=CC=C1 SAMCXPGNUAXAOO-UHFFFAOYSA-N 0.000 description 1
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
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- 239000002649 leather substitute Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- BYSRVCQMGFTUBK-UHFFFAOYSA-N methyl 3-phenylbenzoate Chemical compound COC(=O)C1=CC=CC(C=2C=CC=CC=2)=C1 BYSRVCQMGFTUBK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
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Abstract
本发明公开了一种含季碳中心的多取代手性己二酸化合物的制备方法，属于有机合成技术领域，包括以下步骤：将底物、联硼酸酯、碱和溶剂加入反应容器中，然后在CO2气氛下加入催化剂和配体，50～100℃下搅拌反应12～48h后酸化处理，对反应产物进行分离纯化，制得含季碳中心的多取代手性己二酸化合物。本发明基于过渡金属催化CO2参与多取代1,3‑丁二烯的催化不对称双羧基化反应，首次实现了含季碳中心的多取代手性己二酸化合物的高效构建，具有反应底物范围广、选择性好、官能团兼容性好、反应条件温和、成本低等优点。为手性药物，手性聚合物单体的创制提供可供选择的新途径，也为二氧化碳的高效利用提供新思路。
Description
技术领域
本发明属于有机合成技术领域，具体涉及一种含季碳中心的多取代手性己二酸化合物的制备方法。
背景技术
己二酸是一种重要的二元羧酸，在化工生产、有机合成工业、医药、润滑剂制造等方面都有重要作用。以生产尼龙66和工程塑料为主，同时也是医药、酵母提纯、杀虫剂、粘合剂、合成革、合成染料和香料的原料。己二酸还可以用于生产造纸化学品和合成润滑剂的湿润增强树脂等。因此高效构建结构多样性的己二酸受到有机化学、药物化学以及生物化学领域的广泛关注。
传统上，己二酸主要是利用“硝酸氧化法”制造的，但制造过程会产生及释放破坏臭氧层及造成地球暖化的一氧化二氮(N2O，俗称“笑气”)，既不环保也不稳定。最近德国罗斯托克大学莱布尼茨催化研究所(LIKAT Rostock)的Matthias Beller教授利用1,3-丁二烯和CO发生选择性双羰基化反应，在丁醇存在下直接合成己二酸二酯。但该反应体系需要使用有毒的CO作为羰基源，其安全性面临一定的问题。另一方面现阶段己二酸的合成也面临着产物结构单一，无法构建含多种官能团取代己二酸等难题，尤其是其催化不对称合成更是面临着巨大的挑战。因此探索多官能团取代己二酸的高效不对称合成具有重要的学术意义和应用价值。
二氧化碳作为一种廉价易得、无毒可再生、储量丰富的碳一资源。近年来，受到材料、化学化工领域的极大关注。因此，发展高效的CO2转化方法也具有重要的学术意义和潜在的工业价值。最近，利用CO2参与羧酸构建受到有机化学家的高度重视。其中，CO2参与不饱和碳氢化合物的官能化反应是构建羧酸产物的重要途径。更进一步，CO2参与烯烃的双羧基反应则能同时引入两个羧基官能团，是快速构建多取代复杂二元羧酸的便捷途径。但迄今为止，过渡金属催化CO2参与烯烃的不对称双羧基化反应仍然罕有报道。
因此，利用CO2来代替价格昂贵且有毒的羧基源(CO或者氰基)，通过开发一种新型CO2参与的烯烃的不对称双羧基化反应，为光学纯的多官能团取代手性己二酸化合物的高效合成提供一种方法，是本领域所亟需的。
发明内容
针对现有技术的不足或缺陷，本发明的目的是提供一种含季碳中心的多取代手性己二酸化合物的制备方法，可有效解决现有制备方法中存在步骤繁琐、使用有毒的CO气体或者剧毒的氰基化合物作为羧基源的问题，同时该方法具有产率高、选择性高、反应条件温和、反应试剂毒性低、成本低等优点。
为了达到上述目的，本发明所采用的技术方案是，提供一种含季碳中心的多取代手性己二酸化合物的制备方法，包括以下步骤：
将底物、碱、还原剂和溶剂加入反应容器中，然后在CO2气氛下加入催化剂和配体，50～100℃下搅拌反应后酸化处理，再分离纯化，得含季碳中心的多取代手性己二酸化合物；
反应底物的结构通式如下所示：
其中，X、Y、Z分别独立的为芳基、烷基、氢、卤素、氮、氧、硅基、硼酸酯、三氟甲基、三氟甲氧基、甲巯基、酯基或酯基衍生物；R1、R2分别独立的为芳基、氢、烷基、卤素、酯基或酯基衍生物。
在上述技术方案的基础上，本发明还可以做如下改进。
进一步，底物、催化剂、配体、碱和还原剂的摩尔比为1:0.01～0.5:0.01～0.5:1～5:1～5。
进一步，催化剂为铜催化剂。
进一步，铜催化剂为均三甲苯基亚铜、氯化亚铜、醋酸亚铜或噻吩-2-甲酸亚铜。
进一步，配体为(+)-1,2-双((2S,5S)-2,5-二苯基膦杂戊烷)乙烷、(-)-1,2-双((2R,5R)-2,5-二苯基膦杂戊烷)乙烷、(2S,4S)-2,4-双(二苯基膦)戊烷、(R)-(-)-1-[(Sp)-2-(二苯基膦)二茂铁基]乙基二叔丁基膦或(+)-1,2-双[(2S,5S)-2,5-二甲基磷]苯。
进一步，还原剂为联硼酸酯。
进一步，联硼酸硼酸酯为联硼酸频那醇酯、联硼酸新戊二醇酯、双联(2-甲基-2,4-戊二醇)硼酸酯或双联(2,4-二甲基-2,4-戊二醇)硼酸酯。
进一步，碱为甲醇锂、甲醇钠、甲醇钾、乙醇钠、乙醇钾、叔丁醇锂、叔丁醇钠、叔丁醇钾、叔戊醇钠、碳酸铯或碳酸钾。
进一步，碱为碳酸盐、碳酸氢盐、氟化盐、烷氧基碱、磷酸盐、磷酸氢盐、羧酸盐或有机碱。
进一步，溶剂为苯甲醚、1,4-二氧六环、四氢呋喃、甲基叔丁基醚、二异丙醚、氯苯、甲苯、对二甲苯、正己烷或乙腈。
本发明中，含季碳中心的多取代手性己二酸化合物的合成反应方程式如下：
反应原理如图1所示。首先，利用手性配体配位的L*Cu(I)物种与频哪醇酯发生转金属化得到L*Cu-Bpin物种I，多取代1,3-丁二烯1插入到L*Cu-Bpin物种I生成烯丙基铜中间体II，随后以六元环状过渡态III的形式对CO2亲核进攻得到硼基取代的Cu(I)-羧酸IV，进一步和甲醇锂发生转金属化生成羧酸锂盐V，硼基取代的羧酸锂盐V与手性配体配位的L*Cu(I)物种进一步发生转金属化生成烯丙基铜中间体VI和VI’，随后以六元环状过渡态VII的形式对CO2亲核进攻，经酸化水解后处理得到所需的产物2。
本发明的有益效果是：
1、本发明提供了一种含季碳中心的多取代手性己二酸化合物的制备方法，基于铜硼催化体系的CO2参与多取代1,3-丁二烯的不对称双羧基化反应，首次实现了含季碳中心的多取代手性己二酸化合物的高效构建；具体以二氧化碳作为羧酸源，有效避免了传统制备方法中使用有毒的CO气体作为羧基源的问题；
2、本发明反应底物范围广、选择性好、官能团兼容性好、反应条件温和以及易于放大和后期衍生转化；本发明克服了现有技术试剂毒性高、反应条件苛刻的缺陷，所用原料廉价易得，具有良好的工业应用前景。
附图说明
图1为本发明的合成机理示意图。
具体实施方式
下面结合实施例对本发明的具体实施方式做详细的说明。
实施例1
由1-[1,1’-联苯]-1-甲基-1,3-丁二烯(1a)合成(R,E)-2-([1,1’-联苯]-4)-2-甲基反式-3-己二酸(2a)，反应包括以下步骤：
S1：在N2氛围的手套箱中，向含有搅拌子的干燥Schlenk管(10mL)中，加入底物(0.2mmol)，铜催化剂(0.010mmol,5mol％)，手性配体(0.012mmol,6mol％)，联硼酸频哪醇酯(0.3mmol，1.5当量)，碱(0.4mmol，2.0当量)；
S2：将Schlenk管封死后从手套箱中取出并连接到连有CO2钢瓶的双排管上，拧松盖子并在双排管上抽充置换CO2 3次，使其管中充满CO2气体；
S3：在CO2气氛下加入溶剂(1mL)，将其封死并在80℃下搅拌反应36h后；
S4：冷却至室温，将反应混合物用3mL稀盐酸(2N)淬灭，并用EtOAc萃取(约10mL，3次)，将合并的有机相真空浓缩，得粗产物；
S5：将粗产品通过硅胶快速柱层析纯化(失活硅胶：200-300mm；洗脱液：PE:EA＝4:1to 1:1with 0.1％AcOH)，得到所需的纯产物2a，计算其化学收率和旋光度，经过正相手性HPLC，以确定其对映体纯度。
具体反应条件见下表1，反应式如下：
表1.1-(4-苯基)苯基-1-甲基-1,3-丁二烯1a的反应条件
注：表1中N.R.代表为不反应；配体L*的结构式如下所示：
实施例2
由1-(杂)芳基-1-甲基-1,3-丁二烯合成含季碳中心的多取代手性己二酸化合物，反应包括以下步骤：
S1：在N2氛围的手套箱中，向含有搅拌子的干燥Schlenk管(10mL)中，加入底物(0.2mmol，底物种类如表2所示)，联硼酸频那醇酯(0.3mmol，1.5当量)，LiOMe(0.4mmol，2.0当量)；
S2：将Schlenk管封死后从手套箱中取出并连接到连有CO2钢瓶的双排管上，拧松盖子并在双排管上抽充置换CO2 3次，使其管中充满CO2气体；
S3：在CO2气氛下加入超干溶剂PhOMe(0.9mL)，室温下搅拌备用；
S4：在N2氛围的手套箱中，向含有搅拌子的小反应瓶(1mL)中，加入均三甲苯基亚铜(0.01mmol，5mol％)，(+)-1,2-双((2S,5S)-2,5-二苯基膦杂戊烷)乙烷(0.012mmol，6mol％)，加入超干Dioxane(0.1mL)，搅拌10分钟后加入上述Schlenk管(10mL)中，80℃搅拌反应36小时；
S5：完全转化后(TLC监测)，将反应混合物用3mL 2N HCl水溶液淬灭，并用EtOAc萃取(约10mL，3次)，将合并的有机相真空浓缩，得粗产物；
S6：将粗产品通过硅胶快速柱层析纯化(失活硅胶：200-300mm；洗脱液：PE:EA＝4:1，to 1:1含有0.1％AcOH)，得到所需的纯产物，计算其化学收率和旋光度；
S7：用TMSCHN2的MeOH/Et2O溶液(v/v＝1:1)处理羧化产物。使酯化化合物经过正相手性HPLC，以确定其对映体纯度。
反应方程式如下：
表2.以1-(杂)芳基-1-甲基-1,3-丁二烯为底物及其不对称双羧基化反应收率
以上实验结果表明，1-(杂)芳基-1-甲基-1,3-丁二烯为底物均以较高的产率、良好的区域选择性以及对映选择性得到相应的手性己二酸类的化合物。多种官能团如甲硫基、甲氧基、三氟甲基、三氟甲氧基、卤素原子以及酯基等都可兼容于该反应体系。萘基以及苯并呋喃、噻吩等杂环也能兼容于该反应体系。天然产物以及药物分子，例如石胆酸，丙磺舒衍生的1,3-丁二烯等也能顺利发生目标反应。
实施例3
由1-芳基-1-甲基/乙基/丁基-1,3-丁二烯合成含季碳中心的多取代手性己二酸化合物，反应包括以下步骤：
S1：在N2氛围的手套箱中，向含有搅拌子的干燥Schlenk管(25mL)中，加入均三甲苯基亚铜(0.04mmol，10mol％)，(+)-1,2-双((2S,5S)-2,5-二苯基膦杂戊烷)乙烷(0.06mmol，15mol％)，底物(0.4mmol，底物种类如表3所示)，联硼酸频那醇酯(0.6mmol，1.5当量)，LiOtBu(0.8mmol，2.0当量)；K2CO3(0.8mmol，2.0当量)；
S2：将Schlenk管封死后从手套箱中取出并连接到连有CO2钢瓶的双排管上，拧松盖子并在双排管上抽充置换CO2 3次，使其管中充满CO2气体；
S3：在CO2气氛下加入超干溶剂PhCl(2.0mL)，80℃搅拌反应36小时；
S4：完全转化后(TLC监测)，将反应混合物用3mL 2N HCl水溶液淬灭，并用EtOAc萃取(约10mL，3次)，将合并的有机相真空浓缩，得粗产物；
S5：将粗产品通过硅胶快速柱层析纯化(失活硅胶：200-300mm；洗脱液：PE:EA＝4:1，to 1:1含有0.1％AcOH)，得到所需的纯产物，计算其化学收率和旋光度；
S6：用TMSCHN2的MeOH/Et2O溶液(v/v＝1:1)处理羧化产物。使酯化化合物经过正相手性HPLC，以确定其对映体纯度。
反应方程式如下：
表3.以1-芳基-1-甲基/乙基/丁基-1,3-丁二烯为底物及其不对称双羧基化反应收率
以上实验结果表明，具有较大空间位阻的1-芳基-1-乙基/丙基/丁基-1,3-丁二烯为底物均以中等的产率、优秀的区域选择性以及良好的对映选择性得到相应的手性己二酸类的化合物。多种官能团如甲氧基、三氟甲基、卤素原子以及酯基等都可兼容于该反应体系。呋喃、噻吩等杂环也能兼容于该反应体系。
实施例4
由环状-丁二烯合成含季碳中心的多取代手性己二酸化合物，反应包括以下步骤：
S1：在N2氛围的手套箱中，向含有搅拌子的干燥Schlenk管(10mL)中，加入底物(0.2mmol)，联硼酸频哪醇酯(0.3mmol，1.5当量)，LiOMe(0.4mmol，2.0当量)；
S2：将Schlenk管封死后从手套箱中取出并连接到连有CO2钢瓶的双排管上，拧松盖子并在双排管上抽充置换CO2 3次，使其管中充满CO2气体；
S3：在CO2气氛下加入超干溶剂PhOMe(0.9mL)，室温下搅拌备用；
S4：在N2氛围的手套箱中，向含有搅拌子的小反应瓶(1mL)中，加入噻吩-2-甲酸亚铜铜(0.015mmol，7.5mol％)，(+)-1,2-双((2S,5S)-2,5-二苯基膦杂戊烷)乙烷(0.03mmol，15mol％)，加入超干Dioxane(0.1mL)，搅拌10分钟后加入上述Schlenk管(10mL)中，80℃搅拌反应36小时；
S5：完全转化后(TLC监测)，将反应混合物用3mL 2N HCl水溶液淬灭，并用EtOAc萃取(约10mL，3次)，将合并的有机相真空浓缩，得粗产物；
S6：将粗产品通过硅胶快速柱层析纯化(失活硅胶：200-300mm；洗脱液：PE:EA＝4:1，to 1:1含有0.1％AcOH)，得到所需的纯产物，计算其化学收率和旋光度；
S7：用TMSCHN2的MeOH/Et2O溶液(v/v＝1:1)处理羧化产物。使酯化化合物经过正相手性HPLC，以确定其对映体纯度。
反应方程式如下：
表4.以环状1,3-丁二烯为底物及其不对称双羧基化反应收率
以上实验结果表明，环状-1,3-丁二烯，不管是五元环，六元环或者是氧杂六元环衍生的1,3-丁二烯为底物均以中等的产率、优秀的区域选择性以及优秀的对映选择性得到相应的手性己二酸类的化合物。多种官能团如甲氧基、三氟甲基、卤素原子以及酯基等都可兼容于该反应体系。呋喃、吡咯和噻吩等杂环也能兼容于该反应体系。
对本发明所制得的产物进行了核磁共振和质谱表征分析。核磁和质谱表征数据结果与所得产物一致。具体表征数据如下：
本发明对实施例1-4所制得的产物进行了表征分析，表征数据结果表明与所得产物相符。具体表征数据如下：
(R,E)-2-([1,1’-联苯]-4)-2-甲基反式-3-己烯二酸(2a)
143.03,140.50,139.48,136.72,128.41,126.89,126.70,126.48,126.47,122.68,52.62,37.28,23.16；
HRMS-ESI(m/z)[M+Na]+calcd for C19H18O4:333.1097,found:333.1090；
(R,E)-2-甲基-2-苯基反式-3-己烯二酸(2b)
126.42,122.35,53.04,37.81,23.57；
HRMS(ESI+)for C13H14O4Na[M+Na]:calculated:257.0784,found:257.0779；
(R,E)-2-甲基-2-(4-甲氧基-苯基)反式-3-己烯二酸(2c)
δ181.25,178.07,158.53,137.10,134.61,127.63,122.04,113.84,55.25,52.28,37.82,23.62；
HRMS(ESI+)for C14H16O5Na[M+Na]:calculated:287.0890,found:287.0888；
(R,E)-2-甲基-2-(4-三氟甲基-苯基)反式-3-己烯二酸(2d)
176.07,173.99,148.50,136.06,128.64(q,J＝32Hz),127.11,125.65,124.83(q,J＝3.5Hz),123.58,53.03,37.19,23.14；19F NMR(376MHz,CD3OD)δ-63.96；
HRMS-ESI(m/z)[M+Na]+calcd for C14H13F3O4:325.0658,found:325.0655
(R,E)-2-甲基-2-(4-甲基-苯基)反式-3-己烯二酸(2e)
CD3OD)δ177.07,174.13,140.91,136.94,136.02,128.50,126.01,122.33,52.46,37.27,23.17,19.55；
HRMS(ESI+)for C14H16O4Na[M+Na]:calculated:271.0941,found:271.0941；
(R,E)-2-甲基-2-(4-氟-苯基)反式-3-己烯二酸(2f)
161.60(d,J＝122.2Hz),136.88(d,J＝20.7Hz),128.12(d,J＝4.0Hz),122.57(d,J＝25.3Hz),114.55(d,J＝1.0Hz),114.33(d,J＝1.0Hz),50.89,36.96,23.27(d,J＝2.0Hz)；19F NMR(376MHz,CD3OD)δ-118.60；
HRMS-ESI(m/z)[M+Na]+calcd for C13H13FO4:275.0690,found:275.0695；
(R,E)-2-甲基-2-(4-甲硫基-苯基)反式-3-己烯二酸(2g)
140.74,137.01,136.68,126.75,126.06,122.65,52.49,37.27,23.10,14.31；
HRMS-ESI(m/z)[M+Na]+calcd for C14H16O4S:303.0662,found:303.0659；
(R,E)-2-甲基-2-(4-苯氧基-苯基)反式-3-己烯二酸(2h)
(s,3H)；13C NMR(101MHz,CDCl3)δ180.52,177.53,156.87,156.47,137.30,136.99,129.78,127.96,123.49,122.35,119.15,118.52,52.52,37.82,23.75；
HRMS-ESI(m/z)[M+Na]+calcd for C19H18O5:349.1046,found:349.1044；
(R,E)-2-甲基-2-(4-三氟甲氧基-苯基)反式-3-己烯二酸(2i)
CDCl3)δ180.57,177.90,148.23(q,J＝2.0Hz),141.15,136.35,128.06,122.82,120.88(q,J＝180Hz),52.62,37.71,23.64；19F NMR(376MHz,CDCl3)δ-57.86；
HRMS-ESI(m/z)[M+Na]+calcd for C14H13F3O5:341.0607,found:341.0604；
(R,E)-2-甲基-2-(3-甲氧基-苯基)反式-3-己烯二酸(2j)
13C NMR(101MHz,CDCl3)δ180.68,177.91,159.53,144.30,136.69,129.53,122.44,118.82,112.88,112.04,55.21,53.06,37.91,23.53；
HRMS-ESI(m/z)[M+Na]+calcd for C14H16O5:287.0890,found:287.0886；
(R,E)-2-甲基-2-(3-三氟甲基-苯基)反式-3-己烯二酸(2k)
145.36,136.05,130.36(q,J＝32Hz),128.82,125.61,123.72,123.27(q,J＝3.7Hz),123.02(q,J＝3.7Hz),122.91,52.96,37.23,23.20；19F NMR(376MHz,CD3OD)δ-64.04；
HRMS-ESI(m/z)[M+Na]+calcd for C14H13F3O4:325.0658,found:325.0650；
(R,E)-2-甲基-2-(3-甲基-苯基)反式-3-己烯二酸(2l)
CDCl3)δ180.91,177.90,142.62,138.15,136.93,128.40,127.97,127.06,123.46,122.19,52.91,37.80,23.54,21.55；
HRMS-ESI(m/z)[M+Na]+calcd for C14H16O4:271.0941,found:271.0937；
(R,E)-2-甲基-2-苯基反式-3-己烯二酸(2m)
136.13,134.39,129.76,127.44,126.80,124.83,123.00,37.72,23.53；
HRMS-ESI(m/z)[M+Na]+calcd for C13H13ClO4:291.0395,found:291.0390；
(R,E)-2-甲基-2-(3-溴苯基)反式-3-己烯二酸(2n)
179.89,177.45,144.96,136.17,130.36,130.06,129.66,125.34,123.05,122.63,52.61,37.52,23.58；
HRMS-ESI(m/z)[M+Na]+calcd for C13H13BrO4:334.9889/336.9869,found:334.9885/336.9847；
(R,E)-2-甲基-2-(3-氟-4-甲氧基-苯基)反式-3-己烯二酸(2o)
174.04,151.83(d,J＝123Hz),146.33(d,J＝6Hz),136.87(d,J＝3Hz),136.55,122.79,122.09(d,J＝2Hz),114.10(d,J＝1Hz),112.94(d,J＝2Hz),55.24,52.04(d,J＝1Hz),37.17,23.10；19F NMR(376MHz,CD3OD)δ-136.97
HRMS-ESI(m/z)[M+Na]+calcd for C14H15FO5:305.0796,found:305.0794；
(R,E)-2-甲基-2-(3-溴-4-甲氧基-苯基)反式-3-己烯二酸(2p)
5.67(dt,J＝15.9,7.0Hz,1H),4.93(brs,2H)3.83(s,3H),3.14(dd,J＝7.1,1.4Hz,2H),1.57(s,3H)；13C NMR(101MHz,CD3OD)δ176.56,174.07,154.68,137.39,136.51,131.14,126.61,122.88,111.47,110.85,55.36,52.07,37.35,23.30；
HRMS-ESI(m/z)[M+Na]+calcd for C14H15BrO5:364.9995/366.9975[M+2],found:364.9992/366.9946[M+2]；
(R,E)-2-甲基-2-(2,4-二氟-苯基)反式-3-己烯二酸(2q)
162.22(dd,J＝125,6Hz),160.28(dd,J＝126,6Hz),135.11,128.61(dd,J＝9.6,5.8Hz),126.49(dd,J＝13.7,3.8Hz),123.40,110.99(dd,J＝20.8,3.4Hz),104.33(t,J＝25.8Hz),49.89,37.55,22.57；19F NMR(376MHz,CDCl3)δ-107.91,-111.36
HRMS(ESI+)[M+Na]for C13H12F2O4:calculated:293.0596,found:293.0595；
(R,E)-2-甲基-2-(苯并[d][1,3]二氧杂环戊烯-5-)反式-3-己烯二酸(2r)
146.60,136.86,136.48,122.30,119.69,108.11,107.37,101.14,52.65,37.75,23.71；
HRMS-ESI(m/z)[M+Na]+calcd for C14H14O6:301.0683,found:301.0681；
(R,E)-2-甲基-2-(3,4,5-三甲氧基-苯基)反式-3-己烯二酸(2s)
138.25,137.13,137.02,122.54,104.08,60.77,56.14,53.01,37.74,23.71；
HRMS-ESI(m/z)[M+Na]+calcd for C16H20O7:347.1101,found:347.1103；
(R,E)-2-甲基-2-(4’-甲氧基-[1,1’-联苯]-4-)反式-3-己烯二酸(2t)
174.11,159.28,142.29,139.13,136.80,132.93,127.47,126.61,125.97,122.58,113.79,54.29,52.57,37.28,23.15；
HRMS-ESI(m/z)[M+Na]+calcd for C20H20O5:363.1203,found:363.1204；
(R,E)-2-甲基-2-(4’-三氟甲基-[1,1’]-联苯]-4-)反式-3-己烯二酸(2u)
CD3OD)δ176.65,174.07,144.32,144.23,137.79,136.55,128.95,128.63,127.03,126.98,126.72,125.29(q,J＝3.8Hz),122.89,52.68,37.25,23.12；19F NMR(376MHz,CD3OD)δ-136.97
HRMS(ESI+)[M+Na]for C20H17F3O4:calculated:401.0971,found:401.0971；
(R,E)-2-甲基-2-(4’-羟甲基-[1,1’]-联苯]-4-)反式-3-己烯二酸(2v)
143.03,140.36,139.49,139.19,136.74,127.07,126.70,126.43,126.37,122.69,63.49,37.32,23.17,13.04；
HRMS-ESI(m/z)[M+Na]+calcd for C20H20O5:363.1203,found:363.1199；
(R,E)-2-甲基-2-(4’-(叔丁基二甲基硅氧甲基)-[1,1’]-联苯]-4-)反式-3-己烯二酸(2w)
141.54,140.52,139.97,139.14,136.73,127.17,126.92,126.88,126.49,122.43,64.74,52.82,37.88,25.99,23.56,18.46,-5.21；
HRMS-ESI(m/z)[M+Na]+calcd for C26H34O5Si:477.2068,found:477.2068；
(R,E)-2-甲基-2-(4’-(特戊酰氧基甲基)-[1,1’]-联苯]-4-)反式-3-己烯二酸(2x)
1H),3.23(d,J＝7.0Hz,2H),1.70(s,3H),1.24(s,9H)；13C NMR(101MHz,CDCl3)δ180.67,178.54,177.76,141.90,140.22,139.57,136.69,135.49,128.13,127.21,127.17,126.97,122.52,65.82,52.83,38.84,37.83,27.20,23.59；
HRMS-ESI(m/z)[M+Na]+calcd for C25H28O6:447.1778,found:447.1779；
(R,E)-2-甲基-2-(3’-甲氧基-[1,1’]-联苯]-4-)反式-3-己烯二酸(2y)
13C NMR(101MHz,CD3OD)δ176.73,174.04,160.08,143.15,141.96,139.36,136.73,129.42,126.66,126.52,122.71,118.92,112.25,112.15,54.27,52.49,37.36,23.18；
HRMS-ESI(m/z)[M+Na]+calcd for C20H20O5:363.1203,found:363.1201；
(R,E)-2-甲基-2-(3’-氟-[1,1’]-联苯]-4-)反式-3-己烯二酸(2z)
163.21(d,J＝122.7Hz),143.75,142.95(d,J＝4.0Hz),138.07(d,J＝1.0Hz),136.62,130.13(d,J＝4.0Hz),126.86,126.51,122.80,122.31(d,J＝1.5Hz),113.45(d,J＝11.1Hz),113.08(d,J＝11.1Hz),52.65,37.26,23.13；19F NMR(376MHz,CD3OD)δ-115.12
HRMS-ESI(m/z)[M+Na]+calcd for C19H17FO4:351.1003,found:351.0998；
(R,E)-2-甲基-2-(萘-2-)反式-3-己烯二酸(2aa)
141.29,136.72,133.30,132.31,127.57,127.49,127.00,125.70,125.48,124.86,124.52,122.95,53.01,37.29,23.17；
HRMS-ESI(m/z)[M+Na]+calcd for C17H16O4:307.0941,found:307.0941；
(R,E)-2-甲基-2-(6-甲氧基-萘-2-)反式-3-己烯二酸(2ab)
Hz,1H),6.37(dt,J＝15.8,1.5Hz,1H),5.83(dt,J＝15.9,7.0Hz,1H),3.98(s,3H),3.33–3.26(m,2H),1.80(s,3H)；13C NMR(101MHz,CD3OD)δ177.06,174.19,157.76,138.92,136.88,133.48,129.00,128.68,126.51,125.25,124.33,122.73,118.45,104.96,54.26,52.80,37.32,23.18；
HRMS-ESI(m/z)[M-H]-calcd for C18H18O5:313.1081,found:313.1078；
(R,E)-2-甲基-2-(噻吩-2-)反式-3-己烯二酸(2ac)
140.52,130.00,128.23,127.86,126.24,54.02,41.10,28.00；
HRMS(ESI+)for C11H12O4SNa[M+Na]:calculated:263.0349,found:263.0349；
(R,E)-2-甲基-2-(4-甲基-噻吩-2-)反式-3-己烯二酸(2ad)
(dd,J＝7.0,1.3Hz,2H),2.17(d,J＝1.0Hz,3H),1.66(s,3H)；13C NMR(101MHz,CD3OD)δ175.69,173.93,147.21,136.74,136.52,126.60,122.18,119.08,50.11,37.10,23.83,14.34；HRMS(ESI+)[M+Na]+calcd for C12H14O4S:277.0505,found:277.0501；
(R,E)-2-甲基-2-(3-氯-噻吩-2-)反式-3-己烯二酸(2ae)
173.78,148.61,135.65,124.87,123.74,123.23,118.89,50.29,36.98,23.69；
HRMS(ESI+)[M+Na]calcd for C11H11ClO4S:296.9959,found:296.9964；
(R,E)-2-甲基-2-(苯并[b]噻吩-2-)反式-3-己烯二酸(2af)
CDCl3)δ179.43,177.83,146.81,139.32,135.94,124.33,123.53,122.66,122.08,121.75,50.82,37.60,24.15；
HRMS-ESI(m/z)[M+Na]+calcd for C15H14O4S:313.0505,found:313.0501；
(R,E)-2-甲基-2-(4-(呋喃-2)-苯基-)反式-3-己烯二酸(2ag)
NMR(101MHz,CD3CN)δ175.29,172.52,153.31,142.93,142.54,136.26,129.40,127.02,123.60,123.13,117.36,111.87,105.49,52.53,36.90,23.24；
HRMS-ESI(m/z)[M+Na]+calcd for C17H16O5:363.1203,found:363.1204；
(R,E)-2-(4'-((((R)-4-((3R,5R,8R,9S,10S,13R,14S,17R)-3-((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)oxy)methyl)-[1,1'-biphenyl]-4-yl)-2
13C NMR(101MHz,CDCl3)δ180.51,177.61,174.24,141.92,140.43,139.57,136.68,135.16,128.72,127.22,127.20,126.93,122.49,72.87,65.83,60.45,56.34,55.93,52.81,42.69,42.26,40.14,40.08,37.81,36.85,35.82,35.55,35.30,34.56,31.30,30.95,28.17,27.27,26.37,25.97,24.19,23.57,23.36,21.04,20.77,18.34,18.24,14.17,11.99,-4.62.
HRMS-ESI(m/z)[M+Na]+calcd for C50H72O7SiNa:835.4940,found:835.4941
(R,E)-7-溴-1-(3-羧基-1-丙烯-1)-1,2,3,4-四氢化萘-1-羧酸(2ai)
Hz,2H),2.28(s,3H),2.13(s,3H),1.75–1.67(m,4H),1.63(s,3H),1.23(s,6H)；13CNMR(101MHz,CDCl3)δ180.24,177.59,177.25,156.85,156.29,136.97,136.41,134.50,130.27,127.23,126.95,124.70,123.58,122.17,120.78,112.15,110.24,68.15,61.67,55.36,52.27,42.22,37.72,37.03,25.19,25.10,23.65,21.34,15.72；
HRMS(ESI+)for C30H31O8Na[M+Na]:calculated:549.2459,found:549.2458；
(R,E)-2-(3-(4-(N,N’-二丙基砜基)苯甲酰氧基)甲基)-4-甲氧基)-2-甲基-反式-3-己烯二酸(2aj)
1H),5.72(dt,J＝15.8,7.0Hz,1H),5.38(s,2H),3.84(s,3H),3.19(d,J＝7.0Hz,2H),3.12–3.03(m,4H),1.65(s,3H),1.60–1.45(m,4H),0.85(t,J＝7.4Hz,6H)；13C NMR(101MHz,CDCl3)δ180.04,176.78,165.18,156.81,144.07,136.82,134.60,133.63,130.28,128.20,128.06,126.94,123.65,122.41,110.56,63.00,55.57,52.24,49.89,37.64,23.71,21.89,11.11；
HRMS(ESI+)for C28H35NO9Na[M+Na]:calculated:584.1925,found:584.1920；
(R,E)-2-乙基-2-([1,1’-联苯]-4-)反式-3-己烯二酸(2ak)
140.51,140.20,139.94,135.33,128.72,127.84,127.29,127.03,127.02,123.66,57.06,37.93,29.63,9.33；
HRMS-ESI(m/z)[M+Na]+calcd for C20H20O4:347.1254,found:347.1252；
(R,E)-2-乙基-2-(3’-氟-[1,1’-联苯]-4-)反式-3-己烯二酸(2al)
174.09,163.22(d,J＝122.7Hz),142.96(d,J＝3.5Hz),142.25,137.96(d,J＝1.0Hz),135.13,130.15(d,J＝4.5Hz),127.78,126.30,124.00,122.31(d,J＝1.5Hz),113.45(d,J＝10.6Hz),113.08(d,J＝11.1Hz),56.87,37.48,29.52,8.42；19F NMR(376MHz,CD3OD)δ-115.15
(R,E)-2-乙基-2-(3’-甲氧羰基-[1,1’-联苯]-4-)反式-3-己烯二酸(2am)
0.89(t,J＝7.3Hz,3H)；13C NMR(101MHz,CDCl3)δ180.14,177.83,167.11,144.91,141.26,138.64,135.22,130.11,128.81,128.05,127.17,127.13,126.91,123.83,57.13,52.22,37.94,29.63,9.34；
HRMS-ESI(m/z)[M+Na]+calcd for C22H22O6:405.1309,found:405.1312；
(R,E)-2-乙基-2-(3’-氟-4’-甲基-[1,1’-联苯]-4-)反式-3-己烯二酸(2an)
13CNMR(101MHz,CD3OD)δ176.27,174.03,161.52(d,J＝122.2Hz),141.87,140.27(d,J＝4.1Hz),138.0(d,J＝1.0Hz),135.16,131.46(d,J＝3.1Hz),127.70,126.03,123.94,123.22(d,J＝9.1Hz),121.91(d,J＝1.5Hz),112.61(d,J＝11.6Hz),56.85,37.47,29.52,12.77(d,J＝1.5Hz),8.38；19F NMR(376MHz,CD3OD)δ-119.66
HRMS-ESI(m/z)[M+Na]+calcd for C21H22O4:379.1316,found:379.1310；
(R,E)-2-乙基-2-(3’-氟-4’-甲氧基-[1,1’-联苯]-4-)反式-3-己烯二酸(2ao)
0.86(t,J＝7.2Hz,3H)；13C NMR(101MHz,CD3OD)δ176.31,174.04,152.46(d,J＝122.7Hz),147.04(d,J＝5.6Hz),141.43,137.85(d,J＝1.0Hz),135.20,133.71(d,J＝3.5Hz),127.68,125.81,123.91,122.23(d,J＝1.5Hz),113.79(d,J＝9.6Hz),113.58(d,J＝1.0Hz),56.83,55.33,37.48,29.53,8.37；19F NMR(376MHz,CD3OD)δ-137.07
HRMS-ESI(m/z)[M+Na]+calcd for C21H22O4:395.1265,found:395.1260；
(R,E)-2-乙基-2-(4-(呋喃-3-)苯基)反式-3-己烯二酸(2ap)
0.43(m,3H)；13C NMR(101MHz,CDCl3)δ180.63,178.14,143.66,139.78,138.56,135.29,131.30,127.89,125.89,125.81,123.63,108.77,57.05,37.93,29.55,9.31；
HRMS-ESI(m/z)[M+Na]+calcd for C20H20O4:347.1254,found:347.1252；
(R,E)-2-乙基-2-(4-(噻吩-3-)苯基)反式-3-己烯二酸(2aq)
173.92,141.66,141.17,135.25,134.20,127.61,125.82,125.69,125.60,123.89,119.78,57.04,37.64,29.55,8.42；
HRMS-ESI(m/z)[M+Na]+calcd for C18H18O4S:353.0818,found:353.0818；
(R,E)-2-乙基-2-([1,1’-联苯]-3-)反式-3-己烯二酸(2ar)
(ddq,J＝28.3,14.2,7.1Hz,2H),0.87(t,J＝7.3Hz,3H)；13C NMR(101MHz,CD3OD)δ176.39,174.06,142.95,141.07,140.96,135.26,128.41,128.39,128.22,126.91,126.62,126.03,125.97,125.05,124.04,57.20,37.50,29.58,8.43；
HRMS-ESI(m/z)[M+Na]+calcd for C20H20O4:347.1254,found:347.1251；
(R,E)-2-乙基-2-(3-(噻吩-3-)苯基)反式-3-己烯二酸(2as)
Hz,2H),2.26(dq,J＝14.3,7.2Hz,1H),2.13(dq,J＝13.7,6.9Hz,1H),0.88(t,J＝7.3Hz,1H)；13C NMR(101MHz,CDCl3)δ180.45,178.14,143.63,141.74,138.63,135.35,132.50,128.79,126.31,126.11,124.98,124.74,123.79,108.89,57.24,37.93,29.63,9.37；
HRMS-ESI(m/z)[M+Na]+calcd for C18H18O5:337.1046,found:337.1051；
(R,E)-2-丙基-2-([1,1’-联苯]-4-)反式-3-己烯二酸(2at)
CDCl3)δ180.49,177.89,140.51,140.38,139.94,135.79,128.72,127.77,127.29,127.04,127.01,123.41,56.72,39.09,37.92,29.69,18.16,14.54；
HRMS-ESI(m/z)[M+Na]+calcd for C21H22O4:361.1410,found:361.1411；
(R,E)-2-丁基-2-([1,1’-联苯]-4-)反式-3-己烯二酸(2au)
CDCl3)δ180.45,180.43,177.84,177.82,140.51,140.40,139.92,135.82,128.72,127.79,127.29,127.03,127.01,123.44,56.64,37.92,36.67,29.69,26.93,23.16,13.91；
HRMS-ESI(m/z)[M+Na]+calcd for C22H24O4:375.1567,found:375.1569；
(R,E)-1-(3-羧基-1-丙烯-1)-1,2,3,4-四氢化萘-1-羧酸(2av)
J＝7.5,4.0Hz,2H)；13C NMR(101MHz,CD3OD)δ177.85,174.03,138.57,
137.01,135.54,129.88,128.73,126.42,125.05,124.24,53.59,37.24,33.44,29.11,18.38；
HRMS(ESI+)[M+Na]calculated for C15H16O4:283.0941,found:283.0938；
(R,E)-7-溴-1-(3-羧基-1-丙烯-1)-1,2,3,4-四氢化萘-1-羧酸(2aw)
11.1,7.5,2.9Hz,2H),3.08(d,J＝7.0Hz,2H),2.52(ddd,J＝14.0,7.8,3.1Hz,1H),1.92(ddd,J＝14.1,7.0,3.0Hz,1H)；13C NMR(101MHz,CD3OD)δ176.86,173.94,138.25,138.05,136.38,132.76,130.64,129.53,124.61,118.36,53.68,37.28,33.19,28.63,18.32；
HRMS(ESI+)for C15H15BrO4Na[M+Na]:calculated:361.0046/363.0025[M+2],found:361.0049/363.0020[M+2]；
(R,E)-1-(3-羧基-1-丙烯-1)-7-甲氧基-1,2,3,4-四氢化萘-1-羧酸(2ax)
(ddt,J＝13.3,6.9,3.8Hz,1H),1.88(ddt,J＝12.6,5.9,2.6Hz,1H),1.78(td,J＝6.8,4.6Hz,2H)；13C NMR(101MHz,CD3OD3)δ181.67,178.03,161.23,142.34,140.38,133.50,133.13,128.11,118.40,117.03,58.13,57.75,41.19,37.32,32.26,22.56；
HRMS(ESI+)[M+Na]for:C16H18O5:313.1046,found:313.1047；
(R,E)-1-(3-羧基-1-丙烯-1)-7-苯基-1,2,3,4-四氢化萘-1-羧酸(2ay)
2H),2.79(t,J＝5.6Hz,2H),2.33(dt,J＝13.3,6.3Hz,1H),1.95–1.86(m,1H),1.80(p,J＝6.4Hz,2H)；13CNMR(101MHz,CD3OD)δ177.79,174.05,140.94,138.54,138.21,136.29,135.95,129.25,128.55,128.32,126.58,126.37,125.09,124.45,53.74,37.25,33.55,28.85,18.47；
HRMS(ESI+)[M+Na]for C21H20O4:calculated:359.1254,found:359.1250；
(R,E)-1-(3-羧基-1-丙烯-1)-7-(呋喃-3)-1,2,3,4-四氢化萘-1-羧酸(2az)
Hz,1H),3.04(dd,J＝7.1,1.3Hz,2H),2.75(t,J＝5.7Hz,2H),2.32(ddd,J＝13.0,8.2,4.9Hz,1H),1.88(ddd,J＝13.0,6.1,3.7Hz,1H),1.78(p,J＝5.5Hz,2H)；13C NMR(101MHz,CD3OD)δ177.70,174.08,143.41,138.46,138.16,135.98,135.83,129.61,129.22,127.18,126.28,124.32,124.05,108.20,53.65,37.20,33.50,28.87,18.51；
HRMS(ESI+)[M+Na]+for C19H19O5:327.1227,found:327.1228；
(R,E)-1-(3-羧基-1-丙烯-1)-7-(噻吩-3)-1,2,3,4-四氢化萘-1-羧酸(2aaa)
Hz,3H),2.77(t,J＝5.8Hz,3H),2.33(ddd,J＝13.1,7.8,5.5Hz,1H),1.98–1.80(m,1H),1.84–1.72(m,3H)；13C NMR(101MHz,CD3OD)δ177.72,174.07,142.08,138.49,136.02,135.96,133.07,129.22,127.81,125.67,125.63,124.54,124.38,119.21,53.69,37.21,33.53,28.87,18.50；
HRMS(ESI+)[M+Na]+for C19H19O4S:343.0999,found:343.0997；
(R,E)-1-(3-羧基-1-丙烯-1)-7-(1-氢-吡咯-2)-1,2,3,4-四氢化萘-1-羧酸(2aab)
J＝15.9,7.1Hz,1H),3.30(p,J＝1.6Hz,1H),3.07(dd,J＝7.1,1.4Hz,2H),2.76(dt,J＝8.1,4.6Hz,2H),2.33(ddd,J＝13.2,8.2,5.3Hz,1H),1.91(dt,J＝13.0,4.2Hz,1H),1.80(p,J＝5.6Hz,2H)；13C NMR(101MHz,CD3OD)δ177.92,174.26,138.56,135.87,134.36,130.84,130.80,129.06,125.01,124.24,122.13,118.22,118.05,108.46,108.41,104.37,104.34,53.69,37.21,33.62,28.82,18.53；
HRMS(ESI+)[M-H+]calcd for C19H19NO4:324.1241,found:324.1240；
(R,E)-1-(3-羧基-1-丙烯-1)-7-(4-苯氧基-苯基)-1,2,3,4-四氢化萘-1-羧酸(2aac)
(dd,J＝7.1,1.3Hz,2H),2.78(dt,J＝7.4,4.2Hz,2H),2.33(dt,J＝13.2,6.1Hz,1H),1.95–1.87(m,1H),1.79(p,J＝6.3Hz,2H)；13C NMR(101MHz,CD3OD)δ177.76,174.07,157.27,156.56,138.54,137.47,136.15,136.08,135.98,129.46,129.27,128.37,127.77,124.90,124.43,122.95,118.63,118.42,53.74,37.23,33.58,28.85,18.52；
HRMS(ESI+)[M+Na]+for calcd for C27H24O5:451.1516,found:451.1513；
(R,E)-1-(3-羧基-1-丙烯-1)-7-(3-氟-4-甲氧基-苯基)-1,2,3,4-四氢化萘-1-羧酸(2aad)
3.83(s,3H),3.04(dd,J＝7.1,1.4Hz,2H),2.76(dt,J＝7.4,4.2Hz,2H),2.32(dt,J＝13.2,6.1Hz,1H),1.94–1.84(m,1H),1.78(p,J＝6.4Hz,2H)；13C NMR(101MHz,CD3OD)δ177.73,174.06,152.38(J＝123.2Hz),146.79(J＝5.5Hz),138.50,136.67(J＝1.0Hz),136.24,136.03,134.12(J＝3.0Hz),129.34,128.11,124.71,124.45,122.11(J＝2.0Hz),113.66(J＝9.6Hz),113.47(J＝1.0Hz),55.27,53.72,37.20,33.53,28.83,18.49；19FNMR(376MHz,CD3OD)δ-137.10
HRMS(ESI+)[M+Na]+for calcd for C22H21FO5:407.1265,found:407.1268；
(R,E)-1-(3-羧基-1-丙烯-1)-6-甲氧基-2,3-二氢-1-氢-茚-1-羧酸(2aae)
2.59(m,3H),2.19(ddd,J＝12.9,7.6,5.5Hz,1H)；13C NMR(101MHz,CD3OD)δ175.95,173.93,158.73,144.71,135.64,135.38,124.57,122.32,113.46,110.30,60.95,54.39,37.28,36.94,28.94；
HRMS(ESI+)for C15H16O5Na[M+Na]:calculated:299.0890,found:299.0892；
(R,E)-4-(3-羧基-1-丙烯-1)-色满-4-羧酸(2aaf)
7.5,2.9Hz,2H),3.08(d,J＝7.0Hz,2H),2.52(ddd,J＝14.0,7.8,3.1Hz,1H),1.92(ddd,J＝14.1,7.0,3.0Hz,1H)；13C NMR(101MHz,CDCl3)δ180.21,177.83,154.38,137.17,130.56,129.15,124.61,120.45,120.22,117.35,62.40,49.59,37.47,31.88；
HRMS(ESI+)for C14H14O5Na[M+Na]:calculated:285.0733,found:285.0731；
(R,E)-4-(3-羧基-1-丙烯-1)-6-氯色满-4-羧酸(2aag)
DMSO-d6)δ174.67,173.01,153.30,136.47,130.31,128.79,125.82,124.55,123.85,119.04,63.05,49.63,37.61,31.23；
HRMS(ESI+)[M-H+]calcd for C14H12ClO5:295.0379,found:295.0379；
虽然结合实施例对本发明的具体实施方式进行了详细地描述，但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内，本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (9)
1.一种含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于，包括以下步骤：
将底物、碱、还原剂和溶剂加入反应容器中，然后在CO2气氛下加入催化剂和配体，50～100℃下搅拌反应后酸化处理，再分离纯化，得含季碳中心的多取代手性己二酸化合物；
所述反应底物的结构通式如下所示：
其中，X、Y、Z分别独立的为芳基、烷基、氢、卤素、氮、氧、硅基、硼酸酯、三氟甲基、三氟甲氧基、甲巯基、酯基或酯基衍生物；R1、R2分别独立的为芳基、氢、烷基、卤素、酯基或酯基衍生物。
2.根据权利要求1所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述底物、催化剂、配体、碱和还原剂的摩尔比为1:0.01～0.5:0.01～0.5:1～5:1～5。
3.根据权利要求1或2所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述催化剂为铜催化剂。
4.根据权利要求3所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述铜催化剂为均三甲苯基亚铜、氯化亚铜、醋酸亚铜或噻吩-2-甲酸亚铜。
5.根据权利要求1或2所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述配体为(+)-1,2-双((2S,5S)-2,5-二苯基膦杂戊烷)乙烷、(-)-1,2-双((2R,5R)-2,5-二苯基膦杂戊烷)乙烷、(2S,4S)-2,4-双(二苯基膦)戊烷、(R)-(-)-1-[(Sp)-2-(二苯基膦)二茂铁基]乙基二叔丁基膦或(+)-1,2-双[(2S,5S)-2,5-二甲基磷]苯。
6.根据权利要求1或2所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述还原剂为联硼酸酯。
7.根据权利要求6所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述联硼酸硼酸酯为联硼酸频那醇酯、联硼酸新戊二醇酯、双联(2-甲基-2,4-戊二醇)硼酸酯或双联(2,4-二甲基-2,4-戊二醇)硼酸酯。
8.根据权利要求1所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述碱为甲醇锂、甲醇钠、甲醇钾、乙醇钠、乙醇钾、叔丁醇锂、叔丁醇钠、叔丁醇钾、叔戊醇钠、碳酸铯或碳酸钾。
9.根据权利要求1所述的含季碳中心的多取代手性己二酸化合物的制备方法，其特征在于：所述溶剂为苯甲醚、1,4-二氧六环、四氢呋喃、甲基叔丁基醚、二异丙醚、氯苯、甲苯、对二甲苯、正己烷或乙腈。
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