CN113173854A - Preparation method of chiral beta-acyloxy carboxylic ester compound - Google Patents
Preparation method of chiral beta-acyloxy carboxylic ester compound Download PDFInfo
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- CN113173854A CN113173854A CN202110444041.XA CN202110444041A CN113173854A CN 113173854 A CN113173854 A CN 113173854A CN 202110444041 A CN202110444041 A CN 202110444041A CN 113173854 A CN113173854 A CN 113173854A
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- Prior art keywords
- substituted
- unsubstituted
- alkyl
- aryl
- group
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- 238000006243 chemical reaction Methods 0.000 claims abstract description 121
- 238000000034 method Methods 0.000 claims abstract description 97
- 239000002904 solvent Substances 0.000 claims abstract description 90
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 77
- -1 carboxylic ester compound Chemical class 0.000 claims abstract description 60
- 238000007259 addition reaction Methods 0.000 claims abstract description 44
- 239000003446 ligand Substances 0.000 claims abstract description 44
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 35
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 claims abstract description 32
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 29
- 239000003054 catalyst Substances 0.000 claims abstract description 25
- 239000007800 oxidant agent Substances 0.000 claims abstract description 21
- 230000001590 oxidative effect Effects 0.000 claims abstract description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 165
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 128
- 125000005842 heteroatom Chemical group 0.000 claims description 120
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 98
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 96
- 125000000217 alkyl group Chemical group 0.000 claims description 71
- 229910052760 oxygen Inorganic materials 0.000 claims description 63
- 229910052717 sulfur Inorganic materials 0.000 claims description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 125000001072 heteroaryl group Chemical group 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 41
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 32
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 150000003254 radicals Chemical class 0.000 claims description 27
- 125000002950 monocyclic group Chemical group 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 125000003342 alkenyl group Chemical group 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 150000002431 hydrogen Chemical group 0.000 claims description 21
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 21
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 19
- 238000007069 methylation reaction Methods 0.000 claims description 19
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 19
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 17
- 229910052731 fluorine Inorganic materials 0.000 claims description 17
- 239000011737 fluorine Substances 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 16
- 125000002619 bicyclic group Chemical group 0.000 claims description 14
- 239000012634 fragment Substances 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- 239000002131 composite material Substances 0.000 claims description 10
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 239000007789 gas Substances 0.000 claims description 9
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 8
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical group O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 101710097421 WD repeat and HMG-box DNA-binding protein 1 Proteins 0.000 claims description 7
- 102100029469 WD repeat and HMG-box DNA-binding protein 1 Human genes 0.000 claims description 7
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 150000008282 halocarbons Chemical class 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 6
- 230000011987 methylation Effects 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 5
- 125000006832 (C1-C10) alkylene group Chemical group 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- UKSZBOKPHAQOMP-SVLSSHOZSA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 UKSZBOKPHAQOMP-SVLSSHOZSA-N 0.000 claims description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- IBXMKLPFLZYRQZ-UHFFFAOYSA-N 1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1C=CC(=O)C=CC1=CC=CC=C1 IBXMKLPFLZYRQZ-UHFFFAOYSA-N 0.000 claims description 2
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 claims description 2
- PAGZTSLSNQZYEV-UHFFFAOYSA-L 2,2-dimethylpropanoate;palladium(2+) Chemical compound [Pd+2].CC(C)(C)C([O-])=O.CC(C)(C)C([O-])=O PAGZTSLSNQZYEV-UHFFFAOYSA-L 0.000 claims description 2
- JTXMVXSTHSMVQF-UHFFFAOYSA-N 2-acetyloxyethyl acetate Chemical compound CC(=O)OCCOC(C)=O JTXMVXSTHSMVQF-UHFFFAOYSA-N 0.000 claims description 2
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 claims description 2
- KMHZPJNVPCAUMN-UHFFFAOYSA-N Erbon Chemical compound CC(Cl)(Cl)C(=O)OCCOC1=CC(Cl)=C(Cl)C=C1Cl KMHZPJNVPCAUMN-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 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
- WXNOJTUTEXAZLD-UHFFFAOYSA-L benzonitrile;dichloropalladium Chemical compound Cl[Pd]Cl.N#CC1=CC=CC=C1.N#CC1=CC=CC=C1 WXNOJTUTEXAZLD-UHFFFAOYSA-L 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- JKDRQYIYVJVOPF-FDGPNNRMSA-L palladium(ii) acetylacetonate Chemical compound [Pd+2].C\C([O-])=C\C(C)=O.C\C([O-])=C\C(C)=O JKDRQYIYVJVOPF-FDGPNNRMSA-L 0.000 claims description 2
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-butyl ethyl ether Chemical compound CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 1
- JXASPPWQHFOWPL-UHFFFAOYSA-N Tamarixin Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 JXASPPWQHFOWPL-UHFFFAOYSA-N 0.000 claims 1
- 239000003849 aromatic solvent Substances 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 abstract description 5
- 239000000758 substrate Substances 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 184
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 82
- 239000000047 product Substances 0.000 description 61
- 239000003208 petroleum Substances 0.000 description 51
- 230000014759 maintenance of location Effects 0.000 description 47
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 46
- 238000005160 1H NMR spectroscopy Methods 0.000 description 46
- 238000004440 column chromatography Methods 0.000 description 45
- 239000007788 liquid Substances 0.000 description 45
- 238000004128 high performance liquid chromatography Methods 0.000 description 44
- 238000001514 detection method Methods 0.000 description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 9
- PZVKSFBOPQYWGM-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;pyridine Chemical compound C1CN=CO1.C1=CC=NC=C1 PZVKSFBOPQYWGM-UHFFFAOYSA-N 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 4
- IIVWHGMLFGNMOW-UHFFFAOYSA-N 2-methylpropane Chemical compound C[C](C)C IIVWHGMLFGNMOW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012159 carrier gas Substances 0.000 description 3
- 239000013256 coordination polymer Substances 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- QSRRZKPKHJHIRB-UHFFFAOYSA-N methyl 4-[(2,5-dichloro-4-methylthiophen-3-yl)sulfonylamino]-2-hydroxybenzoate Chemical compound C1=C(O)C(C(=O)OC)=CC=C1NS(=O)(=O)C1=C(Cl)SC(Cl)=C1C QSRRZKPKHJHIRB-UHFFFAOYSA-N 0.000 description 3
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- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 125000006574 non-aromatic ring group Chemical group 0.000 description 2
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 2
- 229910003445 palladium oxide Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
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- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 1
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 1
- 108010070675 Glutathione transferase Proteins 0.000 description 1
- 102000005720 Glutathione transferase Human genes 0.000 description 1
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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Abstract
The invention provides a preparation method of a chiral beta-acyloxy carboxylic ester compound. Specifically disclosed is a preparation method of a carboxylic ester compound, which comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, a compound containing a segment II, a compound containing a segment III and carbon monoxide (CO) are subjected to addition reaction to obtain a compound containing a segment I-1 and/or a compound containing a segment I-2. The method has the advantages of high yield, wide substrate universality, good functional group compatibility, mild reaction conditions and simple operation.
Description
Technical Field
The invention relates to a preparation method of a chiral beta-acyloxy carboxylic ester compound.
Background
Beta-acyloxycarboxylic acid ester compounds with optical activity and derivatives thereof such as beta-hydroxycarboxylic acid esters (acids) are widely present in drug molecules and fine chemical products, and are synthetic building blocks widely used in organic synthesis. It is therefore of great interest to develop methods for the synthesis of such compounds. The most direct and efficient process for the synthesis of such compounds by the oxycarbonylation of inexpensive and readily available olefins as starting materials. Methods for synthesizing such compounds have been extensively studied over the last several decades. Among them, asymmetric hydrogenation of beta-carbonyl carboxylates catalyzed by transition metals such as ruthenium, iridium, rhodium, etc. is currently the most frequently and widely used method for synthesizing chiral beta-hydroxycarboxylic esters (Noyori, R.Angew. chem. int.Ed.2002,41,2008; Xie, J. -H.; Liu, X. -Y.; Yang, X. -H.; Xie, J. -B.; Wang, L. -X.; Zhou, Q. -L.Angew. chem., int.Ed.2012,51,201; Jeulin, S.; Duprat de Paule, S.; Ratovelana Vidal, V.; Gene, J.; Champion, N.; Dellis, P.Angew. chem., int.2004, 43,320). However, such processes, while capable of achieving high enantioselective hydrogenation, require the preparation of complex β -carbonyl carboxylate precursors, poor functional group compatibility, and require high pressure hydrogen conditions. In addition, the asymmetric Aldol reaction of aldehydes and silyl enol ethers (Keck, G.E.; Krishnhamurthy, D.J.Am.chem.Soc.1995,117, 2363; Denmark, S.E.; Wynn, T.; Beutner, G.L.J.Am.chem.Soc.2002,124, 13405; Denmark, S.; Beutner, G.L.; Wynn, T.; Eastgate, M.D.J.Am.chem.Soc.2005,127, 3774) is also a class of methods for synthesizing chiral β -hydroxycarboxylic acid esters, but their reaction precursors aldehydes and silyl enol ethers are not readily synthesized, have very limited substrate ranges, and are sensitive to reaction conditions and not conducive to application. Therefore, there is a need in the art for a method for preparing beta-acyloxycarboxylic acid esters and derivatives thereof with high enantioselectivity, which can be achieved efficiently, simply and under mild conditions.
Despite the transitionPalladium-metal catalyzed asymmetric oxycarbonylation reactions have been reported (Tietze, l.f.; zinnggrebe, j.; Spiegl, d.a.; Stecker, f.hetrocycles 2007,74, 473; Tietze, l.f.; Spiegl, d.a.; Stecker, f.; Major, j.; Raith, c.; Gro β e, c.chem. -eur.j.2008,14,8956; Tietze, l.f.; Jackenkroll, s.; hirolod, j.; Ma, l.; Waldecker, b.chem. -eur.j.2014,20,8628.), but are limited to intramolecular asymmetric oxycarbonylation reactions and are not reported for intermolecular asymmetric oxycarbonylation reactions. The difficulty is that firstly the initiation of intermolecular palladium oxide is difficult, and secondly the enantioselective control of the reaction is difficult to realize in the presence of a strong coordination ligand carbon monoxide. Therefore, to achieve palladium-catalyzed high enantioselective oxycarbonylation reactions requires chiral ligands to increase Pd (OAc)2The Lewis acidity of the catalyst can lead the palladium oxide to be smoothly carried out, and simultaneously can effectively control the enantioselectivity, thereby finally realizing the asymmetric oxygen carbonylation reaction.
Disclosure of Invention
The invention aims to overcome the defects of poor universality of asymmetric hydrogenation substrates of beta-carbonyl carboxylic ester, harsh reaction conditions and poor functional group compatibility in the prior art, and provides a preparation method of a chiral beta-acyloxy carboxylic ester compound. The method has the advantages of high yield, wide substrate universality, good functional group compatibility, mild reaction conditions and simple operation.
The present invention solves the above-mentioned problems by the following technical means.
The invention provides a preparation method of a carboxylic ester compound, which comprises the following steps: in a solvent, carrying out addition reaction on a compound containing a segment II, a compound containing a segment III and carbon monoxide (CO) in the presence of a palladium catalyst, an oxazoline ligand and an oxidant to obtain a compound containing a segment I-1 and/or a compound containing a segment I-2;
wherein the fragment II is
The fragment III is
The fragment I-1 is
Wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
the fragment I-2 is
Wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand is
Wherein R is5And R6Independently of each other is hydrogen, R5-1Substituted or unsubstituted C1-C10Alkyl radical, R5-2Substituted or unsubstituted C3-C8Cycloalkyl, or R5-3Substituted or unsubstituted C6-C30An aryl group;
R7is hydrogen, R7-1Substituted or unsubstituted C1-C10Alkyl, or R7-2Substituted or unsubstituted C6-C30An aryl group;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
wherein the carbon marked with x is an S-configuration chiral carbon;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
in (b), the carbon marked with x is an R configuration chiral carbon.
In the addition reaction, the solvent can be conventional in the field of such reactions, and preferably, the solvent is one or more of alkane solvents, substituted aromatic hydrocarbon solvents, nitrile solvents, halogenated hydrocarbon solvents, ether solvents, ketone solvents, ester solvents and amide solvents. The alkane solvent is preferably n-hexane. The substituted aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, toluene and trifluoromethyl benzene. The nitrile solvent is preferably acetonitrile. The halogenated hydrocarbon solvent is preferably dichloromethane and chloroform. The ether solvent is preferably one or more of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, ethyl tertiary butyl ether, anisole, ethylene glycol dimethyl ether and1, 4-dioxane. The ketone solvent is preferably acetone. The ester solvent is preferably ethyl acetate and/or ethylene glycol diacetate. The amide solvent is preferably N, N-Dimethylformamide (DMF). More preferably, the solvent is an ether solvent and/or a halogenated hydrocarbon solvent; further, the solvent is diethyl ether and/or dichloromethane.
In the addition reaction, the amount of the solvent used may not be particularly limited as long as the reaction is not affected. The solvent may be subjected to anhydrous treatment (anhydrous treatment operations and methods are conventional in the art). Preferably, the concentration of the compound containing segment II in the solvent may be a concentration conventional in the art, preferably 0.01 to 5.00mol/L (e.g. 0.625 or 2.00mol/L), and may be preferably 0.01 to 0.20 mol/L.
In the addition reaction, the palladium catalyst can be the conventional in the field of such reactions, preferably, the palladium catalyst is palladium acetate, palladium trifluoroacetate, palladium pentanate, dichlorodiacetonitrile palladium, bis (benzonitrile) palladium chloride, palladium bromide, palladium iodide, tetranitrile palladium tetrafluoroborate, palladium hexafluoroacetylacetonate, bis (acetylacetonato) palladium, tetranitrile palladium trifluoromethanesulfonate, palladium pivalate, (1E,4E) -bis (dibenzylideneacetone) palladium, bis (dibenzylideneacetone) dipalladium and tris (dibenzylideneacetone) dipalladium; more preferably, the palladium catalyst is palladium acetate.
The amount of palladium catalyst used in the addition reaction may be that conventional in the art for such reactions. Preferably, the molar ratio of the palladium catalyst to the compound containing the segment II is (1-50): 100, respectively; preferably (1-10): 100, respectively; for example, 5:100 or 10: 100.
In the addition reaction, the oxazoline ligand may be used in an amount that is conventional in such reactions in the art. The molar ratio of the oxazoline ligand to the compound containing the tablet section II is (1-75): 100, e.g. 7.5: 100 or 15: 100.
In the addition reaction, the molar ratio of the palladium catalyst to the oxazoline ligand may be a molar ratio conventional in the art for such reactions, and is preferably 1: (0.5 to 3), for example, 1: 1.5.
In the addition reaction, the oxidant may be an oxidant conventional to such reactions in the art, preferably the oxidant is benzoquinone and/or PhI (OAc)2。
In the addition reaction, the molar ratio of the oxidant to the compound containing the segment II is preferably (1.0-5.0): 1, and may be (1.0-3.0): 1, for example, 1.2: 1. or 3: 1.
In the addition reaction, the molar ratio of the compound containing the segment III to the compound containing the segment II is preferably (1.0-100): 1, more preferably (2.5-10): 1, for example, 5:1 or 10: 1.
In the addition reaction, the temperature of the addition reaction can be the temperature conventional in the field, preferably, the temperature of the addition reaction is-20 to 30 ℃, and can also be 0 to 20 ℃.
In the addition reaction, the addition reaction can also be carried out under protective gas. The protective gas can be nitrogen and/or argon.
In the addition reaction, the progress of the addition reaction can be monitored by a detection method (such as TLC, HPLC, HNMR) which is conventional in the art, and the end point of the reaction is preferably the disappearance or no longer reaction of the compound containing the segment II. The time of the addition reaction may be 1 to 168 hours, preferably 10 to 72 hours, for example 16 hours, 24 hours, 36 hours, 48 hours or 72 hours.
Preferably, the addition reaction further comprises the following post-treatment steps: and adding a solvent into the reaction solution, concentrating and purifying to obtain the product. In the post-treatment step, the solvent is an alcohol solvent (such as methanol) or a ketone solvent (such as acetone) and water.
In one embodiment of the invention, certain groups are defined as follows, and undefined groups are as described above (in one embodiment): r5-1、R5-2、R5-3、R7-1And R7-2Independently 1 or more, and when plural, the same or different, the plural is 2,3 or 4.
In one aspect: when R is5And R6Independently is unsubstituted C1-C10When alkyl, said C1-C10Alkyl is C1-C4Alkyl groups, such as methyl or ethyl.
In one aspect: when R is5And R6Independently is unsubstituted C3-C8When there is a cycloalkyl group, said C3-C8Cycloalkyl being C3-C6Monocyclic cycloalkyl groups, such as cyclopentyl or cyclohexyl.
In one aspect: when R is5And R6Independently is unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl radicals, for example phenyl.
In one aspect: when R is7Is unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl radicals, for example phenyl.
In one aspect: r5And R6Independently hydrogen, unsubstituted C1-C10Alkyl, unsubstituted C3-C8Cycloalkyl, or unsubstituted C6-C30And (4) an aryl group.
In one aspect: r7Is unsubstituted C6-C30And (4) an aryl group.
In one aspect: r5And R6Is the same as, or, R5And R6Different, and one is H.
In one aspect: r5And R6Independently hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl or phenyl.
In one aspect: r7Is phenyl.
In one aspect:
R5and R6Independently hydrogen, unsubstituted C1-C10Alkyl, unsubstituted C3-C8Cycloalkyl, or unsubstituted C6-C30An aryl group;
R7is unsubstituted C6-C30And (4) an aryl group.
In one aspect: the oxazoline ligand is any one of the following compounds,
in one embodiment of the present invention, the preparation method of the carboxylic ester compound is the following one or two methods;
the method comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-A, a compound shown as a formula III' and carbon monoxide (CO) to obtain a compound shown as a formula I-1-A and/or a compound shown as a formula I-2-A;
the second method comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-B, a compound shown as a formula III' and carbon monoxide (CO) to obtain a compound shown as a formula I-1-B and/or a compound shown as a formula I-2-B;
in the first and second methods, the operation and conditions of the addition reaction are as described in any one of the above;
wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
R1is hydrogen, or R1-1Substituted or unsubstituted C1-C30An alkyl group;
R1-1is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, R1-1aSubstituted or unsubstituted C6-C30Aryl, 5-15 membered heteroaryl with one or more heteroatoms selected from N, O and S and 1-4 heteroatoms, and C2-C10Alkenyl, -O (CH)2)nR1-1b、-S(＝O)2R1-1c、-OC(＝O)R1-1d、-C(＝O)OR1-1e、
-C(＝O)R1-1hOr
n is an integer of 0 to 10;
R1-1ais halogen, C1-C10Alkyl radical, C1-C10Alkoxy, cyano, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group;
R1-1bis R1-1b-1Substituted or unsubstituted C6-C30Aryl radicals "One or more of N, O and S, 5-15 membered heteroaryl with 1-4 heteroatoms,
R1-1b-1Is nitro, aldehyde, halogen, C1-C10Alkyl radical, C2-C10Alkenyl, -S (═ O)2R1-1b-1a、
-C(＝O)OR1-1b-1for-C (═ O) R1-1b-1g；
R1-1b-1a、R1-1b-1b、R1-1b-1c、R1-1b-1dAnd R1-1b-1eIndependently is C1-C10An alkyl group;
R1-1b-1fand R1-1b-1gIndependently is C2-C10Alkenyl, or substituted by one or more C1-C105-15 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S as alkyl substituted or unsubstituted "heteroatoms;
R1-1c、R1-1fand R1-1gIndependently of one another is hydrogen, C6-C30Aryl or p-toluenesulfonyl;
R1-1dis R1-1d-1Substituted or unsubstituted C1-10Alkyl radical, R1-1d-2Substituted or unsubstituted C2-10Alkenyl radical, R1-1d-3Substituted or unsubstituted C2-10Alkynyl, R1-1d-4Substituted or unsubstituted C6-30Aryl radical, R1-1d-5A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R1-1d-1is-OR1-1d-1aOr
R1-1d-1aIs R1-1d-1a-1Substituted or unsubstituted C6-C30An aryl group; r1-1d-1a-1Is C substituted by one or more halogens3-C15A cycloalkyl group;
R1-1d-2and R1-1d-3Independently is C6-C30An aryl group;
R1-1d-4is-C (═ O) OR1-1d-4a；R1-1d-4aIs C2-C10Alkenyl, or substituted by one or more-OC (═ O) R1-1d-4a-1Substituted C1-C10An alkyl group; r1-1d-4a-1Is C1-C10An alkyl group;
R1-1d-5is p-toluenesulfonyl;
R1-1eis hydrogen, C1-C10Alkyl or
R1-1hIs C2-C10Alkenyl, or substituted by one or more-OC (═ O) R1-1h-1Substituted C1-C10An alkyl group; r1-1h-1Is C1-C10An alkyl group;
R2is hydrogen, R2-1Substituted or unsubstituted C1-C30Alkyl radical, R2-2Substituted or unsubstituted C6-C30Aryl, or C2-C10An alkenyl group;
R2-1is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, R2-1aSubstituted or unsubstituted C6-C30Aryl, 5-15 membered heteroaryl with one or more heteroatoms selected from N, O and S and 1-4 heteroatoms, and C2-C10Alkenyl, -O (CH)2)nR2-1b、-S(＝O)2R2-1c、-OC(＝O)R2-1d、-C(＝O)OR2-1e、
-C(＝O)R2-1hOr
R2-2Is halogen, C1-C10Alkyl radical, C1-C10Alkoxy, cyano, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group;
R2-1ais halogen, C1-C10Alkyl radical, C1-C10Alkoxy, cyano, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group;
R2-1bis R2-1b-1Substituted or unsubstituted C6-C30An aryl group, a 5-to 15-membered heteroaryl group having one or more heteroatoms selected from N, O and S and1 to 4 heteroatoms,
R2-1b-1Is nitro, aldehyde, halogen, C1-C10Alkyl radical, C2-C10Alkenyl, -S (═ O)2R2-1b-1a、
-C(＝O)OR2-1b-1for-C (═ O) R2-1b-1g；
R2-1b-1a、R2-1b-1b、R2-1b-1c、R2-1b-1dAnd R2-1b-1eIndependently is C1-C10An alkyl group;
R2-1b-1fand R2-1b-1gIndependently is C2-C10Alkenyl, or C1-C10The alkyl substituted or unsubstituted heteroatom is selected from one or more of N, O and S, the number of heteroatomsA 5-15 membered heteroaryl group which is 1-4 ";
R2-1c、R2-1fand R2-1gIndependently of one another is hydrogen, C6-C30Aryl or p-toluenesulfonyl;
R2-1dis R2-1d-1Substituted or unsubstituted C1-10Alkyl radical, R2-1d-2Substituted or unsubstituted C2-10Alkenyl radical, R2-1d-3Substituted or unsubstituted C2-10Alkynyl, R2-1d-4Substituted or unsubstituted C6-30Aryl radical, R2-1d-5A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R2-1d-1is-OR2-1d-1aOr
R2-1d-1aIs R2-1d-1a-1Substituted or unsubstituted C6-C30An aryl group; r2-1d-1a-1Is C substituted by one or more halogens3-C15A cycloalkyl group;
R2-1d-2and R2-1d-3Independently is C6-C30An aryl group;
R2-1d-4is-C (═ O) OR2-1d-4a；R2-1d-4aIs C2-C10An alkenyl group;
R2-1d-5is p-toluenesulfonyl;
R2-1eis hydrogen or C1-C10An alkyl group;
R2-1his C2-C10An alkenyl group;
R8is C1-C10Alkylene, or a mixture thereof,
Or- (CH)2)m3-O(C＝O)-(C6-C10Arylene) - (C ═ O) O- (CH)2)m4-；
m1, m2, m3 and m4 are independently 0,1, 2,3, 4,5 or 6.
In one aspect: r1-1、R1-1a、R1-1b-1、R1-1d-1、R1-1d-2、R1-1d-3、R1-1d-4、R1-1d-5、R1-1d-1a-1、R8-1And R8-1a-1Independently 1 or more, and when plural, the same or different, and when plural, the plural is preferably 2,3 or 4.
In one aspect: when R is1Is R1-1Substituted or unsubstituted C1-C30When alkyl, said C1-C30Alkyl is C1-C10Alkyl, preferably C1-C8Alkyl radicals, such as methyl,
In one aspect: when R is1-1In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine.
In one aspect: when R is1-1Is C3-C15In the case of a cycloalkyl group of (A), said C3-C15Cycloalkyl of (A) is monocyclic C3-C15Cycloalkyl of (C), a condensed ring C3-C15Cycloalkyl, spiro C3-C15Cycloalkyl or bridged ring C of3-C15Cycloalkyl of (a), preferably monocyclic C3-C15Cycloalkyl groups of (a);
the monocyclic ring C3-C15Cycloalkyl of (C) is preferably C3-C6Cycloalkyl groups of (a) are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclohexyl.
In one aspect: when R is1-1Is R1-1aSubstituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl or naphthyl.
In one aspect: when R is1-1Is C2-C10When alkenyl, said C2-C10Alkenyl is C2-C6Alkenyl radicals, e.g.
In one aspect: when R is1-1aIn the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or iodine.
In one aspect: when R is1-1aIs C1-C10When alkyl, said C1-C10Alkyl is C1-C6Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, tert-butyl radicals being preferred.
In one aspect: when R is1-1aIs C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl.
In one aspect: when R is1-1bIs R1-1b-1Substituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl or naphthyl.
In one aspect: when R is1-1bWhen the aryl group is a 5-15 membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1-4 heteroatoms", the "one or more heteroatoms selected from N, O and S", and the 5-15 membered heteroaryl group having 1-4 heteroatoms "is a 5-15 membered monocyclic heteroaryl group or a 5-15 membered bicyclic heteroaryl group having" one or more heteroatoms selected from N, O and S, and 1-4 heteroatoms ", preferably the" one or more heteroatoms selected from N, O and S, and the 5-15 membered monocyclic heteroaryl group having 1-4 heteroatoms ", respectively;
the heteroatom is selected from one or more of N, O and S, and the number of the heteroatom is5-15 membered monocyclic heteroaryl group of 1 to 4' is preferably a 5-6 membered monocyclic heteroaryl group of "one or more heteroatoms selected from N, O and S, and1 or 2 heteroatoms, for example thienyl group
In one aspect: n is 0,1, 2,3, 4,5 or 6, preferably n is 0 or 1.
In one aspect: when R is1-1b-1Is C1-C10When alkyl, said C1-C10Alkyl is C1-C6Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, tert-butyl radicals being preferred.
In one aspect: when R is1-1b-1Is C2-C10When alkenyl, said alkenyl is C2-C4Alkenyl radicals, e.g.
In one aspect: when R is1-1b-1a、R1-1b-1b、R1-1b-1c、R1-1b-1dAnd R1-1b-1eIndependently is C1-C10When alkyl, said C1-C10Alkyl is independently C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
In one aspect: when R is1-1b-1fIs C2-C10When alkenyl, said C2-C10Alkenyl is
In one aspect: when R is1-1b-1gIs formed by one or more C1-C10C when the alkyl substituted or unsubstituted "hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-4", and the hetero atom number is 5-15 membered heteroaryl1-C10The number of alkyl groups is 1,2 or 3.
In one aspect: when R is1-1b-1gIs C1-C10When alkyl is substituted or unsubstituted, the heteroatom is selected from one or more of N, O and S, 5-15 membered heteroaryl with 1-4 heteroatoms, the heteroatom is selected from one or more of N, O and S, 5-15 membered heteroaryl with 1-4 heteroatoms is selected from one or more of N, O and S, 5-15 membered monocyclic heteroaryl with 1-4 heteroatoms or 5-15 membered bicyclic heteroaryl, preferably the heteroatom is selected from one or more of N, O and S, 5-15 membered bicyclic heteroaryl with 1-4 heteroatoms;
the 5-to 15-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably an 8-to 10-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a benzofuranyl group
In one aspect: when R is1-1b-1gIs formed by one or more C1-C10When the alkyl substituted or unsubstituted "hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-4", and the C is 5-15 membered heteroaryl1-C10Alkyl is C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably ethyl.
In one aspect: when R is1-1c、R1-1fAnd R1-1gIndependently is C6-C30When aryl, said C6-C30Aryl is independently C6-C10Aryl, preferably phenyl.
In one aspect: when R is1-1dIs R1-1d-1Substituted or unsubstituted C1-10When alkyl, said C1-10Alkyl is C1-C6Alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or isopropyl.
In one aspect: when R is1-1dIs R1-1d-2Substituted or unsubstituted C2-10When alkenyl, said C2-10Alkenyl is C2-4Alkenyl radicals, e.g.
In one aspect: when R is1-1dIs R1-1d-3Substituted or unsubstituted C2-10When it is alkynyl, said C2-10Alkynyl is C2-4Alkynyl radicals, e.g.
In one aspect: when R is1-1dIs R1-1d-4Substituted or unsubstituted C6-30When aryl, said C6-30Aryl is C6-10Aryl, preferably phenyl.
In one aspect: when R is1-1dIs R1-1d-5When the substituted or unsubstituted "heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1-4", the 5-15 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1-4 ", and the 5-15 membered heteroaryl is selected from one or more of N, O and S, and the number of heteroatoms is 1-4", and the 5-15 membered monocyclic heteroaryl or the 5-15 membered bicyclic heteroaryl is selected from.
The 5-to 15-membered monocyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably a 5-to 6-membered monocyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a furyl group
The 5-to 15-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably an 8-to 10-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a benzofuranyl group
Benzothienyl
Or indolyl
In one aspect: when R is1-1d-1aIs R1-1d-1a-1Substituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl.
In one aspect: when R is1-1d-1a-1Is C substituted by one or more halogens3-C15In the case of cycloalkyl, the number of said halogen is 1,2 or 3.
In one aspect: when R is1-1d-1a-1Is C substituted by one or more halogens3-C15In the case of cycloalkyl, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine.
In one aspect: when R is1-1d-1a-1Is C substituted by one or more halogens3-C15When there is a cycloalkyl group, said C3-C15Cycloalkyl being C3-C15Monocyclic cycloalkyl, C3-C15Cycloalkyl having condensed rings, C3-C15Spirocyclic cycloalkyl or C3-C15Bridged cycloalkyl, preferably C3-C15A monocyclic cycloalkyl group.
Said C3-C15Monocyclic cycloalkyl is preferably C3-C6Monocyclic ringAlkyl groups, such as cyclopropyl.
In one aspect: when R is1-1d-2And R1-1d-3Independently is C6-C30When aryl, said C6-C30Aryl is independently C6-C10Aryl, preferably phenyl.
In one aspect: when R is1-1d-4aIs C2-C10When alkenyl, said C2-C10Alkenyl is C2-C4Alkenyl radicals, e.g.
In one aspect: when R is1-1eIs C1-C10When alkyl, said C1-C10Alkyl is C1-C6Alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl.
In one aspect: when R is1-1hIs C2-C10When alkenyl, said C2-C10Alkenyl is C2-C6Alkenyl radicals, e.g.
In one aspect: r2-1、R2-2、R2-1a、R2-1b-1、R2-1d-1、R2-1d-2、R2-1d-3、R2-1d-4、R2-1d-5And R2 -1d-1a-1Independently 1 or more, and when plural, the same or different, and when plural, the plural is preferably 2,3 or 4.
In one aspect: when R is2Is R2-1Substituted or unsubstituted C1-C30When alkyl, said C1-C30Alkyl is C1-C10Alkyl, preferably C1-C6Alkyl radicals, such as the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl radical, and also methyl radicals.
In one aspect: when R is2Is R2-2Substituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl or naphthyl.
In one aspect: when R is2Is C2-C10When alkenyl, said C2-C10Alkenyl is C2-C4Alkenyl groups, such as vinyl.
In one aspect: when R is2-2In the case of halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
In one aspect: when R is2-2Is C1-C10When alkyl, said C1-C10Alkyl is C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In one aspect: when R is2-2Is C1-C10At alkoxy, said C1-C10Alkoxy is C1-C4Alkoxy groups, such as methoxy.
In one aspect: when R is2-2Is C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl.
In one aspect: when R is2-2Is C substituted by one or more halogens1-C10In the case of alkyl, the number of the halogen is 1,2 or 3.
In one aspect: when R is2-2Is C substituted by one or more halogens1-C10In the case of alkyl, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
In one aspect: when R is2-2Is C substituted by one or more halogens1-C10Alkyl radicalWhen, C is said1-C10Alkyl is C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl.
In one aspect: when R is8Is R8-1Substituted or unsubstituted C1-C10When it is alkylene, R8-1The number of (a) is 1,2 or 3.
In one aspect: when R is8Is R8-1Substituted or unsubstituted C1-C10When it is alkylene, said C1-C10Alkylene being C1-C6Alkylene groups such as methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene, and also for example methylene or ethylene.
In one aspect: when R is8Is- (CH)2)m3-O(C＝O)-(C6-C10Arylene) - (C ═ O) O- (CH)2)m4When is C therein6-C10Arylene is preferably phenylene (e.g. phenylene)
)。
In one aspect: m1, m2, m3 and m4 are independently 1,2 or 3.
In one aspect: when R is1-1Is R1-1aSubstituted or unsubstituted C6-C30When aryl is present, R1-1The structure of the composite material is any one of the following structures,
in one aspect: when R is1-1is-O (CH)2)nR1-1bWhen R is1-1The structure of the composite material is any one of the following structures,
in one aspect: when R is1-1is-OC (═ O) R1-1dWhen R is1-1The structure of the composite material is any one of the following structures,
in one aspect: when R is1-1is-C (═ O) OR1-1eWhen R is1-1The structure of the composite material is any one of the following structures,
in one aspect: r1Is R1-1Substituted or unsubstituted C1-C30An alkyl group.
In one aspect: r1-1Is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, R1-1aSubstituted or unsubstituted C6-C30Aryl radical, C2-C10Alkenyl, -O (CH)2)nR1-1b、-S(＝O)2R1-1c、-OC(＝O)R1-1d、-C(＝O)OR1-1e、
-C(＝O)R1-1hOr
In one aspect: r1-1Is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, C2-C10Alkenyl, -O (CH)2)nR1-1b、-S(＝O)2R1-1c、-OC(＝O)R1-1d、-C(＝O)OR1-1e、
-C(＝O)R1-1hOr
In one aspect: r1-1aIs halogen, C1-C10Alkyl or C6-C30And (4) an aryl group.
In one aspect: r1-1dIs R1-1d-1Substituted or unsubstituted C1-10Alkyl radical, R1-1d-2Substituted or unsubstituted C2-10Alkenyl radical, R1-1d-3Substituted or unsubstituted C2-10Alkynyl, unsubstituted C6-30Aryl radical, R1-1d-5Substituted or unsubstituted "hetero atom is selected from one or more of N, O and S, and the number of hetero atoms is 1-4".
In one aspect: r1-1hIs C2-C10An alkenyl group.
In one aspect: r1-1The structure of the composite material is any one of the following structures,
in one aspect: the compound shown in the formula II-A is selected from any one of the following compounds:
in one aspect: the compound shown in the formula II-B is selected from any one of the following compounds:
in one aspect: r2Is hydrogen, unsubstituted C1-C30Alkyl, or R2-2Substituted or unsubstituted C6-C30And (4) an aryl group.
In one aspect: r2-2Is halogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group.
In one aspect: the compound shown in the formula III' is selected from any one of the following compounds:
in one embodiment, the compound of formula I-2-A is:
the invention also provides a preparation method of the chiral beta-acyloxy carboxylic ester compound, which comprises the following steps:
(1) in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound containing a segment II, a compound containing a segment III and carbon monoxide (CO);
(2) in a solvent, performing methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound containing a fragment I;
wherein the fragment II is
The fragment III is
SaidFragment I is
Wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand is
When the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
wherein the carbon marked with x is an S-configuration chiral carbon;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
wherein the carbon marked with x is an R configuration chiral carbon;
wherein, R5、R6And R7Is as defined in any of the preceding items;
the reaction operation and conditions of step (1) are as described in any one of the preceding.
In step (2), the operation and conditions of the methylation reaction may be conventional in the art for such reactions. Specifically, the method comprises the following steps:
in step (2), the solvent may be conventional in the art for such reactions, and preferably, the solvent is an alcohol solvent and/or a substituted aromatic hydrocarbon solvent. The alcohol solvent is preferably methanol and/or ethanol. The substituted aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, toluene and trifluoromethyl benzene. More preferably, the solvent is a mixed solvent of methanol and/or toluene.
In the step (2), the amount of the solvent may not be specifically limited as long as the reaction is not affected.
In step (2), the methylating agent may be a methylating agent conventional in the art for such reactions, and is preferably TMSCHN2。
In step (2), the amount of the methylating agent may be the amount conventionally used in such reactions in the art, and preferably, the molar ratio of the methylating agent to the compound of the present invention in the form of the second paragraph II in step (1) is (2-10): 1, e.g. 4: 1.
In the step (2), the temperature of the methylation reaction can be the temperature conventional in the reaction in the field, and preferably, the temperature of the methylation reaction is 20-30 ℃.
In step (2), the progress of the methylation reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC, HNMR). The methylation reaction time can be 1-10 hours, preferably 2-6 hours, such as 4 hours or 6 hours.
Preferably, step (1) further comprises the following post-processing steps: and adding a solvent into the reaction solution, and concentrating to obtain the next reaction. In the post-treatment step of step (1), the solvent is an alcohol solvent (e.g., methanol).
In one embodiment of the present invention, the preparation method of the carboxylic ester compound is the following method a or method B:
the method A comprises the following steps:
(1) in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-A, a compound shown as a formula III' and carbon monoxide (CO);
(2) in a solvent, performing methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -A;
the method B comprises the following steps:
(1) in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-B, a compound shown as a formula III' and carbon monoxide (CO);
(2) in a solvent, performing methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -B;
in Process A or Process B, the addition reaction is carried out under the conditions and in the manner as described in any of the above;
*、R1、R2and R8Is as defined in any of the preceding claims.
In one aspect: the compound shown in the formula I' -A is selected from any one of the following compounds:
in one aspect: the compound shown in the formula I' -B is selected from any one of the following compounds:
the invention also provides a compound as shown in the following formula,
the unit cell parameters are as follows: monoclinic system, P21 space group, cell parameter of
α＝γ＝90°，β＝106.762(3)°。
Definition of
In the invention, the term "room temperature" means 10 to 30 ℃.
In the present invention, the term "halogen" means fluorine, chlorine, bromine or iodine.
In the present invention, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon group having the specified number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
In the present invention, the term "alkenyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon double bonds and no carbon-carbon triple bonds. The one or more carbon-carbon double bonds may be internal (e.g., in a 2-butenyl group) or terminal (e.g., in a 1-butenyl group).
In the present invention, the term "alkynyl" refers to a straight or branched hydrocarbon group having one or more carbon-carbon triple bonds and optionally one or more carbon-carbon double bonds.
In the present invention, the term "cycloalkyl" refers to a saturated monocyclic ring, or a carbocyclic substituent comprising a fused, bridged or spiro polycyclic ring system.
In the present invention, "heterocycloalkyl" refers to a "heterocycloalkyl" of a non-aromatic ring system. The heterocycloalkyl group can either be monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system (e.g., a bicyclic system ("bicyclic heterocyclyl")) and can be saturated or can be partially unsaturated.
In the present invention, "heterocycloalkenyl" means a "heterocyclic group" containing an ethylenic bond, an unsaturated non-aromatic ring system. The heterocycloalkenyl group can be either monocyclic ("monocyclic heterocycloalkenyl") or a fused, bridged or spiro ring system (e.g., a bicyclic ring system ("bicyclic heterocycloalkenyl")) and can be saturated or can be partially unsaturated. In some embodiments, heterocycloalkenyl refers to heterocycloalkenyl having 1-2, 5-6 members heteroatoms of one or more of N, O and S.
In the present invention, the term "alkoxy" denotes a cyclic or acyclic alkyl group linked via an oxygen bridge, the alkyl and cycloalkyl groups being as defined above.
As used herein, "aryl" refers to a group having 6-14 atoms and zero heteroatoms, a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n +2 aromatic ring system (e.g., having 6,10, or 14 p electrons shared in a cyclic array) ("C)6-C14Aryl ").
In the present invention, "heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n +2 aromatic ring system (e.g., having 6 or 10 shared p electrons in a cyclic array) having carbon atoms and 1-4 heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from one or more of nitrogen, oxygen, and sulfur, and the number of heteroatoms is 1,2, 3, or 4 ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as valency permits.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the preparation method of the beta-acyloxy carboxylic ester compound has the advantages of high yield, wide substrate universality, good functional group compatibility or better corresponding selectivity control, mild reaction conditions and simple operation.
Drawings
FIG. 1 is an X-ray single crystal diffraction pattern of the compound represented by the formula I' -46 in example 1.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 preparation of beta-acyloxycarboxylic acid ester Compounds
General procedure step 1: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5mg,0.0375mmol,7.5 mol%), Pd (OAc)2(5.6mg,0.05mmol,5 mol%) and benzoquinone (162.1mg,1.5mmol,3.0equiv) and) were added to the reaction tube in sequence under the protection of carbon monoxide gas with Et2O (0.25mL), the compound of formula A-2 (290.4mg,2.5mmol,5.0equiv) and the olefin of formula II' (0.5mmol,1.0 equiv). The reaction was stirred at room temperature for 72 hours. After completion of the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise2(2M n-hexane solution) and stirred for 6 hours. The reaction solution is concentrated and separated by flash column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General procedure step 2: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5mg,0.0375mmol,7.5 mol%), Pd (OAc)2(5.6mg,0.05mmol,5 mol%) and benzoquinone (162.1mg,1.5mmol,3.0equiv) and) were added to the reaction tube in sequence under the protection of carbon monoxide gas with Et2O (0.25mL), the compound of formula A-2 (290.4mg,2.5mmol,5.0equiv) and the olefin of formula II' (0.5mmol,1.0 equiv). The reaction was stirred at 0 ℃ for 72 hours. After completion of the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise2(2M n-hexane solution) and stirred for 6 hours. The reaction solution is concentrated and separated by flash column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General procedure step 3: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5mg,0.0375mmol,7.5 mol%), Pd (OAc)2(5.6mg,0.05mmol,5 mol%) and benzoquinone (162.1mg,1.5mmol,3.0equiv) in that order under the protection of carbon monoxide gasEt is added into the reaction tube2O (0.25mL), the compound of formula A-2 (290.4mg,2.5mmol,5.0equiv) and the olefin of formula II' (0.5mmol,1.0 equiv). The reaction was stirred at-10 ℃ for 72 hours. After completion of the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise2(2M n-hexane solution) and stirred for 6 hours. The reaction solution is concentrated and separated by flash column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General procedure 4: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5mg,0.0375mmol,7.5 mol%), Pd (OAc)2(5.6mg,0.05mmol,5 mol%) and benzoquinone (162.1mg,1.5mmol,3.0equiv) and) were added to the reaction tube in sequence under the protection of carbon monoxide gas with Et2O (0.25mL), the compound of formula A-2 (290.4mg,2.5mmol,5.0equiv) and the olefin of formula II' (0.5mmol,1.0 equiv). The reaction was stirred at 0 ℃ for 72 hours. After completion of the reaction, 2mL of acetone and 0.2mL of water were added, stirred for 4 hours, and concentrated. Flash column chromatography (petroleum ether/ethyl acetate/methanol) to obtain the target product.
General procedure 5: in a 10mL reaction tube, pyridine-oxazoline ligand L (R configuration) (9.5mg,0.0375mmol,7.5 mol%), Pd (OAc)2(5.6mg,0.05mmol,5 mol%) and benzoquinone (324.2mg,3mmol,6.0equiv) and) were added to the reaction tube in sequence under carbon monoxide gas protection2O (0.8mL), the compound of formula A-2 (380.8mg,5mmol,10.0equiv) and the olefin of formula II' (0.5mmol,1.0 equiv). The reaction was stirred at room temperature for 72 hours. After completion of the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise2(2M n-hexane solution) and stirred for 6 hours. The reaction solution is concentrated and separated by flash column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
General procedure 6: in a 10mL reaction tube, pyridine-oxazoline ligand L (S configuration) (9.5mg,0.0375mmol,7.5 mol%), Pd (OAc)2(5.6mg,0.05mmol,5 mol%) and benzoquinone (162.1mg,1.5mmol,3.0equiv) and) were added to the reaction tube in sequence under the protection of carbon monoxide gas with Et2O (0.25mL), Compound of formula A-2 (290.4)mg,2.5mmol,5.0equiv) and the olefin represented by formula II' (0.5mmol,1.0 equiv). The reaction was stirred at 0 ℃ for 72 hours. After completion of the reaction, 1mL of methanol was added, stirred for 1 hour, and concentrated. The crude product was dissolved in 1mL of methanol and 1mL of toluene, and 1mL of TMSCHN was added dropwise2(2M n-hexane solution) and stirred for 6 hours. The reaction solution is concentrated and separated by flash column chromatography (petroleum ether/ethyl acetate) to obtain the target product.
Compound I' -1:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product as an oily liquid. (89.2mg, 73% yield, 88% ee)]D 29.0＝-3.47(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ5.26-5.19(m,1H),3.64(s,3H),2.59(dd,J＝3.2,15.2Hz,1H),2.52(dd,J＝5.2,15.2Hz,1H),2.18-2.10(m,1H),1.68-1.41(m,6H),1.40-1.25(m,2H),0.91(t,J＝7.2Hz,3H),0.89-0.84(m,6H).13C NMR(100MHz,CDCl3) Δ 175.49,170.90,69.99,51.64,49.11,39.15,36.12,25.00,24.96,18.35,13.76,11.74,11.67 HRMS M/z (ESI-TOF) calculation [ M + Na]+267.1567, found in practice, 267.1574.IR (ATR) v (cm)-1) 2962,2876,1731,1437,1384,1268,1228,1171,1146,1082,1017,813,742.Chiral GC (CP chiralsil-DEX CB Varian,25m × 0.25mm,0.25 μm film thickness, using nitrogen (10.0psi) as carrier gas, column oven: initial temperature 50 ℃, hold for 2min, then heat (2 ℃/min) to 150 ℃, hold for 20min, detect with FID) retention time 48.99min (secondary) and 49.25min (primary).
Compound I' -2:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product as an oily liquid. (109.6mg, 85% yield, 91% ee) [ α ]]D 28.9＝-2.51(c 0.94,CHCl3).1H NMR(400MHz,CDCl3)δ5.26-5.19(m,1H),3.65(s,3H),2.59(dd,J＝7.6,15.2Hz,1H),2.53(dd,J＝5.2,15.2Hz,1H),2.20-2.12(m,1H),1.69-1.53(m,4H),1.52-1.42(m,2H),1.36-1.25(m,4H),0.90-0.85(m,9H).13C NMR(100MHz,CDCl3) δ 175.48,170.91,70.18,51.66,49.12,39.15,33.67,27.18,25.03,24.98,22.35,13.87,11.76,11.69.HRMS: M/z (ESI-TOF) calculation [ M + Na]+281.1723, measured by 281.1728.IR (ATR) v (cm)-1) 2961,1875,1731,1459,1437,1383,1267,1170,1146,1082,995,813,740 Chiral GC (CP Chirasil-DEX CB Varian,25m × 0.25mm,0.25 μm film thickness, using nitrogen (10.0psi) as carrier gas, column oven: initial temperature 50 ℃, incubation for 2min, then heating (2 ℃/min) to 165 ℃, detection with FID) retention time 53.96min (secondary) and 54.18min (primary).
Compound I' -3:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product as an oily liquid. (124.5mg, 83% yield, 87% ee) [ alpha ]]D 24.3＝0.88(c 0.580,CHCl3).1H NMR(400MHz,CDCl3)δ5.25-5.18(m,1H),3.64(s,3H),2.58(dd,J＝7.6,15.6Hz,1H),2.52(dd,J＝6.0,15.6Hz,1H),2.18-2.10(m,1H),1.62-1.41(m,6H),1.28-1.24(m,8H),0.88-0.83(m,9H).13C NMR(100MHz,CDCl3) δ 175.47,170.90,70.18,51.65,49.11,39.13,33.97,31.61,28.92,25.04,24.99,22.47,13.98,11.75,11.69.HRMS: M/z (ESI-TOF) calculation [ M + Na]+309.2036, the actual measurement is 309.2031.IR (ATR) v (cm)-1) 2960,2930,2860,1731,1459,1437,1383,1268,1227,1170,1146,1082,1014.HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 8.26min (major) and 11.41min (minor).
Compound I' -4:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product as an oily liquid. (140.4mg, 82% yield, 85% ee) [ alpha ]]D 24.6＝0.60(c 0.73,CHCl3).1H NMR(400MHz,CDCl3)δ5.25-5.18(m,1H),3.64(s,3H),2.58(dd,J＝7.2,15.2Hz,1H),2.52(dd,J＝5.6,15.6Hz,1H),2.18-2.11(m,1H),1.62-1.42(m,6H),1.28-1.23(m,16H),0.88-0.84(m,9H).13C NMR(100MHz,CDCl3) Δ 175.47,170.90,70.19,51.66,49.12,39.13,33.98,31.85,29.53,29.46,29.42,29.28,29.26,25.04,25.01,22.64,14.07,11.77,11.70 HRMS M/z (ESI-TOF) calculation [ M + Na]+365.2662, found in 365.2662.IR (ATR) v (cm)-1) 2960,2930,2860,2854,1733,1731,1459,1437,1383,1268,1227,1146,1081,1044,1014,997,734.HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 6.75min (major) and 9.38min (minor).
Compound I' -5:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product as an oily liquid. (160.0mg, 75% yield, 84% ee)]D 22.5＝-0.47(c 1.30,CHCl3).1H NMR(400MHz,CDCl3)δ5.26-5.19(m,1H),3.65(s,3H),2.59(dd,J＝7.6,15.2Hz,1H),2.53(dd,J＝5.6,15.6Hz,1H),2.19-2.12(m,1H),1.67-1.42(m,6H),1.29-1.17(m,22H),0.89-0.84(m,9H).13C NMR(100MHz,CDCl3) δ 175.48,170.92,70.21,51.68,49.13,39.16,34.00,31.89,29.65,29.63,29.62,29.59,29.48,29.44,29.33,29.28,25.06,25.02,22.66,14.09,11.79,11.72 HRMS M/z (ESI-TOF) calculation [ M + Na]+407.3132, measured by 407.3126.IR (ATR) v (cm)-1) 2923,2853,1734,1459,1382,1268,1229,1172,1146,1082,721.HPLC (IG,0.46 × 25cm,5 μm, n-hexane/iso-hexane)90/10 at a flow rate of 0.7mL/min, measured at 214 nm) retention time 5.98min (major) and 7.57min (minor).
Compound I' -6:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 20:1) to give the product as an oily liquid. (160.0mg, 75% yield, 82% ee) [ alpha ]]D 22.8＝0.55(c 1.20,CHCl3).1H NMR(400MHz,CDCl3)δ5.26-5.19(m,1H),3.66(s,3H),2.60(dd,J＝7.6,15.2Hz,1H),2.54(dd,J＝5.6,15.6Hz,1H),2.20-2.12(m,1H),1.66-1.53(m,4H),1.53-1.43(m,2H),1.32-1.24(m,28H),0.90-0.85(m,9H).13C NMR(100MHz,CDCl3) Delta 175.50,170.94,70.24,51.68,49.14,39.18,34.02,31.91,29.68,29.64,29.60,29.49,29.45,29.34,29.29,25.05,25.00,22.67,14.09,11.79,11.71 HRMS M/z (ESI-TOF) calculation [ M + Na, 11.79,11.71]+449.3601, measured 449.3596.IR (ATR) v (cm)-1) 2923,2853,1734,1460,1437,1383,1268,1228,1172,1146,1082,1013,756.HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 5.54min (major) and 6.92min (minor).
Compound I' -7:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (93.2mg, 69% yield, 91% ee) [ alpha ]]D 24.7＝-0.98(c 0.54,CHCl3).1H NMR(400MHz,CDCl3)δ5.25-5.18(m,1H),4.71(s,1H),4.66(s,1H),3.65(s,3H),2.61(dd,J＝7.6,15.6Hz,1H),2.55(dd,J＝5.6,15.6Hz,1H),2.20-2.12(m,1H),2.08-1.97(m,2H),1.83-1.71(m,2H),1.70(s,3H),1.65-1.42(m,4H),0.87(t,J＝7.6Hz,3H),0.84(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3) Delta 175.42,170.74,144.45,110.49,69.86,51.66,49.05,38.97,33.16,31.92,24.99,24.92,22.29,11.76,11.67 HRMS M/z (ESI-TOF) calculation of [ M + Na [ ]]+293.1723, 193.1722.IR (ATR) v (cm)-1) 2965,1935,1734,1459,1438,1269,1228,1174,1147,1083,1019,888, chiralgc (CP chiralsil-DEX CB Varian,25m × 0.25mm,0.25 μm film thickness, using nitrogen (10.0psi) as carrier gas, column oven: initial temperature 50 ℃, hold for 2min, then heat (2 ℃/min) to 160 ℃, hold for 20min, detect with FID) retention time 58.40min (secondary) and 58.63min (primary).
Compound I' -8:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (122.0mg, 92% yield, 91% ee) [ α ]]D 28.9＝-5.39(c 0.73,CHCl3).1H NMR(400MHz,CDCl3)δ5.39-5.31(m,1H),3.66(s,3H),3.58-3.50(m,2H),2.69-2.58(m,2H),2.22-2.04(m,3H),1.66-1.43(m,4H),0.87(t,J＝7.2Hz,3H),0.86(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3) Delta 175.33,170.25,67.64,51.78,48.99,40.30,38.81,36.71,24.98,24.90,11.73,11.65 HRMS M/z (ESI-TOF) calculation [ M + Na]+287.1021, found to be 287.1028.IR (ATR) v (cm)-1) 2964,1732,1437,1385,1267,1226,1168,1142,1079,1042,947,737,660 HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 11.68min (secondary) and 12.13min (primary).
Compound I' -9:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (85.3mg, 55% yield, 92% ee) [ alpha ]]D 28.9＝-23.26(c 0.83,CHCl3).1H NMR(400MHz,CDCl3)δ5.36-5.29(m,1H),3.66(s,3H),3.43-3.32(m,2H),2.69-2.57(m,2H),2.31-2.12(m,3H),1.66-1.43(m,4H),0.90-0.85(m,6H).13C NMR(100MHz,CDCl3) Delta 175.32,170.20,68.56,51.80,48.98,38.67,36.92,27.97,24.97,24.90,11.75,11.66 HRMS M/z (ESI-TOF) calculation [ M + Na]+331.0515, measured 331.0522.IR (ATR) v (cm)-1) HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detected at 214 nm) retention time 15.57min (major) and 16.37min (minor).
Compound I' -10:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (95.7mg, 75% yield, 91% ee) [ α ]]D 28.9＝-11.81(c 0.83,CHCl3).1H NMR(400MHz,CDCl3)δ5.28-5.21(m,1H),3.67(s,3H),2.68(dd,J＝6.4,15.6,Hz,1H),2.57(dd,J＝6.4,16.0,Hz,1H),2.40(t,J＝7.6Hz,2H),2.23-2.15(m,1H),2.12-1.97(m,2H),1.66-1.44(m,4H),0.90-0.84(m,6H).13C NMR(100MHz,CDCl3) Delta 175.33,169.92,118.73,68.44,51.91,48.79,38.45,29.69,24.91,24.70,13.52,11.79,1.62 HRMS M/z (ESI-TOF) calculation of [ M + Na: (M + Na)]+278.1363, measured 278.1368.IR (ATR) v (cm)-1) HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 20.24min (primary) and 22.72min (secondary).
Compound I' -11:
the reaction was carried out according to general procedure 2, column chromatography (stone)Oil ether: ethyl acetate 10:1) gave the product as an oily liquid. (128.5mg, 84% yield, 96% ee) [ alpha ]]D 24.4＝2.63(c 0.96,CHCl3).1H NMR(400MHz,CDCl3)δ7.30-7.26(m,2H),7.21-7.16(m,3H),5.34-5.28(m,1H),3.66(s,3H),2.74-2.55(m,4H),2.25-2.17(m,1H),2.05-1.89(m,2H),1.70-1.49(m,4H),0.94-0.89(m,6H).13C NMR(100MHz,CDCl3) Delta 175.40,170.59,141.03,128.39,128.19,125.97,69.77,51.64,49.02,39.03,35.74,31.44,24.98,24.91,11.80,11.68 HRMS M/z (ESI-TOF) calculation [ M + Na]+329.1723, measured 329.1730.IR (ATR) v (cm)-1) HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 14.27min (minor) and 15.14min (major).
Compound I' -12:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (174.9mg, 81% yield, 97% ee)]D 29.0＝6.35(c 0.8,CHCl3).1H NMR(400MHz,CDCl3)δ7.58(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),5.29-5.22(m,1H),3.65(s,3H),2.67-2.51(m,4H),2.22-2.14(m,1H),2.00-1.84(m,2H),1.68-1.45(m,4H),0.92-0.87(m,6H).13C NMR(100MHz,CDCl3) Δ 175.44,170.53,140.67,137.45, 130.35, 91.08, 69.56, 51.74, 49.01, 39.01, 35.49, 31.01, 24.99, 24.90, 11.85, 11.72 HRMS M/z (ESI-TOF) calculation [ M + Na]+455.0690, it is measured that 455.0692.IR (ATR) v (cm)-1) 2961,2874,1729,1484,1436,1383,1267,1170,1144,1080,1037,1005,829,798,740,508 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 8.61min (major) and 10.68min (minor).
Compound I' -13:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (184.8mg, 80% yield, 93% ee)]D 29.0＝6.35(c 0.8,CHCl3).1H NMR(400MHz,CDCl3)δ7.73(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,2H),5.33-5.28(m,1H),4.00-3.98(m,2H),3.66(s,3H),2.65(dd,J＝7.6,15.6Hz,1H),2.58(dd,J＝5.2,15.2Hz,1H),2.21-2.13(m,1H),1.86-1.79(m,4H),1.63-1.44(m,4H),1.32(s,12H),0.88(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3) Δ 175.48,170.65,161.41,136.45,113.77,83.47,69.75,66.97,51.70,49.04,39.09,30.64,24.96,24.90,24.79,11.79,11.67 HRMS M/z (ESI-TOF) calculation [ M + Na]+485.2681, measured 485.2694.IR (ATR) v (cm)-1) 2964,1732,1604,1437,1358,1317,1272,1243,1168,1141,1089,1011,962,859,831,735,670,654,521.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 7.96min (major) and 9.31min (minor).
Compound I' -14:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (160.4mg, 90% yield, 96% ee) [ α ]]D 29.3＝1.34(c 1.00,CHCl3).1H NMR(400MHz,CDCl3)δ7.82-7.77(m,3H),7.62(s,1H),7.48-7.41(m,2H),7.34-7.31(m,1H),5.40-5.32(m,1H),3.67(s,3H),2.92-2.76(m,2H),2.70(dd,J＝7.6,15.2Hz,1H),2.62(dd,J＝5.6,15.2Hz,1H),2.27-2.19(m,1H),2.15-1.99(m,2H),1.73-1.50(m,4H),0.96-0.91(m,6H).13C NMR(100MHz,CDCl3)δ175.45,170.62,138.53,133.53,131.99,128.01,127.53,127.35,126.96,126.28,125.92,125.21,69.84,51.68,49.04,39.07,35.63,31.64,24.99,24.91,11.83,11.71 HRMS M/z (ESI-TOF) calculation [ M + Na]+379.1880, measured 379.1878.IR (ATR) v (cm)-1) 2962,2933,2875,1729,1507,1458,1436,1383,1310,1268,1227,1171,1143,1081,1040,1014,956,890,853,815,745.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 8.05min (major) and 10.27min (minor).
Compound I' -15:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (120.9mg, 72% yield, 91% ee) [ α ]]D 29.5＝9.07(c 0.94,CHCl3).1H NMR(400MHz,CDCl3)δ8.02-7.99(m,2H),7.57-7.53(m,1H),7.45-7.40(m,2H),5.64-5.57(m,1H),4.50(dd,J＝3.6,12.0Hz,1H),4.44(dd,J＝5.6,12.0Hz,1H),3.67(s,3H),2.81-2.68(m,2H),2.23-2.15(m,1H),1.66-1.42(m,4H),0.87-0.81(m,6H).13C NMR(100MHz,CDCl3) Delta 175.14,169.99,165.97,133.16,129.62,129.51,128.35,67.66,64.84,51.90,48.86,36.01,24.92,24.88,11.62,11.59 HRMS M/z (ESI-TOF) calculation [ M + Na]+359.1465, measured 359.1470.IR (ATR) v (cm)-1) 2964,2877,1722,1451,1438,1383,1265,1171,1143,1109,1069,1026,940,709 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 11.57min (major) and 12.74min (minor).
Compound I' -16:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (168.0mg, 86% yield, 92% ee) [ alpha ]]D 29.6＝2.15(c 0.35,CHCl3).1H NMR(400MHz,CDCl3)δ7.82-7.78(m,2H),7.71-7.66(m,2H),5.28-5.21(m,1H),3.67(t,J＝6.0Hz,2H),3.62(s,3H),2.59(dd,J＝7.6,15.6Hz,1H),2.51(dd,J＝5.6,15.2Hz,1H),2.17-2.09(m,1H),1.76-1.62(m,4H),1.60-1.39(m,4H),0.83(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3) Δ 175.35,170.50,168.20,133.87,131.96,123.13,69.41,51.66,48.90,38.93,37.46,31.22,24.87,24.79,24.26,11.70,11.60 HRMS M/z (ESI-TOF) calculation [ M + Na]+412.1731, found in 412.1742.IR (ATR) v (cm)-1) HPLC (IA,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 23.33min (major) and 25.10min (minor).
Compound I' -17:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (133.7mg, 80% yield, 91% ee) [ α ]]D 29.5＝-6.92(c 0.54,CHCl3).1H NMR(400MHz,CDCl3)δ7.93-7.90(m,2H),7.57-7.52(m,1H),7.47-7.42(m,2H),5.38-5.31(m,1H),3.66(s,3H),3.04(t,J＝7.6Hz,2H),2.69(dd,J＝7.6,15.6Hz,1H),2.61(dd,J＝5.6,15.6Hz,1H),2.20-1.00(m,3H),1.66-1.43(m,4H),0.89-0.84(m,6H).13CNMR(100MHz,CDCl3) Delta 198.67,175.47,170.49,136.58,133.09,128.55,127.88,69.62,51.71,48.94,39.29,34.26,28.32,24.91,24.77,11.75,11.62 HRMS M/z (ESI-TOF) calculation [ M + Na]+357.1673, measured by 357.1681.IR (ATR) v (cm)-1) 2963,2935,2876,1730,1685,1267,1204,1172,1144,1079,1001,742,690.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detected at 214 nm) retention time 12.99min (major) and 21.27min (minor).
Compound I' -18:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (151.6mg, 79% yield, 86% ee) [ alpha ]]D 29.5＝-3.49(c 0.97,CHCl3).1H NMR(400MHz,CDCl3)δ7.87-7.84(m,2H),7.65-7.60(m,1H),7.56-7.51(m,2H),5.17-5.10(m,1H),3.61(s,3H),3.17-3.02(m,2H),2.57(dd,J＝7.2,15.6Hz,1H),2.47(dd,J＝5.6,15.6Hz,1H),2.13-2.05(m,1H),1.81-1.63(m,4H),1.55-1.37(m,4H),0.82-0.76(m,6H).13C NMR(100MHz,CDCl3) Delta 175.33,170.28,138.76,133.65,129.21,127.91,68.89,55.47,51.69,48.82,38.77,32.35,24.81,24.72,18.66,11.69,11.56 HRMS M/z (ESI-TOF) calculation [ M + Na [ ]]+407.1499, measured 407.1498.IR (ATR) v (cm)-1) 2963,2935,2876,1729,1446,1385,1303,1269,1225,1174,1140,1085,1046,999,811,789,752,730,689,594,564,531 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detected at 214 nm) retention time 49.14min (primary) and 72.02min (secondary) compound I' -19:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (114.6mg, 71% yield, 89% ee. [ alpha ] - [ alpha ] in]D 29.7＝-2.97(c 0.5,CHCl3).1H NMR(400MHz,CDCl3)δ6.62(t,J＝2.0Hz,2H),6.12(J＝2.0Hz,,2H),5.25-5.18(m,1H),3.86(dt,J＝1.2,6.8Hz,2H),3.66(s,3H),2.59(dd,J＝7.2,15.2Hz,1H),2.51(dd,J＝5.6,15.6Hz,1H),2.19-2.11(m,1H),1.83-1.71(m,2H),1.70-1.43(m,6H),1.37-1.24(m,2H),0.87(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3) Δ 175.48,170.71,120.36,107.92,69.79,51.70,49.23,49.03,39.01,33.45,31.11,24.97,24.90,22.31,11.79,11.67 HRMS M/z (ESI-TOF) calculation [ M + Na]+346.1989, found 346.1996.IR (ATR) v (cm)-1)＝2962,2934,2875,1729,1500,1458,1437,1383,1269,1228,1172,1145,1112,1087,1061,1015,992,814,720,617.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 7.76min (major) and 11.85min (minor).
Compound I' -20:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (120.9mg, 76% yield, 94% ee) [ alpha ]]D 29.8＝-23.35(c 0.54,CHCl3).1H NMR(400MHz,CDCl3)δ7.63(d,J＝8.0Hz,1H),7.33(d,J＝8.4Hz,1H),7.24-7.19(m,1H),7.14-7.09(m,2H),6.50(dd,J＝0.4,3.2Hz,1H),5.36-5.29(m,1H),4.28-4.12(m,2H),3.63(s,3H),2.64(dd,J＝6.8,15.6Hz,1H),2.53(dd,J＝5.6,15.6Hz,1H),2.29-2.17(m,3H),1.73-1.51(m,4H),0.97-0.91(m,6H).13C NMR(100MHz,CDCl3) Delta 175.53,170.24,135.62,128.71,127.59,121.56,121.08,119.41,109.05,101.49,68.07,51.77,48.98,42.69,38.98,34.42,24.99,24.84,11.91,11.72 HRMS M/z (ESI-TOF) calculation [ M + Na]+368.1832, measured by 368.1835.IR (ATR) v (cm)-1) 2963,2934,1730,1461,1436,1316,1267,1166,1144,1079,1012,738,716 HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 13.03min (minor) and 17.50min (major).
Compound I' -21:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (160.2mg, 76% yield, 86% ee) [ alpha ]]D 29.9＝-3.85(c 0.95,CHCl3).1H NMR(400MHz,CDCl3)δ8.12(d,J＝7.6Hz,2H),7.48(t,J＝8.0Hz,2H),7.40(d,J＝8.4Hz,2H),7.25(t,J＝7.6Hz,2H),5.26-5.19(m,1H),4.30(t,J＝7.2Hz,2H),3.66(s,3H),2.58(dd,J＝7.6,15.2Hz,1H),2.49(dd,J＝5.6,15.2Hz,1H),2.18-2.10(m,1H),1.99-1.85(m,2H),1.73-1.39(m,8H),0.89-0.82(m,6H).13C NMR(100MHz,CDCl3) δ 175.45,170.65,140.29,125.58,122.78,120.28,118.75,108.51,69.73,51.66,48.95,42.67,39.02,33.69,28.62,24.90,24.84,22.89,11.70,11.62 HRMS M/z (ESI-TOF) calculation [ M + Na]+446.2302, found 446.2314.IR (ATR) v (cm)-1) HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 19.22min (primary) and 22.09min (secondary).
Compound I' -22:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (140.4mg, 90% yield, 93% ee) [ alpha ]]D 29.9＝-2.34(c 0.8,CHCl3).1H NMR(400MHz,CDCl3)δ7.26-7.22(m,1H),6.96-6.91(m,2H),5.32-5.25(m,1H),3.65(s,3H),2.75-2.53(m,4H),2.23-2.15(m,1H),2.05-1.89(m,2H),1.68-1.45(m,4H),0.92-0.87(m,6H).13C NMR(100MHz,CDCl3) Delta 175.43,170.60,141.20,127.91,125.51,120.28,69.67,51.68,49.02,39.01,34.74,25.86,24.97,24.91,11.80,11.69.HRMS M/z (ESI-TOF) calculation of [ M + Na: (M + Na-M + T-M]+335.1288, the actual measurement is 335.1285.IR (ATR) v (cm)-1) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 8.46min (primary) and 9.86min (secondary).
Compound I' -23:
the reaction is carried outColumn chromatography (petroleum ether: ethyl acetate 10:1) as per general procedure 2 gave the product as an oily liquid. (140.6mg, 76% yield, 86% ee) [ alpha ]]D 29.9＝0.67(c 0.99,CHCl3).1H NMR(400MHz,CDCl3)δ7.33-7.30(m,1H),7.02-6.99(m,2H),5.32-5.24(m,1H),4.69(s,2H),3.70(s,3H),3.51(t,J＝6.4Hz,2H),2.65(dd,J＝7.2,15.2Hz,1H),2.59(dd,J＝5.6,15.2Hz,1H),2.25-2.17(m,1H),1.76-1.61(m,6H),1.57-1.38(m,4H),0.92(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3) δ 175.43,170.80,141.30,126.50,126.07,125.56,70.02,69.55,67.26,51.64,49.04,39.03,33.70,29.24,24.97,24.91,21.73,11.75,11.66 HRMS M/z (ESI-TOF) calculation [ M + Na]+393.1706, found 393.1712.IR (ATR) v (cm)-1) 2961,2935,2864,1730,1458,1436,1267,1226,1168,1146,1085,1041,1017,993,937,853,830,699.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 8.88min (major) and 11.17min (minor) compound I' -24:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (170.1mg, 81% yield, 91% ee) [ α ]]D 30＝-3.74(c 0.8,CHCl3).1H NMR(400MHz,CDCl3)δ8.56(d,J＝8.0Hz,1H),8.37(s,1H),7.85(d,J＝7.6Hz,1H),7.50-7.45(m,1H),7.41-7.37(m,1H),5.36-5.32(m,1H),4.37-4.35(m,2H),3.65(s,3H),2.66(dd,J＝7.2,15.2Hz,1H),2.58(dd,J＝5.6,15.6Hz,1H),2.21-2.14(m,1H),1.89-1.82(m,4H),1.64-1.45(m,4H),0.88(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3)δ175.42,170.51,162.57,139.93,136.59,136.57,127.00,125.33,124.91,124.57,122.41,69.60,63.99,51.69,48.98,38.98,30.64,24.95,24.86,24.55,11.76,11.64.IR(ATR)ν(cm-1) 2962,2875,1730,1709,1503,1461,1436,1423,1385,1363,1262,1212,1169,1145,1065,1016,864,769,746,723.HRMS: M/z (ESI-TOF) calculation [ M + Na: [ M + Na ] M/z]+:4431499, found 443.1489 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detected at 214 nm) retention time 13.67min (major) and 17.02min (minor).
Compound I' -25:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (139.8mg, 79% yield, 90% ee) [ alpha ]]D 24.3＝-4.48(c 0.77,CHCl3).1H NMR(400MHz,CDCl3)δ7.98-7.97(m,1H),7.39(s,1H),6.70-6.69(m,1H),5.32-5.22(m,1H),4.22(s,2H),3.63(s,3H),2.61(dd,J＝7.2,15.6Hz,1H),2.53(dd,J＝5.6,15.6Hz,1H),2.18-2.10(m,1H),1.77-1.73(m,4H),1.63-1.40(m,4H),0.84(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3) Delta 174.38,170.51,162.92,147.62,143.63,119.21,109.67,69.54,63.80,51.66,48.96,38.93,30.51,24.93,24.85,24.39,11.72,11.61 HRMS M/z (ESI-TOF) calculation [ M + Na [ ]]+377.1571, the actual measurement is 377.1577.IR (ATR) v (cm)-1) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 12.28min (primary) and 15.37min (secondary).
Compound I' -26:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (141.7mg, 80% yield, 86% ee) [ alpha ]]D 24.3＝-1.20(c 0.78,CHCl3).1H NMR(400MHz,CDCl3)δ7.38-7.36(m,1H),6.32-6.26(m,2H),5.24-5.17(m,1H),4.39(s,2H),3.63(s,3H),3.42(t,J＝6.4Hz,2H),2.57(dd,J＝7.2,15.2Hz,1H),2.51(dd,J＝5.6,15.6Hz,1H),2.17-2.10(m,1H),1.67-1.53(m,6H),1.50-1.29(m,4H),0.85(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3) δ 175.56,170.93,152.07,142.73,110.27,109.08,70.16,69.90,64.79,51.77,49.18,39.15,33.82,29.34,25.11,25.06,21.82,11.87,11.79 HRMS M/z (ESI-TOF) calculation [ M + Na]+377.1935, the actual measurement is 377.1941.IR (ATR) v (cm)-1) 2962,2936,2865,1730,1502,1459,1437,1385,1355,1268,1226,1171,1147,1086,1014,994,919,884,812,736,600 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 9.58min (major) and 10.83min (minor).
Compound I' -27:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (136.5mg, 70% yield, 95% ee) [ alpha ]]D 24.3＝-23.26(c 0.78,CHCl3).1H NMR(400MHz,CDCl3)δ7.68(d,J＝8.0Hz,1H),7.59-7.52(m,2H),7.47-7.42(m,1H),7.32-7.28(m,1H),5.47-5.40(m,1H),4.51-4.35(m,2H),3.67(s,3H),2.77-2.65(m,2H),2.23-2.12(m,3H),1.67-1.44(m,4H),0.88(t,J＝6.8Hz,6H).13C NMR(100MHz,CDCl3) Delta 175.36,170.36,159.30,155.75,145.16,127.67,126.87,123.78,122.87,114.13,112.33,67.22,61.31,51.80,48.96,38.96,32.85,24.94,24.84,11.74,11.66 HRMS M/z (ESI-TOF) calculation [ M + Na]+413.1571, measured 413.1572.IR (ATR) v (cm)-1) 2963,2935,2876,1727,1614,1562,1459,1437,1384,1348,1327,1294,1258,1221,1209,1170,1143,1084,1008,970,950,885,836,813,749,613,429 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 14.88min (major) and 15.83min (minor).
Compound I' -28:
the reaction was carried out according to general procedure 3, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (156.8mg, 78% yield, 91% ee) [ α ]]D 29.6＝-0.37(c 0.77,CHCl3).1H NMR(400MHz,CDCl3)δ7.57-7.54(m,2H),7.45-7.40(m,1H),7.37-7.32(m,2H),5.28-5.20(m,1H),4.20(t,J＝6.4Hz,2H),3.64(s,3H),2.61(dd,J＝7.2,15.2Hz,1H),2.54(dd,J＝5.6,15.2Hz,1H),2.19-2.11(m,1H),1.78-1.54(m,6H),1.51-1.38(m,4H),0.89-0.83(m,6H).13C NMR(100MHz,CDCl3) δ 175.45,170.67,154.03,132.89,130.56,128.49,119.52,86.16,80.50,69.74,65.59,51.66,49.02,39.02,33.47,28.05,24.96,24.90,21.49,11.74,11.64 HRMS M/z (ESI-TOF) calculation [ M + Na]+425.1935, measured 425.1937.IR (ATR) v (cm)-1) 2963,2936,2876,2220,1733,1704,1459,1443,1384,1283,1225,1185,1170,1082,1042,1000,937,757,689,534.HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 70/30, flow rate 0.7mL/min, measured at 214 nm) retention time 15.46min (major) and20.12min (minor).
Compound I' -29:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (148.5mg, 79% yield, 86% ee) [ alpha ]]D 24.4＝-24.29(c 0.42,CHCl3).1H NMR(400MHz,CDCl3)δ7.69(d,J＝16.4Hz,1H),7.55-7.51(m,2H),7.40-7.38(m,3H),6.43(d,J＝16.0Hz,1H),5.44-5.36(m,1H),4.35-4.28(m,1H),4.25-4.18(m,1H),3.68(s,3H),2.71(dd,J＝7.2,15.6Hz,1H),2.65(dd,J＝6.0,15.6Hz,1H),2.24-2.16(m,1H),2.12-2.06(m,2H),1.68-1.45(m,4H),0.89(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3) Delta 175.37,170.43,166.73,145.10,134.28,130.32,128.85,128.09,117.70,67.39,60.44,51.78,48.99,38.99,32.91,24.96,24.88,11.75,11.67 HRMS M/z (ESI-TOF) calculation [ M + Na]+399.1778, found 399.1776.IR (ATR))ν(cm-1) 2964,2934,1732,1715,1637,1450,1384,1310,1269,1201,1166,981,864,768,712,685 HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 17.23min (major) and 22.70min (minor).
Compound I' -30:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (185.0mg, 92% yield, 87% ee) [ alpha ]]D 24.5＝-2.23(c 2.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.96(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),6.73(dd,J＝10.8,17.6Hz,1H),5.84(dd,J＝0.4,17.6Hz,1H),5.36(dd,J＝0.8,11.2Hz,1H),5.29-5.22(m,1H),4.29(t,J＝6.8Hz,2H),3.64(s,3H),2.61(dd,J＝7.6,15.6Hz,1H),2.54(dd,J＝5.2,15.2Hz,1H),2.18-2.10(m,1H),1.82-1.66(m,4H),1.62-1.41(m,6H),0.87-0.82(m,6H).13C NMR(100MHz,CDCl3) Δ 175.42,170.66,166.26,141.82,135.94,129.77,129.37,126.00,116.37,69.81,64.51,51.66,49.03,39.06,33.61,28.38,24.96,24.91,21.74,11.75,11.65 HRMS: M/z (ESI-TOF) calculation [ M + Na: (M + Na-M + T-M]+427.2091, measured as 427.2094.IR (ATR) v (cm)-1) 2962,2876,1714,1607,1459,1437,1403,1385,1311,1270,1229,1175,1146,1103,1015,990,916,860,781,713.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 14.03min (major) and 17.64min (minor).
Compound I' -31:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (158.5mg, 91% yield, 87% ee) [ alpha ]]D 24.5＝-17.67(c 0.76,CHCl3).1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.4Hz,2H),6.84(d,J＝8.4Hz,2H),6.64(dd,J＝11.2,17.6Hz,1H),5.61(d,J＝18.0Hz,1H),5.48-5.41(m,1H),5.12(d,J＝10.8Hz,1H),4.02(t,J＝6.0Hz,2H),3.66(s,3H),2.71(d,J＝6.4Hz,2H),2.21-2.12(m,3H),1.64-1.44(m,4H),),0.86(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3) Delta 175.37,170.57,158.22,136.06,130.44,127.29,114.29,111.58,67.83,63.82,51.74,48.99,39.10,33.37,25.00,24.94,11.75,11.67 HRMS M/z (ESI-TOF) calculation of [ M + Na: (M + Na)]+371.1829, measured 371.1839.IR (ATR) v (cm)-1) HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 95/5, flow rate 0.7mL/min, detection at 214 nm) retention time 10.73min (major) and 11.39min (minor) compound I' -32:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (156.2mg, 72% yield, 93% ee) [ alpha ]]D 24.9＝-15.80(c 0.98,CHCl3).1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.8Hz,2H),6.85(d,J＝8.8Hz,2H),5.46-5.39(m,1H),4.80(s,1H),4.78(s,1H),4.37(t,J＝6.8Hz,2H),4.06(t,J＝6.0Hz,2H),3.64(s,3H),2.74-2.64(m,2H),2.44(t,J＝6.8Hz,2H),2.19-2.11(m,3H),1.78(s,3H),1.64-1.40(m,4H),0.87(t,J＝7.6Hz,3H),0.84(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3) δ 175.29,170.42,166.17,162.20,141.73,131.47,122.89,113.92,112.23,67.60,64.04,62.79,51.68,48.93,39.05,36.76,33.28,24.91,24.84,22.43,11.65,11.58 HRMS M/z (ESI-TOF) calculation [ M + Na]+457.2197, found 457.2193.IR (ATR) v (cm)-1) 2963,2935,2877,1733,1711,1605,1510,1458,1437,1380,1249,1165,1145,1102,1046,1010,890,847,769,695.HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 53.40min (secondary) and 57.04min (primary).
Compound I' -33:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (200.8mg, 80% yield, 94% ee) [ alpha ]]D 24.9＝-13.99(c 0.78,CHCl3).1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.8Hz,2H),6.86(d,J＝8.8Hz,2H),5.46-5.40(m,2H),5.09-5.06(m,1H),4.79(d,J＝7.2Hz,2H),4.06(t,J＝6.0Hz,2H),3.65(s,3H),2.71-2.68(m,2H),2.20-2.05(m,7H),1.74(s,3H),1.66(s,3H),1.59(s,3H),1.62-1.43(m,4H),0.84(t,J＝7.6Hz,3H),0.82(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3) δ 175.29,170.42,166.28,162.15,141.98,131.71,131.52,123.70,123.08,118.54,113.88,67.62,64.05,61.53,51.70,48.96,39.47,39.10,33.32,26.23,25.58,24.94,24.87,17.61,16.46,11.68,11.61 HRMS M/z (ESI-TOF) calculation [ M + Na]+525.2823, measured 525.2825.IR (ATR) v (cm)-1) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 17.36min (primary) and 19.85min (secondary).
Compound I' -34:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (230.7mg, 71% yield, 92% ee) [ alpha ]]D 25.3＝-3.36(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.97(s,2H),7.49(d,J＝8.0Hz,1H),7.41-7.38(m,1H),7.33-7.27(m,1H),7.26-7.21(m,1H),5.57-5.50(m,1H),4.17(t,J＝6.4Hz,2H),3.69(s,3H),2.92-2.76(m,4H),2.35-2.27(m,2H),2.26-2.16(m,1H),1.69-1.45(m,4H),1.35(t,J＝7.6Hz,3H),0.89(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3)187.97,175.36,170.57,166.91,156.60,153.65,137.21,133.54,126.33,124.69,123.85,120.98,118.52,115.28,111.11,69.97,67.88,51.74,48.94,39.16,34.26,24.91,24.84,21.98,12.13,11.84,11.68 HRMS M/z (ESI-TOF) calculation [ M + Na]+673.0407, 673.0410.IR (ATR) v (cm)-1) 2963,2936,1732,1648,1452,1377,1256,1171,1145,983,953,747.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 9.67min (minor) and 10.61min (major).
Compound I' -35:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (181.8mg, 90% yield, 91% ee) [ alpha ]]D 25.2＝-5.04(c 1.2,CHCl3).1H NMR(400MHz,CDCl3)δ7.59(d,J＝10.0Hz,1H)，7.32(d，J＝8.8Hz，1H)，6.77(dd，J＝2.4，8.4Hz，1H)，6.72(d，J＝2.0Hz，1H)，6.18(d，J＝9.6Hz，1H)5.32-5.25(m,1H),4.00-3.94(m,2H),3.62(s,3H),2.63(dd,J＝7.2,15.2Hz,1H),2.55(dd,J＝5.6,15.2Hz,1H),2.18-2.10(m,1H),1.88-1.78(m,2H),1.62-1.40(m,4H),0.84(t,J＝7.2Hz,6H).13C NMR(100MHz,CDCl3) Delta 175.38,170.50,161.93,161.06,155.68,143.34,128.65,112.86,112.67,112.38,101.21,69.49,67.75,51.65,48.92,38.95,30.48,24.88,24.80,24.65,11.71,11.58 HRMS M/z (ESI-TOF) calculation [ M + Na [ ]]+427.1727, measured 427.1735.IR (ATR) v (cm)-1) 2962,2876,1725,1610,1556,1508,1459,1436,1388,1349,1277,1229,1170,1120,993,890,833 HPLC (IB,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 46.130min (major) and 50.45min (minor).
Compound I' -36:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (196.7mg, 79% yield, 90% de) [ alpha ]]D 25.3＝83.01(c 0.25,CHCl3).1H NMR(400MHz,CDCl3)δ7.17(d,J＝8.4Hz,1H),6.67(dd,J＝2.8,8.8Hz,1H),6.61(d,J＝2.8Hz,1H),5.47-5.39(m,1H),3.99(t,J＝6.0Hz,2H),3.66(s,3H),2.90-2.85(m,2H),2.72-2.69(m,2H),2.49(dd,J＝8.4,18.8Hz,1H),2.41-2.36(m,1H),2.26-1.92(m,8H),1.67-1.54(m,4H),1.54-1.36(m,6H),0.90(s,3H),0.87(t,J＝7.6Hz,3H),0.86(t,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3)220.85,175.31,170.57,156.52,137.68,132.17,126.25,114.49,111.93,68.01,63.83,51.66,50.32,48.96,47.92,43.89,39.09,38.27,35.78,33.50,31.49,29.54,26.45,25.82,24.92,24.86,21.50,13.76,11.73,11.63 HRMS M/z (ESI-TOF) calculation of [ M + Na]+521.2874, measured 521.2878.IR (ATR) v (cm)-1) 2961,2931,1730,1909,1497,1460,1434,1254,1167,1055,973,813,782.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 18.47min (predominantly) and20.53min (minor).
Compound I' -37:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (216.0mg, 85% yield, 84% ee)]D 25.5＝-1.45(c 1.1,CHCl3).1H NMR(400MHz,CDCl3)δ8.09(d,J＝2.4Hz,1H),7.88-7.85(m,1H),7.55-7.50(m,1H),7.46-7.38(m,2H),7.33(d,J＝7.2Hz,1H),7.00(d,J＝8.4Hz,1H),5.25-5.21(m,1H),5.16(s,2H),4.11-4.07(m,2H),3.63(s,3H),3.61(s,2H),2.59(dd,J＝7.6,15.2Hz,1H),2.51(dd,J＝5.2,15.2Hz,1H),2.18-2.10(m,1H),1.70-1.41(m,8H),0.85(t,J＝7.6Hz,6H).13C NMR(100MHz,CDCl3)δ190.65,175.34,171.24,170.50,160.36,140.30,136.22,135.47,132.67,132.31,129.36,129.13,127.71,127.70,125.01,120.95,73.50,69.51,64.32,51.65,48.93,40.08,38.93,30.43,24.90,24.83,24.31,11.73,11.62 HRMS: M/z (ESI-TOF) calculation of [ M + Na: (M + Na-M + T-M]+533.2146, measured 533.2148.IR (ATR) v (cm)-1) 1962,2875,1728,1647,1611,1598,1489,1412,1380,1298,1165,1138,1120,1013,829,760,641 HPLC (IH-3,0.46 × 15cm,3 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, measured at 214 nm) retention time 24.27min (major) and 27.19min (minor).
Compound I' -38:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (169.4mg, 70% yield, 86% de) [ alpha ]]D 24.1＝5.02(c 0.66,CHCl3).(m.p.60–61℃).1H NMR(400MHz,CDCl3)δ7.11(s,4H),5.28-5.21(m,1H),3.68(s,3H),2.62(dd,J＝7.6,15.2Hz,1H),2.56(dd,J＝5.6,15.6Hz,1H),2.47-2.38(m,1H),2.33(s,3H),2.23-2.14(m,1H),1.93-1.89(m,2H),1.85-1.76(m,6H),1.69-1.59(m,4H),1.55-1.38(m,4H),1.28-1.14(m,6H),1.09-0.97(m,3H),0.93-0.88(m,8H).13C NMR(100MHz,CDCl3) δ 175.39,170.84,144.78,135.05,128.86,126.58,70.38,51.60,49.08,44.14,43.23,42.78,39.06,37.49,34.60,33.42,33.32,32.51,31.37,30.30,29.86,25.01,24.97,20.89,11.76,11.69 HRMS M/z (ESI-TOF) calculation [ M + Na]+507.3445, measured 507.3448.IR (ATR) v (cm)-1) 2914,2847,1730,1514,1437,1386,1271,1211,1175,1146,1081,1054,1013,977,940,814,532.HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 6.52min (major) and 8.37min (minor).
Compound I' -39:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (142.1mg, 78% yield, 91% de) [ alpha ]]D 25.8＝12.08(c 0.84,CHCl3).1H NMR(400MHz,CDCl3)δ8.05-8.02(m,2H),7.58-7.53(m,1H),7.46-7.41(m,2H),5.41-5.34(m,1H),5.28-5.19(m,1H),3.63(s,3H),2.66(d,J＝6.4Hz,2H),2.26-2.14(m,2H),1.97-1.90(m,1H),1.65-1.44(m,4H),1.39(d,J＝6.4Hz,3H),0.90-0.85(m,6H).13C NMR(100MHz,CDCl3) Δ 175.40,170.47,165.89,132.93,130.39,129.58,128.35,68.25,67.41,51.73,48.93,39.77,38.80,24.93,24.80,20.03,11.76,11.67 HRMS M/z (ESI-TOF) calculation [ M + Na]+387.1778, measured 387.1780.IR (ATR) v (cm)-1) HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 11.85min (major) and 15.57min (minor).
Compound I' -40:
the reaction was carried out according to general procedure 6, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (136.6mg, 75% yield, 89% de) [ alpha ]]D 26.0＝40.48(c 0.5，CHCl3).1H NMR(400MHz，CDCl3)δ8.03-8.00(m，2H)7.57-7.52(m,1H),7.45-7.40(m,2H),5.35-5.28(m,1H),5.22-5.13(m,1H),3.67(s,3H),2.72-2.61(m,2H),2.18-1.97(m,3H),1.60-1.41(m,4H),1.38(d,J＝6.4Hz,3H),0.86-0.81(m,6H).13C NMR(100MHz,CDCl3) Δ 175.32,170.51,165.90,132.83,130.48,129.53,128.31,67.89,67.09,51.74,48.82,40.33,39.18,24.84,24.63,20.56,11.68,11.63 HRMS M/z (ESI-TOF) calculation of [ M + Na [ ]]+387.1778, measured 387.1786.IR (ATR) v (cm)-1) HPLC (IG,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214nmMeasured) retention time 11.84min (major) and15.64min (minor).
Compound I' -41:
the reaction was carried out according to general procedure 2, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (138.2mg, 71% yield, 92% de) [ alpha ]]D 26.4＝39.80(c 0.8,CHCl3).1H NMR(400MHz,CDCl3)δ7.81-7.78(m,2H),7.70-7.67(m,2H),5.26-5.19(m,1H),4.46-4.36(m,1H),3.62(s,3H),2.61(d,J＝6.0Hz,2H),2.34-2.19(m,2H),2.14-1.06(m,1H),1.63-1.52(m,2H),1.49-1.40(m,5H),),0.85(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3) Δ 175.34,170.29,168.10,133.88,131.85,123.10,67.84,51.72,48.76,43.63,38.91,37.92,24.79,24.61,18.14,11.69,11.59 HRMS M/z (ESI-TOF) calculation [ M + Na [ ]]+412.1731, found in 412.1734.IR (ATR) v (cm)-1) HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 13.22min (major) and 19.83min (minor).
Compound I' -42:
the reaction was carried out according to general procedure 6, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (136.3mg, 70% yield, 96% de. [ alpha ]]D 25.9＝28.02(c 0.1,CHCl3).1H NMR(400MHz,CDCl3)δ7.83-7.79(m,2H),7.72-7.67(m,2H),5.10-5.03(m,1H),4.52-4.42(m,1H),3.62(s,3H),2.72-2.65(m,1H),2.63(dd,J＝5.2,14.8Hz,1H),2.57(dd,J＝6.4,15.6Hz,1H),2.11-1.97(m,2H),1.63-1.53(m,2H),1.52-1.39(m,5H),0.91-0.89(t,J＝7.2Hz,3H),0.84(t,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3) Δ 175.27,170.25,168.23,133.85,131.92,123.10,67.33,51.70,48.44,43.39,38.85,37.10,24.54,24.15,19.29,11.70,11.48 HRMS M/z (ESI-TOF) calculation [ M + Na]+412.1731, found in 412.1742.IR (ATR) v (cm)-1) HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 13.21min (secondary) and 19.62min (primary).
Compound I' -43:
the reaction was carried out according to general procedure 5, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (240.3mg, 90% yield, 99% ee. (2S, 2' S)/meso ═ 94/6.[ α ]]D 25.5＝-1.98(c 0.76,CHCl3).1H NMR(400MHz,CDCl3)δ7.08(s,4H),5.31-5.24(m,2H),3.65(s,6H),2.69-2.53(m,8H),2.23-2.15(m,2H),2.01-1.85(m,4H),1.68-1.45(m,8H),0.92-0.87(m,12H).13C NMR(100MHz,CDCl3) Delta 175.43,170.64,138.77,128.34,69.78,51.68,49.06,39.06,35.79,31.01,25.00,24.93,11.83,11.71 HRMS M/z (ESI-TOF) calculation [ M + Na]+557.3085, found 557.3080.IR (ATR) v (cm)-1) HPLC (AD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detection at 214 nm) retention time 19.58min (secondary) and 24.31min (primary).
Compound I' -44:
the reaction was carried out according to general procedure 5, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (252.1mg, 89% yield, 98% ee. (2S, 2' S)/meso ═ 87/13.[ α ]]D 25.7＝-16.94(c 0.63,CHCl3).1H NMR(400MHz,CDCl3)δ6.77(s,4H),5.47-5.40(m,2H),3.95(t,J＝5.6Hz,4H),3.65(s,6H),2.70(d,J＝6.4Hz,4H),2.20-2.09(m,6H),1.65-1.43(m,8H),0.87-0.81(m,12H).13C NMR(100MHz,CDCl3) Delta 175.36,170.60,152.73,115.21,67.89,64.36,51.72,48.98,39.12,33.48,24.99,24.93,11.73,11.66 HRMS M/z (ESI-TOF) calculation of [ M + Na: (M + Na)]+589.2983, measured 589.2984.IR (ATR) v (cm)-1) HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 95/5, flow rate 0.7mL/min, detection at 214 nm) retention time 38.86min (major) and 46.84min (minor).
Compound I' -45:
the reaction was carried out according to general procedure 4, column chromatography (petroleum ether: ethyl acetate: 10:1) to give the product as an oily liquid. (2.72g, 93% yield, 96% ee (ee value measured after conversion to I' -11 according to general procedure 2)) - [ alpha ] - []D 26.1＝4.62(c 1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.31-7.27(m,2H),7.22-7.17(m,3H),5.34-5.27(m,1H),2.75-2.60(m,4H),2.26-2.18(m,1H),2.06-1.93(m,2H),1.71-1.47(m,4H),0.92(t,J＝7.2Hz,3H),0.91(t,J＝7.2Hz,3H).13CNMR(100MHz,CDCl3)176.45,175.58,140.97,128.46,128.23,126.06,69.51,49.07,38.86,35.68,31.46,24.99,24.97,11.83,11.69 HRMS M/z (ESI-TOF) calculation [ M + Na]+315.1567, found 315.1573.IR (neat, cm)-1) 2964,2934,2876,1731,1708,1455,1385,1267,1226,1172,1144,1113,1082,1030,939,746,698 Compound I' -46 is obtained by transformation:
LiAlH under nitrogen protection4(38mg,1.0mmol,5equiv.) was dissolved in a dry tetrahydrofuran (2mL) solution, and a solution of I' -45(0.2mmol,1equiv.) in tetrahydrofuran (1mL) was added dropwise at 0 deg.CAfter completion, the reaction mixture was left at room temperature for 3 hours. After the reaction, aqueous NaOH (2mL,2.5M) was added, extracted with ethyl acetate, dried and concentrated, and used in the next reaction without further purification. The crude product obtained above was dissolved in dichloromethane (1mL) and PPh was added at 0 deg.C3(52.4mg,0.2mmol,1equiv.) and NBS (35.6mg,0.2mmol,1 equiv.). After 24 hours at room temperature, the reaction mixture was concentrated and separated by column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain the product I' -46 as a white solid.
Compound I' -46:
(35.6mg, 74% yield, 97% ee) [ α ]]D 26.1＝5.16(c 0.41,CHCl3).(m.p.48–49℃).1H NMR(400MHz,CDCl3)δ7.32-7.28(m,2H),7.22-7.18(m,3H),3.88-3.84(m,1H),3.60-3.50(m,2H),2.85-2.66(m,2H),2.08-1.94(m,2H),1.84-1.78(m,2H),1.60(brs,1H).13C NMR(100MHz,CDCl3) Delta 141.60,128.49,128.34,125.98,69.41,39.92,39.03,31.96,30.37 HRMS M/z (EI-TOF) calculation [ M-H2O]+224.0195, the actual measurement is 224.0195.IR (ATR) v (cm)-1) 3338,2942,2910,2859,1492,1262,1148,1027,896,748,699,607,570,474 HPLC (OD-H,0.46 × 25cm,5 μm, n-hexane/isopropanol 90/10, flow rate 0.7mL/min, detected at 214 nm) retention time 13.08min (major) and 14.77min (minor).
Single crystal preparation of Compound derivative of formula I '-45 Compound of formula I' -46
The product with retention time of 13.08min is subjected to single crystal cultivation. The product, which had a retention time of 13.08min, was dissolved in dichloromethane and the solvent was evaporated at room temperature to give colorless crystals.
Detection method X-ray single crystal diffraction
The crystal system of the compound shown as the formula I' -46 belongs to a monoclinic system, P21 space group and the unit cell parameter is
α ═ γ ═ 90 °, β ═ 106.762(3) °; the single crystal parameters are shown in the following table; the X-ray single crystal diffraction thereof is shown in FIG. 1.
The characterization result of the obtained X-ray single crystal diffraction shows that the configuration of the compound I' -45 can be determined to be
Thereby deriving the ligand
In the presence, the configuration of the main product obtained is S type.
From the use of chiral ligands in such reactions in the art, it is known that enantiomers of such ligands
In the presence of the catalyst, a product with the reverse configuration is obtained.
Example 2 Effect of pyridine-oxazoline ligands on the Oxycarbonylation reaction
The following ligand was used in accordance with the procedure of procedure 1 in example 1, and the reaction results are shown below.
EXAMPLE 3 Effect of oxidizing agent on the Oxycarbonylation reaction
The following oxidizing agents were used in the same manner as in procedure 1 of example 1, and the reaction results were as follows.
EXAMPLE 4 Effect of solvent on the Oxycarbonylation reaction
The following solvents were used in accordance with the procedure of example 1, and the reaction results are shown below.
EXAMPLE 5 Effect of temperature on the Oxycarbonylation reaction
EXAMPLE 6 Effect of acid on the Oxycarbonylation reaction
The following acid was used in accordance with the procedure of operation 2 in example 1, and the reaction results are shown below.
Claims (15)
1. A preparation method of a carboxylic ester compound is characterized by comprising the following steps: in a solvent, carrying out addition reaction on a compound containing a segment II, a compound containing a segment III and carbon monoxide (CO) in the presence of a palladium catalyst, an oxazoline ligand and an oxidant to obtain a compound containing a segment I-1 and/or a compound containing a segment I-2;
wherein, theFragment II of
The fragment III is
The fragment I-1 is
Wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
the fragment I-2 is
Wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand is
Wherein R is5And R6Independently of each other is hydrogen, R5-1Substituted or unsubstituted C1-C10Alkyl radical, R5-2Substituted or unsubstituted C3-C8Cycloalkyl, or R5-3Substituted or unsubstituted C6-C30An aryl group;
R7is hydrogen, R7-1Substituted or unsubstituted C1-C10Alkyl, or R7-2Substituted or unsubstituted C6-C30An aryl group;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
wherein the carbon marked with x is an S-configuration chiral carbon;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
in (b), the carbon marked with x is an R configuration chiral carbon.
2. The method for producing carboxylic ester compounds according to claim 1, wherein the solvent is one or more of an alkane solvent, a substituted aromatic solvent, a nitrile solvent, a halogenated hydrocarbon solvent, an ether solvent, a ketone solvent, an ester solvent and an amide solvent; the alkane solvent is preferably n-hexane; the substituted aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, toluene and trifluoromethyl benzene. The nitrile solvent is preferably acetonitrile; the halogenated hydrocarbon solvent is preferably dichloromethane and chloroform; the ether solvent is preferably one or more of tetrahydrofuran, diethyl ether, methyl tertiary butyl ether, ethyl tertiary butyl ether, anisole, ethylene glycol dimethyl ether and1, 4-dioxane; the ketone solvent is preferably acetone. The ester solvent is preferably ethyl acetate and/or ethylene glycol diacetate; the amide solvent is preferably N, N-dimethylformamide; preferably, the solvent is an ether solvent and/or a halogenated hydrocarbon solvent; further, the solvent is diethyl ether and/or dichloromethane;
and/or the concentration of the compound containing the section II in the solvent is 0.01-5.00 mol/L (such as 0.625 or 2.00mol/L), preferably 0.01-0.20 mol/L;
and/or the palladium catalyst is one or more of palladium acetate, palladium trifluoroacetate, palladium pentanate, dichlorodiacetonitrile palladium, bis (benzonitrile) palladium chloride, palladium bromide, palladium iodide, tetranitrile palladium tetrafluoroborate, palladium hexafluoroacetylacetonate, bis (acetylacetonato) palladium, tetranitrile palladium trifluoromethanesulfonate, palladium pivalate, (1E,4E) -bis (dibenzylidene acetone) palladium, bis (dibenzylidene acetone) dipalladium, and tris (dibenzylidene acetone) dipalladium; preferably, the palladium catalyst is palladium acetate;
and/or the molar ratio of the palladium catalyst to the compound containing the section II is (1-50): 100, respectively; preferably (1-10): 100, respectively; for example, 5:100 or 10: 100;
and/or the molar ratio of the oxazoline ligand to the compound containing the tablet section II is (1-75): 100, e.g. 7.5: 100 or 15: 100;
and/or the molar ratio of the palladium catalyst to the oxazoline ligand is 1: (0.5 to 3), for example 1: 1.5;
and/or the oxidant is benzoquinone and/or PhI (OAc)2；
And/or the molar ratio of the oxidant to the compound containing segment II is (1.0-5.0): 1, preferably (1.0-3.0): 1, for example 1.2: 1. or 3: 1;
and/or the molar ratio of the compound containing the section III to the compound containing the section II is (1.0-100): 1, preferably (2.5-10): 1, such as 5:1 or 10: 1;
and/or the temperature of the addition reaction is-20-30 ℃, and preferably 0-20 ℃;
and/or the time of the addition reaction is 1-168 hours, preferably 10-72 hours, such as 16 hours, 24 hours, 36 hours, 48 hours or 72 hours;
and/or, the addition reaction further comprises the following post-treatment steps: adding a solvent into the reaction solution, concentrating and purifying to obtain the product; in the post-treatment step, the solvent is preferably an alcohol solvent (e.g., methanol), or a ketone solvent (e.g., acetone) and water.
And/or, R5-1、R5-2、R5-3、R7-1And R7-2Independently 1 or more, and when plural, the same or different, said plural is 2,3 or 4;
and/or when R5And R6Independently is unsubstituted C1-C10When alkyl, said C1-C10Alkyl is C1-C4Alkyl groups such as methyl or ethyl;
and/or when R5And R6Independently is unsubstituted C3-C8When there is a cycloalkyl group, said C3-C8Cycloalkyl being C3-C6Monocyclic cycloalkyl, such as cyclopentyl or cyclohexyl;
and/or when R5And R6Independently is unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl groups such as phenyl;
and/or when R7Is unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl radicals, for example phenyl.
3. The process for producing carboxylic ester compounds as claimed in claim 1, wherein,
and/or, R5And R6Independently hydrogen, unsubstituted C1-C10Alkyl, unsubstituted C3-C8Cycloalkyl, or unsubstituted C6-C30An aryl group; preferably, R5And R6Independently hydrogen, methyl, ethyl, cyclopentyl, cyclohexyl or phenyl;
and/or, R7Is unsubstituted C6-C30An aryl group; preferably, R7Is phenyl;
and/or, R5And R6Is the same as, or, R5And R6Different, and one is H.
4. The method for producing carboxylic ester compounds according to claim 1, wherein the oxazoline ligand is any one of the following compounds,
5. the process for producing the carboxylic ester compound according to claim 1, wherein the process for producing the carboxylic ester compound is the following process one or process two;
the method comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-A, a compound shown as a formula III' and carbon monoxide to obtain a compound shown as a formula I-1-A and/or a compound shown as a formula I-2-A;
the second method comprises the following steps: in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-B, a compound shown as a formula III' and carbon monoxide (CO) to obtain a compound shown as a formula I-1-B and/or a compound shown as a formula I-2-B;
in the first and second processes, the operation and conditions of the addition reaction are as defined in any one of claims 1 to 4;
wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
R1is hydrogen, or R1-1Substituted or unsubstituted C1-C30An alkyl group;
R1-1is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, R1-1aSubstituted or unsubstituted C6-C30Aryl, 5-15 membered heteroaryl with one or more heteroatoms selected from N, O and S and 1-4 heteroatoms, and C2-C10Alkenyl, -O (CH)2)nR1-1b、-S(＝O)2R1-1c、-OC(＝O)R1-1d、-C(＝O)OR1-1e、
-C(＝O)R1-1hOr
n is an integer of 0 to 10;
R1-1ais halogen, C1-C10Alkyl radical, C1-C10Alkoxy, cyano, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group;
R1-1bis R1-1b-1Substituted or unsubstituted C6-C30An aryl group, a 5-to 15-membered heteroaryl group having one or more heteroatoms selected from N, O and S and1 to 4 heteroatoms,
R1-1b-1Is nitro, aldehyde, halogen, C1-C10Alkyl radical, C2-C10Alkenyl, -S (═ O)2R1-1b-1a、
-C(＝O)OR1-1b-1for-C (═ O) R1-1b-1g；
R1-1b-1a、R1-1b-1b、R1-1b-1c、R1-1b-1dAnd R1-1b-1eIndependently is C1-C10An alkyl group;
R1-1b-1fand R1-1b-1gIndependently is C2-C10Alkenyl, or substituted by one or more C1-C105-15 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S as alkyl substituted or unsubstituted "heteroatoms;
R1-1c、R1-1fand R1-1gIndependently of one another is hydrogen, C6-C30Aryl or p-toluenesulfonyl;
R1-1dis R1-1d-1Substituted or unsubstituted C1-10Alkyl radical, R1-1d-2Substituted or unsubstituted C2-10Alkenyl radical, R1-1d-3Substituted or unsubstituted C2-10Alkynyl, R1-1d-4Substituted or unsubstituted C6-30Aryl radical, R1-1d-5A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R1-1d-1is-OR1-1d-1aOr
R1-1d-1aIs R1-1d-1a-1Substituted or unsubstituted C6-C30An aryl group; r1 -1d-1a-1Is C substituted by one or more halogens3-C15A cycloalkyl group;
R1-1d-2and R1-1d-3Independently is C6-C30An aryl group;
R1-1d-4is-C (═ O) OR1-1d-4a；R1-1d-4aIs C2-C10Alkenyl, or substituted by one or more-OC (═ O) R1-1d-4a-1Substituted C1-C10An alkyl group; r1-1d-4a-1Is C1-C10An alkyl group;
R1-1d-5is p-toluenesulfonyl;
R1-1eis hydrogen, C1-C10Alkyl or
R1-1hIs C2-C10Alkenyl, or substituted by one or more-OC (═ O) R1-1h-1Substituted C1-C10An alkyl group; r1-1h-1Is C1-C10An alkyl group;
R2is hydrogen, R2-1SubstitutionOr unsubstituted C1-C30Alkyl radical, R2-2Substituted or unsubstituted C6-C30Aryl, or C2-C10An alkenyl group;
R2-1is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, R2-1aSubstituted or unsubstituted C6-C30Aryl, 5-15 membered heteroaryl with one or more heteroatoms selected from N, O and S and 1-4 heteroatoms, and C2-C10Alkenyl, -O (CH)2)nR2-1b、-S(＝O)2R2-1c、-OC(＝O)R2-1d、-C(＝O)OR2-1e、
-C(＝O)R2-1hOr
R2-2Is halogen, C1-C10Alkyl radical, C1-C10Alkoxy, cyano, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group;
R2-1ais halogen, C1-C10Alkyl radical, C1-C10Alkoxy, cyano, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group;
R2-1bis R2-1b-1Substituted or unsubstituted C6-C30An aryl group, a 5-to 15-membered heteroaryl group having one or more heteroatoms selected from N, O and S and1 to 4 heteroatoms,
R2-1b-1Is nitro, aldehyde, halogen, C1-C10Alkyl radical, C2-C10Alkenyl, -S (═ O)2R2-1b-1a、
-C(＝O)OR2-1b-1for-C (═ O) R2-1b-1g；
R2-1b-1a、R2-1b-1b、R2-1b-1c、R2-1b-1dAnd R2-1b-1eIndependently is C1-C10An alkyl group;
R2-1b-1fand R2-1b-1gIndependently is C2-C10Alkenyl, or C1-C105-15 membered heteroaryl with 1-4 heteroatoms selected from one or more of N, O and S as alkyl substituted or unsubstituted "heteroatoms;
R2-1c、R2-1fand R2-1gIndependently of one another is hydrogen, C6-C30Aryl or p-toluenesulfonyl;
R2-1dis R2-1d-1Substituted or unsubstituted C1-10Alkyl radical, R2-1d-2Substituted or unsubstituted C2-10Alkenyl radical, R2-1d-3Substituted or unsubstituted C2-10Alkynyl, R2-1d-4Substituted or unsubstituted C6-30Aryl radical, R2-1d-5A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
R2-1d-1is-OR2-1d-1aOr
R2-1d-1aIs R2-1d-1a-1Substituted or unsubstituted C6-C30An aryl group; r2 -1d-1a-1Is C substituted by one or more halogens3-C15A cycloalkyl group;
R2-1d-2and R2-1d-3Independently is C6-C30An aryl group;
R2-1d-4is-C (═ O) OR2-1d-4a；R2-1d-4aIs C2-C10An alkenyl group;
R2-1d-5is p-toluenesulfonyl;
R2-1eis hydrogen or C1-C10An alkyl group;
R2-1his C2-C10An alkenyl group;
R8is C1-C10Alkylene, or a mixture thereof,
Or- (CH)2)m3-O(C＝O)-(C6-C10Arylene) - (C ═ O) O- (CH)2)m4-；
m1, m2, m3 and m4 are independently 0,1, 2,3, 4,5 or 6.
6. The process for producing carboxylic ester compounds as claimed in claim 5, wherein R is1-1、R1-1a、R1-1b-1、R1 -1d-1、R1-1d-2、R1-1d-3、R1-1d-4、R1-1d-5、R1-1d-1a-1、R8-1And R8-1a-1Independently 1 or more, when plural, the same or different, and when plural, the plural is preferably 2,3 or 4;
and/or when R1Is R1-1Substituted or unsubstituted C1-C30When alkyl, said C1-C30Alkyl is C1-C10Alkyl, preferably C1-C8Alkyl radicals, such as methyl,
And/or said halogen is fluorine, chlorine, bromine or iodine, preferably chlorine or bromine;
and/or when R1-1Is C3-C15In the case of a cycloalkyl group of (A), said C3-C15Cycloalkyl of (A) is monocyclic C3-C15Cycloalkyl of (C), a condensed ring C3-C15Cycloalkyl, spiro C3-C15Cycloalkyl or bridged ring C of3-C15Cycloalkyl of (a), preferably monocyclic C3-C15Cycloalkyl groups of (a); the monocyclic ring C3-C15Cycloalkyl of (C) is preferably C3-C6Cycloalkyl groups of (a), such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, more preferably cyclohexyl;
and/or when R1-1Is R1-1aSubstituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl or naphthyl;
and/or when R1-1Is C2-C10When alkenyl, said C2-C10Alkenyl is C2-C6Alkenyl radicals, e.g.
And/or when R1-1aWhen halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or iodine;
and/or when R1-1aIs C1-C10When alkyl, said C1-C10Alkyl is C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl;
and/or when R1-1aIs C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl;
and/or when R1-1bIs R1-1b-1Substituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl or naphthyl;
and/or when R1-1bWhen the aryl group is a 5-15 membered heteroaryl group having "one or more heteroatoms selected from N, O and S and 1-4 heteroatoms", the "one or more heteroatoms selected from N, O and S", and the 5-15 membered heteroaryl group having 1-4 heteroatoms "is a 5-15 membered monocyclic heteroaryl group or a 5-15 membered bicyclic heteroaryl group having" one or more heteroatoms selected from N, O and S, and 1-4 heteroatoms ", preferably the" one or more heteroatoms selected from N, O and S, and the 5-15 membered monocyclic heteroaryl group having 1-4 heteroatoms ", respectively; the 5-to 15-membered monocyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably a 5-to 6-membered monocyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a thienyl group
And/or n is 0,1, 2,3, 4,5 or 6, preferably n is 0 or 1;
and/or when R1-1b-1Is C1-C10When alkyl, said C1-C10Alkyl is C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably tert-butyl;
and/or when R1-1b-1Is C2-C10When alkenyl, said alkenyl is C2-C4Alkenyl radicals, e.g.
And/or when R1-1b-1a、R1-1b-1b、R1-1b-1c、R1-1b-1dAnd R1-1b-1eIndependently is C1-C10When alkyl, said C1-C10Alkyl is independently C1-C6An alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl;
and/or when R1-1b-1fIs C2-C10When alkenyl, said C2-C10Alkenyl is
Or
And/or when R1-1b-1gIs formed by one or more C1-C10C when the alkyl substituted or unsubstituted "hetero atom is one or more selected from N, O and S, and the number of hetero atoms is 1-4", and the hetero atom number is 5-15 membered heteroaryl1-C10The number of alkyl groups is 1,2 or 3;
and/or when R1-1b-1gIs C1-C10When alkyl is substituted or unsubstituted, the heteroatom is selected from one or more of N, O and S, 5-15 membered heteroaryl with 1-4 heteroatoms, the heteroatom is selected from one or more of N, O and S, 5-15 membered heteroaryl with 1-4 heteroatoms is selected from one or more of N, O and S, 5-15 membered monocyclic heteroaryl with 1-4 heteroatoms or 5-15 membered bicyclic heteroaryl, preferably the heteroatom is selected from one or more of N, O and S, 5-15 membered bicyclic heteroaryl with 1-4 heteroatoms; the 5-to 15-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably an 8-to 10-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a benzofuranyl group
And/or when R1-1b-1gIs formed by one or more C1-C10The alkyl group being substituted or unsubstituted by "hetero atoms" or "hetero atoms" selected fromC when the 5-to 15-membered heteroaryl group has 1 to 4 hetero atoms from one or more of N, O and S1-C10Alkyl is C1-C6An alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably ethyl;
and/or when R1-1c、R1-1fAnd R1-1gIndependently is C6-C30When aryl, said C6-C30Aryl is independently C6-C10Aryl, preferably phenyl;
and/or when R1-1dIs R1-1d-1Substituted or unsubstituted C1-10When alkyl, said C1-10Alkyl is C1-C6An alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or isopropyl;
and/or when R1-1dIs R1-1d-2Substituted or unsubstituted C2-10When alkenyl, said C2-10Alkenyl is C2-4Alkenyl radicals, e.g.
And/or when R1-1dIs R1-1d-3Substituted or unsubstituted C2-10When it is alkynyl, said C2-10Alkynyl is C2-4Alkynyl radicals, e.g.
And/or when R1-1dIs R1-1d-4Substituted or unsubstituted C6-30When aryl, said C6-30Aryl is C6-10Aryl, preferably phenyl;
and/or when R1-1dIs R1-1d-5A substituted or unsubstituted 5-15 membered heteroaryl group having 1 to 4 heteroatoms selected from one or more of N, O and S, and1 to 4 "heteroatoms selected from one or more of N, O and S, and a 5-15 membered heteroaryl group having 1 to 4" heteroatoms selected from one or more of N, O and S, and a 5-15 membered monocyclic heteroaryl group or a 5-15 membered bicyclic heteroaryl group having 1 to 4 "heteroatoms selected from; the 5-to 15-membered monocyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably a 5-to 6-membered monocyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a furyl group
The 5-to 15-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 to 4" is preferably an 8-to 10-membered bicyclic heteroaryl group having "one or more hetero atoms selected from N, O and S and a hetero atom number of 1 or 2", for example, a benzofuranyl group
Benzothienyl
Or indolyl
And/or when R1-1d-1aIs R1-1d-1a-1Substituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl;
and/or when R1-1d-1a-1Is C substituted by one or more halogens3-C15In the case of cycloalkyl, the number of said halogen is 1,2 or 3;
and/or the presence of a gas in the gas,when R is1-1d-1a-1Is C substituted by one or more halogens3-C15When cycloalkyl is used, the halogen is fluorine, chlorine, bromine or iodine, preferably chlorine;
and/or when R1-1d-1a-1Is C substituted by one or more halogens3-C15When there is a cycloalkyl group, said C3-C15Cycloalkyl being C3-C15Monocyclic cycloalkyl, C3-C15Cycloalkyl having condensed rings, C3-C15Spirocyclic cycloalkyl or C3-C15Bridged cycloalkyl, preferably C3-C15A monocyclic cycloalkyl group; said C3-C15Monocyclic cycloalkyl is preferably C3-C6Monocyclic cycloalkyl groups such as cyclopropyl;
and/or when R1-1d-2And R1-1d-3Independently is C6-C30When aryl, said C6-C30Aryl is independently C6-C10Aryl, preferably phenyl;
and/or when R1-1d-4aIs C2-C10When alkenyl, said C2-C10Alkenyl is C2-C4Alkenyl radicals, e.g.
And/or when R1-1eIs C1-C10When alkyl, said C1-C10Alkyl is C1-C6An alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or ethyl;
and/or when R1-1hIs C2-C10When alkenyl, said C2-C10Alkenyl is C2-C6Alkenyl radicals, e.g.
And/or, R2-1、R2-2、R2-1a、R2-1b-1、R2-1d-1、R2-1d-2、R2-1d-3、R2-1d-4、R2-1d-5And R2-1d-1a-1Independently 1 or more, when plural, the same or different, and when plural, the plural is preferably 2,3 or 4;
and/or when R2Is R2-1Substituted or unsubstituted C1-C30When alkyl, said C1-C30Alkyl is C1-C10Alkyl, preferably C1-C6Alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and also such as methyl;
and/or when R2Is R2-2Substituted or unsubstituted C6-C30When aryl, said C6-C30Aryl is C6-C10Aryl, preferably phenyl or naphthyl;
and/or when R2Is C2-C10When alkenyl, said C2-C10Alkenyl is C2-C4Alkenyl groups such as vinyl;
and/or when R2-2When halogen, said halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine;
and/or when R2-2Is C1-C10When alkyl, said C1-C10Alkyl is C1-C6An alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group;
and/or when R2-2Is C1-C10At alkoxy, said C1-C10Alkoxy is C1-C4Alkoxy groups such as methoxy;
and/or when R2-2Is C6-C30When aryl, said C6-C30Aryl is C6-C10An aryl group, a heteroaryl group,preferably phenyl;
and/or when R2-2Is C substituted by one or more halogens1-C10In the case of alkyl, the number of the halogen is 1,2 or 3;
and/or when R2-2Is C substituted by one or more halogens1-C10When alkyl, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine;
and/or when R2-2Is C substituted by one or more halogens1-C10When alkyl, said C1-C10Alkyl is C1-C6An alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl;
and/or when R8Is R8-1Substituted or unsubstituted C1-C10When it is alkylene, R8-1The number of (a) is 1,2 or 3;
and/or when R8Is R8-1Substituted or unsubstituted C1-C10When it is alkylene, said C1-C10Alkylene being C1-C6Alkylene groups such as methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, sec-butylene or tert-butylene, and also such as methylene or ethylene;
and/or when R8Is- (CH)2)m3-O(C＝O)-(C6-C10Arylene) - (C ═ O) O- (CH)2)m4When is C therein6-C10Arylene is preferably phenylene (e.g. phenylene)
And/or m1, m2, m3 and m4 are independently 1,2 or 3.
7. The process for producing carboxylic ester compounds as claimed in claim 5, wherein when R is1-1Is R1-1aSubstituted or unsubstituted C6-C30When aryl is present, R1-1The structure of the composite material is any one of the following structures,
and/or when R1-1is-O (CH)2)nR1-1bWhen R is1-1The structure of the composite material is any one of the following structures,
and/or when R1-1is-OC (═ O) R1-1dWhen R is1-1The structure of the composite material is any one of the following structures,
and/or when R1-1is-C (═ O) OR1-1eWhen R is1-1The structure of the composite material is any one of the following structures,
8. the process for producing carboxylic ester compounds as claimed in claim 5, wherein R is1Is R1-1Substituted or unsubstituted C1-C30An alkyl group;
and/or, R1-1Is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, R1-1aSubstituted or unsubstituted C6-C30Aryl radical, C2-C10Alkenyl, -O (CH)2)nR1-1b、-S(＝O)2R1-1c、-OC(＝O)R1-1d、-C(＝O)OR1-1e、
-C(＝O)R1-1hOr
Preferably, R1-1Is cyano, hydroxy, nitro, halogen, C3-C15Cycloalkyl of, C2-C10Alkenyl, -O (CH)2)nR1-1b、-S(＝O)2R1-1c、-OC(＝O)R1-1d、-C(＝O)OR1-1e、
-C(＝O)R1-1hOr
And/or, R1-1aIs halogen, C1-C10Alkyl or C6-C30An aryl group;
and/or, R1-1dIs R1-1d-1Substituted or unsubstituted C1-10Alkyl radical, R1-1d-2Substituted or unsubstituted C2-10Alkenyl radical, R1-1d-3Substituted or unsubstituted C2-10Alkynyl, unsubstituted C6-30Aryl radical, R1-1d-5A 5-15 membered heteroaryl group having 1-4 heteroatoms selected from one or more of N, O and S as a substituted or unsubstituted "heteroatom;
and/or, R1-1hIs C2-C10An alkenyl group;
and/or, R2Is hydrogen, unsubstituted C1-C30Alkyl, or R2-2Substituted or unsubstituted C6-C30An aryl group;
and/or, R2-2Is halogen, C1-C10Alkyl radical, C1-C10Alkoxy radical, C6-C30Aryl or C substituted by one or more halogens1-C10An alkyl group.
9. As claimed in claim 5The preparation method of the carboxylic ester compound is characterized in that R1-1The structure of the composite material is any one of the following structures,
10. the method for preparing carboxylic ester compounds as claimed in claim 5, wherein the compound represented by formula II-A is selected from any one of the following compounds:
the compound shown in the formula II-B is selected from any one of the following compounds:
the compound shown in the formula III' is selected from any one of the following compounds:
the compound shown in the formula I-2-A is as follows:
11. a preparation method of chiral beta-acyloxy carboxylic ester compounds is characterized by comprising the following steps:
(1) in a solvent, carrying out addition reaction on a compound containing a segment II, a compound containing a segment III and carbon monoxide in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) in a solvent, performing methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound containing a fragment I;
wherein the fragment II is
The fragment III is
The fragment I is
Wherein, the carbon marked by the symbol indicates S configuration chiral carbon or R configuration chiral carbon;
the oxazoline ligand is
Wherein R is5、R6And R7As defined in any one of claims 1 to 10;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
wherein the carbon marked with x is an S-configuration chiral carbon;
when the oxazoline ligand is
When the temperature of the water is higher than the set temperature,
wherein the carbon marked with x is an R configuration chiral carbon;
the reaction operation and conditions of step (1) are as defined in any one of claims 1 to 4.
12. The method for preparing chiral β -acyloxycarboxylic acid ester compounds according to claim 11, wherein in the step (2), the solvent is an alcohol solvent and/or a substituted aromatic hydrocarbon solvent; the alcohol solvent is preferably methanol and/or ethanol; the substituted aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, toluene and trifluoromethyl benzene; preferably, the solvent is a mixed solvent of methanol and/or toluene;
and/or, in the step (2), the methylating agent is TMSCHN2；
And/or, in the step (2), the molar ratio of the methylating agent to the compound containing the section II in the step (1) is (2-10): 1, e.g., 4: 1;
and/or the temperature of the methylation reaction is 20-30 ℃;
and/or the methylation reaction time is 1-10 hours, preferably 2-6 hours, such as 4 hours or 6 hours;
and/or, the step (1) further comprises the following post-treatment steps: adding a solvent into the reaction solution, and concentrating to perform the next reaction; in the post-treatment step of step (1), the solvent is preferably an alcohol solvent (e.g., methanol).
13. The method for preparing chiral β -acyloxycarboxylic acid ester compounds according to claim 11, wherein the method for preparing carboxylic acid ester compounds is the following method a or method B:
the method A comprises the following steps:
(1) in a solvent, in the presence of a palladium catalyst, an oxazoline ligand and an oxidant, carrying out addition reaction on a compound shown as a formula II-A, a compound shown as a formula III' and carbon monoxide;
(2) in a solvent, performing methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -A;
the method B comprises the following steps:
(1) in a solvent, carrying out addition reaction on a compound shown as a formula II-B, a compound shown as a formula III' and carbon monoxide in the presence of a palladium catalyst, an oxazoline ligand and an oxidant;
(2) in a solvent, performing methylation reaction on the product of the addition reaction and a methylation reagent to obtain a beta-acyloxy carboxylic ester compound shown as a formula I' -B;
process A or Process B, wherein the addition reaction is carried out and the conditions are as defined in any one of claims 1 to 4;
*、R1、R2and R8Is as defined in any one of 1 to 10.
14. The method for preparing chiral β -acyloxycarboxylic acid ester compounds according to claim 13, wherein the compound represented by the formula I' -a is selected from any one of the following compounds:
the compound shown in the formula I' -B is selected from any one of the following compounds:
15. a compound of the formula,
the unit cell parameters are as follows: monoclinic system, P21 space group, cell parameter of
α＝γ＝90°，β＝106.762(3)°。
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