CN113912524A - Polypeptide compound containing sulfamide and synthesis method thereof - Google Patents
Polypeptide compound containing sulfamide and synthesis method thereof Download PDFInfo
- Publication number
- CN113912524A CN113912524A CN202111254112.6A CN202111254112A CN113912524A CN 113912524 A CN113912524 A CN 113912524A CN 202111254112 A CN202111254112 A CN 202111254112A CN 113912524 A CN113912524 A CN 113912524A
- Authority
- CN
- China
- Prior art keywords
- glycine
- derivatives
- mmol
- ester hydrochloride
- methyl ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 52
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 27
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 27
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 27
- 238000001308 synthesis method Methods 0.000 title claims abstract description 8
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 title claims abstract 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 42
- 239000002904 solvent Substances 0.000 claims abstract description 42
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 42
- -1 amino aldehyde Chemical class 0.000 claims abstract description 32
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 16
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 16
- 239000011593 sulfur Substances 0.000 claims abstract description 16
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000000654 additive Substances 0.000 claims abstract description 9
- 150000001413 amino acids Chemical class 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 230000009471 action Effects 0.000 claims abstract description 6
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 76
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 68
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 37
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 37
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 claims description 9
- 235000001014 amino acid Nutrition 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 239000010949 copper Substances 0.000 claims description 7
- 229910052802 copper Inorganic materials 0.000 claims description 7
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 claims description 7
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 claims description 7
- DQSIXGDDUJJEQH-QRPNPIFTSA-N 2-aminoacetic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical class NCC(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 DQSIXGDDUJJEQH-QRPNPIFTSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 6
- MEVUPUNLVKELNV-JEDNCBNOSA-N methyl (2s)-2-amino-4-methylsulfanylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCSC MEVUPUNLVKELNV-JEDNCBNOSA-N 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- FCWAUFMDOCOONS-QRPNPIFTSA-N 2-aminoacetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid Chemical class NCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FCWAUFMDOCOONS-QRPNPIFTSA-N 0.000 claims description 4
- ZVEUWSJUXREOBK-DKWTVANSSA-N 2-aminoacetic acid;(2s)-2-amino-3-hydroxypropanoic acid Chemical class NCC(O)=O.OC[C@H](N)C(O)=O ZVEUWSJUXREOBK-DKWTVANSSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- DPLVEEXVKBWGHE-UHFFFAOYSA-N potassium sulfide Chemical compound [S-2].[K+].[K+] DPLVEEXVKBWGHE-UHFFFAOYSA-N 0.000 claims description 4
- 229940048181 sodium sulfide nonahydrate Drugs 0.000 claims description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 4
- WMDLZMCDBSJMTM-UHFFFAOYSA-M sodium;sulfanide;nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[SH-] WMDLZMCDBSJMTM-UHFFFAOYSA-M 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- HVBRJSWZFSWZKB-FVGYRXGTSA-N 2-aminoacetic acid;(2s)-2-amino-3-(1h-indol-3-yl)propanoic acid Chemical class NCC(O)=O.C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 HVBRJSWZFSWZKB-FVGYRXGTSA-N 0.000 claims description 3
- VLQHNAMRWPQWNK-UHFFFAOYSA-N benzyl 2-aminoacetate;hydron;chloride Chemical compound Cl.NCC(=O)OCC1=CC=CC=C1 VLQHNAMRWPQWNK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- XNFNGGQRDXFYMM-PPHPATTJSA-N methyl (2s)-2-amino-3-(1h-indol-3-yl)propanoate;hydrochloride Chemical compound Cl.C1=CC=C2C(C[C@H](N)C(=O)OC)=CNC2=C1 XNFNGGQRDXFYMM-PPHPATTJSA-N 0.000 claims description 3
- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 claims description 3
- KUGLDBMQKZTXPW-JEDNCBNOSA-N methyl (2s)-2-amino-3-methylbutanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)C(C)C KUGLDBMQKZTXPW-JEDNCBNOSA-N 0.000 claims description 3
- SWVMLNPDTIFDDY-FVGYRXGTSA-N methyl (2s)-2-amino-3-phenylpropanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CC1=CC=CC=C1 SWVMLNPDTIFDDY-FVGYRXGTSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 claims description 2
- NYOGGQBMEGUVIX-WCCKRBBISA-N 2-aminoacetic acid;(2s)-2-amino-3-methylbutanoic acid Chemical class NCC(O)=O.CC(C)[C@H](N)C(O)=O NYOGGQBMEGUVIX-WCCKRBBISA-N 0.000 claims description 2
- FSSVRLXFJPQUTM-WCCKRBBISA-N 2-aminoacetic acid;(2s)-2-amino-4-methylsulfanylbutanoic acid Chemical class NCC(O)=O.CSCC[C@H](N)C(O)=O FSSVRLXFJPQUTM-WCCKRBBISA-N 0.000 claims description 2
- ZEEYNQNRMIBLMK-DFWYDOINSA-N 2-aminoacetic acid;(2s)-2-aminopentanedioic acid Chemical class NCC(O)=O.OC(=O)[C@@H](N)CCC(O)=O ZEEYNQNRMIBLMK-DFWYDOINSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical compound [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000005751 Copper oxide Substances 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- 229910021594 Copper(II) fluoride Inorganic materials 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- MFUPLHQOVIUESQ-JEDNCBNOSA-N [(2s)-1,5-dimethoxy-1,5-dioxopentan-2-yl]azanium;chloride Chemical compound Cl.COC(=O)CC[C@H](N)C(=O)OC MFUPLHQOVIUESQ-JEDNCBNOSA-N 0.000 claims description 2
- 229910000431 copper oxide Inorganic materials 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- GWFAVIIMQDUCRA-UHFFFAOYSA-L copper(ii) fluoride Chemical compound [F-].[F-].[Cu+2] GWFAVIIMQDUCRA-UHFFFAOYSA-L 0.000 claims description 2
- JIDMEYQIXXJQCC-UHFFFAOYSA-L copper;2,2,2-trifluoroacetate Chemical compound [Cu+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F JIDMEYQIXXJQCC-UHFFFAOYSA-L 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- NHSCRWJPZDNMBU-UHFFFAOYSA-L dipotassium carbonic acid carbonate Chemical compound [K+].[K+].OC([O-])=O.OC([O-])=O NHSCRWJPZDNMBU-UHFFFAOYSA-L 0.000 claims description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 claims description 2
- NANRHOPPXCBHGI-FVGYRXGTSA-N methyl (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoate;hydrochloride Chemical compound Cl.COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C NANRHOPPXCBHGI-FVGYRXGTSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- HYHCSLBZRBJJCH-UHFFFAOYSA-M sodium hydrosulfide Chemical compound [Na+].[SH-] HYHCSLBZRBJJCH-UHFFFAOYSA-M 0.000 claims description 2
- 235000010265 sodium sulphite Nutrition 0.000 claims description 2
- OSWULUXZFOQIRU-UHFFFAOYSA-N tert-butyl 2-aminoacetate;hydrochloride Chemical compound Cl.CC(C)(C)OC(=O)CN OSWULUXZFOQIRU-UHFFFAOYSA-N 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 9
- BKKWZCSSYWYNDS-JEDNCBNOSA-N 2-aminoacetic acid;(2s)-2,6-diaminohexanoic acid Chemical class NCC(O)=O.NCCCC[C@H](N)C(O)=O BKKWZCSSYWYNDS-JEDNCBNOSA-N 0.000 claims 5
- IVNJKQPHHPMONX-WCCKRBBISA-N 2-aminoacetic acid;(2s)-2-amino-5-(diaminomethylideneamino)pentanoic acid Chemical class NCC(O)=O.OC(=O)[C@@H](N)CCCNC(N)=N IVNJKQPHHPMONX-WCCKRBBISA-N 0.000 claims 4
- AYORUWNJMKYNAD-JEDNCBNOSA-N 2-aminoacetic acid;(2s)-2-amino-4-methylpentanoic acid Chemical class NCC(O)=O.CC(C)C[C@H](N)C(O)=O AYORUWNJMKYNAD-JEDNCBNOSA-N 0.000 claims 2
- XCDJMQRPMLFIHY-PZMMFNHRSA-N 2-aminoacetic acid;(2s)-2-amino-4-methylpentanoic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical class NCC(O)=O.CC(C)C[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 XCDJMQRPMLFIHY-PZMMFNHRSA-N 0.000 claims 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims 1
- CQBYLZOLQTWVOB-QXGOIDDHSA-N 2-aminoacetic acid;(2s)-2-amino-3-phenylpropanoic acid Chemical class NCC(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](N)CC1=CC=CC=C1 CQBYLZOLQTWVOB-QXGOIDDHSA-N 0.000 claims 1
- WLHCBQAPPJAULW-UHFFFAOYSA-N 4-methylbenzenethiol Chemical compound CC1=CC=C(S)C=C1 WLHCBQAPPJAULW-UHFFFAOYSA-N 0.000 claims 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims 1
- NHFPQEWGDJGKPO-OMSMUOAWSA-N NCC(O)=O.CC(C)[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 Chemical class NCC(O)=O.CC(C)[C@H](N)C(O)=O.OC(=O)[C@@H](N)CC1=CC=CC=C1 NHFPQEWGDJGKPO-OMSMUOAWSA-N 0.000 claims 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims 1
- 235000004279 alanine Nutrition 0.000 claims 1
- BWZOPYPOZJBVLQ-UHFFFAOYSA-K aluminium glycinate Chemical compound O[Al+]O.NCC([O-])=O BWZOPYPOZJBVLQ-UHFFFAOYSA-K 0.000 claims 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 claims 1
- GICLSALZHXCILJ-UHFFFAOYSA-N ctk5a5089 Chemical class NCC(O)=O.NCC(O)=O GICLSALZHXCILJ-UHFFFAOYSA-N 0.000 claims 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims 1
- 238000010189 synthetic method Methods 0.000 claims 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 108010016626 Dipeptides Proteins 0.000 abstract description 4
- 238000010168 coupling process Methods 0.000 abstract description 4
- OTYNBGDFCPCPOU-UHFFFAOYSA-N phosphane sulfane Chemical compound S.P[H] OTYNBGDFCPCPOU-UHFFFAOYSA-N 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 3
- 238000005859 coupling reaction Methods 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 238000009509 drug development Methods 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 64
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 64
- 238000002360 preparation method Methods 0.000 description 39
- 239000011734 sodium Substances 0.000 description 39
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- 238000000926 separation method Methods 0.000 description 35
- 238000001514 detection method Methods 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 5
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 4
- 229940079101 sodium sulfide Drugs 0.000 description 4
- 229910052979 sodium sulfide Inorganic materials 0.000 description 4
- ZGHLCBJZQLNUAZ-UHFFFAOYSA-N sodium sulfide nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.[Na+].[Na+].[S-2] ZGHLCBJZQLNUAZ-UHFFFAOYSA-N 0.000 description 4
- 239000000758 substrate Substances 0.000 description 3
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- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 2
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- YLLRPQWLASQXSI-UHFFFAOYSA-N 3-(4b,8a,9,9a-tetrahydro-4aH-pyrido[2,3-b]indol-4-ylamino)phenol Chemical compound Oc1cccc(NC2=CC=NC3NC4C=CC=CC4C23)c1 YLLRPQWLASQXSI-UHFFFAOYSA-N 0.000 description 2
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- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- YWKVMGDEOUPQGN-UHFFFAOYSA-N ethyl 2-[4-[2-(3-hydroxy-1-azabicyclo[2.2.2]octan-3-yl)ethynyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1C#CC1(O)C(CC2)CCN2C1 YWKVMGDEOUPQGN-UHFFFAOYSA-N 0.000 description 2
- MUTCAPXLKRYEPR-ITWZMISCSA-N methyl (e,3r,5s)-7-[4-bromo-2,3-bis(4-fluorophenyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyhept-6-enoate Chemical compound COC(=O)C[C@H](O)C[C@H](O)\C=C\N1C(C(C)C)=C(Br)C(C=2C=CC(F)=CC=2)=C1C1=CC=C(F)C=C1 MUTCAPXLKRYEPR-ITWZMISCSA-N 0.000 description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 2
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- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- HZQYNBVUODRYSW-UHFFFAOYSA-N 2-(3-phenylpropylamino)acetic acid Chemical class OC(=O)CNCCCC1=CC=CC=C1 HZQYNBVUODRYSW-UHFFFAOYSA-N 0.000 description 1
- BHUGZIJOVAVBOQ-UHFFFAOYSA-N 2-(propylazaniumyl)acetate Chemical class CCCNCC(O)=O BHUGZIJOVAVBOQ-UHFFFAOYSA-N 0.000 description 1
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- FCGJFYBKDDSFSJ-UHFFFAOYSA-N 2-aminoacetic acid methyl 2-aminoacetate hydrochloride Chemical compound Cl.COC(CN)=O.NCC(=O)O FCGJFYBKDDSFSJ-UHFFFAOYSA-N 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
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- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
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- 230000000269 nucleophilic effect Effects 0.000 description 1
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- 230000007017 scission Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C327/44—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C325/00—Thioaldehydes; Thioketones; Thioquinones; Oxides thereof
- C07C325/02—Thioketones; Oxides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/38—Amides of thiocarboxylic acids
- C07C327/40—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C327/42—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
Description
技术领域technical field
本发明属于有机化合物合成及应用技术领域，涉及一种含硫酰胺的多肽类化合物及其合成方法。The invention belongs to the technical field of organic compound synthesis and application, and relates to a thioamide-containing polypeptide compound and a synthesis method thereof.
背景技术Background technique
含硫酰胺的多肽类化合物是一类非常重要的化合物，近些年来人们发现如果对多肽上的酰胺键进行硫代后可以进一步提升多肽的代谢稳定性和生物活性，因此，发展高效、环保、步骤经济性的合成含酰胺的多肽类化合物的方法显得尤为重要。Thioamide-containing polypeptide compounds are a very important class of compounds. In recent years, it has been found that the metabolic stability and biological activity of the polypeptide can be further improved if the amide bond on the polypeptide is thiolated. Therefore, the development of efficient, environmentally friendly, The method of synthesizing amide-containing polypeptide compounds with economical steps is particularly important.
含硫酰胺的多肽类化合物的制备方法主要是通过以劳森试剂代表的磷硫试剂直接进行氧硫替换而来。然而，这种制备方法使用了磷硫试剂，使其不能选择性地选择氧硫替换，而且该类试剂具有恶臭味且反应结束后会产生大量地磷氧聚合物。因此，发展一种环保、而且具有应用潜力的含硫酰胺的多肽类化合物的合成方法具有重要意义。The preparation method of the thioamide-containing polypeptide compound is mainly obtained by directly replacing oxygen and sulfur with a phosphorus-sulfur reagent represented by Lawson's reagent. However, this preparation method uses a phosphorus-sulfur reagent, which makes it impossible to selectively replace oxygen-sulfur, and this kind of reagent has a bad odor and produces a large amount of phosphorus-oxygen polymer after the reaction is completed. Therefore, it is of great significance to develop a method for synthesizing thioamide-containing polypeptide compounds that is environmentally friendly and has application potential.
发明内容SUMMARY OF THE INVENTION
为了解决现有技术存在的不足，本发明的目的是提供一种在催化条件下，利用三组分偶联方法直接由氨基醛和氨基酸多组分高效构建含硫酰胺的多肽类化合物的方法。本发明的合成方法简单，原料廉价易得，底物普适性广，产率(33％-92％)较好。本发明提供的含硫酰胺的多肽类化合物，可应用于二肽、三肽、四肽以及肽-药物偶联类化合物的制备中。In order to solve the deficiencies in the prior art, the purpose of the present invention is to provide a method for efficiently constructing a thioamide-containing polypeptide compound directly from aminoaldehyde and amino acid multi-component by using a three-component coupling method under catalytic conditions. The synthesis method of the invention is simple, the raw materials are cheap and easy to obtain, the substrate is widely applicable, and the yield (33%-92%) is good. The thioamide-containing polypeptide compounds provided by the present invention can be used in the preparation of dipeptide, tripeptide, tetrapeptide and peptide-drug conjugated compounds.
本发明提出了含硫酰胺的多肽类化合物的合成方法，在溶剂中，以氨基醛、无机硫试剂和氨基酸为反应原料，在催化剂、添加剂的作用下反应得到含硫酰胺的多肽类化合物且手性保持；所述反应过程如下反应式(I)所示：The invention provides a method for synthesizing thioamide-containing polypeptide compounds. In a solvent, aminoaldehyde, inorganic sulfur reagent and amino acid are used as reaction raw materials, and the thioamide-containing polypeptide compounds are obtained by reacting under the action of catalysts and additives. The property is maintained; the reaction process is shown in the following reaction formula (I):
其中，in,
R1为氢、烷基、苄基和四氢吡咯基；R 1 is hydrogen, alkyl, benzyl and tetrahydropyrrolyl;
R为苄氧羰基、芴甲氧羰基、烯丙氧羰基、叔丁氧羰基和和烷基等；R is benzyloxycarbonyl, fluorenemethoxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl and alkyl, etc.;
R2为氢、烷基、苄基等；R 2 is hydrogen, alkyl, benzyl, etc.;
R3为烷基、苄基。R 3 is alkyl, benzyl.
优选地，Preferably,
R1为氢、甲基、异丁基、苄基和四氢吡咯基；R 1 is hydrogen, methyl, isobutyl, benzyl and tetrahydropyrrolyl;
R为苄氧羰基、芴甲氧羰基、烯丙氧羰基、叔丁氧羰基和烷基等；R is benzyloxycarbonyl, fluorenemethoxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl, alkyl, etc.;
R2为氢、甲基、异丙基、异丁基、苄基等；R 2 is hydrogen, methyl, isopropyl, isobutyl, benzyl, etc.;
R3为甲基、苄基和叔丁基。R 3 is methyl, benzyl and tert-butyl.
进一步优选地，1,1’选自苯丙氨醛、丙氨醛、脯氨醛、亮氨醛、甘氨醛、丙-甘氨醛衍生物、苯丙-甘氨醛衍生物、甘-苯丙氨醛衍生物、布洛芬-甘氨醛衍生物、奈普生-甘氨醛衍生物和依索克酸-甘氨醛衍生物；Further preferably, 1,1' is selected from phenylalaninaldehyde, alaninaldehyde, prolinaldehyde, leucinaldehyde, glycinaldehyde, propan-glycinaldehyde derivative, phenylpropaninaldehyde derivative, glycinaldehyde Phenylalanine Derivatives, Ibuprofen-Glycinaldehyde Derivatives, Naproxen-Glycinaldehyde Derivatives, and Isoxocic Acid-Glycinaldehyde Derivatives;
进一步优选地，2,2’选自甘氨酸甲酯盐酸盐、甘氨酸苄酯盐酸盐、甘氨酸叔丁酯盐酸盐、丙氨酸甲酯盐酸盐、缬氨酸甲酯盐酸盐、亮氨酸甲酯盐酸盐、苯丙氨酸甲酯盐酸盐、蛋氨酸甲酯盐酸盐、丝氨酸甲酯盐酸盐、色氨酸甲酯盐酸盐、谷氨酸二甲酯盐酸盐、N6-叔丁氧羰基赖氨酸甲酯盐酸盐、甘-甘氨酸甲酯盐酸盐、甘-丙氨酸甲酯盐酸盐、甘-缬氨酸甲酯盐酸盐、甘-亮氨酸甲酯盐酸盐、甘-丙氨酸甲酯盐酸盐和苯丙-亮氨酸甲酯盐酸盐。Further preferably, 2,2' is selected from glycine methyl ester hydrochloride, glycine benzyl ester hydrochloride, glycine tert-butyl ester hydrochloride, alanine methyl ester hydrochloride, valine methyl ester hydrochloride, Leucine methyl ester hydrochloride, phenylalanine methyl ester hydrochloride, methionine methyl ester hydrochloride, serine methyl ester hydrochloride, tryptophan methyl ester hydrochloride, glutamate dimethyl ester hydrochloride salt, N6-tert-butoxycarbonyl lysine methyl ester hydrochloride, glycine-glycine methyl ester hydrochloride, glycine-alanine methyl ester hydrochloride, glycerin-valine methyl ester hydrochloride, glycine- Leucine methyl ester hydrochloride, glycine-alanine methyl ester hydrochloride, and phenylpropyl-leucine methyl ester hydrochloride.
本发明中，1,1’即表示式(1)、式(1’)；2,2’即表示式(2)、式(2’)；3,4即表示式(3)、式(4)。In the present invention, 1,1' means formula (1), formula (1'); 2,2' means formula (2), formula (2'); 3,4 means formula (3), formula ( 4).
本发明中，所述反应的温度为25-100℃；优选地，为50℃。In the present invention, the temperature of the reaction is 25-100°C; preferably, it is 50°C.
本发明中，所述反应的时间为1-12小时；优选地，为10小时。In the present invention, the reaction time is 1-12 hours; preferably, it is 10 hours.
本发明中，所述溶剂选自乙腈、甲苯、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、1，2-二氯乙烷、N-甲基吡咯烷酮、乙酸乙酯、氯仿、乙醇、异丙醇等中的一种或多种；优选地，四氢呋喃。In the present invention, the solvent is selected from acetonitrile, toluene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, 1 , one or more of 2-dichloroethane, N-methylpyrrolidone, ethyl acetate, chloroform, ethanol, isopropanol, etc.; preferably, tetrahydrofuran.
本发明中，以氨基醛的用量为基准，所述溶剂的用量为0.5～5mL。In the present invention, based on the amount of aminoaldehyde, the amount of the solvent is 0.5-5 mL.
本发明中，所述无机硫试剂为反应硫源，选自单质硫、硫化钠、九水硫化钠、硫化钾、硫氢化钠、亚硫酸钠、硫代乙酸钾和双(三甲基硫化硅)中的一种或多种；优选地，为单质硫。In the present invention, the inorganic sulfur reagent is a reactive sulfur source, selected from elemental sulfur, sodium sulfide, sodium sulfide nonahydrate, potassium sulfide, sodium hydrosulfide, sodium sulfite, potassium thioacetate and bis(trimethyl silicon sulfide) One or more of ; preferably, elemental sulfur.
本发明中，所述催化剂为铜催化剂，选自选自碘化亚铜、溴化亚铜、氯化亚铜、六氟磷酸四乙氰铜、氯化铜、溴化铜、氟化铜、醋酸铜、二(乙酰丙酮)铜、三氟乙酸铜、氧化铜、硫酸铜中的一种或多种；优选地，为氯化铜。In the present invention, the catalyst is a copper catalyst, selected from the group consisting of cuprous iodide, cuprous bromide, cuprous chloride, tetraethylcyanide hexafluorophosphate, cupric chloride, cupric bromide, cupric fluoride, One or more of copper acetate, copper bis(acetylacetonate), copper trifluoroacetate, copper oxide, and copper sulfate; preferably, copper chloride.
本发明中，所述添加剂选自碳酸钾、碳酸钠、碳酸氢二钾、磷酸二氢钾、碳酸氢钠、十二烷基硫醇、对甲基苯硫醇、硫化钾、硫化钠、九水硫化钠、四丁基氯化铵、四丁基碘化铵、四丁基氟化铵中的一种或多种；优选地，为九水硫化钠。In the present invention, the additive is selected from potassium carbonate, sodium carbonate, dipotassium bicarbonate, potassium dihydrogen phosphate, sodium bicarbonate, dodecyl mercaptan, p-methylbenzene mercaptan, potassium sulfide, sodium sulfide, One or more of sodium sulfide water, tetrabutylammonium chloride, tetrabutylammonium iodide, and tetrabutylammonium fluoride; preferably, it is sodium sulfide nonahydrate.
本发明中，所述氨基醛、无机硫试剂、氨基酸、催化剂、添加剂的用量摩尔比为1：(1-5)：(1-5)：(0.01-0.4)：(0.5-5)；优选地，为1：2：2：0.15：1.2。In the present invention, the molar ratio of the amino aldehydes, inorganic sulfur reagents, amino acids, catalysts and additives is 1:(1-5):(1-5):(0.01-0.4):(0.5-5); preferably ground, is 1:2:2:0.15:1.2.
本发明中，所述反应优选在空气下进行。In the present invention, the reaction is preferably carried out under air.
本发明中，当以氨基醛、单质硫和氨基酸为反应原料，在催化剂、添加剂的作用下，反应机理如反应式(II)所示，首先，氨基醛和氨基酸缩合脱水生成亚胺中间体A，其中亚胺与铜配位络合形成一个五元环中间体a，其中亚胺被激活并避免异构化(中间体B和C)以保持底物的手性。单质硫在硫化钠地作用下开环得到哟个亲核硫物种S，然后再对亚胺进行加成得到中间体D和配体互换的中间体E。接下来，通过中间D的1,2-H迁移过程获得中间F。最后，中间F中S-S键的裂解提供了含硫代酰胺的多肽类化合物3a。In the present invention, when aminoaldehyde, elemental sulfur and amino acid are used as reaction raw materials, under the action of catalyst and additives, the reaction mechanism is shown in reaction formula (II). First, aminoaldehyde and amino acid are condensed and dehydrated to form imine intermediate A , in which the imine is coordinately complexed with copper to form a five-membered ring intermediate a, in which the imine is activated and avoids isomerization (intermediates B and C) to preserve the chirality of the substrate. The elemental sulfur is ring-opened under the action of sodium sulfide to obtain a nucleophilic sulfur species S, and then the imine is added to obtain the intermediate D and the ligand-exchanged intermediate E. Next, intermediate F is obtained through the 1,2-H migration process of intermediate D. Finally, cleavage of the S-S bond in intermediate F provides thioamide-containing polypeptides 3a.
其中，反应式(II)中提到的基团PG与式(I)中的R含义相同。Wherein, the group PG mentioned in the reaction formula (II) has the same meaning as the R in the formula (I).
在一个具体的实施方式中：所述反应过程如下反应式(I’)所示。In a specific embodiment: the reaction process is shown in the following reaction formula (I').
其中，R1、R2、R3和R的定义同式(I)，即，R1为氢、烷基、苄基和四氢吡咯基；R为苄氧羰基、芴甲氧羰基、烯丙氧羰基、叔丁氧羰基和烷基等；R2为氢、烷基、苄基等；R3为烷基、苄基。Wherein, the definitions of R 1 , R 2 , R 3 and R are the same as those of formula (I), that is, R 1 is hydrogen, alkyl, benzyl and tetrahydropyrrolyl; R is benzyloxycarbonyl, fluorenylmethoxycarbonyl, alkene Propoxycarbonyl, tert-butoxycarbonyl and alkyl, etc.; R 2 is hydrogen, alkyl, benzyl, etc.; R 3 is alkyl, benzyl.
本发明还提出了通过上述合成方法获得的含硫代酰胺的多肽类化合物。The present invention also proposes a thioamide-containing polypeptide compound obtained by the above synthesis method.
本发明还提出了如式(3,4)所示的含硫代酰胺的多肽类化合物，The present invention also proposes a thioamide-containing polypeptide compound represented by formula (3, 4),
其中，R1、R2、R3和R的定义同式(I)，即，R1为氢、烷基、苄基和四氢吡咯基；R为苄氧羰基、芴甲氧羰基、烯丙氧羰基、叔丁氧羰基和烷基等；R2为氢、烷基、苄基等；R3为烷基、苄基。Wherein, the definitions of R 1 , R 2 , R 3 and R are the same as those of formula (I), that is, R 1 is hydrogen, alkyl, benzyl and tetrahydropyrrolyl; R is benzyloxycarbonyl, fluorenylmethoxycarbonyl, alkene Propoxycarbonyl, tert-butoxycarbonyl and alkyl, etc.; R 2 is hydrogen, alkyl, benzyl, etc.; R 3 is alkyl, benzyl.
优选地，R1为氢、甲基、异丁基、苄基、四氢吡咯基；R为苄氧羰基、芴甲氧羰基、烯丙氧羰基、叔丁氧羰基、烷基；R2为氢、甲基、异丙基、异丁基、苄基；R3为甲基、苄基、叔丁基。Preferably, R 1 is hydrogen, methyl, isobutyl, benzyl, tetrahydropyrrolyl; R is benzyloxycarbonyl, fluorenemethoxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl, alkyl; R 2 is Hydrogen, methyl, isopropyl, isobutyl, benzyl; R 3 is methyl, benzyl, tert-butyl.
进一步优选地，该式3,4的化合物为：Further preferably, the compound of the formula 3,4 is:
苯丙-甘氨酸衍生物、丙-甘氨酸衍生物、亮-甘氨酸衍生物、脯-甘氨酸衍生物、甘-丙氨酸衍生物、甘-缬氨酸衍生物、甘-亮氨酸衍生物、甘-苯丙氨酸衍生物、甘-蛋氨酸衍生物、甘-丝氨酸衍生物、甘-酪氨酸衍生物、甘-色氨酸衍生物、甘-谷氨酸衍生物、甘-赖氨酸衍生物、丙-甘-丙氨酸衍生物、丙-甘-亮氨酸衍生物、丙-甘-蛋氨酸衍生物、苯丙-甘-丙氨酸衍生物、苯丙-甘-亮氨酸衍生物、甘-苯丙-亮氨酸衍生物、苯丙-甘-甘氨酸衍生物、苯丙-甘-甘-缬氨酸衍生物、苯丙-甘-甘-亮氨酸衍生物、苯丙-甘-甘-苯丙氨酸衍生物、布洛芬-甘-丙氨酸衍生物、布洛芬-甘-亮氨酸衍生物、萘普生-甘-丙氨酸衍生物、依索克酸-甘-丙氨酸衍生物、依索克酸-甘-亮氨酸衍生物、依索克酸-甘-蛋氨酸衍生物。Phenylpropyl-glycine derivatives, propyl-glycine derivatives, leucine-glycine derivatives, pro-glycine derivatives, glycerin-alanine derivatives, glycine-valine derivatives, glycerin-leucine derivatives, glycine - Phenylalanine Derivatives, Glycine-Methionine Derivatives, Glycine-Serine Derivatives, Glycine-Tyrosine Derivatives, Glycine-Tryptophan Derivatives, Glycine-Glutamic Acid Derivatives, Glycine-Lysine Derivatives Propylene Glycine-Alanine Derivatives Compounds, Glycine-Glycine-Leucine Derivatives, Phenylpropan-Glycine-Glycine Derivatives, Phenylpropan-Glyc-Glycine-Valine Derivatives, Phenylpropan-Glyc-Glycine-Leucine Derivatives, Phenylpropane-Glycine-Glycine-Leucine Derivatives -Glycine-Glycine-Phenylalanine Derivatives, Ibuprofen-Glycine-Alanine Derivatives, Ibuprofen-Glycine-Leucine Derivatives, Naproxen-Glycine-Alanine Derivatives, Esso Glycolic acid-glycan-alanine derivatives, isoxocic acid-glycan-leucine derivatives, isoxocic acid-glycan-methionine derivatives.
本发明还提供了式(3,4)所示的含硫代酰胺的多肽类化合物在制备二肽、三肽、四肽以及肽-药物偶联类化合物中的应用。The present invention also provides the application of the thioamide-containing polypeptide compound represented by formula (3, 4) in the preparation of dipeptide, tripeptide, tetrapeptide and peptide-drug coupling compound.
本发明有益效果包括：本发明创新地提出一种合成方法，采用氨基醛、无机硫试剂、氨基酸为反应原料，在催化剂和添加剂的作用下，一锅法构建得到含硫代酰胺的多肽类，避免了传统磷硫试剂合成含硫代酰胺的多肽类的弊端。优选地，本发明创新提出了一种在金属铜催化，利用一锅法直接由无机硫试剂多组分高效构建含硫代酰胺的多肽类化合物的方法。本发明的合成方法简单，原料廉价易得，底物普适性广，产率(33％-92％)较好。通过本发明发展的合成策略可以顺利得到二肽、三肽、四肽以及肽-药物偶联类化合物，这在未来的药物开发领域具有巨大的潜力。The beneficial effects of the present invention include: the present invention innovatively proposes a synthesis method, which adopts aminoaldehyde, inorganic sulfur reagent and amino acid as reaction raw materials, and under the action of catalyst and additives, one-pot method is used to construct thioamide-containing polypeptides, It avoids the disadvantages of synthesizing thioamide-containing polypeptides with traditional phosphorus-sulfur reagents. Preferably, the present invention innovatively proposes a method for efficiently constructing a thioamide-containing polypeptide compound directly from multiple components of an inorganic sulfur reagent using a one-pot method under the catalysis of metallic copper. The synthesis method of the invention is simple, the raw materials are cheap and easy to obtain, the substrate is widely applicable, and the yield (33%-92%) is good. Dipeptide, tripeptide, tetrapeptide and peptide-drug conjugated compounds can be obtained smoothly through the synthetic strategy developed in the present invention, which has great potential in the field of future drug development.
具体实施方式Detailed ways
结合以下具体实施例，对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等，除以下专门提及的内容之外，均为本领域的普遍知识和公知常识，本发明没有特别限制内容。The present invention will be further described in detail with reference to the following specific embodiments. Except for the content specifically mentioned below, the process, conditions, experimental methods, etc. for implementing the present invention are all common knowledge and common knowledge in the field, and the present invention is not particularly limited.
在本发明实施例1～59中，反应温度为50℃。In Examples 1 to 59 of the present invention, the reaction temperature was 50°C.
实施例1Example 1
化合物3a的合成：Synthesis of compound 3a:
化合物3a的制备:在空气氛围下，往反应管中加入氨基醛1a(28.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝2/1)分离得33.2mg无色油状3a(PE/EA＝2:1,Rf＝0.5),收率为86％。1HNMR(400MHz,CDCl3)δ8.44(s,1H),7.24-7.05(m,10H),5.79(d,J＝8.3Hz,1H),4.92(d,J＝7.2Hz,2H),4.78(d,J＝7.0Hz,1H),4.18-4.02(m,2H),3.59(s,3H),3.11-2.87(m,2H).13CNMR(101MHz,CDCl3)δ204.2,168.6,155.9,136.4,136.2,129.3,128.6,128.6,128.2,127.9,127.0,67.1,62.1,52.6,46.8,42.2.IR(neat)3278,2971,1741,1699,1506,1265,1213,698cm-1.HRMS(EI)m/z:Calcd for C20H22N2O4S 386.1300,Found 386.1297.ee值:92％,HPLC的检测参数为(Daicel Chirapak AD,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.997min(主要),tR＝8.703min(次要).Preparation of compound 3a: under air atmosphere, add aminoaldehyde 1a (28.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S. 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =2/1) gave 33.2 mg of colorless oily 3a (PE/EA=2:1, R f =0.5), the yield was 86 %. 1 HNMR (400MHz, CDCl 3 ) δ 8.44 (s, 1H), 7.24-7.05 (m, 10H), 5.79 (d, J=8.3Hz, 1H), 4.92 (d, J=7.2Hz, 2H), 4.78(d, J=7.0Hz, 1H), 4.18-4.02(m, 2H), 3.59(s, 3H), 3.11-2.87(m, 2H). 13 CNMR(101MHz, CDCl 3 )δ204.2,168.6,155.9 .HRMS (EI) m/z: Calcd for C 20 H 22 N 2 O 4 S 386.1300, Found 386.1297.ee value: 92%, the detection parameters of HPLC are (Daicel Chirapak AD, n-hexane/isopropanol=70/30, Flow rate = 1.0 mL/min, column oven temperature is 30 °C, wavelength is 254 nm) tR = 13.997 min (primary), tR = 8.703 min (secondary).
实施例2Example 2
化合物3b的合成：Synthesis of compound 3b:
化合物3b的制备:在空气氛围下，往反应管中加入氨基醛1b(24.9mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝5/1)分离得29.2mg无色油状3b(PE/EA＝5:1,Rf＝0.5)，收率为83％。1H NMR(400MHz,CDCl3)δ8.22(s,1H),7.23-7.10(m,5H),5.30(s,1H),4.59-4.64(q,J＝14.2,7.0Hz,1H),4.13-4.26(m,3.8Hz,2H),3.66(s,3H),3.17-2.94(m,2H),1.31(s,9H).13C NMR(101MHz,CDCl3)δ204.1,168.6,155.3,136.6,129.2,128.6,127.0,80.5,62.4,52.5,46.7,42.0,28.2.IR(neat)3271,2978,2360,1747,1685,1496,1365,1211,727cm- 1.HRMS(ESI)m/z:[M+Na]+Calcd for C17H24N2O4NaS 375.1349,Found 375.1346.ee值:85％,HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝7.890min(主要),tR＝7.107min(次要).Preparation of compound 3b: under air atmosphere, add aminoaldehyde 1b (24.9 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =5/1) gave 29.2 mg of colorless oily 3b (PE/EA=5:1, R f =0.5), the yield was 83 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.22(s, 1H), 7.23-7.10(m, 5H), 5.30(s, 1H), 4.59-4.64(q, J=14.2, 7.0Hz, 1H), 4.13-4.26(m, 3.8Hz, 2H), 3.66(s, 3H), 3.17-2.94(m, 2H), 1.31(s, 9H). 13 C NMR(101MHz, CDCl 3 )δ204.1,168.6,155.3, 136.6,129.2,128.6,127.0,80.5,62.4,52.5,46.7,42.0,28.2.IR(neat)3271,2978,2360,1747,1685,1496,1365,1211,727cm - 1 .HRMS(ESI)m/ z: [M+Na] + Calcd for C 17 H 24 N 2 O 4 NaS 375.1349, Found 375.1346.ee value: 85%, detection parameters by HPLC (Daicel Chirapak AD, n-hexane/isopropanol=85/15, Flow rate = 1.0 mL/min, column oven temperature is 30 °C, wavelength is 254 nm) tR = 7.890 min (primary), tR = 7.107 min (secondary).
实施例3Example 3
化合物3c的合成：Synthesis of compound 3c:
化合物3c的制备:在空气氛围下，往反应管中加入氨基醛1c(23.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝5/1)分离得28.2mg无色油状3c(PE/EA＝5:1,Rf＝0.5)，收率为84％。1H NMR(400MHz,CDCl3)δ8.20(s,1H),7.34-7.04(m,5H),5.81-5.64(m,2H),5.14(dd,J＝25.5,13.8Hz,2H),4.70(q,J＝14.6,7.2Hz,1H),4.43(d,J＝4.6Hz,2H),4.18(q,J＝41.7,18.7Hz,2H),3.65(s,3H),3.06(d,J＝5.0Hz,2H).13C NMR(101MHz,CDCl3)δ203.8,168.6,155.7,136.4,132.4,129.2,128.6,127.8,117.8,66.0,62.4,52.6,46.8,42.1.IR(neat)3277,2953,1743,1697,1508,1211,1180,749cm-1.HRMS(ESI)m/z:[M+H]+Calcd forC16H21N2O4S 337.1217,Found 337.1208.ee值为83％.HPLC的检测参数(Daicel ChirapakAD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝12.737min(主要的),tR＝10.183min(次要的).Preparation of compound 3c: under air atmosphere, add aminoaldehyde 1c (23.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S . 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =5/1) gave 28.2 mg of colorless oily 3c (PE/EA=5:1, R f =0.5), the yield was 84 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.34-7.04 (m, 5H), 5.81-5.64 (m, 2H), 5.14 (dd, J=25.5, 13.8Hz, 2H), 4.70(q,J=14.6,7.2Hz,1H),4.43(d,J=4.6Hz,2H),4.18(q,J=41.7,18.7Hz,2H),3.65(s,3H),3.06(d , J=5.0Hz, 2H). 13 C NMR(101MHz, CDCl 3 )δ203.8,168.6,155.7,136.4,132.4,129.2,128.6,127.8,117.8,66.0,62.4,52.6,46.8,42.1.IR(neat) 3277,2953,1743,1697,1508,1211,1180,749cm -1 .HRMS(ESI)m/z:[M+H] + Calcd for C 16 H 21 N 2 O 4 S 337.1217,Found 337.1208.ee value 83%. Detection parameters of HPLC (Daicel ChirapakAD, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=12.737min (main) , tR=10.183min (minor).
实施例4Example 4
化合物3d的合成：Synthesis of compound 3d:
化合物3d的制备:在空气氛围下，往反应管中加入氨基醛1d(37.1mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得38.3mg无色油状3d(PE/EA＝5:1,Rf＝0.3)，收率为81％。1H NMR(400MHz,CDCl3)δ8.08(s,1H),7.67(d,J＝7.5Hz,2H),7.44(t,J＝8.3Hz,2H),7.31(t,J＝7.3Hz,2H),7.10-7.23(m,J＝23.3,14.0,7.0Hz,7H),5.67(s,1H),4.69(s,1H),4.07-4.31(m,5H),3.60(d,J＝7.3Hz,3H),3.07(d,J＝4.6Hz,2H).13C NMR(101MHz,CDCl3)δ203.6,168.5,155.8,143.8,143.7,141.3,136.3,129.2,128.7,127.8,127.2,127.1,125.1,120.0,67.3,62.4,52.6,47.1,46.8,42.1.IR(neat)3277,2949,2360,1739,1697,1517,1446,1215,700cm-1.HRMS(ESI)m/z:[M+H]+Calcd for C27H27N2O4S 475.1686,Found475.1680.ee值为82％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝11.607min(主要),tR＝8.890min(次要).Preparation of compound 3d: under air atmosphere, add aminoaldehyde 1d (37.1 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S . 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 38.3 mg of colorless oily 3d (PE/EA=5:1, R f =0.3), the yield was 81 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (s, 1H), 7.67 (d, J=7.5 Hz, 2H), 7.44 (t, J=8.3 Hz, 2H), 7.31 (t, J=7.3 Hz) ,2H),7.10-7.23(m,J=23.3,14.0,7.0Hz,7H),5.67(s,1H),4.69(s,1H),4.07-4.31(m,5H),3.60(d,J =7.3Hz, 3H), 3.07(d, J=4.6Hz, 2H). 13 C NMR (101MHz, CDCl 3 )δ203.6, 168.5, 155.8, 143.8, 143.7, 141.3, 136.3, 129.2, 128.7, 127.8, 127.2, 127.1,125.1,120.0,67.3,62.4,52.6,47.1,46.8,42.1.IR(neat)3277,2949,2360,1739,1697,1517,1446,1215,700cm -1 .HRMS(ESI)m/z: [M+H] + Calcd for C 27 H 27 N 2 O 4 S 475.1686, Found475.1680. The ee value is 82%. Detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow Speed=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=11.607min (main), tR=8.890min (secondary).
实施例5Example 5
化合物3e的合成：Synthesis of compound 3e:
化合物3e的制备:在空气氛围下，往反应管中加入氨基醛1a(28.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸苄酯盐酸盐(40.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得31.4mg无色油状3e(PE/EA＝3:1,Rf＝0.5)，收率为68％。1H NMR(400MHz,CDCl3)1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.40-6.98(m,16H),5.65(d,J＝6.7Hz,1H),5.08-4.85(m,4H),4.76-4.63(m,1H),4.26-3.98(m,2H),3.03(s,2H).13CNMR(101MHz,CDCl3)δ203.7,168.0,155.8,136.4,136.1,134.9,129.2,129.2,128.7,128.5,128.4,128.2,127.9,127.8,127.1,67.5,67.1,62.5,47.0,42.2.IR(neat)3277,2360,1739,1697,1508,1259,1190,751cm-1.HRMS(ESI)m/z:[M+H]+Calcd for C26H27N2O4S463.1686,Found 463.1677.ee值为78％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝14.343min(主要),tR＝11.760min(次要).Preparation of compound 3e: under air atmosphere, add aminoaldehyde 1a (28.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S . 9H 2 O (28.8 mg, 0.12 mmol), glycine benzyl ester hydrochloride (40.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 31.4 mg of colorless oily 3e (PE/EA=3:1, R f =0.5), the yield was 68 %. 1 H NMR (400MHz, CDCl 3 ) 1 H NMR (400 MHz, CDCl 3 ) δ 8.16(s, 1H), 7.40-6.98(m, 16H), 5.65(d, J=6.7Hz, 1H), 5.08- 4.85(m, 4H), 4.76-4.63(m, 1H), 4.26-3.98(m, 2H), 3.03(s, 2H). 13 CNMR(101MHz, CDCl 3 )δ203.7,168.0,155.8,136.4,136.1, 134.9,129.2,129.2,128.7,128.5,128.4,128.2,127.9,127.8,127.1,67.5,67.1,62.5,47.0,42.2.IR(neat)3277,2360,1739,1697,1508,1259,1190 , 1. HRMS (ESI) m/z: [M+H] + Calcd for C 26 H 27 N 2 O 4 S463.1686, Found 463.1677. ee value is 78%. Detection parameters of HPLC (Daicel Chirapak AD, n-hexane /isopropanol=70/30, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=14.343min (main), tR=11.760min (minor).
实施例6Example 6
化合物3f的合成：Synthesis of compound 3f:
化合物3f的制备:在空气氛围下，往反应管中加入氨基醛1a(28.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸叔丁酯盐酸盐(33.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝5/1)分离得35.5mg无色油状3f(PE/EA＝5:1,Rf＝0.5)，收率为83％。1H NMR(400MHz,CDCl3)δ8.01(d,J＝33.3Hz,1H),7.27-7.08(m,10H),5.66(s,1H),5.03-4.92(m,2H),4.67(d,J＝7.3Hz,1H),4.01(m,J＝19.1,4.3Hz,2H),3.06(d,J＝6.2Hz,2H),1.36(s,9H).13C NMR(101MHz,CDCl3)δ202.8,167.2,155.7,136.5,136.2,129.2,129.1,128.7,128.6,128.5,128.1,127.9,127.9,127.1,127.0,83.0,67.1,62.6,47.7,42.2,28.0.IR(neat)3271,2360,1739,1695,1521,1274,1157,763cm-1.HRMS(ESI)m/z:[M+Na]+Calcd for C23H28N2O4NaS 451.1662,Found 451.1652.ee值为59％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝11.397min(主要),tR＝10.430min(次要).Preparation of compound 3f: under air atmosphere, add aminoaldehyde 1a (28.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg, 0.12 mmol), tert-butyl glycine hydrochloride (33.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =5/1) gave 35.5 mg of colorless oily 3f (PE/EA=5:1, R f =0.5), the yield was 83 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.01(d, J=33.3Hz, 1H), 7.27-7.08(m, 10H), 5.66(s, 1H), 5.03-4.92(m, 2H), 4.67( d, J=7.3Hz, 1H), 4.01 (m, J=19.1, 4.3Hz, 2H), 3.06 (d, J=6.2Hz, 2H), 1.36 (s, 9H). 13 C NMR (101MHz, CDCl) 3 ) δ202.8,167.2,155.7,136.5,136.2,129.2,129.1,128.7,128.6,128.5,128.1,127.9,127.9,127.1,127.0,13.0,67.1,62.6,47.7,42.2,28.0.IR(neat) 2360,1739,1695,1521,1274,1157,763cm -1 .HRMS(ESI)m/z:[M+Na] + Calcd for C 23 H 28 N 2 O 4 NaS 451.1662,Found 451.1652.ee value is 59 %. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0mL/min, column oven temperature 30℃, wavelength 254nm) tR=11.397min (mainly), tR=10.430min (minor).
实施例7Example 7
化合物3g的合成：Synthesis of compound 3g:
化合物3g的制备:在空气氛围下，往反应管中加入氨基醛1g(20.7mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得27.6mg无色油状3g(PE/EA＝2:1,Rf＝0.5)，收率为89％。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.32(s,5H),5.88(d,J＝6.4Hz,1H),5.20-5.00(m,2H),4.82-4.58(m,1H),4.15-4.48(m,2H),3.75(s,3H),1.47(d,J＝6.8Hz,3H).13C NMR(101MHz,CDCl3)δ206.2,169.0,155.9,136.1,128.6,128.2,127.9,67.1,56.3,52.7,46.8,22.3.IR(neat)3241,2961,1739,1697,1514,1213,1047,696cm-1.HRMS(EI)m/z:Calcd forC14H18N2O4S 310.0987,Found 310.0993.ee值为91％.HPLC的检测参数(Daicel ChirapakID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝17.737min(主要),tR＝25.600min(次要).Preparation of compound 3g: under air atmosphere, add aminoaldehyde 1g (20.7mg, 0.1mmol), S 8 (6.4mg, 0.2mmol), CuCl 2 (2.0mg, 0.015mmol), Na 2 S . 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 27.6 mg of colorless oil 3g (PE/EA=2:1, R f =0.5), the yield was 89 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.87(s, 1H), 7.32(s, 5H), 5.88(d, J=6.4Hz, 1H), 5.20-5.00(m, 2H), 4.82-4.58( m, 1H), 4.15-4.48 (m, 2H), 3.75 (s, 3H), 1.47 (d, J=6.8Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.2, 169.0, 155.9, 136.1, 128.6,128.2,127.9,67.1,56.3,52.7,46.8,22.3.IR(neat)3241,2961,1739,1697,1514,1213,1047,696cm -1 .HRMS(EI)m/z:Calcd forC 14 H 18 N 2 O 4 S 310.0987, Found 310.0993. ee value was 91%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30 ℃, the wavelength is 254nm) tR=17.737min (main), tR=25.600min (secondary).
实施例8Example 8
化合物3h的合成：Synthesis of compound 3h:
化合物3h的制备:在空气氛围下，往反应管中加入氨基醛1h(24.9mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得27.6mg无色油状3h(PE/EA＝2:1,Rf＝0.5)，收率为87％。1H NMR(400MHz,CDCl3)δ8.88(s,1H),7.24(s,5H),5.59(d,J＝6.1Hz,1H),5.01(q,J＝12.4Hz,2H),4.58(d,J＝6.4Hz,1H),4.33(d,J＝5.0Hz,1H),4.20–4.06(m,1H),3.67(s,3H),1.60(s,3H),0.85(t,J＝5.0Hz,6H).13C NMR(101MHz,CDCl3)δ206.6,168.9,156.3,136.1,128.6,128.2,127.9,67.1,59.3,52.6,46.7,45.0,24.8,22.9,22.1.IR(neat)3277,2955,1743,1697,1512,1452,1241,696cm-1.HRMS(EI)m/z:Calcd for C17H24N2O4S352.1457,Found 352.1451.ee值为94％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝14.113min(主要),tR＝11.100min(次要).Preparation of compound 3h: under air atmosphere, aminoaldehyde 1h (24.9 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S . 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 27.6 mg of colorless oil for 3h (PE/EA=2:1, R f =0.5), the yield was 87 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.88 (s, 1H), 7.24 (s, 5H), 5.59 (d, J=6.1 Hz, 1H), 5.01 (q, J=12.4 Hz, 2H), 4.58 (d, J=6.4Hz, 1H), 4.33(d, J=5.0Hz, 1H), 4.20–4.06(m, 1H), 3.67(s, 3H), 1.60(s, 3H), 0.85(t, J=5.0Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 206.6, 168.9, 156.3, 136.1, 128.6, 128.2, 127.9, 67.1, 59.3, 52.6, 46.7, 45.0, 24.8, 22.9, 22.1.IR (neat ) 3277,2955,1743,1697,1512,1452,1241,696cm - 1.HRMS (EI)m/z:Calcd for C17H24N2O4S352.1457 ,Found 352.1451.ee value is 94%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=14.113min (mainly), tR= 11.100min (minor).
实施例9Example 9
化合物3i的合成：Synthesis of compound 3i:
化合物3i的制备:在空气氛围下，往反应管中加入氨基醛1i(23.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，甘氨酸甲酯盐酸盐(25.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝2/1)分离得30.1mg无色油状3i(PE/EA＝2:1,Rf＝0.5)，收率为92％。1H NMR(400MHz,CDCl3～50:50mixture of rotamers A and B)δ8.80(s,0.5H),8.26(s,0.5H),7.37-7.11(m,5H),5.16-4.91(m,2H),4.72(s,1H),4.36-4.30(dd,J＝18.2,5.0Hz,1.5H),4.07(d,J＝17.3Hz,0.5H),3.66(s,3H),3.59–3.37(m,2H),2.23(d,J＝63.8Hz,2H),1.84(dd,J＝34.4,29.3Hz,2H).13C NMR(101MHz,CDCl3)δ204.5,168.9,156.2,155.2,136.3,128.5,128.1,127.8,68.5,67.3,52.6,48.0,47.6,46.9,46.4,34.7,32.7,24.1,23.4.IR(neat)3273,2953,1747,1690,1523,1408,1350,734cm-1.HRMS(EI)m/z:Calcdfor C16H20N2O4S 336.1144,Found 336.1138.ee值为96％.HPLC的检测参数(DaicelChirapak ID,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝14.387min(主要),tR＝9.560min(次要)..Preparation of compound 3i: under air atmosphere, add aminoaldehyde 1i (23.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S . 9H 2 O (28.8 mg, 0.12 mmol), glycine methyl ester hydrochloride (25.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =2/1) gave 30.1 mg of colorless oily 3i (PE/EA=2:1, R f =0.5), the yield was 92 %. 1 H NMR (400MHz, CDCl 3 ～50:50 mixture of rotamers A and B) δ8.80(s, 0.5H), 8.26(s, 0.5H), 7.37-7.11(m, 5H), 5.16-4.91(m ,2H),4.72(s,1H),4.36-4.30(dd,J＝18.2,5.0Hz,1.5H),4.07(d,J＝17.3Hz,0.5H),3.66(s,3H),3.59– 3.37 (m, 2H), 2.23 (d, J=63.8Hz, 2H), 1.84 (dd, J=34.4, 29.3Hz, 2H). 13 C NMR (101MHz, CDCl 3 )δ 204.5, 168.9, 156.2, 155.2, 136.3,128.5,128.1,127.8,68.5,67.3,52.6,48.0,47.6,46.9,46.4,34.7,32.7,24.1,23.4.IR(neat)3273,2953,1747,1690,1523,1408,1350,734cm - 1. HRMS (EI) m/z: Calcd for C 16 H 20 N 2 O 4 S 336.1144, Found 336.1138. ee value is 96%. Detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=70/30, Flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=14.387min (main), tR=9.560min (secondary)..
实施例10Example 10
化合物3j的合成：Synthesis of compound 3j:
化合物3j的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，丙氨酸甲酯盐酸盐(27.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得26.7mg无色油状3j(PE/EA＝3:1,Rf＝0.5)，收率为86％。1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.28(s,5H),5.66(s,1H),5.20–4.88(m,3H),4.25–4.03(m,2H),3.69(s,3H),1.42(d,J＝6.0Hz,3H).13C NMR(101MHz,CDCl3)δ199.3,172.4,156.8,136.0,128.6,128.3,128.1,67.5,53.3,52.8,52.1,16.9.IR(neat)3238,2953,1703,1523,1452,1417,1220,701cm-1.HRMS(EI)m/z:Calcd for C14H18N2O4S310.0987,Found 310.0989.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝21.283min(主要),tR＝31.990min(次要).Preparation of compound 3j: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), alanine methyl ester hydrochloride (27.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 26.7 mg of colorless oily 3j (PE/EA=3:1, R f =0.5), the yield was 86 %. 1 H NMR (400MHz, CDCl 3 )δ8.54(s,1H), 7.28(s,5H), 5.66(s,1H), 5.20-4.88(m,3H), 4.25-4.03(m,2H), 3.69(s, 3H), 1.42(d, J=6.0Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.3, 172.4, 156.8, 136.0, 128.6, 128.3, 128.1, 67.5, 53.3, 52.8, 52.1, 16.9.IR(neat)3238,2953,1703,1523,1452,1417,1220,701cm -1 .HRMS(EI)m/z:Calcd for C 14 H 18 N 2 O 4 S310.0987,Found 310.0989.ee The value is >99%. Detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=21.283min (primary), tR=31.990min (secondary).
实施例11Example 11
化合物3k的合成：Synthesis of compound 3k:
化合物3k的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，缬氨酸甲酯盐酸盐(33.4mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得25.3mg无色油状3k(PE/EA＝3:1,Rf＝0.5)，收率为75％。1H NMR(400MHz,CDCl3)δ8.54(s,1H),7.28(s,5H),5.66(s,1H),5.20–4.88(m,3H),4.25–4.03(m,2H),3.69(s,3H),1.42(d,J＝6.0Hz,3H).13C NMR(101MHz,CDCl3)δ199.3,172.4,156.8,136.0,128.6,128.3,128.1,67.5,53.3,52.8,52.1,16.9.IR(neat)3238,2953,1703,1523,1452,1417,1220,701cm-1.HRMS(EI)m/z:Calcd for C14H18N2O4S310.0987,Found 310.0989.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.703min(主要),tR＝20.480min(次要).Preparation of compound 3k: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), valine methyl ester hydrochloride (33.4 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 25.3 mg of colorless oily 3k (PE/EA=3:1, R f =0.5), the yield was 75 %. 1 H NMR (400MHz, CDCl 3 )δ8.54(s,1H), 7.28(s,5H), 5.66(s,1H), 5.20-4.88(m,3H), 4.25-4.03(m,2H), 3.69(s, 3H), 1.42(d, J=6.0Hz, 3H). 13 C NMR (101MHz, CDCl 3 )δ199.3, 172.4, 156.8, 136.0, 128.6, 128.3, 128.1, 67.5, 53.3, 52.8, 52.1, 16.9.IR(neat)3238,2953,1703,1523,1452,1417,1220,701cm -1 .HRMS(EI)m/z:Calcd for C 14 H 18 N 2 O 4 S310.0987,Found 310.0989.ee The value is >99%. Detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=13.703min (primary), tR=20.480min (secondary).
实施例12Example 12
化合物3l的合成：Synthesis of compound 3l:
化合物3l的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，亮氨酸甲酯盐酸盐(36.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得21.8mg无色油状3l(PE/EA＝3:1,Rf＝0.5)，收率为62％。1H NMR(400MHz,CDCl3)δ8.39(s,1H),7.28(dd,J＝7.4,2.7Hz,6H),5.59(s,1H),5.07(s,3H),4.24-4.11(m,2H),3.67(s,3H),1.76–1.48(m,3H),0.86(t,J＝7.0Hz,6H).13C NMR(101MHz,CDCl3)δ199.9,172.1,157.0,135.9,128.6,128.4,128.2,67.5,56.4,52.6,52.2,40.5,25.0,22.6,22.3.IR(neat)3259,2954,1703,1527,1238,1172,1041,736cm-1.HRMS(EI)m/z:Calcd for C17H24N2O4S 352.1457,Found 352.1461.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝10.463min(主要),tR＝14.463min(次要).Preparation of compound 31: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), leucine methyl ester hydrochloride (36.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 21.8 mg of colorless oily 3l (PE/EA=3:1, R f =0.5), the yield was 62 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.39(s, 1H), 7.28(dd, J=7.4, 2.7Hz, 6H), 5.59(s, 1H), 5.07(s, 3H), 4.24-4.11( m, 2H), 3.67(s, 3H), 1.76-1.48(m, 3H), 0.86(t, J=7.0Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.9, 172.1, 157.0, 135.9, 128.6,128.4,128.2,67.5,56.4,52.6,52.2,40.5,25.0,22.6,22.3.IR(neat)3259,2954,1703,1527,1238,1172,1041,736cm -1 .HRMS(EI)m/ z: Calcd for C 17 H 24 N 2 O 4 S 352.1457, Found 352.1461. ee value >99%. Detection parameters for HPLC (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL /min, column oven temperature is 30℃, wavelength is 254nm) tR=10.463min (main), tR=14.463min (secondary).
实施例13Example 13
化合物3m的合成：Synthesis of compound 3m:
化合物3m的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，苯丙氨酸甲酯盐酸盐(43.1mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得22.8mg无色油状3m(PE/EA＝3:1,Rf＝0.5)，收率为59％。1H NMR(400MHz,CDCl3)δ8.38(s,1H),7.27(d,J＝11.1Hz,5H),7.16(d,J＝7.7Hz,3H),6.99(d,J＝6.1Hz,2H),5.56(s,1H),5.30(dd,J＝12.8,5.8Hz,1H),5.02(s,2H),4.20-4.04(m,2H),3.64(s,3H),3.32–3.22(m,1H),3.10(dd,J＝13.9,5.2Hz,1H).13C NMR(101MHz,CDCl3)δ199.5,170.9,156.8,135.9,135.3,129.3,128.7,128.6,128.4,128.2,127.4,67.4,58.3,52.6,52.1,36.3.IR(neat)3298,2951,1705,1496,1215,1176,1028,705cm- 1.HRMS(EI)m/z:Calcd for C20H22N2O4S 386.1300,Found 386.1305.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.340min(主要),tR＝11.830min(次要).Preparation of compound 3m: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), phenylalanine methyl ester hydrochloride (43.1 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 22.8 mg of colorless oily 3m (PE/EA=3:1, R f =0.5), the yield was 59 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.38 (s, 1H), 7.27 (d, J=11.1 Hz, 5H), 7.16 (d, J=7.7 Hz, 3H), 6.99 (d, J=6.1 Hz ,2H),5.56(s,1H),5.30(dd,J=12.8,5.8Hz,1H),5.02(s,2H),4.20-4.04(m,2H),3.64(s,3H),3.32– 3.22 (m, 1H), 3.10 (dd, J=13.9, 5.2Hz, 1H). 13 C NMR (101MHz, CDCl 3 )δ199.5, 170.9, 156.8, 135.9, 135.3, 129.3, 128.7, 128.6, 128.4, 128.2, 127.4,67.4,58.3,52.6,52.1,36.3.IR(neat)3298,2951,1705,1496,1215,1176,1028,705cm - 1 .HRMS(EI)m/z:Calcd for C 20 H 22 N 2 O 4 S 386.1300, Found 386.1305.ee value >99%. Detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30°C , the wavelength is 254nm) tR=13.340min (main), tR=11.830min (secondary).
实施例14Example 14
化合物3n的合成：Synthesis of compound 3n:
化合物3n的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，蛋氨酸甲酯盐酸盐(32.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得27.0mg无色油状3n(PE/EA＝3:1,Rf＝0.5)，收率为73％。1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.28(s,5H),5.71(s,1H),5.18(d,J＝6.4Hz,1H),5.06(s,2H),4.25-4.12(m,2H),3.69(s,3H),2.42(d,J＝6.6Hz,2H),2.30–2.17(m,1H),2.13–2.02(m,1H),1.98(s,3H).13C NMR(101MHz,CDCl3)δ199.9,171.3,156.9,135.9,128.6,128.4,128.1,67.5,56.9,52.8,52.1,30.5,29.8,15.5.IR(neat)3305,2916,1703,1517,1435,1211,1174,703cm-1.HRMS(EI)m/z:Calcd for C16H22N2O4S2370.1021,Found370.1023.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.930min(主要),tR＝12.077min(次要).Preparation of compound 3n: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), methionine methyl ester hydrochloride (32.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 27.0 mg of colorless oily 3n (PE/EA=3:1, R f =0.5), the yield was 73 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.79(s, 1H), 7.28(s, 5H), 5.71(s, 1H), 5.18(d, J=6.4Hz, 1H), 5.06(s, 2H) ,4.25-4.12(m,2H),3.69(s,3H),2.42(d,J=6.6Hz,2H),2.30-2.17(m,1H),2.13-2.02(m,1H),1.98(s ,3H). 13 C NMR (101MHz, CDCl 3 )δ199.9,171.3,156.9,135.9,128.6,128.4,128.1,67.5,56.9,52.8,52.1,30.5,29.8,15.5.IR(neat)3305,2916,1703 , 1517, 1435, 1211, 1174, 703cm -1 .HRMS(EI)m/z:Calcd for C 16 H 22 N 2 O 4 S 2 370.1021,Found370.1023.ee value>99%.Detection parameters of HPLC (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=13.930min (main), tR=12.077min (time) want).
实施例15Example 15
化合物3o的合成：Synthesis of compound 3o:
化合物3o的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，丝氨酸甲酯盐酸盐(31.0mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得24.1mg无色油状3o(PE/EA＝3:1,Rf＝0.5)，收率为74％。1H NMR(400MHz,CDCl3)δ8.80(s,1H),7.26(s,5H),5.85(s,1H),5.18–5.13(m,1H),5.04(s,2H),4.16(d,J＝5.8Hz,2H),4.06–3.91(m,2H),3.70(s,3H),3.25(s,1H).13C NMR(101MHz,CDCl3)δ200.2,170.2,157.1,135.9,128.6,128.4,128.1,67.5,61.5,59.7,53.0,51.7.IR(neat)3338,2953,1701,1517,1223,1168,1043,696cm-1.HRMS(EI)m/z:Calcd forC14H18N2O5S 326.0936,Found 326.0931.ee值为>99％.HPLC的检测参数(Daicel ChirapakAD,正己烷/异丙醇＝80/20,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝14.540min(主要),tR＝11.637min(次要).Preparation of compound 3o: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), serine methyl ester hydrochloride (31.0 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 24.1 mg of colorless oily 3o (PE/EA=3:1, R f =0.5), the yield was 74 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.80(s, 1H), 7.26(s, 5H), 5.85(s, 1H), 5.18-5.13(m, 1H), 5.04(s, 2H), 4.16( d, J=5.8Hz, 2H), 4.06-3.91 (m, 2H), 3.70 (s, 3H), 3.25 (s, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 200.2, 170.2, 157.1, 135.9, 128.6,128.4,128.1,67.5,61.5,59.7,53.0,51.7.IR(neat)3338,2953,1701,1517,1223,1168,1043,696cm -1 .HRMS(EI)m/z:Calcd forC 14 H 18 N 2 O 5 S 326.0936, Found 326.0931.ee value > 99%. HPLC detection parameters (Daicel Chirapak AD, n-hexane/isopropanol=80/20, flow rate=1.0 mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=14.540min (main), tR=11.637min (secondary).
实施例16Example 16
化合物3p的合成：Synthesis of compound 3p:
化合物3p的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，酪氨酸甲酯盐酸盐(46.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝1/1)分离得22.9mg无色油状3p(PE/EA＝1:1,Rf＝0.5)，收率为57％。1H NMR(400MHz,CDCl3)δ8.33(s,1H),7.26(s,5H),6.79(s,2H),6.59(d,J＝7.9Hz,2H),5.64(s,1H),5.25(d,J＝4.9Hz,1H),5.03(s,2H),4.21-3.97(m,2H),3.66(d,J＝12.7Hz,3H),3.17(s,1H),3.02(dd,J＝13.9,4.5Hz,1H).13C NMR(101MHz,CDCl3)δ199.4,171.2,156.9,155.3,135.9,130.4,128.6,128.4,128.2,126.7,115.7,67.6,58.4,52.7,51.9,35.4.IR(neat)3327,2953,2360,1699,1519,1436,1225,1172,741cm-1.HRMS(ESI)m/z:[M+H]+Calcd for C20H23N2O5S 403.1322,Found 403.13141.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝10.030min(主要),tR＝17.653min(次要).Preparation of compound 3p: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), tyrosine methyl ester hydrochloride (46.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =1/1) gave 22.9 mg of colorless oily 3p (PE/EA=1:1, R f =0.5), the yield was 57 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.33(s, 1H), 7.26(s, 5H), 6.79(s, 2H), 6.59(d, J=7.9Hz, 2H), 5.64(s, 1H) ,5.25(d,J＝4.9Hz,1H),5.03(s,2H),4.21-3.97(m,2H),3.66(d,J＝12.7Hz,3H),3.17(s,1H),3.02( dd, J=13.9, 4.5 Hz, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.4, 171.2, 156.9, 155.3, 135.9, 130.4, 128.6, 128.4, 128.2, 126.7, 115.7, 67.6, 58.4, 52.7, 51.9 ,35.4.IR(neat)3327,2953,2360,1699,1519,1436,1225,1172,741cm -1 .HRMS(ESI)m/z:[M+H] + Calcd for C 20 H 23 N 2 O 5 S 403.1322, Found 403.13141.ee value > 99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0mL/min, column oven temperature is 30 ℃, The wavelength is 254nm) tR=10.030min (main), tR=17.653min (secondary).
实施例17Example 17
化合物3q的合成：Synthesis of compound 3q:
化合物3q的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，色氨酸甲酯盐酸盐(20.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得31.9mg无色油状3q(PE/EA＝3:1,Rf＝0.5)，收率为75％。1H NMR(400MHz,CDCl3)δ8.30(s,1H),7.91(d,J＝45.9Hz,1H),7.37(d,J＝7.8Hz,1H),7.23(dd,J＝35.4,14.8Hz,1H),7.06(dd,J＝11.1,3.9Hz,1H),6.99(t,J＝7.4Hz,1H),6.76(s,1H),5.35(d,J＝28.4Hz,1H),4.96(dd,J＝29.3,11.7Hz,1H),4.12–3.97(m,1H),3.59(s,1H),3.42(t,J＝10.3Hz,1H),3.29(dd,J＝14.9,4.7Hz,1H).13C NMR(101MHz,CDCl3)δ199.3,171.2,156.6,136.1,128.6,128.3,128.1,127.4,123.2,122.3,119.7,118.3,111.4,109.0,67.3,57.9,52.6,52.0,26.1.IR(neat)3291,2981,1716,1521,1230,1176,1085,696cm-1.HRMS(EI)m/z:Calcd for C22H23N3O4S 425.1409,Found 425.1412..ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝15.163min(主要),tR＝31.783min(次要).Preparation of compound 3q: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), tryptophan methyl ester hydrochloride (20.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 31.9 mg of colorless oily 3q (PE/EA=3:1, R f =0.5), the yield was 75 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (s, 1H), 7.91 (d, J=45.9 Hz, 1H), 7.37 (d, J=7.8 Hz, 1H), 7.23 (dd, J=35.4, 14.8Hz, 1H), 7.06(dd, J＝11.1, 3.9Hz, 1H), 6.99(t, J＝7.4Hz, 1H), 6.76(s, 1H), 5.35(d, J＝28.4Hz, 1H) ,4.96(dd,J=29.3,11.7Hz,1H),4.12–3.97(m,1H),3.59(s,1H),3.42(t,J=10.3Hz,1H),3.29(dd,J=14.9 , 4.7Hz, 1H). 13 C NMR (101MHz, CDCl 3 )δ199.3, 171.2, 156.6, 136.1, 128.6, 128.3, 128.1, 127.4, 123.2, 122.3, 119.7, 118.3, 111.4, 109.0, 67.3, 57.9, 52.6 52.0,26.1.IR(neat)3291,2981,1716,1521,1230,1176,1085,696cm -1 .HRMS(EI)m/z:Calcd for C 22 H 23 N 3 O 4 S 425.1409,Found 425.1412. .ee value is >99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR= 15.163min (main), tR=31.783min (secondary).
实施例18Example 18
化合物3r的合成：Synthesis of compound 3r:
化合物3r的制备:在空气氛围下，往反应管中加入氨基醛1j 19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，谷氨酸二甲酯盐酸盐(42.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得30.2mg无色油状3r(PE/EA＝3:1,Rf＝0.5)，收率为79％。1H NMR(400MHz,CDCl3)δ8.76(s,1H),7.29-7.24(m,5H),5.62(s,1H),5.10–5.05(m,1H),4.24–4.13(m,1H),3.68(s,1H),3.58(s,1H),2.37–2.23(m,1H),2.09(dd,J＝13.9,6.6Hz,1H).13C NMR(101MHz,CDCl3)δ200.3,173.3,171.0,156.8,136.0,128.6,128.3,128.1,67.4,57.0,52.7,52.1,52.0,29.9,26.0.IR(neat)3291,2923,1705,1521,1213,1174,1041,698cm-1.HRMS(EI)m/z:Calcd for C17H22N2O6S 382.1199,Found 382.1194.ee值为>99％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝17.493min(主要),tR＝18.710min(次要).Preparation of compound 3r: under air atmosphere, add aminoaldehyde 1j 19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S 9H to the reaction tube 2 O (28.8 mg, 0.12 mmol), dimethyl glutamate hydrochloride (42.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 30.2 mg of colorless oily 3r (PE/EA=3:1, R f =0.5), the yield was 79 %. 1 H NMR (400MHz, CDCl 3 )δ8.76(s,1H), 7.29-7.24(m,5H), 5.62(s,1H), 5.10-5.05(m,1H), 4.24-4.13(m,1H) ), 3.68(s, 1H), 3.58(s, 1H), 2.37–2.23(m, 1H), 2.09(dd, J=13.9, 6.6Hz, 1H). 13 C NMR (101MHz, CDCl 3 )δ200. 3, 173.3, 171.0, 156.8, 136.0, 128.6, 128.3 , 128.1, 67.4, 57.0, 52.7, 52.1, 52.0, 29.9, 26.0. HRMS (EI) m/z: Calcd for C 17 H 22 N 2 O 6 S 382.1199, Found 382.1194. ee value >99%. Detection parameters for HPLC (Daicel Chirapak AD, n-hexane/isopropanol = 85/15 , flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=17.493min (main), tR=18.710min (secondary).
实施例19Example 19
化合物3s的合成：Synthesis of compound 3s:
化合物3s的制备:在空气氛围下，往反应管中加入氨基醛1j(19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，N6(叔丁基碳基)-L-赖氨酸甲酯盐酸盐(32.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得32.2mg无色油状3s(PE/EA＝3:1,Rf＝0.5)，收率为69％。1H NMR(400MHz,CDCl3)δ8.48(d,J＝108.7Hz,1H),7.29–7.24(m,1H),5.80(t,J＝10.0Hz,1H),5.07(d,J＝3.3Hz,1H),5.04(q,J＝6.4Hz,1H),4.61(s,1H),4.17(t,J＝5.1Hz,1H),3.67(d,J＝4.7Hz,1H),2.99(d,J＝5.4Hz,1H),1.93(d,J＝5.5Hz,1H),1.81-1.72(m,1H),1.39–1.34(m,1H),1.27–1.17(m,1H).13C NMR(101MHz,CDCl3)δ199.8,171.6,156.9,156.2,136.0,128.5,128.3,128.1,79.3,67.4,57.4,52.6,52.1,40.0,30.5,30.2,29.6,28.4,22.2.IR(neat)3281,2923,1697,1521,1244,1167,1039,705cm-1.HRMS(EI)m/z:Calcd for C22H33N3O6S 467.2090,Found 467.2083.ee值为>99％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝12.937min(主要),tR＝25.547min(次要).Preparation of compound 3s: under air atmosphere, aminoaldehyde 1j (19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S were added to the reaction tube . 9H 2 O (28.8 mg, 0.12 mmol), N6 (tert-butylcarbonyl)-L-lysine methyl ester hydrochloride (32.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50 °C 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 32.2 mg of colorless oily 3s (PE/EA=3:1, R f =0.5), the yield was 69 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, J=108.7 Hz, 1H), 7.29-7.24 (m, 1H), 5.80 (t, J=10.0 Hz, 1H), 5.07 (d, J= 3.3Hz, 1H), 5.04(q, J=6.4Hz, 1H), 4.61(s, 1H), 4.17(t, J=5.1Hz, 1H), 3.67(d, J=4.7Hz, 1H), 2.99 (d, J=5.4Hz, 1H), 1.93 (d, J=5.5Hz, 1H), 1.81-1.72 (m, 1H), 1.39-1.34 (m, 1H), 1.27-1.17 (m, 1H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.8, 171.6, 156.9, 156.2, 136.0, 128.5, 128.3, 128.1, 79.3, 67.4, 57.4, 52.6, 52.1, 40.0, 30.5, 30.2, 29.6, 28.4, 22.2.IR (neat )3281,2923,1697,1521,1244,1167,1039,705cm -1 .HRMS(EI)m/z:Calcd for C 22 H 33 N 3 O 6 S 467.2090,Found 467.2083.ee value is >99%. HPLC detection parameters (Daicel Chirapak ID, n-hexane/isopropanol=70/30, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=12.937min (mainly), tR= 25.547min (minor).
实施例20Example 20
化合物4a的合成：Synthesis of compound 4a:
化合物4a的制备:在空气氛围下，往反应管中加入氨基醛1a’(26.4mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，丙氨酸甲酯盐酸盐(27.9mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得21.3mg无色油状4a(PE/EA＝3:1,Rf＝0.5)，收率为56％。1H NMR(400MHz,CDCl3)δ8.85(d,J＝6.6Hz,1H),7.26(d,J＝1.6Hz,6H),5.53(d,J＝5.1Hz,1H),5.15–4.82(m,3H),4.34(dd,J＝16.9,4.9Hz,1H),4.21-4.14(m,J＝13.5,6.6Hz,2H),3.65(s,3H),1.43(d,J＝7.2Hz,3H),1.33(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ199.0,173.2,172.3,156.2,136.0,128.6,128.3,128.0,67.2,53.6,52.6,51.0,50.1,18.1,16.8.IR(neat)3286,2953,1697,1521,1226,1174,1035,737cm-1.HRMS(EI)m/z:Calcd for C17H23N3O5S 381.1358,Found 381.1351.ee值为>99％.HPLC的检测参数(DaicelChirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.037min(主要),tR＝15.133min(次要).Preparation of compound 4a: Under air atmosphere, add aminoaldehyde 1a' (26.4 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube • 9H2O (28.8 mg, 0.12 mmol), alanine methyl ester hydrochloride (27.9 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 21.3 mg of colorless oily 4a (PE/EA=3:1, R f =0.5), the yield was 56 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.85 (d, J=6.6 Hz, 1H), 7.26 (d, J=1.6 Hz, 6H), 5.53 (d, J=5.1 Hz, 1H), 5.15-4.82 (m,3H),4.34(dd,J=16.9,4.9Hz,1H),4.21-4.14(m,J=13.5,6.6Hz,2H),3.65(s,3H),1.43(d,J=7.2 Hz, 3H), 1.33 (d, J=7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.0, 173.2, 172.3, 156.2, 136.0, 128.6, 128.3, 128.0, 67.2, 53.6, 52.6, 51.0, 50.1,18.1,16.8.IR(neat)3286,2953,1697,1521,1226,1174,1035,737cm -1 .HRMS(EI)m/z:Calcd for C 17 H 23 N 3 O 5 S 381.1358,Found 381.1351.ee value is >99%. HPLC detection parameters (DaicelChirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR= 13.037min (main), tR=15.133min (secondary).
实施例21Example 21
化合物4b的合成：Synthesis of compound 4b:
化合物4b的制备:在空气氛围下，往反应管中加入氨基醛1a’(26.4mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，亮氨酸甲酯盐酸盐(36.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得23.3mg无色油状4b(PE/EA＝3:1,Rf＝0.5)，收率为55％。1H NMR(400MHz,CDCl3)δ8.83(d,J＝7.1Hz,1H),7.39–7.22(m,6H),5.51(d,J＝6.0Hz,1H),5.05(dd,J＝21.9,9.9Hz,3H),4.42–4.29(m,1H),4.24–4.12(m,2H),3.63(s,3H),2.12–1.83(m,1H),1.72-1.56(m,3H),1.33(d,J＝7.1Hz,3H),0.86(dd,J＝7.9,6.6Hz,6H).13C NMR(101MHz,CDCl3)δ199.5,173.2,172.1,156.2,136.0,128.6,128.3,128.1,67.2,56.6,52.5,50.9,50.2,40.3,25.0,22.6,22.2,18.1.IR(neat)3273,2971,1697,1533,1242,1172,1026,696cm-1.HRMS(EI)m/z:Calcd for C20H29N3O5S 423.1828,Found423.1826.ee值为>99％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝90/10,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝15.177min(主要),tR＝11.400min(次要).Preparation of compound 4b: under air atmosphere, add aminoaldehyde 1a' (26.4 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg , 0.12 mmol), leucine methyl ester hydrochloride (36.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 23.3 mg of colorless oily 4b (PE/EA=3:1, R f =0.5), the yield was 55 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.83 (d, J=7.1 Hz, 1H), 7.39-7.22 (m, 6H), 5.51 (d, J=6.0 Hz, 1H), 5.05 (dd, J= 21.9, 9.9Hz, 3H), 4.42–4.29 (m, 1H), 4.24–4.12 (m, 2H), 3.63 (s, 3H), 2.12–1.83 (m, 1H), 1.72–1.56 (m, 3H) , 1.33 (d, J=7.1Hz, 3H), 0.86 (dd, J=7.9, 6.6Hz, 6H). 13 C NMR (101MHz, CDCl 3 )δ199.5, 173.2, 172.1, 156.2, 136.0, 128.6, 128.3, 128.1, 67.2, 56.6, 52.5, 50.9, 50.2, 40.3, 25.0, 22.6, 22.2, 18.1.IR(neat)3273,2971,1697,1533,1242,1172,1026,696cm -1 .HRMS(EI)m/ z: Calcd for C 20 H 29 N 3 O 5 S 423.1828, Found 423.1826. ee value >99%. Detection parameters for HPLC (Daicel Chirapak AD, n-hexane/isopropanol=90/10, flow rate=1.0 mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=15.177min (main), tR=11.400min (minor).
实施例22Example 22
化合物4c的合成：Synthesis of compound 4c:
化合物4c的制备:在空气氛围下，往反应管中加入氨基醛1a’(26.4mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，蛋氨酸甲酯盐酸盐(26.4mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得16.7mg无色油状4c(PE/EA＝3:1,Rf＝0.5)，收率为38％。1H NMR(400MHz,CDCl3)δ8.95(d,J＝7.0Hz,1H),7.27(s,6H),5.49(d,J＝5.5Hz,1H),5.20(d,J＝5.7Hz,1H),5.03(q,J＝12.1Hz,2H),4.44–4.29(m,1H),4.24–4.10(m,2H),3.66(s,3H),2.45(t,J＝7.4Hz,2H),2.20(dd,J＝22.6,17.1Hz,2H),2.00(s,3H),1.34(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ199.6,173.2,171.2,156.3,136.0,128.6,128.3,128.1,67.3,57.0,52.7,51.0,50.3,30.4,30.0,18.0,15.5.IR(neat)3329,2980,1693,1512,1223,1176,1026,748cm-1.HRMS(EI)m/z:Calcd for C19H27N3O5S2441.1392,Found441.1386.ee值为>99％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.587min(主要),tR＝19.503min(次要).Preparation of compound 4c: under air atmosphere, add aminoaldehyde 1a' (26.4 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube • 9H 2 O (28.8 mg, 0.12 mmol), methionine methyl ester hydrochloride (26.4 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 16.7 mg of colorless oily 4c (PE/EA=3:1, R f =0.5), the yield was 38 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.95 (d, J=7.0 Hz, 1H), 7.27 (s, 6H), 5.49 (d, J=5.5 Hz, 1H), 5.20 (d, J=5.7 Hz ,1H),5.03(q,J＝12.1Hz,2H),4.44-4.29(m,1H),4.24-4.10(m,2H),3.66(s,3H),2.45(t,J＝7.4Hz, 2H), 2.20 (dd, J=22.6, 17.1 Hz, 2H), 2.00 (s, 3H), 1.34 (d, J=7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.6, 173.2, 171.2 -1 .HRMS (EI) m/z: Calcd for C 19 H 27 N 3 O 5 S 2 441.1392, Found441.1386. ee value >99%. Detection parameters for HPLC (Daicel Chirapak AD, n-hexane/isopropanol= 85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=13.587min (main), tR=19.503min (secondary).
实施例23Example 23
化合物4d的合成：Synthesis of compound 4d:
化合物4d的制备:在空气氛围下，往反应管中加入氨基醛1d’(34.0mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，b丙氨酸甲酯盐酸盐(26.4mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得30.6mg无色油状4d(PE/EA＝3:1,Rf＝0.5)，收率为67％。1H NMR(300MHz,CDCl3)δ8.85(d,J＝5.9Hz,1H),7.39–7.24(m,4H),7.02(s,3H),5.45(d,J＝6.6Hz,1H),5.07(s,2H),4.40(d,J＝6.4Hz,1H),4.16(dd,J＝16.7,4.1Hz,1H),3.74(s,2H),3.17(dd,J＝13.8,6.4Hz,1H),3.08(d,J＝7.6Hz,1H),1.52(d,J＝7.1Hz,2H).13CNMR(101MHz,CDCl3)δ198.7,172.2,171.8,156.3,136.0,135.9,129.2,128.8,128.6,128.3,128.0,127.2,67.3,56.8,53.6,52.6,50.3,37.8,16.8.IR(neat)3273,3021,1739,1654,1525,1263,1197,701cm-1.HRMS(EI)m/z:Calcd for C23H27N3O5S 457.1671,Found457.1677.ee值为>99％.HPLC的检测参数(Daicel Chirapak OJ,正己烷/异丙醇＝80/20,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝26.443min(主要),tR＝20.930min(次要).Preparation of compound 4d: under air atmosphere, add aminoaldehyde 1d' (34.0 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg , 0.12 mmol), b alanine methyl ester hydrochloride (26.4 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 30.6 mg of colorless oily 4d (PE/EA=3:1, R f =0.5), the yield was 67 %. 1 H NMR (300 MHz, CDCl 3 ) δ 8.85 (d, J=5.9 Hz, 1H), 7.39-7.24 (m, 4H), 7.02 (s, 3H), 5.45 (d, J=6.6 Hz, 1H) ,5.07(s,2H),4.40(d,J＝6.4Hz,1H),4.16(dd,J＝16.7,4.1Hz,1H),3.74(s,2H),3.17(dd,J＝13.8,6.4 Hz, 1H), 3.08 (d, J=7.6 Hz, 1H), 1.52 (d, J=7.1 Hz, 2H). 13 CNMR (101 MHz, CDCl 3 ) δ 198.7, 172.2, 171.8, 156.3, 136.0, 135.9, 129.2 ,128.8,128.6,128.3,128.0,127.2,67.3,56.8,53.6,52.6,50.3,37.8,16.8.IR(neat)3273,3021,1739,1654,1525,1263,1197,701cm -1 .HRMS(EI ) m/z: Calcd for C 23 H 27 N 3 O 5 S 457.1671, Found457.1677. ee value >99%. Detection parameters for HPLC (Daicel Chirapak OJ, n-hexane/isopropanol=80/20, flow Speed=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=26.443min (main), tR=20.930min (secondary).
实施例24Example 24
化合物4e的合成：Synthesis of compound 4e:
化合物4e的制备:在空气氛围下，往反应管中加入氨基醛1d’(34.0mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，b亮氨酸甲酯盐酸盐(26.4mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得28.9mg无色油状4e(PE/EA＝3:1,Rf＝0.5)，收率为58％。1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.27-7.20(m,8H),7.08-7.06(m,2H),5.36(s,1H),5.07(q,J＝7.2Hz,1H),4.98(s,1H),4.39-4.27(m,J＝14.1,7.0Hz,2H),4.07-4.02(m,1H),3.68-3.63(s,1H),3.11-3.06(m,1H),2.98-2.93(m,J＝13.6,7.8Hz,1H),1.71(dd,J＝13.3,6.4Hz,2H),1.66-1.57(m,J＝13.4,6.7Hz,1H),0.87(dd,J＝8.4,6.5Hz,6H)..13C NMR(101MHz,CDCl3)δ199.2,172.1,171.8,156.2,136.1,135.8,129.1,128.8,128.6,128.3,128.1,127.2,67.3,56.6,52.4,50.4,40.3,37.7,25.0,22.6,22.2.IR(neat)3291,2953,1745,1660,1521,1230,1028,748cm-1.HRMS(ESI)m/z:[M+Na]+Calcd for C26H33N3NaO5S522.2039,Found 522.2059.ee值为>99％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝90/10,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝21.530min(主要),tR＝18.090min(次要).Preparation of compound 4e: under air atmosphere, add aminoaldehyde 1d' (34.0 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg , 0.12 mmol), b leucine methyl ester hydrochloride (26.4 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 28.9 mg of colorless oily 4e (PE/EA=3:1, R f =0.5), the yield was 58 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.72(s, 1H), 7.27-7.20(m, 8H), 7.08-7.06(m, 2H), 5.36(s, 1H), 5.07(q, J=7.2 Hz,1H),4.98(s,1H),4.39-4.27(m,J=14.1,7.0Hz,2H),4.07-4.02(m,1H),3.68-3.63(s,1H),3.11-3.06( m, 1H), 2.98-2.93 (m, J=13.6, 7.8Hz, 1H), 1.71 (dd, J=13.3, 6.4Hz, 2H), 1.66-1.57 (m, J=13.4, 6.7Hz, 1H) The _ ,56.6,52.4,50.4,40.3,37.7,25.0,22.6,22.2.IR(neat)3291,2953,1745,1660,1521,1230,1028,748cm -1 .HRMS(ESI)m/z:[M+ Na] + Calcd for C 26 H 33 N 3 NaO 5 S522.2039, Found 522.2059. ee value >99%. Detection parameters for HPLC (Daicel Chirapak AD, n-hexane/isopropanol=90/10, flow rate= 1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=21.530min (main), tR=18.090min (secondary).
实施例25Example 25
化合物4f的合成：Synthesis of compound 4f:
化合物4f的制备:在空气氛围下，往反应管中加入氨基醛1j’(19.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，2f’(77.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得16.5mg无色油状4f(PE/EA＝3:1,Rf＝0.5)，收率为33％。1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.43-7.15(m,10H),6.04(s,1H),5.56(s,1H),5.13(dd,J＝13.1,7.6Hz,1H),5.02(d,J＝4.4Hz,2H),4.49-4.39(m,1H),4.20-4.07(m,2H),3.66-3.59(m,3H),3.24(dd,J＝13.6,4.9Hz,1H),3.01(dd,J＝13.3,8.0Hz,1H),1.51-1.33(m,3H),0.78(d,J＝5.4Hz,6H).13C NMR(101MHz,CDCl3)δ199.1,172.5,169.3,156.7,135.9,129.4,128.8,128.6,128.6,128.3,128.2,127.3,67.5,59.4,52.4,51.1,41.2,37.0,29.7,24.7,22.7,21.9.IR(neat)3298,2951,1716,1533,1456,1226,1107,696cm-1.HRMS(EI)m/z:Calcdfor C26H33N3O5S 499.2141,Found 499.2138.ee值为98％.HPLC的检测参数(DaicelChirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝19.247min(主要),tR＝12.813min(次要).Preparation of compound 4f: under air atmosphere, add aminoaldehyde 1j' (19.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H2O (28.8 mg , 0.12 mmol), 2f' (77.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 16.5 mg of colorless oily 4f (PE/EA=3:1, R f =0.5), the yield was 33 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.64 (s, 1H), 7.43-7.15 (m, 10H), 6.04 (s, 1H), 5.56 (s, 1H), 5.13 (dd, J=13.1, 7.6 Hz, 1H), 5.02(d, J=4.4Hz, 2H), 4.49-4.39(m, 1H), 4.20-4.07(m, 2H), 3.66-3.59(m, 3H), 3.24(dd, J= 13.6, 4.9Hz, 1H), 3.01 (dd, J=13.3, 8.0Hz, 1H), 1.51-1.33 (m, 3H), 0.78 (d, J=5.4Hz, 6H). 13 C NMR (101MHz, CDCl) 3 ) δ199.1, 172.5, 169.3, 156.7, 135.9, 129.4, 128.8, 128.6, 128.6, 128.3, 128.2, 127.3, 67.5, 59.4, 52.4, 51.1, 41.2, 37.0, 29.7, 24.7, 22.7, 21.9.IR(neat) 3298, 2951, 1716, 1533, 1456, 1226, 1107, 696 cm -1 .HRMS (EI) m/z: Calcd for C 26 H 33 N 3 O 5 S 499.2141, Found 499.2138.ee value is 98%. HPLC detection Parameters (DaicelChirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature 30℃, wavelength 254nm) tR=19.247min (main), tR=12.813min (times) want).
实施例26Example 26
化合物4g的合成：Synthesis of compound 4g:
化合物4g的制备:在空气氛围下，往反应管中加入氨基醛1a(28.3mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，2g’(36.4mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得29.2mg无色油状4g(PE/EA＝3:1,Rf＝0.5)，收率为66％。1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.19(dtt,J＝17.7,10.9,5.3Hz,10H),6.65(s,1H),5.70(d,J＝7.2Hz,1H),4.95(q,J＝12.3Hz,2H),4.71(q,J＝7.2Hz,1H),4.25-4.08(m,J＝21.8,17.0,4.8Hz,2H),3.95–3.81(m,2H),3.64(s,3H),3.14-2.99(m,J＝20.5,13.4,7.5Hz,2H).13C NMR(101MHz,CDCl3)δ204.1,170.1,167.4,156.0,136.2,136.0,129.2,128.7,128.6,128.2,127.9,127.2,67.2,62.7,52.6,48.2,41.8,41.2.IR(neat)3311,2954,1695,1519,1242,1220,1028,738cm-1.HRMS(EI)m/z:Calcd for C22H25N3O5S 443.1515,Found443.1519.ee值为80％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝21.227min(主要),tR＝35.833min(次要).Preparation of compound 4g: Under air atmosphere, aminoaldehyde 1a (28.3 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S were added to the reaction tube . 9H2O (28.8 mg, 0.12 mmol), 2 g' (36.4 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 29.2 mg of colorless oil 4g (PE/EA=3:1, R f =0.5), the yield was 66 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (s, 1H), 7.19 (dtt, J=17.7, 10.9, 5.3 Hz, 10H), 6.65 (s, 1H), 5.70 (d, J=7.2 Hz, 1H), 4.95(q, J＝12.3Hz, 2H), 4.71(q, J＝7.2Hz, 1H), 4.25-4.08(m, J＝21.8, 17.0, 4.8Hz, 2H), 3.95-3.81(m , 2H), 3.64(s, 3H), 3.14-2.99(m, J=20.5, 13.4, 7.5Hz, 2H). 13 C NMR(101MHz, CDCl 3 )δ204.1,170.1,167.4,156.0,136.2,136.0, 129.2,128.7,128.6,128.2,127.9,127.2,67.2,62.7,52.6,48.2,41.8,41.2.IR(neat)3311,2954,1695,1519,1242,1220,1028,738cm -1 .HRMS(EI) m/z: Calcd for C 22 H 25 N 3 O 5 S 443.1515, Found443.1519. ee value is 80%. Detection parameters of HPLC (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow velocity= 1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=21.227min (main), tR=35.833min (minor).
实施例27Example 27
化合物4h的合成：Synthesis of compound 4h:
化合物4h的制备:在空气氛围下，往反应管中加入氨基醛1d’(34.0mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，2h’(44.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得26.5mg无色油状4g(PE/EA＝3:1,Rf＝0.5)，收率为49％。1H NMR(400MHz,CDCl3)δ8.99(s,1H),7.33–7.04(m,12H),6.80(d,J＝8.7Hz,1H),5.76(d,J＝6.9Hz,1H),5.05–4.84(m,2H),4.48–4.04(m,5H),3.62(d,J＝23.4Hz,3H),3.09-2.89(m,2H),2.12-2.04(m,1H),0.83(t,J＝6.8Hz,6H).13C NMR(101MHz,CDCl3)δ199.5,172.3,172.3,167.4,156.6,136.2,136.0,129.2,128.7,128.5,128.2,128.0,127.1,67.3,57.5,56.7,52.3,50.3,48.5,37.9,31.1,19.0,17.9.IR(neat)3305,2956,1666,1525,1263,1151,737,698cm-1.HRMS(EI)m/z:Calcd for C27H34N4O6S 542.2199,Found 542.2184.Preparation of compound 4h: under air atmosphere, add aminoaldehyde 1d' (34.0 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H2O (28.8 mg , 0.12 mmol), 2h' (44.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 26.5 mg of colorless oil 4g (PE/EA=3:1, R f =0.5), the yield was 49 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.99 (s, 1H), 7.33-7.04 (m, 12H), 6.80 (d, J=8.7Hz, 1H), 5.76 (d, J=6.9Hz, 1H) ,5.05-4.84(m,2H),4.48-4.04(m,5H),3.62(d,J=23.4Hz,3H),3.09-2.89(m,2H),2.12-2.04(m,1H),0.83 (t, J=6.8 Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.5, 172.3, 172.3, 167.4, 156.6, 136.2, 136.0, 129.2, 128.7, 128.5, 128.2, 128.0, 127.1, 67.3, 57.5, 56.7,52.3,50.3,48.5,37.9,31.1,19.0,17.9.IR(neat)3305,2956,1666,1525,1263,1151,737,698cm -1 .HRMS(EI)m/z:Calcd for C 27 H 34 N 4 O 6 S 542.2199, Found 542.2184.
实施例28Example 28
化合物4i的合成：Synthesis of compound 4i:
化合物4i的制备:在空气氛围下，往反应管中加入氨基醛1d’(34.0mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，2i’(47.6mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得28.3mg无色油状4g(PE/EA＝3:1,Rf＝0.5)，收率为51％。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.33–7.07(m,12H),6.64(d,J＝7.9Hz,1H),5.59(d,J＝5.6Hz,1H),5.06–4.91(m,2H),4.52(dd,J＝14.3,8.1Hz,1H),4.39–4.04(m,4H),3.60(s,3H),3.16–2.87(m,2H),1.70–1.41(m,3H),1.21(d,J＝19.1Hz,1H),0.84(t,J＝6.6Hz,6H).13C NMR(101MHz,CDCl3)δ199.6,173.3,172.3,167.3,156.7,136.1,135.9,129.2,128.8,128.8,128.6,128.3,128.1,127.2,67.4,56.8,52.4,51.0,50.6,48.3,41.1,37.8,24.8,22.8,21.7.IR(neat)3282,2964,1666,1516,1263,1213,1147,701cm-1.HRMS(EI)m/z:Calcdfor C28H36N4O6S 556.2356,Found 556.2363.Preparation of compound 4i: under air atmosphere, add aminoaldehyde 1d' (34.0 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H2O (28.8 mg , 0.12 mmol), 2i' (47.6 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 28.3 mg of colorless oil 4g (PE/EA=3:1, R f =0.5), the yield was 51 %. 1 H NMR (400MHz, CDCl 3 ) δ 8.87 (s, 1H), 7.33-7.07 (m, 12H), 6.64 (d, J=7.9Hz, 1H), 5.59 (d, J=5.6Hz, 1H) ,5.06–4.91(m,2H),4.52(dd,J=14.3,8.1Hz,1H),4.39–4.04(m,4H),3.60(s,3H),3.16–2.87(m,2H),1.70 -1.41 (m, 3H), 1.21 (d, J=19.1Hz, 1H), 0.84 (t, J=6.6Hz, 6H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.6, 173.3, 172.3, 167.3, 156.7 ,136.1,135.9,129.2,128.8,128.8,128.6,128.3,128.1,127.2,67.4,56.8,52.4,51.0,50.6,48.3,41.1,37.8,24.8,22.8,21.7.IR(neat)3282,26964, ,1516,1263,1213,1147,701cm -1 .HRMS(EI)m/z:Calcdfor C 28 H 36 N 4 O 6 S 556.2356,Found 556.2363.
实施例29Example 29
化合物4j的合成：Synthesis of compound 4j:
化合物4j的制备:在空气氛围下，往反应管中加入氨基醛1d’(34.0mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，2j’(54.4mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得26.0mg无色油状4g(PE/EA＝3:1,Rf＝0.5)，收率为61％。1H NMR(400MHz,DMSO)δ9.71(t,J＝5.1Hz,1H),8.56(d,J＝7.0Hz,1H),7.58(t,J＝15.8Hz,1H),7.34–7.21(m,1H),4.98–4.91(m,1H),4.54–4.48(m,1H),4.31–4.15(m,1H),4.07(dd,J＝17.0,5.6Hz,1H),3.58(s,1H),3.12(dd,J＝13.9,3.9Hz,1H),3.04(dd,J＝13.8,5.7Hz,1H),2.93(dd,J＝13.7,8.8Hz,1H),2.77(dd,J＝13.7,10.8Hz,1H).13C NMR(101MHz,DMSO)δ200.6,172.4,172.1,167.4,156.5,138.6,137.4,137.4,129.6,129.5,128.7,128.5,128.2,128.0,127.1,126.7,65.8,56.7,54.2,52.3,49.7,47.8,37.6,37.2.IR(neat)3310,2951,1728,1660,1498,1213,1028,738cm-1.HRMS(ESI)m/z:[M+Na]+Calcd forC31H34N4O6SNa 613.2097,Found 613.2075.Preparation of compound 4j: under air atmosphere, add aminoaldehyde 1d' (34.0 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H2O (28.8 mg , 0.12 mmol), 2j' (54.4 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 26.0 mg of colorless oil 4g (PE/EA=3:1, R f =0.5), the yield was 61 %. 1 H NMR(400MHz,DMSO)δ9.71(t,J=5.1Hz,1H),8.56(d,J=7.0Hz,1H),7.58(t,J=15.8Hz,1H),7.34-7.21( m, 1H), 4.98–4.91 (m, 1H), 4.54–4.48 (m, 1H), 4.31–4.15 (m, 1H), 4.07 (dd, J=17.0, 5.6Hz, 1H), 3.58 (s, 1H),3.12(dd,J=13.9,3.9Hz,1H),3.04(dd,J=13.8,5.7Hz,1H),2.93(dd,J=13.7,8.8Hz,1H),2.77(dd,J =13.7,10.8Hz,1H) .13C NMR(101MHz,DMSO)δ200.6,172.4,172.1,167.4,156.5,138.6,137.4,137.4,129.6,129.5,128.7,128.5,128.2,128.0,127.1,126. ,56.7,54.2,52.3,49.7,47.8,37.6,37.2.IR(neat)3310,2951,1728,1660,1498,1213,1028,738cm -1 .HRMS(ESI)m/z:[M+Na] + Calcd for C 31 H 34 N 4 O 6 SNa 613.2097, Found 613.2075.
实施例30Example 30
化合物4k的合成：Synthesis of compound 4k:
化合物4k的制备:在空气氛围下，往反应管中加入氨基醛1k’(24.7mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，丙氨酸甲酯盐酸盐(27.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得22.2mg无色油状4k(PE/EA＝3:1,Rf＝0.5)，收率为61％。1H NMR(400MHz,CDCl3)δ8.92(s,1H),7.14(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.58(s,1H),4.96-4.89(m,1H),4.23–4.10(m,2H),3.69(s,3H),3.56(q,J＝7.2Hz,1H),2.38(d,J＝7.2Hz,2H),1.81-1.74(m,J＝13.5,6.8Hz,2H),1.47(d,J＝7.2Hz,3H),1.40–1.35(m,3H),0.82(d,J＝6.6Hz,6H).13C NMR(101MHz,CDCl3)δ199.3,175.6,172.0,141.0,137.7,129.7,127.4,53.5,52.6,50.4,46.5,45.0,30.2,22.4,18.2,16.8.IR(neat)3253,2967,1734,1653,1541,1417,1201,1174cm-1.HRMS(EI)m/z:Calcd for C19H28N2O3S364.1821,Found 364.1819.ee值为97％.HPLC的检测参数(Daicel Chirapak ID,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝9.627min(主要),tR＝12.937min(次要)..Preparation of compound 4k: under air atmosphere, add aminoaldehyde 1k' (24.7 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg , 0.12 mmol), alanine methyl ester hydrochloride (27.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 22.2 mg of colorless oily 4k (PE/EA=3:1, R f =0.5), the yield was 61 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.92 (s, 1H), 7.14 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.0 Hz, 2H), 6.58 (s, 1H), 4.96 -4.89(m, 1H), 4.23–4.10(m, 2H), 3.69(s, 3H), 3.56(q, J=7.2Hz, 1H), 2.38(d, J=7.2Hz, 2H), 1.81- 1.74 (m, J=13.5, 6.8Hz, 2H), 1.47 (d, J=7.2Hz, 3H), 1.40–1.35 (m, 3H), 0.82 (d, J=6.6Hz, 6H). 13 C NMR (101MHz, CDCl 3 )δ199.3,175.6,172.0,141.0,137.7,129.7,127.4,53.5,52.6,50.4,46.5,45.0,30.2,22.4,18.2,16.8.IR(neat)3253,2967,1734,1653, 1541, 1417, 1201, 1174 cm -1 . HRMS (EI) m/z: Calcd for C 19 H 28 N 2 O 3 S364.1821, Found 364.1819. The ee value is 97%. Detection parameters by HPLC (Daicel Chirapak ID, n-hexane/isopropanol=85/15, flow rate=1.0mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=9.627min (main), tR=12.937min (minor)..
实施例31Example 31
化合物4l的合成：Synthesis of compound 4l:
化合物4l的制备:在空气氛围下，往反应管中加入氨基醛1k’(24.7mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S·9H2O(28.8mg,0.12mmol)，亮氨酸甲酯盐酸盐(36.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得21.1mg无色油状4l(PE/EA＝3:1,Rf＝0.5)，收率为52％。1H NMR(400MHz,CDCl3)δ8.86(s,1H),7.14(s,2H),7.05(d,J＝8.1Hz,2H),6.50(s,1H),4.99-4.94(m,J＝8.0,6.0Hz,1H),4.29–4.05(m,2H),3.67(s,3H),3.55(q,J＝7.2Hz,1H),2.38(d,J＝7.2Hz,2H),1.83-1.69(m,1H),1.71-1.64(m,2H),1.61–1.51(m,1H),1.47(d,J＝7.2Hz,3H),0.87-0.82(m,12H).13C NMR(101MHz,CDCl3)δ200.0,175.9,171.8,141.1,137.6,129.8,127.4,56.6,52.4,50.9,46.5,45.0,40.4,30.2,25.0,22.6,22.4,22.1,18.3.IR(neat)3261,2953,1651,1503,1415,1205,1132,748cm-1.HRMS(EI)m/z:Calcdfor C22H34N2O3S 406.2290,Found 406.2283.ee值为>99％.HPLC的检测参数(DaicelChirapak ID,正己烷/异丙醇＝95/05,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝10.317min(主要),tR＝7.620min(次要).Preparation of compound 41: under air atmosphere, add aminoaldehyde 1k' (24.7 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube • 9H2O (28.8 mg, 0.12 mmol), leucine methyl ester hydrochloride (36.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50°C for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 21.1 mg of colorless oily 4l (PE/EA=3:1, R f =0.5), the yield was 52 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 1H), 7.14 (s, 2H), 7.05 (d, J=8.1 Hz, 2H), 6.50 (s, 1H), 4.99-4.94 (m, J=8.0, 6.0Hz, 1H), 4.29–4.05(m, 2H), 3.67(s, 3H), 3.55(q, J=7.2Hz, 1H), 2.38(d, J=7.2Hz, 2H), 1.83-1.69(m, 1H), 1.71-1.64(m, 2H), 1.61-1.51(m, 1H), 1.47(d, J=7.2Hz, 3H), 0.87-0.82(m, 12H). 13 C NMR(101MHz, CDCl 3 )δ200.0,175.9,171.8,141.1,137.6,129.8,127.4,56.6,52.4,50.9,46.5,45.0,40.4,30.2,25.0,22.6,22.4,22.1,18.3.IR(neat)3261 , 2953, 1651, 1503, 1415, 1205, 1132, 748 cm -1 .HRMS(EI) m/z:Calcdfor C 22 H 34 N 2 O 3 S 406.2290,Found 406.2283.ee value>99%. HPLC detection Parameters (DaicelChirapak ID, n-hexane/isopropanol=95/05, flow rate=1.0mL/min, column oven temperature 30℃, wavelength 254nm) tR=10.317min (main), tR=7.620min (times) want).
实施例32Example 32
化合物4m的合成：Synthesis of compound 4m:
化合物4m的制备:在空气氛围下，往反应管中加入氨基醛1m’(27.1mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(28.8mg,0.12mmol)，丙氨酸甲酯盐酸盐(27.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得28.7mg无色油状4m(PE/EA＝3:1,Rf＝0.5)，收率为74％。1H NMR(400MHz,CDCl3)δ8.86(s,1H),7.62(dd,J＝8.0,6.7Hz,3H),7.31(dd,J＝8.5,1.6Hz,1H),7.10–7.00(m,2H),6.64(s,1H),4.90(t,J＝7.1Hz,1H),4.22–4.07(m,2H),3.83(s,3H),3.74–3.63(m,4H),1.54(d,J＝7.1Hz,3H),1.33(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ199.3,175.5,172.1,157.8,135.7,133.9,129.3,129.0,127.7,126.2,126.1,119.2,105.6,55.3,53.5,52.6,50.5,46.8,18.3,16.8.IR(neat)3271,2937,1734,1653,1503,1237,1028,732cm-1.HRMS(EI)m/z:Calcd for C20H24N2O4S 388.1457,Found388.1451.ee值为>99％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝15.093min(主要),tR＝12.697min(次要).Preparation of compound 4m: under air atmosphere, add aminoaldehyde 1m' (27.1 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (28.8 mg , 0.12 mmol), alanine methyl ester hydrochloride (27.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 28.7 mg of colorless oily 4m (PE/EA=3:1, R f =0.5), the yield was 74 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 1H), 7.62 (dd, J=8.0, 6.7 Hz, 3H), 7.31 (dd, J=8.5, 1.6 Hz, 1H), 7.10-7.00 ( m, 2H), 6.64 (s, 1H), 4.90 (t, J=7.1Hz, 1H), 4.22–4.07 (m, 2H), 3.83 (s, 3H), 3.74–3.63 (m, 4H), 1.54 (d, J=7.1Hz, 3H), 1.33 (d, J=7.2Hz, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 199.3, 175.5, 172.1, 157.8, 135.7, 133.9, 129.3, 129.0, 127.7, 126.2,126.1,119.2,105.6,55.3,53.5,52.6,50.5,46.8,18.3,16.8.IR(neat)3271,2937,1734,1653,1503,1237,1028,732cm -1 .HRMS(EI)m/ z: Calcd for C 20 H 24 N 2 O 4 S 388.1457, Found388.1451. ee value >99%. Detection parameters for HPLC (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature is 30℃, wavelength is 254nm) tR=15.093min (main), tR=12.697min (minor).
实施例33Example 33
化合物4n的合成：Synthesis of compound 4n:
化合物4n的制备:在空气氛围下，往反应管中加入氨基醛1n’(30.9mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(27.8mg,0.12mmol)，丙氨酸甲酯盐酸盐(27.8mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得22.1mg无色油状4n(PE/EA＝3:1,Rf＝0.5)，收率为52％。1H NMR(400MHz,CDCl3)δ8.81(d,J＝6.4Hz,1H),8.05(d,J＝2.3Hz,1H),7.80(dd,J＝7.7,1.1Hz,1H),7.51-7.47(m,1H),7.44–7.35(m,2H),7.31(s,1H),6.98(d,J＝8.4Hz,1H),6.77(s,1H),5.12(s,2H),4.95-4.88(m,1H),4.25-4.13(m,2H),3.67(s,3H),3.58(s,2H),1.39(d,J＝7.2Hz,3H).13CNMR(101MHz,CDCl3)δ199.1,190.8,172.1,171.8,160.7,140.4,136.4,135.5,132.9,132.6,129.5,129.3,128.1,127.9,125.3,121.6,73.7,53.6,52.7,50.4,42.3,16.8.IR(neat)3298,2951,1734,1647,1541,1303,1120,732cm-1.HRMS(EI)m/z:Calcd for C22H22N2O5S 426.1249,Found 426.1246.ee值为>99％.HPLC的检测参数(DaicelChirapak AD,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝13.893min(主要),tR＝16.260min(次要).Preparation of compound 4n: under air atmosphere, add aminoaldehyde 1n' (30.9 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (27.8 mg , 0.12 mmol), alanine methyl ester hydrochloride (27.8 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 22.1 mg of colorless oily 4n (PE/EA=3:1, R f =0.5), the yield was 52 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.81 (d, J=6.4 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.80 (dd, J=7.7, 1.1 Hz, 1H), 7.51 -7.47(m, 1H), 7.44–7.35(m, 2H), 7.31(s, 1H), 6.98(d, J=8.4Hz, 1H), 6.77(s, 1H), 5.12(s, 2H), 4.95-4.88(m, 1H), 4.25-4.13(m, 2H), 3.67(s, 3H), 3.58(s, 2H), 1.39(d, J=7.2Hz, 3H). 13 CNMR(101MHz, CDCl) 3 ) δ199.1, 190.8, 172.1, 171.8, 160.7, 140.4, 136.4, 135.5, 132.9, 132.6, 129.5, 129.3, 128.1, 127.9, 125.3, 121.6, 73.7, 53.6, 52.7, 50.4, 42.3 IR(neat) 3298, 2951, 1734, 1647, 1541, 1303, 1120, 732 cm -1 .HRMS(EI) m/z:Calcd for C 22 H 22 N 2 O 5 S 426.1249,Found 426.1246.ee value >99%.HPLC The detection parameters (DaicelChirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0mL/min, column oven temperature 30℃, wavelength 254nm) tR=13.893min (main), tR=16.260min (secondary).
实施例34Example 34
化合物4o的合成：Synthesis of compound 4o:
化合物4o的制备:在空气氛围下，往反应管中加入氨基醛1n’(30.9mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(27.8mg,0.12mmol)，亮氨酸甲酯盐酸盐(36.2mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得16.4mg无色油状4o(PE/EA＝3:1,Rf＝0.5)，收率为35％。1H NMR(400MHz,CDCl3)δ8.91(d,J＝7.4Hz,1H),8.05(d,J＝2.3Hz,1H),7.80(d,J＝7.6Hz,1H),7.49(t,J＝7.4Hz,1H),7.43–7.33(m,2H),7.29(d,J＝7.4Hz,1H),7.01–6.84(m,2H),5.11(s,2H),4.99-4.94(m,1H),4.30–4.12(m,2H),3.64(s,3H),3.57(s,2H),1.68–1.47(m,3H),0.81(t,J＝5.8Hz,6H).13C NMR(101MHz,CDCl3)δ199.7,190.8,171.9,171.8,160.7,140.4,136.4,135.5,132.9,132.6,129.5,129.3,128.1,128.1,127.9,125.3,121.6,73.6,56.7,52.4,50.4,50.4,42.3,40.3,25.0,22.6,22.1.IR(neat)3293,2954,1734,1647,1411,1205,1174,721cm-1.HRMS(EI)m/z:Calcd for C25H28N2O5S 468.1719,Found 468.1705.ee值为>99％.HPLC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝85/15,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝25.727min(主要),tR＝20.853min(次要).Preparation of compound 4o: under air atmosphere, add aminoaldehyde 1n' (30.9 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (27.8 mg , 0.12 mmol), leucine methyl ester hydrochloride (36.2 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 16.4 mg of colorless oily 4o (PE/EA=3:1, R f =0.5), the yield was 35 %. 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (d, J=7.4 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 7.49 (t , J=7.4Hz, 1H), 7.43-7.33(m, 2H), 7.29(d, J=7.4Hz, 1H), 7.01-6.84(m, 2H), 5.11(s, 2H), 4.99-4.94( m,1H),4.30–4.12(m,2H),3.64(s,3H),3.57(s,2H),1.68–1.47(m,3H),0.81(t,J=5.8Hz,6H). 13 C NMR (101MHz, CDCl 3 )δ199.7,190.8,171.9,171.8,160.7,140.4,136.4,135.5,132.9,132.6,129.5,129.3,128.1,128.1,127.9,125.3,121.6,73.6,56. 50.4,42.3,40.3,25.0,22.6,22.1.IR(neat)3293,2954,1734,1647,1411,1205,1174,721cm -1 .HRMS(EI)m/z:Calcd for C 25 H 28 N 2 O 5 S 468.1719, Found 468.1705.ee value >99%. Detection parameters of HPLC (Daicel Chirapak AD, n-hexane/isopropanol=85/15, flow rate=1.0 mL/min, column oven temperature 30°C , the wavelength is 254nm) tR=25.727min (main), tR=20.853min (secondary).
实施例35Example 35
化合物4p的合成：Synthesis of compound 4p:
化合物4p的制备:在空气氛围下，往反应管中加入氨基醛1n’(30.9mg,0.1mmol)，S8(6.4mg,0.2mmol)，CuCl2(2.0mg,0.015mmol)，Na2S.9H2O(27.8mg,0.12mmol)，蛋氨酸甲酯盐酸盐(39.9mg,0.2mmol)以及重蒸溶剂THF(1mL)于50℃下反应10小时。反应完毕后，萃取，浓缩，经柱层析(VPE/VEA＝3/1)分离得23.3mg无色油状4p(PE/EA＝3:1,Rf＝0.5)，收率为48％。1H NMR(400MHz,CDCl3)δ9.06(d,J＝7.3Hz,1H),8.05(d,J＝2.3Hz,1H),7.80(dd,J＝7.7,1.1Hz,1H),7.51-7.47(m,1H),7.41-7.36(m,2H),7.30(s,1H),6.98(d,J＝8.4Hz,1H),6.90(s,1H),5.16–5.06(m,3H),4.33–4.13(m,2H),3.66(s,3H),3.58(s,2H),2.39(t,J＝7.4Hz,2H),2.19-2.13(m,1H),2.06–1.94(m,4H).13C NMR(101MHz,CDCl3)δ199.7,190.8,171.8,171.0,160.7,140.3,136.4,135.5,132.9,132.6,129.5,129.3,128.1,127.9,125.3,121.6,73.6,57.1,52.7,50.4,42.3,30.3,29.9,15.5.IR(neat)3246,2916,1737,1643,1487,1284,1176,732cm-1.HRMS(EI)m/z:Calcd for C24H26N2O5S2486.1283,Found486.1277.ee值为>99％.HP LC的检测参数(Daicel Chirapak AD,正己烷/异丙醇＝70/30,流动速度＝1.0mL/min,柱温箱温度为30℃,波长为254nm)tR＝16.450min(主要),tR＝19.893min(次要).Preparation of compound 4p: under air atmosphere, add aminoaldehyde 1n' (30.9 mg, 0.1 mmol), S 8 (6.4 mg, 0.2 mmol), CuCl 2 (2.0 mg, 0.015 mmol), Na 2 S to the reaction tube 9H 2 O (27.8 mg , 0.12 mmol), methionine methyl ester hydrochloride (39.9 mg, 0.2 mmol) and redistilled solvent THF (1 mL) were reacted at 50° C. for 10 hours. After the completion of the reaction, extraction, concentration, and separation by column chromatography (V PE /V EA =3/1) gave 23.3 mg of colorless oily 4p (PE/EA=3:1, R f =0.5), the yield was 48 %. 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (d, J=7.3 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.80 (dd, J=7.7, 1.1 Hz, 1H), 7.51 -7.47(m,1H),7.41-7.36(m,2H),7.30(s,1H),6.98(d,J=8.4Hz,1H),6.90(s,1H),5.16-5.06(m,3H) ), 4.33-4.13(m, 2H), 3.66(s, 3H), 3.58(s, 2H), 2.39(t, J=7.4Hz, 2H), 2.19-2.13(m, 1H), 2.06-1.94( m, 4H). 13 C NMR (101MHz, CDCl 3 )δ199.7,190.8,171.8,171.0,160.7,140.3,136.4,135.5,132.9,132.6,129.7,129.3,128.1,127.9,125.3,121.6,73.6,5 52.7,50.4,42.3,30.3,29.9,15.5.IR(neat)3246,2916,1737,1643,1487,1284,1176,732cm -1 .HRMS(EI)m/z:Calcd for C 24 H 26 N 2 O 5 S 2 486.1283, Found486.1277.ee value >99%. Detection parameters of HPLC (Daicel Chirapak AD, n-hexane/isopropanol=70/30, flow rate=1.0 mL/min, column oven temperature is 30℃, the wavelength is 254nm) tR=16.450min (main), tR=19.893min (secondary).
本发明的保护内容不局限于以上实施例。在不背离本发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求书为保护范围。The protection content of the present invention is not limited to the above embodiments. Variations and advantages that can occur to those skilled in the art without departing from the spirit and scope of the inventive concept are included in the present invention, and the appended claims are the scope of protection.
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