CN109535059B - Method for efficiently synthesizing optically active 2-pyrroline compound by asymmetric organic phosphine catalysis - Google Patents
Method for efficiently synthesizing optically active 2-pyrroline compound by asymmetric organic phosphine catalysis Download PDFInfo
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- -1 2-pyrroline compound Chemical class 0.000 title claims abstract description 31
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 title claims abstract description 19
- 229910000073 phosphorus hydride Inorganic materials 0.000 title claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 9
- 238000006555 catalytic reaction Methods 0.000 title description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 40
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 18
- 150000004065 2-pyrrolines Chemical class 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 113
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 239000002904 solvent Substances 0.000 claims description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 4
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 150000003003 phosphines Chemical class 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 abstract description 11
- 150000002466 imines Chemical class 0.000 abstract description 8
- 230000001404 mediated effect Effects 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 3
- 125000006239 protecting group Chemical group 0.000 abstract description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000758 substrate Substances 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 96
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 70
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 48
- 235000019439 ethyl acetate Nutrition 0.000 description 37
- 239000012299 nitrogen atmosphere Substances 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 36
- 239000000203 mixture Substances 0.000 description 35
- 239000003208 petroleum Substances 0.000 description 35
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 31
- 238000004896 high resolution mass spectrometry Methods 0.000 description 27
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 230000014759 maintenance of location Effects 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 14
- 239000012230 colorless oil Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000005712 Baylis-Hillman reaction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 125000005059 halophenyl group Chemical group 0.000 description 3
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- 150000004066 3-pyrrolines Chemical class 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000005037 alkyl phenyl group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 150000003236 pyrrolines Chemical class 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- PHDIJLFSKNMCMI-ITGJKDDRSA-N (3R,4S,5R,6R)-6-(hydroxymethyl)-4-(8-quinolin-6-yloxyoctoxy)oxane-2,3,5-triol Chemical compound OC[C@@H]1[C@H]([C@@H]([C@H](C(O1)O)O)OCCCCCCCCOC=1C=C2C=CC=NC2=CC=1)O PHDIJLFSKNMCMI-ITGJKDDRSA-N 0.000 description 1
- JNPGUXGVLNJQSQ-BGGMYYEUSA-M (e,3r,5s)-7-[4-(4-fluorophenyl)-1,2-di(propan-2-yl)pyrrol-3-yl]-3,5-dihydroxyhept-6-enoate Chemical compound CC(C)N1C(C(C)C)=C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C1 JNPGUXGVLNJQSQ-BGGMYYEUSA-M 0.000 description 1
- VAVHMEQFYYBAPR-ITWZMISCSA-N (e,3r,5s)-7-[4-(4-fluorophenyl)-1-phenyl-2-propan-2-ylpyrrol-3-yl]-3,5-dihydroxyhept-6-enoic acid Chemical compound CC(C)C1=C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)C(C=2C=CC(F)=CC=2)=CN1C1=CC=CC=C1 VAVHMEQFYYBAPR-ITWZMISCSA-N 0.000 description 1
- KQNMNQHOKUHSJP-UHFFFAOYSA-N 3-bromo-1,3-dihydroindol-2-one Chemical class C1=CC=C2C(Br)C(=O)NC2=C1 KQNMNQHOKUHSJP-UHFFFAOYSA-N 0.000 description 1
- MWVKLRSIDOXBSE-UHFFFAOYSA-N 5-(1-piperidin-4-ylpyrazol-4-yl)-3-(6-pyrrolidin-1-yl-1,3-benzoxazol-2-yl)pyridin-2-amine Chemical compound NC1=NC=C(C2=CN(N=C2)C2CCNCC2)C=C1C(OC1=C2)=NC1=CC=C2N1CCCC1 MWVKLRSIDOXBSE-UHFFFAOYSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VCUKKMIXURRDKL-UHFFFAOYSA-N 9-(dimethylamino)-3-(4-ethylphenyl)pyrido[1,2]thieno[3,4-d]pyrimidin-4-one Chemical compound C1=CC(CC)=CC=C1N1C(=O)C(SC=2C3=C(N(C)C)C=CN=2)=C3N=C1 VCUKKMIXURRDKL-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- DGJMHKMYSDYOFP-MRXNPFEDSA-N C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O Chemical compound C=CC(N(CCC1)C[C@@H]1N1N=C(C2=CN(CC(C3=CC=CC=C3)(F)F)N=N2)C2=C(N)N=CN=C12)=O DGJMHKMYSDYOFP-MRXNPFEDSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 229910018105 SCl2 Inorganic materials 0.000 description 1
- BEXZJJQVPWJPOA-VOTSOKGWSA-N [(e)-hept-2-enyl] 6-methyl-4-(4-nitrophenyl)-2-oxo-3,4-dihydro-1h-pyrimidine-5-carboxylate Chemical compound CCCC\C=C\COC(=O)C1=C(C)NC(=O)NC1C1=CC=C([N+]([O-])=O)C=C1 BEXZJJQVPWJPOA-VOTSOKGWSA-N 0.000 description 1
- HGDWHTASNMRJMP-UHFFFAOYSA-N [1-(hydroxyamino)-1-oxo-5-(3-phenoxyphenyl)pentan-2-yl]phosphonic acid Chemical compound ONC(=O)C(P(O)(O)=O)CCCC1=CC=CC(OC=2C=CC=CC=2)=C1 HGDWHTASNMRJMP-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000001361 allenes Chemical class 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- YBFBENHWPRGUMU-UHFFFAOYSA-N chembl398496 Chemical compound OC(=O)C1=CC=CC=C1NC(=O)N1CCN(C=2N=C3C=CC(O)=CC3=NC=2)CC1 YBFBENHWPRGUMU-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000005366 cycloalkylthio group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- JFOZKMSJYSPYLN-QHCPKHFHSA-N lifitegrast Chemical compound CS(=O)(=O)C1=CC=CC(C[C@H](NC(=O)C=2C(=C3CCN(CC3=CC=2Cl)C(=O)C=2C=C3OC=CC3=CC=2)Cl)C(O)=O)=C1 JFOZKMSJYSPYLN-QHCPKHFHSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SWQDRYKDDGFPLL-UHFFFAOYSA-N tert-butyl prop-2-enyl carbonate Chemical compound CC(C)(C)OC(=O)OCC=C SWQDRYKDDGFPLL-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
Classifications
-
- 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
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention belongs to the field of organic synthesis methods, and discloses a method for efficiently synthesizing optically active 2-pyrroline compounds by catalyzing asymmetric organic phosphine, which takes a chiral phosphine compound as a catalyst, and a compound in a formula A and a compound in a formula B react to obtain a compound in a formula C:
wherein Ar is1Selected from phenyl or substituted phenyl, Ar2Selected from phenyl or substituted phenyl, R1Selected from protecting groups of the sulfonyl series, R2The method has good catalytic effect and the enantioselectivity [1+4] of the phosphine-mediated MBH carbonate and α -unsaturated imine]The cyclization is carried out to obtain a series of optically active polysubstituted 2-pyrroline, and the method has the advantages of high yield, good stereoselectivity, high catalytic efficiency, wide substrate application range, simple operation, low cost and very good industrial application prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis methods, and particularly relates to a method for efficiently synthesizing optically active 2-pyrroline compounds by catalysis of asymmetric organic phosphine.
Background
Chiral pyrrolines and derivatives thereof have important significance in natural products, medicaments and enantioselective catalysis, and researchers are dedicated to developing asymmetric synthesis methods of pyrrolines.
The organophosphine catalyzed enantioselective cyclization is an effective synthetic strategy, for example, the asymmetric [3+2] cyclization of imine or alkynate salt with imine mediated by organophosphine can obtain optically active 3-pyrroline compounds, however, the asymmetric catalyzed [1+4] cyclization for synthesizing chiral pyrroline has not been reported.
In 2015, Gregory c.fu et al catalyzed the enantioselective cyclization of cyclamamides with γ -substituted allenes [1+4] using chiral spirocyclic phosphines to synthesize 3-pyrrolines, and in the same year, chengchun et al reported the asymmetric cyclization synthesis of 2-pyrrolines using chiral amine-mediated 3-bromooxindoles and electron deficient 1-azadienes [1+4], and it is noted that increasing the amount of basic additives did not help to provide the enantioselectivity and yield of the cyclization reaction.
In view of the diversity and reactivity of the Morita-Baylis-Hillman (MBH) derivatives, sensitizers et al constructed phosphine-catalyzed cyclization of 2- (tert-butoxycarbonyl) allyl tert-butyl carbonate with oxindole-derived α -unsaturated imine [1+4] to give 2-pyrroline in 78% yield, 61% ee, 7: 1dr Hengjie et al developed highly enantioselective and diastereoselective [1+4] cyclization of MBH carbonate and α -unsaturated imine with the aid of a novel chiral phosphine catalyst, the substituent on the nitrogen atom of α -unsaturated imine had a large effect on the stereoselectivity of phosphine-mediated cyclization, and the substitution of 4-nitrobenzenesulfonyl with other groups (tosyl, benzenesulfonyl) resulted in poor enantioselectivity.
Therefore, a synthetic method for enantioselectively synthesizing the polysubstituted 2-pyrroline compound still needs to be developed.
Disclosure of Invention
The invention aims to provide a method for synthesizing an optically active polysubstituted 2-pyrroline compound with high yield and high selectivity.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for asymmetrically synthesizing 2-pyrroline compounds is characterized in that chiral phosphine compounds are used as catalysts, and a compound of a formula A reacts with a compound of a formula B to obtain a compound of a formula C:
wherein Ar is1Selected from phenyl or substituted phenyl, Ar2Selected from phenyl or substituted phenyl, R1Selected from protecting groups of the sulfonyl series, R2Selected from alkyl or benzyl.
Further, said Ar1Selected from phenyl, halophenyl, said Ar2Selected from phenyl, halophenyl, alkylphenyl, R1Selected from the group consisting of methylsulfonyl, trifluoromethylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, phenylsulfonyl.
Further, said Ar1Selected from phenyl, fluorophenyl, bromophenyl, chlorobenzeneGroup of Ar2Selected from phenyl, fluorophenyl, bromophenyl, chlorophenyl, tolyl, R1Selected from p-toluenesulfonyl, p-nitrobenzenesulfonyl and benzenesulfonyl.
Further, R2Selected from methyl, ethyl, isobutyl, benzyl.
Further, the chiral phosphine compound is selected from one of the following structures:
further, the amount of the chiral phosphine compound is at least 10 mol%.
Further, the reaction takes one or more of acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran and ethyl acetate as a solvent.
Further the molar ratio of the compound of formula a to the compound of formula B is 1: 1 to 14.
Further, the temperature of the reaction is 25 ℃ or higher.
Further, the reaction time is at least 48 h.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl.
The term "substituted phenyl" refers to a phenyl group having at least one substituent, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy, or carboxylate.
The term "halophenyl" refers to a phenyl group having at least one halogen (fluorine, chlorine, bromine, iodine) as a substituent.
The term "alkylphenyl" refers to a phenyl group having at least one alkyl group as a substituent.
The invention has the following beneficial effects:
1. the catalytic effect is good, the phosphine-mediated MBH carbonate and α -unsaturated imine are subjected to enantioselective [1+4] cyclization to obtain a series of optically active polysubstituted 2-pyrrolines, the yield is high, the ee value is mostly more than 90%, and the dr value is more than 20: 1.
2. The substrate has wide application range, the N protecting group of α -unsaturated imine can be various sulfonyl protecting groups, and the electronic property and the steric hindrance of the substituent have no obvious influence on the yield and the enantioselectivity.
3. High catalytic efficiency, small catalyst consumption and capability of obtaining products in a short time.
4. The method has the advantages of simple operation, low cost, high atom economy, environmental friendliness and the like, and has very good industrial application prospect.
Detailed Description
The present invention will be further described with reference to the following specific examples.
The following examples, all reactions were carried out under anhydrous conditions with dry freshly distilled solvent, toluene and THF were distilled from sodium, and CaH was obtained2The dichloromethane was distilled off and used immediately. All chemicals were commercially available without further purification unless otherwise indicated. All reactions were carried out under a dry nitrogen atmosphere. Thin Layer Chromatography (TLC) used 60F254 silica gel plates, 254 and 365nm uv light. Silica gel with the particle size of 300-400 meshes is used for silica gel column chromatography. NMR (400 MHz)1HNMR，100MHz13C NMR) was chloroform or acetone with Tetramethylsilane (TMS) as an internal standard. Chemical shifts are in ppm and coupling constants are in Hz. In that1In H NMR, δ represents chemical shift, s represents singlet, d represents doublet, t represents triplet, q represents quartet, and m represents multiplet. In that13In C NMR, δ represents a chemical shift. High Resolution Mass Spectrometry (HRMS) uses ESI ionization.
Example 1
Sealing the tube under a nitrogen atmosphere, and mixing1a (0.25mmol), Compound 2a (0.30mmol), catalyst I (10 mol%) in CH2Cl2The mixture in (2.0mL) was stirred at 25 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 46%, dr > 20: 1, 88% ee.
White solid, mp 102.4-105.1 ℃.1H NMR(500Hz,CDCl3):δ(ppm)7.71-7.68(m,2H),7.44-7.42(m,3H),7.31(d,J＝8.0Hz,2H),7.12-6.99(m,5H),6.71(d,J＝7.2Hz,2H),6.51(s,1H),6.28(s,1H),5.28(d,J＝3.6Hz,1H),5.01(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.62(t,J＝3.4Hz,1H),2.40(s,3H),2.02-1.92(m,1H),0.95(d,J＝6.8Hz,3H),0.94(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.9,143.9,142.2,141.1,133.6,132.7,129.6,129.1,128.5,128.2,128.0,127.9,127.4,126.3,125.3,116.1,71.1,69.7,53.5,27.8,21.6,19.2,19.1 HRMS accurate Mass calculation [ M + H]+(C30H32NO4S) is m/z 502.20466, found m/z 502.20441 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 75/25, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝15.167min,tR(minor)＝17.977min.[α]30 D＝-176(c＝0.5,CH2Cl2)。
Example 2
In a sealed tube under nitrogen atmosphere, compound 1a (0.25mmol), compound 2a (0.30mmol), and catalyst II (10 mol%) were placed in CH2Cl2The mixture in (2.0mL) was stirred at 25 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 6%, dr > 20: 1, 86% ee.
Example 3
In a sealed tube under nitrogen atmosphere, compound 1a (0.25mmol), compound 2a (0.30mmol), and catalyst III (10 mol%) were placed in CH2Cl2The mixture in (2.0mL) was stirred at 25 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 5%, dr > 20: 1, 67% ee.
Example 4
In a sealed tube under nitrogen atmosphere, compound 1a (0.25mmol), compound 2a (0.30mmol), catalyst I (10 mol%) were in CHCl3The mixture in (2.0mL) was stirred at 25 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 11%, dr > 20: 1, 80% ee.
Example 5
In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25mmol), compound 2a (0.30mmol), catalyst I (10 mol%) in toluene (2.0mL) was stirred at 25 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 49%, dr > 20: 1, 82% ee.
Example 6
A mixture of compound 1a (0.25mmol), compound 2a (0.30mmol), catalyst I (10 mol%) in THF (2.0mL) was stirred at 25 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 28%, dr > 20: 1, 84% ee.
Example 7
A mixture of compound 1a (0.25mmol), compound 2a (0.30mmol), catalyst I (10 mol%) in EtOAc (2.0mL) was stirred at 25 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 38%, dr > 20: 1, 87% ee.
Example 8
In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25mmol), compound 2a (0.30mmol), catalyst I (10 mol%) in MeCN (2.0mL) was stirred at 25 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 37%, dr > 20: 1, 94% ee.
Example 9
In a sealed tube under nitrogen atmosphere, a mixture of compound 1a (0.25mmol), compound 2a (0.30mmol), catalyst I (10 mol%) in MeCN (2.0mL) was stirred at 30 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 42%, dr > 20: 1, 93% ee.
Example 10
A mixture of compound 1a (0.15mmol), compound 2a (0.18mmol), catalyst I (10 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 67%, dr > 20: 1, 91% ee.
Example 11
A mixture of compound 1a (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 75%, dr > 20: 1, 91% ee.
Example 12
A mixture of compound 1a (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 56h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 aa.
Yield 65%, dr > 20: 1, 90% ee.
Example 13
A mixture of compound 1a (0.15mmol), compound 2b (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ab.
Yield 70%, dr > 20: 1, 88% ee.
White solid, mp 131.4-132.6 ℃,56.9mg.1H NMR(400Hz,CDCl3):δ(ppm)7.67-7.65(m,2H),7.41-7.31(m,8H),7.27(d,J＝8.0Hz,2H),7.10-6.94(m,5H),6.66(d,J＝7.2Hz,2H),6.54(s,1H),6.28(s,1H),5.30-5.21(m,3H),5.03(d,J＝2.8Hz,1H),3.60(t,J＝3.4Hz,1H),2.36(s,3H).13C NMR(100Hz,CDCl3) Delta (ppm)165.6,144.9,143.9,142.2,140.9,135.6,133.6,132.7,129.6,129.2,128.6,128.5,128.3,128.2,128.0,127.9,127.4,126.3,126.1,116.0,69.8,66.9,53.5,21.6 HRMS accurate mass calculation [ M + H]+(C33H30NO4S) is m/z536.18901, found m/z536.18842 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝19.861min,tR(minor)＝30.665min.[α]30 D＝-142(c＝0.5,CH2Cl2)。
Example 14
A mixture of compound 1a (0.15mmol), compound 2c (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ac.
Yield 76%, dr > 20: 1, 89% ee.
White solid, mp 115.8-117.0 ℃,51.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.70-7.67(m,2H),7.43-7.42(m,3H),7.30(d,J＝8.4Hz,2H),7.13-7.00(m,5H),6.72(d,J＝7.2Hz,2H),6.50(s,1H),6.26(s,1H),5.27(d,J＝3.6Hz,1H),5.01(d,J＝2.8Hz,1H),4.32-4.25(m,2H),3.62(t,J＝3.2Hz,1H),2.40(s,3H),1.30(t,J＝7.0Hz,3H).13C NMR(126Hz,CDCl3) Delta (ppm)165.9,145.0,143.9,142.4,141.1,133.7,132.7,129.7,129.2,128.6,128.3,128.1,128.0,127.5,126.4,125.6,116.2,69.9,61.2,53.5,21.7,14.3 HRMS accurate mass calculation [ M + H]+(C28H28NO4S) is m/z474.17336, found m/z 474.17212 HPLC conditions daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝15.219min,tR(minor)＝19.67min.[α]30 D＝-122(c＝0.5,CH2Cl2)。
Example 15
A mixture of compound 1a (0.15mmol), compound 2d (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ad.
Yield 86%, dr > 20: 1, 88% ee.
White solid, mp 135.7-137.4 deg.C, 58.9mg.1H NMR(500Hz,CDCl3):δ(ppm)7.69-7.68(m,2H),7.43-7.42(m,3H),7.30(d,J＝8.0Hz,2H),7.13-7.10(m,1H),7.07-7.01(m,4H),6.70(d,J＝7.5Hz,2H),6.51(s,1H),6.29(s,1H),5.27(d,J＝3.5Hz,1H),5.00(d,J＝2.5Hz,1H),3.83(s,3H),3.60(t,J＝3.3Hz,1H),2.40(s,3H).13C NMR(100Hz,CDCl3) Delta (ppm)166.3,145.0,143.9,142.3,140.7,133.8,132.7,129.7,129.3,128.6,128.3,128.1,128.0,127.5,126.4,125.9,116.1,69.9,53.5,52.1,21.7 HRMS accurate mass calculation [ M + H]+(C27H26NO4S) is m/z 460.15771, found m/z 460.15695 HPLC conditions, Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝15.185min,tR(minor)＝20.817min.[α]30 D＝-186(c＝0.5,CH2Cl2)。
Example 16
A mixture of compound 1b (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ba.
Yield 51%, dr > 20: 1, 88% ee.
White solid, mp 144.0-145.5 ℃,42.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.92(d,J＝8.4Hz,2H),7.73-7.71(m,2H),7.49-7.47(m,5H),7.10-6.94(m,5H),6.53(s,1H),6.31(s,1H),5.51(d,J＝3.6Hz,1H),5.19(s,1H),4.06(d,J＝6.8Hz,2H),3.66(s,1H),2.09-1.99(m,1H),1.00(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.9,150.4,144.6,142.4,142.1,140.2,132.0,129.8,128.9,128.5,128.4,127.1,126.8,125.5,124.0,116.9,71.5,70.4,52.2,27.9,19.3 HRMS accurate mass calculation [ M + H]+(C29H29N2O6S) is m/z 533.17408, found m/z 533.17334.HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝21.99min,tR(minor)＝28.041min.[α]30 D＝-122(c＝0.5,CH2Cl2)。
Example 17
A mixture of compound 1b (0.15mmol), compound 2c (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 bc.
Yield 42%, dr > 20: 1, 87% ee.
White solid, mp 128.6-129.6 deg.C, 32.5mg.1H NMR(500Hz,CDCl3):δ(ppm)7.93(d,J＝9.0Hz,2H),7.73-7.71(m,2H),7.49-7.47(m,5H),7.10-7.07(m,1H),7.02-6.94(m,4H),6.54(s,1H),6.30(s,1H),5.51(d,J＝4.0Hz,1H),5.18(s,1H),4.39-4.29(m,2H),3.66(t,J＝2.5Hz,1H),1.37(t,J＝7.3Hz,3H).13C NMR(126Hz,CDCl3) Delta (ppm)165.8,150.3,144.5,142.3,142.0,140.0,131.9,129.7,128.8,128.4,128.3,127.0,126.7,125.6,123.9,116.8,70.3,61.4,52.0,14.3 HRMS accurate mass calculation [ M + H]+(C27H25N2O6S) is m/z 505.14278, found m/z 505.14230 HPLC conditions are Daicel Chiralpak AD-H column, n-hexane/isopropanol 95/5, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝12.7min,tR(minor)＝15.555min.[α]30 D＝-152(c＝0.5,CH2Cl2)。
Example 18
A mixture of compound 1c (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ca.
Yield 69%, dr > 20: 1, 90% ee.
Colorless oil, 53.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.68-7.66(m,2H),7.52-7.41(m,6H),7.32-7.28(m,2H),7.11-7.00(m,3H),6.68(d,J＝7.6Hz,2H),6.50(s,1H),6.26(s,1H),5.25(d,J＝3.6Hz,1H),5.04(d,J＝3.2Hz,1H),4.07-3.95(m,2H),3.63(t,J＝3.2Hz,1H),2.01-1.91(m,1H),0.94(d,J＝6.8Hz,3H),0.93(d,J＝8.4Hz,3H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.8,142.3,141.2,136.9,133.2,132.6,129.3,129.0,128.6,128.5,128.2,128.0,127.5,126.7,125.4,116.3,71.5,70.0,53.8,27.9,19.3,19.2 HRMS accurate mass calculation [ M + H]+(C29H30NO4S) is m/z 488.18901, found m/z 488.18842 HPLC conditions are Daicel Chiralpak IC-3 column, n-hexane/isopropanol 70/30, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝13.928min,tR(minor)＝15.937min.[α]30 D＝-162(c＝0.5,CH2Cl2)。
Example 19
A mixture of compound 1d (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 da.
Yield 72%, dr > 20: 1, 92% ee.
Colorless oil, 54.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.70-7.68(m,2H),7.44-7.42(m,3H),7.28(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),6.78-6.67(m,4H),6.51(s,1H),6.31(s,1H),5.27(d,J＝3.6Hz,1H),5.00(t,J＝1.2Hz,1H),4.06-3.97(m,2H),3.58(t,J＝3.0Hz,1H),2.41(s,3H),2.05-1.95(m,1H),0.97(d,J＝6.4Hz,3H),0.96(d,J＝6.4Hz,3H).13C NMR(100Hz,CDCl3):δ(ppm)1660,161.5(J ═ 243.6Hz),145.2,141.1,140.7,138.3,133.8,132.6,129.6,129.4,129.1(J ═ 7.8Hz),128.5,128.0,125.4,115.7,114.9(J ═ 21.0Hz),71.2,69.8,52.4,27.9,21.6,19.3,19.2 HRMS: exact mass calculation [ M + H]+(C30H31NO4SF) m/z520.19523, found m/z 520.19421 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝9.562min,tR(minor)＝12.394min.[α]30 D＝-180(c＝0.5,CH2Cl2)。
Example 20
A mixture of compound 1e (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ea.
Yield 63%, dr > 20: 1, 93% ee.
White solid, mp 132.7-134.0 ℃,49.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.71-7.69(m,2H),7.44-7.43(m,3H),7.26-7.24(m,2H),7.03-6.96(m,4H),6.79(d,J＝8.4Hz,2H),6.51(s,1H),6.32(s,1H),5.29(d,J＝3.2Hz,1H),5.03(t,J＝1.0Hz,1H),4.06-3.98(m,2H),3.57(t,J＝3.0Hz,1H),2.41(s,3H),2.06-1.96(m,1H),0.97(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)166.0,145.5,144.3,141.1,140.5,133.7,132.5,132.2,129.5,129.4,128.8,128.5,128.3,128.1,127.9,125.5,115.4,71.3,69.7,52.2,27.9,21.6,19.3,19.2 HRMS accurate mass calculation of [ M + H]+(C30H31NO4SCl) m/z 536.16568, found m/z536.16455.HPLC conditions on a Daicel Chiralpak IC-3 column with n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝9.993min,tR(minor)＝13.444min.[α]30 D＝-148(c＝0.5,CH2Cl2)。
Example 21
A mixture of compound 1f (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 fa.
Yield 53%, dr > 20: 1, 93% ee.
White solid, mp 141.9-143.5 ℃,45.9mg.1H NMR(400Hz,CDCl3):δ(ppm)7.71-7.69(m,2H),7.44-7.43(m,3H),7.25-7.23(m,2H),7.12(d,J＝8.4Hz,2H),7.02(d,J＝8.0Hz,2H),6.74(d,J＝8.4Hz,2H),6.51(s,1H),6.32(s,1H),5.29(d,J＝3.6Hz,1H),5.04(d,J＝0.8Hz,1H),4.06-3.98(m,2H),3.55(t,J＝2.8Hz,1H),2.42(s,3H),2.06-1.96(m,1H),0.98(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)166.0,145.6,144.4,141.6,140.5,133.7,132.5,131.2,129.5,129.2,128.5,128.1,127.9,125.5,120.3,115.3,71.3,69.7,52.2,27.9,21.7,19.3,19.2 HRMS accurate mass calculation of [ M + H]+(C30H31NO4SBr) is m/z 580.11517, found m/z580.11359 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝10.412min,tR(minor)＝14.071min.[α]30 D＝-172(c＝0.5,CH2Cl2)。
Example 22
A mixture of compound 1g (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ga.
Yield 54%, dr > 20: 1, 91% ee.
Colorless oil, 42.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.72-7.70(m,2H),7.45-7.43(m,3H),7.28(d,J＝8.0Hz,2H),7.08-7.03(m,3H),6.85-6.77(m,2H),6.52(s,1H),6.31(s,1H),6.18(d,J＝10.0Hz,1H),5.26(d,J＝3.6Hz,1H),5.01(d,J＝2.4Hz,1H),4.07-3.97(m,2H),3.61(t,J＝3.0Hz,1H),2.38(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3) δ (ppm)165.9,162.6 (J244.2 Hz),145.7,145.1,144.5,140.8,133.3,132.6,129.7 (J8.5 Hz),129.4,128.5,128.1,127.9,125.6,123.6,115.2,114.1 (J21.9 Hz),113.4,113.2,71.3,69.6,52.8,27.9,21.6,19.3,19.2 HRMS: accurate mass calculation [ M + H: [ M + H ] accurate mass calculation]+(C30H31NO4SF) m/z520.19523, found m/z 520.19507 HPLC conditions, Daicel ChiralpakIC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝9.266min,tR(minor)＝13.564min,.[α]30 D＝-196(c＝0.5,CH2Cl2)。
Example 23
In a sealed tube under nitrogen atmosphere, a mixture of compound 1h (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ha.
Yield 48%, dr > 20: 1, 92% ee.
Colorless oil, 38.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.71-7.70(m,2H),7.44-7.43(m,3H),7.28-7.25(m,2H),7.08-6.93(m,5H),6.66(s,1H),6.52(s,1H),6.31(s,1H),5.28(d,J＝3.6Hz,1H),5.06(s,1H),4.07-3.98(m,2H),3.59(s,1H),2.36(s,3H),2.03-1.96(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3):δ(ppm)165.9,145.7,144.6,144.3,140.7,1340,133.4,132.5,129.6,129.4,128.5,128.1,127.8,127.5,126.6,126.0,125.7,115.0,71.3,69.5,52.6,27.9,21.8,19.3,19.2 HRMS accurate mass calculation [ M + H]+(C30H31NO4SCl) m/z 536.16568, found m/z 536.16516 HPLC conditions on a Daicel Chiralpak IC-3 column with n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝9.976min,tR(minor)＝14.539min.[α]30 D＝-148(c＝0.5,CH2Cl2)。
Example 24
A mixture of compound 1I (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ia.
Yield 55%, dr > 20: 1, 93% ee.
Colorless oil, 48.8mg.1H NMR(400Hz,CDCl3):δ(ppm)7.70-7.69(m,2H),7.44-7.43(m,3H),7.28-7.22(m,3H),7.04(d,J＝8.0Hz,2H),6.95-6.90(m,3H),6.52(s,1H),6.31(s,1H),5.29(d,J＝3.2Hz,1H),5.07(s,1H),4.07-3.98(m,2H),3.59(s,1H),2.37(s,3H),2.03-1.95(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.9,145.7,144.9,144.2,140.6,133.4,132.5,130.5,129.9,129.6,129.5,129.4,128.5,128.1,127.8,126.4,125.8,122.5,115.0,71.3,69.5,52.6,27.9,21.9,19.3,19.2 HRMS accurate Mass calculation [ M + H]+(C30H31NO4SBr) is m/z 580.11517, found m/z 580.11491 HPLC conditions daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝10.681min,tR(minor)＝15.472min.[α]30 D＝-146(c＝0.5,CH2Cl2)。
Example 25
A mixture of compound 1j (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ja.
Yield 87%, dr > 20: 1, 91% ee.
Colorless oil, 65.6mg.1H NMR(400Hz,CDCl3):δ(ppm)7.66(s,2H),7.29-7.25(m,2H),7.13-6.99(m,7H),6.69(d,J＝6.8Hz,2H),6.49(s,1H),6.22(s,1H),5.24(s,1H),4.99(s,1H),4.07-3.95(m,2H),3.62(s,1H),2.39(s,3H),1.99-1.93(m,1H),0.94(d,J＝6.0Hz,6H).13C NMR(100Hz,CDCl3) δ (ppm)165.7,163.2 (J246.9 Hz),144.0,143.9,142.2,141.0,133.5,130.2 (J8.2 Hz),129.7,128.7 (J2.9 Hz),128.2,128.0,127.4,126.4,125.4,116.0,115.0 (J21.7 Hz),71.1,69.9,53.4,27.8,21.6,19.2,19.1 HRMS: accurate mass calculation [ M + H ] 165.7,163.2 (J246.9 Hz), HRMS: accurate mass calculation [ M + H ] M]+(C30H31NO4SF) m/z520.19523, found m/z 520.19470 HPLC conditions daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝12.982min,tR(minor)＝19.376min.[α]30 D＝-168(c＝0.5,CH2Cl2)。
Example 26
A mixture of compound 1k (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ka.
Yield 72%, dr > 20: 1, 92% ee.
Colorless oil, 58.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.62(d,J＝8.0Hz,2H),7.39(d,J＝7.6Hz,2H),7.29(d,J＝7.6Hz,2H),7.12-6.98(m,5H),6.67(d,J＝7.2Hz,2H),6.49(s,1H),6.21(s,1H),5.27(d,J＝2.8Hz,1H),4.98(s,1H),4.06-3.95(m,2H),3.62(s,1H),2.40(s,3H),1.99-1.93(m,1H),0.94(d,J＝6.0Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.1,142.1,141.0,135.0,133.4,131.2,129.7,128.3,128.1,127.4,126.5,125.5,116.7,71.2,69.9,53.6,27.8,21.7,19.3,19.2 HRMS accurate mass calculation of [ M + H]+(C30H31NO4SCl) m/z 536.16568, found m/z536.16541 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝11.789min,tR(minor)＝17.445min.[α]30 D＝-134(c＝0.5,CH2Cl2)。
Example 27
A mixture of compound 1l (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 la.
Yield 58%, dr > 20: 1, 92% ee.
Colorless oil, 52.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.55(s,4H),7.29(d,J＝8.0Hz,2H),7.12-6.98(m,5H),6.67(d,J＝7.2Hz,2H),6.49(s,1H),6.20(s,1H),5.28(d,J＝3.6Hz,1H),4.98(d,J＝2.4Hz,1H),4.06-3.94(m,2H),3.62(s,1H),2.40(s,3H),2.01-1.91(m,1H),0.94(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.1,143.9,142.1,141.0,133.4,131.7,131.2,130.0,129.8,128.3,128.1,127.4,126.5,125.5,123.3,116.8,71.2,69.9,53.6,27.8,21.7,19.3,19.2 HRMS accurate mass calculation of [ M + H]+(C30H31NO4SBr) is m/z 580.11517, trueMeasured as m/z 580.11493 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min,. lambda.254 nm, retention time tR(major)＝12.814min,tR(minor)＝18.369min.[α]30 D＝-108(c＝0.5,CH2Cl2)。
Example 28
A mixture of compound 1m (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ma.
Yield 77%, dr > 20: 1, 90% ee.
White solid, mp 148.4-149.8 deg.C, 61.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.59(d,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,2H),7.23(d,J＝8.0Hz,2H),7.10-6.97(m,5H),6.70(d,J＝7.6Hz,2H),6.50(s,1H),6.28(s,1H),5.22(d,J＝3.6Hz,1H),5.01(s,1H),4.06-3.95(m,2H),3.59(t,J＝2.8Hz,1H),2.41(s,3H),2.38(s,3H),2.03-1.91(m,1H),0.94(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.9,144.9,143.8,142.4,141.1,139.2,133.7,129.8,129.6,128.7,128.4,128.2,128.1,127.5,126.3,125.4,115.3,71.1,69.7,53.5,27.8,21.6,21.5,19.3,19.2 HRMS accurate mass calculation [ M + H]+(C31H34NO4S) is m/z516.22031, found m/z516.22009.HPLC conditions are Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝10.503min,tR(minor)＝15.169min.[α]30 D＝-180(c＝0.5,CH2Cl2)。
Example 29
A mixture of compound 1n (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 na.
Yield 52%, dr > 20: 1, 91% ee.
Colorless oil, 41.2mg.1H NMR(400Hz,CDCl3):δ(ppm)7.48(d,J＝7.6Hz,1H),7.41-7.30(m,4H),7.12-6.99(m,6H),6.69(d,J＝7.2Hz,2H),6.49(s,1H),6.21(s,1H),5.32(d,J＝3.6Hz,1H),4.99(d,J＝2.4Hz,1H),4.07-3.95(m,2H),3.63(t,J＝3.2Hz,1H),2.40(s,3H),2.01-1.91(m,1H),0.94(d,J＝6.8Hz,6H).13C NMR(100Hz,CDCl3) δ (ppm)165.8,162.4 (J244.3 Hz),144.1,143.8,142.0,141.0,134.9 (J8.0 Hz),133.4,129.7,129.6,129.5,128.3,128.1,127.4,126.5,125.5,124.2 (J2.6 Hz),117.3,116.0 (J21.0 Hz),115.4 (J22.8 Hz),71.2,69.9,53.6,27.8,21.7,19.2 HRMS: exact mass calculation [ M + H ] M + H]+(C30H31NO4SF) m/z520.19523, found m/z 520.19495 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝9.997min,tR(minor)＝12.845min.[α]30 D＝-152(c＝0.5,CH2Cl2)。
Example 30
A mixture of compound 1o (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 oa.
Yield 63%, dr > 20: 1, 91% ee.
Colorless oil, 49.8mg.1H NMR(400Hz,CDCl3):δ(ppm)7.59-7.58(m,2H),7.39-7.30(m,4H),7.13-7.01(m,5H),6.70(d,J＝7.2Hz,2H),6.49(s,1H),6.20(s,1H),5.32(d,J＝3.2Hz,1H),5.00(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.64(s,1H),2.41(s,3H),2.01-1.91(m,1H),0.95(d,J＝6.4Hz,3H),0.94(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.2,143.7,142.0,141.0,134.6,133.9,133.5,129.8,129.3,129.2,128.4,128.3,128.1,127.5,126.8,126.5,125.6,117.4,71.2,69.9,53.7,27.9,21.7,19.3,19.2 HRMS accurate mass calculation of [ M + H]+(C30H31NO4SCl) m/z 536.16568, found m/z536.16541.HPLC conditions on a Daicel Chiralpak IC-3 column with n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝9.751min,tR(minor)＝12.132min.[α]30 D＝-140(c＝0.5,CH2Cl2)。
Example 31
A mixture of compound 1p (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 pa.
Yield 59%, dr > 20: 1, 92% ee.
Colorless oil, 54.3mg.1H NMR(400Hz,CDCl3):δ(ppm)7.73(s,1H),7.63(d,J＝7.6Hz,1H),7.53(d,J＝8.0Hz,1H),7.32-7.25(m,3H),7.13-7.01(m,5H),6.70(d,J＝7.6Hz,2H),6.49(s,1H),6.20(s,1H),5.31(d,J＝3.2Hz,1H),5.00(d,J＝2.8Hz,1H),4.07-3.95(m,2H),3.64(t,J＝3.4Hz,1H),2.41(s,3H),2.01-1.91(m,1H),0.94(d,J＝6.8Hz,3H),0.93(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.2,143.5,142.0,140.9,134.8,133.5,132.1,131.1,129.8,129.6,128.3,128.1,127.4,127.3,126.5,125.6,122.0,117.4,71.2,69.8,53.7,27.8,21.7,19.3,19.2 HRMS accurate mass calculation of [ M + H]+(C30H31NO4SBr) is m/z 580.11517,found m/z 580.11462 HPLC conditions Daicel ChiralpakIC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min,. lambda.254 nm, retention time tR(major)＝10.271min,tR(minor)＝12.423min.[α]30 D＝-140(c＝0.5,CH2Cl2)。
Example 32
In a sealed tube under nitrogen atmosphere, a mixture of compound 1q (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 qa.
Yield 60%, dr > 20: 1, 93% ee.
Colorless oil, 48.7mg.1H NMR(400Hz,CDCl3):δ(ppm)7.49-7.46(m,2H),7.32-7.29(m,3H),7.24-7.21(m,1H),7.12-6.99(m,5H),6.73(d,J＝7.6Hz,2H),6.50(s,1H),6.27(s,1H),5.25(d,J＝3.6Hz,1H),5.03(d,J＝2.8Hz,1H),4.06-3.95(m,2H),3.60(t,J＝3.2Hz,1H),2.41(s,3H),2.39(s,3H),2.03-1.91(m,1H),0.94(d,J＝6.8Hz,3H),0.93(d,J＝6.8Hz,3H).13C NMR(100Hz,CDCl3) Delta (ppm)165.9,145.0,143.8,142.4,141.2,137.5,133.8,132.6,130.0,129.6,129.1,128.2,128.1,127.9,127.5,126.3,125.7,125.4,115.9,71.2,69.7,53.6,27.8,21.6,19.3,19.2 HRMS accurate Mass calculation of [ M + H]+(C31H34NO4S) is m/z516.22031, found m/z 516.21985 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min,. lambda.254 nm, retention time tR(major)＝9.645min,tR(minor)＝12.465min.[α]30 D＝-178(c＝0.5,CH2Cl2)。
Example 33
A mixture of compound 1r (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ra.
Yield 51%, dr > 20: 1, 92% ee.
White solid, mp 54.8-55.1 deg.C, 42.0mg.1H NMR(400Hz,CDCl3):δ(ppm)7.63(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,2H),7.27-7.22(m,3H),7.05(d,J＝8.0Hz,2H),6.95-6.85(m,3H),6.51(s,1H),6.24(s,1H),5.30(d,J＝3.2Hz,1H),5.03(s,1H),4.07-3.97(m,2H),3.60(s,1H),2.38(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.6,144.4,140.5,135.2,133.1,131.0,130.4,129.9,129.7,129.6,128.4,127.8,126.4,125.8,122.5,115.2,71.3,69.6,52.6,27.8,21.9,19.3,19.2 HRMS accurate Mass calculation [ M + H]+(C30H30NO4SClF) is m/z 554.15626, found m/z554.15588 HPLC conditions are Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, lambda 254nm, retention time tR(major)＝10.918min,tR(minor)＝15.753min.[α]30 D＝-98(c＝0.5,CH2Cl2)。
Example 34
In a sealed tube under nitrogen atmosphere, a mixture of compound 1s (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48 h. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 sa.
Yield 40%, dr > 20: 1, 91% ee.
White solid, mp 76.4-78.4 deg.C, 33.5mg.1H NMR(400Hz,CDCl3):δ(ppm)7.64(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),7.27(d,J＝8.0Hz,2H),7.09-6.99(m,4H),6.90(d,J＝7.6Hz,1H),6.61(s,1H),6.51(s,1H),6.24(s,1H),5.30(d,J＝3.6Hz,1H),5.02(d,J＝2.4Hz,1H),4.07-3.97(m,2H),3.60(t,J＝3.2Hz,1H),2.38(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3) Delta (ppm)165.8,144.7,144.5,144.4,140.6,135.3,134.1,133.1,131.0,129.7,128.4,127.8,127.4,126.7,126.0,125.8,115.6,71.3,69.6,52.7,27.9,21.8,19.3,19.2 HRMS accurate Mass calculation [ M + H]+(C30H30NO4SCl2) M/z570.12671, found m/z 570.12628 HPLC conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min, λ 254nm, retention time tR(major)＝10.169min,tR(minor)＝14.851min.[α]30 D＝-134(c＝0.5,CH2Cl2)。
Example 35
A mixture of compound 1t (0.15mmol), compound 2a (0.18mmol), catalyst I (15 mol%) in MeCN (0.8mL) was stirred at 30 ℃ for 48h in a sealed tube under a nitrogen atmosphere. After removal of the solvent, the crude residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the corresponding product 3 ta.
Yield 48%, dr > 20: 1, 92% ee.
White solid, mp 53.0-54.3 ℃,42.4mg.1H NMR(400Hz,CDCl3):δ(ppm)7.62(d,J＝8.0Hz,2H),7.39(d,J＝8.4Hz,2H),7.27(d,J＝8.0Hz,2H),7.05(d,J＝7.6Hz,2H),6.74-6.66(m,4H),6.50(s,1H),6.24(s,1H),5.28(d,J＝3.2Hz,1H),4.97(s,1H),4.06-3.97(m,2H),3.59(s,1H),2.40(s,3H),2.04-1.94(m,1H),0.96(d,J＝6.4Hz,6H).13C NMR(100Hz,CDCl3) δ (ppm)165.9,161.5 (J243.7 Hz),144.3,144.1,140.6,138.1,138.0,135.1,133.5,131.0,129.7,129.0 (J8.0 Hz),128.3,127.9,125.5,116.3,114.9 (J21.1 Hz),71.2,69.9,52.4,27.8,21.6,19.2 HRMS: exact mass calculation [ M + H:]+(C30H30NO4SClF) is m/z55415626, found m/z554.15601.hplc conditions Daicel Chiralpak IC-3 column, n-hexane/isopropanol 80/20, flow rate 1.0mL/min,. lambda.254 nm, retention time tR(major)＝9.897min,tR(minor)＝13.743min.[α]30 D＝-148(c＝0.5,CH2Cl2)。
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (7)
1. A method for asymmetrically synthesizing 2-pyrroline compounds is characterized in that chiral phosphine compounds are used as catalysts, and a compound of a formula A reacts with a compound of a formula B to obtain a compound of a formula C:
wherein, Ar is1Selected from phenyl, fluorophenyl, bromophenyl, chlorophenyl, said Ar2Selected from phenyl, fluorophenyl, bromophenyl, chlorophenyl, tolyl, R1Selected from p-toluenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, R2Selected from alkyl or benzyl;
the chiral phosphine compound is selected from
2. The method of claim 1, wherein R is2Selected from methyl, ethyl, isobutyl, benzyl.
3. The process according to claim 1 or 2, wherein the chiral phosphine compound is used in an amount of at least 10 mol%.
4. The method according to claim 1 or 2, wherein the reaction is carried out with one or more of acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, and ethyl acetate as a solvent.
5. The method according to claim 1 or 2, wherein the molar ratio of the compound of formula a to the compound of formula B is 1: 1 to 1.4.
6. The process according to claim 1 or 2, wherein the temperature of the reaction is 25 ℃ or higher.
7. The process according to claim 1 or 2, wherein the reaction time is at least 48 h.
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| Enantioselective [4 + 1]-Annulation of α,β-Unsaturated Imines with Allylic Carbonates Catalyzed by a Hybrid P‑Chiral Phosphine Oxide−Phosphine;Hanyuan Li，等;《Org. Lett.》;20171003;第19卷;第5637-5640页 * |
| Hanyuan Li，等.Enantioselective [4 + 1]-Annulation of α,β-Unsaturated Imines with Allylic Carbonates Catalyzed by a Hybrid P‑Chiral Phosphine Oxide−Phosphine.《Org. Lett.》.2017,第19卷第5637-5640页. * |
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