CN112358457B - Method for synthesizing chiral endocyclic lactone - Google Patents
Method for synthesizing chiral endocyclic lactone Download PDFInfo
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- CN112358457B CN112358457B CN202011320901.0A CN202011320901A CN112358457B CN 112358457 B CN112358457 B CN 112358457B CN 202011320901 A CN202011320901 A CN 202011320901A CN 112358457 B CN112358457 B CN 112358457B
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- reaction
- solvent
- chiral
- lactone
- metal salt
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 150000002596 lactones Chemical class 0.000 title claims abstract description 27
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- 239000010948 rhodium Substances 0.000 claims abstract description 32
- 239000003446 ligand Substances 0.000 claims abstract description 24
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052751 metal Inorganic materials 0.000 claims abstract description 22
- 239000002184 metal Substances 0.000 claims abstract description 22
- 229910052703 rhodium Inorganic materials 0.000 claims abstract description 21
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 12
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 8
- 238000007037 hydroformylation reaction Methods 0.000 claims abstract description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical group [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000007800 oxidant agent Substances 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 230000001590 oxidative effect Effects 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 11
- 238000004440 column chromatography Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000012043 crude product Substances 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 claims description 5
- 239000011261 inert gas Substances 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- GGRQQHADVSXBQN-FGSKAQBVSA-N carbon monoxide;(z)-4-hydroxypent-3-en-2-one;rhodium Chemical group [Rh].[O+]#[C-].[O+]#[C-].C\C(O)=C\C(C)=O GGRQQHADVSXBQN-FGSKAQBVSA-N 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 125000001624 naphthyl group Chemical group 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 235000011181 potassium carbonates Nutrition 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 239000012298 atmosphere Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- -1 4-substituted cyclopentene Chemical class 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 3
- 238000005580 one pot reaction Methods 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 92
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- LPIQUOYDBNQMRZ-UHFFFAOYSA-N cyclopentene Chemical compound C1CC=CC1 LPIQUOYDBNQMRZ-UHFFFAOYSA-N 0.000 description 8
- 239000007789 gas Substances 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 6
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- RVWUPBARILTZST-UHFFFAOYSA-N 1-phenylcyclopent-3-en-1-ol Chemical compound C=1C=CC=CC=1C1(O)CC=CC1 RVWUPBARILTZST-UHFFFAOYSA-N 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- PXIPIYIAXWNZCU-UHFFFAOYSA-N 3-oxabicyclo[2.2.1]heptan-2-one Chemical compound C1CC2C(=O)OC1C2 PXIPIYIAXWNZCU-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000002253 acid Substances 0.000 description 3
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Chemical compound OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000000975 bioactive effect Effects 0.000 description 2
- BEWYHVAWEKZDPP-UHFFFAOYSA-N bornane Chemical compound C1CC2(C)CCC1C2(C)C BEWYHVAWEKZDPP-UHFFFAOYSA-N 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- DLDZVAUNGCLDHN-SMDDNHRTSA-N (1S,5R)-5-phenyl-6-oxabicyclo[3.2.2]nonan-7-one Chemical compound O=C([C@H](CC1)CCC2)O[C@@]12C1=CC=CC=C1 DLDZVAUNGCLDHN-SMDDNHRTSA-N 0.000 description 1
- AJNZWRKTWQLAJK-VGWMRTNUSA-N (2s,5s)-1-[2-[(2s,5s)-2,5-dimethylphospholan-1-yl]phenyl]-2,5-dimethylphospholane Chemical compound C[C@H]1CC[C@H](C)P1C1=CC=CC=C1P1[C@@H](C)CC[C@@H]1C AJNZWRKTWQLAJK-VGWMRTNUSA-N 0.000 description 1
- DRZBLHZZDMCPGX-VXKWHMMOSA-N (r)-tert-butyl-[3-[tert-butyl(methyl)phosphanyl]quinoxalin-2-yl]-methylphosphane Chemical compound C1=CC=C2N=C([P@](C)C(C)(C)C)C([P@](C)C(C)(C)C)=NC2=C1 DRZBLHZZDMCPGX-VXKWHMMOSA-N 0.000 description 1
- 239000005059 1,4-Cyclohexyldiisocyanate Substances 0.000 description 1
- PSSRAPMBSMSACN-UHFFFAOYSA-N 1,4-dibromobutan-2-ol Chemical compound BrCC(O)CCBr PSSRAPMBSMSACN-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- JRQLZCFSWYQHPI-UHFFFAOYSA-N 4,5-dichloro-2-cyclohexyl-1,2-thiazol-3-one Chemical compound O=C1C(Cl)=C(Cl)SN1C1CCCCC1 JRQLZCFSWYQHPI-UHFFFAOYSA-N 0.000 description 1
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- XETQTCAMTVHYPO-UHFFFAOYSA-N Isocamphan von ungewisser Konfiguration Natural products C1CC2C(C)(C)C(C)C1C2 XETQTCAMTVHYPO-UHFFFAOYSA-N 0.000 description 1
- BUIQRTDBPCHRIR-UHFFFAOYSA-L O[Cr](Cl)(=O)=O Chemical compound O[Cr](Cl)(=O)=O BUIQRTDBPCHRIR-UHFFFAOYSA-L 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229930006742 bornane Natural products 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000005650 intramolecular substitution reaction Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 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 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a method for synthesizing chiral endocyclic lactone, belonging to the field of organic synthesis. The invention takes 4-substituted cyclopentene and synthesis gas as raw materials, takes rhodium metal salt and chiral diphosphine ligand as catalysts, and prepares the chiral bridge ring lactone through asymmetric hydroformylation/intramolecular cyclization/oxidation one-pot series reaction. The synthesis method has the advantages of cheap and easily obtained raw materials, high product yield and good enantioselectivity, and the product yield and enantioselectivity can reach 95% and 96%. The method is simple and convenient, simple to operate, low in cost, good in atom economy of reaction, easy for large-scale production and high in industrial application potential.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing chiral endocyclic lactone.
Background
Chiral endocyclic lactones are important structural units of natural products and bioactive molecules, and particularly 2-oxabicyclo [2,2,1] -heptan-3-one and ring-opened derivatives thereof are widely present in some important pharmaceutically active molecules. For example, chiral DCK (3', 4' -di-O- (S) -camphanoyl- (3'R,4' R) - (+) -cis-khellactone) having this structure is considered as a novel candidate for anti-AIDS. The chiral camphane acid containing the molecular skeleton is an important drug synthesis intermediate. In addition, chiral alcohol and chiral amide formed by ring opening of 2-oxabicyclo [2,2,1] -heptan-3-one are key structural units of various bioactive molecules, and have potential medicinal prospects. Thus, the synthesis of 2-oxabicyclo [2,2,1] -heptan-3-one is of interest and a variety of synthetic routes have been developed. Unfortunately, however, methods for chiral 2-oxabicyclo [2,2,1] -heptan-3-one have been reported only rarely, and only two examples are reported in literature.
The method comprises the following steps:
in 20014 years, the american company of CHDI Foundation limited used chiral 1,2, 4-butanetriol as a starting material in patent WO 2014/159218 a1, selectively brominated with N-bromosuccinimide to obtain 1, 4-dibromo-2-butanol, condensed with substituted arylacetic acid to obtain a chiral ester intermediate, and then subjected to two intramolecular substitution reactions under the action of lithium bis (trimethylsilyl) amide to obtain a target product. Related patents also include WO 2015/187542 a1, and furthermore org.lett.2015,17,1401-. This synthetic route uses relatively expensive chiral starting materials and the selective bromination of the first step is only in 35% isolated yield, resulting in a lower overall yield of the reaction.
The second method comprises the following steps:
in 2018, congratulatory meson research group reported an example of a method for synthesizing 2-oxabicyclo [2,2,1] -hept-3-one skeleton. The method takes symmetrical cyclopentene as a raw material, the symmetrical cyclopentene reacts with an aryl iodine reagent under the catalysis of copper to obtain chiral cyclopentene, the chiral cyclopentene is hydrolyzed to generate corresponding acid, and then molecular internal cyclization reaction is carried out under the action of iodine to obtain a target product. According to the method, an amide guide group needs to be pre-installed in a substrate, and then is hydrolyzed and removed in a subsequent process, so that the synthesis step of the reaction is long, the atom economy of the reaction is poor, and the requirement of green chemistry is not met.
Disclosure of Invention
The invention aims to solve the defects of the existing chiral endocyclic lactone synthesis and provides a novel method for synthesizing chiral endocyclic lactone.
The purpose of the invention is realized by the following technical scheme:
a method for synthesizing chiral endocyclic lactone comprises the following reaction formula:
wherein Rh represents a rhodium metal salt; l represents a chiral diphosphine ligand; oxidant represents an oxidizing agent; base represents a base; solvent-1 represents a first solvent; solvent-2 represents a second solvent; r1Representing different types of substituents and n representing the number of methylene groups.
Specifically, the method for synthesizing the chiral endocyclic lactone comprises the following steps of: in the atmosphere of inert gas or nitrogen, rhodium metal salt and chiral diphosphine ligand are dissolved in a first solvent for reaction to obtain orange clear solution, then a compound 1 is added, a reaction system is placed in an autoclave, and H is filled in the autoclave2And CO to carry out asymmetric hydroformylation reaction; and transferring the reaction solution into a second solvent, and adding an oxidant and alkali to perform intramolecular cyclization and oxidation reaction. And (3) removing the solvent after the reaction is finished to obtain a crude product, and carrying out column chromatography separation and purification on the crude product to obtain the chiral endocyclic lactone 2.
In a preferred embodiment, the rhodium metal salt is Rh (acac) (CO)2、[Rh(COD)2(OAc)]2、[Rh(NBD)Cl]2One kind of (1).
In a preferred embodiment, the chiral bisphosphine ligand is one of the compounds of the following structural formula:
wherein Ar is an aromatic group, and the substituent of the Ar aromatic group comprises hydrogen, alkyl, alkoxy, trifluoromethyl, halogen, phenyl and ester group; r2Including methyl, ethyl, propyl, benzyl.
In a preferred embodiment, the oxidizing agent comprises pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), 2,6, 6-tetramethylpiperidine-N-oxide (TEMP), 4-methylmorpholine-N-oxide (NMO).
In a preferred embodiment, the base is one or more of an organic base, an inorganic base, wherein the organic base comprises trimethylamine, triethylamine, diisopropylethylamine, 1, 8-diazabicycloundece-7-ene (DBU), piperidine, 1,3, 3-tetramethylguanidine; the inorganic base includes sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
In a preferred embodiment, the first reaction solvent is one of toluene, xylene, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane, acetonitrile, and the second reaction solvent is one of dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride, ethyl acetate.
In a preferred embodiment, compoundsR in object 11The aryl group is selected from phenyl, naphthyl and substituted aryl, or heteroaryl such as pyridine, thiophene, furan, quinoline and quinoxaline, or straight-chain alkyl, branched-chain alkyl and cyclic alkyl.
In a preferred embodiment, n is 1,2 or 3.
In a preferred embodiment, the method of synthesizing a chiral bridged lactonolipid comprises the steps of: in an inert gas or nitrogen atmosphere, rhodium metal salt and chiral diphosphine ligand are dissolved in a first solvent, stirred for 0.1-1 hour at 10-35 ℃ to obtain an orange clear solution, then a compound 1 is added, a reaction system is placed in an autoclave, and H at 20-100 ℃ and 5-40 atm is added2Stirring for 18-48 hours under the CO condition; and transferring the reaction solution into a second solvent, adding an oxidant and alkali, and stirring and reacting for 6-24 hours at the temperature of 0-50 ℃. And (3) removing the solvent after the reaction is finished to obtain a crude product, and carrying out column chromatography separation and purification on the crude product to obtain the chiral endocyclic lactone 2. The inert gas is preferably argon gas, and the method for removing the solvent is preferably a reduced pressure method.
In a preferred embodiment, the molar ratio of rhodium metal salt to chiral bisphosphine ligand is 1.0: 1.0-1.0: 3.0. the mol ratio of the compound 1 to the rhodium metal salt is 100: 1-10000: 1; the molar ratio of compound 1, oxidant and base is 1.0: 1.0: 0.1 to 1.0: 3.0: 1.0.
in a preferred embodiment, the reaction time of the rhodium metal salt and the chiral diphosphine ligand is 0.1-1 hour.
In a preferred embodiment, the reaction temperature of the reaction system in the autoclave is 30-80 ℃.
In a preferred embodiment, the reaction system is H in an autoclave2Partial pressure ratio to CO is 1: 2-2: 1, the total pressure is 5-20 atm.
In a preferred embodiment, the reaction time of the reaction system in the autoclave is 18 to 48 hours.
In a preferred embodiment, the temperature of the oxidation reaction is 0 to 50 ℃.
In a preferred embodiment, the reaction time of the oxidation reaction is 6 to 24 hours.
The invention takes 4-substituted cyclopentene and synthesis gas as raw materials, takes rhodium metal salt and chiral diphosphine ligand as catalysts, and prepares the chiral bridge ring lactone through asymmetric hydroformylation/intramolecular cyclization/oxidation one-pot series reaction. The synthesis method has the advantages of cheap and easily-obtained raw materials, high yield and good enantioselectivity of the product. The method is simple and convenient, simple to operate, low in cost, good in atom economy of reaction, easy for large-scale production and high in industrial application potential.
Detailed Description
The following examples illustrate the invention in detail:
the invention is based on asymmetric hydroformylation reaction of transition metal rhodium, and utilizes a series strategy to efficiently synthesize a target compound, namely chiral endocyclic lactone by a one-pot method.
Wherein Rh represents a rhodium metal salt; l represents a chiral diphosphine ligand; oxidant represents an oxidizing agent; base represents a base; solvent-1 represents a first solvent; solvent-2 represents a second solvent; r1Representing different types of substituents and n representing the number of methylene groups.
In a preferred embodiment, the rhodium metal salt is Rh (acac) (CO)2、[Rh(COD)2(OAc)]2、[Rh(NBD)Cl]2One kind of (1).
In a preferred embodiment, the chiral bisphosphine ligand is one of the compounds of the following structural formula:
wherein Ar is an aromatic group, and the substituent of the Ar aromatic group comprises hydrogen, alkyl, alkoxy, trifluoromethyl, halogen, phenyl and ester group; r2Is methyl, ethyl,Propyl and benzyl.
In the invention, the oxidant is pyridinium chlorochromate (PCC), Pyridinium Dichromate (PDC), 2,6, 6-tetramethylpiperidine-N-oxide (TEMP) and 4-methylmorpholine-N-oxide (NMO).
In the invention, the base is one or more of trimethylamine, triethylamine, diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene (DBU), piperidine, 1,3, 3-tetramethylguanidine, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide.
In the invention, the first reaction solvent is one of toluene, xylene, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane and acetonitrile, and the second reaction solvent is one of dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and ethyl acetate.
In the present invention, R in Compound 11The aryl group is selected from phenyl, naphthyl and substituted aryl, or heteroaryl such as pyridine, thiophene, furan, quinoline and quinoxaline, or straight-chain alkyl, branched-chain alkyl and cyclic alkyl.
Preferably, the molar ratio of rhodium metal salt to chiral bisphosphine ligand is 1: 1-1: 3, more preferably 1: 2. the molar ratio of the compound 1 to the rhodium metal salt is 100: 1-10000: 1, more preferably 100: 1; the molar ratio of compound 1, oxidant and base is 1.0: 1.0: 0.1 to 1.0: 3.0: 1.0, preferably 1: 2.5: 0.5.
preferably, the reaction time of the rhodium metal salt and the chiral diphosphine ligand is 0.1-1 hour, and more preferably 10 minutes.
Preferably, the reaction temperature of the reaction system in the autoclave is 30-80 ℃, more preferably 70 ℃.
Preferably, the reaction system is H in an autoclave2Partial pressure ratio to CO is 1: 2-2: 1, the total pressure is 5-20 atm, and H is more preferable2The partial pressure ratio of the catalyst to CO is 1:1, and the total pressure is 10 atm.
Preferably, the reaction time of the reaction system in the autoclave is 18 to 48 hours, more preferably 24 hours.
In a preferred embodiment, the temperature of the oxidation reaction is 0 to 50 ℃, more preferably 25 ℃.
In a preferred embodiment, the reaction time of the oxidation reaction is 6 to 24 hours, more preferably 12 hours.
In order to further illustrate the present invention, preferred embodiments of the present invention are described below with reference to examples. It is to be understood that such descriptions are intended only to further illustrate the features and advantages of the present invention, and not to limit the scope of the present invention, and that all other embodiments obtained by persons skilled in the art without the exercise of inventive faculty are within the scope of the present invention, and any improvements and modifications made thereto without departing from the principles of the present invention are within the scope of the present invention.
Example 1
The general preparation method comprises the following steps: rh (acac) (CO) under high-purity argon atmosphere2(0.5mg, 0.002mmol) and chiral ligand (S, R) -DM-YanPhos (3.6mg, 0.004mmol) L1 were dissolved in toluene (1mL), stirred at room temperature for 10 minutes, and 1-substituted cyclopent-3-en-1-ol (0.2mmol)1 was added. The reaction system was placed in an autoclave, and hydrogen and carbon monoxide (H) were purged into the autoclave25/5atm), stirring at 70 deg.C for 24 hr. After the reaction was completed, the gas in the reaction vessel was slowly released, and the reaction solution was poured into a solution of pyridinium chlorochromate (PCC, 0.5mmol) and triethylamine (0.1mmol) in methylene chloride (4mL) and reacted at room temperature for 12 hours. After the reaction is finished, the solvent is removed under reduced pressure, and the pure endocyclic lactone 2 is separated by column chromatography (petroleum ether/ethyl acetate 10:1, V/V).
By using the general method, the high-efficiency synthesis of 23 kinds of endocyclic lactones is realized under the condition that the reaction conditions are not changed.
The following are the names, numbers, colors, states of matter, yields, enantioselectivities, nuclear magnetic data for the synthesis of chiral endocyclic lactones with 23 different compounds 1 using the general preparation method described above.
(1)
(1R,4S) -1-phenyl-2-oxabicyclo [2,2,1]-hept-3-one (2a), colorless oil. 90% yield, 95% ee, [ alpha ]]20 D＝+42.3(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.47-7.34(m,5H),3.08-3.07(m,1H),2.32-2.29(m,1H),2.21-2.13(m,3H),2.12-2.09(m,1H),2.00-1.91(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.6,136.8,128.5,128.5,125.4,92.4,44.6,44.0,34.6,24.7ppm.
(2)
(1R,4S) -1- (4-fluorophenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2b), colorless oil. 81% yield, 95% ee, [ alpha ]]20 D＝+37.3(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.46-7.41(m,2H),7.12-7.06(m,2H),3.08(s,1H),2.32-2.28(m,1H),2.20-2.12(m,3H),2.08(dd,J＝10.3,1.1Hz,1H),2.01-1.93(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.4,162.7(d,J＝247.6Hz),132.7(d,J＝3.2Hz),127.4(d,J＝8.3Hz),115.5(d,J＝21.6Hz),91.8,44.6,44.0,34.6,24.7ppm.
(3)
(1R,4S) -1- (4-chlorophenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2c), white solid. 96% yield, 95% ee, mp 92-94 ℃ [ alpha ]]20 D＝+34.3(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.41-7.36(m,4H),3.09-3.08(m,1H),2.29-2.26(m,1H),2.19-2.12(m,3H),2.09(dd,J＝10.3,1.0Hz,1H),2.00-1.92(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.2,135.4,134.4,128.8,126.9,91.7,44.6,44.0,34.7,24.7ppm.
(4)
(1R,4S) -1- (4-bromophenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2d), white solid. 50.7mg, 95% yield, 96% ee, mp ═ 100-]20 D＝+27.6(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.55-7.52(m,2H),7.35-7.31(m,2H),3.09-3.08(m,1H),2.27(dd,J＝10.4,1.5Hz,1H),2.19-2.13(m,3H),2.09(dd,J＝10.3,1.0Hz,1H),2.00-1.92(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.2,135.9,131.7,127.1,122.5,91.7,44.6,44.0,34.7,24.7ppm.
(5)
(1R,4S) -1- (2-chlorophenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2e), colorless oil. 90% yield, 94% ee, [ alpha ]]20 D＝+31.8(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.72-7.70(m,1H),7.40-7.38(m,1H),7.33-7.26(m,2H),3.05-3.04(m,1H),2.71(dd,J＝10.5,1.1Hz,1H),2.64(ddd,J＝13.1,10.7,3.7Hz,1H),2.26(ddd,J＝10.5,3.9,2.2Hz,1H),2.21-2.05(m,2H),2.00-1.93(m,1H)ppm.13C NMR(100MHz,CDCl3)δ176.7,134.3,131.0,130.9,129.4,128.4,127.1,91.9,43.5,43.4,32.8,24.8ppm.
(6)
(1R,4S) -1- (3, 4-dichlorophenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2f), white solid. 82% yield, 95% ee, mp 79-82 ℃ [ alpha ]]25 D＝+35.8(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.55(d,J＝2.1Hz,1H),7.48(d,J＝8.3Hz,1H),7.29(dd,J＝8.4,2.2Hz,1H),3.11-3.09(m,1H),2.28-2.24(m,1H),2.20-2.14(m,3H),2.10(dd,J＝10.3,1.3Hz,1H),1.98-1.93(m,1H)ppm.13C NMR(100MHz,CDCl3)δ176.8,137.2,132.9,132.6,130.7,127.7,124.8,90.9,44.8,44.0,34.8,24.6ppm.
(7)
(1R,4S) -1- (3-methoxyphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2g), colorless oil. 90% yield, 96% ee, [ alpha ]]20 D＝+33.3(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.33-7.26(m,1H),7.02-7.00(m,2H),6.91-6.88(m,1H),3.83(s,3H),3.08-3.07(m,1H),2.30-2.27(m,1H),2.20-2.11(m,3H),2.11-2.08(m,1H),1.99-1.91(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.5,159.7,138.4,129.6,117.4,113.9,111.2,92.3,55.3,44.7,44.0,34.8,24.7ppm.
(8)
(1R,4S) -1- (4-tert-butylphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2h), white solid. 80% yield, 94% ee, mp 106-]25 D＝+31.5(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.44-7.38(m,4H),3.07-3.06(m,1H),2.32-2.29(m,1H),2.21-2.11(m,3H),2.07(dd,J＝10.4,0.9Hz,1H),1.97-1.91(m,1H),1.33(s,9H)ppm.13C NMR(100MHz,CDCl3)δ177.7,151.6,133.8,125.4,125.2,92.4,44.6,44.0,34.6,34.4,31.2,24.7ppm.
(9)
(1R,4S) -1- (3, 5-dimethylphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2i), white solid. 73% yield, 94% ee, mp ═ 114-]25 D＝+34.3(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.07(s,2H),6.99(s,1H),3.06-3.05(m,1H),2.34(s,6H),2.29-2.26(m,1H),2.19-2.11(m,3H),2.09-2.06(m,1H),1.99-1.90(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.7,138.2,136.7,130.1,123.1,92.5,44.6,44.0,34.7,24.8,21.3ppm.
(10)
(1R,4S) -1- (3-methylphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2j), white solid. 83% yield, 94% ee, mp 59-61 deg.C]25 D＝+33.6(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.31-7.27(m,2H),7.25-7.22(m,1H),7.18-7.16(m,1H),3.08-3.06(m,1H),2.38(s,3H),2.31-2.28(m,1H),2.20-2.12(m,3H),2.10-2.07(m,1H),1.97-1.91(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.6,138.3,136.8,129.2,128.5,126.1,122.4,92.5,44.6,44.0,34.7,24.8,21.4ppm.
(11)
(1R,4S) -1- (2-methoxyphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2k), light yellow oil. 20.5mg, 47% yield, 91% ee]25 D＝+27.9(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.59-7.56(m,1H),7.34-7.30(m,1H),7.01-6.97(m,1H),6.93-6.91(m,1H),3.84(s,3H),3.00-2.99(m,1H),2.50-2.43(m,2H),2.24-2.19(m,1H),2.15-2.07(m,1H),2.05-1.98(m,1H),1.95-1.88(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.7,156.4,129.3,127.4,125.1,120.7,110.9,91.7,55.3,43.9,43.6,33.1,24.9ppm.
(12)
(1R,4S) -1- (4-trifluoromethylphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2l), white solid. 77% yield, 95% ee, mp ═ 82-84 ℃, [ alpha ]]25 D＝+33.1(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.67(d,J＝8.2Hz,2H),7.58(d,J＝8.2Hz,2H),3.13-3.12(m,1H),2.31-2.28(m,1H),2.23-2.14(m,4H),2.03-1.94(m,1H)ppm.13C NMR(100MHz,CDCl3)δ176.9,140.9,130.61(q,J＝32.6Hz),125.7,125.6(q,J＝3.8Hz),123.9(q,J＝272.2Hz),91.5,44.8,44.0,35.0,24.7ppm.
(13)
(1R,4S) -1- ([1,1' -Diphenyl)]-2-oxabicyclo [2,2,1]]-hept-3-one (2m), white solid. 37.5mg, 71% yield, 94% ee, mp 128-]25 D＝+28.5(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.64-7.34(m,9H),3.10-3.09(m,1H),2.35-2.33(m,1H),2.25-2.11(m,4H),2.00-1.94(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.6,141.5,140.4,135.8,128.8,127.5,127.3,127.1,125.9,92.3,44.7,44.0,34.6,24.8ppm.
(14)
(1R,4S) -1- (4-pinacolborolphenyl) -2-oxabicyclo [2,2,1]-hept-3-one (2n), white solid. 49.6mg, 79% yield, 96% ee, mp 198-]25 D＝+26.1(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.86-7.84(m,2H),7.47-7.45(m,2H),3.09-3.07(m,1H),2.30-2.26(m,1H),2.21-2.10(m,4H),1.97-1.91(m,1H),1.35(s,12H)ppm.13C NMR(100MHz,CDCl3)δ177.5,139.9,135.0,124.6,92.4,84.0,44.8,44.1,34.9,24.9,24.9,24.8ppm.
(15)
(1R,4S) -1- (2-naphthyl) -2-oxabicyclo [2,2,1]-hept-3-one (2o), white solid. 42.9mg, 90% yield, 93% ee, mp 109-]25 D＝+19.6(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.94-7.83(m,4H),7.56-7.49(m,3H),3.13-3.12(m,1H),2.40-2.37(m,1H),2.31-2.16(m,4H),2.04-1.97(m,1H)ppm.13C NMR(100MHz,CDCl3)δ177.6,134.2,133.1,133.0,128.4,128.1,127.7,126.5,126.5,124.5,123.1,92.5,44.8,44.1,34.7,24.8ppm.
(16)
(1R,4S) -1-benzyl-2-oxabicyclo [2,2,1]-hept-3-one (2p), white solid. 75% yield, 97% ee, mp 71-74 ℃ [ alpha ]]25 D＝+44.4(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.33-7.23(m,5H),3.23-3.15(m,2H),2.85-2.84(m,1H),1.96-1.71(m,5H),1.59-1.56(m,1H)ppm.13C NMR(100MHz,CDCl3)δ178.1,135.8,129.9,128.4,126.9,92.5,43.2,42.8,39.4,31.4,24.4ppm.
(17)
(1R,4S) -1-pentyl-2-oxabicyclo [2,2,1]-hept-3-one (2q), colorless oil. 80% yield, 95% ee, [ alpha ]]20 D＝+44.5(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ2.88-2.87(m,1H),1.99-1.91(m,2H),1.88-1.78(m,5H),1.61-1.58(m,1H),1.50-1.41(m,2H),1.36-1.31(m,4H),0.92-0.88(m,3H)ppm.13C NMR(100MHz,CDCl3)δ178.5,93.2,43.5,42.9,32.9,32.0,31.6,24.4,24.1,22.4,13.9ppm.
(18)
(1R,4S) -1-isopropyl-2-oxabicyclo [2,2,1]-hept-3-one (2r), colorless oil. 27.8mg, 90% yield, 96% ee, [ alpha ]]20 D＝+38.1(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ2.88-2.87(m,1H),2.18-2.11(m,1H),1.99-1.91(m,2H),1.87-1.75(m,3H),1.60-1.58(m,1H),1.04(dd,J＝9.3,6.9Hz,6H)ppm.13C NMR(100MHz,CDCl3)δ178.5,96.5,43.4,41.0,30.6,28.5,24.3,17.8,17.5ppm.
(19)
(1R,4S) -1-cyclopropyl-2-oxabicyclo [2,2,1]-hept-3-one (2s), colorless oil. 60% yield, 91% ee, [ alpha ]]20 D＝+36.1(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ2.88-2.87(m,1H),1.99-1.90(m,1H),1.87-1.78(m,4H),1.54-1.51(m,1H),1.33-1.24(m,2H),0.67-0.59(m,2H),0.53-0.45(m,2H)ppm.13C NMR(100MHz,CDCl3)δ178.1,93.9,43.3,41.8,31.3,24.2,12.5,2.3,1.9ppm.
(20)
(1R,4S) -1-cyclopentyl-2-oxabicyclo [2,2,1]-hept-3-one (2t), colorless oil. 87% yield, 96% ee, [ alpha ]]20 D＝+33.6(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ2.87-2.86(m,1H),2.31(p,J＝8.6Hz,1H),2.00-1.91(m,2H),1.85-1.74(m,5H),1.69-1.55(m,5H),1.52-1.43(m,2H)ppm.13C NMR(100MHz,CDCl3)δ178.7,95.2,43.4,42.1,41.7,30.6,27.8,27.8,25.7,25.7,24.6ppm.
(21)
(1R,4S) -1-cyclohexyl-2-oxabicyclo [2,2,1]-hept-3-one (2u), colorless oil. 89% yield, 96% ee, [ alpha ]]20 D＝+34.8(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ2.87-2.86(m,1H),1.97-1.69(m,11H),1.58-1.55(m,1H),1.32-1.08(m,5H)ppm.13C NMR(100MHz,CDCl3)δ178.5,96.2,43.3,41.0,40.4,28.8,28.1,27.6,26.1,26.1,26.0,24.2ppm.
(22)
(1R,4S) -1- (1-adamantyl) -2-oxabicyclo [2,2,1]-hept-3-one (2v), white solid. 43.4mg, 88% yield, mp 158-]25 D＝+25.1(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ2.87-2.86(m,1H),2.05-2.01(m,4H),1.98-1.83(m,2H),1.81-1.66(m,13H),1.58(s,1H),1.49(m,1H)ppm.13C NMR(100MHz,CDCl3)δ178.6,99.1,43.3,37.9,37.3,36.9,34.5,28.1,26.5,24.2ppm.HRMS calculated[M+Na]+for C16H22NaO2＝269.1512,found:269.1509.
(23)
(1S,5R) -5-phenyl-6-oxabicyclo [3.2.2]Nonan-7-one (2w), a colorless oil. 80% yield, 85% ee, [ alpha ]]25 D＝-56.2(c＝1.0,CHCl3).1H NMR(400MHz,CDCl3)δ7.47-7.45(m,2H),7.36-7.32(m,2H),7.27-7.23(m,1H),2.94-2.90(m,1H),2.51-2.41(m,1H),2.20-2.14(m,1H),2.12-2.05(m,3H),2.04-1.77(m,5H)ppm.13C NMR(100MHz,CDCl3)δ176.3,146.4,128.4,127.1,123.9,84.5,41.0,38.2,30.9,28.1,21.4,21.2ppm.
Example 2
Rh (acac) (CO) under high-purity argon atmosphere2(0.5mg, 0.002mmol) and the chiral ligand (S, S) -Ph-BPE (2.0mg, 0.004mmol) L2 were dissolved in toluene (1mL), stirred at room temperature for 10 min, then 1-phenylcyclopent-3-en-1-ol (0.2mmol)1a was added. The reaction system was placed in an autoclave, and hydrogen and carbon monoxide (H) were purged into the autoclave25/5atm) at 70 deg.C for 24 hours. After the reaction was completed, the gas in the reaction vessel was slowly released, and the reaction solution was poured into a solution of pyridinium chlorochromate (PCC, 0.5mmol) and triethylamine (0.1mmol) in methylene chloride (4mL) and reacted at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure and the pure endocyclic lactone 2a (88% yield, 94% ee) is isolated by column chromatography (petroleum ether/ethyl acetate 10: 1).
The yield, enantioselectivity results for the synthesis of chiral endocyclic lactone 2a from compound 1a using different ligands using the general procedure are as follows: (S, S) Ph-BPE (L2, 88% yield, 94% ee), (R)C,SP) -DuanPhos (36% yield, 90% ee), (R, R) -Quinoxp (28%, 73% ee), (S, S) -H8-YanPhos (70% yield, 39% ee), (S, S) -YanPhos (76% yield, 45% ee), (S, S) -DM-YanPhos (78% yield, 50% ee), (S, S) -DTB-YanPhos (91% yield, 79% ee), (S, S) -DTBM-YanPho (82% yield, 70% ee), (S, S) -Me-Duphos (no target product), (S) -Segphos (no target product).
Example 3
Rh (acac) (CO) under high-purity argon atmosphere2(0.5mg, 0.002mmol) and chiral ligand (S, R) -DM-YanPhos (3.6mg, 0.004mmol) L1 were dissolved in toluene (1mL), stirred at room temperature for 10 minutes, and 1-phenylcyclopent-3-en-1-ol (0.2mmol)1a was added. The reaction system was placed in an autoclave, and hydrogen and carbon monoxide (H) were purged into the autoclave25/5atm) at 70 deg.C for 24 hours. After the reaction is finished, slowly releasing the gas in the reaction kettle, and reacting the reaction solutionPyridine chlorochromate (PCC, 0.5mmol) and Cs were poured in2CO3(0.1mmol) in dichloromethane (4mL) and reacted at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure and the pure endocyclic lactone 2a (85% yield, 94% ee) is isolated by column chromatography (petroleum ether/ethyl acetate 10: 1).
Example 4
Rh (acac) (CO) under high-purity argon atmosphere2(0.5mg, 0.002mmol) and chiral ligand (S, R) -DM-YanPhos (3.6mg, 0.004mmol) L1 were dissolved in toluene (1mL), stirred at room temperature for 10 minutes, and 1-phenylcyclopent-3-en-1-ol (0.2mmol)1a was added. The reaction system was placed in an autoclave, and hydrogen and carbon monoxide (H) were purged into the autoclave25/5atm) at 70 deg.C for 24 hours. After the reaction was completed, the gas in the reaction vessel was slowly released, and the reaction solution was poured into a solution of pyridinium chlorochromate (PCC, 0.5mmol) in methylene chloride (4mL) and reacted at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure and the pure endocyclic lactone 2a (61% yield, 94% ee) is isolated by column chromatography (petroleum ether/ethyl acetate 10: 1).
Example 5
Rh (acac) (CO) under high-purity argon atmosphere2(0.5mg, 0.002mmol) and chiral ligand (S, R) -DM-YanPhos (3.6mg, 0.004mmol) L1 were dissolved in toluene (1mL), stirred at room temperature for 10 minutes, and 1-phenylcyclopent-3-en-1-ol (0.2mmol)1a was added. The reaction system was placed in an autoclave, and hydrogen and carbon monoxide (H) were purged into the autoclave25/5atm) at 70 deg.C for 24 hours. After the reaction was completed, the gas in the reaction vessel was slowly released, and the reaction solution was poured into a solution of 4-methylmorpholine-N-oxide (NMP, 0.5mmol) and triethylamine (0.1mmol) in methylene chloride (4mL) and reacted at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure and the pure endocyclic lactone 2a (75% yield, 94% ee) is isolated by column chromatography (petroleum ether/ethyl acetate 10: 1).
Example 6
Rh (acac) (CO) under high-purity argon atmosphere2(0.02mmol) and chiral ligand (S, R) -DM-YanPhos (0.02mmol) were dissolved in toluene (6mL) and stripped at room temperatureStirring was continued for 10 minutes and 1-phenylcyclopent-3-en-1-ol (5mmol)1a was added. The reaction system was placed in an autoclave, and hydrogen and carbon monoxide (H) were purged into the autoclave23/3atm) at 70 deg.C for 72 hours. After the reaction was completed, the gas in the reaction vessel was slowly released, and the reaction solution was poured into a solution of pyridinium chlorochromate (PCC, 10mmol) and triethylamine (2.5mmol) in methylene chloride (5mL) and reacted at room temperature for 12 hours. After the reaction is complete, the solvent is removed under reduced pressure and the pure endocyclic lactone 2a (71% yield, 96% ee) is isolated by column chromatography.
The synthesis method of chiral endocyclic lactone provided by the invention is described in detail above. The present invention uses specific examples to describe the principles and embodiments of the invention in detail. The above embodiments are merely illustrative to facilitate the understanding of the method and core concepts of the present invention. It should be noted that the present disclosure is not limited to the illustrated embodiments, and any modifications and changes made by those skilled in the art without departing from the principle of the present disclosure are also within the protection scope of the present disclosure.
Claims (8)
1. A method for synthesizing chiral endocyclic lactone is characterized in that the synthesis reaction formula is as follows:
wherein R is1Is a straight chain alkyl, branched alkyl, cycloalkyl, phenyl, naphthyl, pyridine, thiophene, furan, quinoline, or quinoxaline; n is 1,2 or 3; rh represents a rhodium metal salt; l represents a chiral diphosphine ligand; oxidant represents an oxidizing agent; base represents a base; solvent-1 represents a first solvent; solvent-2 represents a second solvent; the rhodium metal salt is Rh (acac) (CO)2(ii) a The chiral diphosphine ligand is (A)S,R) -DM-YanPhos or (S, S) Ph-BPE.
2. The method of claim 1, comprising the steps of:in the atmosphere of inert gas or nitrogen, rhodium metal salt and chiral diphosphine ligand are dissolved in a first solvent for reaction to obtain orange clear solution, then a compound 1 is added, a reaction system is placed in an autoclave, and H is filled in the autoclave2And CO to carry out asymmetric hydroformylation reaction; transferring the reaction liquid into a second solvent, and adding an oxidant and alkali to perform intramolecular cyclization and oxidation reaction; and (3) removing the solvent after the reaction is finished to obtain a crude product, and carrying out column chromatography separation and purification on the crude product to obtain the chiral endocyclic lactone 2.
3. The method according to claim 1 or 2, characterized in that: the oxidant is selected from pyridinium chlorochromate, pyridinium dichromate, 2,6, 6-tetramethyl piperidine-N-oxide and 4-methylmorpholine-N-oxide.
4. The method according to claim 1 or 2, characterized in that: the alkali is one or more of organic alkali and inorganic alkali; wherein the organic base is selected from trimethylamine, triethylamine, diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene, piperidine, 1,3, 3-tetramethylguanidine; the inorganic base is selected from sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide.
5. The method according to claim 1 or 2, characterized in that: the first reaction solvent is one of toluene, xylene, tetrahydrofuran, dichloromethane, chloroform, 1, 2-dichloroethane and acetonitrile, and the second reaction solvent is one of dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and ethyl acetate.
6. Method according to claim 1 or 2, characterized in that it comprises the following steps: in an inert gas or nitrogen atmosphere, rhodium metal salt and chiral metal ligand are dissolved in a first solvent, stirred for 0.1-1 hour at 10-35 ℃, then a compound 1 is added, a reaction system is placed in an autoclave, and H at 20-100 ℃ and 5-40 atm2Stirring under CO conditionStirring for 18-48 hours; transferring the reaction solution into a second solvent, adding an oxidant and alkali, and stirring and reacting for 6-24 hours at 0-50 ℃; and after the reaction is finished, removing the solvent to obtain a crude product, and carrying out column chromatography separation and purification on the crude product to obtain the chiral endocyclic lactone 2.
7. The process of claim 6, H in an autoclave with the reaction system2Partial pressure ratio to CO is 1: 2-2: 1, the total pressure is 5-40 atm.
8. The method according to claim 1 or 2, characterized in that: the molar ratio of the rhodium metal salt to the chiral metal ligand is 1.0: 1.0-1.0: 3.0; the molar ratio of the compound 1 to the rhodium metal salt is 100: 1-10000: 1; the molar ratio of compound 1, oxidant and base is 1.0: 1.0: 0.1 to 1.0: 3.0: 1.0.
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