CN105254657B - 金属催化不对称1,4-共轭加成反应产生前列腺素和前列腺素类似物 - Google Patents
金属催化不对称1,4-共轭加成反应产生前列腺素和前列腺素类似物 Download PDFInfo
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- CN105254657B CN105254657B CN201510388413.6A CN201510388413A CN105254657B CN 105254657 B CN105254657 B CN 105254657B CN 201510388413 A CN201510388413 A CN 201510388413A CN 105254657 B CN105254657 B CN 105254657B
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- 150000003180 prostaglandins Chemical class 0.000 title abstract description 42
- 238000007259 addition reaction Methods 0.000 title abstract description 22
- 229910052751 metal Inorganic materials 0.000 title abstract description 7
- 239000002184 metal Substances 0.000 title abstract description 7
- 230000003197 catalytic effect Effects 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 238000000034 method Methods 0.000 claims abstract description 84
- -1 ketone compounds Chemical class 0.000 claims abstract description 69
- 238000006467 substitution reaction Methods 0.000 claims abstract description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 146
- 239000000654 additive Substances 0.000 claims description 46
- 230000000996 additive effect Effects 0.000 claims description 46
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 38
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 37
- 229920002554 vinyl polymer Polymers 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 21
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 19
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 18
- 239000000758 substrate Substances 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 14
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 229910052796 boron Inorganic materials 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 12
- WSNODXPBBALQOF-VEJSHDCNSA-N tafluprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\C(F)(F)COC1=CC=CC=C1 WSNODXPBBALQOF-VEJSHDCNSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- 229910052710 silicon Inorganic materials 0.000 claims description 11
- 239000010703 silicon Substances 0.000 claims description 11
- 229960004458 tafluprost Drugs 0.000 claims description 11
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 8
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 8
- 229960001342 dinoprost Drugs 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- PXGPLTODNUVGFL-YNNPMVKQSA-N prostaglandin F2alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O PXGPLTODNUVGFL-YNNPMVKQSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 125000002837 carbocyclic group Chemical group 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000010948 rhodium Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 6
- 150000001993 dienes Chemical class 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- WGFOBBZOWHGYQH-MXHNKVEKSA-N lubiprostone Chemical compound O1[C@](C(F)(F)CCCC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 WGFOBBZOWHGYQH-MXHNKVEKSA-N 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 229960002470 bimatoprost Drugs 0.000 claims description 5
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 229960000345 lubiprostone Drugs 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229910021645 metal ion Inorganic materials 0.000 claims description 5
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- 229960002368 travoprost Drugs 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 125000002843 carboxylic acid group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 229960002986 dinoprostone Drugs 0.000 claims description 3
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical group [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052737 gold Inorganic materials 0.000 claims description 3
- 239000010931 gold Substances 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 claims description 3
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 claims description 3
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 claims description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052703 rhodium Inorganic materials 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000007836 KH2PO4 Substances 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229960003395 carboprost Drugs 0.000 claims description 2
- DLJKPYFALUEJCK-MRVZPHNRSA-N carboprost Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C\CCCC(O)=O DLJKPYFALUEJCK-MRVZPHNRSA-N 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 2
- 150000002240 furans Chemical class 0.000 claims description 2
- 229960001160 latanoprost Drugs 0.000 claims description 2
- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 2
- 150000002816 nickel compounds Chemical class 0.000 claims description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 4
- 229940113088 dimethylacetamide Drugs 0.000 claims 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims 2
- 150000003284 rhodium compounds Chemical class 0.000 claims 2
- REPVLJRCJUVQFA-UHFFFAOYSA-N (-)-isopinocampheol Natural products C1C(O)C(C)C2C(C)(C)C1C2 REPVLJRCJUVQFA-UHFFFAOYSA-N 0.000 claims 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 claims 1
- 235000000621 Bidens tripartita Nutrition 0.000 claims 1
- 240000004082 Bidens tripartita Species 0.000 claims 1
- 229960000711 alprostadil Drugs 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 229940116229 borneol Drugs 0.000 claims 1
- CKDOCTFBFTVPSN-UHFFFAOYSA-N borneol Natural products C1CC2(C)C(C)CC1C2(C)C CKDOCTFBFTVPSN-UHFFFAOYSA-N 0.000 claims 1
- 229910017052 cobalt Inorganic materials 0.000 claims 1
- 239000010941 cobalt Substances 0.000 claims 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims 1
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical compound O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 claims 1
- DTGKSKDOIYIVQL-UHFFFAOYSA-N dl-isoborneol Natural products C1CC2(C)C(O)CC1C2(C)C DTGKSKDOIYIVQL-UHFFFAOYSA-N 0.000 claims 1
- 208000006637 fused teeth Diseases 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- XXUPXHKCPIKWLR-JHUOEJJVSA-N isopropyl unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(=O)OC(C)C XXUPXHKCPIKWLR-JHUOEJJVSA-N 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 239000001294 propane Substances 0.000 claims 1
- 229950008081 unoprostone isopropyl Drugs 0.000 claims 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 abstract description 41
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 20
- RWMJRMPOKXSHHI-UHFFFAOYSA-N ethenylboron Chemical class [B]C=C RWMJRMPOKXSHHI-UHFFFAOYSA-N 0.000 abstract description 18
- 239000002243 precursor Substances 0.000 abstract description 8
- 150000001336 alkenes Chemical class 0.000 abstract description 6
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 abstract description 4
- 231100000419 toxicity Toxicity 0.000 abstract description 3
- 230000001988 toxicity Effects 0.000 abstract description 3
- 238000007796 conventional method Methods 0.000 abstract description 2
- 150000002576 ketones Chemical class 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 description 88
- 239000002585 base Substances 0.000 description 86
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 58
- 239000000243 solution Substances 0.000 description 54
- 239000000203 mixture Substances 0.000 description 53
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 52
- 238000005160 1H NMR spectroscopy Methods 0.000 description 48
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 44
- 238000004440 column chromatography Methods 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 238000010828 elution Methods 0.000 description 34
- 238000001437 electrospray ionisation time-of-flight quadrupole detection Methods 0.000 description 32
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 29
- 239000010410 layer Substances 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 24
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Natural products C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 23
- 235000010338 boric acid Nutrition 0.000 description 23
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 22
- 238000007792 addition Methods 0.000 description 22
- 239000004327 boric acid Substances 0.000 description 22
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 19
- 229940125782 compound 2 Drugs 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 18
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 239000012267 brine Substances 0.000 description 16
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- 229910000085 borane Inorganic materials 0.000 description 15
- 238000010438 heat treatment Methods 0.000 description 15
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 14
- YFXCNIVBAVFOBX-UHFFFAOYSA-N ethenylboronic acid Chemical class OB(O)C=C YFXCNIVBAVFOBX-UHFFFAOYSA-N 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 12
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 230000004224 protection Effects 0.000 description 11
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
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- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000005619 boric acid group Chemical class 0.000 description 1
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- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
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- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- UOALEFQKAOQICC-UHFFFAOYSA-N chloroborane Chemical class ClB UOALEFQKAOQICC-UHFFFAOYSA-N 0.000 description 1
- 229920005556 chlorobutyl Polymers 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
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- 238000009776 industrial production Methods 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
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- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
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- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 229930006728 pinane Natural products 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
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- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
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- TVHAZVBUYQMHBC-SNHXEXRGSA-N unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O TVHAZVBUYQMHBC-SNHXEXRGSA-N 0.000 description 1
- 238000006886 vinylation reaction Methods 0.000 description 1
- 229940018148 zioptan Drugs 0.000 description 1
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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- C07F7/1804—Compounds having Si-O-C linkages
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Abstract
本发明提供用于制备2,3‑二取代‑4‑氧基‑环戊烷‑1‑酮化合物的新颖方法,所述2,3‑二取代‑4‑氧基‑环戊烷‑1‑酮化合物可用于合成工业相关的前列腺素和前列腺素类似物。所述方法包括乙烯基硼化合物至2‑取代‑4‑氧基‑环戊‑2‑烯‑1‑酮的金属催化的不对称1,4‑共轭加成反应。该方法依靠使用毒性较小的、容易操作的试剂,并且与一些传统方法提供的条件相比,该方法可在更温和的条件下进行,以高产率、对映选择性地和非对映选择性地提供2,3‑二取代‑4‑氧基‑环戊烷‑1‑酮化合物,这些化合物是所述前列腺素和前列腺素类似物的前体。
Description
与相关申请的交叉引用
本申请要求2014年7月10日提交的美国临时专利No.62/022,797的优先权,该临时专利申请通过引用以其整体纳入本文。
发明背景
天然前列腺素具有基于前列腺烷酸(7-[(1S,2S)-2-辛基环戊基]庚酸)的独特化学结构,即使以极少的量存在仍具有广泛的生理活性。大量基于前列腺素和前列腺素类似物的药物已开发用于多种医学指征。例如,局部应用(如作为滴眼液)他氟前列素(ZIOPTAN)、曲伏前列素(TRAVATAN)、和比马前列素(LUMIGAN)以治疗青光眼和高眼压症。鲁比前列酮(AMITIZA)用于慢性便秘的管理。地诺前列酮是一种天然存在的前列腺素(PGE2),临床上用于诱导人类分娩。因此,由于这些化合物和它们的类似物的药用价值,学术界和工业界已经开发并公开了制造前列腺素和前列腺素结构类似物的许多方法。
早期用于合成前列腺素类似物F2α和前列腺素E2的方法由E.J.Corey公开于1969年(J.Am.Chem.Soc.,1969,91,5675–5676)。该方法被称为Corey法,著名的Corey内酯——其本身需要约10个合成步骤并且已经在其中含有所有的三个前列腺素E(PGE)立体化学中心——对于Corey法是非常关键的。通过Horner-Wadsworth-Emmons和Wittig反应依次加入ω-和α-烃基侧链(参见图1)。Corey法及最近对该方法的改进和变换可能是使用和报道最多的用于工业生产前列腺素和前列腺素类似物的合成方法。然而,这种方法的缺点包括,高成本的Corey内酯和为了除去不需要的的异构体和/或杂质而通常需要的繁琐的柱层析纯化。
另一种可用于制备前列腺素及其类似物的方法有时被称为双组分法(J.Am.Chem.Soc.,1972,94,3643–3644和J.Am.Chem.Soc.,1972,94,7827–7832)。这种方法的主要特点是用乙烯基有机铜或有机铜酸盐(organocuprate)试剂以1,4-共轭加成反应向已经有α-侧链的环戊烯酮体系中加入ω-侧链(参见图2)。这种方法(利用了有机铜试剂)在本文中称为传统的双组份法。有许多已知的用于产生α-侧链取代的环戊烯酮的方法可用于传统的双组份法中。传统的双组份法已用于合成多种前列腺素和它们的类似物。
Fried.等(J.Am.Chem.Soc.1972,94,7827–7832)、Lipshutz等(J.Am.Chem.Soc.1988,110,2641–2643)、Lipshutz等(J.Am.Chem.Soc.1990,112,7440–7441)以及Van Hijfte等(Tetrahedron 1992,48,6393–6402)已公开了用双组分法制备前列腺素E1(PGE1)的工艺,其中将作为乙烯化试剂的各种有机铜酸盐在低温下通过1,4-共轭加成反应与环戊烯酮偶合。需要有机锡试剂、有机锂试剂或有机锆试剂作为该方法中使用的上述有机铜化合物的合成前体。
由本申请人公开的美国专利No.7,897,795(‘795专利)和美国专利No.8,846,958(‘958专利)描述了用传统的双组分法(参见图2)合成某些前列腺素类似物(例如,曲伏前列素,比马前列素和鲁比前列酮)。在‘795专利和‘958专利公开的某些工艺中,2-取代-4-氧基-环戊-2-烯-1-酮中间体II通过1,4-共轭加成反应与更高级的铜酸盐反应生成2,3-二取代-4-氧基-环戊烷-1-酮化合物I。这种化合物I可任选被修饰和去保护以提供各种前列腺素E和前列腺素F类似物。
然而,使用双组分法有许多局限性和缺点包括:1,4-共轭加成步骤中需要低温(约-50到-78℃);使用有机金属化合物作为有机铜化合物的前体,诸如有机锡化合物,被认为是有毒的并且难以纯化,或者有机锆化合物,对水分敏感并且制备时可能需要低温;使用反应性的并且难以操作的有机锂化合物制备有机铜化合物;以及需要多个步骤将炔起始材料转化为所需的有机铜化合物。此外,一些铜酸盐试剂中的氰化物是有毒的。铜酸盐不能通过商业途径获得,部分是由于它们在环境条件下的反应性和不稳定性,包括它们对空气的敏感性,这使得它们需要在合成后立即使用。铜酸盐的反应性受与铜原子相邻的碳骨架上的取代基的电子性质调节甚至可以受其限制。实际上,在有些情况下(例如,他氟前列素;参见图4),所希望的对α-侧链取代的环戊烯酮的1,4-共轭加成反应没有作用。并且,需要化学计量的用于制备有机铜化合物的铜盐。
由于本发明相关领域中与使用传统方法相关的效率不高和操作困难,需要开发一种更温和、毒性更小、成本有效和用户友好的工艺以对映选择性和非对映选择性地制备前列腺素类似物并且获得良好的产率。出乎意料地,本发明为本发明相关领域的这一问题和其他问题提供了解决方案。
发明概述
在一个方面,本发明提供一种制备式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物的方法
所述方法包括在溶剂中在金属添加剂存在下,任选地在碱性添加剂存在下,将式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物
与式III所示的化合物接触
以产生式I所示的化合物;
其中,
R1、R3、R4和R5独立地代表氢、芳基、杂芳基、烷基、芳基烷基、芳氧基烷基、烯基、或炔基;
或者R3和R5一起形成5-至7-元碳环,任选地具有一个或两个杂原子作为环顶点,其中所述杂原子选自下组:O、N和S;
或者R3和R4一起形成5-至7-元碳环,任选地具有一个或两个杂原子作为环顶点,其中所述杂原子选自下组:O、N和S,
并且其中R1、R3、R4和R5各任选地被选自下组的1至3个成员取代:卤素、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、硅氧基、芳氧基、酰氧基、杂环、氧代、COOH、CONH2、CONHC1-4烷基、C(O)OCH2C6-10芳基、C(O)OC6-10芳基和C(O)OC1-4烷基;
R2代表氢或羟基-保护基团;
X代表含硼基团。
在附于本公开并形成本公开一部分的权利要求书中详细描述表征本发明的各种特征。为了更好地理解本发明、其操作优点和利用其所获得的具体目的,应参考附图和描述性部分,其中阐释和描述本发明的优选实施方式。
附图简述
图1显示用于前列腺素合成的Corey法。
图2显示用于前列腺素合成的传统双组分法。
图3显示由本申请人公开的用于合成前列腺素和前列腺素类似物的改进的双组分法。
图4显示具有工业和药用价值的一些前列腺素和前列腺素类似物。
图5显示用本发明合成地诺前列素。
图6显示用本发明合成他氟前列素。
发明详述
I.概述
本发明提供一种新颖的方法,该方法使用乙烯基硼化合物和2-取代-4-氧基-环戊-2-烯-1-酮的金属催化不对称1,4-共轭加成反应来产生2,3-二取代-4-氧基-环戊烷-1-酮化合物,所述2,3-二取代-4-氧基-环戊烷-1-酮化合物是具有工业和药用价值的前列腺素和前列腺素类似物的有用的合成前体。与传统的双组分法相比,本发明方法使用毒性较小的、更容易操作的试剂,可在更温和的反应条件下进行,并且能够以高产率、以对映选择性和非对映选择性的方式提供多样的前列腺素和前列腺素类似物。
II.定义
如本文所用,术语“接触”是指使至少两种不同的物质接触从而它们能够反应的过程。然而应理解,产生的反应产物可以由所加入的试剂之间的反应直接产生,或由可在反应混合物中产生的一种或多种加入的试剂的中间体产生。
如本文所用,术语“金属添加剂”是指以亚化学计量的量用于化学反应的催化剂或预催化剂。催化剂是增加一个或多个反应物的化学反应速率的化学物质。应理解,与化学反应中的其他试剂不同,催化剂不被反应消耗。预催化剂是一种化学物质,本身可能在所述反应中不是化学活性的,或化学活性较小,在反应中通过添加剂作用转化为催化剂。此外,术语“亚化学计量的“是指小于化学计量的量。例如,当1摩尔化合物II与1摩尔或更多的化合物III组合时,亚化学计量的量的金属添加剂是小于约1摩尔;一般小于约0.5摩尔;在一些实施方式中,小于约0.1摩尔;在优选实施方式中,从约0.05至约0.0001摩尔。
如本文所用,术语“碱性”是一个形容词,指是碱的化学物质。碱性添加剂是指碱的添加剂。
如本文所用,术语“烷基”本身或作为另一个取代基的一部分,除非另有说明,是指直链或支链的烃基。烷基取代基,以及其他烃取代基,可含有数字指示,表明取代基中碳原子的数目(即,C1-8表示1-8个碳),虽然这种指示可能被省略。除非另外指明,本发明的烷基基团含有1-12个碳原子。例如,烷基基团可含有1-2、1-3、1-4、1-5、1-6、1-7、1-8、1-9、1-10、1-11、1-12、2-3、2-4、2-5、2-6、3-4、3-5、3-6、4-5、4-6或5-6个碳原子。烷基基团的例子包括甲基,乙基,正丙基,异丙基,正丁基,叔丁基,异丁基,仲丁基,正戊基,正己基,正庚基,正辛基,等。
术语“烯基”和“炔基”指上文定义的烷基基团,分别具有一个或多个碳-碳双键(烯基)或碳-碳三键(炔基)。对于既有碳-碳双键又有碳-碳三键的那些基团,使用术语“炔基”。
术语"卤代"或"卤素"本身或作为另一个取代基的一部分,除非另有说明,是指氟、氯、溴、或碘原子。此外,术语诸如"卤代烷基"意在包括单卤代烷基和多卤代烷基。例如,术语"C1-4卤代烷基"意在包括三氟甲基、2,2,2-三氟乙基、4-氯丁基、3-溴丙基等。
术语"芳基",除非另有说明,是指多不饱和的、通常是芳族的烃基,可以是单环或稠合在一起或共价连接的多环(至多3个环)。术语"杂芳基"是指芳基基团(或环),含有1至5个选自N、O、或S的杂原子,其中氮原子和硫原子任选地被氧化,并且氮原子任选地季铵化。杂芳基基团可通过杂原子连接于分子的其余部分。芳基基团的非限制性例子包括苯、萘、和联苯,而杂芳基基团的非限制性例子包括吡啶基、哒嗪基、吡嗪基、嘧啶基、三嗪基、喹啉基、喹喔啉基、喹唑啉基、噌啉基、酞嗪基、苯并三嗪基、嘌呤基、苯并咪唑基、苯并吡唑基、苯并三唑基、苯并异噁唑基、异苯并呋喃基、异氮茚基、吲哚嗪基、苯并三嗪基、噻吩并吡啶基、噻吩并嘧啶基、吡唑并嘧啶基、咪唑并吡啶基、苯并噻唑基、苯并呋喃基、苯并噻吩基、吲哚基、喹啉基、异喹啉基、异噻唑基、吡唑基、吲唑基、蝶啶基、咪唑基、三唑基、四唑基、噁唑基、异噁唑基、噻二唑基、吡咯基、噻唑基、呋喃基、噻吩基等。上述各芳基和杂芳基环体系的取代基选自下述的可接受的取代基。
术语"芳基烷基"意在包括其中芳基连接于烷基的那些基团(例如苯甲基、苯乙基等)。类似地,术语"芳氧基烷基"意在包括其中芳基通过醚键(-O-)连接于烷基的那些基团,例如苯氧基丙基、苯氧基戊基和苯氧基庚基等)。
如本文所用,术语“硅氧基”是指具有式–OSiR3的部分,其中各R独立地是本文定义的烷基或芳基。硅氧基的例子包括但不限于,三甲基硅氧基、三乙基硅氧基和叔丁基二甲基硅氧基。
如本文所用,术语“酰氧基”是指具有式–OC(O)R的部分,其中R是烷基、芳基或本文定义的芳基烷基。酰氧基的例子包括但不限于乙酰氧基和苯甲酰氧基。
如本文所用,术语“保护基团”是指一个部分,形成该部分以使官能团失去反应性或反应性减小。保护基团可被除去从而使官能团回复其原始状态。多种保护基团和保护试剂,包括羟基保护基团,是本领域一般技术人员公知的,包括《有机合成中的保护性基团》(Protective Groups in Organic Synthesis),第4版,T.W.Greene和P.G.M.Wuts,JohnWiley&Sons,New York,2006中公开的化合物,该文献通过参考以其整体纳入本文。
术语“二烯配体”是指含有两个碳-碳双键的有机化合物,所述两个碳-碳双键一起形成二烯系统,该二烯系统可与铑(I)盐配位。二烯配体可以是但不限于降冰片二烯,1,5-环辛二烯,双环[2.2.2]辛-2,5-二烯系统,双环[2.2.1]庚-2,5-二烯系统和双环[2.2.0]辛-2,6-二烯系统。
现在将参考以下实施方式更具体地描述本发明。应注意,本文提供的对本发明优选实施方式的以下描述仅出于说明和描述的目的;不是穷举性的,也不意在限制于所公开的确切形式。提供以下方案作为实施方式来说明但不限制本发明。
III.本发明的实施方式
本发明提供一种制备式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物的方法
所述方法包括在溶剂中在金属添加剂存在下,任选地在碱性添加剂存在下,将式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物
与式III所示的化合物接触
以产生式I所示的化合物;
其中,
R1、R3、R4和R5独立地代表氢、芳基、杂芳基、烷基、芳基烷基、芳氧基烷基、烯基、或炔基;
或者R3和R5一起形成5-至7-元碳环,任选地具有一个或两个杂原子作为环顶点,其中所述杂原子选自下组:O、N和S;
或者R3和R4一起形成5-至7-元碳环,任选地具有一个或两个杂原子作为环顶点,其中所述杂原子选自下组:O、N和S,
并且其中R1、R3、R4和R5各任选地被选自下组的1至3个成员取代:卤素、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、硅氧基、芳氧基、酰氧基、杂环、氧代、COOH、CONH2、CONHC1-4烷基、C(O)OCH2C6-10芳基、C(O)OC6-10芳基和C(O)OC1-4烷基;
R2代表氢或羟基-保护基团;
X代表含硼基团。
不希望受任何特定理论的限制,据信式I的产物是通过1,4-共轭加成反应而形成的。含硼化合物III是乙烯基硼化合物,其中硼原子存在于基团X中并与化合物III的碳-碳双键的碳原子之一共价连接。本发明的方法提供式I所示的化合物,这些化合物可用于制备前列腺素和前列腺素类似物。所述前列腺素和前列腺素类似物包括但不限于,前列腺素E(PGE)和前列腺素F(PGF)系列的化合物及它们的类似物。PGE和PGF系列化合物(参见图4)或它们的类似物的例子包括但不限于,曲伏前列素(一种PGF2α类似物),比马前列素(一种PGF2α类似物),地诺前列素(PGF2α;还参见图5),地诺前列酮(PGE2),鲁比前列酮(一种PGE类似物),他氟前列素(一种PGF2α类似物;还参见图6),卡波前列素(一种PGF2α类似物),前列地尔(PGE1),拉坦前列素(一种PGF2α类似物)和乌诺前列酮(一种PGFα类似物)。
一些实施方式中,式I所示的化合物具有式I′
本发明方法中的反应可在任何合适的温度进行。一些实施方式中,1,4-共轭加成反应步骤可在环境温度(20–30℃)、冷却(约0℃)条件或轻微加热(约50℃)条件下进行。用于给反应提供热的仪器的例子包括但不限于,常规加热设备(诸如油浴,加热夹套(heatingjacket),或加热套(heating mantle))或微波反应器。操作本发明方法时通常不需要低于零度或低温温度。相反,实施传统双组分法的已知方法在相应的1,4-共轭加成反应步骤通常需要低温温度。
反应温度诸如约30℃可比更高的温度诸如50℃、60℃或80℃提供更高产率的2,3-二取代-4-氧基-环戊烷-1-酮化合物I,因为在更高的温度可形成大量的2,3,4-三取代-环戊烷-1-酮化合物VIII。例如,某些情况下可形成约3%至多达约15%(基于2-取代-4-氧基-环戊-2-烯-1-酮II)的副产物化合物VIII。
不希望受任何特定理论的限制,据信化合物VIII形成于反应性前体V,这些反应性前体V本身是化合物I的降解产物并通过4-氧取代基的去除而形成。
支持该理论的是,当1,4-共轭加成产物,前列腺素E2类似物10.1,经历本发明的标准1,4-共轭加成反应条件([RhCl(COD)]2,KOH,60℃,在反式-2-苯基乙烯基硼酸(3.1)存在下)18小时的延长反应时间时,形成化合物6.1作为主要反应产物。
除反应温度之外,形成的化合物VIII的量可取决于其他反应参数,诸如碱性添加剂的类型,反应溶剂和反应时间(诸如当使用延长的反应时间时)。
一般而言,对于每组底物II和III以及反应溶剂和碱性添加剂,选择提供最高产率的2,3-二取代-4-氧基-环戊烷-1-酮化合物I并且不提供或提供低水平的2,3,4-三取代-环戊烷-1-酮化合物VIII的反应温度。作为非限制性例子,表1,编号1–3显示对于用氢氧化钾作为碱性添加剂在甲醇中进行的反应,较低的温度可提供更高的2,3-二取代-4-氧基-环戊烷-1-酮化合物I产率。当使用微波照射(μw)并将反应温度维持在50℃、40℃或30℃时,2,3,4-三取代-环戊烷-1-酮6.1的水平分别从9%降至3%再降至0%产率。同时,所需的2,3-二取代-4-氧基-环戊烷-1-酮化合物10.1分别从65%增加至73%再增加至83%。
表1
a当两个数值被逗号隔开时,表示分批加入添加剂和/或试剂。在时间栏中的时间单位之间相应的逗号表示各相应的添加剂加入之后的反应时间段。bμw表示反应溶液被微波照射。所示的温度是微波反应器报告的温度。
任何合适的溶剂都可用于使用乙烯基硼化合物的1,4-共轭加成反应步骤中。合适的溶剂的例子包括但不限于,水,甲醇,乙醇,异丙醇,异丁醇,1,4–二氧六环,甲苯,四氢呋喃(THF),2-甲基-四氢呋喃(2-Me-THF),二甘醇二甲醚,乙腈,N-甲基吡咯烷酮(NMP),N,N-二甲基甲酰胺(DMF),N,N-二甲基乙酰胺(DMAC),乙二醇及它们的组合。使用乙烯基硼化合物的1,4-共轭加成反应步骤可在质子或非质子溶剂中进行。一些实施方式中,反应在质子溶剂中进行。一些实施方式中,质子溶剂是醇溶剂。一些实施方式中,醇溶剂是甲醇。甲醇不仅为进行本发明的1,4-共轭加成反应提供了良好的介质,而且其价格低廉,容易获得且在生产规模上易于处理和处置。
任何合适的硼化合物都可用于本发明方法中。合适的乙烯基硼化合物的例子包括但不限于,乙烯基硼酸,乙烯基环硼氧烷(vinyl boroxines),乙烯基硼酸酯(例如硼酸频哪醇酯和硼酸儿茶酚酯),三乙烯基硼烷,二烷基乙烯基硼烷,乙烯基硼酸N-亚氨基二乙酸酯(vinyl N-imino diacetic acid boronates),B-乙烯基-9-BBN化合物,硼酸乙烯基三醇酯(vinyltriol borates),三氟乙烯基硼酸盐,和四乙烯基硼酸盐。优选地,所述乙烯基硼化合物是乙烯基硼酸或乙烯基三氟硼酸盐。即,式III所示的化合物的含硼基团X选自下组:B(OH)2(乙烯基硼酸);B(OR)2(乙烯基硼酸酯),其中R为烷基或芳基;BR2(二烷基乙烯基硼烷),其中R是烷基;BR2(三乙烯基硼烷),其中R是乙烯基;9-硼双环[3.3.1]壬烷(9-BBN)基团;BR2,其中R是羧酸基团(carboxylate group);BR,其中R是双齿羧酸基团;BR2,其中R是芳氧基;BR其中R是双齿芳氧基,BF3M(乙烯基三氟硼酸盐) 其中M为金属离子,BF3M其中M是铵或磷鎓离子,BR3M(三烷基乙烯基硼酸盐)其中R为烷基且M是金属离子或铵或磷鎓离子,和BR3M(四乙烯基硼酸盐)其中R是乙烯基且其中M是金属离子或铵或磷鎓离子。
表2,编号1–5显示同样的2-苯基乙烯基基团可在1,4-共轭加成反应中通过乙烯基硼酸3.1(编号1)、乙烯基三氟硼酸钾3.1a(编号2)、乙烯基硼酸儿茶酚酯3.1b(编号3)、乙烯基硼酸频哪醇酯3.1c(编号4)和乙烯基硼酸N-甲基亚氨基二乙酸酯3.1d(编号5)递送到2-取代-4-氧基-环戊-2-烯-1-酮2,以提供保护的前列腺素E2类似物10.1。
表2
aμw表示反应溶液被微波照射。所示的温度是微波反应器报告的温度。在时间栏中的时间单位之间相应的逗号表示各相应的添加剂加入之后的反应时间段。b当两个数值被逗号隔开时,表示分批加入添加剂和/或试剂。
上述乙烯基硼化合物III易于用文献中描述的方法制备,经常可分离为固体,有时候为晶体。另外,乙烯基硼化合物III通常是空气和水分稳定的(即,耐水)并且保质期长,与传统双组分法中所用的相应乙烯基铜酸盐化合物不同,传统二组分方法中所用的相应乙烯基铜酸盐化合物通常必须立即使用或者在制备后很快使用。乙烯基硼化合物III可在实验室或制造厂中容易地操作,或可购自商业来源或自己制备然后存贮在环境条件下直至使用。此外,这些乙烯基硼化合物通常认为是“无毒的”,适用于工业和制药应用。本发明中乙烯基硼化合物III的使用是在传统双组分法使用乙烯基铜化合物(乙烯基铜酸盐)上的显著改进。
出乎意料地,本发明的1,4-共轭加成反应可在结构多样的式III所示的乙烯基硼化合物上发挥作用。如表3编号1–8总结的,用式2所示的2-取代-4-硅氧基-环戊-2-烯-1-酮化合物和乙烯基硼酸3获得高产率的2,3-二取代-4-氧基-环戊烷-1-酮化合物10(受保护的前列腺素E2类似物),其中R4和R5是H,R3是苯基(3.1,编号1),4-甲氧基苯基(3.2,编号2),3-甲氧基苯基(3.12,编号3),4-甲基苯基(3.3,编号4),3-甲基苯基(3.4,编号5),2-甲基苯基(3.11,编号6),4-三氟甲基苯基(3.14,编号7),或4-氟苯基(3.13,编号8)。此外,当R4是H且R3和R5形成碳环时(即,3.20;编号9),获得相应的式10.20所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物。并且,非芳族的乙烯基硼酸3.6(编号10)、3.5(编号11)、3.16(编号12)和3.15(编号13)通常提供良好至较高产率的相应的式10.6、10.5、10.16和10.15所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物(前列腺素E2类似物)。
表3
aμw表示反应溶液被微波照射。所示的温度是微波反应器报告的温度。b当两个数值被逗号隔开时,表示分批加入添加剂和/或试剂。在时间栏中的时间单位之间相应的逗号表示各相应的添加剂加入之后的反应时间段。
本发明方法在合成具有药用价值的前列腺素和前列腺素类似物前体方面的可用性通过总结于表4的非限制性例子得到阐释。式2所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物和乙烯基硼酸3.9a(编号1)、3.17(编号3)、3.18(编号4)或3.7(编号5)的1,4-共轭加成反应分别提供了式10.9a、10.17、10.18和10.7所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物(前列腺素E2类似物)。这些化合物是已知的,并且被报道为分别是地诺前列素、比马前列素、曲伏前列素和他氟前列素的合成前体,地诺前列素、比马前列素、曲伏前列素和他氟前列素本身是用于诱导分娩或用于治疗疾病的前列腺素F2α类似物。参见,例如,‘795专利中用保护的前列腺素E2类似物10.17和10.18分别合成前列腺素F2α类似物比马前列素和曲伏前列素。类似地,乙烯基硼酸频哪醇酯2.9a(编号2)、乙烯基三氟硼酸钾3.7a(编号6)或乙烯基硼酸频哪醇酯2.19(编号7)可用于1,4-共轭加成反应中以提供式10.9a、10.7和10.19所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物,这些化合物是已知的并且被报道分别 是前列腺素F2α类似物地诺前列素和他氟前列素,以及前列腺素E1衍生物鲁比前列酮的合成前体。参见,例如,‘958专利中用保护的前列腺素E2类似物10.19合成鲁比前列酮。
表4
aμw表示反应溶液被微波照射。所示的温度是微波反应器报告的温度。b当两个数值被逗号隔开时,表示分批加入添加剂和/或试剂。在时间栏中的时间单位之间相应的逗号表示各相应的添加剂加入之后的反应时间段。
值得注意的是,虽然用传统双组分法使用相应的乙烯基铜酸盐VII和2-取代-4-硅氧基-环戊-2-烯-1-酮化合物2来制备式10.7所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物(可用于制备他氟前列素)的多次尝试都失败了(参见表5),但是乙烯基硼酸3.7(表4,编号5)和乙烯基三氟硼酸钾3.7a均可用于产生产率良好的式10.7所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物(可用于合成他氟前列素,如图6列出的)。式10.9a和10.7所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物被进一步分别转化(如下文实施例部分公开的)为前列腺素F2α类似物地诺前列素(参见,图5)或他氟前列素(参见,图6),表明了本发明对制备前列腺素药物前体的可用性和有用性。
表5
在1,4-共轭加成反应步骤中,乙烯基硼化合物III和式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物的反应仅需要催化(即,亚化学计量的)量的金属添加剂(例如,铑化合物,钴化合物,镍化合物,或其组合)。例如,相对于式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物的摩尔量,通常3摩尔%的铑二聚体[RhCl(1,5-环辛二烯)]2足以导致式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物和乙烯基硼化合物III至式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物的高产率转化。相反,双组分法的传统有机铜化学需要化学计量的过渡金属Cu(I),某些情况下是Zr(IV),以及金属Li(I),和通常的Sn(IV),均为化学计量的量。在本文公开的发明中,硼方便地替代了传统双组分法的Cu(I)、以及Sn(IV)或Zr(IV)、和/或Li(I)金属并因此减少了制备式I的前列腺素前体化合物所需的过渡金属和其他金属的量。
本发明一些实施方式中,乙烯基硼化合物III与式II化合物的1,4-共轭加成反应步骤中所用的铑化合物添加剂是预催化剂或者是以亚化学计量的量使用的催化剂,包括但不限于,选自下组的铑(I)化合物:[RhCl(1,5-环辛二烯)]2(即,氯代(1,5-环辛二烯)铑(I)二聚体)、[RhCl(C2H4)2]2、具有二烯配体添加物的[RhCl(C2H4)2]2、[RhCl(降冰片二烯)]2以及[Rh(OH)(1,5-环辛二烯)]2(即,羟基(1,5-环辛二烯)铑(I)二聚体)。1,5-环辛二烯经常缩写为COD,因此[RhCl(1,5-环辛二烯)]2缩写为[RhCl(COD)]2。某些实施方式中,铑添加剂是铑二聚体[RhCl(1,5-环辛二烯)]2或铑二聚体[Rh(OH)(1,5-环辛二烯)]2。
相对于式II化合物的摩尔量,金属添加剂的量优选通常小于50摩尔%,诸如相对于式II化合物的摩尔量小于或等于12摩尔%,或相对于式II化合物的摩尔量小于或等于10摩尔%,或相对于式II化合物的摩尔量小于或等于6摩尔%,或相对于式II化合物的摩尔量小于或等于5摩尔%。
任何合适的碱性添加剂都可用于本发明方法中。用于1,4-共轭加成反应步骤的合适的碱性添加剂的例子包括但不限于,KHF2、t-BuOLi、t-BuONa、t-BuOK、K3PO4、K2CO3、Cs2CO3、LiOH、NaOH、KOH、CsOH、KF、CsF、NaHCO3、KH2PO4、1,3-二氨基丙烷、t-BuNH2、i-Pr2NH、哌啶、Et3N、2,6-卢剔啶和它们的组合。某些实施方式中,碱性添加剂是氢氧化物。特定实施方式中,氢氧化物是氢氧化钾。不意于受理论限制,据信碱性添加剂作用于金属添加剂以将其从预催化剂转化为活性催化剂,虽然碱性添加剂也可在反应中发挥其他作用。例如,已报道铑(I)氯化物盐被氢氧化物转化为铑(I)氢氧化物,后面这些化合物具有催化活性并且可催化乙烯基硼化合物与活化的烯烃化合物诸如α,β-不饱和羰基化合物的加成反应(J.Am.Chem.Soc.2002,124,5052–5058)。碱性添加剂的量优选相对于金属添加剂是等摩尔的,或相对于金属添加剂是大于等摩尔的。
不同的溶剂、碱性添加剂和反应温度的各种组合可产生显著不同产率的式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物以及显著不同水平的式VIII所示的2,3,4-三取代-环戊烷-1-酮降解产物。本领域技术人员理解,对于每种式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物和乙烯基硼化合物III,可能需要优化碱性添加剂的相对量和类型、金属添加剂的相对量和类型、溶剂的相对量和类型以及反应温度以找到获得最优产率式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物的条件。
一些实施方式中,式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物的反应产率可通过分批加入式III所示的乙烯基硼化合物和/或分批加入金属添加剂而提高。例如,表1,编号4–7显示各批次加入的硼酸3.1和[RhCl(1,5-环辛二烯)]2的总量以及数目和量的不同排列组合产生不同产率的2,3-二取代-4-氧基-环戊烷-1-酮化合物10.1。
本发明一些实施方式中,式I化合物和式II化合物的R2是羟基-保护基团。羟基-保护基团的例子包括但不限于,四氢吡喃基(THP)、甲氧基甲基(MOM)、[2-(三甲基硅基)乙氧基]甲基(SEM)、三烷基硅基、三芳基硅基、二芳基烷基硅基、苄基、p-甲氧基苄基(PMB)、烷基羰基、芳基羰基和烯丙基。某些实施方式中,羟基-保护基团是三烷基硅基基团。一些实施方式中,三烷基硅基是叔丁基二甲基硅基(TBS)。
本发明一些实施方式中,式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物是IIa或IIb,其中R2是如上定义的H或羟基-保护基团且R6是选自下组的基团:H、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、三甲基硅基、三乙基硅基、三异丙基硅基、叔丁基二甲基硅基和苄基。
本发明进一步的实施方式中,式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物是IIaa,其中R2是H并且R6是异丙基(参见表6,编号4)。本发明其他实施方式中(参见表6),式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物选自IIba组,其中R2是叔丁基二甲基硅基(TBS)并且R6是甲基(编号1);IIbb,其中R2是四氢吡喃基(THP)并且R6是甲基(编号2);和IIbc,其中R2是烯丙基并且R6是甲基(编号3)。
表6
aμw表示反应溶液被微波照射。所示的温度是微波反应器报告的温度。b当两个数值被逗号隔开时,表示分批加入添加剂和/或试剂。在时间栏中的时间单位之间相应的逗号表示各相应的添加剂加入之后的反应时间段。
本发明一些实施方式中,式I化合物和式III化合物的基团R3、R4和/或R5具有一个或多个羟基。一些实施方式中,上述羟基可以是被保护的。合适的羟基-保护基团包括但不限于,四氢吡喃基(THP)、甲氧基甲基(MOM)、[2-(三甲基硅基)乙氧基]甲基(SEM)、三烷基硅基、三芳基硅基、二芳基烷基硅基、苄基、4-甲氧基苄基(PMB)、烷基羰基、芳基羰基和烯丙基。某些实施方式中,保护基团是三烷基硅基基团。一些实施方式中,三烷基硅基是叔丁基二甲基硅基(TBS)。表7,编号1–8,显示了四种不同的羟基保护的乙烯基硼酸衍生物3.8a(叔丁基二甲基硅基保护的,编号1),3.8c(苄基保护的,编号2),3.8e(四氢吡喃基保护的,编号3)和3.8b(乙酰基保护的,编号4),以及四种不同的羟基保护的乙烯基硼酸频哪醇酯衍生物2.8a(叔丁基二甲基硅基保护的,编号8),2.8c(苄基保护的,编号7),2.8e(四氢吡喃基保护的,编号5)和2.8b(乙酰基保护的,编号6)。一些实施方式中,上述羟基可以保持为未保护的,诸如在表7编号9的例子中(如在乙烯基硼酸2.8中)。
表7
a当两个数值被逗号隔开时,表示分批加入添加剂和/或试剂。在时间栏中的时间单位之间相应的逗号表示各相应的添加剂加入之后的反应时间段。bμw表示反应溶液被微波照射。所示的温度是微波反应器报告的温度。
可用于本发明的式III所示的乙烯基硼化合物可通过文献(J.Am.Chem.Soc.2005,127,5766–5767;Angew.Chem.2003,42,3399–3404;J.Org.Chem.2001,66,5359–5365;Angew.Chem.2012,51,9385–9388;Org.Lett.2012,14,6104–6107;Org.Lett.2010,12,2004–2007)中报道的方法来制备。
例如,当R4是H时,一种方法包括:
a)将式IV所示的炔烃化合物
与有机硼试剂接触;和
b)转化步骤a)的产物以提供III。可选的,可用乙烯基卤化物作为起始原料制备式III所示的乙烯基硼化合物,用于该转化的方法是本领域已知的。
上述有机硼试剂是氢化硼烷化合物并选自下组:硼烷醚络合物,诸如BH3·THF或BH3·OEt2;硼烷硫化物络合物,诸如BH3·SMe2;9-硼二环[3.3.1]壬烷;9-硼二环[3.3.1]壬烷二聚体;频哪醇硼烷;儿茶酚硼烷;二烷基硼烷,诸如二环己基硼烷,二异戊基硼烷,二异松蒎基硼烷或二(异丙基异戊烯基)硼烷;以及单-和二氯硼烷或单-和二溴硼烷–路易斯碱络合物,诸如BHCl2·二氧六环,BH2Cl·OEt2,BH2Cl·SMe2,BHBr2·二氧六环,BH2Br·OEt2或BH2Br·SMe2。可用于本发明的式III所示的乙烯基硼化合物包括乙烯基硼酸,乙烯基硼酸酯,乙烯基硼酸N-亚氨基二乙酸酯,乙烯基三有机硼烷(例如,乙烯基三烷基硼烷),乙烯基B-有机-9-BBN化合物(例如,乙烯基B-烷基-9-BBN化合物),乙烯基三氟硼酸盐和四乙烯基硼酸盐。某些实施方式中,乙烯基硼化合物是乙烯基硼酸或乙烯基三氟硼酸盐。
可用于本发明方法中的式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物可用本领域已知方法制备,包括美国专利No.7,897,795、Org.Process Res.Dev.2012,16,1905–1916和Tetrahedron Lett.2003,44,7411–7415中报道的那些。
虽然下文实施例中提供一些指导,但本领域技术人员将理解,本文描述的方法可在与温度和所用一种或多种的溶剂(上文讨论)、以及反应时间、和反应混合物中反应物的浓 度有关的多种条件下实施。下文实施例阐释本发明的某些实施方式,不应被认为以任何方式进行限制。
IV.实施例
实施例1–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅基氧基(silanyloxy))-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
将(Z)-7-[(3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-环戊-1-烯基]-庚-5-烯酸异丙酯(2)(57mg,0.15mmol)、反式-2-苯基乙烯基硼酸(3.1)(33mg,0.22mmol)、[RhCl(1,5-环辛二烯)]2(1.1mg,2.2μmol)和水性KOH(9.5μL,3.0M水性KOH,29μmmol)在MeOH(1.0mL)中的溶液在微波照射下搅拌(CEM,Discover S;或Milestone,Startsynth;温度设为30℃)。5小时后,加入反式-2-苯基乙烯基硼酸(3.1)(11mg,74μmol)和[RhCl(1,5-环辛二烯)]2(1.1mg,2.4μmol),再搅拌反应混合物1小时,并直接真空浓缩。用柱层析(用1:80(v/v)丙酮-己烷洗脱)纯化残留物得到10.1(70mg,96%)。
[α]27 D-57.4(c 1.00,CHCl3);1H NMR(400MHz,CDCl3):δ0.01(s,3H),0.03(s,3H),0.86(s,9H),1.20(d,J=6.2Hz,6H),1.59–1.69(m,2H),2.05(dd,J=7.1,14.1Hz,2H),2.16–2.26(m,4H),2.38–2.42(m,2H),2.58–2.73(m,2H),4.13(dd,J=8.4,16.0Hz,1H),4.97(七重峰,J=6.2Hz,1H),5.32–5.46(m,2H),6.05(dd,J=8.6,15.8Hz,1H),6.50(d,J=15.8Hz,1H),7.22–7.26(m,1H),7.27–7.37(m,4H);13C NMR(125MHz,CDCl3):δ-4.8(CH3),-4.7(CH3),18.1(C),21.8(CH3),24.8(CH2),25.1(CH2),25.7(CH),26.7(CH2),34.1(CH2),47.6(CH2),54.1(CH),54.4(CH),67.4(CH),73.0(CH),126.1(CH),126.5(CH),127.4(CH),128.6(CH),129.8(CH),131.0(CH),132.9(CH),137.1(C),173.1(C),214.7(C);HRMS(ESI-QTOF)计算值[C29H44O4Si+H]+=485.3081,实测值485.3064;FTIR(KBr,无水的)2935,2861,1736,1593,1459,1372,1250,1107,838,745cm-1.
实施例2–合成(Z)-7-[(1R,2R)-5-氧代-2,3-二苯乙烯基-环戊-3-烯基]-庚-5-烯酸异丙酯(6.1)
可用以下程序制备降解产物6.1标样:于60℃搅拌10.1(16mg,33μmol)、反式-2-苯基乙烯基硼酸(3.1)(9.2mg,62μmol)、[RhCl(1,5-环辛二烯)]2(1.1mg,2.25μmol,5.6mol%) 和水性KOH(9.5μL,3.0M水性KOH,28.5μmol)在MeOH(1mL)中的溶液。12小时后,直接真空浓缩混合物。残留物用柱层析(用1:80(v/v)丙酮-己烷洗脱)纯化得到标题化合物6.1(13mg,86%)。
[α]24 D-149.5(c 0.46,CHCl3));1H NMR(400MHz,CDCl3):δ1.20(d,J=6.4,6H),1.58–1.72(m,2H),1.98–2.12(m,2H),2.13–2.34(m,4H),2.36–2.58(m,3H),2.64–2.85(m,2H),4.97(七重峰,J=6.4Hz,1H),5.31–5.50(m,2H),6.06–6.22(m,2H),6.43(dd,J=11.6,16.0Hz,2H),7.17–7.36(m,10H);13C NMR(100MHz,CDCl3):δ21.8(CH3),24.8(CH2),25.0(CH2),26.7(CH2),30.9(CH2),34.1(CH2),44.4(CH),51.7(CH),55.5(CH),67.4(CH),77.2(CH),126.18(CH),126.22(CH),126.5(CH),127.4(CH),127.5(CH),128.5(CH),128.6(CH),130.3(CH),131.0(CH),131.2(CH),132.5(CH),137.0(C),173.1(C),216.7(C);HRMS(ESI-TOF)计算值[C31H36O3+H]+=457.2737,实测值457.2738;FTIR(KBr,无水的)3446,2975,1730,1640,1443,1375,1217,1164,1102,963cm-1.
实施例3–合成(Z)-7-{(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-[2-(4-甲氧基-苯基)-乙烯基]-5-氧代-环戊基}-庚-5-烯酸异丙酯(10.2)
根据实施例1所述的程序,用反式-2-(4-甲氧基-苯基)-乙烯基硼酸(3.2)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到(Z)-7-{(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-[2-(4-甲氧基-苯基)-乙烯基]-5-氧代-环戊基}-庚-5-烯酸异丙酯(10.2,72mg,93%)。
[α]22 D-50.6(c 1.00,CHCl3);1H NMR(400MHz,CDCl3):δ0.00(s,3H),0.02(s,3H),0.85(s,9H),1.20(d,J=6.3Hz,6H),1.60–1.68(m,2H),2.05(dd,J=7.0,14.1Hz,2H),2.14–2.25(m,4H),2.36–2.39(m,2H),2.55–2.71(m,2H),3.81(s,3H),4.09(dd,J=8.5,15.8Hz,1H),4.97(七重峰,J=6.3Hz,1H),5.32–5.45(m,2H),5.89(dd,J=8.4,15.6Hz,1H),6.44(d,J=15.6Hz,1H),6.85(d,J=8.6Hz,2H),7.28(d,J=8.6Hz,2H);13C NMR(100MHz,CDCl3):δ-4.8(CH3),-4.6(CH3),18.0(C),21.8(CH3),24.8(CH2),25.1(CH2),25.7(CH3),26.6(CH2),34.1(CH2),47.6(CH2),54.1(CH),54.4(CH),55.2(CH3),67.4(CH),73.1(CH),114.0(CH),126.5(CH),127.2(CH),127.5(CH),129.9(C),130.9(CH),132.3(CH),159.0(C),173.1(C),214.9(C);HRMS(ESI-QTOF)计算值[C30H46O5Si+H]+=515.3187,实测值515.3182;FTIR(KBr,无水的)2939,2863,1737,1604,1512,1463,1371,1246,1166,1109cm-1.
实施例4–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-(2-p-甲苯基-乙烯基)-环戊基]-庚-5-烯酸异丙酯(10.3)
根据实施例1所述的程序,用反式-2-p-甲苯基-乙烯基硼酸(3.3)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-(2-p-甲苯基-乙烯基)-环戊基]-庚-5-烯酸异丙酯(10.3,71mg,95%)。
[α]23 D-40.2(c 1.00,CHCl3);1H NMR(400MHz,CDCl3):δ0.00(s,3H),0.02(s,3H),0.85(s,9H),1.20(d,J=6.2Hz,6H),1.64(五重峰,J=7.6Hz,2H),2.04(dd,J=7.3,14.2Hz,2H),2.13–2.26(m,4H),2.34(s,3H),2.38–2.40(m,2H),2.57–2.72(m,2H),4.11(dd,J=8.0,15.6Hz,1H),4.97(七重峰,J=6.2Hz,1H),5.31–5.45(m,2H),5.98(dd,J=8.7,15.7Hz,1H),6.46(d,J=15.7Hz,1H),7.13(d,J=8.0Hz,2H),7.25(d,J=8.0Hz,2H);13C NMR(100MHz,CDCl3):δ-4.8(CH3),-4.7(CH3),18.0(C),21.1(CH3),21.8(CH3),24.8(CH2),25.0(CH2),25.7(CH3),26.6(CH2),34.1(CH2),47.6(CH2),54.1(CH),54.4(CH),67.3(CH),73.0(CH),126.0(CH),126.5(CH),128.7(CH),129.3(C),130.9(CH),132.7(CH),134.3(C),137.1(C),173.1(C),214.8(C);HRMS(ESI-QTOF)计算值[C30H46O4Si+H]+=499.3238,实测值499.3244;FTIR(KBr,无水的)2938,2863,1737,1509,1463,1372,1250,1110,964,841cm-1.
实施例5–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-(2-m-甲苯基-乙烯基)-环戊基]-庚-5-烯酸异丙酯(10.4)
根据实施例1所述的程序,用反式-2-m-甲苯基-乙烯基硼酸(3.4)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-(2-m-甲苯基-乙烯基)-环戊基]-庚-5-烯酸异丙酯(10.4,73mg,98%)。
[α]23 D-51.1(c 1.00,CHCl3);1H NMR(400MHz,CDCl3):δ0.01(s,3H),0.03(s,3H),0.86(s,9H),1.20(d,J=6.4Hz,6H),1.65(五重峰,J=7.6Hz,2H),2.05(dd,J=7.0,14.2Hz,2H),2.15–2.26(m,4H),2.35(s,3H),2.36–2.41(m,2H),2.58–2.73(m,2H),4.12(dd,J=8.4,16.0Hz,1H),4.97(七重峰,J=6.4Hz,1H),5.32–5.46(m,2H),6.03(dd,J=8.6,15.8Hz,1H),6.47(d,J=15.8,1H),7.06(d,J=7.3Hz,1H),7.15–7.23(m,3H);13C NMR(100MHz,CDCl3):δ-4.8(CH3),-4.6(CH3),18.0(C),21.4(CH3),21.8(CH3),24.8(CH2),25.1(CH2),25.7(CH3),26.7(CH2),34.1(CH2),47.6(CH2),54.1(CH),54.3(CH),67.4(CH),73.1(CH),123.2(CH), 126.5(CH),126.9(CH),128.2(CH),128.5(CH),129.5(CH),131.0(CH),133.0(CH),137.0(C),138.1(C),173.1(C),214.8(C);HRMS(ESI-QTOF)计算值[C30H46O4Si+H]+=499.3238,实测值499.3242;FTIR(KBr,无水的)2939,2863,1737,1600,1463,1375,1253,1112,971,884cm-1.
实施例6–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-(2-甲基-丙-1-烯基)-5-氧代-环戊基]-庚-5-烯酸异丙酯(10.5)
根据实施例1所述的程序,用2-甲基-丙烯基硼酸(3.5)合成了标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-(2-甲基-丙-1-烯基)-5-氧代-环戊基]-庚-5-烯酸异丙酯(10.5,65mg,99%)。
[α]23 D-68.2(c 1.00,CHCl3);1H NMR(400MHz,CDCl3):δ0.00(s,3H),0.01(s,3H),0.86(s,9H),1.22(d,J=6.4Hz,6H),1.63–1.68(m,5H),1.74(s,3H),1.92–1.99(m,1H),2.01–2.07(m,2H),2.13–2.21(m,1H),2.22–2.27(m,2H),2.27–2.33(m,2H),2.58–2.65(m,1H),2.67–2.76(m,1H),3.95(dd,J=8.0,15.6Hz,1H),4.92(d,J=9.6Hz,1H),5.00(七重峰,J=6.4Hz,1H),5.30–5.43(m,2H);13C NMR(100MHz,CDCl3):δ-5.0(CH3),18.0(C),18.7(CH3),21.8(CH3),24.8(CH2),25.0(CH2),25.6(CH3),25.8(CH3),26.5(CH2),34.1(CH2),47.6(CH2),49.4(CH),55.2(CH),67.4(CH),73.6(CH),125.4(CH),127.0(CH),130.4(CH),135.4(C),173.1(C),215.6(C);HRMS(ESI-QTOF)计算值[C25H44O4Si+H]+=437.3082,实测值437.3096;FTIR(KBr,无水的)2937,2855,1738,1463,1373,1248,1150,1108,880,834cm-1.
实施例7–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-(反式-辛-1-烯基)-5-氧代-环戊基]-庚-5-烯酸异丙酯(10.6)
根据实施例1所述的程序,用反式-辛-1-烯基硼酸(3.6)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-(反式-辛-1-烯基)-5-氧代-环戊基]-庚-5-烯酸异丙酯(10.6,69mg,93%)。
[α]23 D-54.5(c 1.00,CHCl3);1H NMR(400MHz,CDCl3):δ0.02(s,3H),0.03(s,3H),0.86(s,9H),1.21(d,J=6.4Hz,6H),1.26–1.36(m,10H),1.62–1.69(m,3H),1.97–2.07(m,5H), 2.09–2.16(m,1H),2.24(t,J=7.6Hz,2H),2.26–2.43(m,3H),2.61(ddd,J=1.1,7.14,18.3Hz,1H),3.98(dd,J=8.0,15.6Hz,1H),4.99(七重峰,J=6.4Hz,1H),5.26(dd,J=8.4,15.2Hz,1H),5.30–5.42(m,2H),5.50–5.58(m,1H);13C NMR(100MHz,CDCl3):δ-4.7(CH3),14.1(CH3),18.1(C),21.8(CH3),22.6(CH2),24.8(CH2),24.9(CH2),25.7(CH3),26.6(CH2),28.9(CH2),29.3(CH2),31.7(CH2),32.6(CH2),34.1(CH2),47.6(CH2),53.5(CH),54.2(CH),67.3(CH),73.1(CH),126.8(CH),129.6(CH),130.6(CH),134.0(CH),173.1(C),215.3(C);HRMS(ESI-QTOF)计算值[C29H52O4Si+H]+=493.3708,实测值493.3702;FTIR(KBr,无水的)2930,2860,1739,1462,1371,1250,1111,968,839,775cm-1.
实施例8–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-(反式-3,3-二氟-4-苯氧基-丁-1-烯基)-5-氧代-环戊基]-庚-5-烯酸异丙酯(10.7)
根据实施例1所述的程序,用反式-3,3-二氟-4-苯氧基-丁-1-烯基三氟硼酸钾(3.7a)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-2-(反式-3,3-二氟-4-苯氧基-丁-1-烯基)-5-氧代-环戊基]-庚-5-烯酸异丙酯(10.7,52mg,61%)。
[α]24 D-45.0(c 1.00,CHCl3);1H NMR(600MHz,CDCl3):δ0.03(s,3H),0.04(s,3H),0.86(s,9H),1.21(d,J=6.3Hz,6H),1.58–1.63(m,2H),2.01(dd,J=7.2,14.4Hz,2H),2.11–2.22(m,4H),2.35–2.38(m,2H),2.57(dd,J=8.7,20.2Hz,1H),2.66(dd,J=1.0,7.2Hz,1H),4.09(dd,J=8.4,16.2Hz,1H),4.16–4.21(m,2H),4.98(七重峰,J=6.3Hz,1H),5.28–5.32(m,1H),5.37–5.41(m,1H),5.85–5.91(m,1H),6.11(m,1H),6.91(d,J=8.0Hz,2H),7.00(t,J=7.4Hz,1H),7.30(dd,J=7.4,8.0Hz,2H);13C NMR(150MHz,CDCl3):δ-4.8(CH3),-4.7(CH3),18.0(C),21.8(CH3),24.7(CH2),25.0(CH2),25.7(CH3),26.6(CH2),34.0(CH2),47.4(CH2),53.0(CH),53.8(CH),67.4(CH),69.4(t,J=35.0Hz,CH2),72.3(CH),114.7(CH),117.9(t,J=238.5Hz,C),121.8(CH),125.5(t,J=24.8Hz,CH),126.0(CH),129.6(CH),131.4(CH),136.9(t,J=9.0Hz,CH),157.9(C),173.0(C),213.6(C);HRMS(ESI-QTOF):计算值[C31H46F2O5Si+NH4]+=586.3421,实测值582.3406;FTIR(KBr,无水的)2939,2863,1737,1592,1490,1463,1375,1307,1250,1158cm-1.
实施例9–合成(Z)-7-((1R,2R,3R)-3-((叔丁基二甲基硅基)氧基)-2-((E)-2-甲基苯乙烯基)-5-氧代环戊基)庚-5-烯酸异丙酯(10.11)
根据实施例1所述的程序,除了使用反式-2-o-甲苯基-乙烯基硼酸(3.11),粗反应混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物10.11(66mg,88%)。
[α]25 D-53.4(c 1.00,CHCl3);1H NMR(400MHz):0.03(s,3H),0.04(s,3H),0.87(s,9H),1.20(d,J=6.2Hz,6H),1.65(五重峰,J=7.6Hz,2H),2.07(dd,J=6.4,14.0Hz,2H),2.13–2.30(m,4H),2.34(s,3H),2.35–2.45(m,2H),2.60–2.72(m,2H),4.15(dd,J=8.6,15.8Hz,1H),4.97(七重峰,J=6.2Hz,1H),5.32–5.47(m,2H),5.93(dd,J=8.6,15.6Hz,1H),6.72(d,J=15.6Hz,1H),7.12–7.20(m,3H),7.38–7.44(m,1H);13C NMR(100MHz):-4.72(CH3),-4.65(CH3),18.0(C),19.7(CH3),21.8(CH3),24.8(CH2),25.1(CH2),25.7(CH3),26.7(CH2),34.0(CH2),47.6(CH2),54.4(CH),54.5(CH),67.3(CH),73.0(CH),125.5(CH),126.1(CH),126.6(CH),127.3(CH),130.2(CH),130.7(CH),130.9(CH),131.2(CH),135.1(C),136.2(C),173.0(C),214.7(C);HRMS(ESI-QTOF)计算值[C30H46O4Si+H]+=499.3238,实测值499.3234;FTIR(KBr,无水的)3454,2948,1737,1647,1462,1375,1253,1107,969,880cm-1.
实施例10–合成(Z)-7-((1R,2R,3R)-3-((叔丁基二甲基硅基)氧基)-2-((E)-3-甲氧基苯乙烯基)-5-氧代环戊基)庚-5-烯酸异丙酯(10.12)
根据实施例1所述的程序,除了使用反式-2-(3-甲氧基-苯基)-乙烯基硼酸(3.12),粗反应混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物10.12(72mg,93%)。
[α]25 D-65.1(c 1.00,CHCl3);1H NMR(400MHz):0.01(s,3H),0.02(s,3H),0.85(s,9H),1.20(d,J=6.2Hz,6H),1.69–1.70(m,2H),2.05(dd,J=7.1,14.1Hz,2H),2.13–2.27(m,4H),2.33–2.44(m,2H),2.53–2.80(m,2H),3.81(s,3H),4.12(dd,J=8.6,15.8Hz,1H),4.97(七重峰,J=6.2Hz,1H),5.29–5.48(m,2H),6.04(dd,J=8.6,15.7Hz,1H),6.47(d,J=15.7Hz,1H),6.79(dd,J=2.2,8.0Hz,1H),6.89(s,1H),6.94(d,J=7.6Hz,1H),7.19–7.27(m,1H); 13C NMR(100MHz):-4.8(CH3),-4.7(CH3),18.0(C),21.8(CH3),24.8(CH2),25.1(CH2),25.7(CH3),26.6(CH2),34.0(CH2),47.5(CH2),54.0(CH),54.3(CH),55.1(CH3),67.3(CH),73.0(CH),111.6(CH),112.8(CH),118.8(CH),126.4(CH),129.5(CH),130.1(CH),131.0(CH),132.7(CH),138.5(C),159.8(C),173.0(C),214.6(C);HRMS(ESI-QTOF)计算值[C30H46O5Si+H]+=515.3187,实测值515.3172;FTIR(KBr,neat)2945,2862,1737,1666,1590,1463,1375,1257,1156,1108cm-1.
实施例11–合成(Z)-7-((1R,2R,3R)-3-((叔丁基二甲基硅基)氧基)-2-((E)-4-氟苯乙烯基)-5-氧代环戊基)庚-5-烯酸异丙酯(10.13)
根据实施例1所述的程序,除了使用反式-2-(4-氟甲基-苯基)-乙烯基硼酸(3.13),粗反应混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物10.13(69mg,92%)。
[α]30 D-44.7(c 1.00,CHCl3);1H NMR(400MHz):δ-0.01(s,3H),0.01(s,3H),0.85(s,9H),1.19(d,J=6.2Hz,6H),1.64(五重峰,J=7.5Hz,2H),2.04(dd,J=7.1,14.2Hz,2H),2.12–2.28(m,4H),2.32–2.45(m,2H),2.54–2.74(m,2H),4.11(dd,J=8.6,15.8Hz,1H),4.96(七重峰,J=6.2Hz,1H),5.27–5.46(m,2H),5.95(dd,J=8.6,15.7Hz,1H),6.46(d,J=15.7Hz,1H),7.00(dd,J=8.6,8.7Hz,2H),7.26–7.34(m,2H);13C NMR(100MHz):δ-4.8(CH3),-4.7(CH3),18.0(C),21.8(CH3),24.8(CH2),25.1(CH2),25.6(CH3),26.6(CH2),34.1(CH2),47.5(CH2),54.1(CH),54.3(CH),67.4(CH),72.9(CH),115.5(d,J=21.0Hz,CH),126.5(CH),127.5(d,J=8.0Hz,CH),129.5(CH),131.0(CH),131.7(CH),133.2(d,J=3.0Hz,C),162.2(d,J=245.0Hz,C),173.0(C),214.5(C);HRMS(ESI-QTOF)计算值[C29H43FO4Si+H]+=503.2987,实测值503.2970;FTIR(KBr,无水的)2939,1737,1603,1463,1373,1232,1154,1111,845,777cm-1.
实施例12–合成(Z)-7-((1R,2R,3R)-3-((叔丁基二甲基硅基)氧基)-5-氧代-2-((E)-4-(三氟甲基)苯乙烯基)环戊基)庚-5-烯酸异丙酯(10.14)
根据实施例1所述的程序,除了使用反式-2-(4-三氟甲基-苯基)-乙烯基硼酸(3.14),粗反应混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物10.14(66mg,80%)。
[α]29 D-40.4(c 1.00,CHCl3);1H NMR(400MHz):δ-0.01(s,3H),0.02(s,3H),0.85(s,9H),1.18(d,J=6.2Hz,6H),1.64(五重峰,J=7.4Hz,2H),2.04(dd,J=7.2,14.5Hz,2H),2.14–2.28(m,4H),2.35–2.43(m,2H),2.59–2.75(m,2H),4.13(dd,J=8.7,15.9Hz,1H),4.96(七重峰,J=6.2Hz,1H),5.25–5.52(m,2H),6.16(dd,J=8.6,15.7Hz,1H),6.54(d,J=15.7Hz,1H),7.44(d,J=8.2Hz,2H),7.57(d,J=8.2Hz,2H);13C NMR(100MHz):δ-4.7(CH3), 18.0(C),21.8(CH3),24.8(CH2),25.1(CH2),25.6(CH3),26.6(CH2),34.0(CH2),47.5(CH2),54.2(CH),54.3(CH),67.4(CH),72.8(CH),124.2(q,J=270.2Hz,C),125.6(q,J=4.0Hz,CH),126.2(CH),126.4(CH),129.2(q,J=33.0Hz,C),131.1(CH),131.7(CH),132.6(CH),140.4(C),173.0(C),214.1(C);HRMS(ESI-QTOF)计算值[C30H43F3O4Si+H]+=553.2955,实测值553.2936;FTIR(KBr,无水的)2941,2866,1739,1617,1464,1373,1252,1163,1118,840,777cm-1.
实施例13–合成(Z)-7-((1R,2S,3R)-3-((叔丁基二甲基硅基)氧基)-5-氧代-2-(丙-1-烯-2-基)环戊基)庚-5-烯酸异丙酯(10.15)
根据实施例1所述的程序,除了使用丙-1-烯-2-基硼酸(3.15),粗反应混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物10.15(48mg,76%)。
[α]25 D-85.4(c 1.00,CHCl3);1H NMR(400MHz):δ0.016(s,3H),0.024(s,3H),0.86(s,9H),1.22(d,J=6.2Hz,6H),1.58–1.69(m,3H),1.73(s,3H),2.04(q,J=7.0Hz,2H),2.10–2.27(m,3H),2.27–2.34(m,2H),2.50(dd,J=8.3,12.0Hz,1H),2.66(dd,J=7.1,18.4Hz,1H),4.13(dd,J=8.2,15.8Hz,1H),4.85(s,1H),4.93(s,1H),4.99(七重峰,J=6.2Hz,1H),5.28–5.44(m,2H);13C NMR(100MHz):δ-4.9(CH3),-4.8(CH3),18.0(C),19.6(CH3),21.8(CH3),24.8(CH2),25.3(CH2),25.7(CH3),26.6(CH2),34.1(CH2),47.7(CH2),52.2(CH),57.7(CH),67.4(CH),71.3(CH),114.2(CH2),126.5(CH),130.8(CH),142.4(C),173.1(C),215.2(C);HRMS(ESI-QTOF)计算值[C24H42O4Si+H]+=423.2925,实测值423.2927;FTIR(KBr,无水的)3421,2950,2862,1738,1636,1376,1253,1107,888,837,786cm-1.
实施例14–合成(Z)-7-((1R,2S,3R)-2-((E)-丁-2-烯-2-基)-3-((叔丁基二甲基硅基)氧基)-5-氧代环戊基)庚-5-烯酸异丙酯(10.16)
根据实施例1所述的程序,除了使用(Z)-丁-2-烯-2-基硼酸(3.16),粗反应混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物10.16(24mg,37%)。
[α]25 D-43.6(c 1.00,CHCl3);1H NMR(400MHz):δ-0.01(s,3H),0.01(s,3H),0.85(s,9H),1.22(d,J=6.0Hz,6H),1.54–1.71(m,8H),1.99–2.08(m,2H),2.10–2.31(m,6H),2.59–2.72(m,1H),3.04(dd,J=8.8,12.4Hz,1H),4.15(q,J=8.8Hz,1H),4.99(七重峰,J=6.0Hz,1H),5.29–5.42(m,2H),5.48–5.55(m,1H);13C NMR(100MHz):δ-5.0(CH3),-4.9(CH3),13.4(CH3),17.9(C),18.7(CH3),21.8(CH3),24.8(CH2),24.9(CH2),25.7(CH3),26.4(CH2),34.1(CH2),47.7(CH2),50.7(CH),51.7(CH),67.4(CH),70.0(CH),125.0(CH),126.6(CH),130.6(CH),131.4(C),173.1(C),215.4(C);HRMS(ESI-QTOF)计算值[C25H44O4Si+H]+=437.3081,实测值437.3087;FTIR(KBr,无水的)3452,2938,1736,1667,1461,1373,1250,1108,972,838cm-1.
实施例15–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
将2(57mg,0.15mmol)、反式-2-苯基乙烯基硼酸(3.1)(33mg,0.22mmol)、[RhCl(1,5-环辛二烯)]2(1.1mg,2.2μmol)和水性t-BuOK(20μL,1.5M水性t-BuOK,30μmol)在二氧六环(1.0mL)中的溶液用常规加热(加热套)于60℃搅拌4天,然后直接真空浓缩反应混合物。用柱层析(用1:80(v/v)丙酮-己烷洗脱)纯化残留物得到10.1(39mg,54%)。
实施例16–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
将2(57mg,0.15mmol)、反式-2-苯基乙烯基硼酸(3.1)(33mg,0.22mmol)、[RhCl(1,5-环辛二烯)]2(1.1mg,2.2μmol)和水性t-BuOK(20μL,1.5M水性t-BuOK,30μmol)在异丙醇(1.0mL)中的溶液用常规加热(加热套)于60℃搅拌3天,然后直接真空浓缩反应混合物。残留物用柱层析(用1:80(v/v)丙酮-己烷洗脱)纯化得到10.1(43mg,59%)。
实施例17–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
将2(57mg,0.15mmol)、反式-2-苯基乙烯基硼酸(3.1)(33mg,0.22mmol)、[RhCl(1,5-环辛二烯)]2(1.1mg,2.2μmol)和水性KOH(9.5μL,3.0M水性KOH,29μmmol)在异丙醇(1.0mL)中的溶液于25℃搅拌3天,接着直接真空浓缩反应混合物。然后用1H NMR谱分析粗产物混合物,显示70%的10.1产率和22%的化合物2回收。
实施例18–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用水性KHF2(0.3mL,3.0M水性KHF2,0.9mmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示74%的10.1产率和18%的化合物2回收。
实施例19–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用水性NaOH(9.5μL,3.0M水性NaOH,29μmmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示35%的10.1产率和70%的化合物2回收。
实施例20–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用水性LiOH(9.5μL,3.0M水性LiOH,29μmmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示25%的10.1产率和65%的化合物2回收。
实施例21–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用水性CsOH(9.5μL,3.0M水性CsOH,29μmmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示22%的10.1产率和77%的化合物2回收。
实施例22–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用水性K2CO3(0.3mL,3.0M水性K2CO3,0.9mmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示13%的10.1产率和60%的化合物2回收。
实施例23–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用水性K3PO4(0.6mL,1.5M水性K3PO4,0.9mmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示54%的10.1产率和26%的化合物2回收。
实施例24–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例18所述的程序,用二氯双(降冰片二烯)二铑(1.0mg,2.2μmmol)作为金属添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示35%的10.1产率和57%的化合物2回收。
实施例25–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例18所述的程序,用[RhCl(C2H4)2]2(0.9mg,2.3μmmol)作为金属添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示29%的10.1产率和69%的化合物2回收。
实施例26–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用t-BuOH(0.8mL)作为溶剂合成标题化合物。然后用1HNMR谱分析粗产物混合物,显示58%的10.1产率和44%的化合物2回收。
实施例27–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用EtOH(0.8mL)作为溶剂合成标题化合物。然后用1HNMR谱分析粗产物混合物,显示75%的10.1产率和15%的化合物2回收。
实施例28–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用MeOH(0.8mL)作为溶剂合成标题化合物。然后用1HNMR谱分析粗产物混合物,显示80%的10.1产率和17%的化合物2回收。
实施例29–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用MeOH-H2O(0.8mL,1:1v/v)作为溶剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示61%的10.1产率和39%的化合物2回收。
实施例30–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例18所述的程序,用二氧六环(0.8mL)作为溶剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示48%的10.1产率和52%的化合物2回收。
实施例31–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例28所述的程序,用K3PO4(0.6mL,1.5M水性K3PO4,0.9mmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示60%的10.1产率和42%的化合物2回收。
实施例32–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例28所述的程序,用t-BuNH2(0.95mL,9.0mmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示50%的10.1产率和50%的化合物2回收。
实施例33–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例28所述的程序,用哌啶(0.89mL,9.0mmol)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示28%的10.1产率和38%的化合物2回收。
实施例34–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
根据实施例17所述的程序,用1,3-二氨基丙烷(0.8mL,9.6mml)作为碱性添加剂合成标题化合物。然后用1H NMR谱分析粗产物混合物,显示42%的10.1产率和38%的化合物2回收。
实施例35–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
将2(57mg,0.15mmol)、反式-2-苯基乙烯基硼酸(3.1)(33mg,0.22mmol)和[RhOH(1,5-环辛二烯)]2(1.0mg,2.2μmol)在MeOH(1.0mL)中的溶液在微波照射下搅拌6小时,温度设定为30℃,然后直接真空浓缩反应混合物。然后用1H NMR谱分析粗产物混合物,显示29%的10.1产率和74%的化合物2回收。
实施例36–合成(Z)-7-[(2R,3R)-3-(叔丁基-二甲基-硅氧基)-5-氧代-2-苯乙烯基-环戊基]-庚-5-烯酸异丙酯(10.1)
将2(57mg,0.15mmol)、反式-2-苯基乙烯基硼酸(3.1)(33mg,0.22mmol)和[RhOH(1,5-环辛二烯)]2(1.0mg,2.2μmol)在MeOH(1mL)中的溶液用常规加热(加热套)于50℃搅拌3天,然后直接真空浓缩反应混合物。然后用1H NMR谱分析粗产物混合物,显示47%的10.1产率和53%的化合物2回收。
实施例37–合成叔丁基-(1-乙炔基-己氧基)-二甲基-硅烷(1.8a)
于0–5℃向辛-1-炔-3-醇(11.574mL,76.1mmol)、咪唑(10.4g,153mmol)和DMAP(0.929g,7.60mmol)在CH2Cl2(100mL)中的溶液滴加TBSCl(17.2g,114mmol)在CH2Cl2(50mL)中的溶液。允许反应混合物(白色悬浮液)升温至室温。室温搅拌混合物20小时并用CH2Cl2(150mL)和饱和水性NH4Cl(300mL)稀释。分离有机层,水层用CH2Cl2(200mL×2)萃取。合并的有机层用盐水洗涤,MgSO4干燥,并浓缩。柱层析(用1:20(v/v)EtOAc–正庚烷洗脱)得到标题化合物1.8a,为无色液体(18.11g,99%)。
1H NMR(400MHz,CDCl3):δ4.35(td,J=6.4,2.0Hz,1H),2.38(d,,1H),1.72–1.67(m,2H),1.62–1.45(m,2H),1.44–1.30(m,4H),0.91–0.86(m,12H),0.04(s,3H),0.02(s,3H);13C NMR(100MHz,CDCl3):δ85.8,71.8,62.8,38.5,31.4,25.8(CH2×3),24.8,22.6,18.2,14.0, -4.6,-5.1;FTIR(KBr,无水的)3312,2956,2930,2858,1716,1642,1471,1463,1362,1341,1253,1144,1119,1005,969cm-1.
实施例38–合成2-[3-(叔丁基-二甲基-硅氧基)-辛-1-烯基]-4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷(2.8a)
在N2气氛和环境温度下向正庚烷(10.0mL)中加入叔丁基-(1-乙炔基己氧基)-二甲基-硅烷(2.48g,10.3mmol)、5mol%的4-(二甲基氨基)苯甲酸(83mg,0.50mmol)和频哪醇硼烷(4.5mL,30mmol;纯油)。该溶液在100℃加热温育5.5小时并冷却至室温。用EtOAc(30mL)和饱和水性NH4Cl溶液(40mL)稀释混合物并分离层。水层用EtOAc(30mL)反萃取,合并的有机层用盐水(50mL)洗涤,无水MgSO4(2.5g)干燥,过滤并减压浓缩以得到粗混合物,该混合物通过柱层析(50g SiO2;用正庚烷(200mL)然后1:50(v/v)MTBE–正庚烷(750mL)洗脱)纯化以得到标题化合物(2.85g,7.74mmol,75%产率)。
1H NMR(400MHz,CDCl3):δ6.37(1H,dd,J=18.0,5.6),5.43(1H,dd,J=18.0,1.2),4.11(1H,m),1.48(2H,m),1.29(6H,m),1.28(12H,s),0.90(9H,s),0.88(3H,m),0.04(3H,s),0.03(3H,s);13C NMR(100MHz,CDCl3):δ156.2,116.2,83.0(C×2),74.1,37.5,31.9,25.9(CH2×3),24.8(CH×2),24.7(CH×3),22.6,18.2,14.0,-4.4,-4.9;FTIR(KBr,无水的)2956,2929,2857,1715,1642,1463,1471,1362,1339,1255,1165,1087cm-1;HRMS(ESI-QTOF)计算值[C20H41BO3Si+OH]-=385.2951,实测值385.2961.
实施例39–合成(E)-(3-((叔丁基二甲基硅基)氧基)辛-1-烯-1-基)硼酸(3.8a)
向2-[3-(叔丁基-二甲基-硅氧基)-辛-1-烯基]-4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷(2.8a,0.99g,2.69mmol)在丙酮和水(150mL,2:1v/v)中的溶液加入NaIO4(1.80g,8.42mmol;3.1当量)和NH4OAc(0.63g,8.17mmol;3.0当量)。室温搅拌产生的浑浊溶液20小时并减压浓缩以除去丙酮。残留物用EtOAc(50mL)稀释并分离层。水层用EtOAc(50mL)反萃取,合并的有机层用盐水(100mL)洗涤,MgSO4(2.0g)干燥,过滤,并减压浓缩以得到标题化合物硼酸3.8a(820mg,定量)。
1H NMR(400MHz,DMSO-d6):δ7.57(2H,s),6.58(1H,dd,J=17.8,5.0),5.58(1H,dd,J=18.0,1.2),4.16(1H,m),1.39(2H,m),1.37(6H,m),0.84(9H,s),0.83(3H,m),0.01(3H,s), -0.01(3H,s);13C NMR(100MHz,DMSO-d6):δ152.1,122.4,74.0,37.2,31.2,25.7(CH×3),24.2,22.0,17.9,13.8,-4.4,-4.9;FTIR(KBr,无水的)2956,2929,2857,1636,1472,1463,1348,1286,1255,1118,1088,1004,966cm-1;HRMS(ESI-QTOF)计算值[C14H31BO3Si-H]-=285.2063,实测值285.2082.
实施例40–合成1-(4,4,5,5-四甲基-[1,3,2]二氧杂环戊硼烷-2-基)-辛-1-烯-3-醇(2.8)
在N2气氛和环境温度下向正庚烷(10.0mL)中加入辛-1-炔-3-醇(1.5g,11.0mmol)、5mol%的4-(二甲基氨基)苯甲酸(94mg,0.55mmol)和频哪醇硼烷(6.8mL,45mmol;纯油)。该溶液在100℃加热温育24小时并冷却至室温。用EtOAc(50mL)和饱和水性NH4Cl溶液(60mL)稀释混合物并分离层。水层用EtOAc(50mL)反萃取,合并的有机层用盐水(60mL)洗涤,无水MgSO4(3.0g)干燥,过滤并减压浓缩以得到粗混合物,该混合物通过柱层析(80g SiO2;1:20(v/v)MTBE–正庚烷(250mL)然后1:10(750mL)洗脱)纯化以得到标题化合物(2.8,1.06g,7.74mmol,38%产率)。
1H NMR(400MHz,CDCl3):δ6.60(1H,dd,J=18.0,5.2),5.60(1H,dd,J=18.4,1.2),4.12(1H,m),1.93(1H,s),1.52(2H,m),1.30(6H,m),1.28(12H,s),0.88(3H,m);13C NMR(100MHz,CDCl3):δ155.4,117.1,83.2(CH×2),73.6,36.5,31.7,24.9(CH×2),24.7(CH×3),22.5,14.0;HRMS(ESI-QTOF)计算值[C14H27BO3+OH]+=271.2086,实测值271.2106.
实施例41–合成(E)-(3-羟基辛-1-烯-1-基)硼酸(3.8)
向2.8(1.17g,4.6mmol)在丙酮和水(180mL,2:1v/v)中的溶液加入NaIO4(3.05g,14.3mmol)和NH4OAc(1.06g,13.8mmol)。产生的浑浊溶液于40℃搅拌20小时并减压浓缩以除去丙酮。用EtOAc(60mL)稀释残留物并分离层。水层用EtOAc(60mL)反萃取,合并的有机层用盐水(120mL)洗涤,MgSO4(2.5g)干燥,过滤,并减压浓缩以提供标题化合物(3.8,443mg,56%)。
1H NMR(400MHz,DMSO-d6):δ7.55(s,2H),6.39(dd,J=18.0,5.2Hz,1H),5.42(dd,J=18.0,1.2Hz,1H),4.66(d,J=4.4Hz,1H),3.90(m,1H),1.34(m,2H),1.27(m,6H),0.85(m,3H);13C NMR(100MHz,DMSO-d6):δ153.8,122.4,72.5,37.2,31.8,25.1,22.6,14.4;HRMS(ESI-QTOF)计算值[C8H17BO3-H]-=171.1198,实测值171.1210.
实施例42–合成辛-1-炔-3-基乙酸酯(1.8b)
向烧瓶中加入4-二甲基氨基吡啶(610mg,4.9930mmol),辛-1-炔-3-醇(7.3mL,50mmol)和二氯甲烷(100mL)。溶液冷却到0℃并加入三乙基胺(20.9mL,150mmol),然后逐滴加入3mL二氯甲烷中的乙酸酐(7.09mL,75mmol)。将溶液逐渐升温至室温。反应完成后,真空浓缩反应混合物。粗反应混合物在硅胶上(用1:25(v/v)MTBE–己烷洗脱)纯化以得到标题化合物(1.8b,8.21g,97.6%产率),为淡黄色油。
1H NMR(400MHz,CDCl3):δ5.30(t,J=5.2Hz,1H),2.43(d,,1H),2.04(s,3H),1.75–1.70(m,2H),1.41–1.39(m,2H),1.28–1.27(m,4H),0.86–0.84(m,3H);13C NMR(100MHz,CDCl3):δ169.7,81.2,73.4,63.7,34.5,31.2,24.5,22.4,20.9,13.9.
实施例43–合成(E)-1-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)辛-1-烯-3-基乙酸酯(2.8b)
N2下向无水正庚烷(15mL)中加入辛-1-炔-3-基乙酸酯(2.5g,15mmol)、4-二甲基氨基苯甲酸(120mg,0.74mmol)和频哪醇硼烷(6.47mL,43.3mmol)。将溶液加热到90–100℃。反应完成后并冷却到室温后,将反应混合物真空浓缩并在EtOAc(50mL)和10%水性NH4Cl(50mL)之间分配。水相用EtOAc(50mL×2)萃取,合并的有机相用盐水(100mL)洗涤,MgSO4干燥。真空浓缩反应混合物,粗反应混合物在硅胶上(用含有1%Et3N的1:25(v/v)MTBE–正庚烷洗脱)纯化以得到标题化合物(2.8b,1.23g,27.9%产率),为淡黄色油。
1H NMR(400MHz,CDCl3):δ6.38(dd,J=18.4,5.2Hz,1H),5.57(dd,J=17.2,1.2Hz,1H),5.32–5.27(m,1H),2.07(s,3H),1.64–1.59(m,2H),1.34–1.24(m,17H),0.90–0.86(m,4H);13C NMR(100MHz,CDCl3):δ170.3,150.3,83.3(C×2),75.0,33.8,31.6,24.8,24.7(CH3×4),22.5,21.1,14.0(由于强度低,没有观察到ipso碳(连接于B)信号)。
实施例44–合成(I)-(3-乙酰氧基辛-1-烯-1-基)硼酸(3.8b)
向2.8b(950mg,3.2mmol)在丙酮/H2O(3/1,v/v)(142mL)中的溶液加入高碘酸钠(2.13g,9.96mmol)和乙酸铵(742mg,9.63mmol)。于40℃搅拌产生的浑浊溶液。反应完成后,将反应混合物置于减压下以除去丙酮。用EtOAc(100mL)稀释残留物并将各相分开。水层用EtOAc(100mL)萃取,合并的有机层用盐水(50mL)洗涤,MgSO4干燥。真空浓缩反应混合物,粗反应混合物在硅胶上(用1:4(v/v)丙酮–正庚烷洗脱)以得到标题化合物(3.8b,507mg,74%产率)纯化,为淡黄色油。
1H NMR(400MHz,DMSO-d6):δ6.34(dd,J=18,5.2Hz,1H),5.44(dd,J=18.4,1.6Hz,1H),5.17–5.13(m,1H),2.04(s,3H),1.56–1.52(m,2H),1.3–1.26(m,6H),0.88–0.84(m,3H); 13C NMR(100MHz,DMSO-d6):δ170.1,147.2,75.2,33.9,31.4,24.7,22.4,21.3,14.3(由于强度低,没有观察到ipso碳(连接于B)信号);HRMS(ESI-QTOF)计算值[C10H19BO4-H]-=213.1304,实测值213.1316.
实施例45–合成{[(1-戊基丙-2-炔基)氧基]甲基}苯(1.8c)
向烧瓶中加入辛-1-炔-3-醇(6g,47.544mmol)和THF(60mL)。溶液冷却到0–5℃,然后向其中加入60%NaH(2.9g,73mmol)。向该混合物中逐滴加入BnBr(6mL,50.45mmol),然后室温搅拌。反应完成后,通过在0–15℃加入30mL H2O来淬灭混合物。用EtOAc(50mL×2)萃取反应混合物,合并的有机相用盐水(30mL)洗涤,MgSO4干燥。反应混合物真空浓缩,粗反应混合物在硅胶上(0–20%(v/v)EtOAc–正庚烷洗脱)纯化以得到标题化合物,为淡黄色油(1.8c,10.27g,47.5mmol,99.9%产率)。
1H NMR(400MHz,CDCl3):δ7.40–7.28(m,5H),4.84(d,J=12Hz,1H),4.54(d,J=12Hz,1H),4.12–4.08(m,1H),2.49(d,J=2Hz,1H),1.83–1.74(m,2H),1.53–1.50(m,2H),1.37–1.28(m,4H),0.93–0.92(m,3H);13C NMR(100MHz,CDCl3):δ137.9,128.4(CH×2),128.0(CH×2),127.7,83.1,73.7,70.5,68.5,35.6,31.5,24.9,22.5,14.0.
实施例46–合成(E)-2-[3-(苄基氧基)辛-1-烯-1-基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.8c)
N2下向无水正庚烷(15mL)中加入1.8c(2.18g,10.1mmol)、4-二甲基氨基苯甲酸(0.0906g,0.548mmol)和频哪醇硼烷(5mL,33.4mmol)。将溶液加热到90–100℃。反应完成后并冷却到室温后,将反应混合物真空浓缩并在EtOAc(50mL)和10%水性NH4Cl(50mL)之间分配。水相用EtOAc(50mL×2)萃取,合并的有机相用盐水(100mL)洗涤,MgSO4 干燥。真空浓缩反应混合物,粗反应混合物在硅胶上(用1:30(v/v)EtOAc–正庚烷洗脱)纯化以得到标题化合物,为淡黄色油(2.8c,2.75g,79.2%产率)。
1H NMR(400MHz,CDCl3):δ7.36–7.28(m,5H),6.53(dd,J=18,6.8Hz,1H),5.65(dd,J=18.4,0.8Hz,1H),4.62(d,J=12Hz,1H),4.36(d,J=12Hz,1H),3.82–3.80(m,1H),1.65–1.26(m,20H),0.90–0.97(m,3H);13C NMR(100MHz,CDCl3):δ153.6,138.8,128.3(CH×2),127.7(CH×2),127.4,83.3(C×2),81.3,70.5,35.1,31.8,25.0,24.8(CH3×4),22.6,14.1(由于强度低,没有观察到ipso碳(连接于B)信号)。
实施例47–合成(E)-[3-(苄基氧基)辛-1-烯-1-基]硼酸(3.8c)
向2.8c(1.2g,3.5mmol)在丙酮/H2O(3/1,v/v)(150mL)中的溶液加入高碘酸钠(1.8g,8.4mmol)和乙酸铵(0.67g,8.7mmol)。在40℃搅拌产生的浑浊溶液。反应完成后,将反应混合物置于减压下以除去丙酮。用EtOAc(100mL)稀释残留物并将分离各相。水层用EtOAc(100mL)萃取,合并的有机层用盐水洗涤(50mL),MgSO4干燥。真空浓缩反应混合物,粗反应混合物在硅胶上(用35%丙酮–正庚烷洗脱)纯化以得到标题化合物,为淡黄色油(3.8c,0.7g,80%产率)。
1H NMR(400MHz,DMSO-d6):δ7.68(s,2H),7.37–7.26(m,5H),6.33(dd,J=18,6.8Hz,1H),5.52(d,J=18Hz,1H),4.49(d,J=12Hz,1H),4.29(d,J=12Hz,1H),3.79–3.75(m,1H),1.55–1.20(m,8H),0.86–0.83(m,3H);13C NMR(100MHz,DMSO-d6):δ150.0,139.3,128.6,127.9(CH×2),127.7(CH×2),81.1,69.9,35.1,31.7,24.9,22.5,14.4(由于强度低,没有观察到ipso碳(连接于B)信号y);HRMS(ESI-QTOF)计算值[C15H23BO3-H]-=261.1667,实测值261.1681.
实施例48–合成(E)-2-[3-(烯丙基氧基)辛-1-烯-1-基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.8d)
向2.8(1.3g,5.1mmol)在THF(13mL)中的溶液加入预清洗的NaH(0.8g,20mmol)在THF(10mL)中的悬浮液。产生的悬浮液在回流下加热30min,并加入烯丙基溴(2.0mL,23mmol)。产生的悬浮液在回流下加热2小时。反应混合物冷却至环境温度并倒到冰中。混合物用EtOAc(30mL×2)萃取,合并的有机萃取物用MgSO4(2.0g)干燥。真空除去挥发物, 用柱层析(40g SiO2;用1:20(v/v)MTBE–正庚烷(500mL)洗脱)纯化残留物以得到标题化合物(2.8d,861mg,2.93mmol,57%产率)。
1H NMR(400MHz,CDCl3):δ6.45(dd,J=18.0,6.4Hz,1H),5.90(m,1H),5.59(dd,J=18.0,0.8Hz,1H),5.26(dd,J=17.2,3.6Hz,1H),5.15(dd,J=17.2,3.6Hz,1H),4.05(m,1H),3.79(m,2H),1.48(m,2H),1.38(m,6H),1.28(s,12H),0.88(m,3H);13C NMR(100MHz,CDCl3):δ153.5,135.1,119.5,116.5,83.2(CH×2),81.3,69.6,35.0,31.8,25.0,24.8(CH×4),22.5,14.0.
实施例49–合成(E)-[3-(烯丙基氧基)辛-1-烯-1-基]硼酸(3.8d)
向2.8d(1.1g,3.7mmol)在丙酮和水(150mL,2:1v/v)的溶液中加入NaIO4(2.6g,12.0mmol)和NH4OAc(0.9g,11.1mmol)。在40℃搅拌产生的浑浊溶液24小时并在减压下浓缩以除去丙酮。残留物用EtOAc(60mL)稀释并分离层。水层用EtOAc(60mL)反萃取,合并的有机层用盐水(100mL)洗涤,MgSO4(2.0g)干燥,过滤,并减压浓缩以提供粗混合物,该混合物通过柱层析(30g SiO2;用1:10(v/v)MTBE–正庚烷(100mL)然后1:3(400mL)洗脱)纯化以得到标题化合物(3.8d,679mg,3.2mmol,86%产率)。
1H NMR(400MHz,DMSO-d6):δ7.64(s,2H),6.24(dd,J=18.0,7.2Hz,1H),5.85(m,1H),5.46(d,J=18.0,1H),5.21(dd,J=17.2,3.6Hz,1H),5.10(dd,J=10.4,1.6Hz,1H),3.93(m,1H),3.77(m,1H),3.71(m,1H),1.37(m,2H),1.24(m,6H),0.84(m,3H);13C NMR(100MHz,DMSO-d6):δ149.4,135.5,125.9,115.6,80.7,68.4,34.6,31.2,24.4,22.0,13.8;HRMS(ESI-QTOF)计算值[C11H21BO3-H]-=211.1511,实测值211.1527.
实施例50–合成2-(辛-1-炔-3-基氧基)四氢-2H-吡喃(1.8e)
0–5℃向辛-1-炔-3-醇(11.6mL,76.2mmol)、DHP(13.9mL,152mmol)在CH2Cl2(100mL)中的溶液加入在CH2Cl2(2.0mL)中的PPTS(950mg,3.78mmol)。允许反应混合物升温至室温并搅拌4小时。用CH2Cl2(100mL)稀释后,加入饱和水性NH4Cl(200mL)。分离层,水层用CH2Cl2(100mL×2)反萃取。合并有机层,用盐水洗涤,MgSO4干燥,并浓缩。柱层析(用1:20(v/v)EtOAc–正庚烷洗脱)得到标题化合物,为四种非对映异构体的混合物(无色液体)(1.8e,14.22g,89%为非对映异构体混合物)。
1H NMR(400MHz,CDCl3):δ4.98–4.74(m,1H),4.43–4.25(m,1H),4.05–3.77(m,1H),3.56–3.50(m,1H),2.43–2.37(m,1H),1.79–1.60(m,4H),1.59–1.42(m,6H),1.35–1.28(m,4H),0.91–0.84(m,3H);13C NMR(100MHz,CDCl3):δ98.2,95.5,84.0,83.0,73.1,72.5,67.1,64.7,62.3,62.2,35.6,35.5,31.5(×2),30.5(×2),25.5,25.4,25.0,24.7,22.5(×2),19.3,19.1,14.0(×2).
实施例51–合成(E)-2-[3-(四氢-2H-吡喃氧基)辛-1-烯-1-基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.8e)
根据实施例38所述的程序,但使用化合物1.8e(2.02g,9.59mmol)和苯甲酸(79mg,0.49mmol),用柱层析(1:20(v/v)MTBE–正庚烷洗脱)纯化粗产物得到2.8e(2.31g,71%为非对映异构体混合物)。
1H NMR(400MHz,CDCl3):δ6.63(dd,J=18.2,5.4Hz,0.5H),6.42(dd,J=18.0,6.4Hz,0.5H),5.69(dd,J=18.0,1.6Hz,0.5H),5.57(dd,J=18.0,0.8Hz,0.5H),4.73(t,J=3.6Hz,0.5H),4.61(t,J=3.4Hz,0.5H),4.19–4.11(m,1H),3.88–3.84(m,1H),3.51–3.42(m,1H),1.88–1.82(m,1H),1.75–1.68(m,1H),1.65–1.27(m,24H),0.90–0.86(m,3H);13CNMR(100MHz,CDCl3):δ153.9,153.2,119.9(br),96.8,95.7,83.2,83.1,77.3,77.1,62.3,62.1,35.3,33.8,31.9,31.8,30.7,25.5,25.4,25.1,24.79,24.75,24.71,24.67,24.5,22.5,19.6,19.3,14.0.
实施例52–合成(E)-[3-(四氢-2H-吡喃氧基)辛-1-烯-1-基]硼酸(3.8e)
根据实施例39所述的程序,但使用化合物2.8e(950mg,2.80mmol),用柱层析(1:10(v/v)EtOAc–正庚烷洗脱)纯化粗产物得到3.8e(495mg,69%为非对映异构体混合物)。
1H NMR(400MHz,DMSO-d6):δ7.65(s,1H),7.59(s,1H),6.40(dd,J=18.0,5.6Hz,0.5H),6.21(dd,J=18.0,6.8Hz,0.5H),6.45(t,J=18.4Hz,1H),4.65(d,J=3.2Hz,0.5H),4.51(d,J=3.6Hz,0.5H),4.01–3.98(m,1H),3.78–3.71(m,1H),3.43–3.39(m,1H),1.74–1.70(m,1H),1.62–1.58(m,1H),1.51–1.40(m,6H),1.26–1.24(m,6H),0.87–0.84(m,3H);13CNMR(100MHz,DMSO-d6):δ150.74,149.5,126.7,123.8,97.1,95.1,78.0,77.1,61.9,61.7,35.4,34.2,31.81,31.74,31.68,30.98,30.84,28.9,25.62,25.57,25.1,24.5,22.5,19.7,19.6,14.4;HRMS(ESI-QTOF)计算值[C13H25BO4-H]-=255.1773,实测值255.1785.
实施例53–合成(S)-叔丁基二甲基(辛-1-炔-3-基氧基)硅烷(1.9a)
0–5℃向(S)-辛-1-炔-3-醇(5.08g,40.3mmol)、2,6-卢剔啶(8.49g,79.2mmol)和DMAP(0.506g,4.14mmol)在CH2Cl2(70mL)中的溶液逐滴加入TBSOTf(15.8g,59.8mmol)在CH2Cl2(20mL)中的溶液。允许反应混合物(浅黄色溶液)升温至室温并搅拌16小时。加入饱和水性NH4Cl(50mL)后,收集有机层,水层用CH2Cl2(50mL×2)萃取。合并有机层,用盐水(100mL)洗涤,MgSO4(3.0g)干燥,过滤并浓缩。柱层析(用正庚烷然后用1:20(v/v)EtOAc–正庚烷洗脱)得到1.9a,为无色液体(8.52g,88.0%)。
实施例54–合成(S,E)-叔丁基二甲基{[1-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)辛-1-烯-3-基]氧基}硅烷(2.9a)
在N2气氛和环境温度下向正庚烷(20.0mL)中加入1.9a(4.9g,20.0mmol)、5mol%的4-(二甲基氨基)苯甲酸(170mg,1.0mmol)和频哪醇硼烷(9.2mL,62mmol;纯油)。该溶液在100℃加热温育5小时并冷却至室温。混合物用EtOAc(40mL)和饱和水性NH4Cl溶液(50mL)稀释并分离层。水层用EtOAc(40mL)反萃取,合并的有机层用盐水(80mL)洗涤,无水MgSO4(3.0g)干燥,过滤并减压浓缩以得到粗产物2.9a,该粗产物通过柱层析(100g SiO2;用正庚烷(400mL)然后用1:30(v/v)MTBE–正庚烷(900mL)洗脱)纯化以得到标题化合物(2.9a,6.83g,18.5mmol,91%产率)。
实施例55–合成(S,E)-{3-[(叔丁基二甲基硅基)氧基]辛-1-烯-1-基}硼酸(3.9)
向2.9a(9.29g,25.2mmol)在丙酮和水(540mL,2:1v/v)的溶液中加入NaIO4(15.0g,70.13mmol)和NH4OAc(5.15g,66.80mmol)。40℃搅拌产生的浑浊溶液20小时并减压浓缩以除去丙酮。用EtOAc(200mL)稀释残留物并分离层。水层用EtOAc(200mL)反萃取,合并的有机层用盐水(200mL)洗涤,MgSO4(5.0g)干燥,过滤,并减压浓缩以提供标题化合物(3.93.86g,13.5mmol,53.5%)。
[α]20 D=-1.26(c 1.0,MeOH);HRMS(ESI-QTOF)计算值[C14H31BO3Si-H]-=285.2063,实测值285.2078.
实施例56–合成(Z)-7-((1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-2-{(E)-3-[(叔丁基二甲基硅基)氧基]-5-苯基戊-1-烯-1-基)}-5-氧代环戊基)庚-5-烯酸异丙酯(10.17)
根据实施例1所述的程序,除使用(S,E)-{3-[(叔丁基二甲基硅基)氧基]-5-苯基戊-1-烯-1-基}硼酸(3.17,72.0mg,0.225mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到标题化合物10.17(63mg,64%)。
[α]29 D-35.9(c 1.00,CHCl3);1H NMR(400MHz):δ0.03(s,3H),0.05(s,3H),0.06(s,3H),0.07(s,3H),0.87(s,9H),0.92(s,9H),1.22(d,J=6.4Hz,6H),1.57–1.72(m,3H),1.74–1.89(m,2H),1.92–2.11(m,3H),2.11–2.43(m,4H),2.52(dt,J=7.6,10.8Hz,1H),2.56–2.74(m,3H),4.08(q,J=7.6Hz,1H),4.20(q,J=5.5Hz,1H),4.99(七重峰,J=6.4Hz,1H),5.28–5.47(m,2H),5.50–5.68(m,2H),7.10–7.22(m,3H),7.24–7.32(m,2H);13C NMR(100MHz):δ-4.7(CH3),-4.63(CH3),-4.59(CH3),-4.2(CH3),18.0(C),18.2(C),21.8(CH3),24.8(CH2),25.3(CH2),25.8(CH3),25.9(CH3),26.7(CH2),31.6(CH2),34.1(CH2),40.2(CH2),47.7(CH2),52.7(CH),53.9(CH),67.4(CH),72.1(CH),73.3(CH),125.7(CH),126.6(CH),128.27(CH),128.33(CH),129.2(CH),130.9(CH),135.9(CH),142.3(C),173.1(C),215.3(C);HRMS(ESI):计算值[C38H64O5Si2+NH4]+=674.4631,实测值674.4611;FTIR(KBr,无水的)3465,2950,2859,1736,1630,1462,1376,1252,1103,1020,834cm-1.
实施例57–合成(Z)-7-((1R,2R,3R)-3-((叔丁基二甲基硅基)氧基)-2-((E)-3-((叔丁基二甲基硅基)氧基)-4-(3-(三氟甲基)苯氧基)丁-1-烯-1-基)-5-氧代环戊基)庚-5-烯酸异丙酯(10.18)
根据实施例1所述的程序,除使用(R,E)-{3-[(叔丁基二甲基硅基)氧基]-4-[3-(三氟甲基)苯氧基]丁-1-烯-1-基}硼酸(3.17,88mg,0.225mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到标题化合物10.18(71mg,65%)。
[α]29 D-35.6(c 1.00,CHCl3);1H NMR(400MHz):δ0.04(s,3H),0.05(s,3H),0.100(s,3H),0.104(s,3H),0.87(s,9H),0.91(s,9H),1.21(d,J=6.2Hz,6H),1.58–1.72(m,3H),1.92–2.11(m,2H),2.12–2.45(m,4H),2.52(dt,J=7.6,11.2Hz,1H),2.55–2.70(m,1H),3.80–3.92(m,2H),4.07(q,J=8.4Hz,1H),4.50–4.62(m,1H),4.98(七重峰,J=6.4Hz,1H),5.25–5.45(m,2H),5.65–5.82(m,2H),7.03(dd,J=2.0,8.0Hz,1H),7.08(s,1H),7.20(d,J=7.6Hz,2H),7.38(dd,J=8.0,8.0Hz,1H);13C NMR(100MHz):δ-4.5(CH3),-4.6(CH3),-4.7(CH3),18.0(C),18.3(C),21.8(CH3),24.8(CH2),25.1(CH2),25.7(CH3),25.8(CH3),26.7(CH2),30.9(CH3),34.1(CH2),47.6(CH2),53.1(CH),54.1(CH),67.4(CH),70.9(CH),72.6(CH2),72.9(CH),111.0(q,J=4.0Hz,CH),117.5(q,J=4.0Hz,CH),123.9(q,J=271.0Hz,C),126.5(CH),130.0(CH),130.9(CH),131.5(CH),131.9(q,J=32.2Hz,C),132.3(CH),158.9(C),173.0(C),214.7(C);HRMS(ESI):计算值[C38H61F3O6Si2+NH4]+=744.4297,实测值744.4291;FTIR(KBr,无水的)2945,2862,1737,1602,1457,1330,1249,1167,1123,839cm-1.
实施例58–合成(Z)-7-{(1R,2R,3R)-2-[(1E,5E)-3-(苄基氧基)-4,4-二氟辛-1,5-二烯-1-基]-3-[(叔丁基二甲基硅基)氧基]-5-氧代环戊基}庚-5-烯酸异丙酯(10.19)
根据实施例1所述的程序,除使用2-((1E,5E)-3-(苄基氧基)-4,4-二氟辛-1,5-二烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(2.19,85mg,0.225mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到(Z)-7-{(1R,2R,3R)-2-[(1E,5E)-3-(苄氧基)-4,4-二氟辛-1,5-二烯-1-基]-3-[(叔丁基二甲基硅基)氧基]-5-氧代环戊基}庚-5-烯酸异丙酯(10.19,27mg,28%为非对映异构体对)。
[α]22 D-51.8(c 0.33,CHCl3);1H NMR(400MHz):δ0.035(s,1.5H),0.044(s,1.5H),0.052(s,1.5H),0.065(s,1.5H),0.88(s,9H),1.03(t,J=7.4Hz,3H),1.21(d,J=6.4Hz,6H),1.62–1.70(m,1H),2.01–2.16(m,6H),2.16–2.30(m,2H),2.28–2.43(m,2H),2.53–2.60(m,1H),2.62–2.69(m,1H),3.93–4.15(m,2H),4.51(d,J=12.0Hz,0.5H),4.53(d,J=12.0Hz,0.5H),4.67(d,J=12.0Hz,0.5H),4.68(d,J=12.0Hz,0.5H),4.98(七重峰,J=6.4Hz,1H),5.26–5.46(m,2H),5.52–5.68(m,2H),5.69–5.82(m,1H),6.11–6.23(m,1H),7.29–7.32(m,6H);13C NMR(100MHz):δ-4.87(CH3),-4.74(CH3),-4.67(CH3),-4.52(CH3),12.7(CH3),18.0(C),21.8(CH3),24.79(CH2),24.81(CH2),25.0(CH2),25.2(CH2),25.72(CH3),25.74(CH3),26.63(CH2),26.66(CH2),34.05(CH2),34.06(CH2),47.7(CH2),53.1(CH),53.2(CH),53.75(CH),53.82(CH),67.4(CH),71.3(CH2),71.5(CH2),72.8(CH),73.0(CH),81.0(q,J=31.0Hz,CH),121.5(q,J=25.3Hz,CH),126.2(CH),126.3(CH),126.4(CH),127.7(CH),127.80(CH),127.84(CH),128.37(CH),128.41(CH),131.2(CH),131.3(CH),136.8(CH),137.2(CH),137.5(C),137.6(C),138.9(q,J=8.7Hz,CH),173.09(C),173.12(C),214.5(C);HRMS(ESI-QTOF)计算值[C36H54F2O5Si+Na]+=655.3601,实测值655.3620;FTIR(KBr,无水的)3460,2938,2867,1738,1630,1461,1377,1253,1214,1109,974,873cm-1.
实施例59–合成(Z)-7-{(1R,2R,3R,5S)-3-[(叔丁基二甲基硅基)氧基]-2-((E)-3,3-二氟-4-苯氧基丁-1-烯-1-基)-5-羟基环戊基}庚-5-烯酸异丙酯(11.7)
在-78℃向实施例8获得的化合物10.7(1.42g,2.51mmol)的THF(15mL)溶液中加入(3.45mL,1.0M,THF中,3.45mmol)溶液。混合物在-78℃搅拌40分钟,然后加入饱和水性NH4Cl(aq)(5mL)。分离水层并用EtOAc(15mL×3)萃取。合并有机层,无水Na2SO4干燥,过滤并蒸发以得到油性粗产物,该粗产物通过柱层析(1:8(v/v)EtOAc–己烷洗脱)纯化以得到标题化合物11.7(1.34g,94%)。
[α]26 D-9.4(c 0.11,CHCl3);1H NMR(400MHz):δ0.027(s,3H),0.034(s,3H),0.86(s,9H),1.22(d,J=6.2Hz,6H),1.52–1.61(m,1H),1.65(五重峰,J=7.5Hz,2H),1.73–1.82(m,1H),2.03–2.18(m,4H),2.20–2.46(m,5H),4.02(五重峰,J=3.5Hz,1H),4.06–4.32(m,3H),4.99(七重峰,J=6.2Hz,1H),5.28–5.59(m,2H),5.76(dt,J=11.1,15.6Hz,1H),6.14(ddt,J=2.4,9.3,15.7Hz,1H),6.89–6.92(m,2H),7.01(t,J=7.4Hz,1H),7.26–7.31(m,2H);13C NMR(100MHz):δ-4.9(CH3),-4.7(CH3),17.9(C),21.8(CH3),24.9(CH2),25.7(CH3),26.1(CH2),26.6(CH2),34.1(CH2),43.4(CH2),50.4(CH),55.7(CH),67.4(CH),69.5(t,J=35.0Hz,C),73.5(CH),78.5(CH),114.7(CH),118.1(t,J=239.0Hz,C),121.7(CH),123.6(t,J=25.0Hz,CH),128.8(CH),129.5(CH),129.8(CH),138.6(t,J=9.0Hz,CH),158.0(C),173.2(C);HRMS(ESI-QTOF)计算值[C31H48F2O5Si+H]+=567.3312,实测值567.3316;FTIR(KBr,无水的)3451,2954,2879,1724,1595,1498,1463,1375,1301,1246,1101cm-1.
实施例60–合成他氟前列素((Z)-7-[(1R,2R,3R,5S)-2-((E)-3,3-二氟-4-苯氧基丁-1-烯-1-基)-3,5-二羟基环戊基]庚-5-烯酸异丙酯;12.7)
在0℃向实施例59获得的化合物11.7(2.11g,3.73mmol)的THF(7mL)溶液中加入n-Bu4NF(4.5mL,1.0M,THF中,4.5mmol),该混合物在30min分钟内升温至室温,再搅拌3小时。加入饱和水性NH4Cl(aq)以淬灭反应,分离层。水相用EtOAc(20mL×3)萃取,合并有机层,无水Na2SO4干燥,过滤并蒸发以得到粗产物,该粗产物通过柱层析(己烷/EtOAc=1:5)纯化以得到标题化合物他氟前列腺素(12.7,1.52g,90%)。
[α]23 D 21.6(c 1.00,CHCl3);1H NMR(600MHz):δ1.22(d,J=6.3Hz,6H),1.58–1.69(m,3H),1.85(dt,J=1.2,14.4Hz,1H),2.03–2.14(m,6H),2.26(dt,J=3.0,7.4Hz,2H),2.28–2.38 (m,1H),2.47(dt,J=4.2,9.6Hz,1H),4.00–4.04(m,1H),4.15–4.25(m,3H),5.00(七重峰,J=6.3Hz,1H),5.33–5.43(m,2H),5.80(dt,J=11.1,15.7Hz,1H),6.10(ddt,J=2.3,9.1,15.7Hz,1H),6.91–6.92(m,2H),6.97–7.02(m,1H),7.28–7.31(m,2H);13C NMR(150MHz):δ21.80(CH3),21.82(CH3),24.8(CH2),25.7(CH2),26.6(CH2),34.0(CH2),43.0(CH2),50.5(CH),55.8(CH),67.7(CH),69.3(t,J=34.5Hz,CH2),73.3(CH),78.0(CH),114.8(CH),118.2(t,J=240.0Hz,C),121.8(CH),123.6(t,J=24.8Hz,CH),128.6(CH),129.6(CH),130.1(CH),138.6(t,J=8.3Hz,CH),158.0(C),173.4(C);19F NMR(564MHz):δ-103.4(d,J=255.2Hz),-104.1(d,J=255.5Hz);HRMS(ESI-QTOF):计算值[C25H34F2O5+H]+=453.2447,实测值453.2449;FTIR(KBr,无水的)3410,2929,1720,1593,1494,1376,1247,1156,1103,1052cm-1.
实施例61–合成(Z)-7-((1R,2R,3R)-2-{(E)-3-乙酰氧基辛-1-烯-1-基)-3-[(叔丁基二甲基硅基)氧基]-5-氧代环戊基}庚-5-烯酸异丙酯(10.8b)
根据实施例1所述的程序,除使用(E)-(3-乙酰氧基辛-1-烯-1-基)硼酸(3.8b,48mg,0.225mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到(Z)-7-((1R,2R,3R)-2-{(E)-3-乙酰氧基辛-1-烯-1-基)-3-[(叔丁基二甲基硅基)氧基]-5-氧代环戊基}庚-5-烯酸异丙酯(10.8b,20mg,24%为非对映异构体对)。
[α]24 D-94.2(c 0.23,CHCl3);1H NMR(400MHz):δ0.046(s,3H),0.054(s,3H),0.82–0.92(m,12H),1.24(d,J=6.2Hz,6H),1.26–1.36(m,7H),1.60–1.70(m,3H),1.98–2.09(m,6H),2.14(qd,J=2.1,9.1Hz,1H),2.25(t,J=7.6Hz,2H),2.29–2.52(m,3H),2.63(dd,J=7.2,18.3Hz,1H),4.015(q,J=8.4Hz,0.5H),4.023(q,J=8.4Hz,0.5H),4.99(七重峰,J=6.2Hz,1H),5.21–5.34(m,2H),5.35–5.45(m,1H),5.47–5.65(m,2H);13C NMR(100MHz):δ-4.81(CH3),-4.80(CH3),-4.7(CH3),-4.6(CH3),13.99(CH3),18.0(C),21.3(CH3),21.9(CH3),22.50(CH2),22.52(CH2),24.8(CH2),25.0(CH2),25.1(CH2),26.6(CH2),26.7(CH2),30.9(CH2),31.5(CH2),31.6(CH2),34.06(CH2),34.08(CH2),34.5(CH2),34.6(CH2),47.6(CH2),53.3(CH),53.3(CH),53.94(CH),53.3.96(CH),67.4(CH),72.72(CH),72.74(CH),74.2(CH),74.3(CH),126.47(CH),126.53(CH),130.9(CH),131.0(CH),131.77(CH),131.84(CH),133.17(CH),133.24(CH),170.15(C),170.19(C),173.1(C),214.6(C);HRMS(ESI-QTOF)计算值[C31H54O6Si+NH4]+=568.4028,实测值568.4047;FTIR(KBr,无水的):3442,2932,2861,1737,1641,1378,1237,1107,963,838cm-1.
实施例62–合成(Z)-7-((1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-5-氧代-2-{(E)-3-[(四氢-2H-吡喃-2-基)氧基]辛-1-烯-1-基}环戊基)庚-5-烯酸异丙酯(10.8e)
根据实施例1所述的程序,除使用(E)-(3-((四氢-2H-吡喃-2-基)氧基)辛-1-烯-1-基)硼酸(3.8e,58mg,0.225mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到(Z)-7-((1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-5-氧代-2-{(E)-3-[(四氢-2H-吡喃-2-基)氧基]辛-1-烯-1-基}环戊基)庚-5-烯酸异丙酯(10.8e)(56mg,63%为非对映异构体混合物)。
[α]24 D-62.9(c 0.36,CHCl3);1H NMR(400MHz):δ0.03(s,1.5H),0.04(s,1.5H),0.05(s,1.5H),0.06(s,1.5H),0.79–0.94(m,12H),1.21(d,J=6.3Hz,6H),1.28–1.34(m,5H),1.36–1.72(m,10H),1.73–1.83(m,1H),2.03–2.19(m,4H),2.21–2.40(m,4H),2.45–2.71(m,2H),3.33–3.53(m,1H),3.78–3.82(m,1H),3.92–4.12(m,2H),4.68–4.72(m,1H),4.99(七重峰,J=6.3Hz,1H),5.28–5.43(m,2H),5.48–5.66(m,2H);13C NMR(100MHz):δ-4.8(CH3),-4.7(CH3),-4.6(CH3),-4.5(CH3),14.1(CH3),17.95(C),18.0(C),19.42(CH2),19.49(CH2),19.51(CH2),21.9(CH3),22.6(CH2),24.7(CH2),24.8(CH2),24.9(CH2),25.1(CH2),25.2(CH2),25.3(CH2),25.4(CH2),25.5(CH2),25.6(CH2),25.75(CH3),25.77(CH3),26.7(CH2),30.79(CH2),30.82(CH2),31.8(CH2),31.9(CH2),34.09(CH2),34.11(CH2),34.6(CH2),34.8(CH2),36.1(CH2),47.7(CH2),52.7(CH),52.9(CH),53.1(CH),53.8(CH),53.9(CH),62.0(CH2),62.3(CH2),67.38(CH),67.41(CH),73.09(CH),73.13(CH),73.3(CH),75.7(CH),76.5(CH),77.1(CH),94.8(CH),97.0(CH),97.3(CH),126.56(CH),126.62(CH),126.7(CH),130.2(CH),130.3(CH),130.85(CH),130.91(CH),132.8(CH),133.8(CH),134.2(CH),134.8(C),173.0(C),173.09(C),173.12(C),214.8(C),215.3(C),215.4(C);HRMS(ESI):计算值[C34H60O6Si+Na]+=615.4051,实测值615.4063;FTIR(KBr,无水的)3424,2937,2862,1737,1638,1463,1375,1248,1113,1020cm-1.
实施例63–合成(Z)-7-{(1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-2-((E)-3-苄基氧基-1-烯-1-基)-5-氧代环戊基}庚-5-烯酸异丙酯(10.8c)
根据实施例1所述的程序,除使用(E)-(3-(苄氧基)辛-1-烯-1-基)硼酸(3.8c,59mg,0.225mmol),用柱层析纯化(丙酮–己烷=1:80洗脱)反应粗混合物得到 (Z)-7-((1R,2R,3R)-2-((E)-3-(苄氧基)辛-1-烯-1-基)-3-((叔丁基二甲基硅基)氧基)-5-氧代环戊基)庚-5-烯酸异丙酯(10.8c)(44mg,50%为非对映异构体对)。
非对映异构体1:[α]24 D-60.4(c 0.63,CHCl3);1H NMR(400MHz):δ0.06(s,3H),0.07(s,3H),0.83–0.96(m,12H),1.21(d,J=6.2Hz,6H),1.26–1.53(m,7H),1.60–1.73(m,3H),2.02–2.11(m,3H),2.12–2.27(m,3H),2.28–2.45(m,2H),2.54(dt,J=7.6,11.4Hz,1H),2.63(dd,J=6.9,18.2Hz,1H),3.76(q,J=6.5Hz,1H),4.08(q,J=8.3Hz,1H),4.35(d,J=11.9Hz,1H),4.60(d,J=11.9Hz,1H),4.99(七重峰,J=6.2Hz,1H),5.29–5.48(m,2H),5.49–5.64(m,2H),7.27–7.37(m,5H);13C NMR(100MHz):δ-4.7(CH3),-4.5(CH3),14.1(CH3),18.0(C),21.9(CH3),22.6(CH2),24.8(CH2),25.1(CH2),25.3(CH2),25.8(CH3),26.7(CH2),31.8(CH2),34.1(CH2),36.0(CH2),47.7(CH2),53.0(CH),53.9(CH),67.4(CH),70.3(CH2),73.2(CH),79.9(CH),126.6(CH),127.4(CH),127.6(CH),128.3(CH),131.0(CH),132.3(CH),134.2(CH),138.9(C),173.0(C),214.9(C);HRMS(ESI-QTOF)计算值[C36H58O5Si+Na]+=621.3946,实测值621.3961;FTIR(KBr,无水的)3448,2932,2862,1736,1461,1370,1246,1105,974,837cm-1.
非对映异构体2:[α]24 D-37.2(c 0.9,CHCl3);1H NMR(400MHz):δ0.04(s,3H),0.05(s,3H),0.81–0.91(m,12H),1.21(d,J=6.3Hz,6H),1.24–1.58(m,7H),1.62–1.72(m,3H),2.04–2.26(m,6H),2.32–2.60(m,3H),2.65(dd,J=7.0,18.3Hz,1H),3.69–3.80(m,1H),4.08(q,J=8.0Hz,1H),4.35(d,J=12.0Hz,1H),4.59(d,J=12.0Hz,1H),4.98(七重峰,J=6.3Hz,1H),5.30–5.46(m,2H),5.49–5.62(m,2H),7.23–7.37(m,5H);13C NMR(100MHz):δ-4.7(CH3),-4.5(CH3),14.1(CH3),18.0(C),21.9(CH3),22.6(CH2),24.8(CH2),25.1(CH2),25.3(CH2),25.8(CH3),26.7(CH2),31.8(CH2),34.1(CH2),35.9(CH2),47.7(CH2),53.2(CH),54.0(CH),67.4(CH),70.1(CH2),73.0(CH),79.7(CH),126.5(CH),127.4(CH),127.6(CH),128.3(CH),131.1(CH),132.6(CH),134.2(CH),138.8(C),173.1(C),214.8(C);FTIR(KBr,无水的)3443,2931,2853,1736,1459,1373,1246,1106,972,836cm-1.
实施例64–合成(Z)-7-{(1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-2-((E)-3-羟基辛-1-烯-1-基)-5-氧代环戊基}庚-5-烯酸异丙酯(10.8)
根据实施例1所述的程序,除使用(E)-(3-羟基辛-1-烯-1-基)硼酸(3.8,39mg,0.225mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到(Z)-7-{(1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-2-((E)-3-羟基辛-1-烯-1-基)-5-氧代环戊基}庚-5-烯酸异丙酯(10.8,31mg,40%为非对映异构体对)。
[α]24 D-60.7(c 0.6,CHCl3);1H NMR(400MHz):δ0.03–0.05(m,6H),0.83–0.91(m,12H),1.22(d,J=6.2Hz,6H),1.25–1.34(m,4H),1.34–1.58(m,3H),1.58–1.72(m,3H),1.98–2.20(m,5H),2.22–2.52(m,5H),2.58–2.68(m,1H),4.02(q,J=8.1Hz,1H),4.05–4.17(m,1H), 4.99(七重峰,J=6.2Hz,1H),5.28–5.44(m,2H),5.45–5.68(m,2H);13C NMR(100MHz):δ-4.72(CH3),-4.66(CH3),-4.58(CH3),14.0(CH3),18.0(C),18.1(C),21.8(CH3),22.6(CH2),24.8(CH2),24.9(CH2),25.0(CH2),25.1(CH2),25.3(CH2),25.7(CH3),26.7(CH2),31.77(CH2),31.82(CH2),34.04(CH2),34.09(CH2),37.3(CH2),37.4(CH2),47.62(CH2),47.64(CH2),52.8(CH),53.1(CH),53.8(CH),54.1(CH),67.55(CH),67.60(CH),72.56(CH),72.62(CH),72.92(CH),73.13(CH),126.6(CH),126.7(CH),130.2(CH),130.4(CH),130.9(CH),136.3(CH),137.0(CH),173.3(C),173.4(C),214.9(C);HRMS(ESI-QTOF)计算值[C29H52O5Si+NH4]+=526.3922,实测值526.3924;FTIR(KBr,无水的)3446,2934,2861,1736,1461,1374,1250,1110,968,838cm-1.
实施例65–合成(Z)-7-((1R,2R,3R)-3-[(叔丁基二甲基硅基)氧基]-2-{(S,E)-3-[(叔丁基二甲基硅基)]氧基辛-1-烯-1-基}-5-氧代环戊基)庚-5-烯酸异丙酯(10.9a)
根据实施例1所述的程序,但规模更大,使用2(0.30g,0.79mmol)和(S,E){3-[(叔丁基二甲基硅基)氧基]辛-1-烯-1-基}硼酸(3.9,0.34g,1.19mmol),通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化粗反应混合物,得到标题化合物(10.9a,0.48g,98%)。
[α]26 D-29.6(c 1.00,CHCl3);1H NMR(400MHz):δ0.02(s,3H),0.043(s,3H),0.049(s,3H),0.052(s,3H),0.87(s,9H),0.89(s,9H),1.22(d,J=6.4Hz,6H),1.23–1.35(m,8H),1.35–1.52(m,3H),1.66(五重峰,J=7.5Hz,2H),1.98–2.10(m,3H),2.15(dd,J=8.4,18.2Hz,1H),2.25(t,J=7.6Hz,2H),2.27–2.53(m,3H),2.63(ddd,J=1.1,7.0,18.2Hz,1H),3.98–4.13(m,2H),4.99(七重峰,J=6.4Hz,1H),5.27–5.44(m,2H),5.45–5.63(m,2H);13C NMR(100MHz):δ-4.71(CH3),-4.65(CH3),-4.59(CH3),-4.3(CH3),14.0(CH3),18.0(C),18.2(C),21.8(CH3),22.6(CH2),24.8(CH2),25.1(CH2),25.2(CH2),25.8(CH3),25.9(CH3),26.7(CH2),31.9(CH2),34.1(CH2),38.6(CH2),47.7(CH2),52.7(CH),53.9(CH),67.4(CH),72.6(CH),73.3(CH),126.6(CH),128.6(CH),130.8(CH),136.5(CH),173.1(C),215.4(C);HRMS(ESI-QTOF)计算值[C35H66O5Si2+NH4]+=640.4787,实测值640.4775;FTIR(KBr,无水的)2937,2861,1738,1577,1467,1371,1250,1107,835,774cm-1.
实施例66–合成(Z)-7-((1R,2R,3R,5S)-3-[(叔丁基二甲基硅基)氧基]-2-{(S,E)-3-[(叔丁基二甲基硅基)氧基]辛-1-烯-1-基}-5-羟基环戊基)庚-5-烯酸异丙酯(11.9a)
在-78℃向10.9a(80mg,0.13mmol)的THF(6.4mL)溶液中加入(0.15mL,1.0M,THF中,0.15mmol)溶液。混合物在-78℃搅拌20min,直接在环境温度浓缩以获得残留物,该残留物通过柱层析(1:8(v/v)EtOAc–己烷洗脱)纯化以得到标题化合物(11.9a,61mg,76%)。
[α]23 D-6.3(c 1.00,CHCl3);1H NMR(400MHz):δ0.01(s,3H),0.04(s,3H),0.046(s,3H),0.049(s,3H),0.87(s,9H),0.88(s,9H),1.22(d,J=6.2Hz,6H),1.24–1.52(m,10H),1.67(五重峰,J=7.5Hz,2H),1.72–1.92(m,2H),2.04-2.21(m,3H),2.22–2.39(m,4H),2.68(d,J=9.2Hz,1H),3.96–4.15(m,3H),4.99(七重峰,J=6.2Hz,1H),5.26–5.52(m,4H);13CNMR(100MHz):δ-4.9(CH3),-4.8(CH3),-4.6(CH3),-4.3(CH3),14.0(CH3),17.8(C),18.2(C),21.8(CH3),22.6(CH2),25.0(CH2),25.8(CH3),25.9(CH3),26.6(CH2),26.7(CH2),31.8(CH2),34.1(CH2),38.6(CH2),42.9(CH2),51.8(CH),56.4(CH),67.3(CH),73.2(CH),74.7(CH),80.0(CH),129.2(CH),129.5(CH),130.8(CH),134.4(CH),173.2(C);LRMS(ESI):计算值[C35H68O5Si2]=624.5,实测值624.5;HRMS(ESI-QTOF)计算值[C35H68O5Si2+H]+=625.4678,实测值625.4676;FTIR(KBr,无水的)3433,2936,1722,1636,1457,1250,1088,832,659,503cm-1.
实施例67–合成(Z)-7-((1R,2R,3R,5S)-3-[(叔丁基二甲基硅基)氧基]-2-{(S,E)-3-[(叔丁基二甲基硅基)氧基]辛-1-烯-1-基}-5-羟基环戊基)庚-5-烯酸(12.9a)
室温向化合物11.9a(1.70g,2.7mmol)在MeOH(20mL)中的溶液加入25%NaOMe–MeOH(9.3mL,41mmol),搅拌混合物直至如TLC(1:4EtOAc–正庚烷)指示达到完全转化。加入10%水性NaOH(10mL),50℃加热混合物2小时。溶液冷却到室温,加入10%水性柠檬酸(60mL)。分离层,水层用EtOAc(60mL×3)萃取。合并有机层,用盐水(150mL)洗涤,MgSO4(4.0g)干燥,过滤并减压浓缩。产生的残留物通过在硅胶上柱纯化(51g硅胶;用1:2(v/v)EtOAc–正庚烷(800mL)洗脱)以获得标题化合物12.9a(1.42g,2.44mmol,90%产率)。
[α]20 D+12.09(c 1.0,CH2Cl2);1H NMR(400MHz,CDCl3):δ5.52–5.44(m,2H),5.40–5.32(m,2H),4.14(s,1H,br),4.06(m,2H),2.37–2.28(m,4H),2.27–2.19(m,3H)1.93–1.83(m,2H),1.73(m,2H),1.50–1.10(m,3H),1.27(m,7H),0.89(m,21H),0.07–0.03(m,12H);13CNMR(100MHz,CDCl3):δ179.1,134.4,130.7,129.6,129.0,80.0,74.7,73.2,56.4,51.8,42.8,38.5,33.4,31.8,26.6,26.5,25.9(×3),25.8(×3),25.0,24.6,22.6,18.2,17.8,14.0,-4.3,-4.6,-4.8,-4.9;HRMS(ESI-QTOF)计算值[C32H62O5Si2+Na]+=605.4028,实测值605.4018;FTIR(KBr,无水的)2955,2928,2856,1710,1472,1463,1361,1251,1082,870,835cm-1.
实施例68–合成地诺前列素(PGF2α;12.9)
室温下将水性HCl(3N,6.3mL,19mmol)加入搅拌的化合物12.9a(1.1g,1.9mmol)在THF(19mL)中的溶液。6小时后,反应溶液用饱和水性NaHCO3(30mL)中和并用EtOAc(40mL×2)萃取。合并有机层,用饱和水性NaCl(50mL)洗涤,MgSO4干燥,过滤并减压浓缩。产物在硅胶上通过柱层析(33g硅胶;用1:20(v/v)MeOH–CH2Cl2(300mL)然后用1:5(500mL)洗脱)纯化以获得地诺前列腺素,为无色油(12.9,595mg,89%)。
[α]20 D+23.7(c 0.50,THF);1H NMR(400MHz,MeOD):δ5.55–5.43(m,3H),5.38–5.31(m,1H),4.10(td,J=5.6,2.0Hz,1H),4.01(dd,J=12.8,6.4Hz,1H),3.83(ddd,J=7.6,5.6,5.2Hz,1H),2.36–2.26(m,1H),2.26–2.20(m,3H),2.18–2.15(m,1H),2.14–2.07(m,3H),1.69–1.58(m,4H),1.57–1.53(m,2H),1.51–1.29(m,6H),0.91(t,J=6.8Hz,3H);13CNMR(100MHz,MeOD):δ178.5,136.6,134.3,130.5,130.4,77.9,74.1,72.3,56.2,50.9,44.4,38.5,35.0,33.1,27.8,26.5,26.3(×2),23.9,14.6;HRMS(ESI-QTOF)计算值[C20H34O5+Na]+=377.2298,实测值377.2298;FTIR(KBr,无水的)3346,3006,2954,2930,2858,1708,1550,1456,1409,1237,1081,1053,1025,969cm-1.
实施例69–合成(Z)-7-{(1R,2S,3R)-3-[(叔丁基二甲基硅基)氧基]-2-(环己-1-烯-1-基)-5-氧代环戊基}庚-5-烯酸异丙酯(10.20)
根据实施例1所述的程序,用环己-1-烯-1-基硼酸(28mg,0.225mmol)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物(10.20,26mg,38%)。
1H NMR(400MHz,CDCl3):δ0.02(s,3H),0.03(s,3H),0.87(s,9H),1.22(d,J=6.2Hz,6H),1.58–1.70(m,6H),1.85–1.95(m,2H),1.98–2.08(m,4H),2.09–2.31(m,6H),2.38(dd,J=8.5,12.4Hz,1H),2.64(dd,J=7.2,18.5Hz,1H),4.11(q,J=8.4Hz,1H),5.00(七重峰,J=6.2Hz,1H),5.29–5.52(m,2H),5.45–5.60(m,1H);HRMS(ESI-TOF)计算值[C27H46O4Si+H]+=463.3238,实测值463.3240.
实施例70–合成(E)-7-{3-[(叔丁基二甲基硅基)氧基]-5-氧代-2-苯乙烯基环戊基}庚酸甲酯(Iba)
根据实施例1所述的程序,用7-{3-[(叔丁基二甲基硅基)氧基]-5-氧代环戊-1-烯-1-基}庚酸甲酯(IIba,53mg,0.15mmol)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物(Iba,36mg,53%)。
1H NMR(400MHz,CDCl3):δ0.01(s,3H),0.02(s,3H),0.86(s,9H),1.22–1.33(m,6H),1.35–1.48(m,1H),1.50–1.70(m,3H),2.02–2.12(m,1H),2.19–2.30(m,3H),2.54–2.73(m,2H),3.64(s,3H),4.11(q,J=8.5Hz,1H),6.05(dd,J=8.6,15.8Hz,1H),6.52(d,J=15.8Hz,1H),7.22–7.26(m,1H),7.30–7.38(m,4H);HRMS(ESI-TOF)计算值[C27H42O4Si+H]+=459.2925,实测值459.2930.
实施例71–合成(E)-7-{5-氧代-2-苯乙烯基-3-[(四氢-2H-吡喃-2-基)氧基]环戊基}庚酸甲酯(Ibb)
根据实施例1所述的程序,用7-{5-氧代-3-[(四氢-2H-吡喃-2-基)氧基]环戊-1-烯-1-基}庚酸甲酯(IIbb,49mg,0.15mmol)合成标题化合物。然后将粗产物混合物通过柱层析(用1:80(v/v)的丙酮-己烷洗脱)纯化,得到标题化合物(Ibb,20mg,31%),为在乙缩醛碳中心的非对映异构体的1:1混合物。
1H NMR(400MHz,CDCl3):δ1.21–1.36(m,6H),1.38–1.82(m,9H),2.03–2.12(m,1H),2.17(dd,J=8.8,18.4Hz,1H),2.26(td,J=1.5,7.5Hz,2H),2.36(dd,J=9.0,18.7Hz,1H),2.64–2.87(m,2H),3.37–3.52(m,1H),3.64(s,3H),3.77–3.88(m,1H),4.11(q,J=8.6Hz,0.5H),4.27(q,J=8.7Hz,0.5H),4.68–4.77(m,1H),6.09–6.23(m,1H),6.50–6.63(m,1H),7.20–7.25(m,1H),7.29–7.42(m,4H);HRMS(ESI-TOF)计算值[C26H36O5+Na]+=451.2455,实测值451.2459.
实施例72–合成(Z)-7-[(1R,2R,3R)-3-羟基-5-氧代-2-((E)-苯乙烯基)环戊基]庚-5-烯酸异丙酯(Iaa)
(R,Z)-7-(3-羟基-5-氧代环戊-1-烯-1-基)庚-5-烯酸异丙酯(IIaa,50mg,0.19mmol)、3.1(45mg,0.22mmol)、[RhCl(1,5-环辛二烯)]2(1.4mg,2.8μmol)和水性KOH(11.9μL,3.0M水性KOH,36μmmol)在MeOH(1.0mL)中的溶液在微波照射下搅拌(CEM,Discover S;或Milestone,Startsynth;温度设为30℃)。用柱层析(用1:20(v/v)丙酮-己烷洗脱)纯化残留物得到标题化合物(Iaa,27mg,39%)。
1H NMR(400MHz,CDCl3):δ1.19(d,J=6.2Hz,6H),1.58–1.73(m,2H),1.94(br,1H),2.04(q,J=7.2Hz,2H),2.20(t,J=7.6Hz,2H),2.32–2.54(m,4H),2.56–2.65(m,1H),2.72–2.81(m,1H),4.48(t,J=4.2Hz,1H),4.96(七重峰,J=6.2Hz,1H),5.25–5.45(m,2H),6.34(dd,J=7.9,16.1Hz,1H),6.57(d,J=16.1Hz,1H),7.23–7.28(m,1H),7.31–7.41(m,4H);HRMS(EI)计算值[C23H30O4]+=370.2139,实测值370.2141.
实施例73–合成(E)-7-[3-(烯丙基氧基)-5-氧代-2-苯乙烯基环戊基]庚酸甲酯(Ibc)
根据实施例1所述的程序,用7-[3-(烯丙基氧基)-5-氧代环戊-1-烯-1-基]庚酸甲酯(IIbc,42mg,0.15mmol)合成标题化合物。在硅胶柱上过滤粗产物混合物,然后用1H NMR谱分析,显示标题化合物Ibc产率为2%。
HRMS(ESI-TOF)计算值[C24H32O4+H]+=385.2373,实测值385.2375.
虽然出于清楚理解的目的,以阐释和实施例的方式详细描述了前述发明,但本领域技术人员将理解可在所附权利要求书的范围内实施某些改变和改动。此外,本文提供的每一篇参考文献均通过引用以其整体纳入本文,如同每一篇文献通过引用单独纳入本文一样。当本申请和本文提供的参考文献存在冲突时,以本申请为准。
Claims (22)
1.一种制备式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物的方法
所述方法包括在含有金属添加剂的溶剂中,任选地在碱性添加剂存在下,将式II所示的2-取代-4-氧基-环戊-2-烯-1-酮化合物
与式III所示的化合物接触
以产生式I所示的化合物;其中,所述金属添加剂以亚化学计量的量使用;
其中,
R1、R3、R4和R5独立地代表氢、芳基、杂芳基、烷基、芳基烷基、芳氧基烷基、烯基、或炔基;或者R3和R5一起形成5-至7-元碳环,任选地具有一个或两个杂原子作为环顶点,其中所述杂原子选自下组:O、N和S;或者R3和R4一起形成5-至7-元碳环,任选地具有一个或两个杂原子作为环顶点,其中所述杂原子选自下组:O、N和S,并且其中R1、R3、R4和R5各任选地被选自下组的1至3个成员取代:卤素、羟基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、硅氧基、芳氧基、酰氧基、5-至7-元杂环、氧代、COOH、CONH2、CONHC1-4烷基、C(O)OCH2C6-10芳基、C(O)OC6-10芳基和C(O)OC1-4烷基;
R2代表氢或羟基-保护基团;
X代表含硼基团。
2.如权利要求1所述的方法,其特征在于,式I所示的化合物是
3.如权利要求1所述的方法,其特征在于,R3是烷基、芳基、芳基烷基或芳氧基烷基,各任选被选自下组的1至3个成员取代:C1-4烷基、C1-4烷氧基、硅氧基、芳氧基、酰氧基、四氢吡喃基(THP)、三氟甲基和氟。
4.如权利要求1所述的方法,其特征在于,所述溶剂选自下组:水、甲醇、乙醇、异丙醇、异丁醇、1,4–二氧六环、甲苯、四氢呋喃(THF)、2-甲基-四氢呋喃(2-Me-THF)、二甘醇二甲醚、乙腈、N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMAC)、乙二醇及它们的组合。
5.如权利要求4所述的方法,其特征在于,所述溶剂是甲醇。
6.如权利要求1所述的方法,其特征在于,所述金属添加剂选自下组:铑化合物、钴化合物、镍化合物及它们的组合。
7.如权利要求6所述的方法,其特征在于,所述铑化合物是选自下组的铑(I)化合物:[RhCl(1,5-环辛二烯)]2、[RhCl(C2H4)2]2、具有二烯配体添加物的[RhCl(C2H4)2]2、[RhCl(降冰片二烯)]2、[Rh(OH)(1,5-环辛二烯)]2及它们的组合。
8.如权利要求7所述的方法,其特征在于,所述铑(I)化合物选自下组:[RhCl(1,5-环辛二烯)]2和[Rh(OH)(1,5-环辛二烯)]2。
9.如权利要求1所述的方法,其特征在于,所述碱性添加剂选自下组:KHF2、t-BuOLi、t-BuONa、t-BuOK、K3PO4、K2CO3、Cs2CO3、LiOH、NaOH、KOH、CsOH、KF、CsF、NaHCO3、KH2PO4、1,3-二氨基丙烷、t-BuNH2、i-Pr2NH、哌啶、Et3N、2,6-卢剔啶和它们的组合。
10.如权利要求9所述的方法,其特征在于,所述碱性添加剂是氢氧化钾。
11.如权利要求1所述的方法,其特征在于,所述羟基-保护基团选自下组:四氢吡喃基(THP),甲氧基甲基(MOM),[2-(三甲基硅基)乙氧基]甲基(SEM),三烷基硅基,三芳基硅基,二芳基烷基硅基,苄基,4-甲氧基苄基(PMB),烷基羰基,芳基羰基和烯丙基。
12.如权利要求11所述的方法,其特征在于,所述三烷基硅基是叔丁基二甲基硅基(TBS)。
13.如权利要求1所述的方法,其特征在于,所述含硼基团X选自下组:B(OH)2,B(OR)2其中R为烷基或芳基,BR2其中R是烷基,BR2其中R是乙烯基,BR2其中R是羧酸基团,BR其中R是双齿羧酸基团,BR2其中R是芳氧基,BR其中R是双齿芳氧基,9-硼双环[3.3.1]壬烷(9-BBN)基团,BF3M其中M为金属离子,BF3M其中M是铵或磷鎓离子,和BR3M其中R是乙烯基且其中M是金属离子或是铵或磷鎓离子。
14.如权利要求13所述的方法,其特征在于,所述含硼基团X选自下组:B(OH)2和BF3M,其中M是金属离子。
15.如权利要求1所述的方法,其特征在于,所述方法在0至80℃的温度进行。
16.如权利要求1所述的方法,其特征在于,所述碱性添加剂以亚化学计量的量使用。
17.如权利要求1所述的方法,还包括将式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物转化为曲伏前列素、比马前列素、鲁比前列酮、地诺前列素、地诺前列酮、他氟前列素、卡波前列素、前列地尔、拉坦前列素或乌诺前列酮异丙酯。
18.如权利要求1所述的方法,其特征在于,所述式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物是式10.9a所示的化合物:
19.如权利要求1所述的方法,其特征在于,所述式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物是式10.17所示的化合物:
20.如权利要求1所述的方法,其特征在于,所述式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物是式10.18所示的化合物:
21.如权利要求1所述的方法,其特征在于,所述式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物是式10.7所示的化合物:
22.如权利要求1所述的方法,其特征在于,所述式I所示的2,3-二取代-4-氧基-环戊烷-1-酮化合物是式10.19所示的化合物:
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TW201602074A (zh) | 2016-01-16 |
EP3166918B1 (en) | 2019-02-20 |
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WO2016005943A1 (en) | 2016-01-14 |
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