CN112125803B - Preparation of homoallylic alcohol compound, synthetic method and application thereof - Google Patents
Preparation of homoallylic alcohol compound, synthetic method and application thereof Download PDFInfo
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- CN112125803B CN112125803B CN202010985993.8A CN202010985993A CN112125803B CN 112125803 B CN112125803 B CN 112125803B CN 202010985993 A CN202010985993 A CN 202010985993A CN 112125803 B CN112125803 B CN 112125803B
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- alcohol compound
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- cdcl3
- homoallylic
- aldehyde
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- -1 alcohol compound Chemical class 0.000 title claims abstract description 26
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title description 3
- 239000010936 titanium Substances 0.000 claims abstract description 15
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical class C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000001212 derivatisation Methods 0.000 claims abstract description 12
- 150000001299 aldehydes Chemical class 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 9
- 229910052719 titanium Inorganic materials 0.000 claims abstract description 9
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000011261 inert gas Substances 0.000 claims abstract description 6
- 150000002576 ketones Chemical class 0.000 claims abstract description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- SMEROWZSTRWXGI-UHFFFAOYSA-N Lithocholsaeure Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 SMEROWZSTRWXGI-UHFFFAOYSA-N 0.000 claims description 11
- SMEROWZSTRWXGI-HVATVPOCSA-N lithocholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 SMEROWZSTRWXGI-HVATVPOCSA-N 0.000 claims description 11
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 claims description 10
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 claims description 10
- 229960003399 estrone Drugs 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- MKNXBRLZBFVUPV-UHFFFAOYSA-L cyclopenta-1,3-diene;dichlorotitanium Chemical group Cl[Ti]Cl.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 MKNXBRLZBFVUPV-UHFFFAOYSA-L 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000005286 illumination Methods 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 239000013543 active substance Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- LJXTYJXBORAIHX-UHFFFAOYSA-N diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical group CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1 LJXTYJXBORAIHX-UHFFFAOYSA-N 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000001308 synthesis method Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 17
- 229930014626 natural product Natural products 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 32
- 238000002474 experimental method Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 239000007788 liquid Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 13
- 238000004293 19F NMR spectroscopy Methods 0.000 description 11
- PRWATGACIORDEL-UHFFFAOYSA-N 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile Chemical compound C12=CC=CC=C2C2=CC=CC=C2N1C1=C(C#N)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C(N2C3=CC=CC=C3C3=CC=CC=C32)C(N2C3=CC=CC=C3C3=CC=CC=C32)=C1C#N PRWATGACIORDEL-UHFFFAOYSA-N 0.000 description 7
- 239000005445 natural material Substances 0.000 description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical group C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 4
- 239000003613 bile acid Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000010791 quenching Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 229910010068 TiCl2 Inorganic materials 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000027756 respiratory electron transport chain Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- WMDHQEHPOVOEOG-UHFFFAOYSA-N 2-(2-bromoethyl)-1,3-dioxane Chemical compound BrCCC1OCCCO1 WMDHQEHPOVOEOG-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 206010027304 Menopausal symptoms Diseases 0.000 description 1
- 208000019255 Menstrual disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010063146 Uterine hypoplasia Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- ULNDTPIRBQGESN-UHFFFAOYSA-N ethyl 2-bromo-2-fluoroacetate Chemical group CCOC(=O)C(F)Br ULNDTPIRBQGESN-UHFFFAOYSA-N 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001443 photoexcitation Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- CMWCOKOTCLFJOP-UHFFFAOYSA-N titanium(3+) Chemical compound [Ti+3] CMWCOKOTCLFJOP-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C33/40—Halogenated unsaturated alcohols
- C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
- C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
- C07C33/483—Monocyclic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/178—Unsaturated ethers containing hydroxy or O-metal groups
- C07C43/1787—Unsaturated ethers containing hydroxy or O-metal groups containing six-membered aromatic rings and having unsaturation outside the aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- 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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
- C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a homoallylic alcohol compound, a synthetic method and application thereof, belonging to the field of organic chemistry. Under the protection of inert gas at room temperature and in the presence of an organic photosensitizer, a titanium catalyst and an electron donor, aldehyde or ketone reacts with the 1, 3-butadiene derivative and halogenated alkane under the irradiation of blue light to obtain the homoallyl alcohol compound with high selectivity. The method has the advantages of mild reaction conditions, short reaction steps, simple post-treatment, and high stereoselectivity and regional selection of reaction products. Meanwhile, the method can be used for derivatization of natural products.
Description
Technical Field
The invention belongs to the field of organic synthesis, and relates to a homoallyl alcohol compound, a synthesis method and application thereof.
Background
Homoallylic compounds are important components in the synthesis of various drugs and natural substances with biological activity. The addition of allyl metal complexes to the carbonyl group is one of the most efficient methods for obtaining homoallyl alcohols, which has prompted the rapid development of synthetic and pharmaceutical chemistry over the last decades. However, the preparation process which relies on preactivated allylhalohydrocarbons and stoichiometric amounts of metal reducing agents is cumbersome and uneconomical, which limits its use. Therefore, the simple, economical and environment-friendly synthetic method of the homoallylic alcohol compound is developed, and the homoallylic alcohol compound is applied to the synthesis of natural substances with biological activity, and has great promotion effect on synthetic chemistry and pharmaceutical chemistry.
Disclosure of Invention
The invention provides a homoallylic alcohol compound, a synthetic method and application thereof. Under the conditions of room temperature and inert gas protection, illumination, organic photosensitizer, titanium catalyst and electron donor, the halogenated alkane, the 1, 3-butadiene derivative and aldehyde or ketone react to obtain the homoallyl alcohol compound with high selectivity.
The technical scheme adopted by the invention is as follows:
a homoallylic alcohol compound has the following structure:
wherein R is1、R2、R4、R5、R6And R7Each independently selected from hydrogen, C1-C8 alkyl, phenyl, substituted phenyl, naphthyl, benzyl, or heterocyclyl; the substituent in the substituted phenyl is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, C1-C3 alkoxycarbonyl and amino; r3Is C3-C9 alkyl.
The invention also provides a synthetic method of the homoallylic alcohol compound, and the synthetic route is as follows:
the method comprises the following steps: under the conditions of room temperature and inert gas protection, illumination, organic photosensitizer, titanium catalyst and electron donor, halogenated alkane 1 reacts with 1, 3-butadiene derivative 2 and aldehyde or ketone 3 in a solvent to obtain a homoallylic alcohol compound 4; wherein R is1、R2、R3、R4、R5,R6,R7Substituent andas in claim 1.
The organic photosensitizer may be 4 CzIPN.
The titanium catalyst may be titanocene dichloride (Cp)2TiCl2)。
The electron donor may be diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate (HE).
The molar ratio of the halogenated alkane 1, the 1, 3-butadiene derivative 2, the aldehyde or ketone 3, the organic photosensitizer, the titanium catalyst and the HE is 2.0:2.0:1.0:0.01:0.05: 2.0.
The solvent is Tetrahydrofuran (THF).
Based on homoallylation of various compounds and high yield derivatization of natural active substances (such as lithocholic acid and estrone), the method of the invention can be applied to derivatization of natural substances with biological activity, and has a promoting effect on the development of synthetic chemistry and pharmaceutical chemistry.
The method has the advantages of mild reaction conditions, short reaction steps, simple post-treatment, environmental friendliness, suitability for aldehyde ketone and aldehyde ketone reaction substrates, high reaction yield and high selectivity. Meanwhile, the reaction has better application in derivatization of natural active substances.
Drawings
FIG. 1 is a schematic representation of Cp2TiCl2 quenched 4 CzIPN.
FIG. 2 schematic representation of HE quenching 4 CzIPN.
FIG. 3 schematic representation of BrCF2COOEt quenching 4 CzIPN.
Fig. 4 is a schematic diagram of a light/dark experiment.
In the figure: i0 is fluorescence intensity without addition of quencher; i is the fluorescence intensity after addition of the quencher.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to the following specific examples.
Exploration test of reaction conditions: (taking the example of the reaction of 1a, 1, 3-butadiene and 3a to give 4 a)
Typically, the reaction was carried out by reacting compound 1a (2.0mmol), compound 2(2.0mmol), compound 3a (1.0mmol), and Cp2TiCl2(0.05mmol), 4CzIPN (0.01mmol), HE (2.0mmol) and 5mL THF are mixed, and the reaction is irradiated by a 10W 450nm LED lamp for 5h at room temperature under the protection of inert gas, and a thin layer plate (TLC) monitors the complete disappearance of the raw material 3a (5 h); the solvent was dried by spin-drying and column chromatography (eluent petroleum ether/ethyl acetate 20/1) gave colorless liquid 4 a.
The reaction equation is as follows:
as shown in the table, the boundary conditions of the reaction were investigated, and it was found that the target product was obtained in different yields under all other possible reaction conditions. Finally, the optimal reaction conditions are determined as follows: 4CzIPN is used as photosensitizer and Cp in Tetrahydrofuran (THF) solvent under the protection of inert gas at room temperature2TiCl2As catalyst, HE as electron donor, and irradiation with 450nm LED lamp.
Example 1:
the experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 20/1, 92% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.35–7.27(m,2H),7.24–7.17(m,3H),5.71(dt,J=17.2,9.8Hz,1H),5.23–5.08(m,2H),4.28(q,J=7.1Hz,2H),3.62(dt,J=8.3,4.2Hz,1H),2.88–2.58(m,2H),2.51–2.41(m,1H),2.40–2.24(m,2H),2.01(s,1H),1.84–1.65(m,2H),1.34(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ164.08(t,J=33.0Hz),141.62,135.77,128.35,128.29,125.84,118.55,116.57(dd,J=249.2,248.7Hz),72.91,62.67,43.59(dd,J=4.3,2.3Hz),36.24,35.89(t,J=22.7Hz),32.05,13.73.19F NMR(377MHz,CDCl3)δ-101.44(dt,J=261.5,15.0Hz,1F),-105.06(dt,J=260.7,17.9Hz,1F).HRMS-ESI(m/z)[M+Na]+calculated for C17H22F2NaO3,335.1435,found 335.1431.
Example 2:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 20/1, 71% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ5.75(dt,J=18.3,9.3Hz,1H),5.24–4.97(m,2H),4.26(q,J=7.1Hz,2H),2.76(dd,J=9.0,4.2Hz,1H),2.53(dq,J=9.1,4.6Hz,1H),2.47–2.16(m,2H),1.87(s,1H),1.32(t,J=7.1Hz,3H),1.01–0.83(m,1H),0.68–0.40(m,2H),0.37–0.10(m,2H).13C NMR(101MHz,CDCl3)δ164.13(t,J=32.7Hz),136.55,118.19,116.15(dd,J=251.7,248.9Hz),78.85,62.64,44.22(dd,J=4.9,2.5Hz),35.87(t,J=22.8Hz),15.17,13.81,3.12,2.73.19F NMR(377MHz,CDCl3)δ-101.43(dt,J=261.5,15.0Hz,1F),-105.04(dt,J=260.7,17.9Hz,1F).HRMS-ESI(m/z)[M+Na]+calculated for C12H18F2NaO3,271.1122,found 271.1137.
Example 3:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 20/1, 74% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ5.77–5.51(m,1H),5.22–5.12(m,3H),4.27(q,J=7.1Hz,2H),4.21(dd,J=9.0,6.5Hz,1H),2.38(ddt,J=12.9,6.2,2.9Hz,1H),2.34–2.22(m,1H),2.21–2.07(m,1H),1.76(d,J=1.4Hz,3H),1.73(dd,J=3.3,1.4Hz,1H),1.69(d,J=1.4Hz,3H),1.34(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ164.10(t,J=32.8Hz),137.74,136.95,124.51,119.11,116.06(dd,J=252.0,249.0Hz),69.95,62.70,44.94(dd,J=4.7,2.7Hz),35.33(t,J=22.9Hz),25.93,18.48,13.89.19F NMR(377MHz,CDCl3)δ-100.34(t,J=14.8Hz),-101.04(t,J=14.6Hz),-104.02(t,J=18.0Hz),-104.71(t,J=17.8Hz).HRMS-ESI(m/z)[M+Na]+calculated for C13H20F2NaO3,285.1278,found 285.1268.
Example 4:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 20/1, 77% yield, the product was a colorless liquid.1H NMR(400MHz,CDCl3)δ5.87–5.76(m,1H),5.02–4.97(m,2H),4.20(q,J=7.1Hz,2H),3.23–3.19(m,1H),2.39–2.12(m,2H),2.02(d,J=6.9Hz,1H),1.26(t,J=7.2Hz,3H),0.85(s,9H).13C NMR(101MHz,CDCl3)δ165.76,164.41–163.51(m),136.87(s),117.11(s),116.07(dd,J=251.8,248.4Hz),62.47(s),39.56(dd,J=4.9,2.1Hz),38.99(t,J=22.2Hz),35.84(s),26.48(s),13.71(s).19F NMR(377MHz,CDCl3)δ-100.30(t,J=14.7Hz),-100.99(t,J=14.7Hz),-105.79(dd,J=20.4,17.0Hz),-106.49(dd,J=20.6,16.9Hz).HRMS-ESI(m/z)[M+Na]+calculated for C13H22F2NaO3,287.1435,found 287.1426.
Example 5:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 15/1, 79% yield, the product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.42–7.09(m,5H),5.55(dt,J=17.1,9.7Hz,1H),5.17–4.91(m,2H),4.48(d,J=6.4Hz,1H),4.16(qd,J=7.2,1.9Hz,2H),2.60(dq,J=8.9,6.6Hz,1H),2.18(s,1H),2.15–2.02(m,2H),1.23(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ164.00(t,J=32.8Hz),141.19,136.44,128.42,128.02,126.71,119.47,118.61–112.81(m),75.96,62.75,45.97(dd,J=4.6,2.7Hz),35.47(t,J=23.0Hz),13.86.19F NMR(377MHz,CDCl3)δ-100.90(t,J=14.9Hz),-101.59(t,J=15.0Hz),-104.48(t,J=17.6Hz),-105.17(t,J=17.7Hz).HRMS-ESI(m/z)[M+Na]+calculated for C15H18F2NaO3,307.1122,found 307.1118.
Example 6:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 15/1, 81% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.40–7.31(m,2H),6.34(d,J=1.8Hz,1H),5.61(dt,J=17.0,9.7Hz,1H),5.22–5.05(m,2H),4.54(d,J=6.1Hz,1H),4.23(q,J=7.2Hz,2H),2.70–2.56(m,1H),2.33–2.02(m,2H),1.29(td,J=7.2,1.3Hz,3H).13C NMR(101MHz,CDCl3)δ164.04(t,J=32.7Hz),143.42,140.08,136.46,125.99,119.33,115.99(dd,J=251.9,249.3Hz),108.64,68.96,62.79,44.78(dd,J=4.7,2.6Hz),35.25(t,J=23.0Hz),13.80.19F NMR(377MHz,CDCl3)δ-101.04(t,J=15.0Hz),-101.74(t,J=15.0Hz),-104.57(t,J=17.9Hz),-105.26(t,J=17.9Hz).HRMS-ESI(m/z)[M+Na]+calculated for C13H16F2NaO4,297.0914found 297.0899.
Example 7:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:2), eluent: petroleum ether/ethyl acetate 10/1% yield, the product being a colorless liquid.1H NMR(400MHz,CDCl3)δ5.67–5.50(m,1H),5.22–5.03(m,2H),4.23(q,J=7.2Hz,2H),3.80–3.61(m,4H),2.53–2.35(m,1H),2.28–2.04(m,2H),1.85–1.70(m,2H),1.69–1.57(m,1H),1.42–1.33(m,1H),1.31(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ164.02(t,J=32.7Hz),135.97,119.46,116.22(dd,J=251.8,248.7Hz),69.76,63.36,63.34,62.66,49.07(dd,J=5.1,2.2Hz),35.44,34.32,33.18(t,J=22.9Hz),13.77.19F NMR(377MHz,CDCl3)δ-100.53–-101.42(m,1F),-104.73–-105.65(m,1F).HRMS-ESI(m/z)[M+Na]+calculated for C13H20F2NaO4,301.1227,found 301.1219.
Example 8:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 15/1, 62% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.11(d,J=8.5Hz,2H),6.83(d,J=8.6Hz,2H),5.67(dt,J=17.0,9.9Hz,1H),5.23–5.10(m,2H),4.26(q,J=7.2Hz,2H),3.79(s,3H),2.70–2.58(m,2H),2.49–2.35(m,2H),2.28–2.09(m,1H),1.77–1.68(m,2H),1.56(s,1H),1.33(t,J=7.2Hz,3H),1.22(s,3H).13C NMR(101MHz,CDCl3)δ164.13(t,J=34.2Hz),157.81,136.69,134.24,129.21,119.52,115.76(dd,J=280.8,250.3Hz),113.89,72.98,62.69,55.25,48.08(dd,J=4.6,2.6Hz),41.28,34.43(t,J=22.9Hz),28.66,24.72,13.87.19F NMR(377MHz,CDCl3)δ-100.49–-101.72(m,1F),-104.39–-105.58(m,1F).HRMS-ESI(m/z)[M+Na]+calculated for C19H26F2NaO4,379.1697,found 379.1703.
Example 9:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE ═ 1:3), eluent: petroleum ether/ethyl acetate 15/1, 61% yield, the product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.35–7.25(m,4H),7.24–7.15(m,1H),5.43(dt,J=18.4,9.5Hz,1H),5.17–5.01(m,2H),4.13(qd,J=7.1,3.4Hz,2H),2.63–2.48(m,1H),2.33(tdd,J=16.2,14.6,2.1Hz,1H),1.91(s,1H),1.89–1.74(m,1H),1.51(s,3H),1.21(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ164.34(t,J=32.7Hz),144.62,136.80,128.07,127.19,125.81,119.44,116.16(dd,J=249.4,237.7Hz),75.03,62.58,49.89(dd,J=4.6,2.8Hz),34.24(t,J=22.9Hz),26.85,13.81.19F NMR(377MHz,CDCl3)δ-100.07–-101.84(m,1F),-104.26–-105.78(m,1F).HRMS-ESI(m/z)[M+Na]+calculated for C16H20F2NaO3,321.1278,found 321.1281.
Example 10:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 15/1, 52% yield, the product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.89–7.77(m,1H),7.77–7.65(m,1H),7.40–7.27(m,2H),7.15(s,1H),5.69(dt,J=17.2,9.8Hz,1H),5.30–5.19(m,2H),4.19(p,J=7.3Hz,2H),2.78–2.65(m,1H),2.60–2.44(m,1H),2.43(s,1H),2.19–1.98(m,1H),1.68(s,3H),1.26(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ163.95(t,J=32.8Hz),150.24,139.48,139.43,136.08,124.28,124.20,123.45,122.19,120.72,120.37,116.00(dd,J=252.2,249.4Hz),74.76,62.67,50.15(dd,J=4.3,3.0Hz),34.57(t,J=23.1Hz),27.58,13.75.19F NMR(377MHz,CDCl3)δ-101.51(ddd,J=261.1,16.7,13.4Hz,1F),-104.41(ddd,J=260.3,19.0,15.3Hz,1F).HRMS-ESI(m/z)[M+Na]+calculated for C18H20F2NaO3S,377.0999,found 377.0999.
Example 11:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 10/1, 55% yield, the product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.39–7.26(m,7H),7.22–7.15(m,3H),5.73(dt,J=17.3,9.7Hz,1H),5.19–5.05(m,2H),4.58(d,J=2.3Hz,2H),3.68–3.51(m,3H),2.80(ddd,J=13.7,9.8,5.8Hz,1H),2.65(ddd,J=13.7,9.6,6.7Hz,1H),2.44(tt,J=9.0,4.5Hz,1H),2.29–2.00(m,2H),1.84–1.65(m,2H),1.60(d,J=5.1Hz,1H).13C NMR(101MHz,CDCl3)δ141.90,137.33,137.11,128.50,128.41,128.03,127.88,125.87,118.02,73.70,72.85,70.59(t,J=32.7Hz),43.94(t,J=3.2Hz),36.42,34.99(t,J=22.9Hz),32.20.19F NMR(377MHz,CDCl3)δ-100.33–-101.35(m,1F),-101.45–-102.44(m,1F).HRMS-ESI(m/z)[M+Na]+calculated for C22H26F2NaO2,383.1799,found 383.1797.
Example 12:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent:petroleum ether/ethyl acetate 20/1, 59% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.29(t,J=7.6Hz,2H),7.25–7.15(m,3H),5.87(dt,J=56.8,3.4Hz,1H),5.72–5.55(m,1H),5.19(dd,J=44.4,13.7Hz,2H),3.53(dd,J=7.4,3.9Hz,1H),2.98–2.53(m,2H),2.05(h,J=4.9,4.1Hz,1H),1.90–1.58(m,5H),1.55–1.42(m,1H).13C NMR(101MHz,CDCl3)δ141.93,137.32,128.42,125.88,119.04,117.67(t,J=238.9Hz),77.32,77.00,76.68,73.01,49.88,36.57,32.12,32.08(t,J=20.7Hz),23.11.HRMS-ESI(m/z)[M+Na]+calculated for C15H20F2NaO,277.1380,found 277.1384.
Example 13:
by usingReplacement ofThe experimental procedures and purification were carried out according to the search experiment. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 20/1, 58% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.42–7.35(m,2H),7.33–7.27(m,3H),5.74(ddd,J=17.2,10.3,9.3Hz,1H),5.38–5.13(m,2H),3.69–3.51(m,1H),2.98–2.69(m,2H),2.44–2.20(m,2H),2.19–2.09(m,1H),1.98–1.77(m,4H),1.53(s,9H).13C NMR(101MHz,CDCl3)δ173.11,142.13,137.66,128.43,128.34,125.75,118.62,80.22,72.63,50.05,36.52,33.27,32.13,28.07,25.88.HRMS-ESI(m/z)[M+Na]+calculated for C19H28NaO3,327.1936,found 327.1936.
Example 14:
derivatization of lithocholic acid
Lithocholic acid is a secondary bile acid, also known as cholalic acid, 3 a-dihydroxy -carboxylic acid, and is present in higher vertebrate bile. The molecular structure of the bile acid contains both hydrophilic groups and hydrophobic groups, so that the spatial configuration of the bile acid has two properties of hydrophilicity and hydrophobicity, and the bile acid has strong interfacial activity. Meanwhile, lithocholic acid has more pharmacological activities, such as: inhibiting tumor growth, selectively killing breast cancer cells, and selectively inhibiting the activity of mammalian DNA polymerase.
The steps of the derivatization of lithocholic acid in the invention are as follows:
first, reaction of lithocholic acid with p-hydroxybenzaldehyde derivatizes lithocholic acid to aldehyde:
and reacting the derived aldehyde with 1, 3-butadiene and ethyl difluorobromoacetate to obtain the homoallyl alcohol compound derived from lithocholic acid.
And (3) derivatization of lithocholic acid to obtain a homoallyl alcohol compound. RF 0.4(EA: PE 1:3), eluent: petroleum ether/ethyl acetate 5/1% yield, the product being a colorless liquid.1H NMR(400MHz,CDCl3)δ7.31(d,J=8.5Hz,2H),7.06(d,J=8.5Hz,2H),5.69–5.55(m,1H),5.24–5.06(m,2H),4.59(d,J=6.0Hz,1H),4.24(q,J=6.6,6.2Hz,2H),3.61(dt,J=11.0,6.2Hz,1H),2.73–2.53(m,2H),2.53–2.40(m,1H),2.37–2.27(m,1H),2.25–2.09(m,2H),2.01–1.72(m,6H),1.72–1.46(m,7H),1.44–1.34(m,5H),1.34–1.23(m,7H),1.19–1.02(m,5H),0.97(d,J=6.3Hz,3H),0.91(s,3H),0.66(s,3H).13C NMR(101MHz,CDCl3)δ172.69,163.95(t,J=32.7Hz),150.33,138.63,136.12,128.30,127.68,121.48,119.55,115.90(dd,J=250.3,249.5Hz),75.39,71.83,62.76,56.45,55.89,45.81(dd,J=4.3,2.3Hz),42.73,42.02,40.37,40.12,36.36,35.79,35.33,35.32(t,J=28.5Hz),34.52,31.32,30.89,30.46,29.07,27.13,26.37,24.17,23.33,23.06,20.78,18.27,13.84,12.03.HRMS-ESI(m/z)[M+Na]+calculated for C39H56F2NaO6681.3943, found 681.3936 example 15:
derivatization of estrone
Estrone, also known as feminone, is a white crystalline powder, soluble in ethanol and insoluble in water. Is obtained from pregnant woman urine or livestock ovary. It is the original hormone secreted by female animal ovary, has been used in clinic, is an important medical intermediate, is the intermediate of hormone ethinylestradiol for No. 1 contraceptive, and is mainly used for treating uterine hypoplasia, menstrual disorder, climacteric disturbance and the like.
The steps of the derivatization of estrone in the invention are as follows:
firstly, reacting estrone with 2- (2-bromoethyl) -1, 3-dioxane to derive estrone into an acetal compound, and hydrolyzing into aldehyde:
and reacting the derived aldehyde with 1, 3-butadiene and ethyl difluorobromoacetate to obtain the homoallyl alcohol compound derived from the estrone.
A homoallylic alcohol compound derived from estrone derivatization. RF 0.4(EA: PE 1:2), eluent: petroleum ether/ethyl acetate 10/1, 62% yield, product was a colorless liquid.1H NMR(400MHz,CDCl3)δ7.19(d,J=8.6Hz,1H),6.70(dd,J=8.6,2.7Hz,1H),6.63(d,J=2.5Hz,1H),5.85(ddd,J=17.0,10.4,8.7Hz,1H),5.29–5.16(m,2H),4.66(dt,J=9.4,3.6Hz,1H),4.21–3.98(m,2H),2.93–2.82(m,2H),2.65–2.57(m,2H),2.55–2.45(m,1H),2.43–2.33(m,1H),2.27–1.93(m,8H),1.91–1.82(m,1H),1.65–1.44(m,7H),0.91(s,3H).13C NMR(101MHz,CDCl3)δ171.47,156.66,137.82,134.29,132.29,126.37,118.63,114.39,112.17,78.20,77.20,63.48,50.40,48.00,43.96,40.04,38.35,35.86,32.73,31.57,29.63,27.06,26.52,25.90,24.66,21.57,13.84.HRMS-ESI(m/z)[M+Na]+calculated for C27H34NaO4,445.2355,found 445.2352.
Example 16: fluorescence quenching experiments, as shown in fig. 1, 2 and 3.
In FIG. 1, the Stern-Volmer equation: f0/F=1+Kqτ0[Q],Kqτ0=2032L/mol,τ0=557ns,Kq=3.65×109L/(mol*s);
In FIG. 2, the Stern-Volmer equation: f0/F=1+Kqτ0[Q],Kqτ0=22L/mol,τ0=557ns,Kq=3.95×107L/(mol*s)
In FIG. 3, the Stern-Volmer equation: f0/F=1+Kqτ0[Q],Kqτ0=17L/mol,τ0=557ns,Kq=3.05×107L/(mol*s)。
The emission intensity of all experiments was recorded using an Edinburgh FS920 fluorescence spectrophotometer. All 4CzIPN solutions were excited at 468nm and emission intensities were collected at 500-800 nm. In a typical experiment, 4CzIPN (10)-5M) adding a proper amount of quenching agent into the THF solution, placing the solution into a spiral top 4.5cm quartz test tube, degassing by nitrogen, and collecting the emission spectrum of a sample. The results show that Cp2TiCl2HE and BrCF2CO2Et has better inhibition effect on photo-excitation of 4 CzIPN.
Example 17: light/dark experiment scheme, as shown in FIG. 4
To a solution containing 3a (250mg, 1.86mmol, 1.0 eq) according to standard procedures.
HE(945mg,3.73mmol,2.0eq.),Cp2TiCl2(46.3g, 0.19mol, 0.1eq.), 1,3, 5-trimethoxybenzene (104.5mg, 0.62mmol, 0.33eq.) and 4CzIPN (7.3mg, 0.0093mmol, 1.0% mol) in THF were added 1, 3-butadiene derivative (3.0M in toluene, 1.25mL, 3.73mmol) and ethyl difluorobromoacetate (757mg, 480. mu.L, 3.73mmol, 2.0 eq.). The reaction mixture was stirred at room temperature under illumination by 10W 450nm LED lamp with on-off indicator. At different time points, 400 μ Ι _ of reaction mixture was collected and concentrated under vacuum. Using 1,3, 5-trimethoxybenzene as an internal standard by1H NMR calculated scoreAnd (6) analyzing the result.
According to the above experimental results, the reaction mechanism is as follows:
first, bromofluoroacetic acid ethyl ester is substituted with IrIIIThe complex is reduced to generate alkyl free radicals. The resulting alkyl radical can be rapidly added to butadiene to form allyl radical 2, which is then further reduced. At the same time, TiIVIs covered with another IrIIIReduced to TiIII. Ir of strong oxidizing agentsIVThe material is subsequently reduced to Ir by HEIIIAnd produces HE +, which can further participate in excluded electron transfer events because the coordination of Ti is already fully occupied. Final generation pyH+。TiIIIThe allyl group 2 can be captured to form a nucleophilic hydroxy-allyl titanium complex 1, which is subsequently coupled to a carbonyl group. Warp pyH+Hydrolyzing to obtain iso-alcohol, and releasing free TiIV. Finally, the catalyst is cycled in IrIIIAnd TiIVIs turned off by the SET. In view of proton coupling electron transfer process and TiIIIBoth generate carbonyl radicals and the radical-radical coupling pathway II does proceed (at least for electron deficient substrates). In general, the anti-selectivity of homoalcohols can be explained by the Ziegler-Traxler transition state. In this case, however, no non-cyclic transition state is possible.
Therefore, the method for synthesizing the homoallylic alcohol compound can be used for derivatization of natural substances, and natural products comprise natural substances with biological activity such as estrone, lithocholic acid and the like.
The foregoing is a preferred embodiment of the present invention and modifications, without departing from the principles of the invention, will be apparent to those skilled in the art and are intended to be within the scope of the invention.
Claims (5)
1. A synthetic method of a homoallyl alcohol compound is characterized in that the structural formula is as follows:wherein R is1、R2、R4、R5、R6And R7Each independently selected from hydrogen, C1-C8 alkyl, phenyl, substituted phenyl, naphthyl, benzyl, or heterocyclyl; the substituent in the substituted phenyl is selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, hydroxyl, C1-C3 alkoxycarbonyl and amino; r3Is C3-C9 alkyl;
the synthetic method of the homoallylic alcohol compound comprises the following synthetic route:
reacting halogenated alkane with 1, 3-butadiene derivative and aldehyde or ketone in a solvent at room temperature in the presence of inert gas protection, illumination, an organic photosensitizer, a titanium catalyst and an electron donor to obtain a homoallylic alcohol compound;
the organic photosensitizer is 4 CzIPN;
the titanium catalyst is titanocene dichloride;
the electron donor is diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate.
2. The synthesis method according to claim 1, wherein the molar ratio of the haloalkane 1, 3-butadiene derivative 2, aldehyde or ketone 3, the organic photosensitizer, the titanium catalyst and diethyl 2, 6-dimethyl-1, 4-dihydro-3, 5-pyridinedicarboxylate is 2.0:2.0:1.0:0.01:0.05: 2.0.
3. The method of synthesis according to claim 2, wherein the solvent is tetrahydrofuran.
4. The method of synthesizing homoallylic compounds of any of claims 1-3 for derivatization of natural actives.
5. Use according to claim 4, characterized in that: the natural active substances comprise estrone and lithocholic acid.
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