CN116178297B - Drimane type sesquiterpene heterocyclic compound and preparation method and application thereof - Google Patents
Drimane type sesquiterpene heterocyclic compound and preparation method and application thereof Download PDFInfo
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- CN116178297B CN116178297B CN202310070493.5A CN202310070493A CN116178297B CN 116178297 B CN116178297 B CN 116178297B CN 202310070493 A CN202310070493 A CN 202310070493A CN 116178297 B CN116178297 B CN 116178297B
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- -1 sesquiterpene heterocyclic compound Chemical class 0.000 title claims abstract description 247
- 229930004725 sesquiterpene Natural products 0.000 title claims abstract description 73
- CVRSZZJUWRLRDE-PWNZVWSESA-N drimane Chemical compound CC1(C)CCC[C@]2(C)[C@@H](C)[C@@H](C)CC[C@H]21 CVRSZZJUWRLRDE-PWNZVWSESA-N 0.000 title claims abstract description 28
- 229930001542 drimane Natural products 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 claims abstract description 21
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical group C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims abstract description 13
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims abstract description 13
- 244000052616 bacterial pathogen Species 0.000 claims abstract description 12
- 241000123650 Botrytis cinerea Species 0.000 claims abstract description 8
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 55
- 230000009471 action Effects 0.000 claims description 48
- IMKJGXCIJJXALX-SHUKQUCYSA-N Norambreinolide Chemical compound CC([C@@H]1CC2)(C)CCC[C@]1(C)[C@@H]1[C@]2(C)OC(=O)C1 IMKJGXCIJJXALX-SHUKQUCYSA-N 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 37
- IMKJGXCIJJXALX-UHFFFAOYSA-N ent-Norambreinolide Natural products C1CC2C(C)(C)CCCC2(C)C2C1(C)OC(=O)C2 IMKJGXCIJJXALX-UHFFFAOYSA-N 0.000 claims description 37
- 229940096995 sclareolide Drugs 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000007800 oxidant agent Substances 0.000 claims description 30
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 28
- 238000006722 reduction reaction Methods 0.000 claims description 27
- 238000007254 oxidation reaction Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 230000001590 oxidative effect Effects 0.000 claims description 24
- 238000007142 ring opening reaction Methods 0.000 claims description 24
- 238000006297 dehydration reaction Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 238000007363 ring formation reaction Methods 0.000 claims description 19
- 150000001408 amides Chemical class 0.000 claims description 18
- 238000006482 condensation reaction Methods 0.000 claims description 18
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 10
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims description 10
- XVULBTBTFGYVRC-HHUCQEJWSA-N sclareol Chemical compound CC1(C)CCC[C@]2(C)[C@@H](CC[C@](O)(C)C=C)[C@](C)(O)CC[C@H]21 XVULBTBTFGYVRC-HHUCQEJWSA-N 0.000 claims description 10
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical group [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 9
- 229960002218 sodium chlorite Drugs 0.000 claims description 9
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 238000005915 ammonolysis reaction Methods 0.000 claims description 8
- 238000006555 catalytic reaction Methods 0.000 claims description 8
- 235000007164 Oryza sativa Nutrition 0.000 claims description 7
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 7
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 7
- 235000009566 rice Nutrition 0.000 claims description 7
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 claims description 6
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 238000010762 quinoline synthesis reaction Methods 0.000 claims description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims description 6
- XVULBTBTFGYVRC-UHFFFAOYSA-N Episclareol Natural products CC1(C)CCCC2(C)C(CCC(O)(C)C=C)C(C)(O)CCC21 XVULBTBTFGYVRC-UHFFFAOYSA-N 0.000 claims description 5
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 5
- LAEIZWJAQRGPDA-UHFFFAOYSA-N Manoyloxid Natural products CC1(C)CCCC2(C)C3CC=C(C)OC3(C)CCC21 LAEIZWJAQRGPDA-UHFFFAOYSA-N 0.000 claims description 5
- 241000233616 Phytophthora capsici Species 0.000 claims description 5
- 241000209140 Triticum Species 0.000 claims description 5
- 235000021307 Triticum Nutrition 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- 238000006462 rearrangement reaction Methods 0.000 claims description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006476 reductive cyclization reaction Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 4
- 240000008067 Cucumis sativus Species 0.000 claims description 3
- 235000010799 Cucumis sativus var sativus Nutrition 0.000 claims description 3
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 150000003248 quinolines Chemical class 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 241000223218 Fusarium Species 0.000 claims description 2
- 241000526118 Fusarium solani f. radicicola Species 0.000 claims description 2
- 241000233622 Phytophthora infestans Species 0.000 claims description 2
- 241000221662 Sclerotinia Species 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 240000007594 Oryza sativa Species 0.000 claims 2
- 241000198596 Alternaria tomatophila Species 0.000 claims 1
- 241001508365 Gaeumannomyces tritici Species 0.000 claims 1
- 241001617088 Thanatephorus sasakii Species 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 11
- 241000813090 Rhizoctonia solani Species 0.000 abstract description 7
- 241000221696 Sclerotinia sclerotiorum Species 0.000 abstract description 6
- 150000004354 sesquiterpene derivatives Chemical group 0.000 abstract description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000003960 organic solvent Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 241000209094 Oryza Species 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000012544 monitoring process Methods 0.000 description 5
- 239000000575 pesticide Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000011259 mixed solution Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical group [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 3
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 244000052769 pathogen Species 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- FXWFZIRWWNPPOV-UHFFFAOYSA-N 2-aminobenzaldehyde Chemical class NC1=CC=CC=C1C=O FXWFZIRWWNPPOV-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241001290235 Ceratobasidium cereale Species 0.000 description 2
- 241000801593 Pida Species 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001718 carbodiimides Chemical class 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MWGATWIBSKHFMR-UHFFFAOYSA-N 2-anilinoethanol Chemical compound OCCNC1=CC=CC=C1 MWGATWIBSKHFMR-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- 241000860788 Alternaria cerealis Species 0.000 description 1
- 241000213004 Alternaria solani Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000222235 Colletotrichum orbiculare Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 241000221778 Fusarium fujikuroi Species 0.000 description 1
- 241000223195 Fusarium graminearum Species 0.000 description 1
- 241000221779 Fusarium sambucinum Species 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 235000007688 Lycopersicon esculentum Nutrition 0.000 description 1
- 241001330975 Magnaporthe oryzae Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000233614 Phytophthora Species 0.000 description 1
- 241001183191 Sclerophthora macrospora Species 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 240000003768 Solanum lycopersicum Species 0.000 description 1
- XEFCWBLINXJUIV-UHFFFAOYSA-N acetic acid;iodobenzene Chemical compound CC(O)=O.CC(O)=O.IC1=CC=CC=C1 XEFCWBLINXJUIV-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- QIRAYNIFEOXSPW-UHFFFAOYSA-N dimepheptanol Chemical compound C=1C=CC=CC=1C(CC(C)N(C)C)(C(O)CC)C1=CC=CC=C1 QIRAYNIFEOXSPW-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000003483 drimane derivatives Chemical class 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000000361 pesticidal effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- ZTWIEIFKPFJRLV-UHFFFAOYSA-K trichlororuthenium;trihydrate Chemical compound O.O.O.Cl[Ru](Cl)Cl ZTWIEIFKPFJRLV-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
- A01N43/42—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/76—1,3-Oxazoles; Hydrogenated 1,3-oxazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P3/00—Fungicides
-
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Abstract
The invention provides Drimane type sesquiterpene heterocyclic compounds, and a preparation method and application thereof, and belongs to the technical field of organic synthesis. The Drimane-type sesquiterpene heterocyclic compound provided by the invention has a structure shown in a formula I, a formula II or a formula III. According to the invention, drimane type sesquiterpene structure is used as a structural framework, oxazoline groups, quinoline groups or 2H indazole groups are introduced into the 11-position carbon of Drimane type sesquiterpene, and the obtained heterocyclic compound has good antibacterial activity on various agricultural pathogenic bacteria. The result of the example shows that the Drimane-type sesquiterpene heterocyclic compound provided by the invention has good bactericidal activity on Sclerotinia sclerotiorum, rhizoctonia solani and Botrytis cinerea. The invention provides a preparation method of the Drimane-type sesquiterpene heterocyclic compound, which is simple to operate and suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to Drimane type sesquiterpene heterocyclic compounds, and a preparation method and application thereof.
Background
The pesticide is an important means for improving and guaranteeing the grain unit yield, but the problems of increased drug resistance, environmental pollution, food safety and the like are increasingly serious due to the unscientific use of the pesticide. In the research of pesticide creation, the research conducted by taking natural products as the guide is an effective method for developing novel green pesticides. Drimane sesquiterpene compounds widely exist in nature and have biological activities of resisting tumor, HIV, bacteria, food refusal and the like.
Typical structures of the Drimane class of sesquiterpene compounds are as follows:
Recently, research into the synthesis and biological activity of Drimane-type sesquiterpenes and analogues has been receiving increasing attention (Nat. Prod. Rep.,2004,21,449-477; microbiall, 2020,7 (6), 146-159). However, these compounds have been less studied in agrochemical, and Drimane-type sesquiterpene heterocycles having pesticidal pathogen inhibitory activity have been studied in a few cases.
Disclosure of Invention
In view of the above, the invention aims to provide Drimane-type sesquiterpene heterocyclic compounds, and a preparation method and application thereof. The Drimane type sesquiterpene heterocyclic compound provided by the invention has good pesticide pathogenic bacteria inhibition activity.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides Drimane type sesquiterpene heterocyclic compounds, which have a structure shown in a formula I, a formula II or a formula III:
In the formula I, the 7-8 dotted line is a double bond or the 8-9 dotted line is a double bond or the 9-12 dotted line is a double bond, and when the 7-8 dotted line is a double bond or the 8-9 dotted line is a double bond or the 9-12 dotted line is a double bond in the formula I, the rest dotted line is a single bond; heterocycles are oxazoline groups;
In the formula II, the hetercycles are oxazoline groups;
In formula III, the hetercycles are oxazoline groups, quinoline groups or 2H indazole groups.
Preferably, the oxazoline group is
One of the following;
The quinolinyl group is one of quinolinyl, 6-methylquinolinyl, 8-methylquinolinyl, 5-methylquinolinyl, 7-methoxyquinolinyl, 7, 8-dimethoxyquinolinyl, 6-nitroquinolinyl, 7-nitroquinolinyl, 5-chloroquinolinyl, 7-chloroquinolinyl, 6-chloro-2-methylquinolinyl, 5-fluoroquinolinyl, 6, 8-dibromoquinolinyl, 6-bromoquinolinyl, 7-trifluoromethyl quinolinyl and 6-iodoquinolinyl;
The 2H indazole group is one of 2H indazolyl, 5-bromo-2H indazolyl, 6-chloro-2H indazolyl, 4-cyano-2H indazolyl, 5-fluoro-2H indazolyl, 4-chloro-2H indazolyl, 4-trifluoromethyl-2H indazolyl, 4-methoxy-2H indazolyl, 5-methoxy-2H indazolyl, N-dimethyl-2H indazolyl and 4-methyl formate-2H indazolyl.
Preferably, in the formula I, the formula II or the formula III, the carbon atom three-dimensional configuration connected with the oxazoline group is R type or S type.
The invention provides a preparation method of the Drimane-type sesquiterpene heterocyclic compound,
When the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula I, the preparation method comprises the following steps:
(1) Under the action of diisobutyl aluminum hydride, sclareolide undergoes a reduction reaction to obtain a hemiacetal compound with a structure shown in a formula a;
under the action of boron trifluoride diethyl ether, carrying out hydrolysis reaction on the hemiacetal compound with the structure shown in the formula a to obtain an aldehyde compound with a delta 8,9 double bond shown in the formula b;
Under the action of an oxidant, carrying out oxidation reaction on a compound with a structure shown in a formula b to obtain an acid compound with a delta 8,9 -bit double bond with a structure shown in a formula c;
(2) Performing ring-opening reaction on sclareolide and N, O-dimethylhydroxylamine hydrochloride to obtain an amide compound with a structure shown in a formula d;
carrying out dehydration reaction on the amide compound with the structure shown in the formula d to obtain a delta 8,12 -position double bond amide compound with the structure shown in the formula e;
Under the action of diisobutyl aluminum hydride, performing reduction reaction on the delta 8,12 -position double bond amide compound with the structure shown in the formula e to obtain a delta 8,12 -position double bond aldehyde compound with the structure shown in the formula f;
Under the action of an oxidant, carrying out oxidation reaction on an aldehyde compound with a delta 8,12 -position double bond and a structure shown in a formula f to obtain an acid compound with a delta 8,12 -position double bond and a structure shown in a formula g;
(3) Under the acidic condition, carrying out configuration conversion on sclareolide to obtain C8-S sclareolide with a structure shown in a formula h;
performing ring-opening reaction on C8-S-type sclareolide with a structure shown in formula h and N, O-dimethylhydroxylamine hydrochloride to obtain an amide compound with a structure shown in formula i;
Carrying out dehydration reaction on the amide compound with the structure shown in the formula i to obtain a delta 7,8 -position double bond amide compound with the structure shown in the formula j;
Under the action of lithium aluminum hydride, performing reduction reaction on the delta 7,8 -position double bond amide compound with the structure shown in the formula j to obtain a delta 7,8 -position double bond aldehyde compound with the structure shown in the formula k;
Under the action of an oxidant, carrying out oxidation reaction on an aldehyde compound with a delta 7,8 -position double bond and a structure shown in a formula k to obtain an acid compound with a delta 7,8 -position double bond and a structure shown in a formula l;
(4) Performing condensation reaction on an acid compound with a delta 8,9 -position double bond shown in a formula c, an acid compound with a delta 8,12 -position double bond shown in a formula g or an acid compound with a delta 7,8 -position double bond shown in a formula l and a chiral amino alcohol compound to obtain an amide alcohol intermediate;
Under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate undergoes cyclization reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with a structure shown in a formula I;
(II) when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula II, the method comprises the following steps:
Under the catalysis of ruthenium trichloride, sclareol and an oxidant are subjected to oxidation reaction to obtain an intermediate acid with a structure shown in a formula m;
Performing condensation reaction on the intermediate acid with the structure shown in the formula m and a chiral amino alcohol compound to obtain an amide alcohol intermediate;
Under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate undergoes cyclization reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with a structure shown in a formula II;
(III) when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula III, the method comprises the following steps:
(i) When the hetercycles are oxazoline groups, comprising the steps of:
Under the action of organic strong alkali, carrying out hydrolysis reaction on the Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula II to obtain a Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula III;
(ii) When the hetercycles are quinolines, the method comprises the steps of:
performing ring-opening reaction on sclareolide and methyl lithium to obtain an intermediate ketone compound with a structure shown in formula n;
Performing a Foldebrand quinoline synthesis reaction on an intermediate ketone compound with a structure shown in a formula n and a 2-aminobenzaldehyde compound to obtain a Drimane-type sesquiterpene heterocyclic compound with a structure shown in a formula III;
(iii) When the hetercycles are 2H indazole groups, the method comprises the following steps:
Under the catalysis of sodium methoxide, sclareolide and NH 3 are subjected to ammonolysis reaction to obtain a compound with a structure shown in a formula o;
Under alkaline conditions, carrying out Huffman rearrangement reaction on the compound with the structure shown in the formula o to obtain a compound with the structure shown in the formula p;
under the action of diethylenetriamine, carrying out alkaline hydrolysis reaction on a compound with a structure shown in a formula p to obtain an intermediate amine compound with a structure shown in a formula q;
under the action of tri-n-butyl phosphine, an intermediate amine compound with a structure shown in a formula q and a 2-nitrobenzaldehyde compound are subjected to a reduction cyclization reaction to obtain the Drimane type sesquiterpene heterocyclic compound with a structure shown in a formula III.
Preferably, in the step (1) in the step (one), the temperature of the reduction reaction is-80 to-60 ℃;
the oxidant is sodium chlorite;
In the step (2) in the step (one), the temperature of the ring-opening reaction is-10-35 ℃;
the catalyst for the dehydration reaction is thionyl chloride and pyridine, and the temperature of the dehydration reaction is-80 to-60 ℃;
The temperature of the reduction reaction is-80 to-60 ℃;
the oxidant is sodium chlorite;
In the step (3) of the step (one), the temperature of the ring-opening reaction is-10-35 ℃;
the catalyst for the dehydration reaction is thionyl chloride and pyridine, and the temperature of the dehydration reaction is-20 ℃;
The temperature of the reduction reaction is-80 to-60 ℃;
the oxidant is sodium chlorite;
in the step (4) of the step (one), the temperature of the condensation reaction is 0-room temperature;
The temperature of the cyclization reaction is-80 to-60 ℃.
Preferably, in the step (two), the temperature of the oxidation reaction is 40 ℃;
The temperature of the condensation reaction is 0-room temperature;
The temperature of the cyclization reaction is-80 to-60 ℃.
Preferably, in step (i) of the step (three), the hydrolysis reaction temperature is 0 to reflux temperature;
In the step (ii) of the step (three), the temperature of the ring-opening reaction is-80 to-60 ℃;
the temperature of the synthesis reaction of the friedel-crafts quinoline is room temperature;
In the step (iii) of the step (III), the temperature of the ammonolysis reaction is 40-80 ℃;
The temperature of the Huffman rearrangement reaction is 0-room temperature;
the temperature of the alkaline hydrolysis reaction is 120-160 ℃;
The reaction temperature of the reductive cyclization is 60-100 ℃.
The invention provides application of the Drimane-type sesquiterpene heterocyclic compound in resisting agricultural pathogenic bacteria.
Preferably, the method comprises the steps of, the agricultural pathogenic bacteria are one or more of Rhizoctonia solani, rhizoctonia cerealis, sclerotinia sclerotiorum, alternaria cerealis, leucomatous solani, phytophthora capsici, phytophthora solani, phytophthora capsici, phytophthora oryzae, dry rot of potato, anthracnose of cucumber and Pyricularia oryzae.
The invention provides Drimane type sesquiterpene heterocyclic compounds, which have structures shown in a formula I, a formula II or a formula III. The drug similarity of the compound is a key factor in the initial stage of drug discovery, the drug similarity parameter sp 3 hybridized carbon percentage (fractionofsp 3carbons,Fsp3) is an important parameter of drug similarity, the average Fsp 3 of the marketed molecules is 0.45, most of the marketed bactericides contain flat aromatic rings, the Fsp 3 value is low, all carbon atoms on the Drimane sesquiterpene skeleton of the rigid structure are sp 3 hybridized, and the balance is achieved after the connection with aromatic groups, so that the patentability of the bactericide is improved. According to the invention, drimane type sesquiterpene structure is used as a structural framework, oxazoline groups, quinoline groups or 2H indazole groups are introduced into the 11-position carbon of Drimane type sesquiterpene, and the obtained heterocyclic compound has good antibacterial activity on various agricultural pathogenic bacteria. The result of the example shows that the Drimane-type sesquiterpene heterocyclic compound provided by the invention has good bactericidal activity on Sclerotinia sclerotiorum, rhizoctonia solani and Botrytis cinerea.
The invention provides a preparation method of the Drimane-type sesquiterpene heterocyclic compound, which is simple to operate and suitable for industrial mass production.
Detailed Description
The invention provides Drimane type sesquiterpene heterocyclic compounds, which have a structure shown in a formula I, a formula II or a formula III:
In the formula I, the 7-8 dotted line is a double bond or the 8-9 dotted line is a double bond or the 9-12 dotted line is a double bond, and when the 7-8 dotted line is a double bond or the 8-9 dotted line is a double bond or the 9-12 dotted line is a double bond in the formula I, the rest dotted line is a single bond; heterocycles are oxazoline groups;
In the formula II, the hetercycles are oxazoline groups;
In formula III, the hetercycles are oxazoline groups, quinoline groups or 2H indazole groups.
In the present invention, the oxazoline group is preferably
One of them.
In the present invention, the quinoline group is preferably
The quinoline group is one of quinolinyl, 6-methylquinolinyl, 8-methylquinolinyl, 5-methylquinolinyl, 7-methoxyquinolinyl, 7, 8-dimethoxyquinolinyl, 6-nitroquinolinyl, 7-nitroquinolinyl, 5-chloroquinolinyl, 7-chloroquinolinyl, 6-chloro-2-methylquinolinyl, 5-fluoroquinolinyl, 6, 8-dibromoquinolinyl, 6-bromoquinolinyl, 7-trifluoromethyl quinolinyl and 6-iodoquinolinyl.
In the present invention, the 2H indazole group is
The 2H indazole group is one of 2H indazolyl, 5-bromo-2H indazolyl, 6-chloro-2H indazolyl, 4-cyano-2H indazolyl, 5-fluoro-2H indazolyl, 4-chloro-2H indazolyl, 4-trifluoromethyl-2H indazolyl, 4-methoxy-2H indazolyl, 5-methoxy-2H indazolyl, N-dimethyl-2H indazolyl and 4-methyl formate-2H indazolyl.
In the present invention, theMeaning of (c) means the ligation site.
In the present invention, in the formula I, formula II or formula III, the carbon atom steric configuration attached to the oxazoline group is preferably R-type or S-type.
As a specific embodiment of the invention, the structural formula of the Drimane-type sesquiterpene heterocyclic compound is shown in table 1.
Table 1 part of the structural formula of Drimane type sesquiterpene heterocycles
In the invention, the preparation method of the Drimane-type sesquiterpene heterocyclic compound comprises the following steps:
when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula I, the preparation method comprises the following steps:
(1) Under the action of diisobutyl aluminum hydride, sclareolide undergoes a reduction reaction to obtain a hemiacetal compound with a structure shown in a formula a;
under the action of boron trifluoride diethyl ether, carrying out hydrolysis reaction on the hemiacetal compound with the structure shown in the formula a to obtain an aldehyde compound with a delta 8,9 double bond shown in the formula b;
Under the action of an oxidant, carrying out oxidation reaction on a compound with a structure shown in a formula b to obtain an acid compound with a delta 8,9 -bit double bond with a structure shown in a formula c;
(2) Performing ring-opening reaction on sclareolide and N, O-dimethylhydroxylamine hydrochloride to obtain an amide compound with a structure shown in a formula d;
carrying out dehydration reaction on the amide compound with the structure shown in the formula d to obtain a delta 8,12 -position double bond amide compound with the structure shown in the formula e;
Under the action of diisobutyl aluminum hydride, performing reduction reaction on the delta 8,12 -position double bond amide compound with the structure shown in the formula e to obtain a delta 8,12 -position double bond aldehyde compound with the structure shown in the formula f;
Under the action of an oxidant, carrying out oxidation reaction on an aldehyde compound with a delta 8,12 -position double bond and a structure shown in a formula f to obtain an acid compound with a delta 8,12 -position double bond and a structure shown in a formula g;
(3) Under the acidic condition, carrying out configuration conversion on sclareolide to obtain C8-S sclareolide with a structure shown in a formula h;
performing ring-opening reaction on C8-S-type sclareolide with a structure shown in formula h and N, O-dimethylhydroxylamine hydrochloride to obtain an amide compound with a structure shown in formula i;
Carrying out dehydration reaction on the amide compound with the structure shown in the formula i to obtain a delta 7,8 -position double bond amide compound with the structure shown in the formula j;
Under the action of lithium aluminum hydride, performing reduction reaction on the delta 7,8 -position double bond amide compound with the structure shown in the formula j to obtain a delta 7,8 -position double bond aldehyde compound with the structure shown in the formula k;
Under the action of an oxidant, carrying out oxidation reaction on an aldehyde compound with a delta 7,8 -position double bond and a structure shown in a formula k to obtain an acid compound with a delta 7,8 -position double bond and a structure shown in a formula l;
(4) Performing condensation reaction on an acid compound with a delta 8,9 -position double bond shown in a formula c, an acid compound with a delta 8,12 -position double bond shown in a formula g or an acid compound with a delta 7,8 -position double bond shown in a formula l and a chiral amino alcohol compound to obtain an amide alcohol intermediate;
Under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate undergoes cyclization reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with the structure shown in the formula I.
According to the invention, sclareolide undergoes a reduction reaction under the action of diisobutylaluminum hydride to obtain a hemiacetal compound with a structure shown in a formula a. In the present invention, the organic solvent used for the reduction reaction is preferably methylene chloride. In the present invention, the temperature of the reduction reaction is preferably-78 ℃; the molar ratio of sclareolide to diisobutylaluminum hydride is preferably 1:1.2-2, more preferably 1:1.5.
Under the action of boron trifluoride diethyl ether, the hemiacetal compound with the structure shown in the formula a undergoes hydrolysis reaction to obtain the aldehyde compound with the delta 8,9 -site double bond shown in the formula b. In the present invention, the organic solvent used for the hydrolysis reaction is preferably methylene chloride. In the present invention, the temperature of the hydrolysis reaction is preferably 10 to 30 ℃, more preferably 15 to 25 ℃; the molar ratio of the hemiacetal compound with the structure shown in the formula a to the boron trifluoride diethyl etherate is preferably 1:1.1-1.5.
Under the action of an oxidant, the compound with the structure shown in the formula b undergoes an oxidation reaction to obtain the acid compound with the delta 8,9 -position double bond shown in the formula c. In the present invention, the oxidizing agent is preferably sodium chlorite.
In the present invention, the solvent used in the oxidation reaction is preferably a mixed solution of tetrahydrofuran, t-butanol and water; in the present invention, the temperature of the oxidation reaction is preferably 10 to 30 ℃, more preferably 15 to 25 ℃, and the molar ratio of the compound having the structure represented by formula b to the oxidizing agent is preferably 1:2.5 to 3.5.
In the invention, the synthetic route of the acid compound with the delta 8,9 double bond shown in the formula c is shown in a formula ①:
In the invention, sclareolide and N, O-dimethylhydroxylamine hydrochloride undergo a ring-opening reaction to obtain an amide compound with a structure shown in a formula d. In the present invention, the organic solvent for the ring-opening reaction is preferably tetrahydrofuran. In the present invention, the temperature of the ring-opening reaction is preferably-10 to 35 ℃, more preferably 0 to room temperature; the molar ratio of sclareolide to N, O-dimethylhydroxylamine hydrochloride is preferably 1:2-5, more preferably 1:3-4.
In the invention, the amide compound with the structure shown in the formula d is subjected to dehydration reaction to obtain the delta 8,12 -position double bond amide compound with the structure shown in the formula e. In the present invention, the dehydration reaction is preferably performed under thionyl chloride and pyridine conditions. In the present invention, the organic solvent used in the dehydration reaction is preferably methylene chloride; the temperature of the dehydration reaction is preferably-80 to-60 ℃, more preferably-78 ℃.
In the invention, under the action of diisobutyl aluminum hydride, a delta 8,12 -position double bond amide compound with a structure shown in a formula e is subjected to reduction reaction to obtain a delta 8,12 -position double bond aldehyde compound with a structure shown in a formula f. In the present invention, the organic solvent used in the reduction reaction is preferably tetrahydrofuran; the temperature of the reduction reaction is preferably-80 to-60 ℃, more preferably-78 ℃; in the invention, the molar ratio of the delta 8,12 -position double bond amide compound with the structure shown in the formula e to diisobutyl aluminum hydride is preferably 1:1.1-2.
In the invention, under the action of an oxidant, an aldehyde compound with a delta 8,12 -position double bond and a structure shown in a formula f is subjected to oxidation reaction to obtain an acid compound with a delta 8,12 -position double bond and a structure shown in a formula g. In the present invention, the oxidizing agent is preferably sodium chlorite; in the present invention, the solvent used in the oxidation reaction is preferably a mixed solution of tetrahydrofuran, t-butanol and water; in the present invention, the temperature of the oxidation reaction is preferably 10 to 30 ℃, more preferably 15 to 25 ℃; the molar ratio of the compound having the structure represented by formula b to the oxidizing agent is preferably 1:2.5 to 3.5, more preferably 1:3.
In the invention, the synthetic route of the acid compound with the delta 8,12 double bond shown in the formula g is shown in a formula ②:
Under the acidic condition, the sclareolide is subjected to configuration conversion to obtain the C8-S sclareolide with the structure shown in the formula h. In the present invention, the acid providing the acidic condition is preferably concentrated sulfuric acid and formic acid, and the volume ratio of the concentrated sulfuric acid to the formic acid is preferably 7:170. In the present invention, the configuration conversion is preferably performed under room temperature conditions.
In the invention, C8-S type sclareolide with a structure shown in a formula h and N, O-dimethylhydroxylamine hydrochloride undergo a ring-opening reaction to obtain an amide compound with a structure shown in a formula i. In the present invention, the organic solvent used in the ring-opening reaction is preferably tetrahydrofuran; in the present invention, the temperature of the ring-opening reaction is preferably-10 to 35 ℃, more preferably 0 to room temperature. In the present invention, the molar ratio of the C8-S type sclareolide having the structure represented by formula h to N, O-dimethylhydroxylamine hydrochloride is preferably 1:2 to 5, more preferably 1:3 to 4.
In the invention, the amide compound with the structure shown in the formula i is subjected to dehydration reaction to obtain the delta 7,8 -position double bond amide compound with the structure shown in the formula j. In the present invention, the dehydration reaction is preferably performed under thionyl chloride and pyridine conditions. In the present invention, the organic solvent used in the dehydration reaction is preferably methylene chloride; the temperature of the dehydration reaction is preferably-20 to 20 ℃, more preferably 0 ℃.
In the invention, under the action of lithium aluminum hydride, a delta 7,8 -position double bond amide compound with a structure shown in a formula j undergoes a reduction reaction to obtain a delta 7,8 -position double bond aldehyde compound with a structure shown in a formula k. In the present invention, the organic solvent used in the reduction reaction is preferably tetrahydrofuran; in the present invention, the temperature of the reduction reaction is preferably 0 ℃; in the present invention, the molar ratio of the Δ 7,8 -position double bond amide compound having the structure represented by formula j to lithium aluminum hydride is preferably 1:2 to 5, more preferably 1:3 to 4.
In the invention, under the action of an oxidant, an aldehyde compound with a delta 7,8 -position double bond and a structure shown in a formula k is subjected to oxidation reaction to obtain an acid compound with a delta 7,8 -position double bond and a structure shown in a formula l. In the present invention, the oxidizing agent is preferably sodium chlorite; in the present invention, the solvent used in the oxidation reaction is preferably a mixed solution of tetrahydrofuran, t-butanol and water; in the present invention, the temperature of the oxidation reaction is preferably 10 to 30 ℃, more preferably 15 to 25 ℃; in the present invention, the molar ratio of the Δ 7,8 -position double bond aldehyde compound of the structure represented by the formula k to the oxidizing agent is preferably 1:2.5 to 3.5, more preferably 1:3.
In the present invention, the synthetic route of the acid compound having a double bond at position Δ 7,8 of the structure represented by formula l is shown in formula ③:
In the invention, an acid compound with a delta 8,9 -position double bond shown in a formula c, an acid compound with a delta 8 , 12 -position double bond shown in a formula g or an acid compound with a delta 7,8 -position double bond shown in a formula l is subjected to condensation reaction with a chiral amino alcohol compound to obtain an amide alcohol intermediate. In the invention, the structural general formula of the chiral amino alcohol compound is preferably that R represents a substitutable substituent; in the present invention, the condensation reaction is preferably performed in the presence of 4-dimethylaminopyridine and carbodiimide (EDCI). In the present invention, the organic solvent used for the condensation reaction is preferably methylene chloride. In the present invention, the temperature of the condensation reaction is preferably 0 to room temperature.
In the invention, under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate is subjected to cyclization reaction to obtain the Drimane-type sesquiterpene heterocyclic compound with the structure shown in the formula I. In the present invention, the organic solvent used in the cyclization reaction is preferably methylene chloride. In the present invention, the temperature of the cyclization reaction is preferably-80 to-60 ℃, more preferably-78 ℃; in the present invention, the molar ratio of the amide alcohol intermediate to diethylaminosulfur trifluoride is preferably 1:2.5 to 3.5, more preferably 1:3.
In the invention, when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula II, the preparation method comprises the following steps:
Under the catalysis of ruthenium trichloride, sclareol and an oxidant are subjected to oxidation reaction to obtain an intermediate acid with a structure shown in a formula m;
Performing condensation reaction on the intermediate acid with the structure shown in the formula m and a chiral amino alcohol compound to obtain an amide alcohol intermediate;
Under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate undergoes cyclization reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with the structure shown in the formula II.
In the invention, sclareol and an oxidant are subjected to oxidation reaction under the catalysis of ruthenium trichloride to obtain an intermediate acid with a structure shown in a formula m. In the present invention, the oxidizing agent is preferably sodium periodate. In the present invention, the solvent used in the oxidation reaction is preferably a mixed solution of carbon tetrachloride, acetonitrile and water; in the present invention, the temperature of the oxidation reaction is preferably 40 ℃; the molar ratio of sclareol to catalyst and oxidant is preferably 1:12:0.05.
In the invention, the synthetic route of the intermediate acid with the structure shown in the formula m is shown in a formula ④:
In the invention, intermediate acid with a structure shown in a formula m and chiral amino alcohol compounds are subjected to condensation reaction to obtain an amide alcohol intermediate. In the invention, the structural general formula of the chiral amino alcohol compound is preferably that R represents a substitutable substituent; in the present invention, the condensation reaction is preferably performed in the presence of 4-dimethylaminopyridine and carbodiimide (EDCI). In the present invention, the organic solvent used for the condensation reaction is preferably methylene chloride. In the present invention, the temperature of the condensation reaction is preferably 0 to room temperature.
In the invention, under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate is subjected to cyclization reaction to obtain the Drimane-type sesquiterpene heterocyclic compound with the structure shown in the formula II. In the present invention, the organic solvent used in the cyclization reaction is preferably methylene chloride; the temperature of the cyclization reaction is preferably-80 to-60 ℃, more preferably-78 ℃; in the present invention, the molar ratio of the amide alcohol intermediate to diethylaminosulfur trifluoride is preferably 1:2.5 to 3.5, more preferably 1:3.
In the invention, the synthetic route of the Drimane-type sesquiterpene heterocyclic compound with the structure shown in the formula II is shown in a formula ⑤:
In the invention, when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula III, the preparation method comprises the following steps:
(i) When the hetercycles are oxazoline groups, comprising the steps of:
Under the action of organic strong alkali, carrying out hydrolysis reaction on the Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula II to obtain a Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula III;
(ii) When the hetercycles are quinolines, the method comprises the steps of:
performing ring-opening reaction on sclareolide and methyl lithium to obtain an intermediate ketone compound with a structure shown in formula n;
Performing a Foldebrand quinoline synthesis reaction on an intermediate ketone compound with a structure shown in a formula n and a 2-aminobenzaldehyde compound to obtain a Drimane-type sesquiterpene heterocyclic compound with a structure shown in a formula III;
(iii) When the hetercycles are 2H indazole groups, the method comprises the following steps:
Under the catalysis of sodium methoxide, sclareolide and NH 3 are subjected to ammonolysis reaction to obtain a compound with a structure shown in a formula o;
Under alkaline conditions, carrying out Huffman rearrangement reaction on the compound with the structure shown in the formula o to obtain a compound with the structure shown in the formula p;
under the action of diethylenetriamine, carrying out alkaline hydrolysis reaction on a compound with a structure shown in a formula p to obtain an intermediate amine compound with a structure shown in a formula q;
Under the action of tri-n-butyl phosphine, an intermediate amine compound 2-nitrobenzaldehyde compound with a structure shown in a formula q is subjected to reduction cyclization reaction to obtain a Drimane-type sesquiterpene heterocyclic compound with a structure shown in a formula III.
In the present invention, when the hetercycles are oxazoline groups, the steps are as follows:
Under the action of organic alkali, carrying out hydrolysis reaction on the Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula II to obtain the Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula III. In the present invention, the organic strong base is preferably potassium hydroxide. In the present invention, the organic solvent used in the hydrolysis reaction is preferably methanol. In the present invention, the temperature of the hydrolysis reaction is preferably 0 to reflux temperature. In the invention, the synthetic route of the Drimane-type sesquiterpene heterocyclic compound with the structure shown in the formula III is shown in a formula ⑥:
In the present invention, when the Heterocycles are quinoline groups, the method comprises the steps of:
The sclareolide and methyl lithium undergo a ring-opening reaction to obtain an intermediate ketone compound with a structure shown in a formula n. In the present invention, the organic solvent used in the ring-opening reaction is preferably diethyl ether. In the present invention, the temperature of the ring-opening reaction is preferably-80 to-60 ℃, more preferably-78 ℃; the molar ratio of sclareolide to methyllithium is preferably 1:2.3-3.5, more preferably 1:2.5-3. In the invention, the synthetic route of the intermediate ketone compound with the structure shown in the formula n is shown in a formula ⑦:
In the invention, intermediate ketone compounds with a structure shown in a formula n and 2-aminobenzaldehyde compounds are subjected to a Foldebrand quinoline synthesis reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with a structure shown in a formula III. In the invention, the structural general formula of the 2-aminobenzaldehyde compound is R represents a substitutable substituent.
In the present invention, the friedel-crafts quinoline synthesis reaction is preferably performed under an alkaline environment, and the alkaline reagent providing the alkaline environment is preferably potassium hydroxide. In the present invention, the organic solvent used in the synthesis reaction of the friedel-crafts quinoline is preferably ethanol. In the present invention, the temperature of the friedel-crafts quinoline synthesis reaction is preferably room temperature. In the invention, the molar ratio of the intermediate ketone compound with the structure shown in the formula n to the 2-aminobenzaldehyde compound is preferably 0.5-1.5:1, and more preferably 1:1. In the invention, the synthetic route of the Drimane-type sesquiterpene heterocyclic compound with the structure shown in the formula III is shown in a formula ⑧.
In the present invention, when the hetercycles are 2H indazole-type groups, the steps are included as follows:
Under the catalysis of sodium methoxide, sclareolide and NH 3 are subjected to ammonolysis reaction to obtain the compound with the structure shown in the formula o. In the present invention, the organic solvent used in the ammonolysis reaction is preferably methanol; in the present invention, the temperature of the ammonolysis reaction is preferably 40 to 80 ℃, more preferably 60 ℃; the molar ratio of sclareolide to NH 3 is preferably 1:7-10.
In the invention, under alkaline conditions, a compound with a structure shown in a formula o undergoes a Hofmann rearrangement reaction to obtain a compound with a structure shown in a formula p. In the present invention, the alkaline agent providing the alkaline environment is preferably potassium hydroxide. In the present invention, the hofmann rearrangement reaction is preferably performed under iodobenzene diacetic acid PIDA conditions; the PIDA plays an oxidizing role. In the present invention, the temperature of the hofmann rearrangement reaction is preferably 0 to room temperature.
In the invention, under the action of diethylenetriamine, a compound with a structure shown in a formula p is subjected to alkaline hydrolysis reaction to obtain an intermediate amine compound with a structure shown in a formula q. In the present invention, the temperature of the alkaline hydrolysis reaction is preferably 120 to 160 ℃, more preferably 140 ℃; the molar ratio of the compound having the structure represented by formula p to diethylenetriamine is preferably 1:20-25.
In the invention, the synthetic route of the intermediate amine compound with the structure shown in the formula q is shown as a formula ⑨:
In the invention, under the action of tri-n-butyl phosphine, an intermediate amine compound with a structure shown in a formula q and a 2-nitrobenzaldehyde compound undergo a reductive cyclization reaction to obtain a Drimane-type sesquiterpene heterocyclic compound with a structure shown in a formula III. In the invention, the structural general formula of the 2-nitrobenzaldehyde compound is R represents a substitutable substituent.
In the present invention, the temperature of the reductive cyclization reaction is preferably 60 to 100 ℃, more preferably 80 ℃; the molar ratio of the intermediate amine compound with the structure shown in the formula q to tri-n-butyl phosphine is preferably 1:3-4. In the invention, the synthetic route of the Drimane-type sesquiterpene heterocyclic compound with the structure shown in the formula III is shown in a formula ⑩.
The invention provides application of the Drimane-type sesquiterpene heterocyclic compound or the Drimane-type sesquiterpene heterocyclic compound prepared by the preparation method in resisting agricultural pathogenic bacteria.
In the invention, the agricultural pathogenic bacteria are preferably one or more of sheath blight germ (Rhizoctoniasolani) of rice, sheath blight germ (Rhizoctoniacerealis) of wheat, sclerotinia sclerotiorum (Sclerotiniascleotiorum), gibberella wheat (Fusarium graminearum), take-all germ (Gaeumanomycegraminis) of wheat, botrytis cinerea (Botrytiscinerea), late blight germ (Phytophthorainfestans) of potato, phytophthora capsici (Phytophthoracapsici), early blight germ (Alternariasolani) of tomato, bakanae disease germ (Fusariumfujikuroi) of rice, dry rot germ (Fusarium sulphureum) of potato, anthracnose germ (Colletotrichumlagenarium) of cucumber and rice blast germ (Phyricularia cerealis).
The Drimane-type sesquiterpene heterocyclic compounds, the preparation methods and applications thereof provided by the invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the invention.
Example 1
Sclareolide (10 g,32.4 mmol) was weighed and dissolved in a mixture of acetonitrile (21 mL) and carbon tetrachloride (21 mL), ruthenium trichloride trihydrate (428 mg,1.62 mmol) was weighed in a 500mL round bottom flask, sodium periodate (83.0 g, 3838 mmol) was dissolved in a mixture of water (84 mL), carbon tetrachloride (42 mL) and acetonitrile (42 mL), the mixture was heated to 40 ℃, sclareolide solution was slowly dropped into the mixture, the mixture was stirred at 40℃for 5 hours, ethyl acetate (300 mL) was added after cooling to room temperature, washed sequentially with water (100 mL. Times.3), sodium thiosulfate aqueous solution (100 mL. Times.3) and saturated sodium chloride aqueous solution (100 mL. Times.3), the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), the organic phase was combined, dried, concentrated under reduced pressure, and after silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester : 1-2: 1) was obtained as an ACID-OAc, white solid, 55%.
ACID-OAc (470 mg,1.5 mmol) was dissolved in dichloromethane (20 mL), 4-dimethylaminopyridine (38.0 mg,0.3 mmol) and phenylglycinol (315 mg,2.3 mmol) were added, then the above system was transferred to ice bath and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (382 mg,2.0 mmol) was added, stirred at room temperature, monitored by TLC tracking, after completion of the reaction, the organic phase was washed with water, saturated sodium chloride solution, respectively, and dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =1:1), AD-1 was obtained as a white solid in 68% yield.
1HNMR(500MHz,CDCl3)δ7.37–7.33(m,2H),7.31–7.27(m,3H),6.31(d,J＝6.7Hz,1H),5.03(td,J＝6.4,3.8Hz,1H),3.92–3.85(m,2H),2.72–2.66(m,1H),2.42–2.36(m,1H),2.25–2.18(m,2H),1.80(s,3H),1.75–1.65(m,2H),1.58–1.49(m,2H),1.45(s,3H),1.41–1.31(m,2H),1.30–1.19(m,1H),1.18–1.03(m,2H),1.01–0.93(m,1H),0.85(s,3H),0.82(s,3H),0.76(s,3H).
13CNMR(126MHz,CDCl3)δ174.96,170.45,139.14,129.09,128.17,126.92,87.31,67.25,56.58,56.01,55.53,41.70,39.24,39.19,38.86,33.36,33.21,22.82,21.52,20.39,20.00,18.23,15.75.
The amidol AD-1 (399mg, 0.9 mmol) was added to a Schlenk tube equipped with a magnetic stirrer, nitrogen was replaced 3 times, methylene chloride was added to dissolve and transfer to-78deg.C, diethylaminosulfur trifluoride (340 μL,2.8 mmol) was slowly added dropwise, the dropwise addition was completed and the reaction was stirred at-78deg.C, followed by TLC monitoring, after completion of the reaction, the reaction was quenched with water, washed with saturated sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =10:1), oxazoline OZ-1 was obtained as a white solid with a yield of 66%.
1HNMR(500MHz,CDCl3)δ7.35–7.31(m,2H),7.28–7.23(m,3H),5.16(dd,J＝10.1,8.4Hz,1H),4.61(dd,J＝10.2,8.4Hz,1H),4.08(t,J＝8.4Hz,1H),2.69(dt,J＝12.7,3.4Hz,1H),2.53(m,,1H),2.45(m,1H),2.32(dd,J＝6.3,4.0Hz,1H),1.86(s,3H),1.83–1.76(m,1H),1.71–1.65(m,2H),1.63–1.53(m,1H),1.50(s,3H),1.46–1.40(m,1H),1.39–1.34(m,1H),1.32–1.23(m,1H),1.18–1.08(m,3H),0.89(s,3H),0.86(s,3H),0.79(s,3H).
13CNMR(126MHz,CDCl3)δ170.38,170.07,142.64,128.73,127.57,126.78,86.56,74.62,69.70,55.27,55.07,41.75,39.31,39.25,38.66,33.46,33.23,24.52,23.09,21.58,20.35,19.99,18.45,15.50.
Oxazoline OZ-1 (207 mg,0.54 mmol) was weighed into a pear-shaped bottle, methanol (25 mL) was added for dissolution, potassium hydroxide (423 mg,7.56 mmol) was added at 0 ℃ for reflux of the reaction system, TLC was followed by monitoring, after the reaction was completed, 1MHCl was added at 0 ℃ for ph=7 to 8, extraction was performed with ethyl acetate (25 ml×2), washing was performed sequentially with water (30 mL), saturated sodium chloride aqueous solution (30 mL), drying was performed with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and after silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =3:1), a white solid was obtained, yield was 58%.
1HNMR(500MHz,CDCl3)δ7.34–7.31(m,2H),7.28–7.20(m,3H),5.12(t,J＝9.3Hz,1H),4.60(dd,J＝10.3,8.1Hz,1H),4.09–4.04(m,1H),2.58–2.53(m,1H),2.40(dd,J＝16.9,4.6Hz,1H)1.96–1.89(m,2H),1.70–1.63(m,2H),1.60–1.54(m,1H),1.51–1.41(m,2H),1.38–1.34(m,1H),1.30–1.21(m,1H),1.16(s,3H),1.15–0.99(m,3H),0.86(s,3H),0.82(s,3H),0.79(s,3H).
13CNMR(126MHz,CDCl3)δ171.68,142.43,128.81,127.97,127.64,126.78,125.92,75.04,73.32,69.46,58.12,55.85,44.42,41.83,39.50,38.97,33.47,33.38,23.79,23.48,21.59,20.56,18.58,15.35.
Example 2
ACID-89 (406 mg,1.6 mmol) was dissolved in dichloromethane (20 mL), 4-dimethylaminopyridine (40 mg,0.33 mmol) and phenylalaninol (268 mg,2.4 mmol) were added, then the above system was transferred to ice bath and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (405 mg,2.4 mmol) was added, stirred at room temperature, monitored by TLC tracking, after completion of the reaction, the organic phase was washed with water, saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =3:1), AD-9-1 was obtained as a colorless oil with a yield of 60%.
1HNMR(400MHz,CDCl3)δ7.33–7.27(m,2H),7.25–7.16(m,3H),6.10(d,J＝6.8Hz,1H),4.19–4.10(m,1H),3.62(dd,J＝4.9,1.4Hz,2H),3.00–2.93(m,1H),2.92–2.76(m,3H),2.06–1.91(m,2H),1.70–1.61(m,2H),1.58–1.45(m,1H),1.45–1.33(m,6H(s,3H)),1.08–0.92(m,3H),0.89(s,3H),0.84(s,3H),0.81(s,3H).
13CNMR(101MHz,CDCl3)δ172.73,137.15,135.40,131.89,129.30,128.79,126.86,64.64,53.08,51.88,41.65,38.69,36.81,36.05,35.94,33.36,33.34,33.23,21.62,19.95,19.88,18.80,18.78.
AD-9-1 (284 mg,0.75 mmol) was added to a Schlenk tube equipped with a magnetic stirrer, nitrogen was replaced 3 times, methylene chloride was added to dissolve and transfer to-78deg.C, diethylaminosulfur trifluoride (275 μL,2.2 mmol) was slowly added dropwise, the reaction was stirred at-78deg.C after the addition was completed, TLC was followed by monitoring, after the reaction was completed, the reaction was quenched with water, washed with saturated sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =20:1), OZ-9-1 was obtained in the form of a colorless oil with a yield of 50%.
1HNMR(400MHz,CDCl3)δ7.31–7.26(m,2H),7.23–7.17(m,3H),4.38–4.28(m,1H),4.10(t,J＝8.9Hz,1H),3.96–3.91(m,1H),3.11(dd,J＝13.7,4.8Hz,1H),3.00(q,J＝16.6Hz,2H),2.57(dd,J＝13.7,9.1Hz,1H),2.21–2.09(m,1H),2.01(dd,J＝17.9,6.5Hz,1H),1.77(m,1H),1.71–1.63(m,1H),1.60(s,3H),1.58–1.50(m,1H),1.50–1.45(m,1H),1.44–1.36(m,2H),1.28–1.11(m,3H),0.95(s,3H),0.89(s,3H),0.84(s,3H).
13CNMR(101MHz,CDCl3)δ167.94,138.23,134.53,129.94,129.38,128.57,126.49,71.52,67.41,51.41,41.72,41.69,38.85,36.60,33.67,33.41,33.29,26.95,21.77,20.24,19.98,19.10,19.04.
Example 3
ACID-812 (200 mg,0.8 mmol) was dissolved in dichloromethane (10 mL), 4-dimethylaminopyridine (19 mg,0.16 mmol) and phenylalaninol (181 mg,1.2 mmol) were added, then the above system was transferred to ice bath and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (199mg, 1.0 mmol) was added, stirred at room temperature, monitored by TLC tracking, after completion of the reaction, washed with water, saturated sodium chloride solution respectively, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =8:1), AD-12-1 was obtained as a colorless oil in 74% yield.
1HNMR(400MHz,CDCl3)δ7.31–7.26(m,2H),7.24–7.18(m,3H),5.94(s,1H),4.73(s,1H),4.47(s,1H),4.19–4.04(m,1H),3.63(m,1H),3.58–3.50(m,1H),3.23(m,1H),2.84(m,2H),2.40–2.31(m,2H),2.28–2.16(m,2H),2.08–1.97(m,1H),1.71(m,1H),1.57–1.44(m,3H),1.41–1.35(m,1H),1.30(dd,J＝12.9,4.3Hz,1H),1.15(m,3H),0.87(s,3H),0.79(s,3H),0.65(s,3H).
13CNMR(101MHz,CDCl3)δ173.97,149.25,137.81,129.32,128.72,126.71,106.68,64.30,55.19,53.02,52.53,42.05,39.24,38.97,37.78,36.96,33.67,33.60,32.70,24.13,21.81,19.37,14.64.
AD-12-1 (178 mg,0.46 mmol) was added to a Schlenk tube equipped with a magnetic stirrer, nitrogen was replaced 3 times, methylene chloride was added to dissolve and transfer to-78deg.C, diethylaminosulfur trifluoride (171 μL,1.4 mmol) was slowly added dropwise, the dropwise addition was completed and the reaction was stirred at-78deg.C, followed by monitoring by TLC, after completion of the reaction, the reaction was quenched with water, washed with saturated sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =9:1), OZ-12-1 was obtained in the form of a colorless oil with a yield of 49%.
1HNMR(400MHz,CDCl3)δ7.31–7.25(m,2H),7.23–7.16(m,3H),4.80(s,1H),4.64(s,1H),4.31(m,1H),4.09(t,J＝8.9Hz,1H),3.89(dd,J＝8.4,7.0Hz,1H),3.07(dd,J＝13.7,5.1Hz,1H),2.56(dd,J＝13.7,8.8Hz,1H),2.49–2.34(m,3H),2.31(dd,J＝9.5,4.4Hz,1H),2.11(td,J＝13.0,5.3Hz,1H),1.73(m,1H),1.66(m,1H),1.61–1.45(m,2H),1.44–1.36(m,1H),1.32(td,J＝12.8,4.3Hz,1H),1.25–1.12(m,3H),0.88(s,3H),0.82(s,3H),0.71(s,3H).
13CNMR(101MHz,CDCl3)δ168.46,148.63,138.31,129.33,128.59,126.49,107.06,71.53,67.41,55.20,53.02,42.17,41.86,39.32,39.04,37.86,33.75,33.66,24.46,24.16,21.87,19.45,14.31.
Example 4
ACID-78 (330 mg,1.3 mmol) was dissolved in dichloromethane (15 mL), 4-dimethylaminopyridine (32.0 mg,0.26 mmol) and phenylalaninol (319 mg,1.7 mmol) were added, then the above system was transferred to ice bath and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (329 mg,1.7 mmol) was added, stirred at room temperature, monitored by TLC tracking, after completion of the reaction, the organic phase was washed with water, saturated sodium chloride solution, respectively, dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =2:1), AD-8-1 was obtained as a colorless oil with a yield of 76%.
1HNMR(400MHz,CDCl3)δ7.33–7.27(m,2H),7.22(m,3H),5.90(d,J＝7.4Hz,1H),5.39(s,1H),4.23–4.12(m,1H),3.70–3.54(m,2H),3.22(m,1H),2.91(dd,J＝13.8,7.3Hz,1H),2.82(dd,J＝13.8,7.4Hz,1H),2.49–2.42(m,1H),2.25(dd,J＝15.7,2.8Hz,1H),1.96(m,3H),1.81(m,1H),1.61(m,1H),1.55(s,3H),1.51–1.35(m,3H),1.24(dd,J＝12.1,4.7Hz,1H),1.15(td,J＝13.0,4.2Hz,1H),1.03(td,J＝12.8,4.3Hz,1H),0.86(s,3H),0.85(s,3H),0.69(s,3H).
13CNMR(101MHz,CDCl3)δ174.90,137.71,133.97,129.28,128.79,126.81,122.88,64.47,53.15,50.48,49.81,42.12,39.20,37.07,36.05,34.66,33.28,33.03,23.77,21.97,21.81,18.88,14.28.
AD-8-1 (156 mg,0.4 mmol) was added to a Schlenk tube equipped with a magnetic stirrer, nitrogen was replaced 3 times, methylene chloride was added to dissolve and transfer to-78deg.C, diethylaminosulfur trifluoride (146 μL,1.2 mmol) was slowly added dropwise, the dropwise addition was completed and the reaction was stirred at-78deg.C, followed by monitoring by TLC, after completion of the reaction, the reaction was quenched with water, washed with saturated sodium carbonate solution, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. After silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =9:1), OZ-8-1 was obtained in 77% yield as colorless oil.
1HNMR(400MHz,CDCl3)δ7.31–7.26(m,2H),7.24–7.17(m,3H),5.42(s,1H),4.41–4.29(m,1H),4.14(dd,J＝9.3,8.5Hz,1H),3.94(dd,J＝8.5,7.2Hz,1H),3.09(dd,J＝13.7,5.0Hz,1H),2.63(dd,J＝13.7,8.7Hz,1H),2.45(d,J＝9.1Hz,1H),2.35(dt,J＝16.2,2.3Hz,1H),2.16(m,1H),2.05–1.92(m,1H),1.89–1.83(m,1H),1.79(m,1H),1.74(s,1H),1.63(s,3H),1.54(dt,J＝13.4,3.1Hz,1H),1.51–1.45(m,1H),1.45–1.38(m,1H),1.29(dd,J＝12.1,4.8Hz,1H),1.20(dd,J＝13.0,3.8Hz,1H),1.12(td,J＝13.1,3.9Hz,1H),0.88(s,4H),0.86(s,3H),0.77(s,3H).
13CNMR(101MHz,CDCl3)δ169.51,138.11,134.15,129.40,128.61,126.56,122.89,71.60,67.36,51.30,49.90,42.22,41.61,39.22,36.37,33.34,33.10,26.40,23.84,21.98(2C),18.97,13.81.
Example 5
Sclareolide (10.0 g,39.9 mmol) was weighed and dissolved in 150mL diethyl ether, 58mL1.6M methyl lithium was dissolved in 58mL diethyl ether solution, the methyl lithium solution was added dropwise to the sclareolide diethyl ether solution at-78deg.C, stirred for 1.5 hours at-78deg.C, quenched with 50mL10% aqueous H 2SO4, the organic phase was separated, extracted with diethyl ether (100 mL. Times.3), washed with aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give a crude methyl ketone product in 98% yield, which was used directly in the next reaction.
Methyl ketone (118.0 mg,0.43 mmol) was weighed and dissolved in a mixture of 50% aqueous potassium hydroxide (2 mL) and ethanol (2 mL), 2-aminobenzaldehyde (57.0 mg,0.47 mmol) was added, the reaction mixture was stirred at room temperature for 24 hours, ice water was added to quench the reaction system, the mixture was acidified with dilute acetic acid, extracted with ethyl acetate, and after washing with saturated sodium chloride solution (10 mL. Times.2), anhydrous sodium sulfate was dried, the solvent was distilled off under reduced pressure, and after silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =3:1), QL was obtained as a white solid in 91% yield.
1HNMR(500MHz,CDCl3)δ8.05(d,J＝8.4Hz,1H),7.98(d,J＝8.5Hz,1H),7.75(dd,J＝8.0,1.4Hz,1H),7.65(m,1.4Hz,1H),7.46(m,1.2Hz,1H),7.31(d,J＝8.4Hz,1H),3.17(dd,J＝15.5,5.5Hz,1H),2.96(dd,J＝15.5,2.7Hz,1H),2.04(dt,J＝12.5,3.1Hz,1H),1.91(dd,J＝5.5,2.7Hz,1H),1.82–1.77(m,1H),1.69(m,1H),1.64–1.53(m,2H),1.33(m,6H(s,3H)),1.04(td,J＝13.5,4.1Hz),0.95–093(m,4H(s,3H)),0.84(s,3H),0.80(s,3H),0.74(td,J＝13.2,3.9Hz,1H).
13CNMR(126MHz,CDCl3)δ164.50,147.12,137.00,129.75,128.32,127.52,126.57,125.97,121.85,72.53,61.18,56.22,44.35,41.92,39.76,39.54,34.39,33.44,33.38,24.99,21.53,20.61,18.56,15.83.
Example 6
Synthesis of intermediate AMINE
Compound a (2.4. G,9.04mmol,1 equiv.) is weighed into a eggplant-shaped bottle, diethylenetriamine (20 mL,180mmol,20 equiv.) is added, stirred for 12 hours (TLC monitored complete reaction) at 140 ℃, 30mL of water, ethyl acetate and methanol (20 ml×2,10:1, v/v) are slowly added thereto for extraction, the organic phase is washed with saturated sodium chloride, dried over anhydrous sodium sulfate, the solvent is spun dry under reduced pressure, and silica gel column chromatography (200-300 m, etoac/meoh=5:1) is separated to give intermediate AMINE, as a white solid, 1.1g, yield 49%.
2-Nitrobenzaldehyde (45 mg,0.3 mmol) and AMINE (79 mg,0.33 mmol) were weighed into a pear-shaped bottle, i-PrOH (1 mL) was added, stirring was performed at 80℃for 4 hours, tri-n-butylphosphine (225. Mu.L, 0.9 mmol) was added after the reaction system was cooled to room temperature, the reaction system was stirred at 80℃for 16 hours, cooled to room temperature, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride (10 mL) and saturated aqueous sodium chloride (10 mL) in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, after which silica gel column chromatography (eluent: V Petroleum ether /V Acetic acid ethyl ester =1:1) was performed to give IZ as a white solid in 82% yield.
1HNMR(400MHz,CDCl3)δ7.96(s,1H),7.64(m,2H),7.28–7.24(m,1H),7.06(m,1H),4.65(dd,J＝14.3,4.6Hz,1H),4.44(dd,J＝14.3,3.7Hz,1H),4.18(br,1H),2.00–1.92(m,2H),1.84–1.78(m,1H),1.72–1.65(m,1H),1.64–1.56(m,1H),1.56–1.46(m,1H),1.44–1.25(m,7H(s,3H)),1.06(td,J＝13.5,4.1Hz,1H),0.95(s,3H),0.93–0.86(m,1H),0.85(s,3H),0.81(s,3H).
13CNMR(101MHz,CDCl3)δ148.55,126.09,123.42,121.95,121.71,120.16,117.30,72.42,62.56,55.83,50.25,44.08,41.64,39.30,39.06,33.45,33.37,24.85,21.54,20.45,18.40,16.06.
Application example
The bacterial inhibition activity of the drimane type sesquiterpene heterocyclic compound is evaluated by adopting a flat plate hypha inhibition growth rate method, and a test strain is selected to activate PDA flat plates, wherein the test strain comprises common agricultural pathogenic bacteria such as sclerotinia sclerotiorum (Sclerotiniasclerotiorum), rhizoctonia solani (Rhizoctoniasolani) and Botrytis cinerea (Botrytiscinerea). Preparing the compound into PDA drug-containing plates with serial gradient concentration, preparing a test strain into a bacterial cake with the diameter of 5mm, placing the bacterial cake in the center of a drug-containing culture dish, culturing the bacterial cake at the constant temperature of 25 ℃ until the test strain in a blank control dish grows to be close to the edge of the culture dish, measuring the colony diameter of each drug-containing plate by using a crisscross method, calculating the inhibition rate of the compound on hypha growth, and calculating the inhibition rate on diseases according to the following formula:
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the results of the antibacterial activity test of Drimane type sesquiterpene heterocyclic compounds on 3 agricultural fungi are shown in table 2.
Table 2Drimane antibacterial Activity of sesquiterpene heterocycles against agricultural pathogens (EC 50, μM)
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As can be seen from Table 1, the Drimane-type sesquiterpene heterocycles exhibited moderate to excellent bacteriostatic activity against the tested pathogens, where OZ-1 exhibited broad-spectrum bactericidal activity, and EC 50 against Rhizoctonia solani, sclerotinia solani and Botrytis cinerea were 38.20. Mu.M, 27.10. Mu.M and 51.14. Mu.M, respectively. Drimane oxazoline substituent groups have a certain influence on antibacterial activity. Oxazolines with C8-C9 double bond drimane skeleton have better activity on rice sheath blight pathogenic bacteria, and EC 50 of OZ-9-2 and OZ-9-3 are 7.20 mu M and 7.25 mu M respectively. When the skeleton is the same Drimane, the change of the heterocyclic type has a significant effect on the antibacterial activity, and the activity of quinoline QL and 2H-indazole IZ on rice sheath blight pathogenic bacteria is obviously improved compared with that of oxazoline, and the EC 50 is 9.89 mu M and 8.24 mu M respectively for the C8-OHDrimane skeleton.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (8)
1. A Drimane-type sesquiterpene heterocyclic compound, which has a structure shown in a formula I, a formula II or a formula III:
in the formula I, the 8-position and 9-position dotted lines are double bonds or the 8-position and 12-position dotted lines are double bonds, and when the 8-position and 9-position dotted lines in the formula I are double bonds or the 8-position and 12-position dotted lines are double bonds, the rest dotted lines are single bonds; heterocycles are oxazoline groups;
In the formula II, the hetercycles are oxazoline groups;
in the formula III, the hetercycles are oxazoline groups, quinoline groups or 2H indazole groups;
the oxazoline group is
One of the following;
The quinolinyl group is one of quinolinyl, 6-methylquinolinyl, 8-methylquinolinyl, 5-methylquinolinyl, 7-methoxyquinolinyl, 7, 8-dimethoxyquinolinyl, 6-nitroquinolinyl, 7-nitroquinolinyl, 5-chloroquinolinyl, 7-chloroquinolinyl, 6-chloro-2-methylquinolinyl, 5-fluoroquinolinyl, 6, 8-dibromoquinolinyl, 6-bromoquinolinyl, 7-trifluoromethyl quinolinyl and 6-iodoquinolinyl;
The 2H indazole group is one of 2H indazolyl, 5-bromo-2H indazolyl, 6-chloro-2H indazolyl, 4-cyano-2H indazolyl, 5-fluoro-2H indazolyl, 4-chloro-2H indazolyl, 4-trifluoromethyl-2H indazolyl, 4-methoxy-2H indazolyl, 5-methoxy-2H indazolyl, N-dimethyl-2H indazolyl and 4-methyl formate-2H indazolyl.
2. The Drimane-type sesquiterpene heterocyclic compound according to claim 1, wherein in the formula I, the formula II or the formula III, the carbon atom stereo configuration connected with the oxazoline group is R-type or S-type.
3. The process for producing a Drimane-type sesquiterpene heterocycle compound according to any one of claim 1 to 2, characterized in that,
When the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula I, the preparation method comprises the following steps:
(1) Under the action of diisobutyl aluminum hydride, sclareolide undergoes a reduction reaction to obtain a hemiacetal compound with a structure shown in a formula a;
under the action of boron trifluoride diethyl ether, carrying out hydrolysis reaction on the hemiacetal compound with the structure shown in the formula a to obtain an aldehyde compound with a delta 8,9 double bond shown in the formula b;
Under the action of an oxidant, carrying out oxidation reaction on a compound with a structure shown in a formula b to obtain an acid compound with a delta 8,9 -bit double bond with a structure shown in a formula c;
(2) Performing ring-opening reaction on sclareolide and N, O-dimethylhydroxylamine hydrochloride to obtain an amide compound with a structure shown in a formula d;
carrying out dehydration reaction on the amide compound with the structure shown in the formula d to obtain a delta 8,12 -position double bond amide compound with the structure shown in the formula e;
Under the action of diisobutyl aluminum hydride, performing reduction reaction on the delta 8,12 -position double bond amide compound with the structure shown in the formula e to obtain a delta 8,12 -position double bond aldehyde compound with the structure shown in the formula f;
Under the action of an oxidant, carrying out oxidation reaction on an aldehyde compound with a delta 8,12 -position double bond and a structure shown in a formula f to obtain an acid compound with a delta 8,12 -position double bond and a structure shown in a formula g;
(3) Under the acidic condition, carrying out configuration conversion on sclareolide to obtain C8-S sclareolide with a structure shown in a formula h;
performing ring-opening reaction on C8-S-type sclareolide with a structure shown in formula h and N, O-dimethylhydroxylamine hydrochloride to obtain an amide compound with a structure shown in formula i;
Carrying out dehydration reaction on the amide compound with the structure shown in the formula i to obtain a delta 7,8 -position double bond amide compound with the structure shown in the formula j;
Under the action of lithium aluminum hydride, performing reduction reaction on the delta 7,8 -position double bond amide compound with the structure shown in the formula j to obtain a delta 7,8 -position double bond aldehyde compound with the structure shown in the formula k;
Under the action of an oxidant, carrying out oxidation reaction on an aldehyde compound with a delta 7,8 -position double bond and a structure shown in a formula k to obtain an acid compound with a delta 7,8 -position double bond and a structure shown in a formula l;
(4) Performing condensation reaction on an acid compound with a delta 8,9 -position double bond shown in a formula c, an acid compound with a delta 8,12 -position double bond shown in a formula g or an acid compound with a delta 7,8 -position double bond shown in a formula l and a chiral amino alcohol compound to obtain an amide alcohol intermediate;
Under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate undergoes cyclization reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with a structure shown in a formula I;
(II) when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula II, the method comprises the following steps:
Under the catalysis of ruthenium trichloride, sclareol and an oxidant are subjected to oxidation reaction to obtain an intermediate acid with a structure shown in a formula m;
Performing condensation reaction on the intermediate acid with the structure shown in the formula m and a chiral amino alcohol compound to obtain an amide alcohol intermediate;
Under the action of diethylaminosulfur trifluoride, the amide alcohol intermediate undergoes cyclization reaction to obtain Drimane-type sesquiterpene heterocyclic compounds with a structure shown in a formula II;
(III) when the Drimane-type sesquiterpene heterocyclic compound has a structure shown in a formula III, the method comprises the following steps:
(i) When the hetercycles are oxazoline groups, comprising the steps of:
Under the action of organic strong alkali, carrying out hydrolysis reaction on the Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula II to obtain a Drimane type sesquiterpene heterocyclic compound with the structure shown in the formula III;
(ii) When the hetercycles are quinolines, the method comprises the steps of:
performing ring-opening reaction on sclareolide and methyl lithium to obtain an intermediate ketone compound with a structure shown in formula n;
Performing a Foldebrand quinoline synthesis reaction on an intermediate ketone compound with a structure shown in a formula n and a 2-aminobenzaldehyde compound to obtain a Drimane-type sesquiterpene heterocyclic compound with a structure shown in a formula III;
(iii) When the hetercycles are 2H indazole groups, the method comprises the following steps:
Under the catalysis of sodium methoxide, sclareolide and NH 3 are subjected to ammonolysis reaction to obtain a compound with a structure shown in a formula o;
Under alkaline conditions, carrying out Huffman rearrangement reaction on the compound with the structure shown in the formula o to obtain a compound with the structure shown in the formula p;
under the action of diethylenetriamine, carrying out alkaline hydrolysis reaction on a compound with a structure shown in a formula p to obtain an intermediate amine compound with a structure shown in a formula q;
under the action of tri-n-butyl phosphine, an intermediate amine compound with a structure shown in a formula q and a 2-nitrobenzaldehyde compound are subjected to a reduction cyclization reaction to obtain the Drimane type sesquiterpene heterocyclic compound with a structure shown in a formula III.
4. The method according to claim 3, wherein in the step (1) in the step (one), the temperature of the reduction reaction is-80 to-60 ℃;
the oxidant is sodium chlorite;
In the step (2) in the step (one), the temperature of the ring-opening reaction is-10-35 ℃;
the catalyst for the dehydration reaction is thionyl chloride and pyridine, and the temperature of the dehydration reaction is-80 to-60 ℃;
The temperature of the reduction reaction is-80 to-60 ℃;
the oxidant is sodium chlorite;
In the step (3) of the step (one), the temperature of the ring-opening reaction is-10-35 ℃;
the catalyst for the dehydration reaction is thionyl chloride and pyridine, and the temperature of the dehydration reaction is-20 ℃;
The temperature of the reduction reaction is-80 to-60 ℃;
the oxidant is sodium chlorite;
in the step (4) of the step (one), the temperature of the condensation reaction is 0-room temperature;
The temperature of the cyclization reaction is-80 to-60 ℃.
5. The method according to claim 3, wherein in the step (two), the temperature of the oxidation reaction is 40 ℃;
The temperature of the condensation reaction is 0-room temperature;
The temperature of the cyclization reaction is-80 to-60 ℃.
6. The method according to claim 3, wherein in the step (i) of the step (three), the hydrolysis reaction temperature is 0 to reflux temperature;
In the step (ii) of the step (three), the temperature of the ring-opening reaction is-80 to-60 ℃;
the temperature of the synthesis reaction of the friedel-crafts quinoline is room temperature;
In the step (iii) of the step (III), the temperature of the ammonolysis reaction is 40-80 ℃;
The temperature of the Huffman rearrangement reaction is 0-room temperature;
the temperature of the alkaline hydrolysis reaction is 120-160 ℃;
The reaction temperature of the reductive cyclization is 60-100 ℃.
7. Use of the Drimane-type sesquiterpene heterocyclic compound according to any one of claims 1-2 or the Drimane-type sesquiterpene heterocyclic compound prepared by the preparation method according to any one of claims 3-6 in resisting agricultural pathogenic bacteria.
8. The use according to claim 7, wherein the agricultural pathogenic bacteria are one or more of sheath blight of rice, sheath blight of wheat, sclerotinia rot of rape, gibberella wheat, take-all of wheat, botrytis cinerea, late blight of potato, phytophthora capsici, early blight of tomato, bakanae disease of rice, dry rot of potato, anthracnose of cucumber and rice blast.
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