CN110698322A - 一种滨海孪生花烷二萜Stemarin的合成方法 - Google Patents
一种滨海孪生花烷二萜Stemarin的合成方法 Download PDFInfo
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- CN110698322A CN110698322A CN201910978471.2A CN201910978471A CN110698322A CN 110698322 A CN110698322 A CN 110698322A CN 201910978471 A CN201910978471 A CN 201910978471A CN 110698322 A CN110698322 A CN 110698322A
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- FTJVSKZQYPUTJW-UHFFFAOYSA-N stemarin Natural products CC1(O)CC2CCC3C(C)(CO)CCCC3(C)C24CCC1C4 FTJVSKZQYPUTJW-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229930004069 diterpene Natural products 0.000 title claims abstract description 22
- 150000004141 diterpene derivatives Chemical class 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title description 3
- -1 diterpene compounds Chemical class 0.000 claims abstract description 68
- 238000000034 method Methods 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims description 59
- 238000003756 stirring Methods 0.000 claims description 53
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims description 32
- 150000002576 ketones Chemical class 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 21
- 150000003333 secondary alcohols Chemical class 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 18
- 150000002009 diols Chemical class 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 16
- 229910052751 metal Inorganic materials 0.000 claims description 16
- 239000002184 metal Substances 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000004593 Epoxy Substances 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 150000001336 alkenes Chemical group 0.000 claims description 12
- 150000007970 thio esters Chemical class 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 10
- 235000017060 Arachis glabrata Nutrition 0.000 claims description 9
- 241001553178 Arachis glabrata Species 0.000 claims description 9
- 235000010777 Arachis hypogaea Nutrition 0.000 claims description 9
- 235000018262 Arachis monticola Nutrition 0.000 claims description 9
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical group S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001299 aldehydes Chemical class 0.000 claims description 9
- 235000020232 peanut Nutrition 0.000 claims description 9
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 9
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 8
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 claims description 8
- 150000003863 ammonium salts Chemical class 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 229940125758 compound 15 Drugs 0.000 claims description 8
- 125000005594 diketone group Chemical group 0.000 claims description 8
- 238000011065 in-situ storage Methods 0.000 claims description 8
- 150000002596 lactones Chemical class 0.000 claims description 8
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 150000002497 iodine compounds Chemical class 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 7
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 6
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical group N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- 229940126657 Compound 17 Drugs 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 229940126543 compound 14 Drugs 0.000 claims description 6
- 229940126086 compound 21 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 6
- 150000002989 phenols Chemical class 0.000 claims description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical group [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 229940125797 compound 12 Drugs 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 239000003999 initiator Substances 0.000 claims description 5
- 150000003254 radicals Chemical class 0.000 claims description 5
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 4
- 229940126142 compound 16 Drugs 0.000 claims description 4
- 229940125782 compound 2 Drugs 0.000 claims description 4
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 claims description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 4
- 229960002317 succinimide Drugs 0.000 claims description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims description 4
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 claims description 3
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 3
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- RMGJCSHZTFKPNO-UHFFFAOYSA-M magnesium;ethene;bromide Chemical compound [Mg+2].[Br-].[CH-]=C RMGJCSHZTFKPNO-UHFFFAOYSA-M 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical group CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 claims description 3
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- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 claims description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 2
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 claims description 2
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- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- NEGUMGNBGIFXAL-UHFFFAOYSA-N 3-methyl-3-(trifluoromethyl)dioxirane Chemical compound FC(F)(F)C1(C)OO1 NEGUMGNBGIFXAL-UHFFFAOYSA-N 0.000 claims description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 claims description 2
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 claims description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012448 Lithium borohydride Substances 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 2
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- LRIUKPUCKCECPT-UHFFFAOYSA-N [hydroxy(phenyl)-$l^{3}-iodanyl] 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OI(O)C1=CC=CC=C1 LRIUKPUCKCECPT-UHFFFAOYSA-N 0.000 claims description 2
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- KYIKRXIYLAGAKQ-UHFFFAOYSA-N abcn Chemical compound C1CCCCC1(C#N)N=NC1(C#N)CCCCC1 KYIKRXIYLAGAKQ-UHFFFAOYSA-N 0.000 claims description 2
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- NYENCOMLZDQKNH-UHFFFAOYSA-K bis(trifluoromethylsulfonyloxy)bismuthanyl trifluoromethanesulfonate Chemical compound [Bi+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F NYENCOMLZDQKNH-UHFFFAOYSA-K 0.000 claims description 2
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- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000005730 ring rearrangement reaction Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229930004725 sesquiterpene Natural products 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical group [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了一种滨海孪生花烷二萜Stemarin的合成方法,属于有机化学合成领域,该合成方法以环氧烯丙基溴2和硫缩酮3为反应原料,经过阳离子多烯串联反应,拜耳‑维利格氧化重排反应,氧化去芳香化环加成反应等关键步骤,最后通过官能团转化反应得到目标产物滨海孪生花烷二萜Stemarin。本发明的合成路线设计思路新颖,原料易得,制备方法操作简便,条件温和,容易实现各个重要官能团的改造,方便合成多种滨海孪生花烷二萜结构的衍生物,为滨海孪生花烷二萜类化合物结构‑生物活性的全面研究打下基础。
Description
技术领域
本发明涉及天然产物Stemarin的合成方法,具体涉及一种滨海孪生花烷二萜Stemarin的化学合成方法。
背景技术
天然产物是药物发现的重要源泉,在现代药物研发中扮有重要的角色,根据统计,在2008~2018年期间,先后有100个天然产物及其衍生物经美国FDA或欧盟EMA批准进入临床研究,其中有8个最终作为新药批准上市。在当前新药研发资金投入大、时间周期长、成药率低的背景下,不难发现,天然产物及其衍生物在现代药物研发中具有不可替代的位置。
然而,由于通过分离得到的天然产物量通常很少,科学家没有机会对它们中的绝大部分进行深入的研究,因此,天然产物全合成就成为衔接活性成分发现和药物化学研究的重要中间环节。对于具有重要骨架特征和生物活性的天然产物进行全合成不仅可以为药物化学提供足够的实验材料,开发具有自主知识产权的新药,而且对合成化学学科的发展也具有重要的推动作用。
其中,二萜化合物在化学合成上均是以焦磷酸香叶基香叶酯作为前体,经酶催化转化而来的一大类天然产物,多数含有20个碳原子,相当于四个异戊烯基结构单元,根据骨架环系类型主要可分为无环、二环、三环、四环和大环二萜。在萜类化合物中,二萜类化合物是除倍半萜类外迄今为止结构类型最丰富的和发现化合物种类最多的一类天然产物。
这其中,滨海孪生花素Stemarin属于滨海孪生花烷二萜化合物,早在1975 年被发现后,目前仅有一例关于此天然产物的合成报道,该合成路线以外消旋的高度团能团化的三环烯酮出发,主要步骤为联烯参与的光促环加成反应,酸催化的逆-羟醛/羟醛反应以及热促的环重排反应。
该报道路线虽然比较简单,但是不可忽略的是作者是以结构复杂的非商业化的三环烯酮为起始原料,由此增加的整体合成路线的复杂度,其次,该工作并未实现Stemarin的不对称全合成(A total synthesis of(±)-stemarin,a diterpenoid with a uniquebicyclic C/D ring System.J.Can.J.Chem.1980,58,755–756.)。
因此,通过化学合成的方法实现二萜类天然产物的全合成,通过手性诱导的方法使二萜类化合物具有多种多样的生物活性,是有机化学们一直努力的方向。由于滨海孪生花素类化合物在治疗疾病等方面具有极高的价值,虽然该类化合物的合成方法已有公开,但是对于该类化合物的生物活性研究却未见报道,因此制备一定数量的Stemarin及其衍生物对于开展相应的药物活性研究具有重要的意义。
发明内容
本发明采用汇聚式策略,从光学纯原料出发,各步反应位点可控,收率较高,首次实现了滨海孪生花素Stemarin的不对称全合成,为进一步研究滨海孪生花烷二萜类化合物的结构-生物活性打下基础。
一种滨海孪生花烷二萜Stemarin的合成方法,包括:
步骤1:将环氧烯丙基溴化合物2与硫缩酮化合物3溶解于有机溶剂中,加入锂试剂,于-25℃~0℃环境下,搅拌,得到环氧类化合物4;
步骤2:将环氧类化合物4溶解于有机溶剂中,于-78℃~-25℃环境下加入酸,搅拌,得到仲醇类化合物5;
步骤3:将仲醇类化合物5溶解于有机溶剂中,在有机膦化合物和偶氮化合物作用下,反应温度为25℃~50℃下,搅拌,得到烯烃类化合物6;
步骤4:将烯烃类化合物6溶解于有机溶剂中,于-25℃~0℃条件下加入高价碘化合物和碳酸盐,搅拌,得到酮类化合物7;
步骤5:将酮类化合物7溶解于有机溶剂中,于25℃~50℃环境下加入金属催化剂,得到酮类化合物8;
步骤6:将酮类化合物8溶解于有机溶剂中,于25℃~50℃环境中加入脱硅试剂,得到酚类化合物9;
步骤7:将酚类化合物9溶解于有机溶剂中,于-78℃~-25℃环境中加入有机胺和三氟甲磺酰基化试剂,反应得到三氟甲磺酸酯中间体10;
步骤8:将三氟甲磺酸酯中间体10溶解于有机溶剂中,加入金属催化剂、有机膦化合物、有机胺和有机酸,于80℃~120℃条件下,搅拌,得到三环酮类化合物11;
步骤9:将三环酮类化合物11溶解于有机溶剂中,于-25℃~0℃条件下加入无机盐和过氧化合物,得到内酯类化合物12;
步骤10:将内酯类化合物12溶解于有机溶剂中,于-78℃~-25℃条件下加入负氢还原剂,得到醛类化合物13;
步骤11:将醛类化合物13溶解于有机溶剂中,于-78℃~-25℃条件下加入乙烯基溴化镁,反应1-5h后,恢复室温,并在室温加入醇,有机胺和乙酰化试剂,搅拌,得到烯丙醇乙酰酯类化合物14;
步骤12:将烯丙醇乙酰酯类化合物14溶解于有机溶剂中,加入金属催化剂和铵盐后,于80℃~120℃条件下搅拌,得到端烯类化合物15;
步骤13:将端烯类化合物15溶解于有机溶剂中,加入高价碘化合物后,于-25℃~0℃条件下搅拌,得到二酮类化合物16;
步骤14:将二酮类化合物16溶解于有机溶剂中,加入负氢还原剂后于-78℃~-25℃条件下搅拌,得到二醇类化合物17;
步骤15:将二醇类化合物17溶解于有机溶剂中,加入无机盐水溶液、有机铵盐、2,2,6,6-四甲基哌啶氧化物和琥珀酰亚胺类化合物,室温下搅拌,得到仲醇类化合物18;
步骤16:将仲醇类化合物18溶解于有机溶剂中,加入金属催化剂后与氢气氛围下,在-25℃~0℃条件下,搅拌,得到二醇类化合物19;
步骤17:将二醇类化合物19溶解于有机溶剂中,加入锂试剂、有机胺和硫代酯制备试剂,于25℃~50℃条件下,搅拌,得到硫代酯中间体20;
步骤18:将硫代酯中间体20溶解于有机溶剂中,加入自由基引发剂和氢自由基给体试剂后,于80℃~120℃条件下,搅拌,得到酮类化合物21;
步骤19:将酮类化合物21溶解于有机溶剂中,加入甲基金属试剂,反室温下搅拌,得到滨海孪生花烷二萜Stemarin,其结构如式I所示:
优选的,步骤1中,所述锂试剂为正丁基锂、仲丁基锂、叔丁基锂或六甲基二硅基氨基锂;所述硫缩酮化合物3、锂试剂和环氧烯丙基溴化合物2的物质的量比为1:1~2:0.5~1.5;所述硫缩酮化合物3与有机溶剂的比为1mmol:1~10mL。
优选的,步骤2中,所述酸为三氟化硼乙醚络合物、三氟化硼四氢呋喃络合物、二乙基氯化铝、乙基二氯化铝、三甲基铝、四氯化锡、四氯化钛、三溴化铟、三氟甲磺酸酯铋、六水氯化铁、对甲苯磺酸一水合物,对甲苯磺酸吡啶盐、(D)- 樟脑磺酸、盐酸、硫酸、多聚磷酸、氟硼酸、四丁基四氟硼酸铵、四苯基四氟硼酸膦、三氟甲磺酸三甲基硅酯、叔丁基二甲硅基三氟甲磺酸酯或三(五氟苯基)硼烷;所述环氧类化合物4与酸的物质的量比为1:0.5~5;所述环氧类化合物4 的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤3中,所述偶氮化合物为偶氮二甲酸二乙酯或氮二甲酸二异丙酯;所述仲醇类化合物5、有机膦化合物和偶氮化合物的物质的量比为1:1~10: 1~10;所述仲醇类化合物5的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤4中,所述烯烃类化合物6、高价碘化合物和无机盐的物质的量比为1:1~5:1~10;所述烯烃类化合物6的物质的量与有机溶剂的体积比为 1mmol:10~20mL。
优选的,步骤5中,所述酮类化合物7与金属催化剂的重量比为1:0.1~1;所述酮类化合物7的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤6中,所述脱硅试剂为四丁基氟化铵、氟化氢水溶液、氟化氢吡啶、氟化钾、氟化铯或对甲苯磺酸一水合物;所述酮类化合物8与脱硅试剂的物质的量比为1:15;所述酮类化合物8的物质的量与有机溶剂的体积比为1mmol: 10~20mL。
优选的,步骤7中,所述酚类化合物9、有机胺和三氟甲磺酰基化试剂的物质的量比为1:1~5:1~5;所述酚类化合物9的物质的量与有机溶剂的体积比为 1mmol:5~15mL。
优选的,步骤8中,所述有机酸为甲酸、乙酸、丙酸或苯甲酸;所述三氟甲磺酸酯中间体10、钯催化剂、有机膦化合物、有机胺和有机酸的物质的量比为1: 0.01~0.5:0.01~0.5:1~5:1~5;所述三氟甲磺酸酯中间体10的物质的量与有机溶剂的体积比为1mmol:5~15mL。
优选的,步骤9中,所述过氧化合物为间氯过氧苯甲酸、原位制备的二甲基过氧化酮、原位制备的甲基(三氟甲基)二氧杂环丙烷、原位制备的过氧三氟乙酸或原位制备的过氧乙酸;所述三环酮类化合物11、无机盐和过氧化合物的物质的量比为1:1~10:1~5;所述三环酮类化合物11的物质的量与有机溶剂的体积比为1mmol:5~15mL。
优选的,步骤10中,所述负氢还原剂为硼氢化钠、硼氢化锂、硼氢化锌、三叔丁氧基氢化铝锂、三仲丁基硼氢化锂、二异丁基氢化铝、氢化铝锂或硼氢化镍;所述内酯类化合物12和负氢还原剂的物质的量比为1:1~5;所述内酯类化合物12的物质的量与有机溶剂的体积比为1mmol:5~15mL。
优选的,步骤11中,所述醇为甲醇、乙醇或异丙醇;所述乙酰化试剂为乙酸酐、乙酰氯或乙酸异丙烯酯;所述醛类化合物13、乙烯基溴化镁、醇、有机胺和乙酰化试剂的物质的量比为1:1~5:1~5:1~5:1~5;所述醛类化合物13 的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤12中,所述铵盐为甲酸铵、乙酸铵、氯化铵或碳酸铵;所述烯丙醇酯类化合物14、钯催化剂和铵盐的物质的量比为1:0.1~1:1~50;所述烯丙醇酯类化合物14的物质的量与有机溶剂的体积比为1mmol:5~15mL。
优选的,步骤13中,所述端烯类化合物15和高价碘试剂的物质的量比为1: 1~5;所述端烯类化合物15的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤14中,所述二酮类化合物15和负氢还原剂的物质的量比为1: 1~5;所述二酮类化合物15的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤15中,所述有机铵盐为四丁基碘化铵、四丁基溴化铵或四丁基氯化铵;所述琥珀酰亚胺类化合物为N-氯代丁二烯亚胺、N-溴代丁二烯亚胺或N-碘代丁二烯亚胺;所述二醇类化合物17、有机铵盐、2,2,6,6-四甲基哌啶氧化物和琥珀酰亚胺类化合物的物质的量比为1:1~5:0.1~2:10~50;所述二醇类化合物17的物质的量、无机盐水溶液和有机溶剂的体积比为1mmol:5~15mL: 5~15mL。
优选的,步骤16中,所述二醇类化合物19与金属催化剂的重量比为1:0.1~1;所述二醇类化合物19的物质的量与有机溶剂的体积比为1mmol:5~15mL。
优选的,步骤17中,所述硫代酯制备试剂为二硫化碳/碘甲烷、N,N'-硫羰基二咪唑或硫代氯甲酸苯酯;所述仲醇类化合物19、有机胺和硫代酯制备试剂的物质的量比为1:1~5:1~10;所述仲醇类化合物19的物质的量与有机溶剂的体积比为1mmol:10~20mL。
优选的,步骤18中,所述自由基引发剂为偶氮二异丁氰、三乙基硼或1,1'- 偶氮双(环己烷甲腈);所述氢自由基给体试剂为三丁基氢化锡或三(三甲基硅基) 硅烷;所述硫代酯中间体20、自由基引发剂和氢自由基给体试剂的物质的量比为1:0.1~2:1~5;所述硫代酯中间体20的物质的量与有机溶剂的体积比为1mmol: 10~20mL。
优选的,步骤19中,所述甲基金属试剂为甲基锂或甲基溴化镁;所述酮类化合物21与甲基金属试剂的物质的量比为1:1~5;所述酮类化合物21的物质的量与有机溶剂的体积比为1mmol:5~15mL。
优选的,所述有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙醚、甲苯、二氯甲烷、甲醇、乙醇、异丙醇、乙腈、1,2-二氯乙烷、乙酸乙酯、苯、二苯醚、N,N- 二甲基甲酰胺、N,N-二甲基乙酰胺、2,2,2-三氟乙醇、水、六氟异丙醇和硝基甲烷中的一种或几种。
优选的,所述有机胺为三乙胺、二乙胺、叔丁胺、二异丙胺、吡啶、2,6-二叔丁基吡啶或4-二甲氨基吡啶。
优选的,所述金属催化剂为钯/碳、钯/硫酸钡、氢氧化钯、Lindlar钯、二氧化铂或Crabtree催化剂;乙酸钯、四(三苯基膦)钯、氯化钯、双(乙腈)二氯化钯、 [1,1'-双(二苯基膦基)二茂铁]二氯化钯或二(三苯基膦)氯化钯。
优选的,所述无机盐为碳酸钠、碳酸氢钠、碳酸钾、碳酸钙、碳酸铯、碳酸锂、碳酸氢钾、磷酸钠、磷酸氢二钠、磷酸二氢钠、磷酸钾、磷酸氢二钾或磷酸二氢钾。
优选的,步骤3或步骤8中,所述有机膦化合物为三苯基膦、三丁基膦、三乙基膦或三甲基膦、1,2-双(二苯基膦)乙烷、1,3-双(二苯基膦)丙烷、1,4-双(二苯基膦)丁烷或1,5-双(二苯基膦)戊烷。
优选的,步骤4或步骤13中,所述高价碘化合物为碘苯二乙酸、[双(三氟乙酰氧基)碘]苯、2-碘酰基苯甲酸、戴斯-马丁氧化剂或[羟基(对甲苯磺酰氧基)碘] 苯。
本发明具有的有益效果:
(1)本发明所采用的合成路线是以易制备的环氧烯丙基溴化合物2和硫缩酮化合物3为原料,经过阳离子多烯串联反应,拜耳-维利格氧化重排反应,氧化去芳香化环加成反应等关键步骤,最后经过官能团转化得到目标产物。
(2)本发明的制备方法操作简便,条件温和,合成的产物与天然产物的波谱数据一致。
(3)本发明的合成路线设计思路新颖,原料易得,容易实现各个重要官能团的改造,方便合成多种Stemarin的结构衍生物,为全面的结构-生物活性研究打下基础。
附图说明
图1为本发明中滨海孪生花素Stemarin化合物的合成路线图;
图2为本发明中滨海孪生花素Stemarin化合物的氢谱;
图3为本发明中滨海孪生花素Stemarin化合物的碳谱。
具体实施方式
以下再通过实施例形式的具体实施方式对本发明的上述内容作进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限以下的实施例,凡基于本发明上述内容所实现的技术均属于本发明的范围。
步骤1:
其中,TIPS为三异丙基硅烷;
将(35.31g,88.57mmol)硫缩酮(3)溶于四氢呋喃(450mL)中,在0℃下将正丁基锂(55mL,2.4M in THF,132.86mmol)加入到反应液中,0℃下反应1小时,然后在0℃下向反应液中加入(24.04g,70.86mmol)环氧烯丙基溴(2)的四氢呋喃溶液(300mL),0℃下反应1小时,200mL饱和氯化铵溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到黄色油状化合物,即为环氧(4)(40.40g,61.49mmol,87%)。
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.43(dd,J=6.8,2.8Hz,1H), 7.36–7.32(m,4H),7.30–7.27(m,1H),6.86–6.82(m,2H),4.86–4.80(m,1H),4.54 (dd,J=12.0,25.4Hz,2H),3.87(s,3H),3.42(dd,J=11.0,53.6Hz,2H),3.12(d,J =7.0Hz,2H),2.90–2.66(m,6H),2.03–1.91(m,4H),1.60(s,3H),1.59–1.58(m,2 H),1.56–1.46(m,2H),1.33–1.22(m,3H),1.10(s,9H),1.08ppm(s,9H);
13C NMR(100MHz,CDCl3)δ=150.4,150.2,138.3,136.9,135.0,128.5(2C), 127.8(2C),127.7,124.6,122.0,120.4,119.6,75.1,73.2,60.6,60.4,60.0,57.1,39.9, 36.4,28.1(2C),26.8,25.1,18.0(6C),16.8,14.5,13.1ppm(3C);
高分辨质谱结果为:HRMS(ESI):calcd for C37H56NaO4S2Si+[M+Na]+ 679.3281,found 679.3290.
步骤2:
将(30.00g,45.66mmol)环氧(4)溶解于甲苯(600mL)中,在-78℃下将三氟化硼乙醚络合物(14.4mL,114.15mmol)加入到反应液中,-78℃下反应1小时,200mL 饱和碳酸氢钠溶液淬灭反应,经二氯甲烷萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为仲醇(5)(15.13 g,23.03mmol,50%)。
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.41–7.33(m,5H),6.84(dd,J=8.8,14.1Hz,2H),4.61(dd,J=11.8,34.0Hz,2H),4.04(s,3H),3.77–3.68(m,2H), 3.65(s,1H),3.47(d,J=8.4Hz,1H),3.31–3.21(m,1H),3.07–2.95(m,1H),2.90– 2.81(m,2H),2.69–2.63(m,1H),2.47–2.38(m,1H),2.27–2.21(m,1H),2.16–2.05 (m,2H),1.86–1.82(m,1H),1.78–1.75(m,1H),1.69–1,67(m,1H),1.51–1.43(m, 1H),1.37–1.30(m,3H),1.32(s,3H),1.17–1.13ppm(m,21H);
13C NMR(100MHz,CDCl3)δ=151.6,147.8,143.9,137.7,130.0,128.6(2C),128.0,127.9(2C),120.5,119.8,81.5,76.9,74.2,61.7,52.4,42.6,41.6,38.4,37.8,35.2,28.0,27.2,26.9,25.7,24.8,18.2(6C),13.3(3C),12.3ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C37H56NaO4S2Si+[M+Na]+ 679.3281,found 679.3289.
步骤3:
将(20.00g,30.44mmol)仲醇(5)溶解于四氢呋喃(500mL)中,于30℃下搅拌,并向其中加入三苯基膦(31.94g,121.76mmol)和偶氮二甲酸二乙酯(19.2mL, 121.76mmol),反应混合液在70℃下搅拌2小时,200mL饱和氯化铵溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为烯烃(6)(15.62g,24.44mmol,80%)。
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.40–7.27(m,5H),6.84(d,J=8.8Hz,1H),6.80(d,J=8.7Hz,1H),5.76–5.68(m,1H),5.52(dd,J=10.1,2.4Hz, 1H),4.57(d,J=12.2Hz,1H),4.51(d,J=12.2Hz,1H),4.01(s,3H),3.31(d,J= 8.8Hz,1H),3.28–3.15(m,2H),3.22(d,J=8.8Hz,1H),3.13–3.04(m,1H),2.82– 2.73(m,1H),2.51–2.45(m,1H),2.44–2.39(m,1H),2.32–2.23(m,2H),2.08–2.02 (m,1H),2.02–1.85(m,2H),1.33–1.26(m,3H),1.30(s,3H),1.12(d,J=1.9Hz, 9H),1.11(s,3H),1.10ppm(d,J=1.9Hz,9H);
13C NMR(100MHz,CDCl3)δ=151.4,147.7,142.7,138.9,134.0,130.8,128.4(2C),127.6(2C),127.5,124.9,121.0,120.6,80.8,73.8,61.7,52.0,40.7,40.2,39.5,37.8,35.4,27.7,27.3,25.5,24.8,18.2(6C),18.1,13.3ppm(3C);
高分辨质谱结果为:HRMS(ESI):calcd for C37H55O3S2Si+[M+H]+639.3356, found639.3361.
步骤4:
将(20.24g,31.67mmol)烯烃(6)溶解于甲醇与乙腈的混合溶剂(400ml,v/v= 9:4)中,于0℃下搅拌,并向其中加入碳酸钙(15.85g,158.35mmol)和[双(三氟乙酰氧基)碘]苯(16.34g,38.00mmol),反应混合液在0℃下搅拌0.5小时,100mL饱和亚硫酸钠溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为酮(7)(16.10g, 29.33mmol,92%)。
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.35–7.24(m,5H),7.06(d,J= 8.6Hz,1H),6.99(d,J=8.7Hz,1H),5.82–5.76(m,1H),5.56(dd,J=2.5,10.1Hz, 1H),4.49(dd,J=12.5,17.6Hz,2H),3.87(s,3H),3.22(d,J=9.0Hz,1H),3.14(d, J=9.0Hz,1H),2.74–2.61(m,2H),2.61–2.50(m,2H),2.27(d,J=16.7Hz,1H), 1.34–1.26(m,3H),1.30(s,3H),1.13(d,J=2.5Hz,9H),1.11(d,J=2.5Hz,9H), 1.00ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=197.9,150.7,148.3,148.1,138.5,134.1,128.4(2C),127.6,127.4(2C),126.3,125.5,123.9,120.6,78.3,73.4,61.0,40.8,39.4,39.1,38.7,37.3,23.9,18.7,18.0(6C),12.9ppm(3C);
高分辨质谱结果为:HRMS(ESI):calcd for C34H49O4Si+[M+H]+549.3395, found549.3409.
步骤5:
将(20.00g,36.44mmol)酮(7)溶解于甲苯(300mL)中,于40℃下搅拌,并向其中加入钯碳(10.00g,50%w/w),反应混合液在40℃下搅拌4小时,硅藻土过滤除去钯碳,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为酮(8)(14.70 g,26.69mmol,73%)。
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.34–7.26(m,4H),7.26–7.23(m, 1H),7.00(d,J=8.6Hz,1H),6.93(d,J=8.6Hz,1H),4.45(s,2H),3.89(s,3H), 3.19(d,J=9.0Hz,1H),2.96(d,J=9.1Hz,1H),2.66–2.52(m,2H),2.29–2.24(m, 1H),2.23–2.16(m,1H),1.82–1.69(m,2H),1.69–1.53(m,2H),1.44–1.38(m,1H), 1.33–1.26(m,3H),1.17(s,3H),1.13(d,J=6.9Hz,9H),1.11(d,J=7.2Hz,9H), 0.94ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=198.7,150.4,149.8,148.1,138.5,128.4(2C), 127.6(2C),127.0,124.6,118.4,78.6,73.3,61.3,41.9,38.0,37.8,37.6,37.4,35.7, 24.0,18.4,18.0(6C),17.7,12.9ppm(3C);
高分辨质谱结果为:HRMS(ESI):calcd for C34H50NaO4Si+[M+Na]+573.3371,found 573.3376.
步骤6:
将(15.00g,27.23mmol)酮(8)溶解于四氢呋喃(250mL)中,于40℃下搅拌,并向其中加入四丁基氟化铵(1.0M in THF,32.7mL,32.68mmol),反应混合液在室温下搅拌0.5小时,100mL饱和氯化铵溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为酚(9)(10.33g,26.11mmol,96%)。
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.31–7.22(m,5H),7.11(d,J=8.5Hz,1H),7.02(d,J=8.6Hz,1H),6.10(s,1H),4.44(dd,J=12.4,17.2Hz,2H), 3.86(s,3H),3.20(d,J=9.1Hz,1H),2.95(d,J=9.1Hz,1H),2.66–2.53(m,2H), 2.32–2.25(m,1H),2.25–2.16(m,1H),1.81–1.61(m,3H),1.58–1.49(m,1H), 1.43–1.35(m,1H),1.17(s,3H),0.93ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=198.8,149.4,147.7,146.3,138.5,128.4(2C),127.6,127.5(2C),124.4,120.2,119.5,78.6,73.3,62.0,42.1,38.1,37.8,37.6,37.4,35.6,24.1,18.4,17.7ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C25H30NaO4 +[M+Na]+417.2036, found417.2037.
步骤7:
其中,OTf为三氟甲磺酸酯;
将(10.00g,25.35mmol)酚(9)溶解于二氯甲烷(150mL)中,于–78℃下搅拌,并向其中加入三乙胺(14.0mL,101.40mmol)和三氟甲磺酸酐(8.5mL,50.70 mmol),反应混合液在–78℃下搅拌0.5小时,100mL饱和碳酸氢钠溶液淬灭反应,经二氯甲烷萃取,饱和氯化钠洗涤和无水硫酸钠干燥后得到三氟甲磺酸酯中间体 (10),无需进一步纯化,直接用于下一步反应;
步骤8:
将上述三氟甲磺酸酯中间体(10)溶解于N,N-二甲基甲酰胺(150mL)中,于室温下搅拌,并向其中加入1,1'-双(二苯基膦)二茂铁(261mg,0.63mmol)、醋酸钯 (142mg,0.63mmol)、三乙胺(35.1mL,253.50mmol)和甲酸(4.8mL,126.75mmol),反应混合液在90℃下搅拌2小时,100mL饱和碳酸氢钠溶液淬灭反应,经乙醚萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为三环酮(11)(7.30g,19.29mmol,76%over 2steps);
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.45–7.38(m,1H),7.31–7.23(m, 5H),6.95(d,J=7.9Hz,1H),6.83(d,J=8.4Hz,1H),4.43(s,2H),3.89(s,3H), 3.19(d,J=9.2Hz,1H),2.94(d,J=9.2Hz,1H),2.67–2.54(m,2H),2.31–2.18(m, 2H),1.81–1.58(m,4H),1.45–1.36(m,1H),1.18(s,3H),0.94ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=198.8,159.6,158.3,138.6,134.2,128.4(2C), 127.6(3C),121.5,115.3,109.7,78.6,73.4,56.1,41.5,38.1,38.1,38.0,37.6,35.7, 23.7,18.5,17.9ppm;高分辨质谱结果为:HRMS(ESI):calcd for C25H30NaO3 +[M+ Na]+401.2087,found 401.2090.
步骤9:
将(8.00g,21.14mmol)三环酮(11)溶解于二氯甲烷(150mL)中,于0℃下搅拌,并向其中加入Na2HPO4(30.01g,211.40mmol),过氧化脲(3.98g,42.28mmol)和三氟乙酸酐(11.8mL,84.56mmol),反应混合液在0℃下搅拌0.5小时,50mL饱和亚硫酸钠溶液淬灭反应,经二氯甲烷萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为内酯(12)(7.70g,19.52 mmol,92%);
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.32–7.21(m,5H),7.16–7.11(m, 1H),6.96–6.88(m,2H),4.40(dd,J=12.3,26.9Hz,2H),3.86(s,3H),3.28(d,J= 9.6Hz,1H),2.84(d,J=9.6Hz,1H),2.55–2.45(m,2H),2.36–2.29(m,1H),1.97– 1.84(m,2H),1.78–1.67(m,3H),1.52(s,3H),1.37–1.30(m,1H),1.04ppm(s,3 H);
13C NMR(100MHz,CDCl3)δ=172.8,150.3,142.1,140.7,138.4,128.5(2C), 127.7(3C),125.6,116.3,111.0,78.6,73.4,56.2,48.5,40.0(2C),38.8,35.5,31.2, 20.6,18.4,18.1ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C25H30NaO4 +[M+Na]+417.2036, found417.2044.
步骤10:
将(6.00g,15.21mmol)内酯(12)溶解于甲苯(100mL)中,于–78℃下搅拌,并向其中加入二异丁基氢化铝(1.5M in toluene,12.1mL,18.25mmol),反应混合液在–78℃下搅拌0.5小时,50mL饱和酒石酸钾钠溶液淬灭反应,经乙醚萃取,饱和氯化钠洗涤和无水硫酸钠干燥后得到醛,无需进一步纯化,直接用于下一步反应;
步骤11:
将上述醛(13)溶解于四氢呋喃(150mL)中,于–78℃下搅拌,并向其中加入烯丙基溴化镁(1.0M in THF,30.4mL,30.42mmol),反应混合液在–78℃下搅拌0.5 小时,1.9mL甲醇淬灭反应,于–78℃下,向上述混合液中加入吡啶(7.4mL,91.26 mmol)和乙酰氯(4.3mL,60.84mmol),反应混合液在室温下搅拌0.5小时,30mL 饱和碳酸氢钠溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后得到烯丙醇乙酰酯(14),无需进一步纯化,直接用于下一步反应;
步骤12:
将上述烯丙醇乙酰酯(14)溶解于甲苯(150mL)中,于室温下搅拌,并向其中加入Pd(PPh3)4(7.03g,6.08mmol)和HCOONH4(29.00g,456.30mmol),反应混合液在100℃下搅拌2小时,硅藻土过滤,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为端烯(15)(3.70g,9.06mmol,59%over 3steps);
核磁数据为:1H NMR(400MHz,acetone-d6)δ=7.38–7.32(m,4H),7.32–7.22 (m,1H),6.91–6.82(m,2H),6.78–6.69(m,1H),5.48–5.32(m,1H),4.66–4.53(m, 2H),4.46(s,2H),3.85(s,3H),3.20(d,J=8.8Hz,1H),3.08(d,J=8.8Hz,1H), 2.98–2.85(m,2H),1.81–1.69(m,2H),1.68–1.59(m,1H),1.56–1.47(m,2H),1.38 (s,3H),1.31–1.19(m,3H),1.14–1.06(m,1H),0.98ppm(s,3H);
13C NMR(100MHz,acetone-d6)δ=148.5,145.9,140.6,140.4,136.2,129.2 (2C),128.1(3C),121.7,119.2,113.9,110.1,81.7,73.7,56.8,43.7,42.7,39.8,36.8, 36.6,36.0,28.4,22.4,19.7,19.1ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C27H36NaO3 +[M+Na]+431.2557, found431.2564.
步骤13:
将(2.00g,4.89mmol)端烯(15)溶解于六氟异丙醇中(70mL)中,于0℃下搅拌,并向其中加入[双(三氟乙酰氧基)碘]苯(2.52g,5.87mmol),反应混合液在0℃下搅拌0.5小时,50mL饱和碳酸氢钠溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为二酮(16)(1.15g,2.94mmol,60%);
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.37–7.30(m,4H),7.28–7.22(m, 1H),6.47(d,J=7.2Hz,1H),6.32(dd,J=7.1,3.1Hz,1H),4.53(d,J=12.4Hz,1 H),4.44(d,J=12.5Hz,1H),3.63(d,J=3.2Hz,1H),3.17(d,J=8.9Hz,1H), 3.10(dd,J=17.0,9.8Hz,1H),3.03(d,J=8.9Hz,1H),2.80(dd,J=12.4,3.1Hz, 1H),2.33–2.25(m,1H),1.94(d,J=17.0Hz,1H),1.66–1.54(m,4H),1.52–1.46 (m,2H),1.43–1.31(m,3H),1.28–1.21(m,1H),1.16(s,3H),0.83ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=205.9,202.5,139.1,137.9,128.8,128.3(2C), 127.2(3C),80.0,73.3,73.0,63.9,42.6,39.8,37.6,37.4,35.8,33.9,31.4,30.5,21.7, 18.1(2C),17.9ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C26H32NaO3 +[M+Na]+415.2244, found415.2251.
步骤14:
将(1.54g,3.92mmol)二酮(16)溶解于二氯甲烷(50mL)中,于0℃下搅拌,并向其中加入二异丁基氢化铝(1.5M in toluene,7.8mL,11.76mmol),反应混合液在–78℃下搅拌0.5小时,5mL乙酸乙酯和20mL饱和酒石酸钾钠溶液淬灭反应,经二氯甲烷萃取,饱和氯化钠洗涤和无水硫酸钠干燥后得到二醇(17),无需进一步纯化,直接用于下一步反应;
步骤15:
将上述二醇(17)溶解于二氯甲烷中(30mL)中,于室温下搅拌,并向其中加入碳酸氢钠(0.5M aq.20mL),四丁基氯化铵(1.09g,3.92mmol),氯代丁二酰亚胺 (7.85g,58.80mmol)和2,2,6,6-四甲基哌啶氮氧化物(367mg,2.35mmol),反应混合液在室温下下搅拌1小时,20mL饱和亚硫酸钠溶液淬灭反应,经二氯甲烷萃取,饱和氯化钠洗涤和无水硫酸钠干燥后,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为仲醇(18)(1.43g,3.64mmol,92%over 2 steps);
核磁数据为:1H NMR(400MHz,CDCl3)δ=7.35–7.23(m,5H),6.03(d,J= 6.4Hz,1H),5.80(dd,J=6.4,3.3Hz,1H),5.01–4.96(m,1H),4.51(d,J=12.2Hz, 1H),4.39(d,J=12.2Hz,1H),3.22(d,J=9.0Hz,1H),3.08–3.03(m,1H),2.95– 2.86(m,1H),2.88(d,J=9.0Hz,1H),2.39–2.26(m,3H),2.22(dd,J=11.9,3.5 Hz,1H),2.01(d,J=17.7Hz,1H),1.76–1.72(m,1H),1.68–1.60(m,2H),1.60– 1.51(m,2H),1.50–1.44(m,1H),1.35–1.25(m,3H),1.17(s,3H),0.81ppm(s,3 H);
13C NMR(100MHz,CDCl3)δ=212.2,140.6,139.0,128.5(2C),128.1,127.6 (3C),81.0,79.3,73.2,63.3,55.0,43.0,39.9,38.2,37.7,36.4,35.8,33.3,30.7,22.0, 19.1,18.3(2C)ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C26H34NaO3 +[M+Na]+417.2400, found417.2406.
步骤16:
将(1.10g,2.79mmol)仲醇(18)溶解于甲醇(20mL)中,于室温下搅拌,并向其中加入钯碳(0.22g,20%w/w),反应混合液在氢气氛围下40℃下搅拌2小时,硅藻土过滤除去钯碳,用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为二醇(19)(0.80g,2.61mmol,94%);
核磁数据为:1H NMR(400MHz,CDCl3)δ=4.58(d,J=5.5Hz,1H),3.67(br, 1H),3.48(d,J=11.0Hz,1H),3.23(br,1H),2.91(d,J=11.0Hz,1H),2.82(dd,J =16.1,9.5Hz,1H),2.66(t,J=5.8Hz,1H),2.35–2.26(m,1H),2.21(dd,J=12.3, 2.8Hz,1H),2.13–2.00(m,1H),2.00–1.89(m,2H),1.75–1.67(m,1H),1.67–1.42 (m,8H),1.40–1.28(m,2H),1.22–1.16(m,1H),1.00(s,3H),0.73ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=216.3,79.3,71.4,58.0,49.4,42.6,41.7,39.3,39.1,38.1,35.5,32.6,31.9,30.5,21.9(2C),18.9,18.5,17.2ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C19H30NaO3 +[M+Na]+329.2087, found329.2095.
步骤17:
将(503mg,1.64mmol)二醇(19)溶解于四氢呋喃(20mL)中,于0℃下搅拌,并向其中加入钠氢(196mg,60%dispersion in mineral oil,4.92mmol)和二硫化碳 (580μL,9.85mmol),反应混合液在室温下下搅拌1小时,随后0℃下加入碘甲烷(205μL,3.28mmol),反应混合液在0℃下搅拌20min,10mL饱和氯化铵溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥后得到硫代酯中间体(20),无需进一步纯化,直接用于下一步反应;
步骤18:
将上述硫代酯中间体(20)溶解于甲苯(20mL)中,于室温下搅拌,并向其中加入偶氮二异丁腈(134mg,0.82mmol)和三丁基锡氢(1.3mL,4.92mmol),反应混合液在90℃下搅拌2小时,浓缩反应液并用硅胶柱层析法分离提纯产物,得到无色油状化合物,即为酮(21)(260mg,0.90mmol,55%over 2steps);
核磁数据为:1H NMR(400MHz,CDCl3)δ=3.37(d,J=10.9Hz,1H),3.07(d, J=10.9Hz,1H),2.68–2.57(m,2H),2.30–2.17(m,1H),2.06–1.95(m,2H),1.89– 1.76(m,3H),1.70–1.64(m,2H),1.59–1.44(m,8H),1.43–1.31(m,3H),1.29–1.24 (m,1H),1.05(s,3H),0.76ppm(s,3H);
13C NMR(100MHz,CDCl3)δ=215.4,72.1,52.4,52.0,42.7,41.9,40.6,38.8,38.0,35.6,32.3,32.1,30.1,29.9,27.8,22.2,18.3,17.9,17.4ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C19H30NaO2 +[M+Na]+313.2138, found313.2142.
步骤19:
将(394mg,1.34mmol)酮(21)溶解于甲苯(10mL)中,于室温下搅拌,并向其中加入甲基溴化镁(1.4mL,3.0M in Et2O,4.07mmol),反应混合液在室温下下搅拌 2小时,5mL饱和氯化铵溶液淬灭反应,经乙酸乙酯萃取,饱和氯化钠洗涤和无水硫酸钠干燥,浓缩萃取液并用硅胶柱层析法分离提纯产物,得到白色粉末,即为滨海孪生花烷二萜Stemarin(334mg,1.09mmol,80%);
核磁数据为:1H NMR(400MHz,DMSO-d6)δ=4.44(t,J=5.5Hz,1H),3.86 (s,1H),3.15(dd,J=10.6,5.6Hz,1H),2.78(dd,J=10.6,5.4Hz,1H),2.18(d,J= 11.2Hz,1H),2.13–2.03(m,1H),1.83(t,J=5.3Hz,1H),1.59–1.51(m,3H),1.51– 1.45(m,2H),1.45–1.37(m,4H),1.37–1.23(m,4H),1.18–1.11(m,2H),1.11–1.03 (m,3H),0.99(s,3H),0.88(s,3H),0.63ppm(s,3H);
13C NMR(100MHz,pyridine-d5)δ=72.0,71.3,51.9,49.0,42.1,39.8,39.3,38.7,38.3,36.2,32.1,30.8,29.9,29.8,27.5,26.8,22.8,18.7,18.3,17.1ppm;
高分辨质谱结果为:HRMS(ESI):calcd for C20H34NaO2 +[M+Na]+329.2451, found329.2456.。
Claims (10)
1.一种滨海孪生花烷二萜Stemarin的合成方法,其特征在于,包括:
步骤1:将环氧烯丙基溴化合物2与硫缩酮化合物3溶解于有机溶剂中,加入锂试剂,于-25℃~0℃环境下搅拌,得到环氧类化合物4;
步骤2:将环氧类化合物4溶解于有机溶剂中,于-78℃~-25℃环境下加入酸,搅拌,得到仲醇类化合物5;
步骤3:将仲醇类化合物5溶解于有机溶剂中,在有机膦化合物和偶氮化合物作用下,反应温度为25℃~50℃下搅拌,得到烯烃类化合物6;
步骤4:将烯烃类化合物6溶解于有机溶剂中,于-25℃~0℃条件下加入高价碘化合物和碳酸盐,搅拌,得到酮类化合物7;
步骤5:将酮类化合物7溶解于有机溶剂中,于25℃~50℃环境下加入金属催化剂,得到酮类化合物8;
步骤6:将酮类化合物8溶解于有机溶剂中,于25℃~50℃环境中加入脱硅试剂,得到酚类化合物9;
步骤7:将酚类化合物9溶解于有机溶剂中,于-78℃~-25℃环境中加入有机胺和三氟甲磺酰基化试剂,反应得到三氟甲磺酸酯中间体10;
步骤8:将三氟甲磺酸酯中间体10溶解于有机溶剂中,加入金属催化剂、有机膦化合物、有机胺和有机酸,于80℃~120℃条件下搅拌,得到三环酮类化合物11;
步骤9:将三环酮类化合物11溶解于有机溶剂中,于-25℃~0℃条件下加入无机盐和过氧化合物,得到内酯类化合物12;
步骤10:将内酯类化合物12溶解于有机溶剂中,于-78℃~-25℃条件下加入负氢还原剂,得到醛类化合物13;
步骤11:将醛类化合物13溶解于有机溶剂中,于-78℃~-25℃条件下加入乙烯基溴化镁,反应1-5h后,恢复到室温,并在室温加入醇,有机胺和乙酰化试剂,搅拌,得到烯丙醇乙酰酯类化合物14;
步骤12:将烯丙醇乙酰酯类化合物14溶解于有机溶剂中,加入金属催化剂和铵盐后,于80℃~120℃条件下搅拌,得到端烯类化合物15;
步骤13:将端烯类化合物15溶解于有机溶剂中,加入高价碘化合物后,于-25℃~0℃条件下搅拌,得到二酮类化合物16;
步骤14:将二酮类化合物16溶解于有机溶剂中,加入负氢还原剂后于-78℃~-25℃条件下搅拌,得到二醇类化合物17;
步骤15:将二醇类化合物17溶解于有机溶剂中,加入无机盐水溶液、有机铵盐、2,2,6,6-四甲基哌啶氧化物和琥珀酰亚胺类化合物,室温下搅拌,得到仲醇类化合物18;
步骤16:将仲醇类化合物18溶解于有机溶剂中,加入金属催化剂后与氢气氛围下,在-25℃~0℃条件下搅拌,得到二醇类化合物19;
步骤17:将二醇类化合物19溶解于有机溶剂中,加入锂试剂、有机胺和硫代酯制备试剂,于25℃~50℃条件下搅拌,得到硫代酯中间体20;
步骤18:将硫代酯中间体20溶解于有机溶剂中,加入自由基引发剂和氢自由基给体试剂后,于80℃~120℃条件下搅拌,得到酮类化合物21;
步骤19:将酮类化合物21溶解于有机溶剂中,加入甲基金属试剂,反室温下搅拌,得到式I所示结构的滨海孪生花烷二萜Stemarin:
2.根据权利要求1所述滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤1或步骤17中,所述锂试剂为正丁基锂、仲丁基锂、叔丁基锂或六甲基二硅基氨基锂。
3.根据权利要求1所述滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤2中,所述酸为三氟化硼乙醚络合物、三氟化硼四氢呋喃络合物、二乙基氯化铝、乙基二氯化铝、三甲基铝、四氯化锡、四氯化钛、三溴化铟、三氟甲磺酸酯铋、六水氯化铁、对甲苯磺酸一水合物,对甲苯磺酸吡啶盐、(D)-樟脑磺酸、盐酸、硫酸、多聚磷酸、氟硼酸、四丁基四氟硼酸铵、四苯基四氟硼酸膦、三氟甲磺酸三甲基硅酯、叔丁基二甲硅基三氟甲磺酸酯或三(五氟苯基)硼烷。
4.根据权利要求1所述的滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤3或步骤8中,所述有机膦化合物为三苯基膦、三丁基膦、三乙基膦或三甲基膦、1,2-双(二苯基膦)乙烷、1,3-双(二苯基膦)丙烷、1,4-双(二苯基膦)丁烷或1,5-双(二苯基膦)戊烷。
5.根据权利要求1所述的滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤4或步骤13中,所述高价碘化合物为碘苯二乙酸、[双(三氟乙酰氧基)碘]苯、2-碘酰基苯甲酸、戴斯-马丁氧化剂或[羟基(对甲苯磺酰氧基)碘]苯。
6.根据权利要求1所述的滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤6中,所述脱硅试剂为四丁基氟化铵、氟化氢水溶液、氟化氢吡啶、氟化钾、氟化铯或对甲苯磺酸一水合物;
步骤9中,所述过氧化合物为间氯过氧苯甲酸、原位制备的二甲基过氧化酮、原位制备的甲基(三氟甲基)二氧杂环丙烷、原位制备的过氧三氟乙酸或原位制备的过氧乙酸。
7.根据权利要求1所述滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤10或步骤14中,所述负氢还原剂为硼氢化钠、硼氢化锂、硼氢化锌、三叔丁氧基氢化铝锂、三仲丁基硼氢化锂、二异丁基氢化铝、氢化铝锂或硼氢化镍。
8.根据权利要求1所述的滨海孪生花烷二萜Stemarin的合成方法,其特征在于,步骤17中,所述硫代酯制备试剂为二硫化碳/碘甲烷、N,N'-硫羰基二咪唑或硫代氯甲酸苯酯;
步骤18中,所述自由基引发剂为偶氮二异丁氰、三乙基硼或1,1'-偶氮双(环己烷甲腈);所述氢自由基给体试剂为三丁基氢化锡或三(三甲基硅基)硅烷。
9.根据权利要求1所述的滨海孪生花烷二萜Stemarin的合成方法,其特征在于,所述金属催化剂为钯/碳、钯/硫酸钡、氢氧化钯、Lindlar钯、二氧化铂或Crabtree催化剂;乙酸钯、四(三苯基膦)钯、氯化钯、双(乙腈)二氯化钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯或二(三苯基膦)氯化钯。
10.根据权利要求1所述的滨海孪生花烷二萜Stemarin的合成方法,其特征在于,所述有机溶剂为四氢呋喃、2-甲基四氢呋喃、乙醚、甲苯、二氯甲烷、甲醇、乙醇、异丙醇、乙腈、1,2-二氯乙烷、乙酸乙酯、苯、二苯醚、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、2,2,2-三氟乙醇、水、六氟异丙醇和硝基甲烷中的一种或几种。
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