CN117820368A - Compound, synthesis method thereof and application of compound in synthesis method of actin stabilizer - Google Patents
Compound, synthesis method thereof and application of compound in synthesis method of actin stabilizer Download PDFInfo
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- CN117820368A CN117820368A CN202311645681.2A CN202311645681A CN117820368A CN 117820368 A CN117820368 A CN 117820368A CN 202311645681 A CN202311645681 A CN 202311645681A CN 117820368 A CN117820368 A CN 117820368A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 118
- 239000003381 stabilizer Substances 0.000 title claims abstract description 24
- 102000007469 Actins Human genes 0.000 title claims abstract description 21
- 108010085238 Actins Proteins 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 37
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 22
- RAJHHZKPZIVDFF-UHFFFAOYSA-N Rhizopodin Natural products C1C(O)C(C)(C)C(CC(OC)C(C)CCC(=O)C(C)C(CC=CN(C)C=O)OC)OC(=O)CC(O)CC(OC)C=CC=CCC(OC)C2=COC1=N2 RAJHHZKPZIVDFF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 60
- 125000006239 protecting group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 239000002994 raw material Substances 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 239000002243 precursor Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 230000008569 process Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 56
- 239000012074 organic phase Substances 0.000 description 49
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000000243 solution Substances 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000011734 sodium Substances 0.000 description 29
- 238000001914 filtration Methods 0.000 description 22
- 238000003818 flash chromatography Methods 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 238000001035 drying Methods 0.000 description 19
- 239000011541 reaction mixture Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 239000007788 liquid Substances 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 15
- 238000000605 extraction Methods 0.000 description 14
- 239000000758 substrate Substances 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- -1 trimethylacetyl Chemical group 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 10
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 8
- 239000012634 fragment Substances 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000006257 total synthesis reaction Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000006130 Horner-Wadsworth-Emmons olefination reaction Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000003138 primary alcohols Chemical class 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- 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 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 3
- 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 description 3
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 3
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 3
- 229940126657 Compound 17 Drugs 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 3
- 229940126142 compound 16 Drugs 0.000 description 3
- 229940125810 compound 20 Drugs 0.000 description 3
- 229940126208 compound 22 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940125851 compound 27 Drugs 0.000 description 3
- 229940125878 compound 36 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- NJQRKFOZZUIMGW-UHFFFAOYSA-N 1,3,5-trichloro-2-(chloromethyl)benzene Chemical compound ClCC1=C(Cl)C=C(Cl)C=C1Cl NJQRKFOZZUIMGW-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- WGLLSSPDPJPLOR-UHFFFAOYSA-N 2,3-dimethylbut-2-ene Chemical compound CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 241000872931 Myoporum sandwicense Species 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- 125000006000 trichloroethyl group Chemical group 0.000 description 2
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 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 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- ZRPFJAPZDXQHSM-UHFFFAOYSA-L 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazole;dichloro-[(2-propan-2-yloxyphenyl)methylidene]ruthenium Chemical compound CC(C)OC1=CC=CC=C1C=[Ru](Cl)(Cl)=C1N(C=2C(=CC(C)=CC=2C)C)CCN1C1=C(C)C=C(C)C=C1C ZRPFJAPZDXQHSM-UHFFFAOYSA-L 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- JCARTGJGWCGSSU-UHFFFAOYSA-N 2,6-dichlorobenzoquinone Chemical compound ClC1=CC(=O)C=C(Cl)C1=O JCARTGJGWCGSSU-UHFFFAOYSA-N 0.000 description 1
- XARVANDLQOZMMJ-CHHVJCJISA-N 2-[(z)-[1-(2-amino-1,3-thiazol-4-yl)-2-oxo-2-(2-oxoethylamino)ethylidene]amino]oxy-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)O\N=C(/C(=O)NCC=O)C1=CSC(N)=N1 XARVANDLQOZMMJ-CHHVJCJISA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- BMIBJCFFZPYJHF-UHFFFAOYSA-N 2-methoxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine Chemical compound COC1=NC=C(C)C=C1B1OC(C)(C)C(C)(C)O1 BMIBJCFFZPYJHF-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 238000006463 Yamaguchi esterification reaction Methods 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
- 238000005575 aldol reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- YFXCNIVBAVFOBX-UHFFFAOYSA-N ethenylboronic acid Chemical compound OB(O)C=C YFXCNIVBAVFOBX-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000005710 macrocyclization reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- PSBAZVJEUNOIDU-UHFFFAOYSA-L potassium;sodium;diacetate Chemical class [Na+].[K+].CC([O-])=O.CC([O-])=O PSBAZVJEUNOIDU-UHFFFAOYSA-L 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- DHHKPEUQJIEKOA-UHFFFAOYSA-N tert-butyl 2-[6-(nitromethyl)-6-bicyclo[3.2.0]hept-3-enyl]acetate Chemical compound C1C=CC2C(CC(=O)OC(C)(C)C)(C[N+]([O-])=O)CC21 DHHKPEUQJIEKOA-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a compound, a synthesis method thereof and application thereof in a synthesis method of an actin stabilizer, wherein the compound is a side chain compound, and the structural formula of the side chain compound is shown as the following formula:
Description
Technical Field
The invention relates to the technical field related to pharmaceutical chemistry, in particular to a compound, a synthesis method thereof and application thereof in a synthesis method of an actin stabilizer.
Background
Rhizopodin is a novel actin stabilizer which can affect actin cytoskeleton at nanomolar concentration and is effective forA series of tumor cell lines exhibit potent antiproliferative activity, IC 50 Values are in the low nanomolar range. Because of its remarkable biological activity and attractive molecular structure, rhizopodin is a very attractive synthetic target. In 2011, nicolaou first completed the total synthesis of monomeric rhizopodin, while the monomeric compound was found to be inactive. In 2012, menche and its co-workers reported the first rhizopodin total synthesis based on the Suzuki macrocyclization synthesis strategy. In 2013, the Paterson reported the total synthesis of rhizopodin based on the Yamaguchi esterification to construct a macrolide strategy.
In the method of synthesizing rhizopodin reported in the related art, the HWE (Horner-Wadsworth-Emmons) method is carried out by introducing the side chain fragment C23-C31 into the method of compound 2, and the HWE (Horner-Wadsworth-Emmons) method is subjected to 5 transformations. The aldol method needs 4 steps (namely aldol reaction, elimination of hydroxyl, selective reduction of double bond of ketene and deprotection), and the synthesis efficiency is slightly improved compared with the former method. However, the synthesis efficiency is still low, so that the development of a new synthesis route is of great significance.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides a synthesis precursor compound which provides a new direction for the synthesis of actin stabilizers such as rhizopodin and the like.
According to one aspect of the present invention, there is provided a side chain compound having the structural formula:
according to a preferred embodiment of the invention, there is at least the following advantageous effect: the scheme of the invention designs a novel side chain compound structure, and the stabilizer is synthesized through the compound structure only by three steps, so that the operation process is simplified, and the operation efficiency is improved; further, the parent compound when the side chain compound is used for preparing the stabilizer can be synthesized by adopting the route designed by the scheme of the invention, and the yield is more excellent.
According to another aspect of the present invention, the present invention also provides a precursor compound of the aforementioned side chain compound, wherein the precursor compound of the side chain compound has a structural formula as shown in one of the following formulas I to V:
wherein R is 1 、R 2 、R 3 Independently selected from H or hydroxy protecting groups, the same or different.
In some preferred embodiments of the invention, R 1 Is TBS (tert-butyldimethylsilyl), R 2 Is PMB (para-methoxybenzyl), R 3 Ac (acetyl).
According to a further aspect of the present invention, there is also provided a precursor compound of a parent compound having the structural formula shown in one of formulas VII to XXIV below:
wherein R is 1 、R 2 、R 4 、R 5 Independently selected from H or hydroxy protecting groups, the same or different; r is R 6 Selected from H or carboxyl protecting groups, R 7 Selected from H or an amino protecting group, which can be used to protect a hydroxyl group; the substituent X is halogen and is selected from F, cl, br or I.
In some embodiments of the invention, the parent compound is capable of reacting with the aforementioned side chain compounds to synthesize rhizopodin.
In some embodiments of the present invention, the hydroxyl protecting group includes at least one of TBS (tert-butyldimethylsilyl), PMB (para-methoxybenzyl), ac (acetyl), piv (pivaloyl, trimethylacetyl), TES (triethylsilyl).
In some embodiments of the invention, the carboxyl protecting group comprises at least one of Tce (trichloroethyl) or t-Bu (tert-butyl).
In some embodiments of the invention, the amino protecting group comprises at least one of Troc (trichloroethoxycarbonyloxy, 2-trichloroethoxycarbonyloxy) or Boc (tert-butyloxycarbonyl) or Trt (trityl).
In some preferred embodiments of the invention, R 1 Is TBS (tert-butyldimethylsilyl), R 2 Is PMB (para-methoxybenzyl), R 4 Piv (pivaloyl, trimethylacetyl), R 5 TES (triethylsilyl), R 6 Tce (trichloroethyl), R 7 Is Troc (trichloroethoxycarbonyloxy, 2-trichloroethoxycarbonyloxy).
According to still another aspect of the present invention, there is provided a method for synthesizing the above-mentioned side chain compound, comprising the steps of:
to be used forPreparing a compound I as a raw material, preparing a compound II as a raw material, preparing a compound III as a raw material, preparing a compound IV as a raw material, preparing a compound V as a raw material, and preparing the side chain compound by using a compound V as a raw material; wherein, the structures of the compounds I, II, III, IV and V are shown in the following formulas: /> Wherein R is 1 、R 2 、R 3 Independently selected from H or hydroxy protecting groups, the same or different.
The preparation method according to a preferred embodiment of the present invention has at least the following advantageous effects: the synthesis route of the scheme of the invention can be used for efficiently preparing the side chain compound, is simple and convenient to operate, and has good industrial application prospect.
In some preferred embodiments of the invention, the side chain compound is synthesized as follows:
in some preferred embodiments of the invention, the molecular sieve has a pore size of
According to a further aspect of the present invention, there is provided a method of synthesizing the above parent compound, comprising the steps of:
s1, preparing a compound XXI;
s2, reacting the compounds XVII and XXI to generate a compound XXII;
s3, preparing a compound XXIII by taking the compound XXII as a raw material;
s4, preparing a compound XXIV by taking the compound XXIII as a raw material;
wherein the parent compound has the structural formula:
compounds XVII, XXI, XXII, XXIII and XXIV have the structural formula:
wherein R is 1 、R 5 Independently selected from H or hydroxy protecting groups, the same or different; r is R 6 Selected from H or carboxyl protecting groups, R 7 Selected from H or an amino protecting group, which can be used to protect a hydroxyl group; the substituent X is halogen and is selected from F, cl, br or I.
The preparation method according to a preferred embodiment of the present invention has at least the following advantageous effects: the scheme of the invention provides a new synthetic route of the rhizopodin parent compound, which is simple and convenient to operate, high in synthetic yield and good in industrial application prospect.
In some embodiments of the invention, the synthetic route for the parent compound is as follows:
according to a further aspect of the present invention, the present invention also provides a method for synthesizing an actin stabilizer, comprising the steps of:
reacting the above-mentioned side chain compound with a parent compound, wherein the structural formula of the parent compound is as follows:
R 1 、R 5 independently selected from H or hydroxy protecting groups, the same or different.
The synthesis method according to a preferred embodiment of the present invention has at least the following advantageous effects: the synthesis of the actin stabilizer can be realized in three steps through the side chain compound and the parent compound with the structure of the scheme, the operation is simpler and more convenient, and the yield of the actin stabilizer can be further improved.
In some preferred embodiments of the invention, the side chain compound is hydrogen-stripped and reacted with a parent compound to form the actin stabilizer.
In some preferred embodiments of the invention, the hydrogen extracting is performed under the action of a hydrogen extracting agent selected from the group consisting of Ba (OH) 2 At least one of NaH, liHMDS (lithium hexamethyldisilazide), KHMDS (potassium hexamethyldisilazide), LDA (lithium isopropyldisilazide), naOH or potassium tert-butoxide.
In some preferred embodiments of the present invention, the hydrogen extracting agent is selected from Ba (OH) 2 . Barium hydroxide is used as a hydrogen drawing reagent, and the yield is higher.
In some preferred embodiments of the invention, R 1 For TBS, R 5 For TES, the synthesis method further comprises the step of deprotecting the side chain compound after reaction with the parent compound.
In some preferred embodiments of the invention, the actin stabilizer is synthesized by the following route:
additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention. The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available. Unless otherwise indicated, the same parameter is the same in each embodiment. The following examples are illustrative only and are not to be construed as limiting the invention.
The term "room temperature" as used herein means a temperature of 25.+ -. 5 ℃ and in the examples 25 ℃.
Examples
The actin stabilizer rhizopodin is prepared by the method specifically comprising the following steps:
1) The preparation of the side chain compound (shown in formula 6) comprises the following preparation processes:
2) Preparation of the parent Compound (represented by formula 2):
2.1 preparation route of starting compound i (as shown in formula 28) of parent compound is as follows:
2.2 preparation of starting compound ii (represented by formula 34) from starting i, the specific preparation route is as follows:
2.3 preparation of the parent compound from starting compound ii, the specific preparation route is as follows:
3) The steps for preparing actin stabilizers using the side chain compound and parent compound are as follows:
specifically, the synthesis process and characterization data are as follows:
1. synthesis of Compound 6
1. Synthesis of compound S1:
olefin substrate 7 (650 mg,2.46 mmol) was dissolved in dioxane-H 2 To a mixed solvent of O (10 mL-10 mL), 2,6-lutidine (0.43 mL,3.69 mmol) and NaIO were added sequentially at room temperature 4 (2.10g,9.84mmol),OsO 4 (25.0 mg,0.098 mmol). After stirring was continued for 8 hours at room temperature, the reaction was checked by TLC plate for completion. After filtering the solid, na was added to the filtrate 2 S 2 O 3 (2.0 g) the solid was stirred for an additional 3 hours. After dilution with ethyl acetate, the mixture was successively taken up in saturated Na 2 S 2 O 3 After washing with saturated brine, the mixture was dried over sodium sulfate solid. The organic phase is concentrated under reduced pressure and the aldehyde is redissolved in THF-H 2 To the solution of O (10 mL-2 mL), naBH was carefully added at room temperature 4 (372 mg,9.84 mmol) of solid. After stirring for 4 hours, TLC was checked for completion of the reaction and the reaction was quenched with saturated ammonium chloride at 0deg.C. After dilution with ethyl acetate, the mixture was washed with saturated ammonium chloride and saturated brine, and dried over sodium sulfate solid. The organic phase was concentrated under reduced pressure and separated by a silica gel column to give substrate S1 (313 mg, 93%).
1 H NMR(400MHz,CDCl 3 )δ7.30–7.22(m,2H),6.93–6.83(m,2H),4.48–4.39(m,2H),3.79(s,3H),3.66–3.58(m,1H),3.58–3.50(m,3H),3.36(s,3H),3.35–3.31(m,1H),2.93(brs,1H),1.93–1.83(m,1H),1.83–1.70(m,1H),0.91(d,J=7.0Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ159.18,130.39,129.31,113.78,82.90,72.75,66.47,66.23,57.96,55.26,38.21,31.23,13.44.
2. Synthesis of Compound 8:
primary alcohol compound S1 (876 mg,3.27 mmol) was dissolved in anhydrous dichloromethane (30 mL), imidazole (334 mg,4.90 mmol), TBSCl (641 mg,4.25 mmol) was added at 0deg.C, and the reaction was continued for 12 hours after warming to room temperature, and completion of the reaction was detected by TLC plate. After dilution with ethyl acetate, washing with saturated ammonium chloride solution and saturated brine in this order, drying over sodium sulfate, the organic phase was concentrated under reduced pressure, and the residue was separated by a silica gel column to give compound 8 (1.19 g, 95%).
1 H NMR(400MHz,CDCl 3 )δ7.30–7.23(m,2H),6.91–6.85(m,2H),4.51–4.39(m,2H),3.80(s,3H),3.61–3.51(m,4H),3.38–3.34(m,1H),3.33(s,3H),1.97–1.87(m,1H),1.85–1.74(m,1H),1.72–1.60(m,1H),0.90(s,9H),0.88(d,J=6.9Hz,3H),0.05(d,J=2.8Hz,6H).
13 C NMR(100MHz,CDCl 3 )δ159.10,130.74,129.23,113.72,79.13,72.61,67.06,64.96,57.63,55.23,38.41,30.69,25.93,18.27,12.28,-5.42,-5.43.
3. Synthesis of Compound 10
Substrate 8 (926 mg,2.42 mmol) was dissolved in DCM (analytical grade, 15 mL) and DDQ (926 mg,2.42 mmol) was added at room temperature and the reaction was detected to completion by TLC. The reaction solution was concentrated to about 2mL under reduced pressure, and purified by column chromatography on a silica gel column to give primary alcohol substrate S2 (526 mg, 83%).
1 H NMR(400MHz,CDCl 3 )δ3.80–3.73(m,2H),3.59–3.52(m,1H),3.50–3.44(m,2H),3.36(s,3H),2.10–1.98(m,1H),1.76–1.61(m,2H),0.88(s,9H),0.84(d,J=7.0Hz,3H),0.03(d,J=2.8Hz,6H).
13 C NMR(101MHz,CDCl 3 )δ82.11,64.96,61.42,57.04,37.22,31.37,25.86,18.23,11.53,-5.45,-5.50.
Primary alcohol S2 (467 mg,1.78 mmol) was dissolved in dichloromethane (20 mL) -NaHCO 3 To a solution of (10 mL,50 mg/mL) was added TEMPO (10 mg,0.064 mmol) and NaClO solution (2 mL) sequentially at room temperature. After about half an hour of reaction, TLC detects completion of the reaction. Dilute with ethyl acetate, wash with saturated sodium thiosulfate, saturated brine, and dry over anhydrous sodium sulfate. After the organic phase was concentrated under reduced pressure, the residue was separated with a silica gel column to give aldehyde S3 (about 421 mg).
Wittig salt 9 (1.12 g,3.06 mmol) was dissolved in anhydrous THF and LiHMDS (2.7 mL, 1M) was added at 0deg.C and reacted for half an hour at 0deg.C. An anhydrous THF solution of the aldehyde S3 was added to the reaction solution at 0 ℃. The reaction was continued at 0℃for 2 hours, and the reaction was complete by TLC. The reaction was quenched with saturated ammonium chloride, diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine, and dried over anhydrous sodium sulfate. After concentrating the organic phase under reduced pressure, the residue was separated and purified by a silica gel column to give the product 10 (yield in two steps, 437mg,78%, Z: e=4.6:1)
1 H NMR(400MHz,CDCl 3 )δ8.28(s,0.14H),8.20(s,0.65H),8.06(s,0.14H),7.18(d,J=14.7Hz,0.06H),6.51(d,J=14.0Hz,0.14H),6.22(d,J=9.2Hz,0.09H),5.99(d,J=8.6Hz,0.66H),5.42–5.31(m,0.74H),5.20–5.07(m,0.19H),3.63–3.55(m,1.18H),3.55–3.49(m,0.81H),3.38–3.30(m,3H),3.28–3.19(m,0.79H),3.17(s,0.27H),3.06(s,0.21H),3.02(s,2.31H),2.45–2.31(m,1H),2.31–2.12(m,1H),1.95–1.78(m,1H),0.92–0.87(m,9H),0.84(d,J=6.9Hz,3H),0.04(d,J=2.1Hz,6H).
13 C NMR(100MHz,CDCl 3 )δ162.96,162.10,129.67,128.65,120.58,108.82,107.24,81.91,81.31,81.15,64.65,57.51,38.40,38.08,36.06,31.42,30.57,28.49,27.48,27.17,25.86,18.23,12.72,12.55,12.38,-5.49,-5.51.
4. Synthesis of Compound 12
Substrate 10 (300 mg,0.96 mmol) was dissolved in THF (10 mL) and TBAF (2 mL, 1M) was added and the reaction was detected to completion by TLC. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium hydrogencarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate to give a primary alcohol which was used directly in the next reaction.
The primary alcohol obtained in the above step was dissolved in methylene chloride (10 mL), TEA (0.40 mL,2.88 mmol), DMAP (35.0 mg,0.29 mmol) and Ac were added at room temperature 2 O (0.18 mL,1.92 mmol). After 4 hours of reaction, the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with ethyl acetate, diluted with 1M hydrochloric acid, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure and purified by silica gel column, and the residue was used directly for the next reaction.
The product of the previous step was dissolved in dichloromethane (10 mL) and I was added at room temperature 2 (7.2 mg,0.028 mmol) and after stirring for 24 hours the reaction was quenched with thiosulfuric acid. Dilute with ethyl acetate, wash with saturated sodium thiosulfate, and dry with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column to give product 12 (141 mg, 62%).
1 H NMR(500MHz,CDCl 3 )δ8.20(s,0.65H),7.97(s,0.29H),7.09(d,J=14.6Hz,0.29H),6.46(d,J=14.0Hz,0.66H),5.11–4.95(m,1H),4.12–4.03(m,1H),3.95–3.86(m,1H),3.27(s,2H),3.26(s,1H),3.07–3.01(m,1H),2.98(s,1H),2.93(s,2H),2.38–2.25(m,1H),2.21–2.09(m,1H),1.97(s,3H),1.95–1.86(m,1H),0.87–0.83(m,3H).
13 C NMR(125MHz,CDCl 3 )δ170.99,162.06,160.70,130.16,126.10,108.52,107.93,106.77,106.26,82.20,81.62,66.56,66.49,66.31,66.24,57.64,57.46,43.50,35.37,32.90,31.58,30.67,27.42,20.84,13.35,13.30,11.31,11.16.
5. Synthesis of Compound S4
Substrate 12 (136 mg,0.56 mmol) was dissolved in anhydrous methanol (10 mL) and anhydrous potassium carbonate (237 mg,2.24 mmol) was added at room temperature. After stirring at room temperature for 4 hours, concentration under reduced pressure, the resulting residue was separated by a silica gel column to give product S4 (109 mg, 97%).
1 H NMR(400MHz,CDCl 3 )δ8.25(s,0.66H),8.03(s,0.32H),7.15(d,J=14.5Hz,0.32H),6.50(d,J=14.0Hz,0.67H),5.16–4.98(m,1H),3.68–3.50(m,2H),3.37(s,2H),3.37(s,1H),3.22–3.16(m,1H),3.04(s,1H),2.99(s,2H),2.54–2.38(m,1H),2.31–2.16(m,1H),1.89–1.78(m,1H),0.91–0.83(m,3H).
13 C NMR(100MHz,CDCl 3 )δ162.11,160.76,130.10,126.10,107.52,105.90,85.84,85.54,66.76,66.47,57.51,57.28,37.57,37.50,32.99,30.69,30.60,27.46,13.67,13.63.
6. Synthesis of Compound 13
Substrate S4 (365 mg,1.83 mmol) was dissolved in DCM (7 mL) and NaHCO was added sequentially at room temperature 3 (463mg, 5.49 mmol), dess-Martin reagent (1.16 g,2.74 mmol). After stirring at room temperature for half an hour, the reaction solution was poured into 200mL of n-hexane, and after filtration, the aldehyde (about 0.9 g) was obtained by separation and purification on a silica gel column concentrated under reduced pressure.
The aldehyde was dissolved in anhydrous THF (20 mL) and base S5 (2.74 mmol,1.5 eq.) was added in three portions at-78deg.C (from methylphosphite by pulling hydrogen with n-butyllithium in the presence of 4A molecular sieve). After 1 hour of reaction, the reaction was quenched with saturated ammonium chloride. The reaction solution was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine in this order, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure and purified by silica gel column separation to give 13 (171 mg, yield 29% in two steps).
1 H NMR(400MHz,CDCl 3 )δ8.28(d,J=7.4Hz,0.67H),8.05(s,0.33H),7.18(d,J=14.5Hz,0.33H),6.59–6.49(m,0.67H),5.20–4.98(m,1H),4.43–4.22(m,0.4H),4.12–3.88(m,0.6H),3.80–3.71(m,6H),3.42–3.39(m,1.5H),3.37–3.34(s,1.5H),3.34–3.24(m,1H),3.06(s,1H),3.02(s,2H),2.52–2.38(m,1H),2.38–2.13(m,1H),2.13–1.96(m,1.5H),1.96–1.77(m,1.5H),0.97–0.79(m,3H).
13 C NMR(100MHz,CDCl 3 )δ162.19,162.12,160.74,130.54,130.00,126.31,126.06,107.85,107.42,106.44,105.61,84.20,82.80,68.34,65.72,58.10,57.81,57.16,56.98,52.58,52.55,52.42,52.35,41.15,40.99,40.52,40.38,33.00,31.00,30.58,30.20,29.76,29.20,27.48,27.46,11.26,10.24.
7. Synthesis of Compound 6:
substrate 13 (49.0 mg,0.15 mmol) was dissolved in methylene chloride, and sodium bicarbonate (50.0 mg,0.60 mmol) and Dess-Martin reagent (127 mg,0.30 mmol) were added thereto at room temperature. After stirring was continued at room temperature for 1 hour, the reaction solution was poured into n-hexane, the solid was filtered, and the filtrate was concentrated under reduced pressure, and the residue was separated and purified by a silica gel column to give the objective compound, ketone 6 (31.0 mg, 65%).
1 H NMR(500MHz,Methanol-d 4 )exists as rotational conformers:δ8.34(s,0.67H),8.10(s,0.33H),7.15(d,J=14.5Hz,0.33H),6.75(d,J=14.1Hz,0.67H),5.29(ddd,J=14.7,8.3,6.5Hz,0.33H),5.21(ddd,J=14.4,8.2,6.5Hz,0.67H),3.80(s,3H),3.78(s,3H),3.48–3.44(m,1H),3.44–3.37(m,1H),3.33(s,3H),3.13(s,1H),3.04(s,2H),3.03–2.98(m,1H),2.59–2.47(m,1H),2.35–2.18(m,1H),1.06(d,J=6.9Hz,2H),1.04(d,J=6.9Hz,1H).
13 C NMR(125MHz,Methanol-d 4 )exists as rotational conformers:δ205.5,205.5,163.2,161.8,130.6,126.0,107.8,105.7,82.7,82.7,56.4,56.4,52.3,52.2,52.2,52.2,49.6,49.6,32.0,30.0,29.8,26.2,11.1.
2. Synthesis of Compound 2
1. Synthesis of Compound 16
Compound 15 (15.12 g,33.6 mmol) was dissolved in CH 2 Cl 2 In MeOH (50 mL:50 mL) and cooled to 0deg.C, (-) -CSA (0.78 g,3.4 mmol) was added in one portion to the reaction. After warming to room temperature for about 30 minutes and stirring at room temperature for 4 hours, et was added 3 N (0.94 ml,6.8 mmol), the residue was purified by flash column chromatography (ethyl acetate/N-hexane=1/3) to give primary alcohol compound S5 (about 11.06 g).
The compound alcohol S5 (11.06 g) was dissolved in CH 2 Cl 2 (200 mL) and cooled to 0deg.C, followed by sequential addition of Et 3 N (11.5 mL,82.66 mmol), DMAP (40.0 mg,0.33 mmol) and PivCl (6.0 mL,49.10 mmol). The reaction was stirred overnight at room temperature, the disappearance of starting material was detected by thin layer column chromatography, the reaction was quenched with saturated ammonium chloride (30 mL), the organic phase was separated and the aqueous phase was then reused with CH 2 Cl 2 (100 mL. Times.2) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 And (5) drying. After filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/8) to give compound 16 (13.40 g,95% yield in two steps) as a colorless oil.
1 H NMR(500MHz,CDCl 3 )δ7.33–7.21(m,2H),6.91–6.85(m,2H),5.84(ddd,J=17.3,10.7,6.9Hz,1H),5.11–4.98(m,2H),4.54(d,J=2.1Hz,2H),3.98(d,J=10.8Hz,1H),3.92(d,J=10.7Hz,1H),3.81(s,3H),3.63–3.50(m,1H),3.37(s,3H),3.36–3.29(m,1H),2.71–2.57(m,1H),1.52(ddt,J=5.8,4.1,2.0Hz,2H),1.23(s,9H),1.01(d,J=7.0Hz,3H),0.95(s,3H),0.94(s,3H).
13 C NMR(125MHz,CDCl 3 )δ178.4,159.1,139.8,131.3,128.9,114.8,113.8,81.4,80.4,74.8,70.3,56.3,55.3,39.4,39.0,38.7,32.0,27.3,22.1,20.3,15.4.
2. Synthesis of Compound 17
Compound 16 (14.70 g,35.00 mmol) was dissolved in dioxane/H 2 O (150 mL:50 mL) and 2,6-lutidine (14.3 mL,122.50 mmol) NaIO were added sequentially at room temperature 4 (18.72 g,87.50 mmol) and OsO 4 (5.0mL,0.20mmol,0.04M in t-BuOH). The reaction was stirred for 5.5 hours and then unsaturated Na was added 2 S 2 O 3 The solution (50 mL) was stirred for an additional 3 hours with CH 2 Cl 2 (100 mL. Times.3) extraction. The combined organic phases were washed with saturated brine and then dried over anhydrous Na 2 SO 4 And (5) drying. The aldehyde S6 (about 14.10 g) obtained after filtration and concentration under reduced pressure was used directly in the next conversion without further purification.
The aldehyde compound S6 (about 14.10 g) was dissolved in MeOH (150 mL) and cooled to 0deg.C, naBH 4 (1.99 g,52.50 mmol) was added to the reaction system in three portions and stirring was continued at 0℃for 1 hour. The reaction was quenched by slow addition of saturated ammonium chloride solution (30 mL) and the organic phase was separated and taken up in CH 2 Cl 2 (100 mL. Times.3) extraction; the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/3) to give compound 17 (13.52 g, two-step yield 91%) as a colorless oily liquid.
1 H NMR(500MHz,CDCl 3 )δ7.31–7.22(m,2H),6.93–6.84(m,2H),4.56(d,J=10.8Hz,1H),4.48(d,J=10.8Hz,1H),3.98(d,J=10.9Hz,1H),3.94(d,J=10.8Hz,1H),3.80(s,3H),3.69(t,J=9.8Hz,1H),3.56(dd,J=10.0,1.9Hz,1H),3.53–3.47(m,1H),3.43(dt,J=10.6,2.7Hz,1H),3.40(s,3H),2.87(d,J=6.9Hz,1H),2.36–2.25(m,1H),1.66(ddd,J=14.4,10.3,1.9Hz,1H),1.55(ddd,J=14.4,10.0,2.2Hz,1H),1.24(s,9H),0.97(s,6H),0.81(d,J=7.1Hz,3H).
13 C NMR(125MHz,CDCl 3 )δ178.3,159.1,131.0,128.9,113.8,82.3,80.7,74.9,70.3,65.5,57.1,55.3,39.5,39.0,35.3,31.0,27.3,22.0,20.4,13.0.
3. Synthesis of Compound 18
Compound 17 (11.50 g,27.1 mmol) was dissolved in CH 2 Cl 2 (100 mL) and cooled to 0deg.C, et is added sequentially 3 N (8.23 mL,59.20 mmol), DMAP (0.0070 g,0.05 mmol) and TBSCl (5.72 g,37.94 mmol). Stirring overnight at room temperature, with saturated NH 4 Cl solution (30 mL) was quenched, the organic phase was separated and the aqueous phase was then reused with CH 2 Cl 2 (60 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give intermediate S7 (about 11.50 g).
This intermediate S7 (11.50 g) was dissolved in THF (100 mL), cooled to-78deg.C, and DIBAL (59.6mL,59.60mmol,1.0M in hexane) was slowly added dropwise to the inner wall of the flask. The reaction is stirred for 3 hours at the temperature of minus 78 ℃, and then is slowly and naturally heated to the temperature of minus 50 ℃ for 2.5 hours; after careful quenching with MeOH (3.0 mL), the reaction was poured into a saturated potassium sodium acetate solution (100 mL), and after rapid stirring overnight, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 mL. Times.3), and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/3) to give compound 18 as a colorless oily liquid (10.60 g,86% in two steps).
1 H NMR(500MHz,CDCl 3 )δ7.32–7.24(m,2H),6.91–6.84(m,2H),4.57(s,2H),3.79(s,3H),3.62(dd,J=9.9,5.9Hz,1H),3.54(dd,J=11.1,5.1Hz,1H),3.53–3.44(m,3H),3.38(s,3H),3.36–3.32(m,1H),3.05(t,J=5.7Hz,1H),2.01–1.90(m,1H),1.70(ddd,J=14.8,10.2,2.2Hz,1H),1.59(ddd,J=14.8,8.8,2.7Hz,1H),1.00(s,3H),0.93–0.86(m,15H),0.05(s,6H).
13 C NMR(125MHz,CDCl 3 )δ159.2,130.8,129.1,113.8,83.6,80.3,74.4,70.5,64.1,57.5,55.2,39.9,38.3,33.3,25.9,22.2,21.5,18.2,12.4,-5.4,-5.4.
4. Synthesis of Compound 20
Compound 18 (4.00 g,8.80 mmol) was dissolved in CH 2 Cl 2 (35mL),NaHCO 3 (2.96 g,35.24 mmol) and Dess-Martin periodinane (5.61 g,13.22 mmol) were added sequentially at 0deg.C. The reaction was allowed to return to room temperature and stirred for an additional 1 hour with unsaturated Na 2 S 2 O 3 The reaction was quenched with solution (25 mL) and stirred for 20 min before being treated with CH 2 Cl 2 (40 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1:6) to give aldehyde S8 as a colorless liquid (about 3.63g, 91%).
Hand auxiliary 19 (2.65 g,10.54 mmol) was dissolved in CH 2 Cl 2 (25 mL) and cooled to 0deg.C, tiCl was slowly added 4 (5.75mL,11.50mmol,2.0M in DCM) stirring for 10 min, and cooling to-78 ℃; DIPEA (2.90 mL,17.62 mmol) was added dropwise to the reaction; stirring at-78deg.C for 1.5 hr, the freshly prepared aldehyde (3.63 g) was dissolved in CH 2 Cl 2 (10 mL) was slowly added along the inner wall of the reaction flask. After 2 hours of reaction at-78 ℃, saturated NH is used 4 The reaction was quenched with Cl (20 mL). After separation of the organic phase, the aqueous phase is reused with CH 2 Cl 2 (100 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/5) to give 20 as a colourless liquid (4.83 g, total yield of two steps 78%, d.r. =10:1).
1 H NMR(500MHz,CDCl 3 )δ7.41–7.21(m,7H),6.86(dd,J=9.2,2.9Hz,2H),5.35(ddd,J=10.7,7.1,3.6Hz,1H),4.63(s,2H),4.40(d,J=10.3Hz,1H),4.22(s,1H),3.79(s,3H),3.65(dd,J=9.9,6.0Hz,1H),3.62–3.57(m,1H),3.56–3.47(m,3H),3.42(s,3H),3.41–3.34(m,1H),3.31–3.20(m,2H),3.05(dd,J=13.2,10.7Hz,1H),2.87(d,J=11.5Hz,1H),2.03–1.93(m,1H),1.78–1.67(m,2H),1.11(s,3H),0.94(d,J=6.9Hz,3H),0.91(s,9H),0.89(s,3H),0.07(s,6H).
13 C NMR(125MHz,CDCl 3 )δ201.4,173.3,159.3,136.7,130.4,129.5,129.1,128.9,127.2,113.9,86.3,79.6,75.1,72.4,69.0,64.4,57.7,55.3,41.6,41.2,38.7,36.7,33.4,32.2,26.0,22.4,20.7,18.3,12.3,-5.3,-5.4.
5. Synthesis of Compound 22
Compound 20 (1.53 g,2.17 mmol) was dissolved in CH 2 Cl 2 (15 mL) and cooled to-78deg.C, 2,6-lutidine (0.76 mL,6.51 mmol) and TESOTf (0.94 mL,4.34 mmol) were added slowly in sequence. The reaction was stirred at-78deg.C for 2 hours with saturated NH 4 Cl solution (15 mL) was quenched and CH was added 2 Cl 2 (50 mL) the reaction mixture was diluted, the organic phase was separated, and the aqueous phase was reused with CH 2 Cl 2 (100 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/10) to give compound S9 (1.70 g, 95%) as a pale yellow liquid.
1 H NMR(500MHz,CDCl 3 )δ7.41–7.34(m,2H),7.34–7.28(m,5H),6.93–6.84(m,2H),5.33(ddd,J=10.7,7.0,3.7Hz,1H),4.65–4.58(m,2H),4.40(t,J=5.2Hz,1H),3.82(s,3H),3.65(dd,J=9.8,5.9Hz,1H),3.56–3.41(m,5H),3.37(s,3H),3.35–3.30(m,1H),3.24(dd,J=13.2,3.6Hz,1H),3.05(dd,J=13.2,10.8Hz,1H),2.90(d,J=11.5Hz,1H),2.00–1.88(m,1H),1.63–1.53(m,2H),1.01(s,3H),0.97(t,J=8.0Hz,9H),0.96(s,3H),0.93–0.88(m,12H),0.68–0.58(m,6H),0.06(s,3H),0.05(s,3H).
13 C NMR(125MHz,CDCl 3 )δ200.9,172.9,159.0,136.7,131.6,129.5,128.9,128.8,127.2,113.7,82.1,80.0,74.6,73.6,68.7,64.6,57.6,55.3,43.9,43.3,38.8,36.4,33.7,32.0,26.0,20.8,20.3,18.3,12.4,7.1,5.6,-5.4,-5.4.
S9 (1.69 g,2.07 mmol) was dissolved in CH 2 Cl 2 (15 mL) and Et are added sequentially 3 N (1.8 mL,12.95 mmol), DMAP (2.4 mg,0.02 mmol), and cooled to 0deg.C, the hydroxylammonium hydrochloride 21 dissolved in CH 2 Cl 2 (15 mL) was slowly added to the reaction solution, and the mixture was then warmed to room temperature and stirred for 14 hours. The reaction was quenched with saturated ammonium chloride (15 mL) and CH was added 2 Cl 2 (50 mL) the reaction mixture was diluted, the organic phase was separated, and the aqueous phase was reused with CH 2 Cl 2 (50 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/3) to give compound 22 (1.34 g, 86%) as a colorless liquid.
1 H NMR(500MHz,CDCl 3 )δ7.32–7.23(m,2H),6.93–6.81(m,2H),6.50(d,J=7.7Hz,1H),5.91–5.72(m,1H),5.20–5.05(m,2H),4.59(d,J=10.7Hz,1H),4.55(d,J=10.8Hz,1H),4.16–4.06(m,1H),3.99(dd,J=7.6,3.7Hz,1H),3.90(dd,J=11.5,3.8Hz,1H),3.80(s,3H),3.64(dd,J=9.8,6.0Hz,2H),3.52–3.41(m,4H),3.38(s,3H),3.38(s,3H),3.17(s,1H),2.65(dd,J=15.3,3.7Hz,1H),2.47(dddd,J=14.2,7.7,4.6,1.4Hz,1H),2.30(dd,J=15.3,6.5Hz,1H),2.28–2.20(m,1H),1.98–1.87(m,1H),1.62–1.48(m,2H),0.99(s,3H),0.97(t,J=7.3Hz,9H),0.93(s,3H),0.91–0.87(m,12H),0.70–0.60(m,6H),0.04(s,6H).
13 C NMR(125MHz,CDCl 3 )δ172.1,159.0,133.7,131.5,128.8,118.0,113.7,83.0,82.3,80.0,74.7,74.6,64.5,62.1,58.0,57.7,55.3,52.4,44.2,40.6,38.8,35.1,33.8,25.9,21.0,20.4,18.3,12.4,7.1,5.3,-5.4,-5.4.
6. Synthesis of Compound 24
Compound 22 (1.14 g,1.51 mmol) was dissolved in CH 2 Cl 2 (15 mL), cool to 0deg.C, add NaHCO in turn 3 (0.51 g,6.06 mmol), dess-Martin periodinane (0.96 g,2.27 mmol). The reaction was allowed to warm to room temperature and stirred for 1 hour with unsaturated Na 2 S 2 O 3 The reaction was quenched with solution (15 mL) and stirred for an additional 30 min and CH was added 2 Cl 2 (50 mL) the reaction mixture was diluted, the organic phase was separated, and the aqueous phase was reused with CH 2 Cl 2 (50 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/5) to give colorless liquid aldehyde compound S10 (about 1.06 g).
The resulting aldehyde S10 (1.06 g,1.41 mmol) was dissolved in CH 2 Cl 2 (15 mL) and cooled to 0deg.C, 23 (2.33 g,11.3 mmol) were carefully added in sequence, PPh 3 (1.49 g,5.67 mmol) and Br 2 C 2 Cl 4 (1.85 g,5.67 mmol) and the reaction was allowed to warm to room temperature and stirred for 1.5 hours. DBU (1.7 mL,11.3 mmol) was dissolved in CH 3 CN (3.0 mL) was slowly added to the reaction over 25 minutes. After stirring at room temperature for 3 hours, saturated NH 4 Cl solution (15 mL) was quenched and CH was added 2 Cl 2 (50 mL) the reaction mixture was diluted, the organic phase was separated, and the aqueous phase was reused with CH 2 Cl 2 (50 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/7) to give compound 24 (0.90 g, 81% of the total yield in two steps) as a colorless liquid.
1 H NMR(400MHz,CDCl 3 )δ7.49(s,1H),7.34–7.27(m,2H),6.99–6.82(m,2H),5.96–5.74(m,1H),5.21–5.00(m,2H),4.62(d,J=10.8Hz,1H),4.58(d,J=10.7Hz,1H),4.29–4.19(m,2H),3.83(s,3H),3.68(dd,J=9.8,5.9Hz,1H),3.58–3.52(m,1H),3.51–3.46(m,1H),3.47–3.43(m,1H),3.39(s,3H),3.36(s,3H),3.07(dd,J=15.4,2.8Hz,1H),2.92(dd,J=15.4,9.0Hz,1H),2.65–2.55(m,2H),2.04–1.92(m,1H),1.68–1.59(m,2H),0.97(s,6H),0.95–0.91(m,12H),0.90(t,9H),0.50–0.35(m,6H),0.07(s,6H).
13 C NMR(100MHz,CDCl 3 )δ164.0,158.9,140.8,134.8,134.4,131.4,128.7,117.1,113.7,81.8,79.7,76.4,76.0,74.5,64.5,57.4,56.9,55.3,44.0,39.2,38.5,33.2,32.8,25.9,20.8,20.0,18.3,12.4,7.0,5.1,-5.4,-5.4.
7. Synthesis of Compound 27
Compound 24 (0.284 g,0.39 mmol), pinacol ester of vinylboronic acid 25 (0.20 mL,1.19 mmol), 2, 6-dichloro-p-benzoquinone 26 (0.021 g,0.12 mmol) was dissolved in toluene (15.0 mL), heated to 80deg.C, and Hoveyda-Grubbs II (0.025 g,0.04 mmol) was dissolved in toluene (6.0 mL) was added to the reaction system under Ar. After stirring at 85 ℃ for 12 hours, concentrating under vacuum, the residue was purified by flash column on silica gel (ethyl acetate/n-hexane=1/6) to give compound 27 (191.0 mg, 67%) as a colorless liquid.
1 H NMR(400MHz,Methanol-d4)δ7.78(s,1H),7.34–7.24(m,2H),6.98–6.83(m,2H),6.57(dt,J=17.9,6.6Hz,1H),5.47(dt,J=17.9,1.5Hz,1H),4.63(d,J=2.7Hz,2H),4.35–4.24(m,2H),3.80(s,3H),3.68(dd,J=9.8,5.9Hz,1H),3.60(dd,J=8.6,2.8Hz,1H),3.57–3.47(m,2H),3.40(s,3H),3.31(s,3H),3.13(dd,J=15.5,2.7Hz,1H),2.91(dd,J=15.5,9.1Hz,1H),2.79–2.60(m,2H),2.07–1.91(m,1H),1.75–1.59(m,2H),1.25(s,12H),1.00(s,3H),1.00(s,3H),0.95(s,3H),0.94–0.89(m,18H),0.56–0.35(m,6H),0.08(s,6H).
13 C NMR(100MHz,Methanol-d4)δ164.5,159.2,149.3,139.9,136.2,131.1,128.5,113.3,83.0,81.8,79.7,76.0,75.0,74.3,64.1,56.5,55.5,54.3,43.8,40.4,38.3,33.2,32.3,25.1,23.7,19.9,19.2,17.7,11.4,6.1,4.8,-6.6,-6.7.
8. Synthesis of Compound 28
Compound 27 (0.95 g,1.1 mmol) was dissolved in CH 2 Cl 2 /pH=6.8 buffer (24 mL:3 mL) and cooled to 0deg.C; DDQ (0.376 g,1.66 mmol) was carefully added and stirred for 1 hour at room temperature. Cooling to 0deg.C, adding saturated NaHCO 3 The reaction mixture was quenched with ethyl acetate (50 mL), the organic phase was separated, extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were washed with saturated brine (20 mL), and Na was added 2 SO 4 Drying, filtration and concentration in vacuo gave compound 28 (676.0 mg, 83%) as a colorless oily liquid after purification of the residue on a flash column of silica gel (ethyl acetate/n-hexane=1/4).
1 H NMR(300MHz,Methanol-d4)δ7.81(s,1H),6.56(dt,J=17.9,6.6Hz,1H),5.47(dt,J=17.9,1.5Hz,1H),4.37(dd,J=9.1,2.7Hz,1H),4.28(t,J=6.5Hz,1H),3.77(dd,J=10.3,1.7Hz,1H),3.67(dd,J=9.8,5.8Hz,1H),3.62–3.50(m,2H),3.44(s,3H),3.30(s,3H),3.09(dd,J=15.4,2.7Hz,1H),2.89(dd,J=15.3,9.2Hz,1H),2.80–2.58(m,2H),1.92(dt,J=10.6,6.3Hz,1H),1.65–1.53(m,1H),1.53–1.40(m,1H),1.25(s,12H),0.96(d,J=2.0Hz,3H),0.95–0.92(m,18H),0.91(s,3H),0.88(s,3H),0.60–0.37(m,6H),0.09(s,6H).
13 C NMR(75MHz,Methanol-d4)δ164.5,149.3,139.9,136.4,83.0,79.5,77.2,74.9,71.7,64.3,57.6,55.5,41.8,40.4,38.9,33.6,32.0,25.0,23.7,19.1,17.9,17.7,11.3,6.0,4.6,-6.6,-6.7.
9. Synthesis of Compound 29
Compound 20 (1.05 g,1.42 mmol) was dissolved in THF/H 2 O (20.0 mL:5.0 mL) and cooled to 0deg.C, naBH was added 4 (107.0 mg,2.84 mmol) was slowly added to the reaction mixture, and after warming to room temperature, the mixture was vigorously stirred for 3 hours, and saturated NH was added 4 The reaction mixture was quenched with Cl solution (20 mL), diluted with ethyl acetate (50 mL), the organic phase was separated, the aqueous phase was extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were washed with saturated brine (25 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating under reduced pressure to obtain diolCompound S12 (about 0.67 g) was a colorless liquid.
The resulting diol compound S12 (about 0.67 g) was dissolved in CH 2 Cl 2 (20 mL) and cooled to-78deg.C, et is added slowly in sequence 3 N (0.78 mL,5.60 mmol), TESOTf (0.64 mL,2.84 mmol), was stirred for 0.5 h, then warmed to 0deg.C and stirred for another 4 h. Adding saturated NH 4 Cl solution (15 mL) was quenched and CH was added 2 Cl 2 (50 mL) the reaction mixture was diluted, the organic phase was separated, and the aqueous phase was reused with CH 2 Cl 2 (50 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (20 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/10) to give compound S11 (0.908 g, 88% of total yield in two steps) as a pale yellow liquid.
1 H NMR(400MHz,CDCl 3 )δ7.33–7.26(m,2H),6.93–6.85(m,2H),4.61(d,J=10.8Hz,1H),4.56(d,J=10.7Hz,1H),3.82(s,3H),3.78–3.69(m,2H),3.69–3.61(m,2H),3.55–3.46(m,2H),3.46–3.39(m,1H),3.37(s,3H),2.02–1.92(m,1H),1.88–1.78(m,1H),1.65–1.55(m,1H),1.54–1.44(m,2H),1.02–0.96(m,24H),0.91(s,9H),0.89(s,3H),0.67–0.60(m,12H),0.06(s,6H).
13 C NMR(100MHz,CDCl 3 )δ158.9,131.7,128.8,113.6,81.5,79.6,74.6,74.3,64.5,60.7,57.2,55.3,44.1,38.6,35.8,33.0,25.9,20.2,19.6,18.3,12.4,7.2,6.8,5.7,4.4,-5.4,-5.4.
Compound S11 (500.0 mg,0.69 mmol) was dissolved in CH 2 Cl 2 Ph=6.8 buffer (8 ml:1 ml) and cooled to 0 ℃; DDQ (204.0 mg,0.90 mmol) was carefully added and stirred for 1 hour at room temperature. Cooling to 0deg.C, adding saturated NaHCO 3 The reaction mixture was quenched with ethyl acetate (30 mL), the organic phase was separated, extracted with ethyl acetate (60 mL. Times.3), and the combined organic phases were washed with saturated brine (20 mL), and Na was added 2 SO 4 Dried, filtered and concentrated in vacuo, and the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/4) to give compound 29 (356.0 mg, 85%) as a colourless oil.
1 H NMR(500MHz,CDCl 3 )δ4.17(s,1H),3.93–3.87(m,1H),3.79–3.73(m,1H),3.73–3.70(m,1H),3.68–3.61(m,2H),3.55–3.49(m,1H),3.46(dd,J=9.8,7.2Hz,1H),3.43(s,3H),1.96–1.81(m,2H),1.77–1.67(m,1H),1.44–1.36(m,2H),1.01–0.94(m,21H),0.92(d,J=6.9Hz,3H),0.90(s,9H),0.75(s,3H),0.68(q,J=8.2Hz,6H),0.60(q,J=7.9Hz,6H),0.05(s,6H).
13 C NMR(125MHz,CDCl 3 )δ80.2,79.4,72.1,65.0,60.2,58.9,40.5,39.7,35.9,34.4,26.0,22.9,20.1,18.3,12.3,7.0,6.7,5.3,4.5,-5.4,-5.4.
10. Synthesis of Compound 31
Fragment alcohol 29 (70.0 mg,0.12 mmol) and fragment acid 30 (70.0 mg,0.17 mmol) were dissolved in toluene (10 mL) solvent, and Et was added sequentially 3 N (0.07 mL,0.46 mmol) and Yamaguchi reagent TCBC (0.04 mL,0.23 mmol) were stirred at room temperature for 3 hours, and DMAP (42.0 mg,0.35 mmol) was dissolved in toluene (3.0 mL) and added to the reaction system and stirred at room temperature for 12 hours. Adding saturated NH 4 The reaction mixture was quenched with Cl solution (15 mL), diluted with ethyl acetate (15 mL), extracted with ethyl acetate (50 mL. Times.3), and the combined organic phases were washed with saturated brine (20 mL) and then added with Na 2 SO 4 Dried, filtered and concentrated in vacuo, and the residue purified by flash column chromatography (ethyl acetate/n-hexane=1/8) to give compound 31 as a pale yellow oily liquid (105.0 mg, 91%).
1 H NMR(500MHz,CDCl 3 )δ6.41(dd,J=14.6,7.6Hz,1H),6.31(d,J=14.5Hz,1H),5.15(dd,J=9.0,2.9Hz,1H),4.28–4.16(m,1H),3.80–3.73(m,1H),3.73–3.67(m,1H),3.65–3.59(m,3H),3.43–3.39(m,1H),3.32(s,3H),3.25(s,3H),3.02(dt,J=7.6,3.4Hz,1H),2.60–2.49(m,2H),1.90–1.78(m,3H),1.78–1.69(m,1H),1.58–1.54(m,1H),1.54–1.47(m,2H),0.97(t,J=7.9Hz,9H),0.97(t,J=7.9Hz,9H)0.92–0.89(m,12H),0.88(s,9H),0.87(s,3H),0.83(s,3H),0.67–0.56(m,12H),0.07(s,6H),0.05(s,6H).
13 C NMR(125MHz,CDCl 3 )δ170.8,146.5,80.6,79.2,78.1,75.7,74.4,66.1,64.5,60.1,58.3,56.3,42.5,42.5,42.0,39.1,35.8,32.5,26.0,25.9,20.8,19.8,18.3,18.0,12.4,7.1,6.8,5.6,4.5,-4.4,-4.6,-5.4,-5.4.
11. Synthesis of Compound 33
Fragment alcohol 31 (140.0 mg,0.14 mmol) was dissolved in ethyl acetate (10.0 mL) solvent, 1M HCl (2.8 mL,2.8 mmol) was added, and the mixture was stirred at room temperature for half an hour. The reaction mixture was diluted with ethyl acetate (100 mL), the aqueous phase was separated, and the organic phase was washed with saturated brine (10 mL) and then added with anhydrous Na 2 SO 4 The organic phase was concentrated under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/5) to give compound 32 (102.0 mg, 82%) as a pale yellow oil.
1 H NMR(500MHz,CDCl 3 )δ6.40(dd,J=14.6,7.6Hz,1H),6.32(d,J=14.6Hz,1H),5.16(d,J=9.4Hz,1H),4.23(p,J=5.9Hz,1H),3.84–3.72(m,3H),3.62(brs,1H),3.56(dd,J=9.9,5.9Hz,1H),3.45(dd,J=9.9,6.5Hz,1H),3.41(s,3H),3.25(s,3H),3.16–3.11(m,1H),2.55(dd,J=6.2,1.2Hz,2H),2.24–2.13(m,1H),1.95–1.74(m,4H),1.66(dd,J=15.0,10.9Hz,1H),1.60–1.52(m,1H),1.47–1.39(m,1H),0.98(t,J=7.9Hz,9H),0.91(d,J=4.4Hz,3H),0.89(s,9H),0.88(s,9H),0.85(d,J=7.0Hz,3H),0.81(s,3H),0.65(q,J=7.9Hz,6H),0.07(s,6H),0.04(s,6H).
13 C NMR(125MHz,CDCl 3 )δ171.1,146.8,146.4,80.6,80.1,78.1,75.6,73.9,66.1,64.3,60.0,58.9,56.3,42.5,42.5,42.0,39.0,36.0,32.8,26.0,25.9,20.0,18.7,18.2,18.0,12.2,7.1,5.6,-4.4,-4.6,-5.4,-5.4.
Substrate 32 (987.0 mg,1.11 mmol) was dissolvedIn DCM (7 mL) was added NaHCO in succession at room temperature 3 (373.0 mg,4.44 mmol) Dess-Martin reagent (708.0 mg,1.67 mmol). After stirring for half an hour at room temperature, CH was used 2 Cl 2 (40 mL. Times.3) extraction, and the combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1:6) to give colorless liquid aldehyde S13 (about 935.0 mg).
The fragment aldehyde S13 (about 935.0 mg) was dissolved in t-butanol (10 mL) and 2, 3-dimethyl-2-butene (5 mL), to which NaClO was added 2 (301.0 mg,3.33 mmol) and NaH 2 PO 4 (400.0 mg,3.33 mmol) in water (5 mL), the reaction was stirred at room temperature for 1 hour, ethyl acetate (100 mL) was added to dilute the reaction solution, and extracted with ethyl acetate (20 mL. Times.2), and the combined organic phases were washed with saturated sodium thiosulfate (20 mL), brine (20 mL), and Na was added 2 SO 4 The organic phase was dried, concentrated under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/2) to give the pale yellow oily liquid acid S14 (about 860.0 mg).
Dissolving acid S14 (about 860.0 mg) in CH 2 Cl 2 To (10 mL) was added (590.0 mg,4.80 mmol), tceOH (300.0. Mu.L, 3.30 mmol) and EDCI (420.0 mg,2.20 mmol) in this order, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (150 mL), and the organic phase was washed with saturated brine (20 mL) and then added with anhydrous Na 2 SO 4 The organic phase was concentrated under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/6) to give compound 33 (781.0 mg, three steps 68%) as a pale yellow oil.
1 H NMR(400MHz,CDCl 3 )δ6.42(dd,J=14.5,7.5Hz,1H),6.33(d,J=14.6Hz,1H),5.10(dd,J=8.7,2.8Hz,1H),4.83(d,J=11.9Hz,1H),4.68(d,J=11.9Hz,1H),4.34–4.19(m,1H),4.19–4.02(m,1H),3.82–3.74(m,1H),3.61(dd,J=10.0,5.5Hz,1H),3.45(dd,J=9.8,6.9Hz,1H),3.34(s,3H),3.27(s,3H),3.10–3.02(m,1H),2.86(dd,J=16.7,2.9Hz,1H),2.61(d,J=8.5Hz,1H),2.59–2.53(m,2H),1.91–1.81(m,2H),1.80–1.72(m,1H),1.61–1.52(m,2H),0.97(t,J=7.9Hz,9H),0.94–0.83(m,27H),0.67–0.59(m,6H),0.09(s,6H),0.06(s,3H),0.06(s,3H).
13 C NMR(100MHz,CDCl 3 )δ170.9,170.9,146.3,94.8,80.5,79.2,78.2,75.3,74.2,73.9,66.0,64.3,58.4,56.3,42.4,41.9,38.7,38.2,32.6,25.9,25.8,20.5,19.9,18.2,17.9,12.4,7.0,5.2,4.4,-4.4,-4.6,-5.4,-5.4.
12. Synthesis of Compound 34
Under the protection of Ar gas, the substrate 24 (176.0 mg,0.17 mmol), 20 (178.0 mg,0.24 mmol) Ag 2 O (158.0 mg,0.68 mmol) and Pd (PPh) 3 ) 4 (39.0 mg,0.034 mmol) dissolved in degassed THF/H 2 O (12:2 mL) in solvent, stirring at room temperature for 5 hours. The solids were removed by filtration through celite and the filtrate was concentrated under reduced pressure. Purification of the residue using a flash column of silica gel (ethyl acetate/n-hexane=1/6) gave compound 34 (233.0 mg, 90%) as a colourless oil.
1 H NMR(300MHz,CDCl 3 )δ7.50(s,1H),6.27–5.99(m,2H),5.79–5.60(m,1H),5.49–5.32(m,1H),5.08(dd,J=7.0,4.3Hz,1H),4.82(d,J=12.0Hz,1H),4.67(d,J=12.0Hz,1H),4.30–4.14(m,3H),4.10(dd,J=8.4,2.7Hz,1H),4.02(s,1H),3.94(dd,J=7.2,5.0Hz,1H),3.82–3.71(m,1H),3.69–3.48(m,4H),3.46(s,3H),3.45–3.37(m,1H),3.33(s,3H),3.32(s,3H),3.22(s,3H),3.16–2.97(m,3H),2.86(dd,J=16.7,2.7Hz,1H),2.70–2.48(m,5H),1.96–1.77(m,3H),1.71(dt,J=13.9,5.4Hz,1H),1.62–1.51(m,2H),1.45(dd,J=7.1,5.0Hz,2H),1.00(s,3H),0.98(s,3H),0.96(s,6H),0.93(s,6H),0.92–0.84(m,45H),0.67–0.56(m,6H),0.52–0.41(m,6H),0.07(s,6H),0.06–0.02(m,12H).
13 C NMR(75MHz,CDCl 3 )δ171.1,171.0,163.5,140.9,135.1,132.7,132.0,131.9,130.1,94.8,80.9,79.3,79.2,78.7,76.3,75.2,74.2,74.0,71.7,66.3,64.8,64.3,59.0,58.4,56.9,55.9,42.9,42.3,40.8,39.4,38.6,38.2,38.1,34.0,32.5,25.9,25.9,22.4,20.6,20.0,19.7,18.3,18.2,18.0,12.5,12.4,7.0,6.9,6.8,5.2,4.7,4.4,-4.4,-4.6,-5.4,-5.4,-5.4.
13. Synthesis of Compound 36
Alcohol 34 (107.0 mg,0.26 mmol) and acid 30 (107.0 mg,0.260 mmol) were dissolved in tolene (20 mL) solvent, DMAP (35.0 mg,0.29 mmol) was added sequentially, yamaguchi reagent TCBC (0.045 mL,0.29 mmol) was stirred at room temperature for 3 hours, and then saturated NH was added 4 The reaction mixture was quenched with Cl solution (15 mL), diluted with ethyl acetate (150 mL), and the organic phase was washed with saturated brine (20 mL) and then added with Na 2 SO 4 Dried, filtered and concentrated in vacuo, and the residue purified by flash column chromatography (ethyl acetate/n-hexane=1/8) to give compound S15 as a pale yellow oily liquid (244.0 mg, 95%).
1 H NMR(400MHz,CDCl 3 )δ7.49(s,1H),6.42(dd,J=14.5,7.5Hz,1H),6.33(d,J=14.6Hz,1H),6.23–6.07(m,2H),5.73(dt,J=13.9,7.0Hz,1H),5.41(dd,J=14.1,7.8Hz,1H),5.18(dd,J=9.5,2.1Hz,1H),5.13–5.03(m,1H),4.83(d,J=11.9Hz,1H),4.68(d,J=11.9Hz,1H),4.26(td,J=5.9,2.6Hz,2H),4.21(t,J=6.3Hz,1H),4.12(ddd,J=8.4,6.5,2.6Hz,2H),3.83–3.71(m,2H),3.63(ddd,J=11.1,9.8,5.5Hz,2H),3.46(td,J=10.1,6.8Hz,2H),3.36(s,3H),3.35(s,3H),3.33(s,3H),3.27(s,3H),3.23(s,3H),3.12–3.01(m,3H),2.94(dd,J=15.3,9.5Hz,1H),2.87(dd,J=16.8,2.8Hz,1H),2.70–2.45(m,7H),1.94–1.79(m,4H),1.79–1.69(m,2H),1.69–1.60(m,2H),1.60–1.49(m,2H),0.99(s,3H),0.97(s,6H),0.95(s,6H),0.93(s,3H),0.92(s,9H),0.91(s,9H),0.90–0.86(m,36H),0.67–0.58(m,6H),0.40(p,J=7.9Hz,6H),0.09(s,6H),0.08(s,3H),0.08(s,3H),0.07(s,3H),0.07(s,3H),0.06(s,3H),0.06(s,3H).
13 C NMR(100MHz,CDCl 3 )δ171.1,171.0,170.9,163.7,146.4,140.9,134.8,132.7,131.9,131.8,130.4,94.9,80.5,79.3,79.2,78.7,78.2,77.2,76.5,76.2,75.5,75.2,74.2,74.0,66.3,66.0,64.4,64.3,58.5,58.4,57.0,56.3,55.9,42.9,42.5,42.4,42.3,41.9,38.8,38.7,38.2,38.1,32.6,32.5,25.9,25.9,25.8,21.1,20.6,20.4,19.9,18.3,18.2,18.0,12.4,12.4,7.0,5.2,5.0,-4.4,-4.4,-4.6,-4.6,-5.4,-5.4,-5.4.
Under the protection of Ar gas, the substrate S15 (288.0 mg,0.15mmol,35 (137.0 mg,0.220 mmol), ag was reacted with 2 O (105.0 mg,0.45 mmol) and Pd (PPh) 3 ) 4 (25.0 mg,0.022 mmol) and THF/H dissolved in degassing (degaussed) 2 O (12 mL:2 mL) in a solvent was stirred at room temperature for 5 hours. The solids were removed by filtration through celite and the filtrate was concentrated under reduced pressure. Purification of the residue using a flash column of silica gel (ethyl acetate/n-hexane=1/6) gave compound 36 (230.0 mg, 67%) as a colourless oil.
1 H NMR(400MHz,CDCl 3 )δ7.48(s,1H),6.24–6.08(m,4H),5.81–5.61(m,2H),5.51–5.36(m,3H),5.17(dd,J=9.1,2.5Hz,1H),5.12–5.05(m,1H),4.87–4.65(m,6H),4.47(dd,J=11.3,6.4Hz,1H),4.39(dd,J=11.3,3.8Hz,1H),4.31–4.21(m,2H),4.20(t,J=6.4Hz,1H),4.17–4.02(m,3H),3.77(ddd,J=13.4,7.6,5.6Hz,2H),3.65(dd,J=8.7,4.4Hz,1H),3.61(dd,J=8.8,4.4Hz,1H),3.50–3.42(m,3H),3.42(s,3H),3.36(s,3H),3.35(s,3H),3.33(s,3H),3.24(s,3H),3.23(s,3H),3.11–3.01(m,3H),2.94(dd,J=15.3,9.5Hz,1H),2.87(dd,J=16.7,2.8Hz,1H),2.65–2.53(m,7H),2.54–2.44(m,1H),2.45–2.33(m,1H),1.94–1.79(m,4H),1.77–1.70(m,2H),1.68–1.61(m,2H),1.60–1.53(m,2H),1.00–0.85(m,72H),0.67–0.57(m,6H),0.45–0.35(m,6H),0.10–0.04(m,24H).
13 C NMR(100MHz,CDCl 3 )δ171.1,171.1,171.0,163.7,154.1,153.9,141.0,134.8,133.0,132.8,132.7,132.1,131.9,131.8,130.4,128.3,95.4,94.9,94.3,80.2,79.3,78.7,78.6,76.5,76.3,75.4,75.2,74.6,74.2,74.0,67.1,66.3,64.4,64.3,58.5,58.4,58.2,57.0,56.0,55.9,52.6,42.9,42.9,42.5,42.4,38.8,38.7,38.2,33.5,32.6,32.6,32.5,26.0,25.9,21.1,20.6,20.4,20.0,18.3,18.2,18.0,12.5,12.5,7.0,5.2,5.0,-4.4,-4.6,-5.4,-5.4,-5.4.
14. Synthesis of Compound 37
Compound 36 (75.0 mg,0.033 mmol) was dissolved in THF (8 mL) and KH was added 2 PO 4 (8 mL, 1M) and Zn (360.0 mg,5.5 mmol) and Zn (10% Pb) (360.0 mg,5.0 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Diluted with EA, the solids were separated by separation, washed with brine (15 mL), and anhydrous Na was added 2 SO 4 Drying, filtration and concentration in vacuo gave intermediate S17 (about 53 mg) which was directly subjected to the next reaction.
The resulting intermediate S17 (about 53 mg), DAMP (40.0 mg,0.33 mmol) was dissolved in DCM (66.0 mL), BEP (22.0 mg,0.083 mmol) was added after 12 hours of reaction, and after continuing the reaction for 12 hours, concentrated under reduced pressure, the resulting residue was purified using a flash silica gel column (ethyl acetate/n-hexane=1/2) to give compound S16 (30.0 mg, total yield of two steps 51%) as a colorless oil.
1 H NMR(500MHz,CDCl 3 )δ7.47(s,1H),6.36(d,J=6.8Hz,1H),6.22–6.07(m,4H),5.77–5.67(m,2H),5.43(dd,J=14.5,8.3Hz,1H),5.38(dd,J=14.8,8.3Hz,1H),5.20–5.14(m,1H),5.16–5.11(m,1H),4.23–4.16(m,2H),4.16–4.05(m,2H),4.05–3.99(m,1H),3.99–3.94(m,1H),3.85(d,J=10.0Hz,1H),3.73(d,J=7.3Hz,2H),3.68–3.55(m,4H),3.50–3.42(m,3H),3.40(s,3H),3.36(s,3H),3.34(s,6H),3.23(s,3H),3.23(s,3H),3.11–2.97(m,3H),2.65–2.49(m,7H),2.45–2.37(m,1H),2.37–2.23(m,3H),1.91–1.79(m,4H),1.79–1.72(m,2H),1.66–1.61(m,2H),1.61–1.51(m,2H),1.01–0.82(m,72H),0.68–0.58(m,6H),0.49–0.33(m,6H),0.11–0.02(m,24H).
13 C NMR(125MHz,CDCl 3 )δ172.0,170.8,170.6,163.6,140.7,134.8,133.2,132.7,132.3,132.2,131.8,131.6,130.0,129.7,82.3,79.6,79.3,79.1,79.1,76.4,75.6,75.0,74.8,66.4,66.4,64.4,64.3,62.3,58.6,58.4,58.1,56.7,55.8,55.8,53.6,43.1,43.0,42.7,42.5,42.5,40.5,38.9,38.9,37.9,34.0,33.0,32.8,25.9,25.8,21.6,21.1,20.8,19.9,18.2,18.2,17.9,12.4,12.4,7.0,6.9,5.2,5.0,-4.3,-4.3,-4.6,-5.4,-5.5,-5.5.
Compound S16 (25.0 mg,0.014 mmol) was dissolved in CH 2 Cl 2 (4 mL), cool to 0deg.C, add NaHCO in turn 3 (50.0 mg,0.59 mmol), dess-Martin periodinane (25.0 mg,0.059 mmol). The reaction was stirred for 1 hour at room temperature, concentrated to 1mL under reduced pressure, and the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/5) to give intermediate aldehyde S18 (19.0 mg) as a colorless liquid.
The resulting intermediate aldehyde S18 (19.0 mg 0.01 mmol) was dissolved in CH 2 Cl 2 (1.5 mL) and cooled to 0deg.C, 2.6-di-tert-butyl-4-methyl pyridine (20.0 mg,0.095 mmol) was carefully added in sequence, PPh 3 (15.0 mg,0.057 mmol) and Br 2 C 2 Cl 4 (17.0 mg,0.052 mmol) and the reaction was allowed to warm to room temperature and stirred for 1.5 hours until the aldehyde reaction was complete. The DCM solvent was dried under reduced pressure and redissolved in CH 3 To CN (1.5 mL), DBU (8. Mu.L, 11.3 mmol) was added and stirring was continued at room temperature for 3 hours. With saturated NH 4 The reaction mixture was quenched with Cl solution (5 mL), diluted with ethyl acetate (150 mL), and the organic phase was washed with saturated brine (10 mL) and then with anhydrous Na 2 SO 4 After drying, filtration and concentration under reduced pressure, the residue was purified by flash column chromatography (ethyl acetate/n-hexane=1/6) to give cyclized product 37 as a colorless liquid (13.0 mg, total yield of two steps 54%).
1 H NMR(500MHz,CDCl 3 )δ7.45(s,2H),6.22–5.97(m,4H),5.67(dt,J=14.3,7.1Hz,2H),5.37(dd,J=14.7,8.2Hz,2H),5.14(dd,J=9.6,2.1Hz,2H),4.19(t,J=6.1Hz,2H),4.14(q,J=6.0Hz,2H),4.07(dd,J=9.2,2.8Hz,2H),3.69(q,J=7.0Hz,2H),3.62(dd,J=9.8,5.5Hz,2H),3.42(dd,J=9.9,7.1Hz,2H),3.32(s,6H),3.31(s,6H),3.20(s,6H),3.08–3.00(m,4H),2.95(dd,J=15.3,9.2Hz,2H),2.61(t,J=6.7Hz,4H),2.52(d,J=6.2Hz,4H),1.89–1.80(m,4H),1.77–1.71(m,2H),1.69–1.64(m,4H),0.92–0.83(m,72H),0.47–0.30(m,12H),0.05(s,12H),0.05(s,6H),0.05(s,6H).
13 C NMR(125MHz,CDCl 3 )δ170.6,163.7,140.7,135.0,133.1,131.9,131.8,130.0,79.3,79.1,76.6,76.4,75.7,66.5,64.5,58.5,56.8,55.9,43.2,42.7,42.5,39.0,37.7,33.1,33.0,29.7,26.0,25.9,21.6,21.0,18.3,18.0,12.4,7.0,5.0,-4.3,-4.5,-5.4,-5.4.
15. Synthesis of precursor Compound S18 of Compound 2
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A solution of HF. Py-Py-THF (0.4 mL:0.6mL:2 mL) was added to a stirred solution of 37 (18.0 mg, 10.0. Mu. Mol) in THF (4 mL). The reaction mixture was stirred for 17 hours, then with CH 2 Cl 2 (10 mL) dilution with NaHCO 3 (aq.) (10 mL) quenching. The organic phase was separated and the aqueous phase was treated with CH 2 Cl 2 (10 mL. Times.2) extraction, combined organic extracts in anhydrous Na 2 SO 4 Drying, filtering, and concentrating the space. Concentrating in vacuum. The residue was purified by flash column chromatography to give compound S18 (8.3 mg, 54%) as a colorless oil.
1 H NMR(500MHz,C 6 D 6 )δ7.18(s,2H),6.31(dd,J=15.2,10.4Hz,2H),6.19(dd,J=15.2,10.5Hz,2H),5.90(dt,J=14.7,7.2Hz,2H),5.57(d,J=9.9Hz,2H),5.56–5.51(m,2H),4.53–4.43(m,2H),4.40(dd,J=8.6,2.3Hz,2H),4.24(t,J=5.8Hz,2H),3.88(dd,J=7.2,6.6Hz,2H),3.81–3.70(m,2H),3.64–3.56(m,2H),3.41(s,6H),3.39–3.35(m,2H),3.18(s,6H),3.14(s,6H),3.13–3.09(m,2H),2.89(dd,J=15.7,8.5Hz,2H),2.81–2.74(m,6H),2.71(dd,J=15.5,5.2Hz,2H),2.20–2.13(m,2H),2.13–2.04(m,4H),1.99(dt,J=13.9,6.0Hz,2H),1.76(ddd,J=14.9,9.9,2.3Hz,2H),1.09(s,6H),1.04(s,6H),1.01(t,J=8.1Hz,18H),0.99(s,18H),0.90(d,J=7.1Hz,6H),0.63–0.50(m,12H),0.15(s,6H),0.14(s,6H).
13 C NMR(125MHz,C 6 D 6 )δ171.0,164.0,141.8,135.1,133.5,132.4,132.2,130.6,80.9,79.6,77.1,77.0,75.4,67.2,64.9,58.1,56.6,55.8,43.7,43.0,38.1,37.6,33.0,32.0,26.1,21.0,19.9,18.2,12.7,7.3,5.5,-4.2,-4.4.
Substrate S18 (20.0 mg, 13.0. Mu. Mol) was dissolved in methylene chloride, and sodium bicarbonate (44.0 mg, 52.0. Mu. Mol) and Dess-Martin reagent (11.0 mg, 26.0. Mu. Mol) were added thereto at room temperature. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to 2mL, and the aldehyde substrate 2 (about 15 mg) was obtained by separation and purification on a silica gel column.
3. Synthesis of actin stabilizer, rhizopodin
Ba (OH) 2 ·8H 2 O (15.0 mg, 49.0. Mu. Mol) was placed in a 10mL round bottom flask, burned with an alcohol burner for 3-5min, and then a solution of ketone 6 (31.0 mg, 98.0. Mu. Mol) in anhydrous THF (1 mL) was added thereto. After stirring at room temperature for half an hour, THF-H of aldehyde 2 (about 15 mg) was added to the reaction system 2 O (3 mL:0.1 mL). After stirring was continued at room temperature for 10 hours, the reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride and saturated brine in this order, and dried over anhydrous sodium sulfate. The organic phase was separated and purified by silica gel column to give compound 38 (17.2 mg, 69% of total yield in two steps).
1 H NMR(500MHz,C 6 D 6 )δ7.90(s,1.3H),7.57(s,0.7H),7.42(d,J=14.5Hz,1H),7.27(s,0.7H),7.25(s,1.3H),7.20(s,1H),7.19(s,1H),6.37–6.22(m,4H),6.15(dd,J=15.2,10.5Hz,2H),5.96–5.83(m,3.3H),5.57–5.48(m,3.7H),4.93(dt,J=14.5,7.3Hz,0.7H),4.79(dt,J=14.3,7.3Hz,1.3H),4.55–4.45(m,2H),4.31(dd,J=8.4,3.2Hz,2H),4.26–4.17(m,2H),3.87(q,J=7.4Hz,2H),3.53–3.45(m,2H),3.35(s,3.9H),3.35(s,2.1H),3.22(4H,m),3.20(s,2.1H),3.19(s,3.9H),3.18–3.13(m,12H),3.07–3.00(m,4H),2.84–2.77(m,4H),2.77–2.71(m,4H),2.66(s,4H),2.62–2.58(m,2H),2.32–2.27(m,0.7H),2.24–2.20(m,1.3H),2.16(s,2H),2.19–2.11(2H,m),2.07–1.93(m,4H),1.87–1.82(m,2H),1.80–1.75(m,2H),1.09–0.90(m,60H),0.65–0.49(m,12H),0.18(s,6H),0.16(s,6H).
13 C NMR(125MHz,C 6 D 6 )δ201.0,200.9,170.9,163.7,161.5,160.2,148.0,147.8,141.6,135.4,133.5,132.4,132.4,132.3,130.7,130.7,130.2,128.3,126.8,106.8,104.8,82.9,82.9,81.8,79.5,77.1,76.9,75.5,67.1,58.1,57.8,57.6,56.6,55.9,47.5,47.2,43.8,42.9,42.7,39.0,38.9,38.0,33.5,33.4,33.2,31.9,31.4,31.2,26.9,26.2,21.7,18.3,14.8,12.9,12.7,7.4,5.5,-4.1,-4.3.
To a round bottom flask containing substrate 38 (9.2 mg, 4.8. Mu. Mol) was added [ (PPh) under argon 3 )CuH] 6 (9.4 mg, 4.8. Mu. Mol) was added with toluene-H subjected to severe anaerobic treatment 2 O (5 mL, 99:1). After stirring at room temperature for 10 hours, concentration was directly performed under reduced pressure, and the residue was rapidly filtered with a silica gel column to obtain a crude ketene reduction product S19 (about 7 mg) which was directly used for the next reaction.
HF. Py (200. Mu.L) was added to a stirred solution of S19 (about 7 mg) in THF (4 mL). The reaction mixture was stirred for 18 hours, then with CH 2 Cl 2 (10 mL) dilution with NaHCO 3 (aq.) (5 mL) quenching. The organic phase was separated and the aqueous phase was treated with CH 2 Cl 2 (10 mL. Times.2) extraction, combined organic extracts in anhydrous Na 2 SO 4 Drying, filtering, and concentrating the space. Concentrating in vacuum. The residue was purified by flash column chromatography to give rhizopodin (1) (4.2 mg, 60% of total yield in two steps) as a colorless oil.
13 C NMR(125MHz,Methanol-d4)exists as rotational conformers:δ8.32(s,1.3H),8.08(s,0.7H),7.70(s,2H),7.13(d,J=14.6Hz,0.7H),6.73(d,J=14.1Hz,1.3H),6.20(dd,J=15.1,10.5Hz,2H),6.11(dd,J=14.9,10.5Hz,2H),5.64(dt,J=14.8,7.3Hz,2H),5.39(dd,J=15.1,8.3Hz,2H),5.31(dd,J=9.0,2.0Hz,2H),5.27–5.24(m,0.7H),5.19(ddd,J=14.3,8.1,6.5Hz,1.3H),4.22(t,J=6.6Hz,2H),4.13–4.02(m,2H),3.94(dd,J=10.3,2.7Hz,2H),3.81(q,J=7.3Hz,2H),3.51–3.45(m,2H),3.33(s,6H),3.31(s,3H),3.27(s,6H),3.22(s,6H),3.11(s,2H),3.09–3.03(m,2H),3.02(s,4H),2.97(dd,J=15.2,2.7Hz,2H),2.87–2.83(m,2H),2.83–2.78(m,2H),2.65–2.60(m,4H),2.60–2.54(m,6H),2.53–2.47(m,4H),2.24–2.17(m,1H),1.87–1.80(m,2H),1.80–1.78(m,2H),1.78–1.74(m,2H),1.68–1.63(m,2H),1.63–1.58(m,4H),1.28–1.20(m,2H),1.00(d,J=6.9Hz,6H),0.93(s,12H),0.85(d,J=6.6Hz,6H).
13 C NMR(125MHz,Methanol-d4)exists as rotational conformers:δ216.3,174.0,166.5,164.8,163.4,141.0,138.0,135.2,133.5,132.6,132.1,131.6,127.4,109.5,107.4,84.1,83.3,81.5,76.9,76.6,74.5,67.4,58.4,58.1,56.9,56.5,50.4,44.1,44.0,42.8,42.1,38.7,35.6,33.7,32.2,32.2,31.3,27.8,26.0,19.5,19.1,16.1,13.2.
In conclusion, the invention innovatively synthesizes the compound which contains complete C23-C31 and phosphate segments in the side chain of the anticancer natural product rhizopodin. The compound can be subjected to HWE condensation with a macrolide structure (structural formula shown as compound 2 above), and then the newly generated unsaturated double bond is selectively reacted with Stryker reagent ([ (PPh) 3 )CuH] 6 ) The side chain fragment can be introduced into a macrolide structure by reduction, and compared with the prior synthesis steps for introducing the side chain, the scheme of the invention has shorter synthesis steps and higher synthesis efficiency. Meanwhile, the method for introducing the side chain fragment can improve a certain reference and reference for the total synthesis of other natural products with similar Z-enamine aldehyde structures. Further, the present invention has also succeeded in developing a new route for synthesizing compound 2 (total synthesis yield is 0.69%, total yield of the related art synthetic route is at most 0.42%, total synthesis yield of the scheme of the present invention is at least 1.6 times that of the related art), and successfully preparing actin stabilizer rhizopodin by reacting the above strategy with the phosphate fragment compound, wherein the overall total yield in the examples reaches 0.36%, which is at most 1.9 times that of the reported route (total yield of the synthetic route described in the background section is at most about 0.19%).
The embodiments of the present invention have been described in detail, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of those skilled in the art without departing from the spirit of the present invention.
Claims (10)
1. A side chain compound, characterized in that: the structural formula of the side chain compound is shown as the following formula:
2. the precursor compound of the side chain compound of claim 1, wherein: the precursor compound of the side chain compound has a structural formula shown in one of the following formulas I to V:
wherein R is 1 、R 2 、R 3 Independently selected from H or hydroxy protecting groups, the same or different; preferably, the hydroxyl protecting group comprises at least one of TBS, PMB, ac, piv, TES; more preferably, R 1 For TBS, R 2 Is PMB, R 3 Ac.
3. A precursor compound of a parent compound, characterized by: said parent compound being capable of reacting with a side chain compound according to claim 1 to produce rhizopodin; the precursor compound of the parent compound has a structural formula shown in one of the following formulas VII to XXIV:
wherein R is 1 、R 2 、R 4 、R 5 Independently selected from H or hydroxy protecting groups, the same or different; r is R 6 Selected from H or carboxyl protecting groups, R 7 Selected from H or an amino protecting group, which can be used to protect a hydroxyl group; the substituent X is halogen and is selected from F, cl, br or I; preferably, the hydroxyl protecting group comprises at least one of TBS, PMB, ac, piv, TES; and/or the carboxyl protecting group comprises at least one of Tce or t-Bu; and/or the amino protecting group comprises at least one of Troc, boc or Trt; more preferably, R 1 For TBS, R 2 Is PMB, R 4 Is Piv, R 5 TES, R 6 Is Tce, R 7 Is Troc.
4. The method of synthesizing a side chain compound according to claim 1, wherein: the method comprises the following steps:
to be used forPreparing a compound I as a raw material, preparing a compound II as a raw material, preparing a compound III as a raw material, preparing a compound IV as a raw material, preparing a compound V as a raw material, and preparing the side chain compound by using a compound V as a raw material; wherein, the structures of the compounds I, II, III, IV and V are shown in the following formulas: /> Wherein R is 1 、R 2 、R 3 Independently selected from H or hydroxy protecting groups, the same or different.
5. The method of manufacturing according to claim 4, wherein: the synthesis route of the side chain compound is as follows:
6. a method of synthesizing a parent compound according to claim 3, wherein: the method comprises the following steps:
s1, preparing a compound XXI;
s2, reacting the compounds XVII and XXI to generate a compound XXII;
s3, preparing a compound XXIII by taking the compound XXII as a raw material;
s4, preparing a compound XXIV by taking the compound XXIII as a raw material;
wherein the parent compound has the structural formula:
compounds XVII, XXI, XXII, XXIII and XXIV have the structural formula:
wherein R is 1 、R 5 Independently selected from H or hydroxy protecting groups, the same or different; r is R 6 Selected from H or carboxyl protecting groups, R 7 Selected from H or an amino protecting group, which can be used to protect a hydroxyl group; the substituent X is halogen and is selected from F, cl, br or I.
7. The method of manufacturing according to claim 6, wherein: the synthetic route of the parent compound is as follows:
8. a method for synthesizing an actin stabilizer, which is characterized in that: the method comprises the following steps:
reacting the side chain compound of claim 1 with a parent compound, said parent compound having the formula:
R 1 、R 5 independently selected from H or hydroxy protecting groups, the same or different.
9. The method for synthesizing actin stabilizer according to claim 8, wherein: the side chain compound reacts with a parent compound after hydrogen is extracted to generate the actin stabilizer; preferably, the hydrogen extracting is performed under the action of a hydrogen extracting reagent selected from Ba (OH) 2 At least one of NaH, liHMDS, KHMDS, LDA, naOH or potassium tert-butoxide.
10. The method for synthesizing actin stabilizer according to claim 8, wherein: r is R 1 For TBS, R 5 For TES, the synthesis method further comprises the step of deprotecting the protecting group after the reaction of the side chain compound with the parent compound; preferably, the actin stabilizer is synthesized as follows:
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