WO2024032799A1 - Preparation Method of Tetrodotoxin and its Analog - Google Patents
Preparation Method of Tetrodotoxin and its Analog Download PDFInfo
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- WO2024032799A1 WO2024032799A1 PCT/CN2023/112735 CN2023112735W WO2024032799A1 WO 2024032799 A1 WO2024032799 A1 WO 2024032799A1 CN 2023112735 W CN2023112735 W CN 2023112735W WO 2024032799 A1 WO2024032799 A1 WO 2024032799A1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 title claims description 59
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 title claims description 56
- 229950010357 tetrodotoxin Drugs 0.000 title claims description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 133
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- 239000003153 chemical reaction reagent Substances 0.000 claims description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 42
- 125000006239 protecting group Chemical group 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 22
- -1 p-methoxybenzyl Chemical group 0.000 claims description 22
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 15
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 14
- 239000007800 oxidant agent Substances 0.000 claims description 13
- 230000001590 oxidative effect Effects 0.000 claims description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 11
- 239000003054 catalyst Substances 0.000 claims description 11
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 10
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 10
- 229940126657 Compound 17 Drugs 0.000 claims description 10
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 claims description 10
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229940126543 compound 14 Drugs 0.000 claims description 10
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 9
- 229940126142 compound 16 Drugs 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 8
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940125797 compound 12 Drugs 0.000 claims description 8
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 8
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 claims description 8
- 229910052710 silicon Inorganic materials 0.000 claims description 8
- 239000010703 silicon Substances 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 7
- 229910000489 osmium tetroxide Inorganic materials 0.000 claims description 7
- TWYYFYNJOJGNFP-CUXYNZQBSA-N (2s,4r,5s,6s)-2-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-2-carbamoyl-4-[[(e,4s,6s)-4,6-dimethyloct-2-enoyl]oxymethyl]-5-hydroxy-1,3-dioxane-4,5,6-tricarboxylic acid Chemical compound O1[C@H](C(O)=O)[C@](C(O)=O)(O)[C@](COC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)(C(O)=O)O[C@]1(C(N)=O)CCC(=C)[C@@H](OC(C)=O)[C@H](C)CC1=CC=CC=C1 TWYYFYNJOJGNFP-CUXYNZQBSA-N 0.000 claims description 6
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 claims description 6
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 6
- MITGKKFYIJJQGL-UHFFFAOYSA-N 9-(4-chlorobenzoyl)-6-methylsulfonyl-2,3-dihydro-1H-carbazol-4-one Chemical compound ClC1=CC=C(C(=O)N2C3=CC=C(C=C3C=3C(CCCC2=3)=O)S(=O)(=O)C)C=C1 MITGKKFYIJJQGL-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 229910019891 RuCl3 Inorganic materials 0.000 claims description 6
- 229940125758 compound 15 Drugs 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 6
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims description 6
- 239000007858 starting material Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 5
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 5
- 235000001258 Cinchona calisaya Nutrition 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 claims description 5
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 5
- 229960000948 quinine Drugs 0.000 claims description 5
- UQJXXWHAJKRDKY-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-methylsulfanylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(SC)=NC(=O)OC(C)(C)C UQJXXWHAJKRDKY-UHFFFAOYSA-N 0.000 claims description 5
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 4
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 claims description 4
- DIIWSYPKAJVXBV-UHFFFAOYSA-N Hantzch dihydropyridine Natural products CCOC(=O)C1=CC(C(=O)OCC)=C(C)N=C1C DIIWSYPKAJVXBV-UHFFFAOYSA-N 0.000 claims description 4
- 229910010084 LiAlH4 Inorganic materials 0.000 claims description 4
- 229940125810 compound 20 Drugs 0.000 claims description 4
- LJXTYJXBORAIHX-UHFFFAOYSA-N diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1 LJXTYJXBORAIHX-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- RMIODHQZRUFFFF-UHFFFAOYSA-N methoxyacetic acid Chemical compound COCC(O)=O RMIODHQZRUFFFF-UHFFFAOYSA-N 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 claims description 4
- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 claims description 3
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 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 claims description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 3
- WMWSRIHFAVOHSW-UHFFFAOYSA-N lithium;ethane-1,2-diamine;ethyne Chemical compound [Li+].[C-]#C.NCCN WMWSRIHFAVOHSW-UHFFFAOYSA-N 0.000 claims description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 150000003983 crown ethers Chemical class 0.000 claims description 2
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 4
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 2
- 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 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 76
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 230000002829 reductive effect Effects 0.000 description 39
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
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- 150000003333 secondary alcohols Chemical class 0.000 description 1
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- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
Definitions
- the present disclosure relates to a preparation method of tetrodotoxin or its analogs.
- the present disclosure also relates to a variety of compounds useful in preparation of tetrodotoxin or its analog.qackground of the Invention
- Tetrodotoxin TTX
- TTX Tetrodotoxin
- the unique structure is comprised of a densely functionalized, stereochemically complex framework that has an unprecedented dioxa-adamantane with an ortho acid, a cyclic guanidinium hemiaminal moiety, and nine contiguous stereogenic centers including one bridgehead nitrogen-containing quaternary center.
- TTX voltage-gated sodium ion channels
- the present disclosure presents a stereoselective asymmetric synthesis of TTX and its analogue from massively available furfuryl alcohol.
- the highly heteroatoms-substituted and pseudo-symmetric cyclohexane skeleton was assembled via a stereoselective Diels-Alder reaction and a chemoselective cyclic anhydride opening strategy.
- Upjohn dihydroxylation installed the oxygen functionalities at the C-6, 7, 8, and 11 positions, decarboxylative hydroxylation supported the installation of the oxygen at C-5.
- the present disclosure provides a preparation method, the method comprising any one or more of the following steps:
- step (a) converting compound 11 to compound 12,
- step (b) converting compound 12 to compound 13,
- step (c) converting compound 13 to compound 14,
- step (d) converting compound 14 to compound 15,
- step (e) converting compound 15 to compound 16,
- step (f) converting compound 16 to compound 17
- step (g) converting compound 17 to compound A18,
- step (h) converting compound A18 to compound A19
- step (i) converting compound A19 to compound A20
- step (j) converting compound A20 to compound A21
- step (k) converting compound A21 to compound A22,
- step (l) converting compound A22 to compound A23,
- step (m) converting compound A23 to compound A24
- step (n) converting compound A24 to compound A25 and/or A25a
- step (o) converting compound A25 to compound A26
- step (p) converting compound A26 to compound A27,
- step (q) converting compound A27 to compound A28,
- step (r) converting compound A28 to Tetrodotoxin 1,
- step (s) converting compound A27 and/or A27a to compound A33,
- each R 1 independently represents a protecting group, preferably silicon-containing protecting group, preferably TBDPS,
- each R 2 independently represents a protecting group, preferably benzyl-containing protecting group, preferably p-methoxybenzyl (i.e. PMB) ,
- each R 3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
- each R 4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc, and
- each X independently represents a halogen, preferably selected from Cl, or Br.
- the preparation method comprises the step (a) .
- the preparation method comprises the step (b) .
- the preparation method comprises the step (c) .
- the preparation method comprises the step (d) .
- the preparation method comprises the step (e) .
- the preparation method comprises the step (f) .
- the preparation method comprises the step (g) .
- the preparation method comprises the step (h) .
- the preparation method comprises the step (i) .
- the preparation method comprises the step (j) .
- the preparation method comprises the step (k) .
- the preparation method comprises the step (l) .
- the preparation method comprises the step (m) .
- the preparation method comprises the step (n) .
- the preparation method comprises the step (o) .
- the preparation method comprises the step (p) .
- the preparation method comprises the step (q) .
- the preparation method comprises the step (r) .
- the preparation method comprises the step (s) .
- the preparation method further comprises step (x) and/or step (y) :
- step (x) converting compound A33 to compound 34,
- step (y) converting compound 34 to Tetrodotoxin 1,
- the method further comprises any one or more of steps (z1) to (z4) ,
- step (z1) converting compound A25a to compound A35
- step (z2) converting compound A35 to compound A36
- step (z3) converting compound A36 to compound A37
- step (z4) converting compound A37 to compound 1a
- each R 2 independently represents a protecting group, preferably benzyl-containing protecting group, preferably p-methoxybenzyl (i.e. PMB) ,
- each R 3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
- each R 4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc, and
- each X independently represents a halogen, preferably selected from Cl, or Br.
- R 2 is PMB
- R 3 is methyl
- R 4 is methyl
- the step (q) comprises one or two of the following step (q1) and step (q2) ,
- step (q1) converting compound A27 to compound A27a
- step (q2) converting compound A27a to compound A28
- each R 1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,
- each R 2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,
- each R 3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
- each R 4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc., and
- each X independently represents a halogen, preferably selected from Cl, or Br.
- the step (z3) comprises one or two of step (z3-1) and step (z3-2) ,
- step (z3-1) converting compound A36 to compound A36a
- step (z3-3) converting compound A36a to compound A37,
- the step (c) comprises one or two of step (c1) and step (c2) :
- step (c1) converting compound 13 to compound 13a
- step (c2) converting compound 13a to compound 14,
- the step (b) comprises step (b1) and step (b2) :
- step (b1) converting compound 12 to compound 12a
- step (b2) converting compound 12a to compound 13,
- step (f) comprises step (f1) and step (f2) ,
- step (f1) converting compound 16 to compound 16a
- step (f2) converting compound 16a to compound 17,
- step (j) comprises step (j1) and step (j2) ,
- Step (j1) converting compound A20 to compound A20a
- Step (j2) converting compound A20a to compound A21
- the step (l) comprises step (l1) and step (l2)
- Step (l1) converting compound A22 to compound A22a
- Step (l2) converting compound A22a to compound A23
- the step (n) comprises step (n1) and step (n2)
- Step (n1) converting compound A24 to compound A25a
- Step (n2) converting compound A25a to compound A25
- each R 1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,
- each R 2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,
- each R 3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
- each R 4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.
- each X independently represents a halogen, preferably selected from Cl, or Br.
- R 1 is TBDPS.
- R 2 is PMB.
- R 3 is methyl
- R 4 is methyl
- X is Cl.
- the method comprises the step (r) and any one or more of the following steps: the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) .
- the method comprises any two or three more of the following steps: the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
- the present invention comprises any one or two or three or more of the following steps: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
- the present invention comprises the following steps: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
- the method comprises: the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) and/or the step (q) .
- the method comprises: the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (q) .
- the method comprises: the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
- the method comprises:
- the method comprises:
- step (q) the step (q) , and/or the step (r) ;
- step (o) the step (p) , the step (q) , and/or the step (r) ; or
- step (n) the step (o) , the step (p) , the step (q) and/or the step (r) ;
- step (m) the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ;
- step (l) the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ;
- step (j) the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
- step (h) the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
- step (f) the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
- step (c) the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
- reagents used comprise quinine and MeOH
- solvent used comprises CCl 4 and/or toluene (preferably a mixture of CCl 4 and/or toluene preferably 1-2) : (1-2) by volume) .
- reagents used comprise 4-methylmorpholine N-oxide (NMO) , 4-methylmorpholine (NMM) , and/or an oxidant preferably OsO 4
- a solvent used comprises acetone, preferably a mixture of acetone and water.
- reagents used comprise 2, 2-dimethoxypropane and p-toluene sulfonic acid, and a solvent used comprises acetone.
- reagents used comprise N-hydroxyphthalimide and a base preferably an organic base preferably DMAP, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) .
- reagents used comprise Ru (bpy) 3 Cl 2 , TEMPO and Hantzsch ester, and/or a solvent used comprises DMF; and/or in the step (c2) , the conversion is carried out under the radiation of blue LEDs.
- reagents used comprise a base preferably an inorganic base preferably K 2 CO 3 , and/or a solvent used comprises an alcohol, preferably C1-C4 alcohol.
- reagents used comprises I 2 , imidazole and PPh 3 , and/or a solvent used comprises toluene.
- reagents used comprise SmI 2 and preferably further comprise a base preferably an organic base such as Et 3 N, and/or a solvent used comprises ether (preferably THF) .
- reagents used comprise SmI 2
- a solvent used comprises ether (preferably THF) .
- reagents used comprise LiAlH 4
- a solvent used comprises ether (preferably THF) .
- reagents used comprise TBDPSCl, preferably comprises imidazole and/or DMAP.
- reagents used comprise Zinc powder; and/or a solvent used comprise THF and AcOH.
- reagents used comprise 2-methoxyacetic acid, PPh 3 , and diethyl diazenedicarboxylate; and/or a solvent used comprise THF.
- reagents used comprise 4-methylmorpholine N-oxide, and/or an oxidant preferably OsO 4 , and/or a solvent used comprises acetone.
- reagents used comprise 2, 2-dimethoxypropane and camphorsulfonic acid, and/or a solvent used comprises CH 2 Cl 2 .
- reagents used comprise Dess-Martin reagent, preferably further comprises an inorganic base preferably NaHCO 3 .
- reagents used comprise N, N-diisopropylamine, and n-butyllithium.
- reagents used comprise NaHMDS and PMBBr.
- reagents used comprise sodium azide and preferably further comprise a crown ether preferably 15-crown-5 ether.
- reagents used comprises lithium acetylide ethylenediamine complex.
- reagents used comprises an oxidant preferably MnO 2 , and a reducing agent preferably NaBH 4 .
- reagents used comprise an oxidant preferably 2-Iodoxybenzoic acid, pyridinium p-toluenesulfonate, and trimethyl orthoacetate; and/or a solvent used is DMSO.
- reagents used comprise a catalyst preferably RuCl 3 , an oxidant preferably NaIO 4 , preferably further comprises EDCI and MeOH.
- reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
- reagents used comprise 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea and mercury (II) chloride, preferably further comprise an organic base preferably Et 3 N.
- reagents used comprise trifluoroacetic acid.
- reagents used comprises 1, 3-bis (benzyloxycarbonyl) -2-methyl-2-thiopseudoureaand mercury (II) chloride.
- reagents used comprise trifluoroacetic acid.
- reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
- reagents used comprise an oxidant preferably 2-Iodoxybenzoic acid, pyridinium p-toluenesulfonate, and trimethyl orthoacetate; and/or a solvent used is DMSO.
- reagents used comprise a catalyst preferably RuCl 3 , an oxidant preferably NaIO 4 , preferably further comprises EDCI and MeOH.
- reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
- reagents used comprise 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea and mercury (II) chloride, preferably further comprise an organic base preferably Et 3 N.
- reagents used comprise trifluoroacetic acid.
- the preparation method comprises the following step:
- the preparation method comprises any one or more of the following steps:
- the preparation method comprises the following step:
- the preparation method comprises any one or more of the following steps:
- the preparation method comprises any one or more of the following steps:
- each R 1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,
- each R 2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,
- each R 3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
- each R 4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.
- each X independently represents a halogen, preferably selected from Cl, or Br;
- the compound selected from the following:
- a third aspect provided is a use of the compound as described in the second aspect of the disclosure in the preparation of Tetrodotoxin or its analogs.
- a preparation method comprising using one or more of the compounds as described in the second aspect of the disclosure.
- the compound can be used as the starting material or an intermediate compound.
- a preparation method of Tetrodotoxin or its analogs comprising using one or more of the compounds as described in the second aspect of the disclosure.
- the compound can be used as the starting material or an intermediate compound.
- the scope of the invention includes those intermediate compounds used in the preparation method of the application.
- Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Extensive pharmacological investigations, including clinical trials, have demonstrated the potential promise of TTX in pain treatment and detoxification from heroin addiction.
- a new scalable synthetic entry to the neurotoxin family setting the stage for rapid access to highly oxidized natural products and a scalable preparation of TTX and its analog.
- TTX is Pseudo-C2-symmetric
- symmetry of the highly substituted functional groups could be adopted for rapid skeleton assembly.
- a subsequent chemoselective desymmetric cyclic anhydride opening and selective functional group interconversion strategy set the base for the gram-scale synthesis of the highly oxidized carbocyclic building block (-) -24 in just fifteen steps as the advanced intermediate, which was rapidly transferred to the final TTX (1) in a scalable fashion.
- Decarboxylative hydroxylation was carried out to install the TTX hydroxyl group at the C5 position. Initially, classical high-valence metal reagents were examined as oxidants, but this led to substrate decomposition; we, therefore, turned to milder radical reaction conditions, including photocatalytic-directed decarboxylative hydroxylation. Other decarboxylation approaches, such as Barton decarboxylation or organophotoredox-promoted decarboxylation in the presence of a radical initiator and oxygen under UV irradiation failed to produce the product.
- New prepared NHPI actived ester 13a was added to a 100 mL round-bottom flask, followed by Ru (bpy) 3 Cl 2 (96 mg, 0.16 mmol, 0.05 eq) , TEMPO (750 mg, 4.8 mmol, 1.54 eq) and Hantzsch ester (785 mg, 3.1 mmol, 1.0 eq) , DMF (degassed, 40 mL) .
- a flow apparatus was inserted. The system was bubbled with argon for 10 min, the reaction proceeded with a 14 rpm flow rate under the irradiation by a 36 W blue LEDs for 24 h. Then the reaction mixture was concentrated under reduced pressure.
- New prepared 0.1 M SmI 2 solution in THF followed the same process as mentioned before. Above new prepared SmI 2 solution in THF (860 mL) was transferred to the solution of compound 16 (15.0 g, 28.7 mmol, 1.00 eq) dissolved in 20 mL THF in a new flame dry 1 L round bottomed flask using double-ended needle. The whole progress needed to avoid air and carried out under argon atmosphere. Then the mixture was stirred at 55°C for 2 h. After the reaction was complete, the color changes to yellow and then quenched with sat. aq.
- TTX TTX
- C TTX (buy from Tocris bioscience, the ratio of TTX to 4, 9-anhydroTTX was 10: 3 as analyzed by 1 H NMR, Purity>99%) was utilized for comparison.
- TTX buy from Tocris bioscience, the ratio of TTX to 4, 9-anhydroTTX was 10: 3 as analyzed by 1 H NMR, Purity>99%) was utilized for comparison.
- the HEK-Na v 1.7 currents could be successfully induced and were completely blocked by 1 ⁇ M TTX (C) .
- the results suggest that the HEK-Na v 1.7 cells can be used to measure the blocking ability of different sources of TTX and TTX analog.
- TTX (S) has better blocking efficiency than TTX (C) .
- our synthetic pure TTX (S) also exhibited a stronger effect in blocking the sodium current amplitude in wild-type div(days in vitro) hippocampal neurons.
- 9-epiTTX The biological activity of 9-epiTTX was also evaluated based on the blocking of sodium current amplitude in wild-type div hippocampal neurons, however, it didn’t present any inhibition activity.
- the SmI2-mediated sequential reactions of reductive fragmentation, oxo-bridge ring opening, and ester reduction, followed by diastereoselective Upjohn dihydroxylation enable a gram-scale synthesis of highly oxidized intermediate (+) -19.
- the bridged tetrahydrofuran acetal setting simplifies the endgame and facilitates the rapid formation of the cyclic guanidinium hemiaminal and orthoester in one pot.
- the present synthesis served as a testbed for precise functional group manipulations on the densely functionalized and stereochemically complex frameworks and should be readily applicable to the synthesis of other heavily oxygenated polycyclic natural products.
- the concise synthetic strategy is suitable for the production of TTX congeners or derivatives that support further pharmacology investigations and should be amenable to large-scale synthesis of TTX for analgesic drug development, particularly for non-opioid cancer pain treatment.
Abstract
The present disclosure relates to a preparation method of TTX or its analogues, and also relates to compounds useful for preparation method for TTX or its analogues.
Description
Cross reference to related applications
This disclosure claims the priority of PCT patent application No. PCT/CN2022/111861, which is filed on August 11, 2022, and the contents of which are incorporated herein by reference in their entirety as part of this application
The present disclosure relates to a preparation method of tetrodotoxin or its analogs. The present disclosure also relates to a variety of compounds useful in preparation of tetrodotoxin or its analog.qackground of the Invention
Tetrodotoxin (TTX) , a famous marine toxin, was originally isolated from puffer fish and then found in many other species such as newts and octopuses. The biopreparation of TTX remains mysterious, although various lines of evidence support that TTX is produced by microorganisms, and several biosynthetic pathways have been proposed. After the isolation of analytically pure TTX in 1952, its complicated structure was successfully solved by Woodward, Tsuda, Goto, and Mosher in 1964. The unique structure is comprised of a densely functionalized, stereochemically complex framework that has an unprecedented dioxa-adamantane with an ortho acid, a cyclic guanidinium hemiaminal moiety, and nine contiguous stereogenic centers including one bridgehead nitrogen-containing quaternary center. There are three compounds in equilibriums-ortho ester, 4, 9-anhydro, and lactone, that are known to interconvert to each other under acidic conditions, and pure TTX is hard to obtain via isolation from the natural mixture.
Regarding TTX’s bioactivity, disruption of voltage-gated sodium ion channels (Nav) was suggested in the early 1960s, and more recent crystallographic studies have revealed the TTX binding motif with human Nav1.7. Extensive pharmacology investigations have indicated TTX’s immense promise in pain treatment, but its severe systemic toxicity has to date limited its clinic applications. Both structural modifications and the use of innovative delivery systems have been proposed to overcome the limitation of systemic toxicity and low bioavailability, however, a reliable source of pure TTX is highly needed for clinical evaluation.
Given the remarkably dense array of heteroatoms surrounding its complex sp3-hybridized carbon-enriched core, this fascinating molecule also attracted much attention from the organic synthetic community. To date, several research groups have reported the total preparation of TTX, with the first milestone achieved by Kishi in 1972 with a racemic preparation. Subsequently, asymmetric syntheses have been achieved by Isobe, Du Bois, Sato, Fukuyama, and Yokoshima. More recently, Trauner et al. (2022) disclosed an elegant and concise asymmetric preparation of TTX based on a glucose derivative. In addition, Alonso, Ciufolini,
and Hudlicky have also reported creative syntheses of key intermediates for building TTX.
Despite recent impressive progress in the development of a variety of strategies to assemble this complex molecule, chemoselective and stereoselective functionalization of the sterically hindered carbocyclic systems with contiguous sp3-hybridized and highly heteroatoms-substituents from readily and massive available simple starting material remains quite challenging to achieve in a large scale and step-economical manner.
The present disclosure presents a stereoselective asymmetric synthesis of TTX and its analogue from massively available furfuryl alcohol. The highly heteroatoms-substituted and pseudo-symmetric cyclohexane skeleton was assembled via a stereoselective Diels-Alder reaction and a chemoselective cyclic anhydride opening strategy. Upjohn dihydroxylation installed the oxygen functionalities at the C-6, 7, 8, and 11 positions, decarboxylative hydroxylation supported the installation of the oxygen at C-5. An innovative SmI2-mediated concurrent radical elimination, oxo-bridge ring opening and ester reduction sequence followed by Ruthenium-catalyzed oxidative alkyne cleavage, and formation of hemiaminal and orthoester in one pot enabled a scalable total synthesis of TTX. This approach should be readily applicable to other natural (and unnatural) TTX congeners to further support investigations into biosynthesis, physiology, and pharmacology.
In one aspect, the present disclosure provides a preparation method, the method comprising any one or more of the following steps:
step (a) : converting compound 11 to compound 12,
step (b) : converting compound 12 to compound 13,
step (c) : converting compound 13 to compound 14,
step (d) : converting compound 14 to compound 15,
step (e) : converting compound 15 to compound 16,
step (f) : converting compound 16 to compound 17
step (g) : converting compound 17 to compound A18,
Preferably,
step (h) : converting compound A18 to compound A19,
Preferably,
step (i) : converting compound A19 to compound A20,
Preferably,
step (j) : converting compound A20 to compound A21,
Preferably,
step (k) : converting compound A21 to compound A22,
Preferably,
step (l) : converting compound A22 to compound A23,
Preferably,
step (m) : converting compound A23 to compound A24,
Preferably,
step (n) : converting compound A24 to compound A25 and/or A25a,
Preferably,
step (o) : converting compound A25 to compound A26,
Preferably,
step (p) : converting compound A26 to compound A27,
Preferably,
step (q) : converting compound A27 to compound A28,
Preferably,
step (r) : converting compound A28 to Tetrodotoxin 1,
Preferably,
step (s) : converting compound A27 and/or A27a to compound A33,
Preferably,
wherein,
each R1 independently represents a protecting group, preferably silicon-containing protecting group, preferably TBDPS,
each R2 independently represents a protecting group, preferably benzyl-containing protecting group, preferably p-methoxybenzyl (i.e. PMB) ,
each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc, and
each X independently represents a halogen, preferably selected from Cl, or Br.
According to some embodiments of the present invention, the preparation method comprises the step (a) .
According to some embodiments of the present invention, the preparation method comprises the step (b) .
According to some embodiments of the present invention, the preparation method comprises the the step (c) .
According to some embodiments of the present invention, the preparation method comprises the the step (d) .
According to some embodiments of the present invention, the preparation method comprises the the step (e) .
According to some embodiments of the present invention, the preparation method comprises the the step (f) .
According to some embodiments of the present invention, the preparation method comprises the the step (g) .
According to some embodiments of the present invention, the preparation method comprises the step (h) .
According to some embodiments of the present invention, the preparation method comprises the step (i) .
According to some embodiments of the present invention, the preparation method comprises the step (j) .
According to some embodiments of the present invention, the preparation method comprises the step (k) .
According to some embodiments of the present invention, the preparation method comprises the the step (l) .
According to some embodiments of the present invention, the preparation method comprises the step (m) .
According to some embodiments of the present invention, the preparation method comprises the step (n) .
According to some embodiments of the present invention, the preparation method comprises the step (o) .
According to some embodiments of the present invention, the preparation method comprises the step (p) .
According to some embodiments of the present invention, the preparation method comprises the step (q) .
According to some embodiments of the present invention, the preparation method comprises the step (r) .
According to some embodiments of the present invention, the preparation method comprises the step (s) .
According to some embodiments of the present invention, the preparation method further comprises step (x) and/or step (y) :
step (x) : converting compound A33 to compound 34,
Preferably,
step (y) converting compound 34 to Tetrodotoxin 1,
Preferably,
According to some embodiments of the present invention, the method further comprises any one or more of steps (z1) to (z4) ,
step (z1) : converting compound A25a to compound A35,
step (z2) : converting compound A35 to compound A36,
step (z3) : converting compound A36 to compound A37,
step (z4) : converting compound A37 to compound 1a,
wherein,
each R2 independently represents a protecting group, preferably benzyl-containing protecting group, preferably p-methoxybenzyl (i.e. PMB) ,
each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc, and
each X independently represents a halogen, preferably selected from Cl, or Br.
In some examples, R2is PMB, R3 is methyl, andR4is methyl.
According to some embodiments of the present invention, the step (q) comprises one or two of the following step (q1) and step (q2) ,
step (q1) : converting compound A27 to compound A27a,
Preferably,
step (q2) : converting compound A27a to compound A28,
Preferably,
wherein, each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,
each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,
each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc., and
each X independently represents a halogen, preferably selected from Cl, or Br.
According to some embodiments of the present invention, the step (z3) comprises one or two of step (z3-1) and step (z3-2) ,
step (z3-1) : converting compound A36 to compound A36a,
step (z3-3) : converting compound A36a to compound A37,
According to some embodiments of the present invention, the step (c) comprises one or two of step (c1) and step (c2) :
step (c1) : converting compound 13 to compound 13a,
step (c2) : converting compound 13a to compound 14,
According to some embodiments of the present invention, the step (b) comprises step (b1) and step (b2) :
step (b1) : converting compound 12 to compound 12a,
step (b2) : converting compound 12a to compound 13,
According to some embodiments of the present invention, step (f) comprises step (f1) and step (f2) ,
step (f1) : converting compound 16 to compound 16a,
step (f2) : converting compound 16a to compound 17,
According to some embodiments of the present invention, step (j) comprises step (j1) and step (j2) ,
Step (j1) : converting compound A20 to compound A20a,
Preferably
Step (j2) : converting compound A20a to compound A21,
preferably
According to some embodiments of the present invention, the step (l) comprises step (l1) and step (l2)
Step (l1) : converting compound A22 to compound A22a,
preferably
Step (l2) : converting compound A22a to compound A23,
preferably
According to some embodiments of the present invention, the step (n) comprises step (n1) and step (n2)
Step (n1) : converting compound A24 to compound A25a,
Preferably
Step (n2) : converting compound A25a to compound A25,
Preferably
In the above described structures of the present application, each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,
each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,
each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.
each X independently represents a halogen, preferably selected from Cl, or Br.
According to some embodiments of the present invention, R1 is TBDPS.
According to some embodiments of the present invention, R2is PMB.
According to some embodiments of the present invention, R3 is methyl.
According to some embodiments of the present invention, R4is methyl.
According to some embodiments of the present invention, X is Cl.
According to some embodiments of the present invention, the method comprises the step (r) and any one or more of the following steps: the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) .
According to some embodiments of the present invention, the method comprises any two or three more of the following steps: the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
According to some embodiments of the present invention, comprises any one or two or three or more of the following steps: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
According to some embodiments of the present invention, comprises the following steps: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
According to some embodiments of the present invention, the method comprises: the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the
step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises:
the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and/or the step (q) .
According to some embodiments of the present invention, the method comprises:
the step (q) , and/or the step (r) ; or
the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (n) , the step (o) , the step (p) , the step (q) and/or the step (r) ; or
the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; or
the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) .
According to some embodiments of the present invention, in the the step (a) , reagents used comprise quinine and MeOH, solvent used comprises CCl4 and/or toluene (preferably a mixture of CCl4 and/or toluene preferably 1-2) : (1-2) by volume) .
According to some embodiments of the present invention, in the step (b1) , reagents used comprise 4-methylmorpholine N-oxide (NMO) , 4-methylmorpholine (NMM) , and/or an oxidant preferably OsO4, and a solvent used comprises acetone, preferably a mixture of acetone and water.
According to some embodiments of the present invention, in the step (b2) , reagents used comprise 2, 2-dimethoxypropane and p-toluene sulfonic acid, and a solvent used comprises acetone.
According to some embodiments of the present invention, in the step (c1) , reagents used comprise N-hydroxyphthalimide and a base preferably an organic base preferably DMAP, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) .
According to some embodiments of the present invention, in the step (c2) , reagents used comprise Ru (bpy) 3Cl2, TEMPO and Hantzsch ester, and/or a solvent used comprises DMF; and/or in the step (c2) , the conversion is carried out under the radiation of blue LEDs.
According to some embodiments of the present invention, in the step (d) , reagents used comprise a base preferably an inorganic base preferably K2CO3, and/or a solvent used comprises an alcohol, preferably C1-C4 alcohol.
According to some embodiments of the present invention, in the step (e) , reagents used comprises I2, imidazole and PPh3, and/or a solvent used comprises toluene.
According to some embodiments of the present invention, in the step (f) , reagents used comprise SmI2 and preferably further comprise a base preferably an organic base such as Et3N, and/or a solvent used comprises ether (preferably THF) .
According to some embodiments of the present invention, in the step (f1) , reagents used comprise SmI2, and/or a solvent used comprises ether (preferably THF) .
According to some embodiments of the present invention, in the step (f2) , reagents used comprise LiAlH4, and/or a solvent used comprises ether (preferably THF) .
According to some embodiments of the present invention, in the step (g) , reagents used comprise TBDPSCl, preferably comprises imidazole and/or DMAP.
According to some embodiments of the present invention, in the step (h) , reagents used comprise Zinc powder; and/or a solvent used comprise THF and AcOH.
According to some embodiments of the present invention, in the step (i) , reagents used comprise 2-methoxyacetic acid, PPh3, and diethyl diazenedicarboxylate; and/or a solvent used comprise THF.
According to some embodiments of the present invention, in the step (j1) , reagents used comprise 4-methylmorpholine N-oxide, and/or an oxidant preferably OsO4, and/or a solvent used comprises acetone.
According to some embodiments of the present invention, in the step (j2) , reagents used
comprise 2, 2-dimethoxypropane and camphorsulfonic acid, and/or a solvent used comprises CH2Cl2.
According to some embodiments of the present invention, in the step (k) , reagents used comprise Dess-Martin reagent, preferably further comprises an inorganic base preferably NaHCO3.
According to some embodiments of the present invention, in the step (l1) , reagents used comprise N, N-diisopropylamine, and n-butyllithium.
According to some embodiments of the present invention, in the step (l2) , reagents used comprise NaHMDS and PMBBr.
According to some embodiments of the present invention, in the step (m) , reagents used comprise sodium azide and preferably further comprise a crown ether preferably 15-crown-5 ether.
According to some embodiments of the present invention, in the step (n1) , reagents used comprises lithium acetylide ethylenediamine complex.
According to some embodiments of the present invention, in the step (n2) , reagents used comprises an oxidant preferably MnO2, and a reducing agent preferably NaBH4.
According to some embodiments of the present invention, in the step (o) , reagents used comprise an oxidant preferably 2-Iodoxybenzoic acid, pyridinium p-toluenesulfonate, and trimethyl orthoacetate; and/or a solvent used is DMSO.
According to some embodiments of the present invention, in the step (p) , reagents used comprise a catalyst preferably RuCl3, an oxidant preferably NaIO4, preferably further comprises EDCI and MeOH.
According to some embodiments of the present invention, in the step (q1) , reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
According to some embodiments of the present invention, in the step (q2) , reagents used comprise 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea and mercury (II) chloride, preferably further comprise an organic base preferably Et3N.
According to some embodiments of the present invention, in the step (r) , reagents used comprise trifluoroacetic acid.
According to some embodiments of the present invention, in the step (s) , reagents used comprises 1, 3-bis (benzyloxycarbonyl) -2-methyl-2-thiopseudoureaand mercury (II) chloride.
According to some embodiments of the present invention, in the step (x) , reagents used comprise trifluoroacetic acid.
According to some embodiments of the present invention, in the step (y) , reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
According to some embodiments of the present invention, in the step (z1) , reagents used comprise an oxidant preferably 2-Iodoxybenzoic acid, pyridinium p-toluenesulfonate, and trimethyl orthoacetate; and/or a solvent used is DMSO.
According to some embodiments of the present invention, in the step (z2) , reagents used comprise a catalyst preferably RuCl3, an oxidant preferably NaIO4, preferably further comprises EDCI and MeOH.
According to some embodiments of the present invention, in the step (z3-1) , reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
According to some embodiments of the present invention, in the step (z3-2) , reagents used comprise 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea and mercury (II) chloride,
preferably further comprise an organic base preferably Et3N.
According to some embodiments of the present invention, in the step (z4) , reagents used comprise trifluoroacetic acid.
According to some embodiments of the present invention, the preparation method comprises the following step:
According to some embodiments of the present invention, the preparation method comprises any one or more of the following steps:
According to some embodiments of the present invention, the preparation method comprises the following step:
According to some embodiments of the present invention, the preparation method comprises any one or more of the following steps:
According to some embodiments of the present invention, the preparation method comprises any one or more of the following steps:
In a second aspect, provided is a compound selected from the following compounds:
wherein,
each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,
each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,
each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,
each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.
each X independently represents a halogen, preferably selected from Cl, or Br;
Specifically, the compound selected from the following:
In a third aspect, provided is a use of the compound as described in the second aspect of the disclosure in the preparation of Tetrodotoxin or its analogs.
In a fourth aspect, provided is a preparation method comprising using one or more of the compounds as described in the second aspect of the disclosure. In the preparation method, the compound can be used as the starting material or an intermediate compound.
In a fifth aspect, provided is a preparation method of Tetrodotoxin or its analogs, comprising using one or more of the compounds as described in the second aspect of the disclosure. In the preparation method, the compound can be used as the starting material or an intermediate compound.
The scope of the invention includes those intermediate compounds used in the preparation method of the application.
Detailed Embodiments of the Invention
Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Extensive pharmacological investigations, including clinical trials, have demonstrated the potential promise of TTX in pain treatment and detoxification from heroin addiction.
In the present disclosure, provided is a new scalable synthetic entry to the neurotoxin family, setting the stage for rapid access to highly oxidized natural products and a scalable preparation of TTX and its analog.
1. General Information
All reactions were carried out under an atmosphere of nitrogen in flame-dried glassware with magnetic stirring unless otherwise indicated. Reagents were purchased from Aldrich Chemical, Alfa Aesar, TCI, Adamas, Energy Chemical, or J&K at the highest commercial quality and used without further purification. Solvents were dried by passage through an activated alumina column under argon. Liquids and solutions were transferred via syringe. Reactions were monitored by GC/MS, UPLC/MS, and thin layer chromatography (TLC) and visualization was accomplished with a 254 nm UV light and by staining with phosphomolybdic acid solution with heating. All Flash silica gel column chromatography was performed using Tsingdao Haiyang Chemicals silica gel (particle size 300-400 mesh) . 1H and 13C NMR spectra were recorded on Varian Inova-400 spectrometers. Data for 1H NMR spectra are reported relative to CDCl3 (7.26 ppm) , CD3OD (3.31 ppm) , or CD3CO2D (2.06 ppm) as an internal standard and are reported as follows: chemical shift (δppm) , multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, sept =septet, m=multiplet, br=broad) , coupling constant J (Hz) , and integration. Data for 13C NMR spectra are reported relative to CDCl3 (77.00 ppm) , CD3OD (49.00 ppm) , CD3CO2D (22.4 ppm) as an internal standard and are reported in terms of chemical shift (δppm) . UPLC-MS analyses were performed on a Waters system (Column: BEH C18, 1.7μm, 2.1*50 mm) with a Photodiode Array (PDA) detector and a Single Quadrupole (SQ) detector. High Resolution Mass spectra were obtained from on an Agilent 1290 LC-6540 QTOF Mass Spectrometer or an Agilent Technologies 7250 GCQTOF. HPLC analyses were carried out on Waters (Column HILIC Silica, 5μm, 4.6*150 mm and 19*150 mm) with 2998PDA and 3100MS detectors.
Scheme 1. Total Synthesis of Tetrodotoxin.
Scheme 2. Synthesis of 9-epiTetrodotoxin.
Given that the core structure of TTX is Pseudo-C2-symmetric, we envisioned that the symmetry of the highly substituted functional groups could be adopted for rapid skeleton assembly. A subsequent chemoselective desymmetric cyclic anhydride opening and selective functional group interconversion strategy set the base for the gram-scale synthesis of the highly oxidized carbocyclic building block (-) -24 in just fifteen steps as the advanced intermediate, which was rapidly transferred to the final TTX (1) in a scalable fashion.
The synthesis of TTX 1 commenced with the stereoselective construction of the cyclohexane skeleton. Esterification of furfuryl alcohol 9 with chiral auxiliary (-) - (1S) -Camphanic acid 32 afforded ester 10. To achieve the enantiomerically pure 7-oxabicyclo [2.2.1] hept-2-ene derivative 11, we developed an efficient and stereoselective Diels-Alder protocol by heating 10 with maleic anhydride, using isopropyl ether as the solvent. The pseudo-desymmetrization of anhydride 11 was promoted by quinine-mediated chemo-selective methanolysis34, yielding the mono-acid 12 with high regioselectivity. Subsequently, a stereospecific Upjohn exo-dihydroxylation of the olefin and simultaneous 1, 2-diols protection in one pot provided the acid 13, whose structure was confirmed by X-ray crystallography analysis of the single crystal (CCDC#: 2184304) .
Decarboxylative hydroxylation was carried out to install the TTX hydroxyl group at the C5 position. Initially, classical high-valence metal reagents were examined as oxidants, but this led to substrate decomposition; we, therefore, turned to milder radical reaction conditions, including photocatalytic-directed decarboxylative hydroxylation. Other decarboxylation approaches, such as Barton decarboxylation or organophotoredox-promoted decarboxylation in the presence of a radical initiator and oxygen under UV irradiation failed to produce the product. Finally, by leveraging an approach developed by Liang’s group, we subjected the NHPI ester of 13 to Ru-catalyzed photoredox decarboxylative hydroxylation and successfully obtained 14, albeit with an inverted configuration of C5 as compared to TTX. Previous syntheses revealed that the direct construction of the correct stereochemistry of C5 is challenging and the steric effect of the substitution of C5 position is troublesome for the following functional group installation, we, therefore, decided to invert the configuration of C5 at a later stage. Notably, this photoredox decarboxylative hydroxylation could be scaled up to 1.5 g by employing circulating flow photochemistry without compromising the yields.
With compound 14 in hand, we investigated the functional group interconversions of this oxo bridge ring system and developed an innovative reaction cascade to build the oxygen functionalities at the C8a, C6, and C11 positions. The auxiliary (-) -camphanic acid was first removed by transesterification with methanol, providing primary alcohol 15. The chiral auxiliary could be recycled as methyl camphanate. Primary alcohol 15 was subjected to an Appel reaction giving the alkyl iodide 16; however, a variety of reductive conditions applied to the alkyl iodide failed to produce the desired product because of substrate decomposition. After intense exploration of the reductive ring-opening condition, we were delighted to observe a cascade
reaction: the initial Kagan's reagent (SmI2) mediated single electron transfer and loss of iodide generated a primary carbon radical that underwent radical elimination to form the terminal alkene, while SmI2 simultaneously reduced the unactivated methyl ester to a primary alcohol. In the presence of hexamethylphosphoramide (HMPA) , only the eliminated product 17 was obtained (i.e., without the methyl ester being reduced to diol 17a) (Entry 1) . Activation of SmI2 with H2O and Et3N in a 1: 2: 2 ratio created a thermodynamically stronger reductant38allowing the reduction of methyl ester (Entry 2) in 77%1H NMR yield. Either increased proportions of H2O and Et3N or displacement of Et3N with pyrrolidine resulted in complex product mixtures (Entries 3 and 4) . For the scalability problem, the above procedure could also be modified to a two-step protocol involving less equivalent of SmI2 to afford 17a, followed by a LiAlH4 reduction to give 17 in 58%yield on a decagram-scale (Entry 5) . The absolute configuration of 17 was verified by X-ray crystallography of the single crystal (CCDC#: 2182018) .
With 17 in hand, we focused on the construction of the quaternary stereocenter of C8a and configuration inversion of the hydroxyl at C5. The construction of azidoaldehyde 24 started with selective protection of the primary alcohol in 17 using the sterically hindered TBDPSCl (Fig. 3) . The N-O bond of TEMPO in the resulting alkene 18 was reductively cleaved by Zn powder giving the allylic alcohol 19. The incorrect configuration of C5-OH was then inverted using a Mitsunobu reaction with 2-methoxyacetic acid 29, delivering the secondary alcohol 20. Exquisitely diastereoselective Upjohn dihydroxylation of 20 followed by protection as the acetonide afforded 21, whose absolute configuration was verified by X-ray crystallography through the derivative structure 31 (CCDC#: 2184298) , which was obtained via NH3/MeOH hydrolysis of dihydroxylated 20 (See the supplementary materials. )
Intermediate 21 underwent Dess-Martin oxidation (DMP) to afford the ketone 22 in excellent yield. From ketone 22, we aimed to construct the quaternary stereocenter at C8a, which turned out to be challenging. Nucleophile addition to imine, which is derived formed the ketone 22 exclusively produced a diastereomer with the undesired configuration at C8a. Although Darzens condensation of 22 withα-haloester successfully generated the glycidic ester, the corresponding epoxide is inert towards stereoselective aminolysis. Gratifyingly, the nucleophilic addition of dichloromethyl anion was successful in converting ketone 22 into spiro α-chloroepoxide 23 as a single isomer and concurrently interconverting the ester protection groups at C5 to p-methoxybenzyl group (PMB) . The resulting chloroepoxide 23 was treated with NaN3 to afford theα-azido aldehyde 24 on a gram-scale with the correct configuration at C8a.
With the construction of the highly heteroatoms-substituted carbocyclic core accomplished in only fifteen steps, we were poised to tackle the synthetic challenge of the crucial dioxa-adamantane and the guanidinium hemiaminal moieties. Theα-azido aldehyde 24 was subjected to a 1, 2-addition with lithium acetylide, followed by the concurrent removal of the TBDPS protecting group afforded two diastereomers (25 and 25a) in a 1: 15 ratio in favor of the undesired product 25a. Extensive exploration of the reaction conditions revealed that 25a could
be converted to the desired propargyl alcohol 25 in a 2: 1 ratio (25/25a=2: 1) via a sequence comprising MnO2 mediated selective oxidation followed by NaBH4 reduction. IBX oxidation of the primary alcohol 25 provided the corresponding hemiacetal, which was converted to the acetal 26 with trimethylorthoacetate in the presence of pyridinium p-toluenesulfonate (PPTS) . The structure of 26 was confirmed by single crystal X-ray crystallography (CCDC#: 2184305) . Oxidative cleavage of alkyne 26 with RuCl3/NaIO4 followed by esterification with methanol afforded methyl carboxylate 27. Simultaneous PMB deprotection and azido reduction by hydrogenation efficiently delivered the tertiary amine, which was guanidinylated in situ with bis-Boc protected isothiourea 30, leading to the penultimate intermediate 28.
2. Detailed experimental procedures
Example 1
To a stirred solution of furfuryl alcohol 9 (39.6 g, 404 mmol, 1.00 eq) , (1S) - (-) -Camphanic acid (80.0 g, 404 mmol, 1.0 eq) and DMAP (4.93 g, 40.4 mmol, 0.10 eq) in CH2Cl2 (1400 mL) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (116.6 g, 606 mmol, 1.50 eq) was added at 0℃, then stirred slowly from 0℃ to room temperature under argon atmosphere for 27 h. The mixture was quenched with 0.5 N HCl solution (800 mL) , then extracted with CH2Cl2 three times (3 x 800 mL) . The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was re-crystallization with EtOH and petroleum ether to afford compound 10 (101.0 g, 90%) as white solid.
3.3 Hz, 1H) , 6.40–6.33 (m, 1H) , 5.22 (q, J=13.0 Hz, 2H) , 2.43 (ddd, J=14.2, 10.7, 4.2 Hz, 1H) , 2.03 (ddd, J=13.7, 9.5, 4.6 Hz, 1H) , 1.96–1.85 (m, 1H) , 1.68 (ddd, J=13.4, 9.3, 4.1 Hz, 1H) , 1.10 (s, 3H) , 1.00 (s, 3H) , 0.88 (s, 3H) .
3.3 Hz, 1H) , 6.40–6.33 (m, 1H) , 5.22 (q, J=13.0 Hz, 2H) , 2.43 (ddd, J=14.2, 10.7, 4.2 Hz, 1H) , 2.03 (ddd, J=13.7, 9.5, 4.6 Hz, 1H) , 1.96–1.85 (m, 1H) , 1.68 (ddd, J=13.4, 9.3, 4.1 Hz, 1H) , 1.10 (s, 3H) , 1.00 (s, 3H) , 0.88 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ177.96, 167.14, 148.64, 143.44, 111.33, 110.62, 90.96, 58.70, 54.71, 54.29, 30.48, 28.93, 16.67, 16.54, 9.67.
Example 2
To a stirred solution of compound 10 (100.0 g, 360 mmol, 1.00 eq) in 290 mL isopropyl ether, maleic anhydride (35.3 g, 360 mmol, 1.00 eq) was added under dark, then the mixture was warmed to 55℃ and stirred under argon atmosphere overnight. Added another 1.0 eq maleic anhydride and continued reaction. Detected by crude 1H NMR until no compound 10 remained, filter to afford crude compound 11 (131.0 g, contain a little maleic anhydride) as white solid without further purification.
Note: The compound 11 is sensitive to protic solvents, the whole process should be avoided to contact protic solvents such as water or methanol and so on.
1H) , 5.46 (s, 1H) , 4.97 (d, J=12.4 Hz, 1H) , 4.69 (d, J=12.4 Hz, 1H) , 3.31 (dd, J=26.4, 6.9 Hz, 2H) , 2.44 (ddd, J=14.4, 10.5, 3.8 Hz, 1H) , 2.04 (ddd, J=13.7, 9.3, 4.5 Hz, 1H) , 1.93 (ddd, J=12.4, 11.0, 4.4 Hz, 1H) , 1.69 (ddd, J=13.3, 9.3, 4.1 Hz, 1H) , 1.12 (s, 3H) , 1.06 (s, 3H) , 1.00 (s, 3H) .
1H) , 5.46 (s, 1H) , 4.97 (d, J=12.4 Hz, 1H) , 4.69 (d, J=12.4 Hz, 1H) , 3.31 (dd, J=26.4, 6.9 Hz, 2H) , 2.44 (ddd, J=14.4, 10.5, 3.8 Hz, 1H) , 2.04 (ddd, J=13.7, 9.3, 4.5 Hz, 1H) , 1.93 (ddd, J=12.4, 11.0, 4.4 Hz, 1H) , 1.69 (ddd, J=13.3, 9.3, 4.1 Hz, 1H) , 1.12 (s, 3H) , 1.06 (s, 3H) , 1.00 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ178.06, 169.11, 167.81, 166.85, 138.05, 137.34, 90.94, 90.11, 82.34, 61.48, 54.86, 54.50, 51.22, 49.66, 30.75, 28.84, 16.67, 16.62, 9.70.
Example 3
To a stirred solution of compound 11 (131.0 g, 348 mmol, 1.00 eq) in toluene/CCl4 (750 mL/750 mL) , quinine (112.0 g, 348 mmol, 1.00 eq) was added at 0℃, then MeOH (55.7 g, 1740 mmol, 5.00 eq) was added at 0℃. Then stirred slowly from 0℃ to room temperature under
argon atmosphere for 22 h. Concentrated under reduced pressure, the residue was dissolved in CH2Cl2 and acidified with 1.0 N HCl solution to pH=2, extracted by CH2Cl2 (3 x 800 mL) until no quinine in organic layer. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was re-crystallization with CH2Cl2 and petroleum ether to afford compound 12 (127.5 g, 87%for two steps) as white solid.
5.7 Hz, 1H) , 5.46 (d, J=1.7 Hz, 1H) , 4.86 (d, J=12.2 Hz, 1H) , 4.70 (d, J=12.1 Hz, 1H) , 3.71 (s, 3H) , 3.07 (d, J=8.9 Hz, 1H) , 2.95 (d, J=9.0 Hz, 1H) , 2.48–2.34 (m, 2H) , 2.08–1.98 (m, 1H) , 1.98–1.84 (m, 2H) , 1.73–1.62 (m, 1H) , 1.11 (s, 3H) , 1.03 (s, 3H) , 0.96 (s, 3H) .
5.7 Hz, 1H) , 5.46 (d, J=1.7 Hz, 1H) , 4.86 (d, J=12.2 Hz, 1H) , 4.70 (d, J=12.1 Hz, 1H) , 3.71 (s, 3H) , 3.07 (d, J=8.9 Hz, 1H) , 2.95 (d, J=9.0 Hz, 1H) , 2.48–2.34 (m, 2H) , 2.08–1.98 (m, 1H) , 1.98–1.84 (m, 2H) , 1.73–1.62 (m, 1H) , 1.11 (s, 3H) , 1.03 (s, 3H) , 0.96 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ178.09, 175.59, 171.01, 166.85, 137.80, 136.59, 91.07, 89.02, 79.96, 62.30, 54.81, 54.32, 52.46, 49.94, 48.28, 30.65, 28.88, 16.72, 16.61, 9.66.
Example 4
To a stirred solution of compound 12 (70.0 g, 171 mmol, 1.00 eq) in acetone (900 mL) and H2O (36 mL) , 4-methylmorpholine N-oxide (NMO) (30.0 g, 256 mmol, 1.50 eq) and 4-methylmorpholine (NMM) (19.0 g, 188 mmol, 1.10 eq) was added, then 0.05 M aq. OsO4 (34 mL, 1.7 mmol, 0.01 eq) was added slowly under dark, then the mixture was stirred at room temperature for 3 h. Quenched with sat. aq. Na2SO3 and then concentrated under reduced pressure. The residue was acidified with 1.0 N HCl solution to pH=2 and extracted with ethyl acetate three times (3 x 500 mL) , the remained aqueous layer was extracted with n-BuOH until no product. Concentrated under reduced pressure to afford crude compound 12a as pale yellow foam, which was used in the following reaction without further purification.
To a stirred solution of compound 12a in 800 mL acetone, 2, 2-dimethoxypropane (26.6 g, 256 mmol, 1.50 eq) and PTSA·H2O (3.3 g, 17 mmol, 0.10 eq) was added, then stirred at room temperature for 3.5 h. Added 4.0 g NaHCO3 solid to quench reaction and concentrated under reduced pressure. The residue was directly purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100: 1 to 20: 1) to afford the compound 13 (63.7 g, 77%) as white foam.
10.9 Hz, 1H) , 4.55 (d, J=10.9 Hz, 1H) , 4.34 (dd, J=20.7, 5.5 Hz, 2H) , 3.66 (s, 3H) , 3.07 (d, J =9.6 Hz, 1H) , 2.95 (d, J=9.7 Hz, 1H) , 2.42 (ddd, J=14.7, 9.0, 4.1 Hz, 1H) , 2.06 (ddd, J=9.3, 6.9, 2.8 Hz, 1H) , 1.98–1.85 (m, 1H) , 1.69 (ddd, J=17.5, 8.9, 4.3 Hz, 2H) , 1.43 (s, 3H) , 1.28 (s, 3H) , 1.10 (s, 3H) , 1.05 (s, 3H) , 0.94 (s, 3H) .
10.9 Hz, 1H) , 4.55 (d, J=10.9 Hz, 1H) , 4.34 (dd, J=20.7, 5.5 Hz, 2H) , 3.66 (s, 3H) , 3.07 (d, J =9.6 Hz, 1H) , 2.95 (d, J=9.7 Hz, 1H) , 2.42 (ddd, J=14.7, 9.0, 4.1 Hz, 1H) , 2.06 (ddd, J=9.3, 6.9, 2.8 Hz, 1H) , 1.98–1.85 (m, 1H) , 1.69 (ddd, J=17.5, 8.9, 4.3 Hz, 2H) , 1.43 (s, 3H) , 1.28 (s, 3H) , 1.10 (s, 3H) , 1.05 (s, 3H) , 0.94 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ178.74, 174.08, 169.88, 166.47, 113.27, 91.26, 86.69, 81.78, 81.73, 80.46, 60.63, 54.88, 54.51, 52.47, 48.15, 47.43, 30.69, 28.93, 25.90, 25.61, 16.65, 16.52, 9.62.
Example 5
Method A:
To a stirred solution of the compound 13 (30.0 g, 62.2 mmol, 1.0 eq) in CH2Cl2 (600 mL) , N-hydroxyphthalimide (15.2 g, 93.3 mmol, 1.5 eq) and DMAP (756 mg, 6.2 mmol, 0.1 equiv) was added, then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (17.9 g, 93.3 mmol, 1.5 eq) was added at 0℃, stirred slowly from 0℃ to room temperature under argon atmosphere in the dark for 24 h. The resulting mixture was quenched with sat. aq. NH4Cl (800 mL) and then extracted with CH2Cl2 three times (3 x 500 mL) . Dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude NHPI ester 13a was directly used in the next step without further purification.
The solution of the above crude NHPI ester 13a, Ru (bpy) 3Cl2 (1.91 g, 3.2 mmol, 0.05 eq) , TEMPO (14.9 g, 95.8 mmol, 1.54 eq) and Hantzsch ester (15.7 g, 62.2 mmol, 1.0 eq) in DMF (degassed, 500 mL) was stirred vigorously at room temperature under 36 W Blue LEDs for 24 h. Then the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel (petroleum ether/CH2Cl2, 3: 1 to 1: 1) to afford compound 14 (22.7 g, 62%, dr>95: 5) as pale yellow solid.
1H) , 4.52–4.48 (m, 3H) , 3.71 (s, 3H) , 2.84 (d, J=3.2 Hz, 1H) , 2.54–2.45 (m, 1H) , 2.03 (ddd, J=13.7, 9.3, 4.5 Hz, 1H) , 1.92 (ddd, J=13.1, 10.8, 4.6 Hz, 1H) , 1.67 (ddd, J=13.4, 9.4, 4.2 Hz, 1H) ,, 1.59–1.37 (m, 9H) , 1.33 (s, 7H) , 1.21–1.05 (m, 14H) , 0.99 (s, 3H) .
1H) , 4.52–4.48 (m, 3H) , 3.71 (s, 3H) , 2.84 (d, J=3.2 Hz, 1H) , 2.54–2.45 (m, 1H) , 2.03 (ddd, J=13.7, 9.3, 4.5 Hz, 1H) , 1.92 (ddd, J=13.1, 10.8, 4.6 Hz, 1H) , 1.67 (ddd, J=13.4, 9.4, 4.2 Hz, 1H) ,, 1.59–1.37 (m, 9H) , 1.33 (s, 7H) , 1.21–1.05 (m, 14H) , 0.99 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ178.03, 171.84, 166.95, 112.84, 91.25, 86.62, 83.10, 82.70, 81.97, 78.62, 60.56, 54.82, 54.10, 52.31, 48.96, 40.09, 39.75, 34.34, 33.93, 30.62, 28.92, 26.03, 25.59, 20.52, 20.44, 16.87, 16.75, 9.71.
Method B (Flow chemistry procedure) :
To a stirred solution of the compound 13 (1.5 g, 3.1 mmol, 1.0 eq) in CH2Cl2 (25 mL) , N-hydroxyphthalimide (760 mg, 4.65 mmol, 1.5 eq) and DMAP (37 mg, 0.3 mmol, 0.1 equiv) was added, then 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) (892 mg, 4.65 mmol, 1.5 eq) was added at 0℃, stirred slowly from 0℃ to room temperature under argon atmosphere in the dark for 24 h. The resulting mixture was quenched with sat. aq. NH4Cl (20 mL) and then extracted with CH2Cl2 three times (3 x 20 mL) . Dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude NHPI ester was directly used in the next step without further purification.
New prepared NHPI actived ester 13a was added to a 100 mL round-bottom flask, followed by Ru (bpy) 3Cl2 (96 mg, 0.16 mmol, 0.05 eq) , TEMPO (750 mg, 4.8 mmol, 1.54 eq) and Hantzsch ester (785 mg, 3.1 mmol, 1.0 eq) , DMF (degassed, 40 mL) . A flow apparatus was inserted. The system was bubbled with argon for 10 min, the reaction proceeded with a 14 rpm flow rate under the irradiation by a 36 W blue LEDs for 24 h. Then the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to column chromatography on silica gel (petroleum ether/CH2Cl2, 3: 1 to 1: 1) to afford compound 14 (1.22 g, 66%, dr>95: 5) as pale yellow solid.
Materials used in flow procedure: Peristaltic pump (BT02-YZ1515) , PFA tubing, silicone tubing, 36 W 450 nm LED and electric fan (all materials were purchased on Taobao) .
Example 6
To a stirred solution of the compound 14 (20.0 g, 33.7 mmol, 1.00 eq) in 350 mL MeOH, K2CO3 (6.9 g, 50.5 mmol, 1.50 eq) was added and then stirred at room temperature for 1 h. Quenched with 10 mL AcOH, then concentrated under reduced pressure and subjected to column chromatography on silica gel (CH2Cl2/MeOH, 100: 1 to 40: 1) to afford compound 15 (13.2 g, 95%) as colorless oil.
–4.43 (m, 2H) , 4.21 (d, J=12.5 Hz, 1H) , 4.01 (dd, J=12.1, 9.9 Hz, 1H) , 3.72 (s, 3H) , 2.80 (d, J =3.4 Hz, 1H) , 2.33 (br s, 1H) , 1.47–1.36 (m, 8H) , 1.35–1.20 (m, 7H) , 1.15–0.99 (m, 9H) .
–4.43 (m, 2H) , 4.21 (d, J=12.5 Hz, 1H) , 4.01 (dd, J=12.1, 9.9 Hz, 1H) , 3.72 (s, 3H) , 2.80 (d, J =3.4 Hz, 1H) , 2.33 (br s, 1H) , 1.47–1.36 (m, 8H) , 1.35–1.20 (m, 7H) , 1.15–0.99 (m, 9H) .
13C NMR (101 MHz, CDCl3) δ172.40, 112.29, 87.90, 82.89, 82.69, 82.39, 78.86, 61.07, 59.64, 59.22, 52.22, 48.63, 40.45, 40.05, 35.20, 34.19, 25.90, 25.28, 20.39, 20.22, 16.99.
Example 7
To a stirred solution of the compound 15 (13.0 g, 31.5 mmol, 1.00 eq) , PPh3 (30.6 g, 117 mmol, 3.74 eq) and imidazole (6.7 g, 99.5 mmol, 3.16 eq) in 300 mL toulene, I2 (21.2 g, 83.8 mmol, 2.66 eq) dissolved in 100 mL toluene was added and then stirred at 110℃ for 2 h. The resulting mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel (petroleum ether/ethyl acetate, 40: 1 to 25: 1) to afford compound 16 (14.6 g, 89%) as colorless oil.
1H) , 4.63 (d, J=5.5 Hz, 1H) , 4.48 (s, 1H) , 3.79 (d, J=11.3 Hz, 1H) , 3.75 (s, 3H) , 3.56 (d, J=11.5 Hz, 1H) , 2.92 (d, J=3.3 Hz, 1H) , 1.54 (s, 3H) , 1.50–1.30 (m, 12H) , 1.22–1.00 (m, 9H) . 13C NMR (101 MHz, CDCl3) δ171.92, 112.51, 86.51, 84.36, 83.98, 82.28, 77.92, 60.93, 59.33, 52.23, 48.39, 40.54, 40.03, 35.08, 26.01, 25.64, 20.45, 20.39, 16.96, 1.18.
1H) , 4.63 (d, J=5.5 Hz, 1H) , 4.48 (s, 1H) , 3.79 (d, J=11.3 Hz, 1H) , 3.75 (s, 3H) , 3.56 (d, J=11.5 Hz, 1H) , 2.92 (d, J=3.3 Hz, 1H) , 1.54 (s, 3H) , 1.50–1.30 (m, 12H) , 1.22–1.00 (m, 9H) . 13C NMR (101 MHz, CDCl3) δ171.92, 112.51, 86.51, 84.36, 83.98, 82.28, 77.92, 60.93, 59.33, 52.23, 48.39, 40.54, 40.03, 35.08, 26.01, 25.64, 20.45, 20.39, 16.96, 1.18.
Example 8
1. Prepare 0.1 M SmI2 solution in THF
A flame-dried 1 L round bottomed flask was charged with Samarium metal (12.70 g, 86 mmol, 1.00 eq. ) and a stir bar, then thoroughly degassed THF (860 mL) followed by iodine crystals (22.68 g, 86 mmol, 1.00 eq. ) was added sequentially at room temperature under argon atmosphere. The reaction mixture was stirred vigorously at room temperature for over 2 h. As SmI2 was generated, the color of solution changed from orange followed by yellow and green, eventually turned into navy-blue.
Note: In order to ensure full conversion, the solution should be stirred at least 2 h before using.
2. SmI2 induced reduction reaction
Above new prepared 0.1M SmI2 (115 mL, 11.5 mmol, 12.0 eq) solution in THF was transferred to the solution of compound 16 (500 mg, 0.95 mmol, 1.00 eq) , Et3N (318μL, 23.0 mmol, 24.0 eq) and H2O (413μL, 23.0 mmol, 24.0 eq) dissolved in 2 mL THF in a new flame dry 500 mL round bottomed flask using double-ended needle. The whole progress needed to avoid air and carried out under argon atmosphere. Then the mixture was stirred at room temperature for 1.5 h. After the reaction was completed, the color changes to yellow and then quenched with sat. aq. NH4Cl (10 mL) , washed with 0.1N aq. HCl (2 mL) and extracted with ethyl acetate (3 x 10 mL) . Dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product compound was purified with column chromatography on silica gel (CH2Cl2/MeOH, 80: 1) to afford compound 17 (229 mg, 65%) as white solid.
Scalable preparation of compound 17
New prepared 0.1 M SmI2 solution in THF followed the same process as mentioned before. Above new prepared SmI2 solution in THF (860 mL) was transferred to the solution of compound 16 (15.0 g, 28.7 mmol, 1.00 eq) dissolved in 20 mL THF in a new flame dry 1 L round bottomed flask using double-ended needle. The whole progress needed to avoid air and carried out under argon atmosphere. Then the mixture was stirred at 55℃ for 2 h. After the reaction was complete, the color changes to yellow and then quenched with sat. aq. NH4Cl (500 mL) , the mixture was filtered to remove samarium salts before extracted with ethyl acetate (3 x 800 mL) . Dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product compound 16a was directly used in the next step without further purification.
To a stirred solution of the compound 16a in 150 mL THF, the LiAlH4 (1.09 g, 28.7 mmol, 1.00 eq) was added slowly at 0℃. The mixture was stirred slowly from 0℃ to room temperature under argon atmosphere for 12 h. Excess Na2SO4·10H2O was added to quench reaction and then filtered and concentrated under reduced pressure. The crude product compound was purified with column chromatography on silica gel (CH2Cl2/MeOH, 80: 1) to afford compound 17 (6.1 g, 58%for two steps) as white solid.
Hz, 1H) , 4.51 (s, 1H) , 4.45–4.38 (m, 1H) , 4.30 (d, J=3.9 Hz, 1H) , 3.95 (dd, J=10.7, 6.5 Hz, 1H) , 3.76 (dd, J=10.6, 6.8 Hz, 1H) , 2.92 (d, J=4.3 Hz, 1H) , 2.56–2.46 (m, 1H) , 1.57–0.96 (m,24H) .
Hz, 1H) , 4.51 (s, 1H) , 4.45–4.38 (m, 1H) , 4.30 (d, J=3.9 Hz, 1H) , 3.95 (dd, J=10.7, 6.5 Hz, 1H) , 3.76 (dd, J=10.6, 6.8 Hz, 1H) , 2.92 (d, J=4.3 Hz, 1H) , 2.56–2.46 (m, 1H) , 1.57–0.96 (m,24H) .
13C NMR (101 MHz, CDCl3) δ142.43, 115.10, 109.62, 84.93, 76.78, 74.39, 67.62, 62.88, 60.48, 59.94, 45.20, 39.73, 33.82, 33.51, 27.09, 25.32, 20.17, 20.08, 16.61.
Example 9
To a stirred solution of the compound 17 (7.2 g, 19.5 mmol, 1.00 eq) in 100 mL CH2Cl2, imidazole (2.6 g, 39.0 mmol, 2.00 eq) and DMAP (475 mg, 3.9 mmol, 0.20 eq) was added, then TBDPSCl (6.9 g, 25.3 mmol, 1.30 eq) was added slowly at 0℃. The mixture was stirred at room temperature under argon atmosphere for 2 h. MeOH (20 mL) was added to quench reaction, the resulting mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel (petroleum ether/ethyl acetate, 20: 1 to 12: 1) to afford compound 18 (10.0 g, 85%) as white foam.
5.36 (t, J=2.1 Hz, 1H) , 5.09 (t, J=2.0 Hz, 1H) , 4.76–4.69 (m, 1H) , 4.51–4.41 (m, 2H) , 4.33 (d,J=3.8 Hz, 1H) , 4.00 (dd, J=10.1, 7.1 Hz, 1H) , 3.62 (dd, J=10.1, 7.7 Hz, 1H) , 2.87 (d, J=7.5 Hz, 1H) , 2.82–2.75 (m, 1H) , 1.58–0.91 (m, 33H) .
5.36 (t, J=2.1 Hz, 1H) , 5.09 (t, J=2.0 Hz, 1H) , 4.76–4.69 (m, 1H) , 4.51–4.41 (m, 2H) , 4.33 (d,J=3.8 Hz, 1H) , 4.00 (dd, J=10.1, 7.1 Hz, 1H) , 3.62 (dd, J=10.1, 7.7 Hz, 1H) , 2.87 (d, J=7.5 Hz, 1H) , 2.82–2.75 (m, 1H) , 1.58–0.91 (m, 33H) .
13C NMR (101 MHz, CDCl3) δ142.58, 135.47, 133.15, 129.58, 129.55, 127.60, 116.38, 109.88, 86.31, 75.25, 66.86, 62.51, 60.26, 58.71, 46.55, 40.31, 34.59, 34.12, 27.69, 26.67, 26.19, 20.15, 20.08, 19.03, 17.00.
Example 10
To a stirred solution of the compound 18 (9.5 g, 15.6 mmol, 1.00 eq) in 100 mL THF and 130 mL AcOH, Zinc powder (41 g, 624 mmol, 40.00 eq) was added. The mixture was stirred at 55℃ under argon atmosphere for 4.5 h. The resulting mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel (petroleum ether/ethyl acetate, 4: 1) to afford compound 19 (6.5 g, 90%) as white foam.
6H) , 5.42–5.27 (m, 2H) , 4.80 (d, J=6.9 Hz, 1H) , 4.51 (d, J=7.6 Hz, 1H) , 4.31 (dd, J=6.9, 4.3 Hz, 1H) , 4.13 (t, J=3.9 Hz, 1H) , 4.06–3.94 (m, 2H) , 2.66 (s, 2H) , 2.08–1.95 (m, 1H) , 1.47 (s, 3H) , 1.41 (s, 3H) , 1.07 (s, 9H) .
6H) , 5.42–5.27 (m, 2H) , 4.80 (d, J=6.9 Hz, 1H) , 4.51 (d, J=7.6 Hz, 1H) , 4.31 (dd, J=6.9, 4.3 Hz, 1H) , 4.13 (t, J=3.9 Hz, 1H) , 4.06–3.94 (m, 2H) , 2.66 (s, 2H) , 2.08–1.95 (m, 1H) , 1.47 (s, 3H) , 1.41 (s, 3H) , 1.07 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ145.09, 135.54, 132.79, 129.82, 127.79, 127.76, 115.07, 109.81, 76.76, 75.66, 70.10, 66.82, 65.13, 47.43, 26.79, 26.69, 25.17, 19.08.
Example 11
To a stirred solution of the compound 19 (6.4 g, 13.7 mmol, 1.00 eq) in 137 mL dry THF, 2-methoxyacetic acid (1.8 g, 20.5 mmol, 1.50 eq) and PPh3 (7.2 g, 27.4 mmol, 2.00 eq) was added. Then diethyl diazenedicarboxylate (DEAD) (3.7 g, 20.5 mmol, 1.50 eq) was added dropwise at-10℃. The mixture was stirred at-10℃ under argon atmosphere for 12 h. The resulting mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel (petroleum ether/ethyl acetate, 8: 1 to 5: 1) to afford compound 20 (6.6 g, 89%) as colorless oil.
1H NMR (400 MHz, CDCl3) δ7.71–7.63 (m, 4H) , 7.47–7.34 (m, 6H) , 5.43 (d, J=4.1 Hz, 1H) , 5.37 (d, J=1.4 Hz, 1H) , 5.10 (d, J=1.4 Hz, 1H) , 4.54 (d, J=5.2 Hz, 1H) , 4.44–4.38 (m, 1H) , 4.35–4.25 (m, 1H) , 4.17 (t, J=3.9 Hz, 1H) , 3.93–3.75 (m, 3H) , 3.33 (s, 3H) , 2.55 (s, 1H) , 1.48 (s, 3H) , 1.44 (s, 3H) , 1.03 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ168.80, 140.30, 135.43, 132.72, 132.59, 129.85, 129.76, 127.72, 127.69, 113.10, 110.19, 77.58, 74.67, 70.36, 69.36, 68.26, 62.41, 59.27, 43.63, 27.49, 26.63, 26.00, 18.94.
Example 12
To a stirred solution of compound 20 (6.60 g, 12.2 mmol, 1.00 eq) in acetone (70 mL) , 4-methylmorpholine N-oxide (2.85 g, 24.4 mmol, 2.00 eq) was added, then 0.05 M aq. OsO4 (35 mL, 0.7 mmol, 0.06 eq) was added slowly under dark, then the mixture was stirred at room temperature for 12 h. Quenched with sat. aq. NH4Cl (50 mL) and then extracted with CH2Cl2 three times (3 x 200 mL) , then dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude compound 20a as pale yellow solid, which was used in the following reaction without further purification.
To a stirred solution of compound 20a in 80 mL CH2Cl2, 2, 2-dimethoxypropane (2.54 g, 24.4 mmol, 2.00 eq) and camphorsulfonic acid (CSA) (566 mg, 2.44 mmol, 0.20 eq) was added, then stirred at room temperature for 0.5 h. Quenched reaction with sat. aq. NH4Cl (50 mL) and then extracted with CH2Cl2 (3 x 200 mL) . Dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 5: 1) to afford compound 21 (4.90 g, 66%) as white foam.
6H) , 5.52 (s, 1H) , 4.26–4.19 (m, 2H) , 4.15 (d, J=5.5 Hz, 1H) , 4.06 (dd, J=9.4, 1.4 Hz, 1H) , 3.90–3.95 (m, 3H) , 3.84–3.72 (m, 2H) , 3.33 (s, 3H) , 2.52 (brs, 1H) , 2.28 (t, J=6.5 Hz, 1H) , 1.56 (s, 3H) , 1.44 (s, 6H) , 1.41 (s, 3H) , 1.05 (s, 9H) .
6H) , 5.52 (s, 1H) , 4.26–4.19 (m, 2H) , 4.15 (d, J=5.5 Hz, 1H) , 4.06 (dd, J=9.4, 1.4 Hz, 1H) , 3.90–3.95 (m, 3H) , 3.84–3.72 (m, 2H) , 3.33 (s, 3H) , 2.52 (brs, 1H) , 2.28 (t, J=6.5 Hz, 1H) , 1.56 (s, 3H) , 1.44 (s, 6H) , 1.41 (s, 3H) , 1.05 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ168.86, 135.58, 133.25, 129.63, 129.59, 127.62, 127.60, 110.96, 109.65, 79.73, 77.81, 74.81, 71.89, 69.60, 69.10, 66.34, 61.50, 59.37, 40.45, 26.74, 26.68, 26.50, 25.74, 25.52, 19.10.
Example 13
To a stirred solution of compound 20 (54.0 mg, 0.1 mmol, 1.00 eq) in acetone (1 mL) , 4-methylmorpholine N-oxide (23.4 mg, 0.2 mmol, 2.00 eq) was added, then 0.05 M aq. OsO4
(0.12 mL, 0.006 mmol, 0.06 eq) was added slowly under dark, then the mixture was stirred at room temperature overnight. Quenched with sat. aq. NH4Cl (2 mL) and then extracted with CH2Cl2 three times (3 x 10 mL) , then dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude compound as pale yellow solid, which was used in the following reaction without further purification.
To the stirred solution of crude product in 1 mL MeOH, 0.2 mL 7 N NH3 in MeOH was added, stirred at room temperature for 2 h. Then extracted with H2O (10 mL) and CH2Cl2 (3 x 10 mL) . Dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 1: 1) to afford compound 31 (37.5 mg, 75%) as white solid.
4.28 (dd, J=6.1, 5.0 Hz, 1H) , 4.20 (d, J=5.7 Hz, 2H) , 4.13–3.99 (m, 3H) , 3.97 (d, J=10.7 Hz, 1H) , 3.88 (d, J=11.5 Hz, 1H) , 3.70 (d, J=10.6 Hz, 1H) , 2.93 (s, 1H) , 2.73 (s, 1H) , 2.51 (s, 1H) , 2.17 (t, J=7.3 Hz, 1H) , 1.50 (s, 3H) , 1.39 (s, 3H) , 1.06 (s, 9H) .
4.28 (dd, J=6.1, 5.0 Hz, 1H) , 4.20 (d, J=5.7 Hz, 2H) , 4.13–3.99 (m, 3H) , 3.97 (d, J=10.7 Hz, 1H) , 3.88 (d, J=11.5 Hz, 1H) , 3.70 (d, J=10.6 Hz, 1H) , 2.93 (s, 1H) , 2.73 (s, 1H) , 2.51 (s, 1H) , 2.17 (t, J=7.3 Hz, 1H) , 1.50 (s, 3H) , 1.39 (s, 3H) , 1.06 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ135.57, 133.63, 129.60, 127.64, 109.24, 74.53, 73.33, 70.98, 67.25, 64.83, 62.54, 38.60, 26.85, 26.18, 24.72, 19.26.
Example 14
To a stirred solution of compound 21 (4.89 g, 7.96 mmol, 1.00 eq) in 22 mL CH2Cl2, NaHCO3 (2.69 g, 32.0 mmol, 4.00 eq) and Dess-Martin reagent (5.38 g, 12.7 mmol, 1.60 eq) was added at 0℃. The solution was stirred at r.t. for 3 h. The resulting mixture was directly purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 6: 1) to afford compound 22 (4.78 g, 98%) as white foam.
6H) , 5.91 (t, J=2.3 Hz, 1H) , 4.47 (d, J=5.9 Hz, 1H) , 4.41 (dd, J=5.8, 2.1 Hz, 1H) , 4.23 (s, 2H) , 3.96 (dd, J=10.9, 4.8 Hz, 1H) , 3.91–3.76 (m, 2H) , 3.62 (dd, J=10.9, 10.0 Hz, 1H) , 3.45 –3.39 (m, 1H) , 3.37 (s, 3H) , 1.55 (s, 3H) , 1.51 (s, 3H) , 1.36 (s, 3H) , 1.35 (s, 3H) , 1.04 (s, 9H) .
6H) , 5.91 (t, J=2.3 Hz, 1H) , 4.47 (d, J=5.9 Hz, 1H) , 4.41 (dd, J=5.8, 2.1 Hz, 1H) , 4.23 (s, 2H) , 3.96 (dd, J=10.9, 4.8 Hz, 1H) , 3.91–3.76 (m, 2H) , 3.62 (dd, J=10.9, 10.0 Hz, 1H) , 3.45 –3.39 (m, 1H) , 3.37 (s, 3H) , 1.55 (s, 3H) , 1.51 (s, 3H) , 1.36 (s, 3H) , 1.35 (s, 3H) , 1.04 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ205.28, 169.14, 135.62, 135.52, 133.04, 132.81, 129.75, 129.71, 127.69, 111.47, 111.00, 82.03, 78.77, 78.52, 74.47, 69.31, 69.01, 59.28, 57.62, 50.18, 27.02, 26.72, 26.53, 26.09, 19.07.
Example 15
To a stirred solution of N, N-diisopropylamine (4.2 g, 41.6 mmol, 6.40 eq) in 42 mL dry THF, n-butyllithium (2.5 M solution in hexane) (16.6 ml, 41.6 mmol, 6.40 eq) was added dropwise at-78℃ under argon atmosphere. After 1 h, dry CH2Cl2 (11.6 g, 136.5 mmol, 21.00 eq) was added dropwise, and then a solution of compound 22 (4.0 g, 6.5 mmol, 1.00 eq) in dry THF (50 mL) was added dropwise, and stirred at-78℃ under argon atmosphere. After the disappearance of 22 on TLC with 4: 1 petroleum ether/EtOAc. The resulting mixture was quenched by sat. aq. NH4Cl (20 mL) , extracted with EtOAc (3 x 50 mL) , dried over anhydrous MgSO4, concentrated under reduced pressure to afford crude compound 22a as pale yellow oil, which was used in the following reaction without further purification.
To a stirred solution of compound 22a in 15mL dry THF, NaHMDS (2.0 M in THF, 8.1 mL, 16.2 mmol, 2.50 eq) was added into the reaction mixtures and stirred at-78℃ for 1 h, warmed to 0℃ and stirred at 0℃ for 1 h, then the mixture was cooled to-78℃ again and PMBBr (3.3 g, 16.2 mmol, 2.50 eq) was added dropwise, continued to stir at-78℃ for 1 h and then warmed to 0℃, stirred at 0℃ for 1 h, warmed to r.t. and stirred at r.t. for 12h. The resulting mixture was poured into sat. aq. NH4Cl (50 mL) , extracted with EtOAc (3 x 100 mL) , dried over anhydrous MgSO4, and evaporated to give compound 23 (2.76 g, 60%yield) , which was purified on a column of silica gel with petroleum ether: ethyl acetate (10: 1) as colorless oil.
9.3, 8.1, 4.2, 1.8 Hz, 6H) , 7.20 (d, J=8.7 Hz, 2H) , 6.80 (d, J=8.7 Hz, 2H) , 4.91 (s, 1H) , 4.62 (d, J=11.1 Hz, 1H) , 4.50 (d, J=11.1 Hz, 1H) , 4.44 (d, J=6.4 Hz, 1H) , 4.27–4.23 (m, 1H) , 4.22 (s, 1H) , 4.11 (d, J=9.5 Hz, 1H) , 3.89 (dd, J=10.4, 7.7 Hz, 1H) , 3.80 (dd, J=4.2, 1.5 Hz, 1H) , 3.78 (s, 3H) , 3.69 (dd, J=10.4, 5.8 Hz, 1H) , 2.41 (ddd, J=7.6, 5.7, 4.2 Hz, 1H) , 1.42 (s, 3H) , 1.37 (s, 3H) , 1.35 (s, 3H) , 1.30 (s, 3H) , 1.05 (s, 9H) .
9.3, 8.1, 4.2, 1.8 Hz, 6H) , 7.20 (d, J=8.7 Hz, 2H) , 6.80 (d, J=8.7 Hz, 2H) , 4.91 (s, 1H) , 4.62 (d, J=11.1 Hz, 1H) , 4.50 (d, J=11.1 Hz, 1H) , 4.44 (d, J=6.4 Hz, 1H) , 4.27–4.23 (m, 1H) , 4.22 (s, 1H) , 4.11 (d, J=9.5 Hz, 1H) , 3.89 (dd, J=10.4, 7.7 Hz, 1H) , 3.80 (dd, J=4.2, 1.5 Hz, 1H) , 3.78 (s, 3H) , 3.69 (dd, J=10.4, 5.8 Hz, 1H) , 2.41 (ddd, J=7.6, 5.7, 4.2 Hz, 1H) , 1.42 (s, 3H) , 1.37 (s, 3H) , 1.35 (s, 3H) , 1.30 (s, 3H) , 1.05 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ158.89, 135.51, 135.46, 133.17, 130.55, 129.85, 129.78, 128.73, 127.78, 127.75, 113.49, 110.54, 110.40, 79.84, 78.85, 78.72, 74.59, 72.41, 70.55, 70.06, 60.74, 59.81, 55.22, 41.65, 29.70, 27.07, 26.87, 26.63, 25.52, 19.11.
Example 16
To a solution of compound 23 (2.7 g, 3.8 mmol, 1.00 eq) in dry dimethylsulfoxide (38 mL) , sodium azide (1.48 g, 22.8 mmol, 6.00 eq) and 15-crown-5 ether (2.5 g, 11.4 mmol, 3.00 eq) were added and stirred at 70℃ under argon for 21 h. After the disappearance of starting compound on TLC with 4: 1 petroleum ether: ethyl acetate, the reaction mixture was poured into sat. aq. NH4Cl (30 mL) , extracted with CH2Cl2 (3 x 100 mL) , dried over anhydrous MgSO4, and evaporated to give compound 24 (2.13 g, 77%yield) as a white foam, which was purified on a column of silica gel with petroleum ether/ethyl acetate (20: 1) .
–7.30 (m, 6H) , 7.10 (d, J=8.3 Hz, 2H) , 6.83 (d, J=7.9 Hz, 2H) , 4.61 (q, J=11.2 Hz, 2H) , 4.50 (d,J=6.4 Hz, 1H) , 4.38 (d, J=6.4 Hz, 1H) , 4.29–4.14 (m, 3H) , 3.95 (dd, J=10.4, 3.9 Hz, 1H) , 3.80 (s, 3H) , 3.52 (t, J=10.8 Hz, 1H) , 2.34 (d, J=10.3 Hz, 1H) , 1.47 (s, 3H) , 1.46 (s, 3H) , 1.38 (s, 3H) , 1.36 (s, 3H) , 1.08 (s, 9H) .
–7.30 (m, 6H) , 7.10 (d, J=8.3 Hz, 2H) , 6.83 (d, J=7.9 Hz, 2H) , 4.61 (q, J=11.2 Hz, 2H) , 4.50 (d,J=6.4 Hz, 1H) , 4.38 (d, J=6.4 Hz, 1H) , 4.29–4.14 (m, 3H) , 3.95 (dd, J=10.4, 3.9 Hz, 1H) , 3.80 (s, 3H) , 3.52 (t, J=10.8 Hz, 1H) , 2.34 (d, J=10.3 Hz, 1H) , 1.47 (s, 3H) , 1.46 (s, 3H) , 1.38 (s, 3H) , 1.36 (s, 3H) , 1.08 (s, 9H) .
13C NMR (101 MHz, CDCl3) δ197.96, 159.21, 135.54, 135.46, 133.12, 132.82, 129.83, 128.72, 127.79, 127.75, 113.77, 111.13, 110.26, 80.18, 79.72, 79.06, 76.53, 75.89, 74.35, 69.41, 58.77, 55.25, 45.80, 26.99, 26.93, 26.57, 25.51, 24.63, 19.22.
Example 17
To a solution of lithium acetylide ethylenediamine complex (180 mg, 1.96 mmol, 10.00 eq) in 2.5 mL THF, compound 24 (140 mg, 0.20 mmol, 1.00 eq) dissolved in 2.5 mL THF was added dropwise at 0℃, then stirred at 0℃ for 1 h and quenched with sat. aq. NH4Cl (2 mL) , extracted with EtOAc (3 x 10 mL) , dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, which was purified on a column of silica gel with 2: 1 petroleum ether/ethyl acetate to afford compound 25a (65 mg, 66%yield) as colorless oil and its diastereomer 25 (25a: 25=15: 1, the ratio was detected through crude 1H NMR) .
8.0 Hz, 2H) , 5.00 (d, J=1.3 Hz, 1H) , 4.76 (d, J=11.1 Hz, 1H) , 4.62 (d, J=11.2 Hz, 1H) , 4.26 (d,J=6.3 Hz, 1H) , 4.13 (d, J=6.4 Hz, 1H) , 4.01–3.90 (m, 5H) , 3.82–3.75 (m, 4H) , 2.68–2.60 (m, 1H) , 2.53 (d, J=2.2 Hz, 1H) , 1.56 (s, 3H) , 1.47 (s, 3H) , 1.39 (s, 3H) , 1.33 (s, 3H) .
8.0 Hz, 2H) , 5.00 (d, J=1.3 Hz, 1H) , 4.76 (d, J=11.1 Hz, 1H) , 4.62 (d, J=11.2 Hz, 1H) , 4.26 (d,J=6.3 Hz, 1H) , 4.13 (d, J=6.4 Hz, 1H) , 4.01–3.90 (m, 5H) , 3.82–3.75 (m, 4H) , 2.68–2.60 (m, 1H) , 2.53 (d, J=2.2 Hz, 1H) , 1.56 (s, 3H) , 1.47 (s, 3H) , 1.39 (s, 3H) , 1.33 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ159.40, 129.80, 129.56, 113.90, 109.23, 108.64, 85.91, 81.59, 79.81, 75.11, 74.62, 74.27, 66.75, 66.30, 64.89, 58.13, 55.27, 43.29, 29.69, 27.04, 26.26, 26.07, 24.43.
Example 18
Epimerization of 25a to 25
To a stirred solution of compound 25a (148 mg, 0.29 mmol, 1.00 eq) in 5 mL CH2Cl2, MnO2 (121 mg, 1.4 mmol, 10.00 eq) was added and then stirred at r.t. for 2 h. Filtered and concentrated under reduced pressure, which was used in the following reaction without further purification.
To a solution of the above resulted oxidation products in 2 ml dioxane and 200 uL H2O, NaBH4 (421 mg, 1.11 mmol, 4.00 eq) was added at r.t., then stirred at 60℃ for 0.5 h. The mixture was quenched with sat. aq. NH4Cl (2 mL) , extracted with CH2Cl2 (3 x 5 mL) , dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 2: 1) to afford compound 25 (76 mg, 51%, 70%brsm) as colorless oil and 25a (39 mg, 26%) as a white foam. (25: 25a=2: 1, the ratio was detected through crude 1H NMR) .
8.4 Hz, 2H) , 4.83 (d, J=1.9 Hz, 1H) , 4.73 (d, J=10.7 Hz, 1H) , 4.64 (d, J=10.7 Hz, 1H) , 4.36 (dd, J=16.6, 6.8 Hz, 2H) , 4.20 (dd, J=21.0, 8.2 Hz, 2H) , 4.13 (d, J=4.4 Hz, 1H) , 3.80 (s, 3H) , 3.78–3.74 (m, 1H) , 3.69 (dd, J=11.8, 5.7 Hz, 1H) , 2.65–2.63 (m, 1H) , 2.55 (dd, J=12.3, 5.5 Hz,2H) , 1.56 (s, 3H) , 1.48 (s, 3H) , 1.40 (s, 3H) , 1.37 (s, 3H) .
8.4 Hz, 2H) , 4.83 (d, J=1.9 Hz, 1H) , 4.73 (d, J=10.7 Hz, 1H) , 4.64 (d, J=10.7 Hz, 1H) , 4.36 (dd, J=16.6, 6.8 Hz, 2H) , 4.20 (dd, J=21.0, 8.2 Hz, 2H) , 4.13 (d, J=4.4 Hz, 1H) , 3.80 (s, 3H) , 3.78–3.74 (m, 1H) , 3.69 (dd, J=11.8, 5.7 Hz, 1H) , 2.65–2.63 (m, 1H) , 2.55 (dd, J=12.3, 5.5 Hz,2H) , 1.56 (s, 3H) , 1.48 (s, 3H) , 1.40 (s, 3H) , 1.37 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ159.49, 129.78, 129.30, 113.91, 109.56, 108.50, 85.45, 81.54, 79.63, 78.40, 76.76, 74.89, 74.75, 65.85, 65.74, 65.51, 59.22, 55.25, 43.89, 29.68, 26.87, 26.26, 26.09, 24.76.
Example 19
To a stirred solution of compound 25 (120 mg, 238 mmol, 1.00 eq) in 5.0 mL DMSO, IBX (70 mg, 250 mmol, 1.05 eq) was added and stirred at r.t. for 2 h. After the disappearance of 25 on TLC with 4: 1 petroleum ether/EtOAc, MeOH (5 mL) , pyridinium p-toluenesulfonate (PPTS) (90.0 mg, 356 mmol, 1.50 eq) and trimethyl orthoacetate (1.4 mL) was added and then stirred at r.t. for 12 h. The mixture was quenched with sat. aq. NaHCO3 (10 mL) , extracted with CH2Cl2 (3 x 20 mL) , dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 8/1) to afford compound 26 (108 mg, 88%yield) as white foam.
8.7 Hz, 2H) , 5.37 (d, J=4.2 Hz, 1H) , 4.85 (d, J=2.2 Hz, 1H) , 4.51–4.40 (m, 3H) , 4.23–4.09 (m, 3H) , 3.88 (dd, J=8.6, 1.4 Hz, 1H) , 3.79 (s, 3H) , 3.40 (s, 3H) , 2.80 (ddd, J=8.5, 4.2, 0.9 Hz, 1H) , 2.61 (d, J=2.3 Hz, 1H) , 1.39 (s, 3H) , 1.37 (s, 3H) , 1.26 (s, 3H) , 1.26 (s, 3H) .
8.7 Hz, 2H) , 5.37 (d, J=4.2 Hz, 1H) , 4.85 (d, J=2.2 Hz, 1H) , 4.51–4.40 (m, 3H) , 4.23–4.09 (m, 3H) , 3.88 (dd, J=8.6, 1.4 Hz, 1H) , 3.79 (s, 3H) , 3.40 (s, 3H) , 2.80 (ddd, J=8.5, 4.2, 0.9 Hz, 1H) , 2.61 (d, J=2.3 Hz, 1H) , 1.39 (s, 3H) , 1.37 (s, 3H) , 1.26 (s, 3H) , 1.26 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ159.52, 130.29, 129.10, 113.72, 111.08, 110.07, 107.08, 79.55, 77.38, 76.81, 76.62, 75.79, 75.17, 74.95, 73.62, 69.17, 67.74, 56.03, 55.23, 47.35, 27.13, 26.34, 24.73, 24.18.
Example 20
To a stirred solution of compound 26 (27.0 mg, 0.05 mmol, 1.00 eq) in CCl4 (1.0 mL) , MeCN (1.0 mL) and H2O (1.5 mL) , NaIO4 (45 mg, 0.21 mmol, 4.00 eq) and RuCl3·xH2O (2.2 mg, 0.011 mmol, 0.20 eq) was added and then stirred at r.t. for 2 h. The mixture was quenched with H2O (5 mL) , extracted with CH2Cl2 (3 x 100 mL) , dried over anhydrous MgSO4, filtered and concentrated under reduced pressure, which was used in the following reaction without further purification.
To a stirred solution of crude product in 1 mL CH2Cl2, EDCI (20 mg, 0.10 mmol, 2.00 eq) , DMAP (1.2 mg, 0.009 mmol, 0.20 eq) and MeOH (16.77 mg, 0.52 mmol, 10.00 eq) was added and then stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure and purified by flash chromatography on silica gel (petroleum ether: ethyl acetate, 8/1 to 4/1) to afford compound 27 (13.0 mg, 48%yield) as white foam.
8.6 Hz, 2H) , 5.31 (d, J=3.3 Hz, 1H) , 4.72 (s, 1H) , 4.49 (d, J=7.2 Hz, 3H) , 4.20 (dd, J=18.2, 7.9 Hz, 2H) , 4.04 (d, J=9.6 Hz, 1H) , 3.89 (d, J=6.4 Hz, 1H) , 3.80 (d, J=1.8 Hz, 6H) , 3.43 (s, 3H) , 2.83 (dd, J=7.5, 3.3 Hz, 1H) , 1.39 (s, 3H) , 1.37 (s, 3H) , 1.22 (s, 3H) , 1.19 (s, 3H) .
8.6 Hz, 2H) , 5.31 (d, J=3.3 Hz, 1H) , 4.72 (s, 1H) , 4.49 (d, J=7.2 Hz, 3H) , 4.20 (dd, J=18.2, 7.9 Hz, 2H) , 4.04 (d, J=9.6 Hz, 1H) , 3.89 (d, J=6.4 Hz, 1H) , 3.80 (d, J=1.8 Hz, 6H) , 3.43 (s, 3H) , 2.83 (dd, J=7.5, 3.3 Hz, 1H) , 1.39 (s, 3H) , 1.37 (s, 3H) , 1.22 (s, 3H) , 1.19 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ168.60, 159.46, 130.05, 129.29, 113.78, 110.76, 109.19, 106.14, 83.08, 79.15, 76.19, 75.30, 73.57, 69.24, 67.71, 55.99, 55.26, 52.12, 50.72, 27.02, 26.47, 24.73, 24.08.
Example 21
Compound 27 (13.0 mg, 0.024 mmol, 1.00 eq) was hydrogenated in 2.0 mL MeOH in the presence of 20%Pd-C under H2 balloon for 24 h. Then the catalyst was filtered off and evaporated to give compound 27a, which was used in the following reaction without further purification.
To a stirred solution of the crude product in 2.5 mL dry dichloromethane, triethylamine (12.12 mg, 0.12 mmol, 5.00 eq) and 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea (13.9 mg, 0.048 mmol, 2.00 eq) and mercury (II) chloride (17.0 mg, 0.048 mmol, 2.00 eq) was added at room temperature. After stirring for 2 hours, the mixture was quenched with water (10 mL) and extracted with CH2Cl2 three times (3 x 10 mL) . The combined organic layer was dried over anhydrous MgSO4. After filtration, removal of the solvent under reduced pressure gave a crude material, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1: 1) to give the title compound 28 (11.2 mg, 88%yield, 2 steps) as white foam.
1H) , 5.28 (d, J=5.8 Hz, 1H) , 5.24 (s, 1H) , 4.29 (dd, J=16.4, 7.7 Hz, 2H) , 4.19 (d, J=9.6 Hz, 1H) , 3.92 (dd, J=12.0, 6.8 Hz, 1H) , 3.80 (s, 3H) , 3.48 (s, 3H) , 3.35 (d, J=12.3 Hz, 1H) , 2.99–2.90 (m, 1H) , 1.47 (s, 12H) , 1.43 (s, 3H) , 1.39 (s, 3H) , 1.31 (s, 3H) .
1H) , 5.28 (d, J=5.8 Hz, 1H) , 5.24 (s, 1H) , 4.29 (dd, J=16.4, 7.7 Hz, 2H) , 4.19 (d, J=9.6 Hz, 1H) , 3.92 (dd, J=12.0, 6.8 Hz, 1H) , 3.80 (s, 3H) , 3.48 (s, 3H) , 3.35 (d, J=12.3 Hz, 1H) , 2.99–2.90 (m, 1H) , 1.47 (s, 12H) , 1.43 (s, 3H) , 1.39 (s, 3H) , 1.31 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ168.44, 153.94, 152.21, 111.21, 109.59, 104.50, 83.07, 80.70, 79.47, 73.13, 68.49, 68.03, 62.48, 55.82, 54.21, 52.14, 29.69, 28.31, 28.07, 27.27, 25.29.
Example 22
Compound 27 (13.0 mg, 0.024 mmol, 1.00 eq) was hydrogenated in 2.0 mL MeOH in the presence of 20%Pd-C under H2 balloon for 19 h. Then the catalyst was filtered off and evaporated to give compound 27a, which was used in the following reaction without further purification.
To a stirred solution of the crude material in 2.5 mL dry dichloromethane, triethylamine (12.12 mg, 0.12 mmol, 5.00 eq) and 1, 3-bis (benzyloxycarbonyl) -2-methyl-2-thiopseudourea (17.2 mg, 0.048 mmol, 2.00 eq) and mercury (II) chloride (17.0 mg, 0.048 mmol, 2.00 eq) was added at room temperature. After stirring for 3 hours, the mixture was quenched with water (10 mL) and extracted with CH2Cl2 for three times (3 x 10 mL) . The combined organic layer was dried over anhydrous MgSO4. After filtration, removal of the solvent under reduced pressure gave a crude material, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 2: 1) to give the title compound 33 (13.4 mg, 80%yield, 2 steps) as white foam.
7.28 (m, 10H) , 5.45 (d, J=2.8 Hz, 1H) , 5.26–5.21 (m, 1H) , 5.18–5.05 (m, 5H) , 4.31 (d, J=9.7 Hz, 1H) , 4.22–4.16 (m, 2H) , 3.93 (dd, J=12.0, 6.7 Hz, 1H) , 3.61 (s, 3H) , 3.45 (s, 3H) , 3.36 (d,J=12.5 Hz, 1H) , 2.98 (dd, J=6.8, 2.9 Hz, 1H) , 1.48 (s, 3H) , 1.42 (s, 3H) , 1.40 (s, 3H) , 1.20 (s, 3H) .
7.28 (m, 10H) , 5.45 (d, J=2.8 Hz, 1H) , 5.26–5.21 (m, 1H) , 5.18–5.05 (m, 5H) , 4.31 (d, J=9.7 Hz, 1H) , 4.22–4.16 (m, 2H) , 3.93 (dd, J=12.0, 6.7 Hz, 1H) , 3.61 (s, 3H) , 3.45 (s, 3H) , 3.36 (d,J=12.5 Hz, 1H) , 2.98 (dd, J=6.8, 2.9 Hz, 1H) , 1.48 (s, 3H) , 1.42 (s, 3H) , 1.40 (s, 3H) , 1.20 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ168.07, 163.03, 154.15, 152.89, 136.58, 134.61, 128.80, 128.67, 128.40, 127.90, 127.75, 111.35, 109.80, 104.45, 80.58, 79.47, 72.96, 68.51, 68.14, 67.90, 67.01, 62.67, 55.81, 54.15, 52.01, 29.69, 27.22, 25.36, 25.29, 24.11.
Example 23
Method A: One step synthesis of TTX
Compound 28 (11.0 mg, 0.018 mmol, 1.00 eq) was dissolved in trifluoroacetic acid (500μL) and water (500μL) at room temperature. The resulting solution was allowed to warm to 60℃. After stirring for 24 hours, the mixture was concentrated in vacuo and the residue, which was detected by 1H NMR to give a mixture of tetrodotoxin and 4, 9-anhydrotetrodotoxin (1: 1) . Then the mixture was redissolved in TFA-d (20μL) and deuterium oxide (1000μL) at room temperature, and stirred at r.t. for 5 days. The mixture was concentrated in vacuo and the residue, which was purified by HPLC (samples preparation and purity analysis were conducted on Waters HPLC (ColumnHILIC Silica, 5μm, 4.6*150 mm and 19*150 mm) with 2998PDA and 3100MS detectors, mobile phase: H2O (0.1%AcOH) /Acetonitrile (0.1%AcOH) (65%-50%in 10min) ) . The residual solution was lyophilized to give tetrodotoxin 1 and 4, 9-anhydrotetrodotoxin 2 (4: 1) (detected by 1H NMR) (4.2 mg, total 65%yield) as white solid.
4.00 (d, J=12.6 Hz, 1H) , 3.95 (s, 1H) , 2.34 (d, J=9.4 Hz, 1H) .
4.00 (d, J=12.6 Hz, 1H) , 3.95 (s, 1H) , 2.34 (d, J=9.4 Hz, 1H) .
13C NMR (151 MHz, 5%CD3CO2D/D2O) δ156.52, 110.76, 79.59, 75.06, 73.77, 72.72, 71.39, 70.80, 65.45, 59.65, 40.62.
Example 24
Method B: Two steps synthesis of TTX
Compound 33 (13.0 mg, 0.018 mmol, 1.00 eq) was dissolved in trifluoroacetic acid (500μL) and water (500μL) at room temperature. The resulting solution was allowed to warm to 60℃. After stirring for 24 hours, the mixture was concentrated in vacuo and the residue, which was purified by preparative TLC to give hemiaminal 34 (4.1 mg, 49.7%yield) as white foam.
NOTE: Hemiaminal 34 and its anhydrous form could be seperated by PTLC (DCM: MeOH=4: 1) following process described by Fukuyama.
8.8 Hz, 1H) , 5.18 (s, 2H) , 4.19 (d, J=14.8 Hz, 2H) , 3.88–4.10 (m, 4H) , 2.31 (d, J=9.0 Hz, 1H) .
8.8 Hz, 1H) , 5.18 (s, 2H) , 4.19 (d, J=14.8 Hz, 2H) , 3.88–4.10 (m, 4H) , 2.31 (d, J=9.0 Hz, 1H) .
13C NMR (151 MHz, CD3OD) δ169.65, 156.11, 137.49, 129.54, 129.31, 129.25, 109.77, 78.97, 74.80, 73.03, 71.91, 70.03, 68.61, 64.79, 58.81, 39.96.
Compound 34 (4.0 mg, 0.009 mmol, 1.00 eq) was hydrogenated in MeOH (0.5 mL) in the presence of 50%Pd-C under H2 balloon for 6 h. Then the catalyst was filtered off and evaporated to give a crude material, which was purified by HPLC (samples preparation and purity analysis were conducted on Waters HPLC (ColumnHILIC Silica, 5μm, 4.6*150 mm and 19*150 mm) with 2998PDA and 3100MS detectors, mobile phase: H2O (0.1%AcOH) /Acetonitrile (0.1%AcOH) (65%-50%in 10 min) ) . The residual solution was lyophilized to give tetrodotoxin 1 (with traces 4, 9-anhydrotetrodotoxin 2) as a white solid (2.5 mg, 91%yield) .
Synthesis of 9-epiTTX
Example 25
To a stirred solution of compound 25a (50.0 mg, 0.10 mmol, 1.00 eq. ) in DMSO (2.0 mL) , IBX (29.0 mg, 0.10 mmol, 1.00 eq. ) was added at room temperature under argon atmosphere. Then the reaction mixture was stirred at room temperature for 2 h. After the disappearance of 25a on TLC with 4: 1 petroleum ether/EtOAc, MeOH (2 mL) , pyridinium p-toluenesulfonate (PPTS) (37.8 mg, 0.15 mmol, 1.50 eq. ) and trimethyl orthoacetate (0.55 mL) was added into the above solution and then the solution was stirred at room temperature for 12 h. The mixture was
quenched with sat. aq. NaHCO3 (2 mL) , extracted with CH2Cl2 (3×10 mL) . The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate, 8: 1) to afford compound 35 (33.3 mg, 65%yield) as a white foam.
(dd, J=30.7, 11.1 Hz, 2H) , 4.39 (d, J=7.7 Hz, 1H) , 4.30–4.25 (m, 2H) , 4.09 (d, J=9.5 Hz, 1H) , 3.80 (s, 3H) , 3.79 (d, J=0.9 Hz, 1H) , 3.47 (s, 3H) , 2.78 (dd, J=5.9, 3.2 Hz, 1H) , 2.68 (d, J =2.2 Hz, 1H) , 1.42 (s, 3H) , 1.39 (s, 3H) , 1.31 (s, 3H) , 1.29 (s, 3H) .
(dd, J=30.7, 11.1 Hz, 2H) , 4.39 (d, J=7.7 Hz, 1H) , 4.30–4.25 (m, 2H) , 4.09 (d, J=9.5 Hz, 1H) , 3.80 (s, 3H) , 3.79 (d, J=0.9 Hz, 1H) , 3.47 (s, 3H) , 2.78 (dd, J=5.9, 3.2 Hz, 1H) , 2.68 (d, J =2.2 Hz, 1H) , 1.42 (s, 3H) , 1.39 (s, 3H) , 1.31 (s, 3H) , 1.29 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ159.36, 129.39, 113.80, 110.23, 109.55, 106.48, 80.49, 78.71, 78.10, 76.47, 76.33, 76.00, 75.00, 74.64, 69.76, 68.46, 56.33, 55.25, 51.23, 29.69, 26.81, 26.60, 25.25, 23.97.
Example 26
To a stirred solution of compound 35 (20.0 mg, 0.04 mmol, 1.00 eq. ) , NaIO4 (34.2 mg, 0.16 mmol, 4.00 eq. ) in CCl4 (0.7 mL) , MeCN (0.7 mL) and H2O (1.1 mL) , RuCl3·xH2O (1.7 mg, 0.008 mmol, 0.20 eq. ) was added at room temperature under argon atmosphere. Then the reaction mixture was stirred at room temperature for 0.5 h. Then H2O (2.0 mL) and CH2Cl2 (2.0 mL) was added into above solution. The residue was partitioned, the separated organic layer was used directly, EDCI·HCl (15.4 mg, 0.08 mmol, 2.00 eq. ) , DMAP (1.0 mg, 0.008 mmol, 0.20 eq. ) , MeOH (12.8 mg, 0.40 mmol, 10.00 eq. ) was added into above organic solution at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (PE/EtOAc, 8/1 to 4/1) to afford compound 36 (10.4 mg, 49%yield) as a white foam.
=8.7 Hz, 2H) , 5.14 (d, J=6.1 Hz, 1H) , 4.87 (s, 1H) , 4.50 (q, J=11.0 Hz, 2H) , 4.37 (d, J=7.4 Hz, 1H) , 4.26–4.17 (m, 2H) , 4.01 (d, J=9.6 Hz, 1H) , 3.87–3.84 (m, 1H) , 3.84 (s, 3H) , 3.80 (s, 3H) , 3.58 (s, 3H) , 2.72 (t, J=6.4 Hz, 1H) , 1.37 (s, 6H) , 1.25 (s, 6H) .
=8.7 Hz, 2H) , 5.14 (d, J=6.1 Hz, 1H) , 4.87 (s, 1H) , 4.50 (q, J=11.0 Hz, 2H) , 4.37 (d, J=7.4 Hz, 1H) , 4.26–4.17 (m, 2H) , 4.01 (d, J=9.6 Hz, 1H) , 3.87–3.84 (m, 1H) , 3.84 (s, 3H) , 3.80 (s, 3H) , 3.58 (s, 3H) , 2.72 (t, J=6.4 Hz, 1H) , 1.37 (s, 6H) , 1.25 (s, 6H) .
13C NMR (101 MHz, CDCl3) δ168.61, 159.43, 129.88, 129.48, 113.75, 110.61, 109.11, 106.30, 80.97, 79.99, 75.26, 75.14, 75.07, 68.67, 68.29, 57.41, 55.25, 52.28, 49.03, 29.70, 26.94, 26.41, 24.83, 24.17.
Example 27
A suspension of compound 36 (8.0 mg, 0.015 mmol, 1.00 eq. ) and Pd/C (1.6 mg, 20 wt%) in MeOH (1.0 mL) was stirred at room temperature for 24 h under H2 atmosphere (balloon) . The mixture was passed through apad. The filtrate was evaporated to give the crude product 36a, which was subjected to the next step without further purification.
To a stirred solution of the crude product 36a, 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudo urea (8.7 mg, 0.030 mmol, 2.00 eq. ) and mercury (II) chloride (8.2 mg, 0.030 mmol, 2.00 eq. ) in dry dichloromethane (1.5 mL) , Et3N (7.6 mg, 0.075 mmol, 5.00 eq. ) was added at room temperature under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and then was quenched with water (10.0 mL) and extracted with CH2Cl2 (3×10 mL) . The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give a residue, which was purified by flash chromatography on silica gel (PE/EtOAc, 2: 1) to afford compound 37 (7.5 mg, 80%yield, for 2 steps) as a white foam.
3.97 (dd, J=11.7, 7.0 Hz, 1H) , 3.65 (s, 3H) , 3.32 (s, 3H) , 3.10 (d, J=5.0 Hz, 1H) , 3.04 (d, J=12.0 Hz, 1H) , 1.50–1.40 (m, 24H) , 1.37 (s, 3H) , 1.31 (s, 3H) .
3.97 (dd, J=11.7, 7.0 Hz, 1H) , 3.65 (s, 3H) , 3.32 (s, 3H) , 3.10 (d, J=5.0 Hz, 1H) , 3.04 (d, J=12.0 Hz, 1H) , 1.50–1.40 (m, 24H) , 1.37 (s, 3H) , 1.31 (s, 3H) .
13C NMR (101 MHz, CDCl3) δ169.12, 162.69, 154.29, 151.96, 111.28, 109.32, 106.71, 82.62, 82.15, 78.78, 78.47, 77.10, 74.03, 68.89, 68.03, 61.79, 55.15, 54.23, 51.54, 28.26, 28.07, 27.24, 25.46, 25.37, 23.67.
Example 28
Compound 37 (7.0 mg, 0.011 mmol, 1.00 eq. ) was dissolved in trifluoroacetic acid (500μL) and water (500μL) at room temperature under argon atmosphere. Then the reaction mixture was heated to 60℃ and stirred at 60℃ for 12 h. The resulting mixture was concentrated in vacuo to give a residue, which was purified by HPLC (samples preparation and purity analysis were conducted on Waters HPLC (ColumnHILIC Silica, 5μm, 4.6*150 mm and 19*150 mm) with 2998PDA and 3100MS detectors, mobile phase: H2O (0.1%AcOH) /Acetonitrile (0.1%AcOH) (65%-50%in 10 min) ) . The residual solution was lyophilized to give 9-epiTTX-hemilactal and 9-epiTTX-10, 8-lactone (1: 1, detected by 1H NMR) 1a as a white solid (1.9 mg, 55%yield) .
δ 5.24 (d, J=9.2 Hz, 2H) , 4.24 (s, 1H) , 4.22 (s, 1H) , 4.15 (brs, 1H) , 4.05 (d, J=11.6 Hz, 1H) , 3.99 (d, J=11.6 Hz, 1H) , 3.85 (s, 1H) , 2.45 (d, J=9.2 Hz, 1H) .
δ 5.24 (d, J=9.2 Hz, 2H) , 4.24 (s, 1H) , 4.22 (s, 1H) , 4.15 (brs, 1H) , 4.05 (d, J=11.6 Hz, 1H) , 3.99 (d, J=11.6 Hz, 1H) , 3.85 (s, 1H) , 2.45 (d, J=9.2 Hz, 1H) .
9-epiTTX (10, 8-lactone) 1H NMR (400 MHz, 5%CD3CO2D/D2O)
δ 5.44 (s, 1H) , 5.34 (d, J=10.4 Hz, 1H) , 4.18 (d, J=5.2 Hz, 1H) , 4.08 (brs, 1H) , 3.98 (d, J=12.0 Hz, 1H) , 3.85 (d, J=12.0 Hz, 1H) , 2.53 (dd, J=10.2, 2.2 Hz, 1H) .
9-epiTTX (hemilactal and 10, 8-lactone) 13C NMR (151 MHz, 5%CD3CO2D/D2O) δ 180.03, 156.80, 155.14, 110.74, 81.06, 79.64, 76.78, 75.33, 74.25, 73.68, 73.27, 72.99, 71.03, 70.14, 69.42, 68.50, 66.00, 65.30, 63.40, 56.18, 43.90, 43.34.
Biological Evaluation
To investigate the biological activities of a pure TTX, we synthesized and purified a single form of TTX (S) from the methyl carboxylate 24 according to Fukuyama’s strategy. Another sample named TTX (C) (buy from Tocris bioscience, the ratio of TTX to 4, 9-anhydroTTX was 10: 3 as analyzed by 1H NMR, Purity>99%) was utilized for comparison. We compared the blocking capability of two different sources of TTX on a single subtype of sodium channel on human HEK-Nav1.7 cells and HEK-Nav1.5 cells. We determined the normal HEK-Nav1.7
currents under no-TTX condition by voltage clamp from-80 mV to 80 mV. The HEK-Nav1.7 currents could be successfully induced and were completely blocked by 1μM TTX (C) . The results suggest that the HEK-Nav1.7 cells can be used to measure the blocking ability of different sources of TTX and TTX analog. We then measured the HEK-Nav1.7 currents of HEK-Nav1.7 cells that were treated with TTX (S) and TTX (C) under the same conditions. Our results indicated that TTX (S) has better blocking efficiency than TTX (C) . In mice, our synthetic pure TTX (S) also exhibited a stronger effect in blocking the sodium current amplitude in wild-type div(days in vitro) hippocampal neurons.
The biological activity of 9-epiTTX was also evaluated based on the blocking of sodium current amplitude in wild-type div hippocampal neurons, however, it didn’t present any inhibition activity.
In summary, we have achieved the first asymmetric synthesis of 9-epiTTX (1a) (22 steps) and one of the shortest syntheses of TTX (1) (24 steps, following the Rules for Calculating Step Counts. 68, 69) from the easily accessible furfuryl alcohol. The hundred-gram-scale asymmetric preparation of cyclohexane (+) -12 showcases the power of the stereoselective Diels-Alder reaction in the scale-up synthesis of a carbocyclic ring with a dense array of functionalities. 70 The precise introduction of the oxygen functionality at the C-5 position via photochemical decarboxylative hydroxylation highlights the advance of free radical transformation performed on a sterically demanding carbocyclic skeleton. The SmI2-mediated sequential reactions of reductive fragmentation, oxo-bridge ring opening, and ester reduction, followed by diastereoselective Upjohn dihydroxylation enable a gram-scale synthesis of highly oxidized intermediate (+) -19. The bridged tetrahydrofuran acetal setting simplifies the endgame and facilitates the rapid formation of the cyclic guanidinium hemiaminal and orthoester in one pot. Notably, the present synthesis served as a testbed for precise functional group manipulations on the densely functionalized and stereochemically complex frameworks and should be readily applicable to the synthesis of other heavily oxygenated polycyclic natural products. The concise synthetic strategy is suitable for the production of TTX congeners or derivatives that support further pharmacology investigations and should be amenable to large-scale synthesis of TTX for analgesic drug development, particularly for non-opioid cancer pain treatment.
Claims (19)
- A preparation method, comprising any one or more of the following steps:step (a) : converting compound 11 to compound 12,
step (b) : converting compound 12 to compound 13,
step (c) : converting compound 13 to compound 14,
step (d) : converting compound 14 to compound 15,
step (e) : converting compound 15 to compound 16
step (f) : converting compound 16 to compound 17
step (g) : converting compound 17 to compound A18,
Preferably,
step (h) : converting compound A18 to compound A19,
Preferably,
step (i) : converting compound A19 to compound A20,
Preferably,
step (j) : converting compound A20 to compound A21,
Preferably,
step (k) : converting compound A21 to compound A22,
Preferably,
step (l) : converting compound A22 to compound A23,
Preferably,
step (m) : converting compound A23 to compound A24,
Preferably,
step (n) : converting compound A24 to compound A25 and/or A25a,
Preferably,
step (o) : converting compound A25 to compound A26,
Preferably,
step (p) : converting compound A26 to compound A27,
Preferably,
step (q) : converting compound A27 to compound A28,
Preferably,
step (r) : converting compound A28 to Tetrodotoxin 1,
Preferably,
step (s) : converting compound A27 and/or A27a to compound A33,
Preferably,
wherein,each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.each X independently represents a halogen, preferably selected from Cl, or Br. - The method of claim 1, further comprising step (x) and/or step (y) :step (x) : converting compound A33 to compound 34,
Preferably,
step (y) converting compound 34 to Tetrodotoxin 1,Preferably,
- The method of claim 1 or 2, wherein the step (q) comprises the following step (q1) and step (q2) ,step (q1) : converting compound A27 to compound A27a,
Preferably,
step (q2) : converting compound A27a to compound A28,
Preferably,
wherein,each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.each X independently represents a halogen, preferably selected from Cl, or Br. - The method of any one of claims 1 to 3, wherein the step (c) comprises step (c1) and step (c2) :step (c1) : converting compound 13 to compound 13a,
step (c2) : converting compound 13a to compound 14,
- The method of any one of claims 1 to 4, wherein the step (b) comprises step (b1) and step (b2) :step (b1) : converting compound 12 to compound 12a,
step (b2) : converting compound 12a to compound 13,
- The method of any one of claims 1 to 5, wherein the method further comprises step (f1) and step (f2) ,step (f1) : converting compound 16 to compound 16a,
step (f2) : converting compound 16a to compound 17,
- The method of any one of claims 1-6, wherein the step (j) comprises step (j1) and step (j2) ,step (j1) : converting A compound 20 to compound A20a,
preferably
step (j2) : converting compound A20a to compound A21,
preferably
- The method of any one of claims 1-7, wherein the step (l) comprises step (l1) and step (l2) Step (l1) : converting compound A22 to compound A22a,
preferably
step (l2) : converting compound A22a to compound A23,
preferably
- The method of any one of claims 1-8, wherein the step (n) comprises step (n1) and step (n2)step (n1) : converting compound A24 to compound A25a,
preferably
step (n2) : converting compound A25a to compound A25,
preferably
wherein,each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.each X independently represents a halogen, preferably selected from Cl, or Br. - The method of any one of claims 1-9, wherein the method comprises the step (r) .
- The method of any one of claims 1-10, wherein the method comprises the step (r) and any one or more of the following steps: the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) .
- The method of any one of claims 1-11, wherein the method comprises any two or three more of the following steps: the step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
- The method of any one of claims 1-12, wherein the method comprises any one or two or three or more of the following steps: the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , and the step (q) .
- The method of any one of claims 1-13, wherein the method comprises:the step (q) , and/or the step (r) ; orthe step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (n) , the step (o) , the step (p) , the step (q) and/or the step (r) ; orthe step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) ; orthe step (a) , the step (b) , the step (c) , the step (d) , the step (e) , the step (f) , the step (g) , the step (h) , the step (i) , the step (j) , the step (k) , the step (l) , the step (m) , the step (n) , the step (o) , the step (p) , the step (q) , and/or the step (r) .
- The method of any one of claims 1-14, whereinin the step (a) , reagents used comprise quinine and MeOH, solvent used comprises CCl4 and/or toluene (preferably a mixture of CCl4 and/or toluene preferably 1-2) : (1-2) by volume) ; and/orin the step (b1) , reagents used comprise 4-methylmorpholine N-oxide (NMO) , 4-methylmorpholine (NMM) , and/or an oxidant preferably OsO4, and a solvent used comprises acetone, preferably a mixture of acetone and water; and/orin the step (b2) , reagents used comprise 2, 2-dimethoxypropane and p-toluene sulfonic acid, and a solvent used comprises acetone; and/orin the step (c1) , reagents used comprise N-hydroxyphthalimide and a base preferably an organic base preferably DMAP, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) ; and/orin the step (c2) , reagents used comprise Ru (bpy) 3Cl2, TEMPO and Hantzsch ester, and/or a solvent used comprises DMF; and/or in the step (c2) , the conversion is carried out under the radiation of blue LEDs; and/orin the step (d) , reagents used comprise a base preferably an inorganic base preferably K2CO3, and/or a solvent used comprises an alcohol, preferably C1-C4 alcohol; and/orin the step (e) , reagents used comprises I2, imidazole and PPh3, and/or a solvent used comprises toluene; and/orin the step (f) , reagents used comprise SmI2 and preferably further comprise a base preferably an organic base such as Et3N, and/or a solvent used comprises ether (preferably THF) ; and/orin the step (f1) , reagents used comprise SmI2, and/or a solvent used comprises ether (preferably THF) ;in the step (f2) , reagents used comprise LiAlH4, and/or a solvent used comprises ether (preferably THF) ;in the step (g) , reagents used comprise TBDPSCl, preferably comprises imidazole and/or DMAP; and/orin the step (h) , reagents used comprise Zinc powder; and/or a solvent used comprise THF and AcOH; and/orin the step (i) , reagents used comprise 2-methoxyacetic acid, PPh3, and diethyl diazenedicarboxylate; and/or a solvent used comprise THF; and/orin the step (j1) , reagents used comprise 4-methylmorpholine N-oxide, and/or an oxidant preferably OsO4, and/or a solvent used comprises acetone; and/orin the step (j2) , reagents used comprise 2, 2-dimethoxypropane and camphorsulfonic acid, and/or a solvent used comprises CH2Cl2; and/orin the step (k) , reagents used comprise Dess-Martin reagent, preferably further comprises an inorganic base preferably NaHCO3; and/orin the step (l1) , reagents used comprise N, N-diisopropylamine, and n-butyllithium; and/orin the step (l2) , reagents used comprise NaHMDS and PMBBr; and/orin the step (m) , reagents used comprise sodium azide and preferably further comprise a crown ether preferably 15-crown-5 ether; and/orin the step (n1) , reagents used comprises lithium acetylide ethylenediamine complex; and/orin the step (n2) , reagents used comprises an oxidant preferably MnO2, and a reducing agent preferably NaBH4; and/orin the step (o) , reagents used comprise an oxidant preferably 2-Iodoxybenzoic acid, pyridinium p-toluenesulfonate, and trimethyl orthoacetate; and/or a solvent used is DMSO; and/orin the step (p) , reagents used comprise a catalyst preferably RuCl3, an oxidant preferably NaIO4, preferably further comprises EDCI and MeOH; and/orin the step (q1) , reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas; and/orin the step (q2) , reagents used comprise 1, 3-bis (tert-butoxycarbonyl) -2-methyl-2-thiopseudourea and mercury (II) chloride, preferably further comprise an organic base preferably Et3N; and/orin the step (r) , reagents used comprise trifluoroacetic acid; and/orin the step (s) , reagents used comprises 1, 3-bis (benzyloxycarbonyl) -2-methyl-2-thiopseudoureaand mercury (II) chloride; and/orin the step (x) , reagents used comprise trifluoroacetic acid; and/orin the step (y) , reagents used comprise a hydrogenation catalyst (preferably Pd/C) and hydrogen gas.
- The method of any one of claims 1-15, further comprising any one or more of steps (z1) to (z4) ,step (z1) : converting compound A25a to compound A35,
step (z2) : converting compound A35 to compound A36,
step (z3) : converting compound A36 to compound A37,
step (z4) : converting compound A37 to compound 1a,
wherein,each R2 independently represents a protecting group, preferably benzyl-containing protecting group, preferably p-methoxybenzyl (i.e. PMB) ,each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc., andeach R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc;Preferably, the step (z3) comprises one or two of step (z3-1) and step (z3-2) ,step (z3-1) : converting compound A36 to compound A36a,
step (z3-3) : converting compound A36a to compound A37,
- A compound selected from the following compounds:
wherein,each R1 independently represents a protecting group, preferably silicon-containing protecting group, such as TBDPS,each R2 independently represents a protecting group, preferably benzyl-containing protecting group, such as p-methoxybenzyl (i.e. PMB) ,each R3 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,each R4 independently represents C1-C5 alkyl, preferably selected from methyl, ethyl, propyl etc.,each X independently represents a halogen, preferably selected from Cl, or Br;
- A preparation method comprising using one or more of the compounds as claimed in claim 17 as the starting material or an intermediate compound.
- A preparation method of Tetrodotoxin or its analogs, comprising using one or more of the compounds as claimed in claim 17 as a starting material or an intermediate compound.
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Title |
---|
MAEHARA, TOMOAKI ET AL.: "Total Synthesis of (-)-Tetrodotoxin and 11-norTTX-6(R)-ol", ANGEWANDTE CHEMIE, INTERNATIONAL EDITION, vol. 56, no. 6, 11 January 2017 (2017-01-11), XP055889184, DOI: 10.1002/anie.201611574 * |
QI XIANGBING, CHEN PEI-HAO, WANG JING, WANG YAN, SUN YUZE, BAI SONGLIN, WU QINGCUI, ZHANG SHUANGFENG, CHENG XINYU, CAO PENG: "Total Synthesis of Tetrodotoxin and 9-epiTetrodotoxin", CHEMRXIV, AMERICAN CHEMICAL SOCIETY (ACS), 4 January 2023 (2023-01-04), pages 1 - 17, XP093138018, DOI: 10.26434/chemrxiv-2023-76wll-v2 * |
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