CN116411356A - Synthesis method of DNA coding compound ribofuranose derivative - Google Patents
Synthesis method of DNA coding compound ribofuranose derivative Download PDFInfo
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- CN116411356A CN116411356A CN202111619369.7A CN202111619369A CN116411356A CN 116411356 A CN116411356 A CN 116411356A CN 202111619369 A CN202111619369 A CN 202111619369A CN 116411356 A CN116411356 A CN 116411356A
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- -1 compound ribofuranose derivative Chemical class 0.000 title claims abstract description 28
- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical class OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims abstract description 14
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 230000001699 photocatalysis Effects 0.000 claims abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- 238000007342 radical addition reaction Methods 0.000 claims abstract description 3
- 150000003254 radicals Chemical class 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 40
- 239000000243 solution Substances 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000007853 buffer solution Substances 0.000 claims description 8
- 238000005286 illumination Methods 0.000 claims description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000003729 nucleotide group Chemical group 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910021538 borax Inorganic materials 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 claims description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001188 haloalkyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000002773 nucleotide Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 235000011008 sodium phosphates Nutrition 0.000 claims description 2
- 235000010339 sodium tetraborate Nutrition 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract 1
- 108020004414 DNA Proteins 0.000 description 41
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 235000011089 carbon dioxide Nutrition 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 5
- 238000012869 ethanol precipitation Methods 0.000 description 5
- 230000008014 freezing Effects 0.000 description 5
- 238000007710 freezing Methods 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 208000012839 conversion disease Diseases 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 150000002611 lead compounds Chemical class 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000003609 aryl vinyl group Chemical group 0.000 description 3
- 229940116901 diethyldithiocarbamate Drugs 0.000 description 3
- 238000012917 library technology Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 239000004327 boric acid Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229950004394 ditiocarb Drugs 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000013537 high throughput screening Methods 0.000 description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 238000003260 vortexing Methods 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- HMENQNSSJFLQOP-UHFFFAOYSA-N 2-bromoprop-2-enoic acid Chemical compound OC(=O)C(Br)=C HMENQNSSJFLQOP-UHFFFAOYSA-N 0.000 description 1
- VQNDBXJTIJKJPV-UHFFFAOYSA-N 2h-triazolo[4,5-b]pyridine Chemical compound C1=CC=NC2=NNN=C21 VQNDBXJTIJKJPV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- HHRKFGMMAHZWIM-UHFFFAOYSA-N ethenoxyboronic acid Chemical compound OB(O)OC=C HHRKFGMMAHZWIM-UHFFFAOYSA-N 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 125000006357 methylene carbonyl group Chemical group [H]C([H])([*:1])C([*:2])=O 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000007146 photocatalysis Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B50/00—Methods of creating libraries, e.g. combinatorial synthesis
- C40B50/08—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support
- C40B50/10—Liquid phase synthesis, i.e. wherein all library building blocks are in liquid phase or in solution during library creation; Particular methods of cleavage from the liquid support involving encoding steps
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
- C40B40/04—Libraries containing only organic compounds
- C40B40/12—Libraries containing saccharides or polysaccharides, or derivatives thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthesis method of a DNA coding compound ribofuranose derivative, which takes an On-DNA aryl vinyl compound and a 2-carboxylic ribofuranose compound as raw materials, obtains the On-DNA ribofuranose derivative through photocatalytic decarboxylation free radical addition reaction in an alkaline environment, can be carried out in a mixed water phase of an organic solvent/a water phase, has simple operation and environmental protection, and is suitable for synthesizing a DNA coding compound library by using a porous plate.
Description
Technical Field
The invention belongs to the technical field of coding compound libraries, and particularly relates to a synthesis method of On-DNA ribofuranose derivatives in construction of a DNA coding compound library.
Background
In drug development, especially new drug development, high throughput screening against biological targets is one of the main means to rapidly obtain lead compounds. However, conventional high throughput screening based on single molecules requires long time, huge equipment investment, limited numbers of library compounds (millions), and the build-up of compound libraries requires decades of accumulation, limiting the efficiency and possibilities of discovery of lead compounds. The recent advent of DNA-encoded compound library technology (WO 2005058479, WO2018166532, CN 103882532), combining combinatorial chemistry and molecular biology techniques, tagged each compound with a DNA tag at the molecular level, and capable of synthesizing up to hundred million classes of compound libraries in extremely short time, has become a trend for the next generation of compound library screening technology, and began to be widely used in the pharmaceutical industry, producing a number of positive effects (Accounts of Chemical Research,2014,47,1247-1255).
The DNA encoding compound library rapidly generates a huge compound library by combinatorial chemistry, and can screen the lead compound with high flux, so that the screening of the lead compound becomes unprecedented rapid and efficient. One of the challenges in constructing libraries of DNA-encoding compounds is the need to synthesize small molecules with chemical diversity on DNA in high yields. Since DNA needs to be stable under certain conditions (solvent, pH, temperature, ion concentration), higher yields are also required for the On-DNA reaction constructed from DNA encoding compound libraries. Therefore, the kind of the reagent, the kind of the reaction and the reaction condition of the chemical reaction (called On-DNA reaction for short) performed On the DNA directly influence the richness and the selectivity of the DNA coding compound library. Thus, the development of chemical reactions compatible with DNA is also a long-term research and study direction of the current DNA coding compound library technology, and directly influences the application and commercial value of the DNA coding compound library.
Ribofuranose derivatives are an important class of pharmaceutical compound backbone structures, however, no method for synthesizing On-DNA ribofuranose derivatives from On-DNA alkenyl compounds has been reported. Therefore, a novel synthesis method of On-DNA ribofuranose derivatives suitable for large-scale porous plate operation is developed, and ribofuranose derivative structures are introduced through photocatalysis, so that the diversity of DNA coding compound libraries is increased, and the application value of the DNA coding compound library technology is further improved.
Disclosure of Invention
The invention provides a synthetic method of a DNA coding compound library, which has the advantages of stable raw material storage, mild reaction conditions, good substrate universality, small damage to DNA, and suitability for batch operation by using porous plates, and can quickly convert the DNA coding aryl vinyl compound library into an On-DNA ribofuranose derivative compound library through one-step reaction.
The invention provides a synthesis method of a DNA coding compound ribofuranose derivative, which takes an On-DNA aryl vinyl compound and a 2-carboxylic ribofuranose compound as raw materials, and obtains the On-DNA ribofuranose derivative through photocatalytic decarboxylation free radical addition reaction in an alkaline environment.
Wherein the On-DNA aryl vinyl compound has the structure of
The structural formula of the 2-carboxylic acid ribofuranose compound is +.>
Wherein the DNA of the formula comprises a single-or double-stranded nucleotide chain obtained by polymerization of artificially modified and/or unmodified nucleotide monomers, which is linked to R in the compound by one or more chemical bonds or groups 1 Or alkenyl groups;
the length of the DNA is 10-200;
wherein, the DNA in the structural formula and R 1 Or alkenyl groups are linked by a chemical bond or bonds. In the case of one chemical bond, it means DNA and R in the structural formula 1 Or alkenyl is directly attached; in the case of multiple chemical bonds, the terms DNA and R in the structural formula 1 Or alkenyl groups, e.g. DNA and R 1 Or between alkenyl groups via a methylene group (-CH) 2 Amino groups of the (-) linked DNA, i.e.linked by two chemical bonds; or DNA and R 1 Or amino groups connected with DNA through a carbonyl (-CO-) between alkenyl groups are also connected through two chemical bonds; or DNA and R 1 Or alkenyl through a methylenecarbonyl (-CH) 2 CO-) is linked to the amino group of the DNA, also via three consecutive chemical bonds;
preferably, DNA is combined with R 1 Or amino groups connected with DNA through a carbonyl (-CO-) between alkenyl groups.
R 1 A group selected from the group consisting of DNA and alkenyl carbon atoms having a molecular weight of 1000 or less;
R 2 a group selected from the group consisting of those having a molecular weight of 1000 or less and being directly attached to an alkenyl carbon atom;
R 3 selected from the group having a molecular weight of 1000 or less and being directly bonded to an oxygen atom.
As preferable: the R is 1 、R 2 Respectively selected from aryl or heteroaryl with 5-10 membered, R 1 、R 2 The number of substituents of (a) is one or more; r is R 1 、R 2 Is independently selected from one or more of hydrogen, halogen, nitro, cyano, alkyl, alkoxy and halogen alkyl;
said R is 3 Respectively selected from benzoyl, benzyl, acetyl and alkyl; wherein the alkyl group is C 1 ～C 10 An alkyl group.
Further: the R is 1 、R 2 Selected from the following groups:
More specifically: the On-DNA aryl vinyl compound is selected from but not limited to:
preferably, 2-carboxylic acid ribofuranoseThe class of compounds is selected from:
a method for synthesizing a DNA encoding compound ribofuranose derivative, comprising the steps of: adding 10-1000 times of molar equivalent of 2-carboxylic furan nucleus saccharide compound and 10-1000 times of molar equivalent of alkali into an On-DNA aryl vinyl compound solution with molar equivalent of 1 and molar concentration of 0.1-5mM, adding 1-10 times of molar equivalent of catalyst, and carrying out illumination reaction for 0.5-16 hours at 10-100 ℃.
Further, the alkali is selected from one or more of sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, DBU (1, 8-diazabicyclo undec-7-ene), 4-dimethylaminopyridine, 2, 6-dimethylpyridine or N-methylimidazole. Preferably, the base is dipotassium hydrogen phosphate.
As preferable: the reaction is carried out in a solvent, wherein the solvent is any one or a plurality of aqueous mixed solvents of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, inorganic salt buffer solution, organic acid buffer solution and organic base buffer solution. Preferably, the reaction solvent contains water, dimethyl sulfoxide.
Further, the pH of the reaction solvent is 5-11; preferably, the pH is 9.
Further, the catalyst of the reaction is selected from Ir [ dF (CF) 3 )ppy] 2 (dtbbpy)PF 6 、([Ir(dtbbpy)(ppy) 2 ][PF 6 ])、Ir[p-F(Me)ppy] 2 (dtbbpy)PF 6 、Ir(ppy) 2 (bpy)PF 6 Or 4-CzIPN; preferably, the reaction catalyst is Ir [ dF (CF) 3 )ppy] 2 (dtbbpy)PF 6 。
Further, the reaction needs to be carried out under a nitrogen atmosphere.
Further, the illumination output voltage of the reaction is 0 volts, 7.5 volts, or 13.8 volts; preferably, the reactive light output voltage is 13.8 volts. Preferably, the wavelength of the illumination is 470nm; preferably, the photoreactive light source is spaced from the reactor by 0.5cm.
Further, the reaction time of the reaction is 0.5 to 16 hours; preferably, the reaction time is 2 hours.
Further, in the method, the equivalent of the On-DNA aryl vinyl compound is 10 to 1000 of the molar equivalent of the 1, 2-carboxylic acid ribofuranose compound, the molar equivalent of the alkali is 10 to 1000, and the molar equivalent of the catalyst is 1 to 10; preferably, the molar equivalent of the 2-carboxylic acid ribofuranose compound is 50, 100, 200, 300, 400, 500, 600, 800, 1000, the molar equivalent of the base is 50, 100, 120, 200, 300, 400, 500, 600, 800, 1000, and the molar equivalent of the catalyst is 1, 4, 5, 10; most preferably, the molar equivalent of the 2-carboxylic acid ribofuranose is 400 equivalents, the molar equivalent of the base is 120 equivalents, and the molar equivalent of the catalyst is 4 equivalents.
Further, the above method is used for batch multi-well plate operations.
Further, the above method is used for the synthesis of DNA encoding compound libraries in multiwell plates.
The method can obtain the On-DNA ribofuranose derivative from the On-DNA alkenyl compound in the DNA coding compound library, can be widely applied to various On-DNA alkenyl substrates, and can introduce the 2-carboxylic ribofuranose compound On a large scale as a synthesis module. The method has high yield and single product, can be carried out in a mixed water phase of an organic solvent/water phase, is simple to operate and environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
Definition of terms used in connection with the present invention: unless otherwise indicated, the initial definitions provided for groups or terms herein apply to the groups or terms throughout the specification; for terms not specifically defined herein, the meanings that one skilled in the art can impart based on the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The minimum and maximum values of the carbon atom content of the hydrocarbon groups are indicated by a prefix, e.g. the prefix Ca b Alkyl indicates any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, C 1～12 Alkyl refers to straight or branched chain alkyl groups containing 1 to 12 carbon atoms.
Alkyl refers to straight or branched hydrocarbon groups in the alkane molecule, e.g. methyl-CH 3 ethyl-CH 2 CH 3 methylene-CH 2 -; the alkyl group may also be part of another group, such as C 1 ～C 6 Alkoxy, C 1 ～C 6 An alkylamino group.
The halogen is fluorine, chlorine, bromine or iodine.
Alkoxy means that the alkyl group is attached to an oxygen atom to form a substituent, e.g. methoxy is-OCH 3 。
Aryl/aromatic ring refers to an aromatic single cyclic or multiple cyclic group consisting of C atoms without heteroatoms.
The aromatic heterocyclic group means a single cyclic group or a plurality of cyclic groups having aromatic properties, which are constituted by a plurality of atoms such as C, O, S, N.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
Fig. 1: in example 1 of the present invention, 15 corresponding conversion profiles of On-DNA ribofuranose derivatives were obtained.
Detailed Description
The above-described aspects of the present invention will be described in further detail by way of the following embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention.
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
DNA-NH in the present invention 2 Is formed by single-stranded or double-stranded DNA and a linker group and carries-NH 2 DNA structure of linker, e.g. DNA-NH of "component 1" in WO2005058479 2 Structure is as follows. Also for example the following DNA structure:
wherein A is adenine, T is thymine, C is cytosine, and G is guanine.
DIPEA: n, N-diisopropylethylamine; DIC: n, N' -diisopropylcarbodiimide; HATU:2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate; DMA: dimethylacetamide; DMSO: dimethyl sulfoxide; DDTC: sodium diethyldithiocarbamate.
Example 1 method for synthesizing On-DNA ribofuranose
Step 1 Synthesis of On-DNA alkenyl Compound
(1) 1 was dissolved in 250mM boric acid buffer solution of pH=9.4 to prepare a 1mM concentration solution, then 50-fold equivalent of HATU (concentration: 0.4M in DMA), 50-fold equivalent of aromatic carboxylic acid reagent (concentration: 0.4M in DMA) and 50-fold equivalent of DIPEA (concentration: 0.4M in DMA) were mixed in this order at 0℃and the mixture was thoroughly mixed by vortexing, and then left at 0℃for 5 minutes, and the above mixture was added to the 1 solution and uniformly mixed to react at room temperature for 0.5 to 1 hour. Wherein Ar is a different aromatic ring.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging for half an hour at the speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain the solution of the compound 2, quantifying by an enzyme-labeled instrument OD, and sending LCMS to confirm that the reaction conversion rate is 60% -90%.
(2) 1 was dissolved in 250mM boric acid buffer solution (pH=9.4) to prepare a 1mM concentration solution. Then, 50 times equivalent of N-hydroxysuccinimide (NHS) (concentration of 0.4M in DMA), 40 times equivalent of 2-bromoacrylic acid (concentration of 0.2M in DMA), 20 times equivalent of N, N' -Diisopropylcarbodiimide (DIC) (concentration of 0.4M in DMA) were mixed in this order at 0℃and the mixture was thoroughly mixed by vortexing, and then left at 0℃for 5 minutes. Dividing the mixture into two parts, adding one part into the 1 solution, uniformly mixing, reacting for 5 minutes at 0 ℃, adding the rest mixture into the solution, uniformly mixing, reacting for 5 minutes at 0 ℃, and finally standing the reaction solution at room temperature for reacting for 5 minutes.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging for half an hour at the speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain a solution of the compound 4, quantifying by an enzyme-labeled instrument OD, and sending LCMS to confirm that the reaction conversion rate is 56%.
(3) Compound 2 was dissolved in water to prepare a 1mM concentration solution, followed by sequentially adding 10-fold equivalent of pinacol vinylborate (0.2M in concentration in DMSO), 100-fold equivalent of cesium hydroxide (0.5M in concentration in water), 2.5-fold equivalent of chloro (sodium-2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1 '-biphenyl-3' -sulfonate) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (sps Pd G2) (0.01M in concentration in DMSO), mixing well, and reacting at 100 ℃ for 30 minutes. After the reaction was completed, 100 times equivalent of sodium diethyldithiocarbamate (DDTC) (0.4M concentration in water) was added to the reaction system, and the mixture was uniformly mixed and reacted at 100℃for 10 minutes.
After the reaction is finished, the supernatant is centrifugally taken and ethanol precipitation is carried out: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging for half an hour at the speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain the solution of the On-DNA aryl vinyl compound 3, quantifying by an enzyme-labeled instrument OD, and then sending LCMS to confirm that the reaction conversion rate is 70% -90%.
(4) Compound 4 was dissolved in water to prepare a 1mM concentration solution, followed by the sequential addition of 100-fold equivalents of an arylboronic acid compound (0.2M in concentration, dissolved in DMSO), 100-fold equivalents of cesium hydroxide (0.5M in concentration, dissolved in water), 2.5-fold equivalents of chlorine (sodium-2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1 '-biphenyl-3' -sulfonate) [2- (2 '-amino-1, 1' -biphenyl)]Palladium (II) (sSPhos Pd G2) (concentration 0.01M in DMSO), was mixed well and reacted at 90℃for 2 hours. After the reaction was completed, 100 times equivalent of DDTC (0.4M concentration in water) was added to the reaction system, and the mixture was uniformly mixed and reacted at 90℃for 10 minutes. Wherein R is 1 Is a different aromatic ring.
After the reaction is finished, the supernatant is centrifugally taken and ethanol precipitation is carried out: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging for half an hour at the speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain the solution of the On-DNA aryl vinyl compound 5, quantifying by an enzyme-labeled instrument OD, and then sending LCMS to confirm that the reaction conversion rate is 70% -90%.
Step 2, visible light catalysis of 2-carboxylic acid ribofuranose to On-DNA alkene reaction
Dissolving On-DNA aryl vinyl compound 3 or 5 in water to prepare 1mM concentration solution, then sequentially adding 400 equivalents of 2-carboxylic acid ribofuranose compound (0.5M in DMSO), 120 equivalents of dipotassium hydrogen phosphate (0.3M in water), 4 times of catalyst Ir (dF (CF) 3 )ppy] 2 (dtbbpy)PF 6 (0.01M in DMSO), and then adding DMSO to the reaction solution to make the organic phase of the reaction system: water phase volume ratio = 3:2, uniformly mixing, removing air for 2 hours, replacing nitrogen for 2 hours, setting the illumination output voltage of illumination equipment to 13.8V, setting the wavelength to 470nm, and enabling the distance between a light source and a reactor to be 0.5cm, wherein the illumination reaction is carried out for 2 hours.
Ethanol precipitation is carried out after the reaction is finished: adding 5M sodium chloride solution with the total volume of 10% into the reacted solution, continuously adding absolute ethanol with the total volume of 3 times, shaking uniformly, placing the reaction in dry ice, freezing for 0.5 hour, centrifuging for half an hour at the speed of 12000rpm, pouring out supernatant, dissolving the rest precipitate with deionized water to obtain 15 solutions of On-DNA products, quantifying by an enzyme-labeled instrument OD, and sending LCMS to confirm the conversion rate of the reaction. The conversion is shown in FIG. 1.
In summary, the On-DNA ribofuranose derivative can be obtained by reacting an On-DNA alkenyl compound with a 2-carboxylic acid ribofuranose compound under the presence of a base by visible light catalysis by controlling conditions such as a solvent, a temperature, a pH and the like during the reaction. The method has wide substrate application range, can be carried out in a mixed water phase of an organic solvent/water phase, is simple to operate, is environment-friendly, and is suitable for synthesizing the DNA coding compound library by using a porous plate.
Claims (12)
1. A synthesis method of a DNA coding compound ribofuranose derivative is characterized in that: the method takes an On-DNA aryl vinyl compound and a 2-carboxylic acid ribofuranose compound as raw materials, and obtains the On-DNA ribofuranose derivative through photocatalytic decarboxylation free radical addition reaction in an alkaline environment.
2. The method according to claim 1, characterized in that: wherein the On-DNA aryl vinyl compound has the structure of
The structural formula of the 2-carboxylic acid ribofuranose compound is +.>
Wherein the DNA of the formula comprises a single-or double-stranded nucleotide chain obtained by polymerization of artificially modified and/or unmodified nucleotide monomers, which is linked to R in the compound by one or more chemical bonds or groups 1 Or alkenyl groups;
R 1 a group selected from the group consisting of DNA and alkenyl carbon atoms having a molecular weight of 1000 or less;
R 2 a group selected from the group consisting of those having a molecular weight of 1000 or less and being directly attached to an alkenyl carbon atom;
R 3 selected from the group having a molecular weight of 1000 or less and being directly bonded to an oxygen atom.
3. The method according to claim 2, characterized in that: the R is 1 、R 2 Respectively selected from aryl or heteroaryl with 5-10 membered, R 1 、R 2 The number of substituents of (a) is one or more; r is R 1 、R 2 Is independently selected from one or more of hydrogen, halogen, nitro, cyano, alkyl, alkoxy and halogen alkyl;
said R is 3 Selected from benzoyl, benzyl, acetyl, alkyl; wherein the alkyl group is C 1 ～C 10 An alkyl group.
4. A method according to claim 3, characterized in that: the R is 1 、R 2 Respectively selected from
5. The method according to claim 1, characterized in that: the method comprises the following steps: adding 10-1000 times of molar equivalent of 2-carboxylic furan nucleus saccharide compound and 10-1000 times of molar equivalent of alkali into an On-DNA aryl vinyl compound solution with molar equivalent of 1 and molar concentration of 0.1-5mM, adding 1-10 times of molar equivalent of catalyst, and carrying out illumination reaction for 0.5-16 hours at 10-100 ℃.
6. The method according to claim 5, wherein: the alkali is selected from one or more of sodium borate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, dipotassium hydrogen phosphate, N-methylmorpholine, triethylamine, diisopropylethylamine, 1, 8-diazabicyclo undec-7-ene, 4-dimethylaminopyridine, 2, 6-dimethylpyridine or N-methylimidazole.
7. The method according to claim 5, wherein: the reaction is carried out in a solvent, wherein the solvent is any one or a plurality of aqueous mixed solvents of water, methanol, ethanol, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, inorganic salt buffer solution, organic acid buffer solution and organic base buffer solution.
8. The method according to claim 5, wherein: the catalyst is selected from Ir (dF) (CF) 3 )ppy] 2 (dtbbpy)PF 6 、([Ir(dtbbpy)(ppy) 2 ][PF 6 ])、Ir[p-F(Me)ppy] 2 (dtbbpy)PF 6 、Ir(ppy) 2 (bpy)PF 6 Or 4-CzIPN.
9. The method according to claim 5, wherein: the illumination output voltage of the reaction was 0 volts, 7.5 volts, or 13.8 volts.
10. The method according to claim 5, wherein: in the method, the molar equivalent of the On-DNA aryl vinyl compound is 50 equivalents, 100 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents of the 1, 2-carboxylic acid ribofuranose compound, the molar equivalent of the alkali is 50 equivalents, 100 equivalents, 120 equivalents, 200 equivalents, 300 equivalents, 400 equivalents, 500 equivalents, 600 equivalents, 800 equivalents and 1000 equivalents, and the molar equivalent of the catalyst is 1 equivalent, 4 equivalents, 5 equivalents and 10 equivalents.
11. The method according to any one of claims 1-10, wherein the method is used for batch multi-well plate operations.
12. The method according to any one of claims 1 to 10, wherein the method is used for the synthesis of a library of DNA-encoding compounds of a multiwell plate.
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