CN108314655A - 一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法 - Google Patents
一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法 Download PDFInfo
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- 125000002837 carbocyclic group Chemical group 0.000 title claims abstract description 24
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 239000002718 pyrimidine nucleoside Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 20
- 229910052703 rhodium Inorganic materials 0.000 title claims abstract description 20
- 239000010948 rhodium Substances 0.000 title claims abstract description 20
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 18
- 238000006555 catalytic reaction Methods 0.000 title claims abstract description 14
- 229960003405 ciprofloxacin Drugs 0.000 title claims abstract description 12
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- 229940012356 eye drops Drugs 0.000 title claims abstract description 12
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- 229920002554 vinyl polymer Polymers 0.000 claims abstract description 16
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 10
- 150000002148 esters Chemical class 0.000 claims abstract description 9
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 66
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- 239000003054 catalyst Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- LNKDTZRRFHHCCV-UHFFFAOYSA-N 1-ethenyl-2h-pyrimidine Chemical class C=CN1CN=CC=C1 LNKDTZRRFHHCCV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- KDKYADYSIPSCCQ-UHFFFAOYSA-N ethyl acetylene Natural products CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
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- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
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- 239000002994 raw material Substances 0.000 abstract description 5
- 238000011914 asymmetric synthesis Methods 0.000 abstract description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 21
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- 239000000243 solution Substances 0.000 description 19
- -1 Nucleoside compound Chemical class 0.000 description 15
- 239000002777 nucleoside Substances 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004296 chiral HPLC Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 230000014759 maintenance of location Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000012954 diazonium Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- CRZQGDNQQAALAY-UHFFFAOYSA-N Methyl benzeneacetate Chemical compound COC(=O)CC1=CC=CC=C1 CRZQGDNQQAALAY-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical group 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- JXBOFERRSCSVGT-UHFFFAOYSA-N 1-ethenylpyrimidine-2,4-dione Chemical compound C=CN1C=CC(=O)NC1=O JXBOFERRSCSVGT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 1
- SSMBXPJYHMZLOJ-UHFFFAOYSA-N Isopropyl phenylacetate Chemical compound CC(C)OC(=O)CC1=CC=CC=C1 SSMBXPJYHMZLOJ-UHFFFAOYSA-N 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- MIYFJEKZLFWKLZ-UHFFFAOYSA-N Phenylmethyl benzeneacetate Chemical compound C=1C=CC=CC=1COC(=O)CC1=CC=CC=C1 MIYFJEKZLFWKLZ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- KDNSSKPZBDNJDF-UHFFFAOYSA-N [1-[(2-aminopurin-9-yl)methyl]cyclopropyl]oxymethylphosphonic acid Chemical compound C12=NC(N)=NC=C2N=CN1CC1(OCP(O)(O)=O)CC1 KDNSSKPZBDNJDF-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- GNHQSAUHXKRQMC-UHFFFAOYSA-N benzene;chlorine Chemical compound [Cl].C1=CC=CC=C1 GNHQSAUHXKRQMC-UHFFFAOYSA-N 0.000 description 1
- CUOVXSBRIDEVPR-UHFFFAOYSA-N benzyl 2-(4-chlorophenyl)acetate Chemical compound C1=CC(Cl)=CC=C1CC(=O)OCC1=CC=CC=C1 CUOVXSBRIDEVPR-UHFFFAOYSA-N 0.000 description 1
- YVYHORGNKSXSRV-UHFFFAOYSA-N benzyl 2-phenylpropanoate Chemical compound C=1C=CC=CC=1C(C)C(=O)OCC1=CC=CC=C1 YVYHORGNKSXSRV-UHFFFAOYSA-N 0.000 description 1
- 229950002782 besifovir Drugs 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- VXJFEYCXCCIWCQ-UHFFFAOYSA-N ethyl acetate thiophene Chemical compound C(C)(=O)OCC.S1C=CC=C1 VXJFEYCXCCIWCQ-UHFFFAOYSA-N 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- ZENDWEPAVHORFD-UHFFFAOYSA-N pyrimidine;urea Chemical compound NC(N)=O.C1=CN=CN=C1 ZENDWEPAVHORFD-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 229910000144 sodium(I) superoxide Inorganic materials 0.000 description 1
- 229960002063 sofosbuvir Drugs 0.000 description 1
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical group N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/553—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with halogen atoms or nitro radicals directly attached to ring carbon atoms, e.g. fluorouracil
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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Abstract
本发明公开了一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,属于有机化学中的不对称合成领域。以1‑乙烯基取代嘧啶和芳基重氮酯为原料,使用手性铑催化,反应后得到含季碳中心的手性环丙烷碳环嘧啶核苷类似物,反应对映选择性好,收率中等至优秀。
Description
技术领域
本发明涉及手性碳环嘧啶核苷的合成方法,具体涉及一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,属于有机化学中的不对称合成领域。
背景技术
核苷类化合物表现出良好的抗肿瘤抗病毒活性,因此,对天然核苷部分的修饰成为研究的热点。例如,最具代表性的是Sofosbuvir, 糖环上有手性季碳环中心的核苷类药物,2013年已被FDA批准用于治疗丙肝病毒(丙型肝炎病毒)感染。随之,具有特定构象的三元碳环核苷引起了众多研究者的广泛关注。Besifovir,具有季碳中心的三元碳环核苷Ⅰ,在2017年经批准作为anti-HBV(乙型肝炎病毒)药物。此外,具有季碳中心的环丙基胞嘧啶核苷呈现出中等的抗HCMV(人类巨细胞病毒活性。与此同时,也具有季碳中心的环丙基胞嘧啶核苷Ⅱ, 展现出潜在的抗癌活性。此外,环丙基核苷的手性中心的绝对构型在相应的生物活性中也起着至关重要的作用,比如,(1′S,2′R)-A5021 比对映体(1′R,2′S)-A5021活性高近100倍。因此,开发一种更有效的方法来合成季碳中心的手性环丙基碳环核苷类似物是非常必要的。
传统的合成手性三元碳环核苷理论上有两种方法:一:经过多步设计合成手性碳环核苷,三元碳环核苷上引入氨基或脲基,从氨基或脲基出发构筑嘌呤或嘧啶碱基,从而形成手性三元碳环核苷;二:经过多步设计合成具有固定构型的手性三元碳环,在三元环上引入卤素或其它取代基,然后三元碳环和嘌呤或嘧啶碱基发生亲核取代反应,最后形成手性三元碳环核苷,这两种方法构筑环丙烷核苷衍生物的方法过于繁琐,合成成本较高。相对来说,选用低成本的,廉价易得的原料来制备手性环丙烷碳环核苷的方法具有很高的价值。
发明内容
为了克服上述缺陷,本发明采用1-乙烯基取代嘧啶和芳基重氮酯为原料,在手性铑催化剂存在下,反应得到含季碳中心的手性三元碳环嘧啶核苷。该方法为合成手性环丙烷碳环核苷类化合物提供了一种简便、廉价、高效的途径。
一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于,包括如下步骤:以1-乙烯基取代嘧啶1或2和芳基重氮酯 3为原料,在手性铑催化剂存在下,反应分别得到含季碳中心的手性三元碳环嘧啶核苷4或5,反应方程式如下:
其中,R代表下列基团中的一种:氢、甲基、乙基、卤素、三氟甲基、三甲基硅基乙炔;Pg代表下列基团中的一种:Boc、Bz;Ar 代表下列基团中的一种:苯基、3-CH3C6H4、4-CH3C6H4、4-CH3OC6H4、 4-ClC6H4、4-BrC6H4、R2代表下列基团中的一种:甲基、乙基、异丙基或苄基。
其中Pg选择Boc、Bz的原因为:如果嘧啶上没有保护基会发生 N-H插入反应,如果有保护基,胞嘧啶不容易控制得到单Boc产物,所以选择双Boc,脲嘧啶均可选择Boc、Bz保护。
进一步地,在上述技术方案中,所述手性铑催化剂具体结构如下:
进一步地,在上述技术方案中,反应操作为,溶剂溶解1-乙烯基嘧啶1或2和催化剂,缓慢滴加溶剂溶解的芳基重氮酯3。优选地,溶解0.5mmol 1-乙烯基嘧啶1或2溶剂的体积为0.5-1mL,溶解重氮酯3的体积为1-3mL,且芳基重氮酯3的加入方式为逐滴滴加。
进一步地,在上述技术方案中,所述1-乙烯基取代嘧啶1或2、芳基重氮酯3、手性铑催化剂的摩尔比为1:2-8:0.01-0.05。
进一步地,在上述技术方案中,反应温度选自-20℃到-60℃。
进一步地,在上述技术方案中,反应溶剂选自二氯甲烷、1,2- 二氯乙烷、氯仿、氯苯、甲苯或均三甲苯。
在上述反应条件下,经过反应纯化后,对于不同的底物分离收率 75%-96%。
进一步地,在上述技术方案中,将得到的产物手性三元碳环嘧啶核苷4采用TFA脱保护,随后再用DIBAL-H还原得到手性单羟基三元碳环嘧啶核苷6。
发明有益效果:
本发明为合成含季碳中心的手性环丙烷碳环嘧啶核苷的方法提供了一种简便、廉价、高效的合成方法,反应原料易得,产物结构丰富,产物立体选择性高,反应后得到手性环丙烷碳环嘧啶核苷类化合物,收率中等至优秀。
具体实施方式
实施例1
[a]Unless otherwise noted,the reaction conditions are as follows:1a(0.05mmol)and catalyst(x mol%) were dissolved in solvent(1.0mL),then 3a(8.0equiv)in solvent(2.0mL)was added dropwise to the reaction mixture viasyringe pump for 4hours.For all the cases,the dr values were>20:1,which weredetermined by 1H NMR of the crude products.N.R.=No Reaction.[b]Isolatedyield.[c]Determined by chiral HPLC analysis.
在反应条件的筛选过程中,首先考察了催化剂对反应的影响(标号1-7)。同时通过对照不同催化剂对反应的影响,确定了催化剂Rh-L7 为最佳催化剂。
反应条件的考察:在10mL的反应管中加入1-乙烯基胞嘧啶1a (16.9mg,0.05mmol)和Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,苯乙酸苄酯3a(100.9mg,0.4mmol) 溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC 跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得目标化合物4aa,收率92%,98%ee值。
在其它条件固定的情况下,仅考察催化剂的用量对反应的影响,以1a和3a反应生成4aa为例,反应方程式如下:
在其它条件固定的情况下,仅考查溶解重氮的溶剂用量对反应的影响,反应方程式如下:
实施例2:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,对甲基苯乙酸苄酯重氮(106.5mg,0.4mmol)溶解在1mL 甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得27.1mg白色固体 4ab,熔点162.5-163.9℃,收率94%,99%ee(手性HPLC检测,n-hexane /2-propanol=70/30,流速:0.8mL/min,检测波长:250nm,保留时间:8.004min,9.843min),[α]D 20=157.3(c=0.68,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.31–7.18(m,7H),7.01(t,J=7.6 Hz,3H),6.68(d,J=7.2Hz,1H),5.19(d,J=12.4Hz,1H),5.10(d,J= 12.4Hz,1H),4.40(t,J=7.6Hz,1H),2.26(s,3H),2.18(t,J=7.6Hz, 1H),2.01(t,J=6.4Hz,1H),1.52(s,18H);13C NMR(150MHz,CDCl3) δ171.7,162.2,155.9,149.5,144.4,138.1,135.9,131.0,129.3,128.8, 128.6,128.1,127.6,95.8,85.0,67.2,44.8,35.5,27.8,21.3,17.1;HRMS (ESI):m/z calcd.ForC32H37N3NaO7[M+Na]+598.2524,found m/z 598.2525.
实施例3:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,间甲基苯乙酸苄酯(106.5mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得28.8mg黄色固体4ac, 熔点168.0-169.6℃,收率96%,99%ee(手性HPLC检测,n-hexane/ 2-propanol=80/20,流速:0.6mL/min,检测波长:250nm,保留时间: 17.721min,32.616min),[α]D 20=206.3(c=0.69,CH2Cl2).
1H NMR(600MHz,CDCl3)δ7.30–7.21(m,5H),7.11–7.10(m, 3H),7.00–6.98(m,2H),6.66(d,J=7.2Hz,1H),5.19(d,J=13.2Hz, 1H),5.10(d,J=13.2Hz,1H),4.43(t,J=6.6Hz,1H),2.24(s,3H),2.18 (d,J=7.2Hz,1H),2.05(t,J=6.0Hz,1H),1.51(s,18H);13CNMR (150MHz,CDCl3)δ171.5,162.0,155.8,149.4,144.2,137.9,135.7, 131.8,131.7,129.1,128.5,128.3,128.2,128.0,127.4,95.5,84.9,67.1, 44.6,35.6,27.7,21.3,17.0;HRMS(ESI):m/z calcd.For C32H37N3NaO7 [M+Na]+598.2524,found m/z 598.2524.
实施例4:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,间甲基苯乙酸苄酯(112.9mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得目标化合物4ad,收率92%,96%ee。
实施例5:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,对氯苯乙酸苄酯(114.7mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得目标化合物4ae,收率 92%,96%ee。
实施例6:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,对溴苯乙酸苄酯(132.5mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得目标化合物4af,收率 92%,94%ee。
实施例7:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,2-萘乙酸苄酯(120.9mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得26.0mg白色固体4ag, 熔点166.8-168.7℃,收率85%,98%ee(手性HPLC检测,n-hexane/ 2-propanol=70/30,流速:0.8mL/min,检测波长:250nm,保留时间: 9.583min,13.029min),[α]D 20=52.5(c=0.55,MeOH).
1H NMR(600MHz,CDCl3)δ7.75(m,3H),7.69(d,J=9.0Hz, 1H),7.51(dd,J=8.4,1.2Hz,1H),7.45–7.43(m,2H),7.28–7.24(m, 5H),7.02(d,J=7.8Hz,1H),6.60(d,J=7.8Hz,1H),5.21(d,J=12.6 Hz,1H),5.12(d,J=12.6Hz,1H),4.49(dd,J=8.4,6.6Hz,1H),2.30(t, J=6.6Hz,1H),2.20(t,J=6.6Hz,1H),1.48(s,18H);13C NMR(150 MHz,CDCl3)δ171.6,162.2,155.9,149.4,144.2,135.7,133.2,130.0, 129.9,129.2,128.6,128.3,128.1,128.0,127.8,127.7,126.4,126.1,95.8, 84.9,67.4,45.0,36.0,29.8,27.8,17.3;HRMS(ESI)m/z calcd.For C35H37N3NaO7[M+Na]+634.2524,found m/z634.2523.
实施例8:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,噻吩乙酸乙酯重氮(78.5mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得25.3mg黄色油状液体4ah,收率90%,94%ee(手性HPLC检测,n-hexane/2-propanol= 70/30,流速:0.8mL/min,检测波长:250nm,保留时间:11.194min, 13.867min).[α]D 20=196.2(c=0.70,CH2Cl2).
1H NMR(600MHz,CDCl3)δ7.15–7.10(m,3H),7.04(s,1H),6.73 (d,J=7.2Hz,1H),4.24–4.22(m,2H),4.15–4.12(m,1H),2.21(t,J= 7.8Hz,1H),2.01(t,J=6.0Hz,1H),1.53(s,18H),1.23(t,J=7.2Hz, 3H);13C NMR(100MHz,CDCl3)δ171.3,162.2,155.6,149.5,144.7, 133.0,130.0,125.8,125.7,95.6,85.0,62.0,45.0,31.2,27.8,18.0,14.2; HRMS(ESI):m/z calcd.For C24H31N3NaO7S[M+Na]+528.1775,found m/z 528.1771.
实施例9:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,苯乙酸甲酯(70.5mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得21.1mg白色固体4ai,收率87%,熔点169.0-170.8℃,99%ee(手性HPLC检测,n-hexane/ 2-propanol=85/15,流速:0.6mL/min,检测波长:250nm,保留时间: 34.426min,55.581min);[α]D 20=218.8(c=0.48,CH2Cl2).
1H NMR(600MHz,CDCl3)δ7.29–7.22(m,5H),7.00(d,J=7.8 Hz,1H),6.66(d,J=7.8Hz,1H),4.39(t,J=7.2Hz,1H),3.68(s,3H), 2.19(t,J=7.2Hz,1H),2.05(t,J=6.6Hz,1H),1.52(s,18H);13C NMR (100MHz,CDCl3)δ172.2,162.1,155.8,149.4,144.2,132.0,131.2, 128.5,128.4,95.6,85.0,53.0,44.8,35.5,27.7,17.1;HRMS(ESI):m/zcalcd.For C25H31N3NaO7[M+Na]+508.2054,found m/z 508.2058.
实施例10:
在10mL的反应管中加入1-乙烯基胞嘧啶(16.9mg,0.05mmol)和 Rh-L7(1.4mg,2mol%),然后加入1mL的甲苯,将反应管置于-50℃的低温泵中,苯乙酸异丙酯(81.7mg,0.4mmol)溶解在1mL甲苯后使用注射泵逐滴加入到上述反应管中反应。用TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得25.3mg白色固体4ak, 熔点170.1-171.5℃,收率93%,91%ee(手性HPLC检测,n-hexane/ 2-propanol=70/30,流速:0.8mL/min,检测波长:250nm,保留时间: 7.258min,9.719min);[α]D 20=180.1(c=0.87,CH2Cl2).
1H NMR(400MHz,CDCl3)δ7.27–7.19(m,5H),6.98(d,J=7.6 Hz,1H),6.66(d,J=7.6Hz,1H),5.01(m,1H),4.36(dd,J=8.0,6.0Hz, 1H),2.16(dd,J=8.3,6.8Hz,1H),2.02(t,J=6.4Hz,1H),1.50(s,18H), 1.17(dd,J=16.8,6.4Hz,6H);13C NMR(150MHz,CDCl3)δ171.1, 162.1,155.8,149.5,144.2,132.2,131.2,128.4,128.2,95.6,85.0,69.5, 44.6,35.9,27.8,21.8,21.7,16.6;HRMS(ESI):m/z calcd.For C27H35N3 NaO7[M+Na]+536.2367,found m/z 536.2367.
实施例11
根据实施例2-9中的反应条件,仅仅将反应底物进行改变为1- 乙烯基尿嘧啶2,得到如下反应结果:
实施例12
在10mL的反应瓶中加入4aa(50mg,0.09mmol)溶解在三氟乙酸和二氯甲烷的混合溶液中(1:1,1mL)搅拌4h,溶剂减压蒸馏,粗产物经过柱层析获得黄色固体,再将干燥二氯甲烷溶液加到上述黄色固体的密封管中,然后将其置于-78℃低温泵中搅拌,DIBAL-H的正己烷溶液(1.0M in hexane,445.0μL,0.4mmol)逐滴加到反应管中。用 TLC跟踪反应,终止反应后,真空浓缩反应液,然后经柱层析获得白色固体6aa(17mg,81%yield,99%ee)。
代表性化合物表征数据如下:
6aa白色固体,熔点233.2-237.4℃,81%yield,17mg,99%ee.[α]D 20=254.1(c=0.45,MeOH).
Ee值通过手性HPLC检测:n-hexane/2-propanol=85/15,流速:0.6 mL/min,检测波长:250nm,保留时间:38.044min,53.003min.
1H NMR(400MHz,CD3OD)δ7.34–7.32(m,3H),7.22–7.15(m, 4H),5.51(d,J=7.2Hz,1H),3.95(d,J=11.6Hz,1H),3.69(d,J=11.6 Hz,1H),1.87(t,J=8.0Hz,1H),1.51(t,J=8.0Hz,1H);13C NMR(100 MHz,CD3OD)δ167.4,160.3,144.9,138.0,131.2,129.3,128.2,94.8, 68.7,41.8,35.9,12.6;HRMS(ESI):m/z calcd.for C14H15N3NaO2 [M+Na]+280.1056,found m/z 280.1056。
Claims (8)
1.一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:在手性铑催化剂存在下,1-乙烯基取代嘧啶1或2和芳基重氮酯3反应分别得到含季碳中心的手性三元碳环嘧啶核苷4或5,反应方程式如下:
2.根据权利要求1所述一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:R选自:氢、甲基、乙基、卤素、三氟甲基、三甲基硅基乙炔;Pg选自Boc、Bz;Ar选自:苯基、3-CH3C6H4、4-CH3C6H4、4-CH3OC6H4、4-ClC6H4、4-BrC6H4、R2选自:甲基、乙基、异丙基、苄基。
3.根据权利要求1或2中所述一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:所述手性铑催化剂选自Rh-L3-7。
4.根据权利要求1或2中所述一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:反应在有机溶剂中进行,反应溶剂选自二氯甲烷、1,2-二氯乙烷、氯仿、氯苯、甲苯或均三甲苯。
5.根据权利要求1或2中所述一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:所述1-乙烯基取代嘧啶1或2、芳基重氮酯3、手性铑催化剂的摩尔比为1:2-8:0.01-0.05。
6.根据权利要求1或2中所述一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:反应温度选自-20℃到-60℃。
7.根据权利要求4中所述一种铑催化不对称环丙化合成三元碳环嘧啶核苷类似物的方法,其特征在于:反应操作为,溶剂溶解1-乙烯基嘧啶1或2和催化剂,缓慢滴加溶剂溶解的芳基重氮酯3。
8.一种合成手性单羟基三元碳环嘧啶核苷的方法,其特征在于:将权利要求1中得到的产物手性三元碳环嘧啶核苷4采用TFA脱保护,随后再用DIBAL-H还原得到手性单羟基三元碳环嘧啶核苷6。
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CN110015996A (zh) * | 2019-05-07 | 2019-07-16 | 河南师范大学 | 一种合成2′-螺环基取代三元碳环核苷的方法 |
CN111646948A (zh) * | 2020-07-03 | 2020-09-11 | 河南师范大学 | 不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法 |
CN111646948B (zh) * | 2020-07-03 | 2021-08-27 | 河南师范大学 | 不对称环丙烷化合成手性嘧啶取代双酯基环丙烷的方法 |
CN114920733A (zh) * | 2022-05-23 | 2022-08-19 | 河南师范大学 | 一种环加成合成手性异噁唑环及碳环核苷类似物的方法 |
CN114920733B (zh) * | 2022-05-23 | 2023-09-29 | 河南师范大学 | 一种环加成合成手性异噁唑环及碳环核苷类似物的方法 |
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