CN114456217A - 一种烯糖化合物的合成方法 - Google Patents
一种烯糖化合物的合成方法 Download PDFInfo
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- -1 glycal compound Chemical class 0.000 title claims abstract description 21
- 238000010189 synthetic method Methods 0.000 title description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 235000000346 sugar Nutrition 0.000 claims abstract description 15
- 239000012074 organic phase Substances 0.000 claims abstract description 11
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 10
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000003017 phosphorus Chemical class 0.000 claims abstract description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims abstract description 4
- 239000000126 substance Substances 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl 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
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- KIZFHUJKFSNWKO-UHFFFAOYSA-M calcium monohydroxide Chemical compound [Ca]O KIZFHUJKFSNWKO-UHFFFAOYSA-M 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- UNYOJUYSNFGNDV-UHFFFAOYSA-M magnesium monohydroxide Chemical compound [Mg]O UNYOJUYSNFGNDV-UHFFFAOYSA-M 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims 2
- 150000001720 carbohydrates Chemical class 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 6
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 abstract description 3
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- 150000003003 phosphines Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical class OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 13
- 239000012295 chemical reaction liquid Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229930182470 glycoside Natural products 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- NYWRBDSLXCKNAJ-SQOUGZDYSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanoyl bromide Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(Br)=O NYWRBDSLXCKNAJ-SQOUGZDYSA-N 0.000 description 1
- GKHCBYYBLTXYEV-HENWMNBSSA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-6-phenylmethoxyoxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OCC1=CC=CC=C1 GKHCBYYBLTXYEV-HENWMNBSSA-N 0.000 description 1
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 1
- YTNVHUSMDIAWLT-UHFFFAOYSA-N 91374-23-1 Chemical compound CCCN(CCC)CCC1=CC=CC([N+]([O-])=O)=C1C YTNVHUSMDIAWLT-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241001391944 Commicarpus scandens Species 0.000 description 1
- RXVWSYJTUUKTEA-UHFFFAOYSA-N D-maltotriose Natural products OC1C(O)C(OC(C(O)CO)C(O)C(O)C=O)OC(CO)C1OC1C(O)C(O)C(O)C(CO)O1 RXVWSYJTUUKTEA-UHFFFAOYSA-N 0.000 description 1
- 229910007568 Zn—Ag Inorganic materials 0.000 description 1
- UAOKXEHOENRFMP-ZJIFWQFVSA-N [(2r,3r,4s,5r)-2,3,4,5-tetraacetyloxy-6-oxohexyl] acetate Chemical compound CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)C=O UAOKXEHOENRFMP-ZJIFWQFVSA-N 0.000 description 1
- LLPWGHLVUPBSLP-UTUOFQBUSA-N [(2r,3s,4r)-3,4-diacetyloxy-3,4-dihydro-2h-pyran-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1OC(C)=O LLPWGHLVUPBSLP-UTUOFQBUSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- VQPFDLRNOCQMSN-UHFFFAOYSA-N bromosilane Chemical compound Br[SiH3] VQPFDLRNOCQMSN-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940075397 calomel Drugs 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZOMNIUBKTOKEHS-UHFFFAOYSA-L dimercury dichloride Chemical compound Cl[Hg][Hg]Cl ZOMNIUBKTOKEHS-UHFFFAOYSA-L 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RXVWSYJTUUKTEA-CGQAXDJHSA-N maltotriose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 RXVWSYJTUUKTEA-CGQAXDJHSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
-
- 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
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
一种烯糖化合物的合成方法是,以酰基保护、硅烷基或烷氧基保护的糖与三芳基或三烷基膦为原料,于室温条件下加入有机溶剂充分溶解,在20~60℃条件下反应2~36小时,得到磷盐中间化合物,然后在碱性条件下水解,反应结束后萃取,收集有机相,溶剂旋干后重新溶解于甲苯、***或甲基叔丁基醚,过滤去除不溶物,旋干溶剂后经硅胶柱层析分离得到目标烯糖化合物。本发明实现以三取代膦为氧化剂的还原消除反应得到烯糖化合物,另外选择氘代氢氧化钠与氘代水为碱性条件时,可以得到相应的1‑D‑烯糖化合物,反应具有操作简便、原料廉价易得、反应收率高等特点,是一种具有较好应用前景的合成方法。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种烯糖化合物的合成方法。
背景技术
烯糖化合物(Glycals)是一类非常重要的糖化学中间体,被广泛应用于N-苷、O-苷、C-苷、S-苷、寡糖和一些天然产物的构建中。鉴于烯糖化合物在合成中发挥的重要作用,合成化学家们长期致力于发展一种绿色环保、高效实用、廉价简单,可用于工业生产的合成方法。目前,相关合成方法的报道也非常多,但基本都是基于不稳定的1-卤代糖为原料,经过各类金属试剂还原消除得到,比如(Cp2TiCl)2、Al-Hg、Zn-Ag、Li-NH3、Cr(II)盐、钴金属还原等方法。另外,电化学还原的方法也有报道,但由于需要昂贵的电极与独立电解池等条件,该方法并没有得到广泛的应用。从1913年,Ferrier等人首次报道烯糖化合物以来,该合成工艺也被不断地优化和更新,但这些新方法并没有得到本质上的改进,依然无法替代传统的Ferrier-Zach烯糖合成法,即以溴代葡萄糖为原料,锌粉-乙酸体系,-20~0℃反应合成烯糖(Sitz. Ber. Kgl. Preuss. Akad. Wiss., 1913, 16, 311-317.)。以下是合成烯糖的几种常见的方法。
1.1 Ferrier-Zach还原法合成烯糖
Ferrier-Zach还原方法虽然已经被广泛应用,近年来也被不断优化改进,但是这些方法往往都需要非常苛刻的条件,比如惰性气体环境、近10个当量的锌金属、低温条件(-20~-10oC)等。后来发展了Zn/CuSO4、Zn/NaH2PO4、Zn/β-CD与Zn/NH4Cl等体系,虽然改进了实验的可操作性,也提高了反应的产率,但是依然需要远过量的锌粉作为还原试剂和需要惰性气体环境等条件(Methods Carbohydr. Chem.1963, 2, 405–408; J. Carbohydr. Chem., 1996, 15, 955-964; Carbohydr. Res.2010, 345, 168–171; RSC Adv., 2014,4, 46662-46665; Carbohydr. Res., 2016, 431, 42-46; Chin. J. Chem.2011, 29,1434-1440; Green Chem.2009, 11, 1124–1127)。
总而言之,这类方法从五乙酰基糖为起始原料,首先转化成相应的1-溴代糖,再转化成烯糖化合物,这些步骤虽然可以在一个反应器中完成,中间物不用分离,然而该方法产率低、容易发生其它糖苷键的断裂、产生副产物较多、不易提纯、锌粉用量大、操作复杂、危险性大,所以此方法不适合烯糖的工业化生产。
1.2 Ti(III)还原法合成烯糖
Schwantz等人在1995年第一次报道了用(Cp2TiC1)2还原溴代糖,通过自由基机制脱掉2-O-乙酰基和1-Br得到了烯糖。此方法首先用溴硅烷和乙酰化糖在低温条件下反应生成溴代糖,然后在惰性气体保护下再将得到的溴代乙酰化糖溶于THF当中,缓慢的滴加到(Cp2TiCl)2的THF溶液中,大约15分钟后,反应液体的颜色从绿色转为红色,证明反应结束(Tetrahedron Lett., 1996, 37, 4357-4360; J. Org. Chem., 1995, 60, 7055-7057;J. Org. Chem. 1999, 64, 3987-3995; Tetrahedron Lett., 1999, 40, 6087-6090;Tetrahedron Lett.,2000, 41, 8645–8649; )。反应路线如下式:
随后Schwartz等人将该方法进一步扩展到其他的卤代糖化合物,比如氯代糖,溴代呋喃糖等。虽然通过Mn金属的参与可以将 (Cp2TiCl)2的使用当量减少至30%,然而依然要使用到大量的、特别昂贵的、高毒性的(Cp2TiCl)2金属配合物,而且操作复杂,分离困难,所以该方法也无法应用于工业化生产。
1.3 电化学合成方法
Maran与Vianello教授在1989年首次报道了电化学合成方法,该方法也被Rondinini与Daniel Little等人进一步发展,然而这些方法往往需要使用的到昂贵的甘汞电极、复杂的两极分离电解池和强酸性条件,所以该方法应用于工业化依然需要克服昂贵的电极、复杂的操作与对设备的腐蚀等问题(Tetrahedron Lett., 2001, 42, 7371–7374)。
综上所述,烯糖化合物在有机合成中扮演着非常重要角色,烯糖的合成虽引起了广大学者的兴趣,其合成方法也得到了不断的更新和完善,但是这些方法都还存在一些致命的缺点(如使用的试剂昂贵、危险性大、毒性较大、分离提纯困难等),这些缺点给烯糖工业化生产带来了严重困难。所以面临日益增长的对烯糖化合物市场需求,我们必须寻求一种绿色环保、成本低廉与分离简单的合成方法。
发明内容
本发明的目的就是提供一种反应产率高、操作简便、原料易得,具有较大市场需求的烯糖化合物的合成方法。
本发明的一种烯糖化合物的合成方法是,以酰基保护、硅烷基或烷氧基保护的糖(I)与三芳基或三烷基膦为原料,于室温条件下加入有机溶剂充分溶解,在20 ~ 60 ℃条件下反应2 ~ 36 小时,得到磷盐中间化合物(II),然后在碱性条件下水解,反应结束后萃取,收集有机相,溶剂旋干后重新溶解于甲苯、***或甲基叔丁基醚,过滤去除不溶物,旋干溶剂后经硅胶柱层析分离得到目标烯糖化合物(III);
其中式(I)、(II)和(III)中的R为Ar、CH3、(CH2)nCH3、C(CH3)3、(CH2)nAr、O(CH2)nCH3、OC(CH3)3、O(CH2)nAr的任意一种;R1~R10各自独立为H、D、(CH2)nR′、O(CH2)nR′、OCOR′、OSiR′3、(CH2)nO(CH2)mR′、COOR′、C(CH3)3、Ar、F、Cl、Br、I、O-glycosyl的任意一种,其中R′为H、CH3、(CH2)n(CH=CH)mCH3、(CH2)n(CH=CH)mAr、C(CH3)3、Ar、O-glycosyl中的一种;n、m为 0~10的数值。所述反应的反应式如下:
所述的有机溶剂为C1 ~ C4 的卤代烃或乙腈、四氢呋喃、苯、甲苯、DMF、二氧六环中的任意一种。
所述的有机溶剂的质量为,酰基保护、硅烷基或烷氧基保护的糖(I)质量的10 -50 倍。
所述的碱性条件为:NaOH、KOH、LiOH、CaOH、MgOH、K2CO3、Na2CO3、DABCO、DBU、三乙胺、叔丁醇钾、叔丁醇钠和乙醇钠的水溶液中的的一种或几种。
本发明与现有技术相比,其有益效果体现在:1、提供了一种无贵重金属等有剧毒试剂的参与的烯糖合成策略;2、首次实现磷盐水解的还原消除反应;3、首次实现了氘代烯糖化合物的合成;4、本发明方法不仅产率高,而且操作简便,底物适用性也广,解决了以前对于烯糖化合物的合成问题;5、本发明原料简单易得,反应适用范围广泛。
具体实施方式
实施例1: 3,5-二-O-苯甲酰基呋喃糖烯的制备
代表性的实施过程:室温下, 依次向反应瓶中加入1-乙酰氧基-2,3,5-三苯甲酰氧基-1-D-呋喃核糖化合物I-1 (0.925 g, 2 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-1,将反应液加入氢氧化钠水溶液,室温下水解30分钟;加入10 ml水,用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到3,5-二-O-苯甲酰基呋喃糖烯Ⅲ-10.5514 g, 反应总收率85%。
无色油状; yield (85%);1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J =7.3 Hz, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.45 (d, J = 7.7 Hz, 2H), 6.21 (d, J =5.8 Hz, 1H), 5.92 (d, 1H), 5.87 (d, J = 4.2 Hz, 1H), 5.23 (s, 1H), 4.42 (td,2H), 3.41 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 166.46 (C), 133.25 (2C),132.29 (2CH), 130.01 (C), 129.90 (C), 129.81 (4CH), 128.52 (3CH), 128.49(CH), 128.46 (CH), 109.57 (CH), 83.72 (CH), 65.93 (CH), 54.41 (CH2)。
实施例2: 2-甲基-3,5-二-O-苄基呋喃糖烯的制备
代表性的实施过程: 室温下, 依次向反应瓶中加入1-O-甲基-2,3,5-三苄基-2-C-甲基-alpha-D-呋喃核糖I-2 (0.897 g, 2 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-2,将反应液加入氢氧化钠水溶液,室温下水解30分钟;加入10 ml水,用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到3,5-二苄基-2-C-甲基-alpha-D-呋喃核糖烯III-2 0.552 g, 反应总收率89%。
黄色油状; yield (89%); 1H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.32(m, 10H), 6.28 (s, 1H), 4.64 – 4.56 (m, 4H), 4.49 (d, J = 12.3 Hz, 2H), 3.56(dd, J = 9.9, 6.4 Hz, 1H), 3.40 (dd, J = 9.9, 6.3 Hz, 1H), 1.72 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 144.29 (s, CH), 138.35 (d, J = 53.8 Hz, C),133.84 (d, J = 19.4 Hz, C), 128.48 (d, J = 5.2 Hz, 4CH), 127.91 (s, 2CH),127.82 (s, 2CH), 127.67 (s, 2CH), 109.91 (s, CH), 85.90 (s, CH), 84.48 (s,CH), 73.55 (s, CH2), 70.31 (s, CH2), 69.72 (s, CH2), 9.04 (s, CH3)。
实施例3:3,4,6-三-O-乙酰基-D-葡萄烯糖的制备
代表性的实施过程: 室温下, 依次向反应瓶中加入β-D-葡萄糖五乙酸酯化合物I-3 (0.781 g, 2 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-3,将反应液加入氢氧化钠水溶液,室温下水解30分钟;加入10 ml水,用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到3,4,6-三-O-乙酰基-D-葡萄烯糖III-3 0.4574 g, 反应总收率84%。
黄色油状; yield (84%); 1H NMR (400 MHz, Chloroform-d) δ 6.45 (d, J =6.1 Hz, 1H), 5.34 – 5.30 (m, 1H), 5.21 (dd, J = 7.5, 5.8 Hz, 1H), 4.83 (dd, J= 6.1, 3.2 Hz, 1H), 4.38 (dd, J = 12.0, 5.7 Hz, 1H), 4.26 – 4.21 (m, 1H),4.18 (dd, J = 12.0, 3.0 Hz, 1H), 2.08 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H); 13CNMR (101 MHz, Chloroform-d) δ 170.70 (C), 170.52 (C), 169.69 (C), 145.75(CH), 99.11 (CH), 74.07 (CH), 67.55 (CH), 67.31 (CH), 61.49 (CH2), 21.10(CH3), 20.90 (CH3), 20.83 (CH3).
实施例4:3,4,6-三-O-乙酰基-D-半乳烯糖的制备
代表性的实施过程: 室温下, 依次向反应瓶中加入β-D-半乳糖五乙酸酯化合物I-4 (0.781 g, 2 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-4,将反应液加入氢氧化钠水溶液,室温下水解30分钟;加入10 ml水,用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到3,4,6-三-O-乙酰基-D-半乳烯糖III-4 0.4574 g, 反应总收率86%。
黄色油状; yield (86%); 1H NMR (400 MHz, Chloroform-d) δ 6.46 (d, J =6.2 Hz, 1H), 5.55 (s, 1H), 5.43 (d, J = 4.3 Hz, 1H), 4.73 (d, J = 5.3 Hz,1H), 4.33 – 4.29 (m, 1H), 4.28 – 4.18 (m, 1H), 2.13 (s, 3H), 2.09 (s, 3H),2.03 (s, 3H); 13C NMR (101 MHz, Chloroform-d) δ 170.72 (C), 170.45 (C), 170.30(C), 145.57 (CH), 98.99 (CH), 72.95 (CH), 64.04 (CH), 63.90 (CH), 62.07(CH2), 20.96 (CH3), 20.91 (CH3), 20.81 (CH3)。
实施例5:3,4,6-三-O-苄基-D-己烯糖(氘代)的制备
代表性的实施过程: 室温下, 依次向反应瓶中加入1-乙酰基-2,3,4,6-四-O-苄基-D-吡喃葡萄糖化合物I-5 (1.165 g, 2 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-5,将反应液加入叔丁醇钾(0.4937 g, 4.4mmol),室温下水解15分钟;加入0.1 ml重水,蒸除二氯甲烷溶剂。用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到3,4,6-三-O-苄基-D-己烯糖III-5 0.7181 g, 反应总收率86%。
无色油状,1H NMR (400 MHz, Chloroform-d) δ 7.41 – 7.21 (m, 1H), 4.85(dd, J = 15.3, 6.7 Hz, 1H), 4.66 – 4.52 (m, 5H), 4.21 (dd, J = 5.9, 2.2 Hz,1H), 4.06 (dd, J = 7.1, 3.9 Hz, 1H), 3.90 – 3.74 (m, 3H). 13C NMR (101 MHz,Chloroform-d) δ 144.83 (CD), 138.45 (C), 138.28 (C), 138.09 (C), 128.52(3CH), 128.51 (2CH), 128.49 (2CH), 128.02 (2CH), 127.90 (2CH), 127.84 (2CH),127.76 (2CH), 99.85 (CH), 76.84 (CH), 75.81 (CH), 74.50 (CH), 73.86 (CH2),73.61 (CH2), 70.56 (CH2), 68.62 (CH2)。
实施例6: 六乙酰基-D-纤维二糖烯的制备
代表性的实施过程: 室温下, 依次向反应瓶中加入D-(+)-纤维二糖八乙酸酯化合物I-6(1.3572 g, 2 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-6,将反应液加入氢氧化钠水溶液,室温下水解30分钟;加入10 ml水,用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到六乙酰基-D-纤维二糖烯III-6 0.9865 g, 反应总收率88%。
黄色油状; 1H NMR (400 MHz, Chloroform-d) δ 6.40 (d, J = 6.0 Hz, 1H),5.41 ( 1H), 5.18 (t, J = 9.4 Hz, 1H), 5.08 (t, J = 9.6 Hz, 1H), 4.97 (t, J =8.7 Hz, 1H), 4.82 (dd, J = 6.0, 3.2 Hz, 1H), 4.68 (d, J = 7.9 Hz, 1H), 4.44(d, J = 11.3 Hz, 1H), 4.31 (dd, J = 12.3, 4.4 Hz, 1H), 4.21 – 4.11 (m, 2H),4.05 (d, J = 12.3 Hz, 1H), 3.98 (t, 1H), 3.67 (d, 1H), 2.13 – 1.98 (m, 18H).13C NMR (101 MHz, Chloroform-d) δ 170.79 (C), 170.56 (C), 170.41 (C), 170.08(C), 169.44 (C), 169.33 (C), 145.56 (CH), 100.67 (CH), 99.19 (CH), 74.79(CH), 74.46 (CH), 72.86 (CH), 72.13 (CH), 71.48 (CH), 68.73 (CH), 68.17 (CH),61.91 (CH2), 61.89 (CH2), 29.83 (CH3), 21.12 (CH3), 20.98 (CH3), 20.81 (CH3),20.70 (CH3), 20.68 (CH3)。
实施例7: 九乙酰基-D-麦芽三糖烯的制备
代表性的实施过程: 室温下, 依次向反应瓶中加入D-麦芽三糖化合物I-7(966mg, 1 mmol)和 10 ml 二氯甲烷,室温反应6小时。TLC跟踪反应进度,反应结束后得到中间体II-7,将反应液加入氢氧化钠水溶液,室温下水解30分钟;加入10 ml水,用乙酸乙酯萃取,收集有机相,用饱和食盐水洗涤、无水硫酸钠干燥;蒸除乙酸乙酯溶剂,其后经硅胶柱层析分离纯化得到九乙酰基-D-麦芽三糖烯III-7 725 mg, 反应总收率85%。
黄色油状; 1H NMR (400 MHz, Chloroform-d) δ 6.43 (d, J = 6.1 Hz, 1H),5.45 – 5.40 (m, 1H), 5.39 – 5.31 (m, 3H), 5.20 – 5.16 (m, 1H), 5.05 (t, J =9.9 Hz, 1H), 4.84 (dd, J = 10.5, 4.0 Hz, 1H), 4.79 (dd, J = 6.1, 3.3 Hz, 1H),4.68 (dd, J = 10.3, 4.0 Hz, 1H), 4.48 (dd, J = 12.3, 2.1 Hz, 1H), 4.37 (d, J= 4.5 Hz, 2H), 4.30 – 4.25 (m, 1H), 4.23 (dd, J = 12.5, 3.4 Hz, 1H), 4.17(dd, J = 12.3, 3.4 Hz, 1H), 4.06 – 4.02 (m, 1H), 4.01 (d, J = 2.0 Hz, 1H),3.99 (d, J = 9.7 Hz, 1H), 3.96 – 3.90 (m, 2H), 2.13 (s, 3H), 2.13 (s, 3H),2.07 (s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H), 1.99(s, 3H), 1.98 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 170.74 (C), 170.64(2C), 170.56 (C), 170.52 (2C), 169.97 (C), 169.85 (C), 169.56 (C), 145.78(CH), 98.67 (CH), 95.79 (CH), 95.76 (CH), 74.16 (CH), 72.80 (CH), 72.61 (CH),72.02 (CH), 70.99 (CH), 70.12 (CH), 69.89 (CH), 69.44 (CH), 68.76 (CH), 68.56(CH), 68.01 (CH), 62.46 (CH2), 62.10 (CH2), 61.46 (CH2), 21.19 (CH3), 21.03(CH3), 20.92 (2CH3), 20.77 (CH3), 20.69 (3CH3), 20.60 (CH3)。
Claims (4)
1.一种烯糖化合物的合成方法,其特征在于:所述的方法是以酰基保护、硅烷基或烷氧基保护的糖(I)与三芳基或三烷基膦为原料,于室温条件下加入有机溶剂充分溶解,在20 ~60℃条件下反应2 ~ 36 小时,得到磷盐中间化合物(II),然后在碱性条件下水解,反应结束后萃取,收集有机相,溶剂旋干后重新溶解于甲苯、***或甲基叔丁基醚,过滤去除不溶物,旋干溶剂后经硅胶柱层析分离得到目标烯糖化合物(III);
其中式(I)、(II)和(III)中的R为Ar、CH3、(CH2)nCH3、C(CH3)3、(CH2)nAr、O(CH2)nCH3、OC(CH3)3、O(CH2)nAr的任意一种;R1~R10各自独立为H、D、(CH2)nR′、O(CH2)nR′、OCOR′、OSiR′3、(CH2)nO(CH2)mR′、COOR′、C(CH3)3、Ar、F、Cl、Br、I、O-glycosyl的任意一种,其中R′为H、CH3、(CH2)n(CH=CH)mCH3、(CH2)n(CH=CH)mAr、C(CH3)3、Ar、O-glycosyl中的一种;n、m为 0~10的数值。
2.根据权利要求1 所述的一种烯糖化合物的合成方法,其特征在于:所述的有机溶剂为C1 ~ C4 的卤代烃或乙腈、四氢呋喃、苯、甲苯、DMF、二氧六环中的任意一种。
3.根据权利要求1 所述的一种烯糖化合物的合成方法,其特征在于:所述的有机溶剂的质量为酰基保护、硅烷基或烷氧基保护的糖质量的10~50 倍。
4.根据权利要求1 所述的一种烯糖化合物的合成方法,其特征在于:所述的碱性条件为:选自NaOH、KOH、LiOH、CaOH、MgOH、K2CO3、Na2CO3、DABCO、DBU、三乙胺、叔丁醇钾、叔丁醇钠、甲醇钠和乙醇钠的水溶液中的一种或几种。
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