JP7417930B2 - Method for producing sugar chains - Google Patents
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- 238000004519 manufacturing process Methods 0.000 title claims description 21
- 230000004913 activation Effects 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 239000000543 intermediate Substances 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 8
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 8
- 150000001768 cations Chemical class 0.000 claims description 8
- 150000002772 monosaccharides Chemical class 0.000 claims description 8
- -1 pivaloyloxy group Chemical group 0.000 claims description 8
- 238000009825 accumulation Methods 0.000 claims description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- YNJQKNVVBBIPBA-UHFFFAOYSA-M tetrabutylazanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCCC[N+](CCCC)(CCCC)CCCC YNJQKNVVBBIPBA-UHFFFAOYSA-M 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000005543 phthalimide group Chemical group 0.000 claims description 4
- PUZYNDBTWXJXKN-UHFFFAOYSA-M tetraethylazanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CC[N+](CC)(CC)CC PUZYNDBTWXJXKN-UHFFFAOYSA-M 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
- 229910052711 selenium Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 229910052714 tellurium Inorganic materials 0.000 claims description 3
- IGVWFPZXBUTUCG-UHFFFAOYSA-M tetrapropylazanium;trifluoromethanesulfonate Chemical compound [O-]S(=O)(=O)C(F)(F)F.CCC[N+](CCC)(CCC)CCC IGVWFPZXBUTUCG-UHFFFAOYSA-M 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- 239000000126 substance Substances 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 10
- 229920001542 oligosaccharide Polymers 0.000 description 10
- 150000002482 oligosaccharides Chemical class 0.000 description 10
- 238000001228 spectrum Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000007806 chemical reaction intermediate Substances 0.000 description 7
- 229930182475 S-glycoside Natural products 0.000 description 6
- 150000002016 disaccharides Chemical class 0.000 description 6
- 150000004044 tetrasaccharides Chemical class 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 6
- 150000004043 trisaccharides Chemical class 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 150000003569 thioglycosides Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 3
- 230000005611 electricity Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000006116 polymerization reaction Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 238000009739 binding Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005227 gel permeation chromatography Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000001279 glycosylating effect Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- Saccharide Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Description
本発明は、糖鎖の製造方法に関する。 The present invention relates to a method for producing sugar chains.
栄養補助食品（サプリメント）、医薬および農薬等に関する分野を中心に、オリゴ糖の立体選択性の高い合成方法が望まれている。
例えば、特許文献１、非特許文献１および非特許文献２には、電解液中で、電気化学的に糖供与体を酸化してグリコシル化反応を行うことを含む、オリゴ糖の製造方法が記載されている。具体的には、これらの文献に記載の方法は、テトラブチルアンモニウムトリフラート（Ｂｕ4ＮＯＴｆ）の存在下で、糖供与体を低温電解酸化することにより、グリコシル化反応の重要な中間体としてグリコシルトリフラートを生成および蓄積する。その後、その中間体と糖受容体をグリコシル化し、グリコシル化して得たオリゴ糖の前駆体を脱保護することを含む。そして、このような方法によれば、高い立体選択性でオリゴ糖を製造でき、さらに、自動合成にも有用である旨記載されている。
A method for synthesizing oligosaccharides with high stereoselectivity is desired, mainly in the fields of nutritional supplements, medicines, agricultural chemicals, etc.
For example, Patent Document 1, Non-Patent Document 1, and Non-Patent Document 2 describe a method for producing oligosaccharides, which includes performing a glycosylation reaction by electrochemically oxidizing a sugar donor in an electrolytic solution. has been done. Specifically, the methods described in these documents utilize low-temperature electrolytic oxidation of sugar donors in the presence of tetrabutylammonium triflate (Bu 4 NOTf) to produce glycosyl triflate as an important intermediate in the glycosylation reaction. generate and accumulate. Thereafter, the intermediate and the sugar acceptor are glycosylated, and the oligosaccharide precursor obtained by glycosylation is deprotected. It is also described that, according to such a method, oligosaccharides can be produced with high stereoselectivity, and furthermore, it is useful for automatic synthesis.
上述の方法により、液相法によるオリゴ糖の合成において、立体選択されたオリゴ糖の収率が向上した。しかし、これらの従来技術では、活性化させた反応中間体を蓄積させた後、結合形成をする方法を採用している（例えば、特許文献１の段落００５３、００５６参照）。したがって、反応中間体の蓄積を待たなければならならず、反応に要する時間は長くなる。
そこで本発明は、糖鎖の製造方法において、活性化させた反応中間体の蓄積を待たずに、前記反応中間体と糖受容体とを連続的にグリコシル化することで、反応時間を短縮することを目的とする。
The above method improved the yield of stereoselected oligosaccharides in the synthesis of oligosaccharides by a liquid phase method. However, these conventional techniques employ a method in which bond formation is performed after accumulating activated reaction intermediates (see, for example, paragraphs 0053 and 0056 of Patent Document 1). Therefore, it is necessary to wait for the accumulation of reaction intermediates, and the time required for the reaction becomes longer.
Therefore, in the method for producing sugar chains, the present invention shortens the reaction time by continuously glycosylating the reaction intermediate and the sugar acceptor without waiting for the accumulation of the activated reaction intermediate. The purpose is to
上記の課題は、以下の手段により解決された。
〔１〕式（１）で表される６単糖のうち１種類を選定し、これを活性化して－Ｘの部位が解離した式（２）で表される中間体カチオンあるいはその等価体を生成させ、同時に、式（２）で表される中間体カチオンのカチオン部位と、前記と同種の式（１）で表される６単糖のヒドロキシ基の部位とを結合させる工程を含む、糖鎖の製造方法。
〔２〕前記活性化が電気化学的な活性化である、〔１〕に記載の糖鎖の製造方法。
〔３〕前記電気化学的な活性化が、テトラブチルアンモニウムトリフラート、テトラエチルアンモニウムトリフラート、およびテトラプロピルアンモニウムトリフラートの少なくとも１種の存在下で行われる、〔２〕に記載の糖鎖の製造方法。
〔４〕前記電気化学的な活性化において、陽極側に上記式（１）で表される６単糖を添加し、陰極側に酸を添加する〔２〕または〔３〕に記載の糖鎖の製造方法。
〔５〕前記活性化が、－１２０℃～－４０℃の範囲で行われる、〔１〕～〔４〕のいずれか１つに記載の糖鎖の製造方法。
〔６〕Ｒ2およびＲ3の少なくとも一方は立体障害性基である、〔１〕～〔５〕のいずれか１つに記載の糖鎖の製造方法。
〔７〕合成される糖鎖が下記の式（ａ）または（ｂ）で表される、〔１〕～〔６〕のいずれか１つに記載の糖鎖の製造方法。
[1] Select one of the six monosaccharides represented by formula (1) and activate it to form an intermediate cation represented by formula (2) in which the -X moiety is dissociated or its equivalent. a saccharide comprising the step of simultaneously bonding the cation site of the intermediate cation represented by formula (2) with the hydroxy group site of the hexamonosaccharide represented by formula (1) of the same kind as above. How to make chains.
[2] The method for producing a sugar chain according to [1], wherein the activation is electrochemical activation.
[3] The method for producing a sugar chain according to [2], wherein the electrochemical activation is performed in the presence of at least one of tetrabutylammonium triflate, tetraethylammonium triflate, and tetrapropylammonium triflate.
[4] The sugar chain according to [2] or [3], wherein in the electrochemical activation, a hexasaccharide represented by the above formula (1) is added to the anode side, and an acid is added to the cathode side. manufacturing method.
[5] The method for producing a sugar chain according to any one of [1] to [4], wherein the activation is performed at a temperature in the range of -120°C to -40°C.
[6] The method for producing a sugar chain according to any one of [1] to [5], wherein at least one of R 2 and R 3 is a sterically hindered group.
[7] The method for producing a sugar chain according to any one of [1] to [6], wherein the sugar chain to be synthesized is represented by the following formula (a) or (b).
本発明の製造方法により、糖鎖の製造方法において、活性化させた反応中間体の蓄積を待たずに、前記反応中間体と糖受容体とを連続的にグリコシル化することで、反応時間を短縮することができる。 According to the production method of the present invention, in the production method of sugar chains, the reaction intermediate and the sugar acceptor are continuously glycosylated without waiting for the accumulation of the activated reaction intermediate, thereby reducing the reaction time. Can be shortened.
以下、本発明の主要な実施形態について説明する。しかしながら、本発明は、明示した実施形態に限られるものではない。 Main embodiments of the present invention will be described below. However, the invention is not limited to the illustrated embodiments.
本明細書において「～」という記号を用いて表される数値範囲は、「～」の前後に記載される数値をそれぞれ下限値および上限値として含む範囲を意味する。 In this specification, a numerical range expressed using the symbol "~" means a range that includes the numerical values written before and after "~" as the lower limit and upper limit, respectively.
本明細書において「工程」との語は、独立した工程だけではなく、その工程の所期の作用が達成できる限りにおいて、他の工程と明確に区別できない工程も含む意味である。 As used herein, the term "step" includes not only independent steps but also steps that cannot be clearly distinguished from other steps as long as the intended effect of the step can be achieved.
本明細書における基（原子団）の表記について、置換および無置換を記していない表記は、置換基を有しないものと共に、置換基を有するものをも包含する意味である。例えば、単に「アルキル基」と記載した場合には、これは、置換基を有しないアルキル基（無置換アルキル基）、および、置換基を有するアルキル基（置換アルキル基）の両方を包含する意味である。また、単に「アルキル基」と記載した場合には、これは、鎖状でも環状でもよく、鎖状の場合には、直鎖でも分岐でもよい意味である。これらのことは、「アルケニル基」、「アルキレン基」および「アルケニレン基」についても同義とする。 Regarding the notation of groups (atomic groups) in this specification, the notation that does not indicate substituted or unsubstituted is meant to include not only those without a substituent but also those with a substituent. For example, when simply stating "alkyl group", this means that it includes both an alkyl group without a substituent (unsubstituted alkyl group) and an alkyl group with a substituent (substituted alkyl group). It is. Moreover, when simply described as an "alkyl group", this means that it may be chain-like or cyclic, and in the case of chain-like, it may be linear or branched. These terms also apply to "alkenyl group," "alkylene group," and "alkenylene group."
本明細書において、Ａｒはアリール基を、Ｂｕはブチル基を、Ｐｈはフェニル基を、Ｍｅはメチル基を、Ｅｔはエチル基を、ＴｆＯまたはＯＴｆはトリフラート基を、Ｂｎはベンジル基を、Ｂｚはベンゾイル基を、Ａｃはアセチル基を、Ｐｈｔｈはフタロイル基を、ＰｈｔｈＮはフタルイミド基を、ＭＯＭはメトキシメチル基をそれぞれ示している。 In the present specification, Ar represents an aryl group, Bu represents a butyl group, Ph represents a phenyl group, Me represents a methyl group, Et represents an ethyl group, TfO or OTf represents a triflate group, Bn represents a benzyl group, Bz represents a benzoyl group, Ac represents an acetyl group, Phth represents a phthaloyl group, PhthN represents a phthalimide group, and MOM represents a methoxymethyl group.
本発明の糖鎖の製造方法においては、下記式（１）で表される６単糖のうち１種類を選定する。
Ｒxはパラクロロフェニル基、パラフルオロフェニル基、パラメチルフェニル基、フェニル基、炭素数１～６のアルキル基、あるいはヘテロアリール基である。
Ｒ1はベンゾイルオキシ基、アセトキシ基、ベンジルオキシ基あるいはメトキシ基である。
Ｒ2はベンゾイルオキシ基、アセトキシ基、ベンジルオキシ基、メトキシ基あるいは水素である。Ｒ3はベンゾイルオキシ基、アセトキシ基、ピバロイルオキシ基、またはフタルイミド基である。Ｒ2とＲ3はＯＨと反応しない基であることが好ましい。Ｒ2とＲ3の一方は、立体障害基が好ましい。
２つのＲ1、Ｒ2、Ｒ3のいずれか一つはヒドロキシ基またはヒドロキシ基を含む基であり、なかでも、２つのＲ1のいずれか一つがヒドロキシ基またはヒドロキシ基を含む基である態様が好ましく、２つのＲ1のいずれか一つがヒドロキシ基である態様がより好ましい。ここでのヒドロキシ基を含む基としては、ヒドロキシアルキル基（炭素数１～１２が好ましく、１～６がより好ましく、１～３がさらに好ましい）等が挙げられる。
In the method for producing a sugar chain of the present invention, one type is selected from among the six monosaccharides represented by the following formula (1).
R x is a parachlorophenyl group, a parafluorophenyl group, a paramethylphenyl group, a phenyl group, an alkyl group having 1 to 6 carbon atoms, or a heteroaryl group.
R 1 is a benzoyloxy group, an acetoxy group, a benzyloxy group or a methoxy group.
R 2 is benzoyloxy, acetoxy, benzyloxy, methoxy, or hydrogen. R 3 is a benzoyloxy group, an acetoxy group, a pivaloyloxy group, or a phthalimide group. Preferably, R 2 and R 3 are groups that do not react with OH. One of R 2 and R 3 is preferably a sterically hindering group.
Any one of the two R 1 , R 2 , and R 3 is a hydroxy group or a group containing a hydroxy group, and in particular, an embodiment in which any one of the two R 1 is a hydroxy group or a group containing a hydroxy group. is preferable, and an embodiment in which any one of the two R 1 is a hydroxy group is more preferable. Examples of the group containing a hydroxy group include a hydroxyalkyl group (preferably having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 3 carbon atoms).
本発明においては、６単糖のうち１種類を選定する。このように同種の単糖を用いることにより、活性化と結合反応とを同時に進行させても適切な糖鎖が合成できる。また、特に単糖はＸの部位が多糖に比べ格段に活性化されやすく、選択的に活性化される。一方、他の種類の６単糖が混在すると、所望のグルコシル化反応が進行しないことが懸念される。この理由としては、同種の化合物を選定しない場合、６単糖化合物の立体的な障害等により所望の重合反応が進行しないことが推定される。また、基質として１種類のものを選定する理由として、他の種類の６単糖が混在すると生成するオリゴ糖の精製が極めて困難になることが挙げられる。精製が極めて困難になれば、得られたオリゴ糖は混合物としてでしか使うことができず、商品としての価値も著しく損なわれる。また、以下の立体障害性基の利用も難しくなる。ここで他種の６単糖として、グルコースに対する、ガラクトースやグルコサミンが挙げられる。つまり、６単糖の母核に置換する置換基が異なる場合、特には極性のある置換基や立体障害性のある置換基を有するものは他種に該当する。換言すると、同種の６単糖とは、母核となる６員環が同一であることはもとより、置換基においても一致していることが好ましく、相違があっても比較的小さく非極性の置換基の範囲（例えば炭素数１～６のアルキル基、好ましくは炭素数１～３のアルキル基）の範囲であることが求められる。なお、本明細書において「立体障害性基」とは、その基の存在で立体的な制約を受け、反応により目的の化合物を得たり、逆に得られなくなったりする置換基である。炭素原子を含む置換基としていうと、立体障害性基の定義として炭素原子数４以上であることが好ましく、５以上であることがより好ましく、７以上であることがより好ましい。上限は特にないが、５０以下であることが実際的である。 In the present invention, one type of monosaccharide is selected from among the six monosaccharides. By using monosaccharides of the same type in this way, an appropriate sugar chain can be synthesized even if the activation and binding reactions proceed simultaneously. Furthermore, in particular, the X site of monosaccharides is much more easily activated than that of polysaccharides, and is selectively activated. On the other hand, if other types of hexasaccharides are present, there is a concern that the desired glucosylation reaction may not proceed. The reason for this is presumed to be that if similar compounds are not selected, the desired polymerization reaction will not proceed due to steric hindrance of the hexasaccharide compound. Further, one reason why one type of substrate is selected is that if other types of hexasaccharides are mixed, it becomes extremely difficult to purify the produced oligosaccharide. If purification becomes extremely difficult, the resulting oligosaccharides can only be used as a mixture, and their commercial value will be significantly reduced. Furthermore, it becomes difficult to utilize the following sterically hindering groups. Here, examples of other types of hexasaccharides include galactose and glucosamine in contrast to glucose. In other words, when the substituents substituted on the hexasaccharide mother nucleus are different, in particular those having polar substituents or sterically hindered substituents fall under the category of different types. In other words, it is preferable that the same 6-monosaccharides have the same 6-membered mother ring, but also the same substituents, and even if there is a difference, it is a relatively small and non-polar substitution. The range of the group (for example, an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 3 carbon atoms) is required. In this specification, the term "sterically hindering group" refers to a substituent that is subject to steric constraints due to the presence of the group, and may or may not be able to obtain the desired compound through reaction. In terms of a substituent containing carbon atoms, the definition of a sterically hindering group preferably includes 4 or more carbon atoms, more preferably 5 or more carbon atoms, and even more preferably 7 or more carbon atoms. Although there is no particular upper limit, it is practical that it is 50 or less.
次に、活性化と結合反応とを同時に進行させるときの「同時に」の定義を確認する。本明細書において「同時に」とは、逐次に反応することを除外する意味であり、典型的には従来例のように中間体の蓄積を待って、次の反応に進むような態様を除外する意味である。換言すると、「同時に」とは、中間体の蓄積を待つ必要がなく、同一の反応場（反応溶媒等）で所望の反応が滞りなく完結することを意味する。具体的な時間でいうと、反応の間隔が１０秒以下であることが好ましく、２秒以下であることがより好ましく、０．１秒以下であることがさらに好ましい。 Next, we will confirm the definition of "simultaneously" when activation and binding reaction proceed simultaneously. In this specification, "simultaneously" means to exclude sequential reactions, and typically excludes a mode in which the reaction proceeds to the next reaction after waiting for the accumulation of intermediates as in conventional examples. It is the meaning. In other words, "simultaneously" means that the desired reaction is completed without delay in the same reaction site (reaction solvent, etc.) without having to wait for the accumulation of intermediates. In terms of specific time, the reaction interval is preferably 10 seconds or less, more preferably 2 seconds or less, and even more preferably 0.1 seconds or less.
本発明の糖鎖の製造方法においては、上記で選定された１種類の６単糖を活性化して－Ｘの部位が解離した式（２）で表される中間体カチオンあるいはその等価体を生成させる。
式（２）中のＲ1～Ｒ3は式（１）と同義である。 R 1 to R 3 in formula (2) have the same meanings as in formula (1).
本発明において、中間体カチオンの等価体とは、グリコシルトリフラートあるいはグリコシルスルホニウムイオンを指すものとする。 In the present invention, the equivalent of the intermediate cation refers to glycosyl triflate or glycosylsulfonium ion.
本発明において活性化の手法は特に限定されず、直接的が好ましいが、間接的（特定の物質を活性化させ、その活性化した物質が糖を活性化させる）であってもよい。また、試薬等による活性化であってもよい。このときの条件は、所定の化合物の存在下で陽極酸化する態様が挙げられる。 In the present invention, the activation method is not particularly limited, and is preferably direct, but may also be indirect (activating a specific substance, and the activated substance activating sugar). Alternatively, activation may be performed using a reagent or the like. The conditions at this time include an embodiment in which anodic oxidation is performed in the presence of a predetermined compound.
ここで、本発明の製造方法の各ステップ（工程）について、図面を参照しながら一例を示す。ただし、これにより本発明が狭く解されるものではない。 Here, an example of each step (process) of the manufacturing method of the present invention will be shown with reference to the drawings. However, this does not mean that the present invention is narrowly interpreted.
まず、陽極側に基質となる式（１）で表される６単糖、好ましくはチオグリコシド化合物を添加する。（図１のステップＳ１）参照。 First, a hexamonosaccharide represented by formula (1), preferably a thioglycoside compound, serving as a substrate is added to the anode side. (See step S1 in FIG. 1).
本発明においては中でも、両極において、テトラアルキルアンモニウムトリフラート（例えばテトラブチルアンモニウムトリフラート（Ｂｕ4ＮＯＴｆ）、テトラエチルアンモニウムトリフラート（Ｅｔ4ＮＯＴｆ））、およびテトラプロピルアンモニウムトリフラート（Ｐｒ4ＮＯＴｆ）の少なくとも１種の存在下で活性化が行われることが好ましい。テトラアルキルアンモニウムトリフラートの添加量は適宜調節すればよいが、両極合計で、チオグリコシドに対してモル比で０．２以上であることが好ましく、０．５以上であることがより好ましく、０．８以上であることがさらに好ましい。上限は特にないが５以下であることが実際的である（ステップＳ２を参照）。 In the present invention, at least one of tetraalkylammonium triflate (for example, tetrabutylammonium triflate (Bu 4 NOTf), tetraethylammonium triflate (Et 4 NOTf)) and tetrapropylammonium triflate (Pr 4 NOTf) is used at both electrodes. Preferably, activation is carried out in the presence of. The amount of tetraalkylammonium triflate added may be adjusted as appropriate, but the total molar ratio of the two poles to the thioglycoside is preferably 0.2 or more, more preferably 0.5 or more, and 0. More preferably, it is 8 or more. Although there is no particular upper limit, it is practical to set it to 5 or less (see step S2).
化学的に活性化するときの溶媒は適宜選定されればよいが、例えば、ジクロロメタンが挙げられる（ステップ３）。 The solvent for chemical activation may be selected as appropriate, and for example, dichloromethane may be used (step 3).
陰極には酸（特にはＴｆＯＨ（トリフルオロメタンスルホン酸））を添加することが好ましい。酸の添加量は、式（１）で表される６単糖に対して、化学量論量（モル比）で、０．２以上であることが好ましく、０．５以上であることがより好ましく、０．８以上であることがさらに好ましい。上限は特にないが５以下であることが実際的である（ステップＳ４を参照）。 It is preferable to add an acid (particularly TfOH (trifluoromethanesulfonic acid)) to the cathode. The amount of acid added is preferably 0.2 or more, more preferably 0.5 or more in stoichiometric amount (molar ratio) with respect to the six monosaccharides represented by formula (1). It is preferably 0.8 or more, and more preferably 0.8 or more. Although there is no particular upper limit, it is practical to set it to 5 or less (see step S4).
電気化学的に活性化するときの温度は適宜選定されればよいが、－４０℃以下であることが好ましく、－６０℃以下であることがより好ましく、－７０℃以下であることがさらに好ましい。下限値は特に制限されないが、－１２０℃以上であることが実際的である（図１、ステップＳ５参照）。
電気化学的な活性化としては、上記のように、直接的に行うことが好ましいが、間接的であってもよい。電気化学的な活性化において印加する電気は直流であることが好ましい。通電する条件としては、２ｍＡ以上であることが好ましく、４ｍＡ以上であることがより好ましく、５ｍＡ以上であることがさらに好ましい。上限は特にないが、５０ｍＡ以下であることが実際的である。
The temperature during electrochemical activation may be selected as appropriate, but is preferably -40°C or lower, more preferably -60°C or lower, and even more preferably -70°C or lower. . Although the lower limit is not particularly limited, it is practical to set it to -120°C or higher (see step S5 in FIG. 1).
Although electrochemical activation is preferably performed directly as described above, it may be performed indirectly. The electricity applied during electrochemical activation is preferably direct current. The conditions for applying current are preferably 2 mA or more, more preferably 4 mA or more, and even more preferably 5 mA or more. Although there is no particular upper limit, it is practical that it is 50 mA or less.
反応の停止は常法によればよいが、例えば、昇温の後、アミン化合物（トリエチルアミン等）を添加して反応を停止する態様が挙げられる（図１、ステップＳ６，Ｓ７参照）。このときの温度は特に限定されないが、反応時の温度より１０℃以上高いことが好ましく、２０℃以上高いことがより好ましく、２５℃以上高いことが特に好ましい。上限は特にないが、常温にまで昇温する態様が挙げられる。
得られた生成物の処理も常法によればよいが、例えば、室温に昇温し水洗浄した後、乾燥する態様が挙げられる（図１、ステップＳ８参照）。
The reaction may be stopped by a conventional method, but for example, after raising the temperature, an amine compound (such as triethylamine) is added to stop the reaction (see Steps S6 and S7 in FIG. 1). The temperature at this time is not particularly limited, but is preferably 10°C or more higher than the temperature during the reaction, more preferably 20°C or more, and particularly preferably 25°C or more higher. Although there is no particular upper limit, examples include a mode in which the temperature is raised to room temperature.
The obtained product may be treated by a conventional method, but for example, it may be heated to room temperature, washed with water, and then dried (see step S8 in FIG. 1).
合成される糖鎖は特に限定されないが、下記の式（ａ）または（ｂ）で表される糖鎖であることが好ましい。
本発明の好ましい実施形態においては、下記のような利点および特徴がある。
１．反応時間が大幅に短縮される（脱保護工程や結合形成時間の確保が不要）
２．反応中間体の蓄積が不要（極低温は必ずしも必要としない）
３．末端の置換基（Ｘ）は選択的に活性化が可能
Preferred embodiments of the invention have the following advantages and features.
1. Reaction time is significantly shortened (no need for deprotection step or bond formation time)
2. No accumulation of reaction intermediates (cryogenic temperatures are not necessarily required)
3. Terminal substituent (X) can be selectively activated
以下に実施例を挙げて本発明をさらに具体的に説明する。以下の実施例に示す材料、使用量、割合、処理内容、処理手順等は、本発明の趣旨を逸脱しない限り、適宜、変更することができる。従って、本発明の範囲は以下に示す具体例に限定されるものではない。
実施例で用いた測定機器等が廃番等により入手困難な場合、他の同等の性能を有する機器を用いて測定することができる。
The present invention will be explained in more detail with reference to Examples below. The materials, usage amounts, ratios, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention is not limited to the specific examples shown below.
If the measuring equipment used in the examples is difficult to obtain due to discontinuation or the like, measurements can be made using other equipment with equivalent performance.
実施例１
グルコサミン由来のチオグリコシド（下記式（Ａ））を用い、下記式のとおり電解重合によりオリゴ糖を合成した。
Using glucosamine-derived thioglycoside (formula (A) below), oligosaccharides were synthesized by electrolytic polymerization as shown in the following formula.
ガラス隔膜付き電解セルの陽極側に上記式（Ａ）のチオグリコシド（１０９ｍｇ，０．２０ｍｍｏｌ）、両極にＢｕ4ＮＯＴｆ（テトラブチルアンモニウムトリフラート）（３９３ｍｇ，１．０ｍｍｏｌ）を加え、減圧乾燥、Ａｒ置換後、両極にジクロロメタン（塩化メチレン）を１０ｍＬずつ加えた。陰極にはＴｆＯＨ（トリフルオロメタンスルホン酸）（１８μＬ，０．２０ｍｍｏｌ）を加えた。続いて、低温バスにて電解セルを－７０℃に冷却し、電解酸化（通電条件：８ｍＡ，２１ｍｉｎ，０．５２Ｆ／ｍｏｌ）を行った。通電終了後－３０℃まで昇温し、さらに１時間撹拌した。その後トリエチルアミン（０．３ｍＬ）を両極に加えて反応を停止し、室温まで昇温した。反応混合物を濃縮後、酢酸エチルにて希釈した上で分液ロートを用いて水洗浄を行った。得られた有機相に乾燥剤（Ｎａ2ＳＯ4）を加え脱水を行った。ろ過により乾燥剤を除去した後、減圧濃縮を行い、さらに真空乾燥を行った。得られた粗生成物（１４０ｍｇ）に対してＭＡＬＤＩ－ＴＯＦ－ＭＳ分析を行ったのち、ゲル浸透クロマトグラフィー（溶媒：クロロホルム）にて単離精製を行った。単離生成物に対して1ＨＮＭＲ測定、ＭＡＬＤＩ－ＴＯＦ－ＭＳ測定を行い、収量はそれぞれ二糖（３０ｍｇ，３１％収率）、三糖（２３ｍｇ，２４％）、四糖（８．３ｍｇ，９％）、五糖（４．１ｍｇ，５％）、六糖（１．５ｍｇ，２％）であった。 Thioglycoside of the above formula (A) (109 mg, 0.20 mmol) was added to the anode side of an electrolytic cell with a glass diaphragm, and Bu 4 NOTf (tetrabutylammonium triflate) (393 mg, 1.0 mmol) was added to both electrodes, dried under reduced pressure, and Ar. After the substitution, 10 mL of dichloromethane (methylene chloride) was added to both electrodes. TfOH (trifluoromethanesulfonic acid) (18 μL, 0.20 mmol) was added to the cathode. Subsequently, the electrolytic cell was cooled to −70° C. in a low-temperature bath, and electrolytic oxidation (current conditions: 8 mA, 21 min, 0.52 F/mol) was performed. After the electricity was turned off, the temperature was raised to -30°C, and the mixture was further stirred for 1 hour. Thereafter, triethylamine (0.3 mL) was added to both electrodes to stop the reaction, and the temperature was raised to room temperature. After concentrating the reaction mixture, it was diluted with ethyl acetate and washed with water using a separating funnel. A desiccant (Na 2 SO 4 ) was added to the obtained organic phase to perform dehydration. After removing the desiccant by filtration, concentration under reduced pressure was performed, and further vacuum drying was performed. The obtained crude product (140 mg) was subjected to MALDI-TOF-MS analysis, and then isolated and purified by gel permeation chromatography (solvent: chloroform). The isolated product was subjected to 1 HNMR measurement and MALDI-TOF-MS measurement, and the yields were respectively disaccharide (30 mg, 31% yield), trisaccharide (23 mg, 24%), and tetrasaccharide (8.3 mg, 9%), pentasaccharide (4.1 mg, 5%), and hexasaccharide (1.5 mg, 2%).
二糖の構造式
以下に、上記二糖について実施したＮＭＲ測定の結果とＭＳスペクトルの結果とを示す。 Below, the results of NMR measurement and MS spectrum performed on the above disaccharide are shown.
TLC (hexane/EtOAc 1:2): Rf 0.73
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.83 (m, 4 H), 7.71 (m, 4 H), 7.33 (m, 5 H), 7.29 (m, 4 H), 7.22 (d, J = 6.9 Hz, 2 H), 6.82 (pseudo-t , J = 8.6 Hz, 2 H), 5.67 (dd, J = 10.0, 8.9 Hz, 1 H), 5.57 (dd, J = 10.6, 8.9 Hz, 1 H), 5.50 (d, J = 10.6 Hz, 1 H), 5.45 (d, J = 8.4 Hz, 1 H), 4.54 (d, J = 11.8 Hz, 1 H), 4.49 (d, J = 11.8 Hz, 1 H), 4.37 (d, J = 11.8 Hz, 1 H), 4.32 (d, J = 11.8 Hz, 1H), 4.15 (pseudo-t, J = 10.3 Hz, 1 H), 4.11 (dd, J = 10.7, 8.3 Hz, 1 H), 4.03 (pseudo-t, J = 9.2 Hz, 1 H), 3.81 (td, J = 9.2, 3.2 Hz, 1 H), 3.75 (dd, J = 10.0, 4.0 Hz, 1 H), 3.66 (dd, J = 10.0, 4.9 Hz, 1 H), 3.52 (dd, J = 9.8, 2.3 Hz, 2 H), 3.43-3.49 (m, 2 H),
2.98 (s, 1 H), 1.88 (s, 3 H), 1.82 (s, 3 H).
MS (MALDI) m/z calcd for C52H47FN2KO14S [M+K]+, 1013; found 1013.
TLC (hexane/EtOAc 1:2): Rf 0.73
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.83 (m, 4 H), 7.71 (m, 4 H), 7.33 (m, 5 H), 7.29 (m, 4 H), 7.22 (d, J = 6.9 Hz, 2 H), 6.82 (pseudo-t , J = 8.6 Hz, 2 H), 5.67 (dd, J = 10.0, 8.9 Hz, 1 H), 5.57 (dd, J = 10.6, 8.9 Hz, 1 H), 5.50 (d, J = 10.6 Hz, 1 H), 5.45 (d, J = 8.4 Hz, 1 H), 4.54 (d, J = 11.8 Hz, 1 H), 4.49 (d, J = 11.8 Hz, 1 H), 4.37 (d, J = 11.8 Hz , 1 H), 4.32 (d, J = 11.8 Hz, 1H), 4.15 (pseudo-t, J = 10.3 Hz, 1 H), 4.11 (dd, J = 10.7, 8.3 Hz, 1 H), 4.03 (pseudo -t, J = 9.2 Hz, 1 H), 3.81 (td, J = 9.2, 3.2 Hz, 1 H), 3.75 (dd, J = 10.0, 4.0 Hz, 1 H), 3.66 (dd, J = 10.0, 4.9 Hz, 1 H), 3.52 (dd, J = 9.8, 2.3 Hz, 2 H), 3.43-3.49 (m, 2 H),
2.98 (s, 1 H), 1.88 (s, 3 H), 1.82 (s, 3 H).
MS (MALDI) m/z calcd for C 52 H 47 FN 2 KO 14 S [M+K] + , 1013; found 1013.
三糖の構造式
以下に、上記三糖について実施したＮＭＲ測定の結果とＭＳスペクトルの結果とを示す。 Below, the results of NMR measurement and MS spectrum performed on the above trisaccharide are shown.
TLC (hexane/EtOAc 1:2): Rf 0.60
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.81 (m, 6 H), 7.71 (m, 6 H), 7.33 (m, 5 H), 7.29 (m, 5 H), 7.22 (pseudo-t, J = 7.92 Hz, 5 H), 7.14 (pseudo-t, J = 7.8 Hz, 2 H), 7.01 (pseudo-t, J = 7.3 Hz, 1 H), 6.82 (pseudo-t, J = 8.6 Hz, 2 H), 5.58 (pseudo-t, J = 9.4 Hz, 1 H), 5.54 (td, J = 10.6, 1.6 Hz, 1 H), 5.51 (td, J = 10.6, 1.6 Hz, 1 H), 5.46 (d, J = 10.5 Hz, 1 H), 5.38 (d, J = 8.3 Hz, 1 H), 5.27 (d, J = 8.4 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.47 (d, J = 11.8 Hz, 1 H), 4.43 (d, J = 11.8 Hz, 1 H), 4.42 (d, J = 11.6 Hz, 1 H), 4.38 (d, J = 11.7 Hz, 1 H), 4.31 (d, J = 11.6 Hz, 1 H), 4.14 (m, 2 H), 4.07 (dd, J = 10.7, 8.3 Hz, 1 H), 4.02 (dd, J = 10.4, 8.2 Hz, 1 H), 3.98 (d, J = 9.4 Hz, 1 H), 3.79 (td, J = 9.2, 3.2 Hz, 1 H), 3.72 (dd, J = 9.9, 4.0 Hz, 1 H), 3.63 (dd, J = 9.9, 4.9 Hz, 1 H), 3.54 (d, J = 10.4 Hz, 1 H), 3.46 (dd, J = 10.7, 3.7 Hz, 1 H), 3.43 (d, J = 10.9 Hz, 2 H), 3.30 (dd, J = 11.2, 3.5 Hz, 1 H), 3.27 (dd, J = 9.2, 4.4 Hz, 1 H), 3.10 (d, J = 8.8 Hz, 1 H), 2.88 (d, J = 3.3 Hz, 1 H), 1.80 (s, 3 H), 1.71 (s, 3 H), 1.63 (s, 3 H).
MS (MALDI) m/z calcd for C75H68FN3KO21S [M+K]+, 1436; found 1436.
TLC (hexane/EtOAc 1:2): Rf 0.60
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.81 (m, 6 H), 7.71 (m, 6 H), 7.33 (m, 5 H), 7.29 (m, 5 H), 7.22 (pseudo-t, J = 7.92 Hz, 5 H), 7.14 (pseudo -t, J = 7.8 Hz, 2 H), 7.01 (pseudo-t, J = 7.3 Hz, 1 H), 6.82 (pseudo-t, J = 8.6 Hz, 2 H), 5.58 (pseudo-t, J = 9.4 Hz, 1 H), 5.54 (td, J = 10.6, 1.6 Hz, 1 H), 5.51 (td, J = 10.6, 1.6 Hz, 1 H), 5.46 (d, J = 10.5 Hz, 1 H), 5.38 (d, J = 8.3 Hz, 1 H), 5.27 (d, J = 8.4 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.47 (d, J = 11.8 Hz, 1 H ), 4.43 (d, J = 11.8 Hz, 1 H), 4.42 (d, J = 11.6 Hz, 1 H), 4.38 (d, J = 11.7 Hz, 1 H), 4.31 (d, J = 11.6 Hz, 1 H), 4.14 (m, 2 H), 4.07 (dd, J = 10.7, 8.3 Hz, 1 H), 4.02 (dd, J = 10.4, 8.2 Hz, 1 H), 3.98 (d, J = 9.4 Hz , 1 H), 3.79 (td, J = 9.2, 3.2 Hz, 1 H), 3.72 (dd, J = 9.9, 4.0 Hz, 1 H), 3.63 (dd, J = 9.9, 4.9 Hz, 1 H), 3.54 (d, J = 10.4 Hz, 1 H), 3.46 (dd, J = 10.7, 3.7 Hz, 1 H), 3.43 (d, J = 10.9 Hz, 2 H), 3.30 (dd, J = 11.2, 3.5 Hz, 1 H), 3.27 (dd, J = 9.2, 4.4 Hz, 1 H), 3.10 (d, J = 8.8 Hz, 1 H), 2.88 (d, J = 3.3 Hz, 1 H), 1.80 (s , 3 H), 1.71 (s, 3 H), 1.63 (s, 3 H).
MS (MALDI) m/z calcd for C 75 H 68 FN 3 KO 21 S [M+K] + , 1436; found 1436.
四糖の構造式
以下に、上記四糖について実施したＮＭＲ測定の結果とＭＳスペクトルの結果とを示す。 Below, the results of NMR measurement and MS spectrum performed on the above tetrasaccharide are shown.
TLC (hexane/EtOAc 1:2): Rf 0.50
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.86 (m, 4 H), 7.80 (m, 3 H), 7.75 (m, 5 H), 7.71 (m, 2 H), 7.67 (m, 2 H), 7.30 (m, 12 H), 7.21 (m, 8 H), 7.10 (pseudo-t, J = 7.92 Hz, 5 H), 7.00 (pseudo-t, J = 7.9 Hz, 2 H), 6.94 (pseudo-t, J = 7.4 Hz, 1 H), 6.82 (pseudo-t, J = 8.7 Hz, 2 H), 6.70 (pseudo-t, J = 7.4 Hz, 1 H), 5.57 (dd, J = 10.1, 9.1 Hz, 1 H), 5.49 (dd, J = 10.7, 8.9 Hz, 1 H), 5.47 (dd, J = 9.0, 2.0 Hz, 1 H), 5.45 (dd, J = 8.9, 1.8 Hz, 1 H), 5.44 (d, J = 10.5 Hz, 1 H), 5.34 (d, J = 8.3 Hz, 1 H), 5.21 (d, J = 8.3 Hz, 1 H), 5.18 (d, J = 8.4 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.42 (dd, J = 11.8, 9.3 Hz, 3 H), 4.37 (d, J = 11.8 Hz, 1 H), 4.34 (d, J = 11.5 Hz, 1 H), 4.31 (d, J = 11.4 Hz, 1 H), 4.13 (d, J = 10.4 Hz, 1 H), 4.10 (d, J = 9.4 Hz, 1 H), 4.08 (d, J = 9.1 Hz, 1 H), 4.05 (d, J = 8.5 Hz, 1 H), 4.03 (d, J = 8.3 Hz, 1 H), 3.98 (m, 3 H), 3.77 (td, J = 9.2, 3.2 Hz, 1 H), 3.71 (dd, J = 9.8, 3.9 Hz, 1 H), 3.62 (dd, J = 9.8, 4.9 Hz, 1 H), 3.53 (d, J = 9.9 Hz, 1 H), 3.45 (dd, J = 9.9, 4.3 Hz, 2 H), 3.39 (td, J = 7.9, 3.7 Hz, 2 H), 3.25 (dd, J = 10.3, 2.6 Hz, 1 H), 3.23 (d, J = 4.7 Hz, 1 H), 3.22 (dd, J = 10.4, 2.8 Hz, 1 H), 3.01 (dd, J = 9.9, 1.5 Hz, 1 H), 2.85 (d, J = 3.1 Hz, 1 H), 2.79 (d, J = 8.8 Hz, 1 H), 1.87 (s, 3 H), 1.78 (s, 3 H), 1.73 (s, 3 H), 1.67 (s, 3 H).
MS (MALDI) m/z calcd for C98H89FN4KO28S [M+K]+, 1859; found 1859.
TLC (hexane/EtOAc 1:2): Rf 0.50
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.86 (m, 4 H), 7.80 (m, 3 H), 7.75 (m, 5 H), 7.71 (m, 2 H), 7.67 (m, 2 H), 7.30 (m, 12 H), 7.21 ( m, 8 H), 7.10 (pseudo-t, J = 7.92 Hz, 5 H), 7.00 (pseudo-t, J = 7.9 Hz, 2 H), 6.94 (pseudo-t, J = 7.4 Hz, 1 H) , 6.82 (pseudo-t, J = 8.7 Hz, 2 H), 6.70 (pseudo-t, J = 7.4 Hz, 1 H), 5.57 (dd, J = 10.1, 9.1 Hz, 1 H), 5.49 (dd, J = 10.7, 8.9 Hz, 1 H), 5.47 (dd, J = 9.0, 2.0 Hz, 1 H), 5.45 (dd, J = 8.9, 1.8 Hz, 1 H), 5.44 (d, J = 10.5 Hz, 1 H), 5.34 (d, J = 8.3 Hz, 1 H), 5.21 (d, J = 8.3 Hz, 1 H), 5.18 (d, J = 8.4 Hz, 1 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.42 (dd, J = 11.8, 9.3 Hz, 3 H), 4.37 (d, J = 11.8 Hz, 1 H), 4.34 (d , J = 11.5 Hz, 1 H), 4.31 (d, J = 11.4 Hz, 1 H), 4.13 (d, J = 10.4 Hz, 1 H), 4.10 (d, J = 9.4 Hz, 1 H), 4.08 (d, J = 9.1 Hz, 1 H), 4.05 (d, J = 8.5 Hz, 1 H), 4.03 (d, J = 8.3 Hz, 1 H), 3.98 (m, 3 H), 3.77 (td, J = 9.2, 3.2 Hz, 1 H), 3.71 (dd, J = 9.8, 3.9 Hz, 1 H), 3.62 (dd, J = 9.8, 4.9 Hz, 1 H), 3.53 (d, J = 9.9 Hz, 1 H), 3.45 (dd, J = 9.9, 4.3 Hz, 2 H), 3.39 (td, J = 7.9, 3.7 Hz, 2 H), 3.25 (dd, J = 10.3, 2.6 Hz, 1 H), 3.23 (d, J = 4.7 Hz, 1 H), 3.22 (dd, J = 10.4, 2.8 Hz, 1 H), 3.01 (dd, J = 9.9, 1.5 Hz, 1 H), 2.85 (d, J = 3.1 Hz , 1 H), 2.79 (d, J = 8.8 Hz, 1 H), 1.87 (s, 3 H), 1.78 (s, 3 H), 1.73 (s, 3 H), 1.67 (s, 3 H).
MS (MALDI) m/z calcd for C 98 H 89 FN 4 KO 28 S [M+K] + , 1859; found 1859.
五糖の構造式
以下に、上記五糖について実施したＮＭＲ測定の結果とＭＳスペクトルの結果とを示す。 Below, the results of NMR measurements and MS spectra performed on the above pentasaccharide are shown.
TLC (hexane/EtOAc 1:2): Rf 0.30
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.64-7.90 (m, 20 H), 7.25-7.35 (m, 17 H), 7.23 (d, J = 6.8 Hz, 2 H), 7.21 (d, J = 7.3 Hz, 2 H), 7.17 (d, J = 7.4 Hz 2 H), 7.09 (pseudo-t, J = 7.7 Hz, 2 H), 6.96 (pseudo-t, J = 7.7 Hz, 2 H), 6.92 (pseudo-t, J = 7.9 Hz, 2 H), 6.82 (pseudo-t, J = 8.6 Hz, 2 H), 6.64 (pseudo-t, J = 7.5 Hz, 1 H), 6.57 (pseudo-t, J = 7.4 Hz, 1 H), 5.56 (pseudo-t, J = 9.2 Hz, 1 H), 5.48 (dd, J = 11.0, 9.3 Hz, 1 H), 5.44 (d, J = 10.5 Hz, 2 H), 5.37 (dd, J = 10.7, 9.0 Hz, 1 H), 5.32 (d, J = 8.3 Hz, 1 H), 5.19 (d, J = 8.4 Hz, 1 H), 5.12 (dd, J = 10.1, 8.5 Hz, 2 H), 4.51 (d, J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.42 (d, J = 12.2 Hz, 3 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.34 (d, J = 11.3 Hz, 2 H), 4.31 (d, J = 11.2 Hz, 1 H), 4.08 (pseudo-t, J = 9.2 Hz, 1 H), 4.04 (dd, J = 10.2, 8.5 Hz, 2 H), 3.91-4.01 (m, 4 H), 3.77 (td, J = 9.4, 3.3 Hz, 1 H), 3.70 (dd, J = 9.8, 3.8 Hz, 1 H), 3.63 (dd, J = 9.7, 4.8 Hz, 1 H), 3.52 (d, J = 10.0 Hz, 1 H), 3.43 (pseudo-t, J = 9.9 Hz, 2 H), 3.38 (dd, J = 8.3, 4.1 Hz, 2 H), 3.22 (dd, J = 9.5, 5.1, 1 H), 3.19 (dd, J = 13.1, 2.6 Hz, 1 H), 3.15 (dd, J = 10.3, 2.3 Hz, 1 H), 2.99 (d, J = 8.6 Hz, 1 H), 2.84 (d, J = 3.3 Hz, 1 H), 2.72 (d, J = 10.0 Hz, 1 H), 2.66 (d, J = 9.0 Hz, 1 H), 1.87 (s, 3 H), 1.78 (s, 3 H), 1.73 (s, 3 H), 1.70 (s, 3 H), 1.65 (s, 3 H).
MS (MALDI) m/z calcd for C121H110FN5KO35S [M+K]+, 2282; found 2282.
TLC (hexane/EtOAc 1:2): Rf 0.30
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.64-7.90 (m, 20 H), 7.25-7.35 (m, 17 H), 7.23 (d, J = 6.8 Hz, 2 H), 7.21 (d, J = 7.3 Hz, 2 H), 7.17 (d, J = 7.4 Hz 2 H), 7.09 (pseudo-t, J = 7.7 Hz, 2 H), 6.96 (pseudo-t, J = 7.7 Hz, 2 H), 6.92 (pseudo-t, J = 7.9 Hz, 2 H), 6.82 (pseudo-t, J = 8.6 Hz, 2 H), 6.64 (pseudo-t, J = 7.5 Hz, 1 H), 6.57 (pseudo-t, J = 7.4 Hz, 1 H), 5.56 ( pseudo-t, J = 9.2 Hz, 1 H), 5.48 (dd, J = 11.0, 9.3 Hz, 1 H), 5.44 (d, J = 10.5 Hz, 2 H), 5.37 (dd, J = 10.7, 9.0 Hz, 1 H), 5.32 (d, J = 8.3 Hz, 1 H), 5.19 (d, J = 8.4 Hz, 1 H), 5.12 (dd, J = 10.1, 8.5 Hz, 2 H), 4.51 (d , J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.42 (d, J = 12.2 Hz, 3 H), 4.37 (d, J = 11.6 Hz, 1 H), 4.34 (d, J = 11.3 Hz, 2 H), 4.31 (d, J = 11.2 Hz, 1 H), 4.08 (pseudo-t, J = 9.2 Hz, 1 H), 4.04 (dd, J = 10.2, 8.5 Hz , 2 H), 3.91-4.01 (m, 4 H), 3.77 (td, J = 9.4, 3.3 Hz, 1 H), 3.70 (dd, J = 9.8, 3.8 Hz, 1 H), 3.63 (dd, J = 9.7, 4.8 Hz, 1 H), 3.52 (d, J = 10.0 Hz, 1 H), 3.43 (pseudo-t, J = 9.9 Hz, 2 H), 3.38 (dd, J = 8.3, 4.1 Hz, 2 H), 3.22 (dd, J = 9.5, 5.1, 1 H), 3.19 (dd, J = 13.1, 2.6 Hz, 1 H), 3.15 (dd, J = 10.3, 2.3 Hz, 1 H), 2.99 (d , J = 8.6 Hz, 1 H), 2.84 (d, J = 3.3 Hz, 1 H), 2.72 (d, J = 10.0 Hz, 1 H), 2.66 (d, J = 9.0 Hz, 1 H), 1.87 (s, 3 H), 1.78 (s, 3 H), 1.73 (s, 3 H), 1.70 (s, 3 H), 1.65 (s, 3 H).
MS (MALDI) m/z calcd for C 121 H 110 FN 5 KO 35 S [M+K] + , 2282; found 2282.
六糖の構造式
以下に、上記六糖について実施したＮＭＲ測定の結果とＭＳスペクトルの結果を示す。 Below, the results of NMR measurement and MS spectrum performed on the above-mentioned hexasaccharide are shown.
TLC (hexane/EtOAc 1:2): Rf 0.23
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.63-7.90 (m, 24 H), 7.26-7.35 (m, 9 H), 7.21 (dd, J = 14.4, 7.2 Hz, 6 H), 7.15 (pseudo-t, J = 7.8 Hz, 6 H), 7.08 (pseudo-t, J = 7.8 Hz 2 H), 6.95 (pseudo-t, J = 7.8 Hz, 2 H), 6.90 (pseudo-t, J = 7.8 Hz, 2 H), 6.88 (pseudo-t, J = 7.8 Hz, 2 H), 6.81 (pseudo-t, J = 8.4 Hz, 2 H), 6.63 (pseudo-t, J = 7.2 Hz, 1 H), 6.54 (pseudo-t, J = 7.2 Hz, 1 H), 6.51 (pseudo-t, J = 7.2 Hz, 1 H), 5.55 (dd, J = 10.2, 9.0 Hz, 1 H), 5.48 (dd, J = 10.2, 9.0 Hz, 1 H), 5.44 (d, J = 10.2 Hz, 1 H), 5.43 (d, J = 10.2 Hz, 1 H), 5.42 (d, J = 9.6 Hz, 1 H), 5.36 (pseudo-t, J = 9.0 Hz, 1 H), 5.35 (d, J = 8.4 Hz, 1 H), 5.32 (d, J = 7.2 Hz, 1 H), 5.19 (d, J = 8.4 Hz, 1 H), 5.12 (d, J = 8.4 Hz, 1 H), 5.10 (d, J = 7.8 Hz, 1 H), 5.07 (d, J = 8.4 Hz, 1 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.46 (d, J = 11.4 Hz, 1 H), 4.42 (d, J = 11.4 Hz, 5 H), 4.37 (d, J = 8.4 Hz, 1 H), 4.35 (d, J = 12.6 Hz, 1 H), 4.34 (d, J = 11.4 Hz, 1 H), 4.33 (d, J = 10.8 Hz, 1 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.12 ( pseudo-t, J = 10.2 Hz, 1 H), 4.08 (pseudo-t, J = 9.6 Hz, 1 H), 3.89-4.05 (m, 9 H), 3.76 (td, J = 9.6, 3.6 Hz, 1 H), 3.61 (dd, J = 9.6, 4.8 Hz, 1 H), 3.52 (d, J = 10.2 Hz, 1 H), 3.43 (d, J = 9.6 Hz, 2 H), 3.38 (pseudo-t, J = 9.6 Hz, 4 H), 3.16-3.24 (m, 3 H), 3.08-3.15 (m, 3 H), 2.98 (d, J = 8.4 Hz, 1 H), 2.83 (d, J = 3.0 Hz, 1 H), 2.71 (d, J = 9.6 Hz, 1 H), 2.65 (d, J = 8.4 Hz, 1 H), 2.60 (d, J = 9.0 Hz, 1 H), 1.86 (s, 3 H), 1.78 (s, 3 H), 1.73 (s, 3 H), 1.71 (s, 3 H), 1.69 (s, 3 H), 1.64 (s, 3 H).
MS (MALDI) m/z calcd for C144H131FN6KO42S [M+K]+, 2705; found 2705.
TLC (hexane/EtOAc 1:2): Rf 0.23
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.63-7.90 (m, 24 H), 7.26-7.35 (m, 9 H), 7.21 (dd, J = 14.4, 7.2 Hz, 6 H), 7.15 (pseudo-t, J = 7.8 Hz, 6 H), 7.08 (pseudo-t, J = 7.8 Hz 2 H), 6.95 (pseudo-t, J = 7.8 Hz, 2 H), 6.90 (pseudo-t, J = 7.8 Hz, 2 H), 6.88 (pseudo-t, J = 7.8 Hz, 2 H), 6.81 (pseudo-t, J = 8.4 Hz, 2 H), 6.63 (pseudo-t, J = 7.2 Hz, 1 H), 6.54 (pseudo-t, J = 7.2 Hz, 1 H), 6.51 (pseudo-t, J = 7.2 Hz, 1 H), 5.55 (dd, J = 10.2, 9.0 Hz, 1 H), 5.48 (dd, J = 10.2, 9.0 Hz, 1 H), 5.44 (d, J = 10.2 Hz, 1 H), 5.43 (d, J = 10.2 Hz, 1 H), 5.42 (d, J = 9.6 Hz, 1 H), 5.36 (pseudo-t, J = 9.0 Hz, 1 H), 5.35 (d, J = 8.4 Hz, 1 H), 5.32 (d, J = 7.2 Hz, 1 H), 5.19 (d, J = 8.4 Hz, 1 H), 5.12 (d, J = 8.4 Hz , 1 H), 5.10 (d, J = 7.8 Hz, 1 H), 5.07 (d, J = 8.4 Hz, 1 H), 4.50 (d, J = 11.4 Hz, 1 H), 4.46 (d, J = 11.4 Hz, 1 H), 4.42 (d, J = 11.4 Hz, 5 H), 4.37 (d, J = 8.4 Hz, 1 H), 4.35 (d, J = 12.6 Hz, 1 H), 4.34 (d, J = 11.4 Hz, 1 H), 4.33 (d, J = 10.8 Hz, 1 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.12 (pseudo-t, J = 10.2 Hz, 1 H), 4.08 (pseudo-t, J = 9.6 Hz, 1 H), 3.89-4.05 (m, 9 H), 3.76 (td, J = 9.6, 3.6 Hz, 1 H), 3.61 (dd, J = 9.6, 4.8 Hz , 1 H), 3.52 (d, J = 10.2 Hz, 1 H), 3.43 (d, J = 9.6 Hz, 2 H), 3.38 (pseudo-t, J = 9.6 Hz, 4 H), 3.16-3.24 ( m, 3 H), 3.08-3.15 (m, 3 H), 2.98 (d, J = 8.4 Hz, 1 H), 2.83 (d, J = 3.0 Hz, 1 H), 2.71 (d, J = 9.6 Hz , 1 H), 2.65 (d, J = 8.4 Hz, 1 H), 2.60 (d, J = 9.0 Hz, 1 H), 1.86 (s, 3 H), 1.78 (s, 3 H), 1.73 (s , 3 H), 1.71 (s, 3 H), 1.69 (s, 3 H), 1.64 (s, 3 H).
MS (MALDI) m/z calcd for C 144 H 131 FN 6 KO 42 S [M+K] + , 2705; found 2705.
実施例２
実施例１とは異なるグルコース由来のチオグリコシド（下記式（Ｂ））を用いて、下記式のとおり電解重合によりオリゴ糖を合成した。
Using a glucose-derived thioglycoside (formula (B) below) different from that in Example 1, an oligosaccharide was synthesized by electrolytic polymerization as shown in the following formula.
ガラス隔膜付き電解セルの陽極側に上記式（Ｂ）のチオグリコシド（２３６ｍｇ，０．４０ｍｍｏｌ），両極にＥｔ4ＮＯＴｆ（テトラエチルアンモニウムトリフラート）（５５８ｍｇ，２．０ｍｍｏｌ）を加え、減圧乾燥、Ａｒ置換後、両極にジクロロメタン（塩化メチレン）を２０ｍＬずつ加えた。陰極にはＴｆＯＨ（トリフルオロメタンスルホン酸）（３５．２μＬ，０．４０ｍｍｏｌ）を加えた。続いて、低温バスにて電解セルを－８０℃に冷却し、電解酸化（通電条件：８ｍＡ，６３ｍｉｎ，０．７９Ｆ／ｍｏｌ）を行った。通電終了後－５０℃まで昇温し、さらに１時間撹拌した。その後トリエチルアミン（０．３ｍＬ）を両極に加えて反応を停止し、室温まで昇温した。反応混合物を濃縮後、酢酸エチルにて希釈した上で分液ロートを用いて水洗浄を行った。得られた有機相に乾燥剤（Ｎａ2ＳＯ4）を加え脱水を行った。ろ過により乾燥剤を除去した後、減圧濃縮を行い、さらに真空乾燥を行った。得られた粗生成物（２３０．９ｍｇ）に対してＭＡＬＤＩ－ＴＯＦ－ＭＳ分析を行ったのち、ゲル浸透クロマトグラフィー（溶媒：クロロホルム）にて単離精製を行った。単離生成物に対して1ＨＮＭＲ測定、ＭＡＬＤＩ－ＴＯＦ－ＭＳ測定を行い、収量はそれぞれ二糖（２８ｍｇ，１５％収率），三糖（２８ｍｇ，１５％），四糖（２２ｍｇ，１２％），五糖（１２ｍｇ，７％），六糖（８ｍｇ，５％）であった。 Thioglycoside of the above formula (B) (236 mg, 0.40 mmol) was added to the anode side of an electrolytic cell with a glass diaphragm, and Et 4 NOTf (tetraethylammonium triflate) (558 mg, 2.0 mmol) was added to both electrodes, dried under reduced pressure, and replaced with Ar. After that, 20 mL of dichloromethane (methylene chloride) was added to both electrodes. TfOH (trifluoromethanesulfonic acid) (35.2 μL, 0.40 mmol) was added to the cathode. Subsequently, the electrolytic cell was cooled to −80° C. in a low-temperature bath, and electrolytic oxidation (current conditions: 8 mA, 63 min, 0.79 F/mol) was performed. After the electricity was turned off, the temperature was raised to -50°C, and the mixture was further stirred for 1 hour. Thereafter, triethylamine (0.3 mL) was added to both electrodes to stop the reaction, and the temperature was raised to room temperature. After concentrating the reaction mixture, it was diluted with ethyl acetate and washed with water using a separating funnel. A desiccant (Na 2 SO 4 ) was added to the obtained organic phase to perform dehydration. After removing the desiccant by filtration, concentration under reduced pressure was performed, and further vacuum drying was performed. The obtained crude product (230.9 mg) was subjected to MALDI-TOF-MS analysis, and then isolated and purified by gel permeation chromatography (solvent: chloroform). The isolated product was subjected to 1 HNMR measurement and MALDI-TOF-MS measurement, and the yields were respectively disaccharide (28 mg, 15% yield), trisaccharide (28 mg, 15%), and tetrasaccharide (22 mg, 12%). ), pentasaccharide (12 mg, 7%), and hexasaccharide (8 mg, 5%).
二糖の構造式
以下に、上記二糖について実施したＮＭＲ測定の結果とMSスペクトルの結果を示す。 Below, the results of NMR measurement and MS spectrum performed on the above-mentioned disaccharide are shown.
TLC (hexane/EtOAc 2:1): Rf 0.40
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.97-7.91 (m, 4 H), 7.59 (pseudo-t, J = 7.8 Hz, 1 H), 7.56 (pseudo-t, J = 7.8 Hz, 1 H), 7.45 (pseudo-t, J = 7.2 Hz, 2 H), 7.42 (pseudo-t, J = 7.8 Hz, 2 H), 7.39-7.24 (m, 12 H), 7.19-7.12 (m, 5 H), 7.12-7.08 (m, 4 H), 7.04 (dd, J = 12.0, 5.4 Hz, 2 H), 5.21 (pseudo-t, J = 9.0 Hz, 1 H), 5.16 (pseudo-t, J = 9.0 Hz, 1 H), 4.85 (d, J = 11.4 Hz, 1 H), 4.74 (d, J = 12.0 Hz, 1 H), 4.68 (d, J = 8.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.60-4.57 (m, 3 H), 4.42-4.38 (m, 2 H), 4.33 (d, J = 12.0 Hz, 1 H), 4.00 (pseudo-t, J = 9.0 Hz, 1 H), 3.79 (pseudo-t, J = 9.6 Hz, 1 H), 3.71 (pseudo-t, J = 9.0 Hz, 1 H), 3.62 (dd, J = 10.8, 4.2 Hz, 1 H), 3.57 (dd, J = 9.6, 4.8 Hz, 1 H), 3.56-3.52 (m, 2 H), 3.48 (dd, J = 9.6, 6.0 Hz, 1 H), 3.37 (pseudo-t, J = 9.6, 6.0 Hz, 1 H), 3.30 (ddd, J = 9.6, 3.6, 1.2 Hz, 1 H), 3.06 (s, 1 H).
MS (MALDI) m/z calcd for C60H57ClKO12S [M+K]+, 1075; found 1075.
TLC (hexane/EtOAc 2:1): Rf 0.40
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.97-7.91 (m, 4 H), 7.59 (pseudo-t, J = 7.8 Hz, 1 H), 7.56 (pseudo-t, J = 7.8 Hz, 1 H), 7.45 (pseudo-t, J = 7.2 Hz , 2 H), 7.42 (pseudo-t, J = 7.8 Hz, 2 H), 7.39-7.24 (m, 12 H), 7.19-7.12 (m, 5 H), 7.12-7.08 (m, 4 H), 7.04 (dd, J = 12.0, 5.4 Hz, 2 H), 5.21 (pseudo-t, J = 9.0 Hz, 1 H), 5.16 (pseudo-t, J = 9.0 Hz, 1 H), 4.85 (d, J = 11.4 Hz, 1 H), 4.74 (d, J = 12.0 Hz, 1 H), 4.68 (d, J = 8.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.60-4.57 (m, 3 H), 4.42-4.38 (m, 2 H), 4.33 (d, J = 12.0 Hz, 1 H), 4.00 (pseudo-t, J = 9.0 Hz, 1 H), 3.79 (pseudo-t , J = 9.6 Hz, 1 H), 3.71 (pseudo-t, J = 9.0 Hz, 1 H), 3.62 (dd, J = 10.8, 4.2 Hz, 1 H), 3.57 (dd, J = 9.6, 4.8 Hz , 1 H), 3.56-3.52 (m, 2 H), 3.48 (dd, J = 9.6, 6.0 Hz, 1 H), 3.37 (pseudo-t, J = 9.6, 6.0 Hz, 1 H), 3.30 (ddd , J = 9.6, 3.6, 1.2 Hz, 1 H), 3.06 (s, 1 H).
MS (MALDI) m/z calcd for C 60 H 57 ClKO 12 S [M+K] + , 1075; found 1075.
三糖の構造式
以下に、上記三糖について実施したＮＭＲ測定の結果とMSスペクトルの結果を示す。 Below, the results of NMR measurement and MS spectrum performed on the above trisaccharide are shown.
TLC (hexane/EtOAc 2:1): Rf 0.33
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.91-7.87 (m, 5 H), 7.63 (pseudo-t, J = 7.2 Hz, 1 H), 7.58 (pseudo-t, J = 7.2 Hz, 1 H), 7.54 (pseudo-t, J = 7.2 Hz, 1 H), 7.46 (pseudo-t, J = 7.8 Hz, 3 H), 7.43 (pseudo-t, J = 7.8 Hz, 3 H), 7.39 (pseudo-t, J = 7.8 Hz, 3 H), 7.35-7.13 (m, 19 H), 7.13-7.06 (m, 5 H), 7.06-7.01 (m, 5 H), 6.94-6.87 (m, 3 H), 5.22 (pseudo-t, J = 9.6 Hz, 1 H), 5.15 (pseudo-t, J = 9.6 Hz, 1 H), 5.10 (pseudo-t, J = 9.6 Hz, 1 H), 4.89 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 11.4 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.62 (d, J = 7.8 Hz, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 11.4 Hz, 1 H), 4.53 (d, J = 3.6 Hz, 1 H), 4.52 (d, J = 9.6 Hz, 1 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.43 (d, J = 7.8 Hz, 1 H), 4.42 (d, J = 10.2 Hz, 1 H), 4.41 (d, J = 4.2 Hz, 1 H), 4.24 (d, J = 12.0 Hz, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 4.08 (pseudo-t, J = 9.0 Hz, 1 H), 3.91 (pseudo-t, J = 9.0 Hz, 1 H), 3.79 (pseudo-t, J = 9.6 Hz, 1 H), 3.65 (pseudo-t, J = 9.0 Hz, 1 H), 3.60 (dd, J = 10.2, 4.8 Hz, 1 H), 3.57 (dd, J = 10.8, 3.6 Hz, 1 H), 3.53-3.46 (m, 4 H), 3.44 (pseudo-t, J = 9.0 Hz, 1 H), 3.37 (d, J = 11.4 Hz, 1 H), 3.34 (dd, J = 9.6, 4.8 Hz, 1 H), 3.22 (d, J = 9.6 Hz, 1 H), 3.06 (s, 1 H), 2.93 (d, J = 9.6 Hz, 1 H).
MS (MALDI) m/z calcd for C87H83ClKO18S [M+K]+, 1521; found 1521.
TLC (hexane/EtOAc 2:1): Rf 0.33
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.91-7.87 (m, 5 H), 7.63 (pseudo-t, J = 7.2 Hz, 1 H), 7.58 (pseudo-t, J = 7.2 Hz, 1 H), 7.54 (pseudo-t, J = 7.2 Hz , 1 H), 7.46 (pseudo-t, J = 7.8 Hz, 3 H), 7.43 (pseudo-t, J = 7.8 Hz, 3 H), 7.39 (pseudo-t, J = 7.8 Hz, 3 H), 7.35-7.13 (m, 19 H), 7.13-7.06 (m, 5 H), 7.06-7.01 (m, 5 H), 6.94-6.87 (m, 3 H), 5.22 (pseudo-t, J = 9.6 Hz , 1 H), 5.15 (pseudo-t, J = 9.6 Hz, 1 H), 5.10 (pseudo-t, J = 9.6 Hz, 1 H), 4.89 (d, J = 12.0 Hz, 1 H), 4.86 ( d, J = 11.4 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.62 (d, J = 7.8 Hz, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.56 (d, J = 11.4 Hz, 1 H), 4.53 (d, J = 3.6 Hz, 1 H), 4.52 (d, J = 9.6 Hz, 1 H ), 4.49 (d, J = 12.0 Hz, 1 H), 4.43 (d, J = 7.8 Hz, 1 H), 4.42 (d, J = 10.2 Hz, 1 H), 4.41 (d, J = 4.2 Hz, 1 H), 4.24 (d, J = 12.0 Hz, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 4.08 (pseudo-t, J = 9.0 Hz, 1 H), 3.91 (pseudo-t , J = 9.0 Hz, 1 H), 3.79 (pseudo-t, J = 9.6 Hz, 1 H), 3.65 (pseudo-t, J = 9.0 Hz, 1 H), 3.60 (dd, J = 10.2, 4.8 Hz , 1 H), 3.57 (dd, J = 10.8, 3.6 Hz, 1 H), 3.53-3.46 (m, 4 H), 3.44 (pseudo-t, J = 9.0 Hz, 1 H), 3.37 (d, J = 11.4 Hz, 1 H), 3.34 (dd, J = 9.6, 4.8 Hz, 1 H), 3.22 (d, J = 9.6 Hz, 1 H), 3.06 (s, 1 H), 2.93 (d, J = 9.6Hz, 1H).
MS (MALDI) m/z calcd for C 87 H 83 ClKO 18 S [M+K] + , 1521; found 1521.
四糖の構造式
以下に、上記四糖について実施したＮＭＲ測定の結果とMSスペクトルの結果を示す。 Below, the results of NMR measurement and MS spectrum performed on the above tetrasaccharide are shown.
TLC (hexane/EtOAc 2:1): Rf 0.27
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.90-7.83 (m, 8 H), 7.63-7.59 (m, 2 H), 7.57-7.52 (m, 2 H), 7.47-7.36 (m, 9 H), 7.34-7.31 (m, 5 H), 7.29-7.23 (m, 6 H), 7.19-7.01 (m, 26 H), 6.98 (pseudo-t, J = 7.2 Hz, 1 H), 6.94-6.86 (m, 5 H), 5.23 (dd, J = 9.6, 8.4 Hz, 1 H), 5.15 (dd, J = 9.6, 8.4 Hz, 1 H), 5.09 (pseudo-t, J = 9.0 Hz, 1 H), 5.08 (pseudo-t, J = 9.6 Hz, 1 H), 4.91 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 12.6 Hz, 1 H), 4.85 (d, J = 12.6 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.62 (d, J = 8.4 Hz, 1 H), 4.58 (d, J = 12.6 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.51-4.47 (m, 3 H), 4.43-4.39 (m, 2 H), 4.37 (d, J = 7.8 Hz, 1 H), 4.34 (d, J = 8.4 Hz, 1 H), 4.19 (d, J = 12.0 Hz, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 4.07 (pseudo-t, J = 9.6 Hz, 1 H), 4.00 (d, J = 12.0 Hz, 1 H), 3.97 (d, J = 9.6 Hz, 1 H), 3.87 (pseudo-t, J = 9.6 Hz, 1 H), 3.79 (pseudo-t, J = 9.6 Hz, 1 H), 3.62 (pseudo-t, J = 9.0 Hz, 1 H), 3.60 (dd, J = 10.2, 4.8 Hz, 1 H), 3.54-3.44 (m, 6 H), 3.40-3.31 (m, 6 H), 3.19 (ddd, J = 9.6, 3.6, 1.2 Hz, 1 H), 3.07 (s, 1 H), 2.88-2.84 (m, 2 H).
MS (MALDI) m/z calcd for C114H109ClKO24S [M+K]+, 1968; found 1968.
TLC (hexane/EtOAc 2:1): Rf 0.27
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.90-7.83 (m, 8 H), 7.63-7.59 (m, 2 H), 7.57-7.52 (m, 2 H), 7.47-7.36 (m, 9 H), 7.34-7.31 (m, 5 H), 7.29-7.23 (m, 6 H), 7.19-7.01 (m, 26 H), 6.98 (pseudo-t, J = 7.2 Hz, 1 H), 6.94-6.86 (m, 5 H), 5.23 (dd, J = 9.6, 8.4 Hz, 1 H), 5.15 (dd, J = 9.6, 8.4 Hz, 1 H), 5.09 (pseudo-t, J = 9.0 Hz, 1 H), 5.08 (pseudo-t, J = 9.6 Hz , 1 H), 4.91 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 12.6 Hz, 1 H), 4.85 (d, J = 12.6 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.62 (d, J = 8.4 Hz, 1 H), 4.58 (d, J = 12.6 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.51-4.47 (m, 3 H), 4.43-4.39 (m, 2 H), 4.37 (d, J = 7.8 Hz) , 1 H), 4.34 (d, J = 8.4 Hz, 1 H), 4.19 (d, J = 12.0 Hz, 1 H), 4.12 (d, J = 12.0 Hz, 1 H), 4.07 (pseudo-t, J = 9.6 Hz, 1 H), 4.00 (d, J = 12.0 Hz, 1 H), 3.97 (d, J = 9.6 Hz, 1 H), 3.87 (pseudo-t, J = 9.6 Hz, 1 H), 3.79 (pseudo-t, J = 9.6 Hz, 1 H), 3.62 (pseudo-t, J = 9.0 Hz, 1 H), 3.60 (dd, J = 10.2, 4.8 Hz, 1 H), 3.54-3.44 (m , 6 H), 3.40-3.31 (m, 6 H), 3.19 (ddd, J = 9.6, 3.6, 1.2 Hz, 1 H), 3.07 (s, 1 H), 2.88-2.84 (m, 2 H).
MS (MALDI) m/z calcd for C 114 H 109 ClKO 24 S [M+K] + , 1968; found 1968.
五糖の構造式
以下に、上記五糖について実施したＮＭＲ測定の結果とMSスペクトルの結果を示す。
TLC (hexane/EtOAc 1:1): Rf 0.83
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.90-7.81 (m, 10 H), 7.62-7.51 (m, 5 H), 7.45-7.36 (m, 11 H), 7.34-7.31 (m, 5 H), 7.28-7.23 (m, 6 H), 7.17-6.85 (m, 42 H), 5.23 (dd, J = 9.6, 7.8 Hz, 1 H), 5.17 (dd, J = 9.6, 7.8 Hz, 1 H), 5.09 (dd, J = 9.0, 7.8 Hz, 1 H), 5.08-5.05 (m, 2 H), 4.91 (d, J = 12.6 Hz, 1 H), 4.89 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 11.4 Hz, 1 H), 4.85 (d, J = 12.6 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.63 (d, J = 8.4 Hz, 1 H), 4.57 (d, J = 11.4 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.53 (d, J = 13.2 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 10.6 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.45-4.34 (m, 6 H), 4.27 (d, J = 7.8 Hz, 1 H), 4.19 (d, J = 12.0 Hz, 1 H), 4.13 (d, J = 12.0 Hz, 1 H), 4.08 (pseudo-t, J = 9.6 Hz, 1 H), 4.02-3.92 (m, 5 H), 3.85 (pseudo-t, J = 9.6 Hz, 1 H), 3.80 (pseudo-t, J = 9.0 Hz, 1 H), 3.61 (d, J = 9.6 Hz, 1 H), 3.60 (d, J = 10.2 Hz, 1 H), 3.53-3.26 (m, 14 H), 3.18 (ddd, J = 9.6, 3.6, 1.2 Hz, 1 H), 3.06 (s, 1 H), 2.88 (dd, J = 9.6, 1.8 Hz, 1 H), 2.84-2.77 (m, 2 H).
MS (MALDI) m/z calcd for C141H135ClKO30S [M+K]+, 2414; found 2413.
Below, the results of NMR measurement and MS spectrum performed on the above pentasaccharide are shown.
TLC (hexane/EtOAc 1:1): Rf 0.83
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.90-7.81 (m, 10 H), 7.62-7.51 (m, 5 H), 7.45-7.36 (m, 11 H), 7.34-7.31 (m, 5 H), 7.28-7.23 (m, 6 H), 7.17-6.85 (m, 42 H), 5.23 (dd, J = 9.6, 7.8 Hz, 1 H), 5.17 (dd, J = 9.6, 7.8 Hz, 1 H), 5.09 (dd, J = 9.0, 7.8 Hz , 1 H), 5.08-5.05 (m, 2 H), 4.91 (d, J = 12.6 Hz, 1 H), 4.89 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 11.4 Hz, 1 H), 4.85 (d, J = 12.6 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.63 (d, J = 8.4 Hz, 1 H), 4.57 (d, J = 11.4 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.53 (d, J = 13.2 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.49 (d, J = 10.6 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.45-4.34 (m, 6 H), 4.27 (d, J = 7.8 Hz, 1 H), 4.19 (d, J = 12.0 Hz, 1 H), 4.13 (d, J = 12.0 Hz, 1 H), 4.08 (pseudo-t, J = 9.6 Hz, 1 H), 4.02- 3.92 (m, 5 H), 3.85 (pseudo-t, J = 9.6 Hz, 1 H), 3.80 (pseudo-t, J = 9.0 Hz, 1 H), 3.61 (d, J = 9.6 Hz, 1 H) , 3.60 (d, J = 10.2 Hz, 1 H), 3.53-3.26 (m, 14 H), 3.18 (ddd, J = 9.6, 3.6, 1.2 Hz, 1 H), 3.06 (s, 1 H), 2.88 (dd, J = 9.6, 1.8 Hz, 1 H), 2.84-2.77 (m, 2 H).
MS (MALDI) m/z calcd for C 141 H 135 ClKO 30 S [M+K] + , 2414; found 2413.
六糖の構造式
以下に、上記六糖について実施したＮＭＲ測定の結果とMSスペクトルの結果を示す。
TLC (hexane/EtOAc 1:1): Rf 0.76
＜1H NMR (CDCl3, 600 MHz)化学シフト値＞
7.90-7.80 (m, 12 H), 7.62-7.52 (m, 6 H), 7.45-7.36 (m, 13 H), 7.34-7.31 (m, 5 H), 7.28-7.23 (m, 6 H), 7.17-6.85 (m, 52 H), 5.23 (dd, J = 9.6, 7.8 Hz, 1 H), 5.17 (dd, J = 9.0, 7.8 Hz, 1 H), 5.12-5.04 (m, 4 H), 4.91 (d, J = 12.6 Hz, 1 H), 4.88 (d, J = 12.6 Hz, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 11.4 Hz, 1 H), 4.84 (d, J = 12.0 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.63 (d, J = 8.4 Hz, 1 H), 4.58-4.46 (m, 8 H), 4.43-4.33 (m, 6 H), 4.29-4.24 (m, 2 H), 4.18 (d, J = 12.0 Hz, 1 H), 4.13 (d, J = 12.0 Hz, 1 H), 4.08 (pseudo-t, J = 9.6 Hz, 1 H), 4.02 (d, J = 12.0 Hz, 1 H), 4.00-3.93 (m, 5 H), 3.85 (pseudo-t, J = 8.4 Hz, 1 H), 3.79 (pseudo-t, J = 9.0 Hz, 1 H), 3.62-3.59 (m, 2 H), 3.53-3.26 (m, 18 H), 3.18 (d, J = 9.6 Hz, 1 H), 3.05 (s, 1 H), 2.88 (d, J = 9.6 Hz, 1 H), 2.82-2.75 (m, 2 H).
MS (MALDI) m/z calcd for C168H161ClFKO36S [M+K]+, 2860; found 2860.
Below, the results of NMR measurement and MS spectrum performed on the above-mentioned hexasaccharide are shown.
TLC (hexane/EtOAc 1:1): Rf 0.76
< 1H NMR (CDCl 3 , 600 MHz) chemical shift value>
7.90-7.80 (m, 12 H), 7.62-7.52 (m, 6 H), 7.45-7.36 (m, 13 H), 7.34-7.31 (m, 5 H), 7.28-7.23 (m, 6 H), 7.17-6.85 (m, 52 H), 5.23 (dd, J = 9.6, 7.8 Hz, 1 H), 5.17 (dd, J = 9.0, 7.8 Hz, 1 H), 5.12-5.04 (m, 4 H), 4.91 (d, J = 12.6 Hz, 1 H), 4.88 (d, J = 12.6 Hz, 1 H), 4.87 (d, J = 12.0 Hz, 1 H), 4.86 (d, J = 11.4 Hz, 1 H ), 4.84 (d, J = 12.0 Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.67 (d, J = 11.4 Hz, 1 H), 4.63 (d, J = 8.4 Hz, 1 H), 4.58-4.46 (m, 8 H), 4.43-4.33 (m, 6 H), 4.29-4.24 (m, 2 H), 4.18 (d, J = 12.0 Hz, 1 H), 4.13 (d , J = 12.0 Hz, 1 H), 4.08 (pseudo-t, J = 9.6 Hz, 1 H), 4.02 (d, J = 12.0 Hz, 1 H), 4.00-3.93 (m, 5 H), 3.85 ( pseudo-t, J = 8.4 Hz, 1 H), 3.79 (pseudo-t, J = 9.0 Hz, 1 H), 3.62-3.59 (m, 2 H), 3.53-3.26 (m, 18 H), 3.18 ( d, J = 9.6 Hz, 1 H), 3.05 (s, 1 H), 2.88 (d, J = 9.6 Hz, 1 H), 2.82-2.75 (m, 2 H).
MS (MALDI) m/z calcd for C 168 H 161 ClFKO 36 S [M+K] + , 2860; found 2860.
Claims (5)
前記同時にとは、中間体の蓄積を待つことなく、同一の反応場で前記式（１）で表される６単糖のヒドロキシ基の部位とを結合させる反応が滞りなく完結することであり、
前記同種の式（１）で表される６単糖とは、前記１種類を選定した式（１）で表される６単糖と、結合される式（１）で表される６単糖が、ヒドロキシ基またはヒドロキシ基を含む基について、同じ位置に同じ基を有し、かつ、Ｘが同じであることであり、
前記活性化が電気化学的な活性化である、糖鎖の製造方法。
The above-mentioned "simultaneously" means that the reaction of bonding with the hydroxyl group of the hexasaccharide represented by the formula (1) is completed without delay in the same reaction field without waiting for the accumulation of intermediates,
The same type of hexasaccharide represented by the formula (1) refers to the hexasaccharide represented by the formula (1) selected from the above one type, and the hexasaccharide represented by the formula (1) that is combined with the hexasaccharide represented by the formula (1) has the same group at the same position with respect to a hydroxy group or a group containing a hydroxy group, and X is the same,
A method for producing a sugar chain , wherein the activation is electrochemical activation .
The method for producing a sugar chain according to any one of claims 1 to 4 , wherein the sugar chain to be synthesized is represented by the following formula (a) or (b).
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