JP4599505B2 - Method for producing N-acetyl-β-hexosaminide derivative - Google Patents
Method for producing N-acetyl-β-hexosaminide derivative Download PDFInfo
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Description
【0001】
【発明が属する技術分野】
本発明は、N-アセチル-β-ヘキソサミニド誘導体、特に2-アセトアミド-2-デオキシ-β-D-ヘキソピラノシドを有するオリゴ糖の特異的製造方法に関する。N-アセチルヘキソサミンのオキサゾリンとグリコシル受容体とを反応せしめ、N-アセチル-β-ヘキソサミニド誘導体を製造するに当たり、酸触媒、特にリサイクル使用が可能なイオン交換樹脂を使用する事を特徴とする。
【0002】
【従来の技術】
一般にオリゴ糖を合成するためのグリコシド結合形成反応は、グリコシル供与体のC-1位を活性化すると同時に、受容体のヒドロキシル基と反応せしめることによって行われる。しかしながら、多くの方法は活性化剤として高価な、また毒性の高い重金属、または再使用が困難な酸触媒を使用しながら、低い収率や乏しい立体選択性しか得られないという不都合な点を有しているため、産業的な規模での合成が困難であった(K. Toshima, Chem. Rev., 93, 1503 (1993))。特に、N-アセチル-β-ヘキソサミニド誘導体の合成において、1位に活性基を有するN-アセチルヘキソサミン誘導体を糖供与体として用いると、グリコシド結合形成反応時に、C-2位のアセトアミド基とC-1位との間でオキサゾリン環が形成され、収率の低下および反応性が低い糖の水酸基とは反応しないこと等が知られている。この問題を解決するためにN-アセチル-β-ヘキソサミニド誘導体を合成する反応では、C-2位のアセトアミド基を他の置換基、例えばフタルイミド基やアジド基等に置換したN-アセチルヘキソサミン供与体が使用されている(J. Banoub, Chem. Rev., 92, 1167 (1992))。しかし、これらの誘導体の合成には多段階にわたる合成工程が必要である。効率の良い合成を大規模に行うためには、出発物質の調製が容易であることが重要である。
【0003】
グリコシド結合形成反応時に、副生成物として生じるオキサゾリン誘導体を積極的にグリコシル化反応に利用する試みもなされている。しかしながら、木曽らの方法(Carbohydr. Res., 136, 309 (1985))は反応性の高い金属を使用しており大量の工業生産には適さない。またR. L. Thomas らの方法(Carbohydr. Res., 183, 163 (1988))は、再使用が困難な酸触媒を使用しており、これは工業生産の際にはコストが高くなる。これらの反応においては、受容体としてアルコール類を用いた場合はグリコシド結合を与えるが、糖を受容体とした場合は厳密に保護された、限られた糖受容体のみグリコシド結合が得られることが知られており普遍性に欠ける。さらにこれらの反応は、反対に関与しない糖水酸基に保護基を導入する必要があり、多くの工程数が必要となるために大量合成には向かない方法である。
【0004】
N-アセチルヘキソサミンのオキサゾリンを酵素の基質として利用し、グリコシド形成反応を行った例が報告されている(S. Kobayashi, J. Am. Chem. Soc., 118, 13113 (1996))。この場合、オキサゾリンおよび糖受容体の保護基は必要なく、実践的な方法である。しかし、この反応における糖受容体は、酵素の基質特異性により厳密に規制され、全ての糖類およびアルコール類等に適用できる方法であるとはいえない。
【0005】
【発明が解決しようとする課題】
従って、本発明の目的は、糖類、アルコール類、フェノール類等、多くのグリコシド受容体に対して、良好な収率および高いβ選択性で且つ大量調製に対応した容易なN-アセチル-β-ヘキソサミニド誘導体、ずなわち2-アセトアミド-2-デオキシ-β-D-グルコピラノシド誘導体および2-アセトアミド-2-デオキシ-β-D-ガラクトピラノシド誘導体の製造方法を提供することである。
【0006】
【課題を解決するための手段】
本発明者らは、上記課題を解決すべく種々検討した結果、保護基のないN-アセチルヘキソサミンのオキサゾリン化合物を供与体として、陽イオン交換樹脂を触媒として糖類、アルコール類、フェノール類に対するN-アセチル-β-ヘキソサミニド誘導体を合成できることを見い出し本発明を完成した。以下本発明を詳細に説明する。すなわち、本発明は、[1]陽イオン交換樹脂の触媒による、一般式(1)で表されるN-アセチルヘキソサミンのオキサゾリン化合物を糖供与体とし、糖類、アルコール類、またはフェノール類を糖受容体としたN-アセチル-β1-ヘキソサミニド誘導体の製造方法、[2]N-アセチル-β1-ヘキソサミニド誘導体が、2-アセトアミド-2-デオキシ-β1-D-ヘキソピラノシド誘導体である、前記[1]に記載の製造方法、[3]N-アセチル-β1-ヘキソサミニド誘導体が、2-アセトアミド-2-デオキシ-β1-D-グルコピラノシド誘導体および2-アセトアミド-2-デオキシ-β1-D-ガラクトピラノシド誘導体である、前記[1]に記載の製造方法、[4]N-アセチル-β1-ヘキソサミニド誘導体が、GlcNAcβ1-6Man、GlcNAcβ1-3Man、GlcNAcβ1-6Galβ-OpNp、GlcNAcβ1-OMeおよびGalNAcβ1-OMeである、前記[1]に記載の製造方法、[5]溶媒が、非プロトン性の極性溶媒である、前記[1]〜[4]のいずれか1つに記載の製造方法、に関する。
【0007】
【発明の実施の形態】
N-アセチル-β-ヘキソサミニド誘導体を有するオリゴ糖の合成について述べる。オキサゾリン化合物と糖受容体を非プロトン性の極性溶媒に溶解する。非プロトン性溶媒とは、ジメチルスルホキシド、ジメチルホルムアミド、ヘキサメチルホスホルアミド、トリエチルホスファイト等の有機溶媒を指す。オキサゾリン化合物と糖受容体との量比は1/100量から100当量であるが、糖受容体の濃度を高めると反応効率は向上する。オキサゾリン環を活性化してグリコシド形成反応を開始するための触媒としては、パラトルエンスルホン酸、カンファースルホン酸などの有機酸類や塩酸や硫酸等の鉱酸あるいは、陽イオン交換樹脂等、酸であれば何ら差し支えないが、操作性やコストの面から再生可能なイオン交換樹脂が有効である。
イオン交換樹脂としては、強酸性及び弱酸性陽イオン交換樹脂、たとえば、アンバーリスト15、アンバーリスト15E、アンバーリスト15WET、アンバーリスト16WET、アンバーリスト31、アンバーリスト35WET、アンバーリストA26、アンバーリストA21が使用できる。
【0008】
N-アセチルヘキソサミンにアルコールがβグリコシド結合したN-アセチル-β-ヘキソサミニド誘導体の合成は、オキサゾリン化合物を結合させるアルコールに溶解した後に、イオン交換樹脂でグリコシド形成反応を行うことによりほぼ定量的に進行する。また、高融点のアルコールを基質として用いる場合は、オリゴ糖合成と同様に、非プロトン性の極性溶媒に溶解する。オキサゾリン化合物とアルコール受容体との量比は触媒量から100当量であるが、アルコール受容体の濃度を高めると反応効率は向上する。
以下、本発明の実施例を示し、さらに詳しく説明するが本発明はこれらの実施例に限定されない。
【0009】
【実施例】
合成例 N-アセチルクルコサミンのオキサゾリンの合成
N-アセチルグルコサミンを無水酢酸、ピリジンにて反応することにより得られたパーアセチル化誘導体をルイス酸存在下反応することにより、オキサゾリンのアセチル誘導体(3)を得た(Stork, W. et al., J. Carbohydr. Chem. 2, 169-198 (1989))。
得られたオキサゾリンのアセチル誘導体(3)113mgをメタノールに溶解し1NのNaOMe100μL加え、室温で3時間攪拌した。メタノールを減圧除去後得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=4:1, 0.1%トリエチルアミン)にて精製してオキサゾリン(4)69mgを得た(定量的)。(図1)
実施例1:GlcNAcβ1-6Man及びGlcNAcβ1-3Manの合成
マンノース337mg(1.87mmol)と合成例で合成したオキサゾリン(4)38mg(0.18mmol)を0.6 mLの無水ジメチルスルホキシドに溶解し、これに300 mgのアンバーリスト15E(オルガノ社)を加え、室温で12時間撹拌した。イオン交換樹脂を濾別後、濾液を1 Lの水で希釈、活性炭カラム(2cm X 20cm)に供し、10%のエタノール水溶液で溶出することにより目的の2糖の混合物を 20 mg得た。HPLC(TSK、Amide-80カラム、21.5φx30cm、75%アセトニトリル、80℃、7ml/min)にて精製することによりGlcNAcβ1-6Man 9mg(0.023mmol)及びGlcNAcβ1-3Man 4mg(0.010mmol)を得た。(図2)
【0010】
実施例2:GlcNAcβ1-6Galβ-OpNpの合成
パラニトロフェニル-β-D-ガラクトピラノシド(Galβ-O-pNp)124mg(0.41mmol)とオキサゾリン(4)42mg(0.21mmol)を1 mLの無水ジメチルホルムアミドに溶解し、これに100 mgのアンバーリスト15Eを加え、室温で1時間撹拌した。イオン交換樹脂を濾別後、濾液を減圧除去した。得られた残渣を、HPLC(ODSカラム 10% アセトニトリル)を用いて精製する事により目的のGlcNAcβ1-6 Galβ-OpNpを2.5mg(0.024mmol)得た。(図3)
【0011】
実施例3:GlcNAcβ1-OMe の合成
オキサゾリン(4)782mg(3.85mmol)を8mLのメチルアルコールに溶解し、これに300mgのアンバーリスト15Eを加え、室温で1時間撹拌した。イオン交換樹脂を濾別後、濾液を減圧除去した。得られた残渣を、イソプロピルアルコール/イソプロピルエーテルから再結晶をすることによりGlcNAcβ-OMe 320mg(1.36mmol)得た。(図4)
【0012】
実施例4:GalNAcβ1-OMe の合成
N-アセチルガラクトサミンを原料に合成例と同様の方法にて調整したオキサゾリン(5)500mg(3.85mmol)を30mLの無水メチルアルコールに溶解し、水酸化ナトリウム溶液(1M、200μl)を加えて室温で10分攪拌して脱アセチル化を行った。続いてアンバーリスト15Eを中性になるまで加え、室温で1時間攪拌した。イオン交換樹脂を濾別後、濾液を減圧濃縮し生成物(298mg)を得た。得られた化合物の1H NMRは別途合成したGalNAcβ1-OMeのものと一致した。(図5)
【0013】
【発明の効果】
本発明の方法によって得られる化合物は、糖蛋白質糖鎖を構成するオリゴ糖やパラニトロフェニル-2-アセトアミド-2-デオキシ-β-D-グリコサミニド等のN-アセチル-β-ヘキソサミニド誘導体であり、抗体などのプローブとして、またDDSのキャリアーとして、酵素活性測定用の基質として、医薬品および合成原料、研究用試薬等として有用である。
【図面の簡単な説明】
【図1】オキサゾリン誘導体の合成反応式
【図2】オキサゾリン誘導体とマンノースとの反応の合成反応式(実施例1)。
【図3】オキサゾリン誘導体とパラニトラフェニルガラクトピラノシドとの反応の合成反応式(実施例2)。
【図4】グルコオキサゾリン誘導体とメタノールとの反応の合成反応式(実施例3)。
【図5】ガラクトオキサゾリン誘導体とメタノールとの反応の合成反応式(実施例4)。[0001]
[Technical field to which the invention belongs]
The present invention relates to a method for specifically producing an oligosaccharide having an N-acetyl-β-hexosaminide derivative, particularly 2-acetamido-2-deoxy-β-D-hexopyranoside. An N-acetylhexosamine oxazoline and a glycosyl acceptor are reacted to produce an N-acetyl-β-hexosaminide derivative, which is characterized by using an acid catalyst, particularly an ion exchange resin that can be recycled.
[0002]
[Prior art]
In general, the glycosidic bond forming reaction for synthesizing oligosaccharides is performed by activating the C-1 position of the glycosyl donor and simultaneously reacting with the hydroxyl group of the acceptor. However, many methods have the disadvantage that only low yields and poor stereoselectivity can be obtained while using expensive, highly toxic heavy metals or acid catalysts that are difficult to reuse as activators. Therefore, synthesis on an industrial scale was difficult (K. Toshima, Chem. Rev., 93, 1503 (1993)). In particular, in the synthesis of an N-acetyl-β-hexosaminide derivative, when an N-acetylhexosamine derivative having an active group at the 1-position is used as a sugar donor, an acetamide group at the C-2 position and a C- It is known that an oxazoline ring is formed between the 1-position, the yield is lowered, and it does not react with a hydroxyl group of a sugar having low reactivity. In the reaction to synthesize N-acetyl-β-hexosaminide derivatives to solve this problem, N-acetylhexosamine donors in which the acetamido group at the C-2 position is substituted with other substituents such as phthalimide group or azide group (J. Banoub, Chem. Rev., 92, 1167 (1992)). However, the synthesis of these derivatives requires a multi-step synthesis process. In order to perform an efficient synthesis on a large scale, it is important that the starting material is easily prepared.
[0003]
Attempts have been made to positively utilize the oxazoline derivative produced as a by-product during the glycosidic bond formation reaction in the glycosylation reaction. However, the method of Kiso et al. (Carbohydr. Res., 136, 309 (1985)) uses highly reactive metals and is not suitable for large-scale industrial production. In addition, the method of RL Thomas et al. (Carbohydr. Res., 183, 163 (1988)) uses an acid catalyst that is difficult to reuse, which is expensive in industrial production. In these reactions, when alcohols are used as receptors, glycosidic bonds are given, but when sugars are used as receptors, it is possible to obtain glycosidic bonds only with limited sugar receptors that are strictly protected. Known and lacks universality. Furthermore, these reactions are not suitable for mass synthesis because it is necessary to introduce a protecting group to a sugar hydroxyl group that is not involved in the opposite, and many steps are required.
[0004]
An example of a glycoside formation reaction using oxazoline of N-acetylhexosamine as an enzyme substrate has been reported (S. Kobayashi, J. Am. Chem. Soc., 118, 13113 (1996)). In this case, oxazoline and sugar receptor protecting groups are not necessary and are a practical method. However, the sugar receptor in this reaction is strictly regulated by the substrate specificity of the enzyme, and cannot be said to be a method that can be applied to all saccharides, alcohols and the like.
[0005]
[Problems to be solved by the invention]
Therefore, the object of the present invention is to provide an easy N-acetyl-β-type for many glycoside receptors such as sugars, alcohols, phenols, etc., with good yield and high β-selectivity and corresponding to large-scale preparation. It is to provide a process for producing hexosaminide derivatives, namely 2-acetamido-2-deoxy-β-D-glucopyranoside derivatives and 2-acetamido-2-deoxy-β-D-galactopyranoside derivatives.
[0006]
[Means for Solving the Problems]
As a result of various studies to solve the above-mentioned problems, the present inventors have determined that N-acetylhexosamine oxazoline compound having no protecting group is a donor, a cation exchange resin is used as a catalyst, and N--to saccharides, alcohols and phenols. The present invention was completed by finding that an acetyl-β-hexosaminide derivative can be synthesized. The present invention will be described in detail below. That is, the present invention is [1] catalyzed by a cation exchange resin, an N-acetylhexosamine oxazoline compound represented by the general formula (1) is used as a sugar donor, and sugars, alcohols, or phenols are sugar-accepting. manufacturing method of a body N- acetyl -β1- Hekisosaminido derivatives, [2] N- acetyl -β1- Hekisosaminido derivative is 2-acetamido-2-deoxy-beta1-D-hexopyranoside derivative, to the [1] the method of manufacturing described, [3] N-acetyl -β1- Hekisosaminido derivative, 2-acetamido-2-deoxy-beta1-D-glucopyranoside derivative and 2-acetamido-2-deoxy-beta1-D-galactopyranoside derivative The production method according to [1] above, wherein the [4] N-acetyl-β1-hexosaminide derivative is GlcNAcβ1-6Man, GlcNAcβ1-3Man, GlcNAcβ1-6Galβ-OpNp, GlcNAcβ1-OMe and GalNAcβ1-OMe, Product described in [1] above And [5] the production method according to any one of [1] to [4], wherein the solvent is an aprotic polar solvent .
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The synthesis of oligosaccharides having N-acetyl-β-hexosaminide derivatives is described. An oxazoline compound and a sugar acceptor are dissolved in an aprotic polar solvent. The aprotic solvent refers to an organic solvent such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, triethyl phosphite. The amount ratio between the oxazoline compound and the sugar receptor is 1/100 to 100 equivalents, but increasing the concentration of the sugar receptor improves the reaction efficiency. Catalysts for activating the oxazoline ring to initiate the glycoside formation reaction include organic acids such as para-toluenesulfonic acid and camphorsulfonic acid, mineral acids such as hydrochloric acid and sulfuric acid, and cation exchange resins. Although there is no problem, an ion exchange resin that can be regenerated is effective from the viewpoint of operability and cost.
Examples of the ion exchange resin include strongly acidic and weakly acidic cation exchange resins such as Amberlist 15, Amberlist 15E, Amberlist 15WET, Amberlist 16WET, Amberlist 31, Amberlist 35WET, Amberlist A26, and Amberlist A21. Can be used.
[0008]
The synthesis of N-acetyl-β-hexosaminide derivatives, in which alcohol is β-glycosidically bonded to N-acetylhexosamine, proceeds almost quantitatively by dissolving in the alcohol that binds the oxazoline compound and then performing a glycoside formation reaction with an ion exchange resin. To do. When a high melting point alcohol is used as a substrate, it is dissolved in an aprotic polar solvent as in the oligosaccharide synthesis. The amount ratio of the oxazoline compound to the alcohol acceptor is 100 equivalents from the amount of catalyst, but the reaction efficiency is improved by increasing the concentration of the alcohol acceptor.
Examples of the present invention will be described below in more detail, but the present invention is not limited to these examples.
[0009]
【Example】
Synthesis example Synthesis of N-acetylcurcosamine oxazoline
By reacting a peracetylated derivative obtained by reacting N-acetylglucosamine with acetic anhydride and pyridine in the presence of a Lewis acid, an acetyl derivative (3) of oxazoline was obtained (Stork, W. et al. , J. Carbohydr. Chem. 2, 169-198 (1989)).
113 mg of the obtained oxazoline acetyl derivative (3) 113 mg was dissolved in methanol, 100 μL of 1N NaOMe was added, and the mixture was stirred at room temperature for 3 hours. The residue obtained after removing methanol under reduced pressure was purified by silica gel column chromatography (chloroform: methanol = 4: 1, 0.1% triethylamine) to obtain 69 mg of oxazoline (4) (quantitative). (Fig. 1)
Example 1: Synthesis of GlcNAcβ1-6Man and GlcNAcβ1-3Man Mannose 337 mg (1.87 mmol) and oxazoline (4) 38 mg (0.18 mmol) synthesized in the synthesis example were dissolved in 0.6 mL of anhydrous dimethyl sulfoxide, and 300 mg of Amberlyst 15E (Organo) was added and stirred at room temperature for 12 hours. After the ion exchange resin was filtered off, the filtrate was diluted with 1 L of water, applied to an activated carbon column (2 cm × 20 cm), and eluted with a 10% aqueous ethanol solution to obtain 20 mg of the desired disaccharide mixture. GlcNAcβ1-6Man 9 mg (0.023 mmol) and GlcNAcβ1-
[0010]
Example 2: Synthesis of GlcNAcβ1-6Galβ-OpNp Paranitrophenyl-β-D-galactopyranoside (Galβ-O-pNp) 124 mg (0.41 mmol) and oxazoline (4) 42 mg (0.21 mmol) in 1 mL anhydrous It was dissolved in dimethylformamide, 100 mg of Amberlyst 15E was added thereto, and the mixture was stirred at room temperature for 1 hour. After the ion exchange resin was filtered off, the filtrate was removed under reduced pressure. The obtained residue was purified using HPLC (ODS column 10% acetonitrile) to obtain 2.5 mg (0.024 mmol) of the desired GlcNAcβ1-6 Galβ-OpNp. (Figure 3)
[0011]
Example 3 Synthesis of GlcNAcβ1-OMe Oxazoline (4) 782 mg (3.85 mmol) was dissolved in 8 mL of methyl alcohol, 300 mg of Amberlyst 15E was added thereto, and the mixture was stirred at room temperature for 1 hour. After the ion exchange resin was filtered off, the filtrate was removed under reduced pressure. The obtained residue was recrystallized from isopropyl alcohol / isopropyl ether to obtain 320 mg (1.36 mmol) of GlcNAcβ-OMe. (Fig. 4)
[0012]
Example 4: Synthesis of GalNAcβ1-OMe
Oxazoline (5) 500 mg (3.85 mmol) prepared using N-acetylgalactosamine as a raw material in the same manner as in the synthesis example is dissolved in 30 mL of anhydrous methyl alcohol, and sodium hydroxide solution (1 M, 200 μl) is added at room temperature. Deacetylation was carried out by stirring for 10 minutes. Subsequently, Amberlyst 15E was added until neutral and stirred at room temperature for 1 hour. After the ion exchange resin was filtered off, the filtrate was concentrated under reduced pressure to obtain the product (298 mg). 1 H NMR of the obtained compound was consistent with that of GalNAcβ1-OMe synthesized separately. (Fig. 5)
[0013]
【The invention's effect】
The compound obtained by the method of the present invention is an N-acetyl-β-hexosaminide derivative such as an oligosaccharide constituting a glycoprotein sugar chain or paranitrophenyl-2-acetamido-2-deoxy-β-D-glycosaminide, It is useful as a probe such as an antibody, as a carrier for DDS, as a substrate for measuring enzyme activity, as a pharmaceutical, a synthetic raw material, a research reagent, or the like.
[Brief description of the drawings]
1 is a synthetic reaction formula of an oxazoline derivative. FIG. 2 is a synthetic reaction formula of a reaction between an oxazoline derivative and mannose (Example 1).
FIG. 3 shows a synthetic reaction formula of a reaction between an oxazoline derivative and paranitraphenyl galactopyranoside (Example 2).
FIG. 4 is a synthetic reaction formula for the reaction of a glucooxazoline derivative and methanol (Example 3).
FIG. 5 shows a synthetic reaction formula for the reaction of a galactooxazoline derivative and methanol (Example 4).
Claims (5)
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Citations (2)
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JPH06505638A (en) * | 1991-03-18 | 1994-06-30 | ザ スクリップス リサーチ インスティテュート | Oligosaccharide enzyme substrates and inhibitors: methods and compositions |
JPH09216948A (en) * | 1996-02-08 | 1997-08-19 | Kao Corp | Modified polysiloxane and its production |
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JPH06505638A (en) * | 1991-03-18 | 1994-06-30 | ザ スクリップス リサーチ インスティテュート | Oligosaccharide enzyme substrates and inhibitors: methods and compositions |
JPH09216948A (en) * | 1996-02-08 | 1997-08-19 | Kao Corp | Modified polysiloxane and its production |
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