WO2014125967A1 - COMPOSÉ DE PYRANOSE 3,6-O-RÉTICULÉ ET PROCÉDÉ DE PRODUCTION D'α-O-PYRANOSIDE - Google Patents

COMPOSÉ DE PYRANOSE 3,6-O-RÉTICULÉ ET PROCÉDÉ DE PRODUCTION D'α-O-PYRANOSIDE Download PDF

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WO2014125967A1
WO2014125967A1 PCT/JP2014/052564 JP2014052564W WO2014125967A1 WO 2014125967 A1 WO2014125967 A1 WO 2014125967A1 JP 2014052564 W JP2014052564 W JP 2014052564W WO 2014125967 A1 WO2014125967 A1 WO 2014125967A1
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group
compound
reaction
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methylene
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英俊 山田
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学校法人関西学院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a process for producing 3,6-O-bridged pyranose compounds and ⁇ -O-pyranoside.
  • Non-patent Document 1 As a glycosylation method by highly alpha selective chemical synthesis, a chemical preparation method using a benzyl group in which adjacent group participation does not occur as a protecting group at the 2-position of pyranose is shown (Non-patent Document 1). However, this method is a method to prevent the occurrence of ⁇ -selective adjacent group participation when an acyl group is used as the 2-position protecting group, and therefore, a strict reaction is required to cause the reaction to proceed ⁇ -selectively. It is necessary to set conditions.
  • Non-patent Documents 2 and 3 chemical production methods have also been proposed that make use of ⁇ -selective neighboring group participation.
  • Non-patent Documents 2 and 3 chemical production methods have also been proposed that make use of ⁇ -selective neighboring group participation.
  • Non-patent Document 4 a method using a bicyclo compound of pyranose and 1,4-oxathiane ring has also been proposed (Non-patent Document 4). However, this method also has limitations in the 1- and 2-position protecting groups.
  • the object of the present invention is to provide a method for easily producing ⁇ -O-pyranoside with high selectivity and a pyranose donor used for the method, without setting highly versatile and strict reaction conditions. It is to be.
  • the present inventors succeeded in synthesizing a 3,6-O-bridged pyranose compound represented by the following general formula (1). It has been found that the -O-bridged pyranose compound can be the desired ⁇ -O-glycosylation agent. The present invention has been completed based on such findings.
  • the present invention provides a method for producing 3,6-O-bridged pyranose compounds shown in the following items 1 and 2 and ⁇ -O-pyranoside shown in the items 3.
  • R 1 represents a —SR 6 group (R 6 represents a lower alkyl group which may have a substituent or an aryl group which may have a substituent on the aromatic ring), —OR 7]
  • R 7 represents a hydrogen atom, a protecting group of a hydroxyl group or a group acting as a leaving group with a bonded oxygen atom) or a halogen atom.
  • R 2 represents a hydrogen atom or a hydroxyl protective group.
  • R 3 represents a hydrogen atom or a hydroxyl protective group.
  • R 4 and R 5 are the same or different and each represents a lower alkyl group which may be substituted by a halogen atom, a lower alkoxy group which may be substituted by a halogen atom, a nitro group or a halogen atom.
  • n represents an integer of 1 to 4;
  • p and q each represent an integer of 0 to 4;
  • the p R 4 s may be the same or different, and the q R 5 s may be the same or different.
  • the p adjacent R 4 groups may be bonded to each other to form a benzene ring, and the q adjacent R 5 groups may be bonded to each other to form a benzene ring.
  • Item 3. The 3,6-O-bridged pyranose compound according to Item 1, or an enantiomer thereof, wherein R 1 in the general formula (1) is a halogen atom.
  • Item 3. The 3,6-O-bridged pyranose compound according to item 2 is a compound represented by the general formula (2) R 8 OH (2) [Wherein, R 8 represents a residue of a primary, secondary or tertiary alcohol. ]
  • 3,6-O-Bridged Pyranose Compound The 3,6-O-bridged pyranose compound of the present invention is represented by the following general formula (1).
  • the lower alkyl group means an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, n-propyl and iso-propyl.
  • the lower alkoxy group is an alkoxy group having 1 to 6 carbon atoms, preferably an alkoxy group having 1 to 4 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group and an n-butoxy group.
  • the lower alkanoyl group is an alkanoyl group having 1 to 6 carbon atoms, preferably an alkanoyl group having 1 to 4 carbon atoms, and examples thereof include an acetyl group, a propanoyl group, a butanoyl group, a 2-methylpropanoyl group and a pentanoyl group. Examples thereof include 2-methylbutanoyl group, 3-methylbutanoyl group, tert-butylcarbonyl group, hexanoyl group and the like.
  • aryl group a phenyl group, a naphthyl group, etc. are mentioned, for example.
  • aryloxy group a phenoxy group, a naphthyloxy group, etc. are mentioned, for example.
  • the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • the protective group for hydroxyl group may be a conventional protective group for hydroxyl group widely known to date, for example, allyl group; methallyl group; a group comprising a halogen atom as a substituent, a lower alkoxy group and an aryloxy group Or lower alkyl group optionally having 1 to 5 at least one group selected from: at least one group selected from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups as substituents, on an aromatic ring 1 to 3 phenyl groups which may be contained; 1 to 3 at least one group selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups and nitro groups as substituents on aromatic rings Benzyl group which may be substituted; at least one group selected from the group consisting of halogen atoms, lower alkyl groups and lower alkoxy groups as substituents Triphenylmethyl group which may have 1 to 3 on an aromatic ring; formyl group; at least
  • allyl group methallyl group, methyl group, ethyl group, tert-butyl group, methoxymethyl group, 4-methoxyphenyl group, benzyl group, dimethylbenzyl group, 4-methoxybenzyl group, 2-nitrobenzyl group And triphenylmethyl group, formyl group, acetyl group, propionyl group, tert-butylcarbonyl group, benzoyl group, tri-lower alkylsilyl group, tert-butyldiphenylsilyl group and the like.
  • these protecting groups allyl, benzyl, dimethylbenzyl, 4-methoxybenzyl and tri-lower alkylsilyl are preferable.
  • R 6 represents a lower alkyl group
  • substituent on the alkyl include a lower alkoxy group, an aryl group, a halogen atom and the like, and more specifically, a methoxy group, an ethoxy group, a phenyl group, a halogen atom Etc.
  • R 6 represents an aryl group
  • substituent on the aromatic ring include a lower alkyl group, a lower alkoxy group, a halogen atom and the like, and more specifically, a methyl group, an ethyl group, a methoxy group , An ethoxy group, a halogen atom and the like.
  • the group represented by R 7 which acts as a leaving group together with the oxygen atom to be bound may be an existing group which is widely known to date, and has an imide group; 1 to 5 halogen atoms Lower alkylsulfonyl group which may be substituted; benzene which may have on the aromatic ring at least one group selected from the group consisting of halogen atoms, lower alkyl groups, lower alkoxy groups and nitro groups as substituents A sulfonyl group etc. are mentioned.
  • trichloroacetoimido group 4-trifluoromethylbenzylthio-N- (4-trifluoromethylphenyl) formimido group, methanesulfonyl group, trifluoromethanesulfonyl group, 4-toluenesulfonyl group, 2-nitrobenzene sulfonyl group And the like.
  • p adjacent R 4 's are bonded to each other to form a benzene ring, for example, benzene in which two adjacent R 4 ' s are bonded to each other and R 4 is bonded
  • a naphthalene ring is formed with a ring
  • R 2 in the general formula (1) is a hydrogen atom or a hydroxyl protecting group.
  • the protective group for hydroxyl group those similar to the protective group for hydroxyl group described above are used.
  • R 3 in the general formula (1) is a hydrogen atom or a hydroxyl protecting group.
  • the protective group for hydroxyl group those similar to the protective group for hydroxyl group described above are used.
  • n in the general formula (1) is an integer of 1 to 4, preferably an integer of 1 to 3, more preferably an integer of 2 to 3, and particularly preferably 2.
  • p and q in the general formula (1) are each an integer of 0 to 4, but both p and q are preferably an integer of 0 to 2, and particularly preferably 0 or 1.
  • the 3,6-O-bridged pyranose compound represented by the general formula (1) has a chemical structure in which two aromatic rings in the bridge portion thereof are linked via an alkylene group. Therefore, since the cross-linked part of the 3,6-O-crosslinked pyranose compound has an appropriate degree of freedom in structure, it has an advantage that the reaction of removing the cross-linked part from pyranose tends to progress.
  • the enantiomer of the 3,6-O-bridged pyranose compound represented by the general formula (1) means a 3,6-O-bridged pyranose compound represented by the following general formula (1 ').
  • R 1, R 2, R 3, R 4, R 5, n, p and q are as defined above.
  • the 3,6-O-bridged pyranose compound represented by the general formula (1) can also be represented as the following formula in consideration of its conformation.
  • the 3,6-O-bridged pyranose compounds represented by the general formula (1) include compounds represented by the following general formulas (1A), (1B) and (1C).
  • X represents a halogen atom.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , n, p and q are as defined above.
  • These compounds can also be represented as in the following formula in consideration of their conformations.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, n, p and q are as defined above.
  • preferred compounds are those represented by the following general formulas (1a), (1b), (1c), (1d) and (1e) It is a compound represented.
  • R 4 , R 5 , R 6 , n, p and q are as defined above.
  • R 2 ′ and R 3 ′ each represent a hydroxyl protecting group.
  • X 1 and X 2 each represent a halogen atom.
  • the reaction of the compound (4) with the compound (5) can be carried out, for example, by using a basic compound such as sodium hydride in a suitable solvent such as a mixed solvent of toluene and dimethylformamide (DMF) as shown in Example 1 later. It takes place in the presence.
  • the reaction is preferably carried out by dropping the solution of compound (4) and the solution of compound (5) at a suitable rate, respectively, into the solution or suspension of the basic compound.
  • the reaction should be stirred for 10 to 20 hours at a temperature between 70 ° C. and the boiling point of the solvent.
  • the compound (4) used as a starting material is a known compound
  • the compound (5) is a known compound or a compound which can be easily produced from a known compound.
  • the mixing ratio of toluene and DMF can be, for example, a mixed solvent of 0.1 to 1 DMF with 1 L of toluene.
  • the reaction for converting the compound (6) to the compound (1A-1) is carried out, for example, by two steps as shown in Example 1 described later.
  • R 6 SH (wherein R 6 is as defined above) is reacted with compound (6) in the presence of a Lewis acid such as trifluoromethanesulfonic acid trimethylsilyl and molecular sieves in a suitable solvent such as dichloromethane.
  • a Lewis acid such as trifluoromethanesulfonic acid trimethylsilyl and molecular sieves
  • a suitable solvent such as dichloromethane.
  • step A and the step of reacting the product obtained in step A with a basic compound such as sodium methoxide in an alcohol solvent such as methanol
  • the reaction in step A preferably has a reaction temperature of ⁇ 78 to 25 ° C. and a reaction time of 1 to 60 minutes.
  • the reaction in step B preferably has a reaction temperature of 0 to 65 ° C. (more preferably around room temperature) and a reaction time of 5 to 60 minutes.
  • the amount of the basic compound used can be, for example, 0.001 to 10 moles of the basic compound per 1 mole of the compound (6) used in the reaction of step A.
  • the reaction for converting the compound (1A-1) to the compound (1A-2) can be carried out in the presence of a basic compound under the general conditions for introducing a protecting group to a hydroxyl group.
  • a basic compound under the general conditions for introducing a protecting group to a hydroxyl group.
  • it can be carried out in a suitable solvent such as a mixed solvent of toluene and DMF in the presence of a basic compound such as sodium hydride.
  • the reaction is preferably carried out at a reaction temperature of 20 to 100 ° C. and a reaction time of 30 to 120 minutes.
  • the mixing ratio of toluene and DMF can be, for example, a solvent in which 0.2 to 2 L of DMF is mixed with 1 L of toluene in volume ratio.
  • the reaction is preferably carried out by adding copper (II) chloride to a stirred mixture solution of compound (1A-1) and a basic compound, and then adding R 2 ′ X 3 .
  • the desired compound (1A-2) can be obtained from the compound obtained under the general conditions for introducing a protective group to a hydroxyl group in the presence of a basic compound.
  • R 7 ′ represents a hydroxyl-protecting group or a group which acts as a leaving group together with the bonded oxygen atom.
  • the reaction for converting the compound (1A) to the compound (1B-1) is carried out, for example, as shown in Example 3 below, in a suitable solvent such as a mixed solvent of acetone and water, N-halosuccinimide such as N-bromosuccinimide In the presence of The reaction is preferably carried out at a reaction temperature of ⁇ 40 to 30 ° C. and a reaction time of 0.1 to 4 hours.
  • the mixing ratio of acetone and water may be, for example, a solvent in which 0.01 to 0.5 L of water is mixed with 1 L of acetone in volume ratio.
  • the reaction for introducing the compound (1B-1) into the compound (1B-2) is carried out under the general conditions of introducing a protecting group or a group acting as a leaving group together with an oxygen atom bonded to a hydroxyl group in the presence of a basic compound. To be done.
  • the reaction for converting the compound (1B-1) to the compound (1C) is carried out, for example, as described in Example 4 below, in a suitable solvent such as tetrahydrofuran, the presence of a halogenating agent such as diethylaminosulfur trifluoride (DAST) It takes place below.
  • a halogenating agent such as diethylaminosulfur trifluoride (DAST) It takes place below.
  • DAST diethylaminosulfur trifluoride
  • the reaction is preferably carried out at a reaction temperature of ⁇ 20 to 40 ° C. and a reaction time of 1 to 60 minutes. In the reaction, it is preferable to use 1 to 6 moles of a halogenating agent relative to 1 mole of a compound (1B-1).
  • the compounds represented by the general formula (1 ') can also be produced by carrying out the same reaction except that the corresponding enantiomer is used as the starting material in each of the above reaction formulas.
  • the compound represented by the general formula (1) obtained by the above reaction is separated from the reaction mixture by a conventional separation means and purified.
  • separation and purification means may include, for example, distillation, recrystallization, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction, etc. it can.
  • the crosslinking portion can be removed from pyranose depending on the conditions of hydrogenation.
  • the reaction is carried out under a hydrogen atmosphere in the presence of a hydrogenation catalyst.
  • a hydrogenation catalyst an existing hydrogenation catalyst widely known to date may be used, and examples thereof include palladium / carbon, palladium hydroxide / carbon and the like.
  • the compounds represented by the general formula (1) of the present invention are suitable as glycosylation agents as an alpha selective sugar donor.
  • the reason why a glycosidic bond is formed ⁇ -selectively is not clear yet, but since the bridge portion has a shape covering one side of the pyranose ring, it is selected from the ⁇ -plane by steric repulsion on the ⁇ -plane It is presumed that the reaction proceeds in a
  • the compound represented by the general formula (1) of the present invention acts as an ⁇ -selective sugar donor, and then the reaction for removing the cross-linked portion as described above is represented by an ⁇ -O-pyranoside represented by the general formula (3)
  • the reaction for removing the cross-linked portion as described above is represented by an ⁇ -O-pyranoside represented by the general formula (3)
  • R 2 , R 3 , R 4 , R 5 , R 8 , X, n, p and q are as defined above.
  • the residue of the primary, secondary or tertiary alcohol represented by R 8 is the remaining group obtained by removing the hydroxyl group from the primary, secondary or tertiary alcohol.
  • the alcohol of the general formula (2) is a known compound and is not particularly limited, but lower alcohol having a cycloalkyl group having 3 to 8 carbon atoms such as cyclohexylmethanol or sugar having a hydroxyl group, glycolipid and Glycoprotein etc. are mentioned.
  • reaction of the compound of the general formula (1C) with the alcohol of the general formula (2) is carried out, for example, in a suitable solvent such as diethyl ether.
  • a suitable solvent such as diethyl ether.
  • solvents are preferably anhydrous solvents.
  • the proportion of the compound (1C) to the alcohol (2) used is usually 0.5 to 2 moles, preferably 1 to 1.2 moles of alcohol (2) per 1 mole of compound (1C). That's good.
  • an activating agent present in the reaction system.
  • the activating agent include combinations of dicyclopentadienyl zirconium dichloride (Cp 2 ZrCl 2 ) / silver (I) perchlorate (AgClO 4 ), and the like.
  • the amount of the activating agent used is usually about 1 to 5 moles, preferably about 1 to 3 moles of Cp 2 ZrCl 2 and preferably about 1 to 7 moles of AgClO 4 per 1 mole of the compound (1C). Is about 1 to 5 moles.
  • molecular sieves e.g, molecular sieves 4A
  • the presence of molecular sieves further improves the yield of the compound (3) which is the target compound.
  • This reaction usually proceeds suitably at about -90 to 0 ° C, preferably at -80 to -40 ° C.
  • the ⁇ -O-pyranoside obtained by the above reaction is separated from the reaction mixture by, for example, ordinary separation means and purified.
  • separation and purification means those described above can be mentioned.
  • the various ⁇ -O-pyranosides obtained by the above reaction can be used, for example, in important applications such as the synthesis of saccharides, glycolipids and glycoproteins.
  • the 3,6-O-bridged pyranose compound represented by the general formula (1) of the present invention or an enantiomer thereof can be suitably used as an ⁇ -O-glycosylation agent.
  • the invention will be further clarified by the following examples.
  • the reaction was carried out under an atmosphere of nitrogen or argon if necessary.
  • purification by silica gel chromatography used silica gel 60 N (granular, neutral, 40-50 ⁇ m) or silica gel 60 N (granular, neutral, 63-210 ⁇ m) (both manufactured by Kanto Chemical Co., Ltd.).
  • IR JASCO FT / IR-4200 (ATR; total internal reflection method)
  • Specific rotation JASCO DIP-370 (100 mm cell, wavelength: 589 nm, solvent: CHCl 3 )
  • NMR JEOL JNM-ECX-400 ( 1 H: 400 MHz, 13 C: 100 MHz)
  • the number of hydrogen atoms bonded to the carbon is measured by the DEPT method, and is indicated by C (s), CH (d), CH 2 (t), and CH 3 (q), respectively.
  • the HRMS JEOL JMS-700 (ionization method: ESI).
  • Ph represents a phenyl group.
  • the extract solution is dried over anhydrous magnesium sulfate and filtered through a cotton plug, and then the solvent is distilled off, and phenyl 3,6-O- [bibenzyl-2,2'-bis (methylene)]-1-thio-D- A crude product of glucopyranoside was obtained.
  • the physicochemical properties of each are as follows.
  • Ph is the same as above.
  • Bn represents a benzyl group.
  • phenyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-1-thio-D-glucopyranoside ⁇ -isomer and ⁇ -isomer are in Example 2, each separated phenyl 3,6-O- [bibenzyl-2,2'-bis (methylene)]-1-thio- ⁇ -D-glucopyranoside or phenyl 3,6-O- [bibenzyl-2 It was obtained by using 2,2'-bis (methylene)]-1-thio- ⁇ -D-glucopyranoside as a raw material.
  • the physicochemical properties of each are as follows.
  • 1 H-NMR 400 MHz, CDCl 3 ): ⁇ ppm 7.55-7.29 (m, 13 H), 7.25-7. 13 (m, 10 H), 5.
  • the resulting mixture was extracted with ethyl acetate (10 mL ⁇ 2), the extracts were combined, and this was washed with saturated brine (1 ⁇ 5 mL). Further, the extract solution was dried over anhydrous magnesium sulfate and filtered through a cotton plug, and then the solvent was distilled off to obtain a crude product.
  • the resulting mixture was diluted with diethyl ether (20 mL) and then filtered through cotton and celite to remove molecular sieves from the mixture. After separating the organic layer, the organic layer was washed with saturated brine (5 mL ⁇ 1). The organic layer was further dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated to give a crude product as a mixture of anomeric isomers.
  • Examples 6-8 The reaction was carried out in the same manner as in Example 5 except that the reaction temperature and the reaction time were as shown in Table 1 below.
  • the yield and ratio of anomers of the obtained cyclohexylmethyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-D-glucopyranoside are shown in the following table. Shown in 1.
  • the yield and ratio of anomeric isomers in Examples 6 to 8 were determined from 1 H-NMR (solvent: CDCl 3 , standard substance: acetone, and ⁇ / ⁇ is the ratio of the integrated value of anomeric hydrogen peak).
  • Examples 10 to 18 The reaction was carried out in the same manner as in Example 5 except that the reaction temperature was 25 ° C., the reaction solvent and the reaction time were as shown in Table 2 below. Yield and anomer of cyclohexylmethyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-D-glucopyranoside determined by the same method as in Example 6. The proportions of the isomers are shown in Table 2 below. In Table 2, Et is ethyl, i-Pr is isopropyl, t-Bu is tertiary butyl, THF is tetrahydrofuran, and CPME is cyclopentyl methyl ether.
  • Example 3 The reaction was performed in the same manner as in Example 3 except that the alcohol described in Table 3 below was used instead of cyclohexylmethanol.
  • the yield of the resulting compound and the ratio of anomers are shown in Table 3 below.
  • Examples 20 to 23 are the yields determined using 1 H-NMR (solvent: CDCl 3 , standard substance: acetone), and
  • Example 24 is the isolated yield.
  • the resulting compound is subjected to catalytic hydrogenation to deprotect benzyl groups such as 2 and 4 and bibenzyl 2,2'-bismethylene groups at 3 and 6 and then using each alcohol with acetic anhydride and pyridine. Acetylation led to known compounds, and ⁇ / ⁇ isomers were identified.
  • N-bromosuccinimide N-bromosuccinimide
  • cyclohexylmethanol 3.7 mg, 33 ⁇ mol
  • the reaction mixture was then quenched with 10% aqueous sodium sulfite solution (10 mL) and filtered through cotton and celite to remove molecular sieves 4A.
  • the filtrate was extracted with ethyl acetate (20 mL ⁇ 2), the extracts were combined, and this was washed with 10% aqueous sodium sulfite solution (20 mL) and saturated brine (20 mL).
  • the washed extract was dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated to give a crude product.
  • the yield and ratio of anomeric isomers of cyclohexylmethyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-D-glucopyranoside in the crude product are The yield is 71% as determined from 1 H-NMR (solvent: CDCl 3 , standard substance: acetone, ⁇ / ⁇ is the ratio of the integrated value of the OCH 2 hydrogen peaks of the cyclohexylmethoxy group), and the yield is 71%.
  • Example 26 ⁇ -Glycosylation reaction of phenyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-1-thio- ⁇ -D-glucopyranoside
  • Molecular sieves 4A (33.1 mg)
  • phenyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-1-thio- ⁇ -D-glucopyranoside 7.4 mg
  • a mixture of 11 ⁇ mol) and ethyl acetate (0.6 mL) was stirred at 0 ° C. for 5 minutes.
  • N-bromosuccinimide N-bromosuccinimide (NBS; 2.4 mg, 13 ⁇ mol) and cyclohexylmethanol (1.5 mg, 13 ⁇ mol) at 0 ° C. and stirred at 0 ° C. for 1 hour.
  • the reaction mixture was then quenched with 10% aqueous sodium sulfite solution (10 mL) and filtered through cotton and celite to remove molecular sieves 4A.
  • the filtrate was extracted with ethyl acetate (10 mL ⁇ 3), the extracts were combined, and this was washed with 10% aqueous sodium sulfite solution (10 mL) and saturated brine (10 mL).
  • the washed extract was dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated to give a crude product.
  • the yield and ratio of anomeric isomers of cyclohexylmethyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-D-glucopyranoside in the crude product are The yield is 67% as determined from 1 H-NMR (solvent: CDCl 3 , standard substance: acetone, and ⁇ / ⁇ is the ratio of the integrated value of OCH 2 hydrogen peaks of cyclohexylmethoxy group), and the yield is 67%.
  • Activated molecular sieves 4A (85.3 mg), phenyl 2,4-di-O-benzyl-3,6-O- [bibenzyl-2,2'-bis (methylene)]-1-thio- ⁇ -D- Glucopyranoside (18.4 mg, 27.9 ⁇ mol) and (+)-dihydrocholesterol (13.5 mg, 34.7 ⁇ mol) were added to ethyl acetate (1.4 mL) and stirred at 0 ° C. for 5 minutes. While cooling to 0 ° C., N-bromosuccinimide (NBS, 5.8 mg, 33 ⁇ mol) was added to the reaction solution, and the mixture was stirred for 2 hours while maintaining the temperature.
  • N-bromosuccinimide N-bromosuccinimide
  • the reaction was quenched by addition of 10% aqueous sodium sulfite solution.
  • the resulting reaction mixture was filtered through cotton and celite to remove molecular sieves 4A.
  • the filtrate was extracted with ethyl acetate (20 mL ⁇ 2), and the extracts were combined and washed with 10% aqueous sodium sulfite solution (20 mL) and saturated brine (20 mL). Further, the extract solution was dried over anhydrous magnesium sulfate and filtered through a cotton plug, and then the solvent was distilled off to obtain a crude product.
  • -O-benzyl-3,6-O- [bibenzylbis-2,2 '-(methylene)]-D-glucopyranoside (23.6 mg, 25.2 ⁇ mol, yield: 90%) was isolated as a colorless syrup .
  • the reaction mixture was filtered through cotton, Celite, SiO 2 and Celite to remove Cs 2 CO 3 from the reaction mixture.
  • the filtrate is concentrated to give 2,4-di-O- [bibenzylbis-2,2 '-(methylene)]-D-glucopyranosyl-trichloroacetimidate (128 mg, quantitative, 45: 55) as a crude product A mixture of diastereomers was obtained.
  • the resulting crude product was used in Example 29 without further purification.
  • Examples 30 to 39 A reaction was carried out in the same manner as in Example 29 except that TiCl 4 and molecular sieves 4A were replaced by the activators listed in Table 4 below, and the reaction temperature and reaction time were replaced by the ones listed in the following table. .
  • TMS is trimethylsilyl
  • TES is triethylsilyl
  • TBS is tributylsilyl
  • TIPS is triisopropylsilyl
  • Tf is trifluoromethylsulfonyl
  • MS stands for molecular sieves, and other abbreviations are as defined above. In Example 39, only molecular sieves 4A was used as an activating agent.
  • Examples 40 to 44 A reaction was carried out in the same manner as in Example 29 except that the reaction temperature was -10 ° C, TiCl 4 was TBSOTf, the reaction solvent and the reaction time were as described in Table 5 below.
  • the reaction was quenched by the addition of saturated aqueous NaHCO 3 (5 mL) to the reaction mixture. After further addition of diethyl ether (20 mL), the mixture was filtered through cotton and celite to remove molecular sieves 4A. Ethyl acetate (30 mL) was added to the filtrate, extraction was performed, and the organic layer was washed successively with water (5 mL) and saturated brine (5 mL). The organic layer was further dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated to give a crude product as a mixture of anomeric isomers.

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Abstract

La présente invention concerne un procédé hautement polyvalent pour la production aisée d'α-O-pyranosides, présentant un degré élevé de sélectivité sans établir de conditions de réaction sévères, et un donneur de pyranose utilisé dans ledit procédé. Le composé de pyranose 3,6-O-réticulé selon la présente invention est un composé représenté par la formule générale (1) (dans laquelle R1 représente un groupe -SR6 (R6 étant un groupe alkyle inférieur éventuellement substitué ou analogue) ou analogue, R2 représente un atome d'hydrogène ou analogue, R3 représente un atome d'hydrogène ou analogue, R4 et R5 représentent chacun un groupe alkyle inférieur éventuellement halogéné ou analogue, n représente un entier de 1-4 et p et q représentent chacun un entier de 0-4) ou un énantiomère correspondant.
PCT/JP2014/052564 2013-02-18 2014-02-04 COMPOSÉ DE PYRANOSE 3,6-O-RÉTICULÉ ET PROCÉDÉ DE PRODUCTION D'α-O-PYRANOSIDE WO2014125967A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009102022A1 (fr) * 2008-02-15 2009-08-20 Kwansei Gakuin Educational Foundation Composé d'inversion d'un pyranose à pont 3,6-o et procédé de production de β-o-pyranoside
JP2011037740A (ja) * 2009-08-10 2011-02-24 Kwansei Gakuin グルコース化合物及びそれらの製造方法並びにダビジインの製造方法
JP2013166740A (ja) * 2012-02-17 2013-08-29 Kwansei Gakuin ２，４−ｏ−架橋反転ピラノース化合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009102022A1 (fr) * 2008-02-15 2009-08-20 Kwansei Gakuin Educational Foundation Composé d'inversion d'un pyranose à pont 3,6-o et procédé de production de β-o-pyranoside
JP2011037740A (ja) * 2009-08-10 2011-02-24 Kwansei Gakuin グルコース化合物及びそれらの製造方法並びにダビジインの製造方法
JP2013166740A (ja) * 2012-02-17 2013-08-29 Kwansei Gakuin ２，４−ｏ−架橋反転ピラノース化合物

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HIDETOSHI YAMADA ET AL.: "2, 4-O-(2, 2'- Bibenzylbis(methylene)) Kakyo o Mochiita D- Glucose no Kan Rittai Haiza Seigyo", CSJ: THE CHEMICAL SOCIETY OF JAPAN KOEN YOKOSHU, vol. 92, no. 4, 2012, pages 1177 *
HIDETOSHI YAMADA ET AL.: "3, 6-O-(o-xylylene) Kakyoto o Mochiita Ko-a Rittai Sentakuteki Glucosyl-ka Hanno", CSJ: THE CHEMICAL SOCIETY OF JAPAN KOEN YOKOSHU, vol. 91, no. 4, 2011, pages 1147 *
HIDETOSHI YAMADA ET AL.: "Bibenzyl-2,2'-Bis (methylene) Kakyoto o Mochiita a Sentakuteki Glycosyl-ka Hanno", DAI 32 KAI THE JAPANESE SOCIETY OF CARBOHYDRATE RESEARCH NENKAI POSTER HAPPYO, 6 August 2013 (2013-08-06) *
HIDETOSHI YAMADA ET AL.: "Bibenzyl-2,2'-Bis (methylene) Kakyoto o Mochiita a Sentakuteki Glycosyl-ka Hanno", THE JAPANESE SOCIETY OF CARBOHYDRATE RESEARCH NENKAI YOSHISHU, vol. 32, 25 July 2013 (2013-07-25), pages 115 *

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