WO2018124139A1 - Compound having alkoxyalkyl group, production method for acetal compound using same, and measurement method therefor - Google Patents

Compound having alkoxyalkyl group, production method for acetal compound using same, and measurement method therefor Download PDF

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WO2018124139A1
WO2018124139A1 PCT/JP2017/046800 JP2017046800W WO2018124139A1 WO 2018124139 A1 WO2018124139 A1 WO 2018124139A1 JP 2017046800 W JP2017046800 W JP 2017046800W WO 2018124139 A1 WO2018124139 A1 WO 2018124139A1
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group
compound
acetal compound
general formula
producing
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PCT/JP2017/046800
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French (fr)
Japanese (ja)
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浩平 鳥飼
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国立大学法人九州大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention relates to a compound having an alkoxyalkyl group, and more particularly, to a compound having a novel alkoxyalkyl group capable of realizing a stereoselective reaction capable of exhibiting high stereoselectivity and a 1,2-trans-glycoside bond using the same.
  • the present invention relates to a method for producing an acetal compound including a compound having the same, and a measuring method thereof.
  • sugar chain synthesis reaction One important and typical sugar chain synthesis reaction is a 1,2-trans selective glycosylation reaction, which makes it possible to obtain useful compounds such as pharmaceutical compositions.
  • a 1,2-trans selective glycosylation reaction occurs, for example, in the case of a 1,2-trans selective glycosylation reaction with respect to a sugar having an equatorial hydroxy group at the 2-position, as a compound that causes a stereoselective reaction, 2
  • a sugar donor glycosyl donor
  • This sugar donor reacts with a sugar acceptor (glycosyl acceptor) to cause 1,2-trans selective glycosylation.
  • Non-Patent Document 1 for conventional compounds that cause stereoselective reactions (for example, glycosyl donors), for example, a benzyl group having a coordinating substituent as shown in Non-Patent Document 1 is known. Is low and cannot withstand the synthesis process (such as hydride reduction) necessary to obtain a functional acetal compound, or in order to avoid the process, mild conditions must be selected at the expense of the number of processes. There was a problem that I could not get it.
  • an object of the present invention is to provide a production method of a compound having a 1,2-trans-glycoside bond) and a measurement method thereof.
  • a compound having an alkoxyalkyl group was derived as a compound that causes a new type of stereoselective reaction from which a compound having a ratio can be easily obtained.
  • a novel characteristic of the reaction provided in the compound having an alkoxyalkyl group has been newly found, and a compound having a plurality of 1,2-trans-glycoside bonds (for example, 1 , A trisaccharide having two 2-trans-glycosidic bonds, etc.) has been newly derived as a very efficient new synthesis method that can be obtained by one-pot synthesis. Furthermore, the present inventors have also found a new method capable of measuring a compound having a high diastereomeric excess obtained from a compound having such an alkoxyalkyl group with extremely high accuracy and ease.
  • An explanatory view (a) explaining a measuring method concerning other embodiments concerning the present invention, a comparative example (b), and an explanatory view (c) explaining a suitable measuring method are shown.
  • An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown.
  • An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown.
  • An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown.
  • An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown.
  • the compound having an alkoxyalkyl group according to the present invention is represented by the following general formula (I).
  • Ra, Rb and Rc are each independently a hydrogen atom or a hydrogen of a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group and a carboxy group.
  • R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom or a linear or branched lower alkyl group.
  • R 5 is a hydrogen atom, a linear or branched lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.
  • A represents that a ring structure having 1 to 5 rings is formed, and the monocyclic or polycyclic structure is a substituted or unsubstituted 5-membered ring. or consists of six-membered rings may contain a hetero atom, R 6 is a hydrogen atom or a straight or branched lower alkyl group.
  • ring structure represented by including A for example, benzene, cyclohexane, cyclopentane, thiophene, tetrahydrothiophene, pyridine, piperidine, pyrrolidine, pyrrole, furan, tetrahydropyran, naphthalene, anthracene, indole, benzofuran, A benzothiophene, a quinoline ring, etc. are mentioned.
  • a method for producing an acetal compound having a high diastereomeric excess using the compound having an alkoxyalkyl group is also provided.
  • a compound having an alkoxyalkyl group represented by the above general formula (I) and a compound having an acyl group represented by the following general formula (IV) there is also provided a method for producing an acetal compound that selectively produces an acetal compound represented by the following general formula (V) by reacting the mixture in the presence of an activator.
  • a compound having a plurality of 1,2-trans-glycoside bonds for example, trisaccharide having two 1,2-trans-glycoside bonds
  • One-pot synthesis can be achieved very easily.
  • Rc ′ is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which a hydrogen atom is a lower alkyl, alkenyl, alkynyl, aryl group.
  • R 7 is a hydrogen atom, or a linear or branched lower alkyl group or aryl group, n is an integer of 0 or more, and X ′ is a leaving group
  • Y is a hydroxy group, a thiol group, an amino group, a monoalkylamino group, or a carbon nucleophile.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, X, X ′, and n are the above general formula (I) And the definition of (IV).
  • the compound having an alkoxyalkyl group according to this embodiment is represented by the above general formula (I).
  • the above R 1 , R 2 , R 3 , R 4 , and R 5 may be the above-described alkyl groups, but from the viewpoint of availability and ease of handling, the above R 1 , R 2 , R 3 , R 4 and R 5 are preferably hydrogen.
  • Ra, Rb, and Rc are the above-described lower alkyl, alkenyl, alkynyl group, aryl group, cyano group, carboxy group, and carboxy group hydrogen substituted with lower alkyl, alkenyl, alkynyl, aryl group, etc.
  • hydrogen is preferable because it is easily available and easy to handle.
  • the lower alkyl group is not particularly limited, and for example, an alkyl group having 1 to 10 carbon atoms can be used.
  • X is not particularly limited as long as it is a leaving group.
  • an SPh group, a trichloroacetimidate (OC (CCl 3 ) NH) group, a fluorine atom, or a bromine atom can be used, and more preferably, SPh Group, trichloroacetimidate group and fluorine atom, and SPh group is particularly preferred.
  • R 5 can be a functional group represented by the above general formula (Ia).
  • A is formed from a ring structure having 1 to 5 rings, and includes, for example, a ring structure composed of a plurality of rings.
  • a monocyclic structure having only a benzene ring or a monocyclic structure having only a thiophene ring is included, such as a benzyloxymethyl (BOM) group.
  • the alkoxyalkyl group is preferably a benzyloxymethyl (BOM) derivative represented by the following chemical formula (I-1) and a naphthylmethoxymethyl (NAPOM) derivative represented by the following chemical formula (I-2). Some are listed.
  • BOM benzyloxymethyl
  • NAPOM naphthylmethoxymethyl
  • R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.
  • alkoxyalkyl group examples include benzyloxymethyl (BOM) represented by the following chemical formula (I-1-1) and naphthylmethoxymethyl (NAPOM) represented by the following chemical formula (I-2-1). ).
  • an alkoxyalkyl group in which R 5 is a hydrogen atom can be used.
  • a methoxymethyl group (MOM) represented by the following chemical formula (I-3) can be used.
  • ) Can also be used.
  • a method for obtaining a compound having an alkoxyalkyl group according to the present embodiment is not particularly limited.
  • a compound containing an alkoxyalkyl group an alkoxyalkyl group introducing agent in the presence of an amine with respect to a monosaccharide or oligomer.
  • the monosaccharide or oligomer is not particularly limited, and for example, those having an oxygen atom between the 1st and 5th carbon atoms or between the 2nd and 5th carbon atoms can be used.
  • Glucose, galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose can be mentioned, and in addition to these, ribose, arabinose, xylose, lyxose, ribulose, xylulose, etc.
  • a carbon sugar etc. can also be mentioned and it can select arbitrarily according to a desired use (synthesis object).
  • the compound having an alkoxyalkyl group according to this embodiment is represented by the following general formula (II) as a glycosyl donor.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above, and P is any protecting group or hydrogen, preferably protected. It is a group.
  • a glycosyl donor that is a compound having an alkoxyalkyl group according to the present embodiment is represented by the following general formula (II ′).
  • the glycosyl donor according to the present embodiment is, as a preferred example, a compound in which the alkoxyalkyl group is a benzyloxymethyl (BOM) derivative represented by the following chemical formula (II′-1), and Examples thereof include naphthylmethoxymethyl (NAPOM) derivatives represented by the following chemical formula (II′-2).
  • BOM benzyloxymethyl
  • NAPOM naphthylmethoxymethyl
  • R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, as described above. is there.
  • the above alkoxyalkyl group is benzyloxymethyl (BOM) represented by the following chemical formula (II′-1-1), and Examples thereof include naphthylmethoxymethyl (NAPOM) represented by the following chemical formula (II′-1-2).
  • BOM benzyloxymethyl
  • NAPOM naphthylmethoxymethyl
  • glycosyl donor as the above alkoxyalkyl group, a hydrogen atom as R 4 can be used.
  • the glycosyl donor according to the following chemical formula (II-3) can be used. It is also possible to use a methoxymethyl group (MOM).
  • Such a compound having an alkoxyalkyl group according to the present embodiment is reacted with an acceptor (for example, a glycosyl acceptor) in the presence of an activating agent, and the compound having this alkoxyalkyl group by the reaction.
  • an acceptor for example, a glycosyl acceptor
  • This acetal compound is a general term for a group of compounds having a C—O—C—O—C bond, and the type of the acetal compound is not particularly limited as long as it is a compound or group containing such a bond.
  • One example is sugar, but the substitution position is not particularly limited.
  • the acetal compound is, for example, a saccharide
  • the alkoxyalkyl group can substitute the 2-position hydroxy group of glucose, but is not limited thereto.
  • the 6-position of glucose or galactose Can be substituted, i.e., can be a neighboring group participating group on various hydroxy groups of monosaccharides (or oligomers).
  • pentose sugars, natural products having a structure close to sugar chains, and the like are also included as targets of this acetal compound.
  • the three carbon atoms constituting the C—O—C—O—C bond contained in the acetal compound are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a carboxy group, an alkoxycarbonyl group, and a cyano group. It may be substituted with various carbon substituents such as, or may be unsubstituted with hydrogen bonded. Further, such a carbon substituent and other various substituents may be contained on the ring of the acetal compound, and it is not particularly limited.
  • the activator is not particularly limited as long as it activates the reaction in a broad sense.
  • the activator activates the reaction as an oxidant by electrophilic action, or activates the reaction by a catalytic role.
  • Those to be activated are also included as activators.
  • this activator one type can be used, but a plurality of types can also be used together.
  • the activator is combined with the one acting as the oxidant and the one acting as the catalyst. As a result, the activation effect can be increased in a superimposed manner.
  • Such an activator is not particularly limited, and a glucosyl compound can be obtained with high selectivity by using any activator.
  • metal trifluoromethanesulfonate trifluoromethanesulfone, etc.
  • Acid (TfOH) lower alkyl sulfates such as dimethyl sulfate, N-iodosuccinimide (NIS) and iodine chloride (ICl) I + donors can be used.
  • N-iodosuccinimide N-bromosuccinimide
  • N-chlorosuccinimide N-chlorosuccinimide
  • the solvent used in the reaction may be a polar solvent or a nonpolar solvent, and is not particularly limited.
  • an aprotic solvent such as dichloromethane (CH 2 Cl 2 ), propionitrile (EtCN), hexane (C 6 H 14), and the like methyl tertiary butyl ether (t BuOMe).
  • EtCN propionitrile
  • hexane C 6 H 14
  • t BuOMe methyl tertiary butyl ether
  • the polarity of the solvent is low.
  • a solvent for example, two types of dichloromethane (CH 2 Cl 2 ) and hexane (C 6 H 14 ) are used in combination. Is preferred.
  • the acceptor for example, glucosyl acceptor which reacts with the compound (for example, glycosyl donor) having an alkoxyalkyl group according to the present embodiment is not particularly limited, and various saccharides, alcohols, phenols, thiols, amines, and other nucleophiles. (For example, carbon nucleophiles etc.) can be used.
  • saccharides include glucose, galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose, and these saccharides are unsubstituted.
  • alcohol can also be used as an acceptor (for example, glucosyl acceptor).
  • acceptor for example, glucosyl acceptor
  • examples of such alcohols include 3-phenyl-1-propanol, 3-phenyl-1-butanol, benzyl alcohol, phenethyl alcohol, 1-phenyl-1-propanol, 1-phenyl-2-propanol, and 2-phenyl.
  • reaction formula (III) As an intermediate of the reaction process, a 5-membered ring containing two oxygen atoms between the 1st and 2nd carbons of glucose is temporarily formed in the reaction process (neighboring groups are involved) Inferred.
  • the acetal compound (for example, glycoside compound) obtained from the compound having the alkoxyalkyl group (for example, glycosyl donor) according to the present embodiment has a very high diastereomeric excess. (Refer to Examples described later).
  • the glucosyl donor according to this embodiment (2-O-BOM as an example in the example) is confirmed to have extremely high ⁇ selectivity (production of only ⁇ type). It was speculated that the following reactions were caused, including intermediates in the reaction process.
  • an alkoxyalkyl group substituted with a 2-position hydroxy group of a monosaccharide or an oligomer for example, glucose
  • a monosaccharide or an oligomer for example, glucose
  • the compound having an alkoxyalkyl group according to the present embodiment can obtain an acetal compound (for example, a glycoside compound) having a very high diastereomeric excess, and this It is also possible to remove the alkoxyalkyl group by reacting the obtained acetal compound (for example, glycoside compound) with various acids.
  • acids that can be used include proton acids such as hydrochloric acid and p-toluenesulfonic acid, and Lewis acids such as trifluoroborane, trimethylsilyl iodide, and trimethylsilyl bromide. preferable.
  • the alkoxyalkyl group is a BOM group or a NAPOM group, it can be oxidatively removed by hydrogenolysis or DDQ.
  • This removal of the alkoxyalkyl group is different from the conventional removal of the acyl protecting group, even if an ester site is present or an acyl group is present in the starting saccharide or oligomer. It can be easily removed without increasing the number of reaction steps.
  • the matrix substituted with the alkoxyalkyl group constituting the compound having an alkoxyalkyl group for example, a glycosyl donor.
  • the type for example, monosaccharide or oligomer
  • various stereoselectivities such as ⁇ -type ( ⁇ -selectivity) and ⁇ -type ( ⁇ -selectivity) are exhibited.
  • ⁇ is introduced when the alkoxyalkyl group is introduced at the 2-position of glucose. Selectivity can be obtained, and ⁇ -selectivity can be obtained if introduced at the 2nd position of mannose or the 6th position of glucose.
  • the acetal compound (for example, glycoside compound) obtained from the compound (for example, glycosyl donor) having an alkoxyalkyl group according to this embodiment is diverse.
  • examples thereof include glycosides such as Symponoside and Belalloside, and derivatives thereof.
  • Belalloside mentioned above is a glycoside that is represented by the following chemical formula and has been isolated and determined from the roots of the Thai medicinal plant Belamcanda sinensis L, and has medicinal properties against tonsillitis and pharyngitis. It is said that there is currently a limited amount available from nature (only 1.5 mg can be obtained from a 1 kg root).
  • the glycosyl donor according to the present embodiment can be applied to the synthesis of various useful compounds (including natural organic compounds).
  • the glycosyl donor according to the present embodiment can be used.
  • the present inventor has confirmed that ⁇ -D-glucopyranoside (to date, no examples of artificial chemical synthesis are known) can be totally synthesized (see Examples described later).
  • the compound having an alkoxyalkyl group represented by the above general formula (I) and the compound having a conventional acyl group are mixed, and only the former is activated by adding an activator, Only the former substrate can proceed with 1,2-trans-glycosylation (eg, including ⁇ -selective glycosylation of glucose).
  • reaction of the compound having an alkoxyalkyl group represented by the above general formula (I) proceeds faster than a compound having a conventional acyl group.
  • Rc ′ is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which a hydrogen atom is a lower alkyl, alkenyl, alkynyl, aryl group.
  • R 7 is a hydrogen atom, or a linear or branched lower alkyl group or aryl group, n is an integer of 0 or more, and X ′ is a leaving group
  • Y is a hydroxy group, a thiol group, an amino group, a monoalkylamino group, or a carbon nucleophile.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, X, X ′, and n are the above general formula (I) And the definition of (IV).
  • the compound having an alkoxyalkyl group according to this embodiment is represented by the above general formula (I).
  • R 7 may be the hydrogen atom described above or a linear or branched lower alkyl group, but may be a phenyl group for ease of handling. When R 7 is a phenyl group, R 7 constitutes a benzoyl group (Bz).
  • Rc ′ in the general formula (IV) is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, or a carboxy group in which a hydrogen atom is a lower alkyl, alkenyl, alkynyl, aryl group. May be substituted, and is not particularly limited.
  • n in the above general formula (IV) is an integer of 0 or more, and when n is 0, it is directly bonded to an OH group (hydroxy group) without an alkyl chain.
  • X ′ is not particularly limited as long as it is a leaving group, and for example, an SPh group, a trichloroacetimidate (OC (CCl 3 ) NH) group, a fluorine atom, or a bromine atom can be used. An acetimidate group or a fluorine atom can be used, and an SPh group can also be used. In addition, a methyl group, an ethyl group, or a pivaloyl group may be used. In addition, when X ′ is the same leaving group as X, chemical reaction conditions can be unified and simplified such that the additive to be used can be made common, and continuous reaction can be easily performed. .
  • the alkoxyalkyl group constituting the compound having an alkoxyalkyl group represented by the above general formula (I) is a benzyloxymethyl (BOM) derivative represented by the following chemical formula (I-1), and the following And a naphthylmethoxymethyl (NAPOM) derivative represented by the chemical formula (I-2).
  • R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.
  • alkoxyalkyl groups examples include benzyloxymethyl (BOM) represented by the following chemical formula (I-1-1) and naphthylmethoxymethyl (NAPOM) represented by the following chemical formula (I-2-1). Can be mentioned.
  • BOM benzyloxymethyl
  • NAPOM naphthylmethoxymethyl
  • an alkoxyalkyl group in which R 5 is a hydrogen atom can be used.
  • a methoxymethyl group (MOM) represented by the following chemical formula (I-3) can be used.
  • ) Can also be used.
  • Ra, Rb, Rc and X are the same as defined in general formula (I), Rc ′, X ′ and n are the same as defined in general formula (V), and R 6 And R 6 ′ each independently represents a hydrogen atom or a linear or branched lower alkyl group.
  • the reaction is performed by adding a phenol or an aliphatic alcohol and changing the temperature, for example, by raising the temperature.
  • V ′ an acetal compound represented by the following general formula (V ′) in which the leaving group X ′ is replaced by an alkoxy group.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, and n are the same as defined in the general formula (V).
  • R 8 is a hydrogen atom, a linear or branched lower alkyl group, or an aryl group.
  • the compound having an alkoxyalkyl group according to the present embodiment is mixed with a compound having a conventional acyl group and reacted at a low temperature in the presence of an activator, and is represented by the general formula (V).
  • V the general formula (V)
  • the desired acetal compound can be easily obtained by adding an alcohol and then changing the temperature, for example, by raising the temperature, or by controlling the temperature. can get.
  • a very simple synthesis is possible in which compounds having the targeted configuration are selectively obtained one after another.
  • the method for obtaining the compound having an alkoxyalkyl group according to the present embodiment is not particularly limited.
  • the monosaccharide or oligomer is not particularly limited, and for example, those having an oxygen atom between the 1st and 5th carbon atoms or between the 2nd and 5th carbon atoms can be used.
  • Glucose, galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose can be mentioned, and in addition to these, ribose, arabinose, xylose, lyxose, ribulose, xylulose, etc.
  • a carbon sugar etc. can also be mentioned and it can select arbitrarily according to a desired use (synthesis object).
  • the glycosylation reaction of the compound having the alkoxyalkyl group is faster than the glycosylation reaction rate of the compound having an acyl group. That is, the glycosylation reaction of the compound having an alkoxyalkyl group selectively proceeds, and an excellent effect that a compound having a 1,2-trans-glycoside bond, which is an acetal compound, can be selectively produced. Play.
  • the compound having an alkoxyalkyl group according to the present embodiment is mixed with a compound having a conventional acyl group and reacted at a low temperature in the presence of an activator, and is represented by the general formula (V).
  • the desired 1,2-trans-glycoside is produced by a very simple method of adding an alcohol after the generation of the acetal compound and then changing the temperature, for example, by raising the temperature, or only by controlling the temperature. A compound having a bond can be easily obtained. Alternatively, only by controlling the temperature, the target sugar chain having 1,2-trans-glycoside bonds is selectively added and synthesized one after another, and has the desired 1,2-trans-glycoside bonds. An extremely simple synthesis is possible in which a polysaccharide is obtained.
  • the temperature conditions are not particularly limited.
  • the high temperature reaction can be performed at ⁇ 20 ° C. to 0 ° C.
  • the acetal compound thus produced can be reacted with at least an acid to remove the alkoxyalkyl group.
  • This synthesis method does not require a plurality of leaving groups as in the prior art, and the same leaving group X (for example, SPh group) is used all the time, and sugar chain synthesis is continuously performed only by temperature control.
  • a compound having a 1,2-trans-glycoside bond can be obtained by one-pot synthesis with an unprecedented idea. It was confirmed. Furthermore, according to the present inventor, as a method for measuring a compound having a new 1,2-trans-glycoside bond obtained in this manner, a new method that can be measured with extremely high accuracy and simplicity has been found.
  • the timing for measurement using NMR is not particularly limited. For example, it may be immediately after the acetal compound represented by the general formula (V) is formed, or may be a subsequent step.
  • the process to perform, the process to ship, etc. are mentioned.
  • the high peak value of the measurement value for example, the maximum peak value of the NMR measurement result can be used, and as the low peak value of the measurement value, for example, the minimum peak value of the NMR measurement result Can be used.
  • the comparison between the high peak value and the low peak value of the measurement value is not particularly limited.
  • the ratio of the intensity (intensity) of the high peak value and the low peak value is calculated, and the generated acetal compound The content ratio is measured.
  • the integrated intensity of the high peak value and the low peak value can be used as a comparison target.
  • Such a simple measurement method is possible because the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) has extremely high stereoselectivity. Derived from. That is, an acetal compound (for example, based on a 1,2-trans selective glycosylation reaction) produced by using a compound having an alkoxyalkyl group represented by the above general formula (I) is not acetal. There is a possibility that a small amount of a system compound (for example, due to 1,2-cis glycosylation reaction) is present, but the amount is very small. In contrast, conventional acetal compounds have low stereoselectivity, for example, ⁇ -type and ⁇ -type are mixed evenly, and thus the above measurement method cannot be applied.
  • an acetal compound produced using a compound having an alkoxyalkyl group represented by the above general formula (I) for example, 1,2-trans selective glycosylation reaction 3 having the three peak values A ', B', C ', other acetal compounds (for example, due to 1,2-cis glycosylation reaction, have three peak values A', B ', C') )
  • the peak of two types of acetal compound is measured in a mixed state in NMR, but as shown in FIG.
  • L 1 indicating the maximum peak
  • L 1 : L 2 value is 90:10 only by comparing with L 2 indicating the minimum peak (for example, calculating the ratio value)
  • the above general formula (I Embedded image having an alkoxyalkyl group represented by The ratio of the acetal compound produced using the product (for example, due to 1,2-trans selective glycosylation reaction) and the other acetal compound (for example, due to 1,2-cis glycosylation reaction) is 90:10 (that is, the content ratio of the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) is 90%)
  • the content ratio of the acetal compound according to the embodiment can be measured very easily.
  • the acetal compound according to the present embodiment (for example, depending on the 1,2-trans glycosylation reaction, (With peak values A, B, C) mixed with other trace amounts of acetal compounds (eg, with three peak values A ′, B ′, C ′ due to 1,2-cis glycosylation reaction)
  • the peaks of two types of acetal compounds are measured in a mixed state in NMR, but since these two types of acetal compounds are present uniformly (non-selectively), In the first place, there is no concept of a maximum peak or a minimum peak, and the content ratio of each acetal compound is unknown only by this NMR measurement, requires a further analysis method, and increases the analysis cost.
  • the high peak value of the measured value can be measured based on the 1-position hydrogen. Since the 1-position hydrogen is a place where the stereoselectivity peculiar to the generated acetal compound is strongly reflected, a high peak value is measured based on the 1-position hydrogen, thereby making it easier and more accurate.
  • the content ratio of the generated acetal compound can be measured.
  • a high peak value of the measured value exists in the measured value as shown in FIG. It can be measured based on a doublet (doublet) peak that appears in the vicinity of 4.5 ppm.
  • a high peak value based on a doublet peak that appears in the vicinity of 4.5 ppm, which is one of the peaks that are characteristically (specifically) appearing in the generated acetal compound.
  • the content ratio of the acetal compound can be measured more easily and with high accuracy.
  • the content ratio of the obtained acetal compound can be measured with high accuracy. Furthermore, according to the present inventor, a new method has been found that can measure not only the content ratio of the obtained acetal compound but also the chemical structure with extremely high accuracy and simplicity.
  • the measurement method according to the present embodiment comprises a mixture of a compound having an alkoxyalkyl group represented by the above general formula (I) and a compound having an acyl group represented by the above general formula (IV),
  • NMR nuclear magnetic resonance spectroscopy
  • the chemical structure of the acetal compound is measured by ignoring a small peak in the obtained measurement values.
  • a small peak means that it is minute compared to other peaks, and can be defined as, for example, 30% or less of a peak value for a large 1H.
  • an acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) has extremely high stereoselectivity.
  • an acetal compound produced by using a compound having an alkoxyalkyl group represented by the above general formula (I) may contain other acetal compounds.
  • a compound for example, due to 1,2-cis glycosylation reaction
  • the timing for measurement using NMR is not particularly limited. For example, it may be immediately after the acetal compound represented by the general formula (V) is formed, or may be a subsequent step. Are removed by filtration, removal of the solvent, purification (for example, using HPLC), removal of the solvent, identification of the chemical structure, storage at low temperature (for example, ⁇ 20 to 0 ° C.) The process, the process of shipping, etc. are mentioned.
  • Such a simple measurement method is possible because the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) has extremely high stereoselectivity.
  • an acetal compound produced by using a compound having an alkoxyalkyl group represented by the above general formula (I) may contain other acetal compounds.
  • a small amount of a compound for example, due to 1,2-cis glycosylation reaction
  • generated by the conventional method since said stereoselectivity is low, for example, (alpha) type
  • a high peak value of the measured value can be measured based on the 1-position hydrogen. Since the 1-position hydrogen strongly reflects the stereoselectivity, which is a characteristic characteristic of the acetal compound produced according to the present embodiment, it can be simplified by measuring a high peak value based on the 1-position hydrogen. And it becomes possible to measure the chemical structure of the acetal compound produced
  • a high peak value of the measured value appears in the vicinity of 4.5 ppm present in the measured value. It can be measured based on (doublet) peaks.
  • a doublet (doublet) peak appears in the vicinity of 4.5 ppm which is characteristically (specifically) manifested by its high stereoselectivity.
  • the acetal compound produced according to the present embodiment is measured by NMR, for example, as shown in FIG. 2, as shown in FIG. 2, a doublet peak A is clearly observed in the vicinity of 4.5 ppm. Further, as shown in FIGS. 3 to 5, the same doublet peak A is surely around 4.5 ppm for any of the various acetal compounds (MOM body, BOM body, NAPOM body) according to this embodiment. It has been confirmed that From this, the present technique is reliable and easy for various acetal compounds produced according to the present embodiment when a glycoside (for example, glucose) in which hydrogen at the 1-position and 2-position is in an axial orientation is the target product. Is a very versatile technique that enables measurement.
  • a glycoside for example, glucose
  • the chemical structure of the acetal compound produced according to this embodiment can be measured with high accuracy.
  • the measurement method can measure the above-mentioned content ratio using, for example, an NMR apparatus, but is not particularly limited.
  • Example 1 First, as a conventional example (comparative example), methyl isomer 2 was synthesized from diol 1 as shown in the following reaction formula.
  • glycosylation reaction was performed using the obtained methyl derivative 2. That is, ⁇ -glycoside ⁇ 3a and ⁇ -glycoside 3b were produced as shown in the following reaction formula.
  • this solution was added to a suspension of indium trifluoromethanesulfonate (147 mg, 0.262 mmol) and powdered molecular sieves 4A (53 mg) in dichloromethane (0.80 mL), and the temperature was gradually raised to -35 ° C. Stir for minutes. Saturated sodium thiosulfate aqueous solution and sodium hydrogen carbonate aqueous solution were added to stop the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate.
  • Example 2 As Example 2, as shown in the following reaction formula, a MOM body (MOM ether) 6 as a glycosyl donor was synthesized from the diol 1 described above.
  • Example 3 As shown in the following reaction formula, a NAPOM body (NAPOM ether) 9 as a glycosyl donor was synthesized from the diol 1 described above.
  • NAPOM body (NAPOM ether) 9 which is the glycosyl donor obtained above, a glycosylation reaction shown in the following reaction formula was performed.
  • Example 4 In Example 4, the progress of the reaction was confirmed by changing the reaction conditions in the same procedure as described above.
  • the confirmed reaction conditions are activator, glucosyl acceptor, and solvent.
  • the list of the obtained result is shown with the reaction formula which described reaction conditions, respectively.
  • Example 5 In Example 5, as shown in the following reaction formula, the glycosylation reaction was carried out in the presence of NIS using the BOM body (BOM ether) 4 which is the glycosyl donor obtained above.
  • Powdered molecular sieve 4A (50 mg) was added to a solution of BOM ether 4 (50.6 mg, 83.2 ⁇ mol) and Bz ester 12 (48.1 mg, 84.3 ⁇ mol) in dichloromethane (1.00 mL), and the mixture was stirred at room temperature for 30 minutes. After cooling to -78 ° C, N-iodosuccinimide (68.1 mg, 0.303 mmol) and indium trifluoromethanesulfonate (141 mg, 0.251 mmol) were added. The mixture was stirred for 45 minutes while gradually warming from -78 ° C to -40 ° C.
  • ⁇ -glycoside 13 which is an acetal compound having a 1,2-trans-glycoside bond, was selectively produced.
  • Glycosyl acceptor 22 Under an argon atmosphere, add anhydrous ether (4 mL) and anhydrous methylene chloride (1 mL) to a mixture of thioglycoside 4 (280 mg, 0.466 mmol) and molecular sieves 4A (12 mg) at 0 ° C. Stir with. The suspension LiAlH4 (142 mg, 3.73 mmol) and AlCl 3 (472 mg, 3.54 mmol ) was added slowly, followed by stirring for 2 hours at room temperature. After cooling to 0 ° C., ethyl acetate (15 mL) and water (20 mL) were added.
  • Glycosyl donor 15 Alcohol 14 (160 mg, 0.265 mmol) in methylene chloride (5 mL) was added to DCC (164 mg, 0.795 mmol), camphorsulfonic acid (30 mg, 0.132 mmol) and DMAP ( 16 mg, 0.132 mmol) was added. After 15 minutes, the mixture was cooled to 0 ° C., and a solution of p- (benzyloxy) benzoic acid (152 mg, 0.667 mmol) in methylene chloride (5 mL) was slowly added. After warming to room temperature, the mixture was stirred for 24 hours. The resulting DCU was filtered off using celite, and the celite was washed with methylene chloride (3 ⁇ 5 mL).
  • Compound 23 Compound 15 (120 mg, 0.147 mmol) and anhydrous MeOH (0.038 mL, 0.911 mmol) were dissolved in anhydrous CH 2 Cl 2 (4 mL) under an argon atmosphere and activated with molecular sieves 4A (8 mg). Dry for 30 minutes. After cooling to -70 ° C, NIS (50 mg, 0.221 mmol) and indium triflate (99 mg, 0.176 mmol) were added, and the mixture was stirred for 1.5 hours while warming to 0 ° C. The reaction solution was filtered through Celite while washing with ethyl acetate, and then ethyl acetate was added to the filtrate to make a total volume of 20 mL.
  • the obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), saturated Na 2 SO 3 solution (10 mL) and water (50 mL). The organic phase was dried over sodium sulfate, the desiccant was filtered off, and concentrated under reduced pressure to obtain a crude product.
  • Natural product 18 Pd / C (10 wt%, 30 mg, 0.028 mmol) was added to 16 (50 mg, 0.068 mmol) in anhydrous MeOH (5 mL) and stirred at room temperature under a hydrogen atmosphere. After 2 hours, the catalyst was removed by suction filtration using Celite and Celite was washed with MeOH (2 ⁇ 5 mL). When the filtrate and the washing solution were combined and the solvent was removed, ⁇ -D-glucopyranoside 18 (19 mg, 91%) was obtained as a colorless solid.
  • the crude product of 19 was obtained by performing operation similar to 18 by using natural product 19:17 (30 mg, 0.046 mmol) as a raw material.

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Abstract

Provided are: a compound that induces a new type of stereoselective reaction that exhibits stereoselectivity during carbohydrate chain synthesis and produces acetal compounds; a production method for an acetal compound (e.g. a compound having a 1,2-trans-glycoside bond) that exhibits a high diastereoisomer excess using said compound; and a measurement method therefor. A compound having an alkoxyalkyl group represented by general formula (I) induces a stereoselective reaction.

Description

アルコキシアルキル基を有する化合物およびそれを用いたアセタール系化合物の製造方法、ならびにその計測方法Compound having alkoxyalkyl group, method for producing acetal compound using the same, and measuring method thereof
　本発明はアルコキシアルキル基を有する化合物に関し、特に、高い立体選択性を発現させうる立体選択的反応を実現できる新規のアルコキシアルキル基を有する化合物およびそれを用いた１，２－trans-グリコシド結合を有する化合物をはじめとするアセタール系化合物の製造方法、ならびにその計測方法に関する。 The present invention relates to a compound having an alkoxyalkyl group, and more particularly, to a compound having a novel alkoxyalkyl group capable of realizing a stereoselective reaction capable of exhibiting high stereoselectivity and a 1,2-trans-glycoside bond using the same. The present invention relates to a method for producing an acetal compound including a compound having the same, and a measuring method thereof.
　従来から、糖鎖合成における最重要課題は、所望の特性を有する化合物を得るために、糖鎖合成時の立体選択性を制御することにある。重要で代表的な糖鎖合成反応の１つとして、1,2-trans選択的グリコシル化反応が挙げられ、この反応により、医薬用組成物等の有用な化合物を得ることが可能となる。 Conventionally, the most important problem in sugar chain synthesis is to control the stereoselectivity during sugar chain synthesis in order to obtain a compound having desired characteristics. One important and typical sugar chain synthesis reaction is a 1,2-trans selective glycosylation reaction, which makes it possible to obtain useful compounds such as pharmaceutical compositions.
　1,2-trans選択的グリコシル化反応を起こす際、例えば、２位にエカトリアルヒドロキシ基を有する糖に対する1,2-trans選択的グリコシル化反応の場合では、立体選択的反応を引き起こす化合物として、２位ヒドロキシ基にアシル系保護基を導入した糖供与体（グリコシルドナー）を用いることが一般的な手法となっている。この糖供与体（グリコシルドナー）を、糖受容体（グリコシルアクセプター）と反応させることによって、1,2-trans選択的グリコシル化を引き起こす。 When a 1,2-trans selective glycosylation reaction occurs, for example, in the case of a 1,2-trans selective glycosylation reaction with respect to a sugar having an equatorial hydroxy group at the 2-position, as a compound that causes a stereoselective reaction, 2 It is a common technique to use a sugar donor (glycosyl donor) in which an acyl-based protecting group is introduced into the hydroxy group. This sugar donor (glycosyl donor) reacts with a sugar acceptor (glycosyl acceptor) to cause 1,2-trans selective glycosylation.
　１，２－trans-グリコシド結合を有する化合物を得る際には、上述したアシル系保護基を用いることが、一般的な手法として定着している。 When obtaining a compound having a 1,2-trans-glycoside bond, the use of the acyl protecting group described above has been established as a general technique.
　しかしながら、この方法では、分子内に他のアシル基を有するような糖の合成の場合には、同じアシル基であっても、糖の構成に必要なアシル基と、保護基としてのアシル基とが同じ糖内に混在することから、上記の２位アシル系保護基の除去の方法やタイミング等に制約が生じ、場合によっては保護基の架け替えも必要となり、最終生成物を得るための反応工程数が増加し、結果として、合成効率が低いものにとどまっている。 However, in this method, in the case of synthesizing a sugar having another acyl group in the molecule, the acyl group necessary for the constitution of the sugar and the acyl group as a protecting group are used even if the same acyl group is used. Are mixed in the same sugar, there are restrictions on the removal method and timing of the 2-position acyl-protecting group described above. In some cases, it is necessary to replace the protecting group, and the reaction for obtaining the final product. The number of processes has increased, and as a result, the synthesis efficiency remains low.
　従来の立体選択的反応を引き起こす化合物に関する技術としては、２－Ｏ－（２－ニトロベンジル）基や２－Ｏ－（２－シアノベンジル）基のような配位性置換基を有するベンジル基を保護基とするグリコシルドナーを用いることによって、立体選択的なグリコシル化反応を起こして機能性アセタール系化合物を得ることを狙いとする技術が提案されている（例えば、非特許文献１参照）。 Conventional techniques relating to compounds that cause stereoselective reactions include benzyl groups having a coordinating substituent such as 2-O- (2-nitrobenzyl) group and 2-O- (2-cyanobenzyl) group. There has been proposed a technique aimed at obtaining a functional acetal compound by causing a stereoselective glycosylation reaction by using a glycosyl donor as a protecting group (see, for example, Non-Patent Document 1).
　しかしながら、従来の立体選択的反応を引き起こす化合物（例えばグリコシルドナー）については、例えば、非特許文献1に示される、配位性置換基を有するベンジル基が知られているが、保護基の安定性が低く、機能性アセタール系化合物を得るために必要な合成過程（例えばヒドリド還元等）に耐えられないか，もしくは当該過程を回避するために、工程数を犠牲にして穏和な条件を選択せざるをえないという課題があった。 However, for conventional compounds that cause stereoselective reactions (for example, glycosyl donors), for example, a benzyl group having a coordinating substituent as shown in Non-Patent Document 1 is known. Is low and cannot withstand the synthesis process (such as hydride reduction) necessary to obtain a functional acetal compound, or in order to avoid the process, mild conditions must be selected at the expense of the number of processes. There was a problem that I could not get it.
　さらに、糖鎖合成において、１，２－trans-グリコシド結合を有する化合物を合成する際には、上述したようにアシル系保護基を用いて立体選択的グリコシル化反応を引き起こすことが一般的な手法として定着しているものの、アシル系保護基により立体選択的グリコシル化反応を引き起こそうとする場合には、多段階の反応工程が必要となり、個々の反応条件の制御もシビアとなって、結果として、低効率で合成コストの高いものとなっている。 Furthermore, in the synthesis of sugar chains, when synthesizing a compound having a 1,2-trans-glycoside bond, it is common practice to cause a stereoselective glycosylation reaction using an acyl protecting group as described above. However, when an acyl-based protecting group is used to cause a stereoselective glycosylation reaction, a multi-step reaction process is required, and control of individual reaction conditions becomes severe, resulting in a result. As a result, it has low efficiency and high synthesis cost.
　これを克服するために、異なる脱離基を有する複数のドナーやアクセプターを用いるという手法もあるが（例えば最初の糖としてチオ糖を使い、次の糖としてフッ化糖を使い、さらに次の糖としてトリクロロアセトイミデート（ＯＣ(ＣＣｌ３)ＮＨ）基を脱離基に持つ糖を使うなど）、種々の脱離基のうち所望とする脱離基のみを選択的に除去する必要があり、そのため複数の活性剤を用意することや、多段階反応を進行させるために逐次化学反応の進行と停止を繰り返して行うことが要求され、多段階で化学反応の制御が必要となるという煩雑なものとなり、複数の反応を最後まで完結させるまでの時間も多大に要し、依然として合成コストが高いものとなっている。 In order to overcome this, there is a method of using a plurality of donors and acceptors having different leaving groups (for example, using thiosaccharide as the first sugar, fluorinated sugar as the next sugar, and further It is necessary to selectively remove only a desired leaving group among various leaving groups, such as trichloroacetimidate (using a sugar having an OC (CCl 3 ) NH) group as a leaving group, Therefore, it is required to prepare a plurality of activators and to repeat the progress and stop of the chemical reaction in order to advance the multi-step reaction, and it is necessary to control the chemical reaction in multiple steps. Therefore, it takes much time to complete a plurality of reactions to the end, and the synthesis cost is still high.
　そのため、例えば、同じ活性化剤、同じ脱離基を使用して、１，２－trans-グリコシド結合を複数有する化合物を連続的に得られるような簡便で効率的な合成手法が望まれているものの、現状では、そのようなものは糖鎖合成の分野において概念すら存在していない。そのため、そのような１，２－trans-グリコシド結合を有する化合物を高精度かつ簡便に計測する手法も、当然に、概念すら存在していない。 Therefore, for example, there is a demand for a simple and efficient synthesis method that can continuously obtain a compound having a plurality of 1,2-trans-glycoside bonds using the same activator and the same leaving group. However, at present, such a concept does not even exist in the field of sugar chain synthesis. For this reason, there is naturally no concept of a technique for measuring such a compound having a 1,2-trans-glycoside bond with high accuracy and ease.
　本発明では、上記課題を解決すべく、糖鎖合成において簡易に立体選択性を発現させうる新しいタイプの立体選択的反応を引き起こす化合物、さらにそれを用いた高いジアステレオマー過剰率を有する化合物（例えば１，２－trans-グリコシド結合を有する化合物）の製造方法、ならびにその計測方法を提供することを目的とする。 In the present invention, in order to solve the above-mentioned problem, a compound that causes a new type of stereoselective reaction that can easily exhibit stereoselectivity in sugar chain synthesis, and a compound having a high diastereomeric excess using the compound ( For example, an object of the present invention is to provide a production method of a compound having a 1,2-trans-glycoside bond) and a measurement method thereof.
　本発明者は、鋭意研究の結果、ある種のアルコキシアルキル基を特定の位置に含む単糖類またはオリゴマーが、グリコシル反応において優れた立体選択性を発揮することを新たに見出し、高いジアステレオマー過剰率を有する化合物が簡易に得られる新しいタイプの立体選択的反応を引き起こす化合物として、アルコキシアルキル基を有する化合物を導き出した。さらに、当該アルコキシアルキル基を有する化合物に備わった特筆すべき反応の性質も新たに見出し、特に糖鎖合成においてこれまでに無い着想で１，２－trans-グリコシド結合を複数有する化合物（例えば、１，２－trans-グリコシド結合を２箇所有するトリサッカライドなど）をワンポット合成（One-pot synthesis）で得ることが可能となるという極めて効率的な新規の合成手法も新たに導き出した。さらに、そのようなアルコキシアルキル基を有する化合物から得られた高いジアステレオマー過剰率を有する化合物を極めて高精度かつ簡便に計測できる新たな手法も見出した。 As a result of diligent research, the present inventors have newly found that monosaccharides or oligomers containing certain alkoxyalkyl groups at specific positions exhibit excellent stereoselectivity in glycosyl reactions, and have a high diastereomeric excess. A compound having an alkoxyalkyl group was derived as a compound that causes a new type of stereoselective reaction from which a compound having a ratio can be easily obtained. Furthermore, a novel characteristic of the reaction provided in the compound having an alkoxyalkyl group has been newly found, and a compound having a plurality of 1,2-trans-glycoside bonds (for example, 1 , A trisaccharide having two 2-trans-glycosidic bonds, etc.) has been newly derived as a very efficient new synthesis method that can be obtained by one-pot synthesis. Furthermore, the present inventors have also found a new method capable of measuring a compound having a high diastereomeric excess obtained from a compound having such an alkoxyalkyl group with extremely high accuracy and ease.
本発明に係るその他の実施形態に係る計測方法を説明する説明図（ａ）、比較例（ｂ）、および好適な計測方法を説明する説明図（ｃ）を示す。An explanatory view (a) explaining a measuring method concerning other embodiments concerning the present invention, a comparative example (b), and an explanatory view (c) explaining a suitable measuring method are shown. 本発明に係るその他の実施形態に係る計測方法に係るＮＭＲ測定結果の一例およびその説明図を示す。An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown. 本発明に係るその他の実施形態に係る計測方法に係るＮＭＲ測定結果の一例およびその説明図を示す。An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown. 本発明に係るその他の実施形態に係る計測方法に係るＮＭＲ測定結果の一例およびその説明図を示す。An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown. 本発明に係るその他の実施形態に係る計測方法に係るＮＭＲ測定結果の一例およびその説明図を示す。An example of the NMR measurement result which concerns on the measuring method which concerns on other embodiment which concerns on this invention, and its explanatory drawing are shown.
　すなわち、本発明に係るアルコキシアルキル基を有する化合物は、以下の一般式（I）で表される。 That is, the compound having an alkoxyalkyl group according to the present invention is represented by the following general formula (I).
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたもの等でもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。 In the above formula, Ra, Rb and Rc are each independently a hydrogen atom or a hydrogen of a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group and a carboxy group. R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom or a linear or branched lower alkyl group. , R 5 is a hydrogen atom, a linear or branched lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　上記一般式（Ｉ－ａ）中、上記のＡは、環数１～５の環構造が形成されていることを表し、当該単環もしくは多環式構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である。すなわち、このＡを含んで表される環構造としては、例えば、ベンゼン、シクロヘキサン、シクロペンタン，チオフェン、テトラヒドロチオフェン，ピリジン、ピペリジン，ピロリジン，ピロール，フラン、テトラヒドロピラン、ナフタレン、アントラセン、インドール、ベンゾフラン、ベンゾチオフェン、キノリン環などが挙げられる。また、このアルコキシアルキル基を有する化合物を用いて、高いジアステレオマー過剰率を有するアセタール系化合物を製造する方法も提供される。 In the general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the monocyclic or polycyclic structure is a substituted or unsubstituted 5-membered ring. or consists of six-membered rings may contain a hetero atom, R 6 is a hydrogen atom or a straight or branched lower alkyl group. That is, as the ring structure represented by including A, for example, benzene, cyclohexane, cyclopentane, thiophene, tetrahydrothiophene, pyridine, piperidine, pyrrolidine, pyrrole, furan, tetrahydropyran, naphthalene, anthracene, indole, benzofuran, A benzothiophene, a quinoline ring, etc. are mentioned. In addition, a method for producing an acetal compound having a high diastereomeric excess using the compound having an alkoxyalkyl group is also provided.
　さらに、そのアセタール系化合物を製造する方法のうち特に、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物と、以下の一般式（IV）で表されるアシル基を有する化合物の混合物を、活性化剤の存在下で反応させることで、以下の一般式（V）で表されるアセタール系化合物を選択的に生成するアセタール系化合物の製造方法も提供され、特に糖鎖合成に適用した際には、１，２－trans-グリコシド結合を複数有する化合物（例えば、１，２－trans-グリコシド結合を２箇所有するトリサッカライドなど）を、従来の糖鎖合成では成し得なかったワンポット合成（One-pot synthesis）によって、極めて簡便に得ることが実現される。
Figure JPOXMLDOC01-appb-C000027
 Further, among the methods for producing the acetal compound, in particular, a compound having an alkoxyalkyl group represented by the above general formula (I) and a compound having an acyl group represented by the following general formula (IV): There is also provided a method for producing an acetal compound that selectively produces an acetal compound represented by the following general formula (V) by reacting the mixture in the presence of an activator. When applied, a compound having a plurality of 1,2-trans-glycoside bonds (for example, trisaccharide having two 1,2-trans-glycoside bonds) could not be formed by conventional sugar chain synthesis. One-pot synthesis can be achieved very easily.
Figure JPOXMLDOC01-appb-C000027
　上記一般式（IV）中、Ｒｃ’は、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ７は、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基、アリール基であり、ｎは、０以上の整数であり、Ｘ’は、脱離基であり、Ｙは、ヒドロキシ基、チオール基、アミノ基、モノアルキルアミノ基、または炭素求核剤である。
Figure JPOXMLDOC01-appb-C000028
 In the general formula (IV), Rc ′ is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which a hydrogen atom is a lower alkyl, alkenyl, alkynyl, aryl group. R 7 is a hydrogen atom, or a linear or branched lower alkyl group or aryl group, n is an integer of 0 or more, and X ′ is a leaving group And Y is a hydroxy group, a thiol group, an amino group, a monoalkylamino group, or a carbon nucleophile.
Figure JPOXMLDOC01-appb-C000028
　上記一般式（V）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ７、Ｒａ、Ｒｂ、Ｒｃ、Ｒｃ’、Ｘ、Ｘ’、およびｎは、上記一般式（I）および（IV）の定義と同じである。 In the general formula (V), R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, X, X ′, and n are the above general formula (I) And the definition of (IV).
　本実施形態に係るアルコキシアルキル基を有する化合物は、上述の一般式（I）で表される。上記Ｒ１、Ｒ２、Ｒ３、Ｒ４、およびＲ５は、上述したアルキル基であってもよいが、入手の容易さ及び取り扱いの容易さから、上記Ｒ１、Ｒ２、Ｒ３、Ｒ４、およびＲ５は水素であることが好ましい。また、Ｒａ、Ｒｂ、およびＲｃは、上述した、低級アルキル、アルケニル、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたもの等でもよいが、入手の容易さ及び取り扱いの容易さから、水素であることが好ましい。 The compound having an alkoxyalkyl group according to this embodiment is represented by the above general formula (I). The above R 1 , R 2 , R 3 , R 4 , and R 5 may be the above-described alkyl groups, but from the viewpoint of availability and ease of handling, the above R 1 , R 2 , R 3 , R 4 and R 5 are preferably hydrogen. Ra, Rb, and Rc are the above-described lower alkyl, alkenyl, alkynyl group, aryl group, cyano group, carboxy group, and carboxy group hydrogen substituted with lower alkyl, alkenyl, alkynyl, aryl group, etc. However, hydrogen is preferable because it is easily available and easy to handle.
　低級アルキル基としては、特に限定されないが、例えば、炭素数１～１０のアルキル基を用いることができる。 The lower alkyl group is not particularly limited, and for example, an alkyl group having 1 to 10 carbon atoms can be used.
　Ｘは、脱離基であれば、特に限定されないが、例えば、ＳＰｈ基、トリクロロアセトイミデート（ＯＣ(ＣＣｌ３)ＮＨ）基、フッ素原子、臭素原子を用いることができ、より好ましくは、ＳＰｈ基、トリクロロアセトイミデート基、フッ素原子であり、特にＳＰｈ基が好適である。 X is not particularly limited as long as it is a leaving group. For example, an SPh group, a trichloroacetimidate (OC (CCl 3 ) NH) group, a fluorine atom, or a bromine atom can be used, and more preferably, SPh Group, trichloroacetimidate group and fluorine atom, and SPh group is particularly preferred.
　Ｒ５は、上記の一般式（Ｉ－ａ）で表される官能基とすることができる。この一般式（Ｉ－ａ）においては、上記のＡは、環数１～５の環構造から形成されるものであり、例えば、複数環から成る環構造も含まれるが、この他にも、例えば、環数が１の場合には、ベンジルオキシメチル（ＢＯＭ）基のように、ベンゼン環のみの単環性構造やチオフェン環のみの単環性構造も含まれる。 R 5 can be a functional group represented by the above general formula (Ia). In the general formula (Ia), A is formed from a ring structure having 1 to 5 rings, and includes, for example, a ring structure composed of a plurality of rings. For example, when the number of rings is 1, a monocyclic structure having only a benzene ring or a monocyclic structure having only a thiophene ring is included, such as a benzyloxymethyl (BOM) group.
　上記のアルコキシアルキル基は、好ましくは、以下の化学式（I－１）に示すベンジルオキシメチル（ＢＯＭ）誘導体であるもの、および以下の化学式（I－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体であるものが挙げられる。 The alkoxyalkyl group is preferably a benzyloxymethyl (BOM) derivative represented by the following chemical formula (I-1) and a naphthylmethoxymethyl (NAPOM) derivative represented by the following chemical formula (I-2). Some are listed.
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　上記の化学式（I－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体については、ナフチル基の２つの環について、各々の環で、同じ官能基によって置換されていてもよいし、各々の環で、異なる官能基によって置換されていてもよい。すなわち、上記一般式（I－２）中、Ｒ６とＲ６’は、各々独立して、水素原子、または、炭素数１～３の
直鎖もしくは分岐鎖状のアルキル基である。 As for the naphthylmethoxymethyl (NAPOM) derivative represented by the above chemical formula (I-2), two rings of the naphthyl group may be substituted with the same functional group in each ring, or in each ring, It may be substituted with a different functional group. That is, in the general formula (I-2), R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.
　このような好適なアルコキシアルキル基の一例としては、以下の化学式（I－１－１）で示すベンジルオキシメチル（ＢＯＭ）や、以下の化学式（I－２－１）に示すナフチルメトキシメチル（ＮＡＰＯＭ）が挙げられる。 Examples of such a suitable alkoxyalkyl group include benzyloxymethyl (BOM) represented by the following chemical formula (I-1-1) and naphthylmethoxymethyl (NAPOM) represented by the following chemical formula (I-2-1). ).
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　この他にも、上記のアルコキシアルキル基として、上記のＲ５が、水素原子であるものを用いることができ、そのような一例として、以下の化学式（I－３）で示すメトキシメチル基（ＭＯＭ）を用いることも可能である。 In addition to the above, an alkoxyalkyl group in which R 5 is a hydrogen atom can be used. As an example, a methoxymethyl group (MOM) represented by the following chemical formula (I-3) can be used. ) Can also be used.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　本実施形態に係るアルコキシアルキル基を有する化合物を得る方法としては、特に限定されないが、例えば、単糖類またはオリゴマーに対して、アミン存在下で、前記アルコキシアルキル基を含む化合物（アルコキシアルキル基導入剤）と反応させることによって得ることができる。 A method for obtaining a compound having an alkoxyalkyl group according to the present embodiment is not particularly limited. For example, a compound containing an alkoxyalkyl group (an alkoxyalkyl group introducing agent) in the presence of an amine with respect to a monosaccharide or oligomer. ).
　上記の単糖類またはオリゴマーとしては、特に限定されず、例えば、１位と５位の炭素原子間または２位と５位の炭素原子間に酸素原子が存在するものを用いることができ、例えば、グルコース、ガラクトース、アロース、タロース、グロース、アルトロース、マンノース、イドース、グルクロン酸、イズロン酸、およびフコースを挙げることができ、この他にも、リボース、アラビノース、キシロース、リキソース、リブロース、キシルロースなどの五炭糖なども挙げることができ、所望の用途（合成対象）に応じて、任意に選択することができる。 The monosaccharide or oligomer is not particularly limited, and for example, those having an oxygen atom between the 1st and 5th carbon atoms or between the 2nd and 5th carbon atoms can be used. Glucose, galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose can be mentioned, and in addition to these, ribose, arabinose, xylose, lyxose, ribulose, xylulose, etc. A carbon sugar etc. can also be mentioned and it can select arbitrarily according to a desired use (synthesis object).
　なお、本実施形態では、上記の単糖類またはオリゴマーに限定されず、この他にも、糖鎖に近い構造を持つ天然物に対しても、本実施形態に係るアルコキシアルキル基を有する化合物を適用することが可能である。 In addition, in this embodiment, it is not limited to said monosaccharide or oligomer, In addition to this, the compound which has the alkoxyalkyl group which concerns on this embodiment is applied also to the natural product which has a structure close | similar to sugar chain. Is possible.
　例えば、当該単糖類がグルコースの場合を例示すると、本実施形態に係るアルコキシアルキル基を有する化合物は、グリコシルドナーとして、以下の一般式（II）のように示される。 For example, exemplifying the case where the monosaccharide is glucose, the compound having an alkoxyalkyl group according to this embodiment is represented by the following general formula (II) as a glycosyl donor.
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　上記の一般式（II）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、およびＲ５は、上記の定義と同じであり、Ｐは、任意の保護基、もしくは水素であり、好ましくは保護基である。 In the above general formula (II), R 1 , R 2 , R 3 , R 4 , and R 5 are as defined above, and P is any protecting group or hydrogen, preferably protected. It is a group.
　この単糖類がグルコースである場合において、本実施形態に係るアルコキシアルキル基を有する化合物であるグリコシルドナーは、好適なものとして、以下の一般式（ＩＩ’）で表される。 In the case where the monosaccharide is glucose, a glycosyl donor that is a compound having an alkoxyalkyl group according to the present embodiment is represented by the following general formula (II ′).
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　このようなことから、本実施形態に係るグリコシルドナーは、好適な一例として、上記のアルコキシアルキル基が、以下の化学式（II’－１）に示すベンジルオキシメチル（ＢＯＭ）誘導体であるもの、および以下の化学式（II’－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体であるものが挙げられる。 For this reason, the glycosyl donor according to the present embodiment is, as a preferred example, a compound in which the alkoxyalkyl group is a benzyloxymethyl (BOM) derivative represented by the following chemical formula (II′-1), and Examples thereof include naphthylmethoxymethyl (NAPOM) derivatives represented by the following chemical formula (II′-2).
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　上記一般式（II’－２）中、Ｒ６とＲ６’は、上述したように、各々独立して、水素原子、または、炭素数１～３の直鎖もしくは分岐鎖状のアルキル基である。 In the general formula (II′-2), R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, as described above. is there.
　また、このような本実施形態に係る好適なグリコシルドナーの一例としては、上記のアルコキシアルキル基が、以下の化学式（II’－１－１）に示すベンジルオキシメチル（ＢＯＭ）であるもの、および以下の化学式（II’－１－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）であるものが挙げられる。 In addition, as an example of such a suitable glycosyl donor according to this embodiment, the above alkoxyalkyl group is benzyloxymethyl (BOM) represented by the following chemical formula (II′-1-1), and Examples thereof include naphthylmethoxymethyl (NAPOM) represented by the following chemical formula (II′-1-2).
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　この他にも、本実施形態に係るグリコシルドナーは、上記のアルコキシアルキル基として、上記のＲ４として、水素原子であるものを用いることができ、例えば、以下の化学式（II－３）で示すメトキシメチル基（ＭＯＭ）を用いることも可能である。 In addition, as the glycosyl donor according to the present embodiment, as the above alkoxyalkyl group, a hydrogen atom as R 4 can be used. For example, the glycosyl donor according to the following chemical formula (II-3) can be used. It is also possible to use a methoxymethyl group (MOM).
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　このような本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）は、活性化剤の存在下でアクセプター（例えばグリコシルアクセプター）と反応させ、当該反応により、このアルコキシアルキル基を有する化合物に含まれるアルコキシアルキル基が隣接基として作用（隣接基関与）し、アセタール系化合物（例えばグリコシド化合物）を生成することができる。 Such a compound having an alkoxyalkyl group according to the present embodiment (for example, a glycosyl donor) is reacted with an acceptor (for example, a glycosyl acceptor) in the presence of an activating agent, and the compound having this alkoxyalkyl group by the reaction. Can act as an adjacent group (adjacent group participation) to produce an acetal compound (for example, a glycoside compound).
　このアセタール系化合物とは、Ｃ－Ｏ－Ｃ－Ｏ－Ｃ結合を有する化合物群の総称であり、このような結合が含まれる化合物や群であれば、特にその種類は限定されない。その一例としては、糖類が挙げられるが、その置換位置も特に限定されるものではない。このアセタール系化合物が、例えば糖類であれば、前記アルコキシアルキル基は、グルコースの２位ヒドロキシ基を置換することもできるがこれに限定されることはなく、この他にもグルコースの６位やガラクトースの４位を置換することもでき、すなわち単糖類（もしくはオリゴマー）の様々なヒドロキシ基上で、隣接基関与基となり得る。さらに、五炭糖や、糖鎖に近い構造を持つ天然物等も、このアセタール系化合物の対象として含まれる。 This acetal compound is a general term for a group of compounds having a C—O—C—O—C bond, and the type of the acetal compound is not particularly limited as long as it is a compound or group containing such a bond. One example is sugar, but the substitution position is not particularly limited. If the acetal compound is, for example, a saccharide, the alkoxyalkyl group can substitute the 2-position hydroxy group of glucose, but is not limited thereto. In addition to this, the 6-position of glucose or galactose Can be substituted, i.e., can be a neighboring group participating group on various hydroxy groups of monosaccharides (or oligomers). Furthermore, pentose sugars, natural products having a structure close to sugar chains, and the like are also included as targets of this acetal compound.
　なお、このアセタール系化合物は、上述したようにＣ－Ｏ－Ｃ－Ｏ－Ｃ結合を有する化合物群の総称であることから、所謂純粋なアセタールのみに限定されるものではなく、本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）由来の脱離基Ｘが種々の官能基や原子に置換された化合物等も含まれる。例えば、このアセタール系化合物としては、上述した脱離基Ｘが窒素、水素、硫黄、または炭素で置換された化合物等も含まれるものであり、換言すると、各々、Ｏ,Ｎ－アセタール（アミナール）、エーテル（所謂還元的エーテル化反応に拠る）、Ｏ,Ｓ－アセタール（混合チオアセタール）、またはエーテル（所謂Ｃ－グリコシル化反応に拠る）等の化合物も含まれる。 This acetal compound is a general term for a group of compounds having a C—O—C—O—C bond as described above, and is not limited to so-called pure acetal. Also included are compounds in which the leaving group X derived from a compound having such an alkoxyalkyl group (for example, a glycosyl donor) is substituted with various functional groups or atoms. For example, the acetal compound includes a compound in which the above-described leaving group X is substituted with nitrogen, hydrogen, sulfur, or carbon. In other words, each of the acetal compounds is O, N-acetal (aminal). Also included are compounds such as, ethers (based on so-called reductive etherification reactions), O, S-acetals (mixed thioacetals), or ethers (based on so-called C-glycosylation reactions).
　なお、このアセタール系化合物に含まれるＣ－Ｏ－Ｃ－Ｏ－Ｃ結合を構成するこの３つの炭素原子は、アルキル基、アルケニル基、アルキニル基、アリール基、カルボキシ基、アルコキシカルボニル基、シアノ基などの各種の炭素置換基で置換されていてもよく、また水素が結合した無置換のものでもよい。さらに、このアセタール系化合物の環上には、このような炭素置換基やその他の種々の置換基が含まれていてもよく、特に限定されるものではない。 The three carbon atoms constituting the C—O—C—O—C bond contained in the acetal compound are an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a carboxy group, an alkoxycarbonyl group, and a cyano group. It may be substituted with various carbon substituents such as, or may be unsubstituted with hydrogen bonded. Further, such a carbon substituent and other various substituents may be contained on the ring of the acetal compound, and it is not particularly limited.
　この隣接基関与とは、反応中心に近接する官能基が，反応中心に配位する等により反応速度および選択性に重要且つ多大な影響を及ぼすことを意味する。 This participation of adjacent groups means that the functional group close to the reaction center has an important and great influence on the reaction rate and selectivity by coordinating with the reaction center.
　この活性化剤とは、広義に反応を活性化させるものであれば、特に限定されず、例えば、求電子作用によって酸化剤として反応を活性化させるものや、触媒的な役割によって、反応を活性化させるものも、活性化剤として含まれる。この活性化剤は、１種類のものを用いることもできるが、複数種類のものを併用することもでき、例えば、前記酸化剤として作用するものと、前記触媒的な作用をするものとを組み合わせることによって、その活性化作用を重畳的に増大させることもできる。 The activator is not particularly limited as long as it activates the reaction in a broad sense. For example, the activator activates the reaction as an oxidant by electrophilic action, or activates the reaction by a catalytic role. Those to be activated are also included as activators. As this activator, one type can be used, but a plurality of types can also be used together. For example, the activator is combined with the one acting as the oxidant and the one acting as the catalyst. As a result, the activation effect can be increased in a superimposed manner.
　このような活性化剤としては、特に限定されるものではなく、どのような活性化剤を用いても高い選択性でグルコシル化合物が得られるが、例えば、金属トリフルオロメタンスルホン酸塩、トリフルオロメタンスルホン酸（ＴｆＯＨ）、およびジメチル硫酸などの低級アルキル硫酸エステル、Ｎ－ヨードスクシンイミド（ＮＩＳ）や塩化ヨウ素（ＩＣｌ）
など，I＋供与剤を用いることができる。 Such an activator is not particularly limited, and a glucosyl compound can be obtained with high selectivity by using any activator. For example, metal trifluoromethanesulfonate, trifluoromethanesulfone, etc. Acid (TfOH), lower alkyl sulfates such as dimethyl sulfate, N-iodosuccinimide (NIS) and iodine chloride (ICl)
I + donors can be used.
　また、グリコシル化反応における出発原料（グリコシルドナー）に対する生成物の割合を増大させるという観点からは、より多量の塩化ヨウ素（ＩＣｌ）を用いることが好ましい。また、スクシンイミド骨格を持つ化合物を用いることが好ましく、例えば、Ｎ－ヨードスクシンイミド（ＮＩＳ）、Ｎ－ブロモスクシンイミド（ＮＢＳ）、Ｎ－クロロスクシンイミド（ＮＣＳ）を用いることができ、特に反応性の高さから、Ｎ－ヨードスクシンイミド（ＮＩＳ）を用いることが好ましい。 Further, from the viewpoint of increasing the ratio of the product to the starting material (glycosyl donor) in the glycosylation reaction, it is preferable to use a larger amount of iodine chloride (ICl). Further, it is preferable to use a compound having a succinimide skeleton. For example, N-iodosuccinimide (NIS), N-bromosuccinimide (NBS), and N-chlorosuccinimide (NCS) can be used. Therefore, it is preferable to use N-iodosuccinimide (NIS).
　このような活性化剤のより好適な組み合わせとしては、トリフルオロメタンスルホン酸インジウム（Ｉｎ（ＯＴｆ）３）とＮ－ヨードスクシンイミド（ＮＩＳ）、トリフルオロメタンスルホン酸インジウム（Ｉｎ（ＯＴｆ）３）と塩化ヨウ素（ＩＣｌ）、トリフルオロメタンスルホン酸（ＴｆＯＨ）とＮ－ヨードスクシンイミド（ＮＩＳ）などの組み合わせが挙げられ、中でも高い反応性を得るという点から、－７８ ℃でもＩ＋を発生させることが出来るＩＣｌ－Ｉｎ(ＯＴｆ)３の組み合わせが好適であり，より基質の分解を抑制できるという点から、よりマイルドなＮＩＳ－Ｉｎ(ＯＴｆ)３を，－４０～－１０ ℃付近で使用するのが特に好ましい。 More preferred combinations of such activators include indium trifluoromethanesulfonate (In (OTf) 3 ) and N-iodosuccinimide (NIS), indium trifluoromethanesulfonate (In (OTf) 3 ) and iodine chloride. (ICl), a combination of trifluoromethanesulfonic acid (TfOH) and N-iodosuccinimide (NIS), and the like. Among them, ICl- capable of generating I + even at -78 ° C from the viewpoint of obtaining high reactivity. A combination of In (OTf) 3 is preferable, and it is particularly preferable to use milder NIS-In (OTf) 3 at around −40 to −10 ° C. from the viewpoint that decomposition of the substrate can be further suppressed.
　また、反応に用いる溶媒については、極性溶媒でも非極性溶媒でもよく、特に限定されないが、非プロトン性溶媒を用いることが好ましく、例えば、ジクロロメタン(ＣＨ２Ｃｌ２)、プロピオニトリル(ＥｔＣＮ)、ヘキサン（Ｃ６Ｈ１４）、メチルターシャリーブチルエーテル(ｔＢｕＯＭｅ)などが挙げられる。これらの溶媒は、１種類のみ用いることも可能であり、また、複数同時に用いることも可能である。高い収率が得られ易いという点から、溶媒の極性が低いことが好ましく、このような溶媒として、例えば、ジクロロメタン(ＣＨ２Ｃｌ２)とヘキサン（Ｃ６Ｈ１４）の２種類を併用することが好ましい。 Further, the solvent used in the reaction may be a polar solvent or a nonpolar solvent, and is not particularly limited. However, it is preferable to use an aprotic solvent such as dichloromethane (CH 2 Cl 2 ), propionitrile (EtCN), hexane (C 6 H 14), and the like methyl tertiary butyl ether (t BuOMe). One of these solvents can be used, or a plurality of these solvents can be used simultaneously. From the standpoint that high yields are easily obtained, it is preferable that the polarity of the solvent is low. As such a solvent, for example, two types of dichloromethane (CH 2 Cl 2 ) and hexane (C 6 H 14 ) are used in combination. Is preferred.
　本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）と反応するアクセプター（例えばグルコシルアクセプター）は、特に限定されず、各種の糖類、アルコール、フェノール、チオール、アミン、その他の求核剤（例えば、炭素求核剤など）を用いることが可能である。このような糖類としては、例えば、グルコース、ガラクトース、アロース、タロース、グロース、アルトロース、マンノース、イドース、グルクロン酸、イズロン酸、およびフコースを挙げることができ、また、これらの糖類は、無置換のものを用いることもできるが、その一部がアルキル基（例えばメチル基）やフェニル基（例えばベンジル基）によって置換されたものを用いることもでき、所望の用途（合成対象）に応じて、任意に選択することができる。 The acceptor (for example, glucosyl acceptor) which reacts with the compound (for example, glycosyl donor) having an alkoxyalkyl group according to the present embodiment is not particularly limited, and various saccharides, alcohols, phenols, thiols, amines, and other nucleophiles. (For example, carbon nucleophiles etc.) can be used. Examples of such saccharides include glucose, galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose, and these saccharides are unsubstituted. Can be used, but some of which are substituted with an alkyl group (for example, a methyl group) or a phenyl group (for example, a benzyl group) can be used. Can be selected.
　このような糖類の他にも、アルコールをアクセプター（例えばグルコシルアクセプター）として用いることも可能である。このようなアルコールとしては、例えば、３－フェニル－１－プロパノール、３－フェニル－１－ブタノール、ベンジルアルコール、フェネチルアルコール、１－フェニル－１－プロパノール、１－フェニル－２－プロパノール、２－フェニル－１－プロパノール、２－フェニル－２－プロパノール、１－フェニル－２－ブタノール、２－フェニル－１－ブタノール、２－フェニル－２－ブタノール、４－フェニル－１－ブタノール、５－フェニル－１－ペンタノール、６－フェニル－１－ヘキサノール等のアラルキルアルコールが挙げられる。 In addition to such sugars, alcohol can also be used as an acceptor (for example, glucosyl acceptor). Examples of such alcohols include 3-phenyl-1-propanol, 3-phenyl-1-butanol, benzyl alcohol, phenethyl alcohol, 1-phenyl-1-propanol, 1-phenyl-2-propanol, and 2-phenyl. -1-propanol, 2-phenyl-2-propanol, 1-phenyl-2-butanol, 2-phenyl-1-butanol, 2-phenyl-2-butanol, 4-phenyl-1-butanol, 5-phenyl-1 And aralkyl alcohols such as pentanol and 6-phenyl-1-hexanol.
　上記のような活性化剤、溶媒、およびアクセプター（例えばグリコシルアクセプター）を用いて、当該単糖類がグルコースの場合で例示すると、本実施形態に係るアルコキシアルキル基を有する化合物の一例であるグリコシルドナーからグリコシド化合物を生成する反応は、以下の反応式（III）として示される。当該反応過程の中間体として、グルコースの１位と２位炭素間に酸素原子を２つ含む５員環が、反応過程の中で一時的に形成されている（隣接基関与がある）ものと推察される。 Using the activator, solvent, and acceptor as described above (for example, glycosyl acceptor), when the monosaccharide is exemplified by glucose, a glycosyl donor that is an example of a compound having an alkoxyalkyl group according to this embodiment The reaction for producing a glycoside compound from is represented by the following reaction formula (III). As an intermediate of the reaction process, a 5-membered ring containing two oxygen atoms between the 1st and 2nd carbons of glucose is temporarily formed in the reaction process (neighboring groups are involved) Inferred.
Figure JPOXMLDOC01-appb-C000038
 　
Figure JPOXMLDOC01-appb-C000038
 　
　上記の反応によって、本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）から得られるアセタール系化合物（例えばグリコシド化合物）は、極めて高いジアステレオマー過剰率を有していることが確認されている（後述の実施例参照）。 By the above reaction, it is confirmed that the acetal compound (for example, glycoside compound) obtained from the compound having the alkoxyalkyl group (for example, glycosyl donor) according to the present embodiment has a very high diastereomeric excess. (Refer to Examples described later).
　例えば、後述の実施例１で確認されたように、本実施形態に係るグルコシルドナー（実施例における一例としては2-O-BOM体）では、極めて高いβ選択性（β型のみの生成が確認された）でグリコシル化反応が進行しており、反応過程の中間体を含めて、以下の反応が引き起こされたものと推察される。 For example, as confirmed in Example 1 to be described later, the glucosyl donor according to this embodiment (2-O-BOM as an example in the example) is confirmed to have extremely high β selectivity (production of only β type). It was speculated that the following reactions were caused, including intermediates in the reaction process.
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　これに対して、例えば、後述の実施例１で確認されたように、比較例のグルコシルドナー（実施例における一例としては2-O-メチル体）では、非立体選択的（α：β＝１：１）にグリコシル化反応が進行したことから、反応過程の中間体を含めて、以下の反応が引き起こされたものと推察される。 In contrast, for example, as confirmed in Example 1 described later, the glucosyl donor of the comparative example (2-O-methyl as an example in the example) is non-stereoselective (α: β = 1). 1) Since the glycosylation reaction proceeded in 1), it is presumed that the following reaction was caused including intermediates in the reaction process.
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
1） Salmasan, M. R.; Manabe, Y.; Kitakami, Y.; Chang, T.; Fukase, K. Chem. Lett. 2014, 43, 956-958. 1) Salmasan, M. R .; Manabe, Y .; Kitakami, Y .; Chang, T .; Fukase, K. Chem. Lett. 2014, 43, 956-958.
　このように優れた立体選択性を奏するメカニズムは未だ詳細には解明されていないが、前記反応過程の中間体として、単糖類またはオリゴマー（例えばグルコース）の２位ヒドロキシ基に置換されたアルコキシアルキル基が隣接基として作用し、この隣接基関与によって、上述したようにアルコキシアルキル基から極めて嵩高い５員環が一時的に形成され、この５員環が強い立体障害となって、求核剤の下部（α側）からの攻撃をブロックするため立体選択性を生じやすい、つまりβ側からの求核剤の接近が有利な状態が形成されているものと推察される（これに対して、非立体選択的（α：β＝１：１）にグリコシル化反応が進行した比較例の2-O-メチル体では、このような５員環が形成されていないものと推察される）。そして、この隣接基関与による嵩高い５員環の存在下で、グルコシルアクセプターと反応することによって、極めて高い立体選択性が得られているものと推察される。 Although the mechanism for achieving such excellent stereoselectivity has not yet been elucidated in detail, an alkoxyalkyl group substituted with a 2-position hydroxy group of a monosaccharide or an oligomer (for example, glucose) is used as an intermediate in the reaction process. Acts as an adjacent group, and due to the participation of the adjacent group, an extremely bulky 5-membered ring is temporarily formed from the alkoxyalkyl group as described above. This 5-membered ring becomes a strong steric hindrance, and the nucleophile It is presumed that stereoselectivity is likely to occur because the attack from the lower part (α side) is blocked, that is, a state in which the approach of the nucleophile from the β side is advantageous is formed (as opposed to this, It is inferred that such a 5-membered ring is not formed in the 2-O-methyl isomer of the comparative example in which the glycosylation reaction proceeded stereoselectively (α: β = 1: 1)). And it is guessed that very high stereoselectivity is acquired by reacting with a glucosyl acceptor in presence of the bulky 5-membered ring by participation of this adjacent group.
　本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）は、上述のように、極めて高いジアステレオマー過剰率を有するアセタール系化合物（例えばグリコシド化合物）を得ることができ、さらに、この得られたアセタール系化合物（例えばグリコシド化合物）を各種の酸等と反応させて、前記アルコキシアルキル基を除去することも可能である。酸等としては、塩酸やp-トルエンスルホン酸等のプロトン酸や，トリフルオロボラン，トリメチルシリルヨージド，トリメチルシリルブロミド等のルイス酸を用いることができ、特に取り扱いの容易さから、塩酸を用いることが好ましい。またアルコキシアルキル基が、BOM基やNAPOM基の場合、加水素分解やDDQ等による酸化的除去も可能である。 As described above, the compound having an alkoxyalkyl group according to the present embodiment (for example, a glycosyl donor) can obtain an acetal compound (for example, a glycoside compound) having a very high diastereomeric excess, and this It is also possible to remove the alkoxyalkyl group by reacting the obtained acetal compound (for example, glycoside compound) with various acids. Examples of acids that can be used include proton acids such as hydrochloric acid and p-toluenesulfonic acid, and Lewis acids such as trifluoroborane, trimethylsilyl iodide, and trimethylsilyl bromide. preferable. In addition, when the alkoxyalkyl group is a BOM group or a NAPOM group, it can be oxidatively removed by hydrogenolysis or DDQ.
　このアルコキシアルキル基の除去は、従来のアシル系保護基の除去とは異なり、出発原料である単糖類またはオリゴマーに、エステル部位が存在した場合やアシル基が存在した場合であっても、必要な反応工程数を増やすことなく、簡易に除去することができる。 This removal of the alkoxyalkyl group is different from the conventional removal of the acyl protecting group, even if an ester site is present or an acyl group is present in the starting saccharide or oligomer. It can be easily removed without increasing the number of reaction steps.
　また、本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）から引き起こされる立体選択性については、アルコキシアルキル基を有する化合物（例えばグリコシルドナー）を構成する前記アルコキシアルキル基で置換された母体（例えば単糖類またはオリゴマー）の種類に応じて、α型（α選択性）やβ型（β選択性）など、様々な立体選択性が発揮される。例えば、アルコキシアルキル基を有する化合物がグリコシルドナーであって、前記アルコキシアルキル基で置換された母体が単糖類のグルコースである場合には、アルコキシアルキル基が、グルコースの2位に導入されればβ選択性が得られ、マンノースの2位や、グルコースの6位に導入されればα選択性が得られる。 In addition, regarding the stereoselectivity caused by a compound having an alkoxyalkyl group according to the present embodiment (for example, a glycosyl donor), the matrix substituted with the alkoxyalkyl group constituting the compound having an alkoxyalkyl group (for example, a glycosyl donor). Depending on the type (for example, monosaccharide or oligomer), various stereoselectivities such as α-type (α-selectivity) and β-type (β-selectivity) are exhibited. For example, when a compound having an alkoxyalkyl group is a glycosyl donor and the parent substance substituted with the alkoxyalkyl group is monosaccharide glucose, β is introduced when the alkoxyalkyl group is introduced at the 2-position of glucose. Selectivity can be obtained, and α-selectivity can be obtained if introduced at the 2nd position of mannose or the 6th position of glucose.
　本実施形態に係るアルコキシアルキル基を有する化合物（例えばグリコシルドナー）から得られるアセタール系化合物（例えばグリコシド化合物）は多岐にわたる。その一例として、Symponosideや、Belallosideのようなグリコシド、およびそれらの誘導体が挙げられる。 The acetal compound (for example, glycoside compound) obtained from the compound (for example, glycosyl donor) having an alkoxyalkyl group according to this embodiment is diverse. Examples thereof include glycosides such as Symponoside and Belalloside, and derivatives thereof.
　Symponosideとは、以下の化学式で示され、インド産薬用植物シンプロコス・ラケモーサ（Symplocos racemosa）から単離・構造決定されたグリコシドであり、ホスホジエステラーゼおよびチミジンホスホリラーゼに対し阻害活性を示すことが報告されていることから、将来的に優れた薬剤となる可能性が期待されているが、現状では、天然から得られる量が限られており（４０ｋｇの乾燥植物体からわずか１８．６ｍｇしか得られない）、薬学的研究は立ち遅れている。 Symponoside is a glycoside that is expressed by the following chemical formula and isolated and structure-determined from the Indian medicinal plant Symprocos racemosa, and has been reported to exhibit inhibitory activity against phosphodiesterase and thymidine phosphorylase. Therefore, the possibility of becoming an excellent drug in the future is expected, but at present, the amount obtained from nature is limited (only 18.6 mg can be obtained from a 40 kg dry plant), Pharmaceutical research is behind.
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　このような中、本実施形態に係るグリコシルドナーを用いれば、以下の反応によって、β選択性グルコシド化反応が容易に引き起こされることから、従来は合成が困難であったSymponosideが、極めて簡易に製造できるという特筆すべき優れた効果が発揮される。 Under such circumstances, if the glycosyl donor according to the present embodiment is used, a β-selective glucosidation reaction is easily caused by the following reaction. Thus, Symponoside, which has been difficult to synthesize in the past, can be produced very easily. The remarkable effect that can be done is demonstrated.
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　また、上述のBelallosideとは、以下の化学式で示され、タイ産薬用植物ベラムカンダ ・シネンシス L（Belamcanda sinensis L）の根から単離・構造決定されたグリコシドであり、扁桃炎や咽頭炎に対する薬効があるとされているが、現状では、天然から得られる量が限られている（１ｋｇの根からわずか１．５ｍｇしか得られない）。 Belalloside mentioned above is a glycoside that is represented by the following chemical formula and has been isolated and determined from the roots of the Thai medicinal plant Belamcanda sinensis L, and has medicinal properties against tonsillitis and pharyngitis. It is said that there is currently a limited amount available from nature (only 1.5 mg can be obtained from a 1 kg root).
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　本実施形態に係るグリコシルドナーを用いれば、β選択的グリコシル化反応が容易に引き起こされることから、従来は合成が困難であったBelallosideが、極めて簡易に製造できるという特筆すべき優れた効果が発揮される。 If the glycosyl donor according to this embodiment is used, a β-selective glycosylation reaction is easily caused. Therefore, Belalloside, which has been difficult to synthesize in the past, exhibits a remarkable effect that can be produced very easily. Is done.
　この他にも、本実施形態に係るグリコシルドナーは、各種の有用な化合物の合成（天然有機化合物も含む）に適用することができ、そのうちの一例として、例えば、本実施形態に係るグリコシルドナーを用いて、文献（Machida, K. et al., M. Phenolic Compounds of the Leaves of Catalpa ovata G. Don. Natural Medicines, 2001, 55, 64-67.)で示される植物Catalpa ovataから単離されたβ－Ｄ－グルコピラノシド（現在までに、人工的に化学合成された事例は知られていない）が全合成できることを本発明者は確認している（後述の実施例参照）。 In addition, the glycosyl donor according to the present embodiment can be applied to the synthesis of various useful compounds (including natural organic compounds). As an example, for example, the glycosyl donor according to the present embodiment can be used. And was isolated from the plant Catalpa ovata shown in the literature (Machida, K. et al., M. Phenolic Compounds of the Leaves of Catalpa ovata G. Don. Natural Medicines, 2001, 55, 64-67.) The present inventor has confirmed that β-D-glucopyranoside (to date, no examples of artificial chemical synthesis are known) can be totally synthesized (see Examples described later).
　（さらなる実施形態）
　さらに、本発明者が確認したところに拠れば、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物が、従来のアシル基を有する化合物よりも速くグリコシル化反応を受けることが、以下の化学反応によって、確認されている。
Figure JPOXMLDOC01-appb-C000044
 (Further embodiment)
Furthermore, according to what the present inventors have confirmed, a compound having an alkoxyalkyl group represented by the above general formula (I) undergoes a glycosylation reaction faster than a compound having a conventional acyl group. It has been confirmed by the following chemical reaction.
Figure JPOXMLDOC01-appb-C000044
　この事実に拠れば、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物と、従来のアシル基を有する化合物を混合し、活性化剤を加えることによって、前者のみを活性化し、前者基質にのみ１，２－trans-グリコシル化（例えば、グルコースのβ選択的グリコシル化反応も含まれる）を進行させることができる。 Based on this fact, the compound having an alkoxyalkyl group represented by the above general formula (I) and the compound having a conventional acyl group are mixed, and only the former is activated by adding an activator, Only the former substrate can proceed with 1,2-trans-glycosylation (eg, including β-selective glycosylation of glucose).
　上記の一般式（I）で表されるアルコキシアルキル基を有する化合物の反応は、従来のアシル基を有する化合物よりも速く進行する。 The reaction of the compound having an alkoxyalkyl group represented by the above general formula (I) proceeds faster than a compound having a conventional acyl group.
　上記の一般式（I）で表されるアルコキシアルキル基を有する化合物と、従来のアシル基を有する化合物とを混合し、活性化剤を加えることによって、アルコキシアルキル基を有する化合物のみを活性化し、アルコキシアルキル基を有する化合物の基質にのみ立体選択的な反応をおこすことが実現できるものとなる。 By mixing the compound having an alkoxyalkyl group represented by the above general formula (I) with a compound having a conventional acyl group and adding an activator, only the compound having an alkoxyalkyl group is activated, It is possible to realize a stereoselective reaction only on the substrate of the compound having an alkoxyalkyl group.
　かくして、本発明に係るさらなる実施形態としては、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物と、以下の一般式（IV）で表されるアシル基を有する化合物の混合物を、活性化剤の存在下で反応させることで、以下の一般式（V）で表されるアセタール系化合物を選択的に製造する方法が挙げられる。
Figure JPOXMLDOC01-appb-C000045
 Thus, as a further embodiment according to the present invention, a mixture of a compound having an alkoxyalkyl group represented by the above general formula (I) and a compound having an acyl group represented by the following general formula (IV): And a method of selectively producing an acetal compound represented by the following general formula (V) by reacting in the presence of an activator.
Figure JPOXMLDOC01-appb-C000045
　上記一般式（IV）中、Ｒｃ’は、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ７は、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基、アリール基であり、ｎは、０以上の整数であり、Ｘ’は、脱離基であり、Ｙは、ヒドロキシ基、チオール基、アミノ基、モノアルキルアミノ基、または炭素求核剤である。
Figure JPOXMLDOC01-appb-C000046
 In the general formula (IV), Rc ′ is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which a hydrogen atom is a lower alkyl, alkenyl, alkynyl, aryl group. R 7 is a hydrogen atom, or a linear or branched lower alkyl group or aryl group, n is an integer of 0 or more, and X ′ is a leaving group And Y is a hydroxy group, a thiol group, an amino group, a monoalkylamino group, or a carbon nucleophile.
Figure JPOXMLDOC01-appb-C000046
　上記一般式（V）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ７、Ｒａ、Ｒｂ、Ｒｃ、Ｒｃ’、Ｘ、Ｘ’、およびｎは、上記一般式（I）および（IV）の定義と同じである。 In the general formula (V), R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, X, X ′, and n are the above general formula (I) And the definition of (IV).
　本実施形態に係るアルコキシアルキル基を有する化合物は、上述の一般式（I）で表される。 The compound having an alkoxyalkyl group according to this embodiment is represented by the above general formula (I).
　また、本実施形態に係るアルコキシアルキル基を有する化合物と反応させる上記一般式（IV）で表されるアシル基を有する化合物については、従来から公知のものを特に制限なく適用することができ、上記Ｒ７は、上述した水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であってもよいが、取り扱いの容易さからフェニル基であってもよい。上記Ｒ７がフェニル基の場合には、上記Ｒ７はベンゾイル基（Ｂｚ）を構成する。 In addition, as for the compound having an acyl group represented by the general formula (IV) to be reacted with the compound having an alkoxyalkyl group according to the present embodiment, conventionally known compounds can be applied without any particular limitation. R 7 may be the hydrogen atom described above or a linear or branched lower alkyl group, but may be a phenyl group for ease of handling. When R 7 is a phenyl group, R 7 constitutes a benzoyl group (Bz).
　上記一般式（IV）中のＲｃ’は、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、特に限定されない。 Rc ′ in the general formula (IV) is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, or a carboxy group in which a hydrogen atom is a lower alkyl, alkenyl, alkynyl, aryl group. May be substituted, and is not particularly limited.
　上記一般式（IV）中のｎで示されるアルキル鎖は、０以上の整数であり、ｎが０の場合には、アルキル鎖なしで直接ＯＨ基（ヒドロキシ基）に結合する。ｎの好適な範囲としては、当該アルキル鎖が低級アルキル鎖を構成する場合であり、例えば、ｎ＝１～１０であり、例えば、ｎ＝１とすることができる。 The alkyl chain represented by n in the above general formula (IV) is an integer of 0 or more, and when n is 0, it is directly bonded to an OH group (hydroxy group) without an alkyl chain. A preferable range of n is when the alkyl chain constitutes a lower alkyl chain, for example, n = 1 to 10, for example, n = 1.
　Ｘ’は、脱離基であれば、特に限定されないが、例えば、ＳＰｈ基、トリクロロアセトイミデート（ＯＣ(ＣＣｌ３)ＮＨ）基、フッ素原子、臭素原子を用いることができ、ＳＰｈ基、トリクロロアセトイミデート基、フッ素原子を用いることもでき、ＳＰｈ基を用いることもでき、この他にもメチル基や、エチル基や、ピバロイル基でもよい。また、Ｘ’を、Ｘと同じ脱離基とした場合には、使用する添加剤を共通化できることなど化学反応条件が統一化されて簡素化することができ、連続的な反応が行い易くなる。 X ′ is not particularly limited as long as it is a leaving group, and for example, an SPh group, a trichloroacetimidate (OC (CCl 3 ) NH) group, a fluorine atom, or a bromine atom can be used. An acetimidate group or a fluorine atom can be used, and an SPh group can also be used. In addition, a methyl group, an ethyl group, or a pivaloyl group may be used. In addition, when X ′ is the same leaving group as X, chemical reaction conditions can be unified and simplified such that the additive to be used can be made common, and continuous reaction can be easily performed. .
　上述の一般式（I）で表されるアルコキシアルキル基を有する化合物を構成するアルコキシアルキル基としては、以下の化学式（I－１）に示すベンジルオキシメチル（ＢＯＭ）誘導体であるもの、および以下の化学式（I－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体であるものが挙げられる。 The alkoxyalkyl group constituting the compound having an alkoxyalkyl group represented by the above general formula (I) is a benzyloxymethyl (BOM) derivative represented by the following chemical formula (I-1), and the following And a naphthylmethoxymethyl (NAPOM) derivative represented by the chemical formula (I-2).
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　上記の化学式（I－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体については、ナフチル基の２つの環について、各々の環で、同じ官能基によって置換されていてもよいし、各々の環で、異なる官能基によって置換されていてもよい。すなわち、上記一般式（I－２）中、Ｒ６とＲ６’は、各々独立して、水素原子、または、炭素数１～３の直鎖もしくは分岐鎖状のアルキル基である。 As for the naphthylmethoxymethyl (NAPOM) derivative represented by the above chemical formula (I-2), two rings of the naphthyl group may be substituted with the same functional group in each ring, or in each ring, It may be substituted with a different functional group. That is, in the general formula (I-2), R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms.
　このようなアルコキシアルキル基の一例としては、以下の化学式（I－１－１）で示すベンジルオキシメチル（ＢＯＭ）や、以下の化学式（I－２－１）に示すナフチルメトキシメチル（ＮＡＰＯＭ）が挙げられる。 Examples of such alkoxyalkyl groups include benzyloxymethyl (BOM) represented by the following chemical formula (I-1-1) and naphthylmethoxymethyl (NAPOM) represented by the following chemical formula (I-2-1). Can be mentioned.
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　この他にも、上記のアルコキシアルキル基として、上記のＲ５が、水素原子であるものを用いることができ、そのような一例として、以下の化学式（I－３）で示すメトキシメチル基（ＭＯＭ）を用いることも可能である。 In addition to the above, an alkoxyalkyl group in which R 5 is a hydrogen atom can be used. As an example, a methoxymethyl group (MOM) represented by the following chemical formula (I-3) can be used. ) Can also be used.
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　アルコキシアルキル基を有する化合物として、上記の化学式（I－１）に示すベンジルオキシメチル（ＢＯＭ）誘導体であるもの、および上記の化学式（I－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体であるものを用いた場合には、以下の一般式（V-1）または一般式（V-2）で表されるアセタール系化合物が得られる。
Figure JPOXMLDOC01-appb-C000050
 Compounds having an alkoxyalkyl group are benzyloxymethyl (BOM) derivatives represented by the above chemical formula (I-1) and naphthylmethoxymethyl (NAPOM) derivatives represented by the above chemical formula (I-2) When is used, an acetal compound represented by the following general formula (V-1) or general formula (V-2) is obtained.
Figure JPOXMLDOC01-appb-C000050
　上記式中、Ｒａ、Ｒｂ、Ｒｃ、およびＸは、一般式（I）の定義と同じであり、Ｒｃ’、Ｘ’、およびｎは、一般式（V）の定義と同じであり、Ｒ６およびＲ６’は、各々独立して、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である。 In the above formula, Ra, Rb, Rc and X are the same as defined in general formula (I), Rc ′, X ′ and n are the same as defined in general formula (V), and R 6 And R 6 ′ each independently represents a hydrogen atom or a linear or branched lower alkyl group.
　さらに、後続の反応として、上記の一般式（I）のアルコキシアルキル基を有する化合物によるグリコシル化反応後に、フェノール類または脂肪族アルコールを添加して、例えば、昇温するなど温度変化させることで反応させることが可能であり、この反応によって、前記脱離基Ｘ’がアルコキシ基に置き換わった以下の一般式（V’）で表されるアセタール系化合物を選択的に生成することが可能となる。
Figure JPOXMLDOC01-appb-C000051
 Furthermore, as a subsequent reaction, after the glycosylation reaction with the compound having the alkoxyalkyl group of the above general formula (I), the reaction is performed by adding a phenol or an aliphatic alcohol and changing the temperature, for example, by raising the temperature. By this reaction, it becomes possible to selectively produce an acetal compound represented by the following general formula (V ′) in which the leaving group X ′ is replaced by an alkoxy group.
Figure JPOXMLDOC01-appb-C000051
　上記一般式（V’）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ７、Ｒａ、Ｒｂ、Ｒｃ、Ｒｃ’、およびｎは、上記一般式（V）の定義と同じであり、Ｒ８は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基、またはアリール基である。 In the general formula (V ′), R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, and n are the same as defined in the general formula (V). And R 8 is a hydrogen atom, a linear or branched lower alkyl group, or an aryl group.
　このように、本実施形態に係るアルコキシアルキル基を有する化合物を、従来のアシル基を有する化合物に混合して、活性化剤の存在下、低温で反応させ、上記一般式（V）で表されるアセタール系化合物を発生させた後、アルコール類を添加して、例えば、昇温するなど温度変化させるのみという非常に簡便な方法、または温度制御のみによって、所望とするアセタール系化合物が、容易に得られる。または、温度を制御することのみによって、狙いとする立体配置を有する化合物が選択的に次々に得られるという極めて簡易な合成が可能となる。 Thus, the compound having an alkoxyalkyl group according to the present embodiment is mixed with a compound having a conventional acyl group and reacted at a low temperature in the presence of an activator, and is represented by the general formula (V). After the generation of the acetal compound, the desired acetal compound can be easily obtained by adding an alcohol and then changing the temperature, for example, by raising the temperature, or by controlling the temperature. can get. Alternatively, by simply controlling the temperature, a very simple synthesis is possible in which compounds having the targeted configuration are selectively obtained one after another.
　なお、本実施形態に係るアルコキシアルキル基を有する化合物を得る方法としては、特に限定されないが、例えば、単糖類またはオリゴマーに対して、アミン存在下で、前記アルコキシアルキル基を含む化合物（アルコキシアルキル基導入剤）と反応させることによって得ることができる。 The method for obtaining the compound having an alkoxyalkyl group according to the present embodiment is not particularly limited. For example, a compound containing an alkoxyalkyl group (alkoxyalkyl group) in the presence of an amine with respect to a monosaccharide or oligomer. It can be obtained by reacting with an introduction agent.
　上記の単糖類またはオリゴマーとしては、特に限定されず、例えば、１位と５位の炭素原子間または２位と５位の炭素原子間に酸素原子が存在するものを用いることができ、例えば、グルコース、ガラクトース、アロース、タロース、グロース、アルトロース、マンノース、イドース、グルクロン酸、イズロン酸、およびフコースを挙げることができ、この他にも、リボース、アラビノース、キシロース、リキソース、リブロース、キシルロースなどの五炭糖なども挙げることができ、所望の用途（合成対象）に応じて、任意に選択することができる。 The monosaccharide or oligomer is not particularly limited, and for example, those having an oxygen atom between the 1st and 5th carbon atoms or between the 2nd and 5th carbon atoms can be used. Glucose, galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose can be mentioned, and in addition to these, ribose, arabinose, xylose, lyxose, ribulose, xylulose, etc. A carbon sugar etc. can also be mentioned and it can select arbitrarily according to a desired use (synthesis object).
　このように本実施形態に係るアルコキシアルキル基を有する化合物が、単糖類またはオリゴマーに前記アルコキシアルキル基が置換されて成る場合には、上述したように、このアルコキシアルキル基を有する化合物のグリコシル化反応速度が、前記アシル基を有する化合物のグリコシル化反応速度よりも速いことが、本発明者によって確認されている。すなわち、当該アルコキシアルキル基を有する化合物のグリコシル化反応が選択的に進行し、アセタール系化合物である１，２－trans-グリコシド結合を有する化合物を選択的に生成することができるという優れた効果を奏する。 Thus, when the compound having an alkoxyalkyl group according to this embodiment is formed by substituting the alkoxyalkyl group for a monosaccharide or oligomer, as described above, the glycosylation reaction of the compound having the alkoxyalkyl group It has been confirmed by the present inventor that the rate is faster than the glycosylation reaction rate of the compound having an acyl group. That is, the glycosylation reaction of the compound having an alkoxyalkyl group selectively proceeds, and an excellent effect that a compound having a 1,2-trans-glycoside bond, which is an acetal compound, can be selectively produced. Play.
　例えば、以下の反応が進行することが、本発明者によって確認されており、１，２－trans-グリコシド結合を有する化合物が、混合するのみという非常に簡便な方法によって、容易に得られることが実現される。
Figure JPOXMLDOC01-appb-C000052
 For example, it has been confirmed by the present inventor that the following reaction proceeds, and a compound having a 1,2-trans-glycoside bond can be easily obtained by a very simple method of only mixing. Realized.
Figure JPOXMLDOC01-appb-C000052
　さらに、本発明者が確認したところに拠れば、上記の後工程として、以下の反応式に示すように、アルコール類を加えて温度を上げるのみという非常に簡便な方法によって、上記のＳＰｈ基（前記脱離基Ｘ’）がアルコキシ基に置き換わった１，２－trans-グリコシド結合を有するアセタール系化合物が容易に得られる。
Figure JPOXMLDOC01-appb-C000053
   Furthermore, according to what the present inventors have confirmed, as the subsequent step, as shown in the following reaction formula, the above SPh group ( An acetal compound having a 1,2-trans-glycoside bond in which the leaving group X ′) is replaced with an alkoxy group can be easily obtained.
Figure JPOXMLDOC01-appb-C000053
　すなわち、本実施形態に係るアルコキシアルキル基を有する化合物に対するグリコシル化反応後に、フェノール類または脂肪族アルコールを添加して、例えば、昇温するなど温度変化させることで反応させ、当該反応により、ＳＰｈ基（前記脱離基Ｘ’）がアルコキシ基に置き換わった１，２－trans-グリコシド結合を有するアセタール系化合物を選択的に生成することが可能となる。 That is, after the glycosylation reaction for the compound having an alkoxyalkyl group according to this embodiment, phenols or aliphatic alcohols are added, and the reaction is performed by changing the temperature, for example, by raising the temperature. It becomes possible to selectively produce an acetal compound having a 1,2-trans-glycoside bond in which (the leaving group X ′) is replaced with an alkoxy group.
　このように、本実施形態に係るアルコキシアルキル基を有する化合物を、従来のアシル基を有する化合物に混合して、活性化剤の存在下、低温で反応させ、上記一般式（V）で表されるアセタール系化合物を発生させた後、アルコール類を添加して、例えば、昇温するなど温度変化させるのみという非常に簡便な方法、または温度制御のみによって、所望とする１，２－trans-グリコシド結合を有する化合物が、容易に得られるものである。または、温度を制御することのみによって、狙いとする１，２－trans-グリコシド結合を有する糖鎖が選択的に確実に次々に付加合成され、所望とする１，２－trans-グリコシド結合を有する多糖類が得られるという極めて簡便な合成が可能となる。 Thus, the compound having an alkoxyalkyl group according to the present embodiment is mixed with a compound having a conventional acyl group and reacted at a low temperature in the presence of an activator, and is represented by the general formula (V). The desired 1,2-trans-glycoside is produced by a very simple method of adding an alcohol after the generation of the acetal compound and then changing the temperature, for example, by raising the temperature, or only by controlling the temperature. A compound having a bond can be easily obtained. Alternatively, only by controlling the temperature, the target sugar chain having 1,2-trans-glycoside bonds is selectively added and synthesized one after another, and has the desired 1,2-trans-glycoside bonds. An extremely simple synthesis is possible in which a polysaccharide is obtained.
　温度条件については、特に限定されないが、例えば、前記グリコシル化反応を－７８℃～－２０℃で行った後に、前記高温反応を－２０℃～０℃で行うことができる。勿論、上述したように、生成されたアセタール系化合物を少なくとも酸と反応させて、前記アルコキシアルキル基を除去することができる。 The temperature conditions are not particularly limited. For example, after the glycosylation reaction is performed at −78 ° C. to −20 ° C., the high temperature reaction can be performed at −20 ° C. to 0 ° C. Of course, as described above, the acetal compound thus produced can be reacted with at least an acid to remove the alkoxyalkyl group.
　この合成手法は、従来のように複数の脱離基を必要とするものではなく、同じ脱離基Ｘ（例えば、ＳＰｈ基）を終始用いて、温度制御のみによって、糖鎖合成が連続的に為されるという優れた手法であり、本実施形態に係る隣接基関与基としてアルコキシアルキル基を有する化合物が示す、従来のアシル基を有する化合物よりも高い反応性によって、はじめて為されるものである。 This synthesis method does not require a plurality of leaving groups as in the prior art, and the same leaving group X (for example, SPh group) is used all the time, and sugar chain synthesis is continuously performed only by temperature control. This is an excellent technique that is performed for the first time due to a higher reactivity than a compound having a conventional acyl group, which is shown by a compound having an alkoxyalkyl group as an adjacent group participating group according to the present embodiment. .
　従来の糖鎖合成では、反応速度の違いを使って、同じ脱離基を有するビルディングブロックの一方に選択的な反応を引き起こすという概念自体が存在していなかったが、その主な理由としては、反応速度の異質性を引き起こす化合物が知られていなかったためである。そのため、本合成手法は、本実施形態に係るアルコキシアルキル基を有する化合物の反応速度の異質性が本発明者によって明らかとなったことではじめて成し得たものであり、糖鎖合成における重要化合物である１，２－trans-グリコシド結合を有する化合物が従来よりも極めて容易に得られる。 In conventional sugar chain synthesis, the concept of causing a selective reaction on one of the building blocks having the same leaving group using the difference in reaction rate did not exist, but the main reason is as follows: This is because a compound that causes heterogeneity in reaction rate has not been known. Therefore, this synthesis technique can be achieved only when the inventors have clarified the heterogeneity of the reaction rate of the compound having an alkoxyalkyl group according to the present embodiment, and is an important compound in sugar chain synthesis. Thus, a compound having a 1,2-trans-glycoside bond as described above can be obtained extremely easily.
　なお、本実施形態では、上記の単糖類またはオリゴマーに限定されず、この他にも、糖鎖に近い構造を持つ天然物に対しても、本実施形態に係るアルコキシアルキル基を有する化合物を適用することが可能である。 In addition, in this embodiment, it is not limited to said monosaccharide or oligomer, In addition to this, the compound which has the alkoxyalkyl group which concerns on this embodiment is applied also to the natural product which has a structure close | similar to sugar chain. Is possible.
　上記のように、本実施形態では、特に、糖鎖合成において、これまでに無い着想で１，２－trans-グリコシド結合を有する化合物をワンポット合成（One-pot synthesis）で得ることが可能となることが確認された。さらに、本発明者に拠れば、このようにして得られた新たな１，２－trans-グリコシド結合を有する化合物を計測する方法として、極めて高精度かつ簡易に計測できる新たな方法を見出した。 As described above, in this embodiment, particularly in sugar chain synthesis, a compound having a 1,2-trans-glycoside bond can be obtained by one-pot synthesis with an unprecedented idea. It was confirmed. Furthermore, according to the present inventor, as a method for measuring a compound having a new 1,2-trans-glycoside bond obtained in this manner, a new method that can be measured with extremely high accuracy and simplicity has been found.
（含有比率の計測方法）
　すなわち、本実施形態に係る計測方法は、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用して生成されたアセタール系化合物を計測する方法であって、核磁気共鳴分光法（NMR）により測定し、得られた測定値の高ピーク値と低ピーク値の比較に基づいて、生成されたアセタール系化合物の含有比率を計測するものである。 (Measurement method of content ratio)
That is, in the measurement method according to this embodiment, a compound having an alkoxyalkyl group represented by the general formula (I) is reacted with an acceptor in the presence of an activator, and the alkoxyalkyl group is converted by the reaction. A method for measuring an acetal compound produced by the action of an alkoxyalkyl group of a compound having an adjacent group, which is measured by nuclear magnetic resonance spectroscopy (NMR). Based on the comparison of peak values, the content ratio of the generated acetal compound is measured.
　ＮＭＲを用いて測定するタイミングとしては、特に限定されず、例えば、上記の一般式（V）で表されるアセタール系化合物が生成された直後でもよいし、その後の工程でもよく、例えば、反応剤を濾過により除去する工程、除媒を行う工程、精製（例えばＨＰＬＣを用いる）を行う工程、除媒乾燥を行う工程、化学構造を特定する工程、低温保存（例えばー２０～ー１８℃）を行う工程、出荷を行う工程などが挙げられる。 The timing for measurement using NMR is not particularly limited. For example, it may be immediately after the acetal compound represented by the general formula (V) is formed, or may be a subsequent step. The step of removing by filtration, the step of removing the solvent, the step of performing purification (for example using HPLC), the step of removing the solvent, the step of specifying the chemical structure, and the low temperature storage (for example, −20 to −18 ° C.) The process to perform, the process to ship, etc. are mentioned.
　前記測定値の高ピーク値としては、例えば、ＮＭＲ測定結果のうちの最大ピーク値を用いることができ、また、前記測定値の低ピーク値としては、例えば、ＮＭＲ測定結果のうちの最小ピーク値を用いることができる。 As the high peak value of the measurement value, for example, the maximum peak value of the NMR measurement result can be used, and as the low peak value of the measurement value, for example, the minimum peak value of the NMR measurement result Can be used.
　前記測定値の高ピーク値と低ピーク値の比較としては、特に限定されないが、例えば、高ピーク値と低ピーク値の強度（インテンシティ）の比率を算出して、生成されたアセタール系化合物の含有比率を計測する。この他にも、例えば、高ピーク値と低ピーク値の積分強度を比較の対象として用いることも可能である。 The comparison between the high peak value and the low peak value of the measurement value is not particularly limited. For example, the ratio of the intensity (intensity) of the high peak value and the low peak value is calculated, and the generated acetal compound The content ratio is measured. In addition, for example, the integrated intensity of the high peak value and the low peak value can be used as a comparison target.
　このような簡素な計測方法が可能となるのは、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物が、極めて立体選択性が高いことに由来する。すなわち、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物（例えば1,2-trans選択的グリコシル化反応に拠る）には、これ以外のアセタール系化合物（例えば1,2-cisグリコシル化反応に拠る）が微量ながら存在する可能性もあるが、あくまで微量である。これに対して、従来のアセタール系化合物では、立体選択性が低いこと、例えばα型とβ型が均等に混在してしまうことから、上記の測定方法は適用できない。 Such a simple measurement method is possible because the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) has extremely high stereoselectivity. Derived from. That is, an acetal compound (for example, based on a 1,2-trans selective glycosylation reaction) produced by using a compound having an alkoxyalkyl group represented by the above general formula (I) is not acetal. There is a possibility that a small amount of a system compound (for example, due to 1,2-cis glycosylation reaction) is present, but the amount is very small. In contrast, conventional acetal compounds have low stereoselectivity, for example, α-type and β-type are mixed evenly, and thus the above measurement method cannot be applied.
　例えば、図１（ａ）に示すように、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物（例えば1,2-trans選択的グリコシル化反応に拠り、３つのピーク値Ａ、Ｂ、Ｃを有する）は、これ以外のアセタール系化合物（例えば1,2-cisグリコシル化反応に拠り、３つのピーク値Ａ’、Ｂ’、Ｃ’を有する）と混合状態となった場合には、ＮＭＲでは２種類のアセタール系化合物のピークが混合状態で測定されるものの、図１（ａ）に示すように、最大ピークを示しているＬ１と、最小ピークを示しているＬ２とを比較すること（例えばその比率の値を算出すること）のみによって、例えば、このＬ１：Ｌ２値が９０：１０であれば、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物（例えば1,2-trans選択的グリコシル化反応に拠る）と、これ以外のアセタール系化合物（例えば1,2-cisグリコシル化反応に拠る）との比率が９０：１０であること（すなわち、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物の含有比率が９０％であること）が計測され、本実施形態に係るアセタール系化合物の含有比率が極めて簡易に計測可能となる。 For example, as shown in FIG. 1 (a), an acetal compound produced using a compound having an alkoxyalkyl group represented by the above general formula (I) (for example, 1,2-trans selective glycosylation reaction) 3 having the three peak values A ', B', C ', other acetal compounds (for example, due to 1,2-cis glycosylation reaction, have three peak values A', B ', C') ) And a mixed state, the peak of two types of acetal compound is measured in a mixed state in NMR, but as shown in FIG. 1 (a), L 1 indicating the maximum peak, For example, if the L 1 : L 2 value is 90:10 only by comparing with L 2 indicating the minimum peak (for example, calculating the ratio value), the above general formula (I Embedded image having an alkoxyalkyl group represented by The ratio of the acetal compound produced using the product (for example, due to 1,2-trans selective glycosylation reaction) and the other acetal compound (for example, due to 1,2-cis glycosylation reaction) is 90:10 (that is, the content ratio of the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) is 90%) The content ratio of the acetal compound according to the embodiment can be measured very easily.
　これに対して、従来の方法で生成されたアセタール系化合物では、図１（ｂ）に示すように、本実施形態に係るアセタール系化合物（例えば1,2-transグリコシル化反応に拠り、３つのピーク値Ａ、Ｂ、Ｃを有する）は、他の微量のアセタール系化合物（例えば1,2-cisグリコシル化反応に拠り、３つのピーク値Ａ’、Ｂ’、Ｃ’を有する）と混合状態となった場合には、ＮＭＲでは２種類のアセタール系化合物のピークが混合状態で測定されるが、この２種類のアセタール系化合物が均等的に（非選択的に）存在していることから、そもそも最大ピークや最小ピークという概念すら存在せず、各々のアセタール系化合物の含有比率は、このＮＭＲ測定のみでは不明であり、さらなる分析方法を要し、分析コストが嵩むものとなる。 On the other hand, in the acetal compound produced by the conventional method, as shown in FIG. 1 (b), the acetal compound according to the present embodiment (for example, depending on the 1,2-trans glycosylation reaction, (With peak values A, B, C) mixed with other trace amounts of acetal compounds (eg, with three peak values A ′, B ′, C ′ due to 1,2-cis glycosylation reaction) In the case of NMR, the peaks of two types of acetal compounds are measured in a mixed state in NMR, but since these two types of acetal compounds are present uniformly (non-selectively), In the first place, there is no concept of a maximum peak or a minimum peak, and the content ratio of each acetal compound is unknown only by this NMR measurement, requires a further analysis method, and increases the analysis cost.
　また、前記測定値の高ピーク値を、1位水素に基づいて計測されることができる。１位水素は、生成されたアセタール系化合物特有の立体選択性が強く反映される箇所であることから、この１位水素に基づいて高ピーク値が計測されることによって、より簡易かつ高精度に、生成されたアセタール系化合物の含有比率を計測することが可能となる。 Also, the high peak value of the measured value can be measured based on the 1-position hydrogen. Since the 1-position hydrogen is a place where the stereoselectivity peculiar to the generated acetal compound is strongly reflected, a high peak value is measured based on the 1-position hydrogen, thereby making it easier and more accurate. The content ratio of the generated acetal compound can be measured.
　また、１位、２位水素がアキシャル配向であるグリコシド（例えばグルコースなど）が目的物である場合、前記測定値の高ピーク値が、図１（ｃ）に示すように、前記測定値に存在する４．５ｐｐｍ近傍に顕れる２重線（ダブレット）ピークに基づいて計測されることができる。このように、生成されたアセタール系化合物に特徴的に（固有に）顕れるピークの１つである４．５ｐｐｍ近傍に顕れる２重線（ダブレット）ピークに基づいて高ピーク値が計測されることによって、より簡易かつ高精度に、アセタール系化合物の含有比率を計測することが可能となる。 In addition, when a glycoside (for example, glucose or the like) in which hydrogen at the 1-position and 2-position is in an axial orientation is an object, a high peak value of the measured value exists in the measured value as shown in FIG. It can be measured based on a doublet (doublet) peak that appears in the vicinity of 4.5 ppm. Thus, by measuring a high peak value based on a doublet peak that appears in the vicinity of 4.5 ppm, which is one of the peaks that are characteristically (specifically) appearing in the generated acetal compound. Thus, the content ratio of the acetal compound can be measured more easily and with high accuracy.
　実際に、例えば、本実施形態に係るアセタール系化合物に対してＮＭＲで測定した場合には、図２に示すように、４．５ｐｐｍ近傍にダブレットピークＡが確かに顕れる。さらに、図３～５に示すように、各種のアセタール系化合物（ＭＯＭ体、ＢＯＭ体、ＮＡＰＯＭ体）についても、同様のダブレットピークＡが４．５ｐｐｍ近傍に確かに顕れることが確認された。このことから、本手法は、確実かつ容易に各種の本実施形態に係るアセタール系化合物についても適用可能であり、各種のアセタール系化合物の計測が可能となる汎用性の高い手法である。 Actually, for example, when the acetal compound according to the present embodiment is measured by NMR, a doublet peak A certainly appears in the vicinity of 4.5 ppm as shown in FIG. Further, as shown in FIGS. 3 to 5, it was confirmed that the same doublet peak A was clearly observed in the vicinity of 4.5 ppm for various acetal compounds (MOM body, BOM body, NAPOM body). Therefore, this method can be applied to various acetal compounds according to the present embodiment reliably and easily, and is a highly versatile method that enables measurement of various acetal compounds.
　また、前記測定値における高ピーク値：低ピーク値の比率が９５：５～１００：０を示した場合には、当該比率は、９５：５以上として扱うことができる。これは、ＮＭＲ装置特有の測定限界を考慮したものであり、予期しない測定誤差の混入を抑えて、含有比率を正確に計測することが可能となる。 Further, when the ratio of the high peak value to the low peak value in the measured value indicates 95: 5 to 100: 0, the ratio can be handled as 95: 5 or more. This is because the measurement limit peculiar to the NMR apparatus is taken into consideration, and it is possible to accurately measure the content ratio while suppressing the mixing of unexpected measurement errors.
　このように、得られたアセタール系化合物の含有比率を高精度に計測することが可能となることが確認された。さらに、本発明者に拠れば、得られたアセタール系化合物の含有比率のみならず化学構造についても、極めて高精度かつ簡易に計測できる新たな方法を見出した。 Thus, it was confirmed that the content ratio of the obtained acetal compound can be measured with high accuracy. Furthermore, according to the present inventor, a new method has been found that can measure not only the content ratio of the obtained acetal compound but also the chemical structure with extremely high accuracy and simplicity.
（化学構造の計測方法）
　すなわち、本実施形態に係る計測方法は、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物と、上記の一般式（IV）で表されるアシル基を有する化合物の混合物を、活性化剤の存在下で反応させ、当該反応により生成された上記の一般式（V）で表されるアセタール系化合物を計測する方法であって、核磁気共鳴分光法（ＮＭＲ）を用いて測定し、得られた測定値のうち小さいピークを無視し、アセタール系化合物の化学構造を計測するものである。小さいピークとは、他のピークに比べて微小であることを意味し、例えば、大きい1H分のピーク値の３０％以下、などと定義することができる。 (Measurement method of chemical structure)
That is, the measurement method according to the present embodiment comprises a mixture of a compound having an alkoxyalkyl group represented by the above general formula (I) and a compound having an acyl group represented by the above general formula (IV), A method of measuring an acetal compound represented by the above general formula (V) produced by the reaction in the presence of an activator, using nuclear magnetic resonance spectroscopy (NMR). The chemical structure of the acetal compound is measured by ignoring a small peak in the obtained measurement values. A small peak means that it is minute compared to other peaks, and can be defined as, for example, 30% or less of a peak value for a large 1H.
　このような簡素な計測方法が可能となるのは、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物が、極めて立体選択性が高いことに由来する。すなわち、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物（例えば1,2-trans選択的グリコシル化反応に拠る）には、他のアセタール系化合物（例えば1,2-cisグリコシル化反応に拠る）が微量ながら存在する可能性もあるが、あくまで微量であるため、小さいピークとして顕れ得る。この他にも、このような小さいピークは、例えば、1,2-cisグリコシド以外の共雑物を由来としても引き起こされ得る。 Such a simple measurement method is possible because the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) has extremely high stereoselectivity. Derived from. That is, an acetal compound produced by using a compound having an alkoxyalkyl group represented by the above general formula (I) (for example, based on a 1,2-trans selective glycosylation reaction) may contain other acetal compounds. A compound (for example, due to 1,2-cis glycosylation reaction) may be present in a trace amount, but since it is a trace amount, it may appear as a small peak. In addition to this, such a small peak can be caused, for example, from a contaminant other than 1,2-cis glycoside.
　そのため、このような小さいピークを無視することによって、他の物質由来の余分な測定値が除外され、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物のみの測定値を抽出して計測できることから、予期しない測定誤差の混入を抑制することが可能となり、より高精度に化学構造を計測することができる。 Therefore, by neglecting such a small peak, extra measurement values derived from other substances are excluded, and an acetal produced using a compound having an alkoxyalkyl group represented by the above general formula (I) Since it is possible to extract and measure the measured value of only the system compound, it is possible to suppress the introduction of unexpected measurement errors, and the chemical structure can be measured with higher accuracy.
　これに対して、従来のアセタール系化合物では、立体選択性が低いこと、例えばα型とβ型が均等に混在してしまうことから、そもそも小さいピークという概念すら生じ得ず、上記の測定方法は適用できない。 On the other hand, conventional acetal compounds have low stereoselectivity, for example, α and β types are mixed together evenly, so even the concept of a small peak cannot be produced in the first place. Not applicable.
　ＮＭＲを用いて測定するタイミングとしては、特に限定されず、例えば、上記の一般式（V）で表されるアセタール系化合物が生成された直後でもよいし、その後の工程でもよく、例えば、反応剤を濾過により除去する工程、除媒を行う工程、精製（例えばＨＰＬＣを用いる）を行う工程、除媒乾燥を行う工程、化学構造を特定する工程、低温保存（例えばー２０～０℃）を行う工程、出荷を行う工程などが挙げられる。 The timing for measurement using NMR is not particularly limited. For example, it may be immediately after the acetal compound represented by the general formula (V) is formed, or may be a subsequent step. Are removed by filtration, removal of the solvent, purification (for example, using HPLC), removal of the solvent, identification of the chemical structure, storage at low temperature (for example, −20 to 0 ° C.) The process, the process of shipping, etc. are mentioned.
　このような簡素な計測方法が可能となるのは、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物が、極めて立体選択性が高いことに由来する。すなわち、上記の一般式（I）で表されるアルコキシアルキル基を有する化合物を用いて生成されたアセタール系化合物（例えば1,2-trans選択的グリコシル化反応に拠る）には、他のアセタール系化合物（例えば1,2-cisグリコシル化反応に拠る）が微量ながら存在する可能性もあるが、あくまで微量である。これに対して、従来の手法で生成されたアセタール系化合物では、立体選択性が低いこと、例えばα型とβ型が均等に混在してしまうことから、上記の測定方法は適用できない。 Such a simple measurement method is possible because the acetal compound produced using the compound having an alkoxyalkyl group represented by the above general formula (I) has extremely high stereoselectivity. Derived from. That is, an acetal compound produced by using a compound having an alkoxyalkyl group represented by the above general formula (I) (for example, based on a 1,2-trans selective glycosylation reaction) may contain other acetal compounds. A small amount of a compound (for example, due to 1,2-cis glycosylation reaction) may be present, but the amount is extremely small. On the other hand, in the acetal type compound produced | generated by the conventional method, since said stereoselectivity is low, for example, (alpha) type | mold and (beta) type will mix equally, said measurement method cannot be applied.
　また、前記測定値の高ピーク値が、１位水素に基づいて計測されることができる。１位水素は、本実施形態に従って生成されたアセタール系化合物固有の特徴である立体選択性が強く反映されることから、この１位水素に基づいて高ピーク値が計測されることによって、より簡易かつ高精度に、本実施形態に従って生成されたアセタール系化合物の化学構造を計測することが可能となる。 Also, a high peak value of the measured value can be measured based on the 1-position hydrogen. Since the 1-position hydrogen strongly reflects the stereoselectivity, which is a characteristic characteristic of the acetal compound produced according to the present embodiment, it can be simplified by measuring a high peak value based on the 1-position hydrogen. And it becomes possible to measure the chemical structure of the acetal compound produced | generated according to this embodiment with high precision.
　また、１位、２位水素がアキシャル配向であるグリコシド（例えばグルコースなど）が目的物である場合、前記測定値の高ピーク値が、前記測定値に存在する４．５ｐｐｍ近傍に顕れる２重線（ダブレット）ピークに基づいて計測されることができる。本実施形態に従って生成されたアセタール系化合物は、その高い立体選択性によって特徴的に（固有に）顕れる４．５ｐｐｍ近傍に２重線（ダブレット）ピークが顕れる。この４．５ｐｐｍ近傍に顕れる２重線（ダブレット）ピークに基づいて高ピーク値が計測されることによって、より簡易かつ高精度に、本実施形態に従って生成されたアセタール系化合物の化学構造を計測することが可能となる。 In addition, when a glycoside (for example, glucose) in which hydrogen at the 1st and 2nd positions is in an axial orientation is a target product, a high peak value of the measured value appears in the vicinity of 4.5 ppm present in the measured value. It can be measured based on (doublet) peaks. In the acetal compound produced according to the present embodiment, a doublet (doublet) peak appears in the vicinity of 4.5 ppm which is characteristically (specifically) manifested by its high stereoselectivity. By measuring a high peak value based on a doublet (doublet) peak appearing in the vicinity of 4.5 ppm, the chemical structure of the acetal compound produced according to the present embodiment is measured more easily and with high accuracy. It becomes possible.
　実際に、本実施形態に従って生成されたアセタール系化合物に対してＮＭＲで測定した場合には、例えば、図２に示すように、４．５ｐｐｍ近傍にダブレットピークＡが確かに顕れている。さらに、図３～５に示すように、様々な本実施形態に係るアセタール系化合物（ＭＯＭ体、ＢＯＭ体、ＮＡＰＯＭ体）のいずれに対しても、同様のダブレットピークＡが４．５ｐｐｍ近傍に確かに顕れることが確認されている。このことから、本手法は、１位、２位水素がアキシャル配向であるグリコシド（例えばグルコースなど）が目的物である場合、確実かつ容易に、本実施形態に従って生成された様々なアセタール系化合物についても、計測が可能となるという極めて汎用性の高い手法である。 Actually, when the acetal compound produced according to the present embodiment is measured by NMR, for example, as shown in FIG. 2, a doublet peak A is clearly observed in the vicinity of 4.5 ppm. Further, as shown in FIGS. 3 to 5, the same doublet peak A is surely around 4.5 ppm for any of the various acetal compounds (MOM body, BOM body, NAPOM body) according to this embodiment. It has been confirmed that From this, the present technique is reliable and easy for various acetal compounds produced according to the present embodiment when a glycoside (for example, glucose) in which hydrogen at the 1-position and 2-position is in an axial orientation is the target product. Is a very versatile technique that enables measurement.
　このように、本実施形態に従って生成されたアセタール系化合物の化学構造を高精度に計測することが可能となることが確認された。このように化学構造が計測されたアセタール系化合物の含有比率について、その計測方法は、例えば、ＮＭＲ装置を用いて上述の含有比率の測定を行うことも可能であるが、特に限定されない。この他の手法としては、ＨＰＬＣ（高速液体クロマトグラフィー）を用いてアセタール系化合物の含有比率を計測することも好ましく、低廉な装置であるＨＰＬＣを用いることによって、より低コストで含有比率を計測することが可能となる。 Thus, it was confirmed that the chemical structure of the acetal compound produced according to this embodiment can be measured with high accuracy. As for the content ratio of the acetal compound whose chemical structure is measured in this way, the measurement method can measure the above-mentioned content ratio using, for example, an NMR apparatus, but is not particularly limited. As another method, it is also preferable to measure the content ratio of the acetal compound using HPLC (high performance liquid chromatography), and the content ratio is measured at a lower cost by using HPLC, which is an inexpensive apparatus. It becomes possible.
　以下に実施例を示すが、これらの実施例は本発明に係るグリコシルドナーを単に例示するためのものであり、本発明を限定するものではない。 Examples are shown below, but these examples are merely for illustrating the glycosyl donor according to the present invention, and do not limit the present invention.
（実施例１）
　先ず、従来例（比較例）として、以下の反応式に示すように、ジオール1からメチル体 2を合成した。 Example 1
First, as a conventional example (comparative example), methyl isomer 2 was synthesized from diol 1 as shown in the following reaction formula.
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
（メチル体の合成）
　ジオール1(500mg, 1.39mmol)のN,N-ジメチルホルムアミド(4.70mL)溶液に、水素化ナトリウム(251mg, 6.28mmol)およびヨードメタン(0.450mL, 7.23mmol)を0℃で加え，室温で1時間撹拌した．0℃に冷却し、飽和塩化アンモニウム水溶液を加えて反応を停止させた。得られた混合物をエーテルで3回抽出し、有機相を合わせて飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン／酢酸エチル=20/1→10/1→5/1）にて精製することで，メチル体2(524mg, 1.35mmol, 97%)を無色粉末として得た。メチル体2:1H-NMR(400MHz, CDCl3)δ7.54-7.52(m, 2H), 7.49-7.47(m, 2H), 7.40-7.30(m, 6H), 5.54(s, 1H), 4.63(d, J=9.6Hz, 1H), 4.35(dd, J=5.2Hz, 1H), 3.77(dd, J=10.1, 10.1Hz, 1H), 3.64(s, 3H), 3.65(s, 3H), 3.56(dd, J=9.4, 9.2Hz, 1H), 3.49-3.36(m, 2H), 3.16-3.08(dd, J=10.1, 9.4 Hz 1H). (Methyl synthesis)
To a solution of Diol 1 (500 mg, 1.39 mmol) in N, N-dimethylformamide (4.70 mL) was added sodium hydride (251 mg, 6.28 mmol) and iodomethane (0.450 mL, 7.23 mmol) at 0 ° C., and 1 hour at room temperature. Stir. After cooling to 0 ° C., a saturated aqueous ammonium chloride solution was added to stop the reaction. The resulting mixture was extracted three times with ether, and the organic phases were combined, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1). Body 2 (524 mg, 1.35 mmol, 97%) was obtained as a colorless powder. Methyl form 2: 1H-NMR (400MHz, CDCl3) δ7.54-7.52 (m, 2H), 7.49-7.47 (m, 2H), 7.40-7.30 (m, 6H), 5.54 (s, 1H), 4.63 ( d, J = 9.6Hz, 1H), 4.35 (dd, J = 5.2Hz, 1H), 3.77 (dd, J = 10.1, 10.1Hz, 1H), 3.64 (s, 3H), 3.65 (s, 3H), 3.56 (dd, J = 9.4, 9.2Hz, 1H), 3.49-3.36 (m, 2H), 3.16-3.08 (dd, J = 10.1, 9.4 Hz 1H).
　次に、得られたメチル体 2を用いて、グリコシル化反応を行った。すなわち、以下の反応式に示すように、α-グリコシド 3a、およびβ-グリコシド 3bを生成した。 Next, glycosylation reaction was performed using the obtained methyl derivative 2. That is, α-glycoside 式 3a and β-glycoside 3b were produced as shown in the following reaction formula.
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
（メチル体グリコシル化）
　メチル体2(97.1mg, 0.250mmol)のジクロロメタン(0.70mL)溶液に，エタノール(0.10 mL, 1.71mmol)を室温で加え，さらに室温下30分間撹拌した．-78℃に冷却し、一塩化ヨウ素のジクロロメタン溶液(1M, 0.25mL, 0.250mmol)を加えた。-78℃でこの溶液をトリフルオロメタンスルホン酸インジウム(153mg, 0.272mmol)と粉末状モレキュラーシーブス4A(57mg)のジクロロメタン(0.80mL)懸濁液に加え、-78℃で15分間攪拌した。飽和チオ硫酸ナトリウム水溶液と炭酸水素ナトリウム水溶液を加えて反応を停止させた。得られた混合物を酢酸エチルで抽出し、有機相を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=20/1 → 10/1 → 5/1 → 3/1）にて精製することで，α-グリコシド3a(17.6mg, 54.3μmol, 22%)を無色粉末として，β-エトキシド3b(20.8 mg, 64.1 μmol, 26%) を無色粉末として得，原料 2 (24.1 mg,  62.0 μmol, 25%)を回収した。α-グリコシド3a:1H-NMR(400MHz, CDCl3): δ7.50(dd, J=7.6, 2.1Hz, 2H), 7.41-7.32(m, 3H), 5.55(s, 1H), 4.98(d, J=3.7Hz, 1H), 4.27(dd, J=10.3, 5.0Hz, 1H), 3.86(dd, J=10.3, 9.2, 4.8Hz, 1H), 3.81-3.68(m, 3H), 3.65(s, 3H), 3.63-3.57(m, 1H), 3.57-3.50(m, 4H), 3.29 (dd, J=9.2, 3.7 Hz, 1H), 1.29(t, J=7.1 Hz, 3H)。β-グリコシド3b: 1H-NMR(400MHz, CDCl3): δ7.49(m, 2H), 7.40-7.33(m, 3H), 5.54(s, 1H), 4.40(d, J=7.3 Hz, 1H), 4.33 (dd, J=10.5, 5.0Hz, 1H), 4.00-3.90(m, 1H), 3.76(dd, J=10.5, 9.4 Hz, 1H), 3.68-3.60(m, 7H), 3.57(dd, J=10.5, 9.4Hz, 1H), 3.42-3.33(m, 2H), 3.08(dd, J=8.7, 7.8Hz, 1H), 1.27(t, J=6.9 Hz, 3H). (Methyl glycosylation)
Ethanol (0.10 mL, 1.71 mmol) was added to a solution of methyl compound 2 (97.1 mg, 0.250 mmol) in dichloromethane (0.70 mL) at room temperature, and the mixture was further stirred at room temperature for 30 minutes. Cooled to -78 ° C. and iodine monochloride in dichloromethane (1M, 0.25 mL, 0.250 mmol) was added. This solution was added to a suspension of indium trifluoromethanesulfonate (153 mg, 0.272 mmol) and powdered molecular sieves 4A (57 mg) in dichloromethane (0.80 mL) at −78 ° C., and the mixture was stirred at −78 ° C. for 15 minutes. Saturated sodium thiosulfate aqueous solution and sodium hydrogen carbonate aqueous solution were added to stop the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate is purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1 → 3/1). Thus, α-glycoside 3a (17.6 mg, 54.3 μmol, 22%) was obtained as a colorless powder, and β-ethoxide 3b (20.8 mg, 64.1 μmol, 26%) was obtained as a colorless powder, and raw material 2 (24.1 mg, 62.0 μmol) was obtained. , 25%). α-Glycoside 3a: 1 H-NMR (400 MHz, CDCl 3 ): δ 7.50 (dd, J = 7.6, 2.1 Hz, 2H), 7.41-7.32 (m, 3H), 5.55 (s, 1H), 4.98 ( d, J = 3.7Hz, 1H), 4.27 (dd, J = 10.3, 5.0Hz, 1H), 3.86 (dd, J = 10.3, 9.2, 4.8Hz, 1H), 3.81-3.68 (m, 3H), 3.65 (s, 3H), 3.63-3.57 (m, 1H), 3.57-3.50 (m, 4H), 3.29 (dd, J = 9.2, 3.7 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H). β-glycoside 3b: 1 H-NMR (400 MHz, CDCl 3 ): δ 7.49 (m, 2H), 7.40-7.33 (m, 3H), 5.54 (s, 1H), 4.40 (d, J = 7.3 Hz, 1H), 4.33 (dd, J = 10.5, 5.0Hz, 1H), 4.00-3.90 (m, 1H), 3.76 (dd, J = 10.5, 9.4 Hz, 1H), 3.68-3.60 (m, 7H), 3.57 (dd, J = 10.5, 9.4Hz, 1H), 3.42-3.33 (m, 2H), 3.08 (dd, J = 8.7, 7.8Hz, 1H), 1.27 (t, J = 6.9 Hz, 3H).
　得られた結果から、比較例である2-O-メチル体では非立体選択的（α：β＝１：１）にグリコシル化反応が進行した。 From the obtained results, glycosylation proceeded non-stereoselectively (α: β = 1: 1) in the 2-O-methyl compound as a comparative example.
　次に、本実施例として、以下の反応式に示すように、上記のジオール1からグリコシルドナーであるBOM体(BOMエーテル)4を合成した。 Next, as this example, as shown in the following reaction formula, a BOM body (BOM ether) 4 as a glycosyl donor was synthesized from the diol 1 described above.
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
（グリコシルドナー（BOM体(BOMエーテル)）4の合成）
　ジオール1(1.99g, 55.1mmol)のジクロロメタン(11mL) 溶液に、エチルジイソプロピルアミン(5.70mL, 33.8mmol)およびBOMクロリド(3.10mL, 22.4mmol) を室温で加え，さらに60℃で18時間撹拌した．0℃に冷却し、エーテルで希釈後、飽和硫酸水素カリウム水溶液を加えて反応を停止させた。得られた混合物をエーテルで3回抽出し、有機相を合わせて飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=20/1 → 10/1 → 5/1)にて精製することで、BOMエーテル4(3.12 g, 51.9mmol, 94%)を無色粉末として得た。BOMエーテル4: 1H-NMR(400MHz, CDCl3): δ7.51(dd, J=7.8, 1.8Hz, 2H), 7.45-7.41(m, 2H), 7.40-7.21(m, 11H), 7.18-7.16(m, 2H), 5.54(s, 1H), 5.12(d, J=6.4 Hz, 1H), 5.02(t, J=5.7Hz, 2H), 4.97(d, J=6.4 Hz, 1H), 4.90(d, J=11.9Hz, 1H), 4.78(d, J=9.6 Hz, 1H), 4.72(d, J=11.9 Hz, 1H), 4.60(s, 2H), 4.36(dd, J=10.3, 5.0 Hz, 1H), 4.04(t, J=8.9Hz, 1H), 3.78(dd, J=10.3, 10.3Hz, 1H), 3.72(dd, J=9.6 Hz, 1H), 3.66(dd, J=9.6, 8.9 Hz, 1H), 3.52(ddd, J=10.3, 10.3, 5.0Hz, 1H). (Synthesis of glycosyl donor (BOM body (BOM ether)) 4)
Ethyldiisopropylamine (5.70 mL, 33.8 mmol) and BOM chloride (3.10 mL, 22.4 mmol) were added to a solution of diol 1 (1.99 g, 55.1 mmol) in dichloromethane (11 mL) at room temperature, and further stirred at 60 ° C. for 18 hours. . After cooling to 0 ° C. and diluting with ether, a saturated aqueous potassium hydrogen sulfate solution was added to stop the reaction. The resulting mixture was extracted three times with ether, and the organic phases were combined, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1) to obtain BOM. Ether 4 (3.12 g, 51.9 mmol, 94%) was obtained as a colorless powder. BOM ether 4: 1 H-NMR (400 MHz, CDCl 3 ): δ 7.51 (dd, J = 7.8, 1.8 Hz, 2H), 7.45-7.41 (m, 2H), 7.40-7.21 (m, 11H), 7.18 -7.16 (m, 2H), 5.54 (s, 1H), 5.12 (d, J = 6.4 Hz, 1H), 5.02 (t, J = 5.7Hz, 2H), 4.97 (d, J = 6.4 Hz, 1H) , 4.90 (d, J = 11.9Hz, 1H), 4.78 (d, J = 9.6 Hz, 1H), 4.72 (d, J = 11.9 Hz, 1H), 4.60 (s, 2H), 4.36 (dd, J = 10.3, 5.0 Hz, 1H), 4.04 (t, J = 8.9Hz, 1H), 3.78 (dd, J = 10.3, 10.3Hz, 1H), 3.72 (dd, J = 9.6 Hz, 1H), 3.66 (dd, J = 9.6, 8.9 Hz, 1H), 3.52 (ddd, J = 10.3, 10.3, 5.0Hz, 1H).
　次に、以下の反応式に示すように、上記で得られたグリコシルドナーであるBOM体(BOMエーテル)4を使って、ICl存在下で、グリコシル化反応を行った。 Next, as shown in the following reaction formula, a glycosylation reaction was carried out in the presence of ICl using the BOM body (BOM ether) 4 which is the glycosyl donor obtained above.
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
（β－グリコシド 5 (ICl)の合成）
　BOMエーテル4(148mg, 0.247mmol)のジクロロメタン(0.70mL)溶液に、エタノール(0.10mL, 1.71mmol)を室温で加え、さらに室温下30分間撹拌した。-78℃に冷却し、一塩化ヨウ素のジクロロメタン溶液(1M, 0.25mL, 0.250mmol)を加えた。-78℃でこの溶液をトリフルオロメタンスルホン酸インジウム(157mg, 0.279mmol)と粉末状モレキュラーシーブス4A(60mg)のジクロロメタン(0.75mL)懸濁液に加え、-78℃で15分間攪拌した。飽和チオ硫酸ナトリウム水溶液と炭酸水素ナトリウム水溶液を加えて反応を停止させた。得られた混合物を酢酸エチルで抽出し、有機相を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=20/1 → 10/1 → 5/1 → 1/1）にて精製することで、β-グリコシド5(104mg, 0.188mmol, 75%)を無色粉末として得、原料5(11.8mg, 19.6μmol, 8%)を回収した。β-グリコシド5: 1H-NMR(400MHz, CDCl3): δ7.44(dd, J=7.1, 2.1Hz, 2H), 7.38-7.20(m, 16H), 7.19-7.13(m, 2H), 5.53(s, 1H), 5.12-4.88(m, 4H), 4.71(s, 2H), 4.61(dd, J=15.3, 11.7Hz, 2H), 4.48(d, J=7.8Hz, 1H), 4.33(dd, J=10.8, 5.0 Hz, 1H), 4.06-3.92(m, 2H), 3.78(dd, J=10.8, 10.8Hz, 1H), 3.73-3.54(m, 3H), 3.49-3.41(m, 1H), 1.33-1.14(m, 5H). (Synthesis of β-glycoside 5 (ICl))
Ethanol (0.10 mL, 1.71 mmol) was added to a solution of BOM ether 4 (148 mg, 0.247 mmol) in dichloromethane (0.70 mL) at room temperature, and the mixture was further stirred at room temperature for 30 minutes. Cooled to -78 ° C. and iodine monochloride in dichloromethane (1M, 0.25 mL, 0.250 mmol) was added. This solution was added to a suspension of indium trifluoromethanesulfonate (157 mg, 0.279 mmol) and powdered molecular sieves 4A (60 mg) in dichloromethane (0.75 mL) at −78 ° C., and the mixture was stirred at −78 ° C. for 15 minutes. Saturated sodium thiosulfate aqueous solution and sodium hydrogen carbonate aqueous solution were added to stop the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate is purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1 → 1/1). Thus, β-glycoside 5 (104 mg, 0.188 mmol, 75%) was obtained as a colorless powder, and raw material 5 (11.8 mg, 19.6 μmol, 8%) was recovered. β-glycoside 5: 1 H-NMR (400 MHz, CDCl 3 ): δ 7.44 (dd, J = 7.1, 2.1 Hz, 2H), 7.38-7.20 (m, 16H), 7.19-7.13 (m, 2H), 5.53 (s, 1H), 5.12-4.88 (m, 4H), 4.71 (s, 2H), 4.61 (dd, J = 15.3, 11.7Hz, 2H), 4.48 (d, J = 7.8Hz, 1H), 4.33 (dd, J = 10.8, 5.0 Hz, 1H), 4.06-3.92 (m, 2H), 3.78 (dd, J = 10.8, 10.8Hz, 1H), 3.73-3.54 (m, 3H), 3.49-3.41 (m , 1H), 1.33-1.14 (m, 5H).
　次に、上記で得られたグリコシルドナーであるBOM体(BOMエーテル)4を使って、今度はNIS存在下で、グリコシル化反応を行った。 Next, using the BOM body (BOM ether) 4 which is the glycosyl donor obtained above, a glycosylation reaction was performed in the presence of NIS.
（β－グリコシド 5 (NIS)の合成）
　BOMエーテル4(148mg, 0.247mmol)のジクロロメタン(0.80mL)溶液に、エタノール(0.10mL, 1.71mmol)を室温で加え、さらに室温下30分間撹拌した。-78℃に冷却し、N-ヨードスクシンイミド(71.0mg, 0.316mmol)を加えた．-78℃でこの溶液をトリフルオロメタンスルホン酸インジウム(147mg, 0.262mmol)と粉末状モレキュラーシーブス4A(53mg)のジクロロメタン(0.80mL) 懸濁液に加え、-35℃まで徐々に昇温しながら30分間攪拌した。飽和チオ硫酸ナトリウム水溶液と炭酸水素ナトリウム水溶液を加えて反応を停止させた。得られた混合物を酢酸エチルで抽出し、有機相を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=20/1 → 10/1 → 5/1 → 1/1）にて精製することで、β-グリコシド5(113mg, 0.205mmol, 83%)を無色粉末として得た。 (Synthesis of β-glycoside 5 (NIS))
Ethanol (0.10 mL, 1.71 mmol) was added to a solution of BOM ether 4 (148 mg, 0.247 mmol) in dichloromethane (0.80 mL) at room temperature, and the mixture was further stirred at room temperature for 30 minutes. After cooling to -78 ° C, N-iodosuccinimide (71.0 mg, 0.316 mmol) was added. At -78 ° C, this solution was added to a suspension of indium trifluoromethanesulfonate (147 mg, 0.262 mmol) and powdered molecular sieves 4A (53 mg) in dichloromethane (0.80 mL), and the temperature was gradually raised to -35 ° C. Stir for minutes. Saturated sodium thiosulfate aqueous solution and sodium hydrogen carbonate aqueous solution were added to stop the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate is purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1 → 1/1). This gave β-glycoside 5 (113 mg, 0.205 mmol, 83%) as a colorless powder.
　以上の結果から、比較例である2-O-メチル体では非立体選択的（α：β＝１：１）にグリコシル化反応が進行したのに対して、本実施例に係る2-O-BOM体では高いβ選択性（βのみ生成）でグリコシル化反応が進行したことが確認された。 From the above results, the glycosylation reaction proceeded non-stereoselectively (α: β = 1: 1) in the 2-O-methyl compound as a comparative example, whereas the 2-O— It was confirmed that the glycosylation reaction proceeded with high β selectivity (only β was produced) in the BOM body.
（実施例２）
　本実施例２として、以下の反応式に示すように、上記のジオール1からグリコシルドナーであるMOM体(MOMエーテル)6を合成した。 (Example 2)
As Example 2, as shown in the following reaction formula, a MOM body (MOM ether) 6 as a glycosyl donor was synthesized from the diol 1 described above.
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
（グリコシルドナー（MOM体(MOMエーテル))6の合成）
ジオール1(203mg, 0.562mmol)のジクロロメタン(5.60mL)溶液に，エチルジイソプロピルアミン(0.420mL, 2.42mmol) およびMOMクロリド(0.157mL, 1.65mmol)を室温で加え、さらに室温で17時間撹拌した。さらにMOMクロリド(0.157mL, 1.65mmol)を加え，60℃で6時間撹拌した。0℃に冷却し、エーテルで希釈後、飽和硫酸水素カリウム水溶液を加えて反応を停止させた。得られた混合物をエーテルで3回抽出し、有機相を合わせて飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=5/1)にて精製することで、MOMエーテル6(233mg, 0.520mmol, 93%)を無色粉末として得た。MOMエーテル6:1H-NMR(400MHz, CDCl3)δ7.54-7.51(m, 2H), 7.49-7.42(m, 2H), 7.38-7.28(m, 6H), 5.53(s, 1H), 4.97(d, J=6.4Hz, 1H), 4.89(dd, J=8.9, 6.4Hz, 2H), 4.82(d, J=6.4 z, 1H), 4.73(d, J=10.1Hz, 1H), 4.34(dd, J=10.3, 5.0Hz, 1H), 3.90(dd, J=8.9, 8.9Hz, 1H), 3.77(dd, J=10.3, 10.3Hz, 1H), 3.63-3.58(m, 2H), 3.54(s, 3H), 3.51-3.42(m, 1H), 3.37(s, 3H). (Synthesis of glycosyl donor (MOM body (MOM ether)) 6)
Ethyldiisopropylamine (0.420 mL, 2.42 mmol) and MOM chloride (0.157 mL, 1.65 mmol) were added to a solution of diol 1 (203 mg, 0.562 mmol) in dichloromethane (5.60 mL) at room temperature, and the mixture was further stirred at room temperature for 17 hours. Further, MOM chloride (0.157 mL, 1.65 mmol) was added, and the mixture was stirred at 60 ° C. for 6 hours. After cooling to 0 ° C. and diluting with ether, a saturated aqueous potassium hydrogen sulfate solution was added to stop the reaction. The resulting mixture was extracted three times with ether, and the organic phases were combined, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain MOM ether 6 (233 mg, 0.520 mmol, 93%) was obtained as a colorless powder. MOM ether 6: 1 H-NMR (400 MHz, CDCl 3 ) δ 7.54-7.51 (m, 2H), 7.49-7.42 (m, 2H), 7.38-7.28 (m, 6H), 5.53 (s, 1H), 4.97 (d, J = 6.4Hz, 1H), 4.89 (dd, J = 8.9, 6.4Hz, 2H), 4.82 (d, J = 6.4 z, 1H), 4.73 (d, J = 10.1Hz, 1H), 4.34 (dd, J = 10.3, 5.0Hz, 1H), 3.90 (dd, J = 8.9, 8.9Hz, 1H), 3.77 (dd, J = 10.3, 10.3Hz, 1H), 3.63-3.58 (m, 2H) , 3.54 (s, 3H), 3.51-3.42 (m, 1H), 3.37 (s, 3H).
　次に、以下の反応式に示すように、上記で得られたグリコシルドナーであるMOM体(MOMエーテル)6を使ってグリコシル化反応（糖2級）を行った。 Next, as shown in the following reaction formula, a glycosylation reaction (secondary sugar) was carried out using MOM body (MOM ether) 6 which is the glycosyl donor obtained above.
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
（β－グリコシド 8の合成）
　MOMエーテル6(37.5mg, 83.6μmol)のジクロロメタン(0.83mL)溶液に、アルコール7(46.35mg, 99.8μmol)と粉末状モレキュラーシーブス4A(20mg)を室温で加え、さらに室温下30分間撹拌した。-78℃に冷却し、N-ヨードスクシンイミド(24.0mg, 107μmol)トリフルオロメタンスルホン酸インジウム(46.4mg, 82.6μmol)を加え、-10℃まで徐々に昇温しながら30分間攪拌した。飽和チオ硫酸ナトリウム水溶液と炭酸水素ナトリウム水溶液を加えて反応を停止させた。得られた混合物を酢酸エチルで抽出し、有機相を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=5/1 → 3/1）にて精製することで、β-グリコシド8(50.8mg, 63.3μmol, 76%)を無色粉末として得た。β-グリコシド8: 1H-NMR(400MHz, CDCl3) δ7.47(dd, J=7.1, 3.0Hz, 2H), 7.43-7.27(m, 18H), 5.44(s, 1H), 4.91(d, J=10.5Hz, 1H), 4.87-4.73(m, 5H), 4.73-4.57(m, 4H), 4.47(d, J=11.9 Hz, 1H), 4.36(d, J=7.8 Hz, 1H), 4.23-4.14(m, 1H), 4.02-3.86(m, 2H), 3.81(dd, 1H), 3.73-3.57(m, 3H), 3.52(dd, J=9.7, 3.7 Hz, 1H), 3.49-3.40(m, 6H), 3.38(s, 3H), 3.35(s, 3H), 3.11(ddd, J=9.7, 9.7, 4.7 Hz, 1H). (Synthesis of β-glycoside 8)
To a solution of MOM ether 6 (37.5 mg, 83.6 μmol) in dichloromethane (0.83 mL), alcohol 7 (46.35 mg, 99.8 μmol) and powdered molecular sieve 4A (20 mg) were added at room temperature, and the mixture was further stirred at room temperature for 30 minutes. After cooling to −78 ° C., N-iodosuccinimide (24.0 mg, 107 μmol) indium trifluoromethanesulfonate (46.4 mg, 82.6 μmol) was added, and the mixture was stirred for 30 minutes while gradually warming to −10 ° C. Saturated sodium thiosulfate aqueous solution and sodium hydrogen carbonate aqueous solution were added to stop the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 → 3/1) to obtain β-glycoside 8 ( 50.8 mg, 63.3 μmol, 76%) was obtained as a colorless powder. β-glycoside 8: 1 H-NMR (400 MHz, CDCl 3 ) δ 7.47 (dd, J = 7.1, 3.0 Hz, 2H), 7.43-7.27 (m, 18H), 5.44 (s, 1H), 4.91 (d , J = 10.5Hz, 1H), 4.87-4.73 (m, 5H), 4.73-4.57 (m, 4H), 4.47 (d, J = 11.9 Hz, 1H), 4.36 (d, J = 7.8 Hz, 1H) , 4.23-4.14 (m, 1H), 4.02-3.86 (m, 2H), 3.81 (dd, 1H), 3.73-3.57 (m, 3H), 3.52 (dd, J = 9.7, 3.7 Hz, 1H), 3.49 -3.40 (m, 6H), 3.38 (s, 3H), 3.35 (s, 3H), 3.11 (ddd, J = 9.7, 9.7, 4.7 Hz, 1H).
（実施例３）
　本実施例３として、以下の反応式に示すように、上記のジオール1からグリコシルドナーであるNAPOM体(NAPOMエーテル)9を合成した。 (Example 3)
As Example 3, as shown in the following reaction formula, a NAPOM body (NAPOM ether) 9 as a glycosyl donor was synthesized from the diol 1 described above.
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
（グリコシルドナーNAPOM体(NAPOMエーテル)9の合成）
　ジオール1(204mg, 0.562mmol)のジクロロエタン(5.60 mL)溶液に、エチルジイソプロピルアミン(0.840mL, 4.99mmol)およびNAPOMクロリド(749mg, 3.48mmol)を室温で加え、さらに80℃で19.5時間撹拌した．0℃に冷却し、エーテルで希釈後、水を加えて反応を停止させた。得られた混合物をエーテルで3 回抽出し、有機相を合わせて飽和硫酸水素カリウム水溶液と飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=20/1 → 10/1 → 5/1)にて精製することで、NAPOMエーテル9(334mg, 0.477mmol, 86%)を無色粉末として得た。NAPOMエーテル9:1H-NMR(400MHz, CDCl3) δ7.84-7.72(m, 6H), 7.72-7.65(m, 2H), 7.60(s, 1H), 7.53-7.40(m, 9H), 7.32-7.25(m, 7H), 5.55(s, 1H), 5.17(d, J=6.4 Hz, 1H), 5.11-5.00(m, 4H), 4.95-4.84(m, 1H), 4.81(d, J=9.6 Hz, 1H), 4.76(s, 2H), 4.36(dd, J=9.6, 5.2 Hz, 1H), 4.08(dd, J=8.9, 8.9 Hz, 1H), 3.85-3.72(m, 2H), 3.68(dd, J=9.6, 9.6 Hz, 1H), 3.52(dd, J=9.6, 4.9 Hz, 1H). (Synthesis of glycosyl donor NAPOM body (NAPOM ether) 9)
Ethyldiisopropylamine (0.840 mL, 4.99 mmol) and NAPOM chloride (749 mg, 3.48 mmol) were added to a solution of diol 1 (204 mg, 0.562 mmol) in dichloroethane (5.60 mL) at room temperature, and the mixture was further stirred at 80 ° C. for 19.5 hours. After cooling to 0 ° C. and diluting with ether, water was added to stop the reaction. The obtained mixture was extracted three times with ether, and the organic phases were combined, washed with a saturated aqueous potassium hydrogen sulfate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1). Ether 9 (334 mg, 0.477 mmol, 86%) was obtained as a colorless powder. NAPOM ether 9: 1 H-NMR (400 MHz, CDCl 3 ) δ 7.84-7.72 (m, 6H), 7.72-7.65 (m, 2H), 7.60 (s, 1H), 7.53-7.40 (m, 9H), 7.32-7.25 (m, 7H), 5.55 (s, 1H), 5.17 (d, J = 6.4 Hz, 1H), 5.11-5.00 (m, 4H), 4.95-4.84 (m, 1H), 4.81 (d, J = 9.6 Hz, 1H), 4.76 (s, 2H), 4.36 (dd, J = 9.6, 5.2 Hz, 1H), 4.08 (dd, J = 8.9, 8.9 Hz, 1H), 3.85-3.72 (m, 2H ), 3.68 (dd, J = 9.6, 9.6 Hz, 1H), 3.52 (dd, J = 9.6, 4.9 Hz, 1H).
　次に、上記で得られたグリコシルドナーであるNAPOM体(NAPOMエーテル)9を使って、以下の反応式に示すグリコシル化反応を行った。 Next, using the NAPOM body (NAPOM ether) 9 which is the glycosyl donor obtained above, a glycosylation reaction shown in the following reaction formula was performed.
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
（β－グリコシド１１の合成）
NAPOMエーテル9(40.1mg, 57.2μmol)の混合溶媒(ヘキサン0.60mL,ジクロロメタン0.40mL)溶液に、アルコール10(46.35mg, 99.8μmol)と粉末状モレキュラーシーブス4A(20mg)を室温で加え、さらに室温下30分間撹拌した。-78℃に冷却し、N-ヨードスクシンイミド(17.0mg, 75.6μmol)とトリフルオロメタンスルホン酸インジウム(32.1mg, 57.1μmol)を加え、-10℃まで徐々に昇温しながら30分間攪拌した。飽和チオ硫酸ナトリウム水溶液と炭酸水素ナトリウム水溶液を加えて反応を停止させた。得られた混合物を酢酸エチルで抽出し、有機相を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別後、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル=20/1 → 10/1 → 5/1 → 1/1）にて精製することで、β-グリコシド11(37.9mg, 35.9μmol, 63%)を無色粉末として得た。β-グリコシド11: 1H-NMR(400MHz, CDCl3) δ7.87-7.60(m, 8H), 7.58(s, 1H), 7.51-7.37(m, 8H), 7.37-7.26(m, 17H), 5.55(s, 1H), 5.14(d, J=6.4 Hz, 1H), 5.07(d, J=6.9 Hz, 2H), 5.04-4.99(m, 1H), 4.99-4.86(m, 3H), 4.85-4.75(m, 4H), 4.75-4.67(m, 1H), 4.65-4.52(m, 3H), 4.50(d, J=7.8Hz, 1H), 4.32(dd, J=10.3, 5.0Hz, 1H), 4.10(d, J=8.7Hz, 1H), 4.07-3.89(m, 2H), 3.89-3.73(m, 3H), 3.69 (dd, J=10.3, 7.1Hz, 2H), 3.54-3.36(m, 3H), 3.33 (s, 3H). (Synthesis of β-glycoside 11)
To a mixed solvent solution of NAPOM ether 9 (40.1 mg, 57.2 μmol) (hexane 0.60 mL, dichloromethane 0.40 mL), alcohol 10 (46.35 mg, 99.8 μmol) and powdered molecular sieve 4A (20 mg) were added at room temperature. Stirred for 30 minutes. After cooling to −78 ° C., N-iodosuccinimide (17.0 mg, 75.6 μmol) and indium trifluoromethanesulfonate (32.1 mg, 57.1 μmol) were added, and the mixture was stirred for 30 minutes while gradually warming to −10 ° C. Saturated sodium thiosulfate aqueous solution and sodium hydrogen carbonate aqueous solution were added to stop the reaction. The resulting mixture was extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate is purified by silica gel column chromatography (hexane / ethyl acetate = 20/1 → 10/1 → 5/1 → 1/1). As a result, β-glycoside 11 (37.9 mg, 35.9 μmol, 63%) was obtained as a colorless powder. β-Glycoside 11: 1 H-NMR (400 MHz, CDCl 3 ) δ 7.87-7.60 (m, 8H), 7.58 (s, 1H), 7.51-7.37 (m, 8H), 7.37-7.26 (m, 17H) , 5.55 (s, 1H), 5.14 (d, J = 6.4 Hz, 1H), 5.07 (d, J = 6.9 Hz, 2H), 5.04-4.99 (m, 1H), 4.99-4.86 (m, 3H), 4.85-4.75 (m, 4H), 4.75-4.67 (m, 1H), 4.65-4.52 (m, 3H), 4.50 (d, J = 7.8Hz, 1H), 4.32 (dd, J = 10.3, 5.0Hz, 1H), 4.10 (d, J = 8.7Hz, 1H), 4.07-3.89 (m, 2H), 3.89-3.73 (m, 3H), 3.69 (dd, J = 10.3, 7.1Hz, 2H), 3.54-3.36 (m, 3H), 3.33 (s, 3H).
（実施例４）
　本実施例４として、上記の反応と同じ手順にて、反応条件を様々に変えて、反応の進行度合いを確認した。確認した反応条件は、活性化剤、グルコシルアクセプター、および溶媒である。以下では、各々、反応条件を記載した反応式と共に、得られた結果の一覧表を示す。 Example 4
In Example 4, the progress of the reaction was confirmed by changing the reaction conditions in the same procedure as described above. The confirmed reaction conditions are activator, glucosyl acceptor, and solvent. Below, the list of the obtained result is shown with the reaction formula which described reaction conditions, respectively.
（１）活性化剤の適用性
　上記の実施例１と同じ手順に従ったBOM体グリコシル化反応を、以下のように、活性化剤を様々に変更して、実施した。 (1) Applicability of activating agent The BOM glycosylation reaction according to the same procedure as in Example 1 was carried out by changing the activating agent as follows.
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-T000063
Figure JPOXMLDOC01-appb-T000063
2) determined by 1H NMR.
3) Autar, R.; Lisksmp, R. M. J.; Pieters, J. R. Carbohydr. Res. 2005, 340, 2436-2442.
4) Sun, L.; Li, P.; Zhao, K. Tetrahedron Lett. 1994, 35, 7147-7150.
5) Budhadev, D.; Mukhopadhyay, B. Carbohydr. Res. 2014, 394, 26-31. 2) determined by 1H NMR.
3) Autar, R .; Lisksmp, R. M. J .; Pieters, J. R. Carbohydr. Res. 2005, 340, 2436-2442.
4) Sun, L .; Li, P .; Zhao, K. Tetrahedron Lett. 1994, 35, 7147-7150.
5) Budhadev, D .; Mukhopadhyay, B. Carbohydr. Res. 2014, 394, 26-31.
　得られた結果から、いずれの活性化剤を用いても高いβ選択性が発揮されたことが確認された。また、ICｌの当量を増やすと脱保護体が増加したことが確認された。また、NISを酸化剤に用いることによって、収率が向上したことが確認された。 From the obtained results, it was confirmed that any β activator exhibited high β selectivity. It was also confirmed that the deprotection body increased when the equivalent of ICl was increased. It was also confirmed that the yield was improved by using NIS as the oxidizing agent.
（２）グルコシルアクセプターの適用性
　上記の実施例１と同じ手順に従ったBOM体グリコシル化反応を、以下のように、グルコシルアクセプターを様々に変更して、実施した。なお、グルコシルドナーについても、実施例１で示したBOM体のみならず、MOM体、NAPOM体に対しても、反応を実施した。 (2) Applicability of glucosyl acceptor The BOM glycosylation reaction according to the same procedure as in Example 1 was carried out by changing the glucosyl acceptor as follows. For the glucosyl donor, the reaction was performed not only on the BOM body shown in Example 1, but also on the MOM body and NAPOM body.
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-T000065
Figure JPOXMLDOC01-appb-T000065
6） Sato, T.; Oishi, T.; Torikai, K. Org. Lett. 2015, 17, 3110-3113. 6) Sato, T .; Oishi, T .; Torikai, K. Org. Lett. 2015, 17, 3110-3113.
　得られた結果から、アクセプターとして、糖やアルコールのいずれを用いても、極めて高いβ選択性が得られたことが確認された。 From the obtained results, it was confirmed that extremely high β selectivity was obtained regardless of whether sugar or alcohol was used as the acceptor.
（３）溶媒の適用性
　上記の実施例１と同じ手順に従ったグリコシル化反応を、NAPOM体グリコシルドナーを用いて、以下のように、溶媒を様々に変更して実施した。 (3) Applicability of solvent The glycosylation reaction according to the same procedure as in Example 1 was carried out using NAPOM glycosyl donors with various changes of the solvent as follows.
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
　なお、上記の表における符号は、以下を示す。
　7) 他の分離不能な副生成物の混入が発生した(Contaminated by other inseparable by　products)．極微量だがα体の生成も確認された。得られた結果から、極性がより低い溶媒のほうが、より収率が向上したことが確認された。 In addition, the code | symbol in said table | surface shows the following.
7) Contaminated by other inseparable by products. The production of α form was confirmed though it was very small. From the obtained results, it was confirmed that the yield was improved in the solvent having a lower polarity.
（実施例５）
　本実施例５として、以下の反応式に示すように、上記で得られたグリコシルドナーであるBOM体(BOMエーテル)4を使って、ＮＩＳ存在下で、グリコシル化反応を行った。
Figure JPOXMLDOC01-appb-C000068
 (Example 5)
In Example 5, as shown in the following reaction formula, the glycosylation reaction was carried out in the presence of NIS using the BOM body (BOM ether) 4 which is the glycosyl donor obtained above.
Figure JPOXMLDOC01-appb-C000068
　BOMエーテル 4 (50.6 mg, 83.2μmol) とBzエステル12(48.1 mg, 84.3 μmol)のジクロロメタン (1.00 mL) 溶液に，粉末状モレキュラーシーブス4A(50 mg)を加え、室温で30分撹拌した．-78 ℃に冷却し，N-ヨードスクシンイミド (68.1 mg, 0.303 mmol)とトリフルオロメタンスルホン酸インジウム (141 mg, 0.251 mmol) を加えた．-78 ℃から-40 ℃まで徐々に昇温しながら45分間攪拌した．-78℃に冷却し，3-フェニル-1-プロパノールのジクロロメタン溶液(1 M, 0.125 mL, 0.125 mmol)を加え，30分かけ0 ℃まで徐々に昇温し，0 ℃で30分撹拌した．トリエチルアミン(140 μL, 1.00 mmol)と飽和チオ硫酸ナトリウム水溶液と飽和炭酸水素ナトリウム水溶液を加えて反応を停止させた．得られた混合物を酢酸エチルで抽出し，有機相を無水硫酸ナトリウムで乾燥した．乾燥剤をろ別後，ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル = 7/1 → 5/1 → 3/1）にて精製することで，β-グリコシド 13 (58.7 mg, 54.0 μmol, 64%)を無色粉末として得た．β-グリコシド 13: 1H-NMR (400 MHz, CDCl3): δ 8.18 (dd, J = 7.6, 1.2 Hz, 2H), 8.09 (dd, J = 7.6, 1.2 Hz, 2H), 7.58 (dd, J = 7.6, 2.0 Hz, 2H), 7.47 (dd, J = 7.6, 2.0 Hz, 2H), 7.30 (d, J = 6.9 Hz, 2H), 7.22 (dd, J = 7.6, 7.6 Hz, 2H), 7.14-6.88 (m, 21H), 6.07 (dd, J = 10.8, 9.6 Hz, 1H), 5.84 (dd, J = 10.8, 7.8 Hz, 1H), 5.34 (d, J = 6.4 Hz, 1H), 5.26 (s, 1H), 5.17 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 5.06 (d, J = 6.4 Hz, 1H), 4.90 (d, J = 11.9 Hz, 1H), 4.80-4.67 (m, 3H), 4.59 (d, J = 11.2 Hz, 1H), 4.51 (d, J = 7.8 Hz, 1H), 4.43 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 7.8 Hz, 1H), 4.26 (dd, J = 10.3, 4.8 Hz, 1H), 4.22-4.10 (m, 2H), 4.04 (dd, J = 9.2, 7.8 Hz, 1H), 3.87 (ddd, J = 9.6, 6.0, 6.0 Hz, 1H), 3.81-3.66 (m, J = 7.1 Hz, 2H), 3.66-3.38 (m, 3H), 3.34-3.17 (m, 2H), 2.48 (dd, J = 8.0, 6.8 Hz, 2H), 1.79-1.55 (m, 2H). Powdered molecular sieve 4A (50 mg) was added to a solution of BOM ether 4 (50.6 mg, 83.2 μmol) and Bz ester 12 (48.1 mg, 84.3 μmol) in dichloromethane (1.00 mL), and the mixture was stirred at room temperature for 30 minutes. After cooling to -78 ° C, N-iodosuccinimide (68.1 mg, 0.303 mmol) and indium trifluoromethanesulfonate (141 mg, 0.251 mmol) were added. The mixture was stirred for 45 minutes while gradually warming from -78 ° C to -40 ° C. After cooling to -78 ° C, 3-phenyl-1-propanol in dichloromethane (1 M, 0.125 mL, 0.125 mmol) was added, the temperature was gradually raised to 0 ° C over 30 minutes, and the mixture was stirred at 0 ° C for 30 minutes. Triethylamine (140 μL, 1.00 mmol), saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to stop the reaction. The resulting mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtering off the desiccant, the crude product obtained by concentrating the filtrate was purified by silica gel column chromatography (hexane / ethyl acetate = 7/1 → 5/1 → 3/1). -Glycoside 13 (58.7 mg, 54.0 μmol, 64%) was obtained as a colorless powder. β-glycoside 13: 1 H-NMR (400 MHz, CDCl 3 ): δ 8.18 (dd, J = 7.6, 1.2 Hz, 2H), 8.09 (dd, J = 7.6, 1.2 Hz, 2H), 7.58 (dd, J = 7.6, 2.0 Hz, 2H), 7.47 (dd, J = 7.6, 2.0 Hz, 2H), 7.30 (d, J = 6.9 Hz, 2H), 7.22 (dd, J = 7.6, 7.6 Hz, 2H), 7.14-6.88 (m, 21H), 6.07 (dd, J = 10.8, 9.6 Hz, 1H), 5.84 (dd, J = 10.8, 7.8 Hz, 1H), 5.34 (d, J = 6.4 Hz, 1H), 5.26 (s, 1H), 5.17 (d, J = 6.4 Hz, 1H), 5.11 (d, J = 6.4 Hz, 1H), 5.06 (d, J = 6.4 Hz, 1H), 4.90 (d, J = 11.9 Hz , 1H), 4.80-4.67 (m, 3H), 4.59 (d, J = 11.2 Hz, 1H), 4.51 (d, J = 7.8 Hz, 1H), 4.43 (d, J = 11.2 Hz, 1H), 4.36 (d, J = 7.8 Hz, 1H), 4.26 (dd, J = 10.3, 4.8 Hz, 1H), 4.22-4.10 (m, 2H), 4.04 (dd, J = 9.2, 7.8 Hz, 1H), 3.87 ( ddd, J = 9.6, 6.0, 6.0 Hz, 1H), 3.81-3.66 (m, J = 7.1 Hz, 2H), 3.66-3.38 (m, 3H), 3.34-3.17 (m, 2H), 2.48 (dd, J = 8.0, 6.8 Hz, 2H), 1.79-1.55 (m, 2H).
　得られた結果から、確かに、１，２－trans-グリコシド結合を有するアセタール系化合物であるβーグリコシド１３が選択的に生成されることが確認された。 From the obtained results, it was confirmed that β-glycoside 13, which is an acetal compound having a 1,2-trans-glycoside bond, was selectively produced.
（実施例６）
　本実施例６として、以下に示すように、上記で得られたグリコシルドナーであるBOM体(BOMエーテル）４を使って、ＮＩＳ存在下で、グリコシル化反応を行い、文献Machida, K. et al., M. Phenolic Compounds of the Leaves of Catalpa ovata G. Don. Natural Medicines, 2001, 55, 64-67.)で示される植物Catalpa ovataから単離されたβ－Ｄ－グルコピラノシドの全合成を行った。
Figure JPOXMLDOC01-appb-C000069
 (Example 6)
As Example 6, as shown below, a glycosylation reaction was carried out in the presence of NIS using the BOM body (BOM ether) 4 which is the glycosyl donor obtained above, and the document Machida, K. et al. , M. Phenolic Compounds of the Leaves of Catalpa ovata G. Don. Natural Medicines, 2001, 55, 64-67.) Total synthesis of β-D-glucopyranoside isolated from plant Catalpa ovata .
Figure JPOXMLDOC01-appb-C000069
　グリコシルアクセプター22:アルゴン雰囲気下、チオグリコシド4 (280 mg, 0.466 mmol)とモレキュラーシーブス4A(12 mg)の混合物に、無水エーテル(4 mL)と無水塩化メチレン(1 mL)を加え，0 ℃で撹拌した。上記懸濁液にLiAlH4 (142 mg, 3.73 mmol)とAlCl3(472 mg, 3.54 mmol)をゆっくり加え、その後室温で2時間撹拌した。0 ℃に冷却後、酢酸エチル(15 mL)と水(20 mL)を加えた。有機相を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、乾燥剤を除き除媒した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル=4/1）により精製し、14 (188 mg, 67%)を無色液体として得た。1H NMR (400 MHz, CDCl3): 7.43-7.38 (m, 2H), 7.32-7.14 (m, 18H), 5.02 (d, J = 6.5 Hz, 1H), 4.99-4.90 (m, 3H), 4.84 (d, J = 11.8 Hz, 1H), 4.76 (d, J = 11.8 Hz, 1H), 4.68-4.52 (m, 5H), 3.82-3.74 (m, 2H), 3.64-3.54 (m, 2H), 3.49 (dd, J = 9.4, 9.4 Hz, 1H), 3.36-3.29 (m, 1H)。 Glycosyl acceptor 22: Under an argon atmosphere, add anhydrous ether (4 mL) and anhydrous methylene chloride (1 mL) to a mixture of thioglycoside 4 (280 mg, 0.466 mmol) and molecular sieves 4A (12 mg) at 0 ° C. Stir with. The suspension LiAlH4 (142 mg, 3.73 mmol) and AlCl 3 (472 mg, 3.54 mmol ) was added slowly, followed by stirring for 2 hours at room temperature. After cooling to 0 ° C., ethyl acetate (15 mL) and water (20 mL) were added. The organic phase was washed with saturated brine, dried over sodium sulfate, and the solvent was removed by removing the desiccant. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain 14 (188 mg, 67%) as a colorless liquid. 1 H NMR (400 MHz, CDCl 3 ): 7.43-7.38 (m, 2H), 7.32-7.14 (m, 18H), 5.02 (d, J = 6.5 Hz, 1H), 4.99-4.90 (m, 3H), 4.84 (d, J = 11.8 Hz, 1H), 4.76 (d, J = 11.8 Hz, 1H), 4.68-4.52 (m, 5H), 3.82-3.74 (m, 2H), 3.64-3.54 (m, 2H) , 3.49 (dd, J = 9.4, 9.4 Hz, 1H), 3.36-3.29 (m, 1H).
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　グリコシルドナー15：アルコール14 (160 mg, 0.265 mmol)の塩化メチレン(5 mL)溶液に、アルゴン雰囲気下、室温でDCC (164 mg, 0.795 mmol)、camphorsulfonic acid (30 mg, 0.132 mmol)およびDMAP (16 mg, 0.132 mmol)を加えた。15分後0 ℃に冷却し、p-(benzyloxy)benzoic acid (152 mg, 0.667 mmol)の塩化メチレン(5 mL)溶液をゆっくり加えた。室温へと昇温後、24時間撹拌した。生じたDCUをセライトを用いてろ別後、セライトを塩化メチレン(3 × 5 mL)で洗浄した。ろ液を減圧濃縮して得られた粗生成物をカラムクロマトグラフィー(Silica Gel, hexane－EtOAc, 3:1)で精製することで、15 (169 mg, 81%)を無色粉末として得た。1H NMR (400 MHz, CDCl3): 7.93 (d, J = 9.0 Hz, 2H), 7.48-7.20 (m, 22H), 7.14-7.06 (m, 3H), 6.97 (d, J = 9.0 Hz, 2H), 5.12-5.00 (m, 5H), 4.96 (d, J = 6.5 Hz, 1H), 4.88 (d, J = 11.9 Hz, 1H), 4.82 (d, J = 11.9 Hz, 1H), 4.69-4.56 (m, 6H), 4.32 (dd, J = 11.9, 5.8 Hz, 1H), 3.85 (dd, J = 8.8, 8.8 Hz, 1H), 3.69-3.63 (m, 2H), 3.56 (t, J = 9.3, 1H)。
Figure JPOXMLDOC01-appb-C000071
 Glycosyl donor 15: Alcohol 14 (160 mg, 0.265 mmol) in methylene chloride (5 mL) was added to DCC (164 mg, 0.795 mmol), camphorsulfonic acid (30 mg, 0.132 mmol) and DMAP ( 16 mg, 0.132 mmol) was added. After 15 minutes, the mixture was cooled to 0 ° C., and a solution of p- (benzyloxy) benzoic acid (152 mg, 0.667 mmol) in methylene chloride (5 mL) was slowly added. After warming to room temperature, the mixture was stirred for 24 hours. The resulting DCU was filtered off using celite, and the celite was washed with methylene chloride (3 × 5 mL). The crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (Silica Gel, hexane-EtOAc, 3: 1) to obtain 15 (169 mg, 81%) as a colorless powder. 1 H NMR (400 MHz, CDCl 3 ): 7.93 (d, J = 9.0 Hz, 2H), 7.48-7.20 (m, 22H), 7.14-7.06 (m, 3H), 6.97 (d, J = 9.0 Hz, 2H), 5.12-5.00 (m, 5H), 4.96 (d, J = 6.5 Hz, 1H), 4.88 (d, J = 11.9 Hz, 1H), 4.82 (d, J = 11.9 Hz, 1H), 4.69- 4.56 (m, 6H), 4.32 (dd, J = 11.9, 5.8 Hz, 1H), 3.85 (dd, J = 8.8, 8.8 Hz, 1H), 3.69-3.63 (m, 2H), 3.56 (t, J = 9.3, 1H).
Figure JPOXMLDOC01-appb-C000071
　化合物23：化合物15(120 mg, 0.147 mmol)と無水MeOH (0.038 mL, 0.911 mmol)を無水CH2Cl2 (4 mL)にアルゴン雰囲気下溶解させ、活性化したモレキュラーシーブス4A(8 mg)で30分乾燥させた。-70℃に冷却後，NIS(50 mg, 0.221 mmol)とindium triflate (99 mg, 0.176 mmol)を加え、0 ℃まで昇温させながら1.5時間撹拌した。反応液を酢酸エチルで洗いこみながらセライトろ過後、ろ液に酢酸エチルを加えて全量を20 mLとした。得られた酢酸エチル溶液を飽和炭酸水素ナトリウム水溶液(20 mL)、飽和Na2SO3溶液(10 mL)および水(50 mL)で洗浄した。有機相を硫酸ナトリウムで乾燥し、乾燥剤をろ別後、減圧濃縮することで粗生成物を得た。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン/酢酸エチル＝9/1）で精製することで、16 (96 mg, 89%)が無色固体として得られた。1H NMR (400 MHz, CDCl3): 7.91 (d, J = 9.0 Hz, 2H), 7.37-7.13 (m, 20H), 6.90 (d, J = 9.0 Hz, 2H), 5.03-4.97 (m, 4H), 4.93 (d, J = 6.5 Hz, 1H), 4.86 (d, J = 6.5 Hz, 1H), 4.79 (d, J = 10.9 Hz, 1H), 4.66-4.49 (m, 6H), 4.35 (dd, J = 11.9, 4.2 Hz, 1H), 4.24 (d, J = 7.6 Hz, 1H), 3.79 (dd, J = 8.7, 8.7 Hz, 1H), 3.63-3.53 (m, 3H), 3.41 (s, 3H)。 Compound 23: Compound 15 (120 mg, 0.147 mmol) and anhydrous MeOH (0.038 mL, 0.911 mmol) were dissolved in anhydrous CH 2 Cl 2 (4 mL) under an argon atmosphere and activated with molecular sieves 4A (8 mg). Dry for 30 minutes. After cooling to -70 ° C, NIS (50 mg, 0.221 mmol) and indium triflate (99 mg, 0.176 mmol) were added, and the mixture was stirred for 1.5 hours while warming to 0 ° C. The reaction solution was filtered through Celite while washing with ethyl acetate, and then ethyl acetate was added to the filtrate to make a total volume of 20 mL. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), saturated Na 2 SO 3 solution (10 mL) and water (50 mL). The organic phase was dried over sodium sulfate, the desiccant was filtered off, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 16 (96 mg, 89%) as a colorless solid. 1 H NMR (400 MHz, CDCl 3 ): 7.91 (d, J = 9.0 Hz, 2H), 7.37-7.13 (m, 20H), 6.90 (d, J = 9.0 Hz, 2H), 5.03-4.97 (m, 4H), 4.93 (d, J = 6.5 Hz, 1H), 4.86 (d, J = 6.5 Hz, 1H), 4.79 (d, J = 10.9 Hz, 1H), 4.66-4.49 (m, 6H), 4.35 ( dd, J = 11.9, 4.2 Hz, 1H), 4.24 (d, J = 7.6 Hz, 1H), 3.79 (dd, J = 8.7, 8.7 Hz, 1H), 3.63-3.53 (m, 3H), 3.41 (s , 3H).
　化合物17：化合物17は15(45 mg, 0.055 mmol)から16と同様の手法を用いて合成したところ、17(32 mg, 77%)が無色液体として得られた。1H NMR (400 MHz, CDCl3): 7.92 (d, J = 8.9 Hz, 2H), 7.38-7.13 (m, 20H), 6.92 (d, J = 8.9 Hz, 2H), 5.05 (s, 2H), 5.04-4.97 (m, 3H), 4.88 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.65-4.48 (m, 6H), 4.37-4.30 (m, 2H), 3.90-3.76 (m, 2H), 3.63-3.53 (m, 3H), 3.52-3.44 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H)。
Figure JPOXMLDOC01-appb-C000072
 Compound 17: Compound 17 was synthesized from 15 (45 mg, 0.055 mmol) using the same method as in 16. As a result, 17 (32 mg, 77%) was obtained as a colorless liquid. 1 H NMR (400 MHz, CDCl 3 ): 7.92 (d, J = 8.9 Hz, 2H), 7.38-7.13 (m, 20H), 6.92 (d, J = 8.9 Hz, 2H), 5.05 (s, 2H) , 5.04-4.97 (m, 3H), 4.88 (d, J = 6.4 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.65-4.48 (m, 6H), 4.37-4.30 (m, 2H ), 3.90-3.76 (m, 2H), 3.63-3.53 (m, 3H), 3.52-3.44 (m, 1H), 1.13 (t, J = 7.1 Hz, 3H).
Figure JPOXMLDOC01-appb-C000072
　天然物18：Pd/C(10 wt%, 30 mg, 0.028 mmol)を16(50 mg, 0.068 mmol)の無水MeOH(5 mL)溶液に加え、水素雰囲気下室温で撹拌した。2時間後、触媒をCeliteを用いた吸引ろ過により除き、CeliteをMeOH(2 × 5 mL)で洗浄した。ろ液と洗浄液を合わせて除媒するとβ-D-glucopyranoside 18(19 mg, 91%)が無色固体として得られた。1H NMR (400 MHz, CD3OD):7.89 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 4.58 (dd, J = 11.8, 2.0 Hz, 1H), 4.40 (dd, J = 11.8, 5.7 Hz, 1H), 4.21 (d, J = 7.8 Hz, 1H), 3.59-3.53 (m, 1H), 3.48 (s, 3H), 3.41-3.37 (m, 2H), 3.22-3.16 (m, 1H)。 Natural product 18: Pd / C (10 wt%, 30 mg, 0.028 mmol) was added to 16 (50 mg, 0.068 mmol) in anhydrous MeOH (5 mL) and stirred at room temperature under a hydrogen atmosphere. After 2 hours, the catalyst was removed by suction filtration using Celite and Celite was washed with MeOH (2 × 5 mL). When the filtrate and the washing solution were combined and the solvent was removed, β-D-glucopyranoside 18 (19 mg, 91%) was obtained as a colorless solid. 1 H NMR (400 MHz, CD 3 OD): 7.89 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 4.58 (dd, J = 11.8, 2.0 Hz, 1H), 4.40 (dd, J = 11.8, 5.7 Hz, 1H), 4.21 (d, J = 7.8 Hz, 1H), 3.59-3.53 (m, 1H), 3.48 (s, 3H), 3.41-3.37 (m, 2H) , 3.22-3.16 (m, 1H).
　天然物19：17(30 mg, 0.046 mmol)を原料に18と同様の操作を行うことにより19の粗生成物が得られた。粗生成物をシリカゲルカラムクロマトグラフィー（塩化メチレン/メタノール=9/1）で精製することでβ-D-glucopyranoside 19 (11 mg, 86%)が無色固体として得られた。1H NMR (400 MHz, CD3OD): 7.89 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 4.58 (dd, J = 11.8, 2.0 Hz, 1H), 4.39 (dd, J = 11.8, 5.8 Hz, 1H), 4.30 (d, J = 7.8 Hz, 1H), 3.88 (dq, J = 14.3, 7.1 Hz, 1H), 3.65-3.53 (m, 2H), 3.41-3.34 (m, 2H), 3.19 (dd, J = 9.9, 6.6 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H)。
 
  The crude product of 19 was obtained by performing operation similar to 18 by using natural product 19:17 (30 mg, 0.046 mmol) as a raw material. The crude product was purified by silica gel column chromatography (methylene chloride / methanol = 9/1) to give β-D-glucopyranoside 19 (11 mg, 86%) as a colorless solid. 1 H NMR (400 MHz, CD 3 OD): 7.89 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 8.3 Hz, 2H), 4.58 (dd, J = 11.8, 2.0 Hz, 1H), 4.39 (dd, J = 11.8, 5.8 Hz, 1H), 4.30 (d, J = 7.8 Hz, 1H), 3.88 (dq, J = 14.3, 7.1 Hz, 1H), 3.65-3.53 (m, 2H), 3.41 -3.34 (m, 2H), 3.19 (dd, J = 9.9, 6.6 Hz, 1H), 1.21 (t, J = 7.1 Hz, 3H).

Claims (40)

  1. 　以下の一般式（I）で表されることを特徴とする
    Figure JPOXMLDOC01-appb-C000001
     （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。）
    Figure JPOXMLDOC01-appb-C000002
     （上記一般式（Ｉ－ａ）中、Ａは、環数１～５の環構造が形成されていることを表し、当該環構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）
    　アルコキシアルキル基を有する化合物。     It is represented by the following general formula (I)
    Figure JPOXMLDOC01-appb-C000001
     (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which the hydrogen atoms are lower alkyl, R 1 , R 2 , R 3 , and R 4 each independently represents a hydrogen atom or a linear or branched lower alkyl group, which may be substituted with an alkenyl, alkynyl, or aryl group. R 5 is a hydrogen atom, a linear or branched lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.
    Figure JPOXMLDOC01-appb-C000002
     (In the above general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the ring structure is composed of a substituted or unsubstituted 5-membered ring or 6-membered ring. And may contain a hetero atom, and R 6 represents a hydrogen atom or a linear or branched lower alkyl group)
    A compound having an alkoxyalkyl group.
  2. 　請求項１に記載のアルコキシアルキル基を有する化合物において、
    　単糖類またはオリゴマーに、前記アルコキシアルキル基が置換されて成ることを特徴とする
    　アルコキシアルキル基を有する化合物。     The compound having an alkoxyalkyl group according to claim 1,
    A compound having an alkoxyalkyl group, wherein the alkoxyalkyl group is substituted on a monosaccharide or oligomer.
  3. 　請求項１または請求項２に記載のアルコキシアルキル基を有する化合物において、
    　以下の一般式（I’）で表されることを特徴とする
    Figure JPOXMLDOC01-appb-C000003
     （上記式中、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、およびＲ６は、上記の定義と同じである）
    　アルコキシアルキル基を有する化合物。     In the compound having an alkoxyalkyl group according to claim 1 or 2,
    It is represented by the following general formula (I ')
    Figure JPOXMLDOC01-appb-C000003
     (In the above formula, Ra, Rb, Rc, R 1 , R 2 , R 3 , R 4 , and R 6 are the same as defined above)
    A compound having an alkoxyalkyl group.
  4. 　以下の一般式（II）で表されるナフチルメトキシメチル（ＮＡＰＯＭ）誘導体であることを特徴とする
    　アルコキシアルキル基を有する化合物。
    （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ６およびＲ６’は、各々独立して、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｘは、脱離基である。）     A compound having an alkoxyalkyl group, which is a naphthylmethoxymethyl (NAPOM) derivative represented by the following general formula (II):
    (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which the hydrogen atoms are lower alkyl, R 6 and R 6 ′ each independently represent a hydrogen atom or a linear or branched lower alkyl group, and X is a leaving group. Group.)
  5. 　請求項１～４のいずれかに記載のアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用し、アセタール系化合物を生成することを特徴とする
    　アセタール系化合物の製造方法。     The compound having an alkoxyalkyl group according to any one of claims 1 to 4 is reacted with an acceptor in the presence of an activating agent, and the reaction causes the alkoxyalkyl group of the compound having an alkoxyalkyl group to act as an adjacent group. And producing an acetal compound, wherein the acetal compound is produced.
  6. 　請求項５に記載のアセタール系化合物の製造方法において、
    　生成されたアセタール系化合物を少なくとも酸と反応させて、前記アルコキシアルキル基を除去することを特徴とする
    　アセタール系化合物の製造方法。     In the manufacturing method of the acetal compound of Claim 5,
    A method for producing an acetal compound, wherein the produced acetal compound is reacted with at least an acid to remove the alkoxyalkyl group.
  7. 　請求項４に記載のアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用し、アセタール系化合物を生成することを特徴とする
    　アセタール系化合物の製造方法。     The compound having an alkoxyalkyl group according to claim 4 is reacted with an acceptor in the presence of an activator, and the reaction causes the alkoxyalkyl group of the compound having an alkoxyalkyl group to act as an adjacent group, thereby obtaining an acetal compound. A method for producing an acetal compound, characterized in that
  8. 　請求項７に記載のアセタール系化合物の製造方法において、
    　反応に用いる溶媒として、ジクロロメタン(ＣＨ２Ｃｌ２)、トルエン（Ｃ６Ｈ５ＣＨ３）、プロピオニトリル(ＥｔＣＮ)、ヘキサン（Ｃ６Ｈ１４）、およびメチルターシャリーブチルエーテル(ｔＢｕＯＭｅ)からなる群から選択される少なくとも１種類の非プロトン性溶媒を少なくとも用いることを特徴とする
    　アセタール系化合物の製造方法。     In the manufacturing method of the acetal type compound according to claim 7,
    As a solvent used in the reaction, dichloromethane (CH 2 Cl 2 ), toluene (C 6 H 5 CH 3 ), propionitrile (EtCN), hexane (C 6 H 14 ), and methyl tertiary butyl ether ( t BuOMe) are used. A method for producing an acetal compound, comprising using at least one aprotic solvent selected from the group.
  9. 　請求項７または８に記載のアセタール系化合物の製造方法において、
    　極性が低い溶媒を用いることを特徴とする
    　アセタール系化合物の製造方法。     In the manufacturing method of the acetal type compound according to claim 7 or 8,
    A method for producing an acetal compound, wherein a solvent having low polarity is used.
  10. 　請求項７～９のいずれかに記載のアセタール系化合物の製造方法において、
    　複数の溶媒を同時に用いることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 9,
    A method for producing an acetal compound, wherein a plurality of solvents are used simultaneously.
  11. 　請求項７～１０のいずれかに記載のアセタール系化合物の製造方法において、
    　反応に用いる溶媒として、ジクロロメタン(ＣＨ２Ｃｌ２)およびヘキサン（Ｃ６Ｈ１４）の２種類を併用することを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 10,
    A method for producing an acetal compound, wherein two solvents, dichloromethane (CH 2 Cl 2 ) and hexane (C 6 H 14 ), are used in combination as a solvent used in the reaction.
  12. 　請求項７～１１のいずれかに記載のアセタール系化合物の製造方法において、
    　前記活性化剤として、モル等量が１よりも多量の塩化ヨウ素（ＩＣｌ）を用いることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 11,
    A method for producing an acetal compound, characterized in that iodine chloride (ICl) having a molar equivalent greater than 1 is used as the activator.
  13. 　請求項７～１２のいずれかに記載のアセタール系化合物の製造方法において、
    　前記活性化剤として、モル等量が１より大きく２以下の塩化ヨウ素（ＩＣｌ）を用いることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 12,
    A method for producing an acetal compound, characterized in that iodine chloride (ICl) having a molar equivalent greater than 1 and less than or equal to 2 is used as the activator.
  14. 　請求項７～１２のいずれかに記載のアセタール系化合物の製造方法において、
    　前記活性化剤として、Ｎ－クロロスクシンイミド（ＮＣＳ）を用いることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 12,
    A method for producing an acetal compound, wherein N-chlorosuccinimide (NCS) is used as the activator.
  15. 　請求項７～１４のいずれかに記載のアセタール系化合物の製造方法において、
    　前記アクセプターが、アルキル基および／またはフェニル基によって置換されていてもよい、ガラクトース、アロース、タロース、グロース、アルトロース、マンノース、イドース、グルクロン酸、イズロン酸、およびフコースからなる群から選択される少なくとも１つの糖から構成されることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 14,
    The acceptor is at least selected from the group consisting of galactose, allose, talose, gulose, altrose, mannose, idose, glucuronic acid, iduronic acid, and fucose, optionally substituted by an alkyl group and / or a phenyl group. A method for producing an acetal compound comprising a single sugar.
  16. 　請求項７～１４のいずれかに記載のアセタール系化合物の製造方法において、
    　前記アクセプターが、３－フェニル－１－ブタノール、ベンジルアルコール、フェネチルアルコール、１－フェニル－１－プロパノール、１－フェニル－２－プロパノール、２－フェニル－１－プロパノール、２－フェニル－２－プロパノール、１－フェニル－２－ブタノール、２－フェニル－１－ブタノール、２－フェニル－２－ブタノール、４－フェニル－１－ブタノール、５－フェニル－１－ペンタノール、および６－フェニル－１－ヘキサノールからなる群から選択される少なくとも１つのアルコールから構成されることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 14,
    The acceptor is 3-phenyl-1-butanol, benzyl alcohol, phenethyl alcohol, 1-phenyl-1-propanol, 1-phenyl-2-propanol, 2-phenyl-1-propanol, 2-phenyl-2-propanol, From 1-phenyl-2-butanol, 2-phenyl-1-butanol, 2-phenyl-2-butanol, 4-phenyl-1-butanol, 5-phenyl-1-pentanol, and 6-phenyl-1-hexanol A method for producing an acetal compound, comprising at least one alcohol selected from the group consisting of:
  17. 　請求項７～１６のいずれかに記載のアセタール系化合物の製造方法において、
    　生成されたアセタール系化合物を少なくとも酸と反応させて、前記アルコキシアルキル基を除去することを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 7 to 16,
    A method for producing an acetal compound, wherein the produced acetal compound is reacted with at least an acid to remove the alkoxyalkyl group.
  18. 　請求項６または１７に記載のアセタール系化合物の製造方法において、
    　前記酸が、塩酸、硫酸、p-トルエンスルホン酸、カンファースルホン酸、トリフルオロボラン、トリメチルシリルヨージド、およびトリメチルシリルブロミド、トリメチルシリルクロリド、トリメチルシリルトリフルオロメタンスルホネートからなる群から選択される少なくとも１つから構成されることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to claim 6 or 17,
    The acid is composed of at least one selected from the group consisting of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroborane, trimethylsilyl iodide, and trimethylsilyl bromide, trimethylsilyl chloride, trimethylsilyl trifluoromethanesulfonate. A method for producing an acetal compound.
  19. 　請求項６または１７に記載のアセタール系化合物の製造方法において、
    　生成されたアセタール系化合物を少なくとも加水素分解反応または酸化的除去反応により、前記アルコキシアルキル基を除去することを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to claim 6 or 17,
    A method for producing an acetal compound, comprising removing the alkoxyalkyl group from the produced acetal compound by at least a hydrogenolysis reaction or an oxidative removal reaction.
  20. 　請求項１９に記載のアセタール系化合物の製造方法において、
    　前記酸化的除去反応としてＤＤＱを用いることを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to claim 19,
    A method for producing an acetal compound, wherein DDQ is used as the oxidative removal reaction.
  21. 　以下の一般式（I）で表されるアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用し、アセタール系化合物である以下の一般式（III－１）で表されるSymponoside、一般式（III－２）で表されるBelallosideまたはそれらの誘導体を生成することを特徴とする
    　アセタール系化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000005
     （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。）
    Figure JPOXMLDOC01-appb-C000006
     （上記一般式（Ｉ－ａ）中、Ａは、環数１～５の環構造が形成されていることを表し、当該環構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）
    Figure JPOXMLDOC01-appb-C000007
     （上記式中、Ｒ１’およびＲ２’は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基である）
    Figure JPOXMLDOC01-appb-C000008
     （上記式中、Ｒ’は、水素原子、または、直鎖もしくは分岐鎖状の低級アルコキシ基である）     A compound having an alkoxyalkyl group represented by the following general formula (I) is reacted with an acceptor in the presence of an activating agent, and the reaction causes the alkoxyalkyl group of the compound having the alkoxyalkyl group to act as an adjacent group. An acetal compound represented by the following general formula (III-1), symponoside represented by the following general formula (III-2), Belalloside represented by the general formula (III-2), or a derivative thereof: Production method.
    Figure JPOXMLDOC01-appb-C000005
     (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which the hydrogen atoms are lower alkyl, R 1 , R 2 , R 3 , and R 4 each independently represents a hydrogen atom or a linear or branched lower alkyl group, which may be substituted with an alkenyl, alkynyl, or aryl group. R 5 is a hydrogen atom, a linear or branched lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.
    Figure JPOXMLDOC01-appb-C000006
     (In the above general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the ring structure is composed of a substituted or unsubstituted 5-membered ring or 6-membered ring. And may contain a hetero atom, and R 6 represents a hydrogen atom or a linear or branched lower alkyl group)
    Figure JPOXMLDOC01-appb-C000007
     (In the above formula, R 1 ′ and R 2 ′ are each independently a hydrogen atom or a linear or branched lower alkyl group)
    Figure JPOXMLDOC01-appb-C000008
     (In the above formula, R ′ is a hydrogen atom or a linear or branched lower alkoxy group)
  22. 　以下の一般式（I）で表されるアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用し、以下の一般式（III－３）で表されるアセタール系化合物またはその誘導体を生成することを特徴とする
    　アセタール系化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000009
     （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。）
    Figure JPOXMLDOC01-appb-C000010
     （上記一般式（Ｉ－ａ）中、Ａは、環数１～５の環構造が形成されていることを表し、当該環構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）
    Figure JPOXMLDOC01-appb-C000011
     （上記式中、Ｒ３’は、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基である）
    A compound having an alkoxyalkyl group represented by the following general formula (I) is reacted with an acceptor in the presence of an activating agent, and the reaction causes the alkoxyalkyl group of the compound having the alkoxyalkyl group to act as an adjacent group. And producing an acetal compound represented by the following general formula (III-3) or a derivative thereof:
    Figure JPOXMLDOC01-appb-C000009
     (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which the hydrogen atoms are lower alkyl, R 1 , R 2 , R 3 , and R 4 each independently represents a hydrogen atom or a linear or branched lower alkyl group, which may be substituted with an alkenyl, alkynyl, or aryl group. R 5 is a hydrogen atom, a linear or branched lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.
    Figure JPOXMLDOC01-appb-C000010
     (In the above general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the ring structure is composed of a substituted or unsubstituted 5-membered ring or 6-membered ring. And may contain a hetero atom, and R 6 represents a hydrogen atom or a linear or branched lower alkyl group)
    Figure JPOXMLDOC01-appb-C000011
     (In the above formula, R 3 ′ is a hydrogen atom or a linear or branched lower alkyl group)
  23. 　以下の一般式（I）で表されるアルコキシアルキル基を有する化合物と、以下の一般式（IV）で表されるアシル基を有する化合物の混合物を、活性化剤の存在下で反応させ、当該反応により、以下の一般式（V）で表されるアセタール系化合物を選択的に生成することを特徴とする
    　アセタール系化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000012
     （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。）
    Figure JPOXMLDOC01-appb-C000013
     （上記一般式（Ｉ－ａ）中、Ａは、環数１～５の環構造が形成されていることを表し、当該環構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）
    Figure JPOXMLDOC01-appb-C000014
     （上記式中、Ｒｃ’は、水素原子、または、低級アルキル基、アルケニル基、アルキニル基、アリール基、シアノ基、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ７は、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基、アリール基であり、ｎは、０以上の整数であり、Ｘ’は、脱離基であり、Ｙは、ヒドロキシ基、チオール基、アミノ基、モノアルキルアミノ基、または炭素求核剤である。）
    Figure JPOXMLDOC01-appb-C000015
     （上記式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ７、Ｒａ、Ｒｂ、Ｒｃ、Ｒｃ’、Ｘ、Ｘ’、およびｎは、上記一般式（I）および（IV）の定義と同じである）     A mixture of a compound having an alkoxyalkyl group represented by the following general formula (I) and a compound having an acyl group represented by the following general formula (IV) is reacted in the presence of an activator, and A method for producing an acetal compound, wherein an acetal compound represented by the following general formula (V) is selectively produced by a reaction.
    Figure JPOXMLDOC01-appb-C000012
     (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group in which the hydrogen atoms are lower alkyl, R 1 , R 2 , R 3 , and R 4 each independently represents a hydrogen atom or a linear or branched lower alkyl group, which may be substituted with an alkenyl, alkynyl, or aryl group. R 5 is a hydrogen atom, a linear or branched lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.
    Figure JPOXMLDOC01-appb-C000013
     (In the above general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the ring structure is composed of a substituted or unsubstituted 5-membered ring or 6-membered ring. And may contain a hetero atom, and R 6 represents a hydrogen atom or a linear or branched lower alkyl group)
    Figure JPOXMLDOC01-appb-C000014
     (In the above formula, Rc ′ is a hydrogen atom or a lower alkyl group, an alkenyl group, an alkynyl group, an aryl group, a cyano group, a carboxy group, and a carboxy group with a lower alkyl, alkenyl, alkynyl, or aryl group substituted. R 7 is a hydrogen atom, or a linear or branched lower alkyl group or aryl group, n is an integer of 0 or more, X ′ is a leaving group, Y is a hydroxy group, a thiol group, an amino group, a monoalkylamino group, or a carbon nucleophile.)
    Figure JPOXMLDOC01-appb-C000015
     (In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, X, X ′, and n represent the above general formulas (I) and (IV Is the same definition as)
  24. 　請求項２３に記載のアセタール系化合物の製造方法において、
    　前記アルコキシアルキル基を有する化合物が、以下の一般式（I’）で表されることを特徴とする
    　アセタール系化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000016
     （上記式中、Ｒａ、Ｒｂ、Ｒｃ、Ｒ１、Ｒ２、Ｒ３、Ｒ４、およびＲ６は、上記一般式（I）および一般式（I-a）の定義と同じである）     The method for producing an acetal compound according to claim 23,
    The method for producing an acetal compound, wherein the compound having an alkoxyalkyl group is represented by the following general formula (I ′):
    Figure JPOXMLDOC01-appb-C000016
     (In the above formula, Ra, Rb, Rc, R 1 , R 2 , R 3 , R 4 , and R 6 are the same as defined in the general formula (I) and the general formula (Ia)).
  25. 　請求項２３または２４に記載のアセタール系化合物の製造方法において、
    　アルコキシアルキル基を有する化合物が、以下の化学式（I－１）に示すベンジルオキシメチル（ＢＯＭ）誘導体または以下の化学式（I－２）に示すナフチルメトキシメチル（ＮＡＰＯＭ）誘導体であることを特徴とする
    　アセタール系化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000017
     （上記式中、Ｒａ、Ｒｂ、Ｒｃ、およびＸは、上記一般式（I）の定義と同じであり、Ｒ６およびＲ６’は、各々独立して、水素原子、または、炭素数１～３の直鎖もしくは分岐鎖状のアルキル基である）     The method for producing an acetal compound according to claim 23 or 24,
    The compound having an alkoxyalkyl group is a benzyloxymethyl (BOM) derivative represented by the following chemical formula (I-1) or a naphthylmethoxymethyl (NAPOM) derivative represented by the following chemical formula (I-2) A method for producing an acetal compound.
    Figure JPOXMLDOC01-appb-C000017
     (In the above formula, Ra, Rb, Rc, and X are the same as defined in the general formula (I), and R 6 and R 6 ′ are each independently a hydrogen atom or a carbon number of 1 to 3 linear or branched alkyl groups)
  26. 　請求項２３～２５のいずれかに記載のアセタール系化合物の製造方法において、
    　アルコキシアルキル基を有する化合物によるグリコシル化反応後に、フェノール類または脂肪族アルコールを添加して、温度変化させることで反応させ、当該反応により、前記脱離基Ｘ’がアルコキシ基に置き換わった以下の一般式（V’）で表されるアセタール系化合物を選択的に生成することを特徴とする
    　アセタール系化合物の製造方法。
    Figure JPOXMLDOC01-appb-C000018
     （上記式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ７、Ｒａ、Ｒｂ、Ｒｃ、Ｒｃ’、およびｎは、上記一般式（V）の定義と同じであり、Ｒ８は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基、またはアリール基である）     The method for producing an acetal compound according to any one of claims 23 to 25,
    After the glycosylation reaction with a compound having an alkoxyalkyl group, phenols or aliphatic alcohols are added, and the reaction is carried out by changing the temperature. By the reaction, the leaving group X ′ is replaced by an alkoxy group as described below. A method for producing an acetal compound, wherein the acetal compound represented by formula (V ') is selectively produced.
    Figure JPOXMLDOC01-appb-C000018
     (In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, and n are the same as defined in the general formula (V), and R 8 is a hydrogen atom, a linear or branched lower alkyl group, or an aryl group)
  27. 　請求項２３～２６のいずれかに記載のアセタール系化合物の製造方法において、
    　アルコキシアルキル基を有する化合物
    が、単糖類またはオリゴマーに前記アルコキシアルキル基が少なくとも１つ置換されて成り、
    　当該アルコキシアルキル基を有する化合物のグリコシル化反応速度が、前記アシル基を有する化合物のグリコシル化反応速度よりも速いことにより、当該アルコキシアルキル基を有する化合物のグリコシル化反応が選択的に進行し、アセタール系化合物である１，２－trans-グリコシド結合を有する化合物を選択的に生成することを特徴とする
    　アセタール系化合物の製造方法。     In the method for producing an acetal compound according to any one of claims 23 to 26,
    A compound having an alkoxyalkyl group, wherein a monosaccharide or oligomer is substituted with at least one alkoxyalkyl group;
    Since the glycosylation reaction rate of the compound having an alkoxyalkyl group is higher than the glycosylation reaction rate of the compound having an acyl group, the glycosylation reaction of the compound having the alkoxyalkyl group selectively proceeds, and an acetal A method for producing an acetal compound, which selectively produces a compound having a 1,2-trans-glycoside bond, which is a quinone-based compound.
  28. 　請求項２７に記載のアセタール系化合物の製造方法において、
    　アルコキシアルキル基を有する化合物によるグリコシル化反応後に、フェノール類または脂肪族アルコールを添加して、温度変化させることで反応させ、当該反応により、前記脱離基Ｘ’がアルコキシ基に置き換わった１，２－trans-グリコシド結合を有するアセタール系化合物を選択的に生成することを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to claim 27,
    After the glycosylation reaction with the compound having an alkoxyalkyl group, phenols or aliphatic alcohols are added and reacted by changing the temperature, whereby the leaving group X ′ is replaced with an alkoxy group. -A method for producing an acetal compound, which selectively produces an acetal compound having a trans-glycoside bond.
  29. 　請求項２８に記載のアセタール系化合物の製造方法において、
    　前記グリコシル化反応を－７８℃～－２０℃で行った後に、前記高温反応を－２０℃～０℃で行うことを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to claim 28,
    A method for producing an acetal compound, wherein the glycosylation reaction is performed at −78 ° C. to −20 ° C., and then the high temperature reaction is performed at −20 ° C. to 0 ° C.
  30. 　請求項２３～２９のいずれかに記載のアセタール系化合物の製造方法において、
    　生成されたアセタール系化合物を少なくとも酸と反応させて、前記アルコキシアルキル基を除去することを特徴とする
    　アセタール系化合物の製造方法。     The method for producing an acetal compound according to any one of claims 23 to 29,
    A method for producing an acetal compound, wherein the produced acetal compound is reacted with at least an acid to remove the alkoxyalkyl group.
  31. 　請求項２３～３０のいずれかに記載のアセタール系化合物の製造方法により製造され、以下の一般式（V’’）で表されることを特徴とする
    　アセタール系化合物。
    Figure JPOXMLDOC01-appb-C000019
     （上記式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５、Ｒ７、Ｒａ、Ｒｂ、Ｒｃ、Ｒｃ’、およびｎは、一般式（I）および一般式（IV）の定義と同じであり、Ｒ９は、脱離基Ｘ’またはＯＲ８基であり、当該Ｒ８は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基、またはアリール基である）     An acetal compound produced by the method for producing an acetal compound according to any one of claims 23 to 30 and represented by the following general formula (V ''):
    Figure JPOXMLDOC01-appb-C000019
     (In the above formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , Ra, Rb, Rc, Rc ′, and n are as defined in general formula (I) and general formula (IV)). The same, R 9 is a leaving group X ′ or an OR 8 group, and R 8 is a hydrogen atom, a linear or branched lower alkyl group, or an aryl group)
  32. 　請求項３０に記載のアセタール系化合物において、
    　以下の一般式（V’’-1）または一般式（V’’-2）で表されることを特徴とする
    　アセタール系化合物。
    Figure JPOXMLDOC01-appb-C000020
     （上記式中、Ｒａ、Ｒｂ、Ｒｃ、およびＸは、一般式（I）の定義と同じであり、Ｒｃ’、Ｒ９、およびｎは、一般式（V’’）の定義と同じであり、Ｒ６およびＲ６’は、各々独立して、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）
     
    The acetal compound according to claim 30,
    An acetal compound represented by the following general formula (V ″ -1) or general formula (V ″ -2):
    Figure JPOXMLDOC01-appb-C000020
     (In the above formula, Ra, Rb, Rc and X are the same as defined in the general formula (I), and Rc ′, R 9 and n are the same as defined in the general formula (V ″). , R 6 and R 6 ′ are each independently a hydrogen atom or a linear or branched lower alkyl group)

  33. 　以下の一般式（I）で表されるアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用して生成されたアセタール系化合物を計測する方法であって、
    　核磁気共鳴分光法（ＮＭＲ）を用いて測定し、得られた測定値の高ピーク値と低ピーク値の比較に基づいて、アセタール系化合物の含有比率を計測することを特徴とする
    　計測方法。
    Figure JPOXMLDOC01-appb-C000021
     （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、低級アルキル基、または、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。）
    Figure JPOXMLDOC01-appb-C000022
     （上記一般式（Ｉ－ａ）中、Ａは、環数１～５の環構造が形成されていることを表し、当該環構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）     A compound having an alkoxyalkyl group represented by the following general formula (I) is reacted with an acceptor in the presence of an activating agent, and the reaction causes the alkoxyalkyl group of the compound having the alkoxyalkyl group to act as an adjacent group. A method for measuring the acetal compound produced
    A measurement method characterized by measuring the content ratio of an acetal compound based on a comparison between a high peak value and a low peak value of a measurement value obtained by measurement using nuclear magnetic resonance spectroscopy (NMR).
    Figure JPOXMLDOC01-appb-C000021
     (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom, a lower alkyl group, or a carboxy group and a carboxy group in which hydrogen is substituted with a lower alkyl, alkenyl, alkynyl, or aryl group. In general, R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom or a linear or branched lower alkyl group, and R 5 is a hydrogen atom, linear or branched. A chain-like lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.)
    Figure JPOXMLDOC01-appb-C000022
     (In the above general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the ring structure is composed of a substituted or unsubstituted 5-membered ring or 6-membered ring. And may contain a hetero atom, and R 6 represents a hydrogen atom or a linear or branched lower alkyl group)
  34. 　請求項３３に記載の計測方法において、
    　前記測定値の高ピーク値が、１位水素に基づいて計測されることを特徴とする
    　計測方法。     The measurement method according to claim 33,
    A high peak value of the measured value is measured based on 1-position hydrogen.
  35. 　請求項３３に記載の計測方法において、
    　前記測定値の高ピーク値が、前記測定値に存在する４．５ｐｐｍ近傍に顕れる２重線ピークに基づいて計測されることを特徴とする
    　計測方法。     The measurement method according to claim 33,
    The measurement method, wherein a high peak value of the measurement value is measured based on a double line peak that appears in the vicinity of 4.5 ppm existing in the measurement value.
  36. 　請求項３３～３５に記載の計測方法において、
    　前記測定値における高ピーク値：低ピーク値の比率が９５：５～１００：０の場合には、当該比率は、９５：５以上として扱うことを特徴とする
    　計測方法。
    In the measuring method according to claims 33 to 35,
    The method according to claim 1, wherein when the ratio of the high peak value to the low peak value in the measurement value is 95: 5 to 100: 0, the ratio is handled as 95: 5 or more.
  37. 　以下の一般式（I）で表されるアルコキシアルキル基を有する化合物を活性化剤の存在下でアクセプターと反応させ、当該反応により、前記アルコキシアルキル基を有する化合物のアルコキシアルキル基が隣接基として作用して生成されたアセタール系化合物を計測する方法であって、
    　核磁気共鳴分光法（ＮＭＲ）を用いて測定し、得られた測定値のうち小さいピークを無視し、アセタール系化合物の化学構造を計測することを特徴とする
    　計測方法。
    Figure JPOXMLDOC01-appb-C000023
     （上記式中、Ｒａ、Ｒｂ、およびＲｃは、各々独立して、水素原子、低級アルキル基、または、カルボキシ基およびカルボキシ基の水素が低級アルキル，アルケニル，アルキニル，アリール基に置換されたものでもよく、Ｒ１、Ｒ２、Ｒ３、およびＲ４は、各々独立して、水素原子、または、直鎖もしくは分岐鎖状の低級アルキル基であり、Ｒ５は、水素原子、直鎖もしくは分岐鎖状の低級アルキル基もしくは以下の一般式（Ｉ－ａ）で表される官能基であり、Ｘは、脱離基である。）
    Figure JPOXMLDOC01-appb-C000024
     （上記一般式（Ｉ－ａ）中、Ａは、環数１～５の環構造が形成されていることを表し、当該環構造は、置換もしくは無置換の５員環又は６員環からなり、ヘテロ原子を含んでいてもよく、Ｒ６は、水素原子、又は、直鎖もしくは分岐鎖状の低級アルキル基である）     A compound having an alkoxyalkyl group represented by the following general formula (I) is reacted with an acceptor in the presence of an activating agent, and the reaction causes the alkoxyalkyl group of the compound having the alkoxyalkyl group to act as an adjacent group. A method for measuring the acetal compound produced
    A measurement method characterized by measuring using a nuclear magnetic resonance spectroscopy (NMR), ignoring a small peak among the obtained measured values, and measuring the chemical structure of an acetal compound.
    Figure JPOXMLDOC01-appb-C000023
     (In the above formula, Ra, Rb, and Rc are each independently a hydrogen atom, a lower alkyl group, or a carboxy group and a carboxy group in which hydrogen is substituted with a lower alkyl, alkenyl, alkynyl, or aryl group. In general, R 1 , R 2 , R 3 , and R 4 are each independently a hydrogen atom or a linear or branched lower alkyl group, and R 5 is a hydrogen atom, linear or branched. A chain-like lower alkyl group or a functional group represented by the following general formula (Ia), and X is a leaving group.)
    Figure JPOXMLDOC01-appb-C000024
     (In the above general formula (Ia), A represents that a ring structure having 1 to 5 rings is formed, and the ring structure is composed of a substituted or unsubstituted 5-membered ring or 6-membered ring. And may contain a hetero atom, and R 6 represents a hydrogen atom or a linear or branched lower alkyl group)
  38. 　請求項３７に記載の計測方法において、
    　前記測定値の高ピーク値が、１位水素に基づいて計測されることを特徴とする
    　計測方法。     The measurement method according to claim 37,
    A high peak value of the measured value is measured based on 1-position hydrogen.
  39. 　請求項３７に記載の計測方法において、
    　前記測定値の高ピーク値が、前記測定値に存在する４．５ｐｐｍ近傍に顕れる２重線ピークに基づいて計測されることを特徴とする
    　計測方法。     The measurement method according to claim 37,
    The measurement method, wherein a high peak value of the measurement value is measured based on a double line peak that appears in the vicinity of 4.5 ppm existing in the measurement value.
  40. 　請求項３７～３９のいずれかに記載の計測方法において、
    　ＨＰＬＣを用いて前記一般式（V）で表されるアセタール系化合物の含有比率を計測することを特徴とする
    　計測方法。     The measurement method according to any one of claims 37 to 39,
    The measuring method characterized by measuring the content rate of the acetal type compound represented by the said general formula (V) using HPLC.
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