WO2018124139A1 - Composé ayant un groupe alcoxyalkyle, procédé de production de composé acétal l'utilisant et son procédé de mesure - Google Patents

Composé ayant un groupe alcoxyalkyle, procédé de production de composé acétal l'utilisant et son procédé de mesure 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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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

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  • 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

L'invention concerne un composé qui induit un nouveau type de réaction stéréosélective présentant une stéréosélectivité pendant la synthèse de chaîne glucidique et produit des composés acétal ; l'invention concerne également, un procédé de production d'un composé acétal (par exemple un composé ayant une liaison 1,2-trans-glycoside) qui présente un excès de diastéréoisomère élevé à l'aide dudit composé ; et un procédé de mesure associé. selon l'invention, un composé ayant un groupe alcoxyalkyle représenté par la formule générale (I) induit une réaction stéréosélective.
PCT/JP2017/046800 2016-12-28 2017-12-26 Composé ayant un groupe alcoxyalkyle, procédé de production de composé acétal l'utilisant et son procédé de mesure WO2018124139A1 (fr)

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Citations (2)

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CN104592319A (zh) * 2015-01-16 2015-05-06 中国科学院上海有机化学研究所 一种糖胺聚糖类化合物n,o-同时硫酸化的方法及其反应中间体
WO2016056448A1 (fr) * 2014-10-07 2016-04-14 国立大学法人九州大学 Agent introduisant un groupe protecteur destiné à un groupe hydroxy et/ou à un groupe mercapto

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WO2016056448A1 (fr) * 2014-10-07 2016-04-14 国立大学法人九州大学 Agent introduisant un groupe protecteur destiné à un groupe hydroxy et/ou à un groupe mercapto
CN104592319A (zh) * 2015-01-16 2015-05-06 中国科学院上海有机化学研究所 一种糖胺聚糖类化合物n,o-同时硫酸化的方法及其反应中间体

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