3'-Ketoglycoside compounds that slowly release volatile alcohols

Abstract

The present invention relates to a 3'-ketoglycoside compound defined by formula (I) and its use for controlling the release of alcohol, in particular the release of alcohol with an insect repellent effect. The present invention also relates to a method for preparing the 3'-ketoglycoside compound of formula (I). The present invention also relates to a composition comprising the 3'-ketoglycoside compound of formula (I). The present invention also relates to the use of the 3'-ketoglycoside compound of formula (I) for controlled release of alcohols. The present invention also relates to a method for using the composition.

Description

Technical Field

[0001] The present invention relates to a 3'-ketoglycoside compound and its use in alcohol controlled release, in particular to its use in alcohol controlled release with anthelmintic effect. Background Art

[0002] Land- and airborne arthropods are the most common vectors of disease transmission to humans. As global temperatures rise, more habitats suitable for various vectors are available, and the number of areas affected by these diseases has increased.

[0003] One way to combat these insect bites is to use insect repellents. The active ingredients used in most current commercial topical insect repellents are space repellents. There are several approved synthetic topical insect repellents on the market, including DEET, Picaridin, and IR3535, but none of them are ideal insect repellents. For example, DEET has a pungent odor, a waxy feel, and can dissolve plastics and synthetic fabrics. In addition, the public perceives these synthetic molecules as harmful to health, leading to a rapidly growing market for natural alternatives.

[0004] A variety of different natural molecules are known to provide insect repellent effects, but most are too volatile and only provide protection for a short time. In fact, p-menthane-3,8-diol (PMD), which is active against a wide range of insects, is the only natural repellent recognized by the World Health Organization and has a boiling point high enough to evaporate slowly over a period of hours.

[0005] The effective duration of commercial insect repellent products after each application is usually 4 to 6 hours. However, due to the replacement of the relevant insect species in a given environment by other invasive species, existing commercially available insect repellent products may no longer be able to provide appropriate protection. Taking a non-limiting example, commercially available topical insect repellents are designed to be suitable for short-term action against mosquitoes that bite in the morning or evening. Aedes (commonly known as the Asian tiger mosquito) is a mosquito that feeds during the day and spreads Zika virus, dengue virus and chikungunya virus. With the unprecedented increase in the number of such mosquitoes, it is necessary to apply the currently available insect repellents and preparations multiple times. Due to the busy lifestyle, people can easily forget to use insect repellents regularly and are easily infected with diseases after being bitten. In order to alleviate this problem, traditional insect repellent products with increased active ingredient concentrations can be used, but increasing exposure can lead to multiple problems, such as toxicity and irritation.

[0006] Spatial repellents are volatile molecules that evaporate to provide a protective zone above the skin, preventing mosquitoes from landing and / or biting through complex mechanisms that are not fully understood. Each active ingredient has a minimum effective evaporation rate (MEER). Evaporation rates above this threshold result in non-productive losses, shortening the effective time of the repellent, after which concentrations are no longer sufficient to meet the MEER.

[0007] The development of insect repellent products that allow for controlled release of their active ingredients could overcome many of the issues with existing products by extending the duration of action while reducing the concentration of active ingredients required. This would provide additional benefits such as reduced odor, reduced irritation, and avoidance of the greasy feel typically associated with such products due to the reduced amount of active ingredients required.

[0008] Furthermore, these approaches will potentially allow the use of other natural repellents that are currently not available due to their high volatility, which is very attractive due to the wider range of repellent molecules that can be used, which could reduce resistance events.

[0009] Two main technical solutions for sustained release of anthelmintics have been disclosed in the art: encapsulation method and precursor method.

[0010] In the encapsulation method, the insect repellent is, for example, encapsulated in a microcapsule (e.g., EP-A-0348550), lipid sphere (EP-A-0502119), polymer (US4774082) or copolymer (US6180127) matrix, and after it is applied to the entire surface or to a certain area of ​​the body (as in the case of an insect repellent bracelet), the active ingredient is slowly released from the target surface over time, thereby achieving a slow release of the insect repellent.

[0011] In the prodrug approach, altering the physicochemical properties of the active ingredient by preparing a prodrug or conjugating it to an appropriate carrier molecule provides an alternative approach to controlled release, where the active ingredient is released through an environmental mechanism, which can prolong the time of maintaining the MEER while avoiding the need to use a large excess of the active ingredient.

[0012] The use of precursors such as prodrugs and conjugates is well known in the pharmaceutical art. With regard to anthelmintic active ingredients, there have been disclosed the conjugation of volatile anthelmintic molecules with compounds that reduce water solubility, such as fatty acids (US-A-2004 / 014811), the preparation of water-soluble ester and ether prodrugs (EP-A-2439188), five-membered and six-membered cyclic acetals as anthelmintic precursors (WO-A-99 / 00377), water-soluble conjugates with one or more sugar residues (JP-A-2000-096078, JP-A-H01-213291), conjugates with polycarboxylic acids or polyols to increase water solubility (WO-A-2016 / 071521), conjugates with hyaluronic acid (WO-A-2016 / 071521), conjugates with crystalline carriers (WO-A-2010 / 144755) or conjugates with cross-linked polymer gel compositions (US6846491).

[0013] These prior art methods have shortcomings in terms of effective sustained release applications of insect repellents. Both alkyl and aryl-O-pyranoglucosides and glucuronides can decompose on the skin to release volatile alcohol fragrance components, but the release rate is not sufficient for spatial insect repellent applications (i.e., compared to the μg / min / cm 2 The required fragrance release rate on the skin is ng / min / cm 2 ). In addition, the composition of the microbiota varies with skin area (Grice et al. Science, 2009, 324, 1190) and age (Capone et al., J. Invest. Dermatol., 2011, 131, 2026-2032). For example, Ikemoto et al., Flavour Fragr. J., 2002, 17, 452-455 found that a series of glycosides can be decomposed by microorganisms present on the skin, but their selectivity varies with the aglycone used. The same group continued to use different subjects to demonstrate differences in in vivo rates (Ikemoto et al., Flavour Fragr. J., 2003, 18, 45-47). Similar effects were found for glucuronide, with enzymes from different microorganisms showing distinct substrate patterns (US-A-2016 / 0137952).

[0014] Despite the various solutions available in the prior art, there is still a need for new compounds as slow-release anthelmintics which have suitable water solubility and sufficient active substance release rate to have an anthelmintic effect.

[0015] Purpose of the Invention

[0016] The subject of the present invention are 3'-ketoglycoside compounds of formula (I).

[0017] Another aspect of the present invention is a process for preparing the 3'-ketoglycoside compound of formula (I).

[0018] Another aspect of the present invention is a composition comprising a 3'-ketoglycoside compound of formula (I).

[0019] Another aspect of the present invention is the use of the 3'-ketoglycoside compound of formula (I) for controlled release of alcohols.

[0020] Another aspect of the invention is methods of using the compounds of formula (I). DETAILED DESCRIPTION

[0021] The object of the present invention is a 3'-ketoglycoside compound of formula (I)

[0022]

[0023] in

[0024] The stereochemistry of the 1', 2', 4' and 5' positions is independently selected from the α- or β-configuration; the sugar moiety is preferably selected from the group consisting of glucose, galactose, allose, altrose, mannose, gulose, idose, talose, fucose, xylose, N-acetylglucosamine and 2-deoxyglucose; more preferably selected from the group consisting of D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose and DN-acetylglucosamine and D-2-deoxyglucose; still more preferably D-glucose, DN-acetylglucosamine and D-2-deoxyglucose;

[0025] R is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; wherein R is derived from an alcohol of formula R-OH, the alcohol of formula R-OH having an initial boiling point of less than or equal to 350°C at a standard pressure of 101.3 kPa; preferably, R is the rest of an alcohol of formula R-OH, the formula R-OH being selected from the group consisting of: 4-allyl-2-methoxyphenol (eugenol), 3-benzyl-3-pentanol, 4-cyclohexyl-2-methylbutan-2-ol, 2-cyclohexylpropanol, decanol, 9-decenol, (2,4-dimethylcyclohex-3-enyl)methanol, (2,4-dimethylcyclohexyl)methanol, 2-(1,1-dimethylethyl)-4-methylcyclohexanol, 2,6-dimethyl Heptane-2-ol, 3,7-dimethyl-7-hydroxyoctanal, 2,5-dimethyl-2-indenyl alcohol, 3,7-dimethyl-1,6-nonadien-3-ol, 6,8-dimethylnonan-2-ol, 4,8-dimethyl-7-nonen-2-ol, (E)-3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-3,6-octadienol Alcohol, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctan-1,7-diol (hydroxycitronellol), 3,7-dimethyloctanol, 2,6-dimethyloctan-2-ol (tetrahydromyrcenol), 3,7-dimethyloctan-3-ol, 3,7-dimethylocten-3-ol, 3,7-dimethyloctan-6-enol (citronellol), 3,7-dimethyloctan-7-enol, 2,6-dimethyloctan-7- penten-2-ol (dihydromyrcenol), (E)-3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, dodecanol, 2-ethoxy-5-(1-propenyl)phenol, 2-ethyl-1-hexanol, ethyl 3-hydroxyhexanoate, 4-ethyl-2-methoxyphenol, 6-ethyl-3-methyl-5-octenol, 5-ethylnonan-2-ol, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enol, 1-heptanol, 2-hexanol, 3-hexenol, 4-hexenol, 3-hydroxybutan-2-one, 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-3-methoxyphenyl)butan-2-one, 2-(hydroxymethyl)nonan-2-one, 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), 4-isopropyl-1-benzyl alcohol, 4-isopropylcyclohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p- -Menthol, p-menthol-3-ol (menthol), p-menthol-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menthen-8-enol, p-menthen-8-en-2-ol, p-menthen-8-en-3-ol, 4-methoxy-1-benzyl alcohol, 7-methoxy-3,7-dimethyloctan-2-ol, 2-methoxy-4-methylphenol, 2-methoxyphenol (guaiacol), 2-methoxy-2-phenylethanol, (4-methoxyphenyl)methanol (anisyl alcohol), 2-methoxy-4-(1-propenyl)phenol (isoeugenol), 2-methoxy-4-propyl-1-cyclohexanol, 2-methoxy-4-propylphenol, 2-methoxy-4-vinylphenol, 3-(4-methylcyclohexanol) 4-(1-methylethyl)cyclohexylmethanol, 2-methyl-4-phenylbutan-2-ol, 3-methyl-4-phenylbutan-2-ol, 1-(4-methylphenyl)ethanol, 2-(2-methylphenyl)ethanol, 2-methyl-4-phenylpentanol, 2-methyl-5-phenylpentanol, 3-methyl-5-phenylpentanol, 4-methyl-1-phenylpentan-2-ol, 2-methyl-1-phenylpropan-2-ol, 2-(4-methylphenyl)propan-2-ol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, 2-(2-methylpropyl)-4-hydroxy-4-methyl- Tetrahydropyran, 2-methyl-4-(2,3,3-trimethyl-2-cyclopenten-1-yl)-2-butanol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-2-ol, 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-4-enol, 3-methyl-5-(2,2,3-trimethylcyclopentan-3-enyl)pentan-4-en-2-ol, 2,6-nonadienol, 1-nonanol, 6-nonenol, 1,2,3,4,4a,5,8,8a-octahydro-2,2,6,8-tetramethyl-1-naphthol, octahydro-2,5,5-trimethyl-2-naphthol, octan-2-ol, octan-3-ol, 1-octen-3-ol, 3,4,5,6,6-pentamethylheptan-2-ol, 2-pentyl-1-cyclopentanol, perhydro-4,8a-dimethyl-4a-naphthol, 2-phenoxyethanol, 4-phenylbutan-2-ol, 4-phenyl-3-buten-2-ol, 1-phenylethanol, 2-phenylethanol, 1-phenylhexan-2-ol, 1-phenylpentan-2-ol, 2-phenylpropanol, 2-phenylpropanol, 3-phenylpropanol, 1-phenylpropan-2-ol, 3-phenyl-2-propenol, 2-tert-butylcyclohexanol, 4-tert-butylcyclohexanol, 1-(2-tert-butyl-cyclohexyloxy)butan-2-ol, 2-tert-butyl-4-methyl-1-cyclohexanol, tetrahydro-2-isobutyl-4-methyl-(2 H) pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furanyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohexan-1-yl)hexan-3-ol, 2,4,6,8-tetramethylnonan-1-ol, 3,6,7-tetramethylnonan-1-ol, 2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecane-8-ol (cedrene alcohol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo alcohol (fenchol), (+)-(1R,2 (S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ol (branch alcohol), 2,6,6-trimethylbicyclo[3.1.1]hept-3-ol, 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 3,3,5-trimethylcyclohexanol, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)butan-2-ol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol (β-ionol), (E)-4-(2,6,6-trimethyl- 2-cyclohexen-1-yl)-3-buten-2-ol (α-ionol), (2,4,6-trimethylcyclohex-3-enyl)methanol, 1-(2,2,6-trimethyl-1-cyclohexyl)hexan-3-ol, 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol, 4,7,9-trimethyldecan-2-ol, 4,6,8-trimethyldecan-2-ol, 3,8,9-trimethyldecan-2-ol, 3,7,11-trimethyl-2,6,10-dodecatrienol (farnesol), 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol), 3,3,5-Trimethylhexanol, undecanol, undecan-2-ol, 10-undecenol, (6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide (capsaicin), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), p-allylphenol (kamophenol), 2H-1,3-benzodioxane-5-ol (sesamol), butan-2-yl-2-(2-hydroxyethyl)piperidin-1-ol carboxylic acid esters (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD); more preferably selected from 4-allyl-2-methoxyphenol (eugenol), (E)-3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloct-6-enol (citronellol), 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-Hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), p-menthan-3-ol (menthol), (4-methoxyphenyl)methanol (anisyl alcohol), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohex- 1-ol (p-menthane-3,8-diol, PMD); more preferably selected from E-3,7-dimethyl-2,6-octadienol (geraniol), 2-methoxy-4-(2-propenyl)phenol (eugenol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin), 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), 2-methyl-5-propan-2-ylphenol (carvacrol) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD);,

[0026] R 1 It is H, CH3, CH2OH, CH2OR 4 、CH2OCOR 4 、CH2OCOOR 4 、CH2OCONHR 4 、CH2OCONR 4 2. CH2NHR 4 、CH2NR 4 2. CO2X, CO2R 4,CONH2,CONHR 4 ,CONR 4 2. CH2OPO3X2, CH2OPO3XR 4 、CH2OPO3R 4 2. CH2OPO2XNHR 4 、CH2OPO(NHR 4 2. CH2OPO2XR 4 、CH2OPOR 4 2. CH2OSO3X, CH2OSO3R 4 or CH2OSO2R 4 , wherein X is hydrogen, an alkali metal ion, an ammonium ion or an organic counter ion, and R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; preferably R 1 It is CH2OH, CH2OSO3X, CH2OCOR 4 or CO2R 4 , more preferably CH2OH;

[0027] R 2 It is H, OH, OR 4 ,OCOR 4 、OCO2R 4 、OCONHR 4 、OCONR 4 2. NH2, NHR 4 NR 4 2. NHCOR 4 NHOR 4 、OPO3X2、OPO3XR 4 、OPO3R 4 2. OPO2XNHR4, OPO(NHR4)2, OPO2XR 4 OPOR 4 2. OSO3X, OSO3R 4 or OSO2R 4 , where R 4 As defined above; preferably R 2 Yes OH, NHCOR 4 , H or OCOR 4 , more preferably R 2 Yes OH, NHCOR 4 or H;

[0028] R 3 Is H or R 4 -Z, where R 4As defined above, Z is a single bond or a functional group selected from ester, amine, amide, carbonate or carbamate; preferably R 3 It is H;

[0029] Provided that the compound of formula (I) does not include compounds wherein R is the remainder of an alcohol of formula R—OH, wherein the formula R—OH is selected from the group consisting of methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, (hydroxymethyl)2-(hydroxymethyl)benzoic acid allyl ester, 2-(hydroxymethyl)benzoic acid benzyl ester, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethane-1-ol, 5-(hydroxymethyl)furan-2-carbaldehyde, tert-butyldimethylsilanol, cyclohexanol, n-hexanol (1-hexanol), ), prop-2-yn-1-ol, pent-4-en-1-ol, p-cresol, 4,7-bis(hydroxymethyl)-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-1-yl 3-methylbutyrate and 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl 3-methylbutyrate, 7-methyl-5,6,7,7a-tetrahydrocyclopentane[c ]pyran-1,4a,5,7(1H)-tetrol, 1,4a,5-trihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-7-yl acetate, 1,4a,5-trihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-7-yl cinnamate and (2,3-dimethylbutan-2-yl)dimethylsilanol.

[0030] The present inventors have developed 3'-ketoglycoside compounds of formula (I) that can release alcohol on surfaces (e.g. human skin) in the absence and presence of microbiota on human skin and bacteria found in the environment. Surprisingly, the compounds of the present invention are able to release effective concentrations of volatile alcohols that act as insect repellents for longer periods of time than observed with free repellent alcohols, typically for at least 24 hours. Particularly suitable alcohols are, for example, geraniol, eugenol, picaridin, menthol, carvacrol and PMD.

[0031] In this specification and claims, the singular forms "a", "an" and "the" include plural forms unless the context clearly indicates otherwise. The preposition "between" defines a range that also includes both ends. According to IUPAC, the term "part" is used to refer to a portion of a molecule.

[0032] 3'-Ketoside

[0033] The 3'-ketoglycoside of the present invention is composed of a sugar moiety and an alcohol rest R derived from an alcohol of the formula R-OH, as shown below:

[0034]

[0035] In the present specification, the compound of formula (I) may also be referred to as 3'-keto glucopyranoside or 3'-keto-O-glucopyranoside.

[0036] The keto form of the 3'-keto glycoside can be equilibrated to the hydrated form as shown below:

[0037]

[0038] The compounds of formula (I) contain an R group linked to the sugar moiety via a β-glycosidic bond or an α-glycosidic bond.

[0039] The 3'-ketoglycoside compounds may also form imines, oximes, hemiacetals, hemiaminals, bisulfite adducts or similar adducts in the presence of alternative nucleophiles (polysaccharides, such as chitosan; sodium bisulfite, etc.) that may typically be present in a given formulation, and these are expected to further modulate their physicochemical properties, such as stability.

[0040] Sugar part

[0041] The stereochemistry of the 1', 2', 4' and 5' positions of the sugar moiety in formula (I) is independently selected from the α- or β-configuration. The sugar moiety is preferably selected from the group consisting of glucose, galactose, allose, altrose, mannose, gulose, idose, talose, fucose, xylose, N-acetylglucosamine and 2-deoxyglucose; more preferably selected from D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose and DN-acetylglucosamine and D-2-deoxyglucose; still more preferably D-glucose, DN-acetylglucosamine and D-2-deoxyglucose.

[0042] In a more preferred embodiment, the sugar moiety is D-glucose.

[0043] In another preferred embodiment, the sugar moiety is selected from DN-acetylglucosamine and D-2-deoxyglucose.

[0044] In a preferred embodiment, R 1 It is CH2OH, CH2OSO3X, CH2OCOR 4 or CO2R 4 , more preferably R 1 It is CH2OH.

[0045] In a preferred embodiment, R 2 Yes OH, NHCOR 4 , H or OCOR 4 .

[0046] In a preferred embodiment, R 2 NHCOR 4 or H.

[0047] In a preferred embodiment, R 2 NHCOR 4 or H.

[0048] In a preferred embodiment, R 3 It's H.

[0049] In a preferred embodiment, the compound of formula (I) is selected from β-3'-keto glucoside, α-3'-keto glucoside, β-3'-keto-N-acetylglucosaminide and 2'-deoxy-3'-keto glucoside.

[0050] In a more preferred embodiment, the compound of formula (I) is selected from β-3'-keto glucoside and α-3'-keto glucoside.

[0051] In another preferred embodiment, the compound of formula (I) is selected from β-3'-keto-N-acetylglucosamine and 2'-deoxy-3'-ketoglucoside.

[0052] The remainder of alcohol

[0053] In the compound of formula (I), R is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; wherein preferably R is derived from an alcohol of formula R-OH, the initial boiling point of the alcohol of formula R-OH at a standard pressure of 101.3 kPa is less than or equal to 350° C.; more preferably, R is the remainder of the alcohol of formula R-OH, the formula R-OH is selected from the group consisting of: 4-allyl-2-methoxyphenol (eugenol), 3- Benzyl-3-pentanol, 4-cyclohexyl-2-methylbutan-2-ol, 2-cyclohexylpropanol, decanol, 9-decenol, (2,4-dimethylcyclohex-3-enyl)methanol, (2,4-dimethylcyclohexyl)methanol, 2-(1,1-dimethylethyl)-4-methylcyclohexanol, 2,6-dimethylheptan-2-ol, 3,7-dimethyl-7-hydroxyoctanal, 2,5-dimethyl-2-indenylmethanol, 3,7-dimethyl-1,6-nonadien-3-ol, 6,8-dimethylnonan-2-ol, 4,8-dimethyl-7-nonen-2-ol Alcohol, (E)-3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-3,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctan-1,7-diol (hydroxycitronellol), 3,7-dimethyloctanol, 2,6-dimethyloctan-2-ol (tetrahydromyrcenol), 3,7-dimethyloctan-3-ol, 3,7-dimethyloctan-3-ol, 3,7-dimethyloctan- 6-enol (citronellol), 3,7-dimethyloct-7-enol, 2,6-dimethyloct-7-en-2-ol (dihydromyrcenol), (E)-3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, dodecanol, 2-ethoxy-5-(1-propenyl)phenol, 2-ethyl-1-hexanol, ethyl 3-hydroxyhexanoate, 4-ethyl-2-methoxyphenol, 6-ethyl-3-methyl-5-octenol, 5-ethylnonan-2-ol, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enol, 1-heptanol, 2-hexanol, 3-hexenol, 4-hexenol, 3-hydroxybutan-2-one, 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-3-methoxyphenyl)butan-2-one, 2-(hydroxymethyl)nonan-2-one, 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), 4-isopropyl-1-benzyl alcohol, 4-isopropylcyclohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p- -Menthol, p-menthol-3-ol (menthol), p-menthol-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menthen-8-enol, p-menthen-8-en-2-ol, p-menthen-8-en-3-ol, 4-methoxy-1-benzyl alcohol, 7-methoxy-3,7-dimethyloctan-2-ol, 2-methoxy-4-methylphenol, 2-methoxyphenol (guaiacol), 2-methoxy-2-phenylethanol, (4-methoxyphenyl)methanol (anisyl alcohol), 2-methoxy-4-(1-propenyl)phenol (isoeugenol), 2-methoxy-4-propyl-1-cyclohexanol, 2-methoxy-4-propylphenol, 2-methoxy-4-vinylphenol, 3-(4-methylcyclohexanol) 4-(1-methylethyl)cyclohexylmethanol, 2-methyl-4-phenylbutan-2-ol, 3-methyl-4-phenylbutan-2-ol, 1-(4-methylphenyl)ethanol, 2-(2-methylphenyl)ethanol, 2-methyl-4-phenylpentanol, 2-methyl-5-phenylpentanol, 3-methyl-5-phenylpentanol, 4-methyl-1-phenylpentan-2-ol, 2-methyl-1-phenylpropan-2-ol, 2-(4-methylphenyl)propan-2-ol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, 2-(2-methylpropyl)-4-hydroxy-4-methyl- Tetrahydropyran, 2-methyl-4-(2,3,3-trimethyl-2-cyclopenten-1-yl)-2-butanol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-2-ol, 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-4-enol, 3-methyl-5-(2,2,3-trimethylcyclopentan-3-enyl)pentan-4-en-2-ol, 2,6-nonadienol, 1-nonanol, 6-nonenol, 1,2,3,4,4a,5,8,8a-octahydro-2,2,6,8-tetramethyl-1-naphthol, octahydro-2,5,5-trimethyl-2-naphthol, octan-2-ol, octan-3-ol, 1-octen-3-ol, 3,4,5,6,6-pentamethylheptan-2-ol, 2-pentyl-1-cyclopentanol, perhydro-4,8a-dimethyl-4a-naphthol, 2-phenoxyethanol, 4-phenylbutan-2-ol, 4-phenyl-3-buten-2-ol, 1-phenylethanol, 2-phenylethanol, 1-phenylhexan-2-ol, 1-phenylpentan-2-ol, 2-phenylpropanol, 2-phenylpropanol, 3-phenylpropanol, 1-phenylpropan-2-ol, 3-phenyl-2-propenol, 2-tert-butylcyclohexanol, 4-tert-butylcyclohexanol, 1-(2-tert-butyl-cyclohexyloxy)butan-2-ol, 2-tert-butyl-4-methyl-1-cyclohexanol, tetrahydro-2-isobutyl-4-methyl-(2 H) pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furanyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohexan-1-yl)hexan-3-ol, 2,4,6,8-tetramethylnonan-1-ol, 3,6,7-tetramethylnonan-1-ol, 2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecane-8-ol (cedrene alcohol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo alcohol (fenchol), (+)-(1R,2 (S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ol (branch alcohol), 2,6,6-trimethylbicyclo[3.1.1]hept-3-ol, 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 3,3,5-trimethylcyclohexanol, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)butan-2-ol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol (β-ionol), (E)-4-(2,6,6-trimethyl- 2-cyclohexen-1-yl)-3-buten-2-ol (α-ionol), (2,4,6-trimethylcyclohex-3-enyl)methanol, 1-(2,2,6-trimethyl-1-cyclohexyl)hexan-3-ol, 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol, 4,7,9-trimethyldecan-2-ol, 4,6,8-trimethyldecan-2-ol, 3,8,9-trimethyldecan-2-ol, 3,7,11-trimethyl-2,6,10-dodecatrienol (farnesol), 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol), 3,3,5-Trimethylhexanol, undecanol, undecan-2-ol, 10-undenol, (6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide (capsaicin), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), p-allylphenol (kamosanol), 2H-1,3-benzodioxan-5-ol (sesamol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8- diol, PMD); more preferably selected from 4-allyl-2-methoxyphenol (eugenol), (E)-3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloct-6-enol (citronellol), 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), p-menthol-3-ol (menthol), (4-methoxyphenyl)methanol (anisyl alcohol), 2-isopropyl-5-methylphenol (benzene), 2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD); more preferably selected from E-3,7-dimethyl-2,6-octadienol (geraniol), 2-methoxy-4-(2-propenyl)phenol (eugenol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin), 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), 2-methyl -5-propan-2-ylphenol (carvacrol) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD); excluding alcohols of formula R-OH selected from the group consisting of methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, (hydroxymethyl) 2-(hydroxymethyl) benzoic acid allyl ester, 2-(hydroxymethyl) benzoic acid benzyl ester, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethane-1-ol, 5-(hydroxymethyl)furan-2-carbaldehyde, tert-butyldimethylsilanol, cyclohexanol, n-hexanol (1-hexanol), prop-2-yn-1-ol, pent-4-en-1-ol, p-cresol, 4,7-bis(hydroxymethyl)-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-1-yl 3-methylbutyrate and 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl 3-methylbutanoate 7-methyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-1,4a,5,7(1H)-tetrol, 1,4a,5-trihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-7-yl acetate, 1,4a,5-trihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-7-yl cinnamate and (2,3-dimethylbutan-2-yl)dimethylsilanol.

[0054] Most of these alcohols are "volatile alcohols," which, as used herein, means alcohols that evaporate readily at ambient temperature when applied to a surface (e.g., a user's skin) and the link between the alcohol and sugar moieties is broken. The alcohol can then provide an odoriferous vapor layer or vapor zone near a surface, such as a user's skin.

[0055] The alcohols listed above are commercially available as disclosed in WO-A-2014 / 202416.

[0056] The determination of the boiling point of the alcohol can be carried out using standard methods disclosed in the prior art, which are familiar to the person skilled in the art, for example as disclosed in J. Vilarrasa, Introducción al análisis orgánico, page 44, Eunibar, Barcelona, ​​1975.

[0057] Alcohol E-3,7-dimethyl-2,6-octadienol is also known as geraniol and corresponds to the following structure:

[0058]

[0059] In another embodiment, the alcohol remainder is E-3,7-dimethyl-2,6-octadienol (geraniol).

[0060] The alcohol 2-methoxy-4-(2-propenyl)phenol, also known as eugenol, corresponds to the following structure:

[0061]

[0062] In another embodiment, the alcohol remainder is 2-methoxy-4-(2-propenyl)phenol (eugenol).

[0063] In one embodiment, the alcohol residue is one or more stereoisomers of butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (icaridin or picaridin) and corresponds to the following structure, wherein * Indicates stereocenter:

[0064]

[0065] Alcohol 5-methyl-2-(propan-2-yl)cyclohexan-1-ol is also known as menthol. A preferred isomer is L-menthol or (-)-menthol and corresponds to the following structure:

[0066]

[0067] Menthol has the following other isomers: (+)-menthol, (+)- and (-)-isomenthol, (+)- and (-)-neomenthol, and (+)- and (-)-neoisomenthol.

[0068] In another embodiment, the alcohol remainder is 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), preferably L-menthol.

[0069] In another embodiment, the alcohol remainder is 2-methyl-5-propan-2-ylphenol (carvacrol), which corresponds to the following structure:

[0070]

[0071] The alcohol 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol is also known as p-menthane-3,8-diol (PMD) and corresponds to the following structure:

[0072]

[0073] Different stereoisomers of PMD used alone, as a racemic mixture or as a mixture of diastereoisomers have shown anthelmintic effects, as disclosed in Barasa et al., J. Med. Entomol., 2002, 39, 736-741.

[0074] The PMD can be linked to the sugar moiety through the secondary or tertiary hydroxyl groups.

[0075] In one embodiment, the alcohol remainder is one or more stereoisomers of 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (PMD).

[0076] Eugenol, geraniol, picaridin, L-menthol and PMD have well-known insect repellent properties, as disclosed in Carroll et al., J. Am. Mosquito Control Assoc., 2006, 22, 507-514) or Barnard et al., J. Med. Entomol., 2004, 41, 726-730. Carvacrol is more effective than N,N-diethyl-m-methylbenzamide (DEET) in repelling Culex pipiens pallens, as disclosed in Park et al., J. Am. Mosquito Control Assoc., 2005, 21, 80-83.

[0077] The compounds of formula (I) are capable of acting as effective insect repellents. As shown in the Examples section, these compounds readily release alcohol under varying conditions of pH and temperature, in the presence or absence of fresh skin cleansing solution.

[0078] Preparation method of 3'-ketoglycoside

[0079] A process for preparing the 3'-ketoglycoside compounds of formula (I) is one aspect of the present invention.

[0080] The method for preparing the 3'-ketoglycoside compound of formula (I) comprises oxidizing the glycoside compound of formula (II) with an oxidant in the presence of a catalyst [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2

[0081]

[0082] The oxidizing agent is preferably selected from the group consisting of quinones, oxygen, air, peroxides, peracids and hydroperoxides,

[0083] in

[0084] The stereochemistry of the 1', 2', 4' and 5' positions is independently selected from the α- or β-configuration; the sugar moiety is preferably selected from the group consisting of glucose, galactose, allose, altrose, mannose, gulose, idose, talose, fucose, xylose, N-acetylglucosamine and 2-deoxyglucose; more preferably selected from the group consisting of D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose and DN-acetylglucosamine and D-2-deoxyglucose; still more preferably D-glucose, DN-acetylglucosamine and D-2-deoxyglucose;

[0085] R is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; wherein R is derived from an alcohol of formula R-OH, the alcohol of formula R-OH having an initial boiling point of less than or equal to 350° C. at a standard pressure of 101.3 kPa; preferably, R is the remainder of an alcohol of formula R-OH, the formula R-OH being selected from the group consisting of: 4-allyl-2-methoxyphenol (eugenol), 3-benzyl-3-pentanol, 4- Cyclohexyl-2-methylbutan-2-ol, 2-cyclohexylpropanol, decanol, 9-decenol, (2,4-dimethylcyclohex-3-enyl)methanol, (2,4-dimethylcyclohexyl)methanol, 2-(1,1-dimethylethyl)-4-methylcyclohexanol, 2,6-dimethylhept-2-ol, 3,7-dimethyl-7-hydroxyoctanal, 2,5-dimethyl-2-indene methanol, 3,7-dimethyl-1,6-nonadien-3-ol, 6,8-dimethylnon-2-ol, 4,8-dimethyl-7-nonen-2-ol, (E)- 3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-3,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctan-1,7-diol (hydroxycitronellol), 3,7-dimethyloctanol, 2,6-dimethyloctan-2-ol (tetrahydromyrcenol), 3,7-dimethyloctan-3-ol, 3,7-dimethylocten-3-ol, 3,7-dimethyloctan-6-ene alcohol (citronellol), 3,7-dimethyloct-7-enol, 2,6-dimethyloct-7-en-2-ol (dihydromyrcenol), (E)-3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, dodecanol, 2-ethoxy-5-(1-propenyl)phenol, 2-ethyl-1-hexanol, ethyl 3-hydroxyhexanoate, 4-ethyl-2-methoxyphenol, 6-ethyl-3-methyl-5-octenol, 5-ethylnonan-2-ol, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enol, 1-heptanol, 2-hexanol, 3-hexenol, 4-hexenol, 3-hydroxybutan-2-one, 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-3-methoxyphenyl)butan-2-one, 2-(hydroxymethyl)nonan-2-one, 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), 4-isopropyl-1-benzyl alcohol, 4-isopropylcyclohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p- -Menthol, p-menthol-3-ol (menthol), p-menthol-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menthen-8-enol, p-menthen-8-en-2-ol, p-menthen-8-en-3-ol, 4-methoxy-1-benzyl alcohol, 7-methoxy-3,7-dimethyloctan-2-ol, 2-methoxy-4-methylphenol, 2-methoxyphenol (guaiacol), 2-methoxy-2-phenylethanol, (4-methoxyphenyl)methanol (anisyl alcohol), 2-methoxy-4-(1-propenyl)phenol (isoeugenol), 2-methoxy-4-propyl-1-cyclohexanol, 2-methoxy-4-propylphenol, 2-methoxy-4-vinylphenol, 3-(4-methylcyclohexanol) 4-(1-methylethyl)cyclohexylmethanol, 2-methyl-4-phenylbutan-2-ol, 3-methyl-4-phenylbutan-2-ol, 1-(4-methylphenyl)ethanol, 2-(2-methylphenyl)ethanol, 2-methyl-4-phenylpentanol, 2-methyl-5-phenylpentanol, 3-methyl-5-phenylpentanol, 4-methyl-1-phenylpentan-2-ol, 2-methyl-1-phenylpropan-2-ol, 2-(4-methylphenyl)propan-2-ol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, 2-(2-methylpropyl)-4-hydroxy-4-methyl- Tetrahydropyran, 2-methyl-4-(2,3,3-trimethyl-2-cyclopenten-1-yl)-2-butanol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-2-ol, 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-4-enol, 3-methyl-5-(2,2,3-trimethylcyclopentan-3-enyl)pentan-4-en-2-ol, 2,6-nonadienol, 1-nonanol, 6-nonenol, 1,2,3,4,4a,5,8,8a-octahydro-2,2,6,8-tetramethyl-1-naphthol, octahydro-2,5,5-trimethyl-2-naphthol, octan-2-ol, octan-3-ol, 1-octen-3-ol, 3,4,5,6,6-pentamethylheptan-2-ol, 2-pentyl-1-cyclopentanol, perhydro-4,8a-dimethyl-4a-naphthol, 2-phenoxyethanol, 4-phenylbutan-2-ol, 4-phenyl-3-buten-2-ol, 1-phenylethanol, 2-phenylethanol, 1-phenylhexan-2-ol, 1-phenylpentan-2-ol, 2-phenylpropanol, 2-phenylpropanol, 3-phenylpropanol, 1-phenylpropan-2-ol, 3-phenyl-2-propenol, 2-tert-butylcyclohexanol, 4-tert-butylcyclohexanol, 1-(2-tert-butyl-cyclohexyloxy)butan-2-ol, 2-tert-butyl-4-methyl-1-cyclohexanol, tetrahydro-2-isobutyl-4-methyl-(2 H) pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furanyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohexan-1-yl)hexan-3-ol, 2,4,6,8-tetramethylnonan-1-ol, 3,6,7-tetramethylnonan-1-ol, 2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecane-8-ol (cedrene alcohol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo alcohol (fenchol), (+)-(1R,2 (S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ol (branch alcohol), 2,6,6-trimethylbicyclo[3.1.1]hept-3-ol, 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 3,3,5-trimethylcyclohexanol, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)butan-2-ol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol (β-ionol), (E)-4-(2,6,6-trimethyl- 2-cyclohexen-1-yl)-3-buten-2-ol (α-ionol), (2,4,6-trimethylcyclohex-3-enyl)methanol, 1-(2,2,6-trimethyl-1-cyclohexyl)hexan-3-ol, 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol, 4,7,9-trimethyldecan-2-ol, 4,6,8-trimethyldecan-2-ol, 3,8,9-trimethyldecan-2-ol, 3,7,11-trimethyl-2,6,10-dodecatrienol (farnesol), 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol), 3,3,5-Trimethylhexanol, undecanol, undecan-2-ol, 10-undecenol, (6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide (capsaicin), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), p-allylphenol (kamophenol), 2H-1,3-benzodioxane-5-ol (sesamol), butan-2-yl-2-(2-hydroxyethyl)piperidin-1-ol carboxylic acid esters (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD); more preferably selected from 4-allyl-2-methoxyphenol (eugenol), (E)-3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloct-6-enol (citronellol), 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-Hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), p-menthan-3-ol (menthol), (4-methoxyphenyl)methanol (anisyl alcohol), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohex- 1-ol (p-menthane-3,8-diol, PMD); more preferably selected from E-3,7-dimethyl-2,6-octadienol (geraniol), 2-methoxy-4-(2-propenyl)phenol (eugenol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin), 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), 2-methyl-5-propan-2-ylphenol (carvacrol) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD);,

[0086] R 1 It is H, CH3, CH2OH, CH2OR 4 、CH2OCOR 4 、CH2OCOOR 4 、CH2OCONHR 4 、CH2OCONR 4 2. CH2NHR 4 、CH2NR 4 2. CO2X, CO2R 4,CONH2,CONHR 4 ,CONR 4 2. CH2OPO3X2, CH2OPO3XR 4 、CH2OPO3R 4 2. CH2OPO2XNHR 4 、CH2OPO(NHR 4 2. CH2OPO2XR 4 、CH2OPOR 4 2. CH2OSO3X, CH2OSO3R 4 or CH2OSO2R 4 , wherein X is hydrogen, an alkali metal ion, an ammonium ion or an organic counter ion, and R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; preferably R 1 It is CH2OH, CH2OSO3X, CH2OCOR 4 or CO2R 4 , more preferably CH2OH;

[0087] R 2 It is H, OH, OR 4 ,OCOR 4 、OCO2R 4 、OCONHR 4 、OCONR 4 2. NH2, NHR 4 NR 4 2. NHCOR 4 NHOR 4 、OPO3X2、OPO3XR 4 、OPO3R 4 2. OPO2XNHR4, OPO(NHR4)2, OPO2XR 4 OPOR 4 2. OSO3X, OSO3R 4 or OSO2R 4 , where R 4 As defined above; preferably R 2 Yes OH, NHCOR 4 , H or OCOR 4 , more preferably R 2 Yes OH, NHCOR 4 or H;

[0088] R 3 Is H or R 4 -Z, where R 4As defined above, Z is a single bond or a functional group selected from ester, amine, amide, carbonate or carbamate; preferably R 3 It is H;

[0089] Provided that the compound of formula (I) does not include compounds wherein R is the remainder of an alcohol of formula R—OH, wherein the formula R—OH is selected from the group consisting of methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, (hydroxymethyl)2-(hydroxymethyl)benzoic acid allyl ester, 2-(hydroxymethyl)benzoic acid benzyl ester, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethane-1-ol, 5-(hydroxymethyl)furan-2-carbaldehyde, tert-butyldimethylsilanol, cyclohexanol, n-hexanol (1-hexanol), ), prop-2-yn-1-ol, pent-4-en-1-ol, p-cresol, 4,7-bis(hydroxymethyl)-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-1-yl 3-methylbutyrate and 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl 3-methylbutyrate, 7-methyl-5,6,7,7a-tetrahydrocyclopentane[c ]pyran-1,4a,5,7(1H)-tetrol, 1,4a,5-trihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-7-yl acetate, 1,4a,5-trihydroxy-7-methyl-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-7-yl cinnamate and (2,3-dimethylbutan-2-yl)dimethylsilanol.

[0090] The catalyst [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 can be prepared using prior art methods, such as those disclosed in Brink et al., Adv. Synth. Catal., 2003, 345, 1341-1352 and Conley et al., Organometallics, 2007, 26, 5447-5453.

[0091] The molar ratio of the catalyst to the glycoside substrate is preferably 0.01-10 mol%, preferably 0.1-8 mol%, and more preferably 1-6 mol%.

[0092] In the method of the present invention, the oxidation reaction is usually carried out in any suitable solvent or solvent mixture. It is recommended to stir. It can be carried out in water, an organic solvent or a mixture thereof. Suitable organic solvents include DMSO, dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, acetonitrile, hexamethylphosphoramide (HMPA), N-methyl-2-pyrrolidone (NMP) or any mixture thereof.

[0093] The method of the present invention is usually carried out at a temperature of 0°C to 100°C, preferably 10°C to 70°C, more preferably at about room temperature. The total reaction time will depend on the specific circumstances. Usually, the reaction time is about 1-48 hours.

[0094] Glycosides used as starting compounds are commercially available, for example, from Carbosynth Ltd., or can be prepared by prior art methods, for example, as disclosed below.

[0095] Alkyl and aryl glycosides can be prepared by various chemical synthesis methods, such as the Koenigs-Knorr reaction or the Mitsunobu reaction, which have been carried out under a variety of different conditions and generally produce kinetically favorable end isomers alone or as the main product, depending on the alcohol, sugar, sugar protecting group and the reaction conditions used. The impact of some of these on the synthesis of the low-affinity Na+-dependent glucose cotransporter SGLT2 inhibitor Remogliflozin is well demonstrated by Kobayashi et al., Chem. Pharm. Bull., 2016, 64, 1009-1018. The Koenigs-Knorr method requires the use of fully protected sugar derivatives containing a good leaving group at the anomeric position, while the Mitsunobu reaction requires protected sugars containing a free hydroxyl substituent at the anomeric position. These starting materials can be pentaacetylated by a variety of different methods, such as reported by Lee et al., Angew. Chemie, Int. Ed., 2016, 55, 12338-12342, followed by selective deprotection at the anomeric position as described by Yang et al., Bioorg. Chem., 2017, 72, 42-50, and activated to form trichloroacetimidyl esters as described by Ikeuchi et al., Synlett., 2019, 30, 1308–1312.

[0096] In order to increase the number of thermodynamically stable glycosides produced by the glycosylation process that favors the kinetic product, the protected glycosides can be anomeric under various conditions. For example, as reported by Sakata et al., Agric. Biol. Chem., 1979, 43, 307, various Lewis acids (e.g., titanium tetrachloride) can be used to anomeric protected alkyl glycosides to obtain anomeric mixtures that can be separated by chromatography. As disclosed by Montgomery et al., J. Am. Chem. Soc., 1942, 64, 690-694, aryl glycosides are generally anomeric stable in the presence of Lewis acids, but can be anomeric under different conditions, such as using hot phenol and zinc chloride treatment.

[0097] An increasing number of alkyl and aryl glycosides can also be prepared using various biosynthetic methods that have been extensively reviewed. Examples of some recent reviews on the enzymatic synthesis of glycosides include De Bruyn et al., Biotech. Adv., 2015, 33, 288-302 and Desmet et al., Chem. Eur. J., 2012, 18, 10786-10801.

[0098] As reported by Lu et al., Molecules, 2016, 21, 1301, glycosides can be oxidized to uronic acid under various conditions (e.g., 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) catalyzed oxidation). As reported by Lin et al., Eur. J. Org. Chem., 2016, 2653-2664, various methods for preparing uronic acid amides can be used, such as thioesterification of 6'-toluenesulfonated glycosides and subsequent treatment with amines.

[0099] Alternatively, 6'-ols can be selectively functionalized as esters, carbonates or carbamates using a variety of methods including enzymatic reverse hydrolysis (Gotor et al., J. Chem. Soc. Perkin Trans. 1, 1991, 491-492; Pulando et al., J. Chem. Soc. Perkin Trans. 1, 1992, 2891-2898; Garcia-Alles et al., Tetrahedron, 1995, 51, 307-316). 6'-Ether protected glycosides can be readily prepared by the tritylation method of methyl-O-α-D-pyranoglucoside reported by Hearon et al., J. Am. Chem. Soc., 1944, 66, 995-997, and 6'-amines can be prepared by, for example, the azide displacement method used by Souza et al., Carbohydr. Res., 2015, 410, 1-8.

[0100] 6'-alcohol can also be selectively functionalized to sulfuric acid monoester or phosphoric acid monoester using the method reported by, for example, Liu et al., Eur.J.Med.Chem., 2017, 128, 274-286. Alternatively, alcohol can be functionalized to sulfuric acid diester, phosphoric acid diester or triester, sulfonic acid monoester, phosphonic acid monoester or diester, diphosphonic acid monoester, amino phosphoroester or phosphonodiimide using a similar method, and these similar methods generally include 6'-alcohol to the electrophilic sulfur of phosphorus atom and carry out nucleophilic attack, resulting in displacement of leaving group (such as chloride). How to construct examples of such compounds can be found in the following review citations: Simpson et al. J. Am. Chem. Soc., 2006, 128, 1605-1610 and Mehellou et al., Chem. Med. Chem., 2009, 4, 1779-1791.

[0101] In some cases, the phosphorus atom may become chiral, just like phosphoramidate. Given that glycosides are also chiral, this may result in obtaining a diastereoisomer mixture, and there is a method that is conducive to forming a diastereoisomer or selectively separating diastereoisomers. For example, Ross et al., J.Org.Chem., 2011, 76, 8311-8319 found that by carefully optimizing reaction conditions, the content of one of the diastereoisomers in the prepared nucleoside phosphoramidate exceeds 3: 1. Then the pure main isomer can be separated by crystallization.

[0102] A similar approach can also be used to functionalize the 6'-position to prepare a variety of derivatives of 2'- and 4'-position secondary alcohols (where R 1=CH2OH). This can sometimes be achieved selectively, but because the primary alcohol at the 6'-position is usually more reactive and there are often multiple secondary alcohol groups, this is usually achieved by using an appropriate protecting group strategy. Loft et al., Chem. Bio. Chem., 2009, 10, 565-576 have demonstrated examples of how to effectively use protecting group strategies to sulfate glycosides at different positions on the sugar ring.

[0103] For example, Zhang et al., J. Med. Chem., 2019, 62, 7857-7873 discloses a method for preparing a compound of formula (I), wherein the sugar moiety is a glycosylamine.

[0104] In some embodiments, the selective diacetylation of the hydroxyl group of the sugar moiety can be performed according to methods provided in the prior art, such as the method disclosed in MacManus et al., Carbohydrate Res., 1995, 279, 281-291.

[0105] Delivery of compounds of formula (I)

[0106] Another object of the present invention is the use of 3'-ketoglycoside compounds of formula (I),

[0107]

[0108] in

[0109] The stereochemistry of the 1', 2', 4' and 5' positions is independently selected from the α- or β-configuration; the sugar moiety is preferably selected from the group consisting of glucose, galactose, allose, altrose, mannose, gulose, idose, talose, fucose, xylose, N-acetylglucosamine and 2-deoxyglucose; more preferably selected from the group consisting of D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose and DN-acetylglucosamine and D-2-deoxyglucose; still more preferably D-glucose, DN-acetylglucosamine and D-2-deoxyglucose;

[0110] R is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl; wherein preferably R is derived from an alcohol of formula R-OH, whose initial boiling point at a standard pressure of 101.3 kPa is less than or equal to 350° C.; more preferably, R is the remainder of an alcohol of formula R-OH, wherein the formula R-OH is selected from the group consisting of: 4-allyl-2-methoxyphenol (eugenol), 3-benzyl-3-pentanol, 4-cyclohexyl- 2-Methylbutan-2-ol, 2-cyclohexylpropanol, decanol, 9-decenol, (2,4-dimethylcyclohex-3-enyl)methanol, (2,4-dimethylcyclohexyl)methanol, 2-(1,1-dimethylethyl)-4-methylcyclohexanol, 2,6-dimethylhept-2-ol, 3,7-dimethyl-7-hydroxyoctanal, 2,5-dimethyl-2-indene methanol, 3,7-dimethyl-1,6-nonadien-3-ol, 6,8-dimethylnon-2-ol, 4,8-dimethyl-7-nonen-2-ol, (E)-3,7 -Dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-3,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctan-1,7-diol (hydroxycitronellol), 3,7-dimethyloctanol, 2,6-dimethyloctan-2-ol (tetrahydromyrcenol), 3,7-dimethyloctan-3-ol, 3,7-dimethylocten-3-ol, 3,7-dimethyloctan-6-enol ( Citronellol), 3,7-dimethyloct-7-enol, 2,6-dimethyloct-7-en-2-ol (dihydromyrcenol), (E)-3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, dodecanol, 2-ethoxy-5-(1-propenyl)phenol, 2-ethyl-1-hexanol, ethyl 3-hydroxyhexanoate, 4-ethyl-2-methoxyphenol, 6-ethyl-3-methyl-5-octenol, 5-ethylnonan-2-ol, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enol, 1-heptanol, 2-hexanol, 3-hexenol, 4-hexenol, 3-hydroxybutan-2-one, 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-3-methoxyphenyl)butan-2-one, 2-(hydroxymethyl)nonan-2-one, 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), 4-isopropyl-1-benzyl alcohol, 4-isopropylcyclohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p- -Menthol, p-menthol-3-ol (menthol), p-menthol-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menthen-8-enol, p-menthen-8-en-2-ol, p-menthen-8-en-3-ol, 4-methoxy-1-benzyl alcohol, 7-methoxy-3,7-dimethyloctan-2-ol, 2-methoxy-4-methylphenol, 2-methoxyphenol (guaiacol), 2-methoxy-2-phenylethanol, (4-methoxyphenyl)methanol (anisyl alcohol), 2-methoxy-4-(1-propenyl)phenol (isoeugenol), 2-methoxy-4-propyl-1-cyclohexanol, 2-methoxy-4-propylphenol, 2-methoxy-4-vinylphenol, 3-(4-methylcyclohexanol) 4-(1-methylethyl)cyclohexylmethanol, 2-methyl-4-phenylbutan-2-ol, 3-methyl-4-phenylbutan-2-ol, 1-(4-methylphenyl)ethanol, 2-(2-methylphenyl)ethanol, 2-methyl-4-phenylpentanol, 2-methyl-5-phenylpentanol, 3-methyl-5-phenylpentanol, 4-methyl-1-phenylpentan-2-ol, 2-methyl-1-phenylpropan-2-ol, 2-(4-methylphenyl)propan-2-ol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, 2-(2-methylpropyl)-4-hydroxy-4-methyl- Tetrahydropyran, 2-methyl-4-(2,3,3-trimethyl-2-cyclopenten-1-yl)-2-butanol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-2-ol, 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-4-enol, 3-methyl-5-(2,2,3-trimethylcyclopentan-3-enyl)pentan-4-en-2-ol, 2,6-nonadienol, 1-nonanol, 6-nonenol, 1,2,3,4,4a,5,8,8a-octahydro-2,2,6,8-tetramethyl-1-naphthol, octahydro-2,5,5-trimethyl-2-naphthol, octan-2-ol, octan-3-ol, 1-octen-3-ol, 3,4,5,6,6-pentamethylheptan-2-ol, 2-pentyl-1-cyclopentanol, perhydro-4,8a-dimethyl-4a-naphthol, 2-phenoxyethanol, 4-phenylbutan-2-ol, 4-phenyl-3-buten-2-ol, 1-phenylethanol, 2-phenylethanol, 1-phenylhexan-2-ol, 1-phenylpentan-2-ol, 2-phenylpropanol, 2-phenylpropanol, 3-phenylpropanol, 1-phenylpropan-2-ol, 3-phenyl-2-propenol, 2-tert-butylcyclohexanol, 4-tert-butylcyclohexanol, 1-(2-tert-butyl-cyclohexyloxy)butan-2-ol, 2-tert-butyl-4-methyl-1-cyclohexanol, tetrahydro-2-isobutyl-4-methyl-(2 H) pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furanyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohexan-1-yl)hexan-3-ol, 2,4,6,8-tetramethylnonan-1-ol, 3,6,7-tetramethylnonan-1-ol, 2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecane-8-ol (cedrene alcohol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo alcohol (fenchol), (+)-(1R,2 (S)-1,7,7-trimethylbicyclo[2.2.1]hept-2-ol (branch alcohol), 2,6,6-trimethylbicyclo[3.1.1]hept-3-ol, 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 3,3,5-trimethylcyclohexanol, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)butan-2-ol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol (β-ionol), (E)-4-(2,6,6-trimethyl- 2-cyclohexen-1-yl)-3-buten-2-ol (α-ionol), (2,4,6-trimethylcyclohex-3-enyl)methanol, 1-(2,2,6-trimethyl-1-cyclohexyl)hexan-3-ol, 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol, 4,7,9-trimethyldecan-2-ol, 4,6,8-trimethyldecan-2-ol, 3,8,9-trimethyldecan-2-ol, 3,7,11-trimethyl-2,6,10-dodecatrienol (farnesol), 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol (nerolidol), 3,3,5-Trimethylhexanol, undecanol, undecan-2-ol, 10-undecenol, (6E)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide (capsaicin), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), p-allylphenol (kamophenol), 2H-1,3-benzodioxane-5-ol (sesamol), butan-2-yl-2-(2-hydroxyethyl)piperidin-1-ol carboxylic acid esters (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD); more preferably selected from 4-allyl-2-methoxyphenol (eugenol), (E)-3,7-dimethyl-2,6-octadienol (geraniol), (Z)-3,7-dimethyl-2,6-octadienol (nerol), 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloct-6-enol (citronellol), 4-hydroxy-3-ethoxybenzaldehyde (ethyl vanillin), 4-Hydroxy-3-methoxybenzaldehyde (vanillin), 4-(4-hydroxy-1-phenyl)butan-2-one (raspberry ketone), p-menthan-3-ol (menthol), (4-methoxyphenyl)methanol (anisyl alcohol), 2-isopropyl-5-methylphenol (thymol), 5-isopropyl-2-methylphenol (carvacrol), 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol (α-terpineol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohex- 1-ol (p-menthane-3,8-diol, PMD); more preferably selected from E-3,7-dimethyl-2,6-octadienol (geraniol), 2-methoxy-4-(2-propenyl)phenol (eugenol), butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin), 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), 2-methyl-5-propan-2-ylphenol (carvacrol) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD);,

[0111] R 1 It is H, CH3, CH2OH, CH2OR 4 、CH2OCOR 4 、CH2OCOOR 4 、CH2OCONHR 4 、CH2OCONR 4 2. CH2NHR 4 、CH2NR 4 2. CO2X, CO2R 4,CONH2,CONHR 4 ,CONR 4 2. CH2OPO3X2, CH2OPO3XR 4 、CH2OPO3R 4 2. CH2OPO2XNHR 4 、CH2OPO(NHR 4 2. CH2OPO2XR 4 、CH2OPOR 4 2. CH2OSO3X, CH2OSO3R 4 or CH2OSO2R 4 , wherein X is hydrogen, an alkali metal ion, an ammonium ion or an organic counter ion, and R 4 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; preferably R 1 It is CH2OH, CH2OSO3X, CH2OCOR 4 or CO2R 4 , more preferably CH2OH;

[0112] R 2 It is H, OH, OR 4 ,OCOR 4 、OCO2R 4 、OCONHR 4 、OCONR 4 2. NH2, NHR 4 NR 4 2. NHCOR 4 NHOR 4 、OPO3X2、OPO3XR 4 、OPO3R 4 2. OPO2XNHR4, OPO(NHR4)2, OPO2XR 4 OPOR 4 2. OSO3X, OSO3R 4 or OSO2R 4 , where R 4 As defined above; preferably R 2 Yes OH, NHCOR 4 , H or OCOR 4 , more preferably R 2 Yes OH, NHCOR 4 or H;

[0113] R 3 Is H or R 4 -Z, where R 4As defined above, Z is a single bond or a functional group selected from ester, amine, amide, carbonate or carbamate; preferably R 3 It is H;

[0114] Use for the controlled release of alcohol, preferably for the controlled release of alcohol with an insect repellent effect.

[0115] In a preferred embodiment, R 1 It is CH2OH, CH2OSO3X, CH2OCOR 4 or CO2R 4 , more preferably R 1 It is CH2OH.

[0116] In a preferred embodiment, R 2 Yes OH, NHCOR 4 , H or OCOR 4 .

[0117] In a preferred embodiment, R 2 It's OH.

[0118] In a preferred embodiment, R 2 NHCOR 4 or H.

[0119] In a preferred embodiment, R 3 It's H.

[0120] In a preferred embodiment, the 3'-ketoglycoside compound of formula (I) is selected from β-3'-keto glucoside, α-3'-keto glucoside, β-3'-keto-N-acetylglucosaminide and 2'-deoxy-3'-keto glucoside.

[0121] In a preferred embodiment, the 3'-ketoglycoside compound of formula (I) is selected from β-3'-ketoglucoside and α-3'-ketoglucoside.

[0122] In a preferred embodiment, the 3'-ketoglycoside compound of formula (I) is selected from β-3'-keto-N-acetylglucosaminide and 2'-deoxy-3'-ketoglycoside.

[0123] In one embodiment, the use of a compound of formula (I) is a combination of said compound and a compound selected from an alcohol of formula R-OH as defined above and an insect active compound.

[0124] Insect-active compounds within the scope of the present description are compounds which are active towards insects, for example causing a repellent or attractant effect.

[0125] In a preferred embodiment, the insect active compound is selected from, for example, an insect repellent or an insect attractant. In a more preferred embodiment, the insect active compound is selected from terpenes, terpenoids, pyrethrins, pyrethroids, N,N-diethyl-3-methylbenzamide (DEET), ethyl 3-[acetyl(butyl)amino]propionate (IR3535) and mixtures thereof.

[0126] Terpenes and terpenoids are well-known insect repellents, as disclosed, for example, in Boncan et al., Int. J. Mol. Sci., 2020, 21, doi: 10.3390 / ijms21197382.

[0127] Pyrethroids and pyrethrins are well-known insect repellents, as disclosed, for example, in Bowman et al., PLOS One, 2018, 13(5): e0196410 and RL Metcalf, Ullmann's Encyclopedia of Industrial Chemistry, 2012, DOI: 10.1002 / 14356007.a14_263.

[0128] The insect repellent effect of suitable alcohols according to the present invention can be easily determined by known methods disclosed in the prior art (eg Barnard et al., op. cit.).

[0129] Another aspect of the present invention is a composition comprising at least a 3'-ketoglycoside compound of formula (I) and a carrier.

[0130] In one embodiment, the composition further comprises an alcohol of formula R-OH as disclosed above. The composition is suitable for controlling the effect of the released alcohol.

[0131] Delivery of one or more compounds of formula (I) is generally achieved by a variety of formulations and devices widely used and well known to those skilled in the art. Non-limiting examples include solutions, creams, pastes, powders, sprays, lotions, films, or impregnation into or onto materials such as wipes, masks and strips, medical devices or surfaces.

[0132] In preferred embodiments, the composition is in the form of a solution, cream, paste, powder, spray, lotion, film, or impregnation into or onto materials such as wipes, masks and strips, medical devices, or surfaces.

[0133] The composition of the present invention comprises a carrier, which is usually an aqueous solvent comprising water.

[0134] Typically, the composition further comprises a component selected from cosolvents, emulsifiers, humectants, astringents, buffers, emollients, antioxidants, preservatives, cosmetic oils, plant extracts, essential oils (e.g., eucalyptus oil, citronella oil, tea tree oil, neem oil, pine oil) and mixtures thereof. In a preferred embodiment, the essential oil is selected from eucalyptus oil, neem oil, citronella oil, tea tree oil, pine oil and mixtures thereof.

[0135] The 3'-ketoglycoside compounds may also form imines, oximes, hemiacetals, hemiaminals, bisulfite adducts or similar adducts in the presence of alternative nucleophiles (polyol-based polysaccharides, such as chitosan; sodium bisulfite, etc.) that may typically be present in a given formulation, and these are expected to further modulate their physicochemical properties, such as stability.

[0136] The decomposition of the compound of formula (I) is primarily pH dependent, and in one embodiment, the compound of formula (I) is stabilized for storage prior to administration, and the surface pH is appropriately adjusted to provide a suitable decomposition rate after administration.

[0137] The compounds of formula (I) are stable as solids and are mostly stable when dissolved in distilled water and / or aqueous acidic media. In one embodiment, these compounds can be formulated as non-aqueous mixtures that are hydrated by applying water to a surface.

[0138] Typically, the stability of the compound of formula (I) in aqueous solution is controlled by adjusting the pH, for example, adjusting the pH to about 4.5 to about 7.0, preferably about 4.5 to about 5.5. In one embodiment, the application of the solution is accompanied by the application of an alkaline solution to raise the pH to the alkaline region, thereby initiating the release of alcohol from the compound of formula (I) at a suitable rate. In another embodiment, the application of the solution is accompanied by the application of an acidic solution that autonomously increases the pH value when applied (e.g., using a carbonate buffer solution that releases carbon dioxide, such as natural carbonated spring water that has been adjusted to pH with an acid (e.g., citric acid)). Compounds of formula (I) in which R is an alkyl group generally exhibit higher stability than aryl derivatives.

[0139] In a preferred embodiment, delivery of one or more compounds of formula (I) is achieved via a formulation selected from, for example, solutions, creams, pastes, powders, sprays, lotions and films, or a device selected from, for example, wipes, masks and strips, and medical devices.

[0140] These can be used to treat a variety of indications, such as repelling various mosquitoes, ticks, mites, gnats, midges, and head lice.

[0141] In a preferred embodiment, the insect is selected from the group consisting of mosquitoes, ticks, mites, gnats, midges and head lice.

[0142] Also forming part of the present invention are methods of using compounds of formula (I) which comprise applying to a surface a composition comprising a 3'-ketoglycoside compound of formula (I) and a carrier.

[0143] The compounds of formula (I) can be applied to any surface, for example soft surfaces, such as skin, hair, clothing, plants, crops or grain storage spaces, or hard surfaces, such as wood, synthetic materials or ceramic materials.

[0144] In one embodiment, the soft surface is selected from the group consisting of skin, hair, clothing, plants, crops, and grain storage spaces.

[0145] In one embodiment, the hard surface is selected from the group consisting of wood, synthetic materials and ceramic materials.

[0146] Alcohol release

[0147] The compounds of formula (I) are capable of releasing an alcohol linked to the sugar moiety via an α- or β-glycosidic bond or a mixture of both.

[0148] The compounds of formula (I), in particular when the alcohol residue R is derived from an alcohol R-OH (e.g. eugenol, geraniol, picaridin, carvacrol, menthol (preferably L-menthol) or PMD, can be effective insect repellents, especially when in contact with human skin. As shown in the Examples section, these compounds readily release the repellent when incubated at physiological pH and temperature in the presence or absence of a human skin cleanser.

[0149] These compounds are stable in water or at low pH and can be tuned to release alcohol at different rates by adjusting the concentration and pH of the formulation applied to the skin.

[0150] The in vitro model used in the examples was intended to determine the suitability of the compounds of formula (I) as slow-release anthelmintics.

[0151] The compounds of formula (I) wherein R is an alkyl or aryl group unexpectedly provide advantages over the prior art corresponding to O-glycosides because they decompose to release their respective alcohol at a higher rate. This decomposition allows for the controlled release of higher concentrations of alcohol over a longer period of time than the duration of the free alcohol, suitable for providing an insect repellent effect on a wider range of surfaces (e.g., skin areas or clothing or plants).

[0152] Glycosides derived from the same alcohol as the compound of formula (I) and tested at similar concentrations under the same conditions hydrolyze significantly more slowly and the extent of hydrolysis varies greatly.

[0153] The release rate of alcohol in the buffer solution usually depends on aglycone, ketose, 3'-ketoglycoside concentration, pH and temperature, and can be easily adjusted to a suitable rate by those skilled in the art. Therefore, the 3'-ketoglycoside of formula (I) is substantially decomposed in 0.1M sodium phosphate buffer in D2O at pH 7.0 after 60 hours, but keeps relatively stable in deionized water and at a lower pH value. As shown in the examples, other substances (e.g. arginine) can be used to control the release rate of alcohol except phosphate buffer.

[0154] Methyl-O-α-D-3'-ketopyranoglucoside (compound of formula (III)) also slowly releases methanol after being heated to 37°C for 36 hours in 0.1 M sodium phosphate buffer (in D2O, pH 7.0), but remains stable in deionized water and is relatively stable at acidic pH.

[0155]

[0156] At the same temperature and pH, the reaction of methyl-O-α-D-3'-keto glucopyranoside (III) in the presence of skin cleansing solution resulted in the release of significantly greater amounts of methanol than that observed with buffer alone.

[0157] The phenol release profile of phenyl-O-β-D-3′-ketopyranoglucopyranoside (IV) did not change significantly in the presence of skin wash solution compared with buffer alone, but in the former case, phenol was completely released after 60 h, but in the latter case, a small amount of conjugate remained.

[0158]

[0159] The data for these model compounds clearly show that release of alcohol is significantly higher at 37°C and neutral pH, both with and without skin cleansing solutions. In addition, many compounds are only stable in water and partially stable at pH 5.7.

[0160] Surprisingly, compound (V), geranyl-O-β-D-3'-keto glucoside, contains a primary allyl alcohol in the β-configuration, and its degradation rate is significantly faster than compound (III), methyl-O-α-D-3'-keto glucoside, degrading by about 50% after 3 days. The release rate can be further adjusted by adjusting the sugar. For example, surprisingly, by using 3'-keto glycosides with N-Ac-glucosamine or 2'-deoxyglucose instead of glucose, geraniol can be released at a faster rate.

[0161]

[0162] Furthermore, the conversion was independent of concentration, with similar conversions for the 5 mg / mL or 20 mg / mL mixtures. In the latter case, a very pungent geraniol aroma was immediately detectable upon opening the stoppered reaction vessel after 3 days, whereas this aroma was not detectable with the corresponding glucoside: geranyl-O-β-D-pyranoglucopyranoside.

[0163] Formulations containing one or more compounds of formula (I) may be applied to the skin, hair, plants, or even to stored crops and cereals, alone or in combination with, for example, microbial crop sprays.

[0164] In the following examples, specific characteristics of the compounds of the present invention and comparative examples are shown.

[0165] Example

[0166] 1 H- and 13 C NMR spectra were obtained using Varian Mercury 300 (300 MHz), Varian Mercury 400 (400.1 Mz, 1 H and 100.6MHz, 13 C) or Bruker AVIII-500 (PA-BBO probe) (500 MHz) in deuterated chloroform, deuterated water, deuterated methanol or deuterated dimethyl sulfoxide. Tetramethylsilane (TMS) was used as the internal standard, chemical shifts (d) were reported in parts per million (ppm), and coupling constants (J) were reported in Hertz (Hz). The following abbreviations are used 1 H multiplicity: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), septet (sept.), doublet of doublets (dd), triplet of doublets (td), multiplet (m), broad singlet (brs), broad doublet (brd), and broad triplet (brt). High-resolution mass spectra were obtained using an LC / MSD-TOF mass spectrometer (Agilent Technologies) or a Bruker microOTOF mass spectrometer.

[0167] The reaction process and product mixture were analyzed by thin layer chromatography (TLC) on commercial silica gel 60 plates or by using the above instrument. 1 H NMR monitoring. For chromatography, column grade silica gel (0.040-0.063 mm mesh) was used. Chemicals were purchased from Sigma-Aldrich (Merck) or Cymit Quimica unless otherwise stated.

[0168] Racemic cis / trans-p-menthane-3,8-diol (PMD) with a purity of about 95% was purchased from Boc Sciences, and the cis-trans isomers (about 6:4 mixture) were separated by silica gel column chromatography using 1:3 ethyl acetate / hexane. 1 By H NMR, the faster running cis isomer was identical to authentic (1S,2R,5R)-2-(1-hydroxy-1-methylethyl)-5-methylcyclohexanol purchased from Sigma-Aldrich (Merck).

[0169] Crude lyophilized cell-free extract (CFE) of glycosyltransferase (YjiC) from Bacillus licheniformis DSM 13 was prepared from plasmid DNA using standard molecular biology techniques adapted from Bashyal et al., ACS Omega, 2019, 4, 9367-9375: codon optimised genesequence (GenBank sequence accession number AAU40842) using an N-terminal IMAC tag, pET28a vector, Escherichia coli BL21 (DE3), TB (super broth) medium, Prozomix Ltd.

[0170] Lipase was purchased as a kit from Enzagen Ltd.

[0171] The compounds prepared in the examples use non-IUPAC numbers for better understanding of the spectral data.

[0172] Example 1 : Preparation of (2R,3S,6R)-2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-3,5- Dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-O-β-D-3'-ketopyranoglucoside)

[0173]

[0174] Geranyl-O-β-D-glucopyranoside (purchased from Carbosons) (0.33 g, 1 mmol) and p-benzoquinone (0.34 g, 3 mmol) were suspended in acetonitrile (6.4 mL) and water (0.64 mL) and rapidly stirred at room temperature.

[0175] [(2,9-Dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (0.025 g, 2.5 mol%) was added and stirring was continued for 24 hours. 1:5 MeOH / dichloromethane was used as the eluent and 10% concentrated sulfuric acid in ethanol was used. The plate was then strongly heated for color development and TLC analysis was performed on silica gel. The results showed that all the starting materials had been converted into products.

[0176] The mixture was concentrated by distillation under reduced pressure and purified by silica gel chromatography using 3:1 ethyl acetate / hexanes as eluent to remove non-polar UV active impurities and then eluted with 3:1 ethyl acetate / hexanes to give 0.186 g (56% yield) of the title compound as a colorless clear oil.

[0177] The obtained title compound was characterized by the following parameters:

[0178] R f =0.46 (1:5 MeOH / dichloromethane);

[0179] 1 H-NMR (400MHz, CDCl3): 1.57 (s, 3H), 1.65 (s, 6H), 1.97-2.11 (m, 4H), 3.30 (dt, J = 10.0, 2.9Hz, 1H), 3.89 (dd, J = 12.2 ,2.9,1H), 3.98(dd,J=12.2,2.9,1H), 4.22-4.30(m,2H), 4.33-4.44(m,3H), 5.01-5.08(m,1H) and 5.35(t,J=6.8,1H).

[0180] 13 C-NMR (100.6MHz, CDCl3): 16.3, 17.6, 25.6, 26.2, 39.5, 61.7, 66.1, 72.1, 76.3, 76.7, 103.0, 119.1, 123.7, 131.7, 142.1, 206.5.

[0181] HRMS(ESI+):[C 16 H 26 O6+NH4] + The calculated value is 332.2068. The measured value is 332.2073.

[0182] Example 2 : Preparation of sec-butyl-2-(2-(((2R,3S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H- (pyran-2-yl)oxy)ethyl)piperidine-1-carboxylate (picaridin-O-β-D-3'-ketopyranoglucopyranoside)

[0183]

[0184] To a stirred solution of commercial glucose pentaacetate (60.0 g, 0.154 mol) in DMF (120 mL) was added H2N-NH2·AcOH (20.2 g, 0.200 mol, 1.3 eq.) at room temperature, and the reaction mixture was stirred vigorously for 2 h. TLC indicated that the starting material was completely consumed. The mixture was diluted with water (1 L) and extracted with AcOEt (10 x 100 mL). The organic phase was washed with water (4 x 50 mL), dried over anhydrous Na2SO4 and filtered. The solvent was then removed to obtain 2,3,4,6-tetra-O-acetyl-D-pyranose (47.7 g, 0.137 mol, 89%) as a light yellow oil.

[0185] To a stirred solution of crude 2,3,4,6-tetra-O-acetyl-D-pyranose (7.42 g, 21.36 mmol) in anhydrous dichloromethane (150 mL) was added trichloroacetonitrile (6.5 mL, 64.1 mmol, 3.0 equiv) and anhydrous potassium carbonate (15.0 g, 107 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred by (Celite) filtration and removal of volatiles gave 2',3',4',6'-tetra-O-acetyl-D-pyranoglucopyranosyl trichloroacetimidate (10.06 g, 20.46 mmol, 96%) as a light yellow solid. The data for this compound can be found in Ikeuchi et al., Synlett., 2019, 30, 1308-1312.

[0186] To a solution of crude 2',3',4',6'-tetra-O-acetyl-D-pyranosyl glucopyranosyl trichloroacetimidate (0.4 g, 0.81 mmol) in anhydrous CH2Cl2 (8 mL) was added racemic picaridin (0.18 g, 0.81 mmol) at -78°C. After 5 minutes, TMSOTf (0.081 mmol) was added and the resulting solution was stirred at 0°C for 2 hours. After that, TLC (EtOAc / hexane, 1:1) indicated the consumption of the starting material. The solvent was evaporated in vacuo to give a residue which was subjected to silica gel chromatography (EtOAc / hexane, 1:4 to 1:1) to give 178 mg (40% yield) of tetraacetylated picaridin-β-glucoside.

[0187] The obtained tetraacetylated compounds were characterized by the following parameters:

[0188]

[0189] 1H NMR(500MHz, CDCl3)0.94(m,3H),1.27(m,4H),1.64(m,9H),2.08(m,12H), 2.84(m,1H),3.53(m,1H),3.70(m,2H),3.92(m,1H),4.15(m,2H),4.25(ddt ,J=1.4,4.7,12.3,1H),4.47(dd,J=8.0,15.0,1H),4.79(m,1H),4.96(ddd ,J=3.4,8.0,9.6,1H), 5.06(td,J=2.0,9.8,1H) and 5.18(td,J=5.1,9.5,1H).

[0190] 13 C NMR (500 MHz, CDCl3) 9.80, 9.86, 19.06, 19.86, 20.68, 20.76, 20.81, 25.58, 28.64, 29.16, 30.00, 39.09, 48.04, 48.19, 62.01, 68.05, 68.43, 71.37, 71.83, 72.96, 100.91, 155.59, 169.39, 169.51, 170.37 and 170.77.

[0191] HRMS(ESI + ):[C 26 H 41 NO 12 +H] + The calculated value = 560.2705; the measured value is 560.2702.

[0192] To a solution of tetraacetylated picaridin-β-glucoside (0.170 g, 0.308 mmol) in methanol (5 mL) was added NaOMe (25% in methanol) (10 μL) and the resulting solution was stirred at room temperature for 3 hours. Afterwards, TLC (EtOAc) indicated consumption of the starting material. The reaction was quenched with Amberlite (ion exchange resin) (acid form) and filtered. The solvent was evaporated in vacuo to give a residue which was subjected to silica gel chromatography (EtOAc) to give 96 mg (81% yield) of unprotected picaridin-β-glucoside.

[0193] The obtained deacetylated compounds were characterized by the following parameters:

[0194]

[0195] 1H NMR(500MHz,D4-MeOH)0.89-0.98(m,3H),1.21-1.29(m,3H),1.41(m,1H),1.56-1.70(m,7H), 1.81(m,1H),2.07-2.16(m,1H),2.94,tt,J=3.2,13.6,1H),3.19(ddd,J=3.4,7.8,9.2,1H),3. 24-3.30(m,2H),3.37(d,J=2.0,2H),3.68(dd,J=5.3,11.9,1H),3.83-3.89(m,1H),3.89-3.94 (m,1H), 3.97-4.04(m,1H), 4.24(dd,J=5.4,7.9,1H), 4.47(d,J=30.2,1H) and 4.68-4.76(m,1H).

[0196] 13 C NMR (500 MHz, D4-MeOH) 10.04, 10.10, 19.95, 20.14, 26.72, 29.65, 30.02, 30.06, 30.61, 40.04, 62.67, 67.96, 71.49, 74.59, 74.97, 77.80, 104.16 and 157.31.

[0197] HRMS(ESI + ):[C 18 H 33 NO8+H] + The calculated value = 392.2279; the measured value is 392.2279.

[0198] To a stirred solution of unprotected picaridin-β-glucoside (50 mg, 0.128 mmol) in MeCN / H2O 9:1 (1.0 mL) was added benzoquinone (14 mg, 0.383 mmol, 3.0 equiv) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (7 mg, 0.006 mmol, 0.05 equiv). The reaction mixture was heated at 60 °C for 1 h and adsorbed onto silica. The residue was purified by flash column chromatography on silica gel (EtOAc / hexanes 7:3) to give the title compound (36 mg, 0.092 mmol, 72%) as diastereomers of white foam.

[0199] The obtained title compound was characterized by the following parameters:

[0200] 1H-NMR (CDCl3, 400.1MHz): 0.88 (m, 3H), 1.18 (d, J = 6.2, 3H), 1.31-1.78 (m, 7H), 2.02-2.16 (m, 1H), 2.67-2.93 (m, 2H), 3.27 (ddd, J = 10.0, 4.5, 2. 8,1H),3.17-3.76(m,2H),3.87(ddd,J=12.3,4.6,2.2,1H),3.93-4.00( m, 2H), 4.00 (dd, J = 12.1, 2.7, 1H), 4.17-4.38 (m, 3H), 4.46-4.78 (m, 2H).

[0201] 13 C-NMR(CDCl3,100.6MHz):9.74(CH3),19.2(CH2),19.9(CH3),25.8(CH2),29.1(CH2),29.2(CH2),39.1(CH2),39.2( CH2),47.9(CH),62.1(CH2),67.7(CH2),72.6(CH),73.4(CH),76.8(CH),77.0(CH),104.8(CH),156.2(C),206.0(C).

[0202] HRMS(ESI + ):[C 18 H 31 NO8+H] + The calculated value = 390.2122; the measured value is 390.2134.

[0203] Example 3 : Preparation of (2R,3S,4R)-6-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-2-(hydroxymethyl)tetrahydro -2H-pyran-3,4-diol (geranyl-OD-2′-deoxy-3′-ketopyranoside)

[0204]

[0205] To a stirred solution of 2-deoxy-D-glucose (1.0 g, 6.1 mmol, 1.0 equiv) in anhydrous pyridine (12 mL) was added acetic anhydride (4.6 mL, 48.7 mmol, 8.0 equiv) at 0°C. The reaction mixture was slowly warmed to room temperature and then stirred for 15 hours. TLC analysis (hexane / EtOAc, 7 / 3) indicated that the starting material was completely converted to a less polar product (Rf=0.4). The reaction mixture was poured onto ice water (100 mL) and diluted with EtOAc (75 mL). The organic layer was separated and washed with 1.0 M HCl, saturated aqueous NaHCO3, water and brine (75 mL each). The aqueous layer was re-extracted with EtOAc (100 mL), and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting oil was co-evaporated with toluene (3×20 mL) to give 2-deoxy-1,3,4,6-tetra-O-acetyl-α / β-D-glucose (2.02 g, 5.54 mmol, 100%) as a white solid. The data for this compound can be found in Beswick et al., Carbohydrate Res., 2020, 488, 107896.

[0206] At 0 ° C, a saturated solution of methanolic ammonia (25 mL) was added to a stirred solution of 2-deoxy-1,3,4,6-tetra-O-acetyl-α / β-D-glucose (2.01 g, 6.05 mmol) in anhydrous THF (75 mL) within 5 minutes. The reaction mixture was slowly warmed to 40 ° C and then stirred for 5 hours. TLC analysis (hexane / EtOAc, 7: 3) showed that the raw material was completely converted into a spot with a lower Rf (Rf = 0.2). The reaction mixture was concentrated under reduced pressure, and the resulting orange oil was purified by flash column chromatography (hexane / EtOAc 1: 1) to obtain 2-deoxy-3,4,6-tri-O-acetyl-α / β-D-glucose (1.426 g, 4.916 mmol, 83%) as a white solid. 1 H-NMR analysis showed a 1:5 α / β mixture. Data for this compound can be found in Bucher et al., Angew. Chem. Int. Ed., 2010, 49, 8724-8728.

[0207] Trichloroacetonitrile (4.9 mL, 49.3 mmol, 10 equiv) and DBU (74 μL, 0.493 mmol, 0.1 equiv) were added to a stirred solution of crude 2'-deoxy-3', 4', 6'-tri-O-acetyl-α / β-D-glucose (1.43 g, 4.93 mmol) in anhydrous dichloromethane (60 mL) at 0 ° C. The reaction mixture was stirred at room temperature overnight, and then the volatiles were removed to give crude 2'-deoxy-3', 4', 6'-tri-O-acetyl-α / β-D-pyranose glucopyranosyl trichloroacetimidate (2.14 g, 4.93 mmol, 100%) as an orange oil, which was used without further purification. The data for this compound can be found in Bucher et al., Angew. Chem. Int. Ed., 2010, 49, 8724-8728.

[0208] To a stirred solution of crude 2'-deoxy-3',4',6'-tri-O-acetyl-α / β-D-glucopyranosyl trichloroacetimidate (2.14 g, 4.93 mmol) and geraniol (2.57 mL, 14.85 mmol, 3.0 equiv) in dichloromethane (40 mL) was added TMSOTf (16 μL, 88 μmol) slowly at -78 ° C. The reaction mixture was gradually warmed to room temperature over the next 3 hours, quenched with saturated aqueous NaHCO3 (10 mL), extracted with CH2Cl2 (2x50 mL), washed with 1M aqueous NaOH (20 mL), brine (50 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by silica gel flash column chromatography (hexane / EtOAc 8:2) to give geranyl-3',4',6'-tri-O-acetyl-2'-deoxy-α / β-D-pyranoglucoside (1.01 g, 2.37 mmol, 48%) (α / β mixture) as a pale yellow oil. One major isomer was obtained (Rf = 0.25).

[0209] The obtained triacetylated compounds were characterized by the following parameters:

[0210]

[0211] 1H-NMR (CDCl3, 400MHz): 1.60 (d, J = 1.6, 3H, H3), 1.66 ( d, J = 1.6, 3H, H10), 1.68 ( d, J = 1.6, 3H, H1), 1.75 ( ddd, J = 12.6, 11.4, 9.8, 1H, H12), 2.01 ( s,3H,H17),2.02(s,3H,H17),2.07(s,3H,H17),2.00-2.15(m,4H,H5+H 6),2.27(ddd,J=12.6,5.0,2.0,1H,H12),3.57(ddd,J=9.3,5.1,2.4,1H ,H15),4.11(dd,J=12.1,2.4,1H,H16),4.19(dd,J=11.8,7.1,1H,H9),4.27(ddd,J=11.8,7.1,0.8,1H,H9),4.27(dd,J=12.1,5.0,1H,H16),4. 58(dd,J=9.8,2.0,1H,H11),5.01(dd,J=9.3,9.3,1H,H14),5.01(ddd,J =9.3,9.3,5.0,1H,H13),5.10(m,1H,H4),5.30(tq,J=7.1,1.6,1H,H8).

[0212] 13 C-NMR(100.6MHz,CDCl3):16.4(CH3,C10),17.8(CH3,C3),20,9(CH3,C17),20.9(CH3,C17),2 1.0(CH3,C17),25.8(CH3,C1),26.4(CH2,C5),36.3(CH2,C12),39.7(CH2,C6),62.7(CH2,C16 ),65.2(CH2,C9),69.4(CH,C14),70.9(CH,C13),72.1(CH,C15),97.7(CH,C11),119.4(CH,C8 ),123.9(CH,C8),131.9(C,C2),142.1(C,C7),169.9(C,C18),170.5(C,C18),170.9(C,C18).

[0213] MS (ESI + ]:[C 22 H 34 O8+NH4] + The calculated value = 444.2592; the measured value is 444.2579.

[0214] To a stirred solution of geranyl 3',4',6'-tri-O-acetyl-2-deoxy-α / β-D-pyranoglucoside (470 mg, 1.102 mmol) in anhydrous methanol (10 mL) was added NaOMe (12 mg, 0.220 mmol, 0.2 equiv). The reaction mixture was stirred at room temperature for 3 hours and quenched with 3 drops of AcOH. After removing the volatiles, the residue was purified by silica gel flash short column chromatography (CH2Cl2 / MeOH, 93:7) to give the compound geranyl-2'-deoxy-β-D-pyranoglucoside (255 mg, 0.849 mmol, 77%) as a white solid.

[0215] The obtained deacetylated compounds were characterized by the following parameters:

[0216]

[0217] 1 H-NMR(400MHz, CDCl3):1.55-1.64(m,1H,H12),1.57(d,J=1.3,3H,H3),1.63(d,J=1.3,3H,H1 0),1.65(d,J=1.3,3H,H1),1.97-2.10(m,4H,H5+H6),2.10-2.19(m,1H,H12),3.15(d,J=9.3,1 H,H15),3.45(dd,J=9.3,9.3,1H,H14),3.53-3.66(m,1H,H13),3.75-3.92(m,2H,H16),4.12( dd,J=12.0,7.0,1H,H9),4.25(dd,J=12.0,7.0,1H,H9),4.52(dd,J=9.7,1.9,1H,H11),5.05(t sept.J=6.8,1.3,1H,1H).

[0218] 13 C-NMR(100.6MHz,CDCl3):16.4(CH3,C10),17.7(CH3,C3),25.7(CH3,C1),26.3( CH2,C5),38.8(CH2,C12),39.6(CH2,C6),61.6(CH2,C16),65.3(CH2,C9),71.4(2 x CH,C13+C14),75.7(CH,C15),98.6(CH,C11),119.7(CH,C8),123.8(CH,C8),123.8(CH,C4),131.6(C,C2),141.3(C,C7).

[0219] HRMS (ESI+)[C 16 H 28 O5+Na] + The calculated value = 323.1829. The measured value is 323.1824.

[0220] To a stirred solution of geranyl-2'-deoxy-β-D-pyranoglucopyranoside (124 mg, 0.413 mmol) in MeCN / H2O 9:1 (4 mL) was added benzoquinone (134 mg, 1.239 mmol, 3.0 equiv) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (22 mg, 0.021 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature for 6 hours and adsorbed onto silica gel. The residue was purified by flash column chromatography on silica gel (CH2Cl2 / MeOH 95:5) to give the title compound (67 mg, 0.225 mmol, 54%) as a white solid.

[0221] The obtained title compound was characterized by the following parameters:

[0222] 1 H-NMR (400MHz, CDCl3): 1.59(s,3H,H3),1.67(s,6H,H1+H10),1.97-2.15(m,4H,H5+H6),2.73(dd,J=14.2,9.1,1H,H12),2.82(dd,J=14. 2,2.7,1H,H12),3.30(ddd,J=10.1,4.5,3.1,1H,H15),3.55(d,J=3.1,1H,H14),3.85-3.95(m,1H,H16),3.98-4.05(m,1H,H16),4.17(br d,J=10.1,1H,OH),4.22(dd,J=11.8,7.9,1H,H9),4.35(dd,J=11.8,6.4,1H,H9),4.73(dd,J=9.1,2.7,1H,H11),5.06(t sept,J=6.9,1.5,1H,H4),5.31(tq,J=6.4,1.5,1H,H8).

[0223] 13C-NMR(100.6MHz,CDCl3):16.5(CH3,C10),17.8(CH3,C3),25.8(CH3,C1),26.4(CH2,C5),39.7(CH2,C6),48.8(CH2,C12),62.7(CH2,C16), 65.7(CH2,C9),73.4(CH,C14),76.4(CH,C15),99.3(CH,C11),119.2(CH,C8),123.8(CH,C4),132.0(C,C2),142.4(C,C7),205.9(CO,C13).

[0224] HRMS(ESI+):[C 16 H 26 O5+NH4] + The calculated value = 316.2118; the measured value is 316.2125.

[0225] Example 4 : Preparation of N-((2R,3S,5R,6R)-2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy 5-hydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H-pyran-3-yl)acetamide (geranyl-O-β-D-2'-acetylamide 2'-deoxy-3'-keto-glucopyranoside)

[0226]

[0227] To a stirred solution of commercially available 2-acetylamino-1,3,4,6-tetra-O-acetyl-2-deoxy-D-pyranose glucose (12.63 g, 32.44 mmol) in THF (60 mL) was added piperazine (3.1 g, 35.68 mmol, 1.1 equiv) at room temperature, and the reaction mixture was stirred vigorously overnight. TLC indicated complete consumption of the starting material (EtOAc; Rf = 0.3). The mixture was diluted with EtOAc (400 mL) and washed with 0.5 M aqueous HCl (2 x 100 mL). It was dried over anhydrous Na2SO4 and filtered. The solvent was then removed to give 2-acetylamino-3,4,6-tri-O-acetyl-2-deoxy-D-pyranose glucose (7.58 g, 21.82 mmol, 67%) as a white foam, which was used without further purification.

[0228] To a stirred solution of crude 2-acetylamino-3,4,6-tri-O-acetyl-2-deoxy-D-pyranose (7.42 g, 21.36 mmol) in anhydrous dichloromethane (150 mL) was added trichloroacetonitrile (6.5 mL, 64.1 mmol, 3.0 equiv) and anhydrous potassium carbonate (15.0 g, 107 mmol, 5.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred by (Celite) filtration and removal of volatiles gave crude 2'-acetylamino-3',4',6'-tri-O-acetyl-2'-deoxy-D-pyranose glucopyranosyl trichloroacetimidate (10.06 g, 20.46 mmol, 96%) as a light yellow solid. The data for this compound can be found in Zhang et al., J. Med. Chem., 2019, 62, 7857-7873.

[0229] TMSOTf (16 μL, 88 μmol) was slowly added to a stirred solution of crude 2'-acetylamino-3',4',6'-tri-O-acetyl-2'-deoxy-D-pyranose glucopyranosyl trichloroacetimidate (432 mg, 0.879 mmol) and geraniol (0.456 mL, 2.636 mmol, 3.0 equivalents) in dichloromethane (7 mL) at -20°C. The reaction mixture was stirred at room temperature for 2 hours and quenched with saturated aqueous NaHCO3 solution (10 mL), extracted with CH2Cl2 (2x10 mL), washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the residue was purified by silica gel flash column chromatography (EtOAc) to give geranyl-3',4',6'-tri-O-acetyl-2'-deoxy-2'-acetylamino-β-D-glucopyranoside (273 mg, 0.56 mmol, 65%) as a white solid.

[0230] The obtained compounds were characterized by the following parameters:

[0231]

[0232] 1 H-NMR(400MHz, CDCl3):1.55(s,3H),1.60(s,3H),1.63(s,3H),1.88(s,3H,H1 8),1.97(s,3H,H18),1.97(s,3H,H18),2.02(s,3H,H18),1.95-2.07(m,4H,H5 +H6),3.65(ddd,J=10.0,5.0,2.5,1H),3.80(dt,J=10.2,8.6,1H),4.05-4.25 (m,5H),4.68(d,J=8.4,1H),4.97-5.08(m,2H),5.20-5.30(m,2H,H8),5.83(br s,1H).

[0233] 13C-NMR(100.6MHz, CDCl3):16.3,17.7,20.6,20.6,20.7,23.2,25.7,26.3,39.5,54.7,62. 3,65.1,68.8,71.7,72.5,98.9,119.3,123.7,131.7,141.9,169.4,170.2,170.7,170.8.

[0234] HRMS(ESI + ):[C 24 H 37 NO9+H] + The calculated value = 484.2541; the measured value is 484.2539.

[0235] To a stirred solution of geranyl-3',4',6'-tri-O-acetyl-2'-deoxy-2'-acetylamino-β-D-pyranoglucoside (200 mg, 0.413 mmol) in anhydrous methanol (4 mL) was added NaOMe (2.5 mg, 0.041 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 3 hours and quenched with 2 drops of AcOH. After removing the volatiles, the residue was purified by silica gel flash short column chromatography (EtOAc / hexane 1:1) to give the compound geranyl-2'-deoxy-2'-acetylamino-β-D-pyranoglucoside (148 mg, 0.413 mmol, 100%) as a white solid.

[0236] The obtained compounds were characterized by the following parameters:

[0237]

[0238] 1H-NMR(400MHz,CD3OD):1.60(s,3H,H3),1.66(s,6H,H1+H10),1.96(s,3H,H18),2.0-2.06(m,2H,H6) ,2.06-2.15(m,2H,H5),3.23(ddd,J=9.7,5.8,2.3,1H,H15),3.30(m,1H,H14,3.44(dd,J=10.3,8.5, 1H,H13),3.61(dd,J=10.3,8.5,1H,H12),3.67(dd,J=12.0,5.8,1H,H16),3.87(dd,J=12.0,2.3,1H, H16),4.16(dd,J=12.0,6.2,1H,H9),4.28(dd,J=12.0,8.4,1H,H9),4.43(d,J=8.4,1H,H11),5.09(t sept,J=7.0,1.5,1H,H4),5.28(tq,J=6.2,1.3,1H,H8).

[0239] 13 C-NMR(100.6MHz,CD3OD):16.5(CH3,C10),17.8(CH3,C3),23.0(CH3,C18),25.9(CH,C1),27.5(CH2,C5),40.7(CH2,C6),57.4(CH,C12),62.8(CH2,C16), 66.2(CH2,C9),72.2(CH,C13),76.2(CH,C14),78.0(CH,C15),101.2(CH,C11 ),121.4(CH,C8),125.1(CH,C4),132.5(C,C2),142.0(C,C7),173.7(C,C17).

[0240] HRMS(ESI + )[C 18 H 31 NO6+Na] + The calculated value = 380.2044. The measured value is 380.2048.

[0241] To a stirred solution of geranyl 2'-deoxy-2'-acetamido-β-D-pyranoglucopyranoside (50 mg, 0.140 mmol) in MeCN / H2O 9:1 (1 mL) was added benzoquinone (45 mg, 0.420 mmol, 3.0 equiv) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (7.5 mg, 0.007 mmol, 0.05 equiv). The reaction mixture was stirred at 50 °C for 5 h and adsorbed onto silica gel. The residue was purified by flash column chromatography on silica gel (EtOAc / MeOH 98:2) to give the title compound (22 mg, 0.062 mmol, 44%) as a white solid.

[0242] The obtained title compound was characterized by the following parameters:

[0243] 1 H-NMR(400MHz, CDCl3):1.58(s,3H,H3),1.63(s,3H,H10),1.66(s,3H,H1),1 .97-2.12(m,7H,H5+H6+H18),3.39-3.53(m,1H,H15),3.81-4.01(m,2H,H16), 4.14-4.26(m,1H,H9),4.28-4.36(m,1H,H9),4.42-4.55(m,1H,H14),4.59-4 .78(m,2H,H11+H12),5.06(t,J=6.5,1H,H4),5.26(t,J=6.4,1H,H8),7.08(br s,1H,H19).

[0244] 13 C-NMR(100.6MHz,CDCl3):16.4(CH3,C10),17.8(CH3,C3),22.9(CH3,C18),25.8(CH3,C1),26.5(CH3,C5),39.7(CH2,C6),61.0(CH,C12),61.4(CH2,C16), 66.4(CH2,C9),72.9(CH,C14),75.7(CH,C15),101.5(CH,C11),119.1(CH,C8) ,123.9(CH,C4),131.9(CH,C2),142.7(C,C7),172.1(C,C17),204.7(C,C13).

[0245] HRMS(ESI + )[C 18 H 31 NO6+Na] +The calculated value = 378.1887. The measured value is 378.1885.

[0246] Example 5 : Preparation of (2R,3R,5S,6R)-3,5-dihydroxy-2-(hydroxymethyl)-6-(((1S,2R,5R)-2-(2- Hydroxypropan-2-yl)-5-methylcyclohexyl)-oxy)tetrahydro-4H-pyran-4-one (rac-cis-PMD-O-β-D-3'-one pyranose

[0247]

[0248] A mixture of crude freeze-dried cell-free extracts of cis-PMD (30 mg, 0.17 mmol), UDP-α-D-glucose disodium salt (100 mg, 0.16 mmol) and glycosyltransferase (YjiC) Bacillus licheniformis DSM 13 (100 mg) was diluted with 100 mM tris buffer (5 mL) at pH 7.4 and cultured at 30 ° C / 80 rpm for 2 days. The resulting mixture was washed with hexane (2x20 mL) and then extracted into ethyl acetate (2x20 mL). The ethyl acetate fractions were combined and concentrated by distillation under reduced pressure. p-Benzoquinone (32 mg, 0.30 mmol) and [(2,9-dimethyl-1,10-phenanthroline) Pd (μ-OAc)] 2 (OTf) 2 (3 mg, about 2 mol%) were added to the residue, and the mixture was suspended in acetonitrile (2 mL) and water (0.2 mL) and cultured at 25 ° C / 80 rpm for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using 1:20 methanol / dichloromethane to obtain the title compound (10 mg, 17%) as a colorless transparent oil.

[0249] The obtained title compound was characterized by the following parameters:

[0250] 1 H-NMR (400 MHz, CDCl3): 4.44 (d, J = 8, 1H, H-1), 4.31 (m, 2H, H-4 and H12), 4.26 (dd, J = 8 and 2, 1H, H-6), 4.02 (dd, J = 12 and 3, 1H, 1 x H-9), 3.90 (dd, J = 12 and 5 Hz, 1H, 1 x H-9), 3.37 (brs, 1H, OH), 3.33 (dd, J = 10, 5 and 3, 1H, H-3), 2.12–1.50 (m, 8H, 1 x H-13, 2 x H-14, 2x H-15, 1 x H-16 and 2 x H-17), 1.25 (s, 6H, 3 x H-20 and 3 x H-21) and 0.89 (d, J = 8, 3H, 3 xH19).

[0251] 13C-NMR(100.6MHz, CDCl3):21.9(CH2),22.4(CH3),28.5(CH),29.9(2 x CH3), 34.9(CH2), 41.2(CH2), 50.0(CH), 62.7(CH2), 72.4(C), 72.7(CH), 77.0(CH), 77.4(CH), 81.1(CH), 106.5(CH) and 205.6(C).

[0252] HRMS(ESI + )[C 16 H 28 O7+Na] + The calculated value = 355.1727; the measured value is 355.1727.

[0253] Example 6 : Preparation of (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-((2-((S)-4-methylcyclohexane Hex-3-en-1-yl)prop-2-yl)oxy)tetrahydro-4H-pyran-4-one (S-α-terpineol-O-β-D-3'-ketopyranose Glycosides)

[0254]

[0255] A mixture (100 mg) of crude freeze-dried cell-free extract of (S)-α-pineneol (30 mg, 0.19 mmol), UDP-α-D-glucose disodium salt (100 mg, 0.16 mmol) and glycosyltransferase (YjiC) Bacillus licheniformis DSM 13 (100 mg) was diluted with 100 mM tris buffer (5 mL) at pH 7.4 and cultured at 30°C / 80 rpm for 18 hours. The resulting mixture was washed with hexane (2x20 mL) and then extracted into ethyl acetate (2x20 mL). The ethyl acetate fractions were combined and concentrated by distillation under reduced pressure. To the residue were added p-benzoquinone (32 mg, 0.30 mmol) and [(2,9-dimethyl-1,10-phenanthroline) Pd (μ-OAc)] 2 (OTf) 2 (3 mg, about 2 mol%), the mixture was suspended in acetonitrile (2 mL) and water (0.2 mL), and incubated at 25 ° C. / 80 rpm for 20 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography using 1:10 methanol / dichloromethane to obtain the title compound (27 mg, 44%) as a colorless transparent oil.

[0256] The obtained title compound was characterized by the following parameters:

[0257] 1H-NMR (400 MHz, D4-MeOH): 5.38 (d, J = 3, 1H, H-16), 4.60 (d, J = 8, 1H, H-1), 4.24 (dd, J = 10 and 2, 1H, H-4), 4.08 (dd, J = 8 and 2, 1H, H-6), 3.91 (dd, J = 12 and 2, 1H, 1 x H-10), 3.80 (dd, J = 12 and 5, 1H, 1 x H-10), 3.29 (ddd, J = 10, 5 and 2, 1H, H-3), 2.15-1.65 (m, 6H), 1.30 (m, 1H), 1.65 (brs, 3H, 3 x H-22), 1.27 (s, 3H, 3 x H-20 or 21) and 1.22 (s, 3H, 3 x H-20 or 21).

[0258] 13 C-NMR(100.6MHz,D4-MeOH):23.0(CH3),23.6(CH3),25.0(CH2),25.1(CH3),28.0(CH2),32.1(CH2),45.1 (CH), 62.7(CH2), 73.7(CH), 77.7(CH), 78.5(CH), 81.8(C), 100.2(CH), 121.8(CH), 134.8(C) and 207.6(C).

[0259] HRMS(ESI + )[C 16 H 26 O6+Na] + The calculated value = 337.1622; the measured value is 337.1611.

[0260] Example 7 : Preparation of (2S,3S,5R,6R)-2-(4-allyl-2-methoxyphenoxy)-3,5-dihydroxy-6- (Hydroxymethyl)tetrahydro-4H-pyran-4-one (eugenol-O-β-D-3'-ketopyranoglucoside)

[0261]

[0262] A solution of commercially available 2,3,4,6-tetra-O-acetyl-α-D-pyranose glucopyranose bromide (500 mg, 1.216 mmol) in acetone (4 mL) was added to a 1.0 M LiOH solution (2 mL) of eugenol (0.56 mL, 3.648 mmol, 3.0 equivalents), and the green suspension formed was stirred at room temperature for 2 hours. The completion of the reaction was monitored by TLC (EtOAc / hexane 8:2; Rf=0.25). Acetone was removed and the resulting suspension was extracted with dichloromethane (3x15 mL). The crude product was washed with 10% sodium hydroxide (3x10 mL), water, and dried over anhydrous Na2SO4. After filtering and removing the solvent under reduced pressure, the crude product was purified by flash column chromatography to give tetraacetylated eugenol-α-glucoside (500 mg, 1.01 mmol, 83%) as a white solid.

[0263]

[0264] Data on this compound can be found in Mulkens et al., J. Natural Prod., 1988, 51, 496-498.

[0265] To a stirred solution of protected eugenol glucoside (330 mg, 0.666 mmol) in anhydrous methanol (20 mL) was added NaOMe (7 mg, 0.133 mmol, 0.2 equiv). The reaction mixture was stirred at room temperature for 1 hour and quenched with 2 drops of AcOH. After removing the volatiles, the residue was purified by silica gel flash short column chromatography (CH2Cl2 / MeOH, 9:1) to give eugenol-β-glucoside (172 mg, 0.527 mmol, 79%) as a white solid.

[0266]

[0267] Data for this compound can be found in Vijayakumar et al., Biotechnol. Lett., 2007, 29, 575-584.

[0268] To a stirred solution of unprotected eugenyl glucoside (30 mg, 0.092 mmol) in MeCN / H2O 9:1 (1.5 mL) was added benzoquinone (30 mg, 0.276 mmol, 3.0 equiv) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (5 mg, 0.005 mmol, 0.05 equiv). The reaction mixture was heated at 60 °C for 1 h and adsorbed onto silica. The residue was purified by flash column chromatography on silica gel (CH2Cl2 / MeOH 95:5) to give the title compound (22 mg, 0.068 mmol, 74%) as a white solid.

[0269] The obtained title compound was characterized by the following parameters:

[0270] 1 H-NMR(400.6MHz, CDCl3):1.88(dd,6.7,1.6,2H,H3),3.34-3.41(m,1H,H15),3.72-3.77(m,1H),3 .89(s,3H,H10),3.92(dd,J=11.8,4.2,1H,H16),4.06(dd,J=11.8,2.6,1H,H16),4.39(d,J=9.5,1H ,H14),4.55(d,J=7.5,1H,H12),4.86(d,J=7.5,1H,H11),6.17(dd,J=15.3,6.6,1H,H1),6.35(dd, J=15.3,1.6,1H,H1),6.86(dd,J=8.3,1.8,1H,H9),6.91(d,J=1.8,1H,H5),7.05(d,J=8.3,1H,H8).

[0271] 13 C-NMR (100.1MHz, CDCl3): 18.4 (CH2, C3), 56.0 (CH3, C10), 62.2 (CH2, C16), 72.3 (CH, C14), 76.9 (CH, C12), 77.1 (CH, C15), 104.7 (CH ,C11),110.0(CH,C5),118.6(CH,C9),120.0(CH,C8),125.9(),130.2(),135.4(C,C4),144.3(C,C7),150.4(C,C6),204.8(C,C13).

[0272] HRMS(ESI + ):[C 16 H 20 O7+NH4]+ The calculated value is = 342.1547. The measured value is 342.1544.

[0273] Example 8 : Preparation of (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(5-isopropyl-2-methylbenzene Oxy)tetrahydro-4H-pyran-4-one (carvacrol-O-β-D-3'-ketopyranoglucoside)

[0274]

[0275] A mixture of crude freeze-dried cell-free extract of carvacrol (30 mg, 0.20 mmol), UDP-α-D-glucose disodium salt (100 mg, 0.16 mmol) and glycosyltransferase (YjiC) Bacillus licheniformis DSM 13 (100 mg) was diluted with 100 mM tris buffer (5 mL) at pH 7.4 and cultured at 30°C / 80 rpm for 18 hours. The resulting mixture was washed with hexane (2x20 mL) and then extracted into ethyl acetate (2x20 mL). The ethyl acetate fractions were combined and concentrated by distillation under reduced pressure. p-Benzoquinone (32 mg, 0.30 mmol) and [(2,9-dimethyl-1,10-phenanthroline) Pd(μ-OAc)]2(OTf)2 (3 mg, about 2 mol%) were added to the residue, and the mixture was suspended in acetonitrile (2 mL) and water (0.2 mL) and cultured at 25°C / 80 rpm for 14 days. The reaction was not complete, so further [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (3 mg, about 2 mol%) was added. After another 2 days, the reaction was almost complete, so the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography using 1:10 methanol / dichloromethane to give the title compound (20 mg, 32%) as a colorless transparent oil.

[0276] The obtained title compound was characterized by the following parameters:

[0277] 1H-NMR (400 MHz, D4-MeOH) 6.99-7.08 (m, 2H), 6.85-6.77 (m, 1H), 4.96 (t, J = 8, 1H, H-1), 4.45 (dd, J = 8 and 2, 1H, H-6), 4.36 (dd, J = 10 and 2, 1H, H-4), 3.99 (dd, J = 12 and 2, 1H, 1 x H-9), 3.85 (dd, J = 12 and 5, 1H, 1 x H-9), 3.50 (ddd, J = 10, 5 and 2, 1H, H-3), 2.86 (qq, J = 7, 1H, H-19), 2.26 (s, 1H, 3 x H-18), 1.24 (dd, J = 7 and 2, 3H, 3 x H-20 or H-21) and 1.23 (dd, J=7 and 2,3H, 3 x H-20 or H-21).

[0278] 13 C-NMR(100.6MHz,D4-MeOH)16.04(CH3),24.4(CH3),24.5(CH3),35.2(CH),62.5(CH2),73.7(CH),78.2(C H), 78.4(CH), 104.4(CH), 115.0(CH), 121.7(CH), 126.4(C), 131.5(CH), 149.2(C), 156.9(C) and 206.9(C).

[0279] HRMS(ESI + )[C 16 H 22 O6+NH4] + The calculated value = 328.1755; the measured value is 328.1752.

[0280] Example 9 : Preparation of ((2R,3R,5S,6R)-5-acetoxy-6-(((E)-3,7-dimethyloct-2,6-diene- 1-yl)oxy)-3-hydroxy-4-oxotetrahydro-2H-pyran-2-yl)methyl acetate (2',6'-diacetyl-geranyl-O- β-D-3'-Ketopyranoglucoside)

[0281]

[0282] A mixture of geranyl-β-3'-ketoglucoside (100 mg) prepared according to Example 1 and Pseudomonas cepacia lipase (ENZA-05) (50 mg) was suspended in vinyl acetate (5 mL) and incubated at 32°C / 80 rpm. After 5 days, the mixture was filtered through a celite plug and concentrated by distillation under reduced pressure to give the title compound (0.118 g, 63%) as a pale yellow solid.

[0283] The obtained title compound was characterized by the following parameters:

[0284] 1 H-NMR (400MHz, CDCl3)1.53(d,J=1.1,3H,H3),1.60(d,J=1.1,3H,H1),1.62(d,J=1.1, 3H,H10),1.96-2.07(m,4H,H5+H6),2.05(s,3H,H17),2.13(s,3H,H17),3.36(ddd,J=10 .2,5.5,2.2,1H,H15),4.19(dd,J=10.2,1.6,1H,H14),4.23-4.27(m,2H,H9),4.28(dd, J=12.1,5.5,1H,H16),4.48(dd,J=12.1,2.2,1H,H16),4.58(d,J=8.1,1H,H11),5.00(t sept,J=7.0,1.1,1H,H4),5.17(dd,J=8.1,1.6,1H,H12),5.25(tq,J=7.1,1.2,H8).

[0285] 13 C-NMR(100.6MHz,CDCl3)16.4(CH3,C10),17.8(CH3,C3),20.5(CH3,C17),20.9(CH3, C17),25.8(CH3,C1),26.3(CH2,C5),39.6(CH2,C6),63.2(CH2,C16),65.6(CH2,C9), 73.1(CH,C14),74.5(CH,C15),76.9(CH,C12),99.9(CH,C11),118.8(CH,C18),123.7 (CH,C4),132.0(C,C2),143.1(C,C7),169.4(C,C18),170.8(C,C18),200.6(C,C13).

[0286] HRMS(ESI + )[C 20 H 30 O8+NH4] + The calculated value = 416.2279; the measured value is 416.2276.

[0287] Example 10 : Preparation of ((2R,3R,5S,6S)-5-acetoxy-3-hydroxy-4-oxo-6-phenoxytetrahydro-2H- pyran-2-yl) methyl acetate (2',6'-diacetyl-phenyl-O-β-D-3'-ketopyranoside)

[0288]

[0289] The title compound was prepared by a procedure substantially similar to Example 11 using phenyl-O-β-D-3'-ketopyranoglucoside (prepared as shown in Comparative Example 1).

[0290] The obtained title compound was characterized by the following parameters:

[0291] 1 H-NMR (400MHz, CDCl3): 2.11 (s, 3H, H11), 2.22 (s, 3H, H11), 3.64 (ddd, J = 10.2, 5.9, 2.3,1H,H9),4.34(dd,J=10.2,1.6,1H,H8),4.41(dd,J=12.1,5.9,1H,H10),4.55(d d,J=12.1,2.3,1H,H10),5.19(d,J=8.0,1H,H5),5.52(dd,J=8.0,1.6,1H,H6),7.04 (dd, J = 8.7, 1.0, 2H, H3), 7.11 (tt, J = 7.4, 1.0, 1H, H1), 7.32 (dd, J = 8.6, 7.4, 2H, H2).

[0292] 13 C-NMR (100.6MHz, CDCl3): 20.5 (CH3, C11), 20.9 (CH3, C11), 63.2 (CH2, C10), 73.2 (CH, C8), 74.7 (CH, C9), 77.6 (CH, C6), 1 00.2(CH,C5),117.3(CH,C3),123.9(CH,C1),129.8(CH,C2),156.7(C,C4),169.4(C,C12),170.7(C,C12),199.9(C,C7).

[0293] HRMS(ESI + ):[C 16 H 18 O8+NH4] + The calculated value = 356.1340; the measured value is 356.1341.

[0294] Embodiment 11 : Preparation of ((2R,3R,5S,6S)-3,5-dihydroxy-4-oxo-6-phenoxytetrahydro-2H-pyran-2- Pyridinium methyl hydrogen sulfate (phenyl-O-β-D-3'-keto-6'-sulfate glucopyranoside pyridinium salt)

[0295]

[0296] To a stirred solution of phenyl-O-β-D-3'-ketopyranoglucoside (prepared as described in Comparative Example 1) (10 mg, 0.039 mmol) in D6-DMSO (0.7 mL) was added SO3·py (py represents pyridine) (19 mg, 3 equivalents). After stirring at room temperature for 15 minutes, the solution was analyzed by TLC, showing complete conversion to a single more polar compound.

[0297] Without further treatment, the title compound obtained was characterized by the following parameters:

[0298] 1 H-NMR(DMSO-D6,400.1MHz):3.72(ddd,J=10.2,5.9,1.7,1H,H9),3.89(dd,J=11.1,5.9,1H,H10 ),4.11(dd,J=11.1,1.7,1H,H10),4.12(dd,J=10.2,1.7,1H,H8),4.27(dd,J=7.9,1.7,1H,H6), 5.02(d,J=7.9,1H,H5),7.00(t,J=7.4,1H,H1),7.04(d,J=7.7,2H,H3),7.27(dd,J=7.7,7.4,2H ,H2),8.07(dd,J=7.9,7.3,2H,py),8.59(tt,J=7.9,1.6,1H,py),8.92(dd,J=7.3,1.6,2H,py).

[0299] 13 C-NMR(DMSO-D6,100.6MHz):65.9(CH2,C10),72.8(CH,C8),74.8(CH,C9),77.8(CH,C6),101.4(CH,C5),116.7(CH ,C3),122.7(CH,C1),127.7(CH,py),129.9(CH,C2),142.8(CH,py),146.7(CH,py),157.4(C,C4),205.6(CO,C7).

[0300] HRMS(ESI - ):[C 12 H 14 O9S-H] - The calculated value = 333.0286; the measured value is 333.0280.

[0301] Example 12 : Preparation of (2R,3S,6R)-2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-3,5- Dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (racemic-menthyl-O-β-D-3'-ketopyranoside)

[0302]

[0303] To a solution of 2',3',4',6'-tetra-O-acetyl-D-pyranose glucopyranosyl trichloroacetimidate (0.4 g, 0.81 mmol) prepared as described in Example 2 in anhydrous CH2Cl2 (8 mL) was added (+ / -)-menthol (0.12 g, 0.81 mmol) at 0°C. After 5 minutes, TMSOTf (0.081 mmol) was added and the resulting solution was stirred to 0°C for 2 hours. After that, TLC (EtOAc / hexane 1:2 r.f.=0.6) indicated the consumption of the starting material. The solvent was evaporated in vacuo to give a residue which was subjected to silica gel chromatography (EtOAc / hexane, 1:4 to 1:1, Rf=0.7) to give 200 mg of crude tetraacetylated menthyl-β-glucoside.

[0304] NaOMe (25% methanol solution) (20 μL) was added to a solution of crude tetraacetylated menthyl-β-glucoside (0.200 g, 0.412 mmol) in methanol (5 mL), and the resulting solution was stirred at room temperature for 3 hours. Afterwards, TLC (EtOAc, Rf = 0.9) indicated the consumption of the starting material. The reaction was quenched with Amberlite (ion exchange resin) (acid form) and then filtered. The solvent was evaporated in vacuo to obtain a residue, which was analyzed by silica gel chromatography (EtOAc Rf = 0.1) to obtain 50 mg (2', 3', 4', 6'-tetra-O-acetyl-D-pyranose glucoside trichloroacetimidate two-step total yield 20%) of menthyl-β-pyranose glucoside. The data for this compound can be found in Choi et al., AMB Expr., 2017, 7, 167.

[0305] Menthyl-β-pyranoglucoside (72 mg, 0.23 mmol), p-benzoquinone (74 mg, 0.68 mmol, 3 equiv.) and catalyst [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (6 mg, about 2.5 mol%) were suspended in acetonitrile (6 mL) and water (0.6 mL) and stirred at room temperature for 19 hours. TLC analysis (MeOH / dichloromethane, 1:5) showed the formation of a new spot at Rf=0.7, but it was mainly starting material (Rf=0.5). Further catalyst (15 mg, about 6.25 mol%) was added, and the mixture was stirred for another 4 days. The reaction proceeded further but was still incomplete, so more catalyst (15 mg, about 6.25 mol%) was added, and the mixture was stirred for another 6 days. No starting material remained, so the mixture was concentrated by distillation under reduced pressure and the residue was purified by silica gel chromatography using 1:20 methanol / dichloromethane to give the diastereomeric title compound as a clear colorless oil (10 mg, 17%).

[0306] The obtained title compound was characterized by the following parameters:

[0307] 1 H-NMR (400MHz, D4-MeOH): 4.44 (d, J = 8, 1H), 4.44 (d, J = 8, 1H), 4.35 (m, 1H), 4.33 (m, 1H), 4. 24(d,J=8,1H),4.20(d,J=8,1H),4.03(m,2H),3.90(m,2H),3.52(ddd,J=11,11 and 4,1H),3.45 (ddd,J=11,11and4,,1H),3.30(m,4H),2.32(m,2H),2.12(m,2H),2.02(d,J=m,2H),1.66(m,4 H), 1.35 (m, 4H), 1.00 (m, 2H), 0.93 (m, 6H), 0.91 (m, 6H), 0.81 (d, J = 7, 3H), 0.77 (d, J = 7, 3H).

[0308] HRMS(ESI + ):[C 16 H 28 O6+NH4] + The calculated value = 334.2224; the measured value is 334.2230.

[0309] Comparative Example 1 : Preparation of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-phenoxytetrahydro-4H-pyran-4- Ketone (phenyl-O-β-D-3'-ketopyranoglucoside)

[0310]

[0311] Phenyl-O-β-D-glucopyranoside (purchased from Sigma-Aldrich) (0.3 g, 1.2 mmol) and p-benzoquinone (0.38 g, 3.5 mmol) were suspended in acetonitrile (6.4 mL) and water (0.64 mL) and rapidly stirred at room temperature.

[0312] [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)]2(OTf)2 (0.03 g, 2.5 mol%) was added and stirring was continued for 18 hours. 1:5 MeOH / dichloromethane was used as the eluent and 10% concentrated sulfuric acid in ethanol was used for plate color development. Then, it was heated strongly and TLC analysis was carried out on silica gel. The results showed that all the raw materials had been converted into products. The mixture was concentrated by vacuum distillation and purified by silica gel chromatography, using 3:1 ethyl acetate / hexane as the eluent to remove non-polar UV active impurities, and then eluted with 3:1 ethyl acetate / hexane to obtain 0.186 g (52% yield) of the title compound as a colorless transparent oil.

[0313] The obtained title compound was characterized by the following parameters:

[0314] Rf = 0.5 (1:5 MeOH / dichloromethane);

[0315] 1 H-NMR (400MHz, DMSO-d6): 3.49(dd,J=9.9,4.5,1H),3.60(m,1H),3.75(dd,J=11.8,4.5,1H),4.18(dd,J=9.9,5.6,1H),4.27(m,1H),4.89(br t, J = 4.5, 1H), 5.04 (d, J = 7.9, 1H), 5.48 (d, J = 5.6, 1H), 5.70 (d, J = 6.1, 1H), 6.98-7.09 (m, 3H), 7.31 (t, J = 7.7, 2H).

[0316] 13 C-NMR (100.6MHz, DMSO-d6): 60.6, 72.1, 76.4, 76, 7, 101, 1, 116.3, 122.3, 129.6, 157.0, 205.9.

[0317] HRMS(ESI+):[C 12 H 14 O6+NH4] + The calculated value is 272.1129. The measured value is 272.1136.

[0318] Comparative Example 2 : Preparation of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H- Pyran-4-one (4-nitrophenyl-O-β-D-3'-ketopyranoglucoside)

[0319]

[0320] The title compound was prepared using 4-nitrophenyl-O-β-D-glucopyranoside (available from Sigma-Aldrich) in substantially the same manner as in Comparative Example 1. Data for this compound can be found in Sedmera et al., Tetrahedron Lett., 2004, 45, 8677-8680.

[0321] Comparative Example 3: Preparation of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H- Pyran-4-one (4-nitrophenyl-O-α-D-3'-ketopyranoglucoside)

[0322]

[0323] The title compound was prepared using 4-nitrophenyl-O-α-D-glucopyranoside (available from Sigma-Aldrich) in substantially the same manner as in Comparative Example 1. Data for this compound can be found in Takeuchi et al., J. Biochem., 1985, 98, 1631-1638.

[0324] Comparative Example 4 : Preparation of (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran- 4-Keto(methyl-O-β-D-3'-ketopyranoglucoside)

[0325]

[0326] The title compound was prepared using methyl-O-β-D-pyranoglucoside (purchased from Sigma-Aldrich) in a manner substantially similar to that of Comparative Example 1. The data for this compound can be found at et al., Angew. Chem. Int. Ed., 2013, 52, 7809-7812.

[0327] Comparative Example 5 : Preparation of (2R,3R,5R,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran- 4-Keto(methyl-O-α-D-3'-ketopyranoglucoside)

[0328]

[0329] The title compound was prepared using methyl-O-α-D-mannopyranoside (purchased from Sigma-Aldrich) in a manner substantially similar to Comparative Example 1. The data for this compound can be found in Chung et al., ACS Catal., 2016, 6, 4653-4659.

[0330] Comparative Example 6 : Preparation of methyl (2S, 3R, 5S, 6S)-3,5-dihydroxy-6-methoxy-4-oxotetrahydro-2H-pyran- 2-Carboxylate (methyl-O-β-D-3'-keto glucuronide methyl ester)

[0331]

[0332] Methyl-α-D-pyranoglucoside (purchased from Sigma-Aldrich) (1.0 g, 5.1 mmol) was dissolved in acetonitrile (10 mL) and water (10 mL), and the stirred solution was cooled to 0 ° C. 2,2,6,6-tetramethylpiperidinyl 1-oxyl (TEMPO) (0.24 g, 1.5 mmol), iodobenzene diacetate (3.6 g, 11.2 mmol) and sodium bicarbonate (0.43 g, 5.1 mmol) were added. After 1 hour, the mixture was warmed to room temperature and stirred overnight. Ethanol (10 mL) was added and the solvent was removed by vacuum distillation. The residue was dissolved in water (10 mL), washed with ethyl acetate (2×10 mL), and the aqueous portion was concentrated by vacuum distillation to obtain a crude sodium salt of methyl-α-D-glucuronide (1.40 g) as a white solid. The data for this compound can be found in Lu et al., Molecules, 2016, 21, 1301.

[0333] The sodium salt of crude methyl-α-D-glucuronide (0.165 g) was suspended in methanol (3 mL), 3 drops of concentrated sulfuric acid were added, and the mixture was stirred overnight at 70° C. The mixture was then cooled, quenched with solid sodium bicarbonate, filtered through celite, and the filtrate was concentrated by distillation under reduced pressure to give crude methyl-α-D-glucuronide methyl ester (0.209 g).

[0334] The title compound was prepared using crude methyl-α-D-glucuronide in a substantially similar manner to Comparative Example 1, and was prepared from methyl-α-pyranoglucoside in 3 steps with a yield of 52%. The data for this compound can be found in Eisink et al., ACS Catal., 2017, 7, 1438-1445.

[0335] Example 13 : At room temperature and different pH values, the β-3'-ketopyranoglucoside vs β-pyranoglucoside The electron-deficient para-substituted aromatic alcohol-p-nitrophenol is released from the aqueous solution of glycosides

[0336] 4-Nitrophenyl-O-β-D-3′-ketopyranoglucoside prepared in Comparative Example 2.

[0337] In this example, 4-nitrophenyl-O-β-D-3′-ketopyranoside and 4-nitrophenyl-O-β-D-pyranoside were used as model compounds to determine the release rate of aromatic alcohol (4-nitrophenol) under different conditions.

[0338] The release rate of 4-nitrophenol from (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H-pyran-4-one (4-nitrophenyl-O-β-D-3'-ketopyranoside) in 0.1 M deuterated phosphate buffer at different pH values ​​containing 10% D6-DMSO or in water containing 10% D6-DMSO was measured at room temperature and compared with that of (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (p-nitrophenyl-O-β-D-glucopyranoside).

[0339] 1 M sodium dihydrogen phosphate and sodium hydrogen phosphate stock solutions were prepared in deuterated water (D2O). 25 mg of 4-nitrophenyl-O-β-D-3'-ketopyranoside (substrate A), 25 mg of 4-nitrophenyl-O-β-D-pyranoside (substrate B) were prepared in 0.5 mL of D6-DMSO, and a stock solution of 11 mg of 4-nitrophenol in the same volume of D6-DMSO was used for visual comparison.

[0340] Solutions of pH 4.5, 5.8, 7.4 and 9.5 were prepared by diluting the appropriate individual phosphate stock solutions or mixtures of phosphate stock solutions to 0.1 M using a calibrated pH meter.

[0341] To 10 parallel reaction vials, add 0.05 mL of one of the glycoside substrate stock solutions in D6-DMSO, 0.5 mL of the appropriate deuterated buffer solution or 0.5 mL of water, which are listed in Table 1 below. The reaction vials were allowed to stand at room temperature, and the color of the solution observed by the naked eye was recorded and compared with the color of the authentic 4-nitrophenol solution diluted in the same manner, as shown in Table 1:

[0342] Table I

[0343]

[0344]

[0345] +++++ = color intensity is the same as that observed for 4-nitrophenyl solution at the same pH, indicating complete reaction - = no color observed

[0346] -

[0347] After approximately 26 hours, reactions 2 to 5 were carried out using a 400 MHz instrument with 128 scans. 1H-NMR analysis. By observing the aromatic signal, reaction 2 contained only starting material, reaction 3 contained a mixture of starting material and 4-nitrophenol, and reactions 4 and 5 were almost entirely 4-nitrophenol with only trace amounts of starting material. Due to the different extent of ionization, changes in the 4-nitrophenol signal in solutions with different pH values ​​were observed and compared with 4-nitrophenol solutions prepared at the same pH and spiked experiments.

[0348] The experiments clearly showed that the degradation rate of 4-nitrophenyl-O-β-D-3'-ketopyranoside in 0.5 mL of aqueous solution under physiologically relevant conditions can be adjusted from no release at low pH to delivery of several μg of 4-nitrophenol per minute by changing the pH of the solution, a concentration that is relevant for anthelmintic applications and which would translate into a release of 4-nitrophenol per cm when 0.5 mL of the aqueous formulation is applied. 2 In addition, the corresponding glucopyranoside, 4-nitrophenyl-O-β-D-glucopyranoside, released almost no 4-nitrophenol under the same conditions.

[0349] Embodiment 14 : At 32℃ and different pH values, the rich Electron-containing ortho- and para-disubstituted aromatic alcohols - eugenol (anthelmintic alcohol)

[0350] Eugenol-β-3'-ketopyranoside prepared in Example 7.

[0351] In this example, the rate of release of eugenol from solutions of (2S,3S,5R,6R)-2-(4-allyl-2-methoxyphenoxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (eugenyl-O-β-D-3'-ketopyranoglucopyranoside) in 0.1 M deuterated phosphate buffer containing 33% D6-DMSO at different pH values ​​was measured.

[0352] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0353] Prepare a 15 mg eugenol-O-β-D-3'-keto-glucoside stock solution in 1.0 mL D6-DMSO.

[0354] To three parallel reaction bottles shown in the following reaction table, 0.20 mL of D6-DMSO solution of glycoside substrate, 0.40 mL of 0.1 M phosphate buffer solution at low or high pH in D2O, or 0.40 mL of D2O were added, and the mixture was incubated with shaking at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table II:

[0355] Table II

[0356]

[0357] NR = Not Tested

[0358] * The signal of 6.77 ppm (free eugenol) increased after the reaction relative to the signal of 6.91 ppm (starting material).

[0359] At 32 °C, eugenol-O-β-D-3'-keto-glucopyranoside was only slowly degraded at pH 5.8, but the release rate of eugenol was significantly higher at pH 7.4. This scenario suggests that, in addition to electron-deficient aromatic derivatives, alcohols can be released from electron-rich ortho- and para-disubstituted aromatic-O-β-D-3'-keto-glucopyranoside at physiological temperature and pH.

[0360] Embodiment 15 : At 32℃ and different pH values, the rich Electron-containing ortho- and meta-disubstituted aromatic alcohols - carvacrol (anthelmintic alcohol)

[0361] Carvacrol-β-3'-ketopyranoside prepared in Example 8.

[0362] In this example, the rate of release of carvacrol from solutions of ((2R,3R,5S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(5-isopropyl-2-methylphenoxy)tetrahydro-4H-pyran-4-one (carvacrol-O-β-D-3'-ketopyranoglucopyranoside) in 0.1 M deuterated phosphate buffer containing 20% ​​D6-DMSO at different pH values ​​was measured.

[0363] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0364] Prepare a 15 mg stock solution of carvacrol-O-β-D-3'-keto-glucoside in 1.0 mL D6-DMSO.

[0365] To two parallel reaction bottles shown in the following reaction table, 0.20 mL of D6-DMSO solution of glycoside substrate and 0.50 mL of 0.1 M phosphate buffer solution or D2O at low or high pH in D2O were added, and the mixture was incubated with shaking at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table III:

[0366] Table III

[0367]

[0368] * Relative to the singlet at 2.08 ppm, the singlet at 1.99 ppm increased after the reaction.

[0369] At 32° C., carvacrol-O-β-D-3′-ketopyranoside degraded only slowly at pH 5.8, but the rate of carvacrol release was significantly higher at pH 7.4. This example shows that, in addition to electron-deficient and electron-rich ortho- and para-disubstituted aromatic derivatives, alcohols can be released from electron-rich ortho- and meta-disubstituted aromatic-O-β-D-3′-ketopyranoside at physiological temperature and pH.

[0370] Example 16 : The olefins were released from aqueous solutions of β-3'-ketopyranoglucoside at 37°C and different pH values. Propyl-Geraniol (Anthelmintic Alcohol)

[0371] Geranyl-β-3'-ketopyranoside prepared in Example 1.

[0372] In this example, the release rate of geraniol from (2R,3S,6R)-2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-O-β-D-3'-ketopyranoglucopyranoside) in 0.1 M deuterated phosphate buffer at different pH values ​​containing 10% D6-DMSO or in D2O containing 10% D6-DMSO was determined at 37°C in the presence and absence of fresh skin cleansing solution.

[0373] Prepare 1 M sodium phosphate monobasic and sodium phosphate dibasic stock solutions in deuterated water (D2O).

[0374] Prepare a 25 mg geranyl-O-β-D-3'-keto glucoside stock solution in 0.5 mL D6-DMSO.

[0375] In a typical experiment, the samples were collected by using absorbent cotton gauze (5x5cm) soaked in D2O (12.5mL) for 1 minute. 2 ) rubbed the 25cm of the human volunteer vigorously 2 Cheek skin area, then prepare a stock solution of fresh skin wash suspension by resuspending the gauze in the D2O solution, shaking quickly, and removing the gauze after squeezing out as much liquid as possible with a spatula.

[0376] 1 M stock solution phosphate buffers at pH 5.7 and 7.0 were prepared by mixing 1 M phosphate stock solutions appropriately to the appropriate pH value, which was determined using a calibrated pH meter.

[0377] Half of each buffer stock solution was diluted 10-fold with D2O and the other half was diluted with the above skin cleansing stock solution to obtain 0.1 M phosphate buffer with a final pH of 5.7 in D2O, 0.1 M phosphate buffer with a final pH of 7.0 in D2O, 0.1 M phosphate buffer with a final pH of 5.7 in skin cleansing solution, and 0.1 M phosphate buffer with a final pH of 7.0 in skin cleansing solution.

[0378] To three parallel reaction bottles shown in the following reaction table, 0.45 mL of a 0.1 M phosphate buffer solution at a low or high pH in D2O, or 0.45 mL of a 0.1 M phosphate buffer solution at a low or high pH in a skin cleanser, was added, followed by the addition of 0.05 mL of a D6-DMSO solution of a glycoside substrate, and the mixture was incubated at 37°C with shaking. After the time shown in the following table, the reaction was performed by a 400 MHz instrument. 1 H-NMR, using 128 scans, analyzed the mixture. The results are shown in Table IV:

[0379] Table IV

[0380]

[0381] * The multiplet at 1.71 ppm increased after the reaction relative to the singlet at 1.67 ppm. Due to peak overlap, the relative heights were compared to a true mixture of geranyl-O-β-D-3'-ketopyranoside and geraniol.

[0382] At 37°C, geranyl-β-3'-keto-glucopyranoside was only slowly degraded at pH 5.8, but the release rate of geraniol was significantly higher at pH 7.4 and remained unchanged in the presence or absence of skin cleansing solution. This example shows that, in addition to the aryl derivatives, alcohols can be released from allyl-O-β-D-3'-keto-glucopyranoside at physiological temperature and pH.

[0383] Embodiment 17 : Allyl-geraniol (dried from β-3'-ketopyranoglucoside) is released from its higher concentration Insect alcohol)

[0384] Geranyl-β-3'-ketopyranoside prepared in Example 1.

[0385] In this example, the release rate of geraniol from a 40 mg / mL suspension of (2R,3S,6R)-2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-O-β-D-3'-ketopyranoglucoside) in 0.1 M deuterated phosphate buffer at pH 7 containing 10% DMSO was measured at 37°C.

[0386] In a stoppered glass vial, geranyl-O-β-D-3'-ketopyranoside (20 mg) was dissolved in D6-DMSO (0.05 mL), then diluted with 0.1 M sodium phosphate buffer (0.45 mL) at pH 7.0, and the resulting suspension was incubated with shaking at 37°C. After 3 days, the mixture was transferred to an NMR tube, at which time a strong odor of geraniol was detected. The mixture was measured using a 400 MHz instrument. 1 H-NMR analysis showed that the geraniol conversion was the same as that observed for the more dilute sample in reaction 2 of Example 16 (about 50%). NMR data showed that the conversion increased significantly further after this time point, but the conversion data could not be accurately quantified.

[0387] Embodiment 18 : Release of primary fatty alcohol from its β-3'-ketopyranoglucoside at 32°C and different pH values Picaridin (anthelmintic alcohol)

[0388] Picaridin-β-3'-ketopyranoside prepared in Example 2.

[0389] In this example, the release rate of picaridin from aqueous buffered solutions of sec-butyl-2-(2-(((2R,3S,5R,6R)-3,5-dihydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H-pyran-2-yl)oxy)ethyl)piperidine-1-carboxylate (picaridin-O-β-D-3'-ketopyranoglucopyranoside) at different pH was measured.

[0390] 250 μM picaridin-O-β-D-3'-ketopyranoglucoside was dissolved in 0.05 M K2HPO4 0.95 M / KH2PO 4,Parallel mixtures in a buffer solution of pH = 8.5 (reaction 1), a buffer solution of 0.17M Na2HPO4 / 0.02M citric acid, pH = 7 (reaction 2), a buffer solution of 0.12M Na2HPO4 / 0.04M citric acid, pH = 5.8 (reaction 3), and a buffer solution of 0.04M sodium citrate / 0.06M citric acid, pH = 4 (reaction 4) were incubated at 32° C. 10 μl aliquots were taken regularly, diluted with MeCN (90 μl), and analyzed by UPLC using the following instrument and conditions:

[0391] Stationary phase: Acquity BEH C18 1,7μm (2.1mm x 50mm) (Waters Corporation)

[0392] Mobile phase: A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid

[0393] The chromatographic equipment used was UPLC QSM Waters Acquity.

[0394] Gradient conditions:

[0395] Time (minutes) A B 0 95％ 5％ 0.1 95％ 5％ 1 0％ 100％ 2.5 0％ 100％ 2.6 95％ 5％ 3 95％ 5％

[0396] Flow rate (ml / min) 0.6

[0397] Source temperature (℃) 150

[0398] Desolventization temperature (℃) 500

[0399] Cone air flow (L / Hr) 50

[0400] Desolvation gas flow rate (L / Hr) 900

[0401] Target column temperature 35°C

[0402] Target sample temperature 8.0℃

[0403] The release amount of Picaridin at different time points is shown in Table V:

[0404] Table V

[0405]

[0406] At 32°C, the degradation rate of picaridin-O-β-D-3'-keto-pyranoside increases between pH 4 and pH 8.5. This example shows that, in addition to aryl and allylic derivatives, alcohols can be released from primary alkyl-O-β-D-3'-keto-pyranoside containing heterocyclic functional groups at physiological temperature and pH.

[0407] Embodiment 19 : Lipid release from its β-3'-ketopyranoglucoside aqueous solution at 32℃ and different pH values Fatty secondary alcohol-cis PMD (anthelmintic alcohol)

[0408] Cis-PMD-O-β-D-3'-ketopyranoglucoside prepared in Example 5.

[0409] In this example, the rate of release of cis-PMD from (2R,3R,5S)-3,5-dihydroxy-2-(hydroxymethyl)-6-((5-(2-hydroxypropan-2-yl)-2-methylcyclohexyl)oxy)tetrahydro-4H-pyran-4-one (cis-PMD-O-β-D-3'-ketopyranoglucoside) in 0.1 M deuterated phosphate buffer containing 33% D6-DMSO at different pH values ​​was measured.

[0410] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0411] Prepare a 10 mg cis-PMD-O-β-D-3'-keto-glucoside stock solution in 0.5 mL D6-DMSO.

[0412] To two parallel reaction bottles shown in the following reaction table, 0.20 mL of D6-DMSO solution of glycoside substrate and 0.50 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was shaken and incubated at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table VI:

[0413] Table VI

[0414]

[0415] * Relative to the doublet at 4.25 ppm (starting material), the reaction was followed by integration of a singlet at 1.29 ppm (starting material + free PMD).

[0416] At 32°C, cis-PMD-O-β-D-3'-ketopyranoside was only slowly degraded at pH 5.8, but the release rate of cis-PMD was significantly higher at pH 7.4. This example shows that, in addition to aryl, allylic and primary alkyl derivatives, alcohols can be released from secondary alkyl-O-β-D-3'-ketopyranoside at physiological temperature and pH.

[0417] Embodiment 20 : Lipid release from its β-3'-ketopyranoglucoside aqueous solution at 32℃ and different pH values Aliphatic tertiary alcohol-(S)-α-terpineol

[0418] (S)-α-terpineol-β-3′-ketopyranoglucoside prepared in Example 6.

[0419] In this example, the rate of release of (S)-α-terpineol from (2R,3R,5S)-3,5-dihydroxy-2-(hydroxymethyl)-6-((5-(2-hydroxypropan-2-yl)-2-methylcyclohexyl)oxy)tetrahydro-4H-pyran-4-one ((S)-α-terpineol-O-β-D-3'-ketopyranoglucopyranoside) in 0.1 M deuterated phosphate buffer containing 33% D6-DMSO at different pH values ​​was measured.

[0420] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0421] Prepare a 10 mg (S)-α-terpineol-O-β-D-3'-keto glucoside stock solution in 0.5 mL D6-DMSO.

[0422] 0.20 mL of D6-DMSO solution of glycoside substrate and 0.40 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added to two parallel reaction bottles shown in the following reaction table, and the mixture was shaken and incubated at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table VII:

[0423] Table VII

[0424]

[0425]

[0426] * Relative to the multiplet at 3.26 ppm (starting material), after the reaction the multiplet at 1.50 ppm (starting material + free terpineol) was integrated.

[0427] At 32°C, (S)-α-terpineol-O-β-D-3'-ketopyranoside was only slowly degraded at pH 5.8, but the release rate of (S)-α-terpineol was significantly higher at pH 7.4. This suggests that, in addition to aryl, allylic, primary alkyl, and secondary alkyl derivatives, alcohols can be released from tertiary alkyl-O-β-D-3'-ketopyranoside at physiological temperature and pH.

[0428] Embodiment 21 : At room temperature, 37℃ and different pH conditions, the α-3'-ketopyranoglucoside and α-pyranoglucoside Aliphatic primary alcohol-methanol released from aqueous solution of glucopyranosyl ...

[0429] Methyl-β-3'-ketopyranoside prepared in Comparative Example 4.

[0430] In this example, methyl-O-α-D-3′-ketopyranoside and methyl-O-α-D-pyranoside were used as model compounds to determine the release rate of fatty alcohol (methanol) under different conditions.

[0431] Prepare 1 M stock solutions of sodium dihydrogen phosphate and sodium hydrogen phosphate in deuterated water (D2O). Prepare 15 mg of each of methyl-O-α-D-3'-keto-glucopyranoside (substrate A) and methyl-O-α-D-glucopyranoside (substrate B) by dissolving in 0.3 mL of D6-DMSO.

[0432] Solutions of pH 4.5, 5.8 and 7.4 were prepared by diluting the appropriate individual phosphate stock solutions or mixtures of phosphate stock solutions to 0.1 M using a calibrated pH meter.

[0433] To eight parallel reaction bottles, 0.05 mL of one of the glycoside substrates in D6-DMSO solution, 0.5 mL of the appropriate deuterated buffer solution or 0.5 mL of water were added and the mixture was subjected to 128 scans using a 400 MHz instrument. 1 H-NMR analysis to obtain initial time readings.

[0434] After standing at room temperature for a further 22 hours, the mixture was analyzed in the same manner.

[0435] The mixture was then incubated with shaking at 37°C for 44 hours and analyzed in the same manner. At this point, only reaction 4 showed any changes, so the other reactions were discarded and reaction 4 was analyzed in the same manner after a further 72 hours.

[0436] Table VIII shows these results:

[0437] Table VIII

[0438]

[0439]

[0440] * Percent increase of the singlet at 3.35 ppm (3 protons of MeOH) after reactions 1 to 4 relative to the doublet at 5.20 ppm (anomeric proton of methyl-O-α-D-3'ketopyranoside). Correction was made for the 3% MeOH determined to be present in the starting material using the same method.

[0441] *Percent increase of the singlet at 3.35 ppm (3 protons of MeOH) after reactions 5 to 8 relative to the doublet at 3.88 ppm (protons of methyl-O-α-D-pyranoglucopyranoside). Correction was made using the same method for the 7% MeOH determined to be present in the starting material.

[0442] NR = Not Tested

[0443] At 37°C, methyl-O-α-D-glucopyranoside remained stable in the pH range tested and in water, while methyl-O-α-D-3'-keto-glucopyranoside was stable at pH 4.5 and 5.8, but produced methanol very slowly at pH 7.4. This example shows that, in addition to primary aliphatic-O-β-D-3'-keto-glucopyranoside, alcohols can be released from simple primary aliphatic-O-α-D-3'-keto-glucopyranoside at physiological temperature and pH, but simple primary alkyl-O-α-D-glucopyranoside remains stable and does not release alcohol.

[0444] Embodiment 22 : Release rate of p-nitrophenol from aqueous solutions of β- and α-3'-ketopyranoglucoside at 32°C Rate Comparison

[0445] The materials were those prepared in Comparative Examples 2 and 3.

[0446] In this example, the competitive release rate of p-nitrophenol from (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H-pyran-4-one (4-nitrophenyl-O-β-D-3'-ketopyranoside) and (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H-pyran-4-one (4-nitrophenyl-O-α-D-3'-ketopyranoside) in approximately equimolar solutions in D2O containing 1.5% D6-DMSO or in 0.1 M deuterated phosphate buffer at pH 5.8 containing 1.5% D6-DMSO or in D2O was determined.

[0447] Solutions containing approximately 2 mg each of 4-nitrophenyl-O-β-D-3'-ketopyranoside and 4-nitrophenyl-O-α-D-3'-ketopyranoside were prepared in 1 mL of D2O containing 3.3% v / v D6-DMSO. For given reactions 1 and 2, two 0.375 mL portions of the resulting solutions were added with D2O (0.5 mL) or 0.1 M sodium phosphate buffer at pH 5.8 (0.5 mL). Directly after preparation, the mixture was stirred for 2 h. 1 The resulting mixture was analyzed by H NMR and then incubated at 32 °C / 80 rpm and at the recorded time points by 1H NMR analysis was performed periodically.

[0448] The changes in the integrated ratio of the anomeric protons of each ketoglucoside and the ratio of the sum of the anomeric protons to the anomeric protons of each ketoglucoside over time are shown in Table IX:

[0449] Table IX

[0450]

[0451] 1 1 Ratio of the integrated doublet at 6.01 ppm to the integrated doublet at 5.19 ppm in the H NMR spectrum.

[0452] 2 At each time point 1 H NMR spectrum: ratio of the sum of the integrated signals at 8.09, 8.02, 7.11, and 6.81 ppm to the integrated doublet at 6.01 ppm.

[0453] 3 At each time point 1 H NMR spectrum, ratio of the sum of the integrated signals at 8.09, 8.02, 7.11, and 6.81 ppm to the integrated doublet at 5.19 ppm.

[0454] At 32°C, both 4-nitrophenyl-O-α-D-ketopyranoglucoside and O-β-D-ketopyranoglucoside underwent slow degradation, with α-ketopyranoglucoside degrading about 6 times faster than β-ketopyranoglucoside. Both ketopyranoglucosides remained stable in D2O. This example shows that at physiological temperature and pH, the rate of alcohol release from α-3'-ketopyranoglucoside is faster than that from β-3'-ketopyranoglucoside.

[0455] Embodiment 23 : At 32℃ and different pH conditions, the α-3'-ketomannoside vs α-mannopyranose Aliphatic primary alcohol-methanol released from aqueous glycoside solution

[0456] Methyl-O-α-D-3′-ketomannopyranoside prepared in Comparative Example 5.

[0457] In this example, the rate of methanol release from (2R,3R,5R,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran-4-one (methyl-O-α-D-3'-ketomannopyranoside) vs. (2R,3S,4S,5S,6S)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triol (methyl-O-α-D-mannopyranoside) in D2O containing 15% D6-DMSO or in 0.1 M deuterated phosphate buffer containing 15% D6-DMSO at different pH or in D2O was measured.

[0458] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0459] Prepare 25 mg of methyl-O-α-D-3'-ketomannoside stock solution in 1.0 mL of D6-DMSO.

[0460] To five parallel reaction bottles shown in the following reaction table, 0.10 mL of a D6-DMSO solution of the glycoside substrate and 0.50 mL of a 0.1 M phosphate buffer solution at a low or high pH in D2O were added, and the mixture was incubated with shaking at 33°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table X:

[0461] Table X

[0462]

[0463] NR = Not Tested

[0464] * After reactions 1 to 3, the signal of the starting material (3-ketoglycoside) at 3.35 ppm was reduced relative to D6-DMSO. After reactions 4 and 5, the integration of the singlet peak of methanol formed at 3.38 ppm was compared to the integration of the anomeric signal of the starting material at 4.75 ppm.

[0465] At 32°C, methyl-O-α-D-mannopyranoside remained stable in water at pH 7.4, while methyl-O-α-D-3'-ketomannopyranoside produced methanol at both pH 5.8 and pH 7.4. This example shows that, in addition to primary aliphatic-O-α-D-3'-ketomannopyranoside and primary aliphatic-O-β-D-3'-ketomannopyranoside, alcohol can be released from simple primary aliphatic-O-α-D-3'-ketomannopyranoside at physiological temperature and pH, but simple primary alkyl-O-α-D-mannopyranoside remains stable and does not release alcohol.

[0466] Embodiment 24 : The results of the study on the bioavailability of 3'-keto-2'-deoxypyranoglucoside and 2'-deoxypyranoglucoside under different pH conditions at 32℃ were summarized. Allyl alcohol-geraniol released from aqueous solution of oxypyranoglucoside

[0467] Geranyl-3'-keto-2'-deoxyglucopyranoside prepared in Example 3.

[0468] In this example, the rate of release of geraniol from solutions of (2R,3R)-6-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-3-hydroxy-2-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-3'-keto-2'-deoxypyranoglucoside) in 0.1 M deuterated phosphate buffer containing 50% D6-DMSO at different pH values ​​was measured.

[0469] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0470] Prepare a 15 mg geraniol-O-β-D-3'-keto-2'-deoxyglucopyranoside stock solution in 1.5 mL D6-DMSO.

[0471] To the four parallel reaction bottles shown in the following reaction table, 0.35 mL of D6-DMSO solution of glycoside substrate and 0.35 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was shaken and incubated at 33°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table XI:

[0472] Table XI

[0473]

[0474] NR = Not Tested

[0475] * The doublet at 3.91 ppm (geraniol) increased after the reaction relative to the doublet at 3.98 ppm (starting material).

[0476] At 32°C, geranyl-O-2'-deoxyglucopyranoside remained stable at pH 7.4, while geranyl-3'-keto-2'-deoxyglucopyranoside produced geraniol at both pH 5.8 and pH 7.4. This example shows that, at physiological temperature and pH, in addition to 3'-keto-glucopyranoside and 3'-keto-mannopyranoside, 3'-keto-2'-deoxyglucopyranoside can also release alcohol, but 2'-deoxyglucopyranoside remains stable and does not release alcohol. In addition, it was observed that under similar conditions, the rate of geraniol release from geranyl-3'-keto-2'-deoxyglucopyranoside was greater than the rate of geraniol release from geranyl-O-β-D-3'-keto-glucopyranoside (Example 17).

[0477] Embodiment 25 : The results of the study on the biosynthesis of β-2'-acetylamino-2'-deoxy-3'-ketopyran Glucoside vs. β-2'-acetylamino-2'-deoxypyranoglucoside releases allyl alcohol-geraniol in aqueous solution

[0478] Geranyl-O-β-D-2'-acetylamino-2'-deoxy-3'-ketopyranoside prepared from Example 4.

[0479] In this example, N-((2R,3S,5R,6R)-2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H-pyran-3-yl)acetamide (geranyl-O-β-D-2'-acetylamino-2'-deoxy-3'-ketopyranoside) was used to characterize the 2-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H-pyran-3-yl)acetamide (geranyl-O-β-D-2'-acetylamino-2'-deoxy-3'-ketopyranoside) vs. The rate of release of geraniol from (E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (geranyl-β-2'-acetylamino-2'-deoxy-pyranoglucopyranoside) in D2O containing 33% D6-DMSO or in 0.1 M deuterated phosphate buffer at different pH values ​​or in D2O was measured.

[0480] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0481] Prepare a 25 mg geranyl-O-β-D-2'-acetylamino-2'-deoxy-3'-keto glucoside stock solution in 1.0 mL D6-DMSO.

[0482] To the four parallel reaction bottles shown in the following reaction table, 0.20 mL of D6-DMSO solution of glycoside substrate and 0.40 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was incubated with shaking at 32°C. After the time shown in the following table, the 400 MHz instrument was used to 1 The mixture was analyzed by H-NMR. The results are shown in Table XII:

[0483] Table XII

[0484]

[0485] NR = Not Tested

[0486] * The doublet at 3.91 ppm (geraniol) increased after the reaction relative to the doublet at 4.15 ppm (starting material). Reaction 4 was monitored by analyzing the formation of the doublet at 4.12 ppm free geraniol (not observed) relative to the doublet at 4.57 ppm (starting material).

[0487] At 32° C., geranyl-β-2'-acetylamino-2'-deoxyglucopyranoside remained stable at pH 7.4, while geranyl-O-β-D-2'-acetylamino-2'-deoxy-3'-keto-glucopyranoside produced geraniol at both pH 5.8 and pH 7.4. This example shows that, at physiological temperature and pH, in addition to 3'-keto-glucopyranoside and 3'-keto-mannopyranoside, 2'-acetylamino-2'-deoxy-3'-keto-glucopyranoside can also release alcohol, but 2'-acetylamino-2'-deoxy-glucopyranoside remains stable and does not release alcohol. Furthermore, it was observed that, under similar conditions, the geraniol release rate of geranyl-O-β-D-2'-acetylamino-2'-deoxy-3'-keto-glucopyranoside was greater than that of geranyl-3'-keto-2'-deoxyglucopyranoside (Example 25) or geranyl-O-β-D-3'-keto-glucopyranoside (Example 17).

[0488] Embodiment 26 : 2',6'-diacetylated β-3'-ketopyranose from β-ketopyranose at 32℃ and different pH values Allyl geraniol

[0489] 2',6'-diacetyl-geranyl-O-β-D-3'-ketopyranoside prepared in Example 9.

[0490] In this example, the rate of release of geraniol from (((2R,3R,5S)-5-acetoxy-6-(((E)-3,7-dimethyloct-2,6-dien-1-yl)oxy)-3-hydroxy-4-oxotetrahydro-2H-pyran-2-yl)methyl acetate (2′,6′-diacetyl-geranyl-O-β-D-3′-ketopyranoglucopyranoside) in 0.1 M deuterated phosphate buffer containing 50% D6-DMSO at different pH values ​​was measured.

[0491] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0492] Prepare a 15 mg 2',6'-diacetyl-geranyl-O-β-D-3'-keto-glucopyranoside stock solution in 1.5 mL D6-DMSO.

[0493] To two parallel reaction bottles shown in the following reaction table, 0.35 mL of D6-DMSO solution of glycoside substrate and 0.35 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was shaken and incubated at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table XIII:

[0494] Table XIII

[0495]

[0496] NR = Not Tested

[0497] * The doublet at 3.91 ppm (geraniol) increased after the reaction relative to the doublet at 4.00 ppm (starting material).

[0498] At 32°C, 2',6'-diacetyl-geranyl-O-β-D-3'-ketopyranoside gave geraniol at both pH 5.8 and pH 7.4. This example shows that, in addition to unprotected 3'-ketopyranoside, alcohols can be released from 2',6' diprotected 3'-ketopyranoside at physiological temperature and pH.

[0499] Embodiment 27 : 2',6'-diacetylated β-3'-ketopyranose from β-ketopyranose at 32℃ and different pH values The aromatic alcohol-phenol is released from the aqueous solution of glycosides

[0500] 2',6'-diacetyl-phenyl-O-β-D-3'-ketopyranoside prepared in Example 10.

[0501] In this example, the rate of release of geraniol from ((2R,3R,5S)-5-acetoxy-3-hydroxy-4-oxo-6-phenoxytetrahydro-2H-pyran-2-yl)methyl acetate (2′,6′-diacetyl-phenyl-O-β-D-3′-ketopyranoglucopyranoside) in 0.1 M deuterated phosphate buffer containing 33% D6-DMSO at different pH values ​​was measured.

[0502] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0503] Prepare a 25 mg 2',6'-diacetyl-phenyl-O-β-D-3'-keto-pyranoglucopyranoside stock solution in 1.0 mL D6-DMSO.

[0504] To three parallel reaction bottles shown in the following reaction table, 0.20 mL of D6-DMSO solution of glycoside substrate and 0.40 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was shaken and incubated at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table XIV:

[0505] Table XIV

[0506]

[0507] NR = Not Tested

[0508] * The triplet at 7.14 ppm (phenol) increased after the reaction relative to the triplet at 7.26 ppm (starting material) (D6-DMSO signal at 2.50 ppm as reference).

[0509] At 32°C, 2',6'-diacetyl-phenyl-O-β-D-3'-ketopyranoside formed phenol at both pH 5.8 and pH 7.4. This example again shows that, in addition to unprotected 3'-ketopyranoside, alcohols can be released from 2',6' diprotected 3'-ketopyranoside at physiological temperature and pH.

[0510] Embodiment 28 : Release from its β-3'-keto glucuronide methyl ester aqueous solution at 32℃ and different pH values Aliphatic primary alcohol - methanol

[0511] From the methyl glucuronide prepared in Comparative Example 6.

[0512] In this example, the rate of methanol release from methyl (2R,3R,5S,6S)-3,5-dihydroxy-6-methoxy-4-oxotetrahydro-2H-pyran-2-carboxylate (methyl-β-3'-keto glucuronide) in D2O containing 10% D6-DMSO or in 0.1 M deuterated phosphate buffer or D2O at different pH values ​​was measured.

[0513] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0514] Prepare a 20 mg methyl-β-3'-keto glucuronide stock solution in 0.25 mL D6-DMSO.

[0515] To two parallel reaction bottles shown in the following reaction table, 0.05 mL of D6-DMSO solution of glycoside substrate and 0.55 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was shaken and incubated at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table XV:

[0516] Table XV

[0517]

[0518] NR = Not Tested

[0519] * The single peak of 3.74 ppm (product methyl ester) increased after the reaction relative to the single peak of 3.79 ppm (starting material).

[0520] At 32° C., methyl-β-3'-keto glucuronide methyl ester formed methanol at both pH 5.8 and pH 7.4. This example shows that alcohol can be released from 3'-keto glucuronide at physiological temperature and pH.

[0521] Embodiment 29 : 6'-sulfated-β-3'-ketopyranoglucoside aqueous solution at 32℃ and different pH values Release of aromatic alcohol-phenol from solution

[0522] Phenyl-O-β-D-3'-keto-6'-sulfate glucopyranoside pyridinium salt prepared in Example 11.

[0523] In this example, the rate of release of phenol from ((2R,3R,5S,6S)-3,5-dihydroxy-4-oxo-6-phenoxytetrahydro-2H-pyran-2-yl)methyl hydrogensulfate pyridinium salt (phenyl-O-β-D-3'-keto-6'-sulfate glucopyranoside pyridinium salt) in 0.1 M deuterated phosphate buffer containing 15% D6-DMSO at different pH values ​​was measured.

[0524] Prepare 0.1 M sodium phosphate monobasic and sodium phosphate dibasic stock buffer solutions at pH 5.8 and 7.4 in deuterated water (D2O).

[0525] Prepare a 20 mg phenyl-O-β-D-3'-keto-6'-sulfate glucopyranoside stock solution in 0.5 mL D6-DMSO.

[0526] To two parallel reaction bottles shown in the following reaction table, 0.10 mL of D6-DMSO solution of glycoside substrate and 0.60 mL of 0.1 M phosphate buffer solution at low or high pH in D2O were added, and the mixture was shaken and incubated at 32°C. After the time shown in the following table, the 400 MHz instrument was used to measure the 1 The mixture was analyzed by H-NMR. The results are shown in Table XVI:

[0527] Table XVI

[0528]

[0529] * The triplet at 7.14 ppm (phenol) increased after the reaction relative to the triplet at 7.26 ppm (starting material).

[0530] At 32°C and pH 7.4, phenyl-O-β-D-3'-keto-6'-sulfate glucopyranoside pyridinium salt yielded phenol. This example shows that alcohol can be released from 6'-sulfate keto-pyranoside at physiological temperature and pH.

[0531] Embodiment 30 : At 37°C and different pH values, in the presence and absence of fresh skin cleansing solution, Comparison of the alcohol release rates of 3'-ketopyranoglucoside in aqueous solution

[0532] In this example, phenyl-O-β-D-3'-keto glucopyranoside, methyl-O-α-D-3'-keto glucopyranoside, phenyl-O-β-D-glucopyranoside, methyl-O-α-D-glucopyranoside and 4-nitrophenyl-O-β-D-glucopyranoside were used as model compounds to determine the release rates of their respective alcohols under different conditions.

[0533] A 1:1 stoichiometric mixture of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-phenoxytetrahydro-4H-pyran-4-one (phenyl-O-β-D-3′-ketopyranoside) or (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran-4-one (methyl-O-α-D-3′-ketopyranoside) and their respective O-glucopyranoside and (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (4-nitrophenyl-O-β-D-glucopyranoside) in the presence and absence of fresh skin wash solution ... of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash solution in the presence of fresh skin wash The competitive rates of release of methanol or phenol and 4-nitrophenol were determined in 0.1 M deuterated phosphate buffer at 5.7 and 7.0.

[0534] Prepare 1 M sodium phosphate monobasic and sodium phosphate dibasic stock solutions in deuterated water (D2O).

[0535] 4-Nitrophenyl-O-β-D-glucopyranoside (50 mg) was dissolved in D6-DMSO (1 mL), and 0.2 mL of the resulting solution was added to 10 mg each of methyl-O-α-D-3'-keto-glucopyranoside, methyl-O-α-D-glucopyranoside, phenyl-O-β-D-3'-keto-glucopyranoside and phenyl-O-β-D-glucopyranoside to obtain substrate stock solutions A, B, C and D, respectively.

[0536] In a typical experiment, the samples were collected by using absorbent cotton gauze (5x5cm) soaked in D2O (12.5mL) for 1 minute. 2 ) rubbed the 25cm of the human volunteer vigorously 2 Cheek skin area, then prepare a stock solution of fresh skin wash suspension by resuspending the gauze in the D2O solution, shaking quickly, and removing the gauze after squeezing out as much liquid as possible with a spatula.

[0537] 1 M stock solution phosphate buffers at pH 5.7 and 7.0 were prepared by mixing 1 M phosphate stock solutions appropriately to the appropriate pH value, which was determined using a calibrated pH meter.

[0538] Half of each buffer stock solution was diluted 10-fold with D2O and the other half was diluted with the above skin cleansing stock solution to obtain 0.1 M phosphate buffer with a final pH of 5.7 in D2O, 0.1 M phosphate buffer with a final pH of 7.0 in D2O, 0.1 M phosphate buffer with a final pH of 5.7 in skin cleansing solution, and 0.1 M phosphate buffer with a final pH of 7.0 in skin cleansing solution.

[0539] To 16 parallel reaction bottles, 0.45 mL of a 0.1 M phosphate buffer solution at low or high pH in D2O, or 0.45 mL of a 0.1 M phosphate buffer solution at low or high pH in a skin cleanser, was added, followed by 0.05 mL of a D6-DMSO solution of one of the glycoside substrates, and the mixture was incubated at 37°C with shaking. After the times indicated in the table below, the mixture was scanned 128 times using a 400 MHz instrument to carry out 1 H-NMR analysis and visual observation of the color, the results are shown in Table XVII:

[0540] Table XVII

[0541]

[0542]

[0543] * The singlet at 3.35 ppm (3 protons of MeOH) increased after reactions 1 to 4 relative to the doublet at 5.20 ppm (anomeric proton of methyl-O-α-D-3'-ketopyranoside). The same method was used to correct for the 3% MeOH determined to be present in the starting material.

[0544] *Singlet at 3.35 ppm (3 protons of MeOH) increases after reactions 5 to 8 relative to the multiplet at 3.95-3.84 ppm. Correction was made for the 7% MeOH determined to be present in the starting material using the same method.

[0545] * Compared to the multiplet at 7.42 ppm (2 aromatic protons of phenyl-O-β-D-3′-ketopyranoglucoside), the singlet at 6.91 ppm (2 aromatic protons of phenol) increased after reactions 9 to 12.

[0546] nr = not tested

[0547] +++++ = same color intensity as observed in p-nitrophenyl solution, indicating complete reaction

[0548] - = No color observed

[0549] The results showed that 3'-keto-glucopyranosides released their respective alcohols at pH 7, in the presence and absence of skin cleansing solutions, but more alcohol was released in the former. In contrast, no reaction was observed for methyl-O-α-D-3'-keto-glucopyranoside at pH 5.7. Phenyl-O-β-D-3'-keto-glucopyranoside reacted more slowly at pH 5.7 than at pH 7 and reacted at the same rate in the presence and absence of skin cleansing solutions. Both methyl and phenyl-OD-glucopyranosides were stable under all conditions tested. 4-Nitrophenyl-O-β-D-glucoside released some 4-nitrophenol at pH 7, generally more in the presence of skin cleansing solutions, but the amount released was so low that no change was detected by NMR.

[0550] In a subsequent experiment, using the same reaction conditions but in the absence of 4-nitrophenyl-O-β-D-glucopyranoside, it was observed that at pH 7, after 72 hours of reaction, the alcohol release rate of methyl-O-α-D-3'-keto-glucopyranoside (substrate A) and phenyl-O-β-D-3'-keto-glucopyranoside (substrate B) in the presence of fresh skin cleansing solution increased slightly compared to in the absence of fresh skin cleansing solution, as shown in Table XVIII:

[0551] Table XVIII

[0552]

[0553] * The singlet at 3.35 ppm (3 protons of MeOH) increased after reactions 1 to 3 relative to the doublet at 5.20 ppm (anomeric proton of methyl-O-α-D-3'-ketopyranoside). The same method was used to correct for the 3% MeOH determined to be present in the starting material.

[0554] * Compared to the multiplet at 7.42 ppm (2 aromatic protons of phenyl-O-β-D-3′-ketopyranoglucoside), the singlet at 6.91 ppm (2 aromatic protons of phenol) increased after reactions 9 to 12.

[0555] Embodiment 31: Stability of Geranyl-O-β-D-3'-Ketopyranoside in D2O

[0556] Geranyl-O-β-D-3′-ketopyranoglucoside (5 mg) obtained according to Example 4 was added to D2O (1 mL) and heated at 50° C. The resulting solution was analyzed periodically by 1H NMR over a 2-week period and no changes in the resulting spectrum were observed, indicating that the ketopyranoside was stable.

[0557] Example 32: Release of Geranyl-O-β-D-3'-ketopyranoside from Porous Surfaces

[0558] Geranyl-O-β-D-3'-ketopyranoglucoside (50 mg) obtained according to Example 4 was dissolved in polyethylene glycol 200 (PEG200) (0.1 mL) under gentle heating. Then 0.1 mL of L-arginine (10 mg) solution dissolved in 0.1 mL of 3:7 w / v anhydrous calcium chloride aqueous solution was added and mixed thoroughly. The resulting solution was spread on a kitchen towel plate with a diameter of 5 cm and allowed to stand at room temperature. The odor of geraniol released from the plate over time was then evaluated as strong, medium or weak and reported in Table XIX:

[0559] Table XIX

[0560] Time / Hour Odor intensity of geraniol 0 powerful 0.3 powerful 2 powerful 3 powerful 4 powerful 6 powerful 11 middle 19 middle

[0561] After 19 hours, the reaction mixture was dissolved in D4-MeOH and analyzed by 1H NMR. The spectrum showed an approximately 1:1 mixture of the starting ketoglucoside and geraniol, judging by the signals at 4.15 and 4.05 ppm, respectively.

[0562] This example clearly shows that geraniol is slowly released from the paper surface over time.

[0563] Embodiment 33 : In vitro mosquito test of geranyl-O-β-D-3'-keto-glucopyranoside

[0564] Aedes albopictus were reared and maintained at a temperature of 26±2°C, relative humidity ≥80%±10, and a 12h:12h (light:dark) photoperiod. Adult mosquito colonies were allowed to feed on sugar solution (10%) but not blood feeding before testing.

[0565] Geranyl-O-β-D-3'-ketopyranoglucoside (100 mg) obtained according to Example 4 was dissolved in polyethylene glycol 200 (PEG200) (0.2 mL) under gentle heating to obtain solution 1. Then 200 mg of L-arginine was dissolved in 2 mL of 3:7 w / v anhydrous calcium chloride aqueous solution to obtain solution 2. Solution 2 (0.2 mL) was added to all of solution 1 to obtain solution 3. The contents of solution 3 were mixed thoroughly, and half of the resulting solution was applied to parallel artificial Hemotek membranes with a diameter of 5 cm, which were covered with kitchen towels of equal diameter. The parallel double membranes covered with kitchen towels were also treated with 0.2 mL of 1:1 v / v PEG200 solution / solution 2, respectively, and the other two parallel membranes were not treated.

[0566] The membranes were heated over a sheep blood pool at 37°C using the Hemotek system and periodically exposed to 5 to 7 day old active host-seeking female mosquitoes, which were selected and collected using an aspirator and divided into individual plastic test containers (15 females). The heating was turned off between exposures to maintain the integrity of the membranes and turned on 5 minutes before each exposure. Each membrane was exposed to a new female mosquito container for 20 minutes immediately after the membrane was prepared and exposed again after 2 hours, 4 hours, 6 hours and 8 hours. At each time point, the number of mosquitoes that landed on each membrane just after exposure and after 5, 10 and 20 minutes of exposure was calculated, and the number of mosquitoes that landed on the membrane after each 20-minute exposure was added and tabulated. The number of mosquitoes that landed on the membrane containing the conjugate was significantly reduced compared to that observed within 8 hours of the membrane treated with the diluent or untreated, as shown in Table XX:

[0567] Table XX

[0568] 0 hours 2 hours 4 hours 6 hours 8 hours GS0010 50mg Falling 0 3 3 4 0 GS0010 50mg Falling 2 0 0 3 0 Control diluent GS0010 Falling 2 5 12 5 5 Control diluent GS0010 Falling 2 0 3 6 7 NEG Falling 9 12 28 10 20 NEG Falling 29 7 25 16 16

[0569] It can be concluded that the geranyl-O-β-D-3'-keto glucopyranoside of the present invention provides an anthelmintic effect.

Claims

1. A 3'-ketoglycoside compound of formula (I) (I) in The stereochemistry at the 1', 2', 4' and 5' positions is independently selected from the α- or β-configuration; Where R 1 is CH2OH, R 2 is OH and R 3 It is H; R 1 It is CH3, R 2 is OH and R 3 It is H; R 1 Yes H, R 2 is OH and R 3 is H; or R 1 is CH2OH, R 2 is H and R 3 is H; and wherein R is the remainder of an alcohol of the formula R—OH selected from the group consisting of 4-allyl-2-methoxyphenol, 3-benzyl-3-pentanol, 4-cyclohexyl-2-methylbutan-2-ol, 2-cyclohexylpropanol, decanol, 9-decenol, (2,4-dimethylcyclohex-3-enyl)methanol, (2,4-dimethylcyclohexyl)methanol, 2-(1,1-dimethylethyl)-4-methylcyclohexanol, 2,6-dimethylheptan-2-ol, 3,7-dimethyl-7-hydroxyoctanal, 2,5-dimethyl-2-indenylmethanol, 3,7-dimethyl-1,6-nonadien-3-ol, 6,8-dimethylnonan-2-ol, 4,8-dimethyl-7-nonen-2-ol, ( E )-3,7-dimethyl-2,6-octadienol, ( Z )-3,7-dimethyl-2,6-octadienol, 3,7-dimethyl-3,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol, 3,7-dimethyloctan-1,7-diol, 3,7-dimethyloctanol, 2,6-dimethyloctan-2-ol, 3,7-dimethyloctan-3-ol, 3,7-dimethylocten-3-ol, 3,7-dimethylocten-6-enol, 3,7-dimethylocten-7-enol, 2,6-dimethyloctan-7-en-2-ol, ( E )-3,3-dimethyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, dodecanol, 2-ethoxy-5-(1-propenyl)phenol, 2-ethyl-1-hexanol, 3-hydroxyhexanoic acid ethyl ester, 4-ethyl-2-methoxyphenol, 6-ethyl-3-methyl-5-octenol, 5-ethylnonan-2-ol, 2-ethyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enol, 1-heptanol, 2-hexanol, 3-hexanol 4-Hexenol, 3-hydroxybutan-2-one, 4-hydroxy-3-ethoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 4-(4-hydroxy-3-methoxyphenyl)butan-2-one, 2-(hydroxymethyl)nonan-2-one, 4-(4-hydroxy-1-phenyl)butan-2-one, 4-isopropyl-1-benzyl alcohol, 4-isopropylcyclohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, (4-isopropylphenyl)methanol, 7- right -Menthol, right - Menth-3-ol, right - Menth-8-ol, right - Menth-8-en-2-ol, right -menth-8-en-3-ol, 4-methoxy-1-benzyl alcohol, 7-methoxy-3,7-dimethyloctan-2-ol, 2-methoxy-4-methylphenol, 2-methoxyphenol, 2-methoxy-2-phenylethanol, (4-methoxyphenyl)methanol, 2-methoxy-4-(1-propenyl)phenol, 2-methoxy-4-propyl-1-cyclohexanol, 2-methoxy-4-propylphenol, 2-methoxy-4-vinylphenol, 3-(4-methylcyclohex-3-enyl)butanol, 4-methyl-3-decenol, 4-methyl-3-decen-5-ol, 4-(1-methylethyl)cyclohexylmethanol, 2-methyl-4-phenylbutan-2-ol, 3-methyl-4-phenylbutan-2-ol, 1-(4-methyl 2-(2-methylphenyl)ethanol, 2-methyl-4-phenylpentanol, 2-methyl-5-phenylpentanol, 3-methyl-5-phenylpentanol, 4-methyl-1-phenylpentan-2-ol, 2-methyl-1-phenylpropan-2-ol, 2-(4-methylphenyl)propan-2-ol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)-4-penten-2-ol, 2-(2-methylpropyl)-4-hydroxy-4-methyl-tetrahydropyran, 2-methyl-4-(2,3,3-trimethyl-2-cyclopenten-1-yl)-2-butanol, 3-methyl-5-(2,2,3-trimethyl-3-cyclopenten-1-yl)pentan-2-ol, 2-methyl-4-(2,2, 3-Trimethyl-3-cyclopenten-1-yl)pent-4-enol, 3-methyl-5-(2,2,3-trimethylcyclopent-3-enyl)pent-4-en-2-ol, 2,6-nonadienol, 1-nonanol, 6-nonenol, 1,2,3,4,4a,5,8,8a-octahydro-2,2,6,8-tetramethyl-1-naphthol, octahydro-2,5,5-trimethyl-2-naphthol, octan-2-ol, octan-3-ol, 1-octen-3-ol, 3,4,5,6,6-pentamethylheptan-2-ol, 2-pentyl-1-cyclopentanol, perhydro-4,8a-dimethyl-4a-naphthol, 2-phenoxyethanol, 4-phenylbutan-2-ol, 4-phenyl-3-buten-2-ol, 1-phenylethanol, 2-phenylethyl alcohol, 1-phenylhexan-2-ol, 1-phenylpentan-2-ol, 2-phenylpropanol, 3-phenylpropanol, 1-phenylpropan-2-ol, 3-phenyl-2-propenol, 2-tert-butylcyclohexanol, 4-tert-butylcyclohexanol, 1-(2-tert-butyl-cyclohexyloxy)butan-2-ol, 2-tert-butyl-4-methyl-1-cyclohexanol, tetrahydro-2-isobutyl-4-methyl(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furanyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohexan-1-yl)hexan-3-ol, 2,4,6,8-tetramethylnonan-1-ol, 3,6,7-tetramethylnonan-1-ol, 2,6,10,10-tetramethyl-1-oxaspiro[4.5]decan-6-ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecane-8-ol, (+)-(. 1R , 2R )-1,3,3-trimethylbicyclo[2.2.1]hept-2-endo-ol, (+)-( 1R , 2S )-1,7,7-trimethylbicyclo[2.2.1]hept-2-ol, 2,6,6-trimethylbicyclo[3.1.1]hept-3-ol, 3-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 4-(5,5,6-trimethylbicyclo[2.2.1]hept-2-yl)cyclohexanol, 3,3,5-trimethylcyclohexanol, 4-(2,6,6-trimethyl-2-cyclohexen-1-yl)butan-2-ol, 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol, ( E )-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-ol, (2,4,6-trimethylcyclohex-3-enyl)methanol, 1-(2,2,6-trimethyl-1-cyclohexyl)hexan-3-ol, 5-(2,2,3-trimethyl-3-cyclopentenyl)-3-methylpentan-2-ol, 4,7,9-trimethyldecan-2-ol, 4,6,8-trimethyldecan-2-ol, 3,8,9-trimethyldecan-2-ol, 3,7,11-trimethyl-2,6,10-dodecatrienol, 3,7,11-trimethyl-1,6,10-dodecatrien-3-ol, 3,3,5-trimethylhexanol, undecane alcohol, undecane-2-ol, 10-undecanol, (6 E )- N -[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol, p-allylphenol, 2H-1,3-benzodioxan-5-ol, butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol.

2. The 3'-ketoglycoside compound according to claim 1, wherein R 1 is CH2OH, R 2 is OH and R 3 is H; or R 1 is CH2OH, R 2 is H and R 3 It's H.

3. The 3'-ketoglycoside compound according to claim 2, wherein R 1 is CH2OH, R 2 is OH and R 3 It's H.

4. A 3'-ketoglycoside compound of formula (I), (I) wherein R is the remainder of an alcohol of the formula R-OH as defined in claim 1, and The 3'-ketoglycoside compound of formula (I) is β-3'-keto-N-acetylglucosamine, wherein R 1 is CH2OH, R 2 is NHAc and R 3 It's H.

5. The 3'-ketoglycoside compound according to claim 1 or 4, wherein R is the remainder of an alcohol of the formula R-OH, wherein the formula R-OH is selected from the group consisting of: 4-allyl-2-methoxyphenol, E )-3,7-dimethyl-2,6-octadienol, ( Z )-3,7-dimethyl-2,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol, 3,7-dimethyloct-6-enol, 4-hydroxy-3-ethoxybenzaldehyde, 4-hydroxy-3-methoxybenzaldehyde, 4-(4-hydroxy-1-phenyl)butan-2-one, right -menth-3-ol, (4-methoxyphenyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, 2-(4-methylcyclohex-3-en-1-yl)propan-2-ol, butan-2-yl-2-(2-hydroxyethyl)piperidine-1-carboxylate and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol.

6. The 3'-ketoglycoside compound according to claim 5, wherein R is the remainder of an alcohol of the formula R-OH, wherein the formula R-OH is selected from the group consisting of: ( E )-3,7-dimethyl-2,6-octadienol, 4-allyl-2-methoxyphenol, butan-2-yl-2-(2-hydroxyethyl)piperidin-1-carboxylate, right -menth-3-ol and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol.

7. A method for preparing a 3'-ketoglycoside compound of formula (I) according to any one of claims 1 to 6, wherein the method comprises oxidizing a glycoside compound of formula (II) with an oxidant in the presence of a catalyst [(2,9-dimethyl-1,10-phenanthroline)Pd(µ-OAc)]2(OTf)2 (AND) (II)。 8. The method of claim 7, wherein the oxidizing agent is selected from the group consisting of quinones, oxygen, air, peroxides and peracids.

9. The method of claim 8, wherein the peroxide comprises a hydroperoxide. 10 . A composition comprising the 3′-ketoglycoside compound of formula (I) according to claim 1 and a carrier.

11. The composition according to claim 10, further comprising a compound selected from an alcohol of formula R-OH as defined in claim 1, 5 or 6 and an insect active compound.

12. The composition of claim 11, wherein the insect active compound is selected from the group consisting of terpenoids, pyrethrins, pyrethroids, N,N-diethyl-3-methylbenzamide, ethyl 3-[acetyl(butyl)amino]propionate, and mixtures thereof.

13. The composition of claim 12, wherein the terpenoid comprises a terpene.

14. Use of a 3'-ketoglycoside compound of formula (I) for the controlled release of an alcohol of formula R-OH, (I) in The stereochemistry at the 1', 2', 4' and 5' positions is independently selected from the α- or β-configuration; Where R 1 is CH2OH, R 2 is OH and R 3 It is H; R 1 It is CH3, R 2 is OH and R 3 It is H; R 1 Yes H, R 2 is OH and R 3 is H; or R 1 is CH2OH, R 2 is H and R 3 is H; and wherein R is the remainder of an alcohol of the formula R-OH as defined in claim 1.

15. Use of a 3'-ketoglycoside compound of formula (I) for the controlled release of an alcohol of formula R-OH, (I) wherein R is the remainder of an alcohol of the formula R-OH as defined in claim 1, and The 3'-ketoglycoside compound of formula (I) is β-3'-keto-N-acetylglucosamine, wherein R 1 is CH2OH, R 2 is NHAc and R 3 It's H.

16. Use according to claim 14 or 15, wherein R is the remainder of an alcohol of the formula R-OH as defined in claim 5.

17. The use according to claim 14 or 15, wherein R is the remainder of an alcohol of the formula R-OH as defined in claim 6.

18. A method of using a compound of formula (I) for non-therapeutic purposes comprising applying a composition as claimed in any one of claims 10 to 13 to a surface.

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