3'-Ketoglycoside compounds for the slow release of volatile alcohols

Abstract

The present invention relates to 3'-ketoglycoside compounds defined by formula (I) and their use for the controlled release of alcohol, particularly alcohol that exhibits insect repellent effects. It also relates to a method for preparing the 3'-ketoglycoside compounds of formula (I). It also relates to compositions containing the 3'-ketoglycoside compounds of formula (I). It also relates to the use of the 3'-ketoglycoside compounds of formula (I) for the controlled release of alcohol. It also relates to methods of using such compositions.

Description

[Technical Field]

[0001] The present invention relates to 3'-ketoglycoside compounds and their use for the controlled release of alcohols, in particular for the controlled release of alcohols having insect repellent effects. [Background technology]

[0002] Land-borne and airborne arthropods are the most common vectors for the transmission of diseases to humans, and rising global temperatures are increasing the number of areas affected by these diseases by providing suitable habitats for their respective vectors.

[0003] One way to combat bites from these insects is to use insect repellents. The active ingredients currently used in most commercially available topical insect repellents are spatial repellents. Several synthetic topical insect repellents, including DEET, picaridin, and IR3535, are approved on the market, but none are ideal. For example, DEET has a strong odor, leaves a waxy feel, and can dissolve plastics and synthetic fibers. Furthermore, the public recognition that these synthetic molecules are harmful to health has led to a rapidly growing market for natural alternatives.

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

[0005] Typically, commercially available repellent formulations remain effective for 4 to 6 hours after each application. However, as problematic insect species in a given environment are replaced by other invasive species, existing commercially available repellent formulations may no longer provide adequate protection. To use one non-limiting example, a commercially available topical insect repellent has been designed to combat mosquitoes that bite in the morning or evening, when a short duration of action is preferred. The ever-increasing populations of daytime-feeding Aedes species mosquitoes (commonly known as Aedes albopictus), responsible for the transmission of Zika, dengue, and chikungunya viruses, necessitate multiple applications of currently available repellents and formulations. Due to busy lifestyles, regular repellent application is often forgotten until a bite occurs, leaving users vulnerable to disease. To mitigate this issue, traditional repellent formulations containing high concentrations of active ingredients can be applied, but increased exposure can lead to multiple problems, including toxicity and irritation.

[0006] Spatial repellents are volatile molecules that, upon evaporation, create a protective zone above the skin that prevents mosquitoes from landing and / or biting through a complex mechanism that is not fully understood. Each active ingredient has a minimum effective evaporation rate (MEER). Evaporation rates above this threshold result in non-productive losses, reducing the duration for which the repellent is effective, after which the concentration is no longer sufficient to meet the MEER.

[0007] The development of insect repellent formulations that allow for controlled release of the active ingredient could overcome many of the problems associated with current insect repellent formulations by increasing duration while simultaneously reducing the concentration of active ingredient required. Because a lower amount of active ingredient is required, this would result in additional benefits such as reduced odor, reduced irritation, and avoidance of the greasy feel often associated with these formulations.

[0008] Furthermore, these methods would be attractive because they would potentially allow the use of other natural repellents that are currently unavailable due to their relatively high volatility, which is important because it could broaden the range of viable repellent molecules that would reduce resistance development.

[0009] Two main technical solutions for the slow release of insect repellents have been disclosed in the art: the encapsulation approach and the precursor approach.

[0010] In the encapsulation approach, the slow release of insect repellents is achieved by encapsulation within matrices such as microcapsules (e.g., European Patent Application No. 0348550), lipospheres (European Patent Application No. 0502119), polymers (U.S. Patent No. 4774082), or copolymers (U.S. Patent No. 6180127). After application of the repellent formulation to the entire body surface or to a region of the body, as in the case of a repellent bracelet, the active ingredients from these matrices are slowly released from the surface of interest over time.

[0011] In the precursor approach, altering the physicochemical properties of the active ingredient by preparing a prodrug or by conjugation to a suitable carrier molecule provides an alternative method of controlled release, where the active ingredient is released by an environmental mechanism that can extend the period over which the MEER is maintained while avoiding the need to apply large excesses of the active ingredient.

[0012] The use of precursors such as prodrugs and conjugates is well known in the pharmaceutical field. With regard to insect repellent active ingredients, conjugation of volatile insect repellent molecules to compounds with reduced water solubility such as fatty acids (US Patent Application Publication No. 2004 / 014811 (Patent Document 5)), preparation of water-soluble ester and ether prodrugs (European Patent Application No. 2439188 (Patent Document 6)), five- and six-membered cyclic acetals as insect repellent precursors (WO 99 / 00377 (Patent Document 7)), water-soluble conjugates to one or more sugar residues (JP Patent Publication No. 2000-096078 (Patent Document 8)), etc. Conjugates to polycarboxylic acids or polyols to improve water solubility (WO 2016 / 071521 (Patent Document 10)), conjugates to hyaluronic acid (WO 2016 / 071521), conjugates to crystalline carriers (WO 2010 / 144755 (Patent Document 11)), or conjugates to crosslinked polymer gel compositions (U.S. Pat. No. 6,846,491 (Patent Document 12)) have been disclosed.

[0013] These prior art methods exhibit shortcomings for effective slow-release application of insect repellents. Both alkyl and aryl O-glycopyranosides and glucuronides can be degraded on the skin to deliver volatile alcohol fragrance components, but the rate is insufficient for spatial insect repellent applications (i.e., the release rate required for fragrance on the skin is ng / min / cm). 2 units, whereas the required release rate of the repellent is μg / min / cm 2(The unit is the number of units.) Furthermore, the composition of the microbiota varies depending on the 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 range of glycosides can be degraded by microorganisms present on the skin, but the selectivity of the microorganisms differs depending on the aglycone used. The same group subsequently demonstrated rate differences in vivo using different subjects (Ikemoto et al., Flavour Fragr. J., 2003, 18, 45-47). A similar effect is seen with glucuronides, with enzymes from different microorganisms exhibiting very different substrate patterns (US Patent Application Publication No. 2016 / 0137952).

[0014] Despite various proposals available in the state of the art, there remains a need for new compounds to be used as slow-release insect repellents that exhibit suitable water solubility and a sufficient release rate of the active ingredient to perform a repellent effect. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] European Patent Application No. 0348550 [Patent Document 2] European Patent Application No. 0502119 [Patent Document 3] U.S. Patent No. 4,774,082 [Patent Document 4] U.S. Patent No. 6,180,127 [Patent Document 5] U.S. Patent Application Publication No. 2004 / 014811 [Patent Document 6] European Patent Application No. 2439188 [Patent Document 7] International Publication No. 99 / 00377 [Patent Document 8] Patent Publication No. 2000-096078 [Patent Document 9] Japanese Patent Application Publication No. 01-213291 [Patent Document 10] International Publication No. 2016 / 071521 [Patent Document 11] International Publication No. 2010 / 144755 [Patent Document 12] U.S. Patent No. 6,846,491 [Patent Document 13] U.S. Patent Application Publication No. 2016 / 0137952 [Non-patent literature]

[0016] [Non-Patent Document 1] Grice et al. Science, 2009, 324, 1190 [Non-patent document 2] Capone et al., J. Invest. Dermatol., 2011, 131, 2026-2032 [Non-patent document 3] Ikemoto et al., Flavor Fragr. J., 2002, 17, 452-455 [Non-patent document 4] Ikemoto et al., Flavor Fragr. J., 2003, 18, 45-47 Summary of the Invention

[0017] Object of the invention The object of the present invention is a 3'-ketoglycoside compound of formula (I).

[0018] Another aspect of the present invention is a method for preparing the 3'-ketoglycoside compounds of formula (I).

[0019] Another aspect of the present invention is a composition comprising a 3'-ketoglycoside compound of formula (I).

[0020] Another aspect of the present invention is the use of the 3'-ketoglycoside compounds of formula (I) for the controlled release of alcohol.

[0021] Another aspect of the present invention is a method of using the compounds of formula (I). [The present invention 1001] 3'-ketoglycoside compounds of formula (I): TIFF0007727647000001.tif37128 During the ceremony, the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from an α-configuration or a β-configuration; R represents 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; where R is derived from an alcohol of formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; R 1 H, CH 3 , C.H. 2 OH, CH 2 OR 4 , C.H. 2 OCOR 4 , C.H. 2 OCOOR 4 , C.H. 2 OCONHR 4 , C.H. 2 OCONR 4 2 , C.H. 2 NHR 4 , C.H. 2 NR 4 2 , CO 2 X, CO 2 R 4 , CONH 2 ,CONHR 4 ,CONR 4 2 , C.H. 2 OPO 3 X 2 , C.H. 2 OPO 3 XR 4 , C.H. 2 OPO 3 R 4 2 , C.H. 2 OPO 2 XNHR 4 , C.H. 2 OPO(NHR 4 ) 2 , C.H. 2 OPO 2 XR 4 , C.H. 2 OPOR 4 2 , C.H. 2 OSO 3 X, C.H. 2 OSO 3 R 4 , or CH 2 OSO 2 R 4 where X represents hydrogen, an alkali metal ion, an ammonium ion, or an organic counterion; R 4 represents 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 is CH 2 OH, CH 2 OSO 3 X, C.H. 2 OCOR 4 , or CO 2 R 4 and more preferably CH 2 OH; R 2 H, OH, OR 4 ,OCOR 4 , OCO 2 R 4 , OCONHR 4 , OCONR 4 2 , N.H. 2 , NHR 4 , N.R. 4 2 , NHCOR 4 , NHOR 4 , OPO 3 X 2 , OPO 3 XR 4 , OPO 3 R 4 2 , OPO 2 XNHR 4 , OPO(NHR 4 ) 2 , OPO 2 XR 4 ,OPOR 4 2 , OSO 3 X, OSO 3 R 4 , or OSO 2 R 4 where R 4 is as defined above; preferably, R 2 OH, NHCOR 4 , H, or OCOR 4 and more preferably, R 2 OH, NHCOR 4 , or H; R 3 is H or R 4 -Z, where R 4 is as defined above, Z represents a single bond or a functional group selected from ester, amine, amide, carbonate, or carbamate; preferably, R 3 is H, However, the compound of formula (I) is not limited to the case where R is methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenyl alcohol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, allyl 2-(hydroxymethyl)benzoate, benzyl 2-(Hydroxymethyl)benzoate, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethan-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-methylbutanoate, 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl The present invention does not include compounds where R—OH is the residue of an alcohol of the formula selected from the group consisting of 3-methylbutanoate, 7-methyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-1,4a,5,7(1H)-tetraol, 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. [The present invention 1002] 1001. A 3'-ketoglycoside compound of the present invention, wherein the sugar moiety is selected from the group consisting of glucose, galactose, allose, altrose, mannose, gulose, idose, talose, fucose, xylose, N-acetylglucosamine, and 2-deoxyglucose. [The present invention 1003] The 3'-ketoglycoside compound of the present invention 1002, wherein the sugar moiety is selected from the group consisting of D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose. [The present invention 1004] 1003. The 3'-ketoglycoside compound of the present invention, wherein the sugar moiety is selected from the group consisting of D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose. [The present invention 1005] 1004. A 3'-ketoglycoside compound of the present invention, wherein the sugar moiety is D-glucose. [The present invention 1006] 1004. The 3'-ketoglycoside compound of the present invention, wherein the sugar moiety is selected from the group consisting of DN-acetylglucosamine and D-2-deoxyglucose. [The present invention 1007] R is 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-indanemethanol, 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 (ne ol), 3,7-dimethyl-3,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-Dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclo Hexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-5-ol (sesamol), butan-2-yl The 3'-ketoglycoside compound of any one of claims 1001 to 1006, wherein R is a residue of an alcohol of the formula R—OH selected from the group consisting of 2-(2-hydroxyethyl)piperidine-1-carboxylate (picaridin) and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD). [The present invention 1008] R is 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 1007. The 3'-ketoglycoside compound of the present invention, wherein R-OH is the residue of an alcohol of the formula R-OH selected from the group consisting of methylpropional (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 (carbocrol), 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-methylcyclohexan-1-ol (p-menthan-3,8-diol, PMD). [The present invention 1009] 1008. The 3'-ketoglycoside compound of the present invention, wherein R is a residue of an alcohol of the formula R-OH selected from the group consisting of 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), and 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD). [The present invention 1010] R 1 But CH 2 OH, CH 2 OSO 3<h2 style=";text-align:left;direction:ltr"> X, C.H. <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> OCOR <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> , or CO <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> The 3'-ketoglycoside compound of any one of the present inventions 1001 to 1009, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1011] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> is CH <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> 1010. A 3'-ketoglycoside compound of the present invention, wherein the 3'-ketoglycoside compound is OH. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1012] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> But, OH, NHCOR <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> , H, or OCOR <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> The 3'-ketoglycoside compound of any one of the present inventions 1001 to 1011, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1013] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> The 3'-ketoglycoside compound of the present invention 1012, wherein is OH. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1014] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 2 <h2 style=";text-align:left;direction:ltr"> However, NHCOR <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> or H. 1012. A 3'-ketoglycoside compound according to the present invention. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1015] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 3 <h2 style=";text-align:left;direction:ltr"> The 3'-ketoglycoside compound of any one of the present inventions 1001 to 1014, wherein is H. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1016] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The 3'-ketoglycoside compound of any one of 1001 to 1015 of the present invention, which is selected from β-3'-ketoglucosides, α-3'-ketoglucosides, β-3'-keto-N-acetylglucosaminosides, and 2'-deoxy-3'-ketoglucosides. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1017] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1016. The 3'-ketoglycoside compound of the present invention, wherein the compound of formula (I) is selected from β-3'-ketoglucosides and α-3'-ketoglucosides. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1018] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1016. The 3'-ketoglycoside compound of the present invention, wherein the compound of formula (I) is selected from β-3'-keto-N-acetylglucosaminoside and 2'-deoxy-3'-ketoglucoside. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1019] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A method for preparing a 3'-ketoglycoside compound of formula (I) according to any one of claims 1001 to 1018 of the present invention, comprising oxidizing a glycoside compound of formula (II) with [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)] as a catalyst by an oxidizing agent. <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> (OTf) <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> the process comprising oxidizing in the presence of: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007727647000002.tif37128<h2 style=";text-align:left;direction:ltr"> During the ceremony, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from the α-configuration or the 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 D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose, even more preferably D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R represents 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; where R is derived from an alcohol of the formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; preferably, R is selected from the group consisting of 4-allyl-2-methoxyphenol (eugenol), 3-benzyl-3-pentanol, 4-cyclohexyl-2-methylbutane-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-indanemethanol, 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, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclo Hexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-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 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 the residue of an alcohol of formula R—OH selected from 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); <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H, CH <h2 style=";text-align:left;direction:ltr"> 3<h2 style=";text-align:left;direction:ltr"> , C.H. <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> OH, CH <h2 style=";text-align:left;direction:ltr"> 2 OR 4 , C.H. 2 OCOR 4 , C.H. 2 OCOOR 4 , C.H. 2 OCONHR 4 , C.H. 2 OCONR 4 2 , C.H. 2 NHR 4 , C.H. 2 NR 4 2 , CO 2 X, CO 2 R 4 , CONH 2 ,CONHR 4 ,CONR 4 2 , C.H. 2 OPO 3 X 2 , C.H. 2 OPO 3 XR 4 , C.H. 2 OPO 3 R 4 2 , C.H. 2 OPO 2 XNHR 4 , C.H. 2 OPO(NHR 4 ) 2 , C.H. 2 OPO 2 XR 4 , C.H. 2 OPOR 4 2 , C.H. 2 OSO 3 X, C.H. 2 OSO 3 R 4 , or CH 2 OSO 2 R 4 where X represents hydrogen, an alkali metal ion, an ammonium ion, or an organic counterion; R 4 represents 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 is CH 2 OH, CH 2 OSO 3 X, C.H. 2 OCOR4 , or CO 2 R 4 and more preferably CH 2 OH; R 2 H, OH, OR 4 ,OCOR 4 , OCO 2 R 4 , OCONHR 4 , OCONR 4 2 , N.H. 2 , NHR 4 , N.R. 4 2 , NHCOR 4 , NHOR 4 , OPO 3 X 2 , OPO 3 XR 4 , OPO 3 R 4 2 , OPO 2 XNHR 4 , OPO(NHR 4 ) 2 , OPO 2 XR 4 ,OPOR 4 2 , OSO 3 X, OSO 3 R 4 , or OSO 2 R 4 where R 4 is as defined above; preferably, R 2 OH, NHCOR 4 , H, or OCOR 4 and more preferably, R 2 OH, NHCOR 4 , or H; R 3 is H or R 4 -Z, where R 4 is as defined above, Z represents a single bond or a functional group selected from ester, amine, amide, carbonate, or carbamate; preferably, R 3<h2 style=";text-align:left;direction:ltr"> is H, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> However, the compound of formula (I) is not limited to the case where R is methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenyl alcohol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, allyl 2-(hydroxymethyl)benzoate, benzyl 2-(Hydroxymethyl)benzoate, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethan-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-methylbutanoate, 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl The present invention does not include compounds where R—OH is the residue of an alcohol of the formula selected from the group consisting of 3-methylbutanoate, 7-methyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-1,4a,5,7(1H)-tetraol, 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. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1020] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The method of claim 1019, wherein the oxidizing agent is selected from the group consisting of quinones, oxygen, air, peroxides, peracids, and hydroperoxides. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1021] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The process of claim 1019 or 1020, wherein the catalyst is used in a molar ratio of 0.01 to 10 mol %, preferably 0.1 to 8 mol %, more preferably 1 to 6 mol %, relative to the glycoside substrate. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1022] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1022. The process of any of claims 1019 to 1021, wherein the oxidation reaction is carried out in any suitable solvent or solvent mixture. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1023] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> 1023. The process of claim 1022, wherein the solvent is selected from DMSO, dimethylformamide (DMF), tetrahydrofuran (THF), dioxane, acetonitrile, hexamethylphosphoramide (HMPA), N-methyl-2-pyrrolidone (NMP), or any mixture thereof. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1024] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The method of any one of inventions 1019 to 1023, which is carried out at a temperature of 0°C to 100°C, preferably 10°C to 70°C, more preferably around room temperature. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1025] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> A composition comprising a 3'-ketoglycoside compound of formula (I) according to any one of the present inventions 1001 to 1018 and a carrier. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1026] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The composition of invention 1025, further comprising a compound selected from the alcohols of formula R-OH as defined in any of inventions 1007 to 1009, and an insect active compound. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1027] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The composition of claim 1026, wherein the insect-active compound is selected from terpenes, terpenoids, pyrethrins, pyrethrinoids, N,N-diethyl-3-methylbenzamide, ethyl 3-[acetyl(butyl)amino]propanoate, and mixtures thereof. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1028] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Any of the compositions of inventions 1025 to 1027 in the form of a solution, cream, paste, powder, spray, lotion, film, or impregnated in or on a material, medical device, or surface such as wipes, masks, and sticks. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1029] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The composition of any one of claims 1025 to 1028, wherein the carrier is an aqueous solvent. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1030] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Any of the compositions of claims 1025 to 1029, further comprising an ingredient selected from cosolvents, emulsifiers, humectants, astringents, buffers, emollients, antioxidants, preservatives, cosmetic oils, plant extracts, essential oils, and mixtures thereof. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1031] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> The composition of claim 1030, wherein the essential oil is selected from eucalyptus oil, neem oil, citronella oil, tea tree oil, pine oil, and mixtures thereof. <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> [The present invention 1032] <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Use of 3'-ketoglycoside compounds of formula (I) for the controlled release of alcohol: <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> TIFF0007727647000003.tif37128<h2 style=";text-align:left;direction:ltr"> During the ceremony, <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from the α-configuration or the 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 D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose, even more preferably D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose; <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R represents 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; wherein preferably, R is derived from an alcohol of formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; more preferably, R is derived from an alcohol of formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; and more preferably, R is derived from an alcohol of formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; 2-Butanol, 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-indanethanol, 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, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclo Hexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-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 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 the residue of an alcohol of formula R—OH selected from 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); <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> R <h2 style=";text-align:left;direction:ltr"> 1 <h2 style=";text-align:left;direction:ltr"> H, CH <h2 style=";text-align:left;direction:ltr"> 3<h2 style=";text-align:left;direction:ltr"> , C.H. <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> OH, CH <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> OR <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> , C.H. <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> OCOR <h2 style=";text-align:left;direction:ltr"> 4 <h2 style=";text-align:left;direction:ltr"> , C.H. <h2 style=";text-align:left;direction:ltr"> 2<h2 style=";text-align:left;direction:ltr"> OCOOR4 , C.H. 2 OCONHR 4 , C.H. 2 OCONR 4 2 , C.H. 2 NHR 4 , C.H. 2 NR 4 2 , CO 2 X, CO 2 R 4 , CONH 2 ,CONHR 4 ,CONR 4 2 , C.H. 2 OPO 3 X 2 , C.H. 2 OPO 3 XR 4 , C.H. 2 OPO 3 R 4 2 , C.H. 2 OPO 2 XNHR 4 , C.H. 2 OPO(NHR 4 ) 2 , C.H. 2 OPO 2 XR 4 , C.H. 2 OPOR 4 2 , C.H. 2 OSO 3 X, C.H. 2 OSO 3 R 4 , or CH 2 OSO 2 R 4 where X represents hydrogen, an alkali metal ion, an ammonium ion, or an organic counterion; R 4 represents 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 is CH 2 OH, CH 2 OSO 3 X, C.H. 2 OCOR 4 , or CO 2 R 4 and more preferably CH 2 OH; R 2 H, OH, OR 4 ,OCOR 4 , OCO 2 R 4 , OCONHR 4 , OCONR 4 2 , N.H. 2 , NHR 4 , N.R. 4 2 , NHCOR 4 , NHOR 4 , OPO 3 X 2 , OPO 3 XR 4 , OPO 3 R 4 2 , OPO 2 XNHR 4 , OPO(NHR 4 ) 2 , OPO 2 XR 4 ,OPOR 4 2 , OSO 3 X, OSO 3 R 4 , or OSO 2 R 4 where R 4 is as defined above; preferably, R 2 OH, NHCOR 4 , H, or OCOR 4 and more preferably, R 2 OH, NHCOR 4 , or H; R 3 is H or R 4 -Z, where R 4 is as defined above, Z represents a single bond or a functional group selected from ester, amine, amide, carbonate, or carbamate; preferably, R 3 is H. [The present invention 1033] Use of the present invention 1032, wherein the use of the compound of formula (I) is a combination of said compound with a compound selected from the alcohols of formula R-OH as defined in the present invention 1032, and an insect active compound. [The present invention 1034] The use of invention 1033, wherein the insect active compound is selected from terpenes, terpenoids, pyrethrins, pyrethrinoids, N,N-diethyl-3-methylbenzamide, ethyl 3-[acetyl(butyl)amino]propanoate, and mixtures thereof. [This invention 1035] In the 3'-ketoglycoside compound of formula (I), R 1 is CH 2 OH, CH 2 OSO 3 X, C.H. 2 OCOR 4 , or CO 2 R 4 Use of any one of inventions 1032 to 1034. [The present invention 1036] In the 3'-ketoglycoside compound of formula (I), R 1 is CH 2 The use of the present invention 1035, which is OH. [This invention 1037] In the 3'-ketoglycoside compound of formula (I), R 2 OH, NHCOR 4 , H, or OCOR 4 Use of any one of inventions 1032 to 1036. [The present invention 1038] In the 3'-ketoglycoside compound of formula (I), R 2 The use of the present invention 1037, wherein is OH. [This invention 1039] In the 3'-ketoglycoside compound of formula (I), R 2 NHCOR 4 or H. Use of the present invention 1037. [The present invention 1040] In the 3'-ketoglycoside compound of formula (I), R 3 Use of any one of claims 1032 to 1039 of the present invention, wherein is H. [The present invention 1041] The use of any of claims 1032 to 1040, wherein the 3'-ketoglycoside compound of formula (I) is selected from β-3'-ketoglucosides, α-3'-ketoglucosides, β-3'-keto-N-acetylglucosaminosides, and 2'-deoxy-3'-ketoglucosides. [The present invention 1042] The use of invention 1041, wherein the compound of formula (I) is selected from β-3'-ketoglucosides and α-3'-ketoglucosides. [This invention 1043] The use of invention 1041, wherein the compound of formula (I) is selected from β-3'-keto-N-acetylglucosaminosides and 2'-deoxy-3'-ketoglucosides. [This invention 1044] Use of any one of claims 1032 to 1043, wherein the alcohol has an insect repellent effect. [This invention 1045] A method for using a compound of formula (I), comprising applying any one of the compositions of inventions 1025 to 1031 to a surface. [The present invention 1046] The method of claim 1045, wherein the surface is selected from a soft surface and a hard surface. [This invention 1047] The method of claim 1046, wherein the soft surface is selected from skin, hair, fabric, plants, crops, and stored grains. [This invention 1048] The method of claim 1046, wherein the hard surface is selected from wood, synthetic materials, and ceramic materials. DETAILED DESCRIPTION OF THE INVENTION

[0022] Detailed Description of the Invention The object of the present invention is a 3'-ketoglycoside compound of formula (I): TIFF0007727647000004.tif37128In formula, the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from the α-configuration or the 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 D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose, even more preferably D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose; R represents 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; wherein R is derived from an alcohol of the formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; preferably, R is 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-indanemethanol, 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, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-Dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclo Hexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-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 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 the residue of an alcohol of formula R—OH selected from 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); R 1 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. CH2OPO2XNHR4 , CH2OPO(NHR 4 )2, CH2OPO2XR 4 , CH2OPOR 4 2, CH2OSO3X, CH2OSO3R 4 , or CH2OSO2R 4 where X represents hydrogen, an alkali metal ion, an ammonium ion, or an organic counterion; R 4 represents 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 are CH2OH, CH2OSO3X, CH2OCOR 4 , or CO2R 4 is more preferably CHOH; R 2 is H, OH, OR 4 ,OCOR 4 , OCO2R 4 , OCONHR 4 , OCONR 4 2, NH2, NHR 4 , N.R. 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 is as defined above; preferably, R 2 OH, NHCOR 4 , H, or OCOR 4 and more preferably, R 2 OH, NHCOR 4 , or H; R 3 is H or R 4 -Z, where R 4is as defined above, Z represents a single bond or a functional group selected from ester, amine, amide, carbonate, or carbamate; preferably, R 3 is H, However, the compound of formula (I) is not limited to the case where R is methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenyl alcohol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, allyl 2-(hydroxymethyl)benzoate, benzyl 2-(Hydroxymethyl)benzoate, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethan-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-methylbutanoate, 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl The present invention does not include compounds where R—OH is the residue of an alcohol of the formula selected from the group consisting of 3-methylbutanoate, 7-methyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-1,4a,5,7(1H)-tetraol, 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.

[0023] The present inventors have developed 3'-ketoglycoside compounds of formula (I) that can release alcohols on surfaces such as human skin, both in the absence and presence of microflora on human skin and bacteria found in the environment.Surprisingly, the compounds of the present invention can release concentrations of volatile alcohols effective to act as insect repellents for periods longer than those typically observed with the delivery of free repellent alcohols, which lasts at least 24 hours.Particularly suitable alcohols include, for example, geraniol, eugenol, picaridin, menthol, carvacrol, and PMD.

[0024] In this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Ranges defined by the preposition "between" are inclusive. According to IUPAC, the term "moiety" is used to mean a portion of a molecule.

[0025] 3'-ketoglycosides The 3'-ketoglycosides of the present invention are comprised of a sugar moiety and an alcohol residue R derived from an alcohol of the formula R-OH, as shown below. TIFF0007727647000005.tif45128

[0026] The compounds of formula (I) are sometimes referred to herein as 3'-ketoglycopyranosides or 3'-keto-O-glycopyranosides.

[0027] The keto form of a 3'-ketoglycoside can be in equilibrium with the hydrated form as shown below. TIFF0007727647000006.tif35128

[0028] The compounds of formula (I) contain an R group attached to a sugar moiety by a β-glycosidic or α-glycosidic bond.

[0029] 3'-Ketoglycoside compounds may form imine, oxime, hemiacetal, hemiaminal, bisulfite, or similar adducts in the presence of alternative nucleophiles that may be commonly present in a given formulation (polysaccharides such as chitosan; sodium bisulfite, etc.) and that would be expected to further modulate its physicochemical properties, e.g., stability.

[0030] sugar part The stereochemical configurations at the 1', 2', 4', and 5' positions of the sugar moiety represented in formula (I) are independently selected from the α-configuration or the 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 D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose, and even more preferably D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose.

[0031] In a more preferred embodiment, the sugar moiety is D-glucose.

[0032] In another preferred embodiment, the sugar moiety is selected from DN-acetylglucosamine and D-2-deoxyglucose.

[0033] In a preferred embodiment, R 1 are CH2OH, CH2OSO3X, CH2OCOR 4 , or CO2R 4 and more preferably, R 1 is CH2OH.

[0034] In a preferred embodiment, R 2 OH, NHCOR 4 , H, or OCOR 4 is.

[0035] In a preferred embodiment, R 2 is OH.

[0036] In a preferred embodiment, R 2 NHCOR 4 Or H.

[0037] In a preferred embodiment, R 3 is H.

[0038] In one preferred embodiment, the compound of formula (I) is selected from β-3′-ketoglucosides, α-3′-ketoglucosides, β-3′-keto-N-acetylglucosaminosides, and 2′-deoxy-3′-ketoglucosides.

[0039] In a more preferred embodiment, the compounds of formula (I) are selected from β-3′-ketoglucosides and α-3′-ketoglucosides.

[0040] In another preferred embodiment, the compound of formula (I) is selected from β-3′-keto-N-acetylglucosaminosides and 2′-deoxy-3′-ketoglucosides.

[0041] Alcohol residue In the compounds of formula (I), R represents 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; wherein preferably, R is derived from an alcohol of formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; more preferably, R is 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-indanmethanol, 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, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-Dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclohexyl Isohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-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 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-methylcyclohexan-1-ol (p-menthane-3,8-diol, PMD), more preferably E-3,7-dimethyl-2,6-octadienol (geraniol), 2-methoxy-4-(2-propenyl)phenol (eugenol), butan-2-yl The solvent is selected from 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), and isopropanol, ethanol, isopropanol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenyl alcohol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, allyl 2-(hydroxymethyl)benzoate, benzyl 2-(hydroxymethyl)benzoate, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,The residue of an alcohol of the formula R—OH is selected from the group consisting of 2-diol, 2-(trimethylsilyl)ethan-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-methylbutanoate, 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl 3-methylbutanoate, and (2,3-dimethylbutan-2-yl)dimethylsilanol.

[0042] Most of the alcohols are "volatile alcohols," which means herein that alcohols that readily evaporate at ambient temperatures when applied to a surface, such as a user's skin, and the coupling between the alcohol and the sugar moiety is cleaved, so the alcohol may produce a scented vapor layer or zone adjacent to the surface, such as a user's skin.

[0043] As disclosed in WO 2014 / 202416, the alcohols listed above are commercially available.

[0044] The determination of the boiling point of the alcohol can be carried out using standard methods disclosed in the prior art, well known to those skilled in the art, for example as disclosed in J. Vilarrasa, Introduccion al analisis organico, page 44, Eunibar, Barcelona, ​​1975.

[0045] The alcohol E-3,7-dimethyl-2,6-octadienol, also known as geraniol, corresponds to the following structure: TIFF0007727647000007.tif15128

[0046] In another embodiment, the alcohol residue is E-3,7-dimethyl-2,6-octadienol (geraniol).

[0047] The alcohol 2-methoxy-4-(2-propenyl)phenol, also known as eugenol, corresponds to the following structure: TIFF0007727647000008.tif20128

[0048] In another embodiment, the alcohol residue is 2-methoxy-4-(2-propenyl)phenol (eugenol).

[0049] In one aspect, 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, where * indicates an asymmetric center: TIFF0007727647000009.tif56128

[0050] The alcohol 5-methyl-2-(propan-2-yl)cyclohexan-1-ol is also known as menthol. One preferred isomer is L-menthol or (-)-menthol, which corresponds to the following structure: TIFF0007727647000010.tif27128

[0051] Additional isomers of menthol are available: (+)-menthol, (+)- and (-)-isomenthol, (+)- and (-)-neomenthol, and (+)- and (-)-neoisomenthol.

[0052] In another embodiment, the alcohol residue is 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), preferably L-menthol.

[0053] In another embodiment, the alcohol residue is 2-methyl-5-propan-2-ylphenol (carvacrol), which corresponds to the structure: TIFF0007727647000011.tif38128

[0054] The alcohol 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol, also known as p-menthane-3,8-diol (PMD), corresponds to the following structure: TIFF0007727647000012.tif42128

[0055] As disclosed in Barasa et al., J. Med. Entomol., 2002, 39, 736-741, different stereoisomers of PMD exhibit repellent effects either alone, as racemic blends, or as diastereomeric mixtures.

[0056] The PMD may be attached to the sugar moiety by a secondary or tertiary hydroxyl group.

[0057] In one embodiment, the alcohol residue is one or more stereoisomers of 2-(2-hydroxypropan-2-yl)-5-methylcyclohexan-1-ol (PMD).

[0058] Eugenol, geraniol, picaridin, L-menthol, and PMD have well-known insect repellent properties, as disclosed by Carroll et al., J. Am. Mosquito Control Assoc., 2006, 22, 507-514 or Barnard et al., J. Med. Entomol., 2004, 41, 726-730. Carvacrol outperformed N,N-diethyl-m-methylbenzamide (DEET) against Culex pipiens pallens mosquitoes, as disclosed by Park et al., J. Am. Mosquito Control Assoc., 2005, 21, 80-83.

[0059] Compounds of formula (I) can be effective insect repellents. As shown in the Examples section, these compounds are capable of releasing alcohol in different pH and temperature conditions, both in the presence and absence of fresh skin washes.

[0060] Methods for preparing 3'-ketoglycosides A method for preparing the 3'-ketoglycoside compounds of formula (I) is an aspect of the present invention.

[0061] The method for preparing the 3'-ketoglycoside compound of formula (I) comprises oxidizing the glycoside compound of formula (II) with an oxidizing agent preferably selected from the group consisting of quinone, oxygen, air, peroxide, peracid, and hydroperoxide in the presence of [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) as a catalyst: TIFF0007727647000013.tif37128In formula, the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from the α-configuration or the 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 D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose, even more preferably D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose; R represents 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; wherein R is derived from an alcohol of the formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; preferably, R is 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-indanemethanol, 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, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-Dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclo Hexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-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 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 the residue of an alcohol of formula R—OH selected from 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); R 1 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. CH2OPO2XNHR4 , CH2OPO(NHR 4 )2, CH2OPO2XR 4 , CH2OPOR 4 2, CH2OSO3X, CH2OSO3R 4 , or CH2OSO2R 4 where X represents hydrogen, an alkali metal ion, an ammonium ion, or an organic counterion; R 4 represents 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 are CH2OH, CH2OSO3X, CH2OCOR 4 , or CO2R 4 is more preferably CHOH; R 2 is H, OH, OR 4 ,OCOR 4 , OCO2R 4 , OCONHR 4 , OCONR 4 2, NH2, NHR 4 , N.R. 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 is as defined above; preferably, R 2 OH, NHCOR 4 , H, or OCOR 4 and more preferably, R 2 OH, NHCOR 4 , or H; R 3 is H or R 4 -Z, where R 4is as defined above, Z represents a single bond or a functional group selected from ester, amine, amide, carbonate, or carbamate; preferably, R 3 is H, However, the compound of formula (I) is not limited to the case where R is methanol, ethanol, propan-1-ol, isopropanol, 2-(hydroxymethyl)but-2-ene-1,4-diol, 4-methoxyphenol, n-octanol (1-octanol), 2-propenyl alcohol (allyl alcohol), benzyl alcohol, phenol, 4-nitrophenol, 4-(3-hydroxybutyl)phenol, allyl 2-(hydroxymethyl)benzoate, benzyl 2-(Hydroxymethyl)benzoate, 4-hydroxyphenol, 2-(hydroxymethyl)phenol, 1H-indol-3-ol, 4-(2-hydroxyethyl)benzene-1,2-diol, 2-(trimethylsilyl)ethan-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-methylbutanoate, 4,7-bis(hydroxymethyl)-1,4a,5,7a-tetrahydrocyclopenta[c]pyran-1-yl The present invention does not include compounds where R—OH is the residue of an alcohol of the formula selected from the group consisting of 3-methylbutanoate, 7-methyl-5,6,7,7a-tetrahydrocyclopenta[c]pyran-1,4a,5,7(1H)-tetraol, 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.

[0062] The catalyst [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) 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.

[0063] The catalyst is preferably used in a molar ratio of 0.01 to 10 mol %, preferably 0.1 to 8 mol %, more preferably 1 to 6 mol %, relative to the glycoside substrate.

[0064] In the method of the present invention, the oxidation reaction is typically carried out in any suitable solvent or solvent mixture. Stirring is recommended. 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.

[0065] The process of the present invention is typically carried out at temperatures between 0°C and 100°C, preferably between 10°C and 70°C, and more preferably at or near room temperature. The total reaction time will depend on the particular circumstances. Typically, the reaction is carried out for a period ranging from about 1 to 48 hours.

[0066] The glycosides used as starting compounds are commercially available, for example through Carbosynth Ltd., or can be prepared by prior art methods, such as those disclosed below.

[0067] Alkyl and aryl glycosides can be prepared using a variety of chemical synthesis methods, such as the Koenigs-Knorr or Mitsunobu reactions, which are carried out under a variety of different conditions and typically produce only or as the major kinetically favored anomer, depending on the alcohol, sugar, sugar-protecting group, and reaction conditions used. Kobayashi et al., Chem. Pharm. Bull., 2016, 64, 1009–1018, elegantly demonstrated the effectiveness of some of these methods for the synthesis of remogliflozin, a low-affinity Na+-dependent glucose cotransporter SGLT2 inhibitor. The Koenigs-Knorr procedure requires the use of a fully protected sugar derivative containing a good leaving group at the anomeric position, whereas the Mitsunobu reaction requires a protected sugar containing a free hydroxyl substituent at the anomeric position. These starting materials are accessible by a variety of different methods, such as pentaacetylation 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 activation as trichloroacetimidates as described by Ikeuchi et al., Synlett., 2019, 30, 1308-1312.

[0068] To improve the quality of thermodynamically stable glycosides obtained by glycosylation procedures that preferentially produce kinetic products, protected glycosides can be anomerized under various conditions. For example, protected alkyl glycosides can be anomerized using various Lewis acids, such as titanium tetrachloride, as reported by Sakata et al., Agric. Biol. Chem., 1979, 43, 307, to yield anomeric mixtures that can be chromatographically separated. Aryl glycosides, which are usually anomerically stable in the presence of Lewis acids, may also be anomerized under different conditions, such as treatment with hot phenol and zinc chloride, as disclosed by Montgomery et al., J. Am. Chem. Soc., 1942, 64, 690-694.

[0069] Additionally, an increasing number of alkyl and aryl glycosides can be prepared using a variety of well-explored biosynthetic methods. Some examples of recent reviews of 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.

[0070] Glycosides can be oxidized to uronic acids under various conditions, such as 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO)-catalyzed oxidation, as reported by Lu et al., Molecules, 2016, 21, 1301. Various methods for the preparation of uronamides can be used, such as the thioesterification of 6'-tosylated glycosides followed by treatment with amines, as reported by Lin et al., Eur. J. Org. Chem., 2016, 2653-2664.

[0071] Alternatively, the 6'-alcohol may be selectively functionalized as an ester, carbonate, or carbamate 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 methods such as that reported by Hearon et al., J. Am. Chem. Soc., 1944, 66, 995-997 for the tritylation of methyl-O-α-D-glucopyranoside, and 6'-amines can be readily prepared by methods such as the azide substitution used by de Souza et al., Carbohydr. Res., 2015, 410, 1-8.

[0072] 6'-Alcohols can be selectively functionalized as sulfate or phosphate monoesters using procedures such as those reported by Liu et al., Eur. J. Med. Chem., 2017, 128, 274-286. Alternatively, alcohols can be functionalized as sulfate diesters, phosphate diesters or triesters, sulfonate monoesters, phosphonate monoesters or diesters, diphosphonate monoesters, phosphoramidates, or phosphonodiamidites using similar procedures, which typically involve nucleophilic attack on the electrophilic sulfur of the phosphorus atom by the 6'-alcohol, resulting in displacement of a leaving group such as chloride. Examples of how these compounds can be constructed can be found in the review citations of Simpson et al., J. Am. Chem. Soc., 2006, 128, 1605-1610 and Mehellou et al., Chem. Med. Chem., 2009, 4, 1779-1791.

[0073] In some cases, the phosphorus atom can be chiral, as in the case of phosphoramidates. Considering that glycosides are also chiral, this can result in diastereomeric mixtures, and methods exist to promote the formation of one diastereomer or selectively isolate it. For example, Ross et al., J. Org. Chem., 2011, 76, 8311-8319, discovered that nucleoside phosphoramidates can be prepared with a 3:1 excess of one diastereomer by careful optimization of reaction conditions. The major isomer can then be isolated purely by crystallization.

[0074] Also, the 6' position (where R 1 Using similar methodology for functionalizing glycosides (=CHOH), a wide variety of derivatives of secondary alcohols at the 2' and 4' positions can be prepared. While this can be done selectively, it is usually accomplished through the use of appropriate protecting group strategies, since primary alcohols at the 6' position are usually relatively reactive, and because more than one secondary alcohol group is often present. An example of how protecting group strategies can be effectively used to sulfate glycosides at different positions on the sugar ring is given in Loft et al., Chem. Bio. Chem., 2009, 10, 565-576.

[0075] The preparation of compounds of formula (I) in which the sugar moiety is a glycosylamine is disclosed, for example, in Zhang et al., J. Med. Chem., 2019, 62, 7857-7873.

[0076] In some embodiments, selective deacetylation of the hydroxyl groups of the sugar moiety can be carried out according to methods available in the prior art, for example, the method disclosed in MacManus et al., Carbohydrate Res., 1995, 279, 281-291.

[0077] Delivery of compounds of formula (I) Another aspect of the subject matter of the present invention is the use of 3'-ketoglycoside compounds of formula (I) for the controlled release of alcohol, preferably for the controlled release of alcohol with insect repellent effect: TIFF0007727647000014.tif37128In formula, the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from the α-configuration or the 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 D-glucose, D-galactose, D-allose, D-altrose, D-mannose, D-gulose, D-idose, D-talose, DN-acetylglucosamine, and D-2-deoxyglucose, even more preferably D-glucose, DN-acetylglucosamine, and D-2-deoxyglucose; R represents 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; wherein preferably R is derived from an alcohol of formula R—OH having an initial boiling point of 350° C. or less at a standard pressure of 101.3 kPa; more preferably R is 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-indanmethanol, 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, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-Dimethyloct-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-hexanediol, 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-benzenemethanol, 4-isopropylcyclo Hexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, 2-isopropyl-5-methylphenol, 5-isopropyl-2-methylphenol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menthen-4-ol, p-menthen-8-ol, p-menth-8-enol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-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-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-butenol, 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-trimethylcyclopentyl-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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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]decane-6 -ol, 2,6,6,8-tetramethyltricyclo[5.3.1.0(1,5)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-endo-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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 ol, 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 (chavicol), 2H-1,3-benzodioxol-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 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 the residue of an alcohol of formula R—OH selected from 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); R 1 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. CH2OPO2XNHR4 , CH2OPO(NHR 4 )2, CH2OPO2XR 4 , CH2OPOR 4 2, CH2OSO3X, CH2OSO3R 4 , or CH2OSO2R 4 where X represents hydrogen, an alkali metal ion, an ammonium ion, or an organic counterion; R 4 represents 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 are CH2OH, CH2OSO3X, CH2OCOR 4 , or CO2R 4 is more preferably CHOH; R 2 is H, OH, OR 4 ,OCOR 4 , OCO2R 4 , OCONHR 4 , OCONR 4 2, NH2, NHR 4 , N.R. 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 is as defined above; preferably, R 2 OH, NHCOR 4 , H, or OCOR 4 and more preferably, R 2 OH, NHCOR 4 , or H; R 3 is H or R 4 -Z, where R 4is as defined above, Z represents a single bond or a functional group selected from ester, amine, amide, carbonate, or carbamate; preferably, R 3 is H.

[0078] In a preferred embodiment, R 1 are CH2OH, CH2OSO3X, CH2OCOR 4 , or CO2R 4 and more preferably, R 1 is CH2OH.

[0079] In a preferred embodiment, R 2 OH, NHCOR 4 , H, or OCOR 4 is.

[0080] In a preferred embodiment, R 2 is OH.

[0081] In a preferred embodiment, R 2 NHCOR 4 Or H.

[0082] In a preferred embodiment, R 3 is H.

[0083] In a preferred embodiment, the 3'-ketoglycoside compounds of formula (I) are selected from β-3'-ketoglucosides, α-3'-ketoglucosides, β-3'-keto-N-acetylglucosaminosides, and 2'-deoxy-3'-ketoglucosides.

[0084] In one preferred embodiment, the 3'-ketoglycoside compounds of formula (I) are selected from β-3'-ketoglucosides and α-3'-ketoglucosides.

[0085] In one preferred embodiment, the 3'-ketoglycoside compounds of formula (I) are selected from β-3'-keto-N-acetylglucosaminosides and 2'-deoxy-3'-ketoglucosides.

[0086] In one embodiment, the use of a compound of formula (I) is the combination of said compound with a compound selected from the alcohols of formula R-OH as defined above, and with an insect-active compound.

[0087] An insect-active compound, for purposes of this specification, is a compound that is active against insects, for example causing a repellent or attractive effect.

[0088] In a preferred embodiment, the insect-active compound is selected from, for example, insect repellents or insect attractants. In a more preferred embodiment, the insect-active compound is selected from terpenes, terpenoids, pyrethrins, pyrethrinoids, N,N-diethyl-3-methylbenzamide (DEET), ethyl 3-[acetyl(butyl)amino]propanoate (IR3535), and mixtures thereof.

[0089] 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.

[0090] Pyrethrinoids and pyrethrins are well-known insect repellents, as disclosed, for example, in Bowman et al., PLOS One, 2018, 13(5): e0196410 and R.L. Metcalf, Ullmann's Encyclopedia of Industrial Chemistry, 2012, DOI: 10.1002 / 14356007.a14_263.

[0091] The insect repellent efficacy of alcohols suitable according to the present invention can be readily determined by known methods disclosed in the prior art, such as Barnard et al., supra.

[0092] Another aspect of the present invention is a composition comprising at least a 3'-ketoglycoside compound of formula (I) and a carrier.

[0093] In one embodiment, the composition further comprises an alcohol of formula R-OH as disclosed above, the combination being suitable for managing the effects of the released alcohol.

[0094] In general, delivery of one or more compounds of formula (I) is accomplished by a variety of formulations and devices that are widely used and known to those skilled in the art, including, but not limited to, solutions, creams, pastes, powders, sprays, lotions, films, or compositions impregnated into or onto materials, medical devices, or surfaces such as wipes, masks, and sticks.

[0095] In a preferred embodiment, the composition is in the form of a solution, cream, paste, powder, spray, lotion, film, or is impregnated into or onto a material, medical device, or surface such as wipes, masks, and sticks.

[0096] The compositions of the present invention comprise a carrier, which is usually an aqueous solvent comprising water.

[0097] Typically, the composition further comprises ingredients selected from cosolvents, emulsifiers, humectants, astringents, buffering agents, emollients, antioxidants, preservatives, cosmetic oils, plant extracts, essential oils such as 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.

[0098] 3'-Ketoglycoside compounds may form imine, oxime, hemiacetal, hemiaminal, bisulfite, or similar adducts in the presence of alternative nucleophiles that may be commonly present in a given formulation (polyols, such as polysaccharides, e.g., chitosan; sodium bisulfite; etc.), which would be expected to further modulate its physicochemical properties, e.g., stability.

[0099] 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 application, and the surface pH is suitably adjusted to achieve the correct decomposition rate upon application.

[0100] The compounds of formula (I) are stable as solids and are largely stable when dissolved in distilled water and / or aqueous acidic media. In one embodiment, these compounds may be formulated as non-aqueous mixtures for hydration with water on the surface to which they are applied.

[0101] In general, the stability of a compound of formula (I) in aqueous solution is controlled by adjusting the compound to a pH value of, for example, about 4.5 to about 7.0, preferably about 4.5 to about 5.5. In one embodiment, application of the solution involves application of an alkaline solution to raise the pH to the alkaline range, thereby releasing the alcohol from the compound of formula (I) at a suitable rate. In another embodiment, application of the solution involves application of an acidic solution whose pH spontaneously increases upon application (e.g., the use of a carbonate buffer solution, e.g., natural carbonated spring water, whose pH is adjusted with an acid such as citric acid, which releases carbon dioxide). Compounds of formula (I) in which R is alkyl generally exhibit greater stability than aryl derivatives.

[0102] In a preferred embodiment, delivery of one or more compounds of formula (I) is by a formulation selected from, for example, a solution, a cream, a paste, a powder, a spray, a lotion, and a film, or by a device selected from, for example, a wipe, a mask, and a stick, and a medical device.

[0103] They can be applied to treat a variety of indications, for example, to repel a wide range of pests such as mosquitoes, ticks, mites, midges, midges, and head lice.

[0104] In a preferred embodiment, the insect is selected from mosquitoes, ticks, mites, midges, midges, and head lice.

[0105] Methods of using the compounds of formula (I) which comprise applying to a surface a composition comprising a 3'-ketoglycoside compound of formula (I) and a carrier also form part of the invention.

[0106] The compounds of formula (I) can be applied to any surface, for example soft surfaces such as skin, hair, fabric, plants, crops, or stored grains, or hard surfaces such as wood, synthetic materials, or ceramic materials.

[0107] In one embodiment, the soft surface is selected from skin, hair, fabric, plants, crops, and stored grains.

[0108] In one embodiment, the hard surface is selected from wood, synthetic materials, and ceramic materials.

[0109] Alcohol release The compounds of formula (I) are capable of releasing an alcohol linked to the sugar moiety through an α- or β-glycosidic bond, or a mixture of both.

[0110] Compounds of formula (I), particularly when the alcohol residue R is derived from an R-OH alcohol such as eugenol, geraniol, picaridin, carvacrol, menthol (preferably L-menthol), or PMD, can be effective insect repellents, especially upon contact with human skin. As shown in the Examples section, these compounds are capable of releasing insect repellents from the human body when incubated at physiological pH and temperature, in the presence or absence of skin cleansing fluids.

[0111] The compounds are stable in water or at low pH and can be tailored to release alcohol at different rates by adjusting the concentration and pH of the formulation applied to the skin.

[0112] The in vitro model used in the examples is designed to determine the suitability of compounds of formula (I) as slow-release insect repellents.

[0113] Surprisingly, compounds of formula (I) where R is alkyl or aryl exhibit advantages over the state of the art O-glycosides by decomposing to release their respective alcohols at a much greater rate, allowing for the controlled release of higher concentrations of alcohol onto a wider range of surfaces, such as skin areas or clothing or plants, for a period of time that is longer than the duration of the free alcohol and suitable for achieving insect repellency.

[0114] Glycosides derived from the same alcohol as the compound of formula (I) and tested under the same conditions and at similar concentrations are hydrolyzed much more slowly and to very different extents.

[0115] The rate of alcohol release in a buffer solution generally depends on the concentration of the aglycone, ketosugar, 3'-ketoglycoside, pH, and temperature, and can be conveniently adjusted to a suitable rate by those skilled in the art. Thus, the 3'-ketoglycoside of formula (I) is substantially decomposed after 60 hours in 0.1 M sodium phosphate buffer in DO at pH 7.0, but remains relatively stable in deionized water and at lower pH levels. As shown in the examples, the rate of alcohol release can be controlled by using other substances, such as arginine, in addition to phosphate buffer.

[0116] Methyl-O-α-D-3′-ketoglucopyranoside (compound of formula (III)) also slowly released methanol after 36 hours when heated to 37° C. in 0.1 M sodium phosphate buffer in DO at pH 7.0, but also remained stable in deionized water and relatively stable at acidic pH. TIFF0007727647000015.tif42128

[0117] When methyl-O-α-D-3′-ketoglucopyranoside (III) was reacted in the presence of skin wash at the same temperature and pH, much more methanol was released than was observed in the buffer alone.

[0118] The difference in the amount of phenol released from phenyl-O-β-D-3'-ketoglucopyranoside (IV) in the presence of skin wash solution versus buffer alone was not very significant, but in the former case, phenol was completely released after 60 h, whereas in the latter case, a small amount of the conjugate remained. TIFF0007727647000016.tif42128

[0119] These data for these model compounds clearly demonstrate that alcohol release is much greater in the presence and absence of skin at 37°C and neutral pH, and many of these compounds are stable in water alone and partially stable at pH 5.7.

[0120] Surprisingly, compound (V), i.e., geranyl-O-β-D-3'-ketoglucoside, containing a primary allylic alcohol in the β-configuration, degraded much more rapidly than compound (III), i.e., methyl-O-α-D-3'-ketoglucoside, with approximately 50% degraded after 3 days. The release rate can be further tuned by adjusting the sugar. For example, surprisingly, using 3'-ketoglycosides of N-Ac-glucosamine or 2'-deoxyglucose instead of glucose allows for a greater release rate of geraniol. TIFF0007727647000017.tif42128

[0121] Furthermore, the conversion was concentration-dependent, with similar conversions obtained with the 5 mg / mL or 20 mg / mL mixtures. In the latter case, when the stoppered reaction vessel was opened after 3 days, the very strong aroma of geraniol was immediately noticeable, which was not present when the corresponding glucoside, geranyl-O-β-D-glucopyranoside, was used.

[0122] Formulations containing one or more compounds of formula (I) can be applied to skin, hair, plants, and even stored crops and grains, either alone or in combination with, for example, microbial crop spays.

[0123] The following examples illustrate certain features of the compounds of the present invention and comparative examples. [Example]

[0124] 1 H and 13 C NMR spectra were recorded on a Varian Mercury 300 (300 MHz) and a Varian Mercury 400 ( 1 400.1Mz in H, 13 C at 100.6 MHz, or on a Bruker AVIII-500 (PA-BBO probe) at 500 MHz in deuterated chloroform, deuterium oxide, deuterated methanol, or deuterated dimethyl sulfoxide. Chemical shifts (d) are reported in parts per million (ppm) with tetramethylsilane (TMS) as the internal standard, and coupling constants (J) are reported in hertz (Hz). The following abbreviations are used: 1 The following H multiplicities were used: singlet (s), doublet (d), triplet (t), quartet (q), quintet (quint), septet (sept.), doublet (dd), triplet (td), multiplet (m), broad singlet (brs), broad doublet (brd), and broad triplet (brt). High-resolution mass spectra were acquired using an LC / MSD-TOF mass spectrometer (Agilent Technologies) or a Bruker microTOFmass spectrometer.

[0125] The reaction course and product mixtures were analyzed by thin layer chromatography (TLC) on commercially available silica gel 60 plates or by using the above-mentioned instruments. 1 The analysis was monitored by H NMR. Chromatography was performed using column-grade silica gel (mesh size 0.040–0.063 mm). Chemicals were purchased from Sigma-Aldrich (Merck) or Cymit Quimica unless otherwise stated.

[0126] Racemic cis- / trans-p-menthane-3,8-diol (PMD) of approximately 95% purity was purchased from Boc Sciences, and the cis and trans isomers (approximately a 6:4 mixture) were separated by silica column chromatography using 1:3 ethyl acetate / hexane. The faster-running cis isomer was 1 H NMR was identical to authentic (1S,2R,5R)-2-(1-hydroxy-1-methylethyl)-5-methylcyclohexanol purchased from Sigma-Aldrich (Merck).

[0127] A crude lyophilized cell-free extract (CFE) of glycosyltransferase (YjiC) from Bacillus licheniformis DSM 13 was prepared by Prozomix Ltd from plasmid DNA using standard molecular biology techniques with some modifications from Bashyal et al., ACS Omega, 2019, 4, 9367-9375: a codon-optimized gene sequence with an N-terminal IMAC tag (GenBank sequence accession number AAU40842), pET28a vector, E. coli BL21(DE3), and TB medium.

[0128] Lipase enzyme was purchased as a kit from Enzagen Ltd.

[0129] The non-IUPAC numbering used in the compounds prepared in the examples is to allow a better understanding of the spectral data.

[0130] Example 1 Preparation of (2R,3S,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-O-β-D-3'-ketoglucopyranoside) TIFF0007727647000018.tif44128 Geranyl-O-β-D-glucopyranoside (available from Carbosynth) (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 stirred rapidly at room temperature.

[0131] [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (0.025 g, 2.5 mol%) was added, and stirring was continued for 24 h, after which all starting material was converted to product based on silica gel TLC analysis using 1:5 MeOH / dichloromethane as eluent and plate development with 10% concentrated sulfuric acid in ethanol, followed by vigorous heating.

[0132] The mixture was concentrated by distillation under reduced pressure and purified by silica chromatography using 3:1 ethyl acetate / hexane as eluent to remove non-polar UV-active impurities, followed by purification with 3:1 ethyl acetate / hexane to give the title compound as a clear, colorless oil, 0.186 g (56% yield).

[0133] The title compound obtained was characterized by the following parameters: R f = 0.46 (1:5 MeOH / dichloromethane); TIFF0007727647000019.tif38145HRMS (ESI+). [C 16 H 26 O6+ NH4] + Calculated value: 332.2068. Measured value: 332.2073.

[0134] 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'-ketoglucopyranoside) To a stirred solution of commercially available glucose pentaacetate (60.0 g, 0.154 mol) in DMF (120 mL) at room temperature, H2N-NH2·AcOH (20.2 g, 0.200 mol, 1.3 equiv.) was added, and the reaction mixture was vigorously stirred for 2 h. TLC indicated complete consumption of the starting material. 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 give 2,3,4,6-tetra-O-acetyl-D-glucopyranose (47.7 g, 0.137 mol, 89%) as a pale yellow oil.

[0135] To a stirred solution of crude 2,3,4,6-tetra-O-acetyl-D-glucopyranose (7.42 g, 21.36 mmol) in dry dichloromethane (150 mL) at room temperature, trichloroacetonitrile (6.5 mL, 64.1 mmol, 3.0 equiv.) and anhydrous potassium carbonate (15.0 g, 107 mmol, 5.0 equiv.) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite®, and the volatiles were removed to give 2',3',4',6'-tetra-O-acetyl-D-glucopyranosyl trichloroacetimidate (10.06 g, 20.46 mmol, 96%) as a light yellow solid. Data for this compound are available in Ikeuchi et al., Synlett., 2019, 30, 1308-1312.

[0136] To a solution of crude 2',3',4',6'-tetra-O-acetyl-D-glucopyranosyl trichloroacetimidate (0.4 g, 0.81 mmol) in anhydrous CHCl (8 mL) was added racemic picaridin (0.18 g, 0.81 mmol) at -78 °C. After 5 min, TMSOTf (0.081 mmol) was added, and the resulting solution was stirred at 0 °C for 2 h. TLC then indicated the consumption of the starting material (EtOAc / hexane, 1:1). The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (EtOAc / hexane, 1:4 to 1:1) to afford 178 mg (40% yield) of tetraacetylated picaridin-β-glucoside.

[0137] The resulting tetraacetylated compounds were characterized by the following parameters: TIFF0007727647000021.tif66128TIFF0007727647000022.tif48140HRMS (ESI + ): [C 26 H 41 NO 12 + H] + Calculated value = 560.2705; Measured value 560.2702.

[0138] To a solution of tetraacetylated picaridin-β-glucoside (0.170 g, 0.308 mmol) in methanol (5 mL) was added 10 μL of 25% NaOMe in methanol, and the resulting solution was stirred at room temperature for 3 h. After this time, TLC indicated consumption of the starting material (EtOAc). The reaction was quenched with Amberlite (acid form) and then filtered. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (EtOAc) to afford 96 mg (81% yield) of unprotected picaridin-β-glucoside.

[0139] The resulting deacetylated compounds were characterized by the following parameters: TIFF0007727647000023.tif67128TIFF0007727647000024.tif54145HRMS (ESI + ): [C 18 H 33 NO8+ H] + Calculated value = 392.2279; Measured value 392.2279.

[0140] To a stirred solution of unprotected picaridin-β-glucoside (50 mg, 0.128 mmol) in 9:1 MeCN / HO (1.0 mL) was added benzoquinone (14 mg, 0.383 mmol, 3.0 equiv.) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (7 mg, 0.006 mmol, 0.05 equiv.). The reaction mixture was heated at 60 °C for 1 h and absorbed onto silica. The residue was purified by silica gel flash column chromatography (7:3 EtOAc / hexanes) to afford the diastereomeric title compounds as white foams (36 mg, 0.092 mmol, 72%).

[0141] The title compound obtained was characterized by the following parameters: TIFF0007727647000025.tif55140HRMS (ESI + ): [C 18 H 31 NO8+ H] + Calculated value = 390.2122; Measured value 390.2134.

[0142] Example 3 Preparation of (2R,3S,4R)-6-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3,4-diol (geranyl-OD-2'-deoxy-3'-ketoglucopyranoside) To a stirred solution of 2-deoxy-D-glucose (1.0 g, 6.1 mmol, 1.0 equiv.) in anhydrous pyridine (12 mL) at 0 °C was added acetic anhydride (4.6 mL, 48.7 mmol, 8.0 equiv.) dropwise. The reaction mixture was allowed to warm slowly to room temperature and then stirred for 15 h, at which point TLC analysis (hexane / EtOAc, 7 / 3) indicated complete conversion of the starting material to a less polar product (Rf = 0.4). The reaction mixture was poured into ice-water (100 mL) and diluted with EtOAc (75 mL). The organic layer was separated and washed sequentially 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 x 20 mL) to give 2-deoxy-1,3,4,6-tetra-O-acetyl-α / β-D-glucose as a white solid (2.02 g, 5.54 mmol, 100%). Data for this compound are available in Beswick et al., Carbohydrate Res., 2020, 488, 107896.

[0143] To a stirred solution of crude 2-deoxy-1,3,4,6-tetra-O-acetyl-α / β-D-glucose (2.01 g, 6.05 mmol) in anhydrous THF (75 mL) at 0 °C was added saturated methanolic ammonia solution (25 mL) over 5 min. The reaction mixture was slowly warmed to 40 °C and stirred for 5 h, at which point TLC analysis (hexane / EtOAc, 7:3) showed complete conversion of the starting material to a lower R spot (R = 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 give 2-deoxy-3,4,6-tri-O-acetyl-α / β-D-glucose as a white solid (1.426 g, 4.916 mmol, 83%). 1H-NMR analysis indicates a 1:5 α / β mixture. Data for this compound are available in Bucher et al., Angew. Chem. Int. Ed., 2010, 49, 8724-8728.

[0144] 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 dry dichloromethane (60 mL) at 0 °C, trichloroacetonitrile (4.9 mL, 49.3 mmol, 10 equiv.) and DBU (74 μL, 0.493 mmol, 0.1 equiv.) were added. The reaction mixture was stirred overnight at room temperature, and the volatiles were removed to give crude 2'-deoxy-3',4',6'-tri-O-acetyl-α / β-D-glucopyranosyl trichloroacetimidate (2.14 g, 4.93 mmol, 100%) as an orange oil, which was used without further purification. Data for this compound are available in Bucher et al., Angew. Chem. Int. Ed., 2010, 49, 8724-8728.

[0145] 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 then allowed to warm slowly to room temperature over 3 h, quenched with saturated aqueous NaHCO (10 mL), extracted with CHCl (2×50 mL), washed with 1 M aqueous NaOH (20 mL), brine (50 mL), dried over anhydrous NaSO, 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-glucopyranoside (1.01 g, 2.37 mmol, 48%) as a yellowish oil (α / β mixture). One major isomer (Rf = 0.25) was obtained.

[0146] The resulting triacetylated compounds were characterized by the following parameters: TIFF0007727647000027.tif32128TIFF0007727647000028.tif88140MS (ESI + ]: [C 22 H 34 O8+ NH4] + Calculated value = 444.2592; measured value 444.2579.

[0147] To a stirred solution of geranyl 3',4',6'-tri-O-acetyl-2-deoxy-α / β-D-glucopyranoside (470 mg, 1.102 mmol) in dry methanol (10 mL) was added NaOMe (12 mg, 0.220 mmol, 0.2 equiv). The reaction mixture was stirred at room temperature for 3 h, and the reaction was quenched with 3 drops of AcOH. After removal of volatiles, the residue was purified by silica gel short flash column chromatography (CHCl / MeOH, 93:7) to give compound geranyl 2'-deoxy-β-D-glucopyranoside as a white solid (255 mg, 0.849 mmol, 77%).

[0148] The resulting deacetylated compounds were characterized by the following parameters: TIFF0007727647000029.tif29128TIFF0007727647000030.tif65141HRMS (ESI+) [C 16 H 28 O5+ Na] + Calculated value = 323.1829. Measured value 323.1824.

[0149] To a stirred solution of geranyl 2'-deoxy-β-D-glucopyranoside (124 mg, 0.413 mmol) in 9:1 MeCN / HO (4 mL) was added benzoquinone (134 mg, 1.239 mmol, 3.0 equiv.) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (22 mg, 0.021 mmol, 0.05 equiv.). The reaction mixture was stirred at room temperature for 6 h and absorbed onto silica gel. The residue was purified by silica gel flash column chromatography (CHCl / MeOH 95:5) to give the title compound as a white solid (67 mg, 0.225 mmol, 54%).

[0150] The title compound obtained was characterized by the following parameters: TIFF0007727647000031.tif68140HRMS (ESI+): [C 16 H 26 O5+ NH4] + Calculated value = 316.2118; measured value 316.2125.

[0151] Example 4 Preparation of N-((2R,3S,5R,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H-pyran-3-yl)acetamide (geranyl-O-β-D-2'-acetamido-2'-deoxy-3'-ketoglucopyranoside) TIFF0007727647000032.tif35128 To a stirred solution of commercially available 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranose (12.63 g, 32.44 mmol) in THF (60 mL) at room temperature, piperazine (3.1 g, 35.68 mmol, 1.1 equiv.) was added, and the reaction mixture was vigorously stirred 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). The mixture was dried over anhydrous Na2SO4 and filtered. The solvent was then removed to give 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranose (7.58 g, 21.82 mmol, 67%) as a white foam which was used without further purification.

[0152] To a stirred solution of crude 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-D-glucopyranose (7.42 g, 21.36 mmol) in dry dichloromethane (150 mL) at room temperature was added trichloroacetonitrile (6.5 mL, 64.1 mmol, 3.0 equiv.) and anhydrous potassium carbonate (15.0 g, 107 mmol, 5.0 equiv.). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite® and the volatiles removed to give crude 2'-acetamido-3',4',6'-tri-O-acetyl-2'-deoxy-D-glucopyranosyl trichloroacetimidate (10.06 g, 20.46 mmol, 96%) as a light yellow solid. Data for this compound is available in Zhang et al., J. Med. Chem., 2019, 62, 7857-7873.

[0153] To a stirred solution of crude 2'-acetamido-3',4',6'-tri-O-acetyl-2'-deoxy-D-glucopyranosyl trichloroacetimidate (432 mg, 0.879 mmol) and geraniol (0.456 mL, 2.636 mmol, 3.0 equiv) in dichloromethane (7 mL) was added TMSOTf (16 μL, 88 μmol) slowly at −20° C. The reaction mixture was stirred at room temperature for 2 h, quenched with saturated aqueous NaHCO (10 mL), extracted with CHCl (2×10 mL), washed with brine (10 mL), dried over anhydrous NaSO, and filtered. After removal of the solvent, the residue was purified by silica gel flash column chromatography (EtOAc) to give the compound geranyl 3′,4′,6′-tri-O-acetyl-2′-deoxy-2′-acetamido-β-D-glucopyranoside (273 mg, 0.56 mmol, 65%) as a white solid.

[0154] The obtained compounds were characterized by the following parameters: TIFF0007727647000033.tif34128TIFF0007727647000034.tif55140HRMS (ESI + ): [C 24 H 37NO9+ H] + Calculated value = 484.2541; measured value 484.2539.

[0155] To a stirred solution of geranyl 3',4',6'-tri-O-acetyl-2'-deoxy-2'-acetamido-β-D-glucopyranoside (200 mg, 0.413 mmol) in dry 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 h, and the reaction was quenched with two drops of AcOH. After removal of volatiles, the residue was purified by silica gel short flash column chromatography (1:1 EtOAc / hexanes) to give the compound geranyl 2'-deoxy-2'-acetamido-β-D-glucopyranoside as a white solid (148 mg, 0.413 mmol, 100%).

[0156] The obtained compounds were characterized by the following parameters: TIFF0007727647000035.tif31128TIFF0007727647000036.tif75140HRMS (ESI + ) [C 18 H 31 NO6+ Na] + Calculated value = 380.2044. Measured value 380.2048.

[0157] To a stirred solution of geranyl 2'-deoxy-2'-acetamido-β-D-glucopyranoside (50 mg, 0.140 mmol) in 9:1 MeCN / HO (1 mL) was added benzoquinone (45 mg, 0.420 mmol, 3.0 equiv.) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (7.5 mg, 0.007 mmol, 0.05 equiv.). The reaction mixture was stirred at 50 °C for 5 h and absorbed onto silica gel. The residue was purified by silica gel flash column chromatography (EtOAc / MeOH 98:2) to give the title compound as a white solid (22 mg, 0.062 mmol, 44%).

[0158] The title compound obtained was characterized by the following parameters: TIFF0007727647000037.tif68140HRMS (ESI + ) [C 18 H 31 NO6+ Na] + Calculated value = 378.1887. Measured value 378.1885.

[0159] 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'-ketoglucopyranoside) A mixture of cis-PMD (30 mg, 0.17 mmol), UDP-α-D-glucose disodium salt (100 mg, 0.16 mmol), and glycosyltransferase (YjiC) from lyophilized crude cell-free extract (100 mg) of Bacillus licheniformis DSM 13 was diluted with 100 mM Tris buffer (5 mL), pH 7.4, and incubated at 30 °C / 80 rpm for 2 days. The resulting mixture was washed with hexane (2 x 20 mL) and then extracted with ethyl acetate (2 x 20 mL). The ethyl acetate portions were combined and concentrated by vacuum distillation. To the residue were added p-benzoquinone (32 mg, 0.30 mmol) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (3 mg, ca. 2 mol%), and the mixture was suspended in acetonitrile (2 mL) and water (0.2 mL) and incubated at 25 °C / 80 rpm for 20 h. The solvent was removed under reduced pressure, and the residue was purified by silica chromatography using 1:20 methanol / dichloromethane to give the title compound as a clear, colorless oil (10 mg, 17%).

[0160] The title compound obtained was characterized by the following parameters: TIFF0007727647000039.tif55150HRMS (ESI + ): [C 16 H 28 O7+ Na] + Calculated value = 355.1727; Measured value 355.1727.

[0161] Example 6 Preparation of (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-((2-((S)-4-methylcyclohex-3-en-1-yl)propan-2-yl)oxy)tetrahydro-4H-pyran-4-one (S-α-terpineol-O-β-D-3'-ketoglucopyranoside) A mixture of (S)-α-terpineol (30 mg, 0.19 mmol), UDP-α-D-glucose disodium salt (100 mg, 0.16 mmol), and lyophilized crude cell-free extract (100 mg) of Bacillus licheniformis DSM 13 containing glycosyltransferase (YjiC) was diluted with 100 mM Tris buffer (5 mL), pH 7.4, and incubated at 30 °C / 80 rpm for 18 h. The resulting mixture was washed with hexane (2 x 20 mL) and then extracted with ethyl acetate (2 x 20 mL). The ethyl acetate portions were combined and concentrated by vacuum distillation. To the residue were added p-benzoquinone (32 mg, 0.30 mmol) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (3 mg, ca. 2 mol%), and the mixture was suspended in acetonitrile (2 mL) and water (0.2 mL) and incubated at 25 °C / 80 rpm for 20 h. The solvent was removed under reduced pressure, and the residue was purified by silica chromatography using 1:10 methanol / dichloromethane to give the title compound as a clear, colorless oil (27 mg, 44%).

[0162] The title compound obtained was characterized by the following parameters: TIFF0007727647000041.tif52150HRMS (ESI + ): [C 16 H 26 O6+ Na] + Calculated value = 337.1622; measured value 337.1611.

[0163] Example 7 Preparation 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'-ketoglucopyranoside) A solution of commercially available 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (500 mg, 1.216 mmol) in acetone (4 mL) was added to a solution of eugenol (0.56 mL, 3.648 mmol, 3.0 equiv) in 1.0 M LiOH solution (2 mL), and the resulting green suspension was stirred at room temperature for 2 h. Completion of the reaction was monitored by TLC (8:2 EtOAc / hexanes; Rf = 0.25). The acetone was removed, and the resulting suspension was extracted with dichloromethane (3 x 15 mL). The crude product was washed with 10% sodium hydroxide (3 x 10 mL), water, and dried over anhydrous Na2SO4. After filtration and removal of the solvent under reduced pressure, the crude product was purified by flash column chromatography to give tetraacetylated eugenyl-α-glucoside (500 mg, 1.01 mmol, 83%) as a white solid.

[0164] TIFF0007727647000043.tif42128Data for this compound is available in Mulkens et al., J. Natural Prod., 1988, 51, 496-498.

[0165] To a stirred solution of protected eugenyl glucoside (330 mg, 0.666 mmol) in dry methanol (20 mL) was added NaOMe (7 mg, 0.133 mmol, 0.2 equiv.). The reaction mixture was stirred at room temperature for 1 h, and the reaction was quenched with 2 drops of AcOH. After removal of volatiles, the residue was purified by silica gel short flash column chromatography (CHCl / MeOH, 9:1) to give eugenyl-β-glucoside as a white solid (172 mg, 0.527 mmol, 79%).

[0166] TIFF0007727647000044.tif41128 Data for this compound is available in Vijayakumar et al., Biotechnol. Lett., 2007, 29, 575-584.

[0167] To a stirred solution of unprotected eugenyl glucoside (30 mg, 0.092 mmol) in 9:1 MeCN / HO (1.5 mL) was added benzoquinone (30 mg, 0.276 mmol, 3.0 equiv.) and [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (5 mg, 0.005 mmol, 0.05 equiv.). The reaction mixture was heated at 60 °C for 1 h and absorbed onto silica. The residue was purified by silica gel flash column chromatography (CHCl / MeOH, 95:5) to give the title compound as a white solid (22 mg, 0.068 mmol, 74%).

[0168] The title compound obtained was characterized by the following parameters: TIFF0007727647000045.tif68140HRMS (ESI + ): [C 16 H 20 O7+ NH4] + Calculated value = 342.1547. Measured value 342.1544.

[0169] Example 8 Preparation of (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(5-isopropyl-2-methylphenoxy)tetrahydro-4H-pyran-4-one (carvacrol-O-β-D-3'-ketoglucopyranoside) A mixture of carvacrol (30 mg, 0.20 mmol), UDP-α-D-glucose disodium salt (100 mg, 0.16 mmol), and glycosyltransferase (YjiC) from lyophilized crude cell-free extract (100 mg) of Bacillus licheniformis DSM 13 was diluted with 100 mM Tris buffer (5 mL), pH 7.4, and incubated at 30 °C / 80 rpm for 18 h. The resulting mixture was washed with hexane (2 x 20 mL) and then extracted with ethyl acetate (2 x 20 mL). The ethyl acetate portions 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)](OTf) (3 mg, ca. 2 mol%), and the mixture was suspended in acetonitrile (2 mL) and water (0.2 mL) and incubated at 25 °C / 80 rpm for 14 days. Since the reaction was incomplete, additional [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (3 mg, ca. 2 mol%) was added. After an additional 2 days, the reaction was nearly complete, so the solvent was removed under reduced pressure, and the residue was purified by silica chromatography using 1:10 methanol / dichloromethane to give the title compound as a clear, colorless oil (20 mg, 32%).

[0170] The title compound obtained was characterized by the following parameters: TIFF0007727647000047.tif62162HRMS (ESI + ): [C 16 H 22 O6+ NH4] + Calculated value = 328.1755; measured value 328.1752.

[0171] Example 9 Preparation of ((2R,3R,5S,6R)-5-acetoxy-6-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-hydroxy-4-oxotetrahydro-2H-pyran-2-yl)methyl acetate (2',6'-diacetyl-geranyl-O-β-D-3'-ketoglucopyranoside) A mixture of geranyl-β-3'-ketoglucoside (100 mg), prepared as in 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 plug of Celite and concentrated by distillation under reduced pressure to give the title compound as a light yellow solid (0.118 g, 63%).

[0172] The title compound obtained was characterized by the following parameters: TIFF0007727647000049.tif75140HRMS (ESI + ): [C 20 H 30 O8+ NH4] + Calculated value = 416.2279; measured value 416.2276.

[0173] 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'-ketoglucopyranoside) TIFF0007727647000050.tif49128 Following a process substantially similar to that of Example 11, the title compound was prepared using phenyl-O-β-D-3′-ketoglucopyranoside (prepared as shown in Comparative Example 1).

[0174] The title compound obtained was characterized by the following parameters: TIFF0007727647000051.tif62140HRMS (ESI + ): [C 16 H 18 O8+ NH4] + Calculated value = 356.1340; measured value 356.1341.

[0175] Example 11 Preparation of ((2R,3R,5S,6S)-3,5-dihydroxy-4-oxo-6-phenoxytetrahydro-2H-pyran-2-yl)methyl pyridinium hydrogen sulfate (phenyl-O-β-D-3'-keto-6'-sulfatoglucopyranoside pyridinium salt) To a stirred solution of phenyl-O-β-D-3'-ketoglucopyranoside (prepared as described in Comparative Example 1) (10 mg, 0.039 mmol) in D6-DMSO (0.7 mL) was added SO3·pyridine (19 mg, 3 equiv.). After stirring at room temperature for 15 min, analysis of the solution by TLC showed complete conversion to a single, much more polar compound.

[0176] Without further treatment, the title compound obtained was characterized by the following parameters: TIFF0007727647000053.tif62140HRMS (ESI - ): [C 12 H 14 O9S-H] - Calculated value = 333.0286; measured value 333.0280.

[0177] Example 12 Preparation of (2R,3S,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (rac-menthyl-O-β-D-3'-ketoglucopyranoside) To a solution of 2',3',4',6'-tetra-O-acetyl-D-glucopyranosyl trichloroacetimidate (0.4 g, 0.81 mmol) prepared as described in Example 2 in anhydrous CHCl (8 mL) was added (+ / -)-menthol (0.12 g, 0.81 mmol) at 0 °C. After 5 min, TMSOTf (0.081 mmol) was added, and the resulting solution was stirred at 0 °C for 2 h. TLC then indicated consumption of the starting material (EtOAc / hexane 1:2, rf = 0.6). The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (EtOAc / hexane 1:4 to 1:1, Rf = 0.7) to yield 200 mg of crude tetraacetylated menthyl-β-glucoside.

[0178] To a solution of the crude tetraacetylated menthyl-β-glucoside (0.200 g, 0.412 mmol) in methanol (5 mL), 20 μL of 25% NaOMe in methanol was added, and the resulting solution was stirred at room temperature for 3 h. After this time, TLC showed the consumption of the starting material (EtOAc, Rf = 0.9). The reaction was quenched with Amberlite (acid form) and filtered. The solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel chromatography (EtOAc Rf = 0.1) to afford 50 mg of menthyl-β-glucopyranoside (20% overall yield over two steps from 2',3',4',6'-tetra-O-acetyl-D-glucopyranosyl trichloroacetimidate). Data for this compound are available in Choi et al., AMB Expr., 2017, 7, 167.

[0179] A mixture of menthyl-β-glucopyranoside (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)](OTf) (6 mg, ca. 2.5 mol%) was suspended in acetonitrile (6 mL) and water (0.6 mL) and stirred at room temperature for 19 h. Analysis by TLC (MeOH / dichloromethane, 1:5) showed the formation of a new spot at Rf = 0.7, but primarily starting material (Rf = 0.5). Additional catalyst (15 mg, ca. 6.25 mol%) was added, and the mixture was stirred for an additional 4 days. The reaction proceeded further but was still incomplete, so additional catalyst (15 mg, ca. 6.25 mol%) was added, and the mixture was stirred for an additional 6 days. As no starting material remained, the mixture was concentrated by distillation under reduced pressure and the residue purified by silica chromatography using 1:20 methanol / dichloromethane to give the diastereomeric title compounds as clear, colorless oils (10 mg, 17%).

[0180] The title compound obtained was characterized by the following parameters: TIFF0007727647000055.tif31140HRMS (ESI + ): [C16 H 28 O6+ NH4] + Calculated value = 334.2224; measured value 334.2230.

[0181] Comparative Example 1 Preparation of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-phenoxytetrahydro-4H-pyran-4-one (phenyl-O-β-D-3'-ketoglucopyranoside) TIFF0007727647000056.tif36128 Phenyl-O-β-D-glucopyranoside (available 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 stirred rapidly at room temperature.

[0182] [(2,9-Dimethyl-1,10-phenanthroline)Pd(μ-OAc)](OTf) (0.03 g, 2.5 mol%) was added, and stirring was continued for 18 h, after which nearly all of the starting material had been converted to product based on silica gel TLC analysis using 1:5 MeOH / dichloromethane as eluent and plate development with 10% concentrated sulfuric acid in ethanol, followed by vigorous heating. The mixture was concentrated by distillation under reduced pressure and purified by silica chromatography using 3:1 ethyl acetate / hexane as eluent to remove nonpolar UV-active impurities, followed by purification with 3:1 ethyl acetate / hexane to give the title compound as a clear, colorless oil, 0.186 g (52% yield).

[0183] The title compound obtained was characterized by the following parameters: Rf = 0.5 (1:5 MeOH / dichloromethane); TIFF0007727647000057.tif41140HRMS (ESI+). [C 12 H 14 O6+ NH4] + Calculated value: 272.1129. Measured value: 272.1136.

[0184] 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'-ketoglucopyranoside) The title compound was prepared using 4-nitrophenyl-O-β-D-glucopyranoside (available from Sigma-Aldrich) following a process substantially similar to that of Comparative Example 1. Data for this compound are available in Sedmera et al., Tetrahedron Lett., 2004, 45, 8677-8680.

[0185] 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'-ketoglucopyranoside) The title compound was prepared using 4-nitrophenyl-O-α-D-glucopyranoside (available from Sigma-Aldrich) following a process substantially similar to that of Comparative Example 1. Data for this compound are available in Takeuchi et al., J. Biochem., 1985, 98, 1631-1638.

[0186] Comparative Example 4 Preparation of (2R,3R,5S,6S)-3,5-dihydroxy-2(hydroxymethyl)-6-methoxytetrahydro-4H-pyran-4-one (methyl-O-β-D-3'-ketoglucopyranoside) The title compound was prepared using methyl-O-β-D-glucopyranoside (available from Sigma-Aldrich) following a process substantially similar to that of Comparative Example 1. Data for this compound are available in Jager et al., Angew. Chem. Int. Ed., 2013, 52, 7809-7812.

[0187] Comparative Example 5 Preparation of (2R,3R,5R,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran-4-one (methyl-O-α-D-3'-ketomannopyranoside) The title compound was prepared using methyl-O-α-D-mannopyranoside (available from Sigma-Aldrich) following a process substantially similar to that described in Comparative Example 1. Data for this compound are available in Chung et al., ACS Catal., 2016, 6, 4653-4659.

[0188] 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'-ketoglucuronide methyl ester) TIFF0007727647000062.tif28128 Methyl-α-D-glucopyranoside (available 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-Tetramethylpiperidine 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 h, the mixture was allowed to warm to room temperature and stirred overnight. Ethanol (10 mL) was added, and the solvent was removed under reduced pressure. The residue was dissolved in water (10 mL), washed with ethyl acetate (2 x 10 mL), and the aqueous portion was concentrated by vacuum distillation to give the crude product, methyl α-D-glucuronide as the sodium salt, as a white solid (1.40 g). Data for this compound are available in Lu et al., Molecules, 2016, 21, 1301.

[0189] The crude product methyl-α-D-glucuronide as the sodium salt (0.165 g) was suspended in methanol (3 mL), 3 drops of concentrated sulfuric acid was 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 product methyl-α-D-glucuronide methyl ester (0.209 g).

[0190] The title compound was prepared in 52% yield over three steps from methyl-α-glucopyranoside using crude methyl-α-D-glucuronide methyl ester following a process substantially similar to that described in Comparative Example 1. Data for this compound are available in Eisink et al., ACS Catal., 2017, 7, 1438-1445.

[0191] Example 13 Comparison of the release of the electron-deficient para-substituted aromatic alcohol p-nitrophenol from its β-3'-ketoglucopyranoside and β-glucopyranoside in aqueous solution at room temperature and various pH values From 4-nitrophenyl-O-β-D-3′-ketoglucopyranoside prepared in Comparative Example 2.

[0192] In this example, 4-nitrophenyl-O-β-D-3'-ketoglucopyranoside and 4-nitrophenyl-O-β-D-glucopyranoside were used as model compounds to determine the release rate of aromatic alcohol (4-nitrophenol) under different conditions.

[0193] 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'-ketoglucopyranoside) was determined in comparison with that from (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (p-nitrophenyl-O-β-D-glucopyranoside) at room temperature in 0.1 M deuterated phosphate buffer solutions of different pHs containing 10% D6-DMSO or in water containing 10% D6-DMSO.

[0194] 1 M stock solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate were prepared in deuterium oxide (DO). Stock solutions of 25 mg of 4-nitrophenyl-O-β-D-3'-ketoglucopyranoside (Substrate A) and 25 mg of 4-nitrophenyl-O-β-D-glucopyranoside (Substrate B) in 0.5 mL of D6-DMSO were prepared, respectively. A stock solution of 11 mg of 4-nitrophenol in an equal volume of D6-DMSO was also prepared for visual comparison.

[0195] Solutions of pH 4.5, 5.8, 7.4, and 9.5 were prepared by diluting the appropriate individual stock phosphate solution or mixture to 0.1 M using a calibrated pH meter.

[0196] Ten parallel reaction vials were charged with 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, as shown in Table I below. The reaction vials were allowed to stand at room temperature, and the color of the solutions was recorded by visual observation and comparison with the color of an identically diluted authentic 4-nitrophenol solution, as shown in Table I.

[0197] (Table I) TIFF0007727647000063.tif119142+++++ = Color of the same intensity as observed in 4-nitrophenyl solution at the same pH, indicating reaction completion - = no color observed

[0198] After about 26 hours, all of the reaction mixtures 2 to 5 were 1 The samples were analyzed by H-NMR using 128 scans on a 400 MHz instrument. Based on the observation of aromatic signals, reaction 2 contained only the starting material, reaction 3 contained a mixture of the starting material and 4-nitrophenol, and reactions 4 and 5 contained almost exclusively 4-nitrophenol with traces of the starting material. The 4-nitrophenol signal was observed to shift due to differences in the degree of ionization in solutions of different pH, and these were compared by spiking experiments with 4-nitrophenol solutions prepared at the same pH.

[0199] Experiments clearly demonstrate that by varying the solution pH, the rate of 4-nitrophenyl-O-β-D-3'-ketoglucopyranoside degradation can be tuned from no release at low pH to delivery of μg amounts of 4-nitrophenol per minute from 0.5 mL of aqueous solution under physiologically relevant conditions. This is consistent with the application of 0.5 mL of the aqueous formulation to 1 cm of skin. 2 This corresponds to the required amount of insect repellent, converted into the amount released per unit area. Furthermore, the corresponding glucopyranoside, 4-nitrophenyl-O-β-D-glucopyranoside, does not release substantially any 4-nitrophenol under the same conditions.

[0200] Example 14 Release of eugenol, an electron-rich ortho- and para-disubstituted aromatic alcohol (insect repellent alcohol), from its β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From eugenyl-β-3′-ketoglucopyranoside prepared in Example 7.

[0201] In this example, the release rate of eugenol from (2S,3S,5R,6R)-2-(4-allyl-2-methoxyphenoxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (eugenyl-O-β-D-3′-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 33% D6-DMSO was determined.

[0202] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0203] A stock solution of 15 mg of eugenyl-O-β-D-3′-ketoglucopyranoside in 1.0 mL of D6-DMSO was prepared.

[0204] As shown in the reaction table below, three parallel reaction vials were added with 0.20 mL of glycoside substrate solution in D6-DMSO and 0.40 mL of low or high pH 0.1 M phosphate buffer in D2O or D2O, and the mixture was incubated with shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table II.

[0205] (Table II) TIFF0007727647000064.tif74148NR = No Driving *The reaction was followed by the increase in the signal at 6.77 ppm (free eugenol) relative to the signal at 6.91 ppm (starting material).

[0206] At 32°C, eugenyl-O-β-D-3'-ketoglucopyranoside decomposes only slowly at pH 5.8 but releases eugenol at a much greater rate at pH 7.4, indicating that alcohol can be released at physiological temperature and pH from electron-rich ortho- and para-disubstituted aromatic-O-β-D-3'-ketoglucopyranosides in addition to electron-deficient aryl derivatives.

[0207] Example 15 Release of carvacrol, an electron-rich ortho- and meta-disubstituted aromatic alcohol (an insect repellent alcohol), from its β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From carvacrol-β-3'-ketoglucopyranoside prepared in Example 8.

[0208] In this example, the release rate of carvacrol from ((2R,3R,5S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(5-isopropyl-2-methylphenoxy)tetrahydro-4H-pyran-4-one (carvacrol-O-β-D-3′-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 20% ​​D6-DMSO was determined.

[0209] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0210] A stock solution of 15 mg of carvacrol-O-β-D-3′-ketoglucopyranoside in 1.0 mL of D6-DMSO was prepared.

[0211] To two parallel reaction vials, 0.20 mL of glycoside substrate solution in D6-DMSO and 0.50 mL of low or high pH 0.1 M phosphate buffer in D2O or D2O were added, as shown in the reaction table below, and the mixture was incubated with shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table III.

[0212] (Table III) TIFF0007727647000065.tif59134* The reaction was followed by the increase in singlet at 1.99 ppm relative to the singlet at 2.08 ppm.

[0213] At 32°C, carvacrol-β-3'-ketoglucopyranoside decomposes only slowly at pH 5.8 but releases carvacrol at a much greater rate at pH 7.4, indicating that alcohol can be released at physiological temperature and pH from electron-rich ortho- and meta-disubstituted aromatic-O-β-D-3'-ketoglucopyranosides in addition to electron-deficient and electron-rich ortho- and para-disubstituted aryl derivatives.

[0214] Example 16 Release of the allyl alcohol geraniol (an insect repellent alcohol) from its β-3'-ketoglucopyranoside in aqueous solution at 37°C and various pH values From geranyl-β-3′-ketoglucopyranoside prepared in Example 1.

[0215] In this example, the release rate of geraniol from (2R,3S,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-O-β-D-3′-ketoglucopyranoside) was determined in 0.1 M deuterated phosphate buffer solutions of different pHs containing 10% D6-DMSO or in DO containing 10% D6-DMSO in the presence or absence of fresh skin wash at 37°C.

[0216] 1 M stock solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate were prepared in deuterium oxide (DO).

[0217] A stock solution of 25 mg of geranyl-O-β-D-3′-ketoglucopyranoside in 0.5 mL of D6-DMSO was prepared.

[0218] In a typical experiment, a piece of absorbent cotton gauze (5x5cm) soaked in DO (12.5mL) for 1 minute is used. 2 ) in human volunteers at 25 cm 2A new stock solution of skin cleansing suspension was prepared by wiping the area with firm rubbing of the cheek skin, then resuspending the gauze in the D2O solution, shaking quickly, and removing the gauze after squeezing out as much liquid as possible with a spatula.

[0219] 1M stock solutions of phosphate buffer at pH 5.7 and 7.0 were prepared by appropriate mixing of the 1M stock phosphate solution to the correct pH as determined using a calibrated pH meter.

[0220] Half of each buffer stock solution was diluted 10-fold with DO and the other half with the above skin cleanser stock solution to give 0.1 M phosphate buffer in DO with a final pH of 5.7, 0.1 M phosphate buffer in DO with a final pH of 7.0, 0.1 M phosphate buffer in skin cleanser with a final pH of 5.7, and 0.1 M phosphate buffer in skin cleanser with a final pH of 7.0.

[0221] As shown in the reaction table below, three parallel reaction vials were added with 0.45 mL of 0.1 M phosphate buffer in D2O at low or high pH, ​​or 0.45 mL of 0.1 M phosphate buffer in skin cleansing solution at low or high pH, ​​followed by 0.05 mL of glycoside substrate solution in D6-DMSO, and the mixture was incubated with shaking at 37°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR using a 400 MHz instrument with 128 scans, and the results are shown in Table IV.

[0222] (Table IV) The reaction was followed by the increase in the multiplet at 1.71 ppm relative to the singlet at 1.67 ppm. Due to peak overlap, the relative heights were compared to an authentic mixture of geranyl-O-β-D-3'-ketoglucopyranoside and geraniol.

[0223] At 37°C, geranyl-β-3'-ketoglucopyranoside decomposes only slowly at pH 5.8 but releases geraniol at a much greater rate at pH 7.4, and this rate remains unchanged in the presence or absence of skin cleansers, indicating that alcohol can be released from allyl-O-β-D-3'-ketoglucopyranoside at physiological temperature and pH, in addition to the aryl derivatives.

[0224] Example 17 Release of the allylic alcohol geraniol (an insect repellent alcohol) from its β-3'-ketoglucopyranoside at higher concentrations From geranyl-β-3′-ketoglucopyranoside prepared in Example 1.

[0225] In this example, the release rate of geraniol from a 40 mg / mL suspension of (2R,3S,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-O-β-D-3′-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer, pH 7, containing 10% DMSO was determined at 37°C.

[0226] Geranyl-O-β-D-3'-ketoglucopyranoside (20 mg) was dissolved in D6-DMSO (0.05 mL) in a stoppered glass vial, 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 point a strong odor of geraniol was observed. The mixture 1 Analysis by H-NMR using a 400 MHz instrument showed the same conversion to geraniol (approximately 50%) as that observed from the less concentrated sample from Reaction 2 in Example 16. The NMR data indicated that the conversion increased significantly after this point, although the conversion data could not be precisely quantified.

[0227] Example 18 Release of the primary aliphatic alcohol picaridin (an insect repellent alcohol) from its β-3'-ketoglucopyranoside at 32°C and various pH values From picaridin-β-3′-ketoglucopyranoside prepared in Example 2.

[0228] In this example, the release rate of picaridin from 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′-ketoglucopyranoside) in aqueous buffers of different pH was determined.

[0229] Parallel mixtures containing 250 μM picaridin-O-β-D-3'-ketoglucopyranoside in 0.05 M KHPO / KHPO buffer, pH 8.5 (Reaction 1), 0.17 M NaHPO / 0.02 M citrate buffer, pH 7 (Reaction 2), 0.12 M NaHPO / 0.04 M citrate buffer, pH 5.8 (Reaction 3), and 0.04 M sodium citrate / 0.06 M citrate buffer, pH 4 (Reaction 4) were incubated at 32°C. 10 μl aliquots were periodically withdrawn, diluted with MeCN (90 μl), and analyzed by UPLC using the following equipment and conditions: Stationary phase: Acquity UPLC(R)BEH C18 1.7μm(2.1mmx50mm)(Waters) Mobile phase: A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid The chromatography equipment used was UPLC QSM Waters Acquity. Gradient conditions: TIFF0007727647000067.tif55128Flow rate (mL / min) 0.6 Source temperature (℃) 150 Desolvation temperature (℃) 500 Cone gas flow rate (L / hr) 50 Desolvation gas flow rate (L / h) 900 Target column temperature: 35°C Target sample temperature: 8.0℃

[0230] The amount of picaridin released at different time points is shown in Table V.

[0231] (Table V) TIFF0007727647000068.tif60133

[0232] At 32°C, picaridin-O-β-D-3'-ketoglucopyranoside decomposes at increasing rates between pH 4 and pH 8.5, indicating that alcohol can be released at physiological temperature and pH from primary alkyl-O-β-D-3'-ketoglucopyranosides containing heterocyclic functional groups, in addition to aryl and allyl derivatives.

[0233] Example 19 Release of a secondary aliphatic alcohol, cis-PMD (insect repellent alcohol), from its β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From cis-PMD-O-β-D-3′-ketoglucopyranoside prepared in Example 5.

[0234] In this example, the release rate 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′-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 33% D6-DMSO was determined.

[0235] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0236] A stock solution of 10 mg of cis-PMD-O-β-D-3′-ketoglucopyranoside in 0.5 mL of D6-DMSO was prepared.

[0237] To two parallel reaction vials, 0.20 mL of glycoside substrate solution in D6-DMSO and 0.50 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table VI.

[0238] (Table VI) TIFF0007727647000069.tif64146* The reaction was followed by integration of the singlet at 1.29 ppm (starting material + free PMD) versus the doublet at 4.25 ppm (starting material).

[0239] At 32°C, cis-PMD-O-β-D-3'-ketoglucopyranoside decomposes only slowly at pH 5.8 but releases cis-PMD at a much greater rate at pH 7.4, indicating that alcohol can be released from secondary alkyl-O-β-D-3'-ketoglucopyranosides at physiological temperature and pH, in addition to aryl, allyl, and primary alkyl derivatives.

[0240] Example 20 Release of tertiary aliphatic alcohol (S)-α-terpineol from its β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From (S)-α-terpineol-β-3′-ketoglucopyranoside prepared in Example 6.

[0241] In this example, the release rate 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′-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 33% D6-DMSO was determined.

[0242] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0243] A stock solution of 10 mg of (S)-α-terpineol-O-β-D-3′-ketoglucopyranoside in 0.5 mL of D6-DMSO was prepared.

[0244] To two parallel reaction vials, 0.20 mL of glycoside substrate solution in D6-DMSO and 0.40 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table VII.

[0245] (Table VII) TIFF0007727647000070.tif64148* The reaction was followed by careful integration of the multiplet at 1.50 ppm (starting material + free terpineol) versus the multiplet at 3.26 ppm (starting material).

[0246] At 32°C, (S)-α-terpineol-O-β-D-3'-ketoglucopyranoside decomposes only slowly at pH 5.8 but releases (S)-α-terpineol at a much greater rate at pH 7.4, indicating that alcohol can be released from tertiary alkyl-O-β-D-3'-ketoglucopyranosides at physiological temperature and pH, in addition to aryl, allyl, and primary and secondary alkyl derivatives.

[0247] Example 21 Comparison of the release of the primary aliphatic alcohol, methanol, from its α-3'-ketoglucopyranoside and α-glucopyranoside in aqueous solution at room temperature, then 37°C, and at various pH values. From methyl-β-3'-ketoglucopyranoside prepared in Comparative Example 4.

[0248] In this example, methyl-O-α-D-3′-ketoglucopyranoside and methyl-O-α-D-glucopyranoside were used as model compounds to determine the release rate of aliphatic alcohol (methanol) under different conditions.

[0249] 1 M stock solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate were prepared in deuterium oxide (DO). Stock solutions of 15 mg of methyl-O-α-D-3'-ketoglucopyranoside (Substrate A) and 15 mg of methyl-O-α-D-glucopyranoside (Substrate B) were prepared by dissolving each in 0.3 mL of D6-DMSO.

[0250] Solutions of pH 4.5, 5.8, and 7.4 were prepared by diluting the appropriate individual stock phosphate solution or mixture to 0.1 M using a calibrated pH meter.

[0251] To eight parallel reaction vials, add 0.05 mL of one of the glycoside substrate solutions in D6-DMSO, 0.5 mL of the appropriate deuterated buffer solution, or 0.5 mL of water, as shown in the table below, and mix. 1 The initial reading was obtained by 1 H-NMR using a 400 MHz instrument with 128 scans.

[0252] The mixture was then allowed to stand at room temperature for an additional 22 hours and then analyzed in the same manner.

[0253] The mixtures were then incubated with shaking at 37°C for an additional 44 hours and analyzed in the same manner. At this point, only reaction 4 showed any change, so the other reactions were discarded and, after an additional 72 hours, reaction 4 was analyzed in the same manner.

[0254] Table VIII shows the following results:

[0255] (Table VIII) TIFF0007727647000071.tif106143* Reactions 1-4 were followed by the percent increase of the singlet at 3.35 ppm (the three protons of MeOH) relative to the doublet at 5.20 ppm (the anomeric proton of methyl-O-α-D-3'-ketoglucopyranoside), corrected for the 3% MeOH determined to be present in the starting material using the same method. *Reactions 5-8 were followed by the percent increase of the singlet at 3.35 ppm (three protons of MeOH) relative to the doublet at 3.88 ppm (protons of methyl-O-α-D-glucopyranoside), corrected for the 7% MeOH determined to be present in the starting material using the same method. NR = No Driving

[0256] At 37°C, methyl-O-α-D-glucopyranoside remains stable over the pH range tested and in water, whereas methyl-O-α-D-3'-ketoglucopyranoside is stable at pH 4.5 and 5.8 but very slowly releases methanol at pH 7.4. This indicates that alcohol can be released from simple primary aliphatic-O-α-D-3'-ketoglucopyranosides, as well as primary aliphatic-O-β-D-3'-ketoglucopyranosides, at physiological temperature and pH, but simple primary alkyl-O-α-D-glucopyranosides remain stable and do not release an alcohol residue.

[0257] Example 22 Comparison of the release rate of p-nitrophenol from its β-3'-ketoglucopyranoside and α-3'-ketoglucopyranoside in aqueous solution at 32°C Materials prepared in Comparative Example 2 and Comparative Example 3.

[0258] In this example, a comparison of the release rates of p-nitrophenol from approximately equimolar solutions of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H-pyran-4-one (4-nitrophenyl-O-β-D-3′-ketoglucopyranoside) and (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-4H-pyran-4-one (4-nitrophenyl-O-α-D-3′-ketoglucopyranoside) in DO containing 1.5% D6-DMSO, in 0.1 M deuterated phosphate buffer at pH 5.8 containing 1.5% D6-DMSO, or in DO was determined.

[0259] A solution containing approximately 2 mg each of 4-nitrophenyl-O-β-D-3'-ketoglucopyranoside and 4-nitrophenyl-O-α-D-3'-ketoglucopyranoside was prepared in 1 mL of DO containing 3.3% v / v D6-DMSO. Two 0.375 mL portions of the resulting solution were added with DO (0.5 mL) or 0.1 M sodium phosphate buffer (pH 5.8) (0.5 mL) to obtain reaction solution 1 and reaction solution 2, respectively. The resulting mixtures were immediately diluted after preparation. 1 After analysis by H NMR, the samples were incubated at 32 °C / 80 rpm and the time points recorded. 1 The samples were analyzed periodically by 1 H NMR.

[0260] The ratio between the integrals of the anomeric protons of each ketoglucoside and the ratio between the sum of the aromatic and anomeric protons of each ketoglucoside over time are shown in Table IX.

[0261] (Table IX) TIFF0007727647000072.tif69147 1 1 The ratio between the integrals of the doublet at 6.01 ppm and the doublet at 5.19 ppm in the H NMR spectrum 2 obtained at each time point 1Ratio between the sum of the integrals of the signals at 8.09, 8.02, 7.11, and 6.81 ppm and the doublet at 6.01 ppm in the H NMR spectrum 3 obtained at each time point 1 The ratio between the sum of the integrals of the signals at 8.09, 8.02, 7.11, and 6.81 ppm and the doublet at 5.19 ppm in the H NMR spectrum

[0262] At 32°C, both 4-nitrophenyl-O-α-D-ketoglucopyranoside and O-β-D-ketoglucopyranoside were degraded slowly, with the α-ketoglucopyranoside degrading approximately six times faster than the β-ketoglucoside. Both ketoglucosides remained stable in DO. This indicates that alcohol can be released from the α-3'-ketoglucopyranoside at a greater rate than from the β-3'-ketoglucopyranoside at physiological temperature and pH.

[0263] Example 23 Comparison of the release of the primary aliphatic alcohol, methanol, from its α-3'-ketomannopyranoside and α-mannopyranoside in aqueous solution at 32°C and various pH values. From methyl-O-α-D-3′-ketomannopyranoside prepared in Comparative Example 5.

[0264] In this example, the release rate of methanol from (2R,3R,5R,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran-4-one (methyl-O-α-D-3'-ketomannopyranoside) was determined in comparison with that from (2R,3S,4S,5S,6S)-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triol (methyl-O-α-D-mannopyranoside) in 15% D6-DMSO in DO, in 0.1 M deuterated phosphate buffer solutions of different pHs containing 15% D6-DMSO, or in DO.

[0265] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0266] A stock solution of 25 mg of methyl-O-α-D-3′-ketoglucomannoside in 1.0 mL of D6-DMSO was prepared.

[0267] To five parallel reaction vials, 0.10 mL of glycoside substrate solution in D6-DMSO and 0.50 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 33°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table X.

[0268] (Table X) TIFF0007727647000073.tif90150NR = No Driving *Reactions 1-3 were followed by the decrease in the signal of the starting material (3-ketoglycoside) at 3.35 ppm relative to D6-DMSO. Reactions 4 and 5 were followed by comparing the integral of the singlet signal of the formed methanol at 3.38 ppm with the anomeric signal of the starting material at 4.75 ppm.

[0269] At 32°C, methyl-O-α-D-mannopyranoside remains stable at pH 7.4 and in water, whereas methyl-O-α-D-3'-ketomannopyranoside yields methanol at both pH 5.8 and pH 7.4. This indicates that alcohol can be released from primary aliphatic-O-α-D-3'-ketoglucopyranosides and primary aliphatic-O-β-D-3'-ketoglucopyranosides, as well as simple primary aliphatic-O-α-D-3'-ketomannopyranosides, at physiological temperature and pH, whereas simple primary alkyl-O-α-D-mannopyranosides remain stable and do not release an alcohol residue.

[0270] Example 24 Comparison of the release of the allyl alcohol geraniol from its 3'-keto-2'-deoxyglucopyranoside and 2'-deoxyglucopyranoside in aqueous solution at 32°C and various pH values. From geranyl-3'-keto-2'-deoxyglucopyranoside prepared in Example 3.

[0271] In this example, the release rate of geraniol from (2R,3R)-6-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-hydroxy-2-(hydroxymethyl)tetrahydro-4H-pyran-4-one (geranyl-3'-keto-2'-deoxyglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 50% D6-DMSO was determined.

[0272] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0273] A stock solution of 15 mg of geraniol-O-β-D-3′-keto-2′-deoxyglucopyranoside in 1.5 mL of D6-DMSO was prepared.

[0274] As shown in the reaction table below, four parallel reaction vials were added with 0.35 mL of glycoside substrate solution in D6-DMSO and 0.35 mL of 0.1 M phosphate buffer in D2O at low or high pH, ​​and the mixture was incubated by shaking at 33°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table XI.

[0275] (Table XI) TIFF0007727647000074.tif78160NR = No Driving *The reaction was followed by the increase in the doublet at 3.91 ppm (geraniol) relative to the doublet at 3.98 ppm (starting material).

[0276] At 32°C, geranyl-O-2'-deoxyglucopyranoside remained stable at pH 7.4, while geranyl-3'-keto-2'-deoxyglucopyranoside yielded geraniol at both pH 5.8 and pH 7.4. This indicates that alcohol can be released from 3'-keto-2'-deoxyglucopyranoside, as well as from 3'-ketoglucopyranoside and 3'-ketomannopyranoside, at physiological temperature and pH, whereas 2'-deoxyglucopyranoside remains stable and does not release an alcohol residue. Furthermore, the release rate of geraniol from geranyl-3'-keto-2'-deoxyglucopyranoside is greater than that observed from geranyl-O-β-D-3'-ketoglucopyranoside (Example 17) under similar conditions.

[0277] Example 25 Comparison of the release of the allyl alcohol geraniol from its β-2'-acetamido-2'-deoxy-3'-keto-glucopyranoside and β-2'-acetamido-2'-deoxy-glucopyranoside in aqueous solution at 32°C and various pH values From geranyl-O-β-D-2′-acetamido-2′-deoxy-3′-keto-glucopyranoside prepared in Example 4.

[0278] In this example, N-((2R,3S,5R,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-5-hydroxy-6-(hydroxymethyl)-4-oxotetrahydro-2H-pyran-3-yl)acetamide (geranyl-O-β-D-2′-acetamido-2′-deoxy-3′-keto-) was synthesized in DO containing 33% D6-DMSO, in 0.1 M deuterated phosphate buffer solutions of different pHs containing 33% D6-DMSO, or in DO. The release rate of geraniol from N-((2R,3R,4R,5S,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (geranyl-β-2'-acetamido-2'-deoxy-glucopyranoside) was determined by comparison with the release rate from N-((2R,3R,4R,5S,6R)-2-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)acetamide (geranyl-β-2'-acetamido-2'-deoxy-glucopyranoside).

[0279] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0280] A stock solution of 25 mg of geranyl-O-β-D-2′-acetamido-2′-deoxy-3′-keto-glucopyranoside in 1.0 mL of D6-DMSO was prepared.

[0281] To four parallel reaction vials, 0.20 mL of glycoside substrate solution in D6-DMSO and 0.40 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table XII.

[0282] (Table XII) TIFF0007727647000075.tif77153NR = No Driving *Reactions were followed by the increase in the doublet at 3.91 ppm (geraniol) versus the doublet at 4.15 ppm (starting material). Reaction 4 was monitored by analyzing the formation of the free geraniol doublet at 4.12 (not observed) versus the doublet at 4.57 ppm (starting material).

[0283] At 32°C, geranyl-β-2'-acetamido-2'-deoxy-glucopyranoside remains stable at pH 7.4, while geranyl-O-β-D-2'-acetamido-2'-deoxy-3'-keto-glucopyranoside yields geraniol at both pH 5.8 and pH 7.4. This indicates that alcohol can be released from 2'-acetamido-2'-deoxy-3'-keto-glucopyranoside, as well as 3'-ketoglucopyranoside, 3'-ketomannopyranoside, and 3'-keto-2'-deoxyglucopyranoside, at physiological temperature and pH, but 2'-acetamido-2'-deoxy-glucopyranoside remains stable and does not release an alcohol residue. Furthermore, the release rate of geraniol from geranyl-O-β-D-2'-acetamido-2'-deoxy-3'-keto-glucopyranoside is greater than the release rate observed from geranyl-3'-keto-2'-deoxyglucopyranoside (Example 25) or geranyl-O-β-D-3'-ketoglucopyranoside (Example 17) under similar conditions.

[0284] Example 26 Release of the allylic alcohol geraniol from its 2',6'-diacetylated β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From 2',6'-diacetyl-geranyl-O-β-D-3'-ketoglucopyranoside prepared in Example 9.

[0285] In this example, the release rate of geraniol from (((2R,3R,5S)-5-acetoxy-6-(((E)-3,7-dimethylocta-2,6-dien-1-yl)oxy)-3-hydroxy-4-oxotetrahydro-2H-pyran-2-yl)methyl acetate (2',6'-diacetyl-geranyl-O-β-D-3'-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 50% D6-DMSO was determined.

[0286] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0287] A stock solution of 15 mg of 2',6'-diacetyl-geranyl-O-β-D-3'-ketoglucopyranoside in 1.5 mL of D6-DMSO was prepared.

[0288] To two parallel reaction vials, 0.35 mL of glycoside substrate solution in D6-DMSO and 0.35 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table XIII.

[0289] (Table XIII) TIFF0007727647000076.tif50153NR = No Driving *The reaction was followed by the increase in the doublet at 3.91 ppm (geraniol) versus the doublet at 4.00 ppm (starting material).

[0290] At 32°C, 2',6'-diacetyl-geranyl-O-β-D-3'-ketoglucopyranoside yields geraniol at both pH 5.8 and pH 7.4, indicating that alcohol can be released from 2',6'-diprotected 3'-ketoglucopyranoside as well as unprotected 3'-ketoglucopyranoside at physiological temperature and pH.

[0291] Example 27 Release of the aromatic alcohol phenol from its 2',6'-diacetylated β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From 2',6'-diacetyl-phenyl-O-β-D-3'-ketoglucopyranoside prepared in Example 10.

[0292] In this example, the release rate 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'-ketoglucopyranoside) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 33% D6-DMSO was determined.

[0293] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0294] A stock solution of 25 mg of 2',6'-diacetyl-phenyl-O-β-D-3'-ketoglucopyranoside in 1.0 mL of D6-DMSO was prepared.

[0295] As shown in the reaction table below, three parallel reaction vials were added with 0.20 mL of glycoside substrate solution in D6-DMSO and 0.40 mL of 0.1 M phosphate buffer in D2O at low or high pH, ​​and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table XIV.

[0296] (Table XIV) TIFF0007727647000077.tif74150NR = No Driving *The reaction was followed by the increase in the triplet (phenol) at 7.14 ppm relative to the triplet (starting material) at 7.26 ppm (D6-DMSO signal at 2.50 ppm as reference).

[0297] At 32°C, 2',6'-diacetyl-phenyl-O-β-D-3'-ketoglucopyranoside yields phenol at both pH 5.8 and pH 7.4 and in DO, again demonstrating that alcohol can be released from 2',6'-diprotected 3'-ketoglucopyranoside as well as unprotected 3'-ketoglucopyranoside at physiological temperature and pH.

[0298] Example 28 Release of the primary aliphatic alcohol, methanol, from its β-3'-ketoglucuronide methyl ester in aqueous solution at 32°C and various pH values From the glucuronide methyl ester prepared in Comparative Example 6.

[0299] 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'-ketoglucuronide methyl ester) in D2O containing 10% D6-DMSO, in 0.1 M deuterated phosphate buffer solutions of different pHs containing 10% D6-DMSO, or in D2O was determined.

[0300] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0301] A stock solution of 20 mg of methyl-β-3′-ketoglucuronide methyl ester in 0.25 mL of D6-DMSO was prepared.

[0302] To two parallel reaction vials, 0.05 mL of glycoside substrate solution in D6-DMSO and 0.55 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table XV.

[0303] (Table XV) TIFF0007727647000078.tif65155NR = No Driving *The reaction was followed by the increase in singlet at 3.74 ppm (product methyl ester) relative to the singlet at 3.79 ppm (starting methyl ester).

[0304] At 32°C, methyl-β-3'-ketoglucuronide methyl ester yields methanol at both pH 5.8 and pH 7.4, indicating that alcohol can be released from 3'-ketoglucuronate at physiological temperature and pH.

[0305] Example 29 Release of the aromatic alcohol phenol from its 6'-sulfated β-3'-ketoglucopyranoside in aqueous solution at 32°C and various pH values From phenyl-O-β-D-3′-keto-6′-sulfatoglucopyranoside pyridinium salt prepared in Example 11.

[0306] In this example, the release rate of phenol from (2R,3R,5S,6S)-3,5-dihydroxy-4-oxo-6-phenoxytetrahydro-2H-pyran-2-yl)methyl pyridinium hydrogen sulfate (phenyl-O-β-D-3'-keto-6'-sulfatoglucopyranoside pyridinium salt) in 0.1 M deuterated phosphate buffer solutions of different pH values ​​containing 15% D6-DMSO was determined.

[0307] 0.1 M stock buffer solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate at pH 5.8 and 7.4 were prepared in deuterium oxide (D2O).

[0308] A stock solution of 20 mg of phenyl-O-β-D-3′-keto-6′-sulfatoglucopyranoside in 0.5 mL of D6-DMSO was prepared.

[0309] To two parallel reaction vials, 0.10 mL of glycoside substrate solution in D6-DMSO and 0.60 mL of 0.1 M phosphate buffer in D2O at low or high pH were added, as shown in the reaction table below, and the mixture was incubated by shaking at 32°C. After the time indicated in the table below, the mixture was 1 The compounds were analyzed by H-NMR in a 400 MHz instrument, and the results are shown in Table XVI.

[0310] (Table XVI) The reaction was monitored by monitoring the increase in the triplet (phenol) at 7.14 ppm relative to the triplet (starting material) at 7.26 ppm.

[0311] At 32°C, phenyl-O-β-D-3'-keto-6'-sulfatoglucopyranoside pyridinium salt gives phenol at pH 7.4, indicating that alcohol can be released from 6'-sulfated 3'-ketoglucopyranoside at physiological temperature and pH.

[0312] Example 30 Comparison of the release rate of alcohol from 3'-ketoglucopyranoside in aqueous solution at 37°C and various pH values ​​in the presence and absence of a new skin cleanser. In this example, phenyl-O-β-D-3'-ketoglucopyranoside, methyl-O-α-D-3'-ketoglucopyranoside, 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 rate of each alcohol residue under different conditions.

[0313] The effects of (2R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-phenoxytetrahydro-4H-pyran-4-one (phenyl-O-β-D-3'-ketoglucopyranoside) or (2R,3R,5S,6S)-3,5-dihydroxy-2-(hydroxymethyl)-6-methoxytetrahydro-4H-pyran-4-one (phenyl-O-β-D-3'-ketoglucopyranoside) on the skin surface in 0.1 M deuterated phosphate buffer solutions at pH 5.7 and 7.0 containing 10% D6-DMSO at room temperature in the presence and absence of fresh skin washes. The release rates of methanol or phenol and 4-nitrophenol from 1:1 stoichiometric mixtures of (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (4-nitrophenyl-O-β-D-glucopyranoside) with their respective O-glucopyranosides were determined in comparison with the release rates from (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-(4-nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triol (4-nitrophenyl-O-β-D-glucopyranoside).

[0314] 1 M stock solutions of sodium dihydrogen phosphate and disodium hydrogen phosphate were prepared in deuterium oxide (DO).

[0315] 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'-ketoglucopyranoside, methyl-O-α-D-glucopyranoside, phenyl-O-β-D-3'-ketoglucopyranoside, and phenyl-O-β-D-glucopyranoside to obtain substrate stock solutions A, B, C, and D, respectively.

[0316] In a typical experiment, a cotton gauze (5x5cm) soaked in DO (12.5mL) for 1 minute is used. 2 ) in human volunteers at 25 cm 2 A new stock solution of skin cleansing suspension was prepared by wiping the area with firm rubbing of the cheek skin, then resuspending the gauze in the D2O solution, shaking quickly, and removing the gauze after squeezing out as much liquid as possible with a spatula.

[0317] 1M stock solutions of phosphate buffer at pH 5.7 and 7.0 were prepared by appropriate mixing of the 1M stock phosphate solution to the correct pH as determined using a calibrated pH meter.

[0318] Half of each buffer stock solution was diluted 10-fold with DO and the other half with the above skin cleanser stock solution to give 0.1 M phosphate buffer in DO with a final pH of 5.7, 0.1 M phosphate buffer in DO with a final pH of 7.0, 0.1 M phosphate buffer in skin cleanser with a final pH of 5.7, and 0.1 M phosphate buffer in skin cleanser with a final pH of 7.0.

[0319] Sixteen parallel reaction vials were each treated with 0.45 mL of 0.1 M phosphate buffer in D2O at low or high pH, ​​or 0.45 mL of 0.1 M phosphate buffer in skin cleansing solution at low or high pH, ​​followed by 0.05 mL of one of the glycoside substrate solutions in D6-DMSO, and the mixture was incubated with shaking at 37°C. After the times indicated in the table below, the mixture was 1 The samples were analyzed by H-NMR using a 400 MHz instrument with 128 scans and the color was observed visually. The results are shown in Table XVII.

[0320] (Table XVII) TIFF0007727647000080.tif202151* Reactions 1-4 were followed by the increase in the singlet at 3.35 ppm (the three protons of MeOH) relative to the doublet at 5.20 ppm (the anomeric proton of methyl-O-α-D-3'-ketoglucopyranoside). Corrected for the 3% MeOH determined to be present in the starting material using the same method. *Reactions 5-8 were followed by the increase of the singlet at 3.35 ppm (three protons of MeOH) from the multiplet at 3.95-3.84 ppm, corrected for the 7% MeOH determined to be present in the starting material using the same method. *Reactions 9-12 were followed by the increase in the doublet at 6.91 ppm (the two aromatic protons of phenol) relative to the multiplet at 7.42 ppm (the two aromatic protons of phenyl-O-β-D-3'-ketoglucopyranoside). nr = no driving +++++ = color of the same intensity as observed in the p-nitrophenyl solution, indicating reaction completion - = no color observed

[0321] The results show that both 3'-ketoglucopyranosides release their respective alcohols in both the presence and absence of skin cleanser at pH 7, but to a greater extent in the presence of skin cleanser. In contrast, no reaction is observed from methyl-O-α-D-3'-ketoglucopyranoside at pH 5.7. At pH 5.7, phenyl-O-β-D-3'-ketoglucopyranoside reacts more slowly than at pH 7, and reacts to the same extent in the presence and absence of skin cleanser. Methyl-OD-glucopyranoside and phenyl-OD-glucopyranoside were stable under all test conditions. 4-Nitrophenyl-O-β-D-glucoside was visually observable releasing some 4-nitrophenol at pH 7. Although release is usually greater in the presence of skin cleanser, the extent was so small that no change was observed by NMR.

[0322] In a follow-up experiment using the same reaction conditions but in the absence of 4-nitrophenyl-O-β-D-glucopyranoside, it was observed that the rate of alcohol release from both methyl-O-α-D-3′-ketoglucopyranoside (Substrate A) and phenyl-O-β-D-3′-ketoglucopyranoside (Substrate B) was slightly increased in the presence of fresh skin wash solution compared to its absence after 72 hours at pH 7, as shown in Table XVIII.

[0323] (Table XVIII) Reactions 1-3 were followed by the increase in the singlet (three protons of MeOH) at 3.35 ppm relative to the doublet (anomeric proton of methyl-O-α-D-3'-ketoglucopyranoside) at 5.20 ppm. Corrected for the 3% MeOH determined to be present in the starting material using the same method. *Reactions 9-12 were followed by the increase in the doublet at 6.91 ppm (the two aromatic protons of phenol) relative to the multiplet at 7.42 ppm (the two aromatic protons of phenyl-O-β-D-3'-ketoglucopyranoside).

[0324] Example 31 Stability of geranyl-O-β-D-3'-ketoglucopyranoside in DO Geranyl-O-β-D-3′-ketoglucopyranoside (5 mg) obtained according to Example 4 was added to DO (1 mL) and heated at 50° C. The resulting solution was analyzed periodically by H NMR over a period of 2 weeks, and no changes were observed in the resulting spectra, indicating that the ketoglucoside was stable.

[0325] Example 32 Release of geranyl-O-β-D-3'-ketoglucopyranoside from porous surfaces Geranyl-O-β-D-3'-ketoglucopyranoside (50 mg) obtained according to Example 4 was dissolved in polyethylene glycol 200 (PEG200) (0.1 mL) with gentle heating. Next, 0.1 mL of a solution of L-arginine (10 mg) dissolved in 0.1 mL of a 3:7 w / v solution of anhydrous calcium chloride in water was added and mixed thoroughly. The resulting solution was spread onto a 5 cm diameter paper kitchen towel disc and allowed to stand at room temperature. The odor of released geraniol emanating from the disc was then rated as strong, medium, or weak over time and is reported in Table XIX.

[0326] (Table XIX) TIFF0007727647000082.tif94128

[0327] After 19 hours, the reaction mixture was dissolved in D4-MeOH and analyzed by H NMR. The spectrum showed a ca. 1:1 mixture of the starting ketoglucoside and geraniol, as determined by signals at 4.15 ppm and 4.05 ppm, respectively.

[0328] This example clearly demonstrates that geraniol is slowly released from the surface of the paper over time.

[0329] Example 33 In vitro mosquito assay of geranyl-O-β-D-3'-ketoglucopyranoside Aedes albopictus mosquitoes were reared and maintained under a 12-h:12-h (light:dark) photoperiod at a temperature of 26 ± 2°C and a relative humidity of 80% or higher ± 10. Prior to testing, adult mosquito populations were fed a sugar solution (10%) but not blood.

[0330] Geranyl-O-β-D-3'-ketoglucopyranoside (100 mg) obtained according to Example 4 was dissolved in polyethylene glycol 200 (PEG200) (0.2 mL) with gentle heating to obtain Solution 1. Next, 200 mg of L-arginine was dissolved in 2 mL of a 3:7 w / v solution of anhydrous calcium chloride in water to obtain Solution 2. 0.2 mL of Solution 2 was added to the entire volume of Solution 1 to obtain Solution 3. The contents of Solution 3 were thoroughly mixed, and half of the resulting solution was applied to parallel 5 cm-diameter artificial Hemotek membranes covered with paper kitchen towels of equal diameter. Duplicate parallel membranes covered with paper kitchen towels were each treated with 0.2 mL of a 1:1 v / v solution of PEG200 / Solution 2, while two additional parallel membranes were left untreated.

[0331] These membranes were heated at 37°C using a Hemotek system over a reservoir of sheep blood and periodically exposed to 5- to 7-day-old, active, host-seeking female mosquitoes that had been selected and collected using an aspirator and organized into batches (15 females) in plastic test containers. Heat was turned off between exposures to maintain membrane integrity and turned on 5 min before each exposure. Immediately after membrane preparation, and again at 2, 4, 6, and 8 hours, each membrane was exposed to a new container of female mosquitoes for 20 min. At each time point, the number of mosquitoes landing on each membrane was counted immediately after exposure and at 5, 10, and 20 min after exposure, and the total number of landings over each 20-min exposure was tabulated. As shown in Table XX, membranes containing the conjugate exhibited significantly fewer landings over an 8-h period than those observed on diluent-treated or untreated membranes.

[0332] (Table XX) TIFF0007727647000083.tif63130

[0333] It can be concluded that a repellent effect is provided by the geranyl-O-β-D-3′-ketoglucopyranoside of the present invention.

Claims

1. 3'-ketoglycoside compounds of formula (I): During the ceremony, the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from an α-configuration or a β-configuration; R 1 is CH 2 OH, R 2 is OH, and R 3 is H; R 1 is CH 3 , R 2 is OH, and R 3 is H; R 1 is H, R 2 is OH, and R 3 is H; or R 1 is CH 2 OH, R 2 is H, and R 3 is H; and R is 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-indanemethanol, 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 (ne ol), 3,7-dimethyl-3,6-octadienol, 3,7-dimethyl-1,6-octadien-3-ol (linalool), 3,7-dimethyloctane-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-Dimethyloct-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-hexanediol, 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 p-Menthol, 4-isopropyl-1-benzenemethanol, 4-isopropylcyclohexanol, 1-(4-isopropyl-1-cyclohexyl)ethanol, (4-isopropyl-1-cyclohexyl)methanol, (4-isopropylphenyl)methanol, 7-p-menthanol, p-menthan-3-ol (menthol), p-menthan-8-ol, p-menth-8-en-2-ol, p-menth-8-en-3-ol, 4-methoxy-1-benzenemethanol, 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-methylcyclohex-3-enyl)butanol, 4-methyl-3-decenol, 4-methyl-3-decen-5-ol, 4-(1-methyl (ethylethyl)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-butenol, 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-trimethyl-3-cyclopenten-1-yl)pent-4-enol 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-naphthalenol, octahydro-2,5,5-trimethyl-2-naphthalenol, 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-naphthalenol, 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, 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- ethyl-1-cyclohexanol, tetrahydro-2-isobutyl-4-methyl(2H)pyran-4-ol, 2-(tetrahydro-5-methyl-5-vinyl-2-furyl)propan-2-ol, 1-(2,2,3,6-tetramethylcyclohex-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)]undecan-8-ol (cedrenol), (+)-(1R,2R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-en-ol (fenchol), (+)-(1R,2S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (borneol), 2,6,6-trimethylbicyclo[3.1.1]heptan-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, (2,4,6-trimethylcyclohex-3-enyl)methanol, (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-ol (α-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 (chavicol), 2H-1,The residue of an alcohol of formula R—OH selected from the group consisting of 3-benzodioxol-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). Claim 2: R 1 is CH 2 OH, R 2 is OH, and R 3 is H; or R 1 is CH 2 OH, R 2 is H, and R 3 is H; 3'-ketoglycoside compound of formula (I) according to claim 1.

3. R 1 is CH 2 OH, R 2 is OH, and R 3 is H; 3'-ketoglycoside compound of formula (I) according to claim 2.

4. A 3'-ketoglycoside compound of formula (Ia): During the ceremony, R is the residue of an alcohol of formula R-OH as defined in claim 1; and R 1 is CH 2 OH, R 2 is NHCOCH 3 and R 3 is H; and The 3'-ketoglycoside compound of formula (Ia) is a β-3'-keto-N-acetylglucosaminoside.

5. R is 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 5. The 3'-ketoglycoside compound of claim 1, wherein R-OH is a residue of an alcohol of the formula R-OH selected from the group consisting of methyl aldehyde (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-methylcyclohexan-1-ol (p-menthan-3,8-diol, PMD).

6. The 3'-ketoglycoside compound of claim 1 or 4, wherein R is a residue of an alcohol of the formula R-OH selected from the group consisting of 4-allyl-2-methoxyphenol (eugenol), (E)-3,7-dimethyl-2,6-octadienol (geraniol), 5-methyl-2-(propan-2-yl)cyclohexan-1-ol (menthol), (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).

7. 2. A method for preparing a 3′-ketoglycoside compound of formula (I) according to claim 1, comprising oxidizing a glycoside compound of formula (II) with [(2,9-dimethyl-1,10-phenanthroline)Pd(μ-OAc)] as a catalyst by an oxidizing agent. 2 (OTf) 2 the process comprising oxidizing in the presence of: 。 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 a 3'-ketoglycoside compound of formula (I) according to any one of claims 1 to 6 and a carrier.

11. 11. The composition of claim 10, further comprising a compound selected from alcohols of formula R-OH as defined in claim 1, 5 or 6, and an insect active compound that produces an insect repellent or insect attractant effect.

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

13. Use of a 3'-ketoglycoside compound of formula (I) for the controlled release of an alcohol of formula R-OH: During the ceremony, R is the residue of an alcohol of formula R-OH as defined in claim 1, the stereochemical configurations at the 1', 2', 4', and 5' positions are independently selected from an α-configuration or a β-configuration; and R 1 is CH 2 OH, R 2 is OH, and R 3 is H; R 1 is CH 3 , R 2 is OH, and R 3 is H; R 1 is H, R 2 is OH, and R 3 is H; or R 1 is CH 2 OH, R 2 is H, and R 3 is H.

14. Use of a 3'-ketoglycoside compound of formula (Ia) for the controlled release of an alcohol of formula R-OH: During the ceremony, R is the residue of an alcohol of formula R-OH as defined in claim 1; and R 1 is CH 2 OH, R 2 is NHCOCH 3 and R 3 is H; and The 3'-ketoglycoside compound of formula (Ia) is a β-3'-keto-N-acetylglucosaminoside.

15. Use according to claim 13 or 14, wherein R is the residue of an alcohol of formula R-OH as defined in claim 5.

16. Use according to claim 13 or 14, wherein R is the residue of an alcohol of formula R-OH as defined in claim 6.

17. 15. The use according to claim 13 or 14, wherein the alcohol has an insect repellent effect.

18. 11. A method of using a compound of formula (I) comprising applying the composition of claim 10 to a surface.

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