WO2005121114A2 - 1,5- et 1,4-anhydrocetoses, procedes de preparation de 1,5- et 1,4-anhydrocetoses, intermediaires, et utilisations de 1,5- et 1,4-anhydrocetoses - Google Patents

1,5- et 1,4-anhydrocetoses, procedes de preparation de 1,5- et 1,4-anhydrocetoses, intermediaires, et utilisations de 1,5- et 1,4-anhydrocetoses Download PDF

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WO2005121114A2
WO2005121114A2 PCT/DK2005/000377 DK2005000377W WO2005121114A2 WO 2005121114 A2 WO2005121114 A2 WO 2005121114A2 DK 2005000377 W DK2005000377 W DK 2005000377W WO 2005121114 A2 WO2005121114 A2 WO 2005121114A2
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general formula
optionally substituted
group
anhydroketoses
anhydro
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PCT/DK2005/000377
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English (en)
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WO2005121114A3 (fr
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Inge Lundt
Arnold STÜTZ
Gyula Dekany
Joachim Thiem
Karoly Agoston
Mikkel Andreassen
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Glycom Aps
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Priority claimed from AU2004903036A external-priority patent/AU2004903036A0/en
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Publication of WO2005121114A2 publication Critical patent/WO2005121114A2/fr
Publication of WO2005121114A3 publication Critical patent/WO2005121114A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems

Definitions

  • the present invention relates to 1,4- and 1,5-anhydroketoses, i.e. derivatised and underivatised 1,4- and 1,5-anhydroketoses (e.g. anhydroketopyranoses, anhydroketo- furanoses, anhydroketopyranosides, anhydroketofuranosides, anhydroketopyranose ketals, anhydroketofuranose ketals of diverse glycoderivatives including derivatised and underivatised monosaccharides, oligosaccharides and various glycoconjugates).
  • the invention provides 1,4- and 1,5-anhydroketoses-related novel synthetic methodologies and novel intermediates suitable/required for their preparation.
  • the invention also provides several novel methods suitable for the preparation of novel as well as known 1,4- and 1,5- anhydro-D-ketoses (e.g. 1,5-anhydro-D-fructose) and their derivatives and analogues including regio- and stereoisomers thereof. Furthermore, the present invention provides novel applications of 1,4- and 1,5-anhydroketoses within pharmaceutical, food and cosmetic industries.
  • 1,4- and 1,5-anhydroketoses e.g. 1,5-anhydro-D-fructose
  • their derivatives and analogues including regio- and stereoisomers thereof.
  • the present invention provides novel applications of 1,4- and 1,5-anhydroketoses within pharmaceutical, food and cosmetic industries.
  • 1,4- and 1,5-anhydroketoses belong to a unique group of cyclic ether-type carbohydrates displaying numerous important chemical/biological/physiological properties.
  • One of the most characteristic members of anhydroketoses is 1,5-anhydro-D-fructose (AF) (1) ( Figure 1).
  • 1,5-anhydro-D-fructose itself and a few derivatives and analogues thereof have been considered as the most potential carbohydrate product candidates for pharmaceutical, food and cosmetic applications.
  • the preparation of anhydroketoses is still a challenging task preventing long term commercialization efforts.
  • 1,5-Anhydro-D-fructose (1) has not been known for a long time despite of the fact that its protected precursors/derivatives such as 2-acyloxyglycals 2 have been synthesized ( Figure 2). 1
  • 1,5-anhydro-glucitol 9 was partially protected as cyclic 4,6-O-isopropylidene acetal 10. Poor regioselectivity and low yield has been achieved in the selective silylation of diol 10 affording compound 11.
  • Oxidation of 1,5-anhydro-alditol derivative 11 by pyridinium dichromate provided compound 12, which was deprotected under acidic conditions giving 1,5-anhydro-D-fructose 1 in admixture with the hydrated form I h y d r a t e in an overall poor yield.
  • 1,5-anhydro-D-fructose has been prepared from starch in 40-50% yield.
  • the process has attracted significant commercial interest for enzymatic production of 1,5-anhydro-D-fructose. 13, 14, 1S
  • the 1,5-anhydro-D-fructose- producing enzyme has also been cloned and expressed in Aspergillus niger 16 ' 17 , outlining a more rational and industrially favored production strategy.
  • 1,5-Anhydro-D-fructose has never been isolated in a pure monomeric form due to its hygroscopic nature and its high tendency for dimerization. 1,5-anhydro-D-fructose has been isolated as mixtures consisting of monomeric and dimeric forms 18, 19 or the monomeric and the hydrated form ( Figure 6).
  • Novel 1,4- and 1,5-anhydroketoses have the potentials to find wide applications in food industry 23"25 - preventing pigment discoloration, enzymic browning, protecting flavour, aroma and nutrient content, extending shelf life -, in cosmetics industry 26 - replacing the unstable and ionic L-ascorbic acid - and in pharmaceutical industry - increasing hormone secretion of insulin via stimulating glucagon-like peptide 1 (GLP 1) expression. 27 ' 28
  • glycogen degrades by ⁇ -(l->4) ⁇ glucan lyase to 1,5-anhydro-D-fructose 29 ' 30 which subsequently is reduced to 1,5-anhydro-D-glucitol by a NADPH-dependent 1,5-anhydro-D-fructose specific reductas. 31
  • 1,5-Anhydro-D-fructose and its derivatives are important carbohydrates attracting industrial interest. Only a few substituted/derivatised 1,5-anhydro-D-fructose derivatives and other anhydroketoses have been synthesized due to the high base sensitivity of anhydroketose products and intermediates. Furthermore, structural analysis of anhydroketoses has greatly suffered from the strong dimer formation tendency of anhydroketoses, including unprotected 1,5-anhydro-D-fructose ( Figure 6). It was not until recently that the correct structure of 1,5- anhydro-D-fructose has been elucidated.
  • the present invention represent a characteristic breakthrough in the field by providing a number of simple chemical methods suitable for the preparation of diverse 1,4- and 1,5- anhydroketoses.
  • the present invention also gives the very first synthetic methodologies suitable for bulk production of 1,5-anhydro-D-fructose itself and its numerous derivatives and analogues.
  • the present invention has the power to initiate commercialization of 1,5-anhydro- D-fructose, derivatives and analogues thereof and chemical/biological/physiological exploration of numerous novel 1,4- and 1,5-anhydroketoses.
  • the present invention thus, relates to novel, simple, chemical methods for the synthesis of 1,4- and 1,5-anhydroketoses, in particular 1,5-anhydro-D-fructose, and derivatives and stereoisomers hereof, the hydrated forms, the dimeric forms or any mixture of said forms, from accessible starting materials, which typically are easily prepared from inexpensive and easily available starting materials following literature procedures.
  • the first aspect of the present invention provides novel 1,4- and 1,5-anhydroketoses of a wide variety derivatised/underivatised carbohydrates including mono- and oligosaccharides, iminosugars, carbasugars, thiosugars and C-glycosides characterised by either five- or six- membered ring structures.
  • the second aspect of the present invention provides synthetic methodologies for the preparation of derivatised/underivatised 1,4- and 1,5-anhydroketoses - including 1,5- anhydro-D-fructose and its analogues/derivatives - via any of the following chemical procedures:
  • bicyclic and/or tricyclic 1,4- and 1,5-anhydro-glycoderivatives such as bicyclic 1,4- and/or 1,5-anhydro-glycosides, bicyclic 1,4- and/or 1,5-anhydro- thioglycosides, bicyclic 1,4- and/or 1,5-anhydro-glycosylamines, tricyclic cyclic- acetals of 1,4- and/or 1,5-anhydro-carbohydrates, tricyclic cyclic-ketals of 1,4- and/or 1,5-anhydro-carbohydrates, tricyclic cyclic-orthoesters of 1,4- and/or 1,5- anhydro-carbohydrates, bicyclic open chain acetals of 1,4- and/or 1,5-anhydro- carbohydrates and bicyclic open chain ketals of 1,4- and/or 1,5-anhydro- carbohydrates into 1,4- and 1,5-anhydroke
  • the third aspect of the present invention provides utilities for 1,4- and 1,5-anhydroketoses such as anti-oxidants, sweeteners, non-caloric sweeteners, taste enhancing agents, taste improving agents, emulsifiers, water solubility enhancing agents, antimicrobial agents, food preserving agents, feed preserving agents, chelating agents, starch deterioration inhibiting agents, food colour retaining or stabilising agents, water retaining agents, moisturisers, water-storing agents, fragrance stabilisers, taste stabilisers, protein stabilisers, moisture- releasing agents, bilayer forming agents, micelle forming agents, detergents, bulking agents, tensides, surfactants, functional foods, non-caloric functional foods.
  • 1,4- and 1,5-anhydroketoses such as anti-oxidants, sweeteners, non-caloric sweeteners, taste enhancing agents, taste improving agents, emulsifiers, water solubility enhancing agents, antimicrobial agents, food preserving agents, feed preserving agents,
  • the fourth aspect of the present invention provides novel carbohydrate intermediates suitable for the synthesis of numerous glycoderivatives including but not limiting to preparation of 1,4- and 1,5-anhydroketoses and their derivatives/analogues.
  • the sixth aspect of the present invention provides novel uses of 1,5-anhydro-D-fructose within food-, cosmetic- and pharmaceutical industries.
  • the present invention i.a. relates to preparation methodologies for 1,4- and 1,5-anhydroketoses and to novel compounds within the class of 1,4- and 1,5- anhydroketoses, as well as novel intermediates.
  • R 1 is selected from the group consisting of optionally substituted C ⁇ -20 -alkyl, optionally substituted heteroalkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 2-20 - alkynyl, optionally substituted C 3-10 -cycloalkyl, optionally substituted heterocyciyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 2-20 -acyI, C(0)R 2 , S0 3 H, S0 3 " M + , S0 2 R 2 , C(0)NHR 2 , P(0)(OH) 2 , an acetal or ketal, and a carbohydrate structural motif, in particular R 1 is selected from the group consisting of optionally substituted C 1-6 - alkyl, optionally substituted heteroalkyl, optionally substituted heterocyciyl, optionally substituted aryl, optionally substituted C 2-6 -acyl, C(0)R 2 , C(0)NHR 2
  • R 2 is selected from the group consisting of optionally substituted C 1-20 -alkyl, optionally substituted heteroalkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 2-20 - alkynyl, optionally substituted C 3-10 -cycIoalkyl, optionally substituted heterocyciyl, optionally substituted aryl, and optionally substituted heteroaryl; in particular R 2 is selected from the group consisting of optionally substituted C ⁇ -6 -alkyl, optionally substituted heteroalkyl, optionally substituted heterocyciyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 1 and/or R 2 may further be covalently linked so as to provide a cyclic structure
  • M + is any inorganic or organic cation; and A " is any inorganic or organic anion.
  • C 1-20 -alkyl is intended to mean a linear or branched hydrocarbon group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, /so-propyl, butyl, tert-butyl, / ' so-butyl, pentyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, etc.
  • C ⁇ -6 -alkyl is intended to mean a linear or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, /so-propyl, pentyl, and hexyl
  • C 1-4 -alkyl is intended to cover linear or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, /so-propyl, butyl, /so-butyl, and tert- butyl.
  • C ⁇ -20 -alkyl Whenever the term "C ⁇ -20 -alkyl” is used herein, it should be understood that a particularly interesting embodiments thereof are “C 1-6 -alkyl” and “C 8-20 -alkyl”.
  • alkoxy means "alkyl-oxy”.
  • C 2-20 -alkenyl is intended to cover linear or branched hydrocarbon groups having 2 to 20 carbon atoms and comprising one or more unsaturated bonds.
  • alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, heptadecadienyl, hexatrienyl, heptatrienyl, octatrienyl, and heptadecatrienyl.
  • C 2-20 -alkynyl is intended to mean a linear or branched hydrocarbon group having 2 to 20 carbon atoms and comprising a triple bond. Examples hereof are ethynyl, propynyl, butynyl, octynyl, and dodecaynyl.
  • heteroalkyl is intended to mean a hydrocarbon chain interrupted by one or more heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur.
  • the chain may have a total length of in the range of 4-500 atoms, such as 10-100 atoms.
  • Illustrative examples of heteroalkyl substituent are polyethylene glycols, polyethylene imines, etc.
  • C 3 .i 0 -cycloalkyl is intended to mean a cyclic hydrocarbon group having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • Halogen includes fluoro, chloro, bromo, and iodo.
  • aryl is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example.
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furyl, thienyl, quinolyl, benzothiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl.
  • heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl in particular pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, thienyl, quinolyl, tetrazolyl, and isoquinolyl.
  • heterocyciyl groups are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, t
  • substituted in the definitions of R ⁇ and R 2; and in definitions of other substituents within this specification, means that the substituent is itself substituted with a group which modifies the general chemical characteristics of the chain.
  • Preferred substituents include but are not limited to halogen, nitro, amino, azido, oxo, hydroxyl, thiol, carboxy, carboxy ester, carboxamide, alkylamino, alkyldithio, alkylthio, alkoxy, acylamido, acyloxy, or acylthio, each of 1 to 3 carbon atoms.
  • substituents can be used to modify characteristics of the molecule as a whole, such as stability, solubility, and ability to form crystals.
  • characteristics of the molecule such as stability, solubility, and ability to form crystals.
  • the person skilled in the art will be aware of other suitable substituents of a similar size and charge characteristics, which could be used as alternatives in a given situation.
  • alkyl More generally in connection with the terms “alkyl”, “alkenyl”, “alkynyl” and “cycloalkyl”, the term “optionally substituted” is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from the group consisting of hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), C 1-6 -alkoxy (i.e. C ⁇ -6 -alkyl-oxy), C 2 .
  • the substituents are selected from the group consisting of hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), C 1-6 - alkoxy (i.e. C ⁇ -6 -alkyl-oxy), C 2-6 -alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), C 1-6 -alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroarylamino, heteroaryloxy, heteroarylcarbonyl, amino, mono- and di(C ⁇ -6 -alkyl)amino; carbamoyl, mono- and di(C 1-6 -alkyl)aminocarbonyl, amino-C ⁇ -6 -alkyl-aminocarbonyl, mono- and di(C ⁇ _ 6 -alkyl)arnino-C 1-6 -alkyl-amin
  • Especially preferred examples are hydroxy, C 1-6 -alkoxy, C 2-6 -alkenyloxy, amino, mono- and di(C 1-6 -alkyl)amino, carboxy, C ⁇ -6 -alkyIcarbonylamino, halogen, C 1-5 -alkylthio, C 1-6 -alkyl- sulphonyl-amino, and guanidino.
  • aryl in connection with the terms “aryl”, “heteroaryl”, “heteroalkyl” and “heterocyciyl”
  • group(s) selected from the group consisting of hydroxy (which when present in an enol system may be represented in the tautomeric keto form), C 1-6 -alkyl, C ⁇ -6 -alkoxy, C 2-6 -aIkenyloxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci- ⁇ -alkoxycarbonyl, C ⁇ -6 - alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- and di(C 1-6 -alkyl)amin
  • the substituents are selected from the group consisting of hydroxy, C 1-6 -alkyl, C ⁇ - 6 -alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, C 1-6 - alkylcarbonyl, formyl, amino, mono- and di(C 1-6 -alkyl)amino; carbamoyl, mono- and di(C ⁇ -6 - alkyl)aminocarbonyl, amino-C ⁇ -6 -alkyl-aminocarbonyl, C ⁇ -6 -alkylcarbonylamino, guanidino, carbamido, C ⁇ -6 -alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, d- 6 -alkyl-su
  • carbohydrate structural motif is intended to encompass (but not being limited to) derivatised and underivatised mono- and oligosaccharides, iminosugars, thiosugars, C-glycosides, and carbocycles.
  • the carbohydrate structural motif is directly- and/or indirectly linked via covalent linkages including but not limited to ether, acyl or glycosidic bonds to heteroatoms of which the carbohydrate structural motif is said to be a substitutent (R 1 ).
  • a cyclic structure as a possible meanting for two of R 1 and/or R 2 is in particular referring to cyclic ketals and acetals, and cyclic structures as referred to in General Formulas 94, 95, 96, 97 and 98 (see Figure 22), namely acetals, ketals, carbonates, orthoesters, lactones, etc.
  • salts include acid addition salts and basic salts. Examples of acid addition salts are hydrochloride salts, fumarate, oxalate, etc.
  • Examples of basic salts are salts where the (remaining) counter ion is selected from the group consisting of alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium salts, potassium salts, and ammonium ions ( + N(R') 4 ), where the R's independently designate optionally substituted C 1-6 - alkyl, optionally substituted C 2-5 -alkenyl, optionally substituted aryl, or optionally substituted heteroaryl).
  • Pharmaceutically acceptable salts are, e.g., those described in Remington's - The Science and Practice of Pharmacy, 20th Ed.
  • M + is any inorganic or organic cation.
  • the metal ion can be mono- or multivalent, and may form a complex salt. Examples of cations are sodium, potassium, calcium, magnesium, zinc, ammonium, quaternary ammonium, etc.
  • a " is any inorganic or organic anion known in the art.
  • the anion can be mono- or multivalent, and may form a complex salt.
  • anions are halides, anions of organic acids, anions of mineral acids, etc. Examples hereof are chloride (Cl " ), bromide (Br " ), iodide (F), acetate, lactate, maleate, fumerate, oxalate, sulphate, nitrate, etc.
  • anhydroketose is characterized by General Formula 2.
  • anhydroketose is characterized by General Formula 3.
  • E 2 , E 3 and E 4 are as defined for General Formula la, with the proviso that the compound is not selected from the group consisting of 1,5-anhydro-D-fructose and 1,5- anhydro-D-tagatose.
  • anhydroketose is characterized by General Formula 4.
  • anhydroketose is characterized by General Formula 5.
  • anhydroketoses is characterized by General Formula
  • anhydroketose is characterized by General Formula 7.
  • the compound is characterized by General Formula 11.
  • a further aspect of the present invention relates to various utilities for the 1,4- and 1,5- anhydroketoses characterized by General Formulas la, 2-7, 10 and 11. It is belived that individual compounds or mixtures of such compounds will be useful as an antioxidant, a radical scavenger, a sweetener, a non-caloric sweetener, a taste enhancing agent, a taste improving agent, an emulsifier, a water solubility enhancing agent, an antimicrobial agent, an antidiabetic agent, a glycosidase inhibitor, a food preserving agent, a feed preserving agent, a chelating agent, a starch deterioration inhibiting agent, a food colour retaining or stabilising agent, a water retaining agent, a moisturiser, a water-storing agent, a fragrance stabiliser, a taste stabiliser, a protein stabiliser, a moisture-releasing agent, a bilayer forming agent, a micelle forming agent, a detergents, a bulk
  • 1,4- and 1,5-anhydroketoses characterized by General Formulas la, 2-7, 10 and 11 are used as antioxidant agents applied either alone or in composition with other compounds in food-, cosmetic-, and pharmaceutical products.
  • compounds characterized by General Formulas la, 2-7, 10 and 11 are used as antimicrobal agents applied either alone or in compositions with other compounds in food-, cosmetic- and pharmaceutical products.
  • compounds characterized by General Formulas la, 2-7, 10 and 11 are used as non-caloric sweeteners applied either alone or in compositions with other compounds in food- and pharmaceutical products.
  • compounds characterized by General Formulas la, 2-7, 10 and 11 are used as moisturizing agents applied either alone or in compositions with other compounds in cosmetic- and pharmaceutical products.
  • compounds characterized by General Formulas la, 2-7, 10 and 11 are used as emulsifier or non-ionic surfactant agents applied either alone or in compositions with other compounds in food-, cosmetic- and pharmaceutical products.
  • compounds characterized by General Formulas la, 2-7, 10 and 11 are used as non-caloric functional food additives applied either alone or in compositions with other compounds in food-, cosmetic- and pharmaceutical products.
  • 1,5-anhydro-D-fructose A number of uses are already known for 1,5-anhydro-D-fructose. However, the present inventors believe that hitherto unrealized utilities of 1,5-anhydro-D-fructose are possible, e.g. as a non-caloric sweetener, a non-caloric functional food additive, a functional food, an antidiabetic functional food, a functional food for elderly, a moustehzing agent, a moisture- releasing agent, and/or a protein-stability enhancing agent.
  • a non-caloric sweetener e.g., a non-caloric functional food additive, a functional food, an antidiabetic functional food, a functional food for elderly, a moustehzing agent, a moisture- releasing agent, and/or a protein-stability enhancing agent.
  • Sulfenic acid elimination of derivatised/underivatised ⁇ -hydroxy sulfoxides of carbohydrates derived from monosaccharides, oligosaccharides, iminosugars, thiosugars, carbocycles, C- glycosides and glycoconjugates of thereof is one of the key features of this aspect of the invention.
  • the most general variant of this aspect provides a method for the preparation of a 1,4- or 1,5-anhydroketose of General Formula 1 or General Formula 10, said method comprising the step of subjecting a corresponding ⁇ -hydroxy-sulfoxide to pyrolysis.
  • 1,4- and 1,5-anhydroketoses characterized by General Formulas 1-7, 10 and 11 by using pyrolysis of the corresponding ⁇ -hydroxy-sulfoxides is typically carried out in either organic or aqueous solutions at temperatures ranges 60-120°C in acidic, neutral or slightly basic reaction conditions.
  • Solvents including but not limited to toluene, benzene, 1,4- dioxane, DMF, N-methylpyrrolidine, water, pyridine and the mixtures of thereof can be used for such chemical transformation.
  • Acidic- and/or basic substances such as inorganic/organic acids, inorganic/organic bases and salts of thereof might be preferred during the pyrolysis in order to control pH and catalytic procedures.
  • the reaction time for the pyrolysis typically varies from 3-48 hours depending on the structures of substrates and the set temperature and the 1,4- or 1,5-anhydroketose is typically obtained in yields ranging from 60 to 95%.
  • the invention provides a method for the preparation of a 1,5- anhydroketose of the General Formula 18 or a 1,4-anhydroketose of the General Formula 30, wherein E 2 , E 3 and E 4 are as defined for General Formula 1, said method comprising the steps of subjecting a sulfenic acid of the General Formula 17 or General Formula 29, wherein E 2 , E 3 and E 4 are as defined above for General Formulas 18 and 29, and R is selected from the group consisting of C 1-8 -alkyI and aryl, to pyrolysis
  • the sulfenic acid of the General Formula 17 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethy
  • the protected sulfenic acid of the General Formula 15 may be prepared from the corresponding protected sulphide of the General Formula 14 wherein E 2 , E 3 , E 4 , R and P are as defined for General Formula 15, by oxidation.
  • the sulphide of the General Formula 16 may be prepared from the corresponding protected sulphide of the General Formula 14 wherein E 2 , E 3 , E 4 , R and P are as defined for General Formula 15, by deprotection of the hydroxy group (removal of the group P).
  • the protected sulphide of the General Formula 14 is prepared from the precursor of the General Formula 13 wherein E 4 and R are as defined for General Formula 14, by derivatisation or protection.
  • Unprotected thioglycosides 13 are general building blocks of carbohydrate chemistry. Thioglycosides support selective/unselective acylation, alkylation, glycosylation, cyclic- and acyclic acetal formation, nucleophilic displacement of sulfonates, wide range of nucleophili, electrophilic/acid- and base treatments described in numerous textbooks such as Bertram O. Fraser-Reid, Kuniaki Tatsua, Joachim Thiem, "Glycoscience: Chemistry and Chemical Biology I-III" , Springer, 2001
  • the sulphide of the General Formula 16 is prepared from the precursor of the General Formula 13 wherein E 4 and R are as defined for General Formula 16, by derivatisation or protection.
  • R alkyl, aryl
  • the synthesis of highly functionalized 1,5-anhydroketoses 18 is based upon a flexible thioglycoside derivation and/or protecting group manipulation strategy.
  • unprotected thioglycoside 13 can be modified via regioselective manipulations to produce either intermediate 14 or compound 16.
  • Subsequent selective oxidation of partially protected thioglycosides 14 and 16 into sulfoxide derivatives affords 15 and 17.
  • Intermediate 15 can easily be transformed into compound 17 via removal of the protecting group at 0-2 position.
  • Compound 17 carries the ⁇ -hydroxy-sulfoxide moiety required for subsequent sulfenic acid elimination initiated via pyrolysis providing derivatised 1,5-anhydroketoses 18.
  • 1,5-Anhydro-D-fructose could also be prepared via this approach in a neutral pyrolytic process providing the most straightforward procedure for the preparation of 1,5-anhydro-D- fructose and unsubstituted and derivatised analogues thereof. This represents a very important embodiment of the invention.
  • Substituents E s and E 6 are independently selected among groups defined for E 2 and E 3 in General Formula 1.
  • E 7 is freely selected among groups defined for E 4 in General Formula 1.
  • lactose thioglycoside 24 could extensively be modified by different chemical procedures providing highly functionalized oligosaccharide derivative 25.
  • Oxidation of thioglycoside 25 provided ⁇ -hydroxy-glycosyl sulfoxide 26 suitable for sulfenic acid elimination.
  • pyrolysis of 26 gave access to highly functionalized oligosaccharide-type 1,5-anhydroketoses such as 27.
  • a further important feature of the present invention provides simple and economical methodologies for direct pyrolysis of unprotected ⁇ -hydroxy-sulfoxides of oligosaccharides such as 24 affording unsubstituted 1,5-anhydroketoses of oligomeric glycomolecules such as 1,5-anhydro-D-lactulose 28 ( Figure 10).
  • the formation of anhydroketoses occurs in completely neutral conditions during pyrolysis without any use of additional catalysts/reagents.
  • R alkyl, aryl
  • Figure 10 Preparation of unprotected 1,5-anhydroketoses of oligosaccharides.
  • the synthetic methodologies provided by the present invention could also be used for the pyrolysis of derivatised/un-derivatised ⁇ -hydroxy sulfoxides of furanoses 29 providing access to 1,4-anhydroketofuranoses 30 characterized by five-membered ring structures (Figure 11).
  • R alkyl, aryl
  • An additional object of the present invention provides access to C-derivatised anhydroketoses.
  • ⁇ -hydroxy sulfoxides of C-glycosides such as 33 give C- derivatives of anhydroketoses 34 in pyrolytic sulfenic acid elimination reactions.
  • the present invention gives the methodologies for the preparation of both C-substituted 1,4- anhydro-glycofuranoses and 1,5-anhydro-glycopyranoses. pyrolysis
  • a further object of the present invention provides methodologies for the preparation of S-, N- and C-analogues of 1,4- and 1,5-anhydroketoses by pyrolysis of iminosugar- and carbosugar- type ⁇ -hydroxy sulfoxides ( Figure 14; E 2 -E 4 are as defined for General Formula 1).
  • Figure 14; E 2 -E 4 are as defined for General Formula 1.
  • ⁇ -hydroxy sulfoxides of thiosugars 35, iminosugars 37 and carbocycles 39 could serve as precursors for the synthesis of anhydroketoses 36, 38 and 40 in pyrolytic reaction conditions.
  • N-deprotection of N-substituted-amino-glycals of carbohydrates is a key feature of this aspect of the invention, preferably N-deprotection is obtained via the removal of acyclic vinylogous amide functionalities in acidic, neutral or slighly basic reaction conditions, e.g. of compounds of General Formulas 8, 9 and 12.
  • the invention provides method for the preparation of a 1,4- or 1,5-anhydroketose of General Formula 1 or General Formula 10, said method comprising the step of deprotecting a corresponding N-protected aminoglycal, preferably a compound of General Formulas 8, 9 or 12.
  • a wide range of reagents including but not limited to Cl 2 , Br 2 , ammonia, ammonia/boric acid, ethylene diamine, basic ion exchange resin, hydrazine, hydrazine acetate etc. known by a person skilled in the art are suitable for the indicated chemical transformation of aminoglycals into 1,4- and 1,5-anhydroketoses.
  • a wide range of solvents including but not limited to dichloromethane, chloroform, ethers, alcohols, acetone, acetonitrile, acetic acid, DMF, water and the mixtures of thereof could be used for the indicated reaction. Room temperature is preferred but lower or higher temperatures could also be suitable depending on solubilities of precursors/reagents. Yields related to 1,4- and 1,5-anhydrocarbohydrate formation using acyclic vinylogous deprotection of aminoglycals range from 60% to 95% depending on the presence of sensitive/robust functionalities and applied reaction conditions.
  • Derivatised/underivatised ⁇ /-substituted aminoglycals of monosaccharides 41 and derivatised/underivatised ⁇ /-substituted aminoglycals of oligosaccharides 44 are ideal building blocks for the preparation of diverse 1,4- and 1,5- anhydroketoses via the procedures of the present invention characterized by selective removal of the N-protecting group of aminoglycals followed by aqueous work-up.
  • FIG. 15 Preparation of anhydroketoses from N-protected aminoglycals.
  • X halogen
  • base NaH, DBU
  • X S(0)alkyl or S(O)aryl
  • thermal treatment initiated eliminations It is an important feature of the present invention that extended derivatisation/protecting group manipulations become possible in the N-protected aminoglycal stage of the synthesis.
  • compounds 42 and 44 could stand numerous reaction conditions suitable for the derivatisation of N-protected aminoglycals 43 and 45 providing access to diverse 1,4- and 1,5-anhydroketoses.
  • the applied P-protecting group could be widely selected among blocking groups (carbamates, amides, vinylogous amides, etc.) known in the art, see, e.g. "Protective Groups in Organic Chemistry” by Wuts and Greene, Wiley-Interscience; ISBN : 0471160199; 3nd edition (May 15, 1999).
  • Acyclic vinylogous amides are especially suitable for the synthesis of diverse arrays of anhydroketoses as acyclic vinylogous amide intermediates stand numerous reaction conditions but could easily be removed in acidic, basic or neutral reaction conditions.
  • the present invention related to the preparation of diverse anhydroketoses via N-protected aminoglycals could also be applied for the direct synthesis of 1,5-anhydro-D-fructose using commercially available cheap glucosamine precursor ( Figure 16).
  • aminoglycal approach of the present invention is equivalent in most of the cases with the ⁇ -hydroxy sulfoxide approach described previously for the preparation of 1,4- and 1,5- anhydroketoses.
  • aminoglycal approach could be superior for the preparation of specific 4-thio-, 5-thio-analogues of anhydroketoses - exemplified in the preparation of 55- 57 -, than the ⁇ -hydroxy sulfoxide method, which shows limitations in regioselective manipulations of multiple thioether/sulfoxide/sulfone moieties in this specific area (Figure 17).
  • FIG. 1 Preparation of anhydroketoses of iminosugars, C-glycosides and carbocycles.
  • Q 1 and Q 2 are independently selected from the group consisting of optionally substituted C ⁇ - 20 -alkyl, optionally substituted heteroalkyl, optionally substituted C 2-2 o-alkenyl, optionally substituted C 2-20 -alkynyl, optionally substituted C 3-10 -cycloalkyl, optionally substituted heterocyciyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 1-20 -alkyloxy, and optionally substituted aryloxy.
  • the glycals is characterized by General Formula 9
  • a further aspect of the invention relates to the preparation of such compounds of General Formulas 8-9 and 12.
  • the invention also provides methodologies for the preparation of the en o-glycals characterized by General Formulas 8, 9 and 12 by using either pyrolysis of ⁇ - /-acyclic vinylogous amide protected sulfoxides of carbohydrates in reaction conditions described or base induced elimination of N-acyclic vinylogous amide protected glycosyl halide precursors. Pyrolysis of N-acyclic vinylogous amide protected sulfoxides requires temperatures of 60-120°C using a wide variety of solvents known by a person skilled in the art.
  • Base induced elimination of acyclic vinylogous amides of glycosyl halides such as glycosyl chlorides, glycosyl bromides and glycosyl iodides require inorganic/organic bases including but not limited to sodium hydride, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,8- bis(dimethylamino)naphthalene (proton sponge), potassium t-butoxide, potassium fluoride or any other fluoride ion source, etc.
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • proton sponge 1,8- bis(dimethylamino)naphthalene
  • potassium t-butoxide potassium fluoride or any other fluoride ion source, etc.
  • Applied temperatures of base induced elimination reactions of glycosyl halides vary from -20°C to 40°C depending on the selection of base catalysts
  • O-Deprotection of carbohydrate enolethers and/or O-acyl-substituted carbohydrate enols is a key feature of the method according to this aspect of the invention.
  • the present invention provides methodologies for the preparation of compounds characterized by General Formulas 1-7, 10 and 11 by O-deprotection of carbohydrate enolethers and/or O-acyl- substituted carbohydrate enols in suitable reaction conditions.
  • the invention also relates to a method for the preparation of a 1,4- or 1,5- anhydroketose of the General Formula 1 or General Formula 10, said method comprising the step of deprotecting a corresponding carbohydrate enolether or an O-acyl-substituted carbohydrate enol.
  • Carbohydrate enolethers include, but are not limited to, O-alkyl-enoleters, O-substituted- alkyl-enoleters, O-acyclic/cyclic acetal-type enolethers, O-glycosyl-type enoleters, etc. undergo deprotection in acidic reaction conditions using inorganic/organic acid catalysts, acidic ion-exchange resin, etc known by a person skilled in the art. Application of neutral and slightly basic reaction conditions known in the art for the cleavage of enolethers is also covered by the present invention.
  • O-Acyl carbohydrate enols including but not limited to O- acetyl-, O-benzoyl-, 0-chloroacetyl-, O-trifluoroacetyl, O-phenoxyacetyl, O-pivaloyl etc. are also included in the procedure provided by the present invention.
  • Reagents including but not limited to inorganic/organic acids, acidic or basic ion-exchange resins, metal alkoxides, acidic and basic inorganic/organic salts, organic bases are equally suitable for the preparation of anhydroketoses from O-acyl-substituted enols.
  • Reaction temperature can vary between -40°C to 50°C according to the chosen catalyst and solvent applied. Yields of 60-95% could be achieved depending on the nature of precursors.
  • This special aspect of the present invention is especially suited for the preparation of 1,5- anhydro-D-fructose, the hydrated form, the dimeric form or any mixture of said forms, including derivatives and stereoisomers, characterised by deacylation of a 2-O-acyl-glycals.
  • precursor acyloxyglycal may carry several other O-acyl groups or may be any glyco-motif.
  • glyco-motif is meant any group comprising mono-, oligo- or polysaccharides including glycans, which is a generic term for any sugar or assembly of sugars, in free form or attached to another molecule, used interchangeably with carbohydrate or "sugar".
  • the configuration of the precursor carbohydrate is gluco- and all the substituents are O-acetylated. This particular embodiment results in the preparation of 1,5-anhydro-D-fructose.
  • the deacylation of per-O-acetylated 2-hydroxy-glycals is performed by means of a base preferably of the formula M + OR 2 , wherein M is an alkali or alkaline earth metal cation or a quaternary ammonium group and R 2 is as defined for General Formula 1, preferably R 2 is a C ⁇ -C 6 alkyl group.
  • said base is sodium methoxide.
  • the deacylation method according to the invention is performed at a reaction temperature in the range of -50°C to -30°C, most preferably about -40°C.
  • the deacylation method according to the invention preferably takes place in a solvent wherein said solvent is selected from the group consisting of protic, polar aprotic solvents or mixtures thereof, optionally in combination with a minor proportion of an inert, non-polar solvent.
  • Such solvents are well known to the skilled person and examples of use in the method according to the invention are DMF, DMSO, dioxane, C ⁇ -C 6 alcohols or mixtures thereof, particularly a lower alcohol such as methanol.
  • One of the methodologies of the present invention is based upon acid treatments of acid sensitive carbohydrate enolethers 65 providing 1,4- and 1,5-anhydroketoses 18 of monosaccharides, oligosaccharides, thiosugars, iminosugars, C-glycosides, carbocycles, etc. and glycoconjugates thereof.
  • This method provides a general procedure for the preparation of anhydroketoses independently from the nature of enoleter moiety used for the acid catalyzed removal of P protecting group.
  • 1,4-anhydroketoses could also be prepared by the methodology described in the present invention based upon acid hydrolysis of carbohydrate enolethers.
  • E2 - somebodyE4 . as defined in General Formula 1
  • An additional methodology of the present invention belongs to selective deprotection of O- acylated/carbamoylated carbohydrate enolethers such as 67 affording 1,4- and 1,5- anhydroketoses 18.
  • Several methodologies known in the art have been developed for removal of different O-acyl groups in acidic, neutral and basic reaction conditions from general carbohydrate scaffolds. Acidic/neutral O-acyl deprotection methods applied to acyloxyglycals are directly suitable for the preparation of anhydroketoses by the removal of O-acylated enoleters of carbohydrate precursors.
  • Basic methodologies require extra attention and considerations of tuning deprotection conditions due to base sensitivity of many anhydroketoses.
  • the preferred acetoxyglycal for the preparation of anhydro-D-fructose according to the present invention is tetra-O-acetyl-2-hydroxy-D-glucal.
  • Tetra-O-acetyl-2-hydroxy-D-glucal is readily available by methods known per se.
  • tetra-O-acetyl-2-hydroxy-D-gIucal may be prepared from D-glucose by acetylation and direct conversion to acetylated glucosyl bromide by treatment with hydrogen bromide. Elimination of HBr by an organic base, such as an amine, e.g. diethylamine or DBU (l,5-diazabicyclo[5.4.0]undec-5-ene) gives the acetylated hydroxyglucal.
  • an organic base such as an amine, e.g. diethylamine or DBU (l,5-diazabicyclo[5.4.0]undec-5-ene
  • Tetra-O-acetyl-2-hydroxy-D-glucal may be prepared from acetobromoglucose in a yield of 60-80% by treatment with diethylamine and sodium iodide in acetone as it is known by a person skilled in the art. Alternatively, said process may be carried out in a yield of 83% by treatment glycosyl bromide with DBU in DMF.
  • Chloroacetyl, phenoxyacetyl, trifluoroacetyl groups are especially suitable for the removal of blocking functions from O-acylated carbohydrate enols via gentle base treatment.
  • Application of optimal reaction time and furthermore conducting the deprotection step at low temperatures are also tools to avoid unwanted degradation processes.
  • Application of properly selected protecting groups such as tetrahydropyranyl (THP), tetrahydrofuranyl, methoxybenzyl, etc. known in the art for derivatisation of sulfoxide 22 could also provide benefits at the final removal synthetic step.
  • R', R 2 alkyl, aryl
  • a particular variant of the above relates to a method for the preparation of 1,5-anhydro-D- fructose, the hydrated form, the dimeric form or any mixture of said forms, including derivatives and stereoisomers, characterised by deacylation of a 2-O-acyl-glycal of the General Formula 313
  • R 1 , R 2 , R 3 and R 4 which may be identical or different, are selected independently from the group consisting of hydrogen, optionally substituted, linear, branched or, if applicable, cyclic C ⁇ alkyl, optionally substituted aryl, optionally substituted Ar-(QrC 6 alkyl), optionally substituted Ar-(QrC 6 alkoxy), wherein said substituents are selected among halogen, such as fluoro, chloro, bromo, iodo, C ⁇ -C 6 alkyl, C ⁇ -C 6 alkoxy, or wherein R 2 , R 3 and R 4 , which may be identical or different, are selected independently from any glyco-motif, or wherein any one, two or three of R 2 , R 3 and R 4 may be COR 1 , where R 1 has any of the meanings of above, at a reaction temperature below 0°C with a base to obtain 1,5-anhydro- D-fructose or derivatives and stereoisomers here
  • R A , R B , R c has the meaning of R 2 , R 3 , R 4 above for this variant with the proviso that R A , R B , R c can not be COR 1 .
  • R 2 , R 3 and R 4 may be any glyco-motif, while R 1 is selected from the group consisting of hydrogen, methyl, chloromethyl, ethyl, t-butyl, phenyl, chlorophenyl or methoxy phenyl.
  • glyco-motif is meant any group comprising mono-, oligo- or polysaccharides including glycans, which is a generic term for any sugar or assembly of sugars, in free form or attached to another molecule, used interchangeably with carbohydrate or "sugar”.
  • R 2 , R 3 and R 4 are identical while R 1 is selected from the group consisting of hydrogen, methyl, chloromethyl, ethyl, t-butyl, phenyl, chlorophenyl or methoxy phenyl.
  • R 2 , R 3 and R 4 are each COR 1 , where R 1 has the meaning of above.
  • R 2 , R 3 , R 4 and COR 1 are identical.
  • R 1 is preferably a methyl group.
  • R 2 , R 3 and R are each COR 1 , and R 1 is a methyl group.
  • R 1 is a methyl group.
  • the deacylation of a 2-O-acyl-glycal of the General Formula 313 is performed by means of a base preferably of the formula M + OR 5 , wherein M is an alkali or alkaline earth metal cation or a quaternary ammonium group of the formula (R 6 ) 4 N + , wherein R 5 and R 6 are each C L -C 6 alkyl group.
  • said base is sodium methoxide.
  • the deacylation method is performed at a reaction temperature in the range -100°C to 0°C. More particularly said reaction temperature is in the range -80°C to -20°C depending on the respective acyl groups to be displaced. In an even more preferred embodiment, said reaction temperature is in the range -50°C to -30°C, most preferably about -40°C.
  • the deacylation method according to this variant preferably takes place in a solvent.
  • Said solvent is typically selected from the group consisting of protic, polar aprotic solvents or mixtures thereof, optionally in combination with a minor proportion of an inert, non-polar solvent.
  • Such solvents are well known to the skilled person and examples of use in the method according to the invention are DMF, DMSO, dioxane, C ⁇ -C 6 alcohols or mixtures thereof, particularly a lower alcohol such as methanol.
  • tetra-O-acetyl-2-hydroxy-D-glucal may be prepared from D- glucose by acetylation and direct conversion to acetylated glucosyl bromide by treatment with hydrogen bromide generated in situ (P + Br 2 ) in a two steps-one pot reaction, followed by crystallisation. Elimination of HBr by an organic base, such as an amine, e.g. diethylamine or DBU (l,5-diazabicyclo[5.4.0]undec-5-ene) gives the acetylated hydroxyglucal.
  • an organic base such as an amine, e.g. diethylamine or DBU (l,5-diazabicyclo[5.4.0
  • a crystalline compound of the General Formula 313 aCety ⁇ can be prepared according to the following reaction scheme as disclosed by R. U. Lemieux (R. U. Lemieux, Methods in Carbohydrate Chemistry, Vol. II, 221-222- Eds. R. L. Whistler, M. L. Wolfrom and J. N. BeMiller, Academic Press, 1963, New York).
  • the compound 315 commercially available as D-glucose-pentaacetate, may be treated with a solution of HBr/acetic acid to give acetobromoglucose (316), a reaction which is general for carbohydrates having an acyl group at C-l.
  • Acetobromoglucose (316) is also commercially available from e.g. Sigma-Aldrich or Fluka.
  • Tetra-O-acetyl-2-hydroxy-D-glucal, 13 acety ⁇ may be prepared from acetobromoglucose in a yield of 60-80% by treatment with diethylamine and sodium iodide in acetone as disclosed by R . Ferrier (R . Ferrier, Methods in Carbohydrate Chemistry, Vol. VI, 307-311.- Eds. R. L. Whistler, J. N. BeMiller, Academic Press, 1972, New York).
  • said process may be carried out in a yield of 83% by treatment with DBU in DMF as disclosed by Varela et al (O.Varela, G. M, DE Fina, R. M. Lederkremer, Carbohydr. Res. 167, 1987, 187-196).
  • a further aspect of the present invention provides methodologies for the preparation of 1,5- anhydroketoses, in particular 1,5-anhydro-D-fructose, by chemical modifications based upon the liberation of the hemiketal functionalities of bicyclic- and tricyclic anhydrocarbohydrate precursors characterized by General Formulas 13-15 and 17-24 using either acid catalyzed hydrolysis of glycosides, cyclic ketals, cyclic acetals, cyclic orthoesters and cyclic carbonates or by any other method known by a person skilled in the art such as reductive ring opening of acetals/ketals, activation of thioglycosides, hydrolysis of glycosyl amines, glycosyl amides etc.
  • aqueous acetic acid at 20-80°C, alkyl/arylsulfonic acids in methanol at 40- 65°C or acidic ion exchange resin in water and/or alcohols at 20-60°C are used affording anhydroketoses in 80-98% yield.
  • One preferred embodiment hereof provides methodologies for the preparation of 1,5- anhydro-D-fructose by chemical modifications based upon the liberation of the hemiketal functionalities of tricyclic anhydrocarbohydrate precursors characterized by General Formulas 19 using either acid catalyzed hydrolysis of cyclic ketals or any other method known by a person skilled in the art suitable for the ring opening/removal of the cyclic ketal function.
  • aqueous acetic acid at 20-80°C, alkyl/arylsulfonic acids in methanol at 40-65°C or acidic ion exchange resin in water and/or alcohols at 20-60°C are used affording anhydroketoses in 90-98% yield.
  • Another preferred embodiment hereof provides methodologies for the preparation of 1,5- anhydro-D-fructose by acid catalyzed hydrolysis of the precursor cyclic ketal of tricyclic anhydrocarbohydrate precursor characterized by General Formulas 19 in which R 4 is hydrogen.
  • R 4 is hydrogen.
  • aqueous acetic acid at 20-80°C, alkyl/arylsulfonic acids in methanol at 40-65°C or acidic ion exchange resin in water and/or alcohols at 20-60°C are used affording anhydroketoses in 90-98% yield.
  • ketoses such as fructose, lactulose are cheap chiral building blocks for organic syntheses.
  • Utilisation of such common renewable resources is an important industrial aim.
  • Synthesis of anhydroketoses from naturally occurring ketoses themselves is an absolutely novel approach of the present invention initiating industrial use of such valuable resources.
  • the present invention provides the preparation of 1,4- and 1,5-anhydroketoses from simple ketose precursors such as 72 (fructose) via either bicyclic- or tricyclic- anhydrocarbohydrate intermediates ( Figure 21).
  • bicyclic anhydrocarbohydrate intermediates belongs to the preparation! of glycosides-, thioglycosydes-, glycosylamines-, and glycosyl halides of anhydroglyco- pyranosides and anhydroglycofuranosides. Furthermore, anomeric O-acyl-anhydropyranoses, anomeric O-acyl-anhydrofuranoses, anomeric S-acyl-anhydropyranoses and S-acyl- anhydrofuranoses are also suitable intermediates of anhydroketose syntheses.
  • the present invention provides the very first methodologies suitable for the preparation of these novel bicyclic anhydrocarbohydrates.
  • 6-hydroxy-l,5-anhydroketoses 83 using the above discussed bicyclic anhydrocarbohydrates such as 79-82 via selective ring-opening reactions triggered by chemical modifications taking place at the glycosidic position of intermediates.
  • Figure 21 Preparation of anhydroketoses via ring-opening reactions of bicyclic anhydrocarbohydrates.
  • the invention relates to the preparation of a 6-hydroxy-l,5- anhydroketose of General Formula 83, said method comprising the step of (a) O-deprotecting a corresponding bicylic anhydroglycoside of General Formula 79 by removal of the R 1 group by hydrolysis under acidic conditions;
  • bicyclic anhydrocarbohydrates could occur via derivatisation and/or protecting group manipulation known in the art of common ketoses affording intermediates 73-75.
  • a different aspect of the present invention provides novel tricyclic anhydrocarbohydrates and related methodologies suitable/required for the preparation of 1,4- and 1,5-anhydroketoses via ring-opening processes.
  • tricyclic acetals 94 and tricyclic ketals 95 could be efficiently transformed into 1,5-anhydroketoses by the removal/ring opening of the cyclic acetal/cyclic ketal functions. Both acid catalysed hydrolysis of cyclic acetal/ketal functions and reductive ring opening of the same functionalities assist the formation of the desired 1,5-anhydroketoses 99 ( Figure 22).
  • tricyclic orthoesters such as 97 are also highly suitable for anhydroketose 99 formation via selective ring opening or acid catalysed hydrolysis of the cyclic orthoester functionality. Selective hydrolysis of tricyclic glycosides 98 also provides valuable 1,5- anhydroketoses. Hydrolysis of tricyclic carbohydrate esters such as cyclic carbonate 96 could also be used as precursors for 1,5-anhydroketose formations.
  • the present invention also provides a method for the preparation of a 1,5-anhydroketos of the General Formula 99, said method comprising the steps of subjecting a compound of General Formula 94 or 95 or 96 or 97 or 98 to ring opening conditions, e.g. acidic or basic conditions, so as to liberate the corresponding 1,5-anhydroketose (99).
  • the present invention also provides facile methodologies for the preparation of novel tricyclic anhydrocarbohydrate precursors. Common ketoses such as fructose 72 could be derivatised/protected using methodologies known in the art affording intermediates 84-88. Selective O-sulfonylation of the primary alcohol position leads to the formation of bicyclic sulfonates 89-93.
  • hydrolysis of bicyclic anhydrothiosugar 100 and tricyclic anhydrothiosugar 102 precursors result in the formation of the desired 1,5-anhydroketoses of thiosugars 101 and 103.
  • the described general method is also suitable to provide 1,5-anhydroketoses of carbasugar derivatives.
  • ring-opening chemical modifications at the glycosidic center such as acid catalysed hydrolysis or any other suitable modification known in the art provide 1,5- anhydroketoses of carbasugars 109 and 110 using the corresponding bicyclic anhydrocarbasugar 108 or tricyclic anhydrocarbasugar 111 precursors.
  • Figure 23 Preparation of 1,5-anhydroketoses of thiosugars, iminosugars and carbasugars using bicyclic- and tricyclic anhydrocarbohydrate derivatives.
  • Methodologies of the present invention characterized by selective cyclic acetal/ketal/- orthoester/carbonate/lactone- and glycopyranose-ring-opening of anhydrocarbohydrates affording 1,5-anhydroketose derivatives are also highly suitable for the preparation of 1,5- anhydrofructose.
  • Figure 24 Preparation of 1,5-anhydrofructose using selective ring-opening of tricyclic anhydrocarbohydrates.
  • Step B is a selective removal of one of the cyclic acetal/ketal functions giving intermediate 115 suitable for intramolecular nucleophilic displacement reactions with one of the liberated hydroxyl groups.
  • Step F the same intermediate can also be prepared via selective substitution of the primary hydroxyl function of 114 (Step F) accessible via acid catalyzed hydrolysis (Step E) of compound 112.
  • Reaction step C is a selective intramolecular nucleophilic displacement reaction affording the required tricyclic anhydrocarbohydrate intermediate 116.
  • Step D indicates a method, which removes the cyclic acetal/ketal substituent from the glycosidic position of 116 via ether acid catalyzed hydrolysis or any other suitable methodology affording 1,5-anhydro-D-fructose 1 ( Figure 24).
  • the present invention provides access to site-selectively monosubstituted/derivatised anhydroketoses via regioselective derivatisation of bicyclic and/or tricyclic anhydrocarbohydrate intermediates. This unique opportunity becomes possible by inventing three new chemical transformations of anhydroketoses.
  • the present invention provides the very first examples of selective ring opening of cyclic isopropylidene rings of anhydroketoses such as 117 with alcohols in acidic conditions affording acyclic ketal derivatives of anhydrocarbohydrates such as 119-121 ( Figure 25).
  • D 1 , D 2 , D 3 derivatisation/protecting groups
  • R alkyl, aryl
  • Figure 25 Regioselective derivatisation of tricyclic anhydrocarbohydrates providing monosubstituted 1,5-anhydrofructose derivatives.
  • a second chemical transformation of the present invention belongs to aqueous acid treatment of acyclic ketals of anhydrocarbohydrates such as 121 triggering a ring opening reaction by the hydrolysis of the acyclic ketal moiety leading to the formation of anhydroketoses such as 122. No similar reactions have been published in carbohydrate chemistry.
  • the third reaction of the present invention provides diketals of anhydroketoses such as 127 from tricyclic anhydrocarbohydrate precursors such as 116 using alcohol nucleophiles in acidic conditions. Such a unique chemical reaction has never been described.
  • Nucleophilic substitution reactions including but not limited to alkylation, acylation, halogenation, glycosylation; redoxy reactions such as oxidation, reduction; nucleophilic displacement reactions such as displacement of sulfonates became possible on the unique scaffold of diketals of anhydroketoses.
  • the present invention also provides methodologies for the preparation of 0-6 modified anhydroketoses from intermediate 120 using diketal formation and subsequent derivatisation of compound 123 using diverse derivatisation chemistries including but not limited to alkylation, acylation, glycosylation, etc. Selective removal of D 1 and D 2 protecting functions from 124 gave intermediate 125. Aqueous acid catalyzed treatment of 125 provides examples for the formation of 0-6 selectively derivatised anhydroketoses 126. A person skilled in the art can similarly make all the di-O-substituted and tri-O-substituded anhydroketose derivatives using the above-demonstrated derivatisation synthetic system of the present invention.
  • the present invention also gives procedures for the preparation of anhydroketose derivatives/analogues altered at a selected position. Configuration exchange at certain position is the key chemistry needed for the synthesis of analogues of anhydroketoses. Regioselective oxidation of selected hydroxyl groups of anhydroketoses and subsequent stereoselective reduction of the resulted uloses found to be the best methodology for the synthesis of analogues of anhydroketoses ( Figure 26).
  • R alkyl, aryl
  • Figure 26 Derivatisation of a tricyclic anhydrocarbohydrate at 0-4 position.
  • Tricyclic anhydrocarbohydrate 116 is a key intermediate for all the structural modifications taking place at C-4 position of anhydroketoses.
  • oxidation of the 0-4 hydroxy function at C-4 using general oxidation protocols afforded ulose 128.
  • Aqueous acid treatment provided diulose 129, which exist entirely in enediol tautomeric form.
  • Enediol 129 provided salt 130 with metal ions due to the acidic character of the hydroxyl group of at C-4 position.
  • tricyclic anhydrocarbohydrate 116 was also O-acylated using several different acylating agents affording intermediates 136.
  • a final isopropylidene deprotection of 136 gave unprotected O-acylated anhydroketoses 137.
  • a further aspect of the present invention relates to novel bicyclic anhydrocarbohydrates as precursors of 1,5-anhydroketose preparation characterized by General Formula 13.
  • Another embodiment relates to bicyclic anhydroglycosides suitable for the preparation of 1,5- anhydroketoses, characterized by General Formula 15.
  • a further interesting group of intermediates are those corresponding to General Formula 14 wherein E 2 and R 1 are joined and where E 2 is of the type O-R 1 , and where the joined R 1 groups are cleavable under acidic or basic conditions.
  • the present invention provides tricyclic anhydrocarbohydrates characterized by General Formula 17 suitable as precursors for the preparation of 1,5-anhydroketoses
  • R 3 is selected from the group consisting of hydrogen, optionally substituted C 1-20 -alkyl, optionally substituted heteroalkyl, optionally substituted C 2-20 -alkenyl, optionally substituted C 2-20 -alkynyl, optionally substituted C - ⁇ 0 -cycloalkyl, optionally substituted heterocyciyl, optionally substituted aryl, and optionally substituted heteroaryl and substituted heteroaryl, and Z is selected from the group consisting of 0, S, NH, NR 2 , where R 2 is as defined for General Formula 1.
  • the invention provides novel tricyclic anhydrocarbohydrates suitable for the preparation of 1,5-anhydroketoses, characterized by General Formula 18
  • R 4 is selected from the group consisting of hydrogen, optionally substituted C 1-20 - alkyl, optionally substituted heteroalkyl, optionally substituted C 2 . 20 -alkenyl, optionally substituted C 2-20 -alkynyI, optionally substituted C 3- ⁇ 0 -cycloalkyl, optionally substituted heterocyciyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C 2-20 -acyl, CH 2 OR 2 , any substituted/unsubstituted carbohydrate moiety including mono- and oligo- and polysaccharides, a polymeric moiety (including, but not limited to, any poly(ethyleneglycol)-containing moiety), and an insoluble solid support.
  • An even still further embodiment provides tricyclic anhydrocarbohydrates characterized by General Formula 20 suitable as precursors for the preparation of 1,5-anhydroketoses
  • a still further embodiment provides novel tricyclic anhydrocarbohydrates characterized by General Formula 21 suitable for the preparation of 1,5-anhydroketoses
  • a still further embodiment provides novel tricyclic anhydrocarbohydrate orthoesters characterized by General Formula 22 suitable for the preparation of 1,5-anhydroketoses
  • R 1 and R 2 are as defined for General Formula 1
  • R 4 is as defined for General Formula 19
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl, and phenyl.
  • a still futher embodiment provides novel tricyclic anhydrocarbohydrates characterized by General Formula 23 suitable as precursors for the preparation of 1,5-anhydroketoses
  • R is as defined for General Formula 19.
  • An even still further embodiment provides novel tricyclic anhydrocarbohydrates characterized by General Formula 24 suitable as precursors for the preparation of 1,5-anhydroketoses
  • R 4 is as defined for General Formula 19, and R 3 is as defined for General Formula 17.
  • the present invention also provides novel methodologies for the preparation of specific carbohydrate intermediates characterized by General Formula 18 suitable for the preparation of 1,5-anhydroketoses by base catalyzed intramolecular cyclization of molecules described by General Formulas 25 and 26.
  • Inorganic and organic bases including but not limited to sodiumhydride, sodium hydroxide, potassiumhydroxide, potassium carbonate, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), etc or any other base known by a person skilled in the art could be used for intramolecular cyclization in DMF, water, alcohols, acetonitrile, etc.
  • Temperature of the cyclization can take place in the range of 20-100°C depending on the chosen base.
  • a further aspect of the present invention provides novel bicyclic carbohydrate intermediates characterized by General Formula 25 suitable for the preparation of 1,5-anhydroketoses
  • R 1 and E 3 are as defined for General Formula 1, and W is selected from the group consisting of halogen, OS0 2 R 2 , OS0 2 CI, OSOzNR ⁇ 2 ; where R 1 and R 2 are as defined for General Formula 1.
  • a still further preferred embodiment of the present invention provides bicyclic carbohydrate intermediates characterized by General Formula 26 suitable for the preparation of 1,5- anhydroketoses
  • a further aspect provides novel methodologies for the preparation of novel bicyclic carbohydrate intermediates characterized by General Formulas 25 and 26 supporting the synthesis of novel 1,5-anhydrocarbohydrates charactarized by General Formulas 17-24.
  • These methodologies are based upon the derivatisation of known bicyclic carbohydrates including but not limited to either regioselective 0-1 alkyl/arylsulfonylation or C-l halogenation.
  • One of the preferred embodiments relates to methodologies using methylsulfonyl chloride, tosyl chloride, triflic anhydride, imidazoylsulfonate etc. or any other similar reagent known by a person skilled in the art.
  • Organic solvents including but not limited to dichloromethane, piridine, DMF, ethers are suitable for the transformation.
  • Organic and/or inorganic base could be preferred to catalyze the reaction such as triethylamine, N,N- dimetylaminopyridine, potassium carbonate etc.
  • the temperature range of the transformation is -20°C to 80°C.
  • the preferred reaction temperature is 0°C at the beginning of the reaction and room temperature in the later stages of the O-sulfonylation.
  • the selective sulfonylateion/halogenation could be characterized by avarage yields of 75-95%.
  • a further aspect of the present invention provides novel methodologies for the preparation of diketals of 1,4- and 1,5-anhydroketoses characterized by General Formulas 16a, 16b and 16c from bicyclic- and tricyclic-anhydroketoses defined for General Formulas 17-24 via acid catalyzed trans-ketalization processes in the presence of appropriate alchols.
  • Transketallization of bicyclic- and tricyclic-anhydrocarbohydrates could be catalyzed by any inorganic/organic acid including but not limited to dry HCI, HBr, acidic ion-exchange resins, p-toluenesulfonic acid, camphor sulfonic acid, trifluoroacetic acid etc known by a person skilled in the art.
  • Appropriate alcohols could also be used acting as bot solvents and reagents.
  • Numerous dry organic solvents such as dichloromethane, ethers, acetonitrile, DMF could also act os proper solvents assisting the required trans-ketallization processes.
  • the reaction could be carried out at a wide range of temperatures such as 0°C to 120 °C. Preferrably the reaction is carried out at room temperature in alcohols using dry HCL as a catalyst. HCI could be used directly or generated in situ from acetyl chloride in alcohols as it is known by a person skilled in the art. The yields of the trans-ketallization may vary between 75-95%.
  • the present invention also provides a method for the preparation of diketals of 1,4- and 1,5-anhydroketoses characterized by General Formulas 16a, 16b and 16c, said method comprising the step of subjecting a compound selected from the group consisting of bicyclic- and tricyclic-anhydroketoses of General Formulas 17-24 to an acid catalyzed trans-ketalization process in the presence of an alcohol of formula R 2 -OH, in particular EtOH, and in particular not MeOH.
  • a further preferred embodiment of the present invention provides novel diketals of anhydroglycosides characterized by General Formulas 16a and 16b suitable for the preparation of 1,5-anhydroketoses
  • E 2 , E 3 , E 4 and R 2 are as defined for General Formula 1, with the proviso that R 2 is not a methyl group.
  • a preferred embodiment of the above provides novel diethyl ketals of anhydroglycosides characterized by General Formula 16c. Such diketals are able to release 1,5-anhydroketoses and ethanol in physiological conditions acting as a non-toxic antioxidant alcoholic food additive.
  • a further aspect of the present invention provides utilities of diethylketals of anhydro-D- fructose and other novel diethylketals of 1,4- and 1,5-anhydrocarbohydrates characterized by General Formulas 16a, 16b and 16c as novel food additives in situ producing anhydroketoses - including but not limited to anhydro-D-fructose - and ethanol in physiological conditions which are characteristic to digestion conditions in stomach.
  • TSAHS tetrabutylammonium hydrogen sulphate
  • E is defined as E or E
  • glycosyl bromide (1 equiv) A mixture of glycosyl bromide (1 equiv), molecular sieves (1 g / 1 g of glycosyl bromide) in anhydrous CH 2 CI 2 (15 mL / 1 g glycosyl bromide) was stirred at room temperature and terabutylammonium bromide (0.6 g / 1 g of glycosyl bromide), i-Pr 2 EtN (0.1 mL / g glycosyl bromide) and thiophenol (2 equiv) were added. The reaction mixture was stirred at room temperature for 5 hours and filtered.
  • E 2 - E as defined in General Formula 1
  • E 5 is as E 2 or E 3
  • R alkyl, aryl
  • R alkyl, aryl
  • Method B Water-soluble sulfoxide was dissolved in water or a mixture of i-PrOH /H 2 0. The reaction mixture was refluxed for 2-8 hours keeping the pH neutral by the addition of aqueous NaHC0 3 solution (5%) while the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuum and the resulted residue was purified by chromatography giving anhydroketoses in 60-90% yield.
  • Anomeric O-acetate of acyclic vinylogous amide (lequiv) was dissoved in CH 2 CI 2 (10 mL / 1 g of anomeric O-acetate) and cooled to 0°C. Hydrogen bromide in acetic acid (30%) was added and the reaction mixture was allowed to warm to room temperature. The yellowish solution was stirrred at room temperature for 3 hours and dilited with cold CH 2 CI 2 (20 mL / 1 g of anomeric O-acetate).
  • Acyclic vinylogous amide-type glycosyl bromide (1 equiv) was dissolved in THF (10 mL / 1 g of glycosyl bromide/ and cooled to 0°C. Subsequently, l,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise to the cold solution. The reaction mixture was stirred for 3 hours and evaporated. The residue was dissolved in CH 2 CI 2 (20 mL / 1 g of glycosyl bromide) and washed with water (10 mL / 1 g of glycosylbromide), dried and concentrated. The residue was purified by chromatography giving the desired acyclic vinylogous amide-protected aminoglycal in 75-85% yield.
  • 1,2-Di-O-acyl-derivative of carbohydrates (1 equiv.) was dissoved in CH 2 CI 2 (10 mL / 1 g of 1,2-di-O-acyl-carbohydrate) and cooled to 0°C. Hydrogen bromide in acetic acid (30%) (1 mL / 1 g of 1,2-di-O-acyl-carbohydrate) was added and the reaction mixture was allowed to warm to room temperature. The yellowish solution was stirrred at room temperature for 3 hours and diluted with cold CH 2 CI 2 (20 mL / 1 g of 1,2-di-O-acyl-carbohydrate).
  • R , R , E , E as defined in General Formula 1
  • R 3 as defined in General Formula 17
  • Alkyl/arylsulfonyl chloride (1.1 equiv) in dichloromethane (5 mL / 1 g of bicyclic ketopyranose) was added dropwise to the stirred ketopyranose solution. The addition was completed within 30 minutes and the reaction mixture was let to warm to room temperature. The progress of the reaction was followed by TLC.
  • reaction mixture was diluted with CH 2 CI 2 (5 mL / 1 g bicyclic ketopyranose) and washed with water, 5% HCI solution, water and a 1: 1 v/v mixture of saturated NaCl and saturated NaHC0 3 solution.
  • the organic phase was dried over Na 2 S0 4 and evaporated.
  • the desired product was purified by either crystallization or chromatography giving 1-O-sulfonates of bicyclic ketopyranoses in 93-97% yield.
  • R 1 , R , E 2 , E 3 as defined in General Formula 1
  • R as defined in General Formula 17
  • Method A An appripriate 5-hydroxy-l-O-alkyl/aryldulfonyl-ketopyranose (1 equiv) was dissolved in aquous sodium hydroxide solution (containing 1.3-1.5 equivalent sodium hydroxide). The reaction mixture was refluxed for 10-30 minutes, then concentrated under reduced pressure. The resulting residue was titurated with CH 2 CI 2 (20 mL / 1 g of 5-hydroxy- 1-O-alkyl/aryldulfonyl-ketopyranose) and filtered. The filtrate was concentrated and the product was purified by crystallization giving the desired crude tricyclic 1,5-anhydro- carbohydrate in 85-95% yield.
  • Method B An appripriate 5-hydroxy-l-O-alkyl/aryldulfonyl-ketopyranose (1 equiv) was dissolved in anhydrous DMF and sodium hydride (1.5 equiv) (60%) was added at 0°C. The reaction mixture was let to warm to room temperature and stirred for 3 hours. Subsequently the solvent was removed by evaporation under reduced pressure. The resulting residue was titurated with CH 2 CI 2 (20 mL / 1 g of 5-hydroxy-l-O-alkyI/aryldulfonyI-ketopyranose) and filtered. The filtrate was concentrated and the product was purified by crystallization giving the desired crude tricyclic 1,5-anhydro-carbohydrate in 85-95% yield.
  • the organic layer was consecutively washed with 5% aqueous HCI and saturated aqueous sodium bicarbonate, dried (sodium sulfate), filtered and concentrated under reduced pressure.
  • the material obtained was used immediately for the next step or was further purified by crystallization or chromatography.
  • the acid catalyst was quenched with pyridine and ethyl acetate was added. The mixture was filtered and the filtrate was washed with aqueous sodium bicarbonate and dried (sodium sulfate). After filtration, the solvent was removed under reduced pressure and the residue was either immediately used in the next step or further purified by (re-)crystallisation or chromatography. Yields ranged between 60 -75%.
  • reaction mixture could be concentrated under reduced pressure and either extracted with a suitable solvent or chromatographed to obtain purified product. Yields ranged between 65 and 95%.
  • Method A The mixture was stirred under an atmosphere of hydrogen at ambient pressure and ambient temperature until all starting material had been converted to a final more polar product. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The remaining material was either immediately employed in the next step or further purified by (re-) crystallisation or chromatography. Yields ranged between 81 and 95%.
  • Method B Excess ammonium formiate was added and the mixture was stirred at ambient temperature until all starting material had been converted to a final more polar product. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The remaining material was further purified by (re-) crystallisation or chromatography. Yields ranged between 45 and 78%.
  • Procedure A The dry alcohol was used as the solvent: To a 5% solution of the respective tricyclic-l,5-anhydrocarbohydrate in the desired alcohol, a catalytic amount of a suitable acid (e. g., camphor sulfonic acid or 4-toluenesulfonic acid) was added to adjust to a suitable pH value between 1 and 3. The reaction mixture was kept at ambient or suitable elevated temperature until all starting acetal had been converted. Solid sodium bicarbonate (excess) was added and the mixture was stirred for 30 minutes. After filtration, the solution was concentrated under reduced pressure and the product was immediately used in the next step or further purified by (re-)crystallisation or chromatography. Yields ranged between 35 and 87%.
  • a suitable acid e. g., camphor sulfonic acid or 4-toluenesulfonic acid
  • Procedure B An inert solvent was employed : To a 5% solution of the respective tricyclic-1,5- anhydrocarbohydrate in dry dichloromethane, the respective thiol (2-5 equivalents) was added and the mixture was adjusted to pH 1-3 by addition of appropriate amounts of 4- toluenesulfonic or camphor sulphonic acid or other suitable acidic catalysts. When all starting material had been converted, the reaction mixture was washed with aqueous sodium bicarbonate until neutral, the organic layer was dried (sodium sulfate) and the solvent was removed under reduced pressure. The product obtained was immediately used in the next step or further purified by (re-)crystallisation or chromatography. Yields ranged between 35 and 82%.
  • Method A To a 5% solution of the starting material in acetonitrile/water 1 : 1 (v/v), acidic ion exchange resin (e. g., Amberiite IR 120) was added and the mixture was stirred at a suitable temperature between ambient temperature and 75°C until all starting material had reacted. The resin was removed by filtration and washed with water, the filtrate and washings were concentrated under reduced pressure and the remaining residue was purified by (re-)crystallisation or chromatography. Yields ranged between 75 and 90%.
  • acidic ion exchange resin e. g., Amberiite IR 120
  • Method B A 5% solution of the starting material in 80% aqueous acetic acid was stirred at a suitable temperature between ambient temperature and 80°C until all starting material had formed a more polar main product. The reaction mixture was concentrated at ambient temperature followed by co-concentration of the residue with toluene. The remaining material was dissolved in water and lyophilised or (re-)crystallised or chromatographed to obtain pure deprotected product. Yields ranged between 85 and 92%.
  • the resulting residue was taken up in a mixture of water (400 mL) and dichloromethane (200 mL) and the two phases were intensively mixed. The phases were separated. The aqueous phase was further extracted with dichloromethane (2 x 200 mL). The combined organic phase (approx. 600 mL) was washed with water (300 mL) and saturated NaCl solution (300 mL). The dichloromethane solution was dried over anhydrous Na2S04 and evaporated to dryness. The warm residue was taken up in petroleum ether (50-70°C) using intensive stirring. The resulting suspension was refluxed for 5 minutes. The suspension was let to cool to room temperature. The crystallization is completed by reducing the crystallization temperature to 0°C. The white crystalline product was filtered and dried to give 2,3:4,5-Di-0-isopropylidene- ⁇ -D-fructopyranose (141) (58.4 g, 85%).
  • the reaction mixture was diluted with CH2CI2 (250 mL) and washed with water (150 mL), 5% HCI solution (150 mL), water (150 mL) and a 1: 1 v/v mixture of saturated NaCl and saturated NaHC03 solution (150 mL).
  • the organic solution was dried over Na2S04 and evaporated.
  • Petroleum ether (50-70°C) (150 mL) was added to the residue and the suspension was refluxed for 5 minutes.
  • the precipitate was washed with MeCN (100 mL) on the funnel.
  • the filtrate and the MeCN washing were combined and evaporated to dryness under reduced pressure.
  • the residue was taken up in CH 2 CI 2 (200 mL) and the resulting solution was separated from the insoluble part of the residue.
  • the CH 2 CI 2 solution was washed with distilled water (20 mL).
  • the organic phase was kept for further work-up and the aqueous phase was extracted with CH 2 CI 2 (3 x 100 mL). Petroleum ether (50-70°C) (100 mL) was added to the combined organic phases (approx. 500 mL) and the resulting solution was extracted with distilled water (3 x 200 mL).
  • 2,3-O-Isopropylidene-l-O-methanesulfonyl- ⁇ -D-fructopyranose (143) (30 g, 100 mmol) was dissolved in aqueous sodium hydroxide solution made from NaOH (7.24 g) and water (83 mL). The reaction mixture was stirred under gentle reflux for 15 minutes.
  • Aqueous ammonia solution (25%) (2 mL) was added to make the pH of the reaction mixture basic.
  • the reaction mixture was evaporated to dryness under reduced pressure.
  • the residue was taken up in CHC1 3 (500 mL) during vigorous stirring at room temperature and filtered.
  • the solid was intensively washed with CHCI 3 (300 mL) on the funnel.
  • the combined CHCI3 solution was evaporated.
  • the resulting solid residue was refluxed in toluene (150 mL) and the solution was let to cool to room temperature.
  • the cystallization was finalized by stirring the crystalline suspension at 0°C for two hours.
  • the crystalline product was collected by filtration and dried to give 2,3-0-Isopropylidene-l,5-anhydro- ⁇ -D-fructopyranose (144)(18 g, 90%).
  • 2,3-0-Isopropylidene-l,5-anhydro- ⁇ -D-fructopyranose (144) (lOg, 49.5 mmol) was dissolved in 80% aqueous acetic acid solution (30 mL). The reaction mixture was stirred for 15 minutes at 65°C and evaporated under reduced pressure. The warm oily residue was taken up in abs. MeOH (50 mL) and let to cool to room temperature. The methanolic solution was added dropwise to vigorously stirred cold ether (1000 mL) at 0°C. The resulting suspension was stirred at 0°C for two hours and filtered. The solid was washed with ether (300 mL) on the funnel. The still ether-wet precipitate was dried in vacuum to give 1,5- Anhydro-D-fructose (1) (8 g, 94%) as a fluffy white powder.
  • Method B Acetobromoglucose (50 g, 121.7 mmol) was dissolved in dry tetrahydrofurane (THF) (300 mL) in a 3-necked bottle and cooled to 0 oC after which 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) (20 ml, 134 mmol) was slowly added. The cooling bath was removed and the mixture was stirred for 2 hours, or until TLC (ethyl acetate- hexane, 1:2) indicated that the starting material had disappeared. Filtration and concentration left a residue, which was dissolved in dichloromethane (300 mL). This solution was washed with water and aq. HCI (5%). The aqueous phases were again extracted with dichloromethane, and the combined organic phases were washed with brine, and dried
  • a 13 C-NMR spectrum in D20 immediately after dissolution shows the presence of both the hydrate and the two different dimeric forms, but after 2-5 hours all compounds were converted into the hydrated form of 1,5-anhydro-D-fructose showing 6 peaks in the 13 C-NMR spectrum.
  • 1,5-anhydro-D-fructose could be isolated and handled as a freeze dried product, consisting of the monomer 1, the dimeric forms l d im er i » l d i mer 2 and some of the hydrated 1,5-anhydro-D- fructose I h ydrate-
  • H-la 4.25 (dd, 1 H, J5,6a 2 Hz, J6a,6b 10.6 Hz, H-6a), 4.07 (d, 1 H, J3,4 3.9 Hz, H-3), 4.01 (dd, 1 H, J5,6b 1.7 Hz, H-6b), 4.00 (bs, 1 H, H-5), 3.92 (d, 1 H, H-lb), 3.85 (d, 1 H, H- 4), 3.58 (m, H-l'a), 3.48 (m, 1 H, H-l'b), 1.63 (m, 2 H, H-2'), 1.38-1.22 (m, 26 H), 0.85 (t, 3 H).
  • Hi-N R (DMSO-d6): ⁇ 5.24 (dd, 1 H, J2',3' 9.7 Hz, J3',4' 9.7 Hz, H-3'), 5.00 (d, 1 H, Jl',2' 8.1 Hz, H-1'), 4.95 (dd, 1 H, J4',5' 9.7 Hz, H-4'), 4.79 (dd, 1 H, H-2'), 4.21 (dd, 1 H, J5'6'a 4.4 Hz, J6'a,6'b 12.3 Hz, H-6'a), 4.19 (m, 1 H, H-4), 4.13 (1 H, d, Jla,lb 8.5 Hz, H-la), 4.08 (m, 1 H, H-6a), 4.07 (d, 1 H, .73,4 3.8 Hz, H-3), 4.03 (dd, 1 H, J5',6b' 2.2 Hz, H-6'b), 3.97 (m, 1 H, H-6b), 3.97 (m
  • Hl-N R (DMSO-d6): ⁇ 4.90 (d, 1 H, J2',OH 4.7 Hz, 2'-0H), 4.73 (d, 1 H, J3',0H 5.7 Hz, 3'- OH), 4.38 (m, 2 H, 4'-OH, 6'-OH), 4.28 (d, 1 H, Jl',2' 7.6 Hz, H-1'), 4.18 (m, 2 H, H-3, H-4), 4.15 (d, 1 H, H-la) 3.86 (d, 1 H, H-lb), 4.08 (m, 1 H, H-6a), 4.05 (m, 1 H, H-5), 3.98 (m, 1 H, H-6b), 3.64 (m, 1 H, H-4'), 3.51 (m, 2 H, H-6'), 3.36 (m, 1 H, H-5'), 3.34 (m, 1 H, H-2'), 3.28 (m, 1 H, H-3').
  • Ketose ⁇ 214.1, 82.0, 73.9, 71.7, 70.0, 63.8.
  • Minor component 105.45, 79.8, 73.4, 72.2, 68.9, 63.0. 1,5-Anhvdrofructose diethylacetal
  • Acetobromoglucose (316) (80 g, 194.7 mmol) was dissolved in dry acetone (150 ml) containing sodium iodide (40 g) and after 15 min dry diethylamine (80 ml, 777 mmol) was added. After stirring for 1 h at room temperature the mixture was diluted with dichloromethane (300 ml) followed by water (500 ml). The organic phase was washed with aqueous hydrochloric acid and water, dried (MgS0 4 ), filtered and concentrated to give a residue, which was crystallized from ethanol. Yield 41 g (65%), m.p. 59-61°C (lit. Ferrier: m.p. 61-62°C).
  • 1,5-anhydro-D-fructose can be isolated and handled as a freeze dried product, consisting of the monomer 1,5-anhydro-D-fructose (1), the dimeric forms l d im er i ldim er 2/ and some of the hydrated 1,5-anhydro-D-fructose l hydrate -

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Abstract

L'invention concerne 1,4- et 1,5-anhydro-D-cétoses (monosaccharides, oligosaccharides et divers glycoconjugués), par exemple, 1,5-anhydro-D-fructose. De plus, l'invention concerne des procédés synthétiques, de nouveaux intermédiaires ainsi que des précurseurs qui conviennent à leur préparation. Ces procédés impliquent l'élimination catalytique et/ou pyrolithique de l'acide sulfénique des sulfoxydes ß-hydroxy correspondants, la N-déprotection d'aminoglycals N-substitués, la O-déprotection d'enoléthers glucidiques et/ou d'énols glucidiques O-acyl-substitués, ainsi que la modification régio- et stéréosélective et la transformation chimique consécutive de 1,4- et 1,5-anhydro-glycodérivés bicycliques et/ou tricycliques. Par ailleurs, l'invention concerne de nouvelles applications de 1,4- et 1,5-anhydrocétoses dans l'industrie pharmaceutique, alimentaire et cosmétique.
PCT/DK2005/000377 2004-06-07 2005-06-07 1,5- et 1,4-anhydrocetoses, procedes de preparation de 1,5- et 1,4-anhydrocetoses, intermediaires, et utilisations de 1,5- et 1,4-anhydrocetoses WO2005121114A2 (fr)

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CN102936268A (zh) * 2012-11-13 2013-02-20 江苏吉贝尔药业有限公司 一种托吡酯中间体丙酮叉的制备方法

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