EP1017683A4 - Groupes protecteurs et de liaison pour la synthese organique - Google Patents

Groupes protecteurs et de liaison pour la synthese organique

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Publication number
EP1017683A4
EP1017683A4 EP98946145A EP98946145A EP1017683A4 EP 1017683 A4 EP1017683 A4 EP 1017683A4 EP 98946145 A EP98946145 A EP 98946145A EP 98946145 A EP98946145 A EP 98946145A EP 1017683 A4 EP1017683 A4 EP 1017683A4
Authority
EP
European Patent Office
Prior art keywords
substituted
resin
group
oligosaccharide
linker
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98946145A
Other languages
German (de)
English (en)
Other versions
EP1017683A1 (fr
Inventor
Istvan Toth
Gyula Dekany
Barry Kellam
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alchemia Pty Ltd
Original Assignee
Alchemia Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from AUPO9375A external-priority patent/AUPO937597A0/en
Application filed by Alchemia Pty Ltd filed Critical Alchemia Pty Ltd
Publication of EP1017683A1 publication Critical patent/EP1017683A1/fr
Publication of EP1017683A4 publication Critical patent/EP1017683A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids

Definitions

  • This invention relates to methods for synthesis of organic compounds, and in particular to compounds useful as protecting and linking groups for use in the synthesis of peptides, oligosaccharides, glycopeptides and glycolipids.
  • the invention provides protecting and linking groups which are useful in both solid phase and solution synthesis, and are particularly applicable to combinatorial synthesis .
  • oligosaccharide synthesis a variety of protective groups are required. It is necessary to place groups regioselectively at specific locations; on primary alcohols, on cis-diol ⁇ , on trans-diols, on 1,2-diols, on 1,3-diols, or on particular secondary alcohols.
  • aminosugars are important constituents of oligosaccharides, and their amino-protection should be compatible with the hydroxy group protection strategy.
  • the properties of the protective group adjacent to the anomeric centre are also important . Whether this group is participating or non-participating plays a significant role in control of glycoside stereochemistry.
  • orthogonal deprotection sets are based upon the well-known Fmoc and Boc protection of amino acids.
  • the construction of complex peptides or glycopeptides often requires a third orthogonal protecting group for side-chain amino functionalities, whose removal will not affect the protecting groups in the other orthogonal sets, or vice versa .
  • N-Acyl Derivatives a) Phthali ides are especially useful in the protection of amino functions in aminoglycoside synthesis
  • Racemization occurs during the base-catalysed coupling reaction of an N-protected, carboxyl-activated amino acid, and takes place via the intermediate oxazolone that forms readily from an N-acyl protected amino acid.
  • Many carbamates for example Boc (McKay and Albertson, 1957), Cbz (Bergman and Zervas , 1932), Alloc (Kunz and Unverzagt, 1984), Teoc (Carpino et al , 1978), and Troc (Windholz and Johnston, 1967), have been used as protective groups for amino protection.
  • Sulfonamide derivatives are frequently used in nitrogen heterocycles (Gribble et al , 1992), and arylsulfonyl (Fischer and Livschitz, 1915) groups are effective protective groups for a wide range of primary and secondary amines, but their deprotection requires drastic conditions.
  • ⁇ - (Trimethylsilyl) ethanesulfonyl (Weinreb et al , 1986) derivatives are as stable as arylsulfonyl groups, but the cleavage step requires only gentle warming with TBAF or CsF.
  • Sulfenamides are much more labile than sulfonamides , being sensitive to acids as well as to attack by nucleophiles . Their deprotection requires exceptionally mild conditions.
  • Several sulfenyl groups are used for the protection of the amino function including tritylsulfenyl (Brandchaud, 1983), o-nitrophenylsulfenyl (Goerdeler and Hoist, 1959) , and pentachlorphenylsulfenyl (Kessler and Iselin, 1966) . 4. N-Alkyl derivatives
  • Benzylamines give useful protection in reactions in which metal hydrides are used and the carbamates are not stable. Benzylamines are less susceptible to catalytic hydrogenolysis than benzyl ethers or benzyl esters, and thus selective deprotection can often be achieved (Goldstein et al , 1992).
  • the trityl group (Sieber and Riniker, 1991) is used to protect amino acids, although its steric bulk and high acid lability is detrimental to peptide coupling.
  • the 9-phenylfluorenyl (PhFl; Koskinen and Rapoport, 1989) group is used for the protection of primary and secondary amines. Its hydrophobicity, steric bulk and ease of introduction are similar to the trityl group, but the PhFl group is about 6000 times more stable to acid than the trityl group.
  • N-l- (4, 4- dimethyl-2 , 6-dioxocyclohexylidene) ethyl Dde-protective group improving the stability towards secondary amines (Bycroft et al , 1993).
  • the N-l- (4 , 4-dimethyl-2 , 6- dioxocyclohexylidene) -3-methylbutyl-protected amino acids (Chan et al , 1995), carrying a bulkier group at the enamine double bond, had excellent base stability.
  • Douglas and coworkers described the synthesis of D-mannopentose using a polyethyleneglycol w-monomethylether co-polymer and a succinoyl or an ⁇ , ⁇ ' -dioxyxylyl diether linker (Douglas et al , 1995) .
  • the reactions were carried out in solution phase, with removal of unused reactants being achieved by precipitation of the oligosaccharide-polymer complex and subsequent washing.
  • cleavage of the oligosaccharide-polymer bond was achieved through catalytic hydrogenation, which required exposure of the conjugate to 1 atm of H2 for 48 h to achieve respectable yields.
  • the critical element in solid phase synthesis is the nature of the linker between the solid support and the initial synthon.
  • the linker must display excellent stability to the conditions of coupling and deprotection, yet in the case of solid phase oligosaccharide synthesis, it should also be rapidly and efficiently cleaved to allow monitoring of the progress of individual coupling reactions.
  • the cleavage should ideally be achieved by the use of a relatively innocuous chemical reagent .
  • the Dde-protected aminosugars are not stable in the presence of sodium cyanoborohydride and metal hydrides . These reagents are often used in benzylidene ring opening reactions and during benzyl protection of hydroxyl groups. This hydride sensitivity of the Dde group limits its application in carbohydrate chemistry. The preparation of 2-acyl-dimedones is very often difficult. One of the major side reactions is O-acylation, which lowers the overall yields and causes difficult chromatographic purification problems .
  • Nde-protection of primary amines always gives a mixture of E/Z isomers which may not be separable, causing difficult characterisation problems.
  • the formation of 2- acetyl-4-nitroindan-l , 3-dione involves the reaction between 4-nitrophthalic anhydride and 2 , 4-pentanedione via a condensation and two rearrangements . This synthetic strategy does not give an opportunity to prepare Nde-OH analogues .
  • the ring is a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl , substituted cycloheteroalkyl , saturated bicyclo[p, q, r] , substituted saturated bicyclo[p, q, r] , saturated heterobicyclo [p, q, r] , substituted saturated heterobicyclo [p, q, r] , unsaturated bicyclo[p, q, r] , substituted unsaturated bicyclo[p, q, r] , unsaturated heterobicyclo [p, q, r] , substituted unsaturated heterobicyclo [p, q, r] , saturated tricyclo[p, q, r, s] , substituted saturated tricyclo[p, q, r, s] , substituted saturated tricyclo[p, q, r, s] , substituted saturated tricyclo[p,
  • X is oxygen, sulphur, imino or substituted imino
  • R 1 is hydrogen; an alkyl , alkenyl, alkynyl , heteroalkyl, aryl, heteroaryl, cycloheteroaryl , cycloalkyl, heterocycloalkyl , alkanal, or thioalkanal group, each of which may be substituted or unsubstituted; NH 2 , guanidino,
  • R 2 is an alkylamino, dialkylamino, arylamino, or diarylamino group, each of which may be substituted or unsubstituted; O-substituted hydroxylamino , substituted or unsubstituted hydrazino, substituted or unsubstituted hydrazido, substituted or unsubstituted thiohydrazido, semicarbazido, thiosemicarbazido, OH, 0 " M,NH 2 , NHOH, SH, SM + , halogen; O-alkyl, O-acyl, O-aryl, alkylthio, S-aryl, acylthio, alkylsulfonyl or arylsulfonyl, each of which may be substituted or unsubstituted; and M is a metal ion/ or an organic or inorganic cation such as a quaternary amine group, a
  • the metal ion can be mono- or multivalent, and may form a complex salt.
  • the 1 ring is 4- to 8-membered cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl.
  • the ring is a 5- to 8-membered ring of the lactone or lactarn type, or a 6- to 8-membered ring of the carbamido or substituted carbamido type, as follows:
  • each R is independently H, substituted or unsubstituted alkyl, aryl, alkenyl, alkynyl or acyl, or may be a 6- to 8-membered ring of the carbonate type, as follows :
  • each of the substituent groups R, R 1 , R 2 and R 3 may itself be substituted, ie. one or more hydrogen atoms may be replaced by a substituent group .
  • substituted in the definitions of R, R 1 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, carboxyamide, 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.
  • the person skilled in the art will be aware of other suitable substituents of similar size and charge characteristics which could be used as alternatives in a given situation.
  • the compound is of general formula II
  • each R is independently H or a substituted or unsubstituted alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocycloalkyl ;
  • R 1 and R 2 are as defined in general formula I-.
  • each R has 1 to 6, more preferably 1 to 4 carbon atoms .
  • the compound is of general formula III
  • R 1 and R 2 are as defined in general formula I.
  • the compounds of the invention are useful in a wide variety of areas of organic chemistry.
  • the compounds are especially useful in the solution and/or solid phase synthesis of oligosaccharides and peptides.
  • Uses of the compounds of the invention thus include but are not limited to the following:
  • N-side chain and/or N ⁇ protecting groups for solid or solution phase peptide synthesis 6.
  • Certain compounds of the invention are chiral; these are useful in resolution of enantiomers and in stereospecific synthesis.
  • Linker groups for coupling of a starter group to a resin for solid phase synthesis of oligosaccharides, peptides and other organic compounds 8.
  • the invention provides an N-protecting group for oligosaccharides, amino acids, peptides or organic compounds .
  • N-protecting group for oligosaccharides, amino acids, peptides or organic compounds is shown in general formula IV.
  • R 3 is a protected, unprotected or substituted sugar amino-, a glycosylamino- , or a glycosylamino group of an oligosaccharide; or a mono- or oligosaccharide coupled through a substituted or unsubstituted alkylamino-, arylamino-, cycloalkylamino, heteroalkylamino, heteroarylamino or heterocycloalkylamino group.
  • the compound is of general formula V
  • R and R 1 are as defined in general formula II, and R 3 is as defined in general formula IV.
  • R 3 is a protected, unprotected or substituted sugar amino-, a glycosylamino-, or a glycosylamino group of an oligosaccharide.
  • R 3 is an oligosaccharide-0-CH2-
  • the invention provides a support of general formula VI for solid-phase synthesis of oligosaccharides, peptides or organic compounds, comprising a resin and a linker covalently attached to the resin:
  • R 1 is a substituted or unsubstituted alkyl, cycloalkyl, heteroalkyl, heteroaryl, heterocycloalkyl or carboxylamido spacer group which is directly coupled to the resin support, or which may optionally be coupled to the resin support via a suitable covalent linkage, which is stable to conditions of oligosaccharide synthesis and cleavage .
  • the linker is a barbituric acid of general formula VII
  • R and R 2 are as defined in general formula I, and R 1 is as defined in general formula VI, in which a compound of general formula II is directly coupled to the resin support, or may optionally be coupled to the resin support via a suitable covalent linkage which is stable to conditions of oligosaccharide synthesis and cleavage.
  • Other possible covalent linking groups will be known to those skilled in the art.
  • the resin may be any resin which swells in water and/or in an organic solvent, and which comprises one of the following substituents: halogen, hydroxy, carboxyl, SH, NH 2 , formyl, S0 2 NH 2 , or NHNH 2 , for example methylbenzhydrylamine (MBHA) resin, amino or carboxy tentagel resins, or 4-sulphamylbenzyl AM resin.
  • MBHA methylbenzhydrylamine
  • supports such as controlled-pore glass or soluble polymer supports may be used. These are well known in the art .
  • the invention also provides a method of solid- phase synthesis of oligosaccharides, comprising the step of sequentially linking mono- or oligosaccharide groups to a support as described above.
  • the linker may be synthesised directly on the resin in a stepwise manner prior to the coupling of the initial sugar group, or the linker-initial sugar conjugate may be synthesised in solution phase and subsequently coupled to the solid support, with subsequent sugars being sequentially attached.
  • the second and all subsequent sugar groups are coupled to the oligosaccharide chain-resin conjugate after the last sugar in the oligosaccharide chain is partially deprotected.
  • the first sugars attached to the resin-linker unit may be unprotected, partially protected or fully protected glycosides, aminoglycosides , or ether- or amino-linked sugars.
  • the first sugar coupled to the resin is an aminosugar, an aminoglycoside or an amino- oligosaccharide, or a glycosyl amines of an oligosaccharide .
  • the support comprises a resin, a linker and a saccharide selected from the group consisting of monosaccharide, oligosaccharides, or aminosaccharides and aminooligosaccharides .
  • the building block mono- or oligosaccharide- donors may be any activated sugar, including but not limited to orthoesters, thio-orthoesters, cyanoalkylidene derivatives, 1-O-acyl sugars, amino sugars, acetimidates , trichloroacetimidates , thioglycosides , aminoglycosides, aminoligosaccharides , glycosylamines of oligosaccharides, glycosyl thiocyanates , pentenyl glycosides, pentenoylglycosides , isopropenyl glycosides, glycals, - tetramethylphosphoro diamidates, sugar diazirines, selenoglycosides , phosphorodithioates , glycosyl- dialkylphosphites , glycosylsulphoxides and glycosylfluorides .
  • partial sugar deprotection is achieved by using acyl-type, trityl, methoxytrityl , methoxybenzyl, various silyl and/or photolabile protecting groups in addition to permanent ether-type protecting groups.
  • This permits the synthesis of branched oligosaccharides by using two orthogonal hydroxy-protecting groups on a single sugar donor .
  • the synthesised oligosaccharide can be cleaved from the resin using ammonia, hydrazine or a primary amine, such as butylamine or cyclohexylamine .
  • ammonia or a suitable primary amine in an organic solvent is preferably employed.
  • hydrazides hydrazine in water or an organic solvent is preferably employed.
  • oligosaccharides ammonia in water or organic solvent is preferably employed, followed by acidification.
  • the linker contains a 4-aminobenzyl moiety
  • the linker contains a 4-aminobenzyl moiety
  • the invention provides a reagent for solution phase synthesis of sugar-containing compounds, comprising a barbituric acid derivative compound of general formula II as defined above.
  • the compounds of the invention are suitable for use as protecting groups in methods of solid-phase oligosaccharide synthesis, in which sugar units are linked to a resin.
  • Any suitable linker compound may be used, including compounds of the invention. It is contemplated that linkers and methods described in our earlier application, PCT/AU97/00544 , are also suitable for use with the compounds of this invention.
  • the invention provides a linker-saccharide complex, comprising a linker group and a starting compound comprising a protecting group of general formula I or II as defined above. Any suitable linker may be used, including the compounds of the invention. Again, it is contemplated that linkers and methods described in PCT/AU95/00544 may be used.
  • the invention provides a method of solution phase synthesis of oligosaccharides, comprising the step of sequentially linking mono- or oligosaccharide groups to a linker-saccharide complex as described above. These methods are particularly useful for combinatorial synthetic applications .
  • the solution phase method of the invention may, for example, be used for combinatorial synthesis of aminoglycoside compounds.
  • kits useful in solution phase synthesis or combinatorial synthesis of oligosaccharides or peptides comprising either a) a resin-linker-saccharide or resin-linker- peptide (or amino acid) support, b) a linker-saccharide or linker-peptide (or amino acid) complex, or c) a resin-linker support, according to the invention, as described above.
  • kit may optionally also comprise one or more further reagents such as protecting agents, deprotecting agents, and/or solvents suitable for solid phase or combinatorial synthesis.
  • further reagents such as protecting agents, deprotecting agents, and/or solvents suitable for solid phase or combinatorial synthesis.
  • the invention also provides a kit useful in solid phase synthesis or combinatorial synthesis of oligosaccharides, comprising a linker-saccharide complex according to the invention, as described above.
  • the kit may optionally also comprise one or more further reagents such as protecting agents, deprotecting agents, and/or solvents suitable for solid phase or combinatorial synthesis.
  • further reagents such as protecting agents, deprotecting agents, and/or solvents suitable for solid phase or combinatorial synthesis.
  • suitable further reagents can then be chosen according to the desired use.
  • the 5-acyl-l , 3-dimethylbarbituric acids were easily crystallized from polar solvents, avoiding the need for chromatographic purifications. These reagents are very cheap and easy to synthesize in a single reaction from the readily available 1 , 3 -dimethyl-barbituric acid.
  • the ADA-protected aminosugars can be used as aminosugar acceptors and aminosugar donors for solid or solution phase oligosaccharide synthesis.
  • the ADA- protected amino acids are particularly useful as reagents for solid-phase peptide and glycopeptide syntheses, because they are unable to form oxazolones during the coupling reactions. Thus, no racemization can occur during the peptide bond formation (racemization can only occur in base-catalyzed proton abstraction) .
  • the ADA-protection is ideally orthogonal to the Boc-protection and quasi- orthogonal to the Fmoc system.
  • the ADA-protected derivatives are very stable in a wide range of reactions and work-up conditions.
  • Example 12 N- [1- (1, 3 -dimethyl-2 , 4, 6 (IH, 3H, 5H) - trioxopyrimidin-5-ylidene) ethyl] 1-butylamine 2 5-Acetyl-l, 3 -dimethyl-2 , 4, 6 (IH, 3H, 5H) - pyrimidinetrione (100 mg, 0.50 mmol) was dissolved in - n-butylamine (10 ml) and stirred at room temperature overnight.
  • 1-butylamine 4 A mixture of 5-benzoyl-l , 3-dimethyl- 2 , 4, 6 (IH, 3H, 5H) -pyrimidinetrione (500 mg, 1.92 mmol) and N, N-diisopropylethylamine (248 mg, 1.92 mmol) in n-butylamine (10 ml) was refluxed for 2 hours. The solvent was evaporated, the residue was washed 1 M KHSO 4 solution, dried and evaporated.
  • Example 14 N- [1- (1 , 3 -dimethyl-2 , 4 , 6(1H,3H,5H) - trioxopyrimidin-5-ylidene) ethyl] glycine 14
  • EtOH (10 ml) was stirred under reflux overnight.
  • Example 15 N- [1- (1 , 3 -dimethyl-2 , 4 , 6 (1H,3H,5H)- trioxopyrimidin-5-y1idene) phenylmethy1 ] glycine 15
  • a mixture of 5-benzoyl-l, 3-dimethyl- 2, 4, 6 (1H,3H, 5H) -pyrimidinetrione (519 mg, 2.00 mmol), glycine (100 mg, 1.33 mmol) and N, -diisopropylethyl-amine (172 mg, 1.33 mmol) in abs.
  • EtOH (10 ml) was stirred under reflux overnight.
  • Example 16 N- [1- (1 , 3 -dimethyl-2 , 4 , 6 (IH, 3H, 5H) - trioxopyrimidin-5-ylidene) phenylethyl] glycine 16
  • a mixture of 5-phenylacetyl-l , 3-dimethyl- 2, 4, 6 (IH, 3H, 5H) -pyrimidinetrione (548 mg, 2.00 mmol), glycine (100 mg, 1.33 mmol) and N, N-diisopropylethyl-amine (172 mg, 1.33 mmol) in abs.
  • EtOH (10 ml) was stirred under reflux overnight.
  • Example 17 Cleavage of 5-acyl-l , 3-dimethylbarbituric acid protected primary amines affording 5-acyl-l, 3-dimethylbarbituric acid protected hydroxylamines 34 N- [l-( 1,3 -Dimethyl-2, 4, 6 (1H,3H, 5H) - trioxopyrimidin-5-ylidene)phenylmethyl] hydroxylamine 17 and Benzyl 2-deoxy-2-amino- ⁇ -D-glucopyranoside 34 Benzyl 2-deoxy-2- [1- (1 , 3-dimethyl-2 , 4 , 6 (IH, 3H, 5H) -trioxo- pyrimidin-5-ylidene) phenylmethylammo] - ⁇ -D-glucopyranoside 22 (100 mg, 0.19 mmol) in NH 2 OH/MeOH (20%, 10 ml) was stirred at room temperature for 30 min. The solution was evaporated, the residue was suspended with ether (20
  • Example 24 Benzyl 2-deoxy-2- [1- (1 , 3 -dimethyl- 2,4, 6 (IH, 3H, 5H) -trioxopyrimidin-5-ylidene) (9- fluorenylmethylamino) ] - ⁇ -D-glucopyranoside 23
  • EtOH (10 ml) was stirred under reflux overnight.
  • Example 25 Benzyl 2-deoxy-2- [1- (1 , 3 -dimethyl- 2,4,6 (1H,3H, 5H) -trioxopyrimidin-5- ylidene) phenylethylamino] - ⁇ -D-glucopyranoside 24
  • a mixture of 5-phenylacetyl-1, 3 -dimethyl- 2 , 4 , 6 ( IH, 3H, 5H) -pyrimidinetrione 8 (305 mg, 1.11 mmol), benzyl 2-amino-2-deoxy- ⁇ -D-glucopyranoside 34 (200 mg,
  • Example 31 Chiral 5-acyl-l , 3-dimethylbarbituric acid derivatives for primary amine protection N, N' -Bis- (benzyl 2-deoxy-a-D-glucopyranosid-2-yl ) - [5- (2- aminoacet imino) -1 , 3 -dimethyl -2 , 4 , 6 (IE, 3E, 5E) - pyrimidinetrione] 30 and 5- [N- (benzyl 2-deoxy- ⁇ -D- glucopyranosid-2 -yl ) aminoacetyl ] -1 , 3 -dimethyl - 2, 4 , 6 (IE, 3H, 5E) -pyrimidinetrione 31
  • the TNBS test was faintly positive so using the above conditions, a double coupling was performed, this time producing a negative TNBS test result.
  • the resin was washed with DMF, methanol and finally ether. The resin was then allowed to dry in vacuum over KOH overnight.
  • Example 33 Carbohydrate deprotection and cleavage of the "fully protected sugar - linker - resin conjugate" providing an "amino substituted resin - linker conjugate” 35
  • the resin from Example 32 was gently agitated with sodium methoxide (100 mg, 1.85 mmol) in abs. MeOH (5 ml) at room temperature for 1 h. The resin was washed with abs. MeOH (5x10 ml), DMF(5xlO ml), ether (5x10 ml) and dried under high vacuum for 1 h, giving the resin bonded unprotected benzyl 2-amino-2-deoxy- ⁇ -D-glucopyranoside .
  • Example 35 Preparation of a "hydroxy-substituted resin- linker conjugate" 36 MBHA resin (Subst. ratio: 0.42 mmol/g) (200 mg) bearing a total amine functionality of 0.084 mmol was swelled in DMF for 20 min. The resin was then washed with fresh DMF and 5- (4-carboxybutyryl ) -1, 3 -dimethyl- 2, 4, 6 (IH, 3H, 5H) -pyrimidinetrione 10 (68 mg, 0.25 mmol) and N, N' -diisopropylcarbodiimide (40 ml, 3.0 equiv.) were added in DMF (5 ml) and the resin gently agitated for 30 min.
  • 5- (4-carboxybutyryl ) -1, 3 -dimethyl- 2, 4, 6 (IH, 3H, 5H) -pyrimidinetrione 10 68 mg, 0.25 mmol
  • the TNBS test was faintly positive so using the above conditions, a double coupling was performed, this time producing a negative TNBS test result.
  • the resin was washed with DMF, methanol and finally ether. The resin was then allowed to dry in vacuum over KOH overnight to give 36.

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Abstract

L'invention concerne des procédés qui permettent de synthétiser des composés organiques, notamment des composés utiles comme groupes protecteurs et de liaison pour la synthèse des peptides, des oligosaccharides, des glycopeptides et des glycolipides. Elle concerne également des groupes protecteurs et de liaison qui sont utiles pour la synthèse aussi bien en phase solide qu'en solution, et qui conviennent particulièrement pour la synthèse combinatoire. Dans un aspect plus général, elle concerne un composé cyclique de formule générale (I).
EP98946145A 1997-09-24 1998-09-24 Groupes protecteurs et de liaison pour la synthese organique Withdrawn EP1017683A4 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
AUPO9375A AUPO937597A0 (en) 1997-09-24 1997-09-24 Protecting and linking groups for organic synthesis
AUPO937597 1997-09-24
US6198797P 1997-10-14 1997-10-14
US61987P 1997-10-14
PCT/AU1998/000808 WO1999015510A1 (fr) 1997-09-24 1998-09-24 Groupes protecteurs et de liaison pour la synthese organique

Publications (2)

Publication Number Publication Date
EP1017683A1 EP1017683A1 (fr) 2000-07-12
EP1017683A4 true EP1017683A4 (fr) 2002-03-06

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EP (1) EP1017683A4 (fr)
JP (1) JP2001517660A (fr)
CN (1) CN1276788A (fr)
CA (1) CA2304061A1 (fr)
HU (1) HUP0100163A2 (fr)
WO (1) WO1999015510A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AUPO190596A0 (en) 1996-08-26 1996-09-19 Alchemia Pty Ltd Oligosaccharide synthesis
AUPO937597A0 (en) 1997-09-24 1997-10-16 Alchemia Pty Ltd Protecting and linking groups for organic synthesis
AUPP823099A0 (en) 1999-01-18 1999-02-11 Alchemia Pty Ltd Protecting groups for carbohydrate synthesis
JP2002538163A (ja) 1999-03-05 2002-11-12 マサチューセッツ インスティテュート オブ テクノロジー 固体支持体上におけるオリゴ糖合成のためのリンカー
EP1831241A2 (fr) * 2004-11-24 2007-09-12 AplaGen GmbH Procede de synthese et purification de peptides en phase solide
US20120258891A1 (en) 2011-04-07 2012-10-11 Nimblegen Systems Gmbh Diarylsulfide backbone containing photolabile protecting groups
FR3035787B1 (fr) * 2015-05-07 2018-08-24 L'oreal Procede de traitement des matieres keratiniques a partir de derives de c-glycosides amides, acides ou ester, et la composition cosmetique les contenant
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CN111208284B (zh) * 2018-11-22 2021-08-24 北京大学 糖代谢标记探针、包含其的试剂盒及其应用

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CN1276788A (zh) 2000-12-13
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JP2001517660A (ja) 2001-10-09
CA2304061A1 (fr) 1999-04-01
EP1017683A1 (fr) 2000-07-12

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