WO1995003316A2 - Solution and solid phase stereocontrolled glycosidation - Google Patents
Solution and solid phase stereocontrolled glycosidation Download PDFInfo
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- WO1995003316A2 WO1995003316A2 PCT/CA1994/000396 CA9400396W WO9503316A2 WO 1995003316 A2 WO1995003316 A2 WO 1995003316A2 CA 9400396 W CA9400396 W CA 9400396W WO 9503316 A2 WO9503316 A2 WO 9503316A2
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- alkoxy
- arylalkoxy
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- JRTXHAKFUYCRCV-UHFFFAOYSA-N C[O](C(C1C(CO)OC2Oc3ccccn3)C2O)=[O]1=C Chemical compound C[O](C(C1C(CO)OC2Oc3ccccn3)C2O)=[O]1=C JRTXHAKFUYCRCV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
Definitions
- the present invention primarily relates to a process of providing pure, or significantly higher proportion of alpha anomers in significantly improved yield. Specific donors, acceptors, promoters, and solvents are combined to produce specific anomers. The present invention secondarily provides novel compounds prepared by the process. Although the invention will be described and referred to as it relates to processes of preparation of anomers from specific donors, acceptors, promoters, and solvents, and the resulting anomers, it will be
- alpha bromo 1,2-trans peracetyl glycoside anomer is converted to the equivalent beta (1,2-trans) glycoside in 47%, 64%, and 72% yield while the beta acetyl anomer was similarly converted in 71%, 72% and 80% yield (Hanessian, Carbohdr. Res., 53, C13 (1977) and 59, 261 (1977).
- Particularly of interest are those where the alpha:beta product ratio is known and can be improved, and where the overall yield is high.
- glycosides can be prepared from glycosyl heterocyclic donors without protection of OH groups (S. Hanessian et al. Carbohydrate Res. 80, C17 (1980)).
- reaction mechanisms suggests metal complex formation with beta 2-pyridylthio donor leaving group, that is the activation is remote to the anomeric carbon, which applicant has termed "remote activation.”
- subsidiary object of the invention to develop synthetic methods for the synthesis of glycosides, disaccharides, oligosaccharides and nucleosides, using glycosides including but not restricted to pyridyloxy,
- nucleosides including polymer supported oligosaccharide syntheses, in superior yield -and stereospecificity, faster reaction times and shorter syntheses.
- a still further object is to provide for a solid phase process to prepare oligosaccharides using the MOP glycosides in which process a resin support is employed.
- the invention is directed to a process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl
- glycosides with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent, the improvement providing that the donor is selected from the group consisting of glycosides substituted by leaving groups D of formula XII and related heterocyclic bases.
- R14 is H or alkoxy of 1 to 5 carbon atoms, or two adjacent R14 together form a four carbon portion of a fused benzenoid ring.
- the promoter is selected from the group consisting of MeOTf, TfOH, BF 3 , AgOTf, Cu(OTf) 2 , ZnCl 2 , and other acids, Lewis acids, and chelating metals.
- the solvent is selected from the group consisting of CH 3 NO 2 , and CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
- the invention is directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent.
- a donor selected from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
- n 0 or 1
- W is a heterocyclic
- biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof, A is N, or CH, and R1 is H, alkoxy-alkyl in which the alkoxy and alkyl group contain up to 5 carbon atoms each, or alkoxy of 1 to 5 carbon atoms, said promoter is selected from the group consisting of MeOTf, TfOH, BF 3 , Cu(OTf) 2 , ZnCl 2 , and other acids, Lewis acids, and N-haloimides, and chelating metals.
- the promoter is selected from the group consisting of MeOTf, TfOH, BF 3 , Cu(OTf) 2 , ZnCl 2 , and other acids, Lewis acids and
- the solvent is selected from the group consisting of CH 3 NO 2 , and CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
- the donor is an O-pyranosyl glycoside
- the promoter is selected from the group consisting of MeOTf, TfOH, BF 3 , Cu(OTf) 2 , and ZnCl 2
- the solvent is selected from the group consisting of CH 3 NO 2 , and CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF and THF, and mixtures thereof.
- the donor is selected from the group consisting of glycosides of formula RX wherein X has formula I and related heterocyclic structures, and R has formula II,
- R2 is azido, acyloxy of 2 to 6 carbon atoms, acylamino of 2 to 5 carbon atoms, hydroxy, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen
- R3, and R4 are substituted, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are
- R5 is independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R5 is independently hydroxy, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R.
- the promoter is selected from the group consisting of MeOTf, TMSOTf, TfOH, BF 3 , Cu(OTf) 2 , and ZnCl 2
- the solvent is selected from the group consisting of CH 3 NO 2 , CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, and THF and mixtures thereof.
- the acceptor is selected from the group consisting of R'OH, wherein R' is alkyl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl of 1 to 27 carbon atoms, including N-substituted amino-alcohols and S-substituted thio-alcohols, esters of alkanols of 1 to 10 carbon atoms with hydroxyalkanoic acids of 2 to 6 carbon atoms, esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, wherein R" has formula III,
- R7 is azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms
- R8 is hydrogen, hydroxyl, alkenyloxy of 1 to 5 carbon atoms, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms unsubstituted or
- X is 3-methoxy-pyridyl-2-oxy.
- the s may be considered as two distinct groups
- R2 is azido, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms.
- the promoter is Cu(OTf) 2 .
- the solvent is selected from the group consisting of CH 2 Cl 2 , Et 2 O, and mixtures thereof.
- the acceptor is selected from the group consisting of glycosides of formula R"Y, containing at least one unprotected
- alcoholic hydroxyl wherein Y is alkoxy of 1 to 12 carbon atoms, R7 is hydroxy, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, hydroxyl, acyloxy of 2 to 6 carbon atoms arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, or acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 and R10 may together be aralkylidenyldioxy of 7 to 10 carbon atoms.
- R5 is
- R2, R3, R4, R5 may be R, and at least one of R2, R3, R4 and R5 is hydroxyl.
- the promoter is selected from the group consisting of MeOTf, TMSOTf, BF 3 , Cu(OTf) 2 , and ZnCl 2 .
- the solvent is selected from the group
- the acceptor may be selected from the group consisting of alkanols, alkenols and cycloalkanols of 1 to 6 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y and R7 together are alkylidenyldioxy of 3 to 9 carbon atoms, R8 and R9 together are alkylidenyldioxy of 3 to 9 carbon atoms. More preferably wherein R2, R3, R4 and R5 are hydroxyl, that it is the donor is unprotected.
- protecting groups may be
- R2, R3, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms.
- the promoter is selected from the group consisting of MeOTf, and Cu(OTf)2.
- the solvent is selected from the group consisting of CH 3 NO 2 , CH 2 Cl 2 , Et 2 O, and CH 3 CN and mixtures thereof.
- the acceptor is selected from the group consisting of alkanols of 1 to 5 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is selected from the group consisting of alkoxy of 1 to 12, and preferably 1 to 5 carbon atoms and 3-methoxy-pyridyl-2-oxy, R7 is azido, hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydrogen, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydroxyl, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, or alkyl
- Y and R7 may together be alkylidenyldioxy of 3 to 9 carbon atoms
- R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms
- R9 and R10 may together be aralkylidenyldioxy of 7 to 10 carbon atoms.
- the protecting groups may be esters, here R2, R3, and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen
- the acceptor is preferably a glycoside of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 12, preferably 1 to 5 carbon atoms, R7 is arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is alkenyloxy of 1 to 5 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R9 is hydroxyl, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10 is hydroxyl, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R10 is hydroxyl, arylalkoxy of 7 to 10 carbon atoms
- R2 is acylamino of 2 to 5 carbon atoms
- R3, R4 and R5 are hydroxyl.
- the promoter is selected from the group consisting of MeOTf, and TfOH.
- the solvent is selected from the group consisting of CH 3 NO 2 and DMF and mixtures thereof.
- the acceptor is selected from the group consisting of alkanols of 1 to 5 carbon atoms and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is 3-methoxy-pyridyl-2-oxy, R7 is azido, R8 is acyloxy of 2 to 6 carbon atoms, R9 is acyloxy of 2 to 6 carbon atoms, R10 is hydroxyl, Y and R7 may together be
- R8 and R9 may together be alkylidenyldioxy of 3 to 9 carbon atoms.
- R2 is azido
- R3, is arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms or R wherein R2, R3, R4, and R5 are acyloxy of 2 to 6 carbon atoms, R4 and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, or R4 and R5 together are
- alkylidenyldioxy of 3 to 9 carbon atoms The promoter is Cu(OTf)2, while the solvent is selected from the group consisting of CH 2 Cl 2 , and CH 3 CN and mixtures thereof.
- the acceptor is selected from the group consisting of esters of alkanols of 1 to 10 carbon atoms with hydroxyaminoalkanoic acids of 2 to 6 carbon atoms having the amino function acylated by an acid of 2 to 10 carbon atoms, and glycosides of formula R"Y, containing at least one unprotected alcoholic hydroxyl, wherein Y is alkoxy of 1 to 12 carbon atoms, R7 is acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, hydroxyl, or aminocarbalkoxy of 2 to 10 carbon atoms, R8 is hydrogen, acyloxy of 2 to 6 carbon atoms, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, or hydroxyl, R9 is hydroxyl, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substitute
- glycosides with an acceptor including a trialkylsilyl ether of a pyrimidine, in the presence of a promoter and a solvent.
- the improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
- n 0 or 1
- W is a heterocyclic
- biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof, A is N, or CH, and R1 is H, alkoxy-alkyl in which the alkoxy and alkyl group contain up to 5 carbon atoms each, or alkoxy of 1 to 5 carbon atoms.
- the promoter is TMSOTf, and other acids, Lewis acids and chelating metals.
- the solvent is selected from the group consisting of toluene, benzene, dioxane, CH 2 Cl 2 , Et 2 O, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
- the donor is an O-pyranosyl or O-furanosyl glycoside, of formulae II or VI
- the trialkyl silyl pyrimidine ether has formula VII (or a corresponding 5 or 6 position analog having an N thereat).
- R2, R3, R4, and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R10 is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R13 is trialkylsiloxy wherein the alkyls are
- R14 is
- trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms.
- R2, R3, R4, R5, R11, R12 are benzyloxy
- Rll is hydrogen or benzyloxy
- R13 is trimethylsiloxy
- R14 is trimethylsiloxy or benzamido
- R15 is hydrogen or methyl.
- the invention is further directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl
- glycosides with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent.
- the improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups X of formula I and related heterocyclic bases:
- n 0 or 1
- W is a heterocyclic
- biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof
- A is N, or CH
- R1 is H, alkoxy-alkyl in which the alkoxy and alkyl group contain up to 5 carbon atoms each, or alkoxy of 1 to 5 carbon atoms.
- the promoter is selected from the group consisting of MeOTf, TfOH, BF 3 , Cu(OTf) 2 , ZnCl 2 , and other acids, Lewis acids and chelating metals.
- the solvent is selected from the group consisting of CH 3 NO 2 , and CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
- the glycoside is coupled to a supporting resin by a coupling group integral to the resin, and a linking element bonded to coupling group and the glycoside.
- the coupling group is
- the linking element is a
- dicarboxylic acid residue forming an amido bond with the coupling group and an ester bond with the glycoside.
- the glycoside comprises a plurality of saccharide units.
- the invention is directed to an improved process of glycoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an alcoholic hydroxyl, in the presence of a promoter and a solvent.
- the improvement comprising selecting the donor from the group consisting of glycosides substituted by leaving groups of formula VIII:
- n 0 or 1
- W is a heterocyclic
- biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof and where B is O or S.
- the promoter is selected from the group consisting of MeOTf, TfOH, BF 3 , AgOTf, Cu(OTf) 2 , ZnCl 2 , and other acids, Lewis acids and chelating metals.
- the solvent is selected from the group consisting of CH 3 NO 2 , and CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
- the promoter is selected from the group consisting of AgOTf and Cu(OTf) 2
- the solvent is selected from the group consisting of CH 3 NO 2 , and CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF and THF, and mixtures thereof.
- the donor is selected from the group consisting of glycosides of formula IX wherein Z has formula VIII,
- R2 is acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen
- R3, and R4 are substituted, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are
- R5 is independently acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted, arylalkoxy of 7 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or R2, R3, R4, R5, may be R.
- the promoter is selected from the group consisting of AgOTf, and Cu(OTf) 2 .
- the solvent is selected from the group consisting of CH 3 NO 2 , CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, and THF and mixtures thereof.
- R2, R3 and R4 are independently acyloxy of 2 to 6 carbon atoms, or arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen substituted
- R5 is alkyl of 1 to 5 carbon atoms.
- the promoter is selected from the group consisting of AgOTf, and Cu(OTf) 2
- the solvent is selected from the group consisting of CH 3 NO 2 , CH 2 Cl 2 , Et 2 O, CH 3 CN, DMF, and THF and mixtures thereof.
- n 0 or 1
- W is a heterocyclic
- biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof
- A is N, or CH
- R1 is H, alkoxyalkyl in which the alkoxy and alkyl group contain up to 5 carbon atoms each, or alkoxy of 1 to 5 carbon atoms
- R2 is azido, acyloxy of 2 to 6 carbon atoms, arylcarboxy of 7 to 10 carbon atoms unsubstituted or halogen
- R3, and R4 are substituted, arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms, R3, and R4 are
- R5 is independently hydroxy.
- the invention is directed to an improved process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including a trialkysilyl pyrimidine ether, or a corresponding 5 or 6 position analog having an N thereat, in the presence of a promoter and a solvent, the improvement lies in selecting the donor from the group consisting of glycosides substituted by leaving groups of formula VIII:
- B is O or S
- n is 0 or 1
- W is a heterocyclic or biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof.
- the promoter is selected from the group consisting of TMSOTf, MeOTf, TfOH, BF 3 , AgOTf, Cu(OTf) 2 , ZnCl 2 , and other acids, Lewis acids and
- the solvent is selected from the group consisting of toluene, THF, and other solvents of like polarity and dipole moment and mixtures thereof.
- the donor is an O-pyranosyl or O-furanosyl glycoside, of formulae IX, X, or XI, and the trialkyl silyl pyrimidine ether (or a corresponding 5 or 6 position analog having an N thereat) has formula VII
- R2, R3, R4, and R5 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R10 is hydrogen or arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R11 and R12 are arylalkoxy of 7 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms
- R13 is trialkylsiloxy wherein the alkyls are
- R14 is
- trialkylsiloxy wherein the alkyls are independently of 1 to 5 carbon atoms, or acylamino of 7 to 10 carbon atoms, R15 is hydrogen, or alkyl of 1 to 5 carbon atoms, and Z has formula VIII.
- the invention is directed to an improved process of nucleoside synthesis comprising reaction of a donor selected from O-pyranosyl and O-furanosyl glycosides, with an acceptor including an acylated purine in the presence of bromine or a like oxidiser, and a solvent, the improvement comprising the donor is selected from the group consisting of glycosides substituted by leaving groups of formula VIII:
- B is O or S and where n is 0 or 1
- W is a heterocyclic or biheterocyclic ring with each ring having from 5 to 7 atoms of which up to 2 atoms can be S, O or N, or a combination thereof.
- the solvent is selected from the group consisting of DMF and other solvents of like polarity and dipole moment and mixtures thereof.
- the purine is 6-benzoyl adenine.
- the 2-acetamido-2-deoxy-beta-D-glucopyranosyl MOP donor was treated first with MeOTf (0.2 eq.) in CH 3 NO 2 , at room temperature for 10 minutes, followed addition of 14 eq, of 1,2-3,4 di-O-cyclohexylidenyl-D- galactopyranose acceptor with a free 6-hydroxyl, then acetic anhydride- pyridine, which gave 68% of the peracetylated beta disaccharide, Table VII.
- O-acyl protected 1,2-trans MOP glycosyl donors are coupled with glycoside acceptors containing a single free hydroxyl, using Cu(OTf) 2 (2 eq.), CH 2 Cl 2 solvent at room temperature for 2 to 8 h, gave beta linked D-glycopyranosyl disaccharides in 60-85% yield, Table XIII.
- Perbenzylated glucopyranosyl beta MOP donor was treated in the presence MeOTf 0.2 eq., in ether at room temperature with 1.5 eq. of 6-hydroxy acceptors protected with isopropylidene, and acetyl groups, for 24 and 20 hours respectively to give 66% yield of 5.7:1 alpha:beta and 64% yield of 5:1 alpha:beta Table XIV.
- Perbenzylated glucopyranosyl beta MOP donor was treated in the presence of MeOTf 0.5 eq., in ether at room temperature, 15 h, with 1.5 eq. of 6-hydroxy
- galactopyranosyl beta MOP donor in the presence of MeOTf 1 eq., in CH 3 NO 2 /DMF, 15 m, with 0.5 eq. of 6-hydroxy tri- p-fluorobenzoyl galactopyranosyl beta MOP latent donor as acceptor, to give 62% yield of disaccharide alpha:beta 6:1.
- the identical procedure was used for glucopyranosyl beta MOP donor with 6-hydroxy tri-p-fluorobenzoyl glucopyranosyl beta MOP latent donor as acceptor, to give 68% yield of disaccharide alpha:beta 4:1;
- galactopyranosyl beta MOP donor with 6-hydroxy tri-p- fluorobenzoyl glucopyranosyl beta MOP latent donor as acceptor, to give 65% yield of disaccharide (after acetylation) alpha:beta 6:1.
- Perbenzylated glucopyranosyl beta MOP donor was treated in the presence of Cu(OTf) 2 1.0 eq., in ether at room temperature, 12 h, with methyl 2,3,4, tri-O-acetyl beta-D-glucopyranoside as acceptor, to give 75% yield of disaccharide, alpha: beta 5.8:1.
- the same reaction in CH 3 CN in 15 minutes gave 67% yield alpha: beta 1:2.6, favoring a beta-glycosidic linkage in this solvent.
- Perbenzylated glucopyranosyl beta MOP donor was treated with Cu(OTf) 2 1.0 eq., in ether at room temperature, 3.5 h, with cholesterol acceptor, to give 78% yield, alpha:beta 4:1.
- Perbenzylated glucopyranosyl alpha MOP donor was treated with Cu(OTf) 2 1.0 eq., in ether at room temperature, 20 min, 4A MS, with methyl 2,3,4-tri-O- acetyl-alpha-D-glucopyranoside as acceptor, to give 73% yield of disaccharide alpha:beta 4.3:1, Table XVI.
- MOP donor was treated with Cu(OTf) 2 1.2 eq. in CH 2 Cl 2 at room temperature, 6 h, with methyl 2, 3,4-tri-O-acetyl- alpha-D-glucopyranoside acceptor, to give 90% yield of disaccharide, alpha: beta 3.2:1.
- MOP donor was treated with Cu(OTf) 2 1.2 eq., in CH 2 Cl 2 at room temperature, 30 min, with the following: 6-hydroxy,
- Perbenzylated glucopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq. in CH 2 Cl 2 at room temperature, 8 h, with methyl 3-O-acetyl-4,6-O- benzylidene-alpha-D-glucopyranoside as acceptor to give yield 45% of disaccharide, alpha:beta 2.4:1.
- Perbenzylated glucopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq., in CH 2 Cl 2 /ether (1:4) at room temperature, 15 h, and methyl 2-O-acetyl-4,6-O- benzylidene-alpha-D-glucopyranoside acceptor to give yield 60% of disaccharide, alpha:beta 10:1.
- Perbenzylated glucopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq., in CH 2 Cl 2 at room
- Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq. in CH 2 Cl 2 at room temperature, 6 h, with 3-O-acetyl 4, 6-O-benzylidehealpha-D-glucopyranoside acceptor to give yield 85%. of disaccharide, alpha 100%.
- Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq., in CH 2 Cl 2 at room temperature, 7 h, and methyl 2-O-acetyl-4,6-benzylidene-alpha-D-glucopyranoside acceptor to give yield 60% of disaccharide, alpha 100%.
- Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq., in CH 2 Cl 2 at room temperature, 24 h, with methyl 2,3,6 tri-O-benzyl alpha-D-glucopyranoside as acceptor to give yield 60% of disaccharide, alpha 100% Table XX.
- Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq., in CH 2 Cl 2 at room temperature, 9 h, and methyl 4,6-O-benzylidene-2-benzyloxycarbonylamino-2-deoxy-alpha-D-glucopyranoside acceptor to give yield 45% of disaccharide, alpha 100%.
- Perbenzylated galactopyranosyl beta MOP donor (1.5 eq.) was treated with Cu(OTf) 2 1 eq., in CH 2 Cl 2 at room
- MOP (3-methoxypyridyl-2-oxy) was shown superior (shorter) in reaction time to 2- oxypyridyl, and 4-methoxypyridyl-2-oxy, although closely similar in yield and alpha proportion.
- the unprotected beta 2-acetamido MOP glycosides gave exclusively beta products under similar conditions.
- the peracetylated MOP glycosides were unreactive as glycosyl donors.
- Ether protected equivalents were reactive as donors to give alpha products, in the presence of Cu(OTf) 2 .
- Increasing degree of protection lengthened reaction time and
- Perbenzylated beta MOP glycosides gave alpha disaccharide products. Solvent dependency was noted, water miscible alcohols may be used as solvent and donor with excellent results, apart from this coincidence, the solvent is fairly critical CH 3 NO 2 CH 2 Cl 2 , and ether, gave satisfactory to excellent results for alpha glycosides while CH 3 CN, favored the formation of beta-glycosides.
- benzylated MOP glycosides in the formation of C-glycosides, for example C-acyl, C-allyl, C-alkyl, etc., can be used.
- nucleosides have been utilized to prepare nucleosides.
- Clinically relevant nucleosides including AZT, used in the treatment of AIDS are known in the art.
- Prior syntheses of 1,2 cis-pyrimidine nucleosides, using hemiacetal sugar acetates with trimethylsilyl substituted ethyl and butyl uracils, and of 1,2 trans-pyrimidine nucleosides, and thymine derivatives are similarly prepared from
- Perbenzylated galactopyranosyl beta MOP donor is allowed to react with trimethylsilyl uracil, thymine and cytosine in THF and toluene at room temperature using TMSOTf promoter, Table XXII, to give the expected beta-D-galactopyranosyl nucleosides in 55 to 95% yield with alpha:beta ratios of 6 to 9:91 to 94, showing excellent stereocontrol.
- Perbenzylated furanosyl nucleosides were prepared from trimethylsilyl thymine, Table XXIII, uracil, Table XXIV, and cytosine, Table XXV, and MOP perbenzylated furanosides, from inspection generally best yields and highest alpha proportion are obtained using toluene.
- Table XXVI shows a synthetic route to thymidines.
- nucleoside preparation is detailed, Table XXXVI, while ribofuranosyl nucleoside preparation is similarly
- solid phase oligosaccharides can prepared via MOP glycosides.
- the process involves bonding of a MOP glycoside to a benzyl moiety on a resin support, the fixed glycoside is then allowed to react with an acetylated (inactive) MOP glycoside forming a stereospecific linkage.
- the acetate is then saponified and the process repeated, Table XLIV. Details of the base strategy, Table XLV, first experiment, Table XLVI, and test recovery of unchanged MOP glycoside, Table XLVII are shown.
- the obtained resin was dried in vacuo overnight, then treated with 1.5 ml of Et 3 N/ 1 ml of Ac 2 O in 10 ml of DMF for 4 h. Filtration, washing with DMF, CH 2 Cl 2 ( 4 x ), MeOH ( 4 x ) and CH 2 Cl 2 , and drying in vacuo for 24 h provided 1.219 g of resin.
- TR Umax 3400, 1730, 1670 cm - 1 : 1760 cm - 1 ( absent ) general procedure for cleavage ( Estimation of the amount of glycosyl donor attached to the polymer )
- IR spectra of finally obtained resin indicated the highly increased intensity of ester group bands at 1740 cm -1 .
- the disaccharide-containing polymaer was treated with 1 ml of 0.04M of NaOMe solution in MeOH for 24 h, followed by filtration and concentration of the filtrate to afford the residue which was subjected to acetylation ( Ac 2 O / Py ) overnight. After usual work up, 15.5 mg of acetylated disaccharide was obtained by purification by flash column chromatography using EtOAc / hexane ( 2 : 1 - 3 : 1 ) as the irrigant in 46% yield ( ⁇ : ⁇ , 4.5 : 1, unseparable )
Abstract
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Claims
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US08/403,813 US5767256A (en) | 1993-07-19 | 1994-07-19 | Solution and solid phase stereocontrolled glycosidation |
AU72620/94A AU7262094A (en) | 1993-07-19 | 1994-07-19 | Solution and solid phase stereocontrolled glycosidation |
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CA002100821A CA2100821C (en) | 1993-07-19 | 1993-07-19 | Stereocontrolled glycosidation |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003022860A1 (en) * | 2001-09-07 | 2003-03-20 | Alchemia Pty Ltd | Synthetic heparin pentasaccharides |
WO2013091660A1 (en) * | 2011-12-23 | 2013-06-27 | Glycom A/S | A method for obtaining crystalline lacto-n-tetraose and lacto-n-neotetraose precursors and mixtures thereof |
WO2014210397A1 (en) * | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
CN113926472A (en) * | 2021-07-29 | 2022-01-14 | 山东大学 | Glycosylation reaction catalyst, glycosylation method and application |
Families Citing this family (1)
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KR101639160B1 (en) * | 2015-06-10 | 2016-07-12 | 건국대학교 산학협력단 | Benzyltriazole derivatized dextran for removing methyl violet dye |
-
1993
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-
1994
- 1994-07-19 WO PCT/CA1994/000396 patent/WO1995003316A2/en active Application Filing
Non-Patent Citations (7)
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CHEM. LETT., 1979 pages 847 - 848 MUKAIYAMA, T. 'A new method for the synthesis of beta-glucosides' * |
CHEM. LETT., 4 April 1984 pages 557 - 560 MUKAIYAMA, T. 'Stereoselective synthesis of alpha-ribonucleosides' * |
CHEMICAL ABSTRACTS, vol. 107, no. 23, 1987, Columbus, Ohio, US; abstract no. 217957, NIKOLAEV, A.V 'Use of 2-pyridyl 2,3,4,6-tetra-O-benzyl-beta-D-glucoside in the synthesis of 1,2-cis-bonded disaccharides' page 625 ; & IZV. AKAD. NAUK SSSR SER. KHIM., 1986 pages 2556 - 2565 * |
TERAHEDRON, vol.48, 1992 pages 4259 - 4270 GARNER, P. 'Synthesis of 2-aminopurine nucleosides' * |
TETRAHEDR. LETT., vol.32, 1991 pages 3627 - 3630 KNAPP. S. 'Nucleoside synthesis from thioglycosides' * |
TETRAHEDRON, vol.47, 1991 pages 6435 - 6448 MEREYALA, H.B 'Stereoselective synthesis of alpha-linked saccharides' * |
TETRAHEDRON, vol.47, 1991 pages 9985 - 92 VANKAR, Y.D. 'Synthesis of beta-O-glycosides' * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003022860A1 (en) * | 2001-09-07 | 2003-03-20 | Alchemia Pty Ltd | Synthetic heparin pentasaccharides |
US7541445B2 (en) | 2001-09-07 | 2009-06-02 | Alchemia Limited | Synthetic heparin pentasaccharides |
US8114970B2 (en) | 2001-09-07 | 2012-02-14 | Alchemia Limited | Synthetic heparin monosaccharides |
US8404833B2 (en) | 2001-09-07 | 2013-03-26 | Alchemia Limited | Synthetic heparin disaccharides |
US8686131B2 (en) | 2001-09-07 | 2014-04-01 | Alchemia Limited | Synthetic heparin trisaccharides |
US9243018B2 (en) | 2001-09-07 | 2016-01-26 | Dr. Reddy's Laboratories, Sa | Synthetic heparin pentasaccharides |
WO2013091660A1 (en) * | 2011-12-23 | 2013-06-27 | Glycom A/S | A method for obtaining crystalline lacto-n-tetraose and lacto-n-neotetraose precursors and mixtures thereof |
WO2014210397A1 (en) * | 2013-06-26 | 2014-12-31 | Academia Sinica | Rm2 antigens and use thereof |
CN113926472A (en) * | 2021-07-29 | 2022-01-14 | 山东大学 | Glycosylation reaction catalyst, glycosylation method and application |
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CA2100821A1 (en) | 1995-01-20 |
CA2100821C (en) | 2001-01-16 |
WO1995003316A3 (en) | 1995-03-30 |
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