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Details for Patent: 4,943,630

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Details for Patent: 4,943,630

Title: Method for carrying out the organic synthesis of oligosaccharides containing galactosamine-uronic acid patterns, new oligosaccharides obtained and biological applications thereof
Abstract:Novel processes for synthesizing acid mucopolysaccharide fragments having from 2-12 saccharides and substantially pure products of a single structure produced thereby. Condensation are disclosed between a first protected saccharide and a second protected saccharide to form a protected condensation product having units linked in the manner found in chondroitin sulfate and dermatan sulfate and having protecting groups thereon which allow selective positioning of functional groups, in particular sulfate, at desired positions. Other condensations are disclosed in which a protected condensation product is formed which can be elongated, and has protecting groups thereon which allow selective positioning of functional groups, in particular sulfate, at desired positions. Also disclosed is a process for selectively positioning functional groups on a protected acid mucopolysaccharide having from 2-12 units.
Inventor(s): Jacquinet; Jean-Claude (Orleans-La Source, FR), Petitou; Maurice (Paris, FR), Sinay; Pierre (Orleans, FR), Choay; Jean (Paris, FR)
Assignee: Choay, S.A. (Paris, FR)
Filing Date:Apr 21, 1986
Application Number:06/856,855
Claims:1. A process for synthesizing an acid mucopolysaccharide condensation product having from 2-12 saccharides which process comprises condensing a first saccharide with a second saccharide to form a condensation product having a 1-4 beta linkage between the first saccharide and the second saccharide,

wherein the first saccharide is selected from the group consisting of a protected D-galactosamine unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal D-galactosamine at the reducing end, and

wherein the second saccharide is selected from the group consisting of a uronic acid unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal uronic acid at the now reducing end, further

wherein any uronic acid unit is selected from the group consisting of D-glucuronic acid and L-iduronic acid and further

wherein any D-galactosamine units have nitrogen containing groups at carbon 2, which nitrogen containing groups can be treated to form an amine.

2. A process for synthesizing a protected acid mucopolysaccharide condensation product having from 2-12 saccharide units and having semi-permanent protecting groups and permanent protecting groups as substituents at carbon positions thereon to allow selective positioning of functional groups at desired positions, and further having other protecting groups which form an ester at carboxyl groups, and having nitrogen containing groups as substituents at position 2 of D-galactosamine units, which process comprises the step of condensing a first protected saccharide with a second protected saccharide to form a protected condensation product,

wherein the first protected saccharide is selected from the group consisting of a protected D-galactosamine unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal D-galactosamine at the reducing end, further wherein the first protected saccharide has a reactive group as a substituent at carbon 1 at the reducing end which reactive group allows a stereospecific linkage during the condensation, and

wherein the second protected saccharide is selected from the group consisting of a protected uronic acid unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal uronic acid at the nonreducing end, wherein any uronic acid units are selected from the group consisting of D-glucuronic acid and L-iduronic acid, and

wherein the protected condensation product formed has a 1-4 beta linkage between the first protected saccharide and the second protected saccharide, the protected condensation product further having at least one each of semi-permanent protecting groups, permanent protecting groups, other protecting groups, and nitrogen containing groups as substituents at carbon positions thereon which protecting groups and nitrogen containing groups were present on the first protected saccharide and second protected saccharide, which semi-permanent protecting groups are removable in the presence of permanent protecting groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, which permanent protecting groups are stable and do not migrate to different carbon positions during the removal of the semi-permanent protecting groups and the introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O--SO.sub.3 groups and --O--PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, and which other protecting groups form an ester at the carboxyl groups of the uronic acid units and are stable during the condensation, and which nitrogen containing groups are substituents at carbon 2 of the D-galactosamine units, can be treated to form an amine, are stable during the condensation, and allow a stereospecific linkage during the condensation.

3. A process for synthesizing a protected acid mucopolysaccharide condensation product having from 2-12 saccharide units and having semi-permanent protecting groups and permanent protecting groups as substituents at carbon positions thereon to allow selective positioning of functional groups at desired positions, further having other protecting groups which form an ester at the carboxyl groups and having nitrogen containing groups as substituents at position 2 of D-galactosamine units, which process comprises condensing a first protected saccharide with a second protected saccharide to form a protected condensation product

wherein the first protected saccharide is selected from the group consisting of a protected uronic acid unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal uronic acid at the reducing end, further wherein the first protected saccharide has a reactive group as a substituent at carbon 1 at the reducing end which reactive group allows a stereospecific linkage during the condensation, and

wherein the second protected saccharide is selected from the group consisting of a protected D-galactosamine unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal D-galactosamine at the nonreducing end, wherein any uronic acid units are selected from the group consisting of D-glucuronic acid and L-iduronic acid, and

wherein the protected condensation product formed has a 1-3 beta linkage between the first protected saccharide and the second protected saccharide where the first protected saccharide is a D-glucuronic acid or an oligosaccharide having a terminal D-glucuronic acid, and wherein the protected condensation product formed has a 1-3 alpha linkage between the first protected saccharide and the second protected saccharide where the first protected saccharide is an L-iduronic acid or an oligosaccharide having a terminal L-iduronic acid, the protected condensation product further having at least one each of semi-permanent protecting groups, permanent protecting groups, other protecting groups, and nitrogen containing groups as substituents at carbon positions thereon which protecting groups and nitrogen containing groups were present on the first protected saccharide and second protected saccharide, which semi-permanent protecting groups are removable in the presence of permanent protecting groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, which permanent protecting groups are stable and do not migrate to different carbon positions during the removal of the semi-permanent protecting groups and the introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O--SO.sub.3 groups and --O--PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, and which other protecting groups form an ester at the carboxyl groups of the uronic acid units, and are stable during the condensation, and which nitrogen containing groups are substituents at carbon 2 of the D-galactosamine units, can be treated to form an amine, are stable during the condensation, and allow a stereospecific linkage during the condensation.

4. A process for synthesizing a protected acid mucopolysaccharide condensation product having from 2-12 saccharide units and having semi-permanent protecting groups and permanent protecting groups as substituents at carbon positions thereon to allow selective positioning of functional groups at desired positions, further having other protecting groups which form an ester at the carboxyl groups and further having nitrogen containing groups as substituents at position 2 of D-galactosamine units which process comprises a first step of condensing a first protected saccharide with a second protected saccharide having a 1,6 anhydro group, to form a protected condensation product

wherein the first protected saccharide is selected from the group consisting of a protected uronic acid unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal uronic acid at the reducing end, further wherein the first protected saccharide has a reactive group as a substituent at carbon 1 at the reducing end which reactive group allows a stereospecific linkage during the condensation, wherein any uronic acid units are selected from the group consisting of D-glucuronic acid and L-iduronic acid, and

wherein the second protected saccharide is a D-galactosamine precursor, which D-galactosamine precursor has a 1,6 anhydro group, and

wherein the protected condensation product formed has a 1-3 beta linkage between the first protected saccharide and the second protected saccharide where the first protected saccharide is a D-glucuronic acid or an oligosaccharide having a terminal D-glucuronic acid, and wherein the protected condensation product formed has a 1-3 alpha linkage between the first protected saccharide and the second protected saccharide where the first protected saccharide is a L-iduronic acid or an oligosaccharide having a terminal L-iduronic acid, the protected condensation product further having protecting groups which are selected from the group consisting of semi-permanent protecting groups and permanent protecting groups, the protected condensation product further having other protecting groups which form an ester at the carboxyl, nitrogen containing groups, and a 1,6 anhydro group as substituents at carbon positions thereon, which protecting groups, other protecting groups, nitrogen containing groups, and 1,6 anhydro group were present on the first protected saccharide and second protected saccharide,

further comprising the step of treating the 1,6 anhydro precursor group to form semi-permanent protecting groups or permanent protecting groups at carbons 1 and 6, which semi-permanent protecting groups are removable in the presence of permanent protecting groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, which permanent protecting groups are stable and do not migrate to different carbon positions during the removal of the semi-permanent protecting groups and the introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O--SO.sub.3 groups and --O--PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, and allow a stereospecific linkage during the condensation, and which other protecting groups form an ester at the carboxyl groups of the uronic acid units and are stable during the condensation, which nitrogen containing groups occupy carbon 2 of the D-galactosamine units, can be treated to form an amine, are stable during the condensation and allow a stereospecific linkage during the condensation.

5. A process as in claim 1, 2 or 3 wherein the functional groups are --O--SO.sub.3 groups.

6. A process as in claim 5 wherein the semi-permanent protecting groups are substituents at one or more carbon positions at any of carbons 4 and 6 of the D-galactosamine units, and carbons 2 and 3 of uronic acid units, and wherein the permanent protecting groups are substituted at positions at any of carbons 4 and 6 of the D-galactosamine units and carbons 2 and 3 of the uronic acid units which are not substituted by the semi-permanent protecting groups.

7. The process of claim 6 wherein

(a) The nitrogen containing groups are selected from the group consisting of

1. N.sub.3,

2. NH--lower acyl, and

3. N-phthalimido;

(b) the protecting groups at the carboxyl are selected from the group consisting of

1. lower alkyl, and

2. lower aryl;

(c) the semi-permanent protecting groups are --O-- lower acyl;

(d) the permanent protecting groups are --O--benzyl; and

(e) the reactive group is selected from the group consisting of

1. halogen,

2. o-lower imidoyl, and

3. an orthoester formed between carbon 1 and carbon 2 of uronic acid.

8. The process of claim 7 wherein

(a) The nitrogen containing groups are selected from the group consisting of

1. N.sub.3,

2. NH--acetyl, and

3. N-phthalimido;

(b) the protecting groups which forms an ester at the carboxyl are methyl;

(c) the semi-permanent groups are --O--acetyl;

(d) the permanent protecting groups are --O--benzyl; and

(e) the reactive group is selected from the group consisting of

1. Br,

2. Cl,

3. an orthoester having between 3 and 6 carbons, and

4. OC(NH)CCl.sub.3.

9. A process according to claim 3 wherein the second protected saccharide is a D-galactosamine precursor and contains a 1,6 anhydro group, wherein the 1,6 anhydro group is treated with an acetolysing agent to obtain --O--acetyl semi-permanent protecting groups.

10. A process according to claim 9 further comprising the step of removing the --O--acetyl group at carbon 1 of D-galactosamine and replacing it with a reactive group in order to allow the protected condensation product to be elongated.

11. A process according to claim 10 wherein the reactive group is selected from the group consisting of bromine and chlorine.

12. A process as in claim 1 or 2 wherein the carbon 1 at the reducing end of the protected condensation product is substituted by a protecting group which is selected from the group consisting of a semi-permanent protecting group and a permanent protecting group.

13. A process as in claim 1 or 2 wherein the carbon 4 of any uronic acid at the non-reducing end of the protected condensation product, or the carbon 3 of any D-galactosamine at the non-reducing end of the protected condensation product is substituted by a protecting group which is selected from the group consisting of a semi-permanent protecting group and a permanent protecting group.

14. A process as in claim 1 or 2 further wherein the carbon 1 at the reducing end of the protected condensation product is substituted by an inert protecting group, which inert protecting group is stable during the condensation and during removal of the permanent protecting groups.

15. A process for synthesizing a protected mucopolysaccharide condensation product having from 2-12 saccharide units which can be elongated, and having semi-permanent protecting groups and permanent protecting groups as substituents at carbon positions thereon to allow selective positioning of functional groups at desired positions, and further having other protecting groups which form an ester at carboxyl groups, and having nitrogen containing groups as substituents at position 2 of D-galactosamine units, and further having temporary protecting groups positioned thereon to allow elongation of the protected condensation product, which process comprises condensing a first protected saccharide with a second protected saccharide to form a protected condensation product

wherein the first protected saccharide is selected from the group consisting of a protected D-galactosamine unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal D-galactosamine at the reducing end, further wherein the first protected saccharide has a reactive group as a substituent at carbon 1 at the reducing end which reactive group allows a stereospecific linkage during the condensation, and

wherein the second protected saccharide is selected from the group consisting of a protected uronic acid unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal uronic acid at the nonreducing end, wherein any uronic acid is selected from the group consisting of D-glucuronic acid and L-iduronic acid, and

wherein the protected condensation product has a 1-4 beta linkage between the first protected saccharide and the second protected saccharide, the protected condensation product further having at least one each of semi-permanent protecting groups, permanent protecting groups, temporary protecting groups, other protecting groups, and nitrogen containing groups as substituents at carbon positions thereon which protecting groups and nitrogen containing groups were present on the first protected saccharide and second protected saccharide, which semi-permanent protecting groups are removable in the presence of permanent protecting groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, which permanent protecting groups are stable and do not migrate to different carbon positions during introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O--SO.sub.3 groups and --O--PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, and which allow a stereospecific linkage during the condensation, which other protecting groups form an ester at the carboxyl groups of the uronic acid units and are stable during the condensation, which temporary protecting groups are substituted at any of carbon 1 at the reducing end of the protected condensation product, carbon 4 of any uronic acid at the non-reducing end of the protected condensation product, and carbon 3 of any D-galactosamine at the non-reducing end of the protected condensation product, and which temporary groups are removable in the presence of the semi-permanent protecting groups and permanent protecting groups in order to permit elongation of the protected condensation product, and which nitrogen containing groups are substituents at carbon 2 of the D-galactosamine units, can be treated to form an amine, are stable during the condensation, and allow a stereospecific linkage during the condensation.

16. A process for synthesizing a protected mucopolysaccharide condensation product having from 2-12 saccharide units which can be elongated, and having semi-permanent protecting groups and permanent protecting groups as substituents at carbon positions thereon to allow selective positioning of functional groups at desired positions, and further having other protecting groups which form an ester at carboxyl groups, and having nitrogen containing groups as substituents at position 2 of D-galactosamine units, and further having temporary groups positioned theron to allow elongation of the protected condensation product, which process comprises condensing a first protected saccharide with a second protected saccharide to form a protected condensation product

wherein the first protected saccharide is selected from the group consisting of a protected uronic acid unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid unit linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal uronic acid at the reducing end, further wherein the first protected saccharide has a reactive group as a substituent at carbon 1 at the reducing end which reactive group allows a stereospecific linkage during the condensation, and

wherein the second protected saccharide is selected from the group consisting of a protected D-galactosamine unit and an oligosaccharide comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having a terminal D-galactosamine at the nonreducing end, whererin any uronic acid is selected from the group consisting of D-glucuronic acid and L-iduronic acid, and

wherein the protected condensation product has a 1-3 beta linkage between the first protected saccharide and the second protected saccharide where the first protected saccharide is a D-glucuronic acid unit or an oligosaccaride having a terminal D-glucuronic acid, and a 1-3 alpha linkage between the first protected saccharide and the second protected saccharide where the first protected saccharide is an L-iduronic acid unit or an oligosaccharide having a terminal L-iduronic acid, the protected condensation product further having at least one each of semi-permanent protecting groups, permanent protecting groups, temporary protecting groups, other protecting groups, and nitrogen containing groups thereon which protecting groups and nitrogen containing groups were present on the first protected saccharide and second protected saccharide, which semi-permanent protecting groups are removable in the presence of permanent protecting groups, are stable during the condensation, and allow a stereospecific linkage during the condensation, which permanent protecting groups are stable and do not migrate to different carbon positions during introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O--SO.sub.3 groups and --O--PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, and which allow a stereospecific linkage during the condensation, which other protecting groups which form an ester at the carboxyl groups of the uronic acid units are stable during the condensation, which temporary protecting groups ae substituted at any of carbon 1 at the reducing end of the protected condensation product, carbon 4 of any uronic acid at the non-reducing end of the protected condensation product, and carbon 3 of any D-galactosamine at the non-reducing end of the protected condensation product, and which temporary groups are removable in the presence of the semi-permanent protecting groups and permanent protecting groups in order to permit elongation of the protected condensation product, and which nitrogen containing groups are substituents at carbon 2 of the D-galactosamine units, can be treated to from an amine, are stable during the condensation, and allow a stereospecific linkage during the condensation.

17. A process as in claim 15 or 16 wherein the functional groups are --O--SO.sub.3 groups.

18. A process as in claim 15 or 16 wherein the semi-permanent protecting groups are substituted at one or more carbon positions at any of carbons 4 and 6 of D-galactosamine units, and carbons 2 and 3 of uronic acid units and wherein the permanent protecting groups are substituted at positions at any of carbons 4 and 6 of the D-galactosamine units and carbons 2 and 3 of the uronic acid units which are not substituted by the semi-permanent protecting groups.

19. A process according to claim 18 further comprising the steps of removing a temporary protecting group at the reducing end of the protected condensation product, substituting a reactive group and performing a second condensation to form an elongated protected condensation product comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having protecting groups thereon.

20. A process according to claim 18 further comprising the steps of removing a temporary group at the non-reducing end of the protected condensation product and performing a second condensation to form an elongated condensation product comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having protecting groups thereon.

21. The process of claim 18 wherein

(a) The nitrogen containing groups are selected from the group consisting of

1. N.sub.3,

2. NH--lower acyl, and

3. N-phthalimido;

(b) the protecting groups at the carboxyl are selected from the group consisting of

1. lower alkyl, and

2. lower aryl;

(c) the semi-permanent protecting groups are --O-lower acyl;

(d) the permanent protecting groups are --O-benzyl; and

(e) the reactive group is selected from the group consisting of

1. halogen

2. o-lower imidoyl, and

3. an orthoester formed between carbon 1 and carbon 2 of uronic acid,

(f) the temporary group is selected from the group consisting of

1. --O-lower acyl,

2. --O-allyl,

3. --O-propenyl, and

4. halogenated --O-lower acyl.

22. The process of claim 21 wherein

(a) The nitrogen containing groups are selected from the group consisting of

1. N.sub.3,

2. NH--acetyl, and

3. N-phthalimido;

(b) The protecting groups which forms an ester at the carboxyl are methyl;

(c) The semi-permanent groups are --O-acetyl;

(d) The permanent protecting groups are --O-benzyl; and

(e) the reactive group is selected from the group consisting of

1. Br,

2. Cl,

3. an orthoester having between 3 and 6 carbons, and

4. OC(NH)CCl.sub.3 ;

(f) The temporary protecting groups are selected from the group consisting of

1. --O-acetyl,

2. --O-allyl,

3. --O-propenyl,

4. monochloro--O-acetyl, and

5. trichloro--O-acetyl.

23. A process for selectively positioning sulfate groups or phosphate groups on a protected acid mucopolysaccharide having from 2-12 units, which acid mucopolysaccharide is comprised of alternating protected D-galactosamine and protected uronic acid units linked in the manner found in chondroitin sulfate and dermatan sulfate and having at least one each as substituents of semi-premanent protecting groups, permanent protecting groups, other protecting groups which form an ester at the carboxyl groups of the uronic acid units, and nitrogen containing groups at carbon 2 of the D-galactosamine units, wherein the permanent protecting groups are stable and do not migrate to other carbon positions during removal of the semi-permanent protecting groups and the introduction of functional groups, and wherein any uronic acid units are selected from the group consisting of D-glucuronic acid and L-iduronic acid, which process comprises the steps of

(a) removing the semi-permanent protecting groups,

(b) introducing functional groups in place of the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O-SO.sub.3 groups and --O-PO.sub.3 groups, and

(c) removing the permanent protecting groups and treating the nitrogen containing group to form an amine group.

24. A process as in claim 23 wherein the functional groups are --O-SO.sub.3 groups.

25. A process as in claim 24 wherein the semi-permanent protecting groups are substituted at one or more carbon positions at any of carbons 4 and 6 of D-galactosamine units, and carbons 2 and 3 of uronic acid units, and wherein the permanent protecting groups are substituted at positions at any of carbons 4 and 6 of the D-galactosamine units and carbons 2 and 3 of the uronic acid units which are not substituted by the semi-permanent protecting groups.

26. The process of claim 25 wherein

(a) The nitrogen containing groups are selected from the group consisting of

1. N.sub.3,

2. NH--lower acyl, and

3. N-phthalimido;

(b) the protecting groups at the carboxyl are selected from the group consisting of

1. lower alkyl, and

2. lower aryl;

(c) the semi-permanent protecting groups are --O-lower acyl; and

(d) the permanent protecting groups are --O-benzyl.

27. The process of claim 26 wherein

(a) The nitrogen containing groups are selected from the group consisting of

1. N.sub.3,

2. NH--acetyl, and

3. N-phthalimido;

(b) The protecting groups which forms an ester at the carboxyl are methyl;

(c) The semi-permanent groups are --O-acetyl; and

(D) The permanent protecting groups are --O-benzyl.

28. Process as in claim 23 further comprising the step of substituting the amine group with a group selected from the group consisting of SO.sub.3 and acetyl.

29. A process as in claim 27 further comprising removing the protecting groups at the carboxyl groups of the uronic acid units.

30. The process of claim 27 which further comprises salifying the COO.sup.31 with an alkaline metal cation.

31. The process of claim 23 wherein the semi-permanent protecting groups are acetyl and hyrolysed with a strong base followed by reaction with a sulfation agent.

32. The process of claim 28 wherein the amine group is substituted with a lower acyl.

33. The process of claim 32 wherein the amine group is substituted with acetyl.

34. The process of claim 8 wherein the condensation reaction is between a halide and an OH and is carried out in a solvent medium in the presence of a catalyst.

35. The process of claim 34 wherein the solvent is an organic solvent selected from the group consisting of dichloromethane and dichloroethane and the catalyst is selected from the group consisting of a silver and a mercury salt.

36. The process of claim 35 wherein the catalyst is selected from the group consisting of silver triflouromethane sufonate, silver carbonate, silver oxide, mercuric bromide and mercuric cyanide.

37. The process of claim 3 or 4 wherein the reactive group is 1,2-O-methoxyethylidene, and the condensation is carried out in a solvent which boils above 100 degrees centigrade in the presence of a catalyst.

38. The process of claim 8 wherein the reactive group is O-lower imidoyl and the condensation reaction is carried out in the presence of a catalyst at a temperature below or equal to 0 degrees centigrade.

39. A process for selectively positioning sulfate groups or phosphate groups on a protected acid mucopolysaccharide having from 2-12 units, which protected acid mucopolysaccharide is comprised of alternating units of a first unit and a second unit wherein the first unit is selected from the group consisting of a D-galactosamine, a neutral sugar analog of D-galactosamine, and a desoxy sugar analog of D-galactosamine, and wherein the second unit is selected from the group consisting of uronic acid, a neutral sugar analog of uronic acid, and a desoxy sugar analog of uronic acid, further wherein any uronic acid is selected from the group consisting of D-glucronic acid and L-iduronic acid, the frist and second unit being linked in the manner found in chondroitin sulfate and dermatan sulfate and having at least one each as substituents of semi-permanent protecting groups, permanent protecting groups, other protecting groups which form an ester at the carboxyl groups of the uronic acid units, and nitrogen containing groups at carbon 2 of the D-galactosamine units wherein the permanent protecting groups are stable and do not migrate to other carbon positions during removal of the semi-permanent protecting groups and the introduction of functional groups, which process comprises the steps of

(a) removing the semi-permanent protecting groups,

(b) introducing functional groups in place of the semi-permanent protecting groups, which functional groups are selected from the group consisting of --O--So.sub.3 groups and --O--PO.sub.13 groups, and

(c) removing the permanent protecting groups and treating the nitrogen containing group to form an amine group.

40. A substantially pure compound of a single structure, which compound is selected from the group consisting of: ##STR41## wherein R.sub.1 substituents are not the same, and are selected from the group consisting of

(a) semi-permanent protecing groups, which semi-permanent protecting groups are removable in the presence of permanent protecting groups, are stable during any condensation employed to obtain the compound and allow a stereospecific linkage during the condensation, and are stable during removal of any temporary groups,

(b) permanent protecting groups, which permanent protecting groups are stable and do not migrate to different carbon positions during removal of the semi-permanent protecting groups and the introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the group consisting of SO.sub.3 groups and PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, allow a stereospecific linkage during the condensation, and are stable during removal of any temporary protecting groups,

M is a protecting group which forms an ester at the carboxyl groups, and is stable during any condensation employed to obtain the compound,

N is a nitrogen containing group which is treatable to form an amine, and which allows a stereospecific linkage during any condensation employed to obtain the compound,

R is selected from the group consisting of:

(a) a temporary protecting group which can be removed in the presence of the other protecting groups in order to permit elongation of the compound and which is stable during any condensation employed to obtain the compound,

(b) a permanent protecting group,

(c) a reactive group which can be employed in order to perform a condensation to form a linkage as found in chondroitin sulfate and dermatan sulfate in order to elongate the compound, and which reactive group was positioned following removal of a temproary protecting group and which allows a stereospecific linkage during the condensation,

(d) an inert protecting group, which inert protecting group is stable during removal of the temporary protecting groups, semi-permanent protecting groups and permanent protecting groups, and

R' is selected from the group consisting of

(a) a temporary protecting group,

(b) a permanent protecting group, and

(c) an OH group.

41. The substantially pure compound of claim 40 wherein the compound can be elongated and R is selected from the group consisting of a temporary protecting group and a reactive group.

42. The substantially pure compound of claim 40 wherein the compound can be elongated and R' is selected from the group consisting of a temporary protecting group and OH.

43. A substantially pure compound of a single structure, which compound is selected from the group consisting of: Compounds I, III, V, VI, VII, VIII, IX, X, XI and XII according to claim, 40 wherein

R.sub.1 substituents are not the same, and are selected from the group consisting of

(a) OH groups, and

(b) permanent protecting groups, which permanent protecting groups are stable and do not migrate to different carbon positions during removal of the semi-permanent protecting groups and the introduction of functional groups to replace the semi-permanent protecting groups, which functional groups are selected from the groups consisting of SO.sub.3 groups and PO.sub.3 groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, and allow a stereospecific linkage during any condensation employed to obtain the compound, and are stable during removal of any temporary protecting groups,

M is a protecting group which forms an ester at the carboxyl groups, and is stable during any condensation employed to obtain the compound,

N is a nitrogen containing group which is treatable to form an amine, and which allows a stereospecific linkage during any condensation employed to obtain the compound,

R is selected form the group consisting of:

(a) a permanent protecting group,

(b) an inert protecting group, which inert protecting group is stable during removal of the temporary protecting groups, semi-permanent protecting groups and permanent protecting groups, and

R' is permanent protecting group.

44. A substantially pure compound of a single structure, which compound is selected from the group consisting of: Compounds I, III, V, VI, VII, VIII, IX, X, XI and XII according to claim 40 wherein

R.sub.1 substituents are not the same, and are selected from the group consisting of

(a) fuctional groups which are selected from the group consisting of SO.sub.3 groups and PO.sub.3 groups,

(b) permanent protecting groups, which permanent protecting groups are stable and do not migrate to different carbon positions during removal of the semi-permanent protecting groups and the introduction of the functional groups to replace semi-permanent protecting groups, and which permanent protecting groups also are removable in the presence of the functional groups, are stable during the condensation, allow a stereospecific linkage during any condensation employed to obtain the compound, and are stable during removal of any temporary protecting groups,

M is a protecting group which forms an ester at the carboxyl groups, and is stable during any condensation employed to obtain the compound,

N is a nitrogen containing group which is treatable to form an amine, and which allows a stereospecific linkage during any condensation employed to obtain the compound,

R is selected from the group consisting of:

(a) a permanent protecting group,

(b) an inert protecting group, which inert protecting group is stable during removal of the temporary protecting groups, semi-permanent protecting groups and permanent protecting groups, and

R' is a permanent group.

45. A substantially pure compound of a single structure, which compound is selected from the group consisting of: Compounds I, III, V, VI, VII, VIII, IX, X, XI and XII according to claim 40 wherein

R.sub.1 substituents are not the same, and are selected from the group consisting of

(a) functional groups which are selected from the group consisting of SO.sub.3 groups and PO.sub.3 groups, and

(b) OH groups,

M is a protecting group which forms an ester at the carboxyl groups, and is stable during any condensation employed to obtain the compound,

N is the same or different and is selected from the group consisting of

(a) an amine,

(b) NH acetyl, and

(c) NHSO.sub.3 ;

R is selected from the group consisting of:

(a) An OH group,

(b) an inert protecting group, which inert protecting group is stable during removal of the temporary protecting groups, semi-permanent protecting groups and permanent protecting groups, and

R' is OH.

46. The substantially pure compound of claim 45 wherein N is selected from the group consisting of NH acetyl and NHSO.sub.3 and wherein M is removed and the compound forms an anion.

47. The substantially pure compound of any of claims 41, 42, 43, 44, 45, or 46 wherein

(a) any nitrogen containing group is selected from the group consisting of

1. N.sub.3,

2. NH--lower acyl, and

3. N-phthalimido;

(b) any protecting group at the carboxyl is selected from the group consisting of

1. lower alkyl, and

2. aryl;

(c) any semi-permanent protecting group is lower acyl;

(d) any temporary protecting group is selected from the group consisting of

1. --O-lower acyl,

2. O-allyl,

2. --O-propenyl, and

4. halogenated --O-lower acyl,

(e) any permanent protecting group is benzyl,

(f) any reactive group is selected from the group consisting of

1. halogen,

2. lower imidoyl, and

3. an orthoester formed between the carbon 1and carbon 2 positions where the reactive group occupies a position at carbon 1 of a uronic acid unit,

(g) any inert protecting group is --O-lower alkyl, and

(h) any functional group is SO.sub.3.

48. The substantially pure compound of claim 47 wherein

(a) any nitrogen containing group is selected from the group consisting of

1. N.sub.3,

2. NH--acetyl, and

3. N-phtalimido;

(b) any protecting group which fomrs an ester at the carboxyl is methyl;

(c) any semi-permanent group is acetyl;

(d) any temporary group is selected from the group consisting of

1. --O-acetyl,

2. --O-benzyl,

3. --O-allyl,

4. --O-propenyl,

5. monochloro-O-acetyl, and

6. trichloro-O-acetyl;

(e) any permanent group is benzyl;

(f) any reactive group is selected from the group consisting of

1. Br,

2. Cl

3. an orthoester having between 3 and 6 carbons, and

4. C(NH)CCl.sub.3 ;

(g) any inert blocking group is an --O-lower alkyl group having between 1 and 4 carbons, and

(h) any functional group is SO.sub.3.

49. A substantially pure chondroitin sulfate fragment of a single structure comprised of 2 to 12 saccharide units.

50. A substantially pure dermatan sulfate fragment of a single structure comprised of 2-12 saccharide units.

51. A substantially pure acid mucopolysaccharide of a single structure comprised of 2to 12 altenating D-galactosamine and uronic acid units, wherein the uronic acid units are selected from the group consisting of D-glurcuronic acid and L-iduronic acid and sulfate groups are positioned at any but not all of carbons 4 and 6 of the D-galactosamine units and carbons 2 and 3 of the uronic acid units and further wherein linkage between D-galactosamine and uronic acid are of the 1-4 beta type, and linkage between L-iduronic acid and D-galactosamine are of the 1-3 alpha type, and linkages between D-glucuronic acid and D-galactosamine are of the 1-3 beta type.

52. An effective amount of oligosaccharide according to claim 46, wherein the functional group is SO.sub.3, in combination with a pharmaceutically acceptable carrier.

53. A biological reagent which consists of an oligosaccharide according to claim 46.
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