Synthesis of Solanum Glycosides

Abstract

The present invention relates to the chemical synthesis of solanum glycosides, in particular to the synthesis of solasonine as well as to novel β-monosaccharide intermediate compounds, of Formula (II), where each R1 is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group and each R2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION

It was unexpectedly found that by reacting a D-galacto-pyranosyl donor of the following formula 1

wherein each R₁ is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene groupeach R2 is the same or different and independently represents a benzoyl, acetyl or pivaloyl group and

R₃ is halogen, SPh or SEt

with solasodine the correspondingly protected β-glycoside of formula 2 could be obtained in high yield.

wherein each R₁ is the same or different and independently represents a benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene group and each R₂ is the same or different and independently represents a benzoyl, acetyl or pivaloyl group.

Preferably the reaction is carried out in the presence of a promoter.

Any conventional promoter as used in carbohydrate chemistry may be used.

The following promoters are particularly preferred:

Silver triflate, boron trifluoride diethyl etherate (−10° C.), trimethylsilyl triflate bromide, N-iodosuccinimide, thiomethyl sulfonium triflate.

The reaction is preferably carried out using dichloromethane as the solvent. Preferably the reaction time is 30 min.-1 hr.

The desired end product solasonine may be prepared by partially deprotecting the β-glycoside of formula 2 to give intermediate formula 3(1) and then selectively silylating one of the hydroxyl groups (OH-2 and OH-3) using tert-butyldimethylsilyl chloride, imidazole in DMF at 50° C.

However, due to the small selectivity between the OH-2 and OH-3 hydroxyl groups a mixture of OH-2 and OH-3 silylated protected β-glycosides are formed. The OH-3 silylated protected β-glycoside can mostly be precipitated from the mixture in methanol of the formula 3(2).

wherein each of R₁ is the same or different and represent independently from each other benzylidene, 4-nitrobenzylidene or 4-methoxybenzylidene,

R₂ is tert-butylsilyl or H and R₃ is H.

The OH-3 protected galactose-solasodine adduct is then glycosylated at the OH-2 with a suitable α-L-rhamnopyranosyl donor.

Suitable rhamnose donors include tri-O-benzolyl-α-rhamnopyranosly, tri-O-pivoloyl-L-rhamnopyranosyl, or tri-O-acetyl-4-L-rhamnopyranosyl bromides of formula 4

wherein each of R₁ is the same or different and independently represents acetyl, benzoyl or pivaloyl,and R₂ is halogen or SEt, SPh

Deprotection of the tert-butylsilyl group at the OH-3 position using tetrabutylammonium flouride in THF and glycosidation with a suitable α-D-glucopyranosly donor,

wherein the D-gluco-pyranosyl donor is tetra-O-benzoyl-α-D-glucopyranosyl bromide, tetra-O-acetyl-α-D-glucopyranosyl bromide or tetra-O-pivoloyl-α-D-glucopyranosyl bromide, or a thio-glycoside of the general formula 5

wherein each of R₁ is the same or different an independently represents acetyl, benzoyl or pivaloyl and R₂ is halogen, SEt, SPh gives a fully protected solasonine of formula 6(1).

wherein each R₁ is the same or different and independently represents benzylidene, 4-nitrobenzyilidene or 4-methoxybenzylidene and each R₂ are the same or different and independently represent acetyl, benzoyl or pivaloyl.

The protected solasonine formula 6(1) may be de-acetalised using aqueous acetic acid at 70° C. and de-esterified using sodium methoxide in methanol/dichloromethane mixture to give the fully deprotected solasonine formula 6(2) where in R₁ and R₂ are H.

Claims

1. A galactose-solasodine conjugate of the general formula 2 or a derivative thereof

2. A method for the preparation of the galactose-solasodine conjugate as defined in claim 1, comprising the reaction of solasodine with a galactopyranosyl donor of general formula 1

3. A method for the preparation of solasonine comprising the silylation of the diol of formula 3(1) to give a selectively silylated product in the OH-3 position 3(2)

4. The method according to claim 3, wherein the D-gluco-pyranosyl donor is tetra-O-benzoyl-α-D-glucopyranosyl bromide, tetra-O-acetyl-α-D-glucopyranosyl bromide or tetra-O-pivoloyl-α-D-glucopyranosyl bromide.

5. The method according to claim 2-4, wherein the glycosylation reaction is carried out in the presence of a promoter selected from silver triflate, boron trifluoride diethyl etherate, trimethylsilyl triflate bromide, N-iodosuccinimide or dimethyl thiomethyl sulfonium triflate.

6. The method of claim 3, wherein the protected glycoside is deprotected in methanol-dichloromethane solution by treatment with sodium methoxide, followed by neutralization with a mild acid ion-exchange resin.

7. The method of claim 3-6, wherein the hydroxyl groups (OH-4 and OH-6) are protected by acetalisation with Benzaldehyde dimethoxy acetal in DMF and a catalytic amount of para-toluene sulphonic acid.

8. The method of claim 3-7, wherein the rhamnose donor is tri-O-benzoyl-α-L-rhamnopyranosyl bromide, or a thio-glycoside of the general formula 4

9. The method of claim 3-8, wherein the glucose donor is tetra-O-benzoyl-α-D-glucopyranosyl bromide, or a thio-glycoside of the general formula 5

10. The method of claim 3-9, wherein the protected solasonine is de-acetalised and de-esterified by treatment with 80% acetic and then sodium methoxide solution in methanol-dichloromethane, followed by neutralization mild acid ion-exchange resin.