Anthony C. Richardson

Nucleophilic replacement reactions of sulphonates : Part VI. A summary of steric and polar factors

Abstract Since replacement reactions of sulphonic esters of carbohydrate derivatives normally proceed by an S N 2 mechanism, the formation of the highly polar transition state is subject to polar factors emanating from other electronegative substituents in the molecule. Consideration of these factors offers an explanation for the diminished reactivity of aldopyranoside 2-sulphonates, 1-sulphonates of hexulopyranose derivatives, and 6-sulphonates of galactopyranose derivatives. Furthermore, the presence of an axial, electronegative substituent adjacent to a sulphonate group on a pyranose ring inhibits replacement with charged nucleophiles, because of polar factors in the transition state of the reaction. Steric inhibition of displacement by a β- trans -axial substituent is also discussed.

Some further ring-opening reaction of methyl 4,6-O-benzylidene-2,3-dideoxy-2,3-epimino-α-D-allopyranoside and its derivatives

Modifications have been made to the preparation of methyl 4,6- O-benzylidene-2,3-dideoxy-2,3-epimino-α-D-allopyranoside from derivatives of 2-amino-2-deoxy-D-glucose, which permit it to be prepared in high yield and on a large scale. Further, ring-opening reactions of the epimine and its N-substituted derivatives have been studied with halide ion under neutral and acidic conditions. It has been found that anomalous, diequatorial ring-opening occurs when the free epimine is treated with ammonium halides (except the fluoride) in N,N-dimethylformamide, but, with its N-substituted derivatives, diaxial ring-opening predominates, although diequatorial ring-opening is significant in many cases. Under acidic conditions, the free epimine undergoes hydrolysis of the benzylidene group, without rupture of the epimine ring, but its N-substituted derivatives undergo predominant, diaxial ring-opening before hydrolysis of the benzylidene group. Ring-opening reactions of the N-methanesulphonyl and N-acetyl derivatives with azide occur trans-diaxially and trans-diequatorially, respectively.

Chemical modification of trehalose : Part I. Selective sulphonylation of trehalose, and determination of the conformation of hexa-O-acetyl-6,6′-Dideoxytrehalose

Abstract Selective esterification of α,α-trehalose with sulphonyl chlorides has been investigated. Selective dimethanesulphonylation of the disaccharide gave a mixture of the 6-ester and the 6,6′-diester, but in poor yield. Selective toluene-p-sulphonylation of trehalose gave the 6,6′-diester, readily isolable in 39% yield as the hexa-acetate, which is a useful starting material for the preparation of 6,6′-disubstituted derivatives of α,α-trehalose. The p.m.r. spectrum of hexa-O-acetyl-6,6′-dideoxy-α,α-trehalose, which may be prepared from the ditoluene-p-sulphonate, can be interpreted by first-order analysis and confirms that the D -glucopyranose units are physically equivalent and that they adopt the expected conformation.

Nucleophilic replacement reactions of sulphonates : Part I. The preparation of derivatives of 4,6-diamino-4,6-dideoxy-D-glucose and -D-galactose

Abstract The nucleophilic displacement reactions of some 4,6-disulphonates of methyl α- D -glucopyranoside and methyl α- D -galactopyranoside have been studied by using sodium azide in N , N -dimethylformamide. Displacement occurs at both positions by a bimolecular mechanism, giving the corresponding 4,6-diazides with inversion of configuration at C-4. The azides have been reduced to derivatives of 4,6-diamino-4,6-dideoxy- D -glucose and - D -galactose.

Synthesis of the indolizidine alkaloid swainsonine from d-glucose

Abstract Since the stereochemistry of the alkaloid exactly matches that of 3-amino-3-deoxy- d -mannose, the latter compound is an ideal chiron for the synthesis of the former. Selective tosylation of methyl 3-benzyloxycarbonylamino-3-deoxy-α- d -mannopyranoside, followed by removal of the benzyloxycarbonyl group and cyclisation, afforded the 3,6-imine which was converted into its benzyloxycarbonyl derivative. Hydrolysis of the glycosidic group then afforded 3,6-benzyloxycarbonylimino-3,6-dideoxy- d -mannose. The attempted addition of a C 2 unit at C-1 by the Wittig or the Wadsworth—Emmons—Horner reaction either failed to give the required product or was followed by Michael addition of one of the hydroxyl groups to the newly formed double-bond. 2,4,5-Tri- O -acetyl-3,6-benzyloxycarbonylimino-3,6-dideoxy- aldehydo - d -mannose was prepared via the diethyl dithioacetal and condensed with ethoxycarbonylmethylenetriphenylphosphorane to give the Wittig adduct in good yield, which, on catalytic reduction, underwent hydrogenation of the double bond, loss of the benzyloxycarbonyl group, and attack of the released amino group on either the terminal ethoxycarbonyl group or the 2- O -acetyl group to give a mixture of the required cyclic lactam and the N -acetyl derivative. Reduction of the lactam with the borane—dimethyl sulphide complex afforded swainsonine triacetate, from which the parent alkaloid was obtained.

Derivatives of β-D-fructofuranosyl α-D-galactopyranoside

Abstract De-etherification of 6,6′-di- O -tritylsucrose hexa-acetate ( 2 ) with boiling, aqueous acetic acid caused 4→6 acetyl migration and gave a syrupy hexa-acetate 14 , characterised as the 4,6′-dimethanesulphonate 15 . Reaction of 2,3,3′4′,6-penta- O -acetylsucrose ( 5 ) with trityl chloride in pyridine gave a mixture containing the 1′,6′-diether 6 the 6′-ether 9 , confirming the lower reactivity of HO-1′ to tritylation. Subsequent mesylation, detritylation, acetylation afforded the corresponding 4-methanesulphonate 8 1′,4-dimethanesulphonate 11 . Reaction of these sulphonates with benzoate, azide, bromide, and chloride anions afforded derivatives of β- D -fructofuranosyl α- D -galactopyranoside ( 29 ) by inversion of configuration at C-4. Treatment of the 4,6′-diol 14 the 1,′4,6′-triol 5 , the 4-hydroxy 1′,6′-diether 6 with sulphuryl chloride effected replacement of the free hydroxyl groups and gave the corresponding, crystalline chlorodeoxy derivatives. The same 4-chloro-4-deoxy derivative was isolated when the 4-hydroxy-1′,6′-diether 6 was treated with mesyl chloride in N,N -dimethylformamide.

Nucleophilic replacement reactions of sulphonates : Part II. The synthesis of derivatives of 4,6-dithio-Dgalactose- and -D-glucose, and their conversion into 4,6-Dxylo-hexose

Abstract The replacement reactions of the 2,3-diacetate and 2,3-dibenzoate of methyl 4,6-di-O-mesyl-α- D -glucopyranoside with potassium thiocyanate in N,N-dimethyl-formamide have been studied. They proceed mainly via an SN2 mechanism to give the corresponding 4,6-dideoxy-4,6-dithiocyanato- D -galactopyranosides. In the case of the diacetate, however, a small proportion (≈1%) of the 4,6-dideoxy-4,6-dithio-cyanato- D -glocopyranoside was isolated, which arose by participation of the neighbouring 3-acetoxy substituent. This D -glucopyranoside was also prepared from methyl 2,3-di-O-acetyl-4,6-di-O-toluene-p-sulphonyl-α- D -galactopyranoside by treatment with potassium thiocyanate in N,N-dimethylformamide. The 4,6-dideoxy-4,6-dithiocyanato- D -galactoside undergoes base-catalysed hydrolysis to give, presumably, the 4,6-dithio- D -galactopyranoside which spontaneously oxidises with air to give the intramolecular 4,6-disulphide. Desulphurisation of these 4,6-dithiocyanates and the 4,6-disulphide with Raney nickel, followed by acid hydrolysis, gale 4,6-dideoxy- D -xylo-hexopyranose.

The synthesis of 6-deoxy-6-fluoro-α,α-trehalose and related analogues☆

Abstract Selective acid-catalysed methanolysis of 2,3,2′,3′-tetra-O-benzyl-4,6:4′,6′-di-O-benzylidene-α,α-trehalose yielded the monobenzylidene derivative, which was converted into the 4,6-dimesylate. Selective nucleophilic displacement of the primary sulphonyloxy group then gave 2,3-di-O-benzyl-6-deoxy-6-fluoro-4-O-mesyl-α- d -glucopyranosyl 2,3-di-O-benzyl-4,6-O-benzylidene-α- d -glucopyranoside. Removal of the protecting groups then yielded 6-deoxy-6-fluoro-α,α-trehalose. In addition, 6-deoxy-6-fluoro-4-O-mesyl-α,α-trehalose and a derivative of 4-chloro-4,6-dideoxy-6-fluoro-α- d -galactopyranosyl α- d -glucopyranoside were also prepared from the same substrate. Iodide displacement of 2,3-di-O-benzyl-4,6-di-O-mesyl-α- d -glucopyranosyl 2,3-di-O-benzyl-4,6-di-O-mesyl-α- d -glucopyranoside afforded the 6-iodide and 6,6′-di-iodide in yields of 31 and 36%, respectively. Similarly, the 6-azide and 6,6′-diazide were isolated in yields of 17 and 21%, respectively.

The stereoselective replacement of hydroxyl groups by chlorine, using the mesyl chloride-N,N-dimethylformamide reagent

Abstract The mesyl chloride-N,N-dimethylformamide reagent, previously described as selective for the replacement of primary hydroxyl groups by chlorine, has been shown to cause extensive, but selective, chlorination at secondary positions of glycopyranosides, particularly in the disaccharide series. Thus, reaction with methyl β-maltoside gave initially the 6,6′-dichloro derivative 2, which was then fairly rapidly transformed into the 3,6,6′-trichloro derivative 4. Further reaction, but at a slower rate, gave the 3,4′,6,6′-tetrachloro derivative 6. As anticipated, inversion of configuration accompanied reaction at positions C-3 and C-4′, indicating that the chlorine substituents were introduced by an SN2 mechanism. Benzyl β-cellobioside reacted to give a more-complex mixture from which the 6,6′-di-, 3′,6,6′-tri-, 3,6,6′-tri-, 4′,6,6′-tri-, 3,3′,6,6′-tetra-, and 3,4′,6,6′-tetra-chloro derivatives were isolated, after acetylation. Similarly, methyl glycopyranosides gave products of secondary chlorination, although the reaction proceeded less readily. Methyl α- D -glucopyranoside and methyl α- D -galactopyranoside gave the 4,6-dichloro-galactopyranoside and -glucopyranoside, respectively. On the other hand, methyl β- D -glucopyranoside gave a 2:1 mixture of methyl 3,6-dichloro-3,6-dideoxy-β- D -allopyranoside and methyl 4,6-dichloro-4,6-dideoxy-β- D -galactopyranoside. Structural elucidation of these chlorinated derivatives was based mainly on mass spectrometry and 220-MHz 1H n.m.r. spectroscopy.

Chemical modification of trehalose : Part XV. The synthesis of 4,4′-dideoxy and 4,4′,6,6′-tetradeoxy analogues

Abstract Nucleophilic displacement of 4,4′-di- O -mesyl-α,α-trehalose hexabenzoate occurred very readily to give, by a double inversion, the thermodynamically more stable 4,4′-di-iodide in 93% yield with overall retention of configuration. Reductive dehalogenation of the 4,4′-di-iodide with hydrazine hydrate—Raney nickel followed by debenzoylation afforded 4,4′-dideoxytrehalose in high, overall yield. Alternatively, treatment of trehalose with sulphuryl chloride afforded 4,6-dichloro-4,6-dideoxy-α- D -galactopyranosyl 4,6-dichloro-4,6-dideoxy-α- D -galactopyranoside, which underwent selective dehalogenation at the secondary positions on treatment with hydrazine hydrate—Raney nickel. Subsequent nucleophilic displacement of the primary chlorine substituents with sodium acetate in N,N -dimethylformamide gave, after deacetylation, 4,4′-dideoxy-α,α-trehalose. Repeated treatment of the 4,4′,6,6′-tetrachlorotrehalose derivative with hydrazine hydrate—Raney nickel gave 4,4′,6,6′-tetradeoxy-α,α-trehalose. An alternative route to the tetradeoxy derivative was via thiocyanate displacement of the 4,4′,6,6′-tetramethanesulphonate. The tetrathiocyanate, formed in poor yield, was desulphurized with Raney nickel to give the tetradeoxytrehalose. Treatment of 4,6-dichloro-4,6-dideoxy-α- D -galactopyranosyl 4,6-dichloro-4,6-dideoxy-α- D -galactopyranoside with methanolic sodium methoxide yielded, initially, 3,6-anhydro-4-chloro-4-deoxy-α- D -galactopyranosyl 4,6- dichloro-4,6-dideoxy-α- D -galactopyranoside which was transformed into the 3,6:3′,6′-dianhydro derivative. Reductive dechlorination of the dianhydride proceeded smoothly to give the 3,6:3′,6′-dianhydride of 4,4′-dideoxytrehalose.