REDUCCIÓN DE COSTOS PARA EL CLIENTE

With alcohol 200 in enantiomerically enriched form, the next goal was to synthesise a suitable sugar donor to complete the synthesis of glycoside238.D-Amicetose derivative 214 has been made previously from the alkene211in 3 steps in 91% yield by Spohr et al.103

It was reasoned that 214 could be transformed into a variety of activated donors by subsequent hydrolysis of the anomeric ether followed by activation. Rather than devise new chemistry to 214 which might have been more direct, it was elected to repeat the published synthesis of this material as felt it would be more expedient.

Commercially available β-methoxy D-glucose 208 was treated with dimethoxy

benzylidene acetal in the presence of catalytic iodine to give benzylidene acetal 209 in excellent yield using the modified method developed by Rajib et al.104 To deoxygenate 209, it was converted to dimesylate 210, using methanesulfonyl chloride and pyridine.105 This dimesylate was treated with the Tipson-Cohen reagent to give alkene 211 in good yield,106 which was hydrogenated in the presence of 5% palladium on carbon and triethylamine to give crystalline 212 in excellent yield. Oxidative cleavage of the benzylidene ring with NBS provided 6-bromo deoxysugar 213in excellent yield. Further catalytic reduction of carbon-halogen bond of 213with palladium on carbon in the presence of triethylamine gave β-methoxyamicetose 214 in 95% yield (Scheme 48).103

Scheme 48

β-Methoxyamicetose 214 was hydrolysed in excellent yield to a mixture of α- and β- hydroxyamicetose215 in 1.4 : 1 ratio respectively, using a 1 : 2 : 3 mixture of hot 2M

Chapter 2: Synthesis of Tetra- and Dihydroxanthones and their glycosides Samiullah

59

HCl, AcOH and H2O. Theα- andβ-hydroxyamicetose215were established on the basis of the chemical shift of the anomeric hydrogens. Fortunately the hydroxyl hydrogens of α- andβ-hydroxyamicetose215were also visible in1H NMR spectrum at 2.91 ppm as a singlet and 3.45 ppm as a doublet with 5.9 Hz of coupling constant respectively. The mixture of α- andβ- hydroxyamicetose 215was further acetylated in excellent yield on treatment with acetic anhydride and pyridine in the presence of catalytic DMAP to obtainα- andβ- acetoxyamicetose216 in 1.4 : 1 ratio respectively (Scheme 49).107

Scheme 49 2.4.1 Synthesis ofα-halogenated sugar donors

Most β-glycosidic bonds are constructed by SN2 type reactions of α-sugar donors with the alcohol acceptor. Levels of stereocontrol also depend on the nature of the alcohol and the substitution pattern at the adjacent carbon (C-2). For example, the glycosidation of cholesterol217withα-bromo sugar218proceeds to give exclusively theβ-glycosidic bond as reported by Schneideret al(Scheme 50).108

Scheme 50

With this knowledge in hand, attempts were made to produce sugar donors with exclusively the α-configuration. To the best of our knowledge, no examples of exclusively α-halo sugar donors derived from 2,3,6-trideoxy sugars such as amicetose 216have been reported. The synthesis ofα-bromo anomer220from amicetose216was attempted by treating it with 33% HBr in AcOH. However the substrate was unstable to the strongly acidic conditions and this approach led only to degradation.

Generating HBr in situ by treating acetyl bromide with methanol in acetic acid, followed by the addition of 216 also gave a complex mixture of products (Scheme 51).109

Scheme 51

The synthesis of α-bromo sugar was also attempted under milder conditions by treating 216 with trimethylsilyl bromide in benzene at room temperature. The development of two closely running new spots was observed on thin layer chromatography. However, during the attempted isolation of 220 only α- and β-hydroxy amicetose 215 in 1.2 : 1 ratio respectively was recovered presumably as a result of hydrolysis of 220 (Scheme 52).110

Scheme 52 2.4.2 Synthesis ofα-trichloroacetimidate donors

Since neither theα- or β-bromo derivatives of220 could be produced, it was attempted to convert the anomeric hydroxyl group of 215 into trichloroacetimidate. When activated in the presence of Lewis acids, these are known to be excellent partners in the glycosidation reactions.111 _{In a reversible activation step and with the help of kinetic} and thermodynamic reaction control both the α- and β-anomers could potentially be accessed using this chemistry. The β-trichloroacetimidate 223 is generated from a mixture of α-221andβ-222tetra-O-benzyl-D-glucose preferentially in a very rapid and reversible addition reaction using potassium carbonate in dichloromethane at room temperature (Scheme 53). However, this product can be anomerised in the presence of strong base such as sodium hydride through a retroreaction to form the thermodynamically more stable α-trichloroacetimidate sugar donor 224 exclusively (Scheme 53).112

Chapter 2: Synthesis of Tetra- and Dihydroxanthones and their glycosides Samiullah

61 Scheme 53

However, the synthesis of trichloroacetimidate derivatives of amicetose donors has not yet been reported. Treatment of the α- and β- mixture of amicetose215 in 1.2 : 1 ratio respectively with excess trichloroacetonitile and catalytic sodium hydride (10mol%) produced bothα-225andβ-226trichloroacetimidates within 30 minutes as evidenced by thin layer chromatography. To shift the equilibrium to the thermodynamically more stableα-anomer, namely225, an excess of sodium hydride was added (Scheme 54).113

Scheme 54

Crude 1H NMR analysis showed the presence of both the α-225 and β-226 trichloroacetimidate glycosyl donors in 3 : 1 ratio. This ratio of glycosyl donors remained unchanged when the reaction mixture was left for longer times, and varying amounts of sodium hydride were used. The major α-anomer was assigned on the basis of 1H NMR chemical shifts and coupling constants of anomeric hydrogens. This mixture of trichloroacetimidates was used in further glycosidation reactions as they were unstable to storage or column chromatography on silica gel.