Ho Oh

AcNH IV.10

AcNH IV.10

NaS030 0S03Na

an acetamido group followed by O-sulfation with sulfur trioxide-trimethylamine and subsequent removal of the benzyl ether afforded the desired sulfate IV.7 as its sodium salt.

Alternatively, kinetic isopropylidination of IV.1 was demonstrated, using 2-methoxypropene in dimethylformamide and toluene-^-sulfonic acid monohydrate conditions to produce the 4,6-O-isopropylidene derivative IV.3 in 85% yield. Subsequent methylation of the 3-OH with methyl iodide followed by removal of the isopropylidene protecting group by treatment with aqueous 90% trifluoroacetic acid afforded crystalline IV.8. Catalytic hydrogenolysis (Pd/C) of IV.8 produced the corresponding amine, which was then N-acetylated to provide 90% of crystalline IV.9. Selective O-sulfation of the 6-OH on IV.9 with the sulfur trioxide-trimethylamine complex in dimethylformamide and subsequent ion exchange chromatography produced the crystalline sulfate IV.10 as its sodium salt in 86% yield. Complete 4,6-O-sulfation occurred in the presence of excess sulfating agent to give the disulfate IV.11 in 85% yield.

Construction of the l-idopyranosyluronic acid donor moiety began with the benzylation of 1,6-anhydro-¡-l-idopyranose to give 1,6-anhydro-2,3,4-tri-O-benzyl-¡-l-idopyranose (IV.12). Acetolysis of IV.12 with acetic anhydride-trifluoroacetic acid gave 91% of IV.13 (Scheme 40). Subsequent treatment of IV.13 with methanolic sodium methoxide provided 2,3,4-tri-O-benzyl-l-idopyranose, which was mono-chloroacetylated with chloroacetyl chloride to give IV.14 in 84% yield, as a 5:2 mixture of a and ¡ anomers. Addition of dichloromethane saturated with hydrogen chloride gave 90% of the corresponding chloride IV.15, which was immediately condensed with methyl 4-O-acetyl-2-azido-6-O-benzyl-2-deoxy-¡-d-galactopyrano-side (IV.16). Compound IV.16 was prepared by regioselective ring opening [92] of a methyl orthoester (prepared from IV.5 by treatment with trimethyl orthoacetate and toluene ^-sulfonic acid monohydrate). The glycosylation was carried out in the presence of silver triflate and 2,4,6-trimethylpyridine and, following O-chlorodeacetyla-tion, afforded 58% of the a-linked disaccharide IV.17 and 30% of the corresponding ¡-linked disaccharide IV.18.

Reduction of the azide in the a-linked disaccharide IV.17, by using sodium borohydride in the presence of nickel dichloride hexahydrate and boric acid, followed by N-acylation, gave IV.19 in 81% yield (Scheme 41). Oxidation of the 6-OH on the idopyranosyl moiety was achieved with chromium trioxide in acetone-sulfuric acid and gave, after deacetylation, the crystalline acid IV.20. The free acid was converted to the sodium salt and O-sulfated to afford IV.21 in 81% yield. Finally, catalytic hydrogenolysis (Pd/C) provided 83% of the target disaccharide of N-ace-tyldermosine (IV.22). Additionally, catalytic hydrogenolysis of IV.20 provided the nonsulfated analog IV.23 in 86% yield.

Similarly, the ¡-linked disaccharide IV.18 was converted to the corresponding N-acetylated disaccharide IV.24 (81%) followed by oxidation, deacetylation, and O-sulfation to give IV.25 (Scheme 42). Catalytic hydrogenolysis resulted in IV.26 in 87% yield after purification.

Sinay and coworkers explored different approaches to the synthesis of the N-acetyldermosine disaccharide (IV.22) that resulted in the report of an improved synthetic route [93]. The strategy investigated initially used diol IV.5 (as an alternative glycosyl acceptor to IV.16) that relied on regioselective glycosylation of the more reactive equatorial 3-OH. This would eliminate the need for a deprotection sequence

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