Improved Synthesis of 6-Azido-6-deoxy- and 6,6′-Diazido-dideoxy-α,α-trehaloses

Abstract

An efficient synthesis of 6-azido-6-deoxy and 6,6′-diazido-dideoxy-α,α-trehalose derivatives was achieved by reaction of trifluoromethanesulfonic anhydride with partially trimethylsilylated heptakis- and hexakis-O-(trimethylsilyl)-α,α-trehalose in the presence of pyridine and 4-(N,N-dimethylamino)pyridine. Displacement with azide and desilylation afforded the title compounds, which represent potential precursors for the corresponding 6-amino- and 6,6′-diamino-trehaloses.

Key words

carbohydrate chemistry - regioselectivity - azides - protecting groups

• References and Notes

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• 12 General procedure for sulfonylation: To a dry round-bottom flask, equipped with a magnetic stirring bar, was added trimethylsilylated trehalose 2 or 3 (1 equiv), and a catalytic amount of 4-dimethylaminopyridine (DMAP) and the vessel was sealed with a rubber septum and subjected to high vacuum for 2–3 h to ensure anhydrous conditions. Anhydrous CH₂Cl₂ (10 mL/g) and pyridine (5 equiv for each OH) were added and the reaction mixture was stirred for 15 min at room temperature, and then cooled to –5 °C. Triflic anhydride (2.5 equiv for each OH) was injected dropwise with stirring while the reaction mixture was continually maintained at –5 °C. The reaction mixture was then allowed to warm gradually to room temperature and stirred for a further 30 min, when TLC (toluene–EtOAc, 19:1) showed the absence of starting material. The mixture was diluted with CH₂Cl₂, filtered, washed successively with cold aq HCl (1%), aq NaHCO₃ (5%), and water, dried (Na₂SO₄), filtered and evaporated to give an amorphous solid that was used for the next step without further purification.
• 13 General procedure for displacement reaction: To a solution of trehalose derivative 4 or 8 (1 equiv) in anhydrous N,N-dimethylformamide (3 mL/g) were added dicyclopentano-15-crown-5 (0.15 equiv for each OH) and anhydrous sodium azide (3 equiv for each OH). The suspension was stirred at room temperature, and reaction was shown to be complete after 2 h by TLC (toluene–EtOAc, 19:1). The mixture was then diluted with CH₂Cl₂ and then processed by conventional work-up.
• 14 General procedure for deprotection: Compound 5 or 9 was dissolved in a mixture of trifluoroacetic acid–tetrahydrofuran–water (8:17:33) and kept at room temperature until TLC analysis showed the hydrolysis to be complete (ca. 1 h). The product was purified by chromatography on silica, eluting successively with hexane–diethyl ether (19:1) and EtOAc–1-propanol (9:3).