Glycosylidene Carbenes. Part 6. Synthesis of alkyl and fluoroalkyl glycosides

The syntheses of glycosides from the diazirine 1 and a range of alcohols under thermal and/or photolytic conditions are described. Yields and diastereoselectivities depend upon the pKHA values of the alcohols, the solvent, and the reaction temperature. The glycosidation of weakly acidic alcohols (MeOH, EtOH, i-PrOH, and t-BuOH, 1 equiv. each) in CH2Cl2 at room temperature leads to the glycosides 2–5 in yields between 60 and 34% (Scheme 1 and Table 1). At −70 to −60°, yields are markedly higher. In CH2Cl2, diastereoselectivities are very low. In THF, at −70 to −60°, however, glycosidation of i-PrOH leads to α-D-/β-D-4 in a ratio of 8:92. More strongly acidic alcohols, such as CF3CH2OH, (CF3)2 CHOH, and (CF3)2C(Me)OH, and the highly fluorinated long-chain alcohols CF3(CF2)5(CH2)2OH (11) and CHF2(CF2)9CH2OH (13) react (CH2Cl2, r.t.) in yields between 73 and 85% and lead mainly to the β-D-glucosides β-D-6 to β-D-8, β-D-12, and β-D-14 (d.e. 14–68%). Yields and diastereoselectivities are markedly improved, when toluene, dioxane, 1,2-dimetoxyethane, or THF are used, as examined for the glycosidation of (CF3)2C(Me)OH, yielding (1,2-dimethoxyethane, 25°) 80% of α-D-/ β-D-8 in a ratio of 2:98 (d.e. 96%; Table 4). In EtCN, (CF3)2C(Me)OH yields up to 55% of the imidate 10. Glycosidation of di-O-isopropylideneglucose 15 leads to 16 (CH2Cl2, r.t.; 65%, α-D/ β-D = 33:67). That glycosidation occurs by initial protonation of the intermediate glycosylidene carbene is evidenced, for strongly acidic alcohols, by the formation of 10, derived from the attack of (CF3)2MeCO− on an intermediate nitrilium ion (Scheme 4), and for weakly acidic alcohols, by the formation of α-D-9 and β-D-9, derived by attack of i-PrO− on intermediate tetrahydrofuranylium ions. A working hypothesis is presented (Scheme 3). The diastereoselectivities are rationalized on the basis of a protonation in the σ plane of the intermediate carbene, the stabilization of the thereby generated ion pair by interaction with the BnOC(2) group, with the solvent, and/or with the alcohol, and the final nucleophilic attack by RO− in the π plane of the (solvated) oxonium ion.