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 p K HA 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 CH 2 Cl 2 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 CH 2 Cl 2 , 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 CF 3 CH 2 OH, (CF 3 ) 2 CHOH, and (CF 3 ) 2 C(Me)OH, and the highly fluorinated long‐chain alcohols CF 3 (CF 2 ) 5 (CH 2 ) 2 OH ( 11 ) and CHF 2 (CF 2 ) 9 CH 2 OH ( 13 ) react (CH 2 Cl 2 , 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 (CF 3 ) 2 C(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, (CF 3 ) 2 C(Me)OH yields up to 55% of the imidate 10 . Glycosidation of di‐ O ‐isopropylideneglucose 15 leads to 16 (CH 2 Cl 2 , 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 (CF 3 ) 2 MeCO − 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.