Synthesis of 6-deoxy-6-phenylphosphonoyl-D-fructopyranoses: the first phosphorus-in-the-ring analogues of a ketose

Abstract

The title sugar analogues were synthesized through three routes, by starting with three kinds of 6-O-tosyl-D-fructofuranoses. (i) Treatment of the known 2,3-O-isopropylidene-1,6-di-O-tosyl-β-D-fructofuranose successively with methyl iodide–silver oxide, sodium iodide and diethyl phenylphosphonite provided 6-deoxy-6-[(ethoxy)phenylphosphinoyl]-2,3-O-isopropylidene-4-O-methyl-1-O-tosyl-β-D-fructofuranose in 67% overall yield. This was reduced with sodium dihydrobis(2-methoxyethoxy)aluminate, followed by hydrolysis with acid, to afford a mixture of the 4-O-methyl-1-O-tosyl and 1-deoxy-4-O-methyl derivatives of the title compound. (ii) Treatment of D-fructose with 2-methoxypropene in the presence of TsOH and then with TsCl in pyridine afforded 1,3-O-isopropylidene-6-O-tosyl-α-D-fructofuranose (35% yield). This was subjected to the same five-step conversion, to give the 4-O-methyl derivatives of the title compound. (iii) Treatment of D-fructose with 2,2-dimethoxypropane–SnCl₂ and then with TsCl–pyridine gave 1,2-O-isopropylidene-6-O-tosyl-β-D-fructofuranose (23% yield). This was elaborated, in three steps, to either the 3,4-di-O-acetyl-6-deoxy-6[(ethoxy)phenylphosphinoyl] derivative (84%yield) or the 3,4-bis-O-(tetrahydropyran-2-yl) congener (54% yield), both of which furnished, in two steps, the unsubstituted title compound. The products obtained in the three approaches (i–iii) were converted into the corresponding per-O-acetates, whose structures and conformations [²C₅(D), ⁵C₂(D), or B_3,6] were established by spectroscopy.