Design and Synthesis of Cyclofructans as Novel Inclusion Molecules for Clinical Use

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Aiming at creation of novel inclusion molecules for clinical use, we investigated design and chemical synthesis of cyclofructans, for which efficient building blocks have been evolved and utilized for fructosyl-β(2→1)-oligomers as well as their cyclic analogues.D-Fructose was converted into a regioselectively protected intermediate, 3,4,5-tri-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose (1), which in turn was led to a fructosyl donor such as 1-O-acetyl-3,4,5-tri-O-benzyl-β-D-fructopyranosyl fluoride (2) and to fructosyl acceptors, e.g., 3,4,5-tri-O-benzyl-β-D-fructopyranose (3) and 3,4,5-tri-O-benzyl-2-methoxy methyl-β-D- fructopyranose (4) in good yield.Fructosylation of the acceptor 3 with the donor 2 in the presence of Lewis acids (SnCl2ィイD22ィエD2 or CP2ィイD22ィエD2 HfClィイD22ィエD2 /CHィイD22ィエD2ClィイD22ィエD2) resulted in an efficient entry to a minimum size of cyclofructan, CF-2 in quantitative yield. On the other hand, a similar fructosylation (CpィイD22ィエD2 ZrClィイD22ィエD2 / CHィイD22ィエD2 ClィイD22ィエD2) of 4 with 2 afforded a disaccharide building block, I.e., O-β-D-fructopyranosyl-(2→1)- β-D-fructopyranose derivative (5) in 57% yield. The disaccharide 5 was converted into a disaccharide donor (2'-F deriv., 6) and an acceptor (1-OH and 2'-OMOM deriv., 7). We evaluated two types of coupling fashion, I.e., between donor 2 and acceptor 7, or donor 6 and acceptor 4, both of which gave the desired fructosyl trisaccharide (8) in ca. 20% yield (CpィイD22ィエD2 ZrClィイD22ィエD2/CHィイD22ィエD2 ClィイD22ィエD2).Finally, coupling of the disaccharide donor (6) and the acceptor (7) was achieved to give linear β(2→1)-linked fructopyranosyl tetramer (8), which should be subjected to cyclization to generate a cyclofructan, CF-4. Functional analyses of CF-2 and fructosyl oligosaccharides obtained are under investigation.