HIROTANI Seiko Kitasato Univerisity, School of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (20050594)
HARADA Kazuho Kitasato Univerisity, School of Pharmaceutical Sciences, Assistant, 薬学部, 助手 (00189698)
YAGO Kazuo Kitasato Univerisity, School of Pharmaceutical Sciences, Professor, 薬学部, 教授 (10276157)
|Budget Amount *help
¥3,000,000 (Direct Cost : ¥3,000,000)
Fiscal Year 1999 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1998 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1997 : ¥1,400,000 (Direct Cost : ¥1,400,000)
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.