IBUKA Toshiro Kyoto University, Graduated School of Pharmaceutical Sciences, Professor, 薬学研究科, 教授 (80025692)
TAMAMURA Hirokazu Kyoto University, Graduated School of Pharmaceutical Sciences, Assistant Profess, 薬学研究科, 講師 (80217182)
OTAKA Akira Kyoto University, Graduated School of Pharmaceutical Sciences, Asociate Professo, 薬学研究科, 助教授 (20201973)
|Budget Amount *help
¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 1997: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1996: ¥3,600,000 (Direct Cost: ¥3,600,000)
Among various dipeptide isosteres, the potential of (E)-alkene dipeptide isostsres (EADIs) as backbone replacement of amide bonds in peptides has been well documented in the past few years. However, the efficient stereocntrolled synthetic routes for EADIs have not been established. We previously reported the organocopper-mediated anti-S_N2' reactions of gamma, delta-cis-gamma, delta-eepimino-(E)-alpha, beta-enoates or gamma, delta-syn-delta-amino-gamma-mesyloxy-(E)-alpha, beta-enoates, which give L,L-type or L,D-type EADIs respectively. Based on the ab initio molecular orbital calculations, we have developed Pd(0)-catalyzed isomerization reactions of four diastereomixtures of gamma, delta-epimino-alpha, beta-enoates, easily prepared by the sequence of known reactions starting from L-amino acids, which give the desiarble key intermediates, gamma, delta-cis-gamma, delta-epimino-(E)-alpha, beta-enoates, in high yield. Furthermore, a brief treatment of the same substrates with dil. MeSO_3H quantitatively affords the regio-and stereoselectively ring-opened products, gamma, delta-syn-delta-amino-gamma-mesyloxy-(E)-alpha, beta-enoates. Essentially, in the same manner starting from D-amino acids, stereoselective synthesis of D,D-type and D,L-type EADIs is feasible. Thus, the totally stereocontrolled synthetic routes for four sets of homo chiral EADIs have been established.
Application of the above straightforward synthetic strategy to derivatization of the potential peptide-lead anti-cancer compounds involving bombesin/GRP antagonist and Ras-Farnesyl transferase inhibitor has been examined.