Total Synthesis of Antitumor Antibiotic FR900482

抄録

This account describes our first total synthesis of an enantiomeric pair of FR900482 (1 and ent-1), which was accomplished in a convergent manner utilizing the aromatic segment 14 and the aliphatic segment 15 and ent-15 accessible from commercially available 5-hydroxyisophthalic acid (16) and each enantiomer of diethyl tartrate (17 and ent-17), respectively. The method for the total synthesis involves the following four key steps : (i) coupling reaction of 14 with 15 (14+15→32, Scheme 5); (ii) intramolecular aldol reaction of the highly functionalized dialdehyde 13 (13→36, Scheme 6); (iii) epimerization at the C-8 position of the hydroxy ketone 40 (40→41, Scheme 7); (iv) internal hemiacetal formation of the N-hydroxylamino ketone 11 in situ generated from the ketone 45 (45→11→10, Scheme 10). The in vitro cytotoxicity assay of the synthesized compounds (1, ent-1, 50, ent-50, 51, and ent-51) against P388 murine leukemia cells disclosed that 1 and its congeners 50, 51 possessing natural absolute configuration are ca. 100 times more cytotoxic than the corresponding unnatural enantiomers (ent-1, ent-50, ent-51).