Total synthesis of an enantiomeric pair of FR900482. 3. Completion of the synthesis by assembling the two segments

Article abstract of DOI:10.1016/S0040-4020(97)00652-2

The title synthesis was accomplished by a method which features (i) coupling of the aromatic segment 2 with the enantiomerically pure aliphatic segment 3 to install the requisite carbon unit (2+3→4); (ii) intramolecular aldol reaction of the highly functionalized dialdehyde 10 to elaborate the desired eight-membered ring system 12 (10→12); (iii) epimerization at the C-8 position of the hydroxy ketone 15 to obtain the correct stereochemistry (15→16); (iv) internal hemiacetal formation of the N-hydroxylamino ketone 25 in situ generated from the ketone 24 to construct the requisite tetracyclic ring system 26 (24→25→26) as the key steps. The in vitro cytotoxicity assay of the synthesized compounds (1, ent-1, 31, ent-31, 32, and ent-32) against P388 murine leukemia cells disclosed that FR900482 (1) and its congeners 31, 32 bearing natural absolute configuration are 100 times more cytotoxic than the corresponding unnatural enantiomers (ent-1, ent-31, ent-32).