New chiral pool approach to anthracyclinones. The stereoselective synthesis of idarubicinone.
In the present work, a new chiral pool approach has been developed for the synthesis of anthracyclinones. Thus, enone 8, readily available from l-rhamnose, has been converted via addition of 2,5-dimethoxybenzyllithium to the carbonyl group and a series of six reactions into a suitably protected aldehyde 21. The SnCl(4)-promoted stereospecific cyclization of the latter afforded enantiopure key intermediate 22. Silylation of benzylic hydroxyl of 21 followed by anodic oxidation and selective hydrolysis gave ketoacetals 25 and 26 to which 3-cyano-1(3H)-isobenzofuranone 27 was annelated. Removal of the isopropylidene group in the resulting 28, subsequent oxidation of the C(13) hydroxyl and full deprotection led to idarubicinone (4).
Achmatowicz
Osman
O
Pharmaceutical Research Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland. achosman@ifarm.waw.pl
Szechner
Barbara
B
D018943:Anthracyclines / Q000138:chemical synthesis*; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015255:Idarubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D008968:Molecular Conformation; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D018943:Anthracyclines; C476486:idarubicinone; D015255:Idarubicin