Stereospecific Total Synthesis of 9-Aminoanthracyclines: (+)-9-Amino-9-deoxydaunomycin and Related Compounds

Article abstract of DOI:10.1021/jo00229a010

9-amino-9-deoxydaunomycin and related compounds, in which the hydroxyl group at the 9-position of daunomycin is replaced by an amino group, have been synthesized.Asymmetry was introduced into the synthetic sequence for the AB synthon by resolution of the intermediate amino ester or acetamido acid to afford (R)-(-)-2-acetyl-2-acetamido-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene, which was converted to the tetracyclic amido ketones by Friedel-Crafts acylation with phthalic anhydride or its 3-methoxy derivative.The resulting regioisomers 4- and 1-methoxy compounds were separed, after methylation and selective demethylation, by crystallization and preparative TLC.The required introduction of the C7-hydroxyl function proceeded stereosepcifically via a three-step reaction sequence involving formation of an oxazine compound.The silver trifluoromethane assisted glycosidation of the resulting aglycons with 2-deoxy-3,4-di-O-acetyl-D-erythro-pentopyranosyl bromide or N,O-bis(trifluoroacetyl)daunosaminyl chloride, followed by alkaline hydrolysis afforded the target glycosides.The work reported herein comprises an efficient, practical synthesis of 9-amino-9-deoxydaunomycin and its analogues with the same stereochemistry as in the naturally occurring anthracyclines.