The total synthesis of optically pure (9R,13S)- and (9R,13R)-7-deoxy-13-dihydrodaunomycinone

Abstract

13-Dihydrodaunomycin 1 has long been recognized as the major human metabolite of the antineoplastic anthracycline daunomycin 2.1 Whilst 1 has been prepared by microbial2 and chemical reduction3of 2, no attempt to assign the stereochemistry at C134 has been reported. Recently Cassinelli et al. have reported5that 4-demeth-oxydaunomycin 3 (idarubicin) can be reduced microbially to afford an idarubicinol 4 identical with that excreted by patients treated with 3. These authors initially assigned the 13R stereochemistry to this product, although this was subsequently corrected by Broadhurst et al.,6 who showed that the totally synthetic 13S isomer corresponded to the biologically obtained product. As both dihydroderivatives 1 and 4 are active antineoplastic agents,2,7routes leading to their total synthesis are of considerable interest. In addition another dihydro compound, namely 7-deoxy-13-dihydrodaunomycinone 5, has reportedly been isolated from a strain of Streptomyces (PD.J566) originating from Michaelmas Cay in Australia.8 Since this product occurred together with known daunomycin derivatives, it was assumed to have the 9R configuration. However, subsequent attempts to synthesize 5 stereospecifically by borohydride reduction of (−)-7-deoxydaunomycinone yielded unseparated mixtures of the9R,13R and 9R,13S isomers.9 Consequently, the configuration of C13 of the natural product remained undefined. © 1986, American Chemical Society. All rights reserved.