40 光学活性4-デメトキシアドリアマイシン及び4-デメトキシダウノルビシンの全合成研究

抄録

Diels-Alder reaction of chloroprene with qunizaline quinone (6) followed by aromatization and hydrolysis, readily produced the tetracyclic trione (8). This was elaborated to (±)-7-deoxy-4-demethoxy-daunomycinone ((±)-9) by addition of the ethynylcerium reagent followed by hydrolysis. Conventional cyanohydrin formation of 8 and hydrolysis produced (±)-α-hydroxy acid ((±)-10), which could be also converted to (±)-9 by sequential acylimidazole formation and addition of methylmagnesium bromide in the presence of trimethylsilyl triflate (TMSOTf). Optical resolution of (±)-10 by the use of (-)-N-methyl-ephedrine gave (R)-10. Preparation of optically pure (-)-9 was accomplished by optical resolution of (±)-9 with (2R,3R)-(+)-1,4-bis(4-chlorobenzyloxy)butane-2,3-diol or treating (R)-19 in a similar manner to that described for (±)-10. Optically pure (-)-9 was elaborated to optically pure (+)-4-demethoxydaunomycinone ((+)-11) by C_7-bromination and stereoselective hydroxylation. Further C_<14>-bromination of (+)-11 and substitution gave (+)-4-demethoxyadria-mycinone ((+)-12), (+)-14-formyloxy-4-demethoxydaunomycinone ((+)-13), and (+)-14-acethoxy-4-demethoxydaunomycinone ((+)-14). (+)-4-Demethoxydaunorubicin ((+)-4-HCl) was prepared by the novel glycosidation of (+)-11 with (-)-1,4-di-O-p-nitrobenzoly-L-daunosamine ((-)-22) in the presence of TMSOTf followed by sequential O- and N-deprotections. (+)-4-Demethoxyadriamycin ((+)-3-HCl) could be also synthesized starting from (+)-4-HCl or by way of 3'-N-trifluoroacetyl-4-demethoxyadriamycin ((+)-28) prepared from (+)-13 and (+)-14, and was fully characterized by its spectral properties.