Synthetic Studies on Anthracysline Antibiotics

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The anthracycline antibiotics, 4-demethoxydaunomycin (1), daunomycin (2), and 11-deoxydaunomycin (3), are clinically signigicant drugs for the treatment of a broad spectrum of human cancers. In the course of investigations in our labolatory concerning the synthesis of anthra- cyclines, three successful results have been obtained in this project. In the first place, facile and versatile methods suitable for a large scale preparation of the aglycones of 1-3 were established. Three different routes using cycloaddition reaction of 4-acetoxy-homophthalic anhydride to chloroquinone acetal, nucleophilic addition reaction of ethynylcerium reagent to the C-9 ketone of 6-hydroxy(or 6,11-dihydroxy)-4-methoxy(or 4-demethoxy)-7,8-dihydro-naphthacene-5,9(10H),12-trione, and cycloaddition reaction of 6-ethyny1-6-hydroxy-5,6,7,8-tetrahydrohomophthalic anhydride to naphthoquinone-type compounds, have been developed. Secondly, asymmetric synthesis of ortically pure daunomycinone, the aglycone of 2, has been achivevd. That is, highly diastereoselective alkylation reaction to the chiral -keto acetal derived from (-)-(2S,3S)-1,4-dimethoxy-2,3-butane- diol was applied for the construction of chiral AB-ring system. Then, a new chiral AB-synthon, (-)-2-bromo-6-ethyny1-6-hybroxy-5,6,7,8-tetrahydro-1,4-naphthoquinone, was preapred and used for the synthesis of optically pure (-)-7-deoxydaunomycinone, the late stage precursor for daunomycinone. Thirdly, syntheses of antracyclines were achieved. Thus, natural anthracyclines were prepared in optically active form by glycosidation reactions of racemic aglycones with the suitably protected 1-0-acy1 sugar derived from L-daunosamine in the presence of teimethylsilyltriflate. Other anthra- cyclines were synthesized by glycosidation reactions of racemic glycones with 1-chlorosugars, derived from neutral sugars, using mercuric oxide as a catalyst.