Anthracyclines. XI. A short, site-specific synthesis of unsymmetrical 3-Acetyl-5,8-dialkoxy-1,2-dihydronaphthalenes; key precursors to daunomycinone AB-synthons

Abstract

5,8-Dihydronaphthalene-1,4-diol, readily available from benzoquinone and buta-1,3-diene, is isomerized by heating with strong sodium hydroxide, and acetylated (Ac₂O), in situ, to form 5,8-diacetoxy-1,2-dihydronaphthalene. Catalysed (AlCl₃) addition of acetyl chloride followed by dehydrochlorination (LiCI/HCONMe₂) yielded 5,8-diacetoxy-3-acetyl-1,2-dihydronaphthalene (11) in 82% overall yield. Base hydrolysis of (11), followed by methylation (Me₂SO₄) gives 3-acetyl-5,8-dimethoxy-1,2-dihydronaphthalene in 94% yield, the most direct route to this product so far described. More importantly, the diacetate (11) is selectively deacetylated at C5 (Cs₂CO₃ in tetrahydrofuran, or K₂CO₃ in Me₂SO) to form the related phenol, alkylation of which produces the 5-alkoxy compound. Further hydrolysis followed by alkylation yields the unsymmetrically, but regiospecifically substituted, 3-acetyl-5,8-dialkoxy-1,2-dihydronaphthalenes. This method is specifically illustrated by the production of 3-acetyl-5-benzyloxy-8-methoxy-1,2-dihydronaphthalene which is formed in a short, cost effective synthesis in a moderate overall yield (25%) based upon benzoquinone as starting material;significantly, no chromatographic separations are required.