Synthetic Anthracyclines: Regiospecific Total Synthesis of D-Ring Thiophene Analogues of Daunomycin.

The key anhydride 2-acetoxy-[2-carboxy-5-(trimethylsilyl)thiophen-3-yl]acetic acid anhydride (8), prepared from (2-carboxythiophen-3-yl)acetic acid (5), underwent a strong base-induced cycloaddition reaction with the chloroquinone acetal (11) to give the 7,7-ethylenedioxy-2-trimethylsilyl-6,7,8,9- tetrahydroanthra[2,3-b]thiophene-5,10-dione (12) regioselectively. Similarly, the regioisomeric 8,8-ethylenedioxy-2-trimethylsilyl-6,7,8,9-tetrahydroanthra[2,3-b] thiophene- 5,10-dione (30) was obtained by the strong base-induced cycloaddition reaction of 8 with the chloroquinone acetal (29). These cycloadducts (12 and 30) were converted to D-ring thiophene analogues (28 and 38) of daunomycin (1a). Another D-ring thiophene analogue (42) which has a trimethylsilyl substituent in the D-ring was also prepared.