Asymmetric halolactonization reactions. 3. Asymmetric synthesis of optically active anthracyclinones

The asymmetric bromolactonization of (S)-N-(α, β-unsaturated) acylproline ((S)-17a) prepared from the α, β-unsaturated acid (10a) was found to occur stereoselectively to give the bromolactone (18a) in which one diastereomer (18Aa) was predominant. Debromination of 18a followed by acidic hydrolysis, afforded the (R)-α-hydroxy acid ((R)-12a) in 92% optical purity. Reaction of (R)-12a with methylithium gave the (R)-α-hydroxy ketone ((R)-9a), a model compound of the optically active anthracyclinone AB ring system, in good yield. When the reaction scheme established by the model study was applied to 10b, c, which possess the AB and ABCD ring systems of anthracyclinones (2), (R)-α-hydroxy acid methyl esters ((R)-21b, c) could be prepared in 97% and 87% optical yields, respectively. Alkaline hydrolysis of optically pure (R)-21b, c independently prepared from the pure debrominated lactones (19Ab, c) gave (R)-12b, c. Although the reaction of tetracyclic (R)-12c with methyllithium did not proceed in the expected manner, bicyclic (R)-12b was successfully converted to optically pure (R)-9b, which has previously been utilized as a starting material for the synthesis of optically active natural and unnatural 2.