30 光学活性アンスラサイクリノンの不斉合成

抄録

Preparation of optically active anthracyclinones(2), the aglycones of anthracycline antibiotics(1) showing promising anticancer activities, was attempted by employing two different types of asymmetric syntheses. Thus, the asymmetric bromolactonization of (S)-N-(α,β-unsaturated) acylprolines ((S)-13) was found to give the bromolactones(14) in which one diastereomer(14A) was highly predominant. Further chemical elaborations of 14 including debromination and hydrolytic cleavage of the (S)-proline moiety afforded (R)-α-hydroxy acids((R)-16). (R)-16a,b were converted to (R)-α-hydroxy ketone((R)-9a), 92%ee, a model compound of the AB ring system of 2, and (R)-9b, 100%ee, one of the most versatile synthetic intermediates for 2, respectively. On the other hand, the chiral hydride prepared by partially decomposing lithium aluminum hydride with (-)-N-methylephedrine(1eq) and N-ethylaniline(2eq) was found to reduce the methyl ketone (24) highly stereoselectively, giving (S)-allyl alcohol((S)-25), 92%ee, in a quantitative yield. Optically pure (S)-25 obtained in 87% yield based on 24 by recrystallization, was elaborated to (R)-9b, 100%ee, by successive epoxidation, reduction, and oxidation. (R)-α-Hydroxy ketone((R)-9b) was further transformed to (R)-9c, the synthetic intermediate of 2e, the aglycone of 1e having improved therapeutic properties. Based on the above studies, it became possible to prepare various types of 2 by asymmetric synthesis.