Highly effective asymmetric synthesis of 11-deoxydaunomycinone and analogues

Abstract

Optically active 11-deoxydaunomycinone and its 9-hydroxymethyl analogue were synthesized in 95% e.e. by means of tandem Michael/Diels–Alder reaction as a key step in the tetracycle's formation. As a reagent, a chiral pentadienyltin was prepared without loss of optical purity from ethyl 2-[(S)-1-hydroxyethyl]pent-4-enoate, which was obtained in 97% e.e. by reduction (yeast) of the corresponding acetoacetate derivative. The chirality on the tin reagent was transferred to the C-9 of 11-deoxydaunomycinone via diastereoselective epoxidation in high efficiency. For the synthesis of the 9-hydroxymethyl analogue of 11-deoxydaunomycinone, enantioselective epoxidation was applied to the allylic alcohol moiety of the tetracyclic quinonoid compound to afford the corresponding optically active epoxide in high chemical and optical yield. Success in this highly efficient and enantioselective epoxidation was attributed to the protection of the phenolic hydroxy group in the substrate from competitive co-ordination to the Sharpless reagent.