Asymmetric synthesis of the AB ring segments of daunomycin and 4-demethoxydaunomycin

Article abstract of DOI:10.1021/jo00084a042

Asymmetric hydroxylation of the potassium enolate of β-keto ester 14, with (camphorsulfonyl)oxaziridine (-)-7c [tetrahydro-9,9-dimethyl-8,8-dimethoxy-4H-4a,7-methanooxazirino[3,2-i] [2,1]-benzisothiazole 3,3-dioxide] affords α-hydroxy β-keto ester (R)-(+)-15 in >95% ee. The high ee's are attributed to the fact that this enolate probably exists in one geometric form as a consequence of intramolecular chelation. Reduction of the ketone in 15 with triethylsilane and conversion of the ester group into the methyl ketone results in a highly efficient synthesis of the AR ring building block (R)-(-)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol (3b), a key intermediate in the asymmetric synthesis of the antitumor agent 4-demethoxydaunomycin (1c). Selective deprotection of the 8-methoxy group in 3b with BBr₃ gives 3a, important in the enantioselective synthesis of the clinically useful antitumor agent adriamycin (1b). Attempts to prepare 3a and 3b more directly by asymmetric hydroxylation of the enolates of methyl 5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoate (9) or the 8-benzyloxy derivative of 16 resulted in low ee's, attributable to the formation of E/Z enolate mixtures and increased steric congestion in the transition state for hydroxylation.