Studies related to anthracyclines. Part 2. Synthesis of (±)-4-demethoxydaunomycinone

Abstract

A chromatography-free, six-step, diastereocontrolled synthesis of (±)-4-demethoxy-7-O-methyl-daunomycinone (3b) is described. The tetracyclic carbon skeleton is elaborated by a Diels–Alder strategy in which the 6a,7 and 10, 10a bonds are constructed, the epoxytetraone (5) and the diene (10a) serving as precursors. Hydrolysis of the cycloadduct (11a) leads to the epoxypentaone (12a), the structure of which is confirmed by X-ray crystallography. The diastereocontrol is achieved in the reaction of the dihydroxytrione (13a)[obtained by reduction of the epoxypentaone (12a)] with ethynylmagnesium bromide or lithium acetylide, the reagents attacking the 9-carbonyl group from the face away from that bearing the 7-methoxy group to give the ethynyldione (14a). Although epimerisation of the dihydroxytrione (13a) at the 10a-position is a competing reaction when high concentrations of the metal acetylides are employed, the ethynyldione produced, i.e. (20), still possess the trans arrangement of the 7-methoxy and 9-ethynyl groups. The ethynyldiones (14a) and (20) are converted into compound (3b) by an oxidative isomerisation-hydration sequence.

An attempt to effect the de-O-methylation of compound (3b), by the action of trimethylsilyl iodide, failed; a mixture of 4-demethoxy-7-deoxydaunomycinone (22b) and its 9-deoxy derivative (22a) resulted. The conversion of compound (3b) into the title compaund (3a) is brought about by a trifluoroacetolysis–ammonolysis sequence.

The conformation of the A ring of the anthracyclinones (3a) and (3b) and their precursors, as determined by high-field ¹H n.m.r. spectroscopy, is discussed.