Nuclear magnetic resonance conformational study of daunomycin and related antitumour antibiotics in solution. The conformation of ring A

Abstract

The conformational properties of daunomycin (1) and several analogues (2)–(16) have been investigated by ¹H n.m.r. in different solvents, CDCI₃, D₂O, DMSO, dioxane, and pyridine. From H,H three-bond and long-range coupling constants, the geometry of ring A in each solvent has been determined, through a Karplus–Altona equation, which includes a correction for the substiuent electronegativity. Conformers ⁹H₈, ⁸H₉, ⁹S, S₉, and S₈ have been found in solution, and in several cases, especially in DMSO, more than one conformer is present at equilibrium. The equilibrium is always fast compared with n.m.r. times and the relative populations of each conformer have been calculated from experimental and model coupling constants by using a least-squares procedure. Two factors have been recognized to be responsible for the shape of ring A: the intramolecular hydrogen-bond 9–OH ⋯ O(7) and steric interactions between peri substituents on the A and B rings. Evidence for this hydrogen-bonding has been obtained by dilution experiments, and, for the peri interactions, by evaluating the substituent effects on the conformational preference. Other intramolecular hydrogen bonds have been proved not to exist in solution. The influence of the solvents on the shape of ring A has also been studied. All the results are discussed and compared with those obtained in the solid phase. Daunosamine moiety has also been analysed, and the conformation of the sugar ring is always ¹′C₄. (L) in all the solvents examined.