Conformational analysis of 9-deoxydaunorubicin in solution. The application of a quantitative transient 1H nuclear Overhauser effect

Abstract

The preferred conformation of 9-deoxy-N-trifluoroacetyldaunorubicin has been determined by 1H and 13C n.m.r. in CDCl3 solution. The conformation of ring A was easily defined as a pure half-chair 9H8, from the values of proton coupling constants, and on the basis of a preceding study of daunomycin derivatives. The orientation of the sugar with respect to the aglycone moiety has been obtained by quantitative transient nuclear Overhauser experiments (n.O.e.). The interproton distances have been deduced from the cross-relaxation rates determined by measuring the time development of n.O.e.s, after selective inversion of single resonances. The experimental points were fitted to the theoretical curves through a non-linear least-squares procedure. The overall isotropic motion was proved by 13C T1 measurements of all protonated carbons; the interproton reference distance r4′–5′, deduced from the correlation time value, is in satisfactory agreement with those measured by X-ray analyses of daunomycin and carminomycin. The glycoside linkage geometry has also been expressed in terms of the rotational angles φ= H(1′)–C(1′)–O(7)–C(7) and ψ= C(1′)–O(7)–C(7)–H(7). The results have been compared with those obtained through molecular mechanics calculations, performed with the Allinger MMP2 program.