The conformation of vinblastine in solution as determinated by n.O.e. difference spectroscopy

Abstract

The conformation of the binary alkaloid vinblastine has been determined in solution using n.O.e and decoupling difference spectroscopy. Both positive and negative n.O.e.'s have been observed and exploited. On the catharanthine portion, it has been shown that the piperidine ring takes up a severely flattened conformation with the nitrogen lone pair and the ethyl group being pseudo-equatorial. The preferred conformation of the nine-membered ring has also been determined. The spatial relationship between the catharanthine and vindoline halves has been established from several n.O.e. connectivities between them, notably from the indole NH of the catharanthine side and the aromatic 14-H of the vindoline side. The C(17′)–C(18′)–C(15)–C(16) dihedral angle is 140–170°. These are the first complete published assignments for the ¹H n.m.r. spectra of vinblastine and of vindoline.