Structure and Synthesis of Vindolicine and Derivatives

This article describes the reaction of vindoline with formaldehyde and trimethyl orthoformate to prepare vindolicine, tris-vindolicinyl methane and higher molecular weight homologues. The synthesis of 10-formyl vindoline as an intermediate allowed further exploration of its chemistry, in particular the reaction with acetone which yielded a symmetrical dimer, which was further reacted with vindoline to give molecules containing three and four vindoline units. These molecules were characterized by NMR and for some of them (vindolicine, 10-formyl vindoline, 10-(1'-(but-1'-en-3'-one))-vindoline) by X-ray crystallography. Depending on the substitution and on the absence of axes of symmetry, the NMR spectra displayed non-equivalent spin systems for the vindoline moieties. The dimer formed from the double condensation of 10-formyl vindoline with acetone showed cytotoxic activity in the micromolar range.