Title : Copper catalyzed synthesis of the new cytotoxic class of vinca alkaloids: Regiochemistry, stereochemistry, and symmetry considerations
Abstract:
Vindoline and catharanthine are the major alkaloids of Catharanthus roseus and are extracted in large quantities to prepare the pharmaceutically important Vinca-type alkaloids vincaleukoblastine, vincristine and navelbine. The higher yield of vindoline relative to catharanthine makes it an attractive substrate for developing new chemistry and adding value to the plant. In this context, we have reacted vindoline with an electrophile among which benzoquinones. Conditions were developed to optimize the synthesis of a mono-adduct, of five bis-adducts, tri-adducts, and tetra-adducts, several of these adducts being mixtures of conformational isomers. Copper(II) was added to the reactions to promote the reoxidation of the intermediate hydroquinones and simplify the reaction products. The structures were solved by spectroscopic means and by symmetry considerations. Among the bis-isomers, the 2,3-diadduct consists of three inseparable species, two major ones with an axis of symmetry, thus giving a single set of signals and existing as two different species with indistinguishable NMR spectra. The third and minor isomer has no any symmetry and therefore exhibits nonequivalence in the signals of the two vindoline moieties. These isomers are designated as syn (minor) and anti (major) and there exists a high energy barrier between them making their interconversion difficult. DFT calculations on simplified model compounds demonstrate that the syn-anti interconversion is impossible at room temperature on the NMR chemical shift time scale. These molecules are not rigid and calculations showed a back-and-forth conrotatory motion of the two vindolines. This “windshield wiper” effect is responsible for the observation of exchange correlations in the NOESY spectra.
The same phenomenon is observed with the higher molecular weight adducts, which are also mixtures of rotational isomers. The same lack of rotations between syn and anti-isomers is responsible for the formation of four tri-adducts and seven tetra-adducts. We have used various 1,4- benzoquinones different synthetic monomers, dimers, trimers, and tetramers by using 1,4- benzoquinone and copper (II) as an oxidizing agent, and the obtained yield range from 5%-95%.
