Synthesis and Isolation Studies Towards Vinblastine and Vincristine and Their Novel Derivatives

Abstract

A new and much better procedure has been developed for the isolation of vinblastine using tartaric acid/HCl for adjusting the pH followed by solvent ectraction, yielding crystalline vinblastine upon addition of ether, methanol or acetone. The binary alkaloid leurosine exists in the leaves of C.roseus in 8 to 10 fold greater quantity than vinblastine. Leurosine has in one step been converted to anhydrovinblastine which can then be converted to vinblastine. This represents a novel approach to the synthesis of vinblastine and utilize the hitherto useless leurosine. A number of new and known alkaloids have been isolated from the leaves and flowers of Catharanthus roseus namely, 16-epi-19-S-vindolinine, catharanthine, vindoline, vinblastine, 16-epi-19-S-vindolinine-N-oxide, fluorocarpamine-N-oxide, Vindoline-N-oxide, fluorocarpmine, pleiocarpamine, gomaline, rhazimol, rosamine, rosicine, 14,15-dehydroepivincadine, 19-hydroxytabersonine, norharmane, Catharine, cathovaline, bunnucine and leurosinone, whereas coronaridine, 11-methoxytabersonine, tetrahydroalstonine, ajmalicine, mitraphylline and vindorosine were isolated from the flowers of Catharanthus rosues. The physiologically active alkaloids, vinblastine and vincristine, are biogenetically derived from the β-carboline system, and have iboga and aspidosperma types of skeletal systems. Attempts have accordingly been directed to the synthesis of β-carbolines and the biogenetically important secodine systems. It is known that secodine derivatives can be converted to the iboga and Aspidosperma alkaloids. These studies have led us to the first syntheses of N-methysecodine and N-benzylsecodine. The synthesis of the closely related Hunteria alkaloids has also been achieved. They closely resemble the aspidoserma alkaloids which constitute the lower half of vinblastine. These studies have led to a novel synthesis of vincamine, which is convertible to the aspidosperma-type alkaloids in a one step process. Oxidation of vinblastine and vincristine has been successfully carried out by using a number of oxidizing agents. The work is still in a stage of refinement. A new derivative of leurosine (dinitroleursine) has been prepared and submitted to a foreign pharmaceutical company for evaluation of biological activity. The work has resulted in the publication of 23 papers in reputable international journals.