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Abstract

This dissertation describes research towards a feasible synthesis of vinbiastine 1, by coupling of a suitable catharanthine analog with vindoline 4. In this connection a reinvestigation of the modified Polonovski reaction was undertaken in order to gain a better understanding of the factors affecting the yield of the reaction. The Diels-Alder reaction of the methyl α-chloroacrylate 31 with the dihydropyridine 30 afforded the isomeric Diels Alder adducts 32 and 33. The two adducts were separated and transformed into the indole-amides 40 and 51 as well as the corresponding thioamides. Photochemical cyclization of the amides and the thioamides gave lactam 55 and thiolactam 61. However, with a best overall yield of 7% of lactam 55 the investigated strategy did not lead to a practical synthesis of vinbiastine. The low yields obtained in the coupling of catharanthine derivatives with vindoline 4 necessitated a reinvestigation of the modified Polonovski reaction. In using fractional factorial design as experimental strategy and exocatharanthine 89 as a suitable catharanthine analog, a new intermediate was discovered and the yield of dimeric alkaloid was improved from 35% to 70%. The better understanding obtained of the factors influencing the yield of the modified Polonovski reaction