The radical cation mediated cleavage of catharanthine leading to the vinblastine type alkaloids: implications for total synthesis and drug design

Abstract

The landmark synthesis of vinblastine (and analogues) by Boger et al. involves a tandem [4 + 2]/[3 + 2] cycloaddition that resulted in the construction of vindoline followed by FeCl₃ promoted, radical cation mediated, catharanthine fragmentation/vindoline coupling that yields anhydrovinblastine (after NaBH₄ reduction of the iminium ion) or vinblastine directly (by virtue of exposure of the first formed anhydrovinblastine to ferric oxalate-NaBH₄, air, 0 °C). It is important to emphasise that this inspired and versatile innovation is essentially a one-pot vinblastine synthesis resulting from exposure of catharanthine/vindoline to a FeCl₃/Fe₂ (oxalate)₃ combination. The mechanistic hypothesis of Kutney, in which the C(16)–C(21) cleavage in catharanthine leading to the azabenzfulvene is triggered by tertiary amine oxidation to the radical cation, has been subjected to a formidable challenge by Boger who has suggested, based on careful experimentation involving a number of judiciously selected simplified analogues, that indole C(2)–C(3) oxidative radical cation generation rather than tertiary amine radical cation formation is the key event that renders fragmentation/coupling possible. This review will attempt to assess the evidence for this novel and intriguing alternative mechanistic proposal and the practical implications of this FeCl₃/Fe₂ (oxalate)₃ combination. A concise history of the azabenzfulvene intermediate will first be presented by way of introduction.