Catharanthine oxidation in flavin mononucleotide-mediated catharanthine-vindoline coupling reaction for synthesis of dimeric indole alkaloids under near-ultraviolet light

Abstract

A reaction model for the flavin mononucleotide-mediated coupling of catharanthine ( C) and vindoline ( V) under near-ultraviolet light was established based on the results of experiments on the effects of various physical and chemical factors on the disappearance of C and V, and the synthesis of the product, a dihydropyridinium intermediate ( IM). The following events were deduced to occur. (i) C is oxidized in the presence of FMN and oxygen under near-ultraviolet light ( C OX1). (ii) C OX1 then couples with V to form IM. Degradation of C occurs simultaneously with its specific oxidation, as a result of which a part of the C is converted into the product ( C∗) which is incapable of coupling with V. When a reaction in which C OX1 is further oxidized to another form ( C OX2) is added and the counterpart for the coupling with V is changed to C OX2 from C OX1, the reaction model more appropriately describes the exponential increase in the product, IM, that occurs in the early stage of the coupling reaction. (iii) The degradation rate of IM is much greater after C has been consumed than before its disappearance. Using this reaction model, the coupling reactions under basal and optimized conditions were simulated and the results showed a good fit with the experimental values under both conditions. The kinetic study suggests that manganese ion (Mn 2+) stimulates the binding of C OX2 with V in addition to suppressing the degradation of C, resulting in an increased yield of IM. Mn 2+ thus appears to be an important factor in the coupling reaction, in which it plays two different roles.