Total Synthesis of (+)‐ and (−)‐Decursivine and (±)‐Serotobenine through a Cascade Witkop Photocyclization/Elimination/Addition Sequence: Scope and Mechanistic Insights

Abstract

In this article, the total syntheses of antimalarial compound decursivine and its biologically inactive sibling serotobenine are presented. The biomimetic synthesis of (±)-serotobenine was investigated first, but failed. During the subsequent investigation of other synthetic routes, we discovered a new cascade Witkop photocyclization/elimination/addition sequence, which enabled the expedient synthesis of not only racemic decursivine and serotobenine, but also enantiopure (+)- and (-)-decursivine and a variety of their analogues. The present syntheses represent the shortest pathway for the total synthesis of decursivine and serotobenine to date. Moreover, the newly developed cascade sequence for the total synthesis of decursivine does not need any protecting steps. The scope and the reaction mechanism of the cascade sequence were also studied. A rational mechanism for the cascade sequence is proposed, which is consistent with the previous studies and our current experimental results.

Biomimetic Synthesis of Moschamine-Related Indole Alkaloids via Iron-Catalyzed Selectively Oxidative Radical Coupling

“…In 2007, Kerr reported the first total synthesis of (±)-decursivine ( 2 ) starting from a quinone monoamine in 18 linear steps and 3% overall yield . Mascal and Jia independently introduced the expedient synthesis of (±)-decursivine ( 2 ) via a Witkop photocyclization cascade sequence . Jia also reported the total synthesis of (±)-serotobenine ( 1 ) and (±)-decursivine ( 2 ) by using a Pd­(OAc) 2 -mediated cascade sequence .…”

Bioactive Constituents of Safflower plant as potential inhibitors of mutant Leucine-rich repeat kinase 2 (LRRK2): Docking, Pharmacokinetics properties and Molecular Dynamics studies

“…Also, by construction of an optically active dihydrobenzofuran through rhodium mediated intramolecular C-H insertion, (-) -serotobenine has been synthetically generated (Koizumi et al 2008). Other methods have been employed in an attempt to carry out a total synthesis of serotobenine (Hu et al 2013). Though no signi cant activity has been recorded for this compound, it's derivatives alongside Decursivine which is structurally related to it have been shown to have anti-plasmodial activity (Qin et al 2011).…”

Total synthesis of (±)-decursivine via BINOL-phosphoric acid catalyzed tandem oxidative cyclization

“…In 2011, Jia 5 and Mascal 6 independently and simultaneously developed a 4-step total synthesis of (±)-decursivine through a cascade photocyclization/elimination/ O -Michael addition protocol with overall yields of 47.6% and 53.3%, respectively. In 2013, Jia’s group 7 extended this cascade via a Witkop photocyclization approach wherein (+)- and (−)-decursivine were obtained with overall yields of 9.5% and 1.6% in 9 and 8 steps, respectively. The first asymmetric total synthesis of (+)-decursivine was developed in 2011 by Li and co-workers 8 that involves an intramolecular [3 + 2] cycloaddition as the main step with an overall yield of 16.7% over 11 steps.…”