Total Synthesis of the Terpenoid Alkaloid Scholarisine A

The presented proposal comprises the total synthesis of scholarisine A, a monoterpenoid indole alkaloid, isolated from Alstonia Scholaris. Extracts of this tree are widely used in Traditional Chinese Medicine and show remarkable therapeutic effects, but only for a few years, efforts were undertaken to analyze the specific mode of action of their active molecules. As it will be outlined in the following proposal, two different routes towards the target molecule are presented. One, using a methodology developed in the research group of Mark Lautens, and the other, inspired by the proposed biosynthesis presented by Cai et al. Scholarisine A exhibits a novel, hexacyclic structure, bearing an indole core, a highly substituted cyclo hexane ring, a bridging lactone moiety, and an imine moiety. So far no total synthesis or any "towards-publications" are published. These features and possible medicinal applications make scholarisine A an interesting target for an organic chemist. In 2011, Lautens and Newman reported a racemic palladium mediated synthesis of 3,3-di substituted indolinones. This reaction usually proceeds via a beta-hydride elimination step, but interestingly, the authors managed to establish the installation of an alkyl iodide via reductive elimination pathway. Therefore, a very bulky mono dentate phosphine ligand (Q- PHOS) was used. Within this proposal, this reaction should be used to build up the quaternary stereo center on the indole ring. Performing an extensive ligand screening should enable access to a stereoselective formation of the indolinone core. The second fragment of the convergent synthesis should be prepared by a decarboxylative allylation. Subsequent oxidation and glycol cleavage provides two equivalents of the desired building block. After fragment combination and stepwise functionalization, an intramolecular pinacol coupling and subsequent imine formation should provide scholarisine A in a 19-steps longest linear sequence. In the isolation publication of scholarisine A, the authors propose a possible biosynthesis starting from picrinine. Besides the presented synthesis based on Lautens` cyclization, this proposal comprises a biomimetic approach towards scholarisine A. In the first step, picrinine should be synthesized in a 11-steps longest linear sequence, including an oxidative enolate coupling and an oxidative decarboxylation. Furthermore, picrinine should be converted to scholarisine A in one biomimetic step. This step includes several transformations in one pot: starting with a Lewis acid mediated opening of the oxo- bridge, subsequent formation of an aldehyde, double bond migration, an aldol reaction and formation of the bridged lactone ring. This approach should provide scholarisine A in a longest linear sequence of 12 steps.