Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

The development of a titanium(III)-mediated cascade electrocyclisation/rearrangement for the enantioselective total synthesis of indole alkaloids (+)-condyfoline and (-)-tubifoline serve as the basis of the first chapter of this thesis. An introduction will focus on the use of domino sequences incorporating a 1,2-shift in the context of complex natural product synthesis. The design of such a domino process is then presented, along with preliminary results originating from our research group concerning the titanium(III)-mediated Cadogan cyclisation. This novel domino sequence enabled the first enantioselective total synthesis of (+)-condyfoline. These results provided insights into the mechanistic nature of the formal 1,2-shift, indicating that the formal 1,2-migration most likely proceeds via 1,5-sigmatropic rearrangement rather than retro-Mannich/Mannich sequence. The isolation of (+)-condyfoline enabled a re-investigation of its isomerisation process to Strychnos isomer (-)-tubifoline. The chapter concludes with synthetic studies towards (+)-tronoharine and (+)- tubotaiwine. The second chapter of this thesis deals with the development of an integrated Oxidation/Reduction/Cyclisation (iORC) sequence for the enantioselective total synthesis of the Uleine family of monoterpene indole alkaloids. A brief introduction will review our group's previous efforts to implement iORC sequences for the total synthesis of alkaloids. The step-by-step development of the iORC sequence is described, along with the endgame strategy for the synthesis of (+)- nordasycarpidone, (+)-dasycarpidone, (-)-dasycarpidol and (+)-uleine. The chapter ends with the attempted titanium(III)-mediated cyclisation/rearrangement sequence towards (+)-uleine, and attempted iORC sequence towards (+)-condyfoline. The third chapter of this thesis reports a novel synthesis of benzofuro[3,2-b]indolines from onitrostylbene precursors using a titanium(III)-mediated interrupted Cadogan reaction. A rapid investigation of the substrate scope is presented. The remaining of the chapter reports our efforts to apply this newly developed transformation for the total synthesis of bis-indole alkaloid phalarine. The last chapter is dedicated to our synthetic studies towards (+)-pestalustaine A, a recently isolated sesquiterpene possessing a unique 5/6/7-fused tricyclic system. A designed formal [3+2] reaction was envisioned to provide access to this novel sesquiterpene, but resulted in the isolation of a Wilson-Cloke rearrangement product.