Total Synthesis of Alstolactine A & Synthetic Studies Towards Members of Akuammiline Alkaloids

The work presented in this thesis focuses on the synthesis of monoterpene indole alkaloids. The first part describes the development of a general methodology to provide an enantioenriched platform, useful for the convergent synthesis of Akuammiline alkaloids. Despite a series of attempts using chiral phosphoric acids, the enantioselective desymmetrization of meso-1,3-diones turned out to be complex and was unfortunately unsuccessful. The second part details our first approach toward the total synthesis of (±)-alstolactine A, (±)-alstolactine B and (±)-alstolactine C. A robust eighteen-step sequence was developed, however, the numerous issues we encountered while attempting to complete the synthesis led us to re-evaluate our strategy. The third part of this thesis details the 22 steps synthesis of (±)-alstolactine A from commercially available starting materials. Our approach involves: a) creation of a quaternary stereocenter C7 at an early stage; b) rapid build-up of the first lactone; c) diastereoselective azidolactonization; d) [Ni(cod)2]-mediated intramolecular cyclization to construct the azabicyclo[3.3.1]nonane bridged system and e) formation of the last lactone via epoxide opening. Finally, the fourth and fifth parts describe the synthetic studies toward various members of the Akuammiline family: (±)-alstolactine B and (±)-alstolactine C and the possibilities to reach (±)-scholarisine K, (±)-scholarisine L and (±)-scholarisine M starting from an advanced intermediate from our strategy.

Zhu, Jieping
Lausanne, EPFL

 Record created 2019-11-04, last modified 2019-11-05

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