Rémi Julien Sylvain Andres
This thesis consists in an extensive study about the enantioselective Pictet-Spengler reaction (EPSR) and its application to the total synthesis of monoterpene indole alkaloids (MIAs). The general introduction presents the literature background about this powerful yet still unsolved synthetic transformation. The use of ketone derivatives up to date is mainly underlined.The first chapter describes the enantioselective total synthesis of arborisidine for which an unprecedented EPSR with an α-diketone was developed. An oxidative cyclization allowed to build a strained bridged system which was rearranged following a one-pot aza-Cope/Mannich â oxidation â epimerization sequence to reach the natural product. We discovered an interesting epimerization phenomenon between arborisidine and its epimer which, after being conscienciously studied, raised the question of which isomer is the natural product.The development of a new class of single H-bond donor organocatalysts identified in the previous structure-enantioselectivity relationship process is then detailed. These prolinamides present the advantages to be cheap, easier to prepare and to purify than other known catalysts, and provide a new molecular scaffold for enantioselective H-bonding catalysis. They allow a general access to quaternary-center containing tetrahydro-β-carbolines derived from α-diketones, bulky α-ketoesters and α-ketoamides, the latter being extensively explored. They also compete with known methods with aldehydes as substrates. The products can all be obtained in good yields and enantioselectivities. The scope is large and shows excellent functional group tolerance to the exception of acidic protons close to the ketone center and sterically hindered ketone derivatives. In line with Jacobsenâs recent discovery, rearomatization is the rate- and enantioselectivity-determining step. The transformation of α-diketones is investigated by Vincent, Morgane and Julia, and that of α-ketoesters by Fenggang. Of interest, Fenggang showed that the use of two H-bond donor squaramide-organocatalysts was mandatory in order to make the reaction general with α-ketoesters.The power of this method was then further demonstrated. The stereocontrolled divergent total synthesis of voacafricines A and B thanks to an asymmetric PSR is the object of the third chapter. Its application allowed to install all the carbons contained in the natural products in a controlled manner, and a complexity-generating oxidative cleavage â cascade cyclization â selective reduction allowed to reach a key hemiacetal intermediate. On one hand this moiety was activated to generate the desired ammonium which provided voacafricine A after in situ hydrolysis. It could on the other hand be used to functionalize the adjacent carbon atom and the same synthetic sequence was applied to get voacafricine B.The enantioselective total synthesis of alstratine A is finally reported. Believing that the aminal could be made at the last step of the synthesis, we identified a precursor whose structure analysis suggested a possible application of an intramolecular inverse electron demand Diels-Alder reaction. The synthesis began with an EPSR of an α-ketoester. Funtional group manipulations followed by IMDA successfully built most of the contiguous stereocenters in a controlled fashion. The acid-mediated cyclization then took place without any issues. Alstratine A specific rotation reported in the isolation paper is corrected herein.
EPFL2022
