Isocyanoacetates as Synthetic Platform Towards Natural Products and Biologically Relevant Scaffolds

My PhD work started with the development of a racemic access to trigonoliimine B, an hexacyclic alkaloid isolated in 2010. After having explored different strategies, we reported a 7-step synthesis of this natural product. This synthesis features a challenging and unprecedented Bischler-Napieralski reaction for the formation of a 7-membered ring with the concurrent creation of an exocyclic imine at the last step. The choice of sulfolane as solvent for this transformation was critical to the success. Aiming at upgrading our synthesis towards an enantioselective version, we developed an enantioselective synthesis of α-quaternary α-amino acids. The Michael addition between α-aryl isocyanoacetates and phenyl vinyl selenone catalyzed by a quinine derivative affords enantioenriched Michael adducts. Due to the nature of the functional groups, these adducts are easily transformed to useful scaffolds such as pyrrolidinones and oxindoles. We also demonstrated the synthetic utility of this transformation by using it for the enantioselective total synthesis of (+)- and (-)-trigonoliimine A. With the idea to further demonstrate the efficiency of this reaction for natural product synthesis, we are trying to develop the first total synthesis of (+)-hinckdentine A. Finally, during our investigations on the Michael adduct, we observed the formation of 1,3-oxazinan-2-one. We implemented an integrated one-pot process to access biologically relevant 1,3-oxazinan-2-one. We also studied the reaction mechanism demonstrating an unprecedented triple role of phenyl selenonyl group as an electron withdrawing group, a leaving group and a latent oxidant.

Total Synthesis of Alstilobanine C, Undulifoline and Alstilobanine B

Nicolas David Gaeng

The total synthesis of pentacyclic monoterpene indole alkaloids is the focus of this thesis. Total syntheses of (±)-alstilobanine C, (±)-undulifoline and (±)-alstilobanine B, three natural products from the Ulean family of alkaloids, were accomplished. The characteristic features of our synthesis included: a) a domino sequence involving a highly diastereoselective Michael addition followed by chemoselective C-acylation of the resulting enolate by Mander¿s ester; b) an unprecedented Lewis acid mediated intramolecular addition of enolate to oxonium, generated in situ from MOM protective group; c) a sequence of chemoselective reduction/indolization/intramolecular aza-Michael addition. This domino process afforded directly the (±)-alstilobanine C, a pentacyclic monoterpene indole alkaloid in 87% yield. Reductive N-methylation of (±)-alstilobanine C provided (±)-undulifoline which, upon N-oxidation, was further converted to (±)-alstilobanine B. Enantioselective total synthesis of the same natural products through a different synthetic route is presented. After exploring different unsuccessful strategies, an enzymatic desymmetrization of a meso compound was adopted for the synthesis of enantioenriched cyclopentenone intermediate. Applying the two domino sequence developed previously, namely, Michael addition/C-acylation and oxepane formation, an efficient synthesis of the oxobicyclo[4.2.1]nonane was realized. A palladium-catalyzed decarboxylative cross-coupling, a methodology developed in our group, afforded an advanced bicyclic intermediate with all the carbon and functional groups needed to accomplish the total synthesis. However, conversion of the vinyl group to alkylazide or its synthetic equivalent proved to be difficult in spite of the efforts dedicated to this seemingly trivial transformation.

EPFL2018

Synthetic methodologies for C-C and C-N bond formation involving alkyl radicals

Guido Barzanò

C-C and C-N bonds are some of the most common structures in molecules ranging from drugs to catalysts and to food additives. Many coupling reactions were developed to form these types of bonds with excellent selectivity and good performance. Still, the synthesis of some of those species either depends on traditional methods or requires expensive and rare reagents and catalysts. The use of precious metals in chemistry, and particularly in the industry, can make molecular synthesis expensive and energy-intensive since the extraction of those materials is costly. Moreover, in homogeneous catalysis, the recovery of metal-based catalysts is almost impossible, making these processes unsustainable for the future. Thus, the discovery of chemical reactions that donât involve precious materials is indispensable. This thesis concentrates on the development of two chemical transformations, one performing an sp2-sp3 radical reductive coupling, one performing a photocatalyzed alkyl amination, involving inexpensive reagents and catalysts. The first chapter reviews the existing methodologies which use alkyl radicals to form carbon-carbon and carbon-nitrogen bonds. Alkyl radicals are formed from alkyl halides and pseudo-halides (Acids, esters, tosylates, etc.) via oxidation or reduction performed by metal or photoredox catalyst. The wide variety of available methodologies was illustrated, highlighting the advantages and weaknesses of each reaction. The second chapter of this dissertation is devoted to the development of a new iron-based catalytic method to form stereoselectively Z-alkene boron species from the corresponding boron-alkyne. This novel stereoselective method opens a new way to obtain these types of molecules with cheap reagents, in high yields, with excellent stereoselectivity (Z:E ratio >10:1), and with good tolerance of functional group. The reaction is radical based, avoiding the problem of beta-hydride elimination, which usually occurs in ionic reactions involving metal centers. In order to prove the versatility of this method, the vinyl boron compound formed from this reaction was used for further functionalizations. The formal total synthesis of a 5-HT2c receptor agonist was successfully performed, improving the overall yield of the process, and avoiding the use of expensive and polluting chemicals. The third chapter of this thesis is concentrated on the development of a tandem photoredox/metal base catalyzed functionalization of anilines and imines with alkyl carboxylic esters. In this reaction, no late transition metal is used, and the traditional metal-based photocatalyst is substituted with an inexpensive and more efficient organic dye. The alkylation of amines is a challenging topic in organic chemistry and classical nucleophilic substitution lacks selectivity and scope. Harvesting visible light with a photoredox catalyst opens the possibility to a radical pathway, making this coupling easy and with high tolerance for functional groups. In order to understand the catalytic cycle of the reaction, additional mechanistic studies were conducted, leading to some insight on how this reaction works.

EPFL2020

Access to long-chain polyketides by double-elongation reactions

Christopher Flowers

Due to the spongistatins' fascinating and complex molecular architectures, and their important biological activities, these marine macrolides have been the subject of intensive efforts directed towards their total synthesis. As an attractive alternative to isolation from marine microorganisms, which usually provides only minuscule quantities of this family of macrolides, total synthesis aims to deliver sizable amounts of the natural product, along with enabling access to novel structural analogues, for further biological evaluation. These factors, combined with the impressive molecular architectures themselves, present compelling and formidable challenges to contemporary organic synthesis with regard both to strategy and methodology for their total synthesis in the laboratory. To this end, efforts targeting such complex macrolides provide an arena in which the synthetic chemist can develop new and more efficient methodologies and display such advances to the ultimate task of complex target synthesis. Through this process, new levels of stereocontrol and novel strategies to streamline the entire synthetic route help evolve the field as a whole. The synthetic efforts directed at the AB and CD spiroacetals of the northern fragment are herein disclosed. In conjunction with the synthesis of the southern fragment within our group, this renders itself as an original and efficient formal total synthesis of spongistatin 1. The synthesis of these key fragments has been optimized to reduce protections, set up chirality in an efficient and absolute manner and avoid fluctuations in oxidation states. Achievements in these aspects, that are often used to define the art of modern day total synthesis, have resulted in a rapid synthesis of these key fragments. The synthesis of the AB and CD spiroacetals was completed in 7 and 11 steps, respectively, rendering the process competitive with the most rapid previous synthesis to date. The sequences are based around the use of 1,3-bis(trimethylsilyl)-2-methylidenepropane in double elongation Sakurai reactions with both aldehydes and ketones to form advanced functionalized polyketides.