Lewis acid Catalyzed Annulations of Donor-Acceptor Aminocyclopropanes and Aminocyclobutanes

Organic molecules are indispensable have greatly contributed to the confort of our modern life. Nevertheless, humanity is facing now new challenges such as environmental issues and emerging drug resistances. In order to solve these major concerns, chemists are aiming to develop environmental friendly synthetic methods leading more efficiently to complex molecules with new biological modes of action. Nitrogen substituted five and six membered rings are rigid ubiquitous molecules in nature. In particular, these motives are found in DNA, natural products, as well as top selling drugs. Amongst all, the sought after nucleoside analogs, sulfur substituted cyclopentylenamines and Aspidosperma alkaloids, are based on tetrahydrofuryl-, cyclopentyl- and cyclohexyl-amines. A new approach to the synthesis of nitrogen substituted five and six membered rings would be highly valued. Annulations and cycloadditions are convergent synthetic methods, which are providing complex cyclic molecules from simple starting materials. Particularly, strain rings such as DA-cyclopropanes have been reported as efficient dipoles in annulation, providing saturated five membered ring molecules. Analogously, the use of phthalimide donor-acceptor cyclopropanes in [3+2] annulation with various dipolarophile was studied in our group to afford cyclopentylamines and tetrahydrofurylamines. In this thesis, a new Lewis acid catalyzed formal [3+2] cycloaddition between nucleobase donor-acceptor cyclopropanes and dipolarophiles such as ketones, aldehydes and silyl enolethers is applied to the synthesis of potentially bioactive nucleoside and carbonucleoside analogs. Pyrimidines donor-acceptor cyclopropanes were suitable dipoles in the [3+2] annulation, while purines were inert. This methodology was further extended to the synthesis of six membered ring nucleoside derivatives via a formal [4+2] cycloaddition of nucleobase donor-acceptor cyclobutanes and aldehydes. The [3+2] annulation of donor-acceptor cyclopropanes was further investigated and optimized with thioalkynes as dipolarophiles, providing a useful tool for the synthesis of sulfur substituted cyclopentenylamines. Interestingly, during the studies of the [3+2] annulation an unprecedented reactivity of the phthalimide donor-acceptor cyclopropane, involving the carbonyl of the phthalimide and the formation of an oxonium intermediate, leading to complex polycyclic iso-oxindole was discovered. The transformation was further optimized and tolerated a large variety of functional groups. Studies towards the total synthesis of Aspidospermidine and by extension to Aspidosperma alkaloids were performed using a convergent [2+2+2] annulation cascade strategy or alternatively via consecutive [2+2] and [4+2] annulations. This thesis brings new insights on the reactivity of DA-aminocyclopropanes and DA-aminocyclobutanes in presence of Lewis acid catalysts. The development of novel formal cycloaddition of DA-aminocyclopropanes and DA-aminocyclobutanes were successfully achieved providing an efficient routes for the synthesis of valuable nitrogen substituted five or 6 membered rings such as (carbo)nucleoside analogs, sulfur cyclopentylenamines and polycyclic iso-oxindoles. In addition, preliminary results were obtained concerning the [2+2+2] cascade annulation strategy for the synthesis Aspidosperma alkaloids.

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

Nitrogen-containing compounds are an important class of molecules in medicinal chemistry, chemical biology, biochemistry, material sciences or environmental sciences. Organic nitrogen occurs in many forms, ranging from small building blocks such as urea, amino acids, nucleotides, to complex natural products, drug molecules, proteins, nucleic acids, among others. The transformation of easily-accessed nitrogen-containing building blocks into more complex nitrogen-containing structures is therefore important for the synthesis of bioactive compounds or functional materials. Interested in donor-acceptor aminocyclopropanes and aminocyclobutanes, we first developed a Lewis-acid catalyzed formal [4+1] cycloaddition of donor-acceptor aminocyclobutanes with isocyanides, which resulted in the formation of cyclopentene-1,2-diamines. We then attempted to develop a formal [3+2] cycloaddition of donor-acceptor aminocyclopropanes with electron-deficient alkenes, which was mechanistically inspired by the Morita-Baylis-Hillman reaction. Apart from the donor-acceptor system, we were also attracted by simple aminocyclopropanes without electron-withdrawing group at vicinal position. We anticipated that the incorporation of cyclopropylamine into carboxylic-containing compounds followed by ring opening functionalization reactions could be used for the synthesis of more complex products. Therefore, we first disclosed an oxidative ring-opening strategy to transform acyl, sulfonyl or carbamate protected aminocyclopropanes into 1,3-dielectrophilic carbon intermediates bearing a halide atom (Br, I) and a N,O-acetal. Replacing the alkoxy group of the N,O-acetal was achieved under acidic conditions via an elimination-addition pathway, while substitution of the halides by nucleophiles was done under basic conditions via a SN2 pathway, generating a wide range of 1,3-difunctionalized propylamines. Based on the transformation described above, we further discovered an efficient synthesis of 4-amino thiochromans starting from simple aminocyclopropanes and thiophenols through a formal [3+3] annulation reaction. Next, we developed an oxidative ring-opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the terminal position. Both cheap benzophenone with UV A light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry. Finally, we turned our attention to the synthesis of diamines, which are essential building blocks for the synthesis of agrochemicals, drugs and organic materials, yet their synthesis remains challenging, as both nitrogen moieties need to be differentiated and diverse substitution patterns (1,2-, 1,3 or 1,4) are required. We described a new strategy giving access to 1,2-, 1,3- and 1,4- amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes and cyclobutanes.Other unsuccessful efforts over the last four years have also been described, together with some preliminary results of ring-opening cyanation and arylation reactions.

EPFL2022

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

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

EPFL2022