Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed Annulations with Donor-Acceptor Cyclopropanes

Efficient methods for the convergent synthesis of (poly) cyclic scaffolds are urgently needed in synthetic and medicinal chemistry. Herein, we describe new annulation reactions of thioalkynes with phthalimide-substituted donor-acceptor cyclopropanes, which gave access to highly substituted cyclopentenes and polycyclic ring systems. With silyl-thioalkynes, the Lewis acid catalyzed[3+2] annulation reaction with donor-acceptor cyclopropanes took place to afford 1-thio-cyclopenten-3-amines. On the other hand, an unprecedented polycyclic compound was formed with alkyl-thioalkynes through a reaction pathway directly involving the phthalimide group. The two transformations proceeded in good yields and tolerated a large variety of functional groups.

Lewis acid Catalyzed Annulations of Donor-Acceptor Aminocyclopropanes and Aminocyclobutanes

Sophie Lucie Racine

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.

EPFL2016

Investigations of the Chemistry of 1-Alkynyltriazenes

Florian Gérald Perrin

The chemistry of aromatic triazenes is well known, and has been explored for more than a century. These compounds have emerged as very useful intermediates, because of their unique reactivity. This functionality can notably be used to access many other functional groups, and it is present in certain bioactive compounds. Recently, our laboratory has reported a novel synthesis of triazenes using nitrous oxide, which allows the synthesis of 1-alkynyltriazenes. These compounds are poorly known, as their synthesis is not trivial by other routes. This thesis aims to explore the reactivity of these compounds. We have shown that the chemical reactivity of 1-alkynyltriazenes parallels what has been observed for ynamides. The similarity in reactivity of these two classes of compounds is demonstrated by addition reactions with acids and by cycloaddition reactions with ketenes and tetracyanoethene. The presence of the reactive triazene groups in the products allowed for subsequent transformations. We also studied the reactivity of these substrates in Ru-catalyzed [2+2] cycloadditions. The triazenes serve as unique vinyl cation surrogates. Under acidic conditions, the triazene functionality can be replaced by a variety of groups including halides, alkoxides, sulfoxides, amides, arenes and heteroarenes, providing efficient access to a pool of chiral and achiral polycyclic compounds The formation of very reactive cations using cyclic alkenenyl triazenes is described in a short study. It seems that the strained vinyl cation can be formed, but that its high reactivity prevents it to react selectively with weak nucelophiles. In the final part of this work, first results of a rhodium-catalyzed reaction with bifunctional boronic acids are presented. We show that 1-alkynyltriazenes react in the presence of rhodium to form indene derivatives. The unique reactivity of the triazenes lead to the formation of unexpected compounds. Overall, our results suggest that 1-alkynyltriazenes will become valuable reagents in synthetic organic chemistry.

EPFL2018

Synthesis of bicyclo[3.1.0]hexanes by (3+2) annulation of cyclopropenes with aminocyclopropanes

Alec Gagnebin, Bastian Antoine Rodolphe Claude Muriel, Jérôme Waser

We report the convergent synthesis of bicyclo[3.1.0]hexanes possessing an all-carbon quaternary center via a (3 + 2) annulation of cyclopropenes with cyclopropylanilines. Using an organic or an iridium photoredox catalyst and blue LED irradiation, good yields were obtained for a broad range of cyclopropene and cyclopropylaniline derivatives. The reaction was highly diastereoselective when using difluorocyclopropenes together with a removable substituent on the cyclopropylaniline, giving access to important building blocks for medicinal chemistry. With efficient methods existing for the synthesis of both reaction partners, our method grants a fast access to highly valuable bicyclic scaffolds with three contiguous stereocenters.