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.

Waser, Jérôme
Lausanne, EPFL
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis7199-1

Note: The status of this file is: EPFL only

 Record created 2016-10-11, last modified 2018-03-17

Download fulltext

Rate this document:

Rate this document:
(Not yet reviewed)