Cyclopropanation | EPFL Graph Search

In organic chemistry, cyclopropanation refers to any chemical process which generates cyclopropane () rings. It is an important process in modern chemistry as many useful compounds bear this motif; for example pyrethroid insecticides and a number of quinolone antibiotics (ciprofloxacin, sparfloxacin, etc.). However, the high ring strain present in cyclopropanes makes them challenging to produce and generally requires the use of highly reactive species, such as carbenes, ylids and carbanions. Many of the reactions proceed in a cheletropic manner. Approaches From alkenes using carbenoid reagents Several methods exist for converting alkenes to cyclopropane rings using carbene type reagents. As carbenes themselves are highly reactive it is common for them to be used in a stabilised form, referred to as a carbenoid. Simmons–Smith reaction In the Simmons–Smith reaction the reactive carbenoid is iodomethylzinc iodide, which is typically formed by a reaction be

Synthetic studies towards Lundurines A-C

Michele Boghi

Recent advances in transition metal catalyzed C-H activation are revolutionizing synthetic organic chemistry, and application of this powerful synthetic tool in the context of total synthesis of complex natural products is beginning to blossom. This thesis describes synthetic studies towards the total synthesis of lundurines A-C involving Pd(0)-catalyzed C(sp3)-H functionalization methodologies. From a synthetic point of view, the intriguing cyclopropane-fused indoline caged system at the core of lundurines A-C would naturally invoke a C(sp3)-H functionalization of the central cyclopropane moiety. Although methodologies involving cyclopropane activation have been recently reported in literature, their potential in the case of complex substrates is yet to be explored. This approach would allow rapid access to the lundurine scaffold, circumventing an otherwise complicated and tedious preparation of a highly substituted cyclopropane. A C(sp3)-H functionalization closure of the indoline ring in the lundurine scaffold I from precursor II was considered one of the viable options (Scheme I). However, the cyclization precursor II proved to be a difficult synthetic target on its own merit. Various investigated synthetic approaches towards II via intramolecular cyclopropanation reactions were fruitless. Due to the difficulties associated with preparation of II the aforementioned disconnection has not been tested in the variant presented in the Scheme I. Another disconnection, employing this time a more challenging C(sp3)-C(sp3) bond formation on the cyclopropane and closing the 7-membered ring of the lundurine scaffold III, has been also evaluated (Scheme II). The requisite cyclization precursor IV was successfully prepared from the intermediate V utilizing the previously introduced C(sp3)-H functionalization creating the indoline ring. However, the envisioned late-stage cyclization appeared to be incompatible with the conformational rigidity of IV. Although presented studies conducted on the cyclopropane C(sp3)-H functionalization did not deliver the target lundurine alkaloids, the obtained results led to discovery and development of novel C-H activation methodologies.

EPFL2015

Asymmetric Cyclopropanation and Epoxidation via a Catalytically Formed Chiral Auxiliary

Mikus Purins, Jérôme Waser

For the enantioselective diversification of a single starting material, a different chiral catalyst is usually required for each transformation. Herein, we extend the concept of catalytically formed chiral auxiliary from hydrogenation to the asymmetric cyclopropanation and epoxidation of tetra-substituted olefins, alleviating the need for different chiral catalysts in the alkene functionalization step. The chiral auxiliary is catalytically constructed from propargylic amines in a Pd-catalyzed enantioselective carboetherification step using a commercially available trifluoroacetaldehyde hemiacetal tether. The installed auxiliary is then controlling the stereochemistry of the cyclopropanation and the epoxidation using standard highly reactive reagents to give enantioenriched spirocyclic aminomethylcyclopropanols and alpha-amino-alpha-hydroxy ketones.

WILEY-V C H VERLAG GMBH2022

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.