Indole Alkaloids Synthesis via a Selective Cyclization of Aminocyclopropanes

The continuous progress in medicinal chemistry requires more versatile synthetic strategies for the generation of large libraries of active compounds and their analogues. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. In 2008 we developed the first catalytic formal homo-Nazarov reaction starting from activated cyclopropanes. Herein we report the extension of the catalytic formal homo-Nazarov cyclization to aminocyclopropanes. Highly diastereoselective cyclizations were obtained via an acyliminium intermediate generated through opening of the cyclopropane. An excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners was achieved. The utility of the developed methodology was demonstrated by the generation of the polycyclic scaffolds of Aspidosperma and Gonioma natural products starting from a common intermediate. Based on this method, a formal total synthesis of the alkaloid aspidospermidine and the total synthesis of the alkaloid goniomitine are presented. Finally, the scope and limitations of our methodology are discussed on an extended range of vinyl-cyclopropyl ketones with cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane.

Catalytic Formal Homo-Nazarov Reaction and Other Cyclizations of Cyclopropanes

Filippo De Simone

The increasing progress in medicinal chemistry and chemical biology requires more versatile synthetic strategies for the generation of libraries of active compounds and theirs analogues. A wide range of biologically active natural and synthetic compounds contain a complex polycyclic heterocyclic scaffold as core structure. As a result, the research for new effective cyclization and cycloaddition reactions is an essential task in organic chemistry. The goal of my PhD thesis was the development of a new catalytic cyclization reaction – the formal homo-Nazarov reaction. Starting from cyclopropanes as the smallest carbocycles, we were able to build-up complex carbocyclic and heterocyclic molecules, including alkaloid natural products. This thesis is divided in three main chapters, introduction, formal homo-Nazarov reaction and cyclization reactions of aminocyclopropanes. In the introductory part, the electronic properties and synthetic approaches to generate cyclopropanes are first described. Next, important examples of annulation and cyclization reactions involving cyclopropanes are discussed, pointing out the importance of activating and/or polarizing substituents on the three member ring. The second chapter of this thesis is dedicated to the development of a new catalytic method for the cyclization of vinyl cyclopropyl ketones –the formal homo-Nazarov cyclization. Optimization of the catalytic conditions is described, as well as extension of the substrate scope to a wide range of heterocycles and carbocycles. The reaction mechanism is then investigated using kinetic, labeling and trapping experiments. The results of these investigations indicate a stepwise mechanism through carbocationic intermediates. Moreover, the influence of an additional polarizing ester substituent on the cyclopropane is discussed, as well as the resulting scope extension. Finally, a first example of asymmetric induction for the catalytic formal homo-Nazarov cyclization using chiral Lewis acid catalysts is presented. The third chapter reports the extension of the catalytic homo-Nazarov cyclization to aminocyclopropanes. The reaction occurs under mild conditions and highly diastereoselective cyclizations are obtained via an acyliminium intermediate generated through opening of the cyclopropane. The presented methodology allowed an excellent control over the regioselectivity of either the C-C or C-N cyclization in the case of free indoles as nucleophilic partners. The utility of the developed methodology is demonstrated by the generation of two different polycyclic scaffolds of natural products starting from a common intermediate. Based on this method, a formal total synthesis of the Aspidosperma alkaloid aspidospermidine is presented. The scope and limitations of our methodology are presented on an extended range of aryl- and vinyl- cyclopropyl ketones bearing indole, pyrrole, pyran, benzofuran or thiophene groups as electron-rich aryl or alkene substituents, and cyclic or acyclic carbamates, as well as ethers as donor groups on the cyclopropane. Finally, the versatility of our cyclization method is demonstrated by its successful application in the total synthesis of the natural alkaloid goniomitine, accomplished in 13 linear steps with an overall yield of 11%. The availability of goniomitine and several of its analogues in significant amount allowed the first studies of the bioactivity of this class of alkaloids, which displayed only low cytotoxicity (IC50: 15-123 µM).

EPFL2012

Cyclization and Cycloaddition Reactions of Cyclopropyl Carbonyls and Imines

Filippo De Simone, Jérôme Waser

Abstract: Activated cyclopropanes, such as vinyl and carbonyl cyclopropanes, are useful building blocks in organic chemistry due to their exceptional reactivity. This review focuses on the use of cyclopropyl carbonyls and imines in cyclization and cycloaddition reactions for the synthesis of cyclic compounds. Cycloisomerization and other cyclization reactions are treated first, followed by formal cycloaddition reactions and applications in total synthesis. For each class of reactions, key pioneering works are shortly presented and emphasis is then set on recent results. Indeed, the utility of activated cyclopropanes in organic synthesis have been significantly increased in the last years by combining modern catalytic methods with the well-established reactivity of these building blocks. Together with progress in the synthesis of the cyclopropanes, these new methods allowed a better control over the diastereoselectivity and enantioselectivity of the reactions as well as their use for the synthesis of complex natural products.

2009

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.