Formal Homo-Nazarov and Other Cyclization Reactions of Activated Cyclopropanes

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the β position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced β to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.

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 of Cyclopropyl Carbonyls and the Homo-Nazarov Reaction

Filippo De Simone, Jérôme Waser

Ring strain confers to the cyclopropane ring an exceptional reactivity. Nevertheless, activation of the cyclopropane ring is usually needed to allow ring-opening reactions under mild conditions. The introduction of one or several carbonyl functionalities on cyclopropanes is often used to enhance their electrophilic reactivity. When a donor group is also present at the vicinal position to the carbonyl, more reactive donor-acceptor systems are obtained, which are ideally suited for homo-conjugate addition or cycloaddition reactions. This short review focuses on the special case of intramolecular cyclization reactions. Particular emphasis is devoted to the cyclization of vinyl- and aryl- cyclopropyl ketones for the formation of 6 membered rings. This process corresponds to a formal homo-Nazarov cyclization and has been only used rarely in the past. Recently, the scope of the reaction was greatly expanded by the use of a silyl group as cation stabilizing group and by the first catalytic method for the synthesis of vinyl-cyclopropyl ketones. With these new developments, the bases are now set for the application of this special class of cationic cyclizations in the synthesis of more complex synthetic and natural products.

2009

Developing Reactions of Strained Rings

Daniele Perrotta

Carbo- and heterocyclic structures containing nitrogen-substituted stereocenters are recurrent structural motifs in natural and bioactive compounds, therefore constituting a privileged class of synthetic targets. In this regard, substituted three- and four-membered carbocycles are powerful building blocks. Activation by a catalyst allows for an efficient exploitation of their ring strain, enabling a large variety of transformations. In particular, activation via oxidative addition by transition metals has been widely applied in annulations of these rings. Another common mode of activation consists in the use of Lewis acids to promote heterolytic ring opening of electron-poor strained rings, among which donor-acceptor cyclopropanes and cyclobutanes stand out for their well-established and broad chemistry. In this thesis, intermolecular annulations of three-membered carbocycles via oxidative addition by transition metals were first investigated. We mainly focused on the use of aminocyclopropanes as well as more strained aminomethylidenecyclopropanes. Despite a broad screening of transition metal complexes and modifications of the cyclopropane structure, no desired product could be formed. The use of aminomethylidene cyclopropanes in Lewis acid catalyzed intermolecular annulations was also studied. Employing aldehydes as reaction partners delivered highly functionalized 2-aminotetrahydrofurans. Instead, the use of all-carbon dipolarophiles for the synthesis of carbocycles was not successful. Subsequently, we explored enantioselective transformations of donor-acceptor cyclopropanes. We first investigated a new Lewis acid catalyzed DYKAT of donor-acceptor aminocyclopropanes with 2-siloxyfurans as dipolarophiles. After a thorough optimization, the desired product could be obtained in high er. However, the yield was not satisfactory, and any attempt to improve it by modifying the structure of the aminocyclopropane or by screening additives and reaction conditions was unsuccessful. On the other hand, we succeeded in the development of the first Lewis Acid catalyzed enantioselective desymmetrization of donor-acceptor meso-diaminocyclopropanes. The methodology consists in a copper(II) catalyzed Friedel-Crafts alkylation of indoles and a pyrrole, and delivers enantioenriched urea derivatives, which are recurrent structures in natural and bioactive compounds. The reaction tolerates electronically and sterically diverse substituents on the benzene ring of the indole. The choice of appropriate protecting groups on the cyclopropane was required to guarantee its solubility and to maintain good levels of enantioselectivity. The modification of an underexplored subclass of bisoxazoline ligands, bearing bulky diarylmethanol groups in alpha to the nitrogen atoms, was essential for obtaining high enantiomeric ratios, and led to the synthesis of several novel ligands. Finally, we developed Lewis acid catalyzed [4+2] annulations of donor-acceptor aminocyclobutanes with aromatic aldehydes, which afforded useful 2-aminotetrahydropyrans. A scandium catalyst was employed for the annulation of unsubstituted aminocyclobutanes, which delivered products in yields up to 95% and diastereoselectivities up to 17:1. On the other hand, one equivalent of a cheap and non-toxic iron Lewis acid was required for substituted aminocyclobutanes, which afforded densely functionalized six-membered heterocycles bearing three stereocenters in diastereoselectivities up to 5:1.