Cyclization and annulation reactions initiated by ring-opening of small rings, especially cyclopropanes and cyclobutanes are now well-established in synthetic chemistry. Nevertheless, the potential of aminocyclopropanes and cyclobutanes, an important subclass for the synthesis of nitrogen-rich building blocks, has remained unexploited for a long time, despite important pioneering results. In the last decade, the situation has changed dramatically and new catalytic methods have emerged both for cyclization and annulation reactions. The purpose of this feature article is to present recent progress in this area, including our own work using donoracceptor substituted cyclopropanes and cyclobutanes.

Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI). However, the accumulation and persistence of non-biodegradable micron-sized particles in liver and spleen precludes their clinical use and limits the translational potential of MPIO-based contrast agents. Here we show that ligand-targeted MPIO derived from multiple iron oxide nanoparticles may be coupled covalently through peptide linkers that are designed to be cleaved by intracellular macrophage proteases. The synthesized particles possess potential characteristics for targeted MRI contrast agents, including high relaxivity, unappreciable sedimentation, clearance from circulation and no overt toxicity. Importantly, we demonstrate that these particles are rapidly degraded both in vitro and in vivo, and that the targeted probes can be used for detection of inflammation in vivo using MRI. This approach provides a platform for molecular MRI contrast agents that is potentially more suitable for translation to humans.

The first catalytic method for the cyclization of vinyl-cyclopropyl ketones (formal homo-Nazarov reaction) is reported. Starting from activated cyclopropanes, heterocyclic and carbocyclic compounds were obtained under mild conditions using Brønsted acid catalysts. Preliminary investigation of the reaction mechanism indicated a stepwise process.Carbocyclic and heterocyclic scaffolds occupy a privileged position in both natural products and pharmaceuticals. 1 Consequently, the development of cyclization and cycloaddition reactions for the efficient formation of cyclic structures is a very important goal in organic chemistry. In this respect, the development of new, highly stereoselective catalytic methods is crucial to allow a more efficient and environmentally friendly access to polycyclic molecules. 2 One classical approach towards the construction of cyclopentenone rings is the Nazarov reaction, which is the electrocyclic ring closure of a pentadienyl cation, followed by proton transfer (A, Scheme 1). 3 The potential of the Nazarov cyclization was recognized at an early stage in organic synthesis. Solutions to control the termination of the reaction were devised several decades ago, 3b but the necessity of using a stoichiometric amount of strong Lewis or Brønsted acids has limited the use of this reaction. However, in the last five years the first examples of catalytic Nazarov reactions using milder Lewis 3c-3n or Brønsted 3o,3p acids were reported, together with the first examples of asymmetric induction. 3e,3k,3l,3n, 3o Eisenberg, R. J. Am. Chem. Soc. 2004, 126, 6864. (i) This document is the Accepted Manuscript version of a Published Work that appeared in final form in Organic Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/ol802970g. Scheme 1. Nazarov and Homo-Nazarov Cyclizations When considering these recent successes in the Nazarov reaction, we wondered if similar concepts could be successful in other cyclization reactions to access larger ring systems. A viable approach to access homologous rings via electrocyclic reactions is the substitution of a double bond by a cyclopropyl group, as exemplified by the divinylcyclopropyl rearrangement. 4 Intra-and intermolecular ring-opening of cyclopropyl ketones and diesters have been examined extensively. 5 The reaction of vinyl-cyclopropyl ketones has been less studied (B, Scheme 1). 6 Tsuge has reported the cyclization of vinyl-cyclopropyl ketones using an excess of polyphosphoric acid at 80°C, but this reaction was not general and several other products were obtained beside the desired cyclohexenones. 6a More work has been done on the related aryl-cyclopropyl ketones, first by Murphy for the synthesis of tetralones using an excess of SnCl4 as reagent. 6b-6d During completion of our work, Yadav also demonstrated that diverse polycyclic heterocycles could be accessed using 3 equivalents SnCl4 at 80°C,...

Abstract: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 threemembered ring of vinyl-cyclopropyl ketones in order to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group  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  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  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.