Catalytic Formal Homo-Nazarov Cyclization

Abstract

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,...

Cyclization and annulation reactions of nitrogen-substituted cyclopropanes and cyclobutanes

“…Nevertheless, our preliminary investigations showed that the cyclization of vinyl cyclopropyl ketones was most probably a stepwise process via carbocationic intermediates, and therefore best described as a formal homo-Nazarov process. 17 For the reaction to proceed under mild conditions it was necessary to use a DA cyclopropane, whereas an electron-rich aryl substituent was especially successful (Scheme 9, B). At this point, we wondered if a DA aminocyclopropane could be used in the formal homo-Nazarov process.…”

Cyclopropanes and Hypervalent Iodine Reagents: High Energy Compounds for Applications in Synthesis and Catalysis

“…[14] We de veloped the first catalytic homoNazarov reaction of crosspolarized substrates bearing an electronrich aromatic ring on the cyclopropane and a heteroatom on the double bond (Scheme 6). [15] In view of applications in the synthesis of natural products, we wondered if a ni trogen heteroatom could also play the role of activating group on the cyclopropane. Such intermediates could in principle give a general entry to the aspidosperma class of natural products, such as aspidospermi dine (14) (Scheme 7).…”

Cyclization of Aminocyclopropanes in Indole Alkaloids Synthesis

“…Furthermore, the Cbz group is easily removed under mild conditions. To our delight, the cyclization worked well under our previously developed conditions (20 mol % toluenesulfonic acid in acetonitrile) 10 and 74% yield of cyclized product was obtained. Careful NMR analysis of the crude mixture revealed a 1.6:1 mixture of C3 (10) and N1 (11) cyclization products.…”