Synthesis of Cyclopenta[b]piperazinones via an Azaoxyallyl Cation Boubacar Balde ́ , § Guillaume Force, § Lucile Marin, § Re ́ gis Guillot, § Emmanuelle Schulz, § Vincent Gandon,* ,§,† and David Lebœuf* ,§ § Institut de Chimie Molé culaire et des Maté riaux d’Orsay (ICMMO), CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay, Bâ timent 420, 91405 Orsay cedex, France † Laboratoire de Chimie Molé culaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Université Paris-Saclay, route de Saclay, 91128 Palaiseau cedex, France * S Supporting Information ABSTRACT: A new and efficient reaction sequence between 2-furylcarbinols, anilines, and α-haloamides has been developed to afford highly functionalized cyclopenta[b]piperazinones. This transformation was accomplished through an aza-Piancatelli cyclization/azaoxyallyl cation trapping with a complete control of the diastereoselectivity. P iperazinones represent an important class of nitrogen heterocycles, whose scaffold can be encountered in a large variety of natural products and bioactive molecules (Figure 1). 1 As a result, developing original synthetic methods to access these synthons has been a steady endeavor for organic chemists in the past decades, especially since they can also be used as direct precursors to piperazines, which are key players in drug discovery. 2 However, among piperazinone derivatives, the synthesis of cyclopenta[b]piperazinones remains clearly underdeveloped, even if this scaffold is featured in agelastatin A, which possesses a broad range of potent biological properties, notably antitumor activities, and, thus, has prompted widespread efforts toward its total synthesis. 3,4 Moreover, this motif can be found in compound 1, which is a precursor for antidepressants. 5 Surprisingly, to the best of our knowledge, no general method for the synthesis of such skeletons has been reported to date. In this context, our aim was to play our part in addressing this anomaly and open up a new route for the straightforward construction of cyclopenta- [b]piperazinone derivatives. In recent years, our group has been engaged in the development of the aza-Piancatelli cyclization and its utilization to provide a large array of nitrogen-containing molecules, such as 4-aminocyclopentenones, cyclopenta[b]- pyrroles and related compounds. 6,7 From there, we envisioned that combining this reaction with the use of azaoxyallyl cations, 8 which are putative 1,3-dipoles, would allow us to rapidly forge cyclopenta[b]piperazinones in a one-pot fashion (Scheme 1). Combining the aza-Piancatelli reaction with another transformation to access complex molecules is not unprecedented; however, in our case, it would be the first time Received: September 28, 2018 Figure 1. Piperazinones and related compounds occurring in bioactive molecules. Scheme 1. Our Strategic Approach towards Cyclopenta[b]piperazinones Letter pubs.acs.org/OrgLett Cite This: Org. Lett. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.orglett.8b03103 Org. Lett. XXXX, XXX, XXX-XXX Downloaded via KAOHSIUNG MEDICAL UNIV on November 27, 2018 at 19:42:22 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.