Synthetic Methods DOI: 10.1002/anie.200501548 Straightforward Access to a Structurally Diverse Set of Oxacyclic Scaffolds through a Four- Component Reaction** Oscar JimØnez, Guillermo de la Rosa, and Rodolfo Lavilla* Multicomponent reactions (MCRs) constitute an important group of transformations that combine many elements of an ideal synthesis, such as operational simplicity, atom economy, bond-forming efficiency, the access to molecular complexity from simple starting materials, and so on. The modular character of this approach is extremely suitable for drug discovery, and therefore it is widely used for the fast generation of bioactive compounds. [1] Recently, the concept of chemical genomics has sparked the development of diversity-oriented synthesis (DOS) [2] to reach the structural flexibility needed in the small-molecule range, thus demand- ing new and versatile synthetic methodology. We report herein new processes leading to diversely functionalized oxacycles (privileged structures including carbohydrate- related compounds) [3] based on an MCR that allows access to a variety of scaffolds using commercially available reagents. The Povarov reaction (the condensation of an aniline, an aldehyde, and an activated olefin), has been useful in the formation of tetrahydroquinoline adducts, including aza- and oxacyclic fused derivatives. [4] Previous reports [5] suggested that the formal [4+2] cycloaddition was nonconcerted and, consequently, opened the possibility to trap the final oxocar- bonium intermediate with an external nucleophile (termina- tor), thus leading to a four-component reaction. [6] Herein, we describe a Lewis acid catalyzed four-component reaction of an amine, an aldehyde, a cyclic enol ether, and an alcohol, which acts as the terminator of the process [7] (Scheme 1). The first experiment was carried out using equimolar amounts of 3,4-dihydro-2H-pyran (1a), 3-nitroaniline (2a), [*] Dr. R. Lavilla Laboratory of Organic Chemistry Faculty of Pharmacy University of Barcelona Avda Joan XXIII sn, 08028 Barcelona (Spain) Fax:(+ 34)93-403-7114 E-mail: rlavilla@pcb.ub.es Dr. O. JimØnez, G. de la Rosa, Dr. R. Lavilla Barcelona Science Park University of Barcelona Josep Samitier 1–5, 08028 Barcelona (Spain) [**] This work was supported by DGICYT (Spain, project BQU 2003- 00089) and Almirall-Prodesfarma (Barcelona). We also thank InØs Carranco, Prof. F. Albericio, Dr. Miriam Royo, and Marc Vendrell for their assistance with syntheses and analyses. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 6521 Angew. Chem. Int. Ed. 2005, 44, 6521 –6525 # 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim