DOI: 10.1021/jo1019927 Published on Web 01/11/2011 J. Org. Chem. 2011, 76, 833–839 833 r 2011 American Chemical Society pubs.acs.org/joc Phe-Ala-Based Diazaspirocyclic Lactam as Nucleator of Type II 0 β-Turn Alessandro Sacchetti,* ,† Alessandra Silvani,* ,‡ Giordano Lesma, ‡ and Tullio Pilati § † Politecnico di Milano, Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘Giulio Natta’, via Mancinelli 7, 20131 Milano, Italy, ‡ Dipartimento di Chimica Organica e Industriale, Universit  a degli Studi di Milano, via G. Venezian 21, 20133 Milano, Italy, and § Istituto di Scienze e Tecnologie Molecolari - CNR, Via Golgi 19, 20133 Milano, Italy alessandro.sacchetti@polimi.it Received October 13, 2010 The synthesis of a novel Phe-Ala dipeptide mimic, built up on a diazaspirocyclic lactam core, is presented. This new scaffold was evaluated for conformational mimicry of reverse turn by combining molecular modeling, IR, NMR, and X-ray diffraction experiments. All these tools agree on the presence of a strong intramolecular hydrogen bond, thus demonstrating the ability of this spiro compound to act as a type II 0 β-turn inducer. Introduction The importance of reverse turn for the biological proper- ties of peptides has in recent years spurred the search for new scaffolds able to influence the secondary structure when placed into a peptide chain. 1 One of the most studied reverse motifs is the β-turn, a four amino acid fragment capable of inverting the chain direction, which is often stabilized by an intramolecular hydrogen bond between the carbonyl oxygen of the first residue (i) and the amide proton of the fourth one (i þ 3). 2 Among the many proposed β-turn mimics, 3 spirocyclic scaffolds 4 have attracted attention as privileged structures, able to provide, upon the attachment of appro- priate functional groups, useful high-affinity ligands, rele- vant to the field of drug discovery. 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