1 Synthesis of Novel Chiral Spiroisoxazolidine--Lactams from 6- Alkylidenepenicillanates: A 1,3-Dipolar Cycloaddition Approach Américo J. S. Alves and Teresa M. V. D. Pinho e Melo * University of Coimbra, Coimbra Chemistry Centre and Department of Chemistry, 3004- 535 Coimbra, Portugal *tmelo@ci.uc.pt Abstract – The synthesis of a library of 6-alkylidene-β-lactams, derived from 6-aminopenicillanic acid is reported. The 1,3-dipolar cycloaddition of these 6-alkylidenepenicillanates with nitrones was explored as an approach to synthesize novel chiral spiroisoxazolidine-β-lactams. Quantum chemical calculations, at the DFT level of theory, were carried out to elucidate the 3D structure of the synthesized compounds. The reported methodology, which involves the generation of three new consecutive stereogenic centers, proved to be regio- and stereoselective, leading to novel chiral spiroisoxazolidine-penicillanates efficiently. Keywords: Spiro-β-lactams; Isoxazolidines; Penicillanates; Nitrones; 1,3-Dipolar Cycloaddition. Introduction The β-lactam ring is one of the most studied moieties from a synthetic and medicinal chemistry point of view. Since the discovery of penicillins that had a huge impact on medicine, many researchers were inspired and turned their mind to the study of β-lactams. [1] The use of spirocyclic frameworks is a broadly used strategy in drug design to rigidify a molecule by the fusion of two rings in one shared atom. The three-dimensional nature of spirocyclic compounds provides a good balance of conformational rigidity and flexibility for efficient interaction with a given molecular target. In fact, important interactions of a molecule with a three-dimensional binding site can be achieved more easily using a rigid core (e.g. spirocyclic) than a planar one (e.g. aromatic systems), making spiro containing compounds relevant in medicinal chemistry. [2] In the last few years, spiro-β-lactams have attracted the attention of organic chemists since they can be used as building blocks for the synthesis of amino acids, alkaloids and other relevant