One-pot three-component highly diastereoselective synthesis of isoindolin-1-one-3-phosphonates under solvent and catalyst free-conditions José Luis Viveros-Ceballos a , Carlos Cativiela b , Mario Ordóñez a,⇑ a Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico b Departamento de Química Orgánica, ISQCH, Universidad de Zaragoza–CSIC, 50009 Zaragoza, Spain article info Article history: Received 21 July 2011 Accepted 5 August 2011 Available online 7 September 2011 abstract The one-pot three-component reaction of 2-formylbenzoic acid with (S)- and (R)-methylbenzylamine and dimethyl phosphite (Kabachnik–Fields reaction) proceeded in short reaction times under solvent and cat- alyst free-conditions to afford the corresponding (3R,1 0 S)- and (3S,1 0 R)-isoindolin-1-one-3-phosphonates 3, respectively, in good yield and with high diastereoselectivity (95:5 dr). The use of a solvent decreases the diastereoselectivity and slows the reaction rate. The reaction rate was also influenced by CO 2 H func- tionality through protonation of the imine intermediate. The absolute configuration at the new stereo- genic center was determined by X-ray crystal analysis, and a mechanism was proposed to explain the high diastereoselectivity. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction a-Aminophosphonic acids are analogs of a-amino acids in which the planar carboxylic acid (CO 2 H) has been replaced by a sterically more demanding tetrahedral phosphonic acid group [P(O)(OH) 2 ]. This replacement results in not only significant differences in molecular shape and size, but also in acidity and other properties. a-Aminophosphonic acids are currently attracting a great deal of interest in medicinal chemistry and agrochemistry, due to their excellent biological and pharmaco- logical properties. Thus, some of these compounds and their derivatives, including the short peptides that incorporate them, have found application as antibacterial, antiviral and antifungal agents, as well as insecticides and herbicides. Additionally, other aminophosphonic acids have shown potential anticancer activity or have been demonstrated to be effective in the treatment of osteoporosis. 1,2 The relevant properties exhibited by a-aminophosphonic acids and their derivatives have stimulated the development of several synthetic methods for these compounds. 1,2a,3 Over the last few decades, much effort has been dedicated to the preparation of the phosphonic analogs of the 20 proteinogenic a-amino acids and, as a result, procedures for the synthesis of most of them are currently available. 4 Once this goal has been achieved, the remaining challenge is to search for new structures, other than those analogous to the encoded a-amino acids. In this context, a wide variety of non-coded a-amino acids have been synthesized in recent years by the introduction of different types of modifica- tions on proteinogenic residues and have provided an invaluable source of inspiration. In particular, those non-proteinogenic a- amino acids that have already shown exceptional properties are ideal candidates to serve as models for the construction of new a-aminophosphonic acids. On the other hand, the isoindolinone core is a key structural fea- ture of a great number of natural compounds with important bio- logical activities. 5,6 In particular, the ethyl isoindolin-1-one-3- carboxylate 1 bearing the (S)-a-methylbenzylamine fragment, a benzannulated analog of pyroglutamate, is a valuable synthetic intermediate in the synthesis of chiral spirobutyrolactone deriva- tives 2. 7 Additionally, isoindolin-1-one-3-carboxylates have been used for the synthesis of other complex compounds. 8 Despite the diverse biological activities displayed by the a-aminophosphonic acids, the stereoselective synthesis of isoindolin-1-one-3-phospho- nates 3 has not yet been reported. 9 In connection with our current research interest in the develop- ment of new synthetic methodologies 10 and the preparation of novel a-aminophoshonic acids, 11 we herein report the one-pot three-component highly diastereoselective synthesis of dimethyl (3R,1 0 S)- and (3S,1 0 R)-isoindolin-1-one-3-phosphonate 3 under sol- vent and catalyst free-conditions. 0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2011.08.003 ⇑ Corresponding author. Tel./fax: +52 777 329 79 97. E-mail address: palacios@ciq.uaem.mx (M. Ordóñez). Tetrahedron: Asymmetry 22 (2011) 1479–1484 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy