A convenient synthesis of functionalized isoxazolines and related 5-hydroxyisoxazolidine-4-carboxylates Fides Benfatti a , Giuliana Cardillo a, * , Simone Contaldi a , Luca Gentilucci a , Elisa Mosconi a , Alessandra Tolomelli a, * , Eusebio Juaristi b , Gloria Reyes-Rangel b a Dipartimento di Chimica ‘G. Ciamician’, Universita ` di Bologna, Via Selmi 2, 40126 Bologna, Italy b Departamento de Quı ´mica, Centro de Investigacio ´n y de Estudios Avanzados del Instituto Polite ´cnico Nacional, Apartado Postal 14-740, 07000 Me´xico, Mexico article info Article history: Received 31 October 2008 Received in revised form 23 December 2008 Accepted 15 January 2009 Available online 21 January 2009 abstract The effectiveness of Sc(OTf) 3 as a Lewis acid catalyst for the 1,4-addition reaction of carbamates to ap- propriate 2-acetyl-2-pentenoic esters is herein reported. In particular, N-benzyl-(tert-butyldimethyl- silyloxy)carbamate added efficiently to the title substrates to afford a new class of polyfunctionalized isoxazolidines and isoxazolines. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction In the field of organic and medicinal chemistry, the preparation of small heterocyclic rings by means of simple and efficient routes is receiving ever-increasing attention. In this context, substituted isoxazolidines constitute versatile synthetic intermediates as a re- sult of the easy cleavage of the N–O bond under reducing conditions. 1 Indeed, various isoxazolidines are extensively used as 1,3-amino alcohol equivalents, 2 as masked amino acids 3 or as amino-sugar mimetics. 4 Furthermore, substituted isoxazolidines, isoxazolines, and isoxazoles are important substrates for mecha- nistic studies of biologically interesting processes. For example, isoxazolines have been incorporated as conformational constraint element in a v b 3 and a 5 b 1 integrin antagonists, 5 as well as in several transcriptional activators. 6 In a similar way, combretastatin ana- logues containing the isoxazoline or isoxazole ring have been reported, 7 and several AMPA (S-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)-propionic acid) receptor agonists have been synthe- sized and tested. 8 Finally, the use of chiral isoxazolidines as auxiliaries in asymmetric synthesis has been also reported. 9 On the other hand, the synthesis of unnatural nucleoside analogs 3a,10 containing the isoxazolidinic and isoxazolinic ring is currently of significant interest since it has been reported that the presence of an isoxazoline ring increases the antibacterial activity of carbape- nem derivatives. 11 Although 1,3-dipolar cycloaddition 1,12 is the simplest method for the preparation of isoxazolidines, conjugate addition of nitrogen containing nucleophiles to unsaturated car- bonyl compounds represents a useful alternative approach. 13 In this regard, we have been active in the field of aza-Michael addition, especially by means of metal catalyzed 1,4-addition of hydroxyl- amine derivatives to appropriate electrophilic acceptors. 14 This protocol has been applied to the synthesis of several biologically active compounds. Recently, we developed a practical and selective synthesis of 4- carboxylated-5-hydroxyisoxazolidines. 15 In this paper we report a new approach to this class of compounds, using N-benzyl-(tert- butyldimethylsilyloxy)carbamate 16 as nucleophile and highly reactive alkylidene acetoacetates as suitable acceptors. This pro- cedure directly furnished N-Cbz-protected-5-hydroxyisox- azolidines that can be easily transformed into the corresponding dehydrated isoxazolines, which are useful precursors of aromatic oxazoles. The electrophilic substrates were prepared according to the previously reported procedure, 17 by condensation of ethyl acetoa- cetate with aliphatic and aromatic aldehydes. Thus, compounds 1a–e were obtained in 70% yield, as ca. 4:1 mixtures of Z/E isomers, which were easily separable by flash chromatography. With these ketoesters in hand, we carried out the critical carbamate addition under Lewis acid-catalyzed conditions (Scheme 1). 2. Results and discussion 2.1. Addition of N-benzyl-(tert-butyldimethylsilyloxy)- carbamate to alkylidene acetoacetates 1a–e Lewis acids have attracted much attention in organic synthesis because of their strong influence on the rate, the regio-, and the stereochemistry of numerous reactions. 18 In this context, carbamates have only recently been the subject of investigation as nucleophilic reagents for conjugate addition. 19 The low * Corresponding authors. Fax: þ39 051 2099456. E-mail addresses: giuliana.cardillo@unibo.it (G. Cardillo), alessandra.tolomelli@ unibo.it (A. Tolomelli). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2009.01.071 Tetrahedron 65 (2009) 2478–2483 Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet