Enantioselective addition of b-functionalized allylboronates to aldehydes and aldimines. Stereocontrolled synthesis of a-methylene-g-lactones and lactams Isabelle Chataigner * ,y , Franc ¸oise Zammattio, Jacques Lebreton, Jean Villie ´ras Universite ´ de Nantes, Nantes Atlantique Universite ´, CNRS, Faculte ´ des Sciences et des Techniques, Laboratoire de Synthe `se Organique (LSO), UMR CNRS 6513, 2 rue de la Houssinie `re, BP 92208, F-44322 Nantes Cedex 3, France Received 12 November 2007; received in revised form 19 December 2007; accepted 20 December 2007 Available online 15 January 2008 Abstract We report results regarding the development of condensations of chiral b-alkoxycarbonylallylboronates on aldehydes and imines. These allylboronates add in a highly enantioselective and diastereospecific manner to afford biologically and synthetically useful chiral a-methyl- ene-g-butyrolactones and lactams. The nature of the electrophile (aldehyde vs imine) is shown to have a dramatic influence on the mechanism of the reaction, probably directing the stereoselectivity of the process through different transition states. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction The a-methylene-g-butyrolactone framework is widely found in naturally occuring compounds (Fig. 1). 1 In 1985, Hoffmann already reported that more than 2000 natural deriv- atives featured this moiety and evaluated that 10% of the reg- istered products contained this structural motif. 1a The ability of the methylene group of the g-lactone to act as a highly reactive Michael acceptor is the basis of its role as a physiolog- ically important building block. Nucleophiles such as L-cyste- ine or sulfhydryl containing enzymes add in vivo to the unsaturated lactone part, thus inhibiting the incorporation of several aminoacids into proteins. 1,2 The toxicity often associ- ated to their significant in vivo activity has, however, limited the clinical use of these products. 3 Modulations are thus needed to improve the pharmacological properties and decrease the toxicity. In this context, the isosteric replacement of the oxygen by a nitrogen atom is of interest, as it leads to a less reactive and hopefully more selective system. In addition, the supplementary nitrogen atom allows for a large variety of modu- lations by its substitution with electron-withdrawing groups or lipophilic chains for instance. Even if known in the natural world, the a-methylene-g-butyrolactam moiety is much scarcer than the lactone one (Fig. 1). 1c,4 Various synthetic strategies have described an access to these molecules in literature. 1,5 A classical route is based on the a-methylenation of a preformed lactone. 5b Alkoxycarbo- nylallylation reactions have also been largely studied to O O HOOC R 1a: R = C 5 H 11 1b: R = C 13 H 27 O O R O 2a: R = H 2b: R = CH 3 N Me O N O O H 3 CO 3 Figure 1. Examples of naturally occuring a-methylene-g-lactones and lactams: methylenelactocin (1a), protolichesterinic acid (1b), ambrosin (2a), parthenin (2b), and pukelimid E (3). * Corresponding author. E-mail address: isabelle.chataigner@univ-rouen.fr (I. Chataigner). y Present address: Universite ´ de Rouen, INSA de Rouen, CNRS UMR 6014, C.O.B.R.A., I.R.C.O.F., 1 rue Tesnie `res, 76131 Mont Saint Aignan Cedex, France. 0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2007.12.046 Available online at www.sciencedirect.com Tetrahedron 64 (2008) 2441e2455 www.elsevier.com/locate/tet