ORIGINAL ARTICLE New 1,3-amino alcohols derived from enantiopure bridgehead b-aminobicyclo[2.2.2]oct-5-ene-2-carboxylic acids Christophe Andre ´ • Monique Calme `s • Franc ¸oise Escale • Muriel Amblard • Jean Martinez • Olivier Songis Received: 24 June 2011 / Accepted: 19 September 2011 / Published online: 4 October 2011 Ó Springer-Verlag 2011 Abstract Constrained enantiopure bicyclic b-amino acids derived from the asymmetric Diels–Alder reaction of the (R)-benzyl-4-(3-acryloyloxy-4,4-dimethyl-2-oxopyrro- lidin-1-yl)-benzoate and the 1-(benzyloxycarbonyl- amino)cyclohexadiene provide original templates for the construction of new rigid enantiopure 1,3-amino alcohols. Keywords Bicyclic b-amino acid derivatives Á Cyclic amino alcohols Á Constrained chiral b-amino acids Á Reduction Introduction Synthesis of enantiopure amino alcohols is of great importance in synthetic organic chemistry since they are a well established source of ligands for asymmetric synthesis (Blaser 1992; Ager et al. 1996; Lait et al. 2007) including enantioselective borane reduction of prochiral ketones (Corey et al. 1987; Corey and Helal 1998; Deloux and Screbnik 1993; Li et al. 1999; Krzemin ´ski and Wojtczak 2005; Krzemin ´ski and Zaidlewicz 2003; Hobuss et al. 2008) or enantioselective addition of dialkylzinc (Kitamura et al. 1986; Kossenjans and Martens 1998; Garcia Martinez et al. 2002; Oliveira and Costa 2004; Szakonyi et al. 2006; Binder et al. 2009; Scarpi et al. 2009; Wu et al. 2009). Apart from this property, enantiopure amino alcohols are also important derivatives for the synthesis of various chemical com- pounds. They constitute convenient starting materials for the synthesis of various 1,3-heterocycles for example (Ager et al. 1996; Fu ¨lo ¨ p et al. 1997; Gyonfalvi et al. 2003; Kivela ¨ et al. 2003, 2005). Although 1,2-amino alcohols have received much attention because they are generally readily accessible in enantiomerically pure form from natural pre- cursors (Gyonfalvi et al. 2003; Reetz et al. 1987; Delair et al. 1994; Masui and Shiori 1998; Laczkowski et al. 2009; Kiss and Fu ¨lo ¨p 2009), the synthesis and the use of chiral 1,3-amino alcohols are still undergoing development and remain a challenge (Lait et al. 2007; Didier et al. 1991; Barluenga et al. 1993; Bartoli et al. 1994; Kossenjans and Martens 1999; Kochi et al. 2003; Raghavan et al. 2004; Murai et al. 2005; Balazs et al. 2007). This prompted us to synthesize new constrained 1,3- amino alcohols from some enantiopure bicyclic b-amino acids recently developed in our group (Songis et al. 2007, 2008a, b). These bicyclic b-amino acids were obtained by using the asymmetric Diels–Alder cycloaddition between the chiral acrylate (R)-1 (Akkari et al. 2004; Calme `s et al. 2005) and the 1-(benzyloxycarbonylamino)cyclohexadiene 2 (Fig. 1). The resulting Diels–Alder cycloadducts were obtained in high yield and moderate selectivity using optimized conditions mainly contained the two diastereoisomers 3 (60%) and 4 (30%). These two major Diels–Alder adducts (3 0 R,1S,2R,4R)-3 and (3 0 R,1R,2R,4S)-4 (Fig. 2), resulting from an endo and an exo selectivity on the same Ca Si face of the chiral dienophile (R)-1 respectively, were isolated in pure form after column chromatography on silica gel. Stereochemistry of the endo adduct 3, that crystallized from diethyl ether/petroleum ether, has been confirmed unambigously by X-ray diffraction analysis (Songis et al. 2007). C. Andre ´ Á M. Calme `s (&) Á F. Escale Á M. Amblard Á J. Martinez Á O. Songis Institut des Biomole ´cules Max Mousseron (IBMM) UMR 5247 CNRS-Universite ´ Montpellier 1 et 2, Ba ˆtiment Chimie (17), Universite ´ Montpellier 2, place E. Bataillon, 34095 Montpellier Cedex 5, France e-mail: monique.calmes@univ-montp2.fr 123 Amino Acids (2012) 43:415–421 DOI 10.1007/s00726-011-1097-6