Synthesis of amino acid derivatives via enantio- and diastereoselective Pd-catalyzed allylic substitutions with a non-stabilized enolate as nucleophile† Thomas D. Weiß, a Günter Helmchen* a and Uli Kazmaier b a Organisch-Chemisches Institut, Universität Heidelberg, Im Neuenheimer Feld 270, 69120, Heidelberg, Germany. E-mail: en4@ix.urz.uni-heidelberg.de; Fax: +49 6221 4205; Tel: +49 6221 8401 b Institut für Organische Chemie, Universität des Saarlandes, Am Stadtwald, Geb. 33/2, 66123, Saarbrücken, Germany Received (in Cambridge, UK) 18th April 2002, Accepted 1st May 2002 First published as an Advance Article on the web 15th May 2002 Diastereomer ratios of up to 95+5 and enantiomeric excesses of up to 95% were achieved in Pd-catalyzed asymmetric allylic substitutions with zinc enolates of glycine esters as nucleophiles; a remarkable effect of the ligand on the diastereoselectivity of the substitution was found. Pd-catalyzed asymmetric allylic substitution is a valuable synthetic method. 1 Most C-nucleophiles in use are conjugated carbanions prepared from CH-acidic compounds with pK a < ca. 20, i.e. malonates and b-keto esters. With symmetric nucleophiles, giving rise to only one stereogenic center in the coupling step, good yields and high enantioselectivities can now be consistently obtained. With unsymmetrical C-nucleophiles, e.g. b-keto esters or imines of amino acid esters, mixtures of diastereomers are usually generated because of configurational lability of the products. An exception was recently reported by Trost et al. who used substituted azlactones as nucleophiles which gave rise to a-alkylated g,d-unsaturated amino acids with a high degree of stereoselectivity. 2 The epimerization problem does not exist for products generated with more basic carbanions such as enolates of esters and ketones; however, these were found to be problematic because of side reactions, in particular elimination and cyclopropane formation. 3 To overcome this problem, consider- able effort has been expended on varying the counter ion of these enolates. Some success was obtained with tin and boron enolates. 4 In our laboratory, successful alkylations were achieved with the Zn enolates 2 and 4 (Scheme 1), 5 which gave excellent degrees of diastereoselectivity and b made valuable, g,d-unsaturated amino acids available (Scheme 2). With our groupAs background on asymmetric allylic substitu- tions, 6 we of course initiated an investigation on an enantiose- lective version of this reaction. 7 Related work was recently reported by Braun et al. who found examples of highly enantio- and diastereoselective reactions of ketone enolates with 1,3-diphenylallyl acetate 8 and Trost et al. who obtained excellent results for allylic substitutions with enolates of a- tetralones. 9 In order to assess the scope of the reactions with nucleophiles 2 and 4, we not only used the particularly benevolent 1,3-diphenylallyl acetate (7) but selected a representative set of substrates including a large and a small acyclic (Scheme 2) and two cyclic allylic derivatives (Scheme 3). As chiral ligands 10 we used phosphinooxazolines L2 and L3, which are particularly suited for acyclic substrates as well as the cymantrene derivative L4 and the phosphinomyrtanic acid L5 which are better suited for cyclic compounds (Fig. 1). Each of the reactions yields four stereoisomers. These isomers were base-line separable by GLC on the Chiralsil-L-Val phase. Individual isomers are characterized by their GLC retention times as given in Table 1. 11 Absolute and relative configurations were assigned for the full set of compounds 6, 10 † This work is dedicated to Professor Walter Siebert on the occasion of his 65th birthday. Scheme 1 Scheme 2 Scheme 3 Fig. 1 Chiral ligands. This journal is © The Royal Society of Chemistry 2002 1270 CHEM. COMMUN. , 2002, 1270–1271 DOI: 10.1039/b203791m