Synthesis of the enantiomers and N-protected derivatives of 3-amino-3-(4-cyanophenyl)propanoic acid Magdolna Solym ar, a Liisa T. Kanerva b and Ferenc F€ ul € op a, * a Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, PO Box 121, Hungary b Laboratory of Synthetic Drug Chemistry and Department of Chemistry, University of Turku, Lemmink€ aisenkatu 2, FIN-20520 Turku, Finland Received 24 March 2004; accepted 11 May 2004 Abstract—Racemic ethyl 3-amino-3-(4-cyanophenyl)propanoate was synthesized and the enantiomers separated through enantio- selective N-acylation by Candida antarctica lipase A (CAL-A) in neat butyl butanoate. The free amino acid enantiomers were transformed to the Boc and Fmoc-protected derivatives. Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction The design and synthesis of peptide oligomers contain- ing nonnatural amino acids, 1–4 and of other biologically active amino acid derivatives, 5;6 is a challenge in current drug design and peptide secondary structure analysis (b- peptides and foldamers). 7 For peptide structural studies, it is useful to incorporate amino acid scaffolds which possess easy-to-detect func- tional groups as internal local environment markers. One good possibility is to introduce a small, intermedi- ately polar nitrile group, which has a characteristic vibrational stretching band in the IR spectrum, and which is sensitive to the environment. For this purpose, the use of cyano derivatives of enantiomerically pure alanine and phenylalanine has been reported recently. 8;9 Racemic p-cyanophenylalanine is applied in the syn- thesis of aromatase inhibitors, 6 TNFa inhibitors, 10 and antifungal 11 and antiepileptogenic 12 agents. Enantio- merically pure b-amino acid derivatives of p-cyanophen- ylalanine have not yet been described in the literature. Our aim was to find an appropriate method for prepa- ration of the enantiomers of 3-amino-3-(4-cyanophe- nyl)propanoic acid. 2. Results and discussion The lipase-catalysed enantioselective acylation strategy has acquired a valued position for the preparation of highly enantiopure compounds, with the advantage that both enantiomers can be obtained. Relying on this strategy, the racemic amino acid 1 was prepared by the modified Rodionov method 13 and transformed to its ethyl ester (±)-4 in EtOH in the presence of SOCl 2 . The optimization of the N-acylation conditions for (±)-4 with lipase A from Candida antarctica (CAL-A) (Table 1) was started by testing the gram-scale conditions of the previously examined kinetic resolutions of phenyl, thi- enyl and furyl-substituted 3-aminocarboxylates. 14;15 The reaction of (±)-4 exhibited almost no selectivity in ethyl butanoate, which was the solvent (and the acyl donor) of choice for the gram-scale resolution of the heteroaryl- substituted analogues (Table 1, entry 5). 14 N-Acylation of (±)-4 with 2,2,2-trifluoroethyl butanoate revealed solvent dependence with the reactivity decreasing in the sequence i-Pr 2 O, Et 2 O, MeCN, THF, with low to moderate enantioselectivities (entries 1–4). The highest enantioselectivity was observed for the reaction in neat butyl butanoate, although the reactivity was then moderate as compared with that observed for acylation with 2,2,2-trifluoroethyl butanoate in solvents other than THF (entry 6). An elevated substrate concentration in butyl butanoate resulted in a decreased enantio- selectivity and reactivity (entry 7). It is interesting that, taking the same conditions into consideration, the * Corresponding author. Tel.: +36-62-545564; fax: +36-62-545705; e-mail: fulop@pharma.szote.u-szeged.hu 0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetasy.2004.05.012 Tetrahedron: Asymmetry 15 (2004) 1893–1897 Tetrahedron: Asymmetry