Naphthyl-L-a-amino acids via chemo-enzymatic dynamic kinetic resolution Paola D’Arrigo a,b , Lorenzo Cerioli a , Andrea Fiorati a , Stefano Servi a,b,⇑ , Fiorenza Viani c , Davide Tessaro a,b a Dipartimento di Chimica, Materiali ed Ingegneria Chimica ‘Giulio Natta’, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy b Centro Interuniversitario di Ricerca in Biotecnologie Proteiche ‘The Protein Factory’, Politecnico di Milano, Università degli studi dell’Insubria and ICRM, CNR Milano, Via Mancinelli 7, 20131 Milano, Italy c ICRM, CNR Via Mancinelli 7, 20131 Milano, Italy article info Article history: Received 8 May 2012 Accepted 27 June 2012 abstract A double catalyst system (protease + base) was applied to the dynamic kinetic resolution (DKR) of iso- meric 1- and 2-a-naphthyl-glycines and -alanines exploiting the in situ racemization of their thioesters. Due to the different C-acidity of the two sets of compounds, different experimental conditions have been devised to perform the simultaneous resolution/racemization process. In all cases, the racemic N-Boc-thioesters were converted into the aminoacids with an L-configuration almost quantitatively and with complete enantioselectivity. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Non-proteinogenic a-amino acids, because of their absolute config- uration or their chemical structure, are often defined as non-natural even though some of them occur in nature. 1–5 They belong to a group of building blocks that are required for the preparation of peptide mimetics and new bio active compounds. 6–12 They are often chiral and, although they can be obtained by an asymmetric synthesis, 13–16 the most commonly used methods require the preparation of the race- mate followed by a kinetic resolution step. 17–29 Naphthyl amino acids (Fig. 1) form a special group of non-natural a-amino acids because of their resemblance to tryptophan, phenylalanine, and tyrosine. More- over, they are ideal candidates as enzyme inhibitors, components of new drugs or analogues of peptide based existing drugs, 30–41 chiral auxiliaries, components in analytical devices, and in asymmetric synthesis. 42–45 They can be obtained by asymmetric synthesis, 46–48 but many of the approaches also rely on enzymatic catalysis, either via kinetic resolution methods 49,54 or enzymatic deracemization through microbial dynamic kinetic resolution (DKR) 50 or multistep en- zyme catalyzed stereoinversion. 51 We have recently accomplished a multistep cascade deracemi- zation of 3-(2-naphthyl)-L-alanine 3, by tuning the substrate spec- ificity of the key enzyme D-amino acid oxidase from the yeast Rhodotorula gracilis (RgDAAO) by directed evolution to accept this non-natural amino acid. 51 The three enzyme-catalyzed system is summarized in Scheme 1: RgDAAO oxidizes the D-enantiomer to the corresponding ketoacid (2-naphtyl pyruvate 2-NPA), which in turn is transformed into the L-enantiomer by the L-specific aspar- tate amino transferase (L-AspAT). The amino donor cysteine sulfi- nic acid (L-CSA) decomposes into pyruvate and sulfur dioxide, thus shifting the equilibrium toward the product. One advantage 0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetasy.2012.06.020 ⇑ Corresponding author. E-mail address: stefano.servi@polimi.it (S. Servi). NHBoc COOH NHBoc NHBoc COOH NHBoc COOH D,L-1 D,L-2 D,L-3 D,L-4 HOOC Figure 1. Structure of naphthyl amino acids 1–4. Tetrahedron: Asymmetry 23 (2012) 938–944 Contents lists available at SciVerse ScienceDirect Tetrahedron: Asymmetry journal homepage: www.elsevier.com/locate/tetasy