Journal of Chemical Technology and Biotechnology J Chem Technol Biotechnol 82:1082–1086 (2007) Amino acid oxidase-catalysed resolution and Pictet–Spengler reaction towards chiral and rigid unnatural amino acids Peter Benz and Roland Wohlgemuth ∗ Research Specialties, Sigma-Aldrich, Industriestrasse 25, CH-9470, Buchs, Switzerland Abstract BACKGROUND: The biosynthesis of structurally complex isoquinoline alkaloids and other natural products occurs via aromatic amino acids such as tyrosine, and chiral and rigid amino acids. These structures are also key building blocks of many active pharmaceutical ingredients. The aim of this work was the exploration of a rapid and straightforward route to chiral 6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. RESULTS: The preparation of (S)-meta-tyrosine from racemic meta-tyro- sine with aminoacidoxidase has been developed with ee >99% and 88% yield. The combination of this resolution with a subsequent Pictet–Spengler reaction enables straightforward and versatile access to chiral (S)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid in 30% yield. CONCLUSIONS: This new short chemoenzymatic route to (S)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid from commercially available DL-m-tyrosine is more convenient than other chemical procedures and establishes a new link between the pool of easily accessible racemic aromatic amino acids and the corresponding chiral rigidified amino acids, which are of interest as structural elements of many active pharmaceutical ingredients. These results facilitate synthetic access to a range of active pharmaceutical ingredients and metabolites in chiral form from the oxidation of amino acids. This advances the opportunities to study the molecular interactions with enzymes, receptors and effectors more precisely than with the racemic forms.  2007 Society of Chemical Industry Keywords: biocatalysis; chiral amino acids; amino acid oxidase; amino acid resolution; Pictet–Spengler reaction INTRODUCTION Among the unnatural amino acids, chiral and rigid structures have become interesting building blocks for the synthesis of specific biologically active compounds. Unnatural chiral amino acids based on the 1,2,3,4- tetra – hydroisoquinolinecarboxylic acid skeleton can be regarded as conformationally restricted amino acid analogues of phenylalanine and tyrosine because the side chain has been fixed by the bridging methylene unit and the bicyclic nature of the molecules limits the dihedral angle in the N-C(α)-C(β )-C(γ )- and C(α)-C(β )-C(γ )-C(δ)-segments to a small range. 1 The 1,2,3,4-tetrahydroisoquinoline skeleton (THIQ) is a structural element of many alkaloids and active pharmaceutical ingredients. The tetrahydroiso- quinoline family of antitumor antibiotics constitutes a small, yet growing and increasingly important, family of chemotherapeutic agents. 2 Syntheses of a variety of 1,2,3,4-tetrahydroiso- quinolines have therefore been of continued interest. 3–6 The Pictet–Spengler reaction, a special case of the Mannich reaction, has been found to be an efficient method of forming carbon–carbon bonds in heterocyclic synthesis 7,8 and is the most important method of preparation of tetrahydroisoquinolines 9,10 and has been widely used because of generally good yields and mild acid catalysis. 11 The structurally complex isoquinoline alkaloids have been shown by biosynthetic labelling studies to be derived from tyrosine and the stereospecific syntheses of the rep- resentative benzylisoquinoline alkaloids (R)-(+)- and (S)-(−)-laudanosine from L-3,4-dihydroxyphenyl- alanine methylester hydrochloride and sodium (3,4- dimethoxyphenyl)-glycidate included as key step an asymmetric Pictet–Spengler reaction. 12 – 14 While phenylalanine derivatives lead to the 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acids and pyru- vates can be used for the synthesis of 1,2,3,4- tetrahydroisoquinoline-1-carboxylic acids, meta- tyrosines should lead to 6-hydroxy-1,2,3,4-tetrahydro- isoquinole-3-carboxylic acids. 11 As the chirality of the amine and aldehyde components of the Pictet – Spengler reaction are preserved and asymmetry can be transferred to newly formed chiral centers, it is of interest to prepare the required components in chiral ∗ Correspondence to: Roland Wohlgemuth, Research Specialties, Sigma-Aldrich, Industriestrasse 25, CH-9470, Buchs, Switzerland E-mail: rwohlgemuth@sial.com (Received 12 June 2007; accepted 20 July 2007) Published online 15 October 2007; DOI: 10.1002/jctb.1777  2007 Society of Chemical Industry. J Chem Technol Biotechnol 0268–2575/2007/$30.00