Diastereoselective PicteteSpengler condensation of tryptophan with a-amino aldehydes as chiral carbonyl components Karolina Pulka a , Piotr Kulis a , Dagmara Tymecka a , Lukasz Frankiewicz a , Marcin Wilczek a , Wiktor Kozminski a , Aleksandra Misicka a,b, * a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland b Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland Received 26 April 2007; received in revised form 26 October 2007; accepted 8 November 2007 Available online 17 November 2007 Abstract The PicteteSpengler reaction of Trp with a-amino aldehydes derived from L and D-amino acids was studied in terms of double stereodiffer- entiation. The results observed for D-amino aldehydes represent ‘matched’ situation (one diastereoisomer was formed) whereas with L-amino aldehydes ‘mismatched’ (two diastereoisomers were formed). The conformation of newly formed six-membered ring was analyzed. It was found that stable conformers were different for cis and trans isomers. Ó 2007 Elsevier Ltd. All rights reserved. 1. Introduction Since its discovery, the PicteteSpengler reaction 1 has been extensively studied in the areas of syntheses of different het- erocycle systems. One of the possible uses of this reaction is in preparation of restricted analogs of aromatic amino acids occurring in proteins (Phe, Tyr, Trp, His). These aromatic amino acids very often play a crucial role in the interaction of ligand with the corresponding receptor-protein and there- fore many efforts have been done to obtain their cyclic or con- strained analogs. Those analogs have been introduced into the bioactive peptides to obtain local constraints and therefore provide insight into the structures required for bioactivity. Conformational restrictions of such residues have been a suc- cessful strategy to influence the biological activity, potency, selectivity, metabolic stability, and many other pharmacologi- cal properties. 2e6 Tryptophan is often a significant part of peptide ligands, which determines their affinity for receptors therefore different constrained analogs of this amino acid have recently gained considerable importance in the structureeactivity studies of bioactive peptides. One of the most successfully applied ana- logs of constrained tryptophan is the one in which the a-nitro- gen has been linked to the aromatic ring through a methylene unit, resulting in the six-membered ring derivative 1,2,3,4- tetrahydro-b-carboline-3-carboxylic acid (Tcc). It is prepared via a PicteteSpengler cyclization from chiral tryptophan ester and formaldehyde. 7,8 Other aldehydes generate a new stereo- genic center. Moreover, the products of the PicteteSpengler reaction can be treated as 1,3-disubstituted tetrahydro-b- carbolines and cis/trans isomers can be obtained. Therefore, the main challenge of this cyclization is stereoselectivity and the ratio of isomers. Different conditions, such as temperature, solvents, and achiral carbonyl substrates, were studied to im- prove the selectivity of the PicteteSpengler reaction. 9e12 It was found that the major compound was the cis isomer when reactions were carried at low temperature. It is also well known that the N b -benzyl or N b -diphenylmethyl substituted tryptophan esters favored trans isomers. 13e17 Re- cently it has been shown that the PicteteSpengler reaction of tryptophan allyl ester is cis-specific. 18 Other synthetic strate- gies used to influence the results of the PicteteSpengler con- densation include the use of chiral catalysts, 19 chiral auxiliaries, 20,21 or optically active carbonyl compounds. 22 * Corresponding author. E-mail address: misicka@chem.uw.edu.pl (A. Misicka). 0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2007.11.037 Available online at www.sciencedirect.com Tetrahedron 64 (2008) 1506e1514 www.elsevier.com/locate/tet