Pergamon Tetrahedron Letters 41 (2000) 923–927 TETRAHEDRON LETTERS Synthesis of a complete set of L-difluorophenylalanines, L-(F 2 )Phe, as molecular explorers for the CH/π interaction between peptide ligand and receptor Tsugumi Fujita, Takeru Nose, Ayami Matsushima, Kazushi Okada, Daisuke Asai, Yasuko Yamauchi, Naoto Shirasu, Takeshi Honda, Daiki Shigehiro and Yasuyuki Shimohigashi * Laboratory of Structure–Function Biochemistry, Department of Molecular Chemistry, Graduate School of Sciences, Kyushu University, Fukuoka 812-8581, Japan Received 8 October 1999; accepted 19 November 1999 Abstract A complete set of difluorophenylalanines in the L-configuration [L-(F 2 )Phe] (namely, L-(2,3-F 2 )Phe, L-(2,4- F 2 )Phe, L-(2,5-F 2 )Phe, L-(2,6-F 2 )Phe, L-(3,4-F 2 )Phe, L-(3,5-F 2 )Phe) was prepared and incorporated into the thrombin receptor-tethered ligand peptide SFLLRNP to identify the phenyl hydrogens of the Phe-2 residue involved in the CH/π receptor interaction. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: amino acids; amino acid derivatives; fluorine; fluorine compounds; molecular recognition; peptides; polypeptides. 1. Introduction Phenylalanine (Phe), an aromatic amino acid, is often crucially important in biologically active pep- tides to elicit intrinsic activity, and on that occasion, the side-chain phenyl group plays an essential role in the ligand–receptor interaction. 1 The molecular mechanism of this so-called hydrophobic interaction, however, has never been elucidated in detail. When Phe interacts with the alkyl side chains of amino acids Leu, Ile, Val, or Ala, the Phe–phenyl π system would function as a hydrogen acceptor. This interaction is denoted as a CH/π interaction, the concept of which has recently been established by Nishio et al. 2 When Phe interacts with aromatic amino acids such as Phe, Tyr, Trp, and His, Phe–phenyl should be involved in two different types of π–π interactions, i.e., the face-to-face π–π stacking interaction and the edge-to- face CH/π interaction. To better understand the molecular mechanism of peptide interactions involving the Phe residue, differentiation of these Phe–phenyl π interactions is requisite. We have postulated that * Corresponding author. 0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(99)02191-7 tetl 16119