Issue in Honor of Prof. T. Govindachari ARKIVOC 2001 (viii) 20-26
Synthesis of an a-dehydro ß-amino acid derived cyclic peptide as a
constrained ß-turn mimic
S. Rajesh, Jyoti Srivastava, Biswadip Bannerji, and Javed Iqbal*# Department of Chemistry, Indian Institute Of Technology, Kanpur 208 016, India E-mail:
[email protected]
This paper is dedicated to Prof. T. R. Govindachari on the occasion of his 80th birthday (received 11 Jun 01; accepted 08 Aug 01; published on the web 16 Aug 01)
Abstract
Cobalt(II) chloride catalyses the cleavage of epoxy peptides with an a-dehydro ß-amino acid derivative to afford the corresponding dipeptide derivative which exhibits an intramolecular hydrogen bond and thus mimics a ß-turn. This intramolecular hydrogen bonding preorganises the corresponding diallylated peptide for cyclisation via ring closing metathesis to afford the cyclic peptide as a constrained mimic of a ß-turn.
Keywords: Epoxypeptides, ß-turn mimic, cyclic peptide, cobalt (II) chloride catalyst, intramolecular hydrogen bond
Introduction
It is well known that linear peptide fragments are flexible and exhibit numerous conformations in solution and even in the solid state. However, if one can restrict the conformational freedom of these linear peptides by introducing some constraints in the structure, it may render a biologically active peptide more specific and this may give rise to species, which are therapeutically useful. In view of the importance of constrained conformations, there have been several studies1 to lock peptides into turn configurations and to synthesise molecules that might mimic a reverse turn. Among the reverse turns, the ß- and .-turn conformations in proteins have been shown to play important roles during the biochemical recognition process. It has been shown that when peptides are used as an inhibitor they adopt a turn conformation2 while bound to their protein receptors. In connection with our work on the design and synthesis of aspartyl protease inhibitors3 (containing a-hydroxy-ß-amino amide core unit) based on the ß-turn mimetic concept, we reasoned that a double bond when present in the side chain of an amino acid will confer torsional restriction and in the presence of appropriate donor and acceptor sites peptides containing such amino acid residues may be constrained to adopt a turn conformation. Studies
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