Synthesis of backbone modified cyclic peptides bearing dipicolylamino sidearms Stephen J. Butler, Katrina A. Jolliffe * , Wee Yu Gladys Lee, Matthew J. McDonough, Aaron J. Reynolds School of Chemistry, The University of Sydney, 2006 NSW, Australia article info Article history: Received 25 August 2010 Received in revised form 12 November 2010 Accepted 30 November 2010 Available online 7 December 2010 Keywords: Cyclic peptide Oxazole Macrocycle abstract Three analogues of the Lissoclinum class of cyclic peptides, bearing dipicolylamino functionalised side chains, have been synthesised using a stepwise approach followed by macrocyclisation. Attempts to incorporate dipicolylamino functionalised side chains prior to peptide synthesis resulted in epimerisa- tion, but this was overcome by functionalising the ornithine side chains with dipicolylamino groups after the macrocyclisation reaction. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Macrocyclic molecular scaffolds that present multiple functional groups in a preorganised fashion, e.g., calixarenes, resorcinarenes, crown and aza-crown ethers and porphyrins are widely used in molecular recognition research. 1,2 While such scaffolds are often prepared by a cyclooligomerisation reaction, it is generally difficult to access unsymmetrical or highly functionalised scaffolds using this approach. An alternative approach to the preparation of mac- rocyclic scaffolds is to cyclise a linear precursor that has been prepared in a stepwise manner. This allows the sequential in- troduction of individual subunits bearing different functional groups and can be used to prepare both symmetrical and un- symmetrical macrocycles. Cyclic peptides are ideal candidates for synthesis via this approach. The large number of amino acid de- rivatives available for synthesis allows ready incorporation of a wide variety of functionalised pendant arms into these molecules and the stepwise nature of standard peptide synthesis protocols means that the sequence of functional groups in the macrocycle can be systematically varied. In recent years, numerous oxazole and thiazole-containing cy- clic peptides have been isolated from ascidians, cyanobacteria and other sources. In particular, the Lissoclinum family of cyclic peptides contains cyclic hexa-, hepta- and octa-peptides characterised by the presence of oxazoline/oxazole/thiazoline/thiazole heterocycles alternating with proteinogenic amino acid residues. 3 The azole heterocycles present in these natural products are derived from the condensation of cysteine, serine and threonine side chains with the adjacent amino acids in a peptide sequence. The presence of the modified amino acids influences the three dimensional structures and bioactivity of these natural products and provides added ri- gidity to the macrocycles. In addition, the alternating hydrogen bond donor and acceptor sites that line the interior of the mole- cules form a network of bifurcated hydrogen bonds that further rigidifies the macrocycle. This, together with the observation that in all-syn substituted compounds the side chains are presented on the same face of the macrocycle, has led to the recent use of analogues of these natural products as molecular scaffolds for the de- velopment of molecular receptors, chiral ligands, artificial proteins and combinatorial libraries. 4e6 Our interest in the recognition of large, biologically interesting anions [e.g., pyrophosphate (P 2 O 7 4 , PPi) and adenosine tri- phosphate (ATP)] led us to explore the use of this class of cyclic peptide scaffold for the development of anion receptors. 5 The cyclic hexapeptide and octapeptide scaffolds have diameters of approxi- mately 6.6 and 9  A, respectively, 6 allowing binding sites to be po- sitioned at suitable distances to complex these large anions. We report here the use of a stepwise synthetic approach to one such cyclic octapeptide 1 , 5 with pendant dipicolylamino (Dpa) side chains suitable for complexation of Zn(II) ions to in turn bind phosphate oxoanions, together with the related cyclic hexapeptides 2 and 3 (Fig. 1). Compounds 1 and 2 were designed to investigate the effect that changing the size of the scaffold, and hence the distance between the two Dpa side chains, would have on the ability of these compounds to bind pyrophosphate ions, while scaffold 3, which bears only a single Dpa side chain, was prepared as a reference compound. The ornithine side chains were chosen to provide some flexibility in the binding sites, thereby allowing ‘in- duced fit’ of a target anion. * Corresponding author. Tel.: þ61 2 9351 2297; fax: þ61 2 9351 3329; e-mail address: kate.jolliffe@sydney.edu.au (K.A. Jolliffe). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2010.11.100 Tetrahedron 67 (2011) 1019e1029