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Natural and synthetic cyclic peptides represent an important class of bioactive molecules that exhibit a broad range of biological activities [1] and are considered as promising lead compounds in the search for new drugs. In particular, macrocyclic tetrapeptides (MTPs) have potential for development into therapeutic agents because of their low molecular weight, small organic molecule-like properties, membrane permeability, selectivity, expected metabolic stability to proteases, and improved pharmacokinetic properties in vivo [1,2]. However, the small 12-membered ring size can make their synthesis difficult, often resulting in low yields of the desired MTP with resulting dimers and oliogomers as the major products [3-5]. Generally MTPs in which the amino acids are all the same chirality are more difficult to synthesize because the conformations of the linear precursor tetrapeptides limit the close approach of the Nand C-termini needed for macrocyclization to occur [5]. Also to date, almost all reported synthesized MTPs contain at least one turn inducing residue such as Pro, an N-alkyl amino acid, a D-amino acid or an unusual amino acid that favors macrocyclization [1,6]. As part of our long standing interest in peptide ligands for kappa opioid receptors (KOR) we are synthesizing analogs of the natural product macrocyclic tetrapeptide CJ-15,208 (Figure 1) which exhibits modest affinity for KOR [4,7]. We use an improved synthetic protocol to prepare larger quantities of the macrocyclic tetrapeptide CJ-15,208, [D-Trp]CJ-15,208 and their analogs for detailed pharmacological evaluation in vivo [8-10]. To demonstrate the broad applicability of this methodology, here we describe the challenging syntheses of two all L-amino acid macrocyclic tetrapeptides (all L-AA MTPs, Figure 2) based on the CJ-15,208 scaffold that do not contain a turn inducer to promote macrocyclization.

Optimized Method to Generate Synthetically Challenging Macrocyclic Tetrapeptides that do not have a Turn Inducer