Synthesis of a novel 14-membered highly constrained cyclic peptidic scaffold Christopher J. Arnusch and Roland J. Pieters * Department of Medicinal Chemistry, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands Received 26 February 2004; revised 15 March 2004; accepted 22 March 2004 Abstract—The synthesis and NMR analysis of a novel highly constrained scaffold is described. The 14-membered macrocyclic ring structure was inspired by many medicinally relevant natural products that also contain the bi-aryl ether moiety. The synthesis required only commercially available starting materials and involved a base mediated S N Ar cyclization. A conformational search was performed, which indicated a strong preference for a single conformation, which was consistent with observed ROE signals by NMR. Ó 2004 Elsevier Ltd. All rights reserved. Cyclic peptides 1 are important compounds for medicinal purposes and represent an important class of natural products. Compared to their acyclic counterparts, cyclic peptides have more constrained conformations and are more resistant to degradation in vivo. The constriction of a peptide into a certain conformation can greatly enhance its binding to receptors due to reduced entropy loss upon binding. Many efforts have been made to develop methods of cyclization and a variety of reagents and catalysts have been developed for this purpose. Macrolactamization, 2 disulfide formation, 3 ring closing olefin metathesis, 4 and various cycloetherification tech- niques such as S N Ar cyclizations 5 are important meth- ods for a synthetic chemist in the design of a desired cyclic peptide. By the same token, these tools are essential for the synthesis of mimics or derivatives of biologically active compounds aiming at improved activity or function. We here present a short synthesis of a highly constrained cyclic peptide scaffold that includes several sites that allow the introduction of structural variations. The bi-aryl ether moiety is a common element in many natural products and also in synthetically constrained peptides. Numerous examples include the vancomycin class of antibiotics, 6 cycloisodityrosine derivatives, 7 piperazinomycin, 8 deoxybouvardin, 9 K-13, 10 and OF4949 11 (Fig. 1). The medicinal functions of these products range from antitumor agents, enzyme inhibi- tors (including HIV integrase, and angiotensin I con- verting enzyme), and antibiotics. A feature that differentiates the structure of these medicinally relevant molecules is the size of the N O H N H H H OH O OH N O N NH O O HN O HN O N O O HN O NO 2 O 2 N O O N H O (+)-piperazinomycin 1 deoxybouvardin Figure 1. Structures of (þ)-piperazinomycin and deoxybouvardin compared with 1. These 14-membered macrocyclic examples contain a biphenyl ether moiety. Keywords:S N AR reaction; Cyclic peptide; Bi-aryl ether. * Corresponding author. Tel.: +31-30-253-6944; fax: +31-30-253-6655; e-mail: r.j.pieters@pharm.uu.nl 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.03.131 Tetrahedron Letters 45 (2004) 4153–4156 Tetrahedron Letters