Conformationally Assisted Lactamizations for the Synthesis of Symmetrical and Unsymmetrical Bis-2,5-diketopiperazines Khanh Ha, ‡ Iryna Lebedyeva, ‡ Zhiliang Li, ‡ Kristin Martin, ‡ Byron Williams, ‡ Eric Faby, ‡ Amir Nasajpour, ‡ Girinath G. Pillai, ‡,§ Abdulrahman O. Al-Youbi, ∥ and Alan R. Katritzky* ,‡,∥ ‡ Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States § Institute of Chemistry, University of Tartu, Tartu 50411, Estonia ∥ Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, 21589 Saudi Arabia * S Supporting Information ABSTRACT: Open-chain N-Cbz-protected-peptidoyl benzo- triazolides are converted by a novel lactamization strategy using proline as a turn introducer into both symmetrical (5a−c and 11a−c) and unsymmetrical (19a−e) bis-2,5-diketopiper- azines (bis-2,5-DKPs), previously recognized as difficult targets. ■ INTRODUCTION 2,5-Diketopiperazines (2,5-DKPs) occur in numerous natural products, often as such, but also embedded in larger, more complex molecular architectures in a variety of natural products from fungi, bacteria, the plant kingdom, and mammals. 1−3 2,5- DPKs have the ability to bind to a wide range of receptors, together with several characteristics attractive in scaffolds for drug discovery. 4 DKPs are small, conformationally constrained heterocyclic molecules stable to proteolysis. Diversity can be introduced at up to six positions and stereochemistry controlled at up to four positions. 1,5,6 Recent advances in solid-phase methodology have increased their availability for combinatorial drug discovery. 5,7 In sharp contrast to numerous studies dedicated to the synthesis and biological properties of DKPs, relatively few bis- DKPs have been reported. 1,8,9 They have, however, shown considerable biological activity: (i) (+)-WIN 64821, from Aspergillus f lavus cultures is a potent competitive P antagonist with submicromolar potency for both the human neurokinin 1 and the cholecystokinin B receptors; 10 (ii) dimeric diketopiper- azine (−)-ditryptophenaline alkaloids and (−)-N1-(2- phenylethylene)ditryptophenaline inhibit the former recep- tor; 11 (iii) (+)-11,11′-dideoxyverticillin A is a tyrosine kinase inhibitor with potent antitumor activity; 11 (iv, v) naturally occurring bis-DPKs chaetocin and chetomin are inhibitors of HIF-1α-p300/CBP interaction, although the inhibition mech- anism remains unclear 12 (comparative analysis has shown that bis-DKPs impact highly on the expression level of hypoxia- inducible genes and have more genome-wide effects than DPKs); 13 (vi) X-ray crystallographic studies show that xylylene- linked bis-2,5-DKPs obtained by direct C3 alkylation of the N- substituted 2,5-DKP cores via carbanion chemistry can adopt open and closed conformations, which enable them to serve as building blocks for metallo-supramolecular assemblies, metal− organic polygons, and other metal−organic materials. 14 Head-to-tail condensation between the N- and C-termini of the corresponding linear peptides represents the most straightforward synthesis for bis-2,5-DKPs. 15,16 However, head-to-tail condensation may require harsh conditions which cause partial epimerization, other side reactions, and low yields. Dimeric DKPs can also be obtained by radical dimeriza- tion 8,17,18 or direct modification of the N-alkylated DKP core via carbanion chemistry, 13,14 but these procedures are challenging because multiple protection and deprotection steps limit the methodology to specific peptide sequences. As a part of our research program dedicated to the development of innovative and efficient cyclization proce- dures, 19−21 we now report novel and versatile strategies for the synthesis, from peptidoyl benzotriazolides containing proline as a turn introducer, of both symmetrical and unsymmetrical bis- 2,5-DKPs by triethylamine-promoted lactamization (Figure 1). Proline has high tendency to induce reverse turns in polypeptides because it can accommodate both the cis and the trans conformers of a tertiary Xaa-Pro amide bond (where Xaa represents any l-α-amino-acid). 22 It has therefore been utilized to introduce reverse turns to achieve short end-to-end distance in peptide chains. 23 ■ RESULTS AND DISCUSSION Synthesis of Symmetrical Bis-DPKs. Dimeric DKP 5a was synthesized in four steps (Scheme 1): (i) N a ,N a -bis-Cbz-L- cystine (1a) was converted to benzotriazolide 2a in 86% yield; (ii) reaction of l-Cbz-L-cystinyl benzotriazole 2a with D-proline, according to our previously reported procedure, 24−26 was Received: June 7, 2013 Published: July 29, 2013 Article pubs.acs.org/joc © 2013 American Chemical Society 8510 dx.doi.org/10.1021/jo401235k | J. Org. Chem. 2013, 78, 8510−8523