Conformationally Assisted Lactamizations for the Synthesis of Symmetrical and Unsymmetrical Bis-2,5-diketopiperazines

Abstract

Open-chain N-Cbz-protected-peptidoyl benzotriazolides 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-diketopiperazines (bis-2,5-DKPs), previously recognized as difficult targets.

Long‐Range Chemical Ligation from N→N Acyl Migrations in Tryptophan Peptides via Cyclic Transition States of 10‐ to 18‐Members

“…The lowest energy conformer facilitates N→N acyl transfer due to the formation of an amide bond in the ligated peptide. We applied techniques previously employed27, 35, 36 for similar ligation reactions including a full conformation search followed by scoring of the conformers based on the spatial distances between the reactive termini, b (NC). The full conformation search considered both rotatable bonds and the phenyl ring of twenty‐four related compounds, 9 a to 20 c (including Leu/Val‐containing isopeptides, which were used for prediction purposes), and the analysis was performed by using the MMX force field,37 in PCMODEL v.9.3 software 38.…”

Tandem Deprotection–Dimerization–Macrocyclization Route to C2 Symmetric cyclo‐Tetrapeptides

“…27 Cbz‐ N ‐protected β ‐amino acid 1 a was first converted into the benzotriazolide 2 a (Cbz=Carboxybenzyl); reaction of 2 a with proline gave 3 a , which was converted into Cbz‐dipeptidoyl benzotriazolide 4 a 28. 29 Stirring at a concentration of 12 m M under hydrogen in the presence of Pd/C (10 wt %) at 20 °C for 48 h, 4 a afforded 5 a (Scheme ) by tandem dimerization–macrocyclization: HPLC‐MS confirmed the major product is symmetrical cyclic tetrapeptide cyclo ‐( β ‐Ala‐ L ‐Pro‐) 2 5 a which, after purification by gradient chromatography (MeOH/ether) was obtained in 70 % isolated yield. Similarly, 5 a was synthesized in 72 % yield by deprotection/cyclo‐dimerization of Cbz‐ L ‐Pro‐ β ‐Ala‐Bt 4 aa .…”

A benzotriazole-mediated route to protected marine-derived hetero-2,5-diketopiperazines containing proline

“…8 Our longstanding involvement in benzotriazole (Bt)mediated oligopeptide chemistry [26][27][28][29][30] prompted us to design a new, versatile, and flexible strategy to provide these important marine-derived hetero-2,5-DKPs containing proline and Hyp starting from inexpensive L,L-dipeptidoyl benzotriazoles. In this project, we develop our cyclization method 31,32 on protected N-terminal for the synthesis of protected marinederived DKPs (Fig. 2).…”