Pseudopeptidic Macrocycles Research Articles

An experimental re-investigation of the role of aromatic–aromatic interactions in a templated synthesis of a macrocyclic pseudopeptide

The experimental re-investigation of a reported synthesis of a macrocyclic pseudopeptide promoted by bis(tetrabutylammonium)terephthalate allowed us to elucidate the nature of the non-bonding interactions between the reagents and the template; while the involvement of aromatic-aromatic interactions could be ruled out, the relevance of the role of the carboxylate ion was confirmed.

Aza-β3-Cyclohexapeptides: Pseudopeptidic Macrocycles with Interesting Conformational and Configurational Properties Slow Pyramidal Nitrogen Inversion in 24-Membered Rings!

Among pseudopeptidic foldamers, aza-beta3-peptides have the unique property to possess nitrogen stereocenters instead of carbon stereocenters. As the result of pyramidal inversion at N(alpha)-atoms along the backbone, they behave as a set of C8-based secondary structures in equilibrium. This structural modulation is exploited here to prepare 24-membered macrocycles with great efficiency. Both crystal structures and spectroscopic data establish that aza-beta3-cyclohexapeptides adopt a highly organized conformation where the relative configuration of chiral nitrogen atoms is alternated. This makes them an interesting scaffold as the stereocontrol occurs spontaneously through the cyclization. These compounds reveal an unprecedented slow pyramidal nitrogen inversion in macrocycles. Pyramidal ground state stabilization, hindered rotation, steric crowding, and H-bond cooperativity are proposed to participate in this striking phenomenon. The equilibrium between invertomers of aza-beta3-cyclohexapeptides is reminiscent of the interchange between the two chair forms of cyclohexane.

Metal-ion induced amplification of three receptors from dynamic combinatorial libraries of peptide-hydrazones.

Three building blocks of general structure (MeO)2 CH-aromatic linker-Pro-amino acid-NHNH2 have been prepared and tested in acid-catalysed dynamic combinatorial libraries. Exposure of these libraries to LiI and NaI led to the amplification of three macrocyclic pseudopeptide receptors. The receptors were isolated and their interactions with LiI and NaI were analysed using NMR, IR and ITC. Binding of the metal ions to the receptors is invariably entropy-driven. Nevertheless, all receptors were found to be flexible with substantial conformational rearrangements accompanying guest binding. This type of receptor is extremely difficult to access through rational design and the fact that dynamic combinatorial chemistry allows facile access to these challenging molecules underlines the power of the dynamic approach.

Triazinyl-Amino Acids, New Building Blocks for Pseudopeptides

The synthesis of a new heterocyclic building block for unnatural peptide analogues is described, and examples of its application are demonstrated. The 1,3,5-triazine nucleus is readily derivatized to possess an amino and a carboxy terminus, and the third site can be used to incorporate a wide variety of functional groups into an oligomer. This third site can also serve as the point of attachment to a solid-phase resin, allowing convenient construction of macrocyclic pseudopeptides that should be useful as clefts for molecular recognition studies or models of β-strand conformation.

Molecular amplification in a dynamic system by ammonium cations

Using hydrazone chemistry, a simple dynamic system of macrocyclic pseudo-peptides was prepared which contains a cyclic structure that resembles a known receptor for ammonium cations. A series of ammonium salts were tested as templates and the expected receptor was amplified in different degrees according to the template used. Competitive non-covalent interactions with a crown ether were used to demonstrate in situ that the templated system is still dynamic. Formation of host–guest complexes was proven by ESI-MS and 1H ROESY experiments. Relative affinities of the various templates for the isolated receptor correlate well with the effect they produce on the library composition.

ChemInform Abstract: Macrocyclic Pseudopeptides Containing N,N′‐Ethylene‐Bridged‐Dipeptide Units: Synthesis, Binding Properties Toward Metal and Organic Ammonium Cations, and Conformations. The First Step in Designing Artificial Metalloproteins

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of Structurally Reinforced Chiral Macrocyclic Polyamines and Their Metal Complexes

Abstract Two structurally reinforced chiral 15-membered azamacrocycles (2S, 14S)-2,14-diisobutyl-10-methyl-1,4,7,10,13 -pentaazabicyclo[11.2.2]heptadecane and (2S,14S)-2,14-diisobutyl-7,10-dimethyl-1,4,7,10,13-pentaazabicyclo[11.2.2] heptadecane as a new type of ligand were conveniently synthesized by LiA1H4 reduction from their corresponding macrocyclic pseudopeptides cyclo[(2S,3′S)-2-(3′-isobutyl-2′-oxopiperazine-1′-yl)-4-methyl-pentanoyl-glycyl-glycyl-sarcosyl] and cyclo[(2S, 3′S)-2-(3′-isobutyl-2′-oxopiperazine -1′-yl)-4-methyl-pentanoyl-glycyl-sarcosyl-sarcosyl], respectively. Their copper(II) complexes were also prepared and characterized.

Synthesis and Structure of Chiral Dinuclear Copper(II) Complex of Novel Structurally Reinforced Hexaazamacrocyclic Ligand

Abstract A structurally reinforced chiral 18-membered azamacrocycle (2S,8S,11S, 17S)-2,8,11,17-tetraisobutyl-1,4,7,10,13,16 -hexaazatricyclo[14.2.2.27,10]docosane as a new type of ligand was conveniently synthesized by BH3 reduction from the corresponding constrained macrocyclic pseudopeptide cyclo[(2S,3′S)-2-(3′-isobutyl-2′-oxo-piperazine-1′-yl)-4-methyl-pentanoyl-glycyl]2. Its dicopper(II) complexes were prepared and characterized.

Syntheses and Structures of Novel Optically Active Dinuclear Copper(II) Complexes of Structurally Reinforced Macrocyclic Polyamines

Abstract Optically active μ-chloro and μ-hydroxo dinuclear copper(II) complexes of structurally reinforced chiral 18-membered azamacrocycle (2S,8S,11S,17S)-2,8,11,17-tetraisobutyl-1,4,7,10,13,16-hexaazatricyclo[14. 2. 2. 27,10]docosane and 20-membered one (2S,9S,12S,19S)-2,9,12,19-tetraisobutyl-1,4,8,l1,14,18-hexaazatricyclo [16. 2. 2. 28,11] tetracosane obtained by BH3 reduction from structurally constrained macrocyclic pseudopeptides were newly synthesized and characterized.

キラルなＮ，Ｎ′‐エチレン架橋ジペプチドの簡便合成とそれらを含む擬ペプチド

Several workers have synthesized chiral and achiral N, N'-ethylene-bridged dipeptides (piperazin-2-one derivatives), and used them mainly as units of biologically active pseudopeptides such i : as enkephalin analogs because these structurally constrained and lipophilic dipeptides afford the character resisting enzymatic hydrolysis to biologically active peptides. However, their synthetic methods have some problems (nonstereoselective, multi-steps, troublesome techniques, expensive reagents etc.) Therefore; we have developed more convenient procedures for preparing N, N'-ethylene-bridged dipeptides. This article reports four kinds of synthetic methods of chiral N, N'-ethylene-bridged dipeptides, in which various (R) or (S) -α-amino acids are used as starting materials. Moreover, a series of studies on the structures and the functionalities (enantioselective inclusion and transport of (R) - and (S) -ammonium salts, complexing of metal ions) of macrocyclic pseudopeptides and on the enkephalin- and dermorphin-like biological activities of linear pseudopeptides containing these dipeptides as their units are introduced and discussed. Also, the synthesis of a macrocyclic polyamine obtained by the BH3 reduction of macrocyclic pseudopeptide and the structure of its metal complex ion are described.

Enantioselective transport of amino acid ester salts by macrocyclic pseudopeptides containing N, N′-ethylene-bridged-dipeptide units

Macrocyclic pseudopeptides containing N,N′-ethylene-bndged-dipeptide units exhibited specific transport properties toward several amino acid ester salts, while they rarely transported K− or other metal cations. In particular, a 36-membered pseudopeptide extracted amino acid ester salts in an enantioselective fashion and mediated their enantioselective transport.

Macrocyclic peptides, 8. Enantiomeric differentiations of various (R)‐ and (S)‐ ammonium and (R)‐ and (S)‐α‐amino acid ester salts by macrocyclic pseudopeptides

AbstractThe interactions of the hydrobromides of (R)‐ and (S)‐alanine‐N‐methylanilides (1) with 24‐, 27‐ and 36‐membered ring pseudopeptides (H‐24, H‐27 and H‐36, respectively) derived from glycine and (2S,3′ S)‐4‐methyl‐2‐(2′‐oxo‐3′‐isobutyl‐1′‐piperazinyl)pentanoic acid were studied by means of 1H and 13C NMR measurements in CDCl3. It was found from these results that H‐24 and H‐27 distinguished (R)‐ and (S)‐isomers of 1, while H‐36 did not entirely. Moreover, the enantioface‐differentiating abilities of these cyclic peptides were investigated by means of 1H NMR measurements in CDCI3 using (R)‐ and (S)‐1‐phenylethylammonium and (R)‐ and (S)‐p‐methoxy‐1‐phenylethylammonium bromides as the substrates, showing that the enantio‐selectivity of H‐36 is superior to those of H‐24 and H‐27. Also, the chiral recognition ability of H‐24 for the hydrochlorides of (R)‐ and (S)‐alanine (Ala), ‐leucine (Leu), ‐methionine (Met), ‐phenylalanine (Phe), ‐proline (Pro) and ‐valine (Val) methyl esters were examined by 1H and 13C NMR measurements in CDCl3. Among these hydrochlorides, HCl · PheOCH3 was distinguished more effectively with H‐24.