Cyclic Β-amino Acids Research Articles

Discrete Heterogeneous Quaternary Structure Formed by α/β-Peptide Foldamers and α-Peptides

The development of unnatural oligomers that adopt predictable secondary structures has led to increased interest in expanding the conformational repertoire of foldamers to include discrete, cooperatively folded tertiary and quaternary structures. Here we report the first examples of heterogeneous quaternary structure: stable tetrameric helix bundles incorporating both α-peptides and α/β-peptide foldamers. The results suggest that hydrophobic interactions in the core of the helix bundle contribute to the stability of the assembly, as do cyclic β-amino acid residues within the α/β-peptide. These observations demonstrate that secondary structural elements in well-folded tertiary or quaternary structures need not have the same backbone composition. Our findings highlight the prospect that diverse combinations of foldamer and α-peptide subunits could lead to folding and/or assembly behavior reminiscent of that necessary for complex protein function.

Highly constrained bicyclic VLA-4 antagonists

VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic β-amino acids (β-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle ( ϕ) between the amino and the carboxyl termini of the β-aa. Compound 5m where the β-aa is embedded in a bicycle possesses the most preferred ϕ (120°). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig α4β1 IC 50 = 54 nM, rat po F = 49%).

Dimolybdenum Tetraacetate as an Auxiliary Chromophore in Absolute Configuration Determination of Amino Acids from their Circular Dichroism Spectra - Foundations and Developments

A straightforward and versatile method for the determination of the absolute configuration of amino acids is presented. The proposed method involves the in situ formation of chiral complexes of optically active amino acids with the achiral dimolybdenum tetraacetate (Mo2(OAc)4) acting as an auxiliary chromophore. Optically active amino acids in reaction with (Mo2(OAc)4) in DMSO exchange in situ its acetate ligand to form chiral Mo-complexes. These complexes display several CD bands in the spectral range from 600 to 250 nm. The resulting CD spectra are suitable for the assignment of absolute configuration, since the observed sign of Cotton effects arising within the d−d absorption bands of the metal core depends solely upon the chirality of the amino acid ligands. It is shown that two Cotton effects at around 300 nm and 400 nm are especially useful for the correlation between their sign and the stereostructure of amino acids by means of the hexadecant rule. The present study demonstrates that the hexadecant rule can be extended to differently N-protected amino acids. The dimolybdenum method can also be applied for determination of the absolute configuration of cyclic β-amino acids representing precursors of peptidomimetics.

Asymmetric Synthesis of Fluorinated Cyclic β-Amino Acid Derivatives through Cross Metathesis

The asymmetric synthesis of several fluorinated cis-2-aminocycloalkane carboxylic acids (cis-2-ACACs) with a cross metathesis (CM) reaction as the key step has been carried out, constituting the first time a metathesis protocol has been undertaken with fluorinated imidoyl chlorides. Subsequent chemoselective hydrogenation of the olefin moiety, Dieckmann condensation, and stereoselective reduction of the iminic double bond afforded the corresponding beta-amino esters with several ring sizes. The asymmetric version of the process was achieved by using (-)-8-phenylmenthol as a chiral auxiliary.

Columnar Assembly of Cyclic β-Amino Acid Functionalized with Pyranose Rings

A novel cyclic trimer and tetramer of protected beta-glycamino acids were synthesized and investigated on conformation and assembly formation. A characteristic point of these cyclic beta-glycamino acids is their better solubility than other cyclic beta-amino acids due to the pyranose rings. Thus, the assembling process of the cyclic molecules could be examined by CD or NMR spectroscopy. FT-IR and NMR measurements and geometry optimization revealed a highly symmetric and planar conformation for each cyclic beta-peptide with all-trans amide groups. The amide groups in the cyclic peptides took a vertical orientation against the cyclic skeleton to be suitably arranged for intermolecular hydrogen bonds, which should promote formation of molecular assembly in a columnar structure through molecular stacking. These cyclic beta-peptides were successfully crystallized to yield rod-shaped molecular assemblies in nanometer sizes. Evidence for the columnar structure in the crystals was obtained by electron diffraction analysis, which showed a layer spacing of ca. 4.8 A. Interestingly, the molecular assembly of the cyclic trimer showed a high aspect ratio, width less than 40 nm, and length more than 2 mum, suggesting stable molecular stacking in the column.

Synthesis of Cyclic β-Amino Acids by RCM

Synthesis of Cyclic β-Amino Acids by RCM

Application of Oppolzer′s Sultam in the Synthesis of Cyclic α‐Amino Acids and β‐Amino Acids.

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An Efficient Enantioselective Approach to Cyclic β-Amino Acid Derivatives via Olefin Metathesis Reactions

The asymmetric synthesis of polyfunctionalized piperidine- and pyrrolidine-based scaffolds, specifically designed for the preparation of cyclic, conformationally constrained beta-amino acids, is realized combining a biocatalytic access to a versatile chiral building block with a wide range of transformations based on olefin metathesis.

Application of alicyclic β-amino acids in peptide chemistry

The self-organizing beta-peptides have attracted considerable interest in the fields of foldamer chemistry and biochemistry. These compounds exhibit various stable secondary structure motifs that can be exploited to construct biologically active substances and nanostructured tertiary structures. The secondary structures can be controlled via the beta-amino acid sequence, and cyclic beta-amino acid residues play a crucial role in the design. The most important procedures for the preparation of cyclic beta-amino acid monomers and peptides are discussed in this tutorial review. Besides the secondary structure design principles, the methods of folded structure detection are surveyed.

Syntheses of Hydroxylated Cyclic β-Amino Acid Derivatives

This review is intended to give a short summary of the developments in the field of natural and synthetic alicyclic and heterocyclic hydroxylated beta-amino acids and to focus on the main strategies that have been reported for their synthesis. Given the medicinal and biological significance of the hydroxylated beta-amino acids, an increasing volume of research is currently being directed toward regio-, stereo- and enantioselective access to this class of compounds.

Catalytic Enantioselective Desymmetrization of meso‐N‐Acylaziridines with TMSCN.

A catalytic enantioselective desymmetrization of meso-N-p-nitrobenzoylaziridines with TMSCN was developed using a chiral gadolinium catalyst generated from Gd(OiPr)3 and d-glucose-derived ligand 1. In this reaction, the addition of a catalytic amount of trifluoroacetic acid (TFA) improved enantioselectivity. High enantioselectivity was obtained from a range of meso-aziridines at 0−60 °C. The product could be easily transformed into β-amino acids. Thus, the developed catalytic enantioselective desymmetrization reaction allowed for efficient catalytic synthesis of chiral cyclic β-amino acids. The incorporation of TFA into the catalyst complex was observed using ESI-MS. Generation of this new complex might be the origin of the improved enantioselectivity.

Diastereoselective Route to Novel Fused or Bridged Tricyclic β‐Lactams Through Intramolecular Nitrone—Alkene Cycloaddition of 2‐Azetidinone‐Tethered Alkenylaldehydes — Synthetic Applications to Carbacephams and Cyclic β‐Amino Acid Derivatives.

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An Efficient Synthesis of Cyclic β‐Amino Acid Derivatives as β‐Turn Mimetics.

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The Enantioselective Synthesis of Conformationally Constrained Cyclic β- Amino Acids

Enantiomerically pure and conformationally constrained cyclic β-amino acids have been the subject of a vast amount of research across the chemical, biological, and medicinal disciplines. These valuable molecules are synthetic precursors for a wide variety of useful compounds that include natural products and modified peptides. Many methods have been developed to prepare chiral cyclic β-amino acids in high optical purity. This mini-review will discuss some of the most recent and successful approaches.

An Efficient Synthesis of Cyclic β-Amino Acid Derivatives as β-Turn Mimetics

Seven-, eight-, and nine-membered cyclic β-amino acids, precursors of platelet aggregation inhibitors, were synthesized for the first time starting from N-alkenyl amines and ethyl acrylate via ring-closing metathesis (RCM) as the key reaction. Synthesis of the corresponding enantiomerically pure β-amino acids was also accomplished in a similar manner using Evans' asymmetric allylation.

Cyclic β-amino acid derivatives: synthesis via lithium amide promoted tandem asymmetric conjugate addition–cyclisation reactions

The product distribution upon conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to dimethyl-(E,E)-nona-2,7-dienedioate can be controlled to give either the cyclic 1,2-anti-1,6-anti-beta-amino ester (derived from conjugate addition and intramolecular enolate cyclisation) or the acyclic bis-beta-amino ester derivative (derived from double conjugate addition) in high de. The introduction of a protected nitrogen functionality into the diester skeleton facilitates, after conjugate addition and intramolecular enolate cyclisation, the asymmetric construction of piperidines in high de; variation in the N-protecting group indicates that the highest stereoselectivity is observed with alpha-branched N-substituents. Tandem conjugate addition-aldol reactions can also be achieved stereoselectively, with lithium amide conjugate addition to epsilon- and zeta-oxo-alpha,beta-unsaturated esters giving the corresponding five and six membered cyclic beta-amino esters in high de. N-deprotection by hydrogenolysis of the products arising from these reactions furnishes a range of polyfunctionalised transpentacin and transhexacin derivatives in high de and ee.

An Efficient Synthesis of Chiral Cyclic β-Amino Acids via Asymmetric Hydrogenation

Cyclic β-amino acids, homoproline, homopipecolic acid and 3-carboxy-methylmorpholine were obtained in high enantiomeric excesses by transition metal-catalyzed asymmetric hydrogenation of cyclic β-acylamino-alkenoates. These compounds were synthesized by a thio-Wittig reaction on N-protected thiolactames.

A New Strategy To Produce β-Peptides: Use of Alicyclic β-Lactams

On p-methylbenzhydrylamine (MBHA) resin, by means of t-Boc chemistry, several tetrapeptides (H-Ala-ACXC-Ala-Gly-NH(2)) containing cyclic beta-amino acid units were prepared. These units were introduced into the growing peptide chain by using Boc-protected beta-lactams with KCN as catalyst in DMF. The method was applicable for both racemic and enantiomeric beta-lactams.

Synthesis of cyclic beta-amino acid esters from methionine, allylglycine, and serine.

Here we report a versatile ring-closing metathesis-based approach to 5-, 6-, and 7-membered cyclic beta-amino esters starting with simple and readily available building blocks-methionine, allylglycine, and serine-where the nature of the amino acid determines the size of the carbocyclic ring.

Two helical conformations from a single foldamer backbone: "split personality" in short alpha/beta-peptides.

Oligopeptides with heterogeneous backbones, i.e., oligopeptides containing more than one monomer type, may be a fruitful source of new foldamers. This conclusion was suggested by studies on oligomers comprising L-α-amino acid and cyclic β-amino acid residues in a sequentially alternating pattern, which are shown to display helical secondary structure in solution. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2004/z52125_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.