A Multiple Multicomponent Approach to Chimeric Peptide–Peptoid Podands

The success of multi‐armed, peptide‐based receptors in supramolecular chemistry traditionally is not only based on the sequence but equally on an appropriate positioning of various peptidic chains to create a multivalent array of binding elements. As a faster, more versatile and alternative access toward (pseudo)peptidic receptors, a new approach based on multiple Ugi four‐component reactions (Ugi‐4CR) is proposed as a means of simultaneously incorporating several binding and catalytic elements into organizing scaffolds. By employing α‐amino acids either as the amino or acid components of the Ugi‐4CRs, this multiple multicomponent process allows for the one‐pot assembly of podands bearing chimeric peptide–peptoid chains as appended arms. Tripodal, bowl‐shaped, and concave polyfunctional skeletons are employed as topologically varied platforms for positioning the multiple peptidic chains formed by Ugi‐4CRs. In a similar approach, steroidal building blocks with several axially‐oriented isocyano groups are synthesized and utilized to align the chimeric chains with conformational constrains, thus providing an alternative to the classical peptido‐steroidal receptors. The branched and hybrid peptide–peptoid appendages allow new possibilities for both rational design and combinatorial production of synthetic receptors. The concept is also expandable to other multicomponent reactions.     

Decarbonylative Radical Coupling of α‐Aminoacyl Tellurides: Single‐Step Preparation of γ‐Amino and α,β‐Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A

A new radical‐based coupling method has been developed for the single‐step generation of various γ‐amino acids and α,β‐diamino acids from α‐aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α‐aminoacyl tellurides were readily converted into α‐amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (?)‐manzacidin A.     

3-Amino-2H-Azirines. Synthons for α,α-Disubstituted α-Amino Acids in Heterocycle and Peptide Synthesis [New Analytical Methods (43)]

The recent upswing in peptide chemistry has been accompanied by an increasing interest in nonproteinogenic amino acids. These include the α,α-disubstituted glycines, the best known of which is Aib (2-aminoisobutyric acid, 2-methylalanine). These α-amino acids occur in natural oligopeptides such as the peptaibols, a class of membrane-active ionophores that has been isolated from fungal cultures. The twofold substitution at the α-C atom of the amino acids severely restricts the conformational freedom of the peptides and causes particular secondary structures to be favored; thus, α, α-disubstituted α-amino acids induce the formation of β turns or helices. 3-Amino-2H-azirines are ideal synthons for the construction of oligopeptides, cyclic peptides and depsipeptides (peptolides) containing such α,α-disubstituted α-amino acids. The presence of the ring strain in these molecules means that they can be used in peptide coupling without the need for additional activating reagents. Using 3-amino-2H-azirines a large array of heterocycles containing α, α-disubstituted α-amino acids as structural elements within their skeleton can be synthesized. The driving force in these reactions is the release of the strain on the three-membered ring, which usually takes place in a ring-expansion reaction. The mechanistic elucidation of these reactions, which can be quite complex, contains some surprises.     

Modeling nonaqueous proton wires built from helical peptides: biased proton transfer driven by helical dipoles

We report gas-phase electronic structure calculations on helical peptides that act as scaffolds for imidazole-based hydrogen-bonding networks (proton wires). We have modeled various 21-residue polyalanine peptides substituted at regular intervals with histidines (imidazole-bearing amino acids), using a hybrid approach with a semiempirical method (AM1) for peptide scaffolds and density functional theory (B3LYP) for proton wires. We have computed energy landscapes including barriers for Grotthuss-shuttling-type proton motions though wires supported on 3(10)-, α- and π-helical structures, showing the 3(10)- and α-helices to be attractive targets in terms of high proton affinities, low Grotthuss shuttling barriers, and high stabilities. Moreover, bias forces provided by the helical dipole moments were found to promote unidirectional proton translocation.     

Chiral nickel(II) complexes in the preparation of 11C- and 18F-labelled enantiomerically pure α-amino acids

Positron emission tomography (PET) utilises positron emitting radiopharmaceuticals in the study of metabolic and physiological processes. FDG-PET is a useful technique for tumour detection; however FDG has disadvantages. The incorporation of labelled amino acids into brain tumours and into some other organs with high physiological consumption of glucose is a superior diagnostic method due to its much higher selectivity compared to FDG. A Ni(II) complex with a Schiff base of BPB and glycine was one of the first glycine synthons used for asymmetric synthesis of carbon-11 and fluorine-18 labelled α-amino acids. A similar complex was employed for routine preparation of [(18)F]FET. Physico-chemical investigations allowed us to design modified complexes with much stronger stereodiscriminative power including stereospecific ones. Chiral nickel complexes are also used for the preparation of tailored amino acids for the incorporation into peptides followed by labelling the peptides with fluorine-18 labelled "click" reagents. This review covers PET applications of Ni(II) complexes of Schiff base of BPB and α-amino acids from 1989 to date.     

Dihedral-angle dependence of the vicinal 15N,13C spin-coupling constants. A new NMR parameter for the conformational analysis of amino acids and peptides

The first successful observation of the vicinal ¹⁵N,¹³C spin-coupling constants in a series of amino acids, comprising Val, Ile, Leu and Thr, in which the α-nitrogens are fully replaced with ¹⁵N, is described. A Karplus-type dihedral-angle dependence was noted for the coupling constants between the α-nitrogen and γ-carbon nuclei which may, in turn, be applied to the conformational analysis of other amino acids and small peptides. The potential usefulness and limitation of this new parameter in such applications is briefly discussed.     

Copper/DIPEA-catalyzed, aldehyde-induced tandem decarboxylation-coupling of natural α-amino acids and phosphites or secondary phosphine oxides

A copper/DIPEA-catalyzed, aldehyde-induced intermolecular decarboxylative coupling reaction of natural α-amino acids and phosphites or secondary phosphine oxides was developed. In this process, a series of potentially useful ligands for organic synthesis and biologically important unnatural amino acid derivatives (tertiary amino phosphorus compounds) were obtained.     

Fluorinated amino acids: compatibility with native protein structures and effects on protein-protein interactions

Fluorinated analogues of the canonical α-L-amino acids have gained widespread attention as building blocks that may endow peptides and proteins with advantageous biophysical, chemical and biological properties. This critical review covers the literature dealing with investigations of peptides and proteins containing fluorinated analogues of the canonical amino acids published over the course of the past decade including the late nineties. It focuses on side-chain fluorinated amino acids, the carbon backbone of which is identical to their natural analogues. Each class of amino acids--aliphatic, aromatic, charged and polar as well as proline--is presented in a separate section. General effects of fluorine on essential properties such as hydrophobicity, acidity/basicity and conformation of the specific side chains and the impact of these altered properties on stability, folding kinetics and activity of peptides and proteins are discussed (245 references).     

Self-assembly of peptide scaffolds in biosilica formation: computer simulations of a coarse-grained model

The self-assembly of model peptides is studied using Brownian dynamics computer simulations. A coarse-grained, bead-spring model is designed to mimic silaffins, small peptides implicated in the biomineralization of certain silica diatom skeletons and observed to promote the formation of amorphous silica nanospheres in vitro. The primary characteristics of the silaffin are a 15 amino acid hydrophilic backbone and two modified lysine residues near the ends of the backbone carrying long polyamine chains. In the simulations, the model peptides self-assemble to form spherical clusters, networks of strands, or bicontinuous structures, depending on the peptide concentration and effective temperature. The results indicate that over a broad range of volume fractions (0.05-25%) the characteristic structural lengthscales fall in the range 12-45 nm. On this basis, we suggest that self-assembled structures act as either nucleation points or scaffolds for the deposition of 10-100 nm silica-peptide building blocks from which diatom skeletons and synthetic nanospheres are constructed.     

Synthesis of Biaryl-Bridged Cyclic Peptides via Catalytic Oxidative Cross-Coupling Reactions

Biaryl-bridged cyclic peptides comprise an intriguing class of structurally diverse natural products with significant biological activity. Especially noteworthy are the antibiotics arylomycin and its synthetic analogue G0775, which exhibits potent activity against Gram-negative bacteria. Herein, we present a simple, flexible, and reliable strategy based on activating-group-assisted catalytic oxidative coupling for assembling biaryl-bridged cyclic peptides from natural amino acids. The synthetic approach was utilized for preparing a number of natural and unnatural biaryl-bridged cyclic peptides, including arylomycin/G0775 and RP 66453 cyclic cores.     

Design and synthesis of a trans-fused polycyclic ether skeleton as an α-helix mimetic scaffold

Inspired by the common skeletal feature of potent marine toxins, a ladder-like polycyclic ether scaffold was designed as the basis for the synthesis of structurally defined α-helix mimics. A synthetic route to trans-fused 6/6/6/6/6 pentacyclic ether skeletons is presented, involving the iterative assembly of tetrahydropyran rings via the SmI₂-mediated coupling reaction of α-sulfonyl ketones with aldehydes.     

海星动物化学成份的研究-罗氏海盘车中的皂苷元

报导了从罗氏海盘车中分离得到二个甾体皂苷元;20(R)-5α-孕甾-9(11)-烯-3β,6α,20-三醇和5α-孕甾-9(11)-烯-3β,6α-二醇-20-酮,并测定了它们的结构.     

Oxidative modification of native protein residues using cerium(IV) ammonium nitrate

A new protein modification strategy has been developed that is based on an oxidative coupling reaction that targets electron-rich amino acids. This strategy relies on cerium(IV) ammonium nitrate (CAN) as an oxidation reagent and results in the coupling of tyrosine and tryptophan residues to phenylene diamine and anisidine derivatives. The methodology was first identified and characterized on peptides and small molecules, and was subsequently adapted for protein modification by determining appropriate buffer conditions. Using the optimized procedure, native and introduced solvent-accessible residues on proteins were selectively modified with polyethylene glycol (PEG) and small peptides. This unprecedented bioconjugation strategy targets these under-utilized amino acids with excellent chemoselectivity and affords good-to-high yields using low concentrations of the oxidant and coupling partners, short reaction times, and mild conditions.     

Ribosomal synthesis of bicyclic peptides via two orthogonal inter-side-chain reactions

Here we report a new methodology for the synthesis of bicyclic peptides by using a reconstituted cell-free translation system under the reprogrammed genetic code. Cysteine (Cys) and three different nonproteinogenic amino acids, Cab, Aha, and Pgl, were simultaneously incorporated into a peptide chain. The first cyclization occurred between the chloroacetyl group of Cab and the sulfhydryl group in Cys in situ of translation, and the second cyclization on the side chains of Aha-Pgl via Cu(I)-catalyzed azide-alkyne cycloaddition was performed. This offers us a powerful means of mRNA-programmed synthesis of various peptides with uniform bicyclic scaffolds.     

Efficient stereoselective synthesis of gamma-N-glycosyl asparagines by N-glycosylation of primary amide groups

The efficient and elegant synthesis of N-glycosides by N-glycosylation of asparagine-containing peptides is described. Glycosylation of primary amides with glycosyl N-phenyltrifluoroimidates in the presence of a catalytic amount of TMSOTf in nitromethane smoothly proceeded to provide the corresponding N-glycosyl amino acids in excellent yields. This coupling method was adaptable to the coupling of various glycosyl donors with amino acids and peptides.     

General and Facile Route to Isomerically Pure Tricyclic Peptides Based on Templated Tandem CLIPS/CuAAC Cyclizations

We report a one‐pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties. These react via CLIPS/CuAAC reactions with cysteines and azides in the peptide. Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T4 ₁ and T4 ₂ mostly promote the formation of single isomeric tricycles while the rigid scaffolds T4 ₃ and T4 ₄ do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other way round.     

Direct asymmetric intermolecular aldol reactions catalyzed by amino acids and small peptides

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.     

Artificial β‐Double Helices from Achiral γ‐Peptides

Double helices are not common in polypeptides and proteins except in the peptide antibiotic gramicidin A and analogous l,d ‐peptides. In contrast to natural polypeptides, remarkable β‐double‐helical structures from achiral γ‐peptides built from α,β‐unsaturated γ‐amino acids have been observed. The crystal structures suggest that they adopted parallel β‐double helical structures and these structures are stabilized by the interstrand backbone amide H‐bonds. Furthermore, both NMR spectroscopy and fluorescence studies support the existence of double‐helical conformations in solution. Although a variety of folded architectures featuring distinct H‐bonds have been discovered from the β‐ and γ‐peptide foldamers, this is the first report to show that achiral γ‐peptides can spontaneously intertwine into β‐double helical structures.     

Synthesis of Biaryl‐Bridged Cyclic Peptides via Catalytic Oxidative Cross‐Coupling Reactions

Biaryl‐bridged cyclic peptides comprise an intriguing class of structurally diverse natural products with significant biological activity. Especially noteworthy are the antibiotics arylomycin and its synthetic analogue G0775, which exhibits potent activity against Gram‐negative bacteria. Herein, we present a simple, flexible, and reliable strategy based on activating‐group‐assisted catalytic oxidative coupling for assembling biaryl‐bridged cyclic peptides from natural amino acids. The synthetic approach was utilized for preparing a number of natural and unnatural biaryl‐bridged cyclic peptides, including arylomycin/G0775 and RP 66453 cyclic cores.     

o-Nitrobenzoyl group as a new amino protecting group for peptide synthesis and the synthesis of some anthranilyl peptides

N (o-nitrobenzoyl)amino acids can be coupled with other amino acids using DCC and the resulting product on hydrogenation gives peptides, containing the anthranilyl group as —NH₂ end group. N (anthranilyl)amino acids or peptides can also be obtained by reaction of isatoic anhydride on amino acids or peptides. The anthranilyl end group is easily cleaved by metal (Cu⁺²) catalysed hydrolysis to give α-amino acid peptides and the insoluble copper(II) anthranilate.