Pro stabilization in prolyl carbamates influenced by tetrel bonding interactions.

NMR spectral and theoretical analyses of homologous prolyl carbamates reveal subtle charge transfer tetrel bonding interactions (TBIs), selectively stabilizing their Pro rotamers. These TBIs involve C-terminal-amide to N-terminal carbamate carbonyl-carbonyl (n → π* type) followed by intra-carbamate (n → σ* type) charge transfer interactions exclusively in the Pro motif. The number of TBIs and hence the Pro stability increase with increasing number of C groups at the carbamate alcohol.

Understanding the anomaly of cis-trans isomerism in Pro-His sequence.

The anomalous absence of cisPro stabilizing CH···π interactions at Xaa-Pro-Aro exclusively when Aro is His, is understood by NMR structural analyses of model peptides, as due to i → i backbone-side chain C H-bond that forms uniquely when Aro is His, which significantly decreases its χ-g population essential for CH···π formation.

α-Helices propagating from stable nucleators exhibit unconventional thermal folding.

Although the effect of thermal perturbations on protein structure has long been modeled in helical peptides, several details, such as the relation between the thermal stabilities of the propagating and nucleating segments of helices, remain elusive. We had earlier reported on the helix-nucleating propensities of covalent H-bond surrogate-constrained α-turns. Here, we analyze the thermal stabilities of helices that propagate along peptides appended to these α-helix nucleators using their NMR and far-UV CD spectra.

Hydrogen Bond Surrogate-Constrained Dynamic Antiparallel β-Sheets.

Antiparallel β-sheets are important secondary structures within proteins that equilibrate with random-coil states; however, little is known about the exact dynamics of this process. Here, the first dynamic β-sheet models that mimic this equilibrium have been designed by using an H-bond surrogate that introduces constraint and torque into a tertiary amide bond. 2D NMR data sufficiently reveal the structure, kinetics, and thermodynamics of the folding process, thereby leading the way to similar analysis in isolated biologically relevant β-sheets.

Helix-Coil Transition at a Glycine Following a Nascent α-Helix: A Synergetic Guidance Mechanism for Helix Growth.

A detailed understanding of forces guiding the rapid folding of a polypeptide from an apparently random coil state to an ordered α-helical structure following the rate-limiting preorganization of the initial three residue backbones into helical conformation is imperative to comprehending and regulating protein folding and for the rational design of biological mimetics. However, several details of this process are still unknown. First, although the helix-coil transition was proposed to originate at the residue level ( , 526-535; , 1963-1974), all helix-folding studies have only established it between time-averaged bulk states of a long-lived helix and several transiently populated random coils, along the whole helix model sequence.

H-Bond Surrogate-Stabilized Shortest Single-Turn α-Helices: sp Constraints and Residue Preferences for the Highest α-Helicities.

Short α-helical sequences of proteins fail to maintain their native conformation when taken out of their protein context. Several covalent constraints have been designed, including the covalent H-bond surrogate (HBS)-where a peptide backbone + 4 → H-bond is replaced by a covalent surrogate-to nucleate α-helix in short sequences (>7 < 15 amino acids). But constraining the shortest sequences (four amino acids) into a single α-helical turn is still a significant challenge.

Spectral evidence for generic charge → acceptor interactions in carbamates and esters.

The correlations of the H NMR, C NMR and FT-IR spectral data from the R-O-C[double bond, length as m-dash]O groups in the alkyl carbamates and esters of homologous alcohols reveal R-group-dependent negative charge stabilization at the carbonyl oxygen and their donation to generic acceptors at C of even alkyl alcohols (R), which explains several of their apparently anomalous properties.

Exploring the consequences of a representative "disallowed" conformation of Aib on a 3₁₀-helical fold.

The structural effects of a representative "disallowed" conformation of Aib on the 3(10)-helical fold of an octapeptidomimetic are explored. The 1D ((1)H, (13)C) & 2D NMR, FT-IR and CD data reveal that the octapeptide 1, adopts a 3(10)-helical conformation in solution, as it does in its crystal structure. The C-terminal methyl carboxylate (CO2Me) of 1 was modified into an 1,3-oxazine (Oxa) functional group in the peptidomimetic 2.

Steric and electronic interactions controlling the cis/trans isomer equilibrium at X-Pro tertiary amide motifs in solution.

A systematic understanding of the noncovalent interactions that influence the structures of the cis conformers and the equilibrium between the cis and the trans conformers, of the X-Pro tertiary amide motifs, is presented based on analyses of (1)H-, (13)C-NMR and FTIR absorption spectra of two sets of homologous peptides, X-Pro-Aib-OMe and X-Pro-NH-Me (where X is acetyl, propionyl, isobutyryl and pivaloyl), in solvents of varying polarities. First, this work shows that the cis conformers of any X-Pro tertiary amide motif, including Piv-Pro, are accessible in the new motifs X-Pro-Aib-OMe, in solution. These conformers are uniquely observable by FTIR spectroscopy at ambient temperatures and by NMR spectroscopy from temperatures as high as 273 K.

Accessing the disallowed conformations of peptides employing amide-to-imidate modification.

Selective modification of the C-terminal amide in peptides to dihydrooxazine (a novel stable imidate isostere) by intramolecular nucleophilic cyclo-O-alkylation of the corresponding N-(3-bromopropyl)amides results in constraining of the C-terminal residue in natively disallowed conformations both in crystals and in solution.

Synthesis and isolation of 5,6-dihydro-4H-1,3-oxazine hydrobromides by autocyclization of N-(3-bromopropyl)amides.

5,6-Dihydro-4H-1,3-oxazine hydrobromides have been synthesized by the nucleophilic autocyclo-O-alkylation of N-(3-bromopropyl)amides under neutral conditions in chloroform. It is found that electron-donating amide α-substituents influence the autocyclization efficiency.

N-{1-[(3-Bromo-prop-yl)amino-carbon-yl]eth-yl}-2-(2-nitro-benzene-sulfonamido)propionamide.

In the title compound, C(15)H(21)BrN(4)O(6)S, all three NH groups are involved in inter-molecular N-H⋯O inter-actions which, together with two inter-molecular C-H⋯O contacts, lead to a continuous anti-parallel β-sheet structure. There are no π-π inter-actions between mol-ecules, and two C-H⋯π inter-actions primarily govern the linkage between sheets.

Free radical-mediated aryl amination: convergent two- and three-component couplings to chiral 2,3-disubstituted indolines.

5-exo-trig Cyclization of an aryl radical to the nitrogen of an azomethine is used as the key annulating step in a modular preparation of 2,3-cis- and trans-disubstituted indolines. The precursors are readily prepared by phase-transfer-catalyzed Michael addition of a glycine Schiff base to a variety of acceptors. When the more reactive alkylidene malonate Michael acceptors are implemented, a one-pot three-component coupling is possible.

Free radical-mediated aryl amination and its use in a convergent [3 + 2] strategy for enantioselective indoline alpha-amino acid synthesis.

The scope of aryl radical additions to the nitrogen of azomethines is described. Aryl, trifluoromethyl alkyl, and alpha,beta-unsaturated ketimines engage in regioselective aryl-nitrogen bond formation via 5-exo cyclizations of an aryl radical to azomethine nitrogen. Selectivity for carbon-nitrogen over carbon-carbon bond formation is generally high (>95:5) and competes only with direct aryl radical reduction by stannane (0-10%).

Free radical-mediated vinyl amination: access to N,N-dialkyl enamines and their beta-stannyl and beta-thio derivatives.

[reaction: see text] The first examples of free radical-mediated vinyl amination are described by nonconventional vinyl radical addition to azomethine nitrogen. This new vinyl amination protocol is mild and provides convenient synthetic access to nonstabilized N,N-dialkyl enamines and tandem bond-forming processes.