High anti Diastereoselectivity in a Tandem Oxyhomologation-Coupling Protocol for the Preparation of Amides and Peptides Incorporating α-Hydroxy ß-Amino Acids.

The one-pot MAC (Masked Acyl Cyanide) reaction is used to perform the tandem oxyhomologation reaction of N,N-dibenzyl-l-phenylalaninal and coupling with nitrogen nucleophiles to provide a wide selection of amide and peptide derivatives of (2S,3S)-allophenylnorstatin in generally good yields and with high anti selectivity, often with dr >98:2. The procedure works equally well with other selected N,N-dibenzyl α-amino aldehydes, and is used to achieve a very short synthesis of (2S,3S,S)-epibestatin.

Effects of sulfoxide and sulfone sidechain-backbone hydrogen bonding on local conformations in peptide models.

We examine peptide model systems designed to probe short-range N-H⋯OS sidechain-backbone hydrogen bonding involving amino acid residues with sidechain sulfoxide or sulfone functional groups and its effects on local conformations. A strong 7-membered ring hydrogen bond of this type accompanies an intra-residue N-H⋯OC interaction and stabilizes an extended backbone conformation in preference to classical folded structures.

Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds.

Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain-backbone N-H···N C6γ H-bonds that accompany-and thereby stabilize-C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.

Non-covalent interactions reveal the protein chain δ conformation in a flexible single-residue model.

The δ conformation is a local secondary structure in proteins that implicates a πamide N-H⋯N interaction between a backbone N atom and the NH of the following residue. Small-molecule models thereof have been limited so far to rigid proline-type compounds. We show here that in derivatives of a cyclic amino acid with a sulphur atom in the γ-position, specific side-chain/backbone N-H⋯S interactions stabilize the δ conformation sufficiently to allow it to compete with classical C5 and C7 H-bonded conformers.

Preparation of Thietane Derivatives through Domino Photochemical Norrish Type II/Thia-Paternò-Büchi Reactions.

This work describes straightforward access to a large collection of thietane derivatives through an innovative two-step domino photochemical reaction involving a Norrish type II fragmentation and a thia-Paternò-Büchi reaction. Starting from stable phenacyl sulfides, unprecedented thiocarbonyl intermediates were generated in situ and reacted with diverse electron-deficient alkene partners to form a thietane core. The rules governing the regio- and diastereoselectivity of this [2+2] photocycloaddition have been rationalized and fully controlled for many substrates.

Characterization of Asx Turn Types and Their Connate Relationship with ß-Turns.

Invited for the cover of this issue are David J. Aitken, Michel Mons, and co-workers at Université Paris-Saclay. The image depicts the investigation strategies used to document the intrinsic structures of an important secondary structure in proteins, the so-called Asx turn. Read the full text of the article at 10.1002/chem.202104328.

Characterization of Asx Turn Types and Their Connate Relationship with ß-Turns.

Models of asparagine-containing dipeptides specifically designed to favor intrinsic folding into an Asx turn were characterized both theoretically, by using quantum chemistry, and experimentally, by using laser spectroscopy in the gas phase. Both approaches provided evidence for the spontaneous folding of both the Asn-Ala and Asn-Gly dipeptide models into the most stable Asx turn, a conformation stabilized by a C10 H-bond that was very similar to a type II' ß-turn. In parallel, analysis of Asx turns implicating asparagine in crystallized protein structures in the Protein Data Bank revealed a sequence-dependent behavior. In Asn-Ala sequences, the Asx turn was found in conjunction with a type I ß-turn for which the first of the four defining residues was Asn. The observation that the Asx turn in these structures is mostly of type II' (i. e., its most stable innate structure) suggests that this motif might foster the formation and/or enhance the stability of the backbone ß-turn. In contrast, the Asx turns observed in Asn-Gly sequences extensively adopted a type II Asx-turn structure, thus suggesting that their formation should be ascribed to other factors, such as hydration. The fact that the Asx turn in a Asn-Gly sequence is also often found in combination with a hydrated ß-bulge supports the premise that a Asn-Gly sequence might efficiently promote the formation of the ß-bulge secondary structure.

A case study of the MAC (masked acyl cyanide) oxyhomologation of N,N-dibenzyl-L-phenylalaninal with anti diastereoselectivity: preparation of (2S,3S)-allophenylnorstatin esters.

The three-component reaction between a protected α-amino aldehyde, an alcohol and an α-silyloxymalononitrile provides an expedient access to protected α-hydroxy-ß-amino acid derivatives. The prototypical process, performed on N-Cbz-phenylalaninal, is known to proceed with syn diastereoselectivity. The present study demonstrates that the diastereoselectivity of the reaction can be inverted, using the rationale of a Felkin-Anh interaction model. Reactions performed on N,N-dibenzyl-L-phenylalaninal proceed with a high anti diastereoselectivity, providing a panel of synthetically useful ester derivatives of (2S,3S)-allophenylnorstatin. The procedure is exploited to accomplish one of the most efficient syntheses of the title compound to date, in 3 steps (66% yield) from N,N-dibenzyl-L-phenylalaninal.

N-H⋯X interactions stabilize intra-residue C5 hydrogen bonded conformations in heterocyclic α-amino acid derivatives.

Nature makes extensive and elaborate use of hydrogen bonding to assemble and stabilize biomolecular structures. The shapes of peptides and proteins rely significantly on N-H⋯O[double bond, length as m-dash]C interactions, which are the linchpins of turns, sheets and helices. The C5 H-bond, in which a single residue provides both donor and acceptor, is generally considered too weak to force the backbone to adopt extended structures. Exploiting the synergy between gas phase (experimental and quantum chemistry) and solution spectroscopies to decipher IR spectroscopic data, this work demonstrates that the extended C5-based conformation in 4-membered ring heterocyclic α-amino acid derivatives is significantly stabilized by the formation of an N-H⋯X H-bond. In this synergic system the strength of the C5 interaction remains constant while the N-H⋯X H-bond strength, and thereby the support provided by it, varies with the heteroatom.

A Brønsted acid catalyzed tandem reaction for the diastereoselective synthesis of cyclobuta-fused tetrahydroquinoline carboxylic esters.

A novel Brønsted acid catalyzed tandem reaction provides highly functionalized cyclobuta-fused tetrahydroquinoline carboxylic esters from anilines and 2-alkylenecyclobutanones in good to high yield. During the reaction a dynamic diastereoselective cyclization is achieved, resulting in the formation of three contiguous stereocenters with high stereoselectivity.

Ion Pair Supramolecular Structure Identified by ATR-FTIR Spectroscopy and Simulations in Explicit Solvent*.

The present work uses ATR-FTIR spectroscopy assisted by simulations in explicit solvent and frequency calculations to investigate the supramolecular structure of carboxylate alkali-metal ion pairs in aqueous solutions. ATR-FTIR spectra in the 0.25-4.0 M concentration range displayed cation-specific behaviors, which enabled the measurement of the appearance concentration thresholds of contact ion pairs between 1.9 and 2.6 M depending on the cation. Conformational explorations performed using a non-local optimization method associated to a polarizable force-field (AMOEBA), followed by high quantum chemistry level (RI-B97-D3/dhf-TZVPP) optimizations, mode-dependent scaled harmonic frequency calculations and electron density analyses, were used to identify the main supramolecular structures contributing to the experimental spectra. A thorough analysis enables us to reveal the mechanisms responsible for the spectroscopic sensitivity of the carboxylate group and the respective role played by the cation and the water molecules, highlighting the necessity of combining advanced experimental and theoretical techniques to provide a fair and accurate description of ion pairing.

Pyrrolidinyl peptide nucleic acids bearing hydroxy-modified cyclobutane building blocks: Synthesis and binding properties.

The conformationally constrained pyrrolidinyl PNA with a dipeptide consisting of an alternating nucleobase-modified D-proline and a cyclic ß-amino acid "spacer" exhibited improved nucleic acid binding properties compared to the original PNA. The pyrrolidinyl PNA with the four-membered ring spacer (1S,2S)-2-aminocyclobutanecarboxylic acid (acbcPNA) are among the best performed members of the pyrrolidinyl PNA family. However, these PNA suffer some limitations such as aqueous solubility and non-specific interactions due to their extreme hydrophobicity. In the present work, a hydroxy group is introduced onto the cyclobutane ring spacer of the acbcPNA with the aim of decreasing its hydrophobicity. To this end, a Fmoc/tBu ether-protected 4-hydroxy-2-aminocyclobutanecarboxylic acid building block was synthesized and resolved by chiral HPLC. Each enantiomer was used to synthesize the hydroxy-modified acbcPNA employing Fmoc solid-phase peptide synthesis. DNA/RNA binding studies indicated that the introduction of the hydroxy group to the acbcPNA decreases the binding affinity toward complementary DNA and RNA while maintaining the sequence and directional specificity of unmodified acbcPNA. The hydrophobicity of the hydroxy-modified acbcPNA decreased with the number of hydroxy groups added as indicated by the decrease in the logP values. Only two modifications were sufficient to decrease the logP by an order of magnitude without excessively lowering the binding affinity nor the specificity. This work thus demonstrated that the specific structural modifications for this type of PNA model can be performed in a modular fashion, which paves the way toward the future realization of improving hydrophilicity and nucleic acid binding affinity as well as specificity.

A theoretical and experimental case study of the hydrogen bonding predilection of S-methylcysteine.

S-containing amino acids can lead to two types of local NH···S interactions which bridge backbone NH sites to the side chain to form either intra- or inter-residue H-bonds. The present work reports on the conformational preferences of S-methyl-L-cysteine, Cys(Me), using a variety of investigating tools, ranging from quantum chemistry simulations, gas-phase UV and IR laser spectroscopy, and solution state IR and NMR spectroscopies, on model compounds comprising one or two Cys(Me) residues. We demonstrate that in gas phase and in low polarity solution, the C- and N-capped model compound for one Cys(Me) residue adopts a preferred C5-C6γ conformation which combines an intra-residue N-H···O=C backbone interaction (C5) and an inter-residue N-H···S interaction implicating the side-chain sulfur atom (C6γ). In contrast, the dominant conformation of the C- and N-capped model compound featuring two consecutive Cys(Me) residues is a regular type I ß-turn. This structure is incompatible with concomitant C6γ interactions, which are no longer in evidence. Instead, C5γ interactions occur, that are fully consistent with the turn geometry and additionally stabilize the structure. Comparison with the thietane amino acid Attc, which exhibits a rigid cyclic side chain, pinpoints the significance of side chain flexibility for the specific conformational behavior of Cys(Me).

Formation of Tetrahydrothiophenes via a Thia-Paternò-Büchi-Initiated Domino Photochemical Reaction.

We have established photochemical access to thietane or tetrahydrothiophene compounds from thiobenzophenone derivatives and acrylonitrile, wherein the product selectivity is controlled by a simple adjustment of the reagent concentration in solution. Small libraries of five-membered ring sulfur-containing compounds were prepared through a thia-Paternò-Büchi reaction, followed by a previously unknown regioselective photochemical ring enlargement reaction in a domino process or a stepwise fashion. A mechanism is proposed to rationalize this ring enlargement reaction via a carbene species provided from photoexcited thiocarbonyl compounds.

Local versus Global Control of Helical Folding in ß-Peptide Segments Using Hydrazino Turns.

Rational control of the self-organization of ß-peptides sequences to adopt regular secondary structures is an important challenge in peptidomimetic foldamer science. By replacing the N- and C-terminal residues of homooligomers of trans-2-aminocyclobutanecarboxylic acid (tACBC)n with N-aminoazetidine-2-carboxylic acid, an 8-helical topology is shown to dominate for sequences up to n = 7. This constitutes an atomic-level tool to override locally the preferred global 12-helix secondary structure of the corresponding tACBC homooligomers of the same length.

Conformation control through concurrent N-H⋯S and N-H⋯O[double bond, length as m-dash]C hydrogen bonding and hyperconjugation effects.

In addition to the classical N-H⋯O[double bond, length as m-dash]C non-covalent interaction, less conventional types of hydrogen bonding, such as N-H⋯S, may play a key role in determining the molecular structure. In this work, using theoretical calculations in combination with spectroscopic analysis in both gas phase and solution phase, we demonstrate that both these H-bonding modes exist simultaneously in low-energy conformers of capped derivatives of Attc, a thietane α-amino acid. 6-Membered ring inter-residue N-H⋯S interactions (C6γ), assisted by hyperconjugation between the thietane ring and the backbone, combine with 5-membered ring intra-residue backbone N-H⋯O[double bond, length as m-dash]C interactions (C5) to provide a C5-C6γ feature that stabilizes a planar geometry in the monomer unit. Two contiguous C5-C6γ features in the planar dimer implicate an unprecedented three-centre H-bond of the type C[double bond, length as m-dash]O⋯H(N)⋯SR2, while the trimer adopts two C5-C6γ features separated by a Ramachandran α-type backbone configuration. These low-energy conformers are fully characterized in the gas phase and support is presented for their existence in solution state.

Tandem Wittig Reaction-Ring Contraction of Cyclobutanes: A Route to Functionalized Cyclopropanecarbaldehydes.

An original tandem reaction consisting of a Wittig reaction-ring contraction process between α-hydroxycyclobutanone and phosphonium ylides has been developed. Highly functionalized cyclopropanecarbaldehydes are obtained in good to high yield.

Stereocontrolled Preparation of Diversely Trifunctionalized Cyclobutanes.

The expedient and stereoselective syntheses of small libraries of trifunctionalized cyclobutane scaffolds bearing an acid, an amine, and a third functional group are described. Starting from a single precursor, the readily available protected derivative of all-cis-2-amino-3-hydroxycyclobutane-1-carboxylic acid, cis-trans stereoisomers are obtained following an SN2-type reaction, while all-trans stereoisomers are obtained using the same strategy preceded by a C1 epimerization reaction.

Vibrational circular dichroism as a probe of solid-state organisation of derivatives of cyclic ß-amino acids: Cis- and trans-2-aminocyclobutane-1-carboxylic acid.

Peptide models built from cis- and trans-2-aminocyclobutane-1-carboxylic acids (ACBCs) are studied in the solid phase by combining Fourier-transform infrared spectroscopy (FTIR) absorption spectroscopy, vibrational circular dichroism (VCD), and quantum chemical calculations using density functional theory (DFT). The studied systems are N-tert-butyloxycarbonyl (Boc) derivatives of 2-aminocyclobutanecarboxylic acid (ACBC) benzylamides, namely Boc-(cis-ACBC)-NH-Bn and Boc-(trans-ACBC)-NH-Bn. These two diastereomers show very different VCD signatures and intensities, which of the trans-ACBC derivative being one order of magnitude larger in the region of the ν (CO) stretch. The spectral signature of the cis-ACBC derivative is satisfactorily reproduced by that of the monomer extracted from the solid-state geometry of related ACBC derivatives, which shows that no long-range effects are implicated for this system. In terms of hydrogen bonds, the geometry of this monomer is intermediate between the C6 and C8 structures (exhibiting a 6- or 8-membered cyclic NH⋯O hydrogen bond) previously evidenced in the gas phase. The benzyl group must be in an extended geometry to reproduce satisfactorily the shape of the VCD spectrum in the ν (CO) range, which qualifies VCD as a potential probe of dispersion interaction. In contrast, reproducing the IR and VCD spectrum of the trans-ACBC derivative requires clusters larger than four units, exhibiting strong intermolecular H-bonding patterns. A qualitative agreement is obtained for a tetramer, although the intensity enhancement is not reproduced. These results underline the sensitivity of VCD to the long-range organisation in the crystal.

Synthesis of ß-sulfinyl cyclobutane carboxylic amides via a formal α to ß sulphoxide migration process.

An original tandem reaction consisting of a thermal elimination-addition process was developed. Highly substituted ß-sulfinyl cyclobutane carboxylic acid derivatives were obtained from isomeric α-sulfinyl derivatives in a single operation in good to high yields and with high trans diastereoselectivity.