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.

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.

Strategic C to N Replacement in ß-Peptides: Atomic Level Control of Helical Folding.

Single residue control of the helical topology of ß-peptides is a contemporary challenge in foldamer science. We present the conformational preferences of oligomers of trans-2-aminocyclobutanecarboxylic acid ( tACBC), in which a central residue has been replaced by a single N-aminoazetidine-2-carboxylic acid (AAzC) moiety. The latter has such a strong demand for local 8-helical conformers that the usual 12-helix secondary structure of a tACBC octamer is switched to a fully 8-helical conformation as a result of the single residue substitution.

Intrinsic Folding Proclivities in Cyclic ß-Peptide Building Blocks: Configuration and Heteroatom Effects Analyzed by Conformer-Selective Spectroscopy and Quantum Chemistry.

This work describes the use of conformer-selective laser spectroscopy following supersonic expansion to probe the local folding proclivities of four-membered ring cyclic ß-amino acid building blocks. Emphasis is placed on stereochemical effects as well as on the structural changes induced by the replacement of a carbon atom of the cycle by a nitrogen atom. The amide A IR spectra are obtained and interpreted with the help of quantum chemistry structure calculations. Results provide evidence that the building block with a trans-substituted cyclobutane ring has a predilection to form strong C8 hydrogen bonds. Nitrogen-atom substitution in the ring induces the formation of the hydrazino turn, with a related but distinct hydrogen-bonding network: the structure is best viewed as a bifurcated C8/C5 bond with the N heteroatom lone electron pair playing a significant acceptor role, which supports recent observations on the hydrazino turn structure in solution. Surprisingly, this study shows that the cis-substituted cyclobutane ring derivative also gives rise predominantly to a C8 hydrogen bond, although weaker than in the two former cases, a feature that is not often encountered for this building block.

Fine Tuning of ß-Peptide Foldamers: a Single Atom Replacement Holds Back the Switch from an 8-Helix to a 12-Helix.

Cyclic homologated amino acids are important building blocks for the construction of helical foldamers. N-aminoazetidine-2-carboxylic acid (AAzC), an aza analogue of trans-2-aminocyclobutanecarboxylic acid (tACBC), displays a strong hydrazino turn conformational feature, which is proposed to act as an 8-helix primer. tACBC oligomers bearing a single N-terminal AAzC residue were studied to evaluate the ability of AAzC to induce and support an 8-helix along the oligopeptide length. While tACBC homooligomers assume a dominant 12-helix conformation, the aza-primed oligomers preferentially adopt a stabilized 8-helix conformation for an oligomer length up to 6 residues. The (formal) single-atom exchange at the N terminus of a tACBC oligomer thus contributes to the sustainability of the 8-helix, which resists the switch to a 12-helix. This effect illustrates atomic-level programmable design for fine tuning of peptide foldamer architectures.

Direct spectroscopic evidence of hyperconjugation unveils the conformational landscape of hydrazides.

The stereochemistry of hydrazides makes them especially interesting as building blocks for molecular design. An exhaustive conformational analysis of three model hydrazides was conducted in a conformer-selective approach by using a combination of high-level quantum chemistry calculations and vibrational spectroscopy in the gas phase and in solution. The NH stretch frequency was found to be highly sensitive to hyperconjugation, thus making it an efficient probe of the conformation of the neighboring nitrogen atom. This property greatly assisted the identification of the isomers observed experimentally in the conformer pool. A rationalization of the hydrazide conformational landscape is proposed, therefore paving the way for a better characterization of secondary structures in larger systems.

Stereoselective intermolecular [2 + 2]-photocycloaddition reactions of maleic anhydride: stereocontrolled and regiocontrolled access to 1,2,3-trifunctionalized cyclobutanes.

Short synthetic sequences commencing with the photosensitized [2 + 2]-cycloaddition reactions of maleic anhydride with either allyl alcohol or propargyl alcohol have been elaborated to provide access to 1,2,3-trisubstituted cyclobutanes with three differentiated one-carbon substituents and complementary stereochemical patterns. These intermediates were used to prepare three discrete stereo- and regioisomers of hydroxymethylated cyclobutane ß-amino acids in orthogonally protected form.

Fast-pulsing NMR techniques for the detection of weak interactions: successful natural abundance probe of hydrogen bonds in peptides.

Structural investigations of peptides using NMR spectroscopy rarely include the detection of N-H···O=C and N-H···N hydrogen bonds, because the relevant heteronuclei have a low natural abundance while the small trans hydrogen bond scalar couplings reduce the sensitivity. Fast repetition NMR techniques combined with state of the art spectrometer specifications allowed the enhancement of the sensitivity for detection of hydrogen bonds at natural isotopic abundance.

Solution state conformational preferences of dipeptides derived from N-aminoazetidinecarboxylic acid: an assessment of the hydrazino turn.

Four model compounds and four dipeptides containing N-aminoazetidinecarboxylic acid (AAzC) and a particular stereoisomer of 2-aminocyclobutanecarboxylic acid (ACBC) were studied to establish their solution state conformational preferences, particularly regarding the ability of AAzC to induce a three-center hydrogen-bonded folding feature known as a "hydrazino turn". On the basis of IR and NMR experiments, supported by molecular modeling, the AAzC residue adopted a trans configuration amenable to the formation of a cyclic eight-membered hydrogen bond conformation in solution, in all cases studied. The implication of the heterocyclic nitrogen atom of AAzC in the trans-like structure was demonstrated via a refined (1)H-(15)N HMBC experiment giving exploitable data at natural (15)N isotopic abundance, providing unprecedented evidence for the solution state hydrazino turn conformation. The predominance of this secondary structural feature depended on the configuration of the neighboring ACBC residue in the dipeptides: while the trans-ACBC derivatives prefer the hydrazino turn, the cis-ACBC derivatives may also populate low-energy 10-membered hydrogen-bonded ring structures. X-ray diffraction analysis of three compounds confirmed the presence of a solid state hydrazino turn in two cases, with geometries similar to those deduced from the solution state studies, but in the third compound, no intramolecular hydrogen-bonding feature was in evidence.

Poly(ethylene glycol) as reaction medium for mild Mizoroki-Heck reaction in a ball-mill.

Phosphine-free palladium-catalyzed Mizoroki-Heck reaction was performed using ball-milling in polyethylene glycol under mild conditions. Good to excellent yields of coupling products were obtained. This activation technique also allowed the concomitant formation of round shaped Pd-PEG nanoparticles that were characterized by TEM analysis.

A refined synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids.

The synthesis of enantiomerically pure 2-aminocyclobutanecarboxylic acids has been refined to improve both the efficiency and the simplicity. These improvements provide a shorter and easier access to the racemic cis-cyclobutane ß-amino acid core. Derivatization of this material with a chiral non-racemic oxazolidin-2-one allows easy diastereoisomeric separation and presents the advantage of allowing the non-destructive cleavage of the chiral auxiliary either by hydrolysis or by ammonolysis, thus providing an efficacious access to N-protected derivatives of all four stereoisomers of Boc-2-aminocyclobutanecarboxylic acid.

N-aminoazetidinecarboxylic acid: direct access to a small-ring hydrazino acid.

A short and efficient synthesis of the previously unknown N-aminoazetidinecarboxylic acid has been established using a photochemical [2 + 2] cycloaddition strategy starting from 6-azauracil. Chiral derivatization with a nonracemic oxazolidinone provided access to both enantiomers of the title product.

12-Helix folding of cyclobutane beta-amino acid oligomers.

The hexamer and octamer of trans-2-aminocyclobutane carboxylic acid were prepared and their conformational preferences studied experimentally and using molecular modeling. All observations suggest a marked preference for the folding of these oligomers into a well-defined 12-helical conformation, in both solution and the solid state.

Selective [3 + 2] Huisgen cycloaddition. Synthesis of trans-disubstituted triazolodiazepines from aza-Baylis-Hillman adducts.

The 1,3-dipolar cycloaddition of linear azido alkynes derived from protected beta-amino esters proceeds via diastereomeric differentiation to provide trans-disubstituted triazolodiazepines in good yields.

2-Trimethylsilylethanesulfonyl (SES) versus tosyl (Ts) protecting group in the preparation of nitrogen-containing five-membered rings. A novel route for the synthesis of substituted pyrrolines and pyrrolidines.

The 2-trimethylsilylethanesulfonyl (or SES) protecting group was compared to the tosyl (Ts) group in the preparation of a nitrogen-containing five-membered ring obtained by the aza-Baylis-Hillman/alkylation/RCM route. While deprotection of Ts-protected pyrrolines gave only pyrroles, deprotection of the same SES-protected compounds gave either pyrroles or free amine pyrrolines depending on the deprotection conditions. The SES-protected pyrrolines were hydrogenated to yield pyrrolidines with an excellent diastereoselectivity. Free amine pyrrolidines were obtained by HF-mediated deprotection of the SES group.

Sequential aza-Baylis-Hillman/ring closing metathesis/aromatization as a novel route for the synthesis of substituted pyrroles.

A new route to diverse 2-substituted-3-methoxycarbonyl pyrroles has been developed. Diverse SES protected alpha-methylene beta-aminoesters were obtained by a 3-component aza-Baylis-Hillman reaction. Diversity arose from the aryl aldehydes which can be used in this reaction. N-Alkylation with allyl bromide under mild conditions provided the corresponding dienes. These substituted dienes were cyclized by ring closing metathesis at room temperature or under microwave-activation with Grubbs-type II catalyst to yield SES-protected pyrroline intermediates. The final pyrroles were obtained by base-promoted dehydrodesulfinylation/aromatization. The scope of each of these reactions was explored.