Stereoselective Synthesis of All Stereoisomers of Orthogonally Protected Cyclobutane-1,2-diamine and Some Chemoselective Transformations

The four stereoisomers of protected cyclobutane-1,2-diamine have been prepared in an enantio- and diastereocontrolled manner through stereodivergent synthetic routes starting from a half-ester as a common chiral precursor. Orthogonal protection allows the chemoselective manipulation of both amino groups as shown in this work

Chiral Cyclobutane β‑Amino Acid-Based Amphiphiles: Influence of <i>Cis</i>/<i>Trans</i> Stereochemistry on Solution Self-Aggregation and Recognition

Novel diastereomeric anionic amphiphiles based on the rigid cyclobutane β-amino acid scaffold have been synthesized and deeply investigated with the aim of generating new functional supramolecular architectures on the basis of the rational design of original amphiphilic molecules and the control of their self-assembly. The main interest has been focused on the effect that <i>cis/trans</i> stereochemistry exerts on their molecular organization and recognition. In diluted solutions, the relative stereochemistry mainly influences the headgroup solvation and anionic-charge stabilization, i.e., better stabilized in the <i>cis</i> diastereoisomer due to intramolecular hydrogen-bonding and/or charge-dipole interactions. This provokes differences in their physicochemical behavior (p<i>K</i>_a, cmc, conductivity) as well as in the structural parameters of the spherical micelles formed. Although both diastereoisomers form fibers that evolve with time from the spherical micelles, they display markedly different morphology and kinetics of formation. In the lyotropic liquid crystal domain, the greatest differences are observed at the highest concentrations and can be ascribed to different hydrogen-bonding and molecular packing imposed by the stereochemical constraints. Remarkably, the spherical micelles of the two anionic surfactants show dramatically diverse enantioselection ability for bilirubin enantiomers. In addition, both the surfactants form heteroaggregates with bilirubin at submicellar concentrations but with a different expression of supramolecular chirality. This points out that the unlike relative configuration of the two surfactants influences their chiral recognition ability as well as the fashion in which chirality is expressed at the supramolecular level by controlling the molecular organization in both micellar aggregates and surfactant/bilirubin heteroaggregates. All these differential features can be appropriate and useful for the design and development of new soft materials with predictable and tunable properties and reveal the cyclobutane motif as a valuable scaffold for the preparation of new amphiphiles

Chiral Cyclobutane β‑Amino Acid-Based Amphiphiles: Influence of <i>Cis/Trans</i> Stereochemistry on Condensed Phase and Monolayer Structure

New diastereomeric nonionic amphiphiles, <i><b>cis</b></i><b>-</b> and <i><b>trans</b></i><b>-1</b>, based on an optically pure cyclobutane β-amino ester moiety have been investigated to gain insight into the influence exerted by <i>cis/trans</i> stereochemistry and stereochemical constraints on the physicochemical behavior, molecular organization, and morphology of their Langmuir monolayers and dry solid states. All these features are relevant to the rational design of functional materials. <i><b>trans</b></i>-<b>1</b> showed a higher thermal stability than <i><b>cis</b></i><b>-1</b>. For the latter, a higher fluidity of its monolayers was observed when compared with the films formed by <i><b>trans</b></i><b>-1</b> whose BAM images revealed the formation of condensed phase domains with a dendritic shape, which are chiral, and all of them feature the same chiral sign. Although the formation of LC phase domains was not observed by BAM for <i><b>cis</b></i><b>-1</b>, compact dendritic crystals floating on a fluid subphase were observed beyond the collapse, which are attributable to multilayered 3D structures. These differences can be explained by the formation of hydrogen bonds between the amide groups of consecutive molecules allowing the formation of extended chains for <i><b>trans</b></i>-<b>1</b> giving ordered arrangements. However, for <i><b>cis</b></i><b>-1</b>, this alignment coexists with another one that allows the simultaneous formation of two hydrogen bonds between the amide and the ester groups of adjacent molecules. In addition, the propensity to form intramolecular hydrogen bonds must be considered to justify the formation of different patterns of hydrogen bonding and, consequently, the formation of less ordered phases. Those characteristics are congruent also with the results obtained from SAXS–WAXS experiments which suggest a more bent configuration for <i><b>cis</b></i><b>-1</b> than for <i><b>trans</b></i><b>-1</b>

Secondary Structure of Short β‑Peptides as the Chiral Expression of Monomeric Building Units: A Rational and Predictive Model

Chirality of the monomeric residues controls and determines the prevalent folding of small oligopeptides (from di- to tetramers) composed of 2-aminocyclobutane-1-carboxylic acid (ACBA) derivatives with the same or different absolute and relative configuration. The <i>cis</i>-form of the monomeric ACBA gives rise to two conformers, namely, Z6 and Z8, while the <i>trans</i>-form manifests uniquely as an H8 structure. By combining these subunits in oligo- and polypeptides, their local structural preference remains, thus allowing the rational design of new short foldamers. A lego-type molecular architecture evolves; the overall look depends only on the conformational properties of the structural building units. A versatile and efficient method to predict the backbone folds of designed cyclobutane β-peptides is based on QM calculations. Predictions are corroborated by high-resolution NMR studies on selected stereoisomers, most of them being new foldamers that have been synthesized and characterized for the first time. Thus, the chiral expression of monomeric building units results in the defined secondary structures of small oligomers. As a result of this study, a new set of chirality controlled foldamers is provided to probe as biocompatible biopolymers

Replacement of Thr³² and Gln³⁴ in the <i>C</i>‑Terminal Neuropeptide Y Fragment 25–36 by <i>cis</i>-Cyclobutane and <i>cis</i>-Cyclopentane β‑Amino Acids Shifts Selectivity toward the Y₄ Receptor

Neuropeptide Y (NPY) and pancreatic polypeptide (PP) control central and peripheral processes by activating the G protein coupled receptors Y_<i>x</i>R (<i>x</i> = 1, 2, 4, 5). We present analogs of the <i>C</i>-terminal fragments 25–36 and 32–36 of NPY and PP containing (1<i>R</i>,2<i>S</i>)-cyclobutane (βCbu) or (1<i>R</i>,2<i>S</i>)-cyclopentane (βCpe) β-amino acids, which display exclusively Y₄R affinity. In particular, [βCpe³⁴]-NPY-(25–36) is a Y₄R selective partial agonist (EC₅₀ 41 ± 6 nM, <i>E</i>_max 71%) that binds Y₄R with a <i>K</i>_i of 10 ± 2 nM and a selectivity >100-fold relative to Y₁R and Y₂R and >50-fold relative to Y₅R. Comparably, [Y³², βCpe³⁴]-NPY­(PP)-(32–36) selectively binds and activates Y₄R (EC₅₀ 94 ± 21 nM, <i>E</i>_max 73%). The NMR structure of [βCpe³⁴]-NPY-(25–36) in dodecylphosphatidylcholine micelles shows a short helix at residues 27–32, while the <i>C</i>-terminal segment R³³βCpe³⁴R³⁵Y³⁶ is extended. The biological properties of the βCbu- or βCpe-containing NPY and PP <i>C</i>-terminal fragments encourage the future application of these β-amino acids in the synthesis of selective Y₄R ligands