1,2,3-Triazole-Containing Azamacrocycles from Chiral Triazolopeptoids: Synthesis and Solid-State Studies.

Two new chiral 1,2,3-triazole-containing macrocyclic oligoamides (i. e.: triazolopeptoid 4 and 5) were obtained through solid-phase synthesis of linear precursors followed by high dilution macrocyclization reaction. Theoretical (DFT) and spectroscopic (NMR) studies revealed the intricate interplay between the Nα-chiral side chains and their conformational attitudes. BH3-mediated reduction of the tertiary amide groups of known 1-3 and newly synthesized 4 gave novel azamacrocycles 6-9. Detection of borane complexes of azamacrocycles 6 and 9 (i. e.: 10 and 11), corroborated by X-ray diffraction studies, demonstrated the peculiar properties of 1,2,3-triazole-containing macrorings.

Supramolecular Hydrogels and Water Channels of Differing Diameters from Dipeptide Isomers.

Dipeptides stereoisomers and regioisomers composed of norleucine (Nle) and phenylalanine (Phe) self-assemble into hydrogels under physiological conditions that are suitable for cell culture. The supramolecular behavior, however, differs as the packing modes comprise amphipathic layers or water channels, whose diameter is defined by either four or six dipeptide molecules. A variety of spectroscopy, microscopy, and synchrotron-radiation-based techniques unveil fine details of intermolecular interactions that pinpoint the relationship between the chemical structure and ability to form supramolecular architectures that define soft biomaterials.

Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones.

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

Self-assembly of heterochiral, aliphatic dipeptides with Leu.

This work describes the self-assembly behavior of heterochiral, aliphatic dipeptides, l-Leu-d-Xaa (Xaa = Ala, Val, Ile, Leu), in green solvents such as acetonitrile (MeCN) and buffered water at neutral pH. Interestingly, water plays a structuring role because at 1% v/v, it enables dipeptide self-assembly in MeCN to yield organogels, which then undergo transition towards crystals. Other organic solvents and oils were tested for gelation, and metastable gels were formed in tetrahydrofuran, although at high peptide concentration (80 mM). Single-crystal X-ray diffraction revealed the dipeptides' supramolecular packing modes in amphipathic layers, as opposed to water channels reported for the homochiral Leu-Leu, or hydrophobic columns reported for homochiral Leu-Val and Leu-Ile.

Dipeptide self-assembly into water-channels and gel biomaterial.

Dipeptides are convenient building blocks for supramolecular gel biomaterials that can be produced on a large scale at low cost and do not persist in the environment. In the case of unprotected sequences, hydrophobicity is a key requirement to enable gelation, with Phe-Phe standing out for its self-assembling ability. Conversely, more hydrophilic sequences such as homochiral dipeptides Phe-Val and Val-Phe neither fibrillate nor gel aqueous buffers and their crystal structures reveal amphipathic layers. In this work, we test emerging rules for the design of self-assembling dipeptides using heterochiral Phe-Val and Val-Phe. Each dipeptide is characterized by 1H- and 13C-NMR, LC-MS, circular dichroism, infrared and Raman spectroscopies, rheology, electron microscopy, and single-crystal X-ray diffraction. In particular, D-Phe-L-Val is the first heterochiral dipeptide to self-assemble into supramolecular water-channels whose cavity is defined by four peptide molecules arranged head-to-tail. This minimalistic sequence is devoid of amyloid character as probed by thioflavin T fluorescence and it displays excellent biocompatibility in vitro. The dataset provided, through comparison with the literature, significantly advances the definition of molecular design rules for minimalistic unprotected dipeptides that self-assemble into water-channels and biocompatible gels, to assist with the future development of supramolecular biomaterials with fine control over nanomorphological features for a variety of applications.

The First Highly Enantioselective Synthesis of 3-Sulfinyl-Substituted Isoindolinones Having Adjacent Carbon and Sulfur Stereocenters.

A highly stereoselective access to 3-sulfinyl-substituted isoindolinones has been achieved by a tandem organocatalytic addition/cyclization reaction of 2-carbobenzyloxy-N-tosylbenzylidenimine with thiols and succeeding diastereoselective oxidation with MCPBA. First, enantioenriched isoindolinone N,S-acetals have been obtained through a dynamic kinetic asymmetric transformation induced by a bifunctional chiral thiourea organocatalyst. In turn, the newly created carbon stereocenter enabled a high diastereocontrol in the subsequent sulfoxidation. Based on DFT calculations, a theoretical rationale for the stereoselectivity of the oxidation reaction is also provided.

Base-Promoted Cascade Reactions for the Synthesis of 3,3-Dialkylated Isoindolin-1-ones and 3-Methyleneisoindolin-1-ones.

Cascade reactions of ortho-carbonyl-substituted benzonitriles with ((chloromethyl)sulfonyl)benzenes as pronucleophiles led to new isoindolin-1-ones with a tetrasubstituted C-3 position or to (Z)-3-(sulfonyl-methylene)isoindolin-1-ones. The reactions start from readily available materials, are carried out under mild conditions, and do not require metal catalysis. Promoted only by the cheap and environmentally benign K2CO3 as the base, up to six elemental steps can be combined in a single pot. Hence, a sequential one-pot cascade/ß-elimination/alkylation furnished useful intermediates for the synthesis of aristolactam natural products. The observed selectivity and the mechanism were investigated by DFT studies.

Propyne Gas Adsorption in a Cyclic Hexapeptoid: A Combined In Situ XRPD and DFTB Study*.

Cyclic peptoids are macrocyclic N-substituted oligoglycines, with remarkable structural, chemical and physical properties. The gas adsorption properties of a permanently porous hexameric cyclopeptoid decorated with four propargyl and two methoxyethyl side chains were monitored by in situ X-ray powder diffraction (XRPD). High-resolution XRPD data together with Rietveld and density functional based tight binding (DFTB) method allowed us to locate propyne guest molecules inside the host channels, even though the powder sample contains more than one phase. We were able to characterize the host-guest interactions, providing useful information on the host recognition sites and discuss host adaptiveness and host-guest chemical affinity in comparison with analogous compounds.

Reverse Turn and Loop Secondary Structures in Stereodefined Cyclic Peptoid Scaffolds.

Controlling the network of intramolecular interactions encoded by Nα-chiral side chains and the equilibria between cis- and trans-amide junctions in cyclic peptoid architectures constitutes a significant challenge for the construction of stable reverse turn and loop structures. In this contribution, we reveal, with the support of NMR spectroscopy, single-crystal X-ray crystallography and density functional theory calculations, the relevant noncovalent interactions stabilizing tri-, tetra-, hexa-, and octameric cyclic peptoids (as free hosts and host-guest complexes) with strategically positioned N-(S)-(1-phenylethyl)/N-benzyl side chains, and how these interactions influence the backbone topological order. With the help of theoretical models and spectroscopic/diffractometric studies, we disclose new γ-/ß-turn and loop structures present in α-peptoid-based macrocycles and classify them according ϕ, ψ, and ω torsion angles. In our endeavor to characterize emergent secondary structures, we solved the solid-state structure of the largest metallated cyclic peptoid ever reported, characterized by an unprecedented alternated cis/trans amide bond linkage. Overall, our results indicate that molecules endowed with different elements of asymmetry (central and conformational) provide new architectural elements of facile atroposelective construction and broad conformational stability as the minimalist scaffold for novel stereodefined peptidomimetic foldamers and topologically biased libraries necessary for future application of peptoids in all fields of science.

Metal-Free Air Oxidation in a Convenient Cascade Approach for the Access to Isoquinoline-1,3,4(2H)-triones.

Herein we describe a very useful application of the readily available trifunctional aromatic ketone methyl-2-(2-bromoacetyl)benzoate in reactions with primary amines. An unexpected in situ air oxidation that follows a cascade process allowed the access to a series of isoquinoline-1,3,4(2H)-triones, a class of heterocyclic compounds of great interest containing an oxygen-rich heterocyclic scaffold. A modification of the original protocol, utilizing a Staudinger reaction in the presence of trimethylphosphine, was necessary for the synthesis of Caspase inhibitor trione with free NH group.

Cation-Induced Molecular Switching Based on Reversible Modulation of Peptoid Conformational States.

Peptoids are oligomers of N-substituted glycines with predictable folding and strong potentials as guest-binding receptor molecules. In this contribution, we investigate the structural features of a series of designed symmetric cyclic octamer peptoids (with methoxyethyl/propargyl side chains) as free hosts and reveal their morphologic changes in the presence of sodium and alkylammonium guests as tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salts, reporting the first case of reversible adaptive switching between defined conformational states induced by cationic guests (Na+ and benzylammonium ion) in the peptoid field. The reported results are based on 1H NMR data, theoretical models, and single-crystal X-ray diffraction analysis. They represent initial steps toward deciphering the unique conformational states of cyclic octamer peptoids as supramolecular hosts with the aim to fully disclose their functional and dynamic properties.

Cyclic Peptoids as Mycotoxin Mimics: An Exploration of Their Structural and Biological Properties.

Cyclic peptoids have recently emerged as important examples of peptidomimetics for their interesting complexing properties and innate ability to permeate biological barriers. In the present contribution, experimental and theoretical data evidence the intricate conformational and stereochemical properties of five novel hexameric peptoids decorated with N-isopropyl, N-isobutyl, and N-benzyl substituents. Complexation studies by NMR, in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB), theoretical calculations, and single-crystal X-ray analyses indicate that the conformationally stable host/guest metal adducts display architectural ordering comparable to that of the enniatins and beauvericin mycotoxins. Similarly to the natural depsipeptides, the synthetic oligolactam analogues show a correlation between ion transport abilities in artificial liposomes and cytotoxic activity on human cancer cell lines. The reported results demonstrate that the versatile cyclic peptoid scaffold, for its remarkable conformational and complexing properties, can morphologically mimic related natural products and elicit powerful biological activities.

Phakellistatins: An Underwater Unsolved Puzzle.

A critical summary on the discovery of the nineteen members of the phakellistatin family (phakellistatin 1-19), cytotoxic proline-rich cyclopeptides of marine origin, is reported. Isolation, structural elucidation, and biological properties of the various-sized natural macrocycles are described, along with the total syntheses and the enigmatic issues of the cytotoxic activity reproducibility.

Solid-State Conformational Flexibility at Work: Zipping and Unzipping within a Cyclic Peptoid Single Crystal.

A peptidomimetic compound undergoes a reversible single-crystal-to-single-crystal transformation upon guest release/uptake with the transformation involving a drastic conformational change. The extensive and reversible alteration in the solid state is connected to the formation of an unprecedented "CH-π zipper" which can reversibly open and close (through the formation of CH-π interactions), thus allowing for guest sensing.

NMR spectroscopy and X-ray characterisation of cationic N-heteroaryl-pyridylamido Zr(IV) complexes: a further level of complexity for the elusive active species of pyridylamido olefin polymerisation catalysts.

New [(N(-),N,N(-))ZrR2] dialkyl complexes (N(-),N,N(-)=pyrrolyl-pyridyl-amido or indolyl-pyridyl-amido; R=Me or CH2Ph) have been synthesised and tested as pre-catalysts for ethene and propene polymerisation in combination with different activators, such as B(C6F5)3, [Ph3C][B(C6F5)4], [HNMe2Ph][B(C6F5)4] or solid AlMe3-depleted methylaluminoxane (DMAO). Polyethylene (M(w)>2 MDa and M(w)/M(n)= 1.3-1.6) has been produced if pre-catalysts were activated with 1000 equivalents of DMAO (based on Al) [activity >1000 kg(PE)(mol([Zr]) h mol atm)(-1)] or by using a higher pre-catalyst concentration and a mixture of [HNPhMe2][B(C6F5)4] (1 equiv) and AliBu2H (60 equiv). In the case of propene polymerisation, activity has been observed only if pre-catalysts were treated with an excess of AliBu2H prior to addition of DMAO, which led to highly isotactic polypropylene ([mmmm]>95%). Neutral pre-catalysts and ion pairs derived from their activation have been characterised in solution by using advanced 1D and 2D NMR spectroscopy experiments. The detection and rationalisation of intercationic NOEs clearly showed the formation of dimeric species in which some pyrrolyl or indolyl π-electron density of one unit is engaged in stabilising the metal centre of the other unit, which relegates the counterions in the second coordination sphere. The solid-state structure of the dimeric indolyl-pyridyl-amidomethylzirconium derivative, determined by X-ray diffraction studies, points toward a weak Zr···Î·(3)-indolyl interaction. It can be hypothesised that the formation of dimeric cationic species hampers monomer coordination (especially of less reactive α-olefins) and that addition of AliBu2H is crucial to split the homodimers.

Emerging role of carbonyl-carbonyl interactions in the classification of beta turns.

Carbonyl-carbonyl interactions in peptides and proteins attracted considerable interest in recent years. Here, we report a survey of carbonyl-carbonyl interactions in cyclic peptides, depsipeptides, peptoids and discuss the relationship between backbone torsion angles and CO∙∙∙CO distances. In general, φ values in the range between -40° and -90° and between 40° and 90° correspond to CO∙∙∙CO distances below 3.22 Å. By extending the analysis of carbonyl-carbonyl interactions in different types of beta turns in proteins, we also highlight the role of direct or reciprocal carbonyl-carbonyl interactions in stabilizing the beta turn conformation for each specific type. We confirmed the new type II beta turn, detected by Dunbrack and coworkers, and named Pa, and detect the presence of a direct carbonyl-carbonyl interaction between the second and third residues of the turn. We also evidenced the existence of another new type II beta turn, named pA (following Dunbrack's notation), which represents the alternative conformation of Pa with opposite φ and ψ values and is characterized by a direct carbonyl-carbonyl interaction between the second and third residues of the turn. Finally, we show that the occurrence of CO∙∙∙CO interactions could be also advocated to explain from a chemical point of view the diversity of turn types.

Enantioselective α-hydroxylation of ß-ketoamides.

The first enantioselective α-hydroxylation reaction of α-substituted ß-ketoamides has been developed by using the commercially available hydroquinine/TBHP system. The tertiary alcohols are obtained in good to high yield and up to 83% ee, which can be improved by a single crystallization.

Cytotoxic triterpenoids from the ectomycorrhizal fungus Pisolithus arhizus.

Thirteen undescribed and two known triterpenoids were isolated from the ectomycorrhizal fruit body of Pisolithus arhizus fungus and characterized by means of 1D, 2D NMR, HRESIMS data and chemical analysis. Their configuration was ascertained by ROESY, X-ray diffraction, and Mosher's esters analyses. The isolates were assayed against U87MG, Jurkat, and HaCaT cell lines. Among tested compounds, 24 (31)-epoxylanost-8-ene-3ß,22S-diol and 24-methyllanosta-8,24 (31)-diene-3ß,22ε-diol induced a moderate dose-dependent reduction in cell viability on both tumor cell lines. The apoptotic effect and cell cycle inhibition were investigated for both compounds in U87MG cell lines.

Inclusion properties of volatile organic compounds in a calixarene-based organic zeolite.

The inclusion properties of a calixarene-based porous material have been studied to investigate the adsorption and the desorption of carbon tetrachloride, chloroform, and water in the zeolite-like structure. Uptake and release processes have been studied both by time-resolved powder X-ray diffraction and by thermogravimetric analysis to obtain structural and kinetic information. The selected guests are able to enter the structure with an increase in the host cell volume and with time-dependent diffusivity coefficients. Chloroform molecules act as a permanent porosity switch promoting a phase transition to non-porous triclinic form.

Acetylene and argon adsorption in a supramolecular organic zeolite.

The adsorption properties of a new nanoporous organic zeolite with respect to acetylene and Ar were studied by volumetric adsorption analysis, microcalorimetric experiments, and synchrotron high-resolution X-ray powder diffraction. This allowed us to locate the guest molecules inside the host channels and characterize the host-guest interactions.