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.

Flexible and Convergent Enantioselective Total Synthesis of (R)-Juglanaloids A and B: Two Phthalide Spiro Alkaloids with Potential Alzheimer's Disease Inhibitory Activity.

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.

Water-Soluble Chiral Cyclic Peptoids and Their Sodium and Gadolinium Complexes: Study of Conformational and Relaxometric Properties.

Cyclic peptoids are macrocyclic oligomers of N-substituted glycines with specific folding abilities and excellent metal binding properties. In this work, we show how strategic positioning of chiral (S)- and (R)-(1-carboxyethyl)glycine units influences the conformational stability of water-soluble macrocyclic peptoids as sodium complexes. The reported results are based on nuclear magnetic resonance spectroscopy, extensive computational studies, and X-ray diffraction analysis using single crystals grown from aqueous solutions. The studies include 1H relaxometric investigations of hexameric cyclic peptoids in the presence of the Gd3+ ion to assess their thermodynamic stabilities and relaxivities.

Structural dynamism of chiral sodium peraza-macrocycle complexes derived from cyclic peptoids.

A variety of cyclen and hexacyclen derivatives decorated with (S)-1-phenylethyl side chains or (S)-pyrrolidine units have been prepared via a reductive approach from the corresponding cyclic peptoids containing N-(S)-(1-phenylethyl)glycine and l-proline residues. Spectroscopic and DFT studies on their Na+ complexes show that point chirality and ring size play a crucial role in controlling the structural dynamism of 1,2-diaminoethylene units and pendant arms. The detection of highly symmetric C4- and C3-symmetric metalated species demonstrates that a full understanding of the relationship between the structure and conformational properties of peraza-macrocyclic metal complexes is possible.

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.

An Entry to Enantioenriched 3,3-Disubstituted Phthalides through Asymmetric Phase-Transfer-Catalyzed γ-Alkylation.

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

Asymmetric trifluoromethylthiolation of azlactones under chiral phase transfer catalysis.

The first enantioselective method for the installation of the SCF3 group at the C-4 position of azlactones is described in the present communication under quinidinium phase transfer catalysis. The higher performance of substrates containing electron-rich 2-aryl groups at the azlactone was rationalized using DFT calculations.

Antibacterial and ATP Synthesis Modulating Compounds from Salvia tingitana.

A surface extract of the aerial parts of Salvia tingitana afforded a nor-sesterterpenoid (1) and eight new sesterterpenoids (2-̵9), along with five known sesterterpenoids, five labdane and one abietane diterpenoid, one sesquiterpenoid, and four flavonoids. The structures of the new compounds were established by 1D and 2D NMR spectroscopy, HRESIMS, and VCD data and Mosher's esters analysis. The antimicrobial activity of compounds was evaluated against 30 human pathogens including 27 clinical strains and three isolates of marine origin for their possible implications on human health. The methyl ester of salvileucolide (10), salvileucolide-6,23-lactone (11), sclareol (15), and manool (17) were the most active against Gram-positive bacteria. The compounds were also tested for the inhibition of ATP production in purified mammalian rod outer segments. Terpenoids 10, 11, 15, and 17 inhibited ATP production, while only 17 inhibited also ATP hydrolysis. Molecular modeling studies confirmed the capacity of 17 to interact with mammalian ATP synthase. A significant reduction of ATP production in the presence of 17 was observed in Enterococcus faecalis and E. faecium isolates.

Unprecedented Diastereoselective Arylogous Michael Addition of Unactivated Phthalides.

The first highly enantioselective arylogous Michael reaction (AMR) of 3-unsubstituted phthalides has been described. This phase-transfer methodology, which uses catalytic amounts of KOH/18-crown-6 catalyst in mesitylene in the presence of N,O-bis(trimethylsilyl)acetamide (BSA), gives access to a broad range of 3-monosubstituted phthalides with high levels of syn diastereoselectivity and good yields, starting from 3-unsubstituted derivatives and diverse α,ß-unsaturated carbonyl compounds. The reaction also applies to unactivated 3-alkyl phthalides to afford 3,3-dialkyl derivatives. A plausible mechanism has been suggested. DFT analysis of possible transition states gives a rationale of the high syn diastereoselectivity observed and its correlation with the solvent's dielectric constant.

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.

Chimeric XNA: An Unconventional Design for Orthogonal Informational Systems.

The paradigm of homogenous-sugar-backbone of RNA and DNA has reliably guided the construction of many functional and useful xeno nucleic acid (XNA) systems to date. Deviations from this monotonous and canonical design, in many cases, results in oligonucleotide systems that lack base pairing with themselves, or with RNA or DNA. Here we show that nucleotides of two such compromised XNA systems can be combined with RNA and DNA in specific patterns to produce chimeric-backbone oligonucleotides, which in certain cases demonstrate base pairing properties comparable to-or stronger than-canonical systems, while also altering the conventional Watson-Crick pairing behavior. The unorthodox pairing properties generated from these chimeric sugar-backbone oligonucleotides suggest a counterintuitive approach of creating modules consisting of non-base pairing XNAs with RNA/DNA in a set pattern. This strategy has the potential to increase the diversity of unconventional nucleic acids leading to orthogonal backbone-sequence-controlled informational systems.

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 Octamer Peptoids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides.

Cyclic peptoids have recently emerged as an important class of bioactive scaffolds with unique conformational properties and excellent metabolic stabilities. In this paper, we describe the design and synthesis of novel cyclic octamer peptoids as simplified isosters of mycotoxin depsipeptides bassianolide, verticilide A1, PF1022A and PF1022B. We also examine their complexing abilities in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt and explore their general insecticidal activity. Finally, we discuss the possible relationship between structural features of free and Na⁺-complexed cyclic octamer peptoids and bioactivities in light of conformational isomerism, a crucial factor affecting cyclic peptoids' biomimetic potentials.

Switchable Diastereoselectivity in the Fluoride-Promoted Vinylogous Mukaiyama-Michael Reaction of 2-[(Trimethylsilyl)oxy]furan Catalyzed by Crown Ethers.

The fluoride-promoted vinylogous Mukaiyama-Michael reaction of 2-[(trimethylsilyl)oxy]furan with diverse α,ß-unsaturated ketones is described. The TBAF-catalyzed VMMR afforded high anti-diastereoselectivity irrespective of the solvents used. The KF/crown ethers catalytic systems proved to be highly efficient in terms of yields and resulted in a highly diastereoselective unprecedented solvent/catalyst switchable reaction. Anti-adducts were obtained as single diastereomers or with excellent diastereoselectivities when benzo-15-crown-5 in CH2Cl2 was employed. On the other hand, high syn-diastereoselectivities (from 73:27 to 96:4) were achieved by employing dicyclohexane-18-crown-6 in toluene. On the basis of DFT calculations, the catalysts/solvent-dependent switchable diastereoselectivities are proposed to be the result of loose or tight cation-dienolate ion pairs.

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.

Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels.

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

Enantioselective Alkylation of Amino Acid Derivatives Promoted by Cyclic Peptoids under Phase-Transfer Conditions.

The effects of substituents and cavity size on catalytic efficiency of proline-rich cyclopeptoids under phase-transfer conditions were studied. High affinity constants (Ka) for the sodium and potassium cations, comparable to those reported for crown ethers, were observed for an alternated N-benzylglycine/L-proline hexameric cyclopeptoid. This compound was found to catalyze the alkylation of N-(diphenylmethylene)glycine cumyl ester in values of enantioselectivities comparable with those reported for the Cinchona alkaloid ammonium salts derivatives (83-96% ee), and with lower catalyst loading (1-2.5% mol), in the presence of a broad range of benzyl, allyl and alkyl halides.

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.

Ion transport through lipid bilayers by synthetic ionophores: modulation of activity and selectivity.

The ion-coupled processes that occur in the plasma membrane regulate the cell machineries in all the living organisms. The details of the chemical events that allow ion transport in biological systems remain elusive. However, investigations of the structure and function of natural and artificial transporters has led to increasing insights about the conductance mechanisms. Since the publication of the first successful artificial system by Tabushi and co-workers in 1982, synthetic chemists have designed and constructed a variety of chemically diverse and effective low molecular weight ionophores. Despite their relative structural simplicity, ionophores must satisfy several requirements. They must partition in the membrane, interact specifically with ions, shield them from the hydrocarbon core of the phospholipid bilayer, and transport ions from one side of the membrane to the other. All these attributes require amphipathic molecules in which the polar donor set used for ion recognition (usually oxygens for cations and hydrogen bond donors for anions) is arranged on a lipophilic organic scaffold. Playing with these two structural motifs, donor atoms and scaffolds, researchers have constructed a variety of different ionophores, and we describe a subset of interesting examples in this Account. Despite the ample structural diversity, structure/activity relationships studies reveal common features. Even when they include different hydrophilic moieties (oxyethylene chains, free hydroxyl, etc.) and scaffolds (steroid derivatives, neutral or polar macrocycles, etc.), amphipathic molecules, that cannot span the entire phospholipid bilayer, generate defects in the contact zone between the ionophore and the lipids and increase the permeability in the bulk membrane. Therefore, topologically complex structures that span the entire membrane are needed to elicit channel-like and ion selective behaviors. In particular the alternate-calix[4]arene macrocycle proved to be a versatile platform to obtain 3D-structures that can form unimolecular channels in membranes. In these systems, the selection of proper donor groups allows us to control the ion selectivity of the process. We can switch from cation to anion transport by substituting protonated amines for the oxygen donors. Large and stable tubular structures with nanometric sized transmembrane nanopores that provide ample internal space represent a different approach for the preparation of synthetic ion channels. We used the metal-mediated self-assembly of porphyrin ligands with Re(I) corners as a new method for producing to robust channel-like structures. Such structures can survive in the complex membrane environment and show interesting ionophoric behavior. In addition to the development of new design principles, the selective modification of the biological membrane permeability could lead to important developments in medicine and technology.