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The enantioselective preparation of the two isomers of 4-hydroxy-2-cyclohexanone derivatives 1a,b was achieved, starting from a common cyclohexenone, through asymmetric transfer hydrogenation (ATH) reactions using bifunctional ruthenium catalysts. From these versatile intermediates, a stereoselective route to a cytosine analogue built on a bicyclo [4.1.0]heptane scaffold is described. Nucleoside kinase activity assays with this cyclopropyl-fused cyclohexane nucleoside, together with other related nucleosides (2a–e), were performed, showing that thymine- and guanine- containing compounds have affinity for herpes simplex virus Type 1 (HSV-1) thymidine kinase (TK) but not for human cytosolic TK-1, thus pointing to their selectivity for herpetic TKs but not cellular TKs. [ABSTRACT FROM AUTHOR]

The application and scope of chalcogenides as organocatalysts in ylide-mediated synthesis of enantioselective aziridines is reviewed. The chalcogenides can also used in asymmetric synthesis of carbonyl compounds such as indole alkaloids.

Chiral scaffolds have been synthesized through selective transformations from conveniently protected cyclobutane β‐amino acids. The obtained derivatives present additional functional groups, such as hydroxyl, carboxyl, or carbon‐carbon triple bond, linked to the amino acid core through a flexible C1 or C2 alkyl fragment. The resultant molecules are highly versatile to be used as chiral precursors for the production of polyfunctional chemical platforms. These can be suitable for the synthesis of complex molecules, through condensation reactions, such as peptide coupling, dehydration between a carboxylic acid and an alcohol, or click chemistry. To illustrate some of these possibilities, two hybrid tripeptides have been prepared as examples of their synthetic potential. [ABSTRACT FROM AUTHOR]

The stability constants of Mn2+ complexes with ligands containing a trans-1,2-cyclobutanediamine spacer functionalized with picolinate and/or carboxylate functions were determined using potentiometric titrations (25 °C, 0.1 M KCl). The stability constant of the complex with a hexadentate ligand containing four acetate groups (L14−, log KMnL = 10.26) is improved upon replacing one (L24−, log KMnL = 14.71) or two (L34−, log KMnL = 15.81) carboxylate groups with picolinates. The [Mn(L1)]2− complex contains a water molecule coordinated to the metal ion in aqueous solutions, as evidenced by 1H NMRD studies and 17O chemical shifts and transverse relaxation rates. The 1H relaxivities determined at 60 MHz (3.3 and 2.4 mM−1 s−1 at 25 and 37 °C, respectively) are comparable to those of monohydrated complexes such as [Mn(edta)]2−. The exchange rate of the inner-sphere water molecule (k 298ex = 248 × 106 s−1) is slightly lower than that of the edta4− analogue. DFT calculations (M11/def2-TZVP) suggest that the water exchange reaction follows a dissociatively activated mechanism, providing activation parameters in reasonably good agreement with the experimental data. DFT calculations also show that the 17O hyperfine coupling constant A/ is affected slightly by changes in the Mn–Owater distance and the orientation of the water molecule with respect to the Mn–O vector. [ABSTRACT FROM AUTHOR]

Heating one of the most abundant naturally occurring inorganic chemicals like elemental sulfur with homochiral molecules like limonene has produced a one-step synthesis of a chiral sulfide that has displayed selectivities in sulfur ylide mediated asymmetric epoxidations and aziridinations. The epoxidation is used as a major step in a convergent and stereoselective synthesis of each of the diastereoisomers of the cinchona alkaloids, quinine and quinidine.

The one-pot reaction of two C-silylated alpha-diazophosphines with carbonyl derivatives to afford alkynes with chain extension, as well as alpha-hydroxyphosphonamides is discussed. The reaction provides an easy and useful synthetic entry to diversely substituted phosphonamides and alkynes in a neutral medium.

Theoretical calculations are performed to quantify the basicity of phosphino(trimethylsilyl)-carbenes and to compare them with that of N-heterocyclic carbenes. Phosphino(trimethylsilyl)-carbenes is not strong enough as a base to spontaneously deprotonate organic acids such as phenylacetylene, acetonitrile, or acetyltrimethylsilane but its conjugate acid is a strong electrophile.

Research has been conducted on (phosphanyl)(silyl)carbene. The authors report that the [2+1] addition of these compounds to aromatic aldehydes produces phosphoranyl aryloxiranes.

Research has been conducted on chiral trisubstituted 1-pyrazolines. The study of photodenitrogenation of these compounds carried out via the use of laser flash photolysis is presented.

The synthesis of the chiral sulfide isothiocineole from limonene and elemental sulfur on multi-gram scale and its alkylation to make >50 g of the corresponding benzylsulfonium salt are described. The application of this salt to the sulfur ylide-mediated asymmetric epoxidation of aldehydes and the asymmetric aziridination of imines on a >5 g scale is demonstrated. [ABSTRACT FROM AUTHOR]

Several α,β,α- or α,γ,α-tripeptides, consisting of a central cyclobutane β- or γ-amino acid being flanked by two d- or l-proline residues, have been synthesized and tested as organocatalysts in asymmetric aldol additions. High yields and enantioselectivities have been achieved with α,γ,α-tripeptides, being superior to peptides containing a cyclobutane β-amino acid residue. This is probably due to their high rigidity, which hinders some of the peptide catalysts to adopt the proper active conformation. This reasoning correlates with the major conformation of the peptides in the ground state, as suggested by 1H NMR and computational calculations. The configuration of the aldol products is controlled by the proline chirality, and consequently, the R/S configuration of aldol products can be tuned by the use of either commercially available d- or l-proline. The enantioselectivity in the aldol reactions is reversed if the reactions are carried out in the presence of water or other protic solvents such as methanol. Spectroscopic and theoretical investigations revealed that this effect is not the consequence of conformational changes in the catalyst but rather caused by the participation of a water molecule in the rate determining transition state, in such a way that the preferential nucleophilic attack is oriented to the opposite enantiotopic aldehyde face. [ABSTRACT FROM AUTHOR]

Enantiomerically pure C16-alkyl amides derived from cis and trans cycloalkane-1,2-dicarboxylic acids, respectively, have been synthesized and their behavior as organogelators has been investigated. These compounds include cis/trans diastereomeric cyclobutane and cyclohexane derivatives with the aim to explore the influence of the ring size as well as the relative configuration in their hierarchical self-assembly to form gels. High resolution 1H NMR spectroscopy studies allowed the determination of the dynamics of the gelation process in [D8]toluene and the sol-gel transition temperature. The morphology and size of the aggregates have been investigated and results have shown that, in the case of cyclobutane derivatives, the cis/trans stereochemistry is not relevant for the gelation behavior and the properties of the soft-materials obtained, but it is remarkable for cyclohexane diamides, which are better organogelators. The four compounds produce chiral aggregates despite that two of them are meso achiral molecules. We show herein that this fact is an example of stochastic symmetry breaking induced by sonication. The self-assembly of these molecules has been modelled providing information and support about the structure and the chirality of the aggregates. [ABSTRACT FROM AUTHOR]

New diastereomeric nonionic amphiphiles, cis- and trans-1, based on an optically pure cyclobutane β-amino ester moiety have been investigated to gain insight into the influence exerted by cis/trans 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. trans-1 showed a higher thermal stability than cis-1. For the latter, a higher fluidity of its monolayers was observed when compared with the films formed by trans-1 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 cis-1, 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 trans-1 giving ordered arrangements. However, for cis-1, 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 cis-1 than for trans-1. [ABSTRACT FROM AUTHOR]

Stereoselective and efficient synthetic routes to pyrrolidines and amino alcohols anchored to chiral polysubstituted cyclobutane moieties have been developed from (-)-( S)-verbenone. These original frameworks, in particular the diamines and amino alcohols, are appropriate stabilisers of metallic nanoparticles, especially for the synthesis of ruthenium nanomaterials, which found catalytic applications in the hydrogenation of arenes and nitrobenzene derivatives to afford selectively the corresponding cyclohexane or aniline derivatives. [ABSTRACT FROM AUTHOR]

The chiral sulfide, isothiocineole, has been synthesized in one step from elemental sulfur, γ-terpinene, and limonene in 61% yield. A mechanism involving radical intermediates for this reaction is proposed based on experimental evidence. The application of isothiocineole to the asymmetric epoxidation of aldehydes and the aziridination of imines is described. Excellent enantioselectivities and diastereoselectivities have been obtained over a wide range of aromatic, aliphatic, and α,β-unsaturated aldehydes using simple protocols. In aziridinations, excellent enantioselectivities and good diastereoselectivities were obtained for a wide range of imines. Mechanistic models have been put forward to rationalize the high selectivities observed, which should enable the sulfide to be used with confidence in synthesis. In epoxidations, the degree of reversibility in betaine formation dominates both the diastereoselectivity and the enantioselectivity. Appropriate tuning of reaction conditions based on understanding the reaction mechanism enables high selectivities to be obtained in most cases. In aziridinations, betaine formation is nonreversible with semistabilized ylides and diastereoselectivities are determined in the betaine forming step and are more variable as a result. [ABSTRACT FROM AUTHOR]

Three series of new γ-peptides have been synthesized by starting from conveniently protected cis-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid derivatives. The first series is constructed with only one enantiomer of this γ-amino acid, whereas in the second one both enantiomeric cyclobutane residues are joined in alternating fashion. The high degrees of rigidity in these γ-peptides induce the adoption of extended but sterically constrained conformations in both cases. The third series is the product of alternation of a cyclobutane residue with linear γ-aminobutyric acid (GABA). Conformational bias in these three systems accounts for the cyclobutane being a major disrupting factor to the formation of strong intramolecular hydrogen bonds, leading to extended conformations. In contrast, investigation of cyclobutane/GABA hybrid γ-peptides of a fourth series, in which the carbocyclic moiety is not a part of the polyamide skeleton but acts as a chiral polyfunctional platform, reveals that these peptides are able to produce intramolecular hydrogen bonds leading to well defined folded conformations. [ABSTRACT FROM AUTHOR]

The synthesis of chiral cyclobutane containing 1,3-amino alcohols and 1,3-diamines has been accomplished in an efficient and diastereodivergent manner from a common chiral precursor. Regioselective manipulation of functional groups in the prepared products provides an easy entry to several derivatives, such as thioureas. Preliminary results on the use of these compounds as bifunctional organocatalysts are reported. [ABSTRACT FROM AUTHOR]

Abstract: α-(trans-Vinyl) phosphonamides with different substituents at the β-position were stereoselectively synthesized in high yields by treatment of β-substituted α-epoxy-α-trimethylsilyl phosphines with oxidizing agents. The corresponding phosphonamides were unstable in most cases and underwent reductive elimination affording desilylated vinyl derivatives. In turn, α-epoxy phosphines resulted from the [1+2] addition of [bis(diisopropylamino)phosphino](trimethylsilyl)carbene 2 to aliphatic, aromatic, and heteroaromatic aldehydes. In this way, a great variety of vinyl compounds have been efficiently prepared through one-pot procedure. [Copyright &y& Elsevier]

Diversely substituted α-hydroxyphosphonamides and alkynes have been efficiently synthesized through the reaction of C-silylated α-diazophosphines with different types of aldehydes (2 equiv) in a neutral medium under very mild conditions. The reaction with some chiral aldehydes is highly diastereoselective leading to phosphonamides as single diastereomers. The novel reaction is influenced by electronic and steric effects being precluded for aromatic aldehydes containing electron-releasing substituents on the phenyl ring and for bulky aliphatic aldehydes. The mechanistic studies of these processes, which are highly exothermic, provide evidence for a nucleophilic attack of the diazophosphine to the aldehyde leading to a betaine that rapidly rearranges to a diazomethylenephosphorane, which has been detected or captured in some instances. The diazomethylenephosphorane reacts with a second molecule of aldehyde according to a Wittig-type condensation, and the rate-determining step of the whole process is believed to be the decomposition of the resultant oxaphosphetane to afford the hydroxyphosphonamide and a diazocumulene. Finally, this intermediate loses molecular nitrogen giving a transient carbene that rapidly evolves toward the alkyne. [ABSTRACT FROM AUTHOR]

A new family of hybrid β,γ-peptidomimetics consisting of a repetitive unit formed by a chiral cyclobutane-containing trans-β-amino acid plus a Nα-functionalized trans-γ-amino-l-proline joined in alternation were synthesized and evaluated as cell penetrating peptides (CPP). They lack toxicity on the human tumoral cell line HeLa, with an almost negligible cell uptake. The dodecapeptide showed a substantial microbicidal activity on Leishmania parasites at 50 µM but with a modest intracellular accumulation. Their previously published γ,γ-homologues, with a cyclobutane γ-amino acid, showed a well-defined secondary structure with an average inter-guanidinium distance of 8–10 Å, a higher leishmanicidal activity as well as a significant intracellular accumulation. The presence of a very rigid cyclobutane β-amino acid in the peptide backbone precludes the acquisition of a defined conformation suitable for their cell uptake ability. Our results unveiled the preorganized charge-display as a relevant parameter, additional to the separation among the charged groups as previously described. The data herein reinforce the relevance of these descriptors in the design of CPPs with improved properties. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Two series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1S,2R)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a Nα-functionalized cis- or trans-γ-amino-l-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti-Leishmania drug delivery systems (DDS). They lacked cytotoxicity on the tumoral human cell line HeLa with a moderate cell-uptake on these cells. In contrast, both γ-CC and γ-CT tetradecamers were microbicidal on the protozoan parasite Leishmania beyond 25 μM, with significant intracellular accumulation. They were conjugated to fluorescent doxorubicin (Dox) as a standard drug showing toxicity beyond 1 μM, while free Dox was not toxic. Intracellular accumulation was 2.5 higher than with Dox-TAT conjugate (TAT = transactivator of transcription, taken as a standard CPP). The conformational structure of the conjugates was approached both by circular dichroism spectroscopy and molecular dynamics simulations. Altogether, computational calculations predict that the drug-γ-peptide conjugates adopt conformations that bury the Dox moiety into a cavity of the folded peptide, while the positively charged guanidinium groups face the solvent. The favorable charge/hydrophobicity balance in these CPP improves the solubility of Dox in aqueous media, as well as translocation across cell membranes, making them promising candidates for DDS. [ABSTRACT FROM AUTHOR]

Efficient and versatile synthetic methodologies are reported for the preparation of products that are suitable candidates to be used as surfactants, gelators for hydroxylic solvents or metal cation ligands, with potential use in several fields including biomedical applications. The common structural feature of all the synthesized products is the presence of a cis or trans-1,2- or cis-1,3-difunctionalized cyclobutane ring. In the two first cases, the key intermediates including enantiomerically pure 1,3-diamines and 1,3-amino alcohols have been prepared from β-amino acid derivatives obtained, in turn, from a chiral half-ester. This compound is also precursor of γ-amino esters. Furthermore, two kind of polydentate ligands have also been synthesized from a symmetric 1,5-diamine obtained from norpinic acid, which was easily prepared from commercial verbenone. [ABSTRACT FROM AUTHOR]

New enantiomerically pure C16-alkyl diamides derived from trihydroxy cyclohexane-1,2-dicarboxylic acid have been synthesized from (−)-shikimic acid. The hydroxyl groups in these compounds are free or, alternatively, they present full or partial protection. Their gelling abilities towards several solvents have been tested and rationalized by means of the combined use of Hansen solubility parameters, scanning electron microscopy (SEM), and circular dichroism (CD), as well as computational calculations. All the results allowed us to account for the capability of each type of organogelator to interact with different solvents and for the main mode of aggregation. Thus, compounds with fully protected hydroxyl groups are good organogelators for methanol and ethanol. In contrast, a related compound bearing three free hydroxyl groups is insoluble in water and polar solvents including alcohols but it is able to gelate some low-polarity solvents. This last behavior can be justified by strong hydrogen bonding between molecules of organogelator, which competes advantageously with polar solvent interactions. As an intermediate case, an organogelator with two free hydroxyl groups presents an ambivalent ability to gelate both apolar and polar solvents by means of two aggregation patterns. These involve hydrogen bonding interactions of the unprotected hydroxyl groups in apolar solvents and intermolecular interactions between amide groups in polar ones. [ABSTRACT FROM AUTHOR]

The article describes the role of chalcogenides as organocatalysts. According to the authors, chalcogens consist of the elements O, S, Se and Te. They define a catalyst as a compound that takes part in the reaction but is regenerated during the course of the reaction. They add that the catalysts consist of compounds with two single carbon-chalcogen bonds, only where the chalcogen atom is vital to the catalytic activity. They also discuss epoxidation, aziridination and cyclopropanation.

Peptidomimetics, molecules that mimic the activity of natural peptides with improved stability or bioavailability, have emerged as interesting materials with applications in biomedicine. In this study, we describe a hybrid γ,γ-peptidomimetic that efficiently aims at mitochondria, a key therapeutic target associated with several disorders, in living cells. Peptide backbones with a component of cationic and hydrophobic amino acids have been shown to preferentially target mitochondria due to their high negative membrane potential and hydrophobic character of the membranous invaginations of these key organelles. We here exploit the advantageous bioorthogonal properties of a peptidomimetic scaffold that consists of an alternation of (1 S ,3 R )-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and an N α -functionalised cis -γ-amino-L-proline derivative. This peptidomimetic exhibited excellent membrane translocation efficiency, mitochondrial targeting ability, and biocompatibility. Mitochondrial targeting was confirmed to be dependent on the electrochemical potential generated by the electron transport chain. The presence of non-natural amino acids rendered the compound exceptionally stable in the presence of proteases, maintaining its integrity and functionality for targeting the organelle even after 1 week of incubation in serum. This stability, coupled with its targeting abilities and the low cytosolic/endosomal residual signal, facilitated the tracking of relevant mitochondrial dynamics, including fission events and intracellular movement. Additionally, this peptidomimetic scaffold allowed the sustained and precise mitochondrial targeting of a pH sensitive ratiometric probe, 5(6)-carboxy-SNARF-1, which enabled mitochondrial pH monitoring. In summary, our study introduces a biomimetic peptide with exceptional mitochondria-targeting properties, ensuring stability in biological media and offering insights into crucial mitochondrial processes.