Anion-Based Self-assembly of Resorcin[4]arenes and Pyrogallol[4]arenes.

Spatial sequestration of molecules is a prerequisite for the complexity of biological systems, enabling the occurrence of numerous, often non-compatible chemical reactions and processes in one cell at the same time. Inspired by this compartmentalization concept, chemists design and synthesize artificial nanocontainers (capsules and cages) and use them to mimic the biological complexity and for new applications in recognition, separation, and catalysis. Here, we report the formation of large closed-shell species by interactions of well-known polyphenolic macrocycles with anions. It has been known since many years that C-alkyl resorcin[4]arenes (R4C) and C-alkyl pyrogallol[4]arenes (P4C) narcissistically self-assemble in nonpolar solvents to form hydrogen-bonded capsules. Here, we show a new interaction model that additionally involves anions as interacting partners and leads to even larger capsular species. Diffusion-ordered spectroscopy and titration experiments indicate that the anion-sealed species have a diameter of >26 Å and suggest stoichiometry (M)6(X-)24 and tight ion pairing with cations. This self-assembly is effective in a nonpolar environment (THF and benzene but not in chloroform), however, requires initiation by mechanochemistry (dry milling) in the case of non-compatible solubility. Notably, it is common among various polyphenolic macrocycles (M) having diverse geometries and various conformational lability.

Three modes of interactions between anions and phenolic macrocycles: a comparative study.

Macrocyclic polyphenolic compounds such as resorcin[4]arenes can be considered as multidentate anion receptors. In the current work, we combine new experimental data and reports from the previous literature (solution data and deposited crystal structures from the CCDC) to systematically analyze binding motifs between resorcin[4]arene derivatives and anions, determine the role of supporting interactions from CH donors, ion pairing and estimate their relative strength. We have found that in medium polarity solvents (THF) anion binding is a main driving force for the formation of complexes between resorcinarenes and Alk4NX salts. Three binding modes have been detected using 1H NMR and DOSY, depending on the type of additional interactions. Mode I was observed for upper-rim unsubstituted resorcinarenes, which use OH groups and aromatic CH from the upper rim as hydrogen bond donors to form multidentate and multivalent binding sites at the upper rim. Mode II was observed for upper-rim halogenated resorcinarenes (tetrabromo- and tetraiodo-derivatives), which use OH groups and aliphatic CH atoms from the bridges to support the chelation of anions between aromatic units. This binding mode is also multidentate and multivalent, but weaker and more anion-selective than mode I (works effectively for chlorides but not for bromides). For O-substituted derivatives, mode III is observed, with anions bound in a nest formed by aromatic CH atoms in the lower rim (multidentate but monovalent binding). The relative strength of these three binding modes, their solvent-dependence, and emergence in the crystal structures (CCDC) have been evaluated.

Fluorescent Molecular Cages with Sucrose and Cyclotriveratrylene Units for the Selective Recognition of Choline and Acetylcholine.

The synthesis of four fluorescent diastereoisomeric molecular cages containing cyclotriveratrylene and sucrose moieties connected via the naphthalene linkers is reported. These diastereoisomers were found to be selective and efficient receptors for acetylcholine and choline. Compound P-5a has a better affinity for choline over acetylcholine, while cage M-5a exhibits a higher association constant for acetylcholine over choline. The highest selectivity value was observed for compound M-5a (KACh/KCh = 3.1). Cages P-5a, P-5b, M-5a, and M-5b were fully characterized by the advanced NMR techniques, and ECD spectroscopy was supported by DFT calculations. The binding constants Ka of these receptors were determined by fluorescence titration experiments in acetonitrile.

Oxidative Functionalization of Trinor-18α-olean-17(22)-ene Derivatives. Annulation of the E-Ring by an Intramolecular Aldol Reaction.

cis-Dihydroxylation of trinor-18α-olean-17(22)-ene 2 with osmium tetroxide led to diol 9. Its cleavage with lead tetraacetate gave tetracyclic ketoaldehyde 10. By comparison, the ozonation of trinor-18α-olean-17(22)-ene 2 in the presence of p-toluenesulfonic acid gave the corresponding ketoacetal 12. Both products were subjected to an intramolecular aldol reaction under the acidic conditions and yielded unusual triterpenes bearing a bicyclo[4.3.1]decane fragment (22). Further manipulation of the protective groups afforded compounds useful in triterpene synthesis, especially in the preparation of potentially biologically active saponins based on a tetracyclic terpene core.

Rearrangements of the Betulin Core. Synthesis of Terpenoids Possessing the Bicyclo[3.3.1]nonane Fragment by Rearrangement of Lupane-Type Epoxides.

The rearrangements of dihydrobetulin, dihydrobetulinic acid, and abeo-lupane epoxides under acidic conditions (HCl, montmorillonite K10, and BF3·Et2O) were studied. The treatment of dihydrobetulin with HCl or K10 produced abeo-lupane olefins. Their epoxidation afforded epoxides, which, in the presence of protic or Lewis acids, rearranged to dienes or lupanes bearing a bicyclo[3.3.1]nonane fragment. The structure of final products depended on the nature of the catalyst. The HCl promoted 1,4-elimination of water, whereas in the presence of BF3·Et2O bond migration took place preferentially. Montmorillonite K10 favored cyclization to bicyclononane.

Unexpected Reaction Products of Uracil and Its Methyl Derivatives with Acetic Anhydride and Methylene Chloride.

New acetyl derivatives of uracil, 6-methyluracil, and thymine were obtained in the course of an unconventional synthesis in methylene chloride. It was shown that products with the acetyloxymethyl fragment are formed according to a mechanism different from that for products with the acetyloxyethyl group. In particular, for uracil it was proven that the reaction with Ac2O, TEA, and CH2Cl2 leads to 1-acetyloxymethyluracil, where the N1 substituent is composed of the -CH2- fragment that originated from CH2Cl2 and the 1-acetyloxy moiety from Ac2O. The reaction of uracil with Ac2O, TEA, CH2Cl2, and DMAP leads to an acetyloxyethyl derivative in which the -CH2-CH2- fragment originates from TEA and the 1-acetyloxy moiety from Ac2O. A possible mechanism for the formation of new compounds was suggested and supported by the density functional theory/B3LYP quantum mechanical calculations. New compounds (39 in total, including seven deuterated) were fully characterized by nuclear magnetic resonance and high-resolution mass spectrometry techniques.

Dodecameric Anion-Sealed Capsules based on Pyrogallol[5]arenes and Resorcin[5]arenes.

The paper reports formation of exceptionally large capsular species (diameter of c. a. 30 Å) by interactions of polyphenolic macrocycles with 5-fold symmetry with anions. Pyrogallol[5]arenes and resorcin[5]arenes interact with anions via hydrogen bonds involving phenolic OH groups or aromatic CH groups. Based on NMR titration experiments, diffusion coefficients, and geometric requirements, it is postulated that the capsules have (P5H)12 (X- )60 or (R5H)12 (X- )60 stoichiometry and a unique geometry of one of the Platonic solids-a dodecahedron. The capsules exist in THF and in benzene, but not in chloroform, reflecting competitive effects in the solvation of anions. It is also demonstrated that mechanochemical pre-treatment (dry-milling) of solid samples is indispensable to initialize self-assembly in benzene.

New lupane bidesmosides exhibiting strong cytotoxic activities in vitro.

Triterpene bidesmosides are considered as highly cytotoxic saponins, usually less toxic against normal cells than monodesmosides, and less haemolytic. Biological activity of the betulin-type bidesmosides, rarely found in Nature, and seldom prepared due to serious synthetic problems, is poorly recognized. We report herein a protocol for the preparation of disubstituted lupane saponins (betulin bidesmosides) by treatment of their benzoates with potassium carbonate in dichloromethane / methanol solution. Cytotoxicity of all compounds was tested in vitro for a series of cancer cell lines, as well as normal human skin BJ fibroblasts. Presence of l-rhamnose moiety is crucial for cytotoxicity of betulin bidesmosides. On the other hand, l-arabinose fragment connected to lupane C-3 carbon atom significantly decreases activity. Presented results clearly show that betulin bidesmosides have significant clinical potential as anticancer agents.

Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives.

A class of dialkylamino-substituted dibenzodiazepines and their hetero analogues was synthesized by the intramolecular aza-Wittig condensation of the amido group with iminophosphoranes. The one-pot, two-step procedure includes reductive synthesis of the intermediate iminophosphoranes from the corresponding nitroamides and tributylphosphine.

A diversity of alkylation/acylation products of uracil and its derivatives: synthesis and a structural study.

tert-Butyl dicarbonate (Boc2O) and ethyl iodide (EtI) reactions with uracil (U), thymine (T) and 6-methyluracil (6-MU) were performed following routine procedures in pyridine/DMF solvents and with DMAP as the catalyst. Among 20 synthesized compounds, a derivative of 6-methyluracil substituted by the Boc-pyridine moiety at the C5 position appeared unexpectedly. The NMR spectra confirmed the molecular structure of all uracil derivatives. Parallel quantum mechanical DFT calculations supported the experimental findings.

Benzo[4,5]thiazolo[3,2- c][1,3,5,2]oxadiazaborinines: Synthesis, Structural, and Photophysical Properties.

A family of highly emissive benzo[4,5]thiazolo[3,2- c][1,3,5,2]oxadiazaborinines, conjugated with the donor 4-dimethylaminophenyl group, was designed and synthesized. Their photophysical, both in solution and in the solid state, and structural properties were investigated. The influence of donor and acceptor substituents (R) in the benzothiazole unit on photophysical properties of complexes was found out. The tetrafluorobenzothiazole analogue exhibits nonbonded nuclear spin-spin coupling between fluorines from the BF2 group and α-fluorine atom at the benzene ring. Additionally, this boron complex demonstrates a comparatively high solid-state fluorescence quantum yield (Φ = 0.34).

"Choose-a-size" control in the synthesis of sucrose based urea and thiourea macrocycles.

Highly efficient synthesis of monomeric and dimeric thiourea macrocycles with a per-O-benzylated sucrose scaffold is reported. Application of flow synthesis results in exclusive formation of a monomer in 79% yield. Batch synthesis provides two isomeric dimers in 85% yield. Dimers are capable of anion binding via two thiourea groups acting cooperatively.

Multinuclear NMR Measurements and DFT Calculations for Capecitabine Tautomeric Form Assignment in a Solution.

The molecular structure of capecitabine (a widely applied prodrug of 5-fluorouracil) was studied by multinuclear NMR measurements and DFT quantum mechanical calculations. One or two tautomeric forms in a solution were detected depending on the solvent used. In the organic solvents, a mixture of two forms of capecitabine was observed: carbamate and imine tautomers. In the aqueous solution, only the carbamate form was found. The methylation of capecitabine yields mainly two products in different proportions: N³-methylcapecitabine and N7-methylcapecitabine. The protonation of capecitabine in organic solvents with perchloric acid occurs at the N3 nitrogen atom. DFT calculations strongly support the results coming from the analysis of the NMR spectra.

Synthesis and Antioxidant Activity of Caffeic Acid Derivatives.

A series of caffeic acid derivatives were synthesized via a modified Wittig reaction which is a very important tool in organic chemistry for the construction of unsaturated carbon⁻carbon bonds. All reactions were performed in water medium at 90 °C. The aqueous Wittig reaction worked best when one unprotected hydroxyl group was present in the phenyl ring. The olefinations in the aqueous conditions were also conducted with good yields in the presence of two unprotected hydroxyl groups. When the number of the hydroxyl groups was increased to three, the reaction yields were worse, and the derivatives 12, 13, and 18 were obtained with 74%, 37%, and 70% yields, respectively. Nevertheless, the Wittig reaction using water as the essential medium is an elegant one-pot synthesis and a greener method, which can be a safe alternative for implementation in organic chemistry. The obtained compounds were tested for their antioxidant activity, and 12, 13, and 18 showed the highest activities. Moreover, all synthesized compounds displayed no cytotoxicity, and can therefore be used in the pharmaceutical or cosmetic industry.

Transition-metal-free synthesis of 3-(1-pyrrolidinyl)quinolines and 3-(1-pyrrolidinyl)quinoline 1-oxides via a one-pot reaction of 3-(1-pyrrolidinyl)crotonates with nitrobenzenes.

A carbanion of tert-butyl 3-(1-pyrrolidinyl)crotonate adds to nitrobenzenes to form σH-adducts, which in the presence of pivaloyl chloride and triethylamine are converted into 3-(1-pyrrolidinyl)quinolines or 3-(1-pyrrolidinyl)quinoline 1-oxides depending on the nitrobenzene structure. This is the first methodology in which a quinoline ring is constructed from a substrate bearing a pyrrolidinyl ring. Starting from optically pure enamines, the method allows synthesis of the corresponding chiral products without racemisation.

A Novel Convergent Synthesis of the Potent Antiglaucoma Agent Tafluprost.

Tafluprost (AFP-168, 5) is a unique 15-deoxy-15,15-difluoro-16-phenoxy prostaglandin F2α (PGF2α) analog used as an efficacious ocular hypotensive agent in the treatment of glaucoma and ocular hypertension, as monotherapy, or as adjunctive therapy to ß-blockers. A novel convergent synthesis of 5 was developed employing Julia-Lythgoe olefination of the structurally advanced prostaglandin phenylsulfone 16, also successfully applied for manufacturing of pharmaceutical grade latanoprost (2), travoprost (3) and bimatoprost (4), with an aldehyde ω-chain synthon 17. The use of the same prostaglandin phenylsulfone 16, as a starting material in parallel syntheses of all commercially available antiglaucoma PGF2α analogs 2-5, significantly reduces manufacturing costs resulting from its synthesis on an industrial scale and development of technological documentation. Another key aspect of the route developed is deoxydifluorination of a trans-13,14-en-15-one 30 with Deoxo-Fluor. Subsequent hydrolysis of protecting groups and final esterification of acid 6 yielded tafluprost (5). The main advantages are the preparation of high purity tafluprost (5) and the application of comparatively cheap reagents. The preparation and identification of two other tafluprost acid derivatives, tafluprost methyl ester (32) and tafluprost ethyl amide (33), are also described.

Synthesis and Physicochemical Characterization of the Process-Related Impurities of Eplerenone, an Antihypertensive Drug.

Two unknown impurities were observed during the process development for multigram-scale synthesis of eplerenone (Inspra®). The new process-related impurities were identified and fully characterized as the corresponding (7ß,11α,17α)-11-hydroxy- and (7α,11ß,17α)-9,11-dichloroeplerenone derivatives 12a and 13. Seven other known but poorly described in the literature eplerenone impurities, including four impurities A, B, C and E listed in the European Pharmacopoeia 8.4 were also detected, identified and fully characterized. All these contaminants result from side reactions taking place on the steroid ring C of the starting 11α-hydroxy-7α-(methoxycarbonyl)-3-oxo-17α-pregn-4-ene-21,17-carbolactone (12) and the key intermediate (7α,17α)-9(11)-enester 7, including epimerization of the C-7 asymmetric center, oxidation, dehydration, chlorination and lactonization. The impurities were isolated and/or synthesized and fully characterized by infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their ¹H- and 13C-NMR signals were fully assigned. The molecular structures of the eight impurities, including the new (7ß,11α,17α)-11-hydroxy- and (7α,11ß,17α)-9,11-dichloroeplerenone related substances 12a and 13, were solved and refined using single-crystal X-ray diffraction (SCXRD). The full identification and characterization of these impurities should be useful for the quality control and the validation of the analytical methods in the manufacture of eplerenone.

Short-chain polyisoprenoids in the yeast Saccharomyces cerevisiae - New companions of the old guys.

Dolichols are, among others, obligatory cofactors of protein glycosylation in eukaryotic cells. It is well known that yeast cells accumulate a family of dolichols with Dol-15/16 dominating while upon certain physiological conditions a second family with Dol-21 dominating is noted. In this report we identified the presence of additional short-chain length polyprenols - all-trans Pren-7 in three yeast strains (SS328, BY4741 and L5366), Pren-7 was accompanied by traces of putative Pren-6 and -8. Moreover, in two of these strains a single polyprenol mainly-cis-Pren-11 was synthesized at the stationary phase of growth. Identity of polyprenols was confirmed by HR-HPLC/MS, NMR and metabolic labeling. Additionally, simvastatin inhibited their biosynthesis.

Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self-Sorting and Self-Assembly.

Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen-bond-based self-assembly. The dynamic character of the linkers and the preference of the peptides towards self-assembly into ß-barrel-type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800 Å(3) and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self-sorting and chiral self-assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C60 or C70 , is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C70 , and the X-ray structures provide unique information on the modes of peptide-fullerene interactions.

Synthesis of 28a-homoselenolupanes and 28a-homoselenolupane saponins.

A practical synthesis of 28a-homo-28a-selenolupane triterpenes and the corresponding selenosaponins containing d-mannose, l-arabinose, l-rhamnose, and d-idose moieties is described. Selenium containing triterpenes were obtained from the readily available 3-O-allyl-homobetulin mesylate by nucleophilic substitution with the selenocyanate ion which upon reduction of the -SeCN group afforded the free selenol. Glycosylation using classical Schmidt donors gave 1,2-trans selenosaponins as the main product as well as minute amounts of 1,2-cis isomers. This is one of the very few examples of the synthesis of selenoglycosides by direct glycosylation of free selenols. The studied selenol showed high resistance to air oxidation resulting in good stability during the synthesis of selenolupane derivatives. Cytotoxic activities of new homoselenolupane derivatives were also evaluated in vitro and revealed that some triterpenes exhibited an interesting profile against human cancer cell lines.