Controllable Macroscopic Chirality of Coordination Polymers through pH and Anion-Mediated Weak Interactions

Helical architectures with controllable helical sense bias have recently attracted considerable interest for mimicking biological helices and developing novel chiral materials. Coordination polymers (CPs), composed of metal ion nodes and organic linkers, are intriguing systems showing tunable structures and functions. However, CPs with helical morphologies have rarely been explored so far. Particularly, chirality inversion through external stimulus has not been achieved in helical CPs. In this work, we carried out an in-depth investigation on the self-assembly of 1D gadolinium(III) phosphonate CPs using GdX₃ (X=Cl, Br, I) and Gd(RSO₃) (R=CH₃, C₆H₅, CF₃) as metal sources and R-(1-phenylethylamino)methyl phosphonic acid (R-pempH₂) as ligand. Superhelices were formed by precise control of the interchain interactions through different intercalated anions. Furthermore, the twisting direction of superhelices could be controlled by synergistic effect of anions and pH. This study may provide a new route to fabricate helical nanostructures of CPs with a desirable chiral sense and help understand the inner mechanism of the self-assembly process of macroscopic helical structures of molecular systems.     

Highly Oxygenated Triterpenoids and Diterpenoids from Fructus Rubi (Rubus chingii Hu) and Their NF-kappa B Inhibitory Effects

During a phytochemical investigation of the unripe fruits of Rubus chingii Hu (i.e., Fructus Rubi, a traditional Chinese medicine named “Fu-Pen-Zi”), a number of highly oxygenated terpenoids were isolated and characterized. These included nine ursane-type (1, 2, and 4–10), five oleanane-type (3, 11–14), and six cucurbitane-type (15–20) triterpenoids, together with five ent-kaurane-type diterpenoids (21–25). Among them, (4R,5R,8R,9R,10R,14S,17S,18S,19R,20R)-2,19α,23-trihydroxy-3-oxo-urs-1,12-dien-28-oic acid (rubusacid A, 1), (2R*,4S*,5R*,8R*,9R*,10R*,14S*,17S*, 18S*,19R*,20R*)-2α,19α,24-trihydroxy-3-oxo-urs-12-en-28-oic acid (rubusacid B, 2), (5R,8R,9R,10R, 14S,17R,18S,19S)-2,19α-dihydroxy-olean-1,12-dien-28-oic acid (rubusacid C, 3), and (3S,5S,8S,9R, 10S,13R,16R)-3α,16α,17-trihydroxy-ent-kaur-2-one (rubusone, 21) were previously undescribed. Their chemical structures and absolute configurations were elucidated on the basis of spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 1 and 3 are rare naturally occurring pentacyclic triterpenoids featuring a special α,β-unsaturated keto-enol (diosphenol) unit in ring A. Cucurbitacin B (15), cucurbitacin D (16), and 3α,16α,20(R),25-tetrahydroxy-cucurbita-5,23- dien-2,11,22-trione (17) were found to have remarkable inhibitory effects against NF-κB, with IC₅₀ values of 0.08, 0.61, and 1.60 μM, respectively.     

Synthesis of cyclohexane derivatives including Br,Cl, N,O, and S at 1,2,4,5-positions: selectivity in addition reactions

Brominations of mono addition products of 1,4-cyclohexadiene with 2,4-dinitrobenzenesulfenyl chloride (RSCl) selectively gave 1R(S),2R(S),4R(S),5R(S)-4,5-dibromo-2-(2,4-dinitrophenylthio)cyclohexyl acetate and 1R(S),2R(S),4R(S),5R(S)-4,5-dibromo-2-chlorocyclohexyl)(2,4-dinitrophenylthio)sulfane. From series reactions 7-oxabicyclo[4.1.0]hept-3-ene with reagents, such as RSCl, NaN₃, and H₂SO₄/Ac₂O, six 1,2,4,5-tetrasubstituted cyclohexane derivatives including S, O, N, Cl, and Br were selectively obtained. Formations and structures of the products were discussed.     

Helicity-driven chiral self-sorting supramolecular polymerization with Ag+: right- and left-helical aggregates

The study of chiral self-sorting is extremely important for understanding biological systems and for developing applications for the biomedical field. In this study, we attempted unprecedented chiral self-sorting supramolecular polymerization accompanying helical inversion with Ag⁺ in one enantiomeric component. Bola-type terpyridine-based ligands (R-L¹ and S-L¹) comprising R- or S-alanine analogs were synthesized. First, R-L¹ dissolved in DMSO/H₂O (1 : 1, v/v) forms right-handed helical fibers (aggregate I) via supramolecular polymerization. However, after the addition of AgNO₃ (0.2–1.1 equiv.) to the R-L¹ ligand, in particular, it was found that aggregate II with left-handed helicity is generated from the [R-L¹(AgNO₃)₂] complex through the [R-L¹Ag]⁺ complex via the dissociation of aggregate I by a multistep with an off pathway, thus demonstrating interesting self-sorting properties driven by helicity and shape discrimination. In addition, the [R-L¹(AgNO₃)₂] complex, which acted as a building block to generate aggregate III with a spherical structure, existed as a metastable product during the formation of aggregate II in the presence of 1.2–1.5 equiv. of AgNO₃. Furthermore, the AFM and CD results of two samples prepared using aggregates I and III with different volume ratios were similar to those obtained upon the addition of AgNO₃ to free R-L¹. These findings suggest that homochiral self-sorting in a mixture system occurred by the generation of aggregate II composed of the [R-L¹Ag]⁺ complex via the rearrangement of both, aggregates I and III. This is a unique example of helicity- and shape-driven chiral self-sorting supramolecular polymerization induced by Ag⁺ starting from one enantiomeric component. This research will improve understanding of homochirality in complex biological models and contribute to the development of new chiral materials and catalysts for asymmetric synthesis.

Chiral self-sorting supramolecular polymerization of bola-type terpyridine-based ligands (R-L¹ and S-L¹) comprising R- or S-alanine analogs occurred upon addition of Ag⁺ in one enantiomeric component.     

Synthesis,Structural Characterization,and In Vitro and In Silico Antifungal Evaluation of Azo-Azomethine Pyrazoles (PhN2(PhOH)CHN(C3N2(CH3)3)PhR,R = H or NO2)

The azo-azomethine imines, R¹-N=N-R²-CH=N-R³, are a class of active pharmacological ligands that have been prominent antifungal, antibacterial, and antitumor agents. In this study, four new azo-azomethines, R¹ = Ph, R² = phenol, and R³ = pyrazol-Ph-R’ (R = H or NO₂), have been synthesized, structurally characterized using X-ray, IR, NMR and UV–Vis techniques, and their antifungal activity evaluated against certified strains of Candida albicans and Cryptococcus neoformans. The antifungal tests revealed a high to moderate inhibitory activity towards both strains, which is regulated as a function of both the presence and the location of the nitro group in the aromatic ring of the series. These biological assays were further complemented with molecular docking studies against three different molecular targets from each fungus strain. Molecular dynamics simulations and binding free energy calculations were performed on the two best molecular docking results for each fungus strain. Better affinity for active sites for nitro compounds at the “meta” and “para” positions was found, making them promising building blocks for the development of new Schiff bases with high antifungal activity.     

New Alk(en)ylhydroxycyclohexanes with Tyrosinase Inhibition Potential from Harpephyllum caffrum Bernh. Gum Exudate

This work presents the first report on the phytochemical investigation of Harpephyllum caffrum Bernh. gum exudate. A known cardanol, 3-heptadec-12′-Z-enyl phenol (1) and three new alk(en)ylhydroxycyclohexanes, namely, (1R,3R)-1,3-dihydroxy-3-[heptadec-12′(Z)-enyl]cyclohexane (2) (1S,2S,3S,4S,5R)-1,2,3,4,5-pentahydroxy-5-[octadec-13′(Z)-enyl]cyclohexane (3) and (1R,2S,4R)-1,2,4-trihydroxy-4-[heptadec-12′(Z)-enyl]cyclohexane (4) were isolated from the gum. The structures of the compounds were determined by extensive 1D and 2D NMR spectroscopy and HR-ESI-MS data. The ethanolic extract of the gum was found to be the most potent tyrosinase inhibitor with IC₅₀ of 11.32 µg/mL while compounds 2 and 3, with IC₅₀ values of 24.90 and 26.99 µg/mL, respectively, were found to be potential anti-tyrosinase candidates from the gum. Gum exudate may be a potential source for non-destructive harvesting of selective pharmacologically active compounds from plants. The results also provide evidence that H. caffrum gum may find application in cosmetics as a potential anti-tyrosinase agent.     

Six New Phenylpropanoid Derivatives from Chemically Converted Extract of Alpinia galanga (L.) and Their Antiparasitic Activities

Chemical conversion of the extract of natural resources is a very attractive way to expand the chemical space to discover bioactive compounds. In order to search for new medicines to treat parasitic diseases that cause high morbidity and mortality in affected countries in the world, the ethyl acetate extract from the rhizome of Alpinia galanga (L.) has been chemically converted by epoxidation using dioxirane generated in situ. The biological activity of chemically converted extract (CCE) of A. galanga (L.) significantly increased the activity against Leishmania major up to 82.6 ± 6.2 % at 25 μg/mL (whereas 2.7 ± 0.8% for the original extract). By bioassay-guided fractionation, new phenylpropanoids (1–6) and four known compounds, hydroquinone (7), 4-hydroxy(4-hydroxyphenyl)methoxy)benzaldehyde (8), isocoumarin cis 4-hydroxymelein (9), and (2S,3S,6R,7R,9S,10S)-humulene triepoxide (10) were isolated from CCE. The structures of isolated compounds were determined by spectroscopic analyses of 1D and 2D NMR, IR, and MS spectra. The most active compound was hydroquinone (7) with IC₅₀ = 0.37 ± 1.37 μg/mL as a substantial active principle of CCE. In addition, the new phenylpropanoid 2 (IC₅₀ = 27.8 ± 0.34 μg/mL) also showed significant activity against L. major compared to the positive control miltefosine (IC₅₀ = 7.47 ± 0.3 μg/mL). The activities of the isolated compounds were also evaluated against Plasmodium falciparum, Trypanosoma brucei gambisense and Trypanosoma brucei rhodeisense. Interestingly, compound 2 was selectively active against trypanosomes with potent activity. To the best of our knowledge, this is the first report on the bioactive “unnatural” natural products from the crude extract of A. galanga (L.) by chemical conversion and on its activities against causal pathogens of leishmaniasis, trypanosomiasis, and malaria.     

Synthesis,Characterization, and Antiproliferative Activity of Novel Chiral [QuinoxP*AuCl2]+ Complexes

Herein is reported the synthesis of two Au(III) complexes bearing the (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (R,R-QuinoxP*) or (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxaline (S,S-QuinoxP*) ligands. By reacting two stoichiometric equivalents of HAuCl₄.3H₂O to one equivalent of the corresponding QuinoxP* ligand, (R,R)-(–)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (1) and (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) were formed, respectively, in moderate yields. The structure of (S,S)-(+)-2,3-Bis(tert-butylmethylphosphino)quinoxalinedichlorogold(III) tetrachloroaurates(III) (2) was further confirmed by X-ray crystallography. The antiproliferative activities of the two compounds were evaluated in a panel of cell lines and exhibited promising results comparable to auranofin and cisplatin with IC₅₀ values between 1.08 and 4.83 µM. It is noteworthy that in comparison to other platinum and ruthenium enantiomeric complexes, the two enantiomers (1 and 2) do not exhibit different cytotoxic effects. The compounds exhibited stability in biologically relevant media over 48 h as well as inert reactivity to excess glutathione at 37 °C. These results demonstrate that the Au(III) atom, stabilized by the QuinoxP* ligand, can provide exciting compounds for novel anticancer drugs. These complexes provide a new scaffold to further develop a robust and diverse library of chiral phosphorus Au(III) complexes.     

Novel chiral hexaazamacrocycles for the enantiodiscrimination of carboxylic acids

New enantiopure amines (R,R)-1 and (S,S)-1 were obtained from (R)- or (S)-2,2′-diamino-1,1′-binaphthyl and 2,6-diformylpyridine in a synthesis templated by lead(II) or lanthanide(III) ions, reduction with NaBH₄ and subsequent demetallation. Similarly new amines (R,R,R,R)-2 and (S,S,S,S)-2 were obtained from (1R, 2R)- or (1S, 2S)-1,2-diphenylethylenediamine. The X-ray crystal structure of the Pb(II) complex with macrocyclic Schiff base precursor of (R,R)-1 indicates helical twisted conformation of this macrocycle, while the ROESY spectrum of R,R-1 suggests less twisted conformation. (R,R)-1 and (R,R,R,R)-2 were tested as chiral shift reagents (chiral solvating agents) for various α-substituted carboxylic acids, including non steroidal anti-inflammatory drugs. Enantiodiscrimination of carboxylate ¹H NMR signals was observed with ΔΔδ values up to 0.1 ppm.     

Highlighting Recent Crystalline Engineering Aspects of Luminescent Coordination Polymers Based on F-Elements and Ditopic Aliphatic Ligands

Three principal factors may influence the final structure of coordination polymers (CPs): (i) the nature of the ligand, (ii) the type and coordination number of the metal center, and (iii) the reaction conditions. Further, flexible carboxylate aliphatic ligands have been widely employed as building blocks for designing and synthesizing CPs, resulting in a diverse array of materials with exciting architectures, porosities, dimensionalities, and topologies as well as an increasing number of properties and applications. These ligands show different structural features, such as torsion angles, carbon backbone number, and coordination modes, which affect the desired products and so enable the generation of polymorphs or crystalline phases. Additionally, due to their large coordination numbers, using 4f and 5f metals as coordination centers combined with aliphatic ligands increases the possibility of obtaining different crystal phases. Additionally, by varying the synthetic conditions, we may control the production of a specific solid phase by understanding the thermodynamic and kinetic factors that influence the self-assembly process. This revision highlights the relationship between the structural variety of CPs based on flexible carboxylate aliphatic ligands and f-elements (lanthanide and actinides) and their outstanding luminescent properties such as solid-state emissions, sensing, and photocatalysis. In this sense, we present a structural analysis of the CPs reported with the oxalate ligand, as the one rigid ligand of the family, and other flexible dicarboxylate linkers with –CH₂– spacers. Additionally, the nature of the luminescence properties of the 4f or 5f-CPs is analyzed, and finally, we present a novel set of CPs using a glutarate-derived ligand and samarium, with the formula [2,2′-bipyH][Sm(HFG)₂ (2,2′-bipy) (H₂O)₂]•(2,2′-bipy) (α-Sm) and [2,2′-bipyH][Sm(HFG)₂ (2,2′-bipy) (H₂O)₂] (β-Sm).     

Surface chiroselective assembly of enantiopure crystalline porous films containing bichiral building blocks

The development of chiral crystalline porous materials (CPMs) containing multiple chiral building blocks plays an important role in chiral chemistry and applications but is a challenging task. Herein, we report the first example of bichiral building block based enantiopure CPM films containing metal–organic cages (MOCs) and metal complexes. The functionalized substrate was immersed subsequently into homochiral metal complex (R)- or (S)-Mn(DCH)₃ (DCH = 1,2-diaminocyclohexane) and racemic Ti₄L₆ cage (L = embonate) solutions by a layer-by-layer growth method. During the assembly process, the substrate surface coordinated with (R)- or (S)-Mn(DCH)₃ can, respectively, layer-by-layer chiroselectively connect Δ- or Λ-Ti₄L₆ cages to form homochiral (R, Δ)- or (S, Λ)-CPM films with a preferred [111] growth orientation, tunable thickness and homogeneous surface. The resulting enantiopure CPM films show strong chirality, photoluminescence, and circularly polarized luminescence (CPL) properties as well as good enantioselective adsorption toward enantiomers of 2-butanol and methyl-lactate. The present in situ surface chiroselective strategy opens a new route to assemble homochiral CPM films containing multiple chiral building blocks for chiral applications.

Bichiral building block based enantiopure CPM films containing metal–organic cages (MOCs) and metal complexes are chiroselectively assembled on the substrate surface by a layer-by-layer method.     

Highest-Tc single-component homochiral organic ferroelectrics

Organic single-component ferroelectrics with low molecular mass have drawn great attention for application in organic electronics. However, the discovery of high-T_c single-component organic ferroelectrics has been very scarce. Herein, we report a pair of homochiral single-component organic ferroelectrics (R)-10-camphorsulfonylimine and (S)-10-camphorsulfonylimine under the guidance of ferroelectric chiral chemistry. They crystallize in the chiral–polar space group P2₁, and their mirror image relations have been identified using vibrational circular dichroism spectra. They both exhibit 422F2 multiaxial ferroelectricity with T_c as high as 429 K. Besides, they possess superior acoustic impedance characteristics with a value of 2.45 × 10⁶ kg s⁻¹ m⁻², lower than that of PVDF. To our knowledge, enantiomeric (R and S)-10-camphorsulfonylimine show the highest T_c among the known organic single-component ferroelectrics and low acoustic impedance well matching with that of bodily tissues. This work promotes the development of high-performance organic single-component ferroelectrics and is of great inspiration to explore their application in next-generation flexible smart devices.

A pair of enantiomeric organic ferroelectrics (R and S)-10-camphorsulfonylimine show the highest T_c among the known single-component organic ferroelectrics.     

Resolution of P-Sterogenic 1-Phenylphosphin-2-en-4-one 1-Oxide into Two Enantiomers by (R,R)-TADDOL and Conformational Diversity of the Phosphinenone Ring and TADDOL in the Crystal State

The resolution of racemic 1-phenylphosphin-2-en-4-one 1-oxide (2), was achieved through the fractional crystallization of its diastereomeric complexes with (4R,5R)-(−)-2,2-dimethyl -α,α,α′,α′-tetraphenyl-dioxolan-4,5-dimethanol (R,R-TADDOL) followed by the liberation of the individual enantiomers of 2 by flash chromatography on silica gel columns. The resolution process furnished the two enantiomers of 2 of 99.1 and 99.9% e.e. at isolated yields of 62 and 59% (counted for the single enantiomer), respectively. The absolute configurations of the two enantiomers were established by means of X-ray crystallography of their diastereomerically pure complexes, i.e., (R)-2•R,R)-TADDOL and (S)-2•(R,R)-TADDOL. The structural analysis revealed that in the (R)-2•(R,R)-TADDOL complex, the P-phenyl substituent occupied a pseudoequatorial position, whereas in (S)-2•(R,R)-TADDOL, it appeared in both the pseudoequatorial and the pseudoaxial positions in four symmetrically independent molecules. Concurrent conformational changes of the TADDOL molecules were best described by the observed changes of a pseudo-torsional CO...OC angle that could be considered as a possible measure of TADDOL conformation in its receptor–ligand complexes. The structural analysis of the (R,R)-TADDOL molecule revealed that efficiency of this compound for use as an effective resolving factor comes from its ability to flexibly fit its structure to both enantiomers of a ligand molecule, producing a rare case of resolution for both pure enantiomers with one chiral separating agent. The resolved (R)-2 was used to assign the absolute configuration of a recently described (−)-1-phenylphosphin-2-en-4-one 1-sulfide by chemical correlation. In addition, an attempted stereoretentive reduction of (R)-2 by PhSiH₃ at 60 °C revealed an unexpectedly low barrier for P-inversion in 1-phenylphosphin-2-en-4-one.     

Isolation of N-Ethyl-2-pyrrolidinone-Substituted Flavanols from White Tea Using Centrifugal Countercurrent Chromatography Off-Line ESI-MS Profiling and Semi-Preparative Liquid Chromatography

N-Ethyl-2-pyrrolidinone-substituted flavanols (EPSF) are marker compounds for long-term stored white teas. However, due to their low contents and diasteromeric configuration, EPSF compounds are challenging to isolate. In this study, two representative epimeric EPSF compounds, 5′′′R- and 5′′′S-epigallocatechin gallate-8-C N-ethyl-2-pyrrolidinone (R-EGCG-cThea and S-EGCG-cThea), were isolated from white tea using centrifugal partition chromatography (CPC). Two different biphasic solvent systems composed of 1. N-hexane-ethyl acetate-methanol-water (1:5:1:5, v/v/v/v) and 2. N-hexane-ethyl acetate-acetonitrile-water (0.7:3.0:1.3:5.0, v/v/v/v) were used for independent pre-fractionation experiments; 500 mg in each separation of white tea ethyl acetate partition were fractionated. The suitability of the two solvent systems was pre-evaluated by electrospray mass-spectrometry (ESI-MS/MS) analysis for metabolite distribution and compared to the results of the CPC experimental data using specific metabolite partition ratio K_D values, selectivity factors α, and resolution factors R_S. After size-exclusion and semi-preparative reversed-phase liquid chromatography, 6.4 mg of R-EGCG-cThea and 2.9 mg of S-EGCG-cThea were recovered with purities over 95%. Further bioactivity evaluation showed that R- and S-EGCG-cThea possessed in vitro inhibition effects on α-glucosidase with IC₅₀ of 70.3 and 161.7 μM, respectively.     

Helix-mediated over 1 nm-range chirality recognition by ligand-to-ligand interactions of dinuclear helicates

Long-range chirality recognition between the two chiral guest ligands can be tuned based on the helix distances (d_Ln–Ln = 11.5 and 14.0 Å) of bis-diketonate bridged dinuclear lanthanide complexes (2Th and 3Th, respectively) used as mediators. Both 2Th and 3Th form one-dimensional (1D) helical structures upon terminal binding of two chiral guest co-ligands (L^R or L^S). Long-range chiral self-recognition is achieved in self-assembly of 2Th with L^R and L^S to preferentially form homochiral assemblies, 2Th-L^R·L^R and 2Th-L^S·L^S, whereas there is no direct molecular interaction between the two guest ligands at the terminal edges. X-ray crystal structure analysis and density functional theory studies reveal that long-range chiral recognition is achieved by terminal ligand-to-ligand interactions between the bis-diketonate ligands and chiral guest co-ligands. Conversely, in self-assembly of 3Th with a longer helix length, statistical binding of L^R and L^S occurs, forming heterochiral (3Th-L^R·L^S) and homochiral (3Th-L^R·L^R and 3Th-L^S·L^S) assemblies in an almost 1 : 1 ratio. When phenyl side arms of the chiral guest co-ligands are replaced by isopropyl groups (L′^R and L′^S), chiral self-recognition is also achieved in the self-assembly process of 3Th with the longer helix length to generate homochiral (3Th-L′^R·L′^R and 3Th-L′^S·L′^S) assemblies as the favored products. Thus, subtle modification of the chiral guests is capable of achieving over 1.4 nm-range chirality recognition.

Long-range chirality recognition between the two chiral guest ligands can be tuned based on the helix distances (d_Ln–Ln = 11.5 and 14.0 Å) of bis-diketonate bridged dinuclear lanthanide complexes (2Th and 3Th, respectively).     

Synthesis of pseudopeptidic (S)-6-amino-5-oxo-1,4-diazepines and (S)-3-benzyl-2-oxo-1,4-benzodiazepines by an Ugi 4CC Staudinger/aza-Wittig sequence

Sequential Ugi reaction between p-substituted arylglyoxals, alkylamines, cyclohexyl isocyanide and 3-azido-(S)-2-(tert-butoxycarbonylamino)propanoic acid, followed by a Staudinger/aza-Wittig cyclization in the presence of triphenylphosphine, gave rise to enantiomerically pure N-cyclohexyl 4-alkyl-2-aryl-5-oxo-(S)-6-(tert-butoxycarbonylamino)-4,5,6,7-tetrahydro-1H-1,4-diazepine-3-carboxamides, that can be useful for new drug design. By the same sequence, p-substituted benzaldehydes, 2-aminobenzophenone, cyclohexyl isocyanide and (S)-3-phenyl-2-azidopropionic acid gave rise to N-cyclohexyl 2-((S)-3-benzyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-1-yl)-(R/S)-2-arylacetamides.     

Biotransformation of (−)-α-Bisabolol by Absidia coerulea

(−)-α-Bisabolol, a bioactive monocyclic sesquiterpene alcohol, has been used in pharmaceutical and cosmetic products with anti-inflammatory, antibacterial and skin-caring properties. However, the poor water solubility of (−)-α-bisabolol limits its pharmaceutical applications. It has been recognized that microbial transformation is a very useful approach to generate more polar metabolites. Fifteen microorganisms were screened for their ability to metabolize (−)-α-bisabolol in order to obtain its more polar derivatives, and the filamentous fungus Absidia coerulea was selected for scale-up fermentation. Seven new and four known metabolites were obtained from biotransformation of (−)-α-bisabolol (1), and all the metabolites exhibited higher aqueous solubility than that of the parent compound 1. The structures of newly formed metabolites were established as (1R,5R,7S)- and (1R,5S,7S)-5-hydroxy-α-bisabolol (2 and 3), (1R,5R,7S,10S)-5-hydroxybisabolol oxide B (4), (1R,7S,10S)-1-hydroxybisabolol oxide B (5), 12-hydroxy-α-bisabolol (7), (1S,3R,4S,7S)- and (1S,3S,4S,7S)-3,4-dihydroxy-α-bisabolol (8 and 10) on the basis of spectroscopic analyses. These compounds could also be used as reference standards for the detection and identification of the metabolic products of 1 in the mammalian system.     

Stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone

A stereoselective synthesis of (1′S,3R,4R)-4-acetoxy-3-(2′-fluoro-1′-trimethylsilyloxyethyl)-2-azetidinone as a new fluorine-containing intermediate towards β-lactams, is described. The synthetic key step relies upon the dynamic kinetic resolution (DKR) of ethyl 2-benzamidomethyl-4-fluoro-3-oxo-butanoate via asymmetric transfer hydrogenation catalyzed by [Ru(η⁶-arene)(S,S)-R₂NSO₂DPEN].     

Antileishmanial Effects of Acetylene Acetogenins from Seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae) and Semisynthetic Derivatives

As part of our continuous studies involving the prospection of natural products from Brazilian flora aiming at the discovery of prototypes for the development of new antiparasitic drugs, the present study describes the isolation of two natural acetylene acetogenins, (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-yn-19′-enyl)butanolide (1) and (2S,3R,4R)-3-hydroxy-4-methyl-2-(n-eicos-11′-ynyl)butanolide (2), from the seeds of Porcelia macrocarpa (Warm.) R.E. Fries (Annonaceae). Using an ex-vivo assay, compound 1 showed an IC₅₀ value of 29.9 μM against the intracellular amastigote forms of Leishmania (L.) infantum, whereas compound 2 was inactive. These results suggested that the terminal double bond plays an important role in the activity. This effect was also observed for the semisynthetic acetylated (1a and 2a) and eliminated (1b and 2b) derivatives, since only compounds containing a double bond at C-19 displayed activity, resulting in IC₅₀ values of 43.3 μM (1a) and 23.1 μM (1b). In order to evaluate the effect of the triple bond in the antileishmanial potential, the mixture of compounds 1 + 2 was subjected to catalytic hydrogenation to afford a compound 3 containing a saturated side chain. The antiparasitic assays performed with compound 3, acetylated (3a), and eliminated (3b) derivatives confirmed the lack of activity. Furthermore, an in-silico study using the SwissADME online platform was performed to bioactive compounds 1, 1a, and 1b in order to investigate their physicochemical parameters, pharmacokinetics, and drug-likeness. Despite the reduced effect against amastigote forms of the parasite to the purified compounds, different mixtures of compounds 1 + 2, 1a + 2a, and 1b + 2b were prepared and exhibited IC₅₀ values ranging from 7.9 to 38.4 μM, with no toxicity for NCTC mammalian cells (CC₅₀ > 200 μM). Selectivity indexes to these mixtures ranged from >5.2 to >25.3. The obtained results indicate that seeds of Porcelia macrocarpa are a promising source of interesting prototypes for further modifications aiming at the discovery of new antileishmanial drugs.     

Characterization of Diastereomeric Equilibria of Pseudotetrahedral Bis[(R or S)‐N‐1‐(Ar)Ethylsalicylaldiminato‐κ2N,O]zinc(II) with Λ/Δ‐Chirality‐At‐Metal Induction

A family of bis[(R or S)‐N‐1‐(Ar)ethylsalicylaldiminato‐κ²N,O]‐Δ/Λ‐zinc(II) {Ar=C₆H₅ (ZnRL¹ or ZnSL¹), p‐CH₃OC₆H₄ (ZnRL² or ZnSL²) and p‐ClC₆H₄ (ZnRL³ or ZnSL³)} compounds was synthesized and investigated by multiple methods. They feature Λ/Δ‐chirality‐at‐metal induction along the pseudo‐C ₂ axis of the molecules. The chirality induction is quantitative in the solid state, explored by X‐ray crystallography and powder X‐ray diffraction (PXRD), where R or S‐ligated complexes diastereoselectively yield Λ or Δ‐configuration at the metal. On the other hand, Λ and Δ‐diastereomers co‐exist in solution. The Λ⇆Δ equilibrium is solvent‐ and temperature‐dependent. Electronic circular dichroism (ECD) spectra confirm the existence of a diastereomeric excess of Λ‐ZnRL¹⁻³ or Δ‐ZnSL¹⁻³ in solution. DSC analysis reveals thermally induced irreversible phase transformation from a crystalline solid to an isotropic liquid phase. ECD spectra were reproduced by DFT geometry optimizations and time‐dependent DFT (TD‐DFT) calculations, providing ultimate proof of the dominant chirality atmetal in solution.