Modern Synthetic Methods for the Stereoselective Construction of 1,3-Dienes.

The 1,3-butadiene motif is widely found in many natural products and drug candidates with relevant biological activities. Moreover, dienes are important targets for synthetic chemists, due to their ability to give access to a wide range of functional group transformations, including a broad range of C-C bond-forming processes. Therefore, the stereoselective preparation of dienes have attracted much attention over the past decades, and the search for new synthetic protocols continues unabated. The aim of this review is to give an overview of the diverse methodologies that have emerged in the last decade, with a focus on the synthetic processes that meet the requirements of efficiency and sustainability of modern organic chemistry.

Ionic Liquids and Ohmic Heating in Combination for Pd-catalyzed Cross-coupling Reactions: Sustainable Synthesis of Flavonoids.

In order to meet the increasing demand for environmentally benign chemical processes, we developed a Suzuki-Miyaura reaction protocol based on the combination of ohmic heating (ΩH) and supported ionic liquid phase catalysis (SILPC) in aqueous media. This methodology was applied to the synthesis of a series of flavonoid derivatives, including isoflavones, styrylisoflavones, and diarylalkenylisoflavones.

Temperature-Controlled Stereodivergent Synthesis of 2,2'-Biflavanones Promoted by Samarium Diiodide.

In this work, the first example of a radical stereodivergent reaction directed towards the stereoselective synthesis of both (R*,R*)- and (R*,S*)-2,2'-biflavanones promoted by samarium diiodide is reported. Control experiments showed that the selectivity of this reaction was exclusively controlled by the temperature. It was possible to generate a variety of 2,2'-biflavanones bearing different substitution patterns at the aromatic ring in good-to-quantitative yields, being both stereoisomers of the desired compounds obtained with total or high control of selectivity. A mechanism that explains both the generation of the corresponding 2,2'-biflavanones and the selectivity is also discussed. The structure and stereochemistry determination of each isomer was unequivocally elucidated by single-crystal X-ray diffraction experiments.

Synthesis of Spironucleosides: Past and Future Perspectives.

Spironucleosides are a type of conformationally restricted nucleoside analogs in which the anomeric carbon belongs simultaneously to the sugar moiety and to the base unit. This locks the nucleic base in a specific orientation around the N-glycosidic bond, imposing restrictions on the flexibility of the sugar moiety. Anomeric spiro-functionalized nucleosides have gained considerable importance with the discovery of hydantocidin, a natural spironucleoside isolated from fermentation broths of Streptomyces hygroscopicus which exhibits potent herbicidal activity. The biological activity of hydantocidin has prompted considerable synthetic interest in this nucleoside and also in a variety of analogues, since important pharmaceutical leads can be found among modified nucleoside analogues. We present here an overview of the most important advances in the synthesis of spironucleosides.

Preparation of indium nitronates and their Henry reactions.

Indium nitronates were readily prepared from commercially available nitroalkanes by transmetallation of the corresponding lithium nitronates with indium salts. The Henry reaction of this indium organometallics with aldehydes afforded ß-nitroalkanols in moderate to high yields. The use of chiral sugar aldehydes furnished the corresponding carbohydrate-derived ß-nitroalkanols with excellent stereoselectivity.

Coordination of azol(in)ium dithiocarboxylate ligands to Au(III): unexpected formation of a novel family of cyclometallated Au(III) complexes, DFT calculations and catalytic studies.

A series of cyclometallated gold(III) complexes 21-27 of general formula [Au(dppta)(azdtc)Cl] (dppta = N,N-diisopropyl-P,P-diphenylphosphinothioic amide-κ2C,S; azdtc = azol(in)ium-2-dithiocarboxylate-κ1S) were prepared and characterized by spectroscopic and diffractometric techniques. Treatment of [Au(dppta)(azdtc)Cl] complexes with methanol led to their quantitative transformation into a novel family of (C^S, S^S)-cyclometallated gold(III) complexes of general formula [Au(dppta)(azmtd)] (azmdt = azol(in)ium-2-(methoxy)methanedithiol-κ2S,S) 28-34. All the [Au(dppta)(azdtc)Cl] complexes 21-27 catalyzed the alkylation of indoles, whereas [Au(dppta)(azmtd)] complexes 28-34 were inactive. Among the synthesized derivatives, complex 22 displayed the highest catalytic activity, leading to a series of functionalized indoles in excellent yields.

Heteroleptic (S

Despite the increasingly widespread clinical impact of adenovirus (HAdV) infections in healthy individuals and the associated high morbidity in immunosuppressed patients, particularly among the paediatric population, a specific treatment for this virus has yet to be developed. In this study, we report the anti-HAdV activity of sub-micromolar concentrations of four heteroleptic (C^S)-cycloaurated complexes bearing a single thiophosphinamide [Au(dpta)Cl2, Au(dpta)(mrdtc), and Au(dpta)(dedtc)] or thiophosphonamide [Au(bpta)(dedtc)] chelating ligand and a dithiocarbamate moiety. In addition to their low cytotoxicity, the findings of mechanistic assays revealed that these molecules have antiviral activity by targeting stages of the viral replication cycle subsequent to DNA replication. Additionally, all four compounds showed a significant inhibition of human cytomegalovirus (HCMV) DNA replication, thereby providing evidence for potential broad-spectrum antiviral activity.

Synthesis of enantiopure 2-C-glycosyl-3-nitrochromenes.

A novel methodology has been developed to obtain enantiopure 2-C-glycosyl-3-nitrochromenes. First, (Z)-1-bromo-1-nitroalkenes were prepared from the corresponding sugar aldehydes through a sodium iodide-catalyzed Henry reaction with bromonitromethane followed by elimination of the resulting 1-bromo-1-nitroalkan-2-ols. In the next step, reaction of the sugar-derived (Z)-1-bromo-1-nitroalkenes with o-hydroxybenzaldehydes afforded enantiopure (2S,3S,4S)-3-bromo-3,4-dihydro-4-hydroxy-3-nitro-2H-1-benzopyrans, which, upon SmI2-promoted ß-elimination, yielded chiral enantiopure 2-C-glycosyl-3-nitrochromenes.

Novel gold(III)-dithiocarbamate complex targeting bacterial thioredoxin reductase: antimicrobial activity, synergy, toxicity, and mechanistic insights.

Introduction: Antimicrobial resistance is a pressing global concern that has led to the search for new antibacterial agents with novel targets or non-traditional approaches. Recently, organogold compounds have emerged as a promising class of antibacterial agents. In this study, we present and characterize a (C^S)-cyclometallated Au(III) dithiocarbamate complex as a potential drug candidate. Methods and results: The Au(III) complex was found to be stable in the presence of effective biological reductants, and showed potent antibacterial and antibiofilm activity against a wide range of multidrug-resistant strains, particularly gram-positive strains, and gram-negative strains when used in combination with a permeabilizing antibiotic. No resistant mutants were detected after exposing bacterial cultures to strong selective pressure, indicating that the complex may have a low propensity for resistance development. Mechanistic studies indicate that the Au(III) complex exerts its antibacterial activity through a multimodal mechanism of action. Ultrastructural membrane damage and rapid bacterial uptake suggest direct interactions with the bacterial membrane, while transcriptomic analysis identified altered pathways related to energy metabolism and membrane stability including enzymes of the TCA cycle and fatty acid biosynthesis. Enzymatic studies further revealed a strong reversible inhibition of the bacterial thioredoxin reductase. Importantly, the Au(III) complex demonstrated low cytotoxicity at therapeutic concentrations in mammalian cell lines, and showed no acute in vivo toxicity in mice at the doses tested, with no signs of organ toxicity. Discussion: Overall, these findings highlight the potential of the Au(III)-dithiocarbamate scaffold as a basis for developing novel antimicrobial agents, given its potent antibacterial activity, synergy, redox stability, inability to produce resistant mutants, low toxicity to mammalian cells both in vitro and in vivo, and non-conventional mechanism of action.

Gold-Derived Molecules as New Antimicrobial Agents.

Antimicrobial resistance is considered one of the three most important health problems by the World Health Organization. The emergence and spread of an increasing number of antimicrobial-resistant microorganisms make this a worldwide problem. Antibiotic-resistant bacteria are estimated to be the cause of 33,000 deaths in Europe and 700,000 worldwide each year. It is estimated that in 2050 bacterial infections will cause 10 million deaths across the globe. This problem is concomitant with a decrease in the investment and, therefore, the discovery and marketing of new antibiotics. Recently, there have been tremendous efforts to find new effective antimicrobial agents. Gold complexes, with their broad-spectrum antimicrobial activities and unique modes of action, are particularly relevant among several families of derivatives that have been investigated. This mini review revises the role of gold-derived molecules as antibacterial agents.

Gold(III) Complexes Activity against Multidrug-Resistant Bacteria of Veterinary Significance.

The emergence and spread of multidrug-resistant bacteria are a global concern. The lack of new antibiotics in the pipeline points to the need for developing new strategies. In this sense, gold(III) complexes (G3Cs) could be a promising alternative due to their recently described antibacterial activity. The aim of this study was to evaluate the antimicrobial activity of G3Cs alone and in combination with colistin against pathogenic bacteria from veterinary sources. Minimal inhibitory concentration (MIC) values were determined by broth microdilution and compared with clinically relevant antibiotics. Antibiofilm activity was determined by crystal violet staining. Combinations of selected G3Cs with colistin and cytotoxicity in commercial human cell lines were evaluated. Four and seven G3Cs showed antibacterial effect against Gram-negative and Gram-positive strains, respectively, with this activity being higher among Gram-positive strains. The G3Cs showed antibiofilm activity against Gram-negative species at concentrations similar or one to four folds higher than the corresponding MICs. Combination of G3Cs with colistin showed a potential synergistic antibacterial effect reducing concentrations and toxicity of both agents. The antimicrobial and antibiofilm activity, the synergistic effect when combined with colistin and the in vitro toxicity suggest that G3Cs would provide a new therapeutic alternative against multidrug-resistant bacteria from veterinary origin.

Polyhydroxylated Cyclopentane ß-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides.

A stereoselective synthesis of polyhydroxylated cyclopentane ß-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic ß-amino acids into peptides is also reported.

Synthesis of Optically Active syn- and anti-Chlorohydrins through a Bienzymatic Reductive Cascade.

A bienzymatic cascade has been designed and optimized to obtain enantiopure chlorohydrins starting from the corresponding 1-aryl-2-chlorobut-2-en-1-ones. For the synthesis of these α-chloroenones, a two-step sequence was developed consisting of the allylation of the corresponding aldehyde with 3-dichloroprop-1-ene, followed by oxidation and further isomerization. The selective cooperative catalytic system involving ene-reductases (EREDs) and alcohol dehydrogenases (ADHs) afforded the desired optically active chlorohydrins under mild reaction conditions in excellent conversions (up to >99%) and selectivities (up to >99:1 diastereomeric ratio (dr), >99% enantiomeric excess (ee)).

Chromium-mediated stereoselective synthesis of carbohydrate-derived (E)-α,ß-unsaturated esters or amides.

A chromium-mediated novel synthesis of carbohydrate-derived di- and trisubstituted (E)-α,ß-unsaturated esters or amides from a range of dichloroesters or amides and a variety of sugar aldehydes is reported. The process took place with total stereoselectivity and in high yields. A mechanism based on a sequential chromium-promoted aldol-type reaction and a completely stereoselective ß-elimination reaction is proposed to explain these results.

Therapeutic Potential of Glycosyl Flavonoids as Anti-Coronaviral Agents.

The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread all over the world, creating a devastating socio-economic impact. Even though protective vaccines are starting to be administered, an effective antiviral agent for the prevention and treatment of COVID-19 is not available yet. Moreover, since new and deadly CoVs can emerge at any time with the potential of becoming pandemics, the development of therapeutic agents against potentially deadly CoVs is a research area of much current interest. In the search for anti-coronaviral drugs, researchers soon turned their heads towards glycosylated flavonoids. Glycosyl flavonoids, widespread in the plant kingdom, have received a lot of attention due to their widely recognized antioxidant, anti-inflammatory, neuroprotective, anticarcinogenic, antidiabetic, antimicrobial, and antiviral properties together with their capacity to modulate key cellular functions. The wide range of biological activities displayed by glycosyl flavonoids, along with their low toxicity, make them ideal candidates for drug development. In this review, we examine and discuss the up-to-date developments on glycosyl flavonoids as evidence-based natural sources of antivirals against coronaviruses and their potential role in the management of COVID-19.

Ethyl 1-O-tert-butyl-dimethyl-silyl-2,3-O-isopropyl-idene-5-[(2'S)-tetra-hydro-pyran-2-yl-oxy]-d-glycero-α-d-manno-hepto-furonate.

The title compound {systematic name: (2S,3R)-ethyl 3-[(3aS,4R,6S,6aS)-6-tert-butyl-dimethyl-silyl-oxy-2,2-dimethyl-per-hydro-furo[3,4-d][1,3]dioxol-4-yl]-2-nitro-3-[(S)-tetra-hydro-2H-pyran-2-yl-oxy]propanoate}, C(23)H(41)NO(10)Si, is the product of the Henry reaction of 1-O-tert-butyl-dimethyl-silyl-2,3-O-isopropyl-idene-α-d-lyxo-penta-dialdo-1,4-furan-ose with ethyl nitro-acetate and the subsequent protection of its C-5 hydr-oxy group as tetra-hydro-pyranyl, in order to avoid the retro-Henry reaction. The tetra-hydro-pyranyl group adopts a chair conformation. The absolute configuration, assumed from the synthesis, was confirmed from the diffraction data.

Preliminary studies on the transformation of nitrosugars into branched chain iminosugars: synthesis of 1,4-dideoxy-4-C-hydroxymethyl-1,4-imino-pentanols.

A novel promising strategy for the transformation of nitrosugars into branched pyrrolidines, based on double Henry reaction with formaldehyde followed by reductive ring closure, allowed the first enantiospecific synthesis of a 4-C-hydroxymethyl branched derivative of the well-known glycosidase inhibitor 1,4-dideoxy-1,4-imino-pentanol. This strategy also afforded a new route to some other interesting derivatives, such as N-hydroxy, N-propyloxy, and imino derivatives, a new kind of compounds with promising biological properties. [reaction: see text].

Stereocontrolled transformation of nitrohexofuranoses into cyclopentylamines via 2-oxabicyclo[2.2.1]heptanes: incorporation of polyhydroxylated carbocyclic beta-amino acids into peptides.

A promising new strategy for the transformation of nitrohexofuranoses into cyclopentylamines, based on intramolecular cyclization followed by controlled opening of the resulting 2-oxabicyclo[2.2.1]heptane derivatives, allowed the first total synthesis of a carbocyclic beta-amino acid and its incorporation into peptides. This strategy also afforded a new route to cyclopentylamines with well-known glycosidase inhibition properties. [reaction: see text]

Transformation of D-glucose into 1D-3-deoxy-3-hydroxymethyl-myo-inositol by stereocontrolled intramolecular Henry reaction.

[reaction: see text] An intramolecular Henry cyclization provides a promising new strategy for the transformation of nitroheptofuranoses into deoxyhydroxymethylinositols. This method has allowed a stereospecific transformation of d-glucose into 1D-3-deoxy-3-hydroxymethyl-myo-inositol.

Spirocyclic nucleosides in medicinal chemistry: an overview.

This review describes some spiro- and pseudospironucleoside derivatives as well as their biological and pharmacological applications.