Synthesis Of Bioactive Molecules Research Articles

Organomediated electrochemical fluorosulfonylation of aryl triflates via selective C–O bond cleavage

Although aryl triflates are essential building blocks in organic synthesis, the applications as aryl radical precursors are limited. Herein, we report an organomediated electrochemical strategy for the generation of aryl radicals from aryl triflates, providing a useful method for the synthesis of aryl sulfonyl fluorides from feedstock phenol derivatives under very mild conditions. Mechanistic studies indicate that key to success is to use catalytic amounts of 9, 10-dicyanoanthracene as an organic mediator, enabling to selectively active aryl triflates to form aryl radicals via orbital-symmetry-matching electron transfer, realizing the anticipated C–O bond cleavage by overcoming the competitive S–O bond cleavage. The transition-metal-catalyst-free protocol shows good functional group tolerance, and may overcome the shortages of known methods for aryl sulfonyl fluoride synthesis. Furthermore, this method has been used for the modification and formal synthesis of bioactive molecules or tetraphenylethylene (TPE) derivative with improved quantum yield of fluorescence.

Current approaches to the genetic modification of mesenchymal stromal cells to increase their therapeutic efficacy

One of the extensively developing innovative approaches to the treatment of socially significant diseases is the use of cell technologies based on the transplantation and co-transplantation of mesenchymal stromal cells (MSCs) or on the use of their secretome components. The interest in these cell therapies is driven by the low immunogenicity of MSCs, relative simplicity of the cell isolation and handling, a wide range of therapeutic effects and proven efficacy of reparative and immunosuppressive action thereof.
 By now, more than 2,000 clinical trials on the use of MSCs or their products in various pathological conditions have been completed, with more than 200 in the last five years. Both the immunosuppressive and the regenerative effects of MSCs are mediated to a great extent by their secretome which includes chemokines, growth factors, non-coding RNAs, and other active molecules. At the same time, the degree and character of MSCs effects depend not only on the microenvironment or body state, but also on the characteristics of MSCs themselves, including the genetic determinants governing levels of synthesis of bioactive molecules. In this review, options of genetic modification of MSCs in order to increase their therapeutic efficacy were considered.

Exploiting and Engineering Neuroglobin for Catalyzing Carbene N-H Insertions and the Formation of Quinoxalinones.

It is desired to design and construct more efficient enzymes with better performance to catalyze carbene N-H insertions for the synthesis of bioactive molecules. To this end, we exploited and designed a series of human neuroglobin (Ngb) mutants. As shown in this study, a double mutant, A15C/H64G Ngb, with an additional disulfide bond and a modified heme active site, exhibited yields up to >99% and total turnover numbers up to 33000 in catalyzing the carbene N-H insertions for aromatic amine derivatives, including those with a large size such as 1-aminopyrene. Moreover, for o-phenylenediamine derivatives, they underwent two cycles of N-H insertions, followed by cyclization to form quinoxalinones, as confirmed by the X-ray crystal structures. This study suggests that Ngb can be designed into a functional carbene transferase for efficiently catalyzing carbene N-H insertion reactions with a range of substrates. It also represents the first example of the formation of quinoxalinones catalyzed by an engineered heme enzyme.

Transition-Metal-Catalyzed Silylation and Borylation of C-H Bonds for the Synthesis and Functionalization of Complex Molecules.

The functionalization of C-H bonds in organic molecules containing functional groups has been one of the holy grails of catalysis. One synthetically important approach to the diverse functionalization of C-H bonds is the catalytic silylation or borylation of C-H bonds, which enables a broad array of downstream transformations to afford diverse structures. Advances in both undirected and directed methods for the transition-metal-catalyzed silylation and borylation of C-H bonds have led to their rapid adoption in early-, mid-, and late-stage of the synthesis of complex molecules. In this Review, we review the application of the transition-metal-catalyzed silylation and borylation of C-H bonds to the synthesis of bioactive molecules, organic materials, and ligands. Overall, we aim to provide a picture of the state of art of the silylation and borylation of C-H bonds as applied to the synthesis and modification of diverse architectures that will spur further application and development of these reactions.

Copper‐Catalyzed Highly Stereoselective Hydrodifluoroallylation of Cyclopropenes and Alkenyl Boronates with 3,3‐Difluoroallyl Sulfonium Salts†

Comprehensive SummaryDespite the paramount applications of organofluorine compounds in life and materials sciences, efficient strategies for stereoselectively constructing the C(sp3)‐CF2R bond at the stereogenic center remain limited. Here, we report a copper‐catalyzed hydrodifluoroallylation of cyclopropenes and alkenyl boronates with 3,3‐difluoroallyl sulfonium salts (DFASs). The use of DFASs overcomes the previous challenge of suppressing the reduction of fluoroalkylating reagents with M‐H species. The reaction provides an array of gem‐difluoroallyl cyclopropanes and borylalkanes with high efficiency and stereoselectivity under mild reaction conditions. Using chiral phosphine ligand could provide gem‐difluoroallyl borylalkanes with high enantioselectivities, paving a new way for the catalytic asymmetric fluoroalkylation with ubiquitous alkenes. The advantages of this protocol are synthetic convenience, high functional group tolerance, and the synthetic versatility of the resulting gem‐difluoroallyl cyclopropanes and borylalkanes. The synthetic utility of this approach has also been demonstrated by the diversified transformations of the gem‐difluoroallylated products and the rapid synthesis of bioactive molecule analogs.

Three-Component Synthesis of Quinoline-4-carboxylic Acids Based on Doebner Hydrogen-Transfer Reaction.

The Doebner hydrogen-transfer reaction has been developed for the synthesis of substituted quinolines from anilines possessing electron-withdrawing groups, which are known to give products in low yields when used in the conventional Doebner reaction. This reaction can be applied to not only anilines having electron-withdrawing groups but also those having electron-donating groups and can be used in the large-scale synthesis of bioactive molecules.

1,5,7-Triazabicyclo[4.4.0]dec-5-ene: An Effective Catalyst for Amide Formation by Lactone Aminolysis.

The amide is one of the most prevalent functional groups throughout natural and engineered chemical space. Among various methods of constructing amide bonds, lactone aminolysis remains one of the most atom economical. Herein, we report 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as an effective catalyst for lactone aminolysis under mild conditions. This methodology is compatible with a wide range of lactones and amines (>50 examples), including various natural products and pharmaceuticals, and applicable to the synthesis of bioactive molecules. Detailed mechanistic studies under synthetically relevant conditions, including reaction progress kinetic analysis and variable time normalization analysis, reveal a likely mechanism for this reaction involving acyl-TBD as the reactive intermediate.

Which boronic acids are used most frequently for synthesis of bioactive molecules?

Boronic acids are essential building blocks used for the synthesis of bioactive molecules, the generation of chemical libraries and the exploration of structure–activity relationships. As a result, more than ten thousand boronic acids are commercially available. Medicinal chemists are therefore facing a challenge; which of them should they select to maximize information obtained by the synthesis of new target molecules. The present article aims to help them to make the right choices. The boronic acids used frequently in the synthesis of bioactive molecules were identified by mining several large molecular and reaction databases and their properties were analyzed. Based on the results a diverse set of boronic acids covering well the bioactive chemical space was selected and is suggested as a basis for library design for the efficient exploration of structure–activity relationships. A Boronic Acid Navigator web tool which helps chemists to make their own selection is also made available at https://bit.ly/boronics.

Ambient Temperature Dehydrogenative C(Ar)–H Carbonylative Lactamization of 2-Arylanilines Using DMF as C1-Source

The direct dehydrogenative C-H cleaving carbonylative lactamization of 2-arylanilines promoted by visible light and potassium bases is reported. Solvent DMF acts as the sole carbonyl source in the absence of an oxidant. The irreversible release of hydrogen gas drags this reaction to the stable phenanthridinone products. This work provides a direct conversion of a broad range of 2-arylanilines to various phenanthridinones. This method could be applied in the synthesis of bioactive molecules and organic optoelectronic materials.

Three-Component Electrochemical Aminoselenation of 1,3-Dienes

Azoles and organoselenium compounds are pharmacologically important scaffolds in medicinal chemistry and natural products. We developed an efficient regioselective electrochemical aminoselenation reaction of 1,3-dienes, azoles, and diselenide derivatives to access selenium-containing allylazoles skeletons. This protocol is more economical and environmentally friendly and features a broad substrate scope; pyrazole, triazole, and tetrazolium were all tolerated under the standard conditions, which could be applied to the expedient synthesis of bioactive molecules and in the pharmaceutical industry.

Occurrence, Chemistry and Synthesis of Various Novel Methods of Oxadiazole

Oxadiazoles are a kind of heterocyclic molecule that can be identified by their five-membered ring structure, two azo groups, and a single oxygen atom in their make-up. These characteristics allow them to be distinguished from other heterocyclic compounds. Because of these features, it is possible to differentiate them from several other heterocyclic compounds. They have the highest importance and relevance in the area of heterocyclic chemistry, which is also where they have the most value. They are of the biggest significance. Research is being conducted on it in substantial amounts due to the fact that it has the potential to function as a starting point for the synthesis of bioactive molecules that are beneficial to the body. This article provides a brief discussion of the physicochemical features of oxadiazole, including its spectra and a few examples of how it may be synthesised. The article can be found here. The pharmacological effects of oxadiazole derivatives were investigated by our team of researchers, and the findings indicated that these compounds had a number of positive benefits, including anti-inflammatory, anti-cancer, anti-fungal, anti-osteoporotic, and anti-microbial properties. In this piece, we will have a brief discussion on both synthetic and naturally occurring medications that include the oxadiazole ring in addition to the moiety. This talk will focus on pharmaceuticals that have been manufactured. The production of these compounds may take place in a laboratory, or they may be found occurring naturally in their natural environments.

Expedient Access to Underexplored Chemical Space: Deoxygenative C(sp3)-C(sp3) Cross-Coupling.

Alcohols are commercially abundant and structurally diverse reservoirs of sp3-hybridized chemical space. However, the direct utilization of alcohols in C-C bond-forming cross-couplings remains underexplored. Herein we report an N-heterocyclic carbene (NHC)-mediated deoxygenative alkylation of alcohols and alkyl bromides via nickel-metallaphotoredox catalysis. This C(sp3)-C(sp3) cross-coupling exhibits a broad scope and is capable of forming bonds between two secondary carbon centers, a longstanding challenge in the field. Highly strained three-dimensional systems such as spirocycles, bicycles, and fused rings were excellent substrates, enabling the synthesis of new molecular frameworks. Linkages between pharmacophoric saturated ring systems were readily forged, representing a three-dimensional alternative to traditional biaryl formation. The utility of this cross-coupling technology is highlighted with the expedited synthesis of bioactive molecules.

Photocatalytic Sulfonyl Fluorination of Alkyl Organoboron Substrates.

Sulfonyl fluorides are highly versatile molecules for click chemistry that have found applications in many areas of chemistry and biology. Recent chemical approaches have focused on the synthesis of alkyl sulfonyl fluorides from readily available starting materials. Here, we report a photocatalytic synthesis of alkyl sulfonyl fluorides from organotrifluoroborates and boronic acid pinacol esters, which are building blocks commonly employed by medicinal chemists in the synthesis of bioactive molecules. Steady-state and time-resolved spectroscopy have confirmed that the absorption of photons by the acridinium catalysts leads to the oxidation of the organotrifluoroborate substrates. The reaction exhibits broad functional group tolerance, which can be attributed to the mild activation with visible light. Importantly, this general approach provides easy access to primary, secondary, and tertiary alkyl sulfonyl fluorides.

Transcriptome Sequencing of the Diatom Asterionellopsis thurstonii and In Silico Identification of Enzymes Potentially Involved in the Synthesis of Bioactive Molecules

Microalgae produce a plethora of primary and secondary metabolites with possible applications in several market sectors, including cosmetics, human nutrition, aquaculture, biodiesel production and treatment/prevention of human diseases. Diatoms, in particular, are the most diversified microalgal group, many species of which are known to have anti-cancer, anti-oxidant, anti-diabetes, anti-inflammatory and immunomodulatory properties. Compounds responsible for these activities are often still unknown. The aim of this study was to de novo sequence the full transcriptome of two strains of the diatom Asterionellopsis thurstonii, sampled from two different locations and cultured in both control and phosphate starvation conditions. We used an RNA-sequencing approach to in silico identify transcripts potentially involved in the synthesis/degradation of compounds with anti-cancer and immunomodulatory properties. We identified transcript coding for L-asparaginase I, polyketide cyclase/dehydrase, bifunctional polyketide phosphatase/kinase, 1-deoxy-D-xylulose-5-phosphate synthase (fragment), inositol polyphosphate 5-phosphatase INPP5B/F, catechol O-Methyltransferase, digalactosyldiacylglycerol synthase (DGD1), 1,2-diacylglycerol-3-beta-galactosyltransferase and glycerolphosphodiester phosphodiesterase. Differential expression analysis also allowed to identify in which culturing condition these enzymes are more expressed. Overall, these data give new insights on the annotation of diatom genes, enzymatic pathways involved in the generation of bioactive molecules and possible exploitation of Asterionellopsis thurstonii.

Photocatalytic coupling of electron-deficient alkenes using oxalic acid as a traceless linchpin

•Oxalic acid is used as a traceless linchpin •CO2 radical anion formation via photocatalytic oxidation of oxalic acid is achieved •Homo- and cross-coupling of electron-poor alkenes is achieved Reductive alkene cross-coupling represents a straightforward strategy for the construction of C–C bonds from readily available alkene feedstocks. A one-pot protocol, utilizing oxalic acid as a traceless linchpin, has been developed to achieve direct cross-coupling of electron-deficient alkenes. The overall process is a two-step transformation involving hydrocarboxylation followed by decarboxylative cross-coupling. A dual-photocatalyst system is crucial for success and promotes the two reaction steps synergistically. This reaction supports the efficient synthesis of bioactive molecules. Photoredox catalysis provides an easy and mild pathway for the generation of a CO2 radical anion from oxalic acid, which paves the way for the broad utilization of this reactive intermediate in the synthesis of fine chemicals. Reductive alkene cross-coupling represents a straightforward strategy for the construction of C–C bonds from readily available alkene feedstocks. A one-pot protocol, utilizing oxalic acid as a traceless linchpin, has been developed to achieve direct cross-coupling of electron-deficient alkenes. The overall process is a two-step transformation involving hydrocarboxylation followed by decarboxylative cross-coupling. A dual-photocatalyst system is crucial for success and promotes the two reaction steps synergistically. This reaction supports the efficient synthesis of bioactive molecules. Photoredox catalysis provides an easy and mild pathway for the generation of a CO2 radical anion from oxalic acid, which paves the way for the broad utilization of this reactive intermediate in the synthesis of fine chemicals.

Taming diamines and acyl chlorides by carbon dioxide in selective mono-acylation reactions

Selective monoacylation and unsymmetric diamide formation reactions using acyl chlorides and diamines under ambient CO2 pressure (400 ppm – 1 atm), enabling facile synthesis of bioactive molecules.

Synthesis of 3-aminoquinolines from α-imino rhodium carbenes and 2-aminobenzaldehydes.

A facile and efficient synthetic method for 3-aminoquinolines has been reported. The straightforward process starts from easily available triazoles and 2-aminobenzaldehydes. Low catalyst loading and good functional group compatibility are the other two merits of this transformation. Easy decoration of the 3-aminoquinoline motifs enabled the convenient synthesis of bioactive molecules, demonstrating the potential of this protocol in organic synthesis.

Cyrene: A Green Solvent for the Synthesis of Bioactive Molecules and Functional Biomaterials.

In the panorama of sustainable chemistry, the use of green solvents is increasingly emerging for the optimization of more eco-friendly processes which look to a future of biocompatibility and recycling. The green solvent Cyrene, obtained from biomass via a two-step synthesis, is increasingly being introduced as the solvent of choice for the development of green synthetic transformations and for the production of biomaterials, thanks to its interesting biocompatibility, non-toxic and non-mutagenic properties. Our review offers an overview of the most important organic reactions that have been investigated to date in Cyrene as a medium, in particular focusing on those that could potentially lead to the formation of relevant chemical bonds in bioactive molecules. On the other hand, a description of the employment of Cyrene in the production of biomaterials has also been taken into consideration, providing a point-by-point overview of the use of Cyrene to date in the aforementioned fields.

Cobalt(II)-Catalyzed C–H Alkylation of N-Heterocycles with 1,4-Dihydropyridines

The rapid incorporation of alkyl and acyl groups into C–H bonds of N-heterocycles is in demand for the development of lead candidates in drug discovery. Herein, we report the cobalt(II)-catalyzed C–H alkylation and acylation of N-heterocycles with 1,4-dihydropyridines (DHPs) as alkylating and acylating agents. Notably, a combination of KBrO3 and a Co(II) catalyst was successfully employed for the generation of alkyl and acyl radicals from DHPs. A series of heterocycles, including azauracils, quinoxalinones, pyrazinones, pyridones, quinolones, quinazolinones, xanthines, chromones, and azine N-oxides, were compatible under the developed conditions. The applicability of the developed protocol in challenging contexts is highlighted by the selective modification of drug candidates as well as the gram-scale synthesis of bioactive molecules. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.

Chirality transfer strategy in asymmetric total syntheses

Chirality transfer arises when a new stereogenic element is introduced in the target molecule while the original chirality is lost. Recent advances of this strategy in the assembly of complex chiral centers and to facilitate the interconversion of chirality elements illustrate its wide applications in asymmetric total syntheses of bioactive molecules.