Efficient Synthetic Methodologies Research Articles

Transition-Metal- and Photocatalyst-Free Photoinduced Formation of Carbon–Pnictogen (–N, –P) Bonds

AbstractPnictogens, classified within group 15 elements, play a pivotal role in the constitution of a diverse array of drug molecules, natural products, and functional materials. Recent research has increasingly prioritized the exploration of mild conditions for synthesizing C–Pnictogen (C–N and C–P) bonds, highlighting a growing emphasis on efficient and sustainable synthetic methodologies. This Short Review explores fundamental mechanisms, addresses constraints, and assesses diverse methodologies, underscoring the potential of photocatalyst- and transition-metal-free photochemical reactions in advancing sustainability. Divided into two segments, it encompasses recent advancements in reactions facilitating C–N and C–P bond formation.1 Introduction2 Carbon–Nitrogen (C–N) Bond Formation3 Carbon–Phosphorus (C–P) Bond Formation4 Summary and Outlook

Bromopyrene Symphony: Synthesis and Characterisation of Isomeric Derivatives at Non-K Region and Nodal Positions for Diverse Functionalisation Strategies.

Pyrene, a renowned aromatic hydrocarbon, continues to captivate researchers due to its versatile properties and potential applications across various scientific domains. Among its derivatives, bromopyrenes stand out for their significance in synthetic chemistry, materials science, and environmental studies. The strategic functionalisation of pyrene at non-K region and nodal positions is crucial for expanding its utility, allowing for diverse functionalisation strategies. Bromo-substituted precursors serve as vital intermediates in synthetic routes; however, the substitution pattern of bromoderivatives significantly impacts their subsequent functionalisation and properties, posing challenges in synthesis and purification. Understanding the distinct electronic structure of pyrene is pivotal, dictating the preferential electrophilic aromatic substitution reactions at specific positions. Despite the wealth of literature, contradictions and complexities persist in synthesising suitably substituted bromopyrenes due to the unpredictable nature of substitution reactions. Building upon historical precedents, this study provides a comprehensive overview of bromine introduction in pyrene derivatives, offering optimised synthesis conditions based on laboratory research. Specifically, the synthesis of mono-, di-, tri-, and tetrabromopyrene isomers at non-K positions (1-, 3-, 6-, 8-) and nodal positions (2-, 7-) is systematically explored. By elucidating efficient synthetic methodologies and reaction conditions, this research contributes to advancing the synthesis and functionalisation strategies of pyrene derivatives, unlocking new possibilities for their utilisation in various fields.

Carbon quantum dots-based palladium complex: A versatile nano-catalyst for the green synthesis of pyrazoles

The palladium complex based on the magnetic carbon quantum dots [Fe3O4@CQDS@Si(CH2)3 NH@CC@ATT@Pd (CQDPd = F)] was synthesized by preparation of Fe3O4, its further reactions with carbon quantum dots (CQDs), (3-aminopropyl)triethoxysilane [Si(OEt)3(CH2)3NH2], cyanuric chloride (CC), and 3-amino-1,2,4-triazole-5-thiol (ATT), and complexation of the product with PdCl2. Then, it was characterized by several techniques such as FT-IR, XRD, EDX, SEM, TEM, VSM, and used as a novel catalyst for the green synthesis of diverse pyrazoles from the reaction of aldehydes, ethyl acetoacetate and phenylhydrazine at 70 °C under solvent-free conditions with high yields and short reaction times. Aldehydes bearing the electron-withdrawing groups exhibit the superior reactivity. Remarkably, the F catalyst showed strong recyclability over six consecutive cycles with negligible loss of activity, emphasizing its sustainability and high efficiency in chemical transformations as well as the catalytic potential of the used magnetic carbon quantum dots and their ability to revolutionize green and efficient synthetic methodologies.

Nickel‐Catalyzed Regiodivergent Acylzincation of Styrenes with Organozincs and CO†

Comprehensive SummaryTransition metal‐catalyzed carbometallation of unsaturated hydrocarbons constitutes one of the most efficient synthetic methodologies for the construction of C—C bond. Recently, the incorporation of organometallic reagent with the CO gas as a nucleophilic acyl synthon could enable the acylmetallation reaction, which greatly increases the horizon of carbometallation chemistry. Herein, we report a nickel‐catalyzed regiodivergent acylzincation of o‐cyano cinnamate ester and o‐cyano styrene, in which the cyano moiety intramolecularly captures zinc intermediates to trigger the tandem cyclization process. This protocol features mild conditions, broad substrate scope and excellent functional group tolerance, thus affording a diverse array of highly functionalized carbocyclic compounds.

Catalytic enantioselective reductive alkynylation of amides enables one-pot syntheses of pyrrolidine, piperidine and indolizidine alkaloids

The primary objective in synthetic organic chemistry is to develop highly efficient, selective, and versatile synthetic methodologies, which are essential for discovering new drug candidates and agrochemicals. In this study, we present a unified strategy for a one-pot, catalytic enantioselective synthesis of α-alkyl and α,α′-dialkyl pyrrolidine, piperidine, and indolizidine alkaloids using readily available amides and alkynes. This synthesis is enabled by the identification and development of an Ir/Cu/N-PINAP catalyzed highly enantioselective and chemoselective reductive alkynylation of α-unbranched aliphatic amides, which serves as the key reaction. This reaction is combined with Pd-catalyzed tandem reactions in a one-pot approach, enabling the collective, catalytic enantioselective total syntheses of eight alkaloids and an anticancer antipode with 90–98% ee. The methodology’s enantio-divergence is exemplified by the one-step access to either enantiomer of alkaloid bgugaine.

Synthesis and characterization of octopamine sulfate, norfenefrine sulfate and etilefrine sulfate reference materials for doping control

AbstractBACKGROUNDDoping is the use of prohibited substances by athletes to improve their performance. World Anti‐Doping Agency (WADA)‐accredited laboratories require various metabolite reference standards of the prohibited chemical substances or drugs for routine quality control. Therefore, it was proposed to develop efficient synthetic methodologies for highly pure reference materials of Phase II metabolites of octopamine, norfenefrine and etilefrine, which are prohibited in sports by WADA under the S6 stimulant category. The reference materials were characterized using various analytical techniques. New high‐performance liquid chromatography with diode‐array detection (HPLC‐DAD) methods were developed for purity assessment.RESULTSThe synthesized Phase II metabolite reference standards, i.e. octopamine sulfate, norfenefrine sulfate and etilefrine sulfate, were confirmed by 1H NMR, 13C NMR, liquid chromatography–high‐resolution mass spectrometry (LC‐HRMS), attenuated total reflectance Fourier transform infrared and thermogravimetric analysis. In the LC‐HRMS study, the mass error value of synthesized compounds was less than 10 ppm (error) which confirms the identity of the reference materials. New HPLC‐DAD method were developed to ensure the purity of the reference materials. We used the HILIC column as metabolite reference standards are highly polar. The mobile phase was composed of water and acetonitrile in fixed composition. The HPLC‐DAD purity of the developed reference materials was observed as 100%.CONCLUSIONWe have developed reproducible synthetic routes for octopamine sulfate, norfenefrine sulfate and etilefrine sulfate, which are prohibited in sports by WADA. The synthesized metabolites were characterized using different advanced analytical techniques. These reference standards will be helpful to all WADA‐accredited laboratories in routine anti‐doping testing. © 2023 Society of Chemical Industry (SCI).

Synthesis of sugar enones and their use as powerful synthetic precursors of thiodisaccharides

Monosaccharide derivatives having a double bond conjugated to a carbonyl (sugar enones or enuloses) are relevant synthetic tools. They are also suitable starting materials, or versatile intermediates, for the synthesis of a wide variety of natural or synthetic compounds with a broad spectrum of biological and pharmacological activities. The preparation of enones is mainly focused on the search for more efficient and diastereoselective synthetic methodologies. The usefulness of enuloses relies on the diverse reaction possibilities offered by alkene and carbonyl double bonds, which are prone to undergo varied reactions such as halogenation, nitration, epoxidation, reduction, addition, etc. The addition of thiol groups that led to sulfur glycomimetics, such as thiooligosaccharides, is particularly relevant. Therefore, the synthesis of enuloses and the Michael addition of sulfur nucleophiles to give thiosugars or thiodisaccharides are discussed here. Chemical modifications of the conjugate addition products to afford biologically active compounds are also reported.

Highlighting the Rich Chemistry of the Allenone Moiety

AbstractConjugated and non‐conjugated allenones appear as recurring motifs in organic synthesis, natural products and mechanistic investigations showing unique properties and applications. The ability of allenones to build cycles has provided a direct access to strained systems, medium‐sized rings, arenes, heterocycles and complex polycycles. In addition, allenones have served as models in mechanistic investigations and catalysis. The critic compilation herein presented will provide an exhaustive overview of the synthetic possibilities allenones may offer, which certainly will inspire our community in their search of more efficient synthetic methodologies, preparation of biological and pharmaceutical targets, and improve our knowledge in theoretical organic chemistry. Great part of this review will discuss synthetic aspects, catalysis innovation and mechanistic insights of the chemical transformations implying the allenone motif. In addition, many examples on total synthesis and pharmacologically active compounds will be described. We hope that this overview will be attractive to the organic chemistry, synthetic chemistry, catalysis, theoretical chemistry, natural products and medicinal chemistry communities.magnified image

Efficient Synthesis of Chlorin e6 and Its Potential Photodynamic Immunotherapy in Mouse Melanoma by the Abscopal Effect.

Photodynamic therapy (PDT) can eradicate not only cancer cells but also stimulate an antitumor immune response. Herein, we describe two efficient synthetic methodologies for the preparation of Chlorin e6 (Ce6) from Spirulina platensis and address the phototoxic effect of Ce6 in vitro along with antitumor activity in vivo. Melanoma B16F10 cells were seeded and phototoxicity was monitored by the MTT assay. The C57BL/6 mice were subcutaneously inoculated on the left and right flank with B16F10 cells. The mice were intravenously injected with Ce6 of 2.5 mg/kg and then exposed to red light (660 nm) on the left flank tumors 3 h after the injection. The immune response was studied by analyzing Interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and Interleukin-2 (IL-2) of the right flank tumors through qPCR. Our results revealed that the tumor was suppressed not only in the left flank but also in the right flank, where no PDT was given. The upregulated gene and protein expression of IFN-γ, TNF-α, and IL-2 revealed antitumor immunity due to Ce6-PDT. The findings of this study suggest an efficient methodology of Ce6 preparation and the efficacy of Ce6-PDT as a promising antitumor immune response.

Development of L-Proline-Based Chiral Ionic Liquids for Asymmetric Michael Reaction

Different Chiral Ionic Liquids (CIL) based on L-proline have been developed. Simple and efficient synthetic methodologies are used, allowing preparation in good yields for twelve novel CILs using L-proline as a cation or anion combined with suitable counter-ions. A detailed physical and chemical characterization of the CILs was performed to evaluate the influence of counter-ions on the final properties. The most promissory CILs were tested as efficient chiral catalysts in IL media for asymmetric Michael addition reactions of ketones and aldehydes to nitro-olefins. Similar or even better conversions and enantioselectivities (ee up to 95%) compared to the original L-proline were achieved. Additionally, a good product extraction performance using supercritical CO2 processes was obtained.

Covalent modification of poly(vinyl chloride) via organometallic Barbier reaction

The development of efficient synthetic methodologies for chemical functionalization and modification of existing polymers to improve or diversify the physicochemical and mechanical properties is an ongoing quest in macromolecular science. This is especially true for the generation of polymeric materials out of commercial/commodity polymers via structural tailoring since these polymers are produced in vast quantities and are structurally diverse. In this study, we report on benign chemical modification of an important commercial polymer, poly(vinyl chloride) (PVC) via Barbier reaction. The methodology is based on the employment of magnesium metal to generate nucleophilic alkyl-magnesium chloride groups on polymer backbone and addition of these nucleophilic centers to electrophilic carbonyl groups. The synthetic procedure can be implemented in a one-pot fashion by utilizing commonly available aldehyde or epoxide bearing compounds along with elemental magnesium. The Barbier addition of PVC backbone generated alkyl-magnesium chloride groups on the model aldehyde substrates with different structures were achieved with > 84 % functionalization degrees. It was shown that the functionalization degrees can easily be regulated by the simple alteration of employed magnesium ratio to backbone present alkyl chloride groups. Functionalization studies were investigated via 1H NMR, FT-IR and SEC analyses as well as contact angle measurements. Considering the wide industrial/ research utilization of poly(vinyl chloride) together with commercial availability, abundant reactive alkyl chloride bonds in backbone chains of this polymer offer easy to implement structural tailoring via proposed organometallic Barbier reaction.

Multicomponent Synthesis of Unsaturated γ-Lactam Derivatives. Applications as Antiproliferative Agents through the Bioisosterism Approach: Carbonyl vs. Phosphoryl Group.

We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure–activity profile is presented. In addition, the bioisosteric replacement of the flat ester group by a tetrahedral phosphonate or phosphine oxide moiety in γ-lactam substrates leads to increased growth inhibition activity. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.

Recent Advances in the Functionalization of Terminal and Internal Alkynes

AbstractAlkynes are one of the most fundamental and diverse functional groups utilized in organic synthesis. Over the past few years, the development of efficient synthetic methodologies for the functionalization of alkynes has been an active area of research. A plethora of alkyne functionalization reactions have been reported in the literature to construct functionalized alkynes and alkene scaffolds, which are important building blocks in many natural products, pharmaceuticals, and key intermediates in various synthetic transformations. In this review, we describe the most recent advances in the functionalization of alkynes with an emphasis on substrate scope, limitations, regioselectivity control and applications of these reactions. This review covers the literature from 2016 to 2021.

Skin Depigmenting Agents in Anti-Aging Cosmetics: A Medicinal Perspective on Emerging Ingredients

Human skin aging results from intrinsic and extrinsic factors. Uneven pigmentation is one of the major changes of extrinsic aging. Many compounds have been tested for depigmenting activity but only a few are actually used by the cosmetic industry, which is continually looking for new ingredients. In this study, the trends in the use of skin depigmenting ingredients in a panel of anti-aging formulations commercialized in the Portuguese pharmacy market were analyzed, by comparing the composition of the products marketed in 2011 with products launched or reformulated in 2018 (59% and 74%, respectively). The analysis of the top 12 ingredients put forward three novelties for 2018: tranexamic acid, bakuchiol, and 4-butylresorcinol. Regarding their mechanisms of action, tranexamic acid inhibits melanin synthesis through inhibition of the plasminogen/plasmin system. Bakuchiol depigmenting efficacy was attributed to the ability to block both α-melanocyte-stimulating hormone and tyrosinase activation, while 4-butylresorcinol exerts its action through the inhibition of both tyrosinase and tyrosinase-related protein-1 (TRP-1). Industry-optimized and efficient synthetic methodologies that embrace green chemistry, reducing the environmental impact, are commonly used. This analysis aims to bring insights to both formulators, involved in the development of depigmenting cosmetic products, and chemists performing the synthesis of new and existing compounds intended for this purpose.

Catalytic asymmetric synthesis of enantioenriched α-deuterated pyrrolidine derivatives.

The recent promising applications of deuterium-labeled pharmaceutical compounds have led to an urgent need for the efficient synthetic methodologies that site-specifically incorporate a deuterium atom into bioactive molecules. Nevertheless, precisely building a deuterium-containing stereogenic center, which meets the requirement for optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of chiral drug candidates, remains a significant challenge in organic synthesis. Herein, a catalytic asymmetric strategy combining H/D exchange (H/D-Ex) and azomethine ylide-involved 1,3-dipolar cycloaddition (1,3-DC) was developed for the construction of biologically important enantioenriched α-deuterated pyrrolidine derivatives in good yields with excellent stereoselectivities and uniformly high levels of deuterium incorporation. Directly converting glycine-derived aldimine esters into the deuterated counterparts with D2O via Cu(i)-catalyzed H/D-Ex, and the subsequent thermodynamically/kinetically favored cleavage of the α-C–H bond rather than the α-C–D bond to generate the key N-metallated α-deuterated azomethine ylide species for the ensuing 1,3-DC are crucial to the success of α-deuterated chiral pyrrolidine synthesis. The current protocol exhibits remarkable features, such as readily available substrates, inexpensive and safe deuterium source, mild reaction conditions, and easy manipulation. Notably, the synthetic utility of a reversed 1,3-DC/[H/D-Ex] protocol has been demonstrated by catalytic asymmetric synthesis of deuterium-labelled MDM2 antagonist idasanutlin (RG7388) with high deuterium incorporation.

An Orthogonally Protected Cyclitol for the Construction of Nigerose- and Dextran-Mimetic Cyclophellitols.

Cyclophellitols are potent inhibitors of exo- and endoglycosidases. Efficient synthetic methodologies are needed to fully capitalize on this intriguing class of mechanism-based enzyme deactivators. We report the synthesis of an orthogonally protected cyclitol from d-glucal (19% yield over 12 steps) and its use in the synthesis of α-(1,3)-linked di- and trisaccharide dextran mimetics. These new glycomimetics may find use as Dextranase inhibitors, and the developed chemistries in widening the palette of glycoprocessing enzyme-targeting glycomimetics.

Recent Advances in Organophosphorus‐Catalyzed Borylation and Silylation Reactions

AbstractOver the past few decades, organophosphorus catalysis has emerged as a robust platform for the preparation of highly functionalized molecules with excellent control of reactivity and selectivity. Organophosphorus catalysis has the advantages of mild and metal‐free reaction conditions. The easy‐to‐tune electronic and steric properties of phosphorus provide an easy handle for developing efficient synthetic methodologies with high stereochemical fidelity. This review describes the efforts to introduce boron and silicon functionalities into organic substrates catalyzed by organophosphorus compounds. These catalysts are categorized into nucleophilic, electrophilic, and biphilic phosphorus catalysts. Phosphorus compounds efficiently catalyze hydroboration of various unsaturated systems, carbonyl compounds, imines, etc.; hydro‐/cyano‐silylation of carbonyls; and silylation of alcohols. The present review emphasizes the scope of nucleophilic, electrophilic, and biphilic phosphorus‐based catalysis to introduce boron and silicon functionalities into organic compounds, mainly from the recent decade.magnified image

Recent Developments in the Palladium‐Catalyzed/Norbornene‐Mediated Synthesis of Carbo‐ and Heterocycles

AbstractHeterocycles and carbocyclic cores are ubiquitous scaffolds in organic molecules and important components of many natural products, pharmaceuticals, agrochemicals and organic materials. Thus, developing efficient synthetic methodologies for the easy generation of carbo‐ and heterocycles is an important goal in synthetic chemistry. This review is mainly focused on the recent developments in the synthesis of various carbo‐ and heterocyclic compounds via palladium catalyzed/norbornene mediated cascade process triggered byorthoC−H alkylation, amination or arylation of aryl iodides and covers the literature from 2010‐2021.

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

AbstractMedium N‐heterocycles, azepines and azocines, serve as important skeletons that occurred widely in natural products, however, due to the lack of efficient synthetic methodologies, their application potential in biologically active molecules, pharmaceuticals and agrochemicals remained to be explored. In this context, rhodium catalysis in this field featured good reactivity and functional group tolerance, with readily available starting materials, and enabled rapid access to the azepines and azocines. Delightfully, great achievements in the concise construction of these 7 and 8‐membered N‐heterocycles under rhodium catalysis have been made, which mainly included cycloisomerization of unsaturated C−X bonds (which might also combine the ring‐opening strategy on strained rings), metal carbenoid or nitrene insertion involved transformations and direct C−H activation reactions. Considering the great performance of rhodium catalyst in the synthesis of azepines and azocines, herein, we summarized the recent results in this field, and wish to give further insight and inspired more encouraging methodologies and new drug discovery based on these 7 and 8‐membered N‐heterocycles.magnified image

Natural and Synthetic Spirobutenolides and Spirobutyrolactones

AbstractSpirobutenolides and spirobutyrolactones structural motifs are widespread in various natural products that exhibit a broad array of biological activities. Additionally, their synthetic analogues also serve as biologically active compounds and building blocks of complex molecules. Owing to the wide range of pharmacological activities and structural diversity of the spirobutenolides and spirobutyrolactones, various efficient synthetic methodologies have been established to construct such interesting scaffolds. In the past decades, numerous total syntheses of spirobutenolides and spirobutyrolactones containing natural products have been reported. Structurally diverse spirobutenolides and spirobutyrolactones have been synthesized by using singlet oxygen, Mannich reaction, aldol condensation, rearrangement reaction, Reformatsky reaction, Michael‐addition cyclization, Diels‐Alder reaction, photocyclization reaction, and pericyclic reactions. Recently, metal‐catalyzed cyclization, photocatalyzed radical cyclization, Baylis‐Hillman reaction, asymmetric organocatalysis, NHC catalysis, ring contraction reactions, and hypervalent iodine catalysis have emerged as powerful tools to architect these nuclei. This review gives an overview of advancements in chemically and biologically relevant spirobutenolides and spirobutyrolactones of natural and synthetic origin. It also covers the newer methodologies for the construction of natural as well as synthetic spirobutenolides and spirobutyrolactones along with their potential applications.