Chiral amino acids: evolution in atroposelective C-H activation.

This review covers the journey of chiral amino acids as ligands in atroposelective C-H bond activation/functionalization via transition metal catalysis. Herein, we intend to demonstrate how these chiral amino acids have evolved and flourished in this stimulating field. Unprotected amino acids, mono-N-protected amino acids, and di-N-protected amino acids have been devised for atroposelective C-H activation. In each section, we have briefly discuss the key successes of amino acids in the atroposelective synthesis of biaryls, heterobiaryls, and non-biaryl atropisomers and their advantages in atroposelective C-H activation.

Cyperus rotundus L.: Invasive weed plant with insecticidal potential against Aphis craccivora Koch and Planococcus lilacinus (Cockerell).

Cyperus rotundus L. is a widely distributed invasive weed plant with vast traditional medicinal uses. Herein, the methanolic root extract of C. rotundus and its fractions (n-hexane, chloroform, n-butanol, and aqueous) were evaluated for insecticidal activity against nymphs of Aphis craccivora Koch and crawlers of Planococcus lilacinus (Cockerell) to find promising lead (s). In contact topical assay, among extract/fractions, n-hexane fraction exhibited more toxicity against A. craccivora (LD50 = 1.12 µg/insect) and P. lilacinus (LD50 = 0.94 µg/insect). The chemical analysis of n-hexane fraction revealed a volatile composition similar to that of the essential oil (EO) of C. rotundus roots. Hence, EO was extracted using water and deep eutectic solvents (DESs) as cosolvent, which revealed enhancement in EO yield (from 0.28 to 0.46% w/w) on implementing DESs. A total of 35 diverse volatile metabolites were identified in all EO samples, accounting for 85.0 to 91.8% of chemical composition, having cyperotundone, cyperene mustakone, isolongifolen-5-one, boronia butenal as major constituents. The EO obtained with DES-7 [choline chloride: ethylene glycol (1:4)] and DES-6 [choline chloride: lactic acid (1:3)] were found effective against A. craccivora (LD50 = 0.62-0.87 µg/insect) and P. lilacinus (LD50= 0.59-0.67 µg/insect) after 96 h. NMR analysis of EO revealed cyperotundone as a major compound, which was isolated along with cyperene and cyperene epoxide. All the molecules were found effective against P. lilacinus, whereas against A. craccivora cyperotundone, cyperene and cyperene epoxide showed promising toxicity (LD50 = 0.74-0.86 µg/insect). Extract/fractions, EO, and isolated molecules showed a significant reproductive inhibition rate of A. craccivora at higher concentrations. All the tested concentrations of cyperotundone showed significant inhibition of acetylcholinesterase (AChE) and glutathione-S-transferase (GST) in A. craccivora and P. lilacinus. Based upon the present study, C. rotundus can be recommended to control targeted insects in the greenhouse/field conditions after performing bio-efficacy and phytotoxicity studies.

Exploring Steroidal Saponin Composition and Morphometric Characteristics of Rhizomes from Trillium govanianum Wall. ex D. Don: Inference for Medicinal Properties and Genetic Stock Improvement.

Trillium govanianum, a medicinal herb, exhibiting diverse morphometric traits and phytochemicals across developmental stages of plants. The changes in the chemical profile and steroidal saponin levels in the rhizome of T. govanianum across different developmental stages were previously unknown. This study categorizes rhizomes into three types based on scar presence: juvenile (5-10 scars, Type I), young (11-19 scars, Type II), and mature (21-29 scars, Type III). Rhizomes show varying sizes (length 1.2-4.7 cm, girth 0.3-1.6 cm), weight (0.18-5.0 g), and extractive yields (9.7-16.1 % w w-1), with notable differences in saponin content (5.95-21.9 mg g-1). Ultra-high performance liquid chromatography-MS/MS (UHPLC-QTOF-MS/MS)-based chemical profiling identifies 31 phytochemicals, mainly including diverse saponins. Ultra-high performance liquid chromatography coupled with evaporative light scattering detection (UHPLC-ELSD)-based quantitative analysis of seven key saponins reveals stage-specific accumulation patterns, with protodioscin (P) and dioscin (DS) predominant in mature rhizomes. Statistical analysis confirms significant variation (p=0.001) in saponin levels across developmental stages with chemical constituent protodioscin (P=4.03±0.03-15.76±0.14 mg g-1, PAve=9.79±3.03 mg g-1) and dioscin (DS=1.23±0.06-3.93±0.07 mg g-1, DSAve=2.59±0.70 mg g-1), with acceptable power (p=0.738; |δ|>0.5) statistics for effective sample size (n=27 samples used in the study) of T. govanianum. Principal Component Analysis (PCA) and Euclidean clustering further highlighted chemotype distinctions.

NADES extraction, UHPLC-ELSD-based quantification, and network pharmacology-guided target identification of fourteen specialised metabolites from Trillium govanianum Wall. ex D.Don.

INTRODUCTION: Trillium govanianum Wall. ex D.Don is a folk medicinal herb rich in structurally diverse steroidal saponins. The annual demand for this herb in India is about 200-500 metric tons, highlighting the need for a thorough quality assessment. OBJECTIVE: The objective of this study is to develop an easy and reliable ultrahigh-performance liquid chromatography-evaporative light scattering detector (UHPLC-ELSD)-based quality assessment method with 14 specialised metabolites of T. govanianum and identify the potential targets of this herb using network pharmacology. MATERIAL AND METHODS: A UHPLC-ELSD method was developed and validated with 14 markers of T. govanianum. The developed method and natural deep eutectic solvent (NADES)-assisted extraction were utilised for the recovery enhancement study of targeted specialised metabolites from rhizome samples (collected from five geographically distinct areas). In addition, the network pharmacology approach was performed for these 14 markers to predict the plausible biological targets of T. govanianum. RESULT: The developed method showed good linearity (r2: 0.940-0.998), limit of detection (LOD) (2.4-9.0 µg), limit of quantification (LOQ) (7.92-29.7 µg), precision (intra-day relative standard deviations [RSDs] 0.77%-1.96% and inter-day RSDs 2.19-4.97%), and accuracy (83.24%-118.90%). NADES sample TG-1* showed the highest recovery (yield: 167.66 ± 4.39 mg/g of dry weight) of total saponin content (TSC) as compared to its hydroethanolic extract (yield: 103.95 ± 5.36 mg/g of dry weight). Sample TG-1* was the most favourable (yield: 167.66 ± 4.39 mg/g) in terms of TSC as compared to other analysed samples (32.68 ± 1.04-88.22 ± 6.79 mg/g). Govanoside D (yield: 3.43-28.06 mg/g), 22ß-hydroxyprotodioscin (yield: 3.22-114.79 mg/g), and dioscin (yield: 1.07-20.82 mg/g) were quantified as the major metabolites. Furthermore, network pharmacology analysis of targeted 14 markers indicated that these molecules could be possible therapeutic agents for managing neuralgia, diabetes mellitus, and hyperalgesia. CONCLUSION: The current study represents the first report for the simultaneous quantification and a network pharmacology-based analysis of 14 chemical marker compounds isolated from T. govanianum.

Experimental and Computational Studies on RuII -Catalyzed C7-Allylation of Indolines with Allyl Bromide.

The selective C7-allylation of indolines with allyl bromide under ruthenium catalysis has been revealed here. Under established reaction conditions, C7-allylation of various indolines, including drug compounds, was accomplished with good selectivity and yields. Based on combined experimental and density functional theory (DFT) studies, the olefin insertion route was energetically favorable among four possible pathways. Experimental and DFT studies further revealed that the C-H activation is a reversible rate-limiting step.

Photoredox Minisci-Type Hydroxyfluoroalkylation of Isoquinolines with N-Trifluoroethoxyphthalimide.

A straightforward photocatalytic approach has been demonstrated to incorporate a trifluoroethanol unit onto the isoquinolines. Herein, we report N-trifluoroethoxyphthalimide as a hydroxyfluoroalkyl radical precursor, enabling efficient synthesis of trifluoroethanol-substituted heteroarenes. Radical quenching experiments confirmed the involvement of a free-radical pathway under developed photocatalytic conditions. The DFT calculations confirmed the intramolecular 1,2-HAT reactivity of the O-centered trifluoroethoxy radical (generated from N-trifluoroethoxyphthalimide under photocatalytic condition) to the C-centered trifluoroethanol radical. Fluorescence quenching studies suggested that isoquinoline was responsible for the quenching of Ir-photocatalyst emission. A catalytic cycle involving trifluoroethanol radical reaction with isoquinolines has been proposed.

Multicomponent reactions and photo/electrochemistry join forces: atom economy meets energy efficiency.

Visible-light photoredox catalysis has been regarded as an extremely powerful tool in organic chemistry, bringing the spotlight back to radical processes. The versatility of photocatalyzed reactions has already been demonstrated to be effective in providing alternative routes for cross-coupling as well as multicomponent reactions. The photocatalyst allows the generation of high-energy intermediates through light irradiation rather than using highly reactive reagents or harsh reaction conditions. In a similar vein, organic electrochemistry has experienced a fruitful renaissance as a tool for generating reactive intermediates without the need for any catalyst. Such milder approaches pose the basis toward higher selectivity and broader applicability. In photocatalyzed and electrochemical multicomponent reactions, the generation of the radical species acts as a starter of the cascade of events. This allows for diverse reactivity and the use of reagents is usually not covered by classical methods. Owing to the availability of cheaper and more standardized photo- and electrochemical reactors, as well as easily scalable flow-setups, it is not surprising that these two fields have become areas of increased research interest. Keeping these in view, this review is aimed at providing an overview of the synthetic approaches in the design of MCRs involving photoredox catalysis and/or electrochemical activation as a crucial step with particular focus on the choice of the difunctionalized reagent.

Going with the µFlow: Reinterpreting Energy Input in Organic Synthesis.

The popularity of microflow chemistry has skyrocketed in the last 20 years, more and more chemists are switching from macro-batch reactors to miniaturized flow devices. As a result, microfluidics is paving its way into the future by consolidating its position in organic chemistry not only as a trend but as a new, effective, and sustainable way of conducting chemistry, that clearly will continue to grow and evolve. This perspective highlights the most relevant examples of innovative enhancing technologies applied to microflow reactors aimed to improve and intensify chemical processes. The extensive applicability of microflow chemistry is further illustrated by briefly discussing examples of complex integrated microsystems and scale-up technologies, demonstrating ultimately that microflow chemistry has the potential to become the ideal technology for the future.

Iridoid glycosides from Picrorhiza genus endemic to the Himalayan region: phytochemistry, biosynthesis, pharmacological potential and biotechnological intercessions to boost production.

Iridoid glycosides are monoterpenoids synthesized in several plant species known to exhibit a diverse range of pharmacological activities. They are used as important bioactive ingredients in many commercially available drug formulations and as lead compounds in pharmaceutical research. The genus Picrorhiza comprises two medicinally important herbs endemic to the Himalayan region viz. Picrorhiza kurrooa Royle and Picrorhiza scrophulariiflora Hong. The medicinal properties of these two species are mainly due to iridoid glycosides present in their root, rhizome, and leaves. Unregulated harvesting from the wild, habitat specificity, narrow distribution range, small population size and lack of organized cultivation led to the enrolling of these species in the endangered category by the International Union for Conservation of Nature and Natural Resources (IUCN). Therefore, there is a need for immediate biotechnological and molecular interventions. Such intercessions will open up new vistas for large-scale propagation, development of genomic/transcriptomic resources for understanding the biosynthetic pathway, the possibility of genetic/metabolic manipulations, and possible commercialization of iridoid glycosides. The current review article elucidates the phytochemistry and pharmacological importance of iridoid glycosides from the genus Picrorhiza. In addition, the role of biotechnological approaches and opportunities offered by next-generation sequencing technologies in overcoming challenges associated with the genetic engineering of these species are also discussed.

Recent Advances in the High-Valent Cobalt-Catalyzed C-H Functionalization of N-Heterocycles.

Direct functionalization of heterocycles using C-H activation widely relies on the precious metal complexes. In past decade, the use of earth abundant and inexpensive transition metal to functionalize heterocycles has become an attractive alternate strategy. This concept is also interesting due to the unique reactivity pattern of these inexpensive metals. In this context we and other research groups have utilized the high-valent cobalt complexes as an inexpensive and readily available catalyst for the functionalization of heterocycles. In this review, we intend to brief recent progress made in the area of high-valent cobalt complexes catalyzed C-H functionalization of N-containing heterocycles.

Cp*Co(III)-Catalyzed Selective C8-Olefination and Oxyarylation of Quinoline N-Oxides with Terminal Alkynes.

Herein we report Cp*Co(III)-catalyzed site-selective (C8)-H olefination and oxyarylation of quinoline N-oxides with terminal alkynes. The selectivity for C8-olefination and oxyarylation is sterically and electronically controlled. In the case of quinoline N-oxides (unsubstituted at the C2 position), only the olefination product was obtained irrespective of the nature of the alkynes. In contrast, oxyarylation was observed exclusively when 2-substituted quinoline N-oxides were reacted with 9-ethynylphenanthrene. However, alkynes with electron-withdrawing groups provided only olefination products with 2-substituted quinoline N-oxides. The developed strategy allowed a facile functionalization of quinoline N-oxides bearing natural molecules and an estrone-derived terminal alkyne to deliver the corresponding olefinated and oxyarylated products. To understand the reaction mechanism, control experiments, deuterium-labeling experiments, and kinetic isotope effect (KIE) studies were performed.

Insecticidal Activity of Extracts, Fractions, and Pure Molecules of Cissampelos pareira Linnaeus against Aphid, Aphis craccivora Koch.

Aphis craccivora Koch is a polyphagous and major pest of leguminous crops causing significant damage by reducing the yield. Repeated application of synthetic insecticides for the control of aphids has led to development of resistance. Therefore, the present study aimed to screen the insecticidal activity of root/stem extracts/fractions, and pure molecules from Cissampelos pareira Linnaeus against A. craccivora for identification of lead(s). Among root extract/fractions, the n-hexane fraction was found most effective (LC50 = 1828.19 mg/L) against A. craccivora, followed by parent extract (LC50 = 2211.54 mg/L). Among stem extract/fractions, the n-hexane fraction (LC50 = 1246.92 mg/L) was more effective than the water and n-butanol fractions. Based on GC and GC-MS analysis, among different compounds identified in the n-hexane fraction of root and stem, ethyl palmitate (known to possess insecticidal activity) was present in the highest concentration (24.94 to 52.95%) in both the fractions. Among pure molecules, pareirarineformate was found most effective (LC50 = 1491.93 mg/L) against A. craccivora, followed by cissamine (LC50 = 1556.31 mg/L). Parent extract and fractions of C. pareira possess promising activity against aphid. Further, field bio-efficacy studies are necessary to validate the current findings for the development of botanical formulation.

Targeting Akt/NF-κB/p53 Pathway and Apoptosis Inducing Potential of 1,2-Benzenedicarboxylic Acid, Bis (2-Methyl Propyl) Ester Isolated from Onosma bracteata Wall. against Human Osteosarcoma (MG-63) Cells.

Onosma bracteata Wall. is an important medicinal and immunity-enhancing herbs. This plant is commonly used in the preparation of traditional Ayurvedic drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the present study aimed to investigate the antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human osteosarcoma (MG-63) cells. Among all the fractions isolated from O. bracteata, ethyl acetate fraction (Obea) showed good antioxidant activity in superoxide radical scavenging assay and lipid peroxidation assay with an EC50 value of 95.12 and 80.67 µg/mL, respectively. Silica gel column chromatography of ethyl acetate (Obea) fraction of O. bracteata yielded a pure compound, which was characterized by NMR, FTIR, and HR-MS analysis and was identified as 1,2-benzene dicarboxylic acid, bis (2-methyl propyl) ester (BDCe fraction). BDCe fraction was evaluated for the antiproliferative potential against human osteosarcoma MG-63, human neuroblastoma IMR-32, and human lung carcinoma A549 cell lines by MTT assay and exhibited GI50 values of 37.53 µM, 56.05 µM, and 47.12 µM, respectively. In MG-63 cells, the BDCe fraction increased the level of ROS and simultaneously decreased the mitochondria membrane potential (MMP) potential by arresting cells at the G0/G1 phase, suggesting the initiation of apoptosis. Western blotting analysis revealed the upregulation of p53, caspase3, and caspase9 while the expressions of p-NF-κB, p-Akt and Bcl-xl were decreased. RT-qPCR studies also showed upregulation in the expression of p53 and caspase3 and downregulation in the expression of CDK2, Bcl-2 and Cyclin E genes. Molecular docking analysis displayed the interaction between BDCe fraction with p53 (-151.13 kcal/mol) and CDK1 (-133.96 kcal/mol). The results of the present work suggest that the BDCe fraction has chemopreventive properties against osteosarcoma (MG-63) cells through the induction of cell cycle arrest and apoptosis via Akt/NF-κB/p53 pathways. This study contributes to the understanding of the utilization of BDCe fraction in osteosarcoma treatment.

Study of Yang's Onion Flap Technique for Release of Scarred Eponychium and Nail Fold Reconstruction in Burn Patients.

Background Abnormalities of fingernail growth and appearance are among the most common deformities encountered after burn injury to the hand. Various techniques used for resurfacing defects include incision of the scarred eponychium and advancement of the distal segment, flap reconstruction-distally, and proximally based transposition/advancement flaps, composite graft techniques, microvascular transfer. In the present study, we used an onion flap to release scarred eponychium and nail fold reconstruction in a single stage without using soft tissue from another area. Materials and methods Forty-four burnt fingers were operated using Yang's onion flap technique. Patients were assessed for flap necrosis, hematoma and infection in the early postoperative period and for donor site scar, nail appearance, and symptomatic relief in a follow-up for at least 4 months. Results The flap was successfully performed on all fingers. Only two fingers had flap necrosis. There was no incidence of hematoma or infection. The donor site scar and nail plate appearance improved and was acceptable to most patients after surgery. There was also significant relief in daily activities in 19 out of 28 symptomatic patients. Conclusion Yang's flap to correct nail deformities in burn patients is feasible in Indian scenario. It is associated with a low complication rate and improved nail appearance. There is also significant symptomatic relief in performing daily activities after surgery.

Cp*Rh(III)-Catalyzed Regioselective C(sp3)-H Electrophilic Trifluoromethylthiolation of 8-Methylquinolines.

Rh(III)-catalyzed regioselective trifluoromethylthiolation of the unactivated C(sp3)-H bond of 8-methylquinolines with bench-stable electrophilic trifluoromethylthiolating reagent via C(sp3)-H activation is explored. Various substituted 8-methylquinolines provided the products in good yields with high regioselectivity. Current reaction conditions are also applicable for the late-stage functionalization of natural molecule santonin and caffeine-substituted 8-methylquinoline.

Rh(III)-Catalyzed Regioselective C8-Alkylation of Quinoline N-Oxides with Maleimides and Acrylates.

Herein, we disclose the Rh(III)-catalyzed selective C8-alkylation of quinoline N-oxides with maleimides and acrylates. The main features of the reaction include complete C8-selectivity and broad substrate scope with good to excellent yields. The reaction also proceeded well with unprotected maleimide. The applicability of the developed methodology is demonstrated with gram-scale synthesis and post-modification of the alkylated product. Preliminary mechanistic study revealed that the reaction proceeds through a five-membered rhodacycle and involves proto-demetalation step.

C70 Fullerene Catalyzed Photoinduced Aerobic Oxidation of Benzylamines to Imines and Aldehydes.

C70 fullerene catalyzed photoinduced oxidation of benzylic amines at ambient conditions has been explored here. The developed strategy's main feature includes the additive/oxidant-free conversion of benzylic amine to corresponding imine and aldehydes. The reaction manifests broad substrate scope with excellent function group leniency and is applicable up to the gram scale. Further, symmetrical secondary amines can also be synthesized from benzylic amine in a one-pot two-step process. Various experiments and density functional theory studies revealed that the current reaction involves the generation of reactive oxygen species, single electron transfer reaction, and benzyl radical formation as key steps under photocatalytic conditions.

Merging kinetic resolution with C-H activation: an efficient approach for enantioselective synthesis.

In the last two decades tremendous progress has been made in transition-metal (TM)-catalyzed C-H bond functionalization, paving the way to design complex molecules. Despite significant advances, enantioselective C-H activation is still in the age of infancy. For the enantioselective synthesis, several TM catalyst based approaches are well known, including kinetic resolution (KR) and its advanced versions [dynamic kinetic resolution (DKR) and parallel kinetic resolution (PKR)]. These strategies have recently been successfully applied synergetically with the TM catalyzed C-H activation to achieve enantioselective synthesis in a more economical and sustainable way. This review will summarize the recent advancements made towards merging KR with TM-catalysed C-H activation for enantioselective synthesis.

Predictable site-selective functionalization: Promoter group assisted para-halogenation of N-substituted (hetero)aromatics under metal-free condition.

Herein, regioselective para-C-H halogenation of N-pyrimidyl (hetero)aromatics through SEAr (electrophilic aromatic substitution) type reaction is disclosed. SEAr type reaction has been utilized for the C5-bromination of indolines (para-selective) with N-bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. The pyrimidyl group is identified as a reactivity tuner that also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge maps also support the observed p-selectivity. Post-functionalization of the title compound into the corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, and chlorzoxazone) to demonstrate the applicability of the developed protocol.

Sequential and direct multicomponent reaction (MCR)-based dearomatization strategies.

Dearomatization strategies in a multicomponent fashion often result in complex heterocyclic frameworks, which have attracted the attention of chemists due to their natural product-like structures. The combination of these two processes can easily achieve extended molecular complexity and diversity from simple starting materials with high atom economy. Thus, this field has attracted extensive interest owing to its potential significance in both asymmetric catalysis and convenient build-up of libraries of molecules with novel three-dimensional scaffolds, which may find application in medicinal chemistry. Accordingly, a systematic review on this topic will provide the synthetic organic community with a conceptual overview and comprehensive understanding of the different multicomponent reaction (MCR) cascades involving dearomatization as the characteristic step. In addition, this review will help researchers to look at this promising area from a different perspective with respect to drug discovery, new MCR-based disconnections and often hidden opportunities.