Transition-metal catalyzed C-H activation as a means of synthesizing complex natural products.

Over the past few decades, the advent of C-H activation has led to a rethink among chemists about the synthetic strategies employed for multi-step transformations. Indeed, deploying innovative and masterful tricks against the numerous classical organic transformations has been the need of the hour. Despite this, the immense importance of C-H activation remains unfulfilled unless the methodology can be deployed for large-scale industrial processes and towards the concise, step-economic synthesis of prodigious natural products and pharmaceutical drugs. Lately, the growing potential of C-H activation methodology has indeed driven the pioneers of synthetic organic chemists into finding more efficient methods to accelerate the synthesis of such complex molecular scaffolds. This review aims to draw a general overview of the various C-H activation procedures that have been adopted for synthesizing these vast majority of structurally complicated natural products. Our objective lies in drawing a complete picture and taking the readers through the synthesis of a series of such complex organic compounds by simplified techniques, making it step-economic on a larger scale and thus instigating the readers to trigger the use of such methodology and uncover new, unique patterns for future synthesis of such natural products.

Identification and characterization of a novel begomovirus, Withania leaf curl virus associated with leaf curl disease of Withania somnifera.

Begomovirus is the largest genus of the family Geminiviridae with wide host range and responsible for a considerable amount of economic damage to many important crops globally. Withania somnifera (Indian ginseng) is an important medicinal plant with high demand in pharmaceutical industries worldwide. During the routine survey in 2019, typical characteristic viral symptoms such as severe leaf curling, downward rolling of the leaves, vein clearing, and poor growth of Withania plants with 17-20% disease incidence were observed in Lucknow, India. Typical symptoms, abundant presence of whiteflies, PCR and RCA based detection indicated the amplification of ~ 2.7 kb and suspected the causal pathogen to be a begomovirus, associated with a betasatellite (~ 1.3 kb). Transmission electron microscopy revealed the presence of twinned particles of ~ 18-20 nm in diameter. Full genome sequencing (2758 bp) of the virus and its analysis showed only 88% sequence identity with the begomovirus sequences present in the database. Hence, based on the nomenclature guidelines we concluded that the virus associated with the present disease of W. somnifera is a novel begomovirus and its name is proposed as Withania leaf curl virus.

Recent advances in transition metal-mediated trifluoromethylation reactions.

Fluorine compounds are known for their abundance in more than 20% of pharmaceutical and agrochemical products mainly due to the enhanced lipophilicity, metabolic stability and pharmacokinetic properties of organofluorides. Consequently, the last decade has seen enormous growth in the incorporation of a trifluoromethyl group into organic motifs. With due significance, this review aims to provide a complete picture of the transition metal-mediated construction of C(sp3, sp2, and sp)-CF3 bonds via C-H/X bond functionalization or addition processes in both aliphatic and aromatic hydrocarbons. Diversified reagents ranging from radical and electrophilic to nucleophilic trifluoromethylating agents and their respective mechanisms have been further deliberated in this comprehensive overview. The comprehensive coverage on this topic is expected to make this review unique and beneficial for further future applications enriching the community towards further improvements in the field of trifluoromethylation reactions, in turn improving the propensity towards further development of agrochemical drugs.

Dual Ligand Enabled Nondirected C-H Chalcogenation of Arenes and Heteroarenes.

Chalcogenide motifs are present as principal moieties in a vast array of natural products and complex molecules. Till date, the construction of these chalcogen motifs has been restricted to either the use of directing groups or the employment of a large excess of electronically activated arenes, typically employed as a cosolvent. Despite being highly effective, these methods have their own limitations in the step economy and the deployment of an excess amount of arenes. Herein, we report the evolution of a catalytic system employing arene-limited, nondirected thioarylation of arenes and heteroarenes using a complimentary dual-ligand approach. The reaction is controlled by a combination of steric and electronic factors, and the utilization of a suitable ligand enables the generation of products on a complimentary spectrum to that generated by classical methods. The combination of ligands remains imperative in the reaction protocol with theoretical calculations pointing towards a monoprotected amino acid ligand being crucial in the concerted metalation deprotonation (CMD) mechanism by a characteristic [5,6]-palladacyclic transition state, while the pyridine moiety assists in the active catalyst species formation and product release. Combined experimental and computational mechanistic investigations point toward the C-H activation step being both regio- and rate-determining. Interestingly, oxidative addition of the diphenyl disulfide substrate is found to be unlikely, and an alternative transmetalation-like mechanism involving the Pd-Ag heterometallic complex is proposed to be operative.

Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites.

The Fujiwara-Moritani reaction has had a profound contribution in the emergence of contemporary C-H activation protocols. Despite the applicability of the traditional approach in different fields, the associated reactivity and regioselectivity issues had rendered it redundant. The revival of this exemplary reaction requires the development of a mechanistic paradigm that would have simultaneous control on both the reactivity and regioselectivity. Often, the high thermal energy required to promote olefination leads to multiple site functionalizations. To this aim, we established a photoredox catalytic system constituting a merger of palladium/organo-photocatalyst (PC) that forges oxidative olefination in an explicit regioselective fashion with diverse arenes and heteroarenes. Visible light plays a significant role in executing "regioresolved" Fujiwara-Moritani reactions without the requirement of silver salts and thermal energy. The catalytic system is also amenable toward proximal and distal olefination aided by the respective directing groups (DGs), which entails the versatility of the protocol in engaging the entire spectrum of C(sp2)-H olefination. Furthermore, streamlining the synthesis of natural products, chiral molecules, drugs, and diversification through late-stage functionalizations underscore the importance of this sustainable protocol. The photoinduced attainment of this regioselective transformation is mechanistically established through control reactions and kinetic studies.

Toolbox for Distal C-H Bond Functionalizations in Organic Molecules.

Transition-metal-catalyzed C-H activation has developed a contemporary approach to the omnipresent area of retrosynthetic disconnection. Scientific researchers have been tempted to take the help of this methodology to plan their synthetic discourses. This paradigm shift has helped in the development of industrial units as well, making the synthesis of natural products and pharmaceutical drugs step-economical. In the vast zone of C-H bond activation, the functionalization of proximal C-H bonds has gained utmost popularity. Unlike the activation of proximal C-H bonds, the distal C-H functionalization is more strenuous and requires distinctly specialized techniques. In this review, we have compiled various methods adopted to functionalize distal C-H bonds, mechanistic insights within each of these procedures, and the scope of the methodology. With this review, we give a complete overview of the expeditious progress the distal C-H activation has made in the field of synthetic organic chemistry while also highlighting its pitfalls, thus leaving the field open for further synthetic modifications.

Characterization and evolutionary analysis of Cucumber mosaic virus isolate infecting Salvia sclarea in India.

Cucumber mosaic virus (CMV) is one of the most widespread viruses that infects a large number of cultivated crops worldwide and causes severe losses. Besides vegetables and ornamental crops, it is also spreading on medicinal and aromatic plants (MAPs) at an alarming rate. Natural occurrence of green mosaic, leaf curling, necrosis, and distortion were observed on the leaves of Salvia sclarea in the experimental field of CSIR-CIMAP, Lucknow, India. Mechanical transmission assay, morphological features, CP gene, and RNA3-based genomic characterization revealed the association of a new CMV isolate with the present disease. Virus is mechanically sap transmissible to the test plants. Transmission electron microscopy showed the presence of isodiametric particles of ~ 28 nm in diameter. Phylogenetic studies revealed that RNA3 (~ 2.2 kb) belongs to the subgroup IA of CMV. Multiple sequence alignment of amino acid sequences showed that MP possesses two unique changes in the RNA-binding domain and CP was found to be the conserved one with one change only. To the best of our knowledge, this is the first report of a CMV isolate infecting S. sclarea.

Enabling the Facile Synthesis of Arenes by Transition Metal Catalyzed Decarbonylation Methodology.

Transition metal-catalyzed decarbonylation is an essential paradigm of synthetic organic chemistry. Decarbonylation offers a unique pathway to decoding the skeletal structure of arenes and enabling easy synthesis of structurally complicated molecules. Due to the omnipresence of carbonyl groups in a wide array of synthetically important complex molecules, the variety and scope of these transformations are enormous. As a result, the development of transition metal catalysts in such a simple decarbonylation reaction ranks among one of the most important topics in synthetic organic chemistry. Transition metals that have been employed range from 3d metals like V to second-row transition metals like Pd. The growing potential of this methodology has driven the pioneers of synthetic organic chemistry into delving into the details of this transition metal-catalyzed decarbonylation pathways. This review aims to take the readers through the employment of transition metals in various decarbonylation processes developed by our group, sticking not only to the scope and diversification of synthetically complex molecules, but also enabling the readers to understand the mechanistic insights, through computational and kinetic studies put forward in such reaction protocol, hoping to pave the way for future organic chemists to delve and hopefully solve the unique problems associated with this protocol.

First Report of Downy Mildew on Sweet Basil Caused By Peronospora belbahrii in India.

Sweet basil (Ocimum basilicum L.; Family Lamiaceae) is an annual aromatic and medicinal plant grown in tropical and subtropical regions of the world. In India, it is cultivated as a commercial crop on ~8,000 ha. Aerial plant parts and essential oil of sweet basil are used in pharmaceutical, perfumery, food industries and in different formulations of traditional Ayurvedic and Unani medicines (Shahrajabian et al. 2020). The leaves have the highest concentrations of secondary metabolites such as terpenes and phenylpropanoids which provide the distinctive aroma (Viuda-Martos et al. 2011). During October 2020, severe foliar disease was observed in experimental fields of sweet basil at Council of Scientific and Industrial Research (CSIR)-Central Institute of Medicinal and Aromatic Plants (CIMAP) in Lucknow, India. Initial symptoms included large, interveinal chlorotic lesions on the adaxial surface of the leaves and black sporulation on the abaxial surface. Within a few days, the abaxial side of leaves turned necrotic, and leaf senescence and defoliation occurred on plants with severe symptoms. Disease incidence was 20 to 30% of plants. The pathogen was characterized morphologically using a light microscope. Sporangiophores were hyaline, dichotomously branched, 186.9 to 423.07 × 6.85 to 9.06 µm and, branched 3 to 5 times with each branch, terminating in two slightly curved branchlets, the longer one 7.05 to 25.31 µm and the shorter one 4.98 to 15.92 µm. Each branchlet had a single sporangium at the tip. Conidia were ellipsoidal to sub-globose, olive-brown in color, and typically measured 25.21 to 33.86 × 17.92 to 26.24 µm, each, without a pedicel. Based on these morphological characteristics, the foliar disease was identified as downy mildew was caused by Peronospora belbahrii (Thines et al. 2009). Eight symptomatic and two asymptomatic plant samples were collected from different locations in the field, and genomic DNA was extracted from the conidia of the eight naturally infected tissues of sweet basil samples as well as leaf tissues from two asymptomatic plants, using the CTAB method. The internal transcribed spacer region was amplified using ITS1 and ITS4 primers. Only eight infected samples amplified products of expected size (~ 700 bp) and two asymptomatic samples showed no amplification. Only five amplified PCR products were sequenced (White et al. 1990). All five sequences were identical and were a 98.1% match with five P. belbahrii isolates (MN450330.1, MN308051.1, MH620351.1, KJ960193, and MF693898). The consensus sequence was deposited into the NCBI database (GenBank Accession No. MW689257). Downy mildew caused by P. belbahrii previously has been reported on sweet basil from several countries (Wyenandt et al. 2015). To confirm the pathogenicity of these isolates on sweet basil (cv. CIM-Saumya), 25 - day-old sweet basil plants were sprayed with a suspension (1 × 105 sporangia/ml) of P. belbahrii. All plants were kept in a growth chamber with a 23/18°C diurnal cycle with 65 to 85% relative humidity for 24 h. Non-inoculated plants treated with sterile water served as a control treatment. After 8 days, typical symptoms of downy mildew appeared on all the inoculated plants while non-inoculated plants remained asymptomatic. Inoculated leaves with symptoms consistent of downy mildew were collected and the causal agent again identified as P. belbahrii on the basis of microscopic examination and ITS rDNA sequence data. To our knowledge, this is the first report of downy mildew caused by P. belbahrii on sweet basil in India. The pathogen has a broad host range and may pose a serious threat to the cultivation of this valuable crop in India. Thus, it is pertinent to develop effective control measures to avoid further spread and mitigate economic loss. References: Shahrajabian, M. H., et al. 2020. Int. J. Food Prop. 23:1961-1970. Wyenandt, C. A., et al. 2015. Phytopathology 105:885. Thines, M., et al. 2009. Mycol. Res. 113:532. White, T. J., et al. 1990. Page 315 in: PCR Protocols: A Guide to Methods and Applications. Viuda-Martos, M., et al. 2011. Food Control. 22:1715.

Imine as a linchpin approach for meta-C-H functionalization.

Despite the widespread applications of C-H functionalization, controlling site selectivity remains a significant challenge. Covalently attached directing groups (DGs) served as ancillary ligands to ensure ortho-, meta- and para-C-H functionalization over the last two decades. These covalently linked DGs necessitate two extra steps for a single C-H functionalization: introduction of DG prior to C-H activation and removal of DG post-functionalization. Here we report a temporary directing group (TDG) for meta-C-H functionalization via reversible imine formation. By overruling facile ortho-C-H bond activation by imine-N atom, a suitably designed pyrimidine-based TDG successfully delivered selective meta-C-C bond formation. Application of this temporary directing group strategy for streamlining the synthesis of complex organic molecules without any necessary pre-functionalization at the meta position has been explored.

A directing group-assisted ruthenium-catalyzed approach to access meta-nitrated phenols.

meta-Selective C-H nitration of phenol derivatives was developed using a Ru-catalyzed σ-activation strategy. Cu(NO3)2·3H2O was employed as the nitrating source, whereas Ru3(CO)12 was found to be the most suitable metal catalyst for the protocol. Mechanistic studies suggested involvement of an ortho-CAr-H metal intermediate, which promoted meta-electrophilic aromatic substitution and silver-assisted free-radical pathway.

Accessing Remote meta- and para-C(sp2 )-H Bonds with Covalently Attached Directing Groups.

Directing group assisted ortho-C-H activation has been known for the last few decades. In contrast, extending the same approach to achieve activation of the distal meta- and para-C-H bonds in aromatic molecules remained elusive for a long time. The main challenge is the conception of a macrocyclic transition state, which is needed to anchor the metal catalyst close to the target bond. Judicious modification of the chain length, the tether linkage, and the nature of the catalyst-coordinating donor atom has led to a number of successful studies in the last few years. This Review compiles the significant achievements made in this field of both meta- and para-selectivity using covalently attached directing groups, which are systematically classified on the basis of their mode of covalent attachment to the substrate as well as their chemical nature. This Review aims to create a more heuristic approach for recognizing the suitability of the directing groups for use in future organic transformations.

Ruthenium-Mediated Distal C-H Activation.

Addressing remote C-H functionalization is a prominent challenge in the field of homogeneous catalysis. The past two decades have accounted for major developments in this domain, proclaiming efficient selectivity at the meta and para positions. Recognizing such transformations remains significant, owing to their importance in the biological and chemical industries. This focus review aims to summarize the relatively new concept of σ-C-H activation enabled by a ruthenium metal center.

'Pitted' to 'Pleasing' in 20 min.

In recent times, as a result of extensive drinking water fluoridation, the number of patients affected by fluorosis has increased considerably. The purpose of this clinical report is to describe the use of enamel microabrasion for a patient with severe fluorosis using 37% phosphoric acid and pumice mixture. The results were pleasing, and hence 37% phosphoric acid can be recommended as a safe and easily available alternative in microabrasion procedures.

Microabrasion using 18% hydrochloric acid and 37% phosphoric acid in various degrees of fluorosis - an in vivo comparision.

AIMS AND OBJECTIVES: The aim of this study was to assess the efficacy of 18% hydrochloric acid and 37% phosphoric acid by an in vivo comparison. METHODS: Sixty fluorotic permanent maxillary central incisors from 30 patients were divided into 3 categories. The teeth received 5 seconds (mild fluorosis), 20 seconds (moderate fluorosis) and 30 seconds (severe fluorosis) application of 18% hydrochloric acid on 11 and 37% phosphoric acid on 21. Standardized intraoral photographies were taken immediately before, after, and one month after treatment. Vinyl polysiloxane impression of the patient were made before and after the treatment. A scanning electron microscopic (SEM) evaluation was carried out on the models to judge the surface alterations. Wilcoxon and Mann-Whitney tests were used to verify the hypothesis. RESULTS: A statistically significant result was obtained in the reduction of white spot opacities, intensity of stains and the total area occupied by the stains in mild and moderate fluorosis teeth. Results of severe fluorosis had an unpredictable outcome. An SEM evaluation revealed good improvement in the surface texture of mild and moderate fluorosis teeth. Teeth with severe fluorosis showed only a slight improvement. CONCLUSION: A microabrasion procedure is effective for treating mild and moderate fluorosis cases.

Effects of citric acid and EDTA on periodontally involved root surfaces: a SEM study.

AIM: Root debridement by scaling and root planing may not completely remove contaminated cementum particularly in more apical areas. The smear layer formed during root planing inhibits cell migration and attachment leading to impaired marginal periodontal healing. The present study was done to compare the morphological effects of root surface demineralization using citric acid and EDTA as root-conditioning agents. MATERIALS AND METHODS: Thirty fragments of human dental roots previously exposed to periodontal disease were scaled and randomly divided into the following groups of treatment: Group I: Hand instrumentation and conditioning with normal saline for 5 minutes as control; group II: Hand instrumentation and conditioning with citric acid (pH 1) for 5 minutes and group III: Hand instrumentation and conditioning with EDTA (pH-7.4) for 5 minutes. Scanning electron microscopy was used to check for the presence of residual smear layer and for measuring the number and area of exposed dentin tubules. RESULTS: The mean efficacy of smear layer removal was compared between groups I and II, groups I and III and groups II and III, it was found to be statistically significant at 5%. When the mean diameter of the dentinal tubules and mean total surface area occupied by the dentinal tubule orifices was compared between groups II and III it was found to be statistically significant at 1% level of significance. CONCLUSION: Citric acid causes greater degree of morphological alterations than EDTA and is considered to be a better root-conditioning agent. However, the use of EDTA cannot be ruled out. CLINICAL SIGNIFICANCE: This study supports the hypothesis that demineralizing agents can be used as an adjunct to the periodontal treatment aiming at restoring the biocompatibility of roots and helps in choosing an appropriate agent for root conditioning.

Hereditary gingival fibromatosis with distinctive facies.

Hereditary gingival enlargement also known as gingivitis or familial elephantiasis is a rare type of gingival enlargement. It appears as an isolated autosomal dominant disorder or maybe associated with other conditions. Oral manifestations may vary from minimal involvement of only tuberosity area and the buccal gingiva around the lower molars to a generalized enlargement inhibiting eruption of the teeth. This paper discusses the case of a 13-year-old female patient with distinctive facial characteristics who presented to the department with a chief complaint of swollen gums since 1 year. She had severe diffuse gingival enlargement of the maxilla and mandible. Diagnosis was made based upon clinical examination and family history. Quadrant wise internal bevel gingivectomy procedure was done for the patient to restore her functional and esthetic needs.

Maxillary molar with two palatal canals.

The endodontic treatment of maxillary molar with an aberrant root canal morphology can be diagnostically and technically challenging.1 Unusual root canal morphology in multirooted teeth is a constant challenge for diagnosis and successful endodontic treatment. Presence of extra canals, lateral canals, deltas is commonly encountered.2 This case report is presented to illustrate and describe the endodontic treatment of maxillary first molar with an unusual morphological variation of palatal root. The palatal root had two canals that appeared to unite in the apical third of the canal.