Site-Selective Cross-Coupling of Polyhalogenated Arenes and Heteroarenes with Identical Halogen Groups.

Methods to functionalize arenes and heteroarenes in a site-selective manner are highly sought after for rapidly constructing value-added molecules of medicinal, agrochemical, and materials interest. One effective approach is the site-selective cross-coupling of polyhalogenated arenes bearing multiple, but identical, halogen groups. Such cross-coupling reactions have proven to be incredibly effective for site-selective functionalization. However, they also present formidable challenges due to the inherent similarities in the reactivities of the halogen substituents. In this Review, we discuss strategies for site-selective cross-couplings of polyhalogenated arenes and heteroarenes bearing identical halogens, beginning first with an overview of the reaction types that are more traditional in nature, such as electronically, sterically, and directing-group-controlled processes. Following these examples is a description of emerging strategies, which includes ligand- and additive/solvent-controlled reactions as well as photochemically initiated processes.

Strain-Inducing Positional Alkene Isomerization.

Small, strained ring systems are important pharmacophores in medicinal chemistry and versatile intermediates in organic synthesis. However, the kinetic and thermodynamic instability of many strained organic molecules renders them challenging to prepare. Here, we report a strain-inducing positional alkene isomerization reaction that provides mild and selective access to cyclobutene building blocks from readily obtained cyclobutylidene precursors. This endergonic isomerization relies on the sequential and synergistic action of a decatungstate polyanion photocatalyst and cobaloxime co-catalyst to store potential energy in the form of ring strain. The versatility of the cyclobutene products is demonstrated through diverse subsequent strain-releasing transformations. Mechanistic studies reveal a steric basis for strain-selective product formation.

Catalytic, contra-Thermodynamic Positional Alkene Isomerization.

The positional isomerization of C═C double bonds is a powerful strategy for the interconversion of alkene regioisomers. However, existing methods provide access to thermodynamically more stable isomers from less stable starting materials. Here, we report the discovery of a dual catalyst system that promotes contra-thermodynamic positional alkene isomerization under photochemical irradiation, providing access to terminal alkene isomers directly from conjugated, internal alkene starting materials. The utility of the method is demonstrated in the deconjugation of diverse electron-rich/electron-poor alkenes and through strategic application to natural product synthesis. Mechanistic studies are consistent with a regiospecific bimolecular homolytic substitution (SH2') mechanism proceeding through an allyl-cobaloxime intermediate.

A Unified Strategy for the Enantiospecific Total Synthesis of Delavatine A and Formal Synthesis of Incarviatone A.

We describe a symmetry-inspired synthetic approach that has enabled a short synthesis of delavatine A and a formal synthesis of incarviatone A, which are two likely biosynthetically related natural products. The indane core of these natural products was constructed through a cascade sequence involving five transformations that occur in a single pot. Leveraging symmetry has allowed us to trace both natural products back to a versatile building block, 3,5-dibromo-2-pyrone, and studies related to site-selective cross-coupling of this polyhalogenated heterocycle are described. In addition, our strategy gave access to a putative biogenetic precursor, from which the syntheses of both natural products were attempted.

Calyciphylline B-Type Alkaloids: Total Syntheses of (-)-Daphlongamine H and (-)-Isodaphlongamine H.

The first total synthesis of the complex hexacylic Daphniphyllum alkaloid (-)-daphlongamine H has been accomplished. Key to the success of the strategy are a complexity-building Mannich reaction, efficient cyclizations, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. Following construction of the hydro-indene substructure by means of a Pauson-Khand reaction, endgame redox manipulations delivered the natural product. Importantly, the synthetic studies have also given access to (-)-isodaphlongamine H and led to a revision of the reported structure of deoxyisocalyciphylline B.

A Short Synthesis of Delavatine A Unveils New Insights into Site-Selective Cross-Coupling of 3,5-Dibromo-2-pyrone.

The recognition of latent symmetry in delavatine A has enabled a short synthesis of the natural product starting from 3,5-dibromo-2-pyrone. The concise synthetic route features a cascade process involving a 6π electrocyclization to construct the indane core of delavatine A. In addition, we have conducted detailed experimental and computational studies to gain an in-depth understanding of the mechanism of the observed site-selective cross-coupling of 3,5-dibromo-2-pyrone. This insight may provide new avenues to achieve the selective cross-coupling of multiply halogenated heteroarenes.

Calyciphylline B-type Alkaloids: Evolution of a Synthetic Strategy to (-)-Daphlongamine H.

We provide a full account of our synthetic studies targeting the hexacyclic calyciphylline B-type alkaloids, a subfamily of the Daphniphyllum natural products. Following an initial set of synthetic strategies focused on constructing the piperidine core of the calyciphylline B-type framework via a 6π-azaelectrocyclization, as well as exploiting the reactivity of underexplored oxazaborinine heterocycles, we ultimately designed a highly functionalized acyclic precursor which underwent carefully orchestrated and efficient cyclizations to forge the architecturally complex natural product scaffold. Our efforts have culminated in the development of the first total synthesis of (-)-daphlongamine H, provided access to its C5-epimer, (-)-isodaphlongamine H, and led to structural revision of deoxyisocalyciphylline B.

Reactions of HDDA-Derived Benzynes with Sulfides: Mechanism, Modes, and Three-Component Reactions.

We report here reactions of alkyl sulfides with benzynes thermally generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization. The initially produced 1,3-betaine (o-sulfonium/aryl carbanion) undergoes intramolecular proton transfer to generate a more stable S-aryl sulfur ylide. This can react in various manners, including engaging weak acids (HA) in the reaction medium. This can produce transient ion pairs ArSR2(+)A(-) that proceed to the products ArSR + RA. When cyclic sulfides are used, A(-) opens the ring and is incorporated into the product, an outcome that constitutes a versatile, three-component coupling process.

Viscoelastic modelling and analysis of two-dimensional woven CNT-based multiscale fibre reinforced composite material system.

Carbon nanotube (CNT) has fostered research as a promising nanomaterial for a variety of applications due to its exceptional mechanical, optical, and electrical characteristics. The present article proposes a novel and comprehensive micromechanical framework to assess the viscoelastic properties of a multiscale CNT-reinforced two-dimensional (2D) woven hybrid composite. It also focuses on demonstrating the utilisation of the proposed micromechanics in the dynamic analysis of shell structure. First, the detailed constructional attributes of the proposed trans-scale composite material system are described in detail. Then, according to the nature of the constructional feature, mathematical modelling of each constituent phase or building block's material properties is established to evaluate the homogenised viscoelastic properties of the proposed composite material system. To highlight the novelty of this study, the viscoelastic characteristics of the modified matrix are developed using the micromechanics method of Mori-Tanaka (MT) in combination with the weak viscoelastic interphase (WI) theory. In the entire micromechanical framework, the CNTs are considered to be randomly oriented. The strength of the material (SOM) approach is used to establish mathematical frameworks for the viscoelastic characteristics of yarns, whereas the unit cell method (UCM) is used to determine the viscoelastic properties of the representative unit cell (RUC). Different numerical results have been obtained by varying the CNT composition, interface conditions, agglomeration, carbon fibre volume percentage, excitation frequency, and temperature. The influences of geometrical parameters like yarn thickness, width, and the gap length to yarn width ratio on the viscoelasticity of such composite material systems are also explored. The current study also addresses the issue of resultant anisotropic viscoelastic properties due to the use of dissimilar yarn thickness. The results of this micromechanical analysis provide valuable insights into the viscoelastic properties of the proposed composite material system and suggest its potential applications in vibration damping. To demonstrate the application of developed novel micromechanics in vibration analysis, as one of the main contributions, comprehensive numerical experiments are conducted on a shell panel. The results show a significant reduction in vibration amplitudes compared to traditional composite materials in the frequency response and transient response analyses. To focus on the aspect of micromechanical behaviour on dynamic response and for the purpose of brevity, only linear strain displacement relationships are considered for dynamic analysis. These insights could inform future research and development in the field of composite materials.

Current Technologies and Future Perspectives in Immunotherapy towards a Clinical Oncology Approach.

Immunotherapy is now established as a potent therapeutic paradigm engendering antitumor immune response against a wide range of malignancies and other diseases by modulating the immune system either through the stimulation or suppression of immune components such as CD4+ T cells, CD8+ T cells, B cells, monocytes, macrophages, dendritic cells, and natural killer cells. By targeting several immune checkpoint inhibitors or blockers (e.g., PD-1, PD-L1, PD-L2, CTLA-4, LAG3, and TIM-3) expressed on the surface of immune cells, several monoclonal antibodies and polyclonal antibodies have been developed and already translated clinically. In addition, natural killer cell-based, dendritic cell-based, and CAR T cell therapies have been also shown to be promising and effective immunotherapeutic approaches. In particular, CAR T cell therapy has benefited from advancements in CRISPR-Cas9 genome editing technology, allowing the generation of several modified CAR T cells with enhanced antitumor immunity. However, the emerging SARS-CoV-2 infection could hijack a patient's immune system by releasing pro-inflammatory interleukins and cytokines such as IL-1ß, IL-2, IL-6, and IL-10, and IFN-γ and TNF-α, respectively, which can further promote neutrophil extravasation and the vasodilation of blood vessels. Despite the significant development of advanced immunotherapeutic technologies, after a certain period of treatment, cancer relapses due to the development of resistance to immunotherapy. Resistance may be primary (where tumor cells do not respond to the treatment), or secondary or acquired immune resistance (where tumor cells develop resistance gradually to ICIs therapy). In this context, this review aims to address the existing immunotherapeutic technologies against cancer and the resistance mechanisms against immunotherapeutic drugs, and explain the impact of COVID-19 on cancer treatment. In addition, we will discuss what will be the future implementation of these strategies against cancer drug resistance. Finally, we will emphasize the practical steps to lay the groundwork for enlightened policy for intervention and resource allocation to care for cancer patients.

Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters.

The stereoselective synthesis of complex targets requires the precise orchestration of chemical transformations that simultaneously establish the connectivity and spatial orientation of desired bonds. In this work, we describe a complementary paradigm for the synthesis of chiral molecules and their isomers, which tunes the three-dimensional structure of a molecule at a late stage. Key to the success of this strategy is the development of a mild and highly general photocatalytic method composed of decatungstate polyanion and disulfide cocatalysts, which enable the interconversion of unactivated tertiary stereogenic centers that were previously configurationally fixed. We showcase the versatility of this method-and the implementation of stereoediting logic-by the rapid construction of chiral scaffolds that would be challenging to access using existing tools and by the late-stage stereoediting of complex targets.

Prevalence of Musculoskeletal Disorders among Sewing Machine Workers in a Leather Industry.

BACKGROUND: Musculoskeletal disorders are the group of disorders which affects the muscles, tendons, ligaments, joints, peripheral nerves and supporting blood vessels in the body. Sewing machine involves continuous, repetitive tasks like cutting, assembly, pressing and finishing. These works are performed in a sitting posture with upper back curved forwards and the head is bent towards the sewing machine. Working in this faulty posture for a long time increases the chance of developing work related musculoskeletal disorder among them. The objective of study is prevalence of musculoskeletal complaints among sewing machine workers in leather industry. METHODS: A non- experimental study with 100 subjects according to inclusion and exclusion criteria. Using the NORDIC QUESTIONNAIRE musculoskeletal pain have been analysed. RESULTS: The statistical analysis of this study show 88% of sewing machine workers had a lower back pain in the last 12 months, 82% sewing machine workers had a lower back and knee pain that has been prevented them over last 12 months during normal activity, 86% sewing machine workers had lower back pain in the last 7 days. CONCLUSION: This study concluded that the 86% experienced low back pain, 84% experienced knee pain and 74% of experienced neck pain in past 7 days. 88% of experienced low back pain, 86% experienced knee pain, 76% experienced neck pain in past 12 months.82% experienced pain in lower back and knee pain and 72% experienced neck pain among sewing machine manual workers that has impacted over last 12 months during normal activity.

A pyrone remodeling strategy to access diverse heterocycles: application to the synthesis of fascaplysin natural products.

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described. The pyrido[1,2-a]indole core was demonstrated to be a versatile scaffold that can be site-selectively functionalized. The utility of this novel annulation strategy was showcased in a concise formal synthesis of three fascaplysin congeners.

Reactions of Diaziridines with Benzynes Give N-Arylhydrazones.

Reactions of thermally generated benzynes with diaziridines are reported. These trapping reactions follow the same pathway as reported earlier by Heine and co-workers with electron-deficient alkynes. The resulting N-arylhydrazones were obtained efficiently in a single step. The preference for the mode of addition of the nucleophilic diaziridine nitrogen atom to the more electrophilic benzyne carbon was consistent with what is predicted on the basis of distortion analysis. The feasibility of converting the hydrazone into a Fisher-indole adduct was demonstrated.

Oxazaborinines from Vinylogous N-Allylic Amides: Reactivities of Underexplored Heterocyclic Building Blocks.

Access to a new class of oxazaborinines using an efficient transition-metal-catalyzed rearrangement is demonstrated. The method overcomes the synthetic challenge of achieving an aza-Claisen rearrangement of vinylogous N-allylic amide substrates, giving rise to a variety of highly modifiable oxazaborinine products. An investigation of the unique reactivity of these boron-based heterocycles has unveiled their underexplored potential as valuable building blocks and intermediates for organic synthesis.

Atypical Mode of [3 + 2]-Cycloaddition: Pseudo-1,3-dipole Behavior in Reactions of Electron-Deficient Thioamides with Benzynes.

Thioamides bearing electron-withdrawing groups on the thiocarbonyl carbon atom react with benzynes [generated by the hexadehydro-Diels-Alder cycloisomerization] in an unprecedented fashion. Namely, the dihydrobenzothiazole products are consistent with a pathway involving initial formation of a stabilized ammonium ylide by a rare type of [3 + 2]-cycloaddition reaction. The fate of this species depends upon the nature of the R group(s) attached to the ylide nitrogen atom. The demonstration of new modes of reactivity represents the major advance arising from this study.

Reactions of Hexadehydro-Diels-Alder (HDDA)-Derived Benzynes with Thioamides: Synthesis of Dihydrobenzothiazino-Heterocyclics.

Reaction of thioamides (e.g., II) with benzynes generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization (e.g., I) produces dihydrobenzothiazines (e.g., III). It is postulated that the reaction proceeds via benzothietene (cf. IV) and o-thiolatoaryliminium (cf. V) intermediates and that the latter undergoes intramolecular 1,3-hydrogen atom migration to produce the penultimate isomeric iminium zwitterions VI.