Selective 1,4-syn-Addition to Cyclic 1,3-Dienes via Hybrid Palladium Catalysis.

1,4-cis-Disubstituted cyclic compounds play a pivotal role in pharmaceutical development, offering enhanced potency and bioavailability. However, their stereoselective and modular synthesis remains a long-standing challenge. Here, we report an innovative strategy for accessing these structures via mild conditions employing cyclic 1,3-dienes/alkyl(aryl)halides and amines. This procedure exhibits a wide substrate scope that tolerates various functional groups. The utility of this method is demonstrated in the efficient synthesis of a TRPV6 inhibitor, CFTR modulator, and other bioactive molecules. Combined experimental and computational studies suggest that the hybrid palladium-catalyzed radical-polar crossover mechanism is crucial for achieving exceptional 1,4-syn-addition selectivity (dr > 20:1).

Initial decomposition pathways of 1,1-diamino-2,2-dinitroethylene (α-FOX-7) in the condensed phase.

The initial decomposition pathways of α-FOX-7 in the condensed phase (crystal) were investigated via density functional theory. Calculations were carried out using three FOX-7 systems with increasing complexity from 1-layer (sheet) via 2-layer (surface) to 3-layer (bulk). The encapsulated environment of the central α-FOX-7 molecule, where decomposition takes place, is reconstructed by neighbouring molecules following a crystal structure. A minimal number of neighbouring molecules that have an impact on the energetics of decomposition are identified among all surrounding molecules. The results show that the presence of intermolecular hydrogen bonds due to the encapsulated environment in the condensed phase decreases the sensitivity of α-FOX-7, i.e. it increases the barrier of decomposition, but it does not alter the initial decomposition pathways of the reaction compared to the gas phase. Moreover, increasing the complexity of the system from a single gas phase molecule via sheet and surface to bulk increases the decomposition barriers. The calculations reveal a remarkable agreement with experimental data [A. M. Turner, Y. Luo, J. H. Marks, R. Sun, J. T. Lechner, T. M. Klapötke and R. I. Kaiser, Exploring the Photochemistry of Solid 1, 1-Diamino-2, 2-Dinitroethylene (FOX-7) Spanning Simple Bon Ruptures, Nitro-to-Nitrite Isomerization, and Nonadiabatic Dynamics, J. Phys. Chem. A, 2022, 126, 29, 4747-4761] and suggest that the initial decomposition of α-FOX-7 likely takes place at the surface of the crystal.

[2+4] Cycloaddition Product of an Amidinate Substituted Dialumene with Toluene.

Reduction of LAlI2 (L=PhC(Ni Pr2 C6 H3 )2 ) with two equivalents of KC8 in toluene affords the [2+4]cycloaddition product of a dialumene with toluene. The mechanism for the formation of product complex was investigated using density functional theory (DFT) methods.

Influence of second-order saddles on reaction mechanisms.

The transition state, a first-order saddle point on the potential energy surface, plays a central role in understanding the mechanism, dynamics, and rate of chemical reactions. However, we recently identified energetically accessible second-order saddles (SOS) in certain reactions and showed that the SOS plays a crucial role in the dynamics of the reactions [Pradhan et al., Phys. Chem. Chem. Phys., 2019, 21, 12837; Rashmi et al., Regul. Chaotic Dyn., 2021, 26, 119]. In the present work, we investigated the role of second-order saddle points on the dynamics of the thermal denitrogenation of 1-pyrazoline using ab initio classical trajectory simulations at the CASSCF(4,4)/6-31+G* level of theory, for total energies of 130, 140, and 150 kcal mol-1 available to the system. In this unimolecular dissociation reaction, the SOS point is 4 kcal mol-1 higher in energy than the synchronous bond-breaking transition state and opens up an additional reaction pathway. We found that the fraction of molecules following the synchronous bond-breaking pathway decreased with an increase in the total available energy in the reaction, accompanied by an increase in the fraction following the asynchronous pathway. To further understand the competition between the transition state and the SOS pathways, we investigated the mechanism of halogen-substituted 1-pyrazolines where the SOS energies are comparable to that of the transition states.

Palladium-catalyzed selective C-C bond cleavage and stereoselective alkenylation between cyclopropanol and 1,3-diyne: one-step synthesis of diverse conjugated enynes.

The stereoselective synthesis of 1,3-enynes from 1,3-diynes is demonstrated by palladium-catalyzed selective C-C bond cleavage of cyclopropanol. Exclusive formation of mono-alkenylated adducts was achieved by eliminating the possibility of di-functionalization with high stereoselectivity. Indeed, this protocol worked very well with electronically and sterically diverse substrates. Several studies, including deuterium labeling experiments and intermolecular competitive experiments, were carried out to understand the mechanistic details. The atomic-level mechanism followed in the catalytic process was also validated using DFT calculations, and the rate-controlling states in the catalytic cycle were identified. Furthermore, preliminary mechanistic investigations with radical scavengers revealed the non-involvement of the radical pathway in this transformation.

Synthesis and Photophysical Study of Heteropolycyclic and Carbazole Motif: Nickel-Catalyzed Chelate-Assisted Cascade C-H Activations/Annulations.

Herein, nickel-catalyzed synthesis of polyarylcarbazole through sequential C-H bond activations has been described. Regioselective indole C2/C3 functionalization has been achieved in the presence of indole C7-H, which is quite challenging. In addition, this approach also gives easy access to building a heteropolycyclic motif through C6/C7 C-H functionalization of indoline. This methodology is not limited to aromatic internal alkynes as coupling partners; aliphatic alkynes have also shown good tolerance. Notably, during the optimization the catalytic enhancement with sodium iodide as an additive has been observed. We have also studied the photophysical properties of these highly conjugated molecules.

Performance of shear wave elastography: A single centre pilot study of mixed etiology liver disease patients with normal BMI.

PURPOSE: To assess the performance of shear wave ultrasound elastography (SWE) for non-invasive grading of fibrosis in normal BMI patients with varied aetiology chronic liver disease. METHOD: Prospective SWE liver and spleen stiffness (LS, SS respectively) of 124 patients (94 men, mean age 45.4 ± 12.4 years, mean BMI 19.66 ± 1.49) with CLD of mixed aetiology, who underwent liver biopsy, between January 2019-20 was analysed using receiver operating curve (ROC) and classification analysis regression tree (CART) to determine fibrosis cut-off values and nominal logistical regression to quantify fibrosis. RESULTS: Of 124 patients, 50 (40%) had non-alcoholic steatohepatitis (NASH), 31 (25%) chronic hepatitis B (CHB) and 43 (35%) alcoholic liver disease (ALD) on biopsy. Overall mean LS and SS of the study population was 11.81 ± 5.9 and 16.88 ± 10.8 kPa, respectively. LS cut-off value <8 kPa was consistent with F0, 9-14 kPa for F1-F2 and >14.9 kPa for F3-F4 fibrosis on biopsy. On application of CART, LS value < 5.3 kPa was discriminative for NASH, 5.32 to <12.64 kPa for CHB, >12.64 kPa for ALD, SS <15.3 kPa was discriminative for NASH, 15.3-30 kPa for CHB and >30 kPa for ALD in our study population. CONCLUSION: SWE is a viable non-invasive tool for assessment of liver fibrosis grading in a population of mixed aetiology CLD. LS values in conjunction with SS are promising predictors of F2-F3 fibrosis with potential to discriminate select categories like CHB and NASH in such a population.

Material decomposition using iodine quantification on spectral CT for characterising nodules in the cirrhotic liver: a retrospective study.

BACKGROUND: There is limited scientific evidence on the potential of spectral computed tomography (SCT) for differentiation of nodules in the cirrhotic liver. We aimed to assess SCT-generated material density (MD) parameters for nodule characterisation in cirrhosis. METHODS: Dynamic dual-energy SCT scans of cirrhotic patients performed over 3 years were retrospectively reviewed. They were classified as hepatocellular carcinoma (HCC), regenerative or indeterminate, according to the European Association for the Study of the Liver criteria. MD maps were generated to calculate the area under the curve (AUC) and cutoff values to discriminate these nodules in the hepatic arterial phase (HAP) and portal venous phase (PVP). MD maps included iodine concentration density (ICD) of the liver and nodule, lesion-to-normal liver ICD ratio (LNR) and difference in nodule ICD between HAP and PVP. RESULTS: Three hundred thirty nodules belonging to 300 patients (age 53.0 ± 12.7 years, mean ± standard deviation) were analysed at SCT (size 2.3 ± 0.8 cm, mean ± SD). One hundred thirty-three (40.3%) nodules were classified as HCC, 147 (44.5%) as regenerative and 50 (15.2%) as indeterminate. On histopathology, 136 (41.2%) nodules were classified as HCC, 183 (55.5%) as regenerative and 11 (3.3%) as dysplastic. All MD parameters on HAP and the nodule  difference in ICD could discriminate pathologically proven HCC or potentially malignant nodules from regenerative nodules (p < 0.001). The AUC was 82.4% with a cutoff > 15.5 mg/mL for nodule ICD, 81.3% > 1.8 for LNR-HAP and 81.3% for difference in ICD > 3.5 mg/mL. CONCLUSION: SCT-generated MD parameters are viable diagnostic tools for differentiating malignant or potentially malignant from benign nodules in the cirrhotic liver.

Transition between [R]- and [S]-stereoisomers without bond breaking.

The fifty-year old proposal of a nondissociative racemization reaction of a tetracoordinated tetrahedral center from one enantiomer to another via a planar transition state by Hoffmann and coworkers has been explored by many research groups over the past five decades. A number of stable molecules with planar tetracoordinated and higher-coordinated centers have been designed and experimentally realized; however, there has not been a single example of a molecular system that can possibly undergo such racemization. Here we show examples of molecular species that undergo inversion of stereochemistry around tetrahedral centers (Si, Al- and P+) either via a planar transition state or an intermediate state using quantum mechanical, ab initio quasi-classical dynamics calculations, and Born-Oppenheimer molecular dynamics (BOMD) simulations. This work is expected to provide potential leads for future studies on this fundamental phenomenon in chemistry.

Diagnostic efficacy of dynamic liver imaging using qualitative diagnostic algorithm versus LI-RADS v2018 lexicon for atypical versus classical HCC lesions: A decade of experience from a tertiary liver institute.

OBJECTIVE: To analyze and evaluate the diagnostic performance of conventional diagnostic (qualitative) imaging features versus LI-RADSv2018 lexicon for indeterminate and atypical Hepatocellular carcinoma (HCC) on dynamic liver imaging with reference to histopathology. PATIENTS AND METHODS: This retrospective study (June 2009-June 2019) evaluated the performance characteristics of conventional imaging findings, versus the Liver Imaging Reporting and Data System (LIRADS) v2018, for interpretation of indeterminate and atypical HCC, in patients who underwent subsequent histopathological analysis (gold standard). A total of 100,457 dynamic hepatobiliary CT and MR examinations were performed over ten years at our institute. Using current international imaging guidelines, 3218 patients were found to have suspected liver cancer lesions on imaging. Classical enhancement pattern of typical HCC was seen in 2916 of these patients. These patients did not require further biopsy. We enrolled, the remaining (n = 302) patients, who underwent biopsy, into our study group. Two radiologists, blinded to pathology findings, reviewed and classified these lesions, in consensus, according to LI-RADS® lexicon and as per 'conventional' (Indeterminate, Atypical HCC, Classical HCC, other malignancies) imaging. The histopathology diagnosis was considered as the final diagnosis. Alpha feto protein (AFP) levels amongst various subgroups were compared. Statistical analysis was performed to calculate the efficacy of LIRADS versus qualitative imaging parameters in comparison with histopathology. RESULTS: A total of n = 302 patients, [89 % men (n = 269), mean age 57.08 ± 12.43 years] underwent biopsy for suspected liver lesions. Qualitative imaging had 92.3 % (CI 88.53-94.91) sensitivity, 41.4 % (CI 25.51-59.26) specificity, positive predictive value (PPV) of 93.7 % (CI 90.11-96.02), negative predictive value (NPV) of 36.4 % (CI 22.19-53.38), positive likelihood ratio (PLHR) of 1.575 (CI 1.40-1.77) and negative likelihood ratio of (NLHR) 0.19 (CI 0.13-0.26). It correctly classified 87.4 % of lesions diagnosed on pathology. In comparison, LI-RADS was found to have 92 % sensitivity, 55.5 % specificity, 97 % PPV, 30.3 %, NPV, PLHR 2.068 (CI 1.62-2.64), NLHR 0.15 (CI 0.11-0.18) and 89.7 % diagnostic accuracy. A total of 38 patients (17 false negative, 21 false positive lesions) had discordant diagnoses on imaging versus histopathology. The kappa agreement between LIRADs and qualitative Imaging was found to be 0.77 ± .07 (p < 0.001). LIRADS and qualitative imaging collectively had 97 % sensitivity, 30 % specificity, 91.9 % PPV, 55.6 % NPV, PLHR of 1.39 (CI 1.27-1.51) and NLHR of 0.09 (0.048-0.19) which was better than, either reporting system, independently. CONCLUSION: It was observed that the LI-RADS v2018 lexicon with qualitative imaging as a combination technique added extra value in interpretation of atypical HCC or indeterminate lesions on dynamic CT and MRI compared to either as 'stand- alone' reporting systems.

Amniotic membrane - A Novel material for the root coverage: A case series.

BACKGROUND: Periodontal plastic surgical procedures aimed at coverage of exposed root surface. Owing to the second surgical donor site and difficulty in procuring a sufficient graft for the treatment of root coverage procedures, various alternative additive membranes have been used. A recent resorbable amniotic membrane, not only maintains the structural and anatomical configuration of regenerated tissues, but also enhances gingival wound healing, provides a rich source of stem cells. Therefore, amniotic membrane is choice of material these days in augmenting the better results in various periodontal procedures. AIM: The aim of this observational case series was to evaluate the effectiveness, predictability and the use of a novel material, amniotic membrane in the treatment of shallow-to-moderate isolated recession defects. MATERIALS AND METHODS: A total of three cases, showing Miller's Class I or Class II gingival recession, participated in this study. Recession depth, recession width, keratinized gingiva (KG) tissue width, clinical attachment level (CAL) were recorded at baseline, 3 and 6 months postoperatively. RESULTS: Six months following root coverage procedures, the mean root coverage was found to be 70.2 ± 6.8%. CAL significantly decreased from 6.4 ± 0.54 mm preoperatively to 3.5 ± 0.9 mm postoperatively at 6 months while KG showed significant improvement from 3.2 ± 0.28 mm preoperatively to 5.9 ± 0.74 mm postoperatively at 6 months. CONCLUSION: Autogenous graft tissue procurement significantly increases patient morbidity while also lengthening the duration of surgery in placing the graft, while self-adherent nature of amniotic membrane significantly reduces surgical time and made the procedure easier to perform, making it membrane of choice.

Periodontal status among tibetan refugees residing in jodhpur city

AIM: The present study is an attempt to evaluate the periodontal characteristics of this Tibetan refugee population and discuss possible oral health promotion activities. MATERIAL AND METHODS: 124 Tibetan were examined for the periodontal status using CPI and LOA index in Tibetan refugee camps in Jodhpur city, Rajasthan. RESULTS: Overall prevalence of periodontal disease among Tibetan refugees was 69%. Majority of the study participants {253(34%)} had CPI score 2. Periodontal status in Tibetan refugees is significantly (p≤0.05) associated with age group. Majority of study participants 232(32%) had LOA score 0. CONCLUSION: As age increases the periodontal diseases increases among study participants. There is significant association between age groups and periodontal status of Tibetan refugees.