A palladium-catalyzed dearomative diarylation of C2-deuterated or C2-nonsubstituted indoles through domino Heck/Suzuki coupling is established. Relying on electron-deficient phosphite ligand, side reactions including intermolecular Suzuki coupling and intramolecular C-D/H arylation are inhibited and a wide range of 2,3-diarylated indolines bearing vicinal tertiary stereocenters including deuterated ones are afforded in moderate to excellent yields (up to 94%) and excellent diastereoselectivities (>20:1). The catalyst loading can be lowered to 0.02 mol % at elevated temperature.

The concerted mechanism of thermal BBr3-mediated [2+2] carbonyl-olefin cycloaddition is intriguing considering the conflict against the Woodward-Hoffmann rule. In this work, we report a mechanistic study of the titled reaction using density functional theory calculations. The concerted [2+2] cycloaddition mechanism is operative even for the truncated model system of 2-methyl-2-butene and butanone. Intrinsic reaction coordinate analysis and potential surface mapping showed the asynchronous nature of the apparent concerted [2+2] cycloaddition, resulting from the proximity of carbocation-oxyanion in the transient zwitterionic structure. Solvent effects can change the reaction to a stepwise mechanism, highlighting the importance of zwitterion stability. Building upon this finding of the asynchronous concerted or stepwise [2+2] cycloaddition mechanism, two mechanistic classifications were elaborated based on substrates containing varied substituents and Lewis acids, with a focus on manipulating the stability of positive carbocation and negative oxyanion in the transient zwitterionic species.

The arylation of sterically hindered amines represents one of the long-standing challenges in synthetic chemistry. Herein, we report a highly efficient Ni-catalysed arylation of sterically hindered primary and secondary amines with aryl chlorides or phenol derivatives enabled by an unsymmetric N-heterocyclic carbene (NHC) ligand. The protocol provides general, efficient, and scalable access to various sterically demanding anilines in excellent yields under mild conditions. A wide range of functional groups and heterocycles are compatible (>50 examples), including those present in biologically relevant molecules. Computational studies suggest that the unsymmetric bulky and flexible NHC ligand was critical to balance the oxidative addition and reductive elimination elementary steps, thus promoting this challenging transformation.

Objective:To explore the threshold and efficacy of thyroglobulin assessment in the needle washout after fine needle aspiration (FNA-Tg) in the preoperative diagnosis of cervical lymph metastasis of thyroid papillary carcinoma (PTC).Methods:A retrospective analysis was performed on the FNA-Tg results of a total of 541 lymph nodes in 410 patients who underwent thyroid node surgery at the Department of Head Neck Surgery, Sir Run Run Shaw Hospital of Zhejiang University College of Medicine from July 2016 to January 2018. Taking the postoperative lymph node pathological results as the "gold standard", the ROC curve was plotted to obtain the optimal diagnostic threshold of FNA-Tg for cervical lymph node metastasis and evaluate its diagnostic efficacy. According to the level of serum thyroglobulin (sTg), the lymph nodes were divided into either a low sTg group (sTg ≤10 ng/ml) or a high sTg group (sTg >10 ng/ml), the ROC curve was plotted to analyze the diagnostic threshold of FNA-Tg in the two groups. The diagnostic threshold and efficacy of FNA-Tg/sTg ratio and FNA-Tg-sTg difference were then analyzed.Results:The ROC curve of FNA-Tg for diagnosis of lymph node metastasis was plotted, and the optimal diagnostic threshold of FNA-Tg was determined to be 0.835 ng/ml. Using this threshold as the cut-off point, the sensitivity and specificity were 88.5% and 97.5%, respectively, and the area under the ROC curve (AUC) was 0.944 (95%CI: 0.914~0.974). The level of FNA-Tg was correlated with the level of sTg (r=0.350, P＜0.001). Then, the lymph nodes were divided into either a low sTg group (n = 296) or a high sTg group (n = 245) according to the level of sTg, and the optimal diagnostic threshold for the two groups was determined to be 0.825 ng/ml (AUC = 0.909, 95%CI: 0.838~0.981) and 0.875 ng/ml (AUC = 0.951, 95%CI: 0.918~0.984), respectively. The optimal diagnostic cut-off of FNA-Tg/sTg ratio was determined to be 0.145; using this cut-off, the AUC of FNA-Tg/sTg ratio was 0.922 (95%CI: 0.889~0.955), and the sensitivity, specificity, positive predictive value, and negative predictive value were 82.7%, 95.5%, 85.3%, and 94.3%, respectively. The optimal diagnostic cut-off of FNA-Tg-sTg difference was determined to be >0; using this cut-off, the AUC of FNA-Tg-sTg difference was 0.841 (95%CI: 0.802~0.879), and the sensitivity, specificity, positive predictive value, and negative predictive value were 74.8%, 93.3%, 79.4%, and 91.5%, respectively.Conclusion:FNA-Tg can be used for the preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma. When 0.835 ng/ml is used as the cut-off value of FNA-Tg, the diagnostic performance is better. To avoid the possible impact of sTg level, FNA-Tg/sTg ratio and FNA-Tg-sTg difference could be used in combination.

Enantioselectivity prediction in asymmetric catalysis has been a long-standing challenge in synthetic chemistry because of the high-dimensional nature of the structure–enantioselectivity relationship. A lack of understanding of the synthetic space results in laborious and time-consuming efforts in the discovery of asymmetric reactions, even if the same transformation has already been optimized on model substrates. Here we present a data-driven workflow to achieve a holistic enantioselectivity prediction of asymmetric pallada-electrocatalysed C–H activation by implementing transition state knowledge in machine learning. The vectorization of transition state knowledge allowed for an excellent description and extrapolation of the machine learning model, and enabled the quantitative evaluation of 846,720 possibilities. Model interpretation revealed the non-intuitive olefin effect on the enantioselectivity determination. Subsequent density functional theory calculations unravelled mechanistic knowledge that the rate-determining step depends on the olefin reactivity in the insertion step. Therefore, the olefin insertion step can be involved in the overall enantioselectivity determination. These results highlight the complementary features of knowledge-based machine learning with an interpretation-driven mechanistic study, which provides the opportunity to harness widely existing catalysis screening data and transition state models in molecular synthesis.

Controlling the conformation of medium-sized rings is challenging because of their flexibility and ring strain effects. Herein, we report non-Curtin-Hammett conditions for the precise control of the conformation of cyclodecenones to effect the first cis-selective transannular Prins cyclization, which enabled concise syntheses of the 5(10→1)abeo-steroids bufospirostenin A and ophiopogonol A in only seven steps from inexpensive starting materials. Computational results indicated that the key cyclization was kinetically controlled and proceeded via either a Prins pathway or a carbonyl-ene pathway, depending on the reaction conditions. Moreover, conformational isomerization played a critical role in determining the stereochemistry of the products.

Objective:To establish a predictive model of lateral lymph node metastasis in patients with papillary thyroid carcinoma(PTC), and further to compare the diagnostic efficiency of this model with the suspected abnormal lymph node thyroglobulin in fine-needle aspirate fluid (FNA-Tg) for lateral lymph node metastasis.Methods:The preoperative clinical and ultrasonographic data of 110 patients (257 lymph nodes) who underwent PTC cervical lymph node dissection were retrospectively analyzed. According to the postoperative pathological results, they were divided into lateral lymph node metastasis and non-metastasis group. Regression analysis was used to screen out independent risk factors affecting lateral lymph node metastasis and establish a predictive model. The ROC curve was used to evaluate the diagnostic efficacy and the best diagnostic cut-off point.Results:Prediction model: Logit( P)=-2.987+ 2.189(S/L ratio of lymph nodes)+ 1.748(hilum absent)+ 2.030(hyperechoic)+ 1.849(vascular abnormalities). The sensitivity, specificity, accuracy and AUC of the prediction model in the diagnosis of lateral lymph node metastasis were 92.1%, 83.9%, 87.9% and 0.929, respectively. The Homser-Lemeshow goodness of fit test showed that the Logistic model has a good fitting effect. The sensitivity, specificity, accuracy, and AUC of FNA-Tg in the diagnosis of lateral lymph node metastasis were 87.4%, 95.4%, 90.3% and 0.968, respectively. The sensitivity, specificity, accuracy, and AUC of the combined diagnosis of the predictive model and FNA-Tg were 92.9%, 96.9%, 94.2% and 0.989, respectively. Conclusions:The model has a good predictive value for PTC cervical lymph node metastasis. Combined with FNA-Tg, it can improve its diagnostic efficiency and provide more valuable information for the decision-making of clinical surgical procedures.

Objective To evaluate the correlation between ultrasound features of papillary thyroid carcinoma(PTC)and lymph node metastasis by preoperative ultrasound elemental observation of thyroid nodules.Methods Three hundred and seventy-six patients who underwent primary thyroid surgery and confirmed by ultrasound and pathological data as single-focal PTC from Jannary to December 2017 in Sir Run Run Shaw Hospital of Zhejiang Univbersity College of Medicine were retrospectively analyzed. According to the presence or absence of lymph node metastasis,they were divided into central and lateral lymph node metastasis group and non-metastasis group.Independent risk factors for central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM) were analyzed byχ2 test and multivariate Logistic regression.Results Multivariate analysis showed that the posterior margin of the cancer was <0.25 cm from the posterior wall of the thyroid gland as an independent risk factor for CLNM(P=0.025). Compared with the tumor volume ≤0.38 cm3 ,the cancer volume >0.38 cm3(P=0.000),was more prone to CLNM.And multivariate analysis showed that the anterior margin of the cancer was <0.17 cm(P =0.006)from the anterior thyroid capsule and the inner wall of the foci was <0.26 cm (P =0.014) as independent risk factors for LLNM.Compared with the maximum diameter of the tumor lesion ≤1 cm,the maximum diameter >2 cm (P =0.001) group was more prone to LLNM.Compared with the tumor volume ≤0.38 cm3 ,the tumor volume >0.38 cm3(P =0.000)was more prone to LLNM.ConclusionsThe larger volume of single focal PTC carcinoma and the closer to the posterior thyroid capsule are independent risk factors for CLNM.The larger volume and diameter of single focal PTC,and the closer to the anterior and medial wall capsule are independent risk factors for LLNM.