Enantioselective and Regiodivergent Synthesis of Propargyl- and Allenylsilanes through Catalytic Propargylic C-H Deprotonation.

We report a highly enantioselective intermolecular C-H bond silylation catalyzed by a phosphoramidite-ligated iridium catalyst. Under reagent-controlled protocols, propargylsilanes resulting from C(sp3)-H functionalization, as well the regioisomeric and synthetically versatile allenylsilanes, could be obtained with excellent levels of enantioselectivity and good to excellent control of propargyl/allenyl selectivity. In the case of unsymmetrical dialkyl acetylenes, good to excellent selectivity for functionalization at the less-hindered site was also observed. A variety of electrophilic silyl sources (R3SiOTf and R3SiNTf2), either commercial or in situ-generated, were used as the silylation reagents, and a broad range of simple and functionalized alkynes, including aryl alkyl acetylenes, dialkyl acetylenes, 1,3-enynes, and drug derivatives were successfully employed as substrates. Detailed mechanistic experiments and DFT calculations suggest that an η3-propargyl/allenyl Ir intermediate is generated upon π-complexation-assisted deprotonation and undergoes outer-sphere attack by the electrophilic silylating reagent to give propargylic silanes, with the latter step identified as the enantiodetermining step.

[Predictive effect of combined procalcitonin, interleukin-6 and antithrombin III on the severity and prognosis of patients with sepsis].

OBJECTIVE: To investigate the correlation of procalcitonin (PCT), interleukin-6 (IL-6) and antithrombin III (AT III) with the severity of sepsis, and to compare the predictive value of the above indicators alone or in combination. METHODS: A retrospective cohort study was conducted. Eighty-five patients with sepsis admitted to the department of intensive care medicine of Shandong Provincial Hospital Affiliated to Shandong First Medical University from April 2021 to September 2022 were enrolled. General information, sequential organ failure assessment (SOFA) score and acute physiology and chronic health evaluation II (APACHE II) score within 24 hours of admission, inflammatory indicators [PCT, IL-6, serum amyloid A (SAA), neutrophil to lymphocyte ratio (NLR), and C-reactive protein (CRP)] and coagulation indicators (D-dimer and AT III) levels at admission, and 28-day prognosis were collected. The differences of the above indicators were compared among patients with different prognosis at 28 days and different severity of sepsis. The correlation between PCT, IL-6, AT III and the severity of sepsis was analyzed by Spearman rank correlation method. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of PCT, IL-6 and AT III alone or in combination on the 28-day death of patients with sepsis. RESULTS: Eighty-five patients were enrolled finally, 67 cases survived and 18 cases died at 28 days. The mortality was 21.2%. There were no statistical significant differences in gender, age and other general data between the two groups. The patients in the death group were more serious than those in the survival group, and PCT, IL-6, and CRP levels were significantly higher than those in the survival group [PCT (µg/L): 4.34 (1.99, 14.42) vs. 1.17 (0.31, 3.94), IL-6 (ng/L): 332.40 (50.08, 590.18) vs. 61.95 (31.64, 194.20), CRP (mg/L): 149.28 (75.34, 218.60) vs. 83.23 (48.22, 174.96), all P < 0.05], and AT III activity was significantly lower than that in the survival group [(53.67±28.57)% vs. (80.96±24.18)%, P < 0.01]. However, there were no significant differences in D-dimer, NLR and SAA between the two groups. Among the 85 patients, 36 had sepsis with single organ dysfunction, 29 had sepsis with multiple organ dysfunction, and 20 had septic shock with multiple organ dysfunction. With the increase of the severity of sepsis, PCT and IL-6 levels gradually increased [PCT (µg/L): 0.36 (0.19, 1.10), 3.00 (1.22, 9.94), 4.34 (2.18, 8.86); IL-6 (ng/L): 43.99 (20.73, 111.13), 100.00 (45.37, 273.00), 332.40 (124.4, 693.65)], and the activity of AT III decreased gradually [(89.81±21.42)%, (71.97±24.88)%, and (53.50±25.41)%], all with statistically significant differences (all P < 0.01). Spearman rank correlation analysis showed that PCT and IL-6 levels in sepsis patients were significantly positively correlated with the severity of the disease (r values were 0.562 and 0.517, respectively, both P < 0.01), and AT III activity was significantly negatively correlated with the severity of the disease (r = -0.523, P < 0.01). ROC curve analysis showed that PCT, IL-6, and AT III alone or in combination had some predictive value for the death of sepsis patients at 28 days. The area under the ROC curve (AUC) of the above three indicators in combination was higher than that of the individual tests (0.818 vs. 0.722, 0.725, and 0.770), with a sensitivity of 83.3% and a specificity of 73.1%. CONCLUSIONS: PCT, IL-6, and AT III were significantly correlated with the severity of sepsis patients. The combined assay of the above three indicators can effectively improve the prediction of the prognosis of sepsis patients.

Synthesis of 1,1-Disubstituted Allenylic Silyl Ethers Through Iron-Catalyzed Regioselective C(sp2)─H Functionalization of Allenes.

We report a synthesis of allenylic silyl ethers through iron-catalyzed functionalization of the C(sp2)─H bonds of monosubstituted alkylallenes. In the presence of a cyclopentadienyliron dicarbonyl based catalyst and triisopropylsilyl triflate as a silylation agent, a variety of aryl aldehydes were suitable coupling partners in this transformation, furnishing a collection of 1,1-disubstituted allenylic triisopropylsilyl ethers as products in moderate to excellent yields as a single regioisomer. Lithium bistriflimide was identified as a critical additive in this transformation. The optimized protocol was scalable, and the products were amenable to further transformation to give a number of unsaturated, polyfunctional derivatives.

Designed Iron Catalysts for Allylic C-H Functionalization of Propylene and Simple Olefins.

Propylene gas is produced worldwide by steam cracking on million-metric-ton scale per year. It serves as a valuable starting material for π-bond functionalization but is rarely applied in transition metal-catalyzed allylic C-H functionalization for fine chemical synthesis. Herein, we report that a newly-developed cationic cyclopentadienyliron dicarbonyl complex allows for the conversion of propylene to its allylic C-C bond coupling products under catalytic conditions. This approach was also found applicable to the allylic functionalization of simple α-olefins with distinctive branched selectivity. Experimental and computational mechanistic studies supported the allylic deprotonation of the metal-coordinated alkene as the turnover-limiting step and led to insights into the multifaceted roles of the newly designed ligand in promoting allylic C-H functionalization with enhanced reactivity and stereoselectivity.

Machine Learning of Histomorphological Features Predict Response to Neoadjuvant Therapy in Locally Advanced Rectal Cancer.

AIM: We hypothesize that machine learning of histomorphological features can predict response to neoadjuvant therapy (NAT) in locally advanced rectal cancer (LARC). METHOD: This retrospective study included 146 LARC patients who received NAT followed by surgery. The pathologists scanned the H&E slides of pretreatment tumor biopsy into whole slide images (WSIs). We randomly split patients into the primary and validation sets with a ratio of 80%:20%. We cut the WSIs into smaller parts (sample amount: 200-500) and used a convolutional neural network (CNN) to process these blocks directly. Then, a graph neural network (GNN) was applied to train the model in the primary set. The independent validation set was used to assess the performance of the model. RESULT: Our model could provide indicative information to identify the patients who were most likely to benefit from NAT. When the sample amount reached 500, the tile-level classifier for distinguishing poor response from good response produced an AUC of 0.779 in the primary set and 0.733 in the validation set. CONCLUSION: In this pilot study, we propose a novel predictive model of therapeutic response to NAT in LARC using a routine diagnostic tool employed in daily practice.

Highly chemoselective synthesis of hindered amides via cobalt-catalyzed intermolecular oxidative hydroamidation.

α-Tertiary amides are of great importance for medicinal chemistry. However, they are often challenging to access through conventional methods due to reactivity and chemoselectivity issues. Here, we report a single-step approach towards such amides via cobalt-catalyzed intermolecular oxidative hydroamidation of unactivated alkenes, using nitriles of either solvent- or reagent-quantities. This protocol is selective for terminal alkenes over groups that rapidly react under known carbocation amidation conditions such as tertiary alcohols, electron-rich alkenes, ketals, weak C-H bonds, and carboxylic acids. Straightforward access to a diverse array of hindered amides is demonstrated, including a rapid synthesis of an aminoadamantane-derived pharmaceutical intermediate.