Z-Selective α-Arylation of α,ß-Unsaturated Nitriles via [3,3]-Sigmatropic Rearrangement.

The Morita-Baylis-Hillman (MBH) reaction and [3, 3]-sigmatropic rearrangement are two paradigms in organic synthesis. We have merged the two types of reactions to achieve [3,3]-rearrangement of aryl sulfoxides with α,ß-unsaturated nitriles. The reaction was achieved by sequentially treating both coupling partners with electrophilic activator (Tf2 O) and base, offering an effective approach to prepare synthetically versatile α-aryl α,ß-unsaturated nitriles with Z-selectivity through direct α-C-H arylation of unmodified α,ß-unsaturated nitriles. The control experiments and DFT calculations support a four-stage reaction sequence, including the assembly of Tf2 O activated aryl sulfoxide with α,ß-unsaturated nitrile, MBH-like Lewis base addition, [3,3]-rearrangement, and E1cB-elimination. Among these stages, the Lewis base addition is diastereoselective and E1cB-elimination is cis-selective, which could account for the remarkable Z-selectivity of the reaction.

Probing long COVID through a proteomic lens: a comprehensive two-year longitudinal cohort study of hospitalised survivors.

BACKGROUND: As a debilitating condition that can impact a whole spectrum of people and involve multi-organ systems, long COVID has aroused the most attention than ever. However, mechanisms of long COVID are not clearly understood, and underlying biomarkers that can affect the long-term consequences of COVID-19 are paramount to be identified. METHODS: Participants for the current study were from a cohort study of COVID-19 survivors discharged from hospital between Jan 7, and May 29, 2020. We profiled the proteomic of plasma samples from hospitalised COVID-19 survivors at 6-month, 1-year, and 2-year after symptom onset and age and sex matched healthy controls. Fold-change of >2 or <0.5, and false-discovery rate adjusted P value of 0.05 were used to filter differentially expressed proteins (DEPs). In-genuity pathway analysis was performed to explore the down-stream effects in the dataset of significantly up- or down-regulated proteins. Proteins were integrated with long-term consequences of COVID-19 survivors to explore potential biomarkers of long COVID. FINDINGS: The proteomic of 709 plasma samples from 181 COVID-19 survivors and 181 matched healthy controls was profiled. In both COVID-19 and control group, 114 (63%) were male. The results indicated four major recovery modes of biological processes. Pathways related to cell-matrix interactions and cytoskeletal remodeling and hypertrophic cardiomyopathy and dilated cardiomyopathy pathways recovered relatively earlier which was before 1-year after infection. Majority of immune response pathways, complement and coagulation cascade, and cholesterol metabolism returned to similar status of matched healthy controls later but before 2-year after infection. Fc receptor signaling pathway still did not return to status similar to healthy controls at 2-year follow-up. Pathways related to neuron generation and differentiation showed persistent suppression across 2-year after infection. Among 98 DEPs from the above pathways, evidence was found for association of 11 proteins with lung function recovery, with the associations consistent at two consecutive or all three follow-ups. These proteins were mainly enriched in complement and coagulation (COMP, PLG, SERPINE1, SRGN, COL1A1, FLNA, and APOE) and hypertrophic/dilated cardiomyopathy (TPM2, TPM1, and AGT) pathways. Two DEPs (APOA4 and LRP1) involved in both neuron and cholesterol pathways showed associations with smell disorder. INTERPRETATION: The study findings provided molecular insights into potential mechanism of long COVID, and put forward biomarkers for more precise intervention to reduce burden of long COVID. FUNDING: National Natural Science Foundation of China; Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences; Clinical Research Operating Fund of Central High Level Hospitals; the Talent Program of the Chinese Academy of Medical Science; Training Program of the Big Science Strategy Plan; Ministry of Science and Technology of the People's Republic of China; New Cornerstone Science Foundation; Peking Union Medical College Education Foundation; Research Funds from Health@InnoHK Program.

Dearomatization of aryl sulfoxides: a switch between mono- and dual-difluoroalkylation.

Herein we describe the dearomatization of aryl sulfoxides with difluoroenol silyl ether (DFESE) using a rearrangement/addition protocol. The selection of the sulfoxide activator determines whether one or two difluoroalkyl groups are incorporated into dearomatized products. Using TFAA can deliberately halt the reaction at the mono-difluoroalkylated dearomatized intermediate formed via a [3,3]-rearrangement, which can be further trapped by external nucleophiles to give mono-difluoroalkylated alicycles. In contrast, switching to Tf2O enhances the electrophilicity of dearomatized intermediates, thus allowing for the adoption of a second DFESE to produce dual-difluoroalkylated alicycles.