Catalytic asymmetric dearomatization (CADA) reactions have evolved into an efficient strategy for accessing chiral polycyclic and spirocyclic scaffolds from readily available planar aromatics. Despite the significant developments, the CADA reaction of naphthalenes remains underdeveloped. Herein, we report a Gd(III)-catalyzed asymmetric dearomatization reaction of naphthalene with a chiral PyBox ligand via visible-light-enabled [4 + 2] cycloaddition. This reaction features application of a chiral Gd/PyBox complex, which regulates the reactivity and selectivity simultaneously, in excited-state catalysis. A wide range of functional groups is compatible with this protocol, giving the highly enantioenriched bridged polycycles in excellent yields (up to 96%) and selectivity (up to >20:1 chemoselectivity, >20:1 dr, >99% ee). The synthetic utility is demonstrated by a 2 mmol scale reaction, removal of directing group, and diversifications of products. Preliminary mechanistic experiments are performed to elucidate the reaction mechanism.

An efficient Rh(iii)-catalyzed enantioselective C-H alkynylation of isoquinolines is disclosed. The C-H alkynylation of 1-aryl isoquinolines with hypervalent iodine-alkyne reagents proceeded in DMA at room temperature in the presence of 2.5 mol% chiral SCpRh(iii) complex along with 20 mol% AgSbF6, providing axially chiral alkynylated 1-aryl isoquinolines in excellent yields (up to 93%) and enantioselectivity (up to 95% ee). The diverse transformations of the product further enhance the potential utility of this reaction.

Due to the instability and weak O-nucleophilicity of enol, carbonyl compounds prefer to function as C-nucleophiles instead of O-nucleophiles in the extensively studied transition metal-catalyzed hydrofunctionalizations of unsaturated bonds. The corresponding hydroalkenoxylation reaction has thus long been unexplored. Here, we describe a chemodivergent protocol for the challenging hydroalkenoxylation reactions. Dictated by the Pd catalyst bearing different ligands, both 5-exo-trig and 6-endo-trig hydroalkenoxylation processes are demonstrated to be feasible between the reaction of 1,3-enynes and ketoesters, and polysubstituted hydrofurans and hydropyrans are achieved in good yields and excellent chemoselectivities. In addition, the enantioselective hydroalkenoxylation reaction is also explored under an Rh catalyst in moderate efficiency but with high stereoselectivities. Mechanistic studies corroborate the designed tandem hydroalkylation and hydroalkenoxylation processes and uncover that a ligand-to-ligand hydrogen transfer process might be involved as the turnover-limiting step in the 5-exo-trig hydroalkenoxylation.

Bench-stable 3,3-difluoroallyl sulfonium salts (DFASs), featuring tunable activity and their editable C-beta and gem-difluoroallyl group, proved to be versatile fluoroalkylating reagents for site-selective S-gem-difluoroallylation of cysteine residues in unprotected peptides. The reaction proceeds with high efficiency under mild conditions (ambient temperature and aqueous and weak basic conditions). Various protected/unprotected peptides, especially bioactive peptides, are site-selectively S-gem-difluoroallylated. The newly added gem-difluoroallyl group and other functional groups derived from C-beta of DFASs are poised for ligation with bio-functional groups through click and radical chemistry. This stepwise doubly orthogonal modification of peptides enables the construction of bioconjugates with enhanced complexity and functionality. This proof of principle is successfully applied to construct a peptide-saccharide-biotin chimeric bioconjugate, indicating its great potential application in medicinal chemistry and chemical biology.

An unprecedented 1,5-addition/N-1,4-addition cascade reaction is established via palladium hydride catalysis. A variety of polysubstituted dihydropyrrole skeletons are constructed in high yield and with exclusively >20 : 1 diastereoselectivity. An enantioselective protocol of this design is also developed to provide a novel access to enantioenriched dihydropyrroles.

A hydrogen bonded calix[5]arene cavitand has been designed and prepared, which has a bowl-like cavity of about 0.85 nm width. The binding affinity of the container for ferrocene and eight of its derivatives in chloroform is modest. In a binary perfluoro-1-iodohexane and chloroform mixture (9 : 1 v/v), binding constants for the complexes of the seven fluorine-free guests increase by 14.0-144.1 times. In contrast, binding constants for the complexes of two guests that bear a perfluoroheptyl group do not exhibit similar increases. Similar enhancement of binding affinity can also be observed in binary solvents of perfluoro-1-iodobutane or perfluoro-1-iodooctane and chloroform. The results support that perfluoro-1-iodoalkanes in the cavity of the calix[5]arene container function as high-energy solvent molecules and their release into the bulk phase is the major driving force for enhanced inclusion by the calix[5]arene container of the fluorine-free guests. The release of high-energy perfluoro-1-iodohexane molecules has been demonstrated as a major driving force for enhanced binding between calix[5]arene containers and ferrocene guests.

Living crystallization-driven self-assembly (CDSA) provides robust access to uniform pi-conjugated nanostructures (CNSs) from block copolymers (BCPs) containing a crystalline pi-conjugated segment with controlled dimension, morphology and composition, which show appealing applications in biomedicine, photocatalysis and microelectronics. To further expand the application spectrum of these CNSs, the development of facile strategies toward diverse CNSs with varying structures/functionalities is highly desired. Herein, BCPs consisting of oligo(p-phenylene ethynylene)-b-poly(polypropyl-3-methanethiol acrylate) (OPE9-b-PMTPA(35) and OPE9-b-PMTPA(58); the subscript represents the number of repeat unit of each block) consisting of a crystalline pi-conjugated core-forming OPE9 segment and a corona-forming PMTPA block are synthesized. By efficient click-type alkylation of methylthio groups, OPE9-b-PMTPA with varying contents of sulfonium unit is obtained. Uniform ribbon-like micelles with different widths and lengths can then be generated in a controlled manner via the self-seeding approach of living CDSA. Additionally, negatively charged polymeric and Ag nanoparticles can be immobilized on sulfonium/methylthio-containing shells by taking advantage of electrostatic attraction and coordination interaction, respectively. Interestingly, the ribbon-like micelles with positively charged shells exhibit antibacterial activity against E. coli. Given the ease of modification of PMTPA-based shell and attractive opto-electronic/photocatalytic properties of pi-conjugated units, the combination of methylthio-chemistry and living CDSA opens a new avenue to generate multi-functional CNSs for widespread applications from biomedicine to photocatalysis.

Major depressive disorder (MDD) is a psychiatric illness that can jeopardize the normal growth and development of adolescents. Approximately 40% of adolescent patients with MDD exhibit resistance to conventional antidepressants, leading to the development of Treatment-Resistant Depression (TRD). TRD is associated with severe impairments in social functioning and learning ability and an elevated risk of suicide, thereby imposing an additional societal burden. In this study, we conducted plasma metabolomic analysis on 53 adolescents diagnosed with first-episode drug-na & iuml;ve MDD (FEDN-MDD), 53 adolescents with TRD, and 56 healthy controls (HCs) using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) and reversed-phase liquid chromatography-mass spectrometry (RPLC-MS). We established a diagnostic model by identifying differentially expressed metabolites and applying cluster analysis, metabolic pathway analysis, and multivariate linear support vector machine (SVM) algorithms. Our findings suggest that adolescent TRD shares similarities with FEDN-MDD in five amino acid metabolic pathways and exhibits distinct metabolic characteristics, particularly tyrosine and glycerophospholipid metabolism. Furthermore, through multivariate receiver operating characteristic (ROC) analysis, we optimized the area under the curve (AUC) and achieved the highest predictive accuracy, obtaining an AUC of 0.903 when comparing FEDN-MDD patients with HCs and an AUC of 0.968 when comparing TRD patients with HCs. This study provides new evidence for the identification of adolescent TRD and sheds light on different pathophysiologies by delineating the distinct plasma metabolic profiles of adolescent TRD and FEDNMDD.

The structural identification and efficient synthesis of bioactive 2,6-dideoxyglycosides are daunting challenges. Here, we report the total synthesis and structural revision of a series of 2,6-dideoxyglycosides from folk medicinal plants Ecdysanthera rosea and Chonemorpha megacalyx, which feature pregnane steroidal aglycones bearing an 18,20-lactone and glycans consisting of 2,6-dideoxy-3-O-methyl-beta-pyranose residues, including ecdysosides A, B, and F and ecdysantheroside A. All the eight possible 2,6-dideoxy-3-O-methyl-beta-pyranoside stereoisomers (of the proposed ecdysantheroside A) have been synthesized that testify the effective gold(I)-catalyzed glycosylation methods for the synthesis of various 2-deoxy-beta-pyranosidic linkages and lays a foundation via nuclear magnetic resonance data mapping to identify these sugar units which occur promiscuously in the present and other natural glycosides. Moreover, some synthetic natural compounds and their isomers have shown promising anticancer, immunosuppressive, anti-inflammatory, and anti-Zika virus activities.

The mechanism of the Rh-catalyzed oxidative coupling cyclization of 2,3-allenols has been studied by DFT calculations. The whole process of the current reaction involves the nucleophilic cyclic oxyrhodation/ stereodefined carborhodation/ beta-H elimination/ reductive elimination. Calculated results reveal that the carborhodation step is not only the rate-limiting step but also determines the stereo-selectivity.

Cyclolithistide A is a peptide lactone isolated from marine lithistid sponges. Its entire structure, including absolute configurations, has been reported except the relative and absolute configurations of its characteristic residue, 4-chloroisoleucine (4-CIle). We synthesized four isomers of 4-CIle from furfural-derived N-Boc imine and propionaldehyde. Analysis of the acid hydrolysate of cyclolithistide A and the synthetic samples of 4-CIle after derivatization with l- and d-FDAA permitted us to propose the absolute configuration of the 4-chloroisoleucine residue in cyclolithistide A as 2S,3R,4R.

Centromere protein A (CENP-A), a histone H3 variant specific to centromeres, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure-activity relationship (SAR) study of the cell-cycle-arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis reveals that both molecules bind to the colchicine-binding site of beta-tubulin. Treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, results in CENP-A accumulation by destabilizing Cdh1, a co-activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis. The indole terpenoid mimic (+)-6-Br-JP18 disrupts spindle microtubule assembly by targeting the colchicine-binding site of beta-tubulin, which leads to downregulation of Cdh1, a co-activator of the APC/C E3 ubiquitin ligase, and accumulation of its substrate CENP-A in human cells. image

New heteroaromatic azomethine building blocks with multiple hydrogen bonds have been synthesized for degradable n-conjugated polymers. The hydrogen bonds ensured the planarity of the building blocks, therefore enhanced n-conjugation. Two n-conjugated polymers of PPD and PTDD based on the building blocks were also synthesized. The organic field effect transistors (OFETs) based on PPD displayed a balanced ambipolar charge carrier transport, and the maximum hole/electron mobility were 0.08/0.14 cm 2 V -1 s -1 . While the OFETs based on PTDD exhibited a n -type dominant ambipolar charge transport, with the maximum hole/electron mobility of 6.0 x 10 -4 / 3 .8 x 10 -3 cm 2 V -1 s -1 . The microstructures of the polymer thin films were studied by two-dimensional grazing incidence wide-angle X-ray scattering (2D-GIWAXS). The n-conjugated polyazomethines were stable in ambient and could be degraded in acidic solutions. The main degradation products of the polymers were also identified.