Genomic analysis of spermatocytic tumors demonstrates recurrent molecular alterations in cases with malignant clinical behavior.

Spermatocytic tumor (ST) is a rare type of germ cell tumor that occurs exclusively in the postpubertal testis and typically affects elderly men. Most STs are benign, but rare cases exhibit aggressive clinical behavior, often in association with transition to sarcomatoid histology. Limited molecular analyses have been performed on STs; therefore, their genomic and epigenomic features remain incompletely described. Twenty-seven samples from 25 individual patients were analyzed with a combination of DNA sequencing panels, genomic methylation profiling, SNP array, isochromosome (12p) [i(12p)] FISH, and immunohistochemistry. The series included five metastasizing tumors (three with sarcomatoid transformation, one anaplastic, and one conventional) and 20 non-metastasizing tumors (14 anaplastic and six conventional). Anaplastic tumors comprised a monomorphic population of intermediate-sized neoplastic cells, as previously described. Multiomic analyses demonstrated that there were two genomic subgroups of STs: one with diploid genomes and hotspot RAS/RAF variants and the other with global ploidy shift and absence of recurrent mutations. Relative gain of chromosome 9 was a consistent finding in both subgroups. A comparison of metastasizing and non-metastasizing cases demonstrated that aggressive behavior was associated with the acquisition of pathogenic TP53 mutations and/or relative gains of 12p/i(12p). In cases with sarcomatoid transformation, TP53 mutations seem to underlie the transition to sarcomatoid histology. Genomic methylation analysis demonstrated that aggressive cases with gains of 12p cluster closer to pure seminomas than to STs without gains of 12p. In conclusion, STs include two genomic subgroups, characterized by global ploidy shifts without recurrent mutations and diploid genomes with RAS/RAF hotspot mutations, respectively. Biologic progression was associated with relative gains of 12p and TP53 mutations. The findings in STs with relative gains of 12p suggest that they may exhibit biologic characteristics akin to those seen in germ cell neoplasia in situ-related germ cell tumors rather than non-germ cell neoplasia in situ-derived STs. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

DFT Calculations Rationalize Unconventional Regioselectivity in PdII-Catalyzed Defluorinative Alkylation of gem-Difluorocyclopropanes with Hydrazones.

Density functional theory (DFT) calculations have been conducted to gain insight into the unique formation of the branched alkylation product in the PdII-catalyzed defluorinative alkylation of gem-difluorocyclopropanes with hydrazones. The reaction is established to occur in sequence through oxidative addition, ß-F elimination, η1-η3 isomerization, transmetalation, η3-η1 isomerization, 3,3'-reductive elimination, deprotonation/N2 extrusion, and proton abstraction. The rate-determining step of the reaction is identified as the ß-F elimination, featuring an energy barrier of 28.6 kcal/mol. The 3,3'-reductive elimination transition states are the regioselectivity-determining transition states. The favorable noncovalent π-π interaction between the naphthyl group of gem-difluorocyclopropane and the phenyl group of hydrazone is found to be mainly responsible for the observed regioselectivity.

Cobalt-Catalyzed Borylative Reduction of Azobenzenes to Hydrazobenzenes via a Diborylated-Hydrazine Intermediate.

Cobalt-catalyzed borylative reduction of azobenzenes using pinacolborane is developed. The simple cobalt chloride catalyst and reaction conditions make this protocol attractive for hydrazobenzene synthesis. This borylative reduction shows good functional group compatibility and can be readily scaled up to the gram scale. Preliminary mechanistic studies clarified the proton source of the hydrazine products. This cobalt-catalyzed azobenzene borylative reaction provides a practical protocol to prepare synthetically useful diborylated hydrazines.

Theoretical Insight into the Palladium-Catalyzed Prenylation and Geranylation of Oxindoles with Isoprene.

This work presents a comprehensive mechanistic study of the ligand-controlled palladium-catalyzed prenylation (with C5 added) and geranylation (with C10 added) reactions of oxindole with isoprene. The calculated results indicate that the prenylation with the bis-phosphine ligand and geranylation with the monophosphine ligand fundamentally share a common mechanism. This mechanism involves the formation of two crucial species: a η3-allyl-Pd(II) cation and an oxindole carbon anion. Furthermore, the reactions necessitate the assistance of a second oxindole molecule, which serves as a Brønsted acid, providing a proton to generate the oxindole nitrogen anion. The oxindole nitrogen anion then acts as a Brønsted base, abstracting a C-H proton from another oxindole molecule to form an oxindole carbon anion. These mechanistic details differ significantly from those proposed in the experimental work. The present calculations do not support the presence of the Pd-H species and the η3, η3-diallyl-Pd(II) intermediate, which were previously suggested in experiments. The theoretical results rationalize the experimental finding that the bis-phosphine ligand favors the prenylation of oxindole, while the monophosphine ligand enables the geranylation of oxindole.

DFT Insight into a Strain-Release Mechanism in Bicyclo[1.1.0]butanes via Concerted Activation of Central and Lateral C-C Bonds with Rh(III) Catalysis.

Transition-metal-catalyzed, strain-release-driven transformations of "spring-loaded" bicyclo[1.1.0]butanes (BCBs) are considered potent tools in synthetic organic chemistry. Previously proposed strain-release mechanisms involve either the insertion of the central C-C bond of BCBs into a metal-carbon bond, followed by ß-C elimination, or the oxidative addition of the central or lateral C-C bond on the transition metal center, followed by reductive elimination. This study, employing DFT calculations on a Rh(III)-catalyzed model system in a three-component protocol involving oxime ether, BCB ester, and ethyl glyoxylate for constructing diastereoselective quaternary carbon centers, introduces an unusual strain-release mechanism for BCBs. In this mechanism, the catalytic reaction is initiated by the simultaneous cleavage of two C-C bonds (the central and lateral C-C bonds), resulting in the formation of a Rh-carbene intermediate. The new mechanism exhibits a barrier of 21.0 kcal/mol, making it energetically more favorable by 11.1 kcal/mol compared to the previously suggested most favorable pathway. This unusual reaction mode rationalizes experimental observation of the construction of quaternary carbon centers, including the excellent E-selectivity and diastereoselectivity. The newly proposed strain-release mechanism holds promise in advancing our understanding of transition-metal-catalyzed C-C bond activation mechanisms and facilitating the synthesis of transition metal carbene complexes.

Hostile attribution bias's role in perceived stress among college freshman students: A latent growth modelling approach.

This study's objective was to examine the growth trajectories of freshman students' perceived stress and whether hostile attribution bias predicts the pattern of perceived stress change using latent growth analyses. A longitudinal dataset with fourth measurement points was gathered from a total of 1109 college students enrolled at a university in Guizhou Province in the first 3 months after college freshmen enrollment. The freshman students' levels of perceived stress tend to show a piecewise linear decline during the transition period, which manifests as a faster decline in the first stage (within the first month) than in the second stage (after the first month). Moreover, hostile attribution bias not only positively predicted the initial level of perceived stress but also positively predicted the slope of perceived stress in the first and second stages. In addition, there was a significant sex difference in the initial level of perceived stress where the initial level of perceived stress was higher in females than in males, but there was no significant sex difference in the rate of perceived stress decline. These results highlight the longitudinal relationship between hostile attribution bias and perceived stress and have implications for improving freshmen' college adaptation.

DNA Methylation Identifies Epigenetic Subtypes of Triple-Negative Breast Cancers With Distinct Clinicopathologic and Molecular Features.

Triple-negative breast cancers (TNBC) include diverse carcinomas with heterogeneous clinical behavior. DNA methylation is a useful tool in classifying a variety of cancers. In this study, we analyzed TNBC using DNA methylation profiling and compared the results to those of mutational analysis. DNA methylation profiling (Infinium MethylationEPIC array, Illumina) and 50-gene panel-targeted DNA sequencing were performed in 44 treatment-naïve TNBC. We identified 3 distinct DNA methylation clusters with specific clinicopathologic and molecular features. Cluster 1 (phosphoinositide 3-kinase/protein kinase B-enriched cluster; n = 9) patients were significantly older (mean age, 71 years; P = .008) with tumors that were more likely to exhibit apocrine differentiation (78%; P < .001), a lower grade (44% were grade 2), a lower proliferation index (median Ki-67, 15%; P = .002), and lower tumor-infiltrating lymphocyte fractions (median, 15%; P = .0142). Tumors carried recurrent PIK3CA and AKT1 mutations and a higher percentage of low HER-2 expression (89%; P = .033). Cluster 3 (chromosomal instability cluster; n = 28) patients were significantly younger (median age, 57 years). Tumors were of higher grade (grade 3, 93%), had a higher proliferation index (median Ki-67, 75%), and were with a high fraction of tumor-infiltrating lymphocytes (median, 30%). Ninety-one percent of the germline BRCA1/2 mutation carriers were in cluster 3, and these tumors showed the highest level of copy number alterations. Cluster 2 represented cases with intermediate clinicopathologic characteristics and no specific molecular profile (no specific molecular profile cluster; n = 7). There were no differences in relation to stage, recurrence, and survival. In conclusion, DNA methylation profiling is a promising tool to classify patients with TNBC into biologically relevant groups, which may result in better disease characterization and reveal potential targets for emerging therapies.

Cancer occurrence after SLE: effects of medication-related factors, disease-related factors and survival from an observational study.

OBJECTIVES: To explore the survival and risk factors for cancer occurrence after SLE (SLE-CA). METHODS: Patients with cancer diagnosed after SLE in Peking Union Medical College Hospital between January 2006 and September 2017 were recruited and followed. Data regarding medication-related and disease-related factors and survival were collected and compared with matched controls. Logistic regressions were applied to identify risk factors. The Kaplan-Meier method with a log-rank test was performed to evaluate survival. RESULTS: Forty-five SLE-CA patients and 128 controls were included, with the most common cancer site being the female genital system. SLE-CA patients were exposed to a higher cumulative dosage of CYC, with less mucocutaneous and haematologic involvement and higher anti-dsDNA positivity. At the time of cancer diagnosis, SLE-CA patients had lower SLEDAI 2000 (SLEDAI-2K), tended to achieve Definitions of Remission in SLE remission and minimal disease activity, but had higher SLICC/ACR Damage Index. Multivariable analysis identified high dosage of CYC [odds ratio (OR) 1.027, 95% CI 1.008, 1.046; P = 0.005] and low SLEDAI-2K at cancer diagnosis (OR 0.756, 95% CI 0.579, 0.986; P = 0.039) as risk factors. Mucocutaneous (OR 0.330, 95% CI 0.110, 0.991; P = 0.048) and haematologic involvement (OR 0.304, 95% CI 0.103, 0.902; P = 0.032) were negatively associated with cancer occurrence after SLE. The 5- and 10-year survival rates in SLE-CA patients were 95.2% and 92.1%, respectively. No significant difference of survival was observed between SLE-CA patients and controls (P = 0.177). CONCLUSION: High dosage of CYC and disease-related factors (low SLEDAI-2K, less mucocutaneous and haematologic involvement) were related factors for cancer occurrence after SLE, while no survival difference was observed.

Pumilio proteins utilize distinct regulatory mechanisms to achieve complementary functions required for pluripotency and embryogenesis.

Gene regulation in embryonic stem cells (ESCs) has been extensively studied at the epigenetic-transcriptional level, but not at the posttranscriptional level. Pumilio (Pum) proteins are among the few known translational regulators required for stem-cell maintenance in invertebrates and plants. Here we report the essential function of two murine Pum proteins, Pum1 and Pum2, in ESCs and early embryogenesis. Pum1/2 double-mutant ESCs display severely reduced self-renewal and differentiation, and Pum1/2 double-mutant mice are developmentally delayed at the morula stage and lethal by embryonic day 8.5. Remarkably, Pum1-deficient ESCs show increased expression of pluripotency genes but not differentiation genes, whereas Pum2-deficient ESCs show decreased pluripotency markers and accelerated differentiation. Thus, despite their high homology and overlapping target messenger RNAs (mRNAs), Pum1 promotes differentiation while Pum2 promotes self-renewal in ESCs. Pum1 and Pum2 achieve these two complementary aspects of pluripotency by forming a negative interregulatory feedback loop that directly regulates at least 1,486 mRNAs. Pum1 and Pum2 regulate target mRNAs not only by repressing translation, but also by promoting translation and enhancing or reducing mRNA stability of different target mRNAs. Together, these findings reveal distinct roles of individual mammalian Pum proteins in ESCs and their essential functions in ESC pluripotency and embryogenesis.

Clinicopathologic and molecular spectrum of testicular sex cord-stromal tumors not amenable to specific histopathologic subclassification.

A subset of testicular sex cord-stromal tumors (SCST), which includes neoplasms with mixed histology, cannot be classified into a specific histologic subtype. This study evaluated the clinicopathologic, immunophenotypic and molecular features of 26 SCST not amenable to specific classification by expert uropathologists. Median age at diagnosis was 43 years and median tumor size was 2.4 cm. Follow-up information was available for 18 (69%) patients, with evidence of an aggressive clinical course in 6 patients (4 alive with disease, 2 dead of disease 3 months and 6 months after orchiectomy). Microscopically, SCST not amenable to specific classification demonstrated monophasic epithelioid (9/26, 35%), monophasic spindle cell (5/26, 19%), and biphasic or mixed histology (12/26, 46%). One or more aggressive histopathologic features were seen in 11 cases. DNA sequencing was successful in 22 tumors. Pathogenic CTNNB1 and APC alterations were seen in 7 (33%) and 2 (10%) cases, respectively, with additional variants (e.g., CDKN2A, RB1, TP53, BRCA2) being identified in individual cases. Combined evaluation of morphology, sequencing data and beta-catenin immunohistochemistry resulted in reclassification of 6 (23%) tumors as Sertoli cell tumor, not otherwise specified. This was supported by comparing the methylation profiles of a subset of these tumors and those of typical Sertoli cell tumors. Additionally, a subset of 5 neoplasms (19%) with spindle cell or biphasic histology and SMA expression was characterized by hyperdiploid genomes with recurrent chromosomal gains and absence of driver mutations, possibly representing a distinct tumor type. The SCST that remained not amenable to specific histologic classification (15/26, 58%) were enriched for aggressive histologic features and malignant clinical behavior. In conclusion, this study demonstrated that a subset of testicular SCST that were originally not amenable to specific classification could be reclassified by combined evaluation of morphology, immunohistochemistry and molecular data.

Molecular correlates of male germ cell tumors with overgrowth of components resembling somatic malignancies.

A small subset of male germ cell tumors (GCT) demonstrates overgrowth of histologic components that resemble somatic malignancies (e.g., sarcoma, carcinoma). The presence of so-called "somatic-type" malignancies (SM) in GCT has been associated with chemotherapy-resistance and poor clinical outcomes in prior studies. However, the molecular characteristics of these tumors remain largely undescribed. In this study, we performed a multi-platform molecular analysis of GCTs with SM diagnosed in 36 male patients (primary site: testis, 29 and mediastinum, 7). The most common histologic types of SM were sarcoma and embryonic-type neuroectodermal tumor (ENT, formerly known as "PNET"), present in 61% and 31% of cases, respectively. KRAS and TP53 mutations were identified by DNA sequencing in 28% of cases each, with enrichment of TP53 mutations in mediastinal tumors (86%). Gains in the short arm of chromosome 12 were seen in 91% of cases, likely reflecting the presence of isochromosome 12p. Numerous copy number changes indicative of widespread aneuploidy were found in 94% of cases. Focal homozygous deletions and amplifications were also detected, including MDM2 amplifications in 16% of cases. Sequencing of paired samples in 8 patients revealed similar mutational and copy number profiles in the conventional GCT and SM components. Oncogenic gene fusions were not detected using RNA sequencing of SM components from 9 cases. DNA methylation analysis highlighted the distinct methylation profile of SM components that sets them apart from conventional GCT components. In conclusion, GCT with SM are characterized by widespread aneuploidy, a distinct epigenetic signature and the presence of mutations that are otherwise rare in testicular GCT without SM. The similarity of the mutational and DNA methylation profiles of different histologic types of SM suggests that the identification of SM components could be more important than their precise histologic subclassification, pending confirmation by further studies.

DFT Mechanistic Study of IrIII/NiII-Metallaphotoredox-Catalyzed Difluoromethylation of Aryl Bromides.

The work by MacMillan et al. ( Angew. Chem., Int. Ed. 2018, 57, 12543-12548) developed an IrIII/NiII-metallaphotoredox-catalyzed difluoromethylation strategy of aryl bromides using CHF2Br as the CHF2 reagent in the presence of tris(trimethylsilyl)silane. Here, we present a density functional theory (DFT)-based computational study to understand special dual catalysis promoting the C(sp2)-C(sp3) coupling. The calculated results show that the energetically more favorable pathway involves the reductive quenching of a photocatalyst (IrIII/*IrIII/IrII/IrIII) and a Ni0-initiated catalytic cycle (Ni0/NiI/NiIII/NiI/Ni0 or Ni0/NiII/NiIII/NiI/Ni0). The calculations reveal not only the mechanistic details delivering the difluoromethylarene product but also the molecular-level picture of the generation of Ni0 species from the NiII precatalyst. Moreover, the calculations also rationalize the observed stoichiometric effect of CHF2Br in the reactions of aryl bromides with different substituted groups.

Stressful events and adolescents' suicidal ideation during the COVID-19 epidemic: A moderated mediation model of depression and parental educational involvement.

This study examined the association between stressful events and adolescents' suicidal ideation and determined the roles of depression as a mediator and parental educational involvement as a moderator during the COVID-19 epidemic. Survey data from a sample of 1595 Chinese adolescents and their parents were subjected to path analysis. The results indicated that stressful events of the COVID-19 epidemic were significantly positively associated with adolescents' suicidal ideation, and this association was mediated by depression. In addition, adolescents' parental educational involvement significantly moderated the path from depression to suicidal ideation. These results highlight the importance of identifying the underlying key mechanisms that moderate the mediated paths between stressful events and adolescents' suicidal ideation during the COVID-19 epidemic. The findings also provide implications for parents and education staff regarding the importance of improving parental educational involvement to prevent adolescents' suicidal ideation during the COVID-19 epidemic.

Site- and Enantiodifferentiating C(sp3)-H Oxidation Enables Asymmetric Access to Structurally and Stereochemically Diverse Saturated Cyclic Ethers.

A manganese-catalyzed site- and enantiodifferentiating oxidation of C(sp3)-H bonds in saturated cyclic ethers has been described. The mild and practical method is applicable to a range of tetrahydrofurans, tetrahydropyrans, and medium-sized cyclic ethers with multiple stereocenters and diverse substituent patterns in high efficiency with extremely efficient site- and enantiodiscrimination. Late-stage application in complex biological active molecules was further demonstrated. Mechanistic studies by combined experiments and computations elucidated the reaction mechanism and origins of stereoselectivity. The ability to employ ether substrates as the limiting reagent, together with a broad substrate scope, and a high level of chiral recognition, represent a valuable demonstration of the utility of asymmetric C(sp3)-H oxidation in complex molecule synthesis.

The mechanism of pulsed electric field (PEF) targeting location on the spatial conformation of pine nut peptide.

In this study, the pine nut peptides, Lys-Asp-His-Cyc-His (KDHCH), was used as the molecule dynamics (MD) simulations subject, which has been proved that the antioxidant activity was improved after pulse electric field (PEF) treatment and the secondary structure was changed as the circular dichroism (CD) results showed. In the present study, we applied the MD simulation to discover the mechanism of the antioxidant activity improvement. The MD results showed that with the PEF treatment of 15 kV/cm, the oxygen atoms of KDHCH changed a lot, especially the atoms No.32 and No.63, of which the distance difference value was -3.02 nm, compared with the 0 kV/cm PEF treatment. The result showed an approach trend between residues Lys-and His-and the α-C atom of Lys, Cys-and His-all got closer after the PEF treatment, which means the structure became tight after the PEF treatment. However, the results of 45 kV/cm PEF treatment presented more effects on the change of KDHCH. The calculations of oxygen atoms show an approach trend between residues Lys, Asp-and His. The α-C atom of Lys, Cys-and His-all got closer after the PEF treatment, which means the structure became tight after the PEF treatment and proved the results of the calculations of the oxygen atoms. The structures of PEF treated and untreated peptide samples were measured by 1D and 2D nuclear magnetic resonance (NMR) in order to verify the results of the molecular dynamics simulations. The 8.37-8.40 ppm (-NH- in chain) and 8.84-8.88 ppm (-NH- in chain) appeared left shift, while at the 8.45-8.47 ppm (-NH- in chain) occurred a right shift. The 7.82 ppm (-NH- in imidazole ring) on His-shifted left after PEF treatment, which reached 7.84 ppm by the 1D-1H NMR spectroscopy. Moreover, the long-range connectivity between -NHα (8.78 ppm) on 2H-ASP and -CHα (2.72 ppm) on 1H-LYS; -SH (2.50 ppm) on 4H-CYS and -OH (3.53 ppm) on 5H-HIS all appeared in spectra of the PEF treatment sample. This study will also be helpful to further mechanism exploration.

Mechanism and Origins of Enantio- and Regioselectivities in Catalytic Asymmetric Minisci-Type Addition to Heteroarenes.

This work presents a density functional theory (DFT) study on the mechanism and origins of enantio- and regioselectivities in dual photoredox/chiral Brønsted acid-catalyzed asymmetric Minisci-type addition of carbon-centered radicals to N-heteroarenes [Science, 2018, 360, 419-422]. The previously proposed mechanism has been partially revised. First, photoexcited *[IrIII] is reductively quenched by TRIP anion rather than the experimentally proposed neutral radical generated from the chiral Brønsted acid cycle. Second, final product formation involves a hydrogen-atom transfer (HAT) from a neutral radical intermediate to the TRIP radical, instead of single-electron transfer (SET) to *[IrIII]. The TRIP catalyst has been shown to play a triple role by reductively quenching *[IrIII] with its anion form, activating the substrate, and inducing asymmetry. The calculated results rationalize the experimentally observed enantio- and regioselectivities and reveal that the enantioselectivity of the reaction originates from the hydrogen-bond interaction between TRIP and the N-H group of the carbon-centered radical, and the regioselectivity arises from the electron-withdrawing inductive effect from the protonated N-atom and the intramolecular hydrogen-bond interaction between the acetylamino group and the protonated pyridine ring. We also provide explanations for the experimentally observed a dramatic decrease in enantioselectivity when changing substrate or radical precursor and rationalize the solvent-controlled switch of regioselectivity.

Theoretical Insight into Palladium(II)-Counterion-Ligand Cooperative Regiodivergent Syntheses of Indolo[3,2-c]coumarins and Benzofuro[3,2-c]quinolinones from Diphenylethyne Derivatives.

With two distinct active sites, 2-hydroxy-2'-amino-diphenylethyne derivatives can offer benzofuro[3,2-c]quinolinones via the O-attack/N-carbonylation cyclization or indolo[3,2-c]coumarins via the N-attack/O-carbonylation cyclization. This work presents a density functional theory-based computational study to understand the mechanism and origin of the palladium(II)-catalyzed regiodivergent reactivity of diphenylethyne derivatives. It is indicated that the reaction features a palladium(II)-counterion-ligand cooperative catalysis. The O-attack/N-carbonylation cyclization mainly benefits from the inductive effect of the rigid electron-withdrawing bidentate nitrogen ligand and the stabilization of the 3c-4e bond between the trifluoroacetate (TFA) anion and the hydroxyl group in the substrate for the precursor and transition state, while the viability of the N-attack/O-carbonylation cyclization stems intrinsically from the stronger nucleophilicity of the N atom as well as the important π-π interaction between the flexible electron-rich bidentate phosphine ligand and the substrate. Moreover, these calculations propose an unconventional reductive elimination mechanism for the transformation from Pd(II) to Pd(0), where the intramolecular nucleophilic attack of the N/O atom on the carbonyl C atom results in the formal reductive elimination product. The calculated overall barriers of 14.8 kcal/mol for Pd(TFA)2 with the bidentate nitrogen ligand and 23.9 kcal/mol for Pd(OTf)2 with the bidentate phosphine ligand are qualitatively consistent with the mild experimental conditions.

DFT Study on Photosensitizer-Free Visible-Light-Mediated Au-Catalyzed cis-Difunctionalization of Alkynes: Mechanism and Selectivities as Compared to Rh Catalysis.

Density functional theory (DFT) calculations were performed to investigate the photosensitizer-free visible-light-mediated gold-catalyzed cis-difunctionalization of alkynes with aryl diazonium salts. The detailed reaction mechanism is established, and the observed regio- and chemoselectivities are rationalized. The results are compared to those of the rhodium-catalyzed cis-difunctionalization of alkynes. It is indicated that the excitation of the aryl diazonium salt initiates the photocatalytic cycle, and the following single-electron transfer between the Au(I) catalyst and the excited aryl diazonium salt affords the key aryl radical. Both gold- and rhodium-catalyzed reactions involve two major steps: alkyne insertion into the M-N or M-C bond (M = Au, Rh), and C-C or C-N reductive elimination from the M(III) center. The cis-difunctionalized product can be obtained by the trimethylsilyl (TMS)-substituted alkyne through the gold catalysis or by the Ph-substituted alkyne through the rhodium catalysis. The catalyst-dependent reactivity switch of TMS- and Ph-substituted alkynes is attributed to the catalyst-induced shift of the rate-determining step.

Theoretical Insight into the Au(I)-Catalyzed Intermolecular Condensation of Homopropargyl Alcohols with Terminal Alkynes: Reactant Stoichiometric Ratio-Controlled Chemodivergence.

The mechanisms and chemoselectivities on the Au(I)-catalyzed intermolecular condensation between homopropargyl alcohols and terminal alkynes were investigated by performing DFT calculations. The reaction was indicated to involve three stages: transformation of the homopropargyl alcohol (R1) via intramolecular cyclization to the cyclic vinyl ether (R1'), formation of the C-2-arylalkynyl cyclic ether (P1) via hydroalkynylation of R1' with phenylacetylene (R2), and conversion from P1 to 2,3-dihydro-oxepine (P2). The results revealed the origin of the reaction divergence and rationalized the experimental observations that a 1:3 reactant stoichiometric ratio affords P1 as the major product, whereas the 1:1.1 ratio results in P2 in high yield. The reactant stoichiometric ratio-controlled divergent reactivity is attributed to different catalytic activities of the gold catalyst toward different reaction stages. In the 1:3 situation, the excess R2 induces the Au catalyst toward its dimerization and/or hydration, inhibiting the conversion of P1 to P2 and resulting in product P1. Without excess R2, the Au catalysis follows a general cascade reaction, leading to product P2. Theoretical results described a general strategy controlling the reaction divergence by a different reactant stoichiometric ratio. This strategy may be enlightening for chemists who are exploring various synthesis methods with high chemo-, regio-, and enantioselectivities.

Theoretical Insight into the Mechanism and Origin of Divergent Reactivity in the Synthesis of Benzo-Heterocycles from o-Alkynylbenzamides Catalyzed by Gold and Platinum Complexes.

This work presents a DFT study on the mechanism and origin of catalyst-controlled divergent reactivity in the synthesis of benzo-heterocycles from o-alkynylbenzamides by Au(I)/Pt(IV) catalysis. The results indicate that the transformations proceed via a nucleophilic cyclization process. In the Au(I) catalysis, the preferred O-attack mode mainly originates from the symmetry match in the dominant bond-forming interaction between the lone-pair orbital of carbonyl-O and the in-plane alkyne π* orbital, and the electronic property of the ligand controls the O-5-exo-dig/O-6-endo-dig selectivity. The preference for the N-attack mode in Pt(IV) catalysis is attributed to the stronger coordinate capability of carbonyl-O than amino-N in the substrate to PtCl4, and the regioselective N-6-endo-dig or N-5-exo-dig cyclization depends on the stronger electrostatic interaction between the amino-N and alkynyl-Cß atoms. The theoretical results provide a fundamental understanding of why and how gold and platinum complexes catalyze the cyclization of o-alkynylbenzamides with different chemo- and regioselectivities.