Site-specific allylic C-H bond functionalization with a copper-bound N-centred radical.

Methods for selective C-H bond functionalization have provided chemists with versatile and powerful toolboxes for synthesis, such as the late-stage modification of a lead compound without the need for lengthy de novo synthesis1-5. Cleavage of an sp3 C-H bond via hydrogen atom transfer (HAT) is particularly useful, given the large number of available HAT acceptors and the diversity of reaction pathways available to the resulting radical intermediate6-17. Site-selectivity, however, remains a formidable challenge, especially among sp3 C-H bonds with comparable properties. If the intermediate radical could be further trapped enantioselectively, this should enable highly site- and enantioselective functionalization of C-H bonds. Here we report a copper (Cu)-catalysed site- and enantioselective allylic C-H cyanation of complex alkenes, in which a Cu(II)-bound nitrogen (N)-centred radical plays the key role in achieving precise site-specific HAT. This method is shown to be effective for a diverse collection of alkene-containing molecules, including sterically demanding structures and complex natural products and pharmaceuticals.

Alumanyl-Samarium(II): Synthesis, Characterization, and Reactivity Studies.

Metal-metal bonded species involving lanthanides are intriguing but rare. The recently reported salt metathesis reaction of an Al anion and SmI2(thf)2 yields novel heterometallic compound possessing two distinctive Al-Sm bonds. Although the Al-Sm bonds were considerably long [3.518(1) and 3.543(1) Å], DFT calculations indicated polar character of the Alδ--Smδ+ bonds. This is the first example of lanthanide species containing X-type Al ligands. Reactivity studies have demonstrated that the introduction of Sm(II) produces unique reactivity. The reaction with carbodiimide led to an insertion of carbodiimide into the Al-Sm bonds and reductive coupling of carbodiimide to create an oxalamidinate moiety, facilitated by Sm(II). Exposure of the Al-Sm-Al complex toward ethylene furnished a Sm(II) salt of anionic aluminacyclopropane that was spontaneously isomerized to a 1,4-dialuminacyclohexane derivative. The important role of Sm(II) to facilitate the ring expansion through an alkyl-relay mechanism was elucidated by DFT calculations.

Reactivity of a Hexaaryldiboron(6) Dianion as Boryl Radical Anions.

Our study unveils a novel approach to accessing boryl radicals through the spontaneous homolytic cleavage of B-B bonds. We synthesized a hexaaryl-substituted diboron(6) dianion, 1, via the reductive B-B coupling of 9-borafluorene. Intriguingly, compound 1 exhibits the ability to undergo homolytic B-B bond cleavage, leading to the formation of boryl radical anions, as confirmed by EPR studies, in the presence of the 2.2.2-cryptand at room temperature. Moreover, it directly reacts with diphenylacetylene, producing an unprecedented 1,6-diborylated allene species, where the phenyl ring is dearomatized. Density functional theory computational studies suggest that homolytic B-B bond cleavage is favored in the reaction path, and the formation of the boryl radical anion is crucial for dearomatization. Additionally, it achieves the dearomative diborylation of anthracene and the activation of elemental sulfur/selenium under mild conditions. The borylation products have been successfully characterized by NMR spectra, HRMS, and X-ray single-crystal diffraction.

Phosphine-Catalyzed 1,2-cis-Diboration of 1,3-Butadiynes.

Trialkyl phosphines PMe3 and PEt3 catalyze the 1,2-cis-diboration of 1,3-butadiynes to give 1,2-diboryl enynes. The products were utilized to synthesize 1,1,2,4-tetraaryl enynes using a Suzuki-Miyaura protocol and can readily undergo proto-deborylation.

Bent π-Conjugation within a Macrocycle: Asymmetric Total Syntheses of Spirohexenolides A and B.

Macrocycles with bent π-conjugation motif are extremely rare in nature and synthetically daunting and anticancer haouamines and spirohexenolides were representative of such rare natural products with synthetically challenging bent π-conjugation within a macrocycle. While the total synthesis of haouamines has been elegantly achieved, spirohexenolides remains an unmet synthetic challenge due to the highly strained bent 1,3,5-triene conjugation within C15 macrocycle. Inspired by the chemical synthesis of cycloparaphenylenes (CPPs) and haouamines, herein we devise a synthetic strategy to overcome the highly strained bent 1,3,5-triene conjugation within the macrocycle and achieve the first, asymmetric total synthesis of spirohexenolides A (>20 mg) and B (>50 mg). Our synthesis features strategic design of ring-closing metathesis (RCM) macrocyclization followed by double dehydration to achieve the C15 macrocycle with the deformed nonplanar 1,3,5-triene conjugation. In addition, we have developed a new enantioselective construction of highly functionalized spirotetronate fragment (northeast moiety) through RCM and Ireland-Claisen rearrangement. Our in vitro bioassay studies reveal that both spirohexenolides are cytotoxic against a panel of human cancer cells with IC50 1.2-13.3 µM and spirohexenolide A is consistently more potent (up to 3 times) than spirohexenolide B, suggesting the importance of alcohol for their bioactivity and for medicinal chemistry development.

Asymmetric Synthesis of Remotely Chiral Naphthols and Naphthylamines via Naphthoquinone Methides.

Quinone methides are well-established intermediates in asymmetric synthesis. In contrast, their extended analogues with the carbonyl and methide units distributed across two different rings have not been exploited in asymmetric synthesis. Herein, we achieved the first asymmetric process involving such intermediates. Specifically, the use of suitable chiral phosphoric acids enabled in situ generation of 2-naphthoquinone 8-methides and the corresponding aza counterparts for mild one-pot asymmetric nucleophilic addition. These processes provided rapid access to a wide range of previously less accessible remotely chiral naphthols and naphthylamines with both high efficiency and excellent enantioselectivity. Control experiment and DFT calculations provided important insights into the reaction mechanism, which likely involves two phosphoric acid molecules in the enantiodetermining transition states. This work serves as a proof of concept for the exploitation of new types of extended quinone methides as versatile intermediates for asymmetric synthesis, thus providing a new platform for the efficient construction of remote benzylic stereogenic centers of aromatic compounds.

Site-Selective sp2 C-H Cyanation of Allenes via Copper-Catalyzed Radical Relay.

Compared with the extensively reported hydrogen atom transfer (HAT) at sp3 C-H, abstraction of hydrogen atoms at the sp2 carbon is extremely rare. Here, we communicate the site-selective cyanation of the sp2 C-H bond of allenes using the strategy of copper-catalyzed radical relay. The reactions afford various allenyl nitriles directly from simple allenes with a broad substrate scope and a remarkable functional group compatibility under mild conditions. These reactions exhibit excellent site-selectivity toward sp2 C-H, which can be attributed to the unique pocket created by the Cu-bound nitrogen-centered radical. The favorable HAT on sp2 C-H is due to crucial hydrogen bonding between the fluoride bonded to the Cu(II) center and the hydrogen atom at the allylic position. These features enable the late-stage functionalization of druglike bioactive molecules containing an allene motif.

Photoinduced Dehydrogenative Borylation via Dihydrogen Bond Bridged Electron Donor and Acceptor Complexes.

Air-stable amine- and phosphine-boranes are discovered as donors to integrate with pyridinium acceptor for generating photoactive electron-donor-acceptor (EDA) complexes. Experimental results and DFT calculations suggest a dihydrogen bond bridging the donor and acceptor. Irradiating the EDA complex enables an intra-complex single electron transfer to give a boron-centered radical for dehydrogenative borylation with no need of external photosensitizer and radical initiator. The deprotonation of Wheland-like radical intermediate rather than its generation is believed to determine the good ortho-selectivity based on DFT calculations. A variety of α-borylated pyridine derivatives have been readily synthesized with good functional group tolerance.

Distance-Triggered Distinct Aryl Migrations on Azidodiboranes.

Derived from structurally similar precursors, two different azidodiboranes went through distinct aryl migration reactions triggered by different boron-boron separation distances. Biphenylene based diborane with a shorter boron-boron distance underwent heterolateral aryl migration to form a seven-membered azadiborepin, while xanthrene based diborane with a longer boron-boron distance afforded a stable bis-azidoborane scaffold. The pyrolysis of such a bis-azidoborane led to eight-membered oxazadiborocine through homolateral aryl migration and subsequent [3+2] cycloaddition. Density functional theory (DFT) calculations unveiled that the boron-boron separation distances were the intrinsic factors for the distinct migrations.

Boosting Ring Strain and Lewis Acidity of Borirane: Synthesis, Reactivity and Density Functional Theory Studies of an Uncoordinated Arylborirane Fused to o-Carborane.

Among the parent borirane, benzoborirene and ortho-dicarbadodecaborane-fused borirane, the latter possesses the highest ring strain and the highest Lewis acidity according to our density functional theory (DFT) studies. The synthesis of this class of compounds is thus considerably challenging. The existing examples require either a strong π-donating group or an extra ligand for B-coordination, which nevertheless suppresses or completely turns off the Lewis acidity. The title compound, which possesses both features, not only allows the 1,2-insertion of P=O, C=O or C≡N to proceed under milder conditions, but also enables the heretofore unknown dearomative 1,4-insertion of Ar-(C=O)- into a B-C bond. The fusion of strained molecular systems to an o-carborane cage shows great promise for boosting both the ring strain and acidity.

Reactions of Tetra(o-tolyl)diborane(4) with Organic Azides: Formation of Fluorescent Boron-Fused Hexazenes.

The reaction of tetra(o-tolyl)diborane(4) with organic azides afforded three different compounds, diborylamines, diboryltriazenes, and B2 -hexazenes having a bicyclic B2 N6 ring system. The reaction with aryl azides gave diborylamines, while the reaction with 1 equiv. of alkyl azides furnished diboryltriazenes. In the case of the reaction with an excess amount of primary alkyl azide, a new heterocyclic B2 -hexazenes were obtained. The formation of the B2 N6 structure could be explained by one general reaction mechanism via the diboryltriazene intermediate according to the control experiments and DFT calculations. The B2 -hexazenes exhibited a strong fluorescence with a remarkably high fluorescent quantum yield of up to 96 %.

Persistent and Predominantly Localized Boron Radical from the Reduction of a Three-Dimensional Analogue of NHC-Stabilized Borafluorenium.

In this contribution, we reported the three-dimensional (3D) analogues of N-heterocyclic carbene (NHC)-stabilized 9-borafluorenium and 9-borafluorene radical. The radical was fully characterized by cyclic voltammetry (CV), UV-Vis absorption spectroscopy, electron paramagnetic resonance (EPR) and single-crystal X-ray diffraction analyses. The distinct boron-centered radical character of 9-borafluorene radical was corroborated by DFT calculations and EPR analysis.

Neutral Boryl Radicals in Mixed-Valent B(III) Br-B(II) Adducts.

The general strategies to stabilize a boryl radical involve single electron delocalization by π-system and the steric hinderance from bulky groups. Herein, a new class of boryl radicals is reported, with intramolecular mixed-valent B(III) Br-B(II) adducts ligated by a cyclic (alkyl)(amino)carbene (CAAC). The radicals feature a large spin density on the boron center, which is ascertained by EPR spectroscopy and DFT calculations. Structural and computational analyses revealed that the stability of radical species was assisted by the CAAC ligand and a weak but significant B(III)Br-B(II) interaction, suggesting a cooperative avenue for stabilization of boryl radicals. Two-electron reduction of these new boryl radicals provides C-H insertion products via a borylene intermediate.

Prediction of postoperative reintervention risk for uterine fibroids using clinical-imaging features and T2WI radiomics before high-intensity focused ultrasound ablation.

OBJECTIVE: To predict the risk of postoperative reintervention for uterine fibroids using clinical-imaging features and T2WI radiomics before high-intensity focused ultrasound (HIFU) ablation. METHODS: Among patients with uterine fibroids treated with HIFU from 2019 to 2021, 180 were selected per the inclusion and exclusion criteria (42 reintervention and 138 non-reintervention). All patients were randomly assigned to either the training (n = 125) or validation (n = 55) cohorts. Multivariate analysis was used to determine independent clinical-imaging features of reintervention risk. The Relief and LASSO algorithm were used to select optimal radiomics features. Random forest was used to construct the clinical-imaging model based on independent clinical-imaging features, the radiomics model based on optimal radiomics features, and the combined model incorporating the above features. An independent test cohort of 45 patients with uterine fibroids tested these models. The integrated discrimination index (IDI) was used to compare the discrimination performance of these models. RESULTS: Age (p < .001), fibroid volume (p = .001) and fibroid enhancement degree (p = .001) were identified as independent clinical-imaging features. The combined model had AUCs of 0.821 (95% CI: 0.712-0.931) and 0.818 (95% CI: 0.694-0.943) in the validation and independent test cohorts, respectively. The predictive performance of the combined model was 27.8% (independent test cohort, p < .001) and 29.5% (independent test cohort, p = .001) better than the clinical-imaging and radiomics models, respectively. CONCLUSION: The combined model can effectively predict the risk of postoperative reintervention for uterine fibroids before HIFU ablation. It is expected to help clinicians to develop accurate, personalized treatment and management plans. Future studies will need to be prospectively validated.

Association between albumin-to-globulin ratio and the risk of overall survival in advanced non-small cell lung cancer patients with anlotinib treatment: a retrospective cohort study.

OBJECTIVE: Researches about the association between serum albumin-to-globulin ratio (AGR) and the prognosis of lung cancer are limited. We aimed to investigate the relationship between AGR and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) treated with anlotinib. METHODS: A retrospective cohort study was conducted on 196 advanced NSCLC patients with anlotinib treatment between June 1, 2018 and June 1, 2021. The exposure was AGR, calculated by baseline serum albumin / (serum total protein - serum albumin). The outcome was OS, defined as the period from the date of initial treatment with anlotinib to death or the last follow-up. The univariate and multivariate linear regression models and generalized additive models (GAM) were used to analyze the relationship between AGR and OS. The Kaplan-Meier method was used to analyze the OS. RESULTS: After adjusting for potential confounders, a non-linear relationship was observed between AGR and OS, which had an inflection point of 1.24. The hazard ratio and the confidence intervals on the left and the right sides of the inflection point were 13.05 (0.52 to 327.64) and 0.20 (0.07 to 0.57), respectively. It suggested that AGR was positively associated with OS when AGR was larger than 1.24, for every 1 unit increase in AGR, the risk of death lowered approximately by 80%. CONCLUSIONS: The relationship between AGR and the OS for advanced NSCLC patients with anlotinib is non-linear. AGR level is an independent protective factor for OS in advanced NSCLC patients who received anlotinib therapy.

Incorporating Domain Knowledge and Structure-Based Descriptors for Machine Learning: A Case Study of Pd-Catalyzed Sonogashira Reactions.

Machine learning has revolutionized information processing for large datasets across various fields. However, its limited interpretability poses a significant challenge when applied to chemistry. In this study, we developed a set of simple molecular representations to capture the structural information of ligands in palladium-catalyzed Sonogashira coupling reactions of aryl bromides. Drawing inspiration from human understanding of catalytic cycles, we used a graph neural network to extract structural details of the phosphine ligand, a major contributor to the overall activation energy. We combined these simple molecular representations with an electronic descriptor of aryl bromide as inputs for a fully connected neural network unit. The results allowed us to predict rate constants and gain mechanistic insights into the rate-limiting oxidative addition process using a relatively small dataset. This study highlights the importance of incorporating domain knowledge in machine learning and presents an alternative approach to data analysis.

BN-Butafulvenes and Their Application in the Synthesis of Highly Substituted BN-9,1-Naphthalenes.

BN-butafulvenes, mono-BN isosteres of butafulvene and highly strained isomers of azaborines and B-amino boroles, have been synthesized via hydrolysis of the urana-borabicyclic complexes obtained from the reactions of bis(alkynyl)boranes with an uranacyclopropene complex. Their 4-dimethylaminopyridine (DMAP) adducts can further isomerize to 1,2,4,6-multisubstituted BN-9,1-naphthalenes. Both NMR reaction monitoring and theoretical calculations point to a reaction mechanism involving dearomative insertion of DMAP followed by two consecutive 1,2-hydrogen shifts. The photophysical studies of the highly substituted BN-9,1-naphthalenes reveal a notable redshift in both the UV/Vis absorption and emission spectra. The (TD)-DFT calculations corroborate the experimental data, suggesting that the strong π-donating amino substitution at the 1- and/or 6-positions destabilizes the HOMO, and thus leading to a notable decrease of the HOMO-LUMO gap.

Rhodium(III)-Catalyzed C-H/O2 Dual Activation and Macrocyclization: Synthesis and Evaluation of Pyrido[2,1-a]isoindole Grafted Macrocyclic Inhibitors for Influenza H1N1.

The development of environment-friendly, step economic couplings to generate structurally diverse macrocyclic compounds is highly desirable but poses a marked challenge. Inspired by the C-H oxidation mechanism of cytochromes P450, an unprecedented and practical RhIII -catalyzed acylmethylation macrocyclization via C-H/O2 dual activation has been developed by us. The process of macrocyclization is facilitated by a synergic coordination from pyridine and ester group. Interestingly, the reaction mode derives from a three-component coupling which differs from established olefination and alkylation paths. Density functional theory (DFT) calculations and control experiments revealed the mechanism of this unique C-H/O2 dual activation. The newly achieved acylmethylation macrocyclic products and their derivatives showed a potent anti-H1N1 bioactivity, which may provide an opportunity for the discovery of novel anti-H1N1 macrocyclic leading compounds.

Isolable Tetragold(0) Clusters with Polarity-Tunable exo-Au-Au Bond via Intramolecular σ-Aromatization.

Intramolecular π-aromatization is a trait of many organic compounds that enhances the stability of their structures and polarizes related C-C π bonds. In contrast, rare study is focused on this phenomenon in metal clusters. Many existing homometallic clusters exhibit aromaticity, often characterized by nonpolar metal-metal bonds and a high degree of symmetry. However, synthesizing low-symmetric homometallic clusters with high-polar metal-metal bonds is challenging due to their limited thermodynamic stability. Herein, we report a facile strategy for the synthesis of [Au(µ2 -ER2 )]3 -AuPMe3 (E=Ge, Sn; R2 =1,1,4,4-tetrakis(trimethylsilyl)butane-1,4-diyl) clusters and reveal a novel stabilization mode, intramolecular σ-aromatization. Our electronic structure analyses show that these low-symmetric clusters possess a ten-electron σ-aromatic system, which is achieved via intramolecular σ-aromatization. Moreover, the strength of σ-aromaticity gives rise to a polarity-tunable exo-Au-Au bond.

[2+2+1+1] Cycloaddition for de novo Synthesis of Densely Functionalized Phenols.

A unique benzannulation strategy for regioselective de novo synthesis of densely functionalized phenols is described. Through metal-mediated formal [2+2+1+1] cycloaddition of two different alkynes and two molecules of CO, a series of densely functionalized phenols were obtained. The benzannulation strategy allows efficient regioselective installation up to five different substituents on a phenol ring. The resulting phenols have a substitution pattern different from those obtained from Dötz and Danheiser benzannulations.