Open-shell carbenes, which feature two unpaired electrons on a carbene carbon centre, are highly unstable compounds and are usually observed as excited-state species. Now, two triplet metallocarbenes have been stabilized by transition-metal and silyl substituents; the compounds have been characterized by various techniques including single-crystal X-ray diffraction, spectroscopy and quantum-chemical analyses.

This work reports synthesis of a germylene based donor-acceptor molecule and its thermal excitation to a triplet state by coordination with a Lewis acid. Products have been characterized by single crystal X-ray diffraction, EPR spectroscopy, and SQUID measurement, in conjunction with DFT calculation. The singlet-triplet energy gap of the donor-acceptor molecule is dramatically reduced from -18.8 to -7.2 kcal/mol by the coordination with B(C6F5)3 (BCF), which enables an intramolecular single electron transfer from one germylene moiety to another upon heating, forming an intramolecular radical ion pair with diradical character. The work provides an approach to the formation of thermally populated open-shell species of heavier main group elements. A germylene-based D-A molecule was synthesized by radical head-to-tail dimerization under mild conditions. The coordination of Lewis acids led to intramolecular single electron transfer upon heating to form a thermally populated triplet diradical. This work provided an approach to the formation of thermally populated open-shell species in main group chemistry. image

Medium-sized rings are important structural units in organic molecules of significant interest. However, their efficient synthesis, especially in a highly enantioselective manner, has been a formidable challenge. Herein, we report an enantioselective synthesis of medium-sized aza-rings by a Z-retentive asymmetric allylic substitution-enabled intermolecular cascade cyclization via iridium/cinchona dual catalysis. The reaction was performed under mild conditions and with good functional group tolerance. Various nine- to eleven-membered aza-rings can be afforded in moderate to high yields (up to 98%) and enantioselectivities (up to 93% ee). The utilization of both Z-linear allylic dipole precursor and iridium/cinchona binary catalyst is critical for the desired reactivity.

The uric acid (UA) level in the human body is one of the important clinical indicators associated with gout and various metabolic diseases. Here, we appeal to side chain-appended tetracationic macrocycles that have intrinsic fluorescence emission to bind UA for its colorimetric detection. We show that the introduction of four aminoethoxy side chains to the naphthalene-derived macrocycle leads to a binding constant of 4.45 x 106 M-1, which is the highest among those achieved using reported receptors. This high binding affinity enables the generation of a visual sensing system for detecting UA of hyperuricemia from that of normal by mixing with rhodamine B, which works in solution as well as paper assays. Uric acid can be detected using a bicolor colorimetric system of tetracationic macrocycles and rhodamine B in solution or a paper assay.

In this work, two azulenyl bis(squaraine) dyes were designed and synthesized, whose main structural difference lies in the connection model between two monomeric units. Their self-assembly behaviors were investigated in mixed solvents of different polarities, compound concentrations and temperatures. In particular, for the single-bond-linked squaraine dimer, J-aggregate nanosheets could be formed in a hexane system mixed with small amounts of tetrahydrofuran as a co-solvent. Meanwhile, additional absorption bands were observed in the second near-infrared (NIR-II, 1000-1700 nm) region for vinylene-bridged bis(squaraine) aggregates, elucidating the impact of the spacer unit on interchromophoric interaction modes. Moreover, in comparison with the monomer compound, organic field-effect transistor and morphological characterizations revealed that dimerization has a significant influence on the charge carrier mobility and thermal responsiveness of film aggregates. This study provides a promising chemical modification approach to improve assembly behavior and optoelectronic performance. Near-Infrared single-bond-linked and vinylene-bridged azulenyl bis(squaraine) dyes were synthesized. Their self-assembly behaviors were investigated under different solvent polarities, compound concentrations and temperatures.

Three iron phosphorus clusters with N-heterocyclic carbene ligation have been synthesized from the reactions of low-coordinate iron(0) complexes [(NHC)Fe(eta(2):eta(2)-dvtms)] (NHC=N-heterocyclic carbene, dvtms=divinyltetramethylisiloxane) with white phosphorus and characterized by spectroscopic methods. The iron phosphorus clusters [(IMes)2Fe2(mu- eta(5):eta(5)-cyclo-P-5)] (1), [(IMes)(3)Fe-3(mu-eta(6):eta(6):eta(6)-P-9)] (2) and [(IMes)(2)Fe-2(mu-eta(2):eta(2)-cyclo-P4P(IMes))(mu-eta(3):eta(3)-P-3)] (3) were isolated from the equimolar reaction of [(IMes)Fe(eta(2):eta(2)-dvtms)] (IMes=1,3-dimesitylimidazol-2-ylidene) with P-4 at low temperature (-30 degrees C to room temperature) upon recrystallization. Complexes 1 and 3 can be synthesized in 18% and 32% isolated yields, respectively, from the reactions of [(IMes)Fe(eta(2):eta(2)-dvtms)] with P4 at different reaction temperature (80 degrees C and -30 degrees C to room temperature, respectively). Complex 2 can only be obtained in trace amount from the low-temperature reaction. The three iron phosphorus clusters 1 similar to 3 have been characterized by single-crystal X-ray diffraction studies. Complex 1 shows an anti-sandwich type structure with the Fe center dot center dot center dot Fe distance of 0.2515(1) nm and the mu-eta(5):eta(5)-P-5 ligand in disorder. Analogous complex [(IDep)(2)Fe-2(mu-eta(5):eta(5)-P-5)] [4, IDep=1,3-di(2',6'-diethylphenyl)imidazol-2-ylidene] can be synthesized from the reaction of [(IDep)Fe(eta(2):eta(2)-dvtms)] with P-4. Its molecular structure established by X-ray diffraction study does not exhibit disorder in the mu-eta(5):eta(5)-P-5 ligand and the two iron centers show nearly identical coordination environment. The zero-field Fe-57 Mossbauer spectrum of 1 measured at 80 K shows a quadrupole doublet with the isomer shift delta=0.32 mm center dot s(-1) and quadrupole splitting |Delta E-Q|=0.61 mm center dot s(-1). Magnetic susceptibility measurements point out a doublet state (S=1/2) for 1. The characterization data suggests that 1 and 4 can be described as the III-type mixed valence complex based on the Robin-Day Models. Complex 2 represents the first example of metal complexes featuring a P-9 ligand. The polyphosphide ligand contains two paralleling P-3 triangles and three boat-shaped P-6 faces. Each P-6 face is coordinating with a Fe(IMes) fragment in eta(6)-fashion. The three Fe atoms form a Fe-3 triangle with the Fe center dot center dot center dot Fe distances close to each other [0.2626(1) nm in average]. Complex 3 features a mu-eta(2):eta(2)-cyclo-P4P(IMes) ligand and a mu-eta(3):eta(3)-P-3 ligand. The bond distances and angles of the two polyphosphide ligands in 3 are close to those of the counterparts in [(IMes)(2)Co-2(mu-eta(2):eta(2)-cyclo-P4P(iPr(2)Im))(mu-eta(3):eta(3)-P-3)]. The H-1 NMR and P-31 NMR spectra of 3 are indicative of its diamagnetic nature. The Fe-57 Mossbauer quadrupole doublet of 3 measured at 80 K has a isomer shift delta=0.26 mm center dot s(-1) and quadrupole splitting |Delta E-Q|=0.91 mm center dot s(-1).

A recyclable polymeric phosphorus ligand, PolyBIDIME, and its palladium complexes was designed and introduced to address the high loadings of palladium catalysts in complex Suzuki-Miyaura coupling reaction. PolyBIDIME, a supported BI-DIME ligand on a polyamide chain, was designed as a soluble ligand in organic solvent applicable to homogeneous catalysis, but insoluble or less soluble in certain solvents for easy recovery from reaction conditions. This polymeric phosphorus ligand was designed in order to provide a practical and efficient example of homogeneous catalysis and heterogeneous recycling in order to achieve a higher turnover number. PolyBIDIME was synthesized by polymerization of 6-vinyl BIDIME with N-isopropylacrylamide in the presence of 2,2'-azobis(isobutyronitrile) (AIBN). The structure of the polymeric ligand was well characterized by 1 H, 31 P NMR, and gel permeation chromatography (GPC). The palladium complex of PolyBIDIME was prepared and characterized as Pd(PolyBIDIME)2Cl2, which was applied as the catalyst to the key Suzuki-Miyaura cross-coupling reaction of herbicide rinskor. Under optimized conditions, the Pd-PolyBIDIME catalyst provided high yields of the coupling product, excellent recyclability (10 times), and high total turnover numbers (up to 1000), showing great potential for industrial applications. The Pd-PolyBIDIME was also applicable as the catalyst to a range of Suzuki-Miyaura couplings, showing great compatibility to steric hindrance and functional groups. Further synthetic applications were demonstrated in the synthesis of herbicides boscalid and fluxapyroxad as Suzuki-Miyaura cross-coupling catalyst, as well as in the synthesis of naproxen as a carbonylation catalyst, showcasing the high potential of Pd-PolyBIDIME as a cross-coupling catalyst in industrial settings. Detailed NMR studies and catalyst weight analysis were conducted to rationalize the catalyst recycling process. Results showed that slight physical loss of the palladium catalyst was confirmed during each run, while partial oxidation of the phosphorus ligand increased gradually after each run, which could be the main reason for the gradual decrease in catalytic efficiency during catalyst recycling.

Organic field-effect transistors (OFETs) is the basic unit of complementary logic circuit, however, the development of n-type OFETs lags behind of p-type ones due to the barrier of electron injection and the interference from oxygen and water, which hinders the development of complementary logic circuit. Therefore, the design and synthesis of high-performance n-type organic semiconductors and the improvement of device performance and stability have important scientific significance. In this work, a novel naphthalene diimide (NDI)-vinylogous tetrathiafulvalene derivative (BDTNDIDTYA)(2) was designed and synthesized via a pi-expanded strategy by fusing the benzene-1,2-dithiol (BDT) and 2-(1,3-dithiol-2-ylidene) acetonitrile (DTYA) moieties onto the NDI core. The chemical structure of the compound was characterized by H-1 NMR, C-13 NMR, Fourier transform infrared spectroscopy (FT-IR) and high-resolution mass spectrometry (HRMS). The thermal, optical and electrochemical properties of (BDTNDI-DTYA)(2) were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), ultraviolet-visible (UV-Vis) absorption spectra and cyclic voltammetry (CV). The energy levels of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of (BDTNDI-DTYA)(2) calculated from CV were -5.66 and -4.01 eV, respectively. The edge absorption of (BDTNDI-DTYA)(2) in thin film showed obvious red-shift (68 nm) relative to that in CHCl3 solution, indicating strong intermolecular interactions in solid state. The bottom-gate and top-contact (BGTC) OFETs based on (BDTNDI-DTYA)2 fabricated by spin-coating method, showed n-type electron transporting characteristics. The average electron mobility of the untreated devices was 0.04 cm(2)center dot V-1 center dot s(-1) when measured in nitrogen atmosphere and was increased of up to 1.00 cm(2) center dot V-1 center dot s(-1) when the thin films of (BDTNDI-DTYA)2 were thermal annealed at 160 degree celsius. On the other hand, azulene was used as an additive to treat the thin films of (BDTNDI-DTYA)2 via sublimation, the average electron mobility of OFETs was increased to 0.98 cm(2)center dot V-1 center dot s(-1). The effect of thermal annealing treatment and azulene-treatment on the performance of (BDTNDIDTYA)(2)-based OFETs were investigated by UV-Vis absorption spectra, atomic force microscopy (AFM) and X-ray diffraction (XRD). For UV-Vis absorption spectra of thin films of (BDTNDI-DTYA)(2), after thermal annealing at 160 degree celsius and azulene-treatment, the absorption peak in long-wavelength was enhanced and widened relative to that of the untreated thin films with obvious shoulder peaks and red-shifts (35 and 39 nm, respectively). The AFM and XRD results indicated that the improvement of device performance originated from the improved (BDTNDI-DTYA)(2) thin film crystallinity and morphology. In this work, a pi-expanded NDI-vinylogous tetrathiafulvalene derivative as n-type organic semiconductor was designed and synthesized, and azulene was used for the first time to effectively regulated the structure and morphology of the active layer of OFETs, which both provide new insights for development of novel organic semiconductors and their high performance OFET devices.

The asymmetric functionalization of unstrained C(sp(3))-C(sp(3)) bonds could be a powerful strategy to stereoselectively reconstruct the backbone of an organic compound, but such reactions are rare. Although allylic substitutions have been used frequently to construct C-C bonds by the cleavage of more reactive C-X bonds (X is usually an O atom of an ester) by transition metals, the reverse process that involves the replacement of a C-C bond with a C-heteroatom bond is rare and generally considered thermodynamically unfavorable. We show that an unstrained, inert allylic C-C sigma bond can be converted to a C-N bond stereoselectively via a designed solubility-control strategy, which makes the thermodynamically unfavorable process possible. The C-C bond amination occurs with a range of amine nucleophiles and cleaves multiple classes of alkyl C-C bonds in good yields with high enantioselectivity. A novel resolution strategy is also reported that transforms racemic allylic amines to the corresponding optically active allylic amine by the sequential conversion of a C-N bond to a C-C bond and back to a C-N bond. Mechanistic studies show that formation of the C-N bond is the rate-limiting step and is driven by the low solubility of the salt formed from the cleaved alkyl group in a nonpolar solvent.

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells. CDK12/13 degradation rapidly triggers gene-length-dependent transcriptional elongation defects, leading to DNA damage and cell-cycle arrest. In vivo, , YJ9069 significantly suppresses prostate tumor growth. Modifications of YJ9069 yielded an orally bioavailable CDK12/13 degrader, YJ1206, which exhibits comparable efficacy with significantly less toxicity. To identify pathways synthetically lethal upon CDK12/13 degradation, phosphorylation pathway arrays were performed using cell lines treated with YJ1206. Interestingly, degradation or genetic knockdown of CDK12/13 led to activation of the AKT pathway. Targeting CDK12/13 for degradation, in conjunction with inhibiting the AKT pathway, resulted in a synthetic lethal effect in preclinical prostate cancer models.

Cobalamin (Cbl)-dependent radical S-adenosyl-L-methionine (SAM) proteins constitute the largest collection of the radical SAM superfamily that has hundreds of thousands of individual members. Many of these proteins are involved in the biosynthesis of pharmaceutically important natural products to catalyze chemically demanding reactions. In the biosynthetic pathway of chuangxinmycin (CXM), a unique indole alkaloid antibiotic with potent anti-infective activity, functionalization of the characteristic thiopyrano[4,3,2-cd]indole scaffold by regio- and stereoselective C3-methylation is believed to rely on a Cbl-dependent radical process, which, however, remained to be reconstituted biochemically. We here report the dissection of this enzymatic process, which requires the incorporation of Cxm8, a Cbl-dependent radical SAM protein, with Cxm9, a DUF5825 family protein that shares no homology to any proteins of known functions. Cxm8 and Cxm9 function together by forming an unexpected heterodimeric complex that selectively catalyzes C3-methylation of the tricyclic indole-S-hetero ring system in a successive manner, achieving CXM and a recently identified, C3-dimethylated congener. Detailed biochemical characterization, isotope labeling, structural simulation and bioinformatics analysis rationalized the catalysis of the Cxm8/Cxm9 complex and particularly the necessity of the DUF5825 protein for C3-methylase activity. This is the first example that a Cbl-dependent protein acts with a partner to exhibit radical SAM activity.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. The compound effectively degraded CDK12 and CDK13 with DC50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that ZLC491 selectively induced CDK12/13 degradation in a cereblon- and proteasome-dependent manner. Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, ZLC491 achieved an oral bioavailability of 46.8% in rats and demonstrated potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.

Biallelic loss of cyclin-dependent kinase 12 ( CDK12 ) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 / Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53- / Trp53- null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12- mutant mCRPC.

An efficient iron catalyzed asymmetric vinylogous Mukaiyama-Michael reaction of silyloxyfuran and alpha,beta-unsaturated acyl imidazoles was developed to afford chiral gamma-butenolide derivatives (25 examples) in moderate to good yields (up to 98%) and with excellent stereoselectivities (up to >20 : 1 dr and 99% ee). The reaction was easily scaled up with high efficiency and excellent selectivities retained.