From Quaternary Carbon to Tertiary C(sp3)-Si and C(sp3)-Ge Bonds: Decyanative Coupling of Malononitriles with Chlorosilanes and Chlorogermanes Enabled by Ni/Ti Dual Catalysis.

Transition-metal-catalyzed C-Si/Ge cross-coupling offers promising avenues for the synthesis of organosilanes/organogermanes, yet it is fraught with long-standing challenges. A Ni/Ti-catalyzed strategy is reported here, allowing the use of disubstituted malononitriles as tertiary C(sp3) coupling partners to couple with chlorosilanes and chlorogermanes, respectively. This method enables the catalytic cleavage of the C(sp3)-CN bond of the quaternary carbon followed by the formation of C(sp3)-Si/C(sp3)-Ge bonds from ubiquitously available starting materials. The efficiency and generality are showcased by a broad scope for both of the coupling partners, therefore holding the potential to synthesize structurally diverse quaternary organosilanes and organogermanes that were difficult to access previously.

Reductive Aza-Pauson-Khand Reaction of Nitriles.

γ-Lactams are valuable heterocycles in synthetic chemistry and drug development. Here, we report a reductive aza-Pauson-Khand reaction (aza-PKR) of an alkyne, a nitrile, and Co2(CO)8. A wide array of bicyclic α,ß-unsaturated γ-lactams containing two adjacent stereocenters, including an all-carbon quaternary center, from alkyne-tethered malononitriles are efficiently accessed in high diastereoselectivity. Preliminary mechanistic investigations by experiments and DFT calculations reveal that the reaction undergoes an aza-PKR process followed by a in situ reduction. The reducing reagent generated in situ from water also provides a practical tool for deuterium incorporation into the γ-position of lactams using D2O as the deuterium source. This study represents a new mode for [2 + 2 + 1] cycloaddition that enables the direct use of nitrile in aza-heterocycle synthesis.

Source-independent quantum random number generator against tailored detector blinding attacks.

Randomness, mainly in the form of random numbers, is the fundamental prerequisite for the security of many cryptographic tasks. Quantum randomness can be extracted even if adversaries are fully aware of the protocol and even control the randomness source. However, an adversary can further manipulate the randomness via tailored detector blinding attacks, which are hacking attacks suffered by protocols with trusted detectors. Here, by treating no-click events as valid events, we propose a quantum random number generation protocol that can simultaneously address source vulnerability and ferocious tailored detector blinding attacks. The method can be extended to high-dimensional random number generation. We experimentally demonstrate the ability of our protocol to generate random numbers for two-dimensional measurement with a generation speed of 0.1 bit per pulse.

All-photonic quantum repeater for multipartite entanglement generation.

Quantum network applications such as distributed quantum computing and quantum secret sharing represent a promising future network equipped with quantum resources. Entanglement generation and distribution over long distances are critical and unavoidable when utilizing quantum technology in a fully connected network. The distribution of bipartite entanglement over long distances has seen some progress, while the distribution of multipartite entanglement over long distances remains unsolved. Here we report a two-dimensional quantum repeater protocol for the generation of multipartite entanglement over long distances with an all-photonic framework to fill this gap. The entanglement generation yield remains proportional to the transmission efficiency regardless of the number of network users and shows long transmission distance under various numbers of network users. With the improved efficiency and flexibility of extending the number of users, we anticipate that our protocol can work as a significant building block for quantum networks in the future.

Enantioselective Nickel-Catalyzed Reductive Aryl/Alkenyl-Cyano Cyclization Coupling to All-Carbon Quaternary Stereocenters.

An enantioselective nickel-catalyzed intramolecular reductive cross-coupling of C(sp2) electrophiles and cyano groups is reported. Enantioenriched CN-containing all-carbon quaternary stereocenters are assembled by desymmetrizing cyclization of aryl/alkenyl halide-tethered malononitriles. The use of an organic reductant, (EtO)2MeSiH, is crucial to the enantioselectivity and reactivity. Applications of the method are demonstrated through the synthesis of bioactive molecules and their cyanated analogues and the total synthesis of the natural product diomuscinone. This study exhibits the potential of desymmetrizing reductive coupling strategies to access structurally rigid and synthetically versatile molecules from readily available starting materials.

Automated machine learning for secure key rate in discrete-modulated continuous-variable quantum key distribution.

Continuous-variable quantum key distribution (CV QKD) with discrete modulation has attracted increasing attention due to its experimental simplicity, lower-cost implementation and compatibility with classical optical communication. Correspondingly, some novel numerical methods have been proposed to analyze the security of these protocols against collective attacks, which promotes key rates over one hundred kilometers of fiber distance. However, numerical methods are limited by their calculation time and resource consumption, for which they cannot play more roles on mobile platforms in quantum networks. To improve this issue, a neural network model predicting key rates in nearly real time has been proposed previously. Here, we go further and show a neural network model combined with Bayesian optimization. This model automatically designs the best architecture of neural network computing key rates in real time. We demonstrate our model with two variants of CV QKD protocols with quaternary modulation. The results show high reliability with secure probability as high as 99.15% - 99.59%, considerable tightness and high efficiency with speedup of approximately 107 in both cases. This inspiring model enables the real-time computation of unstructured quantum key distribution protocols' key rate more automatically and efficiently, which has met the growing needs of implementing QKD protocols on moving platforms.

Simple security proof of coherent-one-way quantum key distribution.

Coherent-one-way quantum key distribution (COW-QKD), which requires a simple experimental setup and has the ability to withstand photon-number-splitting attacks, has been not only experimentally implemented but also commercially applied. However, recent studies have shown that the current COW-QKD system is insecure and can only distribute secret keys safely within 20 km of the optical fiber length. In this study, we propose a practical implementation of COW-QKD by adding a two-pulse vacuum state as a new decoy sequence. This proposal maintains the original experimental setup as well as the simplicity of its implementation. Utilizing detailed observations on the monitoring line to provide an analytical upper bound on the phase error rate, we provide a high-performance COW-QKD asymptotically secure against coherent attacks. This ensures the availability of COW-QKD within 100 km and establishes theoretical foundations for further applications.

DFT Study of Mechanism and Stereochemistry of Nickel-Catalyzed trans-Arylative Desymmetrizing Cyclization of Alkyne-Tethered Malononitriles.

Present here is a density functional theory (DFT) study of the mechanism and origin of enantioselectivity of Ni-catalyzed desymmetric cyclization of alkyne-tethered malononitriles and aryl boronic acids. The reaction starts from transmetalation and arylnickel addition, followed by trans to cis isomerization to give cis-alkenyl nickel species. The stereodetermining step is the CN insertion, which prefers a transition state with the bystander CN group staying away from the ligand to reduce steric repulsion, and gives the final (R)-product.

Rapid, Label-Free Prediction of Antibiotic Resistance in Salmonella typhimurium by Surface-Enhanced Raman Spectroscopy.

The rapid identification of bacterial antibiotic susceptibility is pivotal to the rational administration of antibacterial drugs. In this study, cefotaxime (CTX)-derived resistance in Salmonella typhimurium (abbr. CTXr-S. typhimurium) during 3 months of exposure was rapidly recorded using a portable Raman spectrometer. The molecular changes that occurred in the drug-resistant strains were sensitively monitored in whole cells by label-free surface-enhanced Raman scattering (SERS). Various degrees of resistant strains could be accurately discriminated by applying multivariate statistical analyses to bacterial SERS profiles. Minimum inhibitory concentration (MIC) values showed a positive linear correlation with the relative Raman intensities of I990/I1348, and the R2 reached 0.9962. The SERS results were consistent with the data obtained by MIC assays, mutant prevention concentration (MPC) determinations, and Kirby-Bauer antibiotic susceptibility tests (K-B tests). This preliminary proof-of-concept study indicates the high potential of the SERS method to supplement the time-consuming conventional method and help alleviate the challenges of antibiotic resistance in clinical therapy.

Enantioselective Synthesis of α-All-Carbon Quaternary Center-Containing Carbazolones via Amino-palladation/Desymmetrizing Nitrile Addition Cascade.

An enantioselective Pd(II)-catalyzed amino-cyclization and desymmetrizing nitrile addition cascade reaction of alkyne-tethered malononitriles is reported. This reaction forms two rings and one quaternary carbon center in a single step and serves as an efficient strategy for the construction of α-quaternary carbazolones with high enantioselectivities (up to 98:2 er). The utility of this method is demonstrated by product derivatization into a diverse array of heterocycles and a nitrile-containing leucomidine A analog.

Secure quantum secret sharing without signal disturbance monitoring.

Quantum secret sharing (QSS) is an essential primitive for the future quantum internet, which promises secure multiparty communication. However, developing a large-scale QSS network is a huge challenge due to the channel loss and the requirement of multiphoton interference or high-fidelity multipartite entanglement distribution. Here, we propose a three-user QSS protocol without monitoring signal disturbance, which is capable of ensuring the unconditional security. The final key rate of our protocol can be demonstrated to break the Pirandola-Laurenza-Ottaviani-Banchi bound of quantum channel and its simulated transmission distance can approach over 600 km using current techniques. Our results pave the way to realizing high-rate and large-scale QSS networks.

Overcoming the rate-distance limit of device-independent quantum key distribution.

Device-independent quantum key distribution (DIQKD) exploits the violation of a Bell inequality to extract secure keys even if users' devices are untrusted. Currently, all DIQKD protocols suffer from the secret key capacity bound, i.e., the secret key rate scales linearly with the transmittance of two users. Here we propose a heralded DIQKD scheme based on entangled coherent states to improve entangling rates whereby long-distance entanglement is created by single-photon-type interference. The secret key rate of our scheme can significantly outperform the traditional two-photon-type Bell-state measurement scheme and, importantly, surpass the above capacity bound. Our protocol therefore is an important step towards a realization of DIQKD and can be a promising candidate scheme for entanglement swapping in the future quantum internet.

Overcoming the rate-distance limit of device-independent quantum key distribution: erratum.

In this Erratum the funding and references sections of Opt. Lett.46, 1632 (2021)OPLEDP0146-959210.1364/OL.417851 have been updated.

Enantioselective Synthesis of Fused Isocoumarins via Palladium-Catalyzed Annulation of Alkyne-Tethered Malononitriles.

An enantioselective palladium-catalyzed annulation of alkyne-tethered malononitriles for the synthesis of 3,4-ring-fused isocoumarins is described. This cascade strategy involves oxypalladation of ortho-alkynylbenzoates and desymmetrizing addition onto one cyano group of the pendant malononitriles, which enables the concurrent construction of two rings and an all-carbon quaternary stereocenter in a single operation.

Silylation of C-H bonds in aromatic heterocycles by an Earth-abundant metal catalyst.

Heteroaromatic compounds containing carbon-silicon (C-Si) bonds are of great interest in the fields of organic electronics and photonics, drug discovery, nuclear medicine and complex molecule synthesis, because these compounds have very useful physicochemical properties. Many of the methods now used to construct heteroaromatic C-Si bonds involve stoichiometric reactions between heteroaryl organometallic species and silicon electrophiles or direct, transition-metal-catalysed intermolecular carbon-hydrogen (C-H) silylation using rhodium or iridium complexes in the presence of excess hydrogen acceptors. Both approaches are useful, but their limitations include functional group incompatibility, narrow scope of application, high cost and low availability of the catalysts, and unproven scalability. For this reason, a new and general catalytic approach to heteroaromatic C-Si bond construction that avoids such limitations is highly desirable. Here we report an example of cross-dehydrogenative heteroaromatic C-H functionalization catalysed by an Earth-abundant alkali metal species. We found that readily available and inexpensive potassium tert-butoxide catalyses the direct silylation of aromatic heterocycles with hydrosilanes, furnishing heteroarylsilanes in a single step. The silylation proceeds under mild conditions, in the absence of hydrogen acceptors, ligands or additives, and is scalable to greater than 100 grams under optionally solvent-free conditions. Substrate classes that are difficult to activate with precious metal catalysts are silylated in good yield and with excellent regioselectivity. The derived heteroarylsilane products readily engage in versatile transformations enabling new synthetic strategies for heteroaromatic elaboration, and are useful in their own right in pharmaceutical and materials science applications.

Discovery of Novel Diarylamide N-Containing Heterocyclic Derivatives as New Tubulin Polymerization Inhibitors with Anti-Cancer Activity.

Tubulin has been regarded as an attractive and successful molecular target in cancer therapy and drug discovery. Vicinal diaryl is a simple scaffold found in many colchicine site tubulin inhibitors, which is also an important pharmacophoric point of tubulin binding and anti-cancer activity. As the continuation of our research work on colchicine binding site tubulin inhibitors, we designed and synthesized a series of diarylamide N-containing heterocyclic derivatives by the combination of vicinal diaryl core and N-containing heterocyclic skeletons into one hybrid though proper linkers. Among of these compounds, compound 15b containing a 5-methoxyindole group exhibited the most potent inhibitory activity against the tested three human cancer cell lines (MGC-803, PC-3 and EC-109) with IC50 values of 1.56 µM, 3.56 µM and 14.5 µM, respectively. Besides, the SARs of these compounds were preliminarily studied and summarized. The most active compound 15b produced the inhibition of tubulin polymerization in a dose-dependent manner and caused microtubule network disruption in MGC-803 cells. Therefore, compound 15b was identified as a novel tubulin polymerization inhibitor targeting the colchicine binding site. In addition, the results of molecular docking also suggested compound 15b could tightly bind into the colchicine binding site of ß-tubulin.

Drug Discovery Targeting Focal Adhesion Kinase (FAK) as a Promising Cancer Therapy.

FAK is a nonreceptor intracellular tyrosine kinase which plays an important biological function. Many studies have found that FAK is overexpressed in many human cancer cell lines, which promotes tumor cell growth by controlling cell adhesion, migration, proliferation, and survival. Therefore, targeting FAK is considered to be a promising cancer therapy with small molecules. Many FAK inhibitors have been reported as anticancer agents with various mechanisms. Currently, six FAK inhibitors, including GSK-2256098 (Phase I), VS-6063 (Phase II), CEP-37440 (Phase I), VS-6062 (Phase I), VS-4718 (Phase I), and BI-853520 (Phase I) are undergoing clinical trials in different phases. Up to now, there have been many novel FAK inhibitors with anticancer activity reported by different research groups. In addition, FAK degraders have been successfully developed through "proteolysis targeting chimera" (PROTAC) technology, opening up a new way for FAK-targeted therapy. In this paper, the structure and biological function of FAK are reviewed, and we summarize the design, chemical types, and activity of FAK inhibitors according to the development of FAK drugs, which provided the reference for the discovery of new anticancer agents.

Design, Synthesis, and Anticancer Activity Studies of Novel Quinoline-Chalcone Derivatives.

The chalcone and quinoline scaffolds are frequently utilized to design novel anticancer agents. As the continuation of our work on effective anticancer agents, we assumed that linking chalcone fragment to the quinoline scaffold through the principle of molecular hybridization strategy could produce novel compounds with potential anticancer activity. Therefore, quinoline-chalcone derivatives were designed and synthesized, and we explored their antiproliferative activity against MGC-803, HCT-116, and MCF-7 cells. Among these compounds, compound 12e exhibited a most excellent inhibitory potency against MGC-803, HCT-116, and MCF-7 cells with IC50 values of 1.38, 5.34, and 5.21 µM, respectively. The structure-activity relationship of quinoline-chalcone derivatives was preliminarily explored in this report. Further mechanism studies suggested that compound 12e inhibited MGC-803 cells in a dose-dependent manner and the cell colony formation activity of MGC-803 cells, arrested MGC-803 cells at the G2/M phase and significantly upregulated the levels of apoptosis-related proteins (Caspase3/9 and cleaved-PARP) in MGC-803 cells. In addition, compound 12e could significantly induce ROS generation, and was dependent on ROS production to exert inhibitory effects on gastric cancer cells. Taken together, all the results suggested that directly linking chalcone fragment to the quinoline scaffold could produce novel anticancer molecules, and compound 12e might be a valuable lead compound for the development of anticancer agents.

Precatalyst-Enabled Selectivity: Enantioselective NiH-Catalyzed anti-Hydrometalative Cyclization of Alkynones to Endo- and Heterocyclic Allylic Alcohols.

A highly enantioselective NiH-catalyzed hydrocyclization of alkynones with unparalleled anti- and endocyclic selectivities is described. The choice of the precatalysts has significant influence in tuning the regio- and enantioselectivity. Using Ni(OTs)2 /Phox as a precatalyst and (EtO)2 MeSiH as a hydride source, an array of enantioenriched O-, N-, and S-containing heterocyclic tertiary allylic alcohols are obtained in 24-81 % yields with 80:20-99:1 er. Mechanistic investigations and synthetic application are also carried out. This study represents an efficient access to a set of allylic alcohols that are unable to access by the state-of-the-art coupling reactions.

Enantioselective Assembly of Cycloenones with a Nitrile-Containing All-Carbon Quaternary Center from Malononitriles Enabled by Ni Catalysis.

Chiral nitriles are valuable molecules in modern organic synthesis and drug discovery. Selectively differentiating the two nitrile groups of widely available malononitrile derivatives is a straightforward yet underdeveloped route to construct enantioenriched nitriles. Here we report an enantioselective nickel-catalyzed desymmetrization of malononitriles for the generation of nitrile-containing all-carbon quaternary stereocenters. This protocol involves a nickel-catalyzed addition of aryl boronic acids to alkynes, followed by a selective nitrile insertion, providing unprecedented access to enantioenriched 5-7-membered α-cyano-cycloenones with a fully substituted olefin from a broad range of substrates. The synthetic utility of these nitrile products is demonstrated by gram-scale synthesis and conversion to several useful functional groups.