Site-Selective C−H Alkenylation of N-Heteroarenes by Ligand-Directed Co/Al and Co/Mg Cooperative Catalysis**

We report herein the design and development of Co/Al and Co/Mg bimetallic catalysts, supported by a phosphine/secondary phosphine oxide (PSPO) bifunctional ligand, for the site-selective C−H alkenylation of nitrogen-containing heteroarenes with alkynes. These catalysts enable the alkenylation of pyridine, pyridone, and imidazo[1,2-a]pyridine derivatives at the C−H site proximal to the Lewis basic nitrogen or oxygen atom, which represents a selectivity profile distinct from that of the previously developed cobalt-diphosphine/aluminum catalyst. The alkenylated products were obtained in moderate to good yields using various heterocycles and differently substituted internal alkynes. Kinetic isotope effect experiments suggest the irreversibility of the C−H activation step, the relevance of which to the rate-limiting step depends on the reaction conditions. Density functional theory calculations indicate that ligand-to-ligand hydrogen transfer is the common mechanism of C−H activation.     

Precise Epitope Organization with Self-adjuvant Framework Nucleic Acid for Efficient COVID-19 Peptide Vaccine Construction

Peptide vaccines have advantages in easy fabrication and high safety, but their effectiveness is hampered by the poor immunogenicity of the epitopes themselves. Herein, we constructed a series of framework nucleic acids (FNAs) with regulated rigidity and size to precisely organize epitopes in order to reveal the influence of epitope spacing and carrier rigidity on the efficiency of peptide vaccines. We found that assembling epitopes on rigid tetrahedral FNAs (tFNAs) with the appropriate size could efficiently enhance their immunogenicity. Further, by integrating epitopes from SARS-CoV-2 on preferred tFNAs, we constructed a COVID-19 peptide vaccine which could induce high titers of IgG against the receptor binding domain (RBD) of SARS-CoV-2 spike protein and increase the ratio of memory B and T cells in mice. Considering the good biocompatibility of tFNAs, our research provides a new idea for developing efficient peptide vaccines against viruses and possibly other diseases.     

A Spiro Phosphamide Catalyzed Enantioselective Proton Transfer of Ylides in a Free Carbene Insertion into N−H Bonds

Free carbene readily causes multiple side reactions due to its high energy, thus its asymmetric transformation is very difficult. We present here our findings of high-pK_a Brønsted acid catalysts that enable free carbene insertion into N−H bonds of amines to prepare chiral α-amino acid derivatives with high enantioselectivity. Under irradiation with visible light, diazo compounds produce high-energy free carbenes that are captured by amines to form free ylide intermediates, and then the newly designed high-pK_a Brønsted acids, chiral spiro phosphamides, promote the proton transfer of ylides to afford the products. Computational and kinetic studies uncover the principle for the rational design of proton-transfer catalysts and explain how the catalysts accelerate this transformation and provide stereocontrol.     

Biomimetic Design of a Robustly Stabilized Folded State Enabling Seed-Initiated Supramolecular Polymerization under Microfluidic Mixing**

We have investigated the folding and assembly behavior of a cystine-based dimeric diamide bearing pyrene units and solubilizing alkyl chains. In low-polarity solvents, it forms a 14-membered ring through double intramolecular hydrogen bonds between two diamide units. The spectroscopic studies revealed that the folded state is thermodynamically unstable and eventually transforms into more energetically stable helical supramolecular polymers that show an enhanced chiral excitonic coupling between the transition dipoles of the pyrene units. Importantly, compared to an alanine-based monomeric diamide, the dimeric diamide exhibits a superior kinetic stability in the metastable folded state, as well as an increased thermodynamic stability in the aggregated state. Accordingly, the initiation of supramolecular polymerization can be regulated using a seeding method even under microfluidic mixing conditions. Furthermore, taking advantage of a self-sorting behavior observed in a mixture of l -cysteine- and d -cysteine-based dimeric diamides, a two-step supramolecular polymerization was achieved by stepwise addition of the corresponding seeds.     

Engineered Biocatalytic Synthesis of β-N-Substituted-α-Amino Acids

Non-canonical amino acids (ncAAs) are useful synthons for the development of new medicines, materials, and probes for bioactivity. Recently, enzyme engineering has been leveraged to produce a suite of highly active enzymes for the synthesis of β-substituted amino acids. However, there are few examples of biocatalytic N-substitution reactions to make α,β-diamino acids. In this study, we used directed evolution to engineer the β-subunit of tryptophan synthase, TrpB, for improved activity with diverse amine nucleophiles. Mechanistic analysis shows that high yields are hindered by product re-entry into the catalytic cycle and subsequent decomposition. Additional equivalents of l -serine can inhibit product reentry through kinetic competition, facilitating preparative scale synthesis. We show β-substitution with a dozen aryl amine nucleophiles, including demonstration on a gram scale. These transformations yield an underexplored class of amino acids that can serve as unique building blocks for chemical biology and medicinal chemistry.     

Base-Promoted Glycosylation Allows Protecting Group-Free and Stereoselective O-Glycosylation of Carboxylic Acids**

Here we report a simple and general method to achieve fully unprotected, stereoselective glycosylation of carboxylic acids, employing bench-stable allyl glycosyl sulfones as donors. Running the glycosylation reaction under basic conditions was crucial for the efficiencies and selectivities. Both the donor activation stage and the glycosidic bond forming stage of the process are compatible with free hydroxyl groups, thereby allowing for the use of fully unprotected glycosyl donors. This transformation is stereoconvergent, occurs under mild and metal-free conditions at ambient temperature with visible light (455 nm) irradiation, and displays remarkable scope with respect to both reaction partners. Many natural products and commercial drugs, including an acid derived from the complex anticancer agent taxol, were efficiently glycosylated. Experimental studies provide insights into the origin of the stereochemical outcome.     

A Dynamic Kinetic Resolution Approach to Axially Chiral Diaryl Ethers by Catalytic Atroposelective Transfer Hydrogenation

Diaryl ethers are widespread in biologically active compounds, ligands and catalysts. It is known that the diaryl ether skeleton may exhibit atropisomerism when both aryl rings are unsymmetrically substituted with bulky groups. Despite recent advances, only very few catalytic asymmetric methods have been developed to construct such axially chiral compounds. We describe herein a dynamic kinetic resolution approach to axially chiral diaryl ethers via a Brønsted acid catalyzed atroposelective transfer hydrogenation (ATH) reaction of dicarbaldehydes with anilines. The desired diaryl ethers could be obtained in moderate to good chemical yields (up to 79 %) and high enantioselectivities (up to 95 % ee) under standard reaction conditions. Such structural motifs are interesting precursors for further transformations and may have potential applications in the synthesis of chiral ligands or catalysts.     

Visible Light Induced Copper-Catalyzed Enantioselective Deaminative Arylation of Amino Acid Derivatives Assisted by Phenol

The exploration of value-added conversions of naturally abundant amino acids has received considerable attention from the synthetic community. Compared with the well-established asymmetric decarboxylative transformation, the asymmetric deaminative transformation of amino acids still remains a formidable challenge, mainly due to the lack of effective strategies for the C−N bond activation and the potential incompatibility with chiral catalysts. Here, we disclose a photoinduced Cu-catalyzed asymmetric deaminative coupling reaction of amino acids with arylboronic acids. This new protocol provides a series of significant chiral phenylacetamides in generally good yields and excellent stereoselectivity under mild and green conditions (42–85 % yields, up to 97 % ee). Experimental investigations and theoretical calculations were performed to reveal the crucial role of additional phenols in improving catalytic efficiency and enantiocontrol.     

游离芳香氨基酸和半胱氨酸对光诱导高铁肌红蛋白还原的影响

肌红蛋白(Myoglobin,Mb)中血红素辅基不仅具有储氧功能,也能吸收特定波长的光而影响蛋白功能表达。实验发现,部分游离的氨基酸对光诱导高铁肌红蛋白(metM b,Fe(III)-Mb)的还原过程及还原程度都有重要作用,因此,本文采用紫外-可见吸收光谱、圆二色谱、三维荧光光谱法,在光照体系中加入拥挤试剂来模拟细胞内拥挤环境,研究芳香氨基酸[色氨酸(Trp)、苯丙氨酸(Phe)、酪氨酸(Tyr)、半胱氨酸(Cys)]对metM b还原的影响。结果表明,含-OH或-SH的氨基酸(Tyr、Cys)能使metM b发生较好的光还原,无-OH或-SH基团的氨基酸(Trp、Phe)对metM b的光还原作用较弱,氨基酸促进metM b光还原的整个过程可能是分子间电子转移的过程。metM b在拥挤环境聚蔗糖70(Ficoll 70)中的光诱导还原程度比在稀溶液中高,拥挤试剂Ficoll70对蛋白的二级结构起保护作用,能够稳定血红素微环境。     

The Mechanism of Thionyl Chloride Reaction with Dialkyl Alkylphosphonothionate Using 31 P NMR

Based on 31 P NMR studies of thionyl chloride reaction with dialkyl alkylphosphonothionates, a method for preparation of alkylphosphonic dichloride has been investigated. A mechanism via intermediacy of ester chloride is suggested.