Enantioselective Synthesis of Chiral Amides by a Phosphoric Acid Catalyzed Asymmetric Wolff Rearrangement.

The enantioselective addition of potent nucleophiles to ketenes poses challenges due to competing background reactions and poor stereocontrol. Herein, we present a method for enantioselective phosphoric acid catalyzed amination of ketenes generated from α-aryl-α-diazoketones. Upon exposure to visible light, the diazoketones undergo Wolff rearrangement to generate ketenes. The phosphoric acid not only accelerates ketene capture by amines to form a single configuration of aminoenol intermediates but also promotes an enantioselective proton-transfer reaction of the intermediates to yield the products. Mechanistic studies elucidated the reaction pathway and explained how the catalyst expedited the transformation and controlled the enantioselectivity.

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-pKa 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-pKa 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.

Synthesis of methylene cyclopropane-fused chromenes and dihydroquinolines by sequential [4 + 2]- and [1 + 2]-annulation.

A base promoted sequential [4 + 2]- and [1 + 2]-annulation of 2-hydroxychalcones or 2-tosylaminochalcones with prop-2-ynylsulfonium salts has been developed to give the corresponding methylene cyclopropane fused dihydroquinolines or chromenes in moderate to good yields. This transformation has advantage of wide substrate scope and functional group tolerance as well as excellent regioselectivity. Prop-2-ynylsulfonium salts act as both C2 and C1 synthons in the tandem processes.

Enantioselective synthesis of chiral amides by carbene insertion into amide N-H bond.

Chiral amides are important structure in many natural products and pharmaceuticals, yet their efficient synthesis from simple amide feedstock remains challenge due to its weak Lewis basicity. Herein, we describe our study of the enantioselective synthesis of chiral amides by N-alkylation of primary amides taking advantage of an achiral rhodium and chiral squaramide co-catalyzed carbene N-H insertion reaction. This method features mild condition, rapid reaction rate (in all cases 1 min) and a wide substrate scope with high yield and excellent enantioselectivity. Further product transformations show the synthetic potential of this reaction. Mechanistic studies reveal that the non-covalent interactions between the catalyst and reaction intermediate play a critical role in enantiocontrol.

Catalytic Asymmetric Construction of a 1,2,4-Benzotriazepine Skeleton via Diastereo- and Enantioselective Decarboxylative [4 + 3] Cyclization.

We have developed a protocol for palladium-catalyzed decarboxylative [4 + 3] cycloaddition reactions between 4-vinyl benzoxazinanones and azomethine imines to generate moderate to good yields of structurally diverse 1,2,4-benzotriazepines bearing two stereogenic centers with good to excellent stereoselectivities. This protocol not only addresses the challenge of asymmetrically constructing compounds with a 1,2,4-benzotriazepine skeleton but also demonstrates the utility of decarboxylative cycloadditions for the synthesis of enantioenriched polycyclic compounds.

Accessing Aliphatic Amines in C-C Cross-Couplings by Visible Light/Nickel Dual Catalysis.

A general aminoalkylation of aryl halides was developed, overcoming intolerance of free amines in nickel-mediated C-C coupling. This transformation features broad functional group tolerance and high efficiency. Taking advantage of the fast desilylation of α-silylamines upon single-electron transfer (SET) facilitated by carbonate, α-amino radicals are generated regioselectively, which then engage in nickel-mediated C-C coupling. The reaction displays high chemoselectivity for C-C over C-N bond formation. Highly functionalized pharmacophores and peptides are also amenable.

Multifunctional Building Blocks Compatible with Photoredox-Mediated Alkylation for DNA-Encoded Library Synthesis.

DNA-encoded library (DEL) technology has emerged as a novel interrogation modality for ligand discovery in the pharmaceutical industry. Given the increasing demand for a higher proportion of C(sp3)-hybridized centers in DEL platforms, a photoredox-mediated cross-coupling and defluorinative alkylation process is introduced using commercially available alkyl bromides and structurally diverse α-silylamines. Notably, no protecting group strategies for amines are necessary for the incorporation of a variety of amino-acid-based organosilanes, providing crucial branching points for further derivatization.

Enhancement of the polymerase chain reaction by tungsten disulfide.

In this paper, we demonstrated that the polymerase chain reaction (PCR) could be dramatically enhanced by tungsten disulfide (WS2). The results showed that the PCR efficiency could be increased with the addition of WS2 and at a lower annealing temperature, which simplified the design and operation of PCR. Moreover, PCR with WS2 showed better specificity and efficiency as compared with graphene oxide (GO) for a human genome DNA sample. The mechanism of enhancement of PCR by WS2 was discussed according to the typical structure and the characteristics of selective adsorption of single-stranded DNA by WS2. The results suggested that WS2 as a PCR enhancer can promote the PCR performance and extend the PCR application in biomedical research, clinical diagnostic, and bioanalysis.

Highly Sensitive Detection of Uracil-DNA Glycosylase Activity Based on Self-Initiating Multiple Rolling Circle Amplification.

Sensitive detection of uracil-DNA glycosylase (UDG) activity is very important in the study of many fundamental biochemical processes and clinical applications. Here, we develop a novel assay for the detection of UDG activity by using the self-initiating multiple rolling circle amplification (SM-RCA) strategy. We first design a trigger probe modified with NH2 at its 3'-terminal and uracil base in the middle of sequence, which is complementary to a cyclized padlock probe. In the presence of UDG, a uracil base can be excised by UDG to generate an apurinic/apyrimidinic (AP) site. The AP site is recognized and cleaved by endonuclease IV (Endo IV), releasing the primer with 3'-OH. The primer can trigger the rolling circle amplification (RCA) reaction, producing a long and repeated DNA strand embedded some uracil bases. These uracil bases can be cleaved by UDG and Endo IV again, and then, more primers are generated to initiate SM-RCA reaction, producing large amounts of DNA product. Afterward, the DNA product is measured by a specific DNA fluorescence dye for quantitative detection of UDG activity. The linear range of the method is 5 × 10-5 to 1.25 × 10-3 U/mL, and the detection limit is 1.7 × 10-5 U/mL. This method not only utilizes the target UDG itself to trigger RCA but also further induces SM-RCA reaction, providing a simple, sensitive, and cost-effective strategy for the detection of glycosylase and clinical diagnosis.

Multifunctional Oligonucleotide-Functionalized Conjugated Oligomer Nanoparticles for Targeted Cancer Cell Imaging and Therapy.

A novel and multifunctional oligonucleotide-functionalized conjugated oligomer nanoparticle (CON) is developed for effective cancer cell imaging and therapy by integration of fluorescence imaging, target recognition, photodynamic therapy (PDT), and chemotherapy. The CON itself possesses the high fluorescence emission efficiency for imaging and can generate reactive oxygen species for PDT. Due to its excellent biocompatibility, easy functional modification, and efficient drug loading and release ability, oligonucleotides enable the CON to be functionalized in many forms. For the target recognition, the CONs are functionalized with oligonucleotides labeled with folate molecules, which can specifically bind the CONs to the tumor cells overexpressing folate receptors. Moreover, the designed oligonucleotide on the CON hybridizes with its complementary sequence to form double-stranded DNA, which enables a sequence-specific loading with doxorubicin for chemotherapy. For different situations, the therapy of chemotherapy and PDT can be used solely or combinatorially. Therefore, this study provides a facile strategy for the multifunctional modification of CONs with oligonucleotides and opens a new avenue for targeted cell imaging and tumor treatment.