Modular allylation of C(sp3)−H bonds by combining decatungstate photocatalysis and HWE olefination in flow

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, providing rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner-Wadsworth-Emmons reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and medicinally relevant molecules.

Total Synthesis and Antimicrobial Evaluation of Pagoamide A

Natural products are often the starting point for drug development and also the testing ground for synthetic methods. Herein we describe the total synthesis and antimicrobial evaluation of a marine natural product, pagoamide A, which is a macrocyclic depsipeptide with two backbone thiazole units and a dimethylated N-terminus. The two thiazole building blocks were synthesized from commercially available materials in four or fewer steps and employed directly in solid-phase peptide synthesis (SPPS) to afford pagoamide A. The use of SPPS ensured that the synthetic sequence is operationally straightforward and, if needed, permits modular substitution of building blocks to easily access diverse structural analogs. Our antimicrobial assays showed that pagoamide A has moderate activity against Bacillus subtilis.

Radical Trifluoroacetylation of Alkenes Triggered by a Visible-Light-Promoted C−O Bond Fragmentation of Trifluoroacetic Anhydride

Trifluoromethyl ketones are not only found in drug like substances, but are also considered as key synthons for the preparation of various fluorinated heterocyclic molecules. Access to such trifluoromethyl ketone derivatives typically requires the incorporation of the trifluoromethyl group, or a surrogate moiety, at the beginning of a multi-step synthetic sequence. However, direct trifluoroacylation of alkenes could potentially provide a highly efficient and straightforward method for the synthesis of a,b-unsaturated trifluoromethyl ketones. Here we report a mild and operationally simple trifluoroacylation strategy of olefines, that utilizes trifluoroacetic anhydride as a low-cost and readily available reagent. This light-mediated process is fundamentally different from conventional methodologies and occurs through an trifluoroacyl radical mechanism promoted by a photocatalyst. Beyond simple alkenes, this method allows for chemo- and regioselective functionalization of small-molecule drugs and common pharmacophores.

Radical Trifluoroacetylation of Alkenes Triggered by a Visible-Light-Promoted C−O Bond Fragmentation of Trifluoroacetic Anhydride

Trifluoromethyl ketones are not only found in drug like substances, but are also considered as key synthons for the preparation of various fluorinated heterocyclic molecules. Access to such trifluoromethyl ketone derivatives typically requires the incorporation of the trifluoromethyl group, or a surrogate moiety, at the beginning of a multi-step synthetic sequence. However, direct trifluoroacylation of alkenes could potentially provide a highly efficient and straightforward method for the synthesis of a,b-unsaturated trifluoromethyl ketones. Here we report a mild and operationally simple trifluoroacylation strategy of olefines, that utilizes trifluoroacetic anhydride as a low-cost and readily available reagent. This light-mediated process is fundamentally different from conventional methodologies and occurs through an trifluoroacyl radical mechanism promoted by a photocatalyst. Beyond simple alkenes, this method allows for chemo- and regioselective functionalization of small-molecule drugs and common pharmacophores.

A potential clue for the application of prime editing in tomato, a dicot plant

Precision genome editing is highly desired for crop improvement. The recently emerged CRISPR/Cas technology offers great potential applications in precision plant genome engineering. A prime editing (PE) approach combining a reverse transcriptase (RT) with a Cas9 nickase and a priming extended guide RNA has shown a high frequency for precise genome modification in mammalian cells and several plant species. However, the applications of the PE approach in dicot plants are still limited and inefficient. We designed and tested prime editors for precision editing of a synthetic sequence in a transient assay and for desirable alleles of 10 loci in tomato by stable transformation. However, our data obtained by targeted deep sequencing also revealed inefficient PE activity in both the tobacco and tomato systems. Further assessment of the activities of the PE components uncovered potential reasons for the inefficiency of the PE complexes. These data could also help explain the recent successes of some prime editors in plants using improved expression systems. Our work provides an important clue for the application of the PE approach in crop improvement.

One-Pot Synthesis of Novel Multisubstituted 1-Alkoxyindoles

Studies on a one-pot synthesis of novel multisubstituted 1-alkoxyindoles 1 and their mechanistic investigations are presented. The synthesis of 1 was successfully achieved through consecutive four step reactions from substrates 2. The substrates 2, prepared through a two-step synthetic sequence, underwent three consecutive reactions of nitro reduction, intramolecular condensation, and nucleophilic 1,5-addition to provide the intermediates, 1-hydroxyindoles 8, which then were alkylated in situ with alkyl halide to afford the novel target products 1. We optimized the reaction conditions for 1 focusing on the alkylation step, along with the consideration of formation of intermediates 8. The optimized condition was SnCl2·2H2O (3.3 eq) and alcohols (R1OH, 2.0 eq) for 1–2 h at 40 °C and then, base (10 eq) and alkyl halides (R2Y, 2.0 eq) for 1–4 h at 25–50 °C. Notably, all four step reactions were performed in one-pot to give 1 in good to modest yields. Furthermore, the mechanistic aspects were also discussed regarding the reaction pathways and the formation of side products. The significance lies in development of efficient one-pot reactions and in generation of new 1-alkoxyindoles.

Confident sequence learning: A sequence class-label noise filtering technique to improve scene digit recognition

Reading digits from natural images is a challenging computer vision task central to a variety of emerging applications. However, the increased scalability and complexity of datasets or complex applications bring about inevitable label noise. Because the label noise in the scene digit recognition dataset is sequence-like, most existing methods cannot deal with label noise in scene digit recognition. We propose a novel sequence class-label noise filter called Confident Sequence Learning. Confident Sequence Learning consists of two critical parts: the sequence-like confidence segmentation algorithm and the Confident Learning method. The sequence-like confidence segmentation algorithms slice the sequence-like labels and the sequence-like predicted probabilities, reorganize them in the form of the independent stochastic process and the white noise process. The Confident Learning method estimates the joint distribution between observed labels and latent labels using the segmented labels and probabilities. The TRDG dataset and SVHN dataset experiments showed that the confident sequence learning could find label errors with high accuracy and significantly improve the VGG-Attn and the TPS-ResNet-Attn model’s performance in the presence of synthetic sequence class-label noise.

Design, Synthesis, and Biological Evaluation of Light-Activated Antibiotics

<p>The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different ‘caged’ antibiotic classes that can undergo remote activation with UV-light at λ=365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thus suppressing undesired off-site activity. The antimicrobial activity against <i>Bacillus subtilis</i> ATCC 6633, <i>Staphylococcus aureus</i> ATCC 29213, <i>S. aureus</i> ATCC 43300 (MRSA), <i>Escherichia coli</i> ATCC 25922, and <i>Pseudomonas aeruginosa</i> ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.</p>

Design, Synthesis, and Biological Evaluation of Light-Activated Antibiotics

<p>The spatial and temporal control of bioactivity of small molecules by light (photopharmacology) constitutes a promising approach for study of biological processes and ultimately for the treatment of diseases. In this study, we investigated two different ‘caged’ antibiotic classes that can undergo remote activation with UV-light at λ=365 nm, via the conjugation of deactivating and photocleavable units through a short synthetic sequence. The two widely used antibiotics vancomycin and cephalosporin were thus enhanced in their performance by rendering them photoresponsive and thus suppressing undesired off-site activity. The antimicrobial activity against <i>Bacillus subtilis</i> ATCC 6633, <i>Staphylococcus aureus</i> ATCC 29213, <i>S. aureus</i> ATCC 43300 (MRSA), <i>Escherichia coli</i> ATCC 25922, and <i>Pseudomonas aeruginosa</i> ATCC 27853 could be spatiotemporally controlled with light. Both molecular series displayed a good activity window. The vancomycin derivative displayed excellent values against Gram-positive strains after uncaging, and the next-generation caged cephalosporin derivative achieved good and broad activity against both Gram-positive and Gram-negative strains after photorelease.</p>

Synthesis, crystal structures and properties of carbazole-based [6]helicenes fused with an azine ring

Novel carbazole-based [6]helicenes fused with an azine ring (pyridine, pyrazine or quinoxaline) have been prepared through a five-step synthetic sequence in good overall yields. Commercially available 2,3-dihaloazines were used as starting materials. To discern the effect of merging an azine moiety within a helical skeleton, the X-ray structures, UV–vis absorption and fluorescence spectra of the helicenes were investigated and compared to that of the parent carbazole-based [6]helicene (7H-phenanthro[3,4-c]carbazole).