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4'-Selective alkylation of nucleosides has been recognized as one of the ideal and straightforward approaches to chemically modified nucleosides, but such a transformation has been scarce and less explored. In this Letter, we combine a visible-light-mediated photoredox catalysis and hydrogen atom transfer (HAT) auxiliary to achieve β-C(sp 3 )-H alkylation of alcohol on tetrahydrofurfuryl alcohol scaffolds and exploit it for 4'-selective alkylation of nucleosides. The reaction involves an intramolecular 1,5-HAT process and stereocontrolled Giese addition of the resultant radicals.

Proton-coupled electron transfer (PCET) is a crucial chemical process involving the simultaneous or sequential transfer of protons and electrons, playing a vital role in biological processes and energy conversion technologies. This study investigates the use of an organic photoredox catalyst to facilitate a unimolecular PCET process for the generation of alkyl radicals from benzylic alcohols, with a particular focus on alcohols containing electron-rich arene units. By employing a benzophenone derivative as the catalyst, the reaction proceeds efficiently under photoirradiation, achieving significant yields without the need for a Brønsted base. The findings highlight the potential of this unimolecular PCET mechanism to streamline radical generation in organic synthesis, offering a more efficient and flexible alternative to conventional methods., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

α-Silylalkylamines and α-borylalkylamines are versatile synthetic intermediates and attractive scaffolds found in pharmaceutical drugs and agrochemicals. Despite great progress on synthetic methods for preparation of α-silylalkylamines or α-borylalkylamines, there are no general strategies for preparation of α-boryl-α-silylalkylamines and the reactivity has not been explored. Here we report deoxygenative geminal silylboration of amides using silylboronates in the presence of alkoxide base catalyst, producing α-boryl-α-silylalkylamines. The silicon and boron groups in α-boryl-α-silylalkylamines are found to be utilized to chemoselective transformations, such as protonation and alkylation. This protocol serves various α-silylalkylamines and α-borylalkylamines from readily available amides., (© 2024 Wiley-VCH GmbH.)

We have developed radical C-glycosylation using photoexcitable unprotected glycosyl borate. The direct excitation of glycosyl borate under visible light irradiation enabled the generation of anomeric radical without any photoredox catalysts. The in situ generated anomeric radical was applicable to the radical addition such as Giese-type addition and Minisci-type reaction to introduce alkyl and heteroaryl groups at the anomeric position. In addition, the radical-radical coupling between the glycosyl borate and acyl imidazolide provided unprotected acyl C-glycosides., (© 2024 Wiley-VCH GmbH.)

Xenobiotic metabolic reactions in the hepatocyte endoplasmic reticulum (ER) including UDP-glucuronosyltransferase and carboxylesterase play central roles in the detoxification of medical agents with small- and medium-sized molecules. Although the catalytic sites of these enzymes exist inside of ER, the molecular mechanism for membrane permeation in the ER remains enigmatic. Here, we investigated that organic anion transporter 2 (OAT2) regulates the detoxification reactions of xenobiotic agents including anti-cancer capecitabine and antiviral zidovudine, via the permeation process across the ER membrane in the liver. Pharmacokinetic studies in patients with colorectal cancer revealed that the half-lives of capecitabine in rs2270860 (1324C > T) variants was 1.4 times higher than that in the C/C variants. Moreover, the hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine in primary cultured human hepatocytes was reduced by OAT2 inhibitor ketoprofen, whereas capecitabine hydrolysis directly assessed in human liver microsomes were not affected. The immunostaining of OAT2 was merged with ER marker calnexin in human liver periportal zone. These results suggested that OAT2 is involved in distribution of capecitabine into ER. Furthermore, we clarified that OAT2 plays an essential role in drug-drug interactions between zidovudine and valproic acid, leading to the alteration in zidovudine exposure to the body. Our findings contribute to mechanistically understanding medical agent detoxification, shedding light on the ER membrane permeation process as xenobiotic metabolic machinery to improve chemical changes in hydrophilic compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We demonstrate hydrohalogenation of aliphatic alkenes with collidine·HX salts through dual photoredox/cobalt catalysis. The dual catalysis enables conversion of a proton and a halide anion from collidine·HX salt to a nucleophilic hydrogen radical equivalent and an electrophilic halogen radical equivalent and delivery of them to an alkene moiety. This protocol allows for introduction of fluorine, chlorine, bromine, or iodine atom to alkene, producing highly functionalized alkyl halides.

Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2'-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study., (© 2023. The Author(s).)

The biomimetic design of a transition metal complex based on the iron(iv)-oxo porphyrin π-cation radical species in cytochrome P450 enzymes has been studied extensively. Herein, we translate the functions of this iron(iv)-oxo porphyrin π-cation radical species to an α-ketoacyl phosphonium species comprised of non-metal atoms and utilize it as a light-activated oxygenation auxiliary for ortho -selective oxygenation of anilines. Visible light irradiation converts the α-ketoacyl phosphonium species to the excited state, which acts as a transiently generated oxidant. The intramolecular nature of the process ensures high regioselectivity and chemoselectivity. The auxiliary is easily removable. A one-pot protocol is also described., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A quadruple N-heterocyclic carbene/cobalt/photoredox/Brønsted base catalysis to realize branch-selective hydroacylation of styrenes with aromatic and aliphatic aldehydes is demonstrated. This protocol allows access to branched ketones from readily available materials in an atom-economical manner. The quadruple catalysis can transfer a formyl hydrogen of aldehydes as a hydrogen radical equivalent onto the terminal carbon of an alkene by controlled electron and proton transfers., (© 2023 Wiley-VCH Verlag GmbH.)

Photo-caged methodologies have been indispensable for elucidating the functional mechanisms of pharmacologically active molecules at the cellular level. A photo-triggered removable unit enables control of the photo-induced expression of pharmacologically active molecular function, resulting in a rapid increase in the concentration of the bioactive compound near the target cell. However, caging the target bioactive compound generally requires specific heteroatom-based functional groups, limiting the types of molecular structures that can be caged. We have developed an unprecedented methodology for caging/uncaging on carbon atoms using a unit with a photo-cleavable carbon-boron bond. The caging/uncaging process requires installation of the CH 2 -B group on the nitrogen atom that formally assembles an N -methyl group protected with a photoremovable unit. N -Methylation proceeds by photoirradiation via carbon-centered radical generation. Using this radical caging strategy to cage previously uncageable bioactive molecules, we have photocaged molecules with no general labeling sites, including acetylcholine, an endogenous neurotransmitter. Caged acetylcholine provides an unconventional tool for optopharmacology to clarify neuronal mechanisms on the basis of photo-regulating acetylcholine localization. We demonstrated the utility of this probe by monitoring uncaging in HEK cells expressing a biosensor to detect ACh on the cell surface, as well as Ca 2+ imaging in Drosophila brain cells (ex vivo).

In October 2021, 59 scientists from 14 countries and 13 U.S. states collaborated virtually in the Third Annual Baylor College of Medicine & DNANexus Structural Variation hackathon. The goal of the hackathon was to advance research on structural variants (SVs) by prototyping and iterating on open-source software. This led to nine hackathon projects focused on diverse genomics research interests, including various SV discovery and genotyping methods, SV sequence reconstruction, and clinically relevant structural variation, including SARS-CoV-2 variants. Repositories for the projects that participated in the hackathon are available at https://github.com/collaborativebioinformatics., Competing Interests: Competing interests: Ben Busby is a full-time employee of DNAnexus. Rebecca Lowdon is a full-time employee of Bayer Crop Sciences. Ramanandan Prabhakaran is a full-time employee of Hoffmann-La Roche Limited. Luis F Paulin is sponsored by Genentech, Inc. Wouter De Coster has received travel reimbursement and free consumables from ONT. FJS received research support from ONT and PacBio. Alejandro Rafael Gener is an editorial board member of AIDS, and has received poster bursaries from ONT in 2019., (Copyright: © 2022 Walker K et al.)

Over the past century, significant progress in semipinacol rearrangement involving 1,2-migration of α-hydroxy carbocations has been made in the areas of catalysis and total synthesis of natural products. To access the α-hydroxy carbocation intermediate, conventional acid-mediated or electrochemical approaches have been employed. However, the photochemical semipinacol rearrangement has been underdeveloped. Herein, we report the organophotoredox-catalyzed semipinacol rearrangement via radical-polar crossover (RPC). A phenothiazine-based organophotoredox catalyst facilitates the generation of an α-hydroxy non-benzylic alkyl radical followed by oxidation to the corresponding carbocation, which can be exploited to undergo the semipinacol rearrangement. As a result, the photochemical approach enables decarboxylative semipinacol rearrangement of β-hydroxycarboxylic acid derivatives and alkylative semipinacol type rearrangement of allyl alcohols with carbon electrophiles, producing α-quaternary or α-tertiary carbonyls bearing sp 3 -rich scaffolds., (© 2022. The Author(s).)

We demonstrate Markovnikov hydroalkoxylation of unactivated alkenes using alcohols through a triple catalysis consisting of photoredox, cobalt, and Brønsted acid catalysts under visible light irradiation. The triple catalysis realizes three key elementary steps in a single catalytic cycle: (1) Co(III) hydride generation by photochemical reduction of Co(II) followed by protonation, (2) metal hydride hydrogen atom transfer (MHAT) of alkenes by Co(III) hydride, and (3) oxidation of the alkyl Co(III) complex to alkyl Co(IV). The precise control of protons and electrons by the three catalysts allows the elimination of strong acids and external reductants/oxidants that are required in the conventional methods.

To better understand the immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with COVID-19, it is important to investigate the kinetics of the antibody responses and their associations with the clinical course in different populations, since there seem to be considerable differences between Western and Asian populations in the clinical features and spread of COVID-19. In this study, we serially measured the serum titers of IgM, IgG and IgA antibodies generated against the nucleocapsid protein (NCP), S1 subunit of the spike protein (S1), and receptor-binding domain in the S1 subunit (RBD) of SARS-CoV-2 in Japanese individuals with COVID-19. Among the IgM, IgG, and IgA antibodies, IgA antibodies against all of the aforementioned viral proteins were the first to appear after the infection, and IgG and/or IgA seroconversion often preceded IgM seroconversion. In regard to the timeline of the antibody responses to the different viral proteins (NCP, S1 and RBD), IgA against NCP appeared than IgA against S1 or RBD, while IgM and IgG against S1 appeared earlier than IgM/IgG against NCP or RBD. The IgG responses to all three viral proteins and responses of all three antibody classes to S1 and RBD were sustained for longer durations than the IgA/IgM responses to all three viral proteins and responses of all three antibody classes to NCP, respectively. The seroconversion of IgA against NCP occurred later and less frequently in patients with mild COVID-19. These results suggest possible differences in the antibody responses to SARS-CoV-2 antigens between the Japanese and Western populations., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)