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Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium‐nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se−N to Se−C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se−N to Se−S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high‐yielding, features fast kinetics (k2≥14.43 M−1 s−1), excellent functional group compatibility, and works well at miniaturization (nanomole‐scale), opening up many interesting opportunities for organo‐Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium‐catalyzed azide‐alkyne cycloaddition (RuAAC) and sulfur‐fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole‐scale synthesis of Se‐containing natural product library and DNA‐encoded library (DEL), late‐stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery. [ABSTRACT FROM AUTHOR]

Click chemistry is a powerful molecular assembly strategy for rapid functional discovery. The development of click reactions with new connecting linkage is of great importance for expanding the click chemistry toolbox. We report the first selenium‐nitrogen exchange (SeNEx) click reaction between benzoselenazolones and terminal alkynes (Se−N to Se−C), which is inspired by the biochemical SeNEx between Ebselen and cysteine (Cys) residue (Se−N to Se−S). The formed selenoalkyne connection is readily elaborated, thus endowing this chemistry with multidimensional molecular diversity. Besides, this reaction is modular, predictable, and high‐yielding, features fast kinetics (k2≥14.43 M−1 s−1), excellent functional group compatibility, and works well at miniaturization (nanomole‐scale), opening up many interesting opportunities for organo‐Se synthesis and bioconjugation, as exemplified by sequential click chemistry (coupled with ruthenium‐catalyzed azide‐alkyne cycloaddition (RuAAC) and sulfur‐fluoride exchange (SuFEx)), selenomacrocycle synthesis, nanomole‐scale synthesis of Se‐containing natural product library and DNA‐encoded library (DEL), late‐stage peptide modification and ligation, and multiple functionalization of proteins. These results indicated that SeNEx is a useful strategy for new click chemistry developments, and the established SeNEx chemistry will serve as a transformative platform in multidisciplinary fields such as synthetic chemistry, material science, chemical biology, medical chemistry, and drug discovery. [ABSTRACT FROM AUTHOR]

Conventional direct C−H selenylation suffers from simple selenation with limited atom economy and complicated reaction system. In this work, we designed benzoselenazolone as a novel bifunctional selenide reagent for both off‐ and on‐DNA C−H selenylation under rhodium(III) catalysis. We show that using benzoselenazolone allowed production of a series of selenylation products containing an adjacent aminoacyl group in a fast and efficient way, with high atom economy. The synthetic application of this method was demonstrated by taking advantage of the amide functionality as a nucleophile, directing group, and amide coupling partner. This work shows great potential in facilitating rapid construction of selenium‐containing DNA‐encoded chemical libraries (SeDELs), and lays the foundation for the development of selenium‐containing drugs. [ABSTRACT FROM AUTHOR]

Conventional direct C−H selenylation suffers from simple selenation with limited atom economy and complicated reaction system. In this work, we designed benzoselenazolone as a novel bifunctional selenide reagent for both off‐ and on‐DNA C−H selenylation under rhodium(III) catalysis. We show that using benzoselenazolone allowed production of a series of selenylation products containing an adjacent aminoacyl group in a fast and efficient way, with high atom economy. The synthetic application of this method was demonstrated by taking advantage of the amide functionality as a nucleophile, directing group, and amide coupling partner. This work shows great potential in facilitating rapid construction of selenium‐containing DNA‐encoded chemical libraries (SeDELs), and lays the foundation for the development of selenium‐containing drugs. [ABSTRACT FROM AUTHOR]

Click chemistry is a concept wherein modular synthesis is used for rapid functional discovery. To this end, continuous discovery of clickable chemical transformations is the pillar to support the development of this field. This report details the development of a clickable C3‐H selenylation of indole that is suitable for on‐plate parallel and DNA‐encoded library (SeDEL) synthesis via bioinspired LUMO activation strategy. This reaction is modular, robust and highly site‐selective, and it features a simple and mild reaction system (catalyzed by nonmetallic B(C6F5)3 at room temperature), high yields and excellent functional group compatibility. Using this method, a library of 1350 indole‐selenides was parallel synthesized in an efficient and practical manner, enabling the rapid identification of 3 ai as a promising compound with nanomolar antiproliferative activity in cancer cells via in situ phenotypic screening. These results indicate the great potential of this new clickable selenylation reaction in high‐throughput medicinal chemistry and chemical biology. [ABSTRACT FROM AUTHOR]

Click chemistry is a concept wherein modular synthesis is used for rapid functional discovery. To this end, continuous discovery of clickable chemical transformations is the pillar to support the development of this field. This report details the development of a clickable C3‐H selenylation of indole that is suitable for on‐plate parallel and DNA‐encoded library (SeDEL) synthesis via bioinspired LUMO activation strategy. This reaction is modular, robust and highly site‐selective, and it features a simple and mild reaction system (catalyzed by nonmetallic B(C6F5)3 at room temperature), high yields and excellent functional group compatibility. Using this method, a library of 1350 indole‐selenides was parallel synthesized in an efficient and practical manner, enabling the rapid identification of 3 ai as a promising compound with nanomolar antiproliferative activity in cancer cells via in situ phenotypic screening. These results indicate the great potential of this new clickable selenylation reaction in high‐throughput medicinal chemistry and chemical biology. [ABSTRACT FROM AUTHOR]

Inside Cover: Selenylation Chemistry Suitable for On-Plate Parallel and On-DNA Library Synthesis Enabling High-Throughput Medicinal Chemistry (Angew. Click Chemistry, DNA-Encoded Library, Modular Synthesis, Selenium, Selenylation Keywords: Click Chemistry; DNA-Encoded Library; Modular Synthesis; Selenium; Selenylation EN Click Chemistry DNA-Encoded Library Modular Synthesis Selenium Selenylation 1 1 1 08/23/22 20220826 NES 220826 B Selenium b is an emerging versatile player in medicinal chemistry. [Extracted from the article]

Innentitelbild: Selenylation Chemistry Suitable for On-Plate Parallel and On-DNA Library Synthesis Enabling High-Throughput Medicinal Chemistry (Angew. Keywords: Click Chemistry; DNA-Encoded Library; Modular Synthesis; Selenium; Selenylation EN Click Chemistry DNA-Encoded Library Modular Synthesis Selenium Selenylation 1 1 1 08/23/22 20220826 NES 220826 B Selen b ist ein vielseitiges Element in der medizinischen Chemie. Click Chemistry, DNA-Encoded Library, Modular Synthesis, Selenium, Selenylation. [Extracted from the article]

Click chemistry is a concept wherein modular synthesis is used for rapid functional discovery. To this end, continuous discovery of clickable chemical transformations is the pillar to support the development of this field. This report details the development of a clickable C3‐H selenylation of indole that is suitable for on‐plate parallel and DNA‐encoded library (SeDEL) synthesis via bioinspired LUMO activation strategy. This reaction is modular, robust and highly site‐selective, and it features a simple and mild reaction system (catalyzed by nonmetallic B(C6F5)3 at room temperature), high yields and excellent functional group compatibility. Using this method, a library of 1350 indole‐selenides was parallel synthesized in an efficient and practical manner, enabling the rapid identification of 3 ai as a promising compound with nanomolar antiproliferative activity in cancer cells via in situ phenotypic screening. These results indicate the great potential of this new clickable selenylation reaction in high‐throughput medicinal chemistry and chemical biology. [ABSTRACT FROM AUTHOR]