Alkynone β-trifluoroborates: A new class of amine-specific biocompatible click reagents

Teng, Susanto; Ng, Elvis Wang Hei; Zhang, Zhenguo; Soon, Chee Ning; Xu, Hailun; Li, Ruifang; Hirao, Hajime; Loh, Teck‐Peng

doi:10.1126/sciadv.adg4924

Cited by 8 publications

(6 citation statements)

References 75 publications

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“…Soon, C. N. Xu, H. Li, R. Hirao, H. Loh, T.-P. Sci. Adv.20239eadg4924 . This work introduces an amine-specific biocompatible click reagent using alkynone β-trifluoroborates as the electrophiles.…”

Section: Key Referencesmentioning

confidence: 99%

“…Recently, we also disclosed a practical amine conjugation technology using boron-based alkynone β-trifluoroborates as the electrophiles (Scheme 25B). 4 This new class of aminespecific bioconjugation reagents exhibited exclusive chemoselectivity toward amines over thiols. Under these conditions, both aromatic and aliphatic amines could be effectively converted into the products with excellent Z/E-selectivity.…”

Section: C−n Bond Formation Reactionsmentioning

confidence: 99%

“…Recently, we also disclosed a practical amine conjugation technology using boron-based alkynone β-trifluoroborates as the electrophiles (Scheme B) . This new class of amine-specific bioconjugation reagents exhibited exclusive chemoselectivity toward amines over thiols.…”

Section: Catalyst-free Biocompatible Reactions and Their Applicationsmentioning

confidence: 99%

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Development and Applications of Water-Compatible Reactions: A Journey to Be Continued

Lu,

Loh

2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS:The pursuit of novel and eco-friendly methods in organic synthesis is gaining prominence, with a strong emphasis on green transformations using renewable and sustainable resources. Among these environmentally conscious approaches, water-compatible reactions stand out for their many advantages. Water, as a solvent, offers unmatched abundance, costefficiency, and environmental compatibility compared to organic solvents. Its use eliminates the need for complex protection and deprotection steps for reactive functional groups in multistep synthesis and enables the use of water-soluble substrates like proteins and carbohydrates.Water-compatible reactions also provide opportunities to combine with enzymes, resulting in chemoenzymatic transformations that can increase efficiency. Additionally, these reactions facilitate site-specific modification and the bioconjugation of biomolecules, leading to bioconjugate therapeutics. Over nearly three decades, our research group has been dedicated to developing innovative water-compatible methodologies and concepts. This Account provides a comprehensive overview of our contributions since 1994. Our central strategy revolves around integrating green chemistry principles into our methods, focusing on (i) developing reactions that can operate under mild conditions, including room temperature, atmospheric pressure, and physiological pH; (ii) designing atom-economical reactions that minimize waste production; (iii) replacing toxic and flammable organic solvents with eco-friendly alternatives like water and ethanol; and (iv) reducing reliance on metals or halogenated compounds in specific reactions.In this Account, we detail our achievements in developing efficient methodologies in aqueous media, highlighting their scope, limitations, asymmetric control, and applications for synthesizing complex molecules and functionalizing peptides and proteins. Mechanistic investigations underlying these developments are also discussed when applicable. Furthermore, we offer insights into the reasoning behind our work and address future opportunities and challenges in this area of research. We hope that this Account will inspire continued interest and foster new breakthroughs. By exploring innovative and broadly applicable strategies that expand the water-compatible synthetic toolbox, we aim to pave the way for the truly green and sustainable synthesis of complex molecules and pharmaceuticals.

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Section: Key Referencesmentioning

confidence: 99%

Section: C−n Bond Formation Reactionsmentioning

confidence: 99%

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Development and Applications of Water-Compatible Reactions: A Journey to Be Continued

Lu,

Loh

2023

Acc. Chem. Res.

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“…Their reduction and consequent conjugation with reagents like maleimides can disrupt the overall protein structure and therefore function . More recently, however, elegant strategies have been developed to achieve higher site-selectivity for lysine and cysteine modifications (Scheme a). ,− …”

Section: Introductionmentioning

confidence: 99%

Thermally Triggered Triazolinedione–Tyrosine Bioconjugation with Improved Chemo- and Site-Selectivity

Denijs,

Unal,

Bevernaege

et al. 2024

J. Am. Chem. Soc.

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A bioconjugation strategy is reported that allows the derivatization of tyrosine side chains through triazolinedione-based "Y-clicking". Blocked triazolinedione reagents were developed that, in contrast to classical triazolinedione reagents, can be purified before use, can be stored for a long time, and allow functionalization with a wider range of cargoes and labels. These reagents are benchstable at room temperature but steadily release highly reactive triazolinediones upon heating to 40 °C in buffered media at physiological pH, showing a sharp temperature response over the 0 to 40 °C range. This conceptually interesting strategy, which is complementary to existing photo-or electrochemical bioorthogonal bond-forming methods, not only avoids the classical synthesis and handling difficulties of these highly reactive click-like reagents but also markedly improves the selectivity profile of the tyrosine conjugation reaction itself. It avoids oxidative damage and "off-target" tryptophan labeling, and it even improves site-selectivity in discriminating between different tyrosine side chains on the same protein or different polypeptide chains. In this research article, we describe the stepwise development of these reagents, from their short and modular synthesis to small-molecule model bioconjugation studies and proof-of-principle bioorthogonal chemistry on peptides and proteins.

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“…O coordination (Figure 1B). [35] However, this reagent is amine-specific, which exhibited poor reactivity to thiols. To achieve both thiol-selectivity and the enhanced stability of vinyl-sulfide linker, we envisioned to introduce the β-silyl component to alkynone reagents.…”

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confidence: 99%

Thiol‐Specific Silicon‐Containing Conjugating Reagent: β‐Silyl Alkynyl Carbonyl Compounds

Teng,

Zhang,

et al. 2023

Angewandte Chemie

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Site‐specific modification of thiol‐containing biomolecules has been recognized as a versatile and powerful strategy for probing our biological systems and discovering novel therapeutics. The addition of lipophilic silicon moiety opens up new avenues for multi‐disciplinary research with broad applications in both the medicinal and material sciences. However, adhering to the strict biocompatibility requirements, and achieving the introduction of labile silicon handle and high chemo‐selectivity have been formidable. In this paper, we report silicon‐based conjugating reagents including β‐trialkylsilyl and silyl ether‐tethered alkynones that selectively react with thiols under physiological conditions. The pH‐neutral, metal‐free and additive‐free reaction yields stable products with broad substrate compatibility and full retention of silicon handles in most cases. Besides simple aliphatic and aromatic thiols, this approach is applicable in the labeling of thiols present in proteins, sugars and payloads, thereby expanding the toolbox of thiol conjugation.

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Alkynone β-trifluoroborates: A new class of amine-specific biocompatible click reagents

Cited by 8 publications

References 75 publications

Development and Applications of Water-Compatible Reactions: A Journey to Be Continued

Development and Applications of Water-Compatible Reactions: A Journey to Be Continued

Thermally Triggered Triazolinedione–Tyrosine Bioconjugation with Improved Chemo- and Site-Selectivity

Thiol‐Specific Silicon‐Containing Conjugating Reagent: β‐Silyl Alkynyl Carbonyl Compounds

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