Substituent Effects in Bioorthogonal Diels–Alder Reactions of 1,2,4,5‐Tetrazines

Chemistry - A European Journal, Journal Year: 2023, Volume and Issue: 29(29)

Published: Feb. 28, 2023

1,2,4,5-Tetrazines are increasingly used as reactants in bioorthogonal chemistry due to their high reactivity Diels-Alder reactions with various dienophiles. Substituents the 3- and 6-positions of tetrazine scaffold known have a significant impact on rate cycloadditions; this is commonly explained basis frontier molecular orbital theory. In contrast, we show that differences between classes tetrazines not controlled by interactions. particular, demonstrate mono-substituted decreased Pauli repulsion, which leads more asynchronous approach associated reduced distortion energy. This follows recent Vermeeren-Hamlin-Bickelhaupt model increase asymmetric reactions. addition, reveal ethylene good compound for other alkenes

Language: Английский

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Computation-Guided Discovery of Diazole Monosubstituted Tetrazines as Optimal Bioorthogonal Tools

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(39), P. 26884 - 26896

Published: Aug. 21, 2024

Monosubstituted tetrazines are important bioorthogonal reactive tools due to their rapid ligation with trans-cyclooctene. However, application is limited by the reactivity–stability paradox in biological environments. In this study, we demonstrated that steric effects crucial resolving through theoretical methods and developed a simple synthetic route validate our computational findings, leading discovery of 1,3-azole-4-yl 1,2-azole-3-yl monosubstituted as superior tools. These new surpass previous terms high reactivities elevated stabilities. The most stable tetrazine exhibits reasonable stability (71% remaining after 24 h incubation cell culture medium) an exceptionally reactivity (k2 > 104 M–1 s–1 toward trans-cyclooctene). Due its good systems, noncanonical amino acid containing such side chain was genetically encoded into proteins site-specifically via expanded genetic code. protein can be efficiently labeled using cyclopropane-fused trans-cyclooctene dyes living mammalian cells ultrafast reaction rate exceeding 107 s–1, making it one fastest labeling reactions reported date. Additionally, showed superiority vivo mice, achieving efficient local anchoring proteins. expected optimal within systems.

Language: Английский

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Computational Studies of Reactions of 1,2,4,5-Tetrazines with Enamines in MeOH and HFIP

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(27), P. 18706 - 18713

Published: June 28, 2024

The reaction between 1,2,4,5-tetrazines and alkenes in polar solvents proceeds through a Diels–Alder cycloaddition along the C–C axis (C3/C6 cycloaddition) of tetrazine, followed by dinitrogen loss. By contrast, reactions with enamines hexafluoroisopropanol (HFIP) give 1,2,4-triazine products stemming from formal addition across N–N (N1/N4 cycloaddition). We explored mechanism this interesting solvent effect DFT calculations detail revealed novel pathway characterized C–N bond formation, deprotonation, 3,3-sigmatropic rearrangement. participation an HFIP molecule was found to be crucial N1/N4 selectivity over C3/C6 due more favored initial formation than formation.

Language: Английский

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How cycloalkane fusion enhances the cycloaddition reactivity of dibenzocyclooctynes

Chemical Science, Journal Year: 2024, Volume and Issue: 15(6), P. 2229 - 2235

Published: Jan. 1, 2024

Dibenzoannulated cyclooctynes have emerged as valuable compounds for bioorthogonal reactions. They are commonly used in combination with azides strain-promoted 1,3-dipolar cycloadditions. typically, however, unreactive towards 3,6-disubstituted tetrazines inverse electron-demand Diels-Alder Recently a dibenzoannulated bicyclo[6.1.0]nonyne derivative (DMBO) cyclopropane fused to the cyclooctyne core was described, which showed surprising reactivity tetrazines. To elucidate unusual of DMBO, we performed density functional theory calculations and revealed that tub-like structure transition state results much lower activation barrier than absence fusion. The same geometry is found different cycloalkanes albeit higher barriers observed increased ring sizes. This conformation energetically unfavored previously known allows approach DMBO from face rather edge, trajectory hitherto not this class activated dieno- dipolarophiles.

Language: Английский

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Unraveling the Bürgi-Dunitz Angle with Precision: The Power of a Two-Dimensional Energy Decomposition Analysis

Journal of Chemical Theory and Computation, Journal Year: 2023, Volume and Issue: 19(20), P. 7300 - 7306

Published: Oct. 4, 2023

Understanding the geometrical preferences in chemical reactions is crucial for advancing field of organic chemistry and improving synthetic strategies. One such preference, Bürgi-Dunitz angle, central to nucleophilic addition involving carbonyl groups. This study successfully employs a novel two-dimensional Distortion-Interaction/Activation-Strain Model combination with Energy Decomposition Analysis investigate origins angle reaction CN- (CH3)2C═O. We constructed 2D potential energy surface defined by distance between nucleophile carbonylic carbon atom attack followed an in-depth exploration components, including strain interaction energy. Our analysis reveals that emerges from delicate balance two key factors: High energy, as result compound distorting avoid Pauli repulsion, encountered at high angles, thus setting upper bound. On other hand, shaped dominant repulsion when angles are lower. work emphasizes value refined tool, offering both quantitative qualitative insights into reactivity selectivity.

Language: Английский

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Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Topics in Current Chemistry, Journal Year: 2024, Volume and Issue: 382(2)

Published: May 10, 2024

Computational organic chemistry has become a valuable tool in the field of bioorthogonal chemistry, offering insights and aiding progression this branch chemistry. In review, I present an overview computational work field, including exploration both primary analysis methods used their application main areas chemistry: (3 + 2) [4 2] cycloadditions. context cycloadditions, detailed studies electronic effects have informed evolution cycloalkyne/1,3-dipole Through techniques, researchers found ways to adjust structure via hyperconjugation enhance reactions without compromising stability. For such as distortion/interaction energy decomposition been beneficial, leading development reactants with improved reactivity creation orthogonal reaction pairs. To conclude, touch upon emerging fields cheminformatics machine learning, which promise play role future discovery optimization.

Language: Английский

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Machine Learning Enabling the Prediction of Activation Energies of SPAAC

Journal of Physical Organic Chemistry, Journal Year: 2025, Volume and Issue: 38(2)

Published: Jan. 17, 2025

ABSTRACT This study leverages machine learning to predict the activation energies of strain‐promoted azide‐alkyne cycloaddition (SPAAC) reactions. Using DFT calculations, 631 sets bond angles and Mulliken charges from two acyclic alkynes were collected. Multiple models trained on these data, achieving high accuracy ( R 2 > 0.95). Both angle charge crucial for reliable predictions. The successfully predicted SPAAC reactions with unseen cycloalkynes, within certain limitations.

Language: Английский

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Investigation of Proteome-Tetrazine Reactivity for a Highly Selective Tetrazine Ligation in Live Cells

ACS Central Science, Journal Year: 2025, Volume and Issue: unknown

Published: May 6, 2025

Language: Английский

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Directionality of Halogen‐Bonds: Insights from 2D Energy Decomposition Analysis

Chemistry - An Asian Journal, Journal Year: 2024, Volume and Issue: 19(5)

Published: Feb. 23, 2024

Abstract Halogen bonds are typically observed to have a linear arrangement with 180° angle between the nucleophile and halogen bond acceptor X−R. This linearity is commonly explained using σ‐hole model, although there been alternative explanations involving exchange repulsion forces. We employ two‐dimensional Distortion/Interaction Energy Decomposition Analysis examine archetypal H 3 N⋯X 2 systems. Our results indicate that predominantly electrostatic, their directionality largely due decreased Pauli in configurations as opposed angled ones I Br As we move smaller halogens, Cl F , influence of diminishes, energy surface shaped by orbital interactions electrostatic These support role forces influencing strong bonds. Additionally, demonstrate 2D useful tool for enhancing our understanding nature potential surfaces noncovalent interactions.

Language: Английский

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Ortho-functionalized pyridinyl-tetrazines - breaking the inverse correlation between click reactivity and cleavage yields in click-to-release

Published: May 31, 2024

The bioorthogonal tetrazine-triggered cleavage of trans-cyclooctene(TCO)-linked payloads has strong potential for widespread use in drug delivery and particular click-cleavable ADCs, but clinical translation is hampered by an inverse correlation between click reactivity payload release yield. This requires the high doses relatively less reactive tetrazines to drive vivo TCO reactions completion achieve sufficient release. Herein we report that main cause low when using highly bis-(2-pyridinyl)-tetrazine stability initially formed 4,5-dihydropyridazine product, precluding tautomerization releasing 1,4-dihydropyridazine tautomer. We demonstrate efficient elimination can be achieved ortho-substituting bis-pyridinyl-tetrazines with hydrogen-bonding hydroxyl or amido groups, thereby achieving a.o. yields 96 % 18-fold more tetrazines. Applied on-tumor activation a ADC mice, new afforded near-quantitative conversion at ca. 10- 20-fold lower dose than what was previously needed, resulting therapeutic response.

Language: Английский

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