Organocatalytic and Scalable Syntheses of Unsymmetrical 1,2,4,5‐Tetrazines by Thiol‐Containing Promotors

Abstract

Despite the growing application of tetrazine bioorthogonal chemistry,itisstill challenging to access tetrazines conveniently from easily available materials.Described here is the de novo formation of tetrazine from nitriles and hydrazine hydrate using ab road array of thiol-containing catalysts, including peptides.Using this facile methodology,the syntheses of 14 unsymmetric tetrazines,c ontaining ar ange of reactive functional groups,o nt he gram scale were achieved with satisfactory yields.U sing tetrazine methylphosphonate as ab uilding block, ah ighly efficient Horner-Wadsworth-Emmons reaction was developed for further derivatization under mild reaction conditions.T etrazine probes with diverse functions can be scalably produced in yields of 87-93 %. This methodology may facilitate the widespread application of tetrazine bioorthogonal chemistry.

Application of N-Dodecyl l-Peptide to Enhance Serum Stability while Maintaining Inhibitory Effects on Myometrial Contractions Ex Vivo

“…Dodecanal and farnesol were purchased from commercial sources and used without further purification. Hexanal [60], undecanal [61], tridecanal [62], octadecanal [63], and 2,5,8,11-tetraoxatridecan-13-al [64] all were obtained by oxidation of the corresponding primary alcohol and exhibited characterization consistent with the published literature. Final purity assessments were made based on an analytical RP-HPLC-MS system from Agilent Technologies Inc. (Santa Clara, CA, USA) using the following columns and conditions: Phenomenex Synergi Polar-RP (Phenomenex, Torrance, CA, USA), 4,6 mm × 150 mm, 4 µm, UV detection (Agilent Technologies Inc., Santa Clara, CA, USA) at 250 nm or 280 nm, 5–50% MeCN with 0.1% formic acid (FA) in water (0.1% FA) over 20 min at 0.5 mL/min, or 30–90% MeOH (0.1% FA) in water (0.1% FA) over 20 min at 0.5 mL/min; Phenomenex C18 4.6 mm × 50 mm, 4 µM, UV detection at 280 nm, 10–90% MeCN (0.1% FA) in water (0.1% FA) over 15 min at 0.5 mL/min, or 10–90% MeOH (0.1% FA) in water (0.1% FA) over 15 min at 0.5 mL/min.…”

A General Strategy to Design Highly Fluorogenic Far‐Red and Near‐Infrared Tetrazine Bioorthogonal Probes

“…We first constructed the cyanine‐like probe 1 containing a polymethine conjugated system, using our recently reported Horner–Wadsworth–Emmons reaction for tetrazine derivatization (Table 1). [20] In this probe, the para ‐dimethylaniline acts as the donor, while the hydroxyl group at the 3‐position of tetrazine improves solubility with neutral charge. Probe 1 , which emits no detectable fluorescence, reacted nearly quantitatively with bicyclooctyne (BCN) 6 (Supporting Information, Figure S1).…”

Overview of Syntheses and Molecular-Design Strategies for Tetrazine-Based Fluorogenic Probes

“…Hydrazine is a good reductant and a good nucleophile; thus, the reactions it is employed in usually offer poor substrate scopes and harsh conditions [ 14 ]. To overcome these limitations, organocatalytic approaches for the preparation of unsymmetrical tetrazines were developed by Wu et al in 2019 ( Scheme 1 d) [ 18 ]. It was suggested that a thiol-containing organocatalyst could promote the formation of unsymmetrical tetrazines at room temperature from hydrazine hydrate and nitriles bearing reactive functional groups.…”