Stabilized Carbon Radical-Mediated Assembly of Arylthianthrenium Salts, Alkenes and Amino Acid/Peptide Derivatives

Abstract

Efficiently assembling amino acids and peptides with bioactive molecules facilitates the modular and streamlined synthesis of a diverse library of peptide-related compounds. Particularly notable is their application in pharmaceutical development, leveraging site-selective late-stage functionalization. Here, a visible light-induced three-component reaction involving arylthianthrenium salts, amino acid/peptide derivatives, and alkenes are introduced. This approach utilizes captodatively-stabilized carbon radicals to enable radical-radical C─C coupling, effectively constructing complex bioactive molecules. This method offers a promising alternative route for modular synthesis of peptide-derived bio-relevant compounds.

Keywords: amino acid; captodative effect; late‐stage functionalization; radical coupling; thianthrenium salt.

Figure 1

Radical three‐component reactions of aryl sulfonium salts.

Scheme 1

Substrate scope with amino acid derivatives. a) Standard conditions: 1 0.375 mmol (2.5 equiv.), 2a 0.15 mmol (1.0 equiv.), 3a 0.375 mmol (2.5 equiv.), 4CzIPN 0.0045 mmol (3 mol%), Py 0.15 mmol (1.0 equiv.), MeCN 4.0 mL under blue LED irradiation, under N₂ atmosphere, r.t. (23–25 °C), 12 h. b) Replace ⁻OTf with ⁻BF₄. c) Replacing TT with dibenzo(b,d)thiophene. d) Replacing TT with phenoxathiin. Isolated yields are given. d.r. were determined by ¹H NMR.

Scheme 2

Substrates scope with aryl thianthrenium salts and alkenes. a) Standard conditions: 1 0.375 mmol (2.5 equiv.), 2 0.15 mmol (1.0 equiv.), 3 0.375 mmol (2.5 equiv.), 4CzIPN 0.0045 mmol (3 mol%), Py 0.15 mmol (1.0 equiv.), MeCN 4.0 mL under blue LED irradiation, under N₂ atmosphere, r.t. (23–25 °C), 12 h. b) Replace ⁻OTf with ⁻BF₄. c) On bench reaction. d) Stop‐flow mirco‐tube (SFMT) reaction. Isolated yields are given. d.r. were determined by ¹H NMR. HAT = Hydrogen atom transfer.

Scheme 3

Synthetic applications. a,b) Gram‐scale reactions; c) One‐pot synthesis; d,e) Synthesis of deuterated and ¹³C labeling alkyl amino acid derivatives; f) Synthesis of conjugate (10) of Vorinostat and Abiraterone. EDCI · HCl = 1–ethyl–3–(3–dimethylaminopropyl)carbodiimide; HOBT = 1–hydroxybenzotriazole; Et₃N = triethylamine; DCM = dichloromethane; THF = tetrahydrofuran.

Scheme 4

Control experiments and spectroscopic characterization.

Scheme 5

Electrochemical characterization and proposed mechanism.