Synthesis and characterization of a novel ThDP-gold NHC complex as an artificial metallocofactor for a MenD-based artificial metalloenzyme

Abstract

Thiamine is a water-soluble vitamin, which through its pyrophosphorylated derivative thiamine diphosphate (ThDP), serves as an enzyme cofactor in a multitude of biomolecular reactions via ylide/carbene chemistry. The transient N-heterocyclic carbene (NHC) species generated during its biocatalysis is an attractive ligand for transition metal catalysts as it can confer on them enhanced water solubility and potentially novel activity. A water-soluble NHC-Au(I)Cl complex of thiamine was synthesized by the in situ generation of a thiazolin-2-ylidine carbene from thiamine hydrochloride in the presence of chloro(dimethylsulfide)gold(I) and was thoroughly characterized by ¹H NMR, ¹³C NMR and ESI-HRMS. This complex was utilized as a green catalyst for the A³ coupling reaction. Its catalytic activity matched or exceeded other common A³ coupling catalysts while tolerating a broad range of substrates. A new class of artificial metalloenzymes based on the supramolecular anchoring of ThDP to bacterial enzyme MenD was envisioned; this system aims to promote asymmetric organometallic catalysis in the aqueous and chiral environment of the MenD active site. To this end, the synthesis of a ThDP-AuCl NHC complex was attempted. Attempts at direct synthesis of the complex were not successful. Several strategies towards the indirect synthesis of the complex via the characterized thiamine-AuCl NHC complex were attempted instead, but they too did not yield the desired product. Miscellaneous investigations were conducted which uncovered the relatively unexplored chemistry of thiazolin-2-ylidine carbene metal complexes, helping to rationalize some observations of performed experiments.

Date of Award	2023
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Zhihong GUO (Supervisor)