Cyclometallated gold(III) complexes for organic synthesis and bioconjugation

Abstract

Gold catalysis has attracted considerable attention in organic chemistry as gold compounds are able to exhibit excellent selectivity, high reactivity, and exceptional tolerance to organic transformations performed under air/moisture reaction conditions. Bioconjugation aims to attach biophysical probes to biomolecules including oligosaccharides, peptides and proteins for studying complex biological systems. However, it is a challenging task to conduct biomolecule modification as most of these reactions need to be carried out in aqueous medium, narrow pH (6-8) and temperature (4-37 ℃) range and low biomolecule concentration without protection of sensitive functional groups. In view of the unique advantages of gold catalysis, we set out to develop gold catalysis for efficient organic synthesis and selective bioconjugation. A series of cyclometallated gold(III) (C^N) complexes, [Au(C^N)Cl₂] (HC^N = arylpyridines), and a PEG-supported cyclometallated gold(III) complex were synthesized and characterized. The activity of the gold(III) complexes in catalyzing the synthesis of (1) chiral propargylamines, (2) axially chiral allenes, and (3) isoxazoles were studied. Firstly, propargylamines were synthesized in excellent yields (up to 99%) with turnover number up to 1021 using cyclometallated gold(III) complexes as the catalysts. When chiral galactose aldehydes and chiral prolinol derivatives were employed as the reaction substrates in propargylamine synthesis, excellent diastereoselectivities (up to >99:1) were achieved. Secondly, chiral propargylamines were converted to axially chiral allenes in yields up to 99% and excellent enantioselectivities (up to 98% ee) by using cyclometallated gold(III) complexes as catalysts. Thirdly, isoxazoles were synthesized from cyclometallated gold(III) complex-catalyzed cycloisomerization of α,β-acetylenic oximes in excellent yield (up to 99%). Finally, a PEG-supported cyclometallated gold(III) complex was found to be effective for catalyzing the organic transformation reactions especially in the synthesis of propargylamines (turnover number of 1600). On the basis of the present gold(III)-catalyzed synthesis of propargylamines via a three-component coupling of aldehydes, amines and alkynes, site-selective bifunctional modification of aldehyde-containing oligosaccharides (i.e. D-raffinose and D-stachyose) was developed. This gold-mediated bioconjugation gave excellent conversion (up to 99%) as indicated by LC-MS analysis, with high functional group tolerance in aqueous medium. Propargylamine-modified oligosaccharides were obtained through incorporation of two different functionalities (i.e. fluorescent dye and biotin) linked on amine and/or alkyne components onto a single-site of the oligosaccharide aldehydes. A new class of cyclometallated gold(III) (C^N) complexes with a biuret ligand, [Au(C^N)biuret] (HC^N = arylpyridines), were prepared. These complexes were found to be efficient chemoselective reagent for modification of cysteine-containing peptides STSSSCNLSK, AYEMWCFHQK, and ASCGTN via substitution reaction, with the overall peptide conversion up to 92% by LC-MS analysis. No modification was observed in a peptide YTSSSKNVVR, which has no cysteine in its amino acid sequence.