A General Approach to O-Sulfation by a Sulfur(VI) Fluoride Exchange Reaction

Abstract

O-sulfation is an important chemical code widely existing in bioactive molecules, but the scalable and facile synthesis of complex bioactive molecules carrying O-sulfates remains challenging. Reported here is a general approach to O-sulfation by the sulfur(VI) fluoride exchange (SuFEx) reaction between aryl fluorosulfates and silylated hydroxy groups. Efficient sulfate diester formation was achieved through systematic optimization of the electronic properties of aryl fluorosulfates. The versatility of this O-sulfation strategy was demonstrated in the scalable syntheses of a variety of complex molecules carrying sulfate diesters at various positions, including monosaccharides, disaccharides, an amino acid, and a steroid. Selective hydrolytic and hydrogenolytic removal of the aryl masking groups from sulfate diesters yielded the corresponding O-sulfate products in excellent yields. This strategy provides a powerful tool for the synthesis of O-sulfate bioactive compounds.

Keywords: carbohydrates; glycosylation; hydrolysis; sulfation; synthetic methods.

Figure 1.

Significance of O-sulfation and approaches to O-sulfation in carbohydrate and other substrates.

Figure 2.

Synthesis of aryl sulfate diesters as protected O-sulfation.

Figure 3.

Compatibility of aryl sulfate diesters to common reagents used in carbohydrate and peptide chemistries.

Figure 4.

Preparation of O-sulfated complex molecules.