Synthesis of Galectin Inhibitors by Regioselective 3'- O-Sulfation of Vanillin Lactosides Obtained under Phase Transfer Catalysis

Abstract

Vanillin-based lactoside derivatives were synthetized using phase-transfer catalyzed reactions from per-O-acetylated lactosyl bromide. The aldehyde group of the vanillin moiety was then modified to generate a series of related analogs having variable functionalities in the para- position of the aromatic residue. The corresponding unprotected lactosides, obtained by Zemplén transesterification, were regioselectively 3'-O-sulfated using tin chemistry activation followed by treatment with sulfur trioxide-trimethylamine complex (Men₃N-SO₃). Additional derivatives were also prepared from the vanillin's aldehyde using a Knoevenagel reaction to provide extended α, β-unsaturated carboxylic acid which was next reduced to the saturated counterpart.

Keywords: Knoevenagel-Doebner reaction; cancer; galectins; lactosides; phase transfer catalysis; sulfation; vanillin.

Figure 1

Top panel: Synthetic strategy for simultaneous modifications of lactose at the anomeric position with aromatic vanillin aglycon together with incorporating an anionic sulfate group at O-3′. Lower panel: Left panel: Predicted Connelly surface of the Gal-8 N-terminal (PDB 3AP6) with docked compound 12 that was superimposed to the original O-3′-sulfated lactose. Right panel: Schematic representation of Gal-8 N-terminal illustrating the beta strands and Arg45 and Arg59 (S4 section) are clearly in electrostatic contact with the sulfate group [4,27].

Scheme 1

Phase Transfer Catalysis (PTC)-catalyzed synthetic steps leading to vanillin-based lactosides 5–8 using peracetylated lactosyl bromide 1 and vanillin derivatives 2–4.

Scheme 2

Tin acetal catalyzed regioselective 3′-O-sulfation of vanillin derivatives 5–8.

Scheme 3

Knoevenagel–Doebner condensation reaction for the synthesis of α, β-unsaturated lactosides 17–20.