Diastereoselective Synthesis of the Borylated <span style="font-variant: small-caps">d</span>-Galactose Monosaccharide 3-Boronic-3-Deoxy-<span style="font-variant: small-caps">d</span>-Galactose and Biological Evaluation in Glycosidase Inhibition and in Cancer for Boron Neutron Capture Therapy (BNCT)

Abstract

Drug leads with a high Fsp3 index are more likely to possess desirable properties for progression in the drug development pipeline. This paper describes the development of an efficient two-step protocol to completely diastereoselectively access a diethanolamine (DEA) boronate ester derivative of monosaccharide d-galactose from the starting material 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose. This intermediate, in turn, is used to access 3-boronic-3deoxy-d-galactose for boron neutron capture therapy (BNCT) applications. The hydroboration/borane trapping protocol was robustly optimized with BH3.THF in 1,4-dioxane, followed by in-situ conversion of the inorganic borane intermediate to the organic boron product by the addition of DEA. This second step occurs instantaneously, with the immediate formation of a white precipitate. This protocol allows expedited and greener access to a new class of BNCT agents with an Fsp3 index = 1 and a desirable toxicity profile. Furthermore, presented is the first detailed NMR analysis of the borylated free monosaccharide target compound during the processes of mutarotation and borarotation.

Keywords

• d-galactose%22%2C%22default_operator%22%3A%22AND%22%7D%7D%7D"> <span style="font-variant: small-caps">d</span>-galactose
• boronic acid
• boronate
• organic boron
• BNCT
• glycosidase