Improved Synthesis of a Biologically Active Inositol Glycan

A series of inositol glycan (IG) analogues has been synthesized in our laboratory and found to have anti-cancer activities. The activity of these IGs is believed to be related to their ability to stimulate aerobic metabolism and thereby reverse the Warburg Effect resulting in intrinsic apoptosis. This may be selective for cancer cells since normal cells are already performing aerobic metabolism. A key step in the synthesis of these IGs involves a hydroxylation reaction of a conduritol disaccharide that unselectively produces two isomers of which only one is required for the synthesis. A deoxygenation strategy is being employed to rectify the poor stereoselectivity in this hydroxylation reaction by allowing the recycling of the undesired isomer. The current scheme for the target IG utilizes a precursor that contains an azide group that is very sensitive to reduction, posing a challenge to this strategy. We are exploring two approaches to solving the problem of deoxygenation: first, a triphenylphosphine/triiodoimadazole-induced deoxygenation, and second a chlorotrimethylsilane/sodium iodide-promoted deoxygenation. In the first approach, the triphenylphosphine would certainly also reduce the azide moiety in the IG precursor necessitating reprotection of the product amine, while the second may avoid this complication. The deoxygenation reaction is being developed using a model compound, 3,4,5,6-tetra-O-benzyl-myo-inositol. To date, we have prepared the model compound via a three-step literature synthesis from myo-inositol and we are currently engaged in attempting the deoxygenations. Our progress in solving the problem of deoxygenating the model and its application toward recycling the undesired diol isomer will be reported.