Phase Switching With Productive Tags

A new synthetic approach uses phase switching to separate organic reaction products while saving a tag-removal step required in similar procedures. Traditional phase-switching systems like fluorous synthesis use tags that have to be installed and later removed. Dennis G. Hall and coworkers at the University of Alberta have now developed an alternative method (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200906710). A synthetic substrate derivatized with a boronic acid is reacted in organic solvent. Excess reagents and side-products are then removed by phase switching: The reaction mixture is exposed to a basic phase such as a solution of sorbitol, which forms a water-soluble complex with the hydrophobic boronic acid and its attached substrate but not with other components of the reaction mixture. Single or multiple reaction cycles are possible, after which the boronic acid is converted into a desired functional group. Oxidations, reductions, organometallic additions, and other reactions can be done this way. Hall and coworkers used the technique in a five-step synthesis of the drug ezetimibe, which required purification only at the end, owing to phase-switch purifications after each step.