Gustafson Lab, Asymmetric Catalysis Meets Chemical Biology

Our lab’s research revolves around atropisomerism, a form of chirality that arises from hindered rotation about a bond.  Atropisomerism differs from other forms of chirality as racemization can occur spontaneously via bond rotation, however, when there are large groups adjacent to the axis (as is the case with the famous ligand BINAP) atropisomers can be stereochemically stable.  Atropisomerism is ubiquitous throughout drug discovery, however, is often overlooked as most examples exist as rapidly racemizing mixtures. While these molecules may be optically inactive, they will interact with their protein target in an atroposelective fashion, with the nonrelevant atropisomer contributing little to the desired activities.

At SDSU our lab has set forth to exploit atropisomerism as a design principle towards selective inhibitors of highly conserved classes of enzymes that have remained recalcitrant to selective inhibitors.

“Our hypothesis is that precluding the non-relevant atropisomer will result in increased target selectivity via removal of the non-target binding conformations.”

While there are some precedents of these effects in the medicinal chemical literature, we were the first to deliberately introduce stable atropisomerism as a strategy to increase target selectivity of a promiscuous scaffold. This approach is dependent on the ability to incorporate steric bulk adjacent to the axis in order to rigidify it. This is most efficiently achieved through C-H functionalization, however, as we started these endeavors many literature methods did not prove amenable to our systems. To overcome this we developed a new Lewis base catalyzed aromatic halogenation, leading to a mild catalytic way to incorporate chlorine, and other halogens, on diverse aromatic scaffolds. This Lewis base catalysis has proved vital to our ‘atropisomer preorganization’ studies and has since been extended to other modalities including aromatic sulfenylation. Finally, we have recently begun a program within our group that focuses on atroposelective catalysis.