Indole alkaloids are a large and diverse family of natural products that display a variety of medicinal properties. These natural products have consistently proven difficult to synthesize, due in large part to their complex skeletons and sterically hindered quaternary carbon centers. We have reported the efficient syntheses of polycyclic indole derivatives using gold catalysts, which selectively activate alkynylindoles for tandem cyclizations with high stereospecificity. The facile nature of these methods has allowed previously implausible diversity syntheses to be carried out yielding a large and highly diverse library of polycyclic indolines. Biological screenings revealed compounds that selectively re-sensitize methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics, which may herald a new way of staving off the incursion of drug-resistant strains of common human pathogens.

Tricyclic indolines are common in both natural products and synthetic chemical probes. In this study we demonstrated that enantiomerically pure tricyclic indolines can be prepared from an inexpensive commmercially available chiral starting material, pyroglutamic acid. The synthesis features a highly diastereoselective gold-catalyzed cyclization of alkyne-tethered indoles and subsequent diastereoselective reductive ring-opening reaction. Using this approach, we synthesized analogs of our previously discovered tricyclic indoline probes that possess antibacterial and resistance-modifying activity. The biological activity against methicillin-resistant Staphylococcus aureus (MRSA) of these analogues was evaluated and reported. The synthetic approach reported may be leveraged in the future to prepare diastereopure chemical probes for the determination of biological targets for drug discovery.