Enantioselective Transition-metal-catalyzed Cyclizations via Difunctionalization of Alkenes

Asymmetric synthesis plays a critical role in the synthesis of modern pharmaceutical compounds which often contain complex stereochemical information and require a highly controlled synthesis. The Lautens group has developed numerous strategies to assemble heterocycles which often mirror key frameworks found in pharmaceutically important compounds as well as natural products. Chapters 1-4 describe a copper-catalyzed borylative cyclization strategy to access enantioenriched oxindoles, polycyclic indolines, and cyclobutanols. The in-situ generated chiral copper-boron species is proposed to undergo an enantioselective migratory insertion prior to intramolecular cyclization. The newly installed neopentyl boronate was readily converted to new carbon−carbon and carbon−heteroatom bonds. The methods were developed as a complementary strategy to established palladium-catalyzed domino cyclizations. Chapters 5-6 describe an asymmetric cobalt-catalyzed domino cyclization/C−H functionalization cascade. These reactions forge multiple new bonds in a regio-, diastereo- and enantioselective fashion. Early efforts detail the cleavage of aryl C−H bonds and their addition across 1,6-enynes in a hydroarylation cascade. The second part of the chapter discusses the development of a hydroacylation analog, using aldehydes as C−H bond donors. Chapter 7 describes a norbornene-mediated C−H functionalization Catellani-type reaction wherein two new carbon−nitrogen bonds are formed. The challenge in this process was optimizing an intermolecular process to outcompete an intramolecular cyclization. The second part of the chapter details preliminary efforts to undergo enantioselective palladium-catalyzed cyclizations where the cyclized palladium intermediate catalyzes a second cyclization prior to reductive elimination. The resulting tethered bisheterocyclic scaffolds demonstrated the utility of palladium catalysis in forging numerous new bonds.Ph.D