Stereoselective Heterocycle Synthesis via Alkene Difunctionalization: Bulky Phosphine Ligands Enable Pd-Catalyzed Arylhalogenation, Arylcyanation and Diarylation

Due to the ubiquity of heterocyclic scaffolds in naturally occurring compounds and pharmaceutical drugs, an important longterm goal in organic chemistry has been developing new heterocycle syntheses. Research in the Lautens group has led to many advances in this field, specifically using Rh and Pd as catalysts. Our group recently discovered the Pd-catalyzed aryliodination reaction which proceeds via a challenging C(sp3)–I reductive elimination from Pd(II), and affords access to diverse 5- and 6-membered heterocycles. This reaction was a starting point for the research described herein which involves several new stereoselective heterocycle syntheses. Chapter 1 describes the synthesis of three different classes of heterocycles using the alkene aryliodination methodology: isochromans, chromans, and dihydroisoquinolinones. The use of amine bases was found to be key in these transformations. The dihydroisoquinoline synthesis was employed as the key carbon–carbon bond forming step in the formal synthesis of the polycyclic alkaloid natural product (+)-corynoline. Chapter 2 discusses the development of a two highly diastereoselective Pd-catalyzed arylcyanation methodologies which were inspired by a challanging alkylation step in the aforementioned formal synthesis. The first methodology generates enantioenriched nitrile-containing dihydroisoquinolinones, and was found to irradicate multiple problems that were faced during our initial route to (+)-corynoline. The second method utilized indoles as substrates in order to execute the first dearomative bisfunctionalization via arylcyanation. Chapter 3 discusses the extention of the indole dearomatization methodology wherein both a dearomative syn 1,2-diarylation and a syn 1,2-arylvinylation were achieved. This methodology utilizes readily available aryl and vinyl boroxines as coupling partners, and exhibits an extremely large substrate scope where products can be obtained as single diastereomers. Chapter 4 discusses the use of diiodinated aromatic compounds in a site-selective intramolecular aryliodination, as well as an intramolecular aryliodination/intermolecular Mizoroki-Heck reaction. The Pd/QPhos combination is capable of undergoing reversible oxidative addition to aromatic carbon–halogen bonds, and this rare characteristic is what allows this reaction to proceed to high levels of conversion.Ph.D