1 Department of Chemistry, Technical University of Denmark2 Organic Chemistry, Department of Chemistry, Technical University of Denmark3 Department of Organic Chemistry, Technical University of Denmark
Chapter 1. Build/Couple/Pair Strategy Combining the Petasis 3-Component Reaction with Ru-Catalyzed Ring-Closing Metathesis A “build/couple/pair” strategy for the efficient and concise (2-5 step) synthesis of structurally distinct skeletons is described. A Petasis 3-component reaction is used to synthesize anti-amino alcohols displaying pairwise reactive combinations of alkene moieties. Upon treatment with a ruthenium alkylidene catalyst, these dienes selectively undergo ring-closing metathesis reactions to form skeletally distinct heterocycles. In addition, a ruthenium-catalyzed tandem RCM/isomerization/Nalkyliminium cyclization sequence to hitherto unknown oxazabicyclooctane derivatives is developed which grants an extra element of skeletal diversity. Further skeletal diversification reactions utilizing palladium-catalyzed ring-contraction and intramolecular Diels-Alder reactions are also demonstrated. Chapter 2. Multifunctional Catalysis: Synthesis of Heterocycles from Simple Starting Materials A multifunctional catalysis approach, involving a ruthenium-catalyzed tandem ringclosing metathesis/isomerization/N-acyliminium cyclization sequence, is described. Double bonds created during ring-closing metathesis isomerize to generate reactive Nacyliminium intermediates which undergo intramolecular cyclization reactions with tethered heteroatom and carbon nucleophiles. In the tandem process, two new rings are formed, where a single metal catalyzes two mechanistically distinct reactions in one chemical operation. In this way, a series of interesting indolizidinones are formed in good yields with excellent diastereoselectivities, including a formal total synthesis of the antiparasitic natural product harmicine and the first total synthesis of mescalotam. Furthermore, preliminary asymmetric variants of the tandem process have been identified, affording indolizinoindoles in up to 60% ee.