Intramolecular carbon-carbon bond formation via ruthenium and palladium catalysis: application of ruthenium catalyzed [5+2] cycloaddition for the synthesis of frondosin A and palladium catalyzed cyclizations with carbon nucleophiles

Due to the prevalence of ring systems in natural products with biological activities, methods for their construction have attracted much attention. Ruthenium and palladium catalyzed reactions are powerful tools in organic synthesis. Application of these methods for the synthesis of ring systems via intramolecular C-C bond formation is of particular importance. The total synthesis of bioactive marine natural product (+)-frondosin A employing a ruthenium catalyzed [5+2] cycloaddition and investigations of palladium catalyzed cyclizations are described herein.;The first total synthesis of (+)-frondosin A was accomplished in 19 longest linear and 21 total steps from commercially available materials. The key features include a ruthenium catalyzed [5+2] cycloaddition, a Claisen rearrangement, and a ring expansion to construct the core of the frondosin A in a diasteroselective and regioselective fashion. This is the first application of a ruthenium catalyzed [5+2] cycloaddition in total synthesis of natural products. Through this synthesis, the absolute configuration of the (+)-frondosin A was established by comparing the synthetic product with the naturally isolated one.;Intramolecular cyclizations via palladium catalyzed allylic alkylation were investigated in terms of using both bissulfones and phenols as carbon nucleophiles. Although no desired ring systems were achieved through the C-alkylation of phenols, compounds with an interesting diene moiety were observed during the reactions. The desired 5-membered carbocycle was obtained in the intramolecular allylic alkylations with a bissulfone nucleophile. More importantly, controlled by a C2-symmetric ligand developed in Trost laboratory, this palladium catalyzed process was optimized to yield the product with over 95% enantiometric excess, providing a good foundation for the future development of this reaction for the synthesis of different ring systems.