NHC-Pd-PEPPSI Precatalyst: A tool for heterogeneous catalysis, selective sequential cross-coupling and natural product synthesis

In recent years, homogeneous N-heterocyclic carbene Palladium (NHC-Pd) catalysts have been recognized as efficient promoters for cross-coupling reactions. However, these homogeneous catalysts often suffer from difficulties such as the inability to recover costly noble metals and ligands for reuse. Some of these limitations can be addressed through the development of solid supported NHC-Pd catalysts. Herein, the synthesis of a variety of N-heterocyclic carbene ligands is reported. The use of these ligands to prepare the corresponding NHC-Pd-PEPPSI-Pr catalysts is also reported. The new complexes were then modified to permit easy grafting on to solid surfaces. A silica supported complex was prepared and tested in batch and continuous flow Negishi cross-coupling. The solid-supported catalyst was also shown to be recyclable. PEPPSI-IPr [PEPPSI = Pyridine- Enhanced Precatalyst Preparation, Stabilization and Initiation; IPr = diisopropylphenylimidazolium derivative].;Lastly, a chemoselective Suzuki-Miyaura cross-coupling strategy catalyzed by Pd-PEPPSI- IPr catalyst was developed in an effort to synthesize the long chain natural product-rhizochalin. Rhizochalin has anti-cancer properties and exhibits modest antibacterial activity against staphylococcus aureus and cytotoxicity against mouse Ehrlich carcinoma cells in the regulation of processes of cell growth and apoptosis. The 28-carbon framework of this natural product was rapidly assembled in a sequential manner through key transformations catalyzed by Pd-PEPPSI-IPr. Although the glycosylation step in the first synthetic approach led to an unwanted product, it provided an understanding about the reactivity of the 28-carbon scaffold thus paving the way for the development of an alternate synthetic route for rhizochalin.;Also, a general one pot protocol catalyzed by Pd-PEPPSI-IPr that allows the use of solvent polarity as a "switch" to permit the chemoselective cross-coupling of a Ca1ky1--Br bond in the presence of a dormant Caikyi --Cl bond was developed. This protocol was applied to the alkyl--alkyl Negishi cross-coupling sequence of bifunctional bromochloroalkanes to achieve various products in good yields.