Palladium Catalyzed Cyclization and C‒O Bond Formation Cascade, and Its Application in Total Synthesis

Chapter 1. Total synthesis inspired cascade reactions Total synthesis of complex natural products has long inspired many creative methodologies. Cascade reactions have shown their ability to construct complex structures in total synthesis. In our group's former work on (-)-presilphiperfolan-8-ol, a cascade cyclization was used to construct the highly strained molecule. Inspired by our former results and synthesis of terpenes possessing a 1,3-trans structure, such as botrydial, we designed a cascade reaction. Chapter 2. Palladium catalyzed cyclization and C‒O bond formation cascade Heck type cyclizations and nucleophilic attack cascades matched the stereochemistry demand. However, a C‒O bond formation process, which was required in those terpene syntheses, was not precedented. To find a solution of the challenge, we developed a cyclization and C‒O bond formation cascade. The methodology worked for a wide scope of substrates, resulting in moderate to high yields. We investigated the mechanism and found that a SN2 process though a cyclopropane intermediate would be the most possible, deferent from original proposal. The methodology was used in total synthesis of botrydienal and epi-10-oxodehydro-dihydrobotrydial, indicating the potential power of this methodology in organic synthesis. Chapter 3. Synthetic study towards paraliane family of natural products Paralianes are terpenes with complex tetracyclic structures. They are bioactive in an anti-inflammatory capacity. Though first isolated in 1998, none of the members in this family have been synthesized. We synthesized the east fragment with our palladium catalyzed methodology. The west fragment was synthesized from a commercial chiral starting material. The two fragments were coupled together by the Nozaki–Hiyama–Kishi reaction. In model study we achieved the unprecedented Mukaiyama radical coupling of alkene and aldehyde. Further study is still going on in real system to synthesize the target molecule.