Studies Toward The Synthesis Of Marine Natural Product Clionamine

Clionamines A–D are a family of marine steroidal alkaloids with autophagy bioactivity and unprecedented C3-amino group and γ-lactone ring E. In this thesis, we want to develop a feasible route for natural clionamines and their analogues.Two key intermediates, α-methylene-γ-lactone and α-oxo-γ-lactone, were prepared from pseudo-tigogenin. Pseudo-tigogenin was first oxidized with oxone to give an exocyclic enol ether, which reacts with singlet oxygen to provide α-hydroxyl-γ-lactone via a [2+2]/retro-[2+2] process. Dehydration of α-hydroxyl-γ-lactone gave α-methylene-γ-lactone in high overall yield. After oxidization, pseudo-tigogenin underwent dehydration and the resulting diene was treated with ozone to deliver α-oxo-γ-lactone, another key intermediate.Starting from α-methylene-γ-lactone, we explored four methods for installing the side chains and C20 hydroxyl to synthesizing natural and designed clionamines. A formal synthesis of clionamine B was realized via epoxidation and epoxide opening reaction. A formal synthesis of clionamine D was realized via a Mn(OAc)3-mediated [3+2]-cycloaddition to install the spiro-dilactone unit. The spiro-dilactone unit was also used as a handle to introduce side chains.