Synthesis of Polycyclic Ring Systems Via C-H Bond Insertion and Enantioselective Conjugate Addition

This dissertation presents three main projects. The first discusses synthetic strategies towards the total synthesis of the natural product Maoecrystal V. The second part presents an efficient way to construct complex polycyclic ring systems. The third project describes an organocatalytic asymmetric conjugate addition of organoboronates to indole-appended enones.

A structurally complex natural product, Maoecrystal V, possesses potent biological activity against the HeLa cancer cell line. An efficient synthetic route would allow access to larger quantities of this compound. Our approach is based on a rhodium-catalyzed bridgehead C-H bond insertion method to construct a γ-lactone. Substitution of the molecule’s methylene hydrogens with deuterium or fluorine atoms allows selective functionalization of the methine C-H bond. Installation of two more rings in the molecule will finish the total synthesis of Maoecrystal V.

The alkyne/carbene cascade reaction is highly efficient and predictable in transforming simple, commercially available materials into complex polycyclic molecules, which represent the core structures of many natural products. Subsequently, we discovered an alkyne/carbamate-derived nitrene cascade reaction that leads to the formation of complex polycyclic molecules containing nitrogen atoms. Two products are produced during the reaction and their identity and ratio can be controlled by the relative size of the silyl substituent on the alkyne.

Lastly, an efficient method for the organocatalytic conjugate addition of alkenylboronic acids to indole-appended enones was developed. Most importantly, unprotected indoles can be used as substrates, which further increases the applicability of this method.