Studies towards the total synthesis of nakadomarin A

The complex structure of the marine natural product nakadomarin A, 1, has made it a challenging synthetic target for organic chemists since its discovery in 1997. The Winkler group has had a longtime interest in the total synthesis of architecturally complex alkaloids such as this and other members of the manzamine family. This dissertation describes two approaches to the total synthesis of nakadomarin A 1. Due to the complexity of the precursors desired in our synthesis, a majority of this research was conducted on simpler substrates that would lead to the construction of the ABCD tetracyclic core of the natural product.* The first approach describes our plan to access the ABODE pentacyclic core structure of nakadomarin A via a key step vinylcyclopropane/cyclopentene rearrangement. This rearrangement would involve the use of the C-ring furan as the alkene rearrangement partner. It was believed that the rearrangement precursor could be derived from intermediates from the Winkler synthesis of manzamine A, a congener of nakadomarin A. Also described are the rearrangement studies on two model substrates, both of which lack the A-ring amine moiety as well as the 8-membered E-ring. A second approach to access the ABODE tetracyclic core of nakadomarin A was investigated where formation of the A- and B-rings would be accessed via a key-step Pummerer/Mannich cyclization cascade. Described herein is the application of this methodology to access spirocyclic products of Pummerer cyclization. These products were transformed over several steps into intermediates analogous to those previously described in literature to undergo Mannich cyclization to deliver the nakadomarin A core skeleton. It was demonstrated that modification of the Pummerer/Mannich cascade substrate led to the formation of the tetracyclic core of nakadomarin A via the desired cascade. *Please refer to dissertation for diagram