UC Berkeley

The icetexane diterpenoids is a group of natural products isolated from various members of the Salvia genus. These compounds contain a [6-7-6] tricyclic motif and vary by the level of oxidation on the seven-membered ring and oxygenation of the arene moiety. The synthesis of these compounds has been achieved by our group through the use of a Ga(III)-catalyzed cycloisomerization of indenyl alkynes. This thesis explores the synthesis of the icetexone subclass of diterpenoids, which contain extra functionalization, using a similar cycloisomerization strategy.

The synthesis of icetexone was first attempted through the use of a remote functionalization strategy to form the desired lactone. However, all attempts were unsuccessful. Therefore, a second generation approach using a pre-functionalized indenyl alkyne in the Ga(III)-cycloisomerization reaction yielded the desired tricyclic intermediate. A tandem epoxide opening, lactone formation, and reductive transposition sequence completed the formal synthesis of both icetexone and 5-epi-icetexone. Progress toward anastomosine, another member in this subclass, was also made.

Another family of compounds that was targeted using the Ga(III)- catalyzed cycloisomerization is the C20 diterpenoid alkaloids. This large family of natural products is found in traditional Eastern medicines and has unique and complex structures. The hetisine type of natural products is characterized by their rigid heptacyclic core and a bicyclo[2.2.2]octane motif. We believed that our Ga(III) cycloisomerization methodology would enable access to the [6-7-6] tricyclic core of these molecules as a starting point for their successful synthesis.

The synthesis of nominine was first attempted through an acid catalyzed hydroamination of a cycloheptadiene accessed from the Ga(III)-cycloisomerization. Low yields of the hydroamination as well as later transformations led us to develop a second- generation strategy that involved dihydroxylation of the cycloheptadiene and monoprotection of a resulting diol. Both routes are currently being explored to complete the synthesis of nominine.