UC Berkeley

Abstract

New Reactions and Synthetic Strategies toward Indolizidine Alkaloids and Pallavicinia Diterpenes

by

Alison Rae Hardin Narayan

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Richmond Sarpong, Chair

Strategies toward indolizidine alkaloids and pallavicinia diterpenes have been established. The first six chapters of this thesis are devoted to the development and execution of approaches toward N-fused bicycles and their application to the synthesis of indolizidine alkaloids. The final chapter details efforts toward the synthesis of pallavicinin and related diterpenes.

An overview of the indolizidine alkaloids is provided, including the major structural distinctions of the subclasses of these alkaloids as well as their known biological activity. This sets the stage for a discussion of our synthetic approach toward this class of natural products, aiming to build these molecules from indolizine and indolizinone precursors.

Several methods were developed to rapidly access indolizines and indolizinones. Specifically, the platinum-catalyzed cycloisomerization of propargylic esters to 2,3-disubstituted indolizines was realized. The nuances of the effect of the substrate's electronic properties on the reaction pathway were studied and this knowledge was utilized to develop a reaction selective for the formation of 2,3-disubstituted indolizines over the 1,3-disubstituted products. Subsequently, a metal-free version of a previously established metal-catalyzed cyclization was identified for the formation of 1,3-disubstituted indolizines and indolizinones.

With methods in place to form substituted indolizines and indolizinones, these bicycles were employed in the synthesis of indolizidine alkaloids. First, indolizine precursors were used to accomplish a five-step total synthesis of indolizidine 209D and a formal synthesis of securinine. Next, the innate reactivity of indolizinones was explored and applied to the synthesis of tricyclic marine alkaloids. From indolizinone building blocks, two routes were established to the tricyclic cylindricine core. The first approach toward the cylindricines featured a ring-opening/ring-closing metathesis to assemble the cis-6,6-ring fusion conserved throughout this family of natural products. The second approach toward the cylindricines employed a ring-contractive cyclization to form a tricyclic indolizinone, which served as a common intermediate to both the cylindricine and the closely related lepadiformine alkaloids. The ring-contractive cyclization approach led to the synthesis of the cylindricine core in eight steps. Additionally, progress toward lepadiformine C from an intermediate accessed in the cylindricine synthesis has been achieved.

Finally, a strategy toward pallavicinin and related diterpenes has been tested. The approach features a gold-catalyzed cyclization to construct the [3.2.1]bicycle of pallavicinin and an Eschenmoser-Claisen rearrangement to form a key carbon-carbon bond. This strategy has been successful for the formation of the 8,9-epi,epi-pallavicinin tetracycle.