The development of new synthetic methods and their application towards the total synthesis of natural products constitutes the foundation of organic synthesis. Natural products are a rich pool from which a plethora of compounds with medicinal and industrial significance have been discovered. The development of new synthetic methods allows synthetic chemists to access complex structures in an elegant and economical manner. This dissertation details the development of a new synthetic methodology for the construction of chiral tertiary stereocenters, as well as the development of a route towards the synthesis of a complex marine natural product with fascinating biological activity. The first part of this dissertation describes the development of a method for the enantioselective alkylation of 2-alkypyridines controlled by organolithium aggregation. Chiral pyridines are prevalent motifs in the fields of medicinal chemistry and catalysis; however, these structures are challenging to access by traditional asymmetric alkylation methods that employ covalent chiral auxiliaries. Our study demonstrates that employing a noncovalent chiral lithium amide facilitates the asymmetric alkylation of 2-alkylpyridines via organolithium aggregation. Our model for the transfer of chiral information from the chiral auxiliary to the substrate was confirmed following characterization of the crystal structure of the organolithium aggregate.
The second part of this dissertation focuses on efforts towards the synthesis of portimine A. This marine derived spirocyclic imine is structurally and biologically unique within the cyclic imine family. An Ireland-Claisen rearrangement that utilizes distant stereocontrol from a chiral directing group is utilized to form key contiguous quaternary and tertiary stereocenters, while obviating the need for the synthesis of a chiral secondary alcohol. This strategy is highly convergent and enables rapid access to a complex and extensively functionalized framework. The cyclohexene diene portion was constructed by an elegant enyne metathesis reaction that has not yet been employed to the synthesis of any members of the cyclic imine family. Finally, an unprecedented approach to macrocyclization was accomplished by means of N-heterocyclic carbene catalysis.