Development of an Intramolecular Alkene Aminocyanation Reaction and Progress Toward the Total Synthesis of Drimentine C

Abstract

Part I: The first part of this Thesis describes our work towards transition metal-catalyzed N–CN bond activation and the serendipitous discovery of a metal-free, Lewis acid-promoted intramolecular aminocyanation reaction. This transformation involves the N–CN σ-bond cleavage of a cyanamide and addition across a tethered alkene resulting in indolines bearing a quaternary stereocenter and a versatile cyano group. In Part I, the reaction optimization and the scope of substrates are presented, and initial mechanistic investigations are discussed. Part II: The drimentines are a family of nine alkaloids isolated from two Actinomycete strains characterized by a novel core structure consisting of condensed pyrroloindoline and diketopiperazine moieties tethered to a sesquiterpene through a methylene bridge. In preliminary assays of biological activity, the drimentines were found to exhibit weak to moderate cytotoxicity and antibacterial activity. However, due to their unique structure, the drimentines are of interest for further study. We propose two routes for the total synthesis of drimentine C. The first route, detailed in Chapter 2, highlights the utility of C–CN bond activation. The proposed key step is a palladium-catalyzed asymmetric cyanoamidation reaction wherein the C–CN σ-bond of a cyanoformamide is cleaved and added across a pendant alkene resulting in an oxindole with a newly-formed all-carbon quaternary stereocenter. The cyano group can then be elaborated into the pyrroloindoline ring present in drimentine C. The second proposed route builds drimentine C from naturally-occurring, L-tryptophan, L-proline, and (+)-sclareolide. Three methodologies for construction of the key C–C σ-bond between the pyrroloindoline and sesquiterpene moieties are presented: (1) organocuprate addition to a cyclopropylazetoindoline intermediate; (2) nickel-catalyzed reductive cross-coupling; and (3) photoredox-catalyzed α-alkylation of an enamine. Progress toward the total synthesis of drimentine C via this convergent route is disclosed in Chapter 4.