Cyclic enaminones: methodology development, total synthesis, and library construction.

Abstract

The cyclic enaminone lies at the core of this entire doctoral work. It possesses exceptionally versatile reactivities, and can thus be utilized in the synthesis of various alkaloids. The first chiral-pool approach to synthesize enaminones was reported in 2006 from the Georg group. However, partial racemization was observed in some cases. Also, homologated amino acids were synthesized or purchased as a starting material. To address these issues a novel strategy, that retained the use of amino acids was sought. We found that enaminones can be synthesized using a ketene cyclization. In this approach, a pendant enamine moiety underwent a nucleophilic addition to a ketene generated by the Wolff rearrangement of a diazoketone. The diazoketone can be synthesized from α-amino acid in a one-pot procedure. Although this approach utilizes α-amino acids and provides enantiopure enaminones, the solubility of amino acids as well as the use of diazomethane to prepare diazoketone became major obstacles to the scalable synthesis of various enaminones. In this regard, alternative methods to synthesize the diazoketones were explored. We found that diazoketones could be obtained from three readily available components: a primary amine, an alkyne, and bromo diazoacetone. Although the incorporation of chirality was not achieved, a wide variety of enaminones were synthesized in two steps from commercially available compounds, providing a facile access to an enaminone library. Enantiospecific syntheses of (–)-(5S,8R,9S)-5-(3-furyl)-8-methyloctahydroindolizin and its C8-epimer were accomplished using our enaminone chemistry. The devised synthetic routes are conventional but reliable and scalable, providing access to Nuphar alkaloids in 9 steps from N-Boc-(L)-proline. This work led to the correction of multiple prior publications. We were able to disclose the bindings of the major isomer to the central nervous system receptors. Although phenanthropiperidines are promising anti-cancer agents due to their potency, their neurological toxicities thwart therapeutic use. Assuming that the side-effects are caused by the blood brain barrier permeation of phenanthropiperidines due to their extremely lipophilic nature, endeavors to prepare a polar phenanthropiperidine library were made. Specifically, the synthesis of hydroxylated phenanthroquinolizidines was attempted. However, most of those compounds were found to be unstable.