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
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.
University of Minnesota Ph.D. dissertation. December 2011. Major: Chemistry. Advisor: Gunda I. Georg.1 computer file (PDF): xii, 252 pages.
Cyclic enaminones: methodology development, total synthesis, and library construction..
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