| dc.description.abstract | The iminosugar N-butyl-1-deoxynojirimycin (nB-DNJ) has reversible, nonhormonal
contraceptive effects on C57B/L6 mice at micromolar concentrations.
In order to increase the potency and bioavailability of this lead compound, a
series of novel iminosugars was synthesized as inhibitors of two potential target
enzymes – ceramide-specific glucosyltransferase (CGT) and β-glucosidase 2
(GBA2). The new derivatives were shown to be inactive as inhibitors of CGT and
are awaiting testing in a GBA2 assay. Efforts were made to identify additional
protein targets of the iminosugars by preparing two iminosugar affinity labels that
were used to isolate a potential new iminosugar target.
A method was developed to functionalize 2,3-dihydropyridin-4(1H)-ones
by taking advantage of the nitrogen-induced nucleophilicity of the beta-carbon
(C5) of the enamine moiety. Reaction of 2,3-dihydropyridin-4(1H)-ones with
aliphatic and aromatic aldehydes under acidic conditions furnished 5,5’-
(methylene)bis(2,3-dihydropyridin-4(1H)-ones). In the presence of the reducing
agent triethylsilane, the same reaction provided C5 alkylated derivatives. This
chemistry was extended to 4-(pyrrolidin-1-yl)furan-2(5H)-one, an enaminone with
an exocyclic nitrogen. A three-component Mannich aminomethylation of 2,3-
dihydropyridin-4(1H)-ones and 4-(pyrrolidin-1-yl)furan-2(5H)-one, carbamates,
and formaldehyde was achieved when lithium perchlorate was present in the
reaction mixture. This chemistry was extended to the reaction of exocyclic
enaminones with formaldehyde and malonates to furnish the corresponding
methylmalonates. Mechanist studies suggest that this reaction proceeds via the
formation of 2-methylenemalonates (Knoevenagel condensation), which is
followed by a nucleophilic (Michael) addition of the enaminone to the
methylenemalonates. The methylmalonate reaction products were cyclized
under acidic conditions to form bicyclic lactams (octahydroquinoline-3-
carboxylates and cyclopenta[b]pyridine-3-carboxylates). Oxidation of the
octahydroquinoline-3-carboxylates furnished 2,5-dioxo-1,2,5,6,7,8-
hexahydroquinoline-3-carboxylates, a class of compounds known to possess ionotropic properties. In a related reaction, 3-aminocyclohex-2-enones,formaldehyde and methyl cyanoacetate directly furnished the corresponding bicyclic 2,5-dioxo-1,2,3,4,5,6,7,8-octahydroquinoline-3-carbonitriles. In this case
the reaction was catalyzed by a phosphine, which promoted both, the Knoevenagel reaction and the bicyclic lactam formation. | |
