Synthesis and Evaluation of Novel Iminosugars as Potential Male Contraceptive Agents; and the Chemistry of 2,3-Dihydropyridin-4-(1H)-ones and Related Enaminones in Multicomponent Reactions

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.