Studies directed toward the syntheses of the biologically active alkaloids (-)-galanthamine and (-)-lemonomycin
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Despite the enormous amount of work devoted to the synthesis of the anticholinesterase Amaryllidaceae alkaloid, (-)-galanthamine, and the diversity of the various strategies employed, the para-alkylation of an appropriately substituted phenol to generate the cross-conjugated 2,4-cyclohexadienone has not been reported. As discussed in this dissertation, the successful implementation of the intramolecular phenolate alkylation strategy avoids the low yielding phenolic oxidation reaction used previously to generate similar intermediates. The resultant product requires a reductive amination of the aromatic aldehyde and latent aliphatic aldehyde to arrive at racemic narwedine, a biogenetically related and validated synthetic precursor to (-)-galanthamine. A methodology for the construction of enantio-enriched hydroisoquinolines was also developed, with potential application toward the synthesis of the tetrahydroisoquinoline antitumor antibiotic (-)-lemonomycin. Several approaches are discussed, with the key step being an asymmetric reduction of 1-substituted and 1,3-disubstituted isoquinolines to yield enantio-enriched hydroisoquinoline products.