Synthesis of C-1 Homologues of Narciclasine

Abstract

This thesis describes current progress towards the total synthesis of C1-homologues of the Amaryllidaceae alkaloid narciclasine (1), a powerful anticancer agent which suffers from a poor solubility profile. A 15-step chemoenzymatic total synthesis of C-1 carboxymethyl narciclasine (248) was accomplished. A key step in this convergent synthesis is the formation of the C ring syn-diol moiety via the chemoenzymatic dihydroxylation of ortho-dibromobenzene to provide the corresponding cis-dihydrodiene diol as a single enantiomer, which constitutes an efficient method of generating chiral substrates from readily available commercial materials. The dense A ring functionalities are derived from another commercially available unit; ortho-vanillin, via previously established protocols. Further key steps involve a nitroso Diels-Alder reaction and an intramolecular Heck reaction. The C-1 homologue that was prepared, 248, was then tested for its biological activity against natural narciclasine as the positive control. Experimental and spectral data are provided for all novel compounds.