Synthetic Studies of Bioactive Nature Products: Azaspiracid-1 and Angelmicins

The trioxadispiroketal residue in the marine biotoxin azaspiracid-1, which exists in a configuration capable of a double anomeric effect, is believed to be the thermodynamically most stable bis-acetal diastereomer. In order to get insight into how structural factors affect this equilibrium, a simplified ABC trioxadispiroketal analog of azaspiracid-1 was synthesized and subjected to equilbration and computational studies. These results suggest that while a double anomeric effect may play a major role in the stability of the trioxadispiroketal configuration in the more complex natural product, the substituion pattern of the C ring is also a contributing factor.;Angelmicins B (hibarimicin B) was first isolated from Microbispora rosea by Uehara and co-workers in 1993. It is a potent v-Src protein tyrosine kinase (PTK) inhibitor (IC50=23 muM), and also shows growth inhibiting and differentiation inducing activity on human myeloid leukemia (HL-60) cell lines (IC50=57 nM).;The work reported in this part of the thesis presents a divergent synthetic strategy for the angelimicin family of anthraquinoid natural products, involving conversion of a central highly oxygenated decalin intermediate to the AB and A'B' subunits. The strategy centers on an intramolecular Diels-Alder (IMDA) reaction on a triene to provide the complex highly oxygenated decalin, which is elaborated to tricyclic AB and bicyclic A'B' subunits. The differentiating tact in the two syntheses is control of the Suarez radical fragmentation of lactol precursors by modulation of the structural rigidity of the substrate. A more flexible lactol gave the AB tricyclic framework, whereas a more rigid substrate led to the A'B' bicyclic precursor, presumably through divergent pathways from the radical produced in the initial fragmentation step.;Given the symmetry with respect to the biaryl bond of HMP-Y1 (hibarimicin-mutant product Y1, a biosynthesis precursor of angelmicin B), a bi-directional synthesis is attempted. The bi-directional donors for Hauser annulation and Michael-Dieckmann condensation were synthesized from known 2,3,5-trimethoxytoluene in 27% and 42% yield, respectively. When they are applied to the annulation with cyclohex-2-enone, the Hauser annulation was unsuccessful while Michael-Dieckmann condensation gave 40% yield. However, the subsequent required aromatization of Michael-Dieckmann condensation product was unsuccessful.