R. Gillespie
2020
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Abstract
Quassinoids constitute an intriguing class of natural products which are exclusively isolated as the bitter principles of Simaroubaceae. These triterpenoid lactones possess architecturally complex and highly oxidized scaffolds and exhibit a large spectrum of biological properties including antimalarial, antitumor, and insecticidal activities. One prominent example is javanicolide A I, whose tetracyclic skeleton is decorated with ten contiguous stereocenters and contains nine oxygen atoms within its structure. The first chapter of this thesis details our work towards the synthesis of I. Recognition that many quassinoids, including javanicolide A feature a central 6-oxabicyclo[3.2.1]octan-3-ol scaffold fused to a fiveor six-membered ring (scheme I, highlighted in red) guided our retrosynthetic analysis. EVANS’ charge-affinity analysis revealed that the 6-oxabicyclo[3.2.1]octane core of II could be assembled through a cascade reaction, either from enyne III via cycloisomerization, or from aldehyde IV via a PRINS cyclization. Scheme I. “Structure-goal” guided retrosynthesis of Javanicolide A. Enyne IV (scheme I) was synthesized in four steps and 33% yield from α,β-unsaturated keto ester V (scheme II). Attempted cycloisomerization reactions to forge the oxabicyclo[3.2.1]octane core in a single step were met with failure as we obtained complex mixtures of products upon treatment of III with a variety of π-acids. Aldehyde IV was accessed in five steps and 15% overall yield from V. Exposure of IV to tin(IV) chloride facilitated PRINS cyclization to give tricyclic alcohols VI and VII in 75% combined yield.