In the course of our synthetic and structural studies on highly oxidized and structurally diverse cytotoxic triterpene polyethers, which are thought to be biogenetically squalene-derived natural products (oxasqualenoids), isolated from both marine and terrestrial organisms, we have been interested in the biogenesis of polyTHF rings-containing oxasqualenoids which might be synthesized in a single event by the cascade oxacyclization from acyclic precursor squalene polyepoxides.3 In this symposium, we report that the chemical synthesis of some THE rings-containing oxacyclic terpenoids, (-)-neroplofurol (1), (+)-ekeberin D4 (2), and (±)-glabrescol (3), has been accomplished on the basis of the hypothetical biomimetic oxacyclization triggered by acidic hydrolysis of the terminal epoxide (Scheme 2). In conclusion, we demonstrated that the biomimetic epoxide-opening cascades from acyclic precursor polyepoxides 4-6 to oxacyclic terpenoids 1-3, respectively, can be reproduced in a single event by chemical reaction (Scheme 3-5). These results experimentally support the Cane-Celmer-Westley hypothesis' as a general biogenesis of natural polyethers and accumulate chemical basis for the cyclization mechanism relative to the epoxide hydrolase Lsd19^2 in the biosynthesis of lasalocid A (Scheme 1).
