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UBC Theses and Dissertations

Total synthesis of (±)-kelsoene and synthetic approaches to (±)-isomulinic acid Garcia, Josué Arturo Orellana


The total synthesis of the unique tricyclic terpene natural product (±)-kelsoene was achieved in 15 steps from commercially available cyclopent-2-en-1-one (418) and the Afunctional reagent 4-chloro-2-trimethylstannylbut-1-ene (32). Bicycle rac-34 was constructed in two steps from enone 418 and served as the diquinane core of the natural product. The relative configuration of the carbon chirality center at C-8 was established through a highly diastereoselective homogeneous hydrogenation of rac-34 using Wilkinson's catalyst. Compound rac-59 was converted to enone rac-61 in four steps using established methods. A highly diastereoselective [2+2]-photocycloaddition of ethylene to enone rac-61 served to construct the four-membered ring of ketone rac- 64 and establish the carbon chirality centers at C-2 and C-5. Ketone rac-64 was converted to alkene 143 using Lombardo's reagent. Hydroboration of alkene 143 and subsequent oxidation of the resulting material furnished alcohol 144. This material was transformed into (±)-kelsoene in five steps using established methods. [diagrams not included] The total synthesis of the tricyclic sesquiterpenoid natural product (±)-isomulinic acid (39) was attempted using four distinct strategies. Bicyclic enone 193 has the correct relative configuration at C-3 and C-5 and served as the platform for all the synthetic approaches attempted. Keto ester 189 was constructed from enone 193 in 8 steps. The alkylation of keto ester 189 with bifunctional reagent 36 furnished compound 226, which has the incorrect relative configuration at C-10, as the major product. Alkene 228 was viewed as a key intermediate in the second synthetic approach to (±)-isomulinic acid. It was hoped that a highly diastereoselective [2+2]- photocycloaddition of 228 to a suitable partner would furnish a tricyclic such as 229. Ketone 249 was prepared from enone 193 in 5 steps but did no yield access to alkene 228. Similarly, alkene 273 was constructed from enone 193 in 6 steps but did not yield access tb alkene 228. Enone 293 was efficiently prepared from enone 193 and was transformed into ketone 299 through a heterogeneous hydrogenation. Although ketone 299 possesses the correct relative configuration at C-9 and C-10, it could no be prepared in large scale due to its instability under the conditions used for its preparation. Ketone 309 was prepared from enone 193 using a sequence of reactions similar to those used to prepare ketone 299. Ketone 309 was elaborated to a bicycle 377, using a 12-step sequence of reactions. Due to an unforeseen side reaction, the ettempted homologation of the aldehyde moiety of 377 resulted in the formation of aldehyde 398. It could be shown that tricycle 402 could be prepared from 398. [diagrams not included]

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