Laurallene (1), isolated from the red alga Laurencia Nipponica Yamada in 1979 by Fukuzawa and Kuroswa, is a representative member of the Laurencia C15-acetogenin. This compound is an attractive target for chemical synthesis due to its unique 8,5-bicyclic ether core which has four asymmetric stereocenters and chiral bromoallene side chain, and several groups have reported its total synthesis. However, more than 21 steps were necessary to accomplish the total synthesis because multistep reactions were required for stereoselective construction of such asymmetric stereocenters. Herein, we present a concise asymmetric total synthesis of 1 via a stereospecific palladium-catalyzed alkoxy substitution reaction of α,β-unsaturated-γ,δ-epoxy esters with double inversion of configuration at the γ-position developed by our laboratory as the key step. Our synthesis was commenced with the alkoxy substitution reaction of the α,β-unsaturated-γ,δ-epoxy ester 2 and C2-symmetric chiral diol 3. Because this reaction gave substitution product 4 in low yield under the original condition, we developed a new procedure in which sterically demanding secondary alcohols could be substituted. This procedure allowed stereoselective formation of 4 in good yield after treatment with NaIO4. Mukaiyama’s cobalt-catalyzed aerobic oxidative cyclization of 4 afforded 2,5-disubstituted tetrahydrofuran derivative 5 as a sole isomer. After three-step reaction sequence, diene 6 was converted into 8-membered product 7 by ring-closing metathesis with Nolan’s catalyst. Thus, the 8,5-bicyclic ether core bearing five asymmetric centers was constructed in only 7 steps from epoxy unsaturated ester 2. Primary alcohol 7 was then converted into propargylic trisylate in four-step conversion, and stereoselective SN2’ reaction of the trisylate with LiCuBr2 produced bromoallene 8. Finally, bromination of the secondary alcohol derived from 8 by Appel reaction with inversion of configuration lead to Laurallene. Total synthesis was achieved with the longest liner sequence of 16 steps from commercially available (E)-2-penten-1-ol (starting material of 2).

Total synthesis of laurallene

253rd National Meeting (2017)

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