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UBC Theses and Dissertations

Enantioselective synthesis of the sesterterpenoid (-)-dysidiolide and structurally related analogues Caillé, Sébastien


The enantioselective total synthesis of the marine natural product (-)-dysidiolide (1) is described in this thesis. In addition, six structural analogues of the sesterterpenoid were synthesized in their enantiomerically pure forms. These substances are (-)-6- epidysidiolide (25), (-)-4,6-bisepidysidiolide (148), (-)-15-epidysidiolide (26), (-)-4,15- bisepidysidiolide (181), (-)-6,15-bisepidysidiolide (27), and (-)-4,6,15-trisepidysidiolide (194) The synthesis of (-)-dysidiolide (1) started with the conversion of known racemic alcohol 35 into a,(3-unsaturated ketone 38. Diastereoselective addition of cyanocuprate 33 to the conjugated enone function of racemic 38 provided ketone 46. Ozonolytic cleavage of the alkenic bond of 46 yielded dione 59, which underwent an aldol condensation-dehydration process to afford bicyclic conjugated enone 60. A stereospecific Claisen rearrangement using allylic alcohol 64 (available from 60) as starting material produced racemic tertiary amide 80. A series of transformations were used to obtain racemic alcohol 29 from 80. The two enantiomers of 29 were separated, and enantiomerically pure alcohol (-)-29 was employed to continue the synthetic endeavor towards (-)-l. The mixture of nitriles 28 was synthesized from (-)-29 via a sequence of reactions. Diastereoselective alkylation of the anion of 28 with iodide 119 afforded nitrile (-)-120, which was converted into aldehyde (-)-6 in several steps. (-)-Dysidiolide (1) was constructed from (-)-6 according to a known procedure. The anion of 28 was alternatively alkylated with methyl iodide to produce nitrile (—)-118. Structural analogues (-)-25 and (-)-148 were constructed from the latter material. Enantiomerically pure alcohol (+)-35 was synthesized and converted into (-)-60 as described above for its racemic counterpart. A stereospecific Claisen rearrangement using allylic alcohol (-)-63 (available from (-)-60) as starting material provided tertiary amide (-)-149. The remaining four structural analogues of (-)-l, namely (-)-26, (-)-181, (-)-27, and (-)-194 were constructed from (-)-149 using sequences of reactions similar to those that were used to synthesize (-)-l, (-)-25, and (-)-148.

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