TOTAL SYNTHESIS OF (+/-)-TETRAMETHYLMEDITERRANEOL-B

A diterpenoid having the structure proposed for the tetramethylated derivative 2 of mediterraneol B (1) has been synthesized in a stereocontrolled manner via coupling between the hydroquinone side chain 7 and the bicyclo[4.2.1]nonane core 8 followed by buildup of the 1,3-diketone functionality. The hydroquinone segment 7 was prepared easily according to the reported method. Synthesis of the key component 8 was undertaken starting from tert-butylcyclohexenone 11. The cornerstone of the synthesis is the acid-catalyzed rearrangement of bicyclo[4.2.0]octanone 10 to the ketone 9 which has the bicyclononane skeleton and has clues for further manipulation. As a model study for introduction of the 1,3-diketone functionality, bicyclo[4.2.1]nonane-2,4-dione 43 was also prepared. Methylation of the penultimate intermediate 62 under conditions reported in isolation of the natural product did not give the tetramethyl ether 2 but a mixture of the trimethyl ethers 64 and 65. With Me(3)OBF(4) and Proton Sponge, the transformation to 2 was successfully achieved. The structure of the synthetic 2 was secured by the X-ray crystallographic structure analysis of the key compound 60. However, the difference between the spectra of the synthetic 2 and those of the compound derived from the natural product suggests the structure of the latter is incorrect and requires revision.