The first total synthesis of (À)-rotundone has been accomplished from (+)-(R)-limonene and therefore for the first time from an unrelated monoterpene instead of modifying structurally closely related sesquiterpene precursors such as α-guaiene. Challenges such as intermediates with stereocenters prone to epimerization by enolization were overcome by designing a β-methyl-keto route starting from (+)-(R)-limonene which finally gave (À)-rotundone by Nazarov cyclization of a precursor 13a. Diastereomer (À)-epi-rotundone was separated from (À)-rotundone chromatographically. An alternative route from rac-citronellal provided a diastereomer mixture of racemic Nazarov precursor 13 through a TRIP-catalyzed intramolecular aldolization, thus indicating that the Nazarov cyclization precursor 13a is in principle accessible from (À)-(S)-citronellal. The 11-step synthesis from (+)-(R)-limonene with ca. 1 % overall yield confirmed the absolute configuration of (À)-rotundone and provided samples of good olfactory quality.
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