Acid–induced Favorskii–type Reaction: Regiocontrolled Elimination of Acyloin Mesylates Leading to α,β-Unsaturated Ketones and Application to Formal Total Synthesis of (R)-Muscone from Racemic Muscone

A highly regiocontrolled acid-induced Favorskii-type elimination reaction using unsymmetrically-substituted acyloin mesylates proceeded smoothly to give more substituted α,β-unsaturated ketones under mild conditions. Not only acyclic mesylates but also cyclic acyloin mesylates produced the corresponding higher substituted (thermodynamically stable) α,β-unsaturated ketones via distinctive double-bond-migration pathway. The regioselectivity is nearly exclusive in all 8 examples examined. A plausible fundamental pathway for this regiocontrolled elimination is proposed; (1) isomeric enol and/or cyclopropane formations proceeds to give the cationic intermediate and/or the cyclopropane intermediate, respectively, (2) successive crucial step for regioselective MsOH (or H2O) elimination concomitant with specific proton withdrawal leads to the corresponding intermediates, the major E1’-like dienol and the minor E1-like dienol, (3) final tautomerization affords more substituted α,β-unsaturated ketones. Mechanistic speculations for the plausible mechanism and exo/endo selectivity for cyclic acyloin mesylates are also described. The present reaction was applied to a successful synthesis of “chiral” (R)-muscone precursor from readily available “racemic” muscone.