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Radical Addition of Acetone to Alkenes: Two Short Routes to Muscone

Contact Author David Munro and Ken Palmer
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(–)-3-Methylcyclopentadecanone, known as muscone (Figure 1 [1]) is the principal odorous constituent of the musk deer gland. It represents a benchmark of musk odor that is in great demand for perfumery use. Prior to the elucidation of its structure1 in 1926, the existence of macrocyclic molecules was not widely accepted. Many syntheses of both the optically active material2-11 and racemic muscone12–23 have been reported.

Despite the elegance of these syntheses, most suffer the disadvantage of the large number of steps involved in their production. Where ingenious efforts have minimized the synthetic stages, these have still required specialized equipment and processes which have limited their industrial application. There has not been, as yet, a short, safe, and efficient method of production that employs inexpensive and readily accessible starting materials. Herein, we report two such syntheses that feature, in their initial stage, the radical addition of acetone to a suitable alkene through the in situ generation of manganese (III) by a redox reaction.

Accordingly, the radical reaction of acetone with methyl undecylenate (Figure 2 [2]), mediated by potassium permanganate, gave a good conversion (82% by glc) to methyl 13-oxotetradecanoate (Figure 2 [3]). Wittig-Horner reaction of methyl 13-oxotetradecanoate with trimethyl phosphonoacetate, followed by catalytic hydrogenation, resulted in dimethyl 3-methylpentadecanedioate (Figure 2 [4]). This can be used to give the methyl substituted 15- membered cyclic ketone via intramolecular acyloin condensation, a well-known macrocyclisation technique that, being a heterogenous reaction where both ester groups must come into contact with the metal surface, does not suffer from the usual disadvantage of needing uneconomical high-dilution conditions.