Synthesis of Macrocyclic Ketones through Catalyst-Free Electrophilic Halogen-Mediated Semipinacol Rearrangement: Application to the Total Synthesis of (±)-Muscone

Abstract

A series of macrocycles were successfully prepared using electrophilic halogen-mediated semipinacol rearrangement under mild conditions. Although the expansion from small ring to medium ring is an energetically unfavorable process, the electrophilic halogenation was found to be powerful enough to override such an energy barrier. The rearranged products could further undergo Dowd-Beckwith rearrangement to give the corresponding one-carbon ring-expanded ketones. This approach has been applied to the total synthesis of the natural product (±)-muscone, which is widely used in modern perfumery and medicines, in a two-step sequence.

Electrochemical Radical Selenylation/1,2-Carbon Migration and Dowd–Beckwith-Type Ring-Expansion Sequences of Alkenylcyclobutanols

“…In addition, β-selenated cyclic ketone derivatives under radical-initiated Dowd–Beckwith-type rearrangement could give the corresponding one-carbon ring-expanded ketones (Scheme b). Recently, application of a one-carbon ring-expansion reaction for the synthesis of cyclic ketones has gained increasing interest in organic chemistry due to the availability of substrates as building blocks for bioactive compounds …”

Synthesis of Cyclic Fragrances via Transformations of Alkenes, Alkynes and Enynes: Strategies and Recent Progress

“…Compared to the ring-opening hydrolysis shown in the above example ( Scheme 7 b), ring expansion through rearrangement is a more common procedure. In 2017, Liu and Yeung reported a successive ring expansion strategy for the construction of macrocyclic ketones [ 101 ] ( Scheme 8 a). First, the ketone-derived allyl alcohol substrate triggered a bromide-mediated electrophilic semipinacol rearrangement to conduct the first ring expansion.…”

9‐Membered Carbocycles: Strategies and Tactics for their Synthesis

“…A recent example for the utilization of the semi‐pinacol rearrangement for the synthesis of medium‐sized rings was reported by Liu and Yeung. They treated a variety of 1‐vinylcycloalkan‐1‐ols 53 with 1,3‐dibromo‐5,5‐dimethylhydantoin (DBH, 54 ) to activate the olefin by bromonium ion formation and isolated the corresponding one‐carbon homologated β‐bromo ketones 56 (Scheme ) . These substrates allowed further ring‐expansion by the Dowd–Beckwith reaction to afford ketones 57 .…”

“…Sigmatropic rearrangements werewell explored for the synthesis of medium-sizedr ings in past decades. [35] Previously employed [1,2]-sigmatropic rearrangementsf or the synthesis of nine-membered carbocycles are the pinacol rearrangement, [36] the semi-pinacol rearrangement, [37] the Tiffenau-Demjanow rearrangement [13] and related homologation reactions of cyclic ketones involving diazo compounds. [38] The Tiffenau-Demjanow rearrangement has not found furthera pplicationi n the synthesis of nine-membered carbocycles in recent years, which can be mainly attributedt oi ts harshr eactionc onditions.…”