A practical deca-gram scale ring expansion of (R)-(−)-carvone to (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1

Abstract

A route to enantiopure (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1, an intermediate for terpenoids, has been developed and includes a highly chemo- and regioselective Tiffeneau-Demjanov reaction. Starting from readily available (R)-(-)-carvone, this robust sequence is available on a deca-gram scale and uses flow chemistry for the initial epoxidation reaction. The stereochemistry of the addition of two nucleophiles to the carbonyl group of (R)-(-)-carvone has been determined by X-ray diffraction studies and chemical correlation.

The Chemistry of the Sesquiterpene Alkaloids

“…22 Our laboratory has investigated the guaipyridines, in a diversity oriented synthetic approach to several different sesquiterpene frameworks, based upon the large-scale availability of a chiral enantiopure cycloheptenone intermediate produced from naturally occurring (R)-(−)-carvone (Scheme 13). 23 Alkylation of the cycloheptenone produces the xanthane sesquiterpene carbon skeleton, and then treatment with NH 3 cyclises to guaipyridine. …”

Advances in the Continuous Flow Synthesis of 3‐ and 4‐Membered Ring Systems

“…This method rendered a variety of spirocyclic cyclopropanes under mild conditions and with faster rates than analogous batch reactions [15] . Using a Corey‐Chaykovsky cyclopropanation reaction in this approach is complementary to an earlier report by Ley and Brocksom who demonstrated the scaled formation of an epoxide under analogous conditions whereby carvone was used as a precursor to a cycloheptenone building block [16] …”

“…[15] Using a Corey-Chaykovsky cyclopropanation reaction in this approach is complementary to an earlier report by Ley and Brocksom who demonstrated the scaled formation of an epoxide under analogous conditions whereby carvone was used as a precursor to a cycloheptenone building block. [16] In addition, Mateos and co-workers disclosed a gram-scale flow approach towards cyclopropanes exploiting a Wadsworth-Emmons reaction of epoxide substrates. [17]…”

Continuous flow reactions in the preparation of active pharmaceutical ingredients and fine chemicals

“…In 2015, the ring expansion of (R)-(À)-carvone ( 8) to (R)-(+)-3-methyl-6isopropenylcyclohept-3-enone-1 (10) was reported in collaboration with Steven Ley's laboratory (Scheme 3). 28 This protocol involved as the key step the continuous epoxidation of (R)-(À)-carvone (8), affording product 9 in 95% yield on a multigram scale (9.35 g, 57 mmol). A significant observation is that we were able to use DMSO without any previous treatment.…”