Lewis-Acid-Mediated Union of Epoxy-Carvone Diastereomers with Anisole Derivatives: Mechanistic Insight and Application to the Synthesis of Non-natural CBD Analogues

Abstract

The use of trimethylsilyl trifluoromethanesulfonate as a mild means to unite epoxy-carvone silyl ethers with anisole derivatives to yield products that are structurally similar to the CBD scaffold is reported. Importantly, unlike related methods, this process can utilize both epoxy-carvone diastereomers and does not require the use of air/moisture-sensitive organometallic reagents. Several examples of aryl nucleophiles as well as mechanistic insight based on in silico computational analysis are presented.

A Revised Modular Approach to (–)‐trans‐Δ8‐THC and Derivatives Through Late‐Stage Suzuki–Miyaura Cross‐Coupling Reactions

“…This preference has also been observed in literature, [16,17] and is most likely due to the deactivating effect exerted by the halide on the aromatic ring. Starting from 5-chloro-and 5-iodoresorcinol (8 and 9, respectively) four halide-substituted THC analogues 16/17 and 18/19 were prepared.…”

A Revised Modular Approach to D8-THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

“…Despite the difference in size of the halides, no clear trend in regioselectivity was observed, since in all cases ortho- substitution was preferred over para-substitution. This preference has also been observed in literature, [16][17] and is most likely due to the deactivating effect exerted by the halide on the aromatic ring. Selective para-substitution was only observed in case of the alkyl-substituted THC regioisomers 1 and 2 (see: Supporting Information II).…”

Palladium-catalyzed direct γ-C(sp3)–H arylation of β-alkoxy cyclohexenones: reaction scope and mechanistic insights

“…Next, the robustness of this method was examined in the synthesis of non-natural cannabidiol (CBD) derivatives, which are proven to have potent biological activities. 25 The derivatization were started from a common intermediate 1k , which could be readily prepared from both (+) and (−)-carvone with 78% yields using a three step reaction (Scheme 6). Under the “optimal” conditions, non-natural CBD derivatives 3a–3d could be obtained with 33%–64% yields in one step from intermediates 1k and 1l .…”