A six-step total synthesis of α-thujone and d₆-α-thujone, enabling facile access to isotopically labelled metabolites

Abstract

The short synthesis of α-thujone relies on the functionalization of the readily available dimethylfulvene. Furthermore, the three main metabolites of the natural product were also synthesized. Since d-acetone can be used as a starting material, the route developed allows for the facile incorporation of isotopic labels which are required for detecting and quantifying trace amounts via GC/MS analysis.

Copper‐Catalyzed Enantioselective Arylative Desymmetrization of Prochiral Cyclopentenes with Diaryliodonium Salts

“…Finally, the hydroxy‐group‐directed Simmons–Smith cyclopropanation of 4 a under Furukawa conditions afforded bicycle 10 in 81 % yield as a single diastereomer. This reaction provides efficient access to analogues of thujone ( 11 ), an inhibitor of the γ‐aminobutyric acid A (GABAA) receptor …”

“…Saponification of 3a (NaOH in ethanol, 50 8 8C) furnished carboxylic acid 8 (83 %), which was subsequently converted into the bridged bicycle 9 (73 %) under standard iodolactonization conditions.F inally,t he hydroxy-group-directed Simmons-Smith cyclopropanation of 4a under Furukawa conditions [26] afforded bicycle 10 in 81 %y ield as as ingle diastereomer.T his reaction provides efficient access to analogues of thujone (11), an inhibitor of the g-aminobutyric acid A(GABAA) receptor. [27] In summary,w eh ave developed ac opper-catalyzed enantioselective arylative desymmetrization of prochiral 4substituted or 4,4-disubstituted cyclopent-1-enes with diaryliodonium salts and found that the achiral counteranion of the iodonium salts had an important effect on the enantioselec-…”

Continued Progress towards Efficient Functionalization of Natural and Non‐natural Targets under Mild Conditions: Oxygenation by C−H Bond Activation with Dioxirane

“…[57] The late-stage CÀHo xidations trategy also provedt ob ee ffective for the synthesis of hydroxylated main metabolites of monoterpenen aturalp roduct a-thujone (36), [60] with TFDO, as reported by Tiefenbacher and co-workersi n2 016 (Scheme 13). [61] Further,t he screening of severalo xidants showedt hat TFDO is the reagent of choice to carrying out the direct and clean conversion of 35 into 7-OH-a-thujone (36)i n 69 %y ield (Scheme 13). [61] For example, the use of ozonea ffords considerable overoxidation products,l owering the yield of the hydroxylated product 36 (47 %, Scheme 13).…”

“…[61] Further,t he screening of severalo xidants showedt hat TFDO is the reagent of choice to carrying out the direct and clean conversion of 35 into 7-OH-a-thujone (36)i n 69 %y ield (Scheme 13). [61] For example, the use of ozonea ffords considerable overoxidation products,l owering the yield of the hydroxylated product 36 (47 %, Scheme 13). [62] The bryostatins,ac lass of highly oxygenatedm acrolides, are characterized by ar emarkable range of biological activities, [63] but prevalent is their ability to modulate the activity of protein kinase Cs imilar to that of phorbol( 16)a nd related natural products.…”

A synthesis of deuterated methyleugenol via transition metal‐catalyzed coupling of substituted deuterated benzyl chloride with vinylmagnesium bromide

“…Analytical studies might also benefit from labelled standards, as it was recently shown with the synthesis of deuterated thujone, or deuterated fatty acids . In these studies, multi‐ or fully deuterated compounds were prepared since quantification of trace amounts in complex mixture via GC/MS analysis required multiple labelling.…”