Brønsted acid-induced transannulation of the phytochemical zerumbone

• Published in: Organic & biomolecular chemistry 2021-12, Vol.19 (47), p.1444-1454
• Main Authors: Kashiwazaki, Gengo, Watanabe, Ryo, Tsuzuki, Terutaka, Yamamoto, Chieko, Nishikawa, Atsuya, Ohtomo, Satoru, Yoshikawa, Tomomi, Kitamura, Yuto, Utaka, Yoshimi, Kawai, Yasushi, Tsuchida, Noriko, Kitayama, Takashi
• Format: Article
• Language: English
• Subjects: Acetic acid; Acids - chemistry; Adducts; Coherence; Crystallography; Crystallography, X-Ray; Density functional theory; Ethyl acetate; Gas chromatography; Intermediates; Isomerization; Isomers; Lewis acid; Models, Molecular; Molecular Conformation; Molecular Structure; NMR; Nuclear magnetic resonance; Phytochemicals - chemistry; Phytochemicals - isolation & purification; Protonation; Quantum phenomena; Reaction mechanisms; Sesquiterpenes - chemistry; Sesquiterpenoids; Spectroscopy; Stereoisomerism; X-ray crystallography; Zerumbone
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d1ob01634b

The sesquiterpene zerumbone was treated with HCl in ethyl acetate under the light-protected condition, and the time-dependent conversions were analyzed by gas chromatography. Nine products were isolated, and their structures were revealed by several NMR measurements such as 1 H NMR, 13 C{ 1 H} NMR, distortionless enhancement by polarization transfer (DEPT)-135, 1 H- 1 H correlation spectroscopy (COSY), 1 H- 13 C heteronuclear multiple quantum coherence (HMQC), and 1 H- 13 C heteronuclear multiple bond coherence (HMBC). The X-ray crystallography determined the stereochemistries of the three products and the two derivatives. After all, this acidic reaction was found to provide the (2 Z ,6 E ,10 E )-isomer, the two HCl adducts, the two 7,6-bicyclic compounds, the valence isomers cycloheptatriene and norcaradiene, and the two dihydronaphthalenes. Based on the product analyses of the reactions from the isolated intermediates as well as the mechanistic considerations, these products were arranged into two paths: one of the paths ended in the two dihydronaphthalenes the same as previously reported under the Lewis acid condition; the other ended in the 7,6-bicyclic compound, the epimer of which was known. In addition, density functional theory (DFT) calculations indicated that the (2 Z ,6 E ,10 E )-isomer was more stable than the (2 E ,6 E ,10 Z )-isomer as well as that the activation energy for the isomerization at the C2-C3 double bond decreased to half by protonation. The closely examined reaction mechanisms under the simple acidic condition were established upon the intensive characterization of the intermediates and products, and these findings would add to the attractive value of zerumbone and would help understand the unknown biosynthetic pathway around sesquiterpenoids. The reaction mechanism of zerumbone under HCl was verified by the reactions from each isolated intermediate.