Hinokitiol

Hinokitiol (β-thujaplicin) is a natural monoterpenoid found in the wood of trees in the family Cupressaceae. It is a tropolone derivative and one of the thujaplicins. Hinokitiol is used in oral and skin care products, and is a food additive used in Japan.

Hinokitiol was discovered by a Japanese chemist Tetsuo Nozoe in 1936. It was isolated from the essential oil component of the heartwood Taiwanese hinoki, from which the compound ultimately adopted its name. Hinokitiol is the first non-benzenoid aromatic compound identified. The compound has a heptagonal molecular structure and was first synthesized by Ralph Raphael in 1951. Due to its iron-chelating activity, hinokitiol has been called an "Iron Man molecule" in the scientific media, which is ironic because Tetsuo is translated into English as "Iron Man". Taiwanese hinoki is native to East Asian countries, particularly to Japan and Taiwan. Hinokitiol has also been found in other trees of the Cupressaceae family, including Thuja plicata Donn ex D. Don which is common in the Pacific Northwest.

Woods that are rich in hinokitiol were used by people of ancient Japan for creating long-standing buildings, such as the Konjiki-dō, a japanese national treasure, one of the buildings of Chūson-ji complex, a temple in Iwate Prefecture. It kept it from harm against insects, wood-rotting fungi, and molds for a long time of about 840 years. Additionally, there are some old famous Buddhist temples and Shinto shrines using trees, later known to contain hinokitiol. Beginning in the 2000s, the biological properties of hinokitiol have become of research interest, focusing on its biological properties. And the resistance of cypress trees to wood decay was the leading reason prompting to study their chemical content and to find the substances responsible for those properties.

Hinokitiol has been found in the heartwood of the conifer trees of the Cupressaceae family, including Chamaecyparis obtusa (Hinoki cypress), Thuja plicata (Western red cedar), Thujopsis dolabrata var. hondai (Hinoki asunaro), Juniperus cedrus (Canary Islands juniper), Cedrus atlantica (Atlas cedar), Cupressus lusitanica (Mexican white cedar), Chamaecyparis lawsoniana (Port Orford cedar), Chamaecyparis taiwanensis (Taiwan cypress), Chamaecyparis thyoides (Atlantic white cedar), Cupressus arizonica (Arizona cypress), Cupressus macnabiana (MacNab cypress), Cupressus macrocarpa (Monterey cypress), Juniperus chinensis (Chinese juniper), Juniperus communis (Common juniper), Juniperus californica (California juniper), Juniperus occidentalis (Western juniper), Juniperus oxycedrus (Cade), Juniperus sabina (Savin juniper), Calocedrus decurrens (California incense-cedar), Calocedrus formosana (Taiwan incense-cedar), Platycladus orientalis (Chinese thuja), Thuja occidentalis (Northern white-cedar), Thuja standishii (Japanese thuja), Tetraclinis articulata (Sandarac).

Its concentration in the trees are 0.1-0.2% in Chamaecyparis taiwanensis (2 mg of hinokitiol per 1 g of dry sawdust), 0.04% in Juniperus cedrus and Thujopsis dolabrata var. hondai (0.4 mg of hinokitiol per 1 g of dry sawdust), and 0.02% in Chamaecyparis obtusa (0.2 mg of hinokitiol per 1 g of dry sawdust).

There are three naturally found thujaplicins: α-thujaplicin, β-thujaplicin (hinokitiol) and γ-thujaplicin. Hinokitiol is the most common isomer and it appears to be the only isomer that exerts all biological activities attributed to thujaplicins.

There are different pathways to synthesize thujaplicins. Hinokitiol, as other thujaplicins, can be synthesized by cycloaddition of isopropylcyclopentadiene and dichloro ketene, 1,3-dipolar cycloaddition of 5-isopropyl-1-methyl-3-oxidopyridinium, ring expansion of 2-isopropylcyclohexanone, regiocontrolled hydroxylation of oxyallyl (4+3) cycloadducts, regioselectively from (R)-(+)-limonene, and from troponeirontricarbonyl complex. Hinokitiol can also be isolated through plant cell suspension cultures, or readily extracted from the wood with chemical solvents and ultrasonication.

(1) Synthesis of hinokitiol from troponeirontricarbonyl complex: