Caryophyllenes

The total synthesis of caryophyllene and its Z-isomer involved a photochemical [2 + 2] cycloaddition reaction to generate the 4-membered ring and a fragmentation process Helv. Chim. Acta, 1951, 34, 2338) to establish the 9-membered ring. Caryophyllene and various oxygenated derivatives protect plants against insects. 

The synthesis of i/-caryophyllene was also accomplished starting from the hydroxy ketone A, via a different reduction process as shown below  

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Only relatively few examples of interesting target molecules containing rings are known. These include caryophyllene (E.J. Corey, 1963 A, 1964) and cubane (J.C. Barborak, 1966). The photochemical [2 + 2]-cycloaddition applied by Corey yielded mainly the /ranr-fused isomer, but isomerization with base leads via enolate to formation of the more stable civ-fused ring system. 

Few naturally occurring fused-ring thiiranes are known. Recently, however, humulene-1,2- and -4,5-episulfides (84) and (85), and caryophyllene-4,5-episulfide (86) were isolated from hops which had been heavily dressed with sulfur during the growing period, to control mildew (80JCS(P1)311). 

Menthol (hRf 15) and menthyl acetate hRt 55) yielded blue chromatogram zones caryophyllene hRf 90) and caryophyllene epoxide hRf 20 — 25) appeared red-violet and thymol hRf 40 — 45) appeared brick red in color. 

Fig. 1 Schematic sketch (A) of the separation of essential oil components (ca. 500 ng of each component) and reflectance scan of the mixture (B). Menthol (1), caryophyllene epoxide (2), thymol (3), menthyl acetate (4), caryophyllene (5), mixture (G).

Fig. 1 Sketch of the chromatographic separation of a mixture (G) of cholesterol (1), stearic acid (2), tripalmitin (3) and caryophyllene (4).

Caryophyllene, as isolated from essential oils, and as usually described in literature is, without the slightest doubt, a mixture of at least two, if not three distinct chemical individuals. 

Deussen termed the inactive caryophyllene, as further experiments showed it to be, a-caryophyllene, and the laevo-rotatory compound, )8-caryophyllene. A third body was obtained, which yielded no blue nitrosite at all, to which Deussen assigned the name -y-caryophyllene. This body... 

Terp-caryophyllene and Zim-caryophyllene can be converted the one into the other by the preparation of their nitrosites or their nitroso-chlorides, and subsequent regeneration of the sesquiterpene. They also both yield the same hydrochloride, melting at 69°. 

Schimmel Co. showed that by treating caryophyllene hydrochloride melting at 69° (68° to 70°) with sodium ethylate, an unsaturated tricyclic sesquiterpene resulted. This body has the following characters —... 

Semmler and Mayer agree that the reagent used and the conditions of temperature, etc., govern the character of the sesquiterpene, or mixture of sesquiterpenes which result. By using sodium methylate very cautiously, they obtained a caryophyllene having the following characters —... 

So that by suitable procedure it is possible to regenerate dextro-caryophyllene from the crystalline hydrochloride. 

By using pyridine to split off the hydrochloric acid, Semmler and Mayer obtained a caryophyllene substantially identical with that obtained by Schimmel, but of optical rotation - 57°, indicating that Schimmel s body was a mixture of the two compounds. Semmler and Mayer give the following formulae for the caryophyllenes indicated by the above, together with that of the hydrochloride, to indicate the transpositions which occur —... 

Formula (1) would thus indicate the natural dextro-caryophyllene of clove stems formula (2) indicates the highly laevo-rotatory caryophyllene resulting from regeneration by means of pyridine, and (3) may represent the a-caryophyllene of Deussen. 

If these assumptions be correct, there must be at least four natural sesquiterpenes of the caryophyllene character, namely, those represented by formulae (1) and (3), and the terp-caryophyllene and im-caryo-phyllene of Semmler. The most characteristic derivatives of the caryophyllenes are the following —... 

Caryophyllene dihydrochloride, Cj5H24.2HCl, may be obtained by saturating a quite dry ethereal solution of the sesquiterpene with dry hydrochloric acid gas, and exposing the mixture to very intense cold. It melts at 69° to 70°. 

Caryophyllene nitrosochloride, (CjgHgJjN OoCL, is obtained when a mixture of the sesquiterpene, alcohol, ethyl acetate, and ethyl nitrite is cooled in a freezing mixture, and then treated with a saturated solution of hydrochloric acid in alcohol. The reaction mass is allowed to stand on ice for an hour and is then exposed to sunlight. Thus prepared it melts at about 158° to 163°, and can be separated into two compounds, one being that of a-caryophyllene and the other that of yS-caryophyllene Deussen s sesquiterpenes of natural caryophyllene from clove oil), a-caryophyllene nitrosochloride melts at 177", and /3-caryophyllene nitrosochloride at 159°. They can be separated by fractional crystallisation. The corresponding a-nitrolbenzylamine melts at 126° to 128°, and the /3-nitrolbenzylamine at 172° to 173°. The bimolecular formula given above is probable but not certain. 

Nitroso-caryophyllene, CjgHjgNO, is prepared by splitting off hydrochloric acid from the corresponding nitrosochloride, by means of sodium methylate. a-Nitrosocaryophyllene melts at 116° and is optically inactive (as is the a-nitrosochloride), and yS-nitrosocarj-ophyllene melts at 120° to 121° and has a specific rotation -H 61-77° (as against — 98 07°for the /3-nitrosochloride). 

Caryophyllene nitrosite is an interesting compound. It has the formula CJ5H24N2O3, and was first produced by Schreiner and Kremers. It is form by treating a mixture of equal volumes of the sesquiterpene and petroleum ether with a concentrated solution of sodium nitrite and glacial acetic acid. It crystallises in fine blue needles when re-crvstallised from alcohol it melts at 115° and has a specific rotation -h 103°. 

By treating this blue nitrosite, which Deussen calls )3-caryophyllene nitrosite, with alcoholic potash at 0°, it is converted to a colourless isomer, melting at 139°, which Deussen terms )3-caryophyllene isonitrosite. By treatment with boiling petroleum ether decomposition takes place and a compound melting at 159° is formed, of formula not yet established, and a nitro-compound of the formula Cj5H22N204, melting at 130 5°. 

From the mother liquors of the preparation of the nitrosite from caryophyllene, a sesquiterpene is obtained, which may be the product of inversion by acids, or may be naturally present. It has the following characters —... 

A study of the oxidation products and nitroso-derivatives of caryophyllene, leads Deussen to consider that this sesquiterpene is a naphthalene derivative of the formula—... 

The above considerations indicate the complex nature of the hydrocarbons known as caryophyllene. For practical purposes, however, the compounds indicated are obtained of practically definite melting-points, and, in spite of the complicated isomerism existing amongst most of them, are useful for identification of the sesquiterpene or mixture of sesquiterpenes, occurring naturally and known as caryophyllene . 

Deussen considers that the nitrosate above described is identical with that of a-caryophyllene, and that the nitrosochloride is identical with that of the same sesquiterp ene. He therefore considers that iinmulene is, at all events i in greater part, actually a-caryophyllene. 

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