1- Menthol

Biological target Menthol is a natural terpenoid with agonist activity at the thermoreceptive, non-selective cation channel, transient receptor potential mela-statin type 8 (TRPM8). Present on nerve fibres and skin cells, these channels are activated by a fall in temperature and mediate analgesia. Menthol is also an agonist at GABAa receptors, for which (+)-menthol reveals stereoselectivity. 

Therapeutic profile ( )-Menthol is a household medicament, widely used as a local anaesthetic and analgesic, to reduce itching, as a gastric sedative agent and as a decongestant. 

Synthetic highlight Diastereoselective production of rac-menthol from its aromatic precursor is achieved by site-selective isopropylation and diastereoselective hydrogenation to the all-trans racemate. Enantioselective allylic amine-enamine-imine rearrangement of an acyclic diene-allylic amine, catalyzed by an Rh(I)-(—)-BINAP complex, affords (—)-menthol the process has been scaled-up to production of 1,000 tons/year. 

It should be observed that the word menthol has three separate meanings. Firstly, it is used generically to refer to all of the 3-hydroxy-p-menthanes. Secondly, it is used to mean specifically the thermodynamically most favourable pair of diastereomers in which all of the 

All eight isomers possess characteristic minty odours. The reason for the importance of /-menthol is its ability to interact, not only with odour receptors, but also with the receptors which sense cold. The presence of menthol will induce cold receptors to respond as if they had sensed a drop in temperature. This physiologically induced sensation of cold is used in many products from foodstuffs, such as confectionery, chewing gum, through oral care products such as toothpaste to cosmetic preparations such as shaving products. There is therefore a large market for menthol and, since not all of it can be met from natural mint oils, a demand for synthetic material. Consequently, there has been a lot of work on the synthesis of menthol and all of the synthetic routes considered must take stereochemistry into account as /-menthol is always the preferred target. 

There are two synthetic routes to menthol which are of major commercial importance and these will be discussed below. These two are the most efficient syntheses of menthol at present and therefore account for most of the synthetic menthol produced today. Three other syntheses will also be discussed. These are interesting in that each starts from a chiral precursor which is readily available in the country of production. Therefore, while they were in operation, these processes demonstrated how local factors, often assisted by import restrictions, could affect the total economic balance. 

Unlike enantiomers, diastereoisomers have different physical properties, including boiling points. At atmospheric pressure, d,/-menthol boils 

The key step of the synthesis is the isomerisation of the allylic amine to the corresponding enamine. This is a simple reaction in which a hydrogen atom is moved from the first carbon to the third of the geranyl skeleton. The ingenious feature of this particular case is that the hydrogen atom is added to that third carbon atom from one face only and therefore results in the formation of a single enantiomer of the enamine. When this is hydrolysed, the citronellal produced, is entirely in the dextrorotatory form. The catalyst which performs this transformation is a complex of the Group VIII metal, rhodium. The catalyst which 

Carveol is one of the minor components responsible for the odour of spearmint. It is easily prepared by reduction of carvone. /.vopulegol is prepared from citronellal, as discussed in the section on menthol, and is a precursor to other materials in the group. The phenols carvacrol and thymol are important in some herbal odour types, but the major use for thymol is as a precursor for menthol q.v. Piperitone and pulegone are strong minty odorants. The latter is the major component of pennyroyal oil. 1,8-Cineole is the major component of such eucalyptus oils as Eucalyptus globulus. These oils are inexpensive and so there is no need to prepare cineole synthetically. Menthofuran is a minor component of mint oils and can be prepared from pulegone, though normally, its presence in mint is undesirable because of its odour properties. 

The synthesis of menthol makes an interesting study since it nicely illustrates the balance of economic and technological factors governing the range of production methods, which can be employed commercially. 

Therefore, any synthesis of menthol must be capable of delivering enantiomerically pure 1-menthol to be commercially attractive. 

Menthol can be extracted from various species of mint. Commint (Mentha arvensis) contains the highest levels of 1-menthol and therefore is the major variety cultivated for menthol production. Mint is grown in China, India, Brazil and the United States. Because of the vagaries of climate and competition for land from other agricultural products, the supply of natural menthol is not stable. Price and availability fluctuate and these movements have a major impact on the economics of the various synthetic processes for 1-menthol. When natural menthol is scarce, the synthetic materials command a high price and marginal processes become economically attractive. When the natural material is in abundant supply, only the more efficient of the synthetic processes will compete. The most competitive synthetic processes are those of Symrise and Takasago hence their market domination. 

The fact that menthol is produced from both renewable and fossil feedstocks allows for an interesting study in sustainability. In order to produce the same crop year after year, it is necessary to use fertilisers to replenish the nitrogen and minerals which the plant takes from the soil. Secondary metabolites such as menthol and essential oils occur at a level of, at most, only a few per cent of the dry weight of the herb. Therefore, in order to produce an economic return, it is necessary to use efficient, mechanical methods of cultivation and harvesting. A full life cycle analysis of menthol production reveals that production from cultivation of mint plants consumes more fossil fuel, produces more carbon dioxide effluent and has more environmental impact than either of the leading synthetic routes. 

Methyl Salicylate, Ethyl Salicylate, Glycol Salicylate 

Oil of wintergreen salicylic acid methyl ester methyl sweet birch oil betula oil 

Wintergreen is used as a flavoring in foods, beverages, drugs, and candies. It is also used as a perfume in root beer, and as an ultraviolet light absorber in cosmetics. 

It serves as a pain reliever in liniments and ointments. It is a rubefacient, meaning that it can dilate blood vessels. 

Camphor is a rubefacient—it relieves mild pain and itching, and creates inflammation and redness when rubbed into the skin. Much like menthol, it has a cooling effect when applied to the skin. 

Eau de Chypre family, for example Coriandre (Couturier, 1973) and in Eden (Cacharel, 1994). 

Peppermint Mentha piperita L.) is a hybrid of spearmint (green mint, Mentha spicata) and water mint Mentha aquatica), which was bred in England (Mitcham, Surrey - now part of Greater London) around 1750. The plant also 

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Piperitone is of considerable technical im portance. It is a colourless oil of a pleasant peppermint-like smell. (-)-Piperilone has b.p. 109-5-110-5 C/I5mm. Piperitone yields thymol on oxidation with FeCl. On reduction with hydrogen in presence of a nickel catalyst it yields menthone. On reduction with sodium in alcoholic solution all forms of piperitone yield racemic menthols and womenthols together with some racemic a-phel)andrene. 

In Problem 4 25 you were asked to draw the preferred conformation of menthol on the basis of the information that menthol is the most stable stereoisomer of 2 isopropyl 5 methylcyclo hexanol We can now completely descnbe (—) menthol structurally by noting that it has the R con figuration at the hydroxyl substituted carbon... 

Naphthol Antipyrine, camphor, phenol, iron(III) salts, menthol, oxidizing materials, permanganates, urethane... 

Thymol Acetanilide, antipyrine, camphor, chlorohydrate, menthol, quinine sulfate, ure-thene... 

Human perception creates difficulty ia the characterization of flavor people often, if not always, perceive flavors differently due to both psychological and physiological factors. For example, certain aryl thiocarbamates, eg, phenylthiocarbamide, taste exceedingly bitter to some people and are almost tasteless to others (5). This difference is genetically determined, and the frequency of its occurrence differs from one population to another 40% of U.S. Caucasians are nontasters, whereas only 3% of the Korean population caimot perceive the strong bitter taste of the aryl thiocarbamates (6). Similar differences were found ia the sense of smell for compounds such as menthol, carvone, and ethyl butyrate (7). 

The metallic taste (12,19,20) is not ascribed to any special taste buds or mouth area. Along with pungency (the hot taste of peppers), astringency (the puckering taste of alum), and cold taste (the cool effect of menthol), the metallic taste is called a common chemical sense (21). 

Artificial materials include aUphatic, aromatic, and terpene compounds that are made synthetically as opposed to those isolated from natural sources. As an example, ben2aldehyde may be made synthetically or obtained from oil of bitter almond (51) and t-menthol may be made synthetically or isolated from oil of Mentha arvensis var. to give Bra2iUan mint oil or com mint oil. 

Three general methods exist for the resolution of enantiomers by Hquid chromatography (qv) (47,48). Conversion of the enantiomers to diastereomers and subsequent column chromatography on an achiral stationary phase with an achiral eluant represents a classical method of resolution (49). Diastereomeric derivatization is problematic in that conversion back to the desired enantiomers can result in partial racemization. For example, (lR,23, 5R)-menthol (R)-mandelate (31) is readily separated from its diastereomer but ester hydrolysis under numerous reaction conditions produces (R)-(-)-mandehc acid (32) which is contaminated with (3)-(+)-mandehc acid (33). 

L-Menthol [2216-51-5] (75) and D-menthol [15356-70-4] have been used as chiral auxiharies in the synthesis of optically active mandehc acids. Reduction of (-)-menthol ben2oylfomiate (76) with a stericaHy bulky reducing agent, ie, sodium bis(2-methylethoxy)aluminum hydride (RED-Al), followed by saponification, yields (R)-mandelic acid (32) of 90% ee. 

Uses ndReactions. The largest use of myrcene is for the production of the terpene alcohols nerol, geraniol, and linalool. The nerol and geraniol are further used as intermediates for the production of other large-volume flavor and fragrance chemicals such as citroneUol, dimethyloctanol, citroneUal, hydroxycitroneUal, racemic menthol, citral, and the ionones and methylionones. 

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