Of menthol

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... 

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). 

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. 

Menthol Manufacture. Of the menthol isomers, only (-)-menthol [2216-51 -5] and (+)-menthol [15356-70-4] are of commercial importance. The most important natural sources of (—)-menthol are the oUs of Mentha arvensis (75—90%) and Mentha piperita (50—65%). The main suppUers ate Japan, China, BrazU, and Taiwan for the former and the United States, CIS, Bulgaria, and Italy for the latter. (—)-Menthol is known for its refreshing, diffusive odor characteristic of peppermint. It also is known for its strong physiological cooling effect, which is useful in cigarettes, dentifrices, cosmetics, and pharmaceuticals. 

AH (A)-menthol is made by synthetic methods. One method involves the cyclization of (+)-citroneIlal (68). Using a mild acid catalyst, (+)-citroneIlal [2385-77-5] undergoes an ene-reaction to produce a mixture of isopulegols (142). Catalytic hydrogenation of the isopulegol mixture gives a mixture of menthol and its isomers. The (A)-menthol is obtained after efficient fractional distillation and the remaining isomers can be equilibrated, usually with sodium menthol ate or aluminum isopropoxide. An equilibrium mixture is obtained, comprised of 62 wt % (A)-menthol, 23 wt % (+)-neomenthol, 12 wt % (+)-isomenthol, and 3 wt % (+)-neoisomenthol. The equilibrium mixture can be distilled to recover additional (+)-mentbol. 

The glucosides of menthol, citronellol, nerol, geraniol, cw-myrtenol, L-borneol, linalool and a-terpineol yielded yellow-green fluorescent chromatogram zones in long-wavelength UV light (2 = 365 nm). The same applied to arbutin (hRf 45 — 50). 

Examine the two chair conformers of menthol, and label each substituent in each conformer as equatorial or axial. 

The etfect of shade upon the pcppcrminl plant is to decreaae esterilieation and the Lormation of menthol, and i.s due possibly to the leasened activilv of the elimination of water by the plant. 

Japanese oil of peppermint contains a very high proportion of menthol, a large amount of which is frequently removed, and the de-... 

Pickard and I.ittleljury have isolaled from the oil an iaomei of menthol, which occurs in small quantity, and which ihev havo named neomenthol. This body Is of particular Interest iu regard lo the slcruo-chemiati-y o( this irnpoftaut Ixniv. 

The earlier researches of Charabot have shown that the essential oil of the flowers is richer in menthone than the essential oil of the leaves. And it is in spite of a circulation of menthol, a soluble principle, from the leaf to the inflorescence, that this latter organ contains an essential oil particularly rich in menthone. It must therefore be that the menthol is there converted into menthone by oxidation. 

The differences in composition between the two essential oils examined show well, if they be compared with those which exist between the essential oils of the leaves and the inflorescences, that the distribution of the odorous principles between the leaf, the organ of production, and the flower, the organ of consumption, tends to take place according to their relative solubilities. But this tendency may be inhibited, or on the other hand, it may be favoured by the chemical metamorphoses which the substances undergo at any particular point of their passage or at any particular centre of accumulation. Thus, in the present case, some of the least soluble principles, the esters of menthol, are most abundant in the oil of the leaves, whilst another, menthone, is richest in the oil of an organ to which there go, by circulation, nevertheless, the most soluble portions. This is because this organ (the flower) constitutes the. medium in which the formation of this insoluble principle is particularly active. 

Isopulegol is an oil having an odour resembling that of menthol. Its characters are as follows —... 

Natural menthol is laevo-rotatory. The reduction of both laevo-menthone and dextro-menthone yields a mixture in which laevo-menthol predominates. The constitution of menthol is as follows —... 

Standnikow has prepared several of the esters of menthol by heating magnesium iodo-mentholate with the esters of ethyl alcohol. For example, with ethyl acetate, propionate, and benzoate the corresponding menthyl esters were obtained. These bodies have the following boiling-points —... 

Pure piperitone was subjected to the action of purified hydrogen, in the presence of a nickel catalyst, for six hours, the temperature ranging between 175° to 180° C. The double bond in piperitone was readily opened out with the formation of menthone, but further action of the hydrogen under these conditions did not reduce the carbonyl group, even after continued treatment for two days. Under correct conditions, however, the reduction to menthol should take place. The ease with which menthone is formed in this way is of special interest, not only in connection with the production of this ketone, but also as a stage in the manufacture of menthol. 

Draw the two chair conformations of menthol, and tell which is more stable. 

There are four cis-trans isomers of menthol (Problem 4.3/), including the one shown. Draw the other three. 

Perhaps the most successful industrial process for the synthesis of menthol is employed by the Takasago Corporation in Japan.4 The elegant Takasago Process uses a most effective catalytic asymmetric reaction - the (S)-BINAP-Rh(i)-catalyzed asymmetric isomerization of an allylic amine to an enamine - and furnishes approximately 30% of the annual world supply of menthol. The asymmetric isomerization of an allylic amine is one of a large and growing number of catalytic asymmetric processes. Collectively, these catalytic asymmetric reactions have dramatically increased the power and scope of organic synthesis. Indeed, the discovery that certain chiral transition metal catalysts can dictate the stereo-... 

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

Scheme 12. The Takasago process for the asymmetric synthesis of (-)-menthol (1).

Lewis acids, results in the formation of isopulegol (43) with greater than 98% diastereoselectivity isopulegol (43), wherein all of the ring substituents are equatorially oriented, arises naturally from a chairlike transition state structure in which the C-3 methyl group, the coordinated C-l aldehyde carbonyl, and the A6,7 double bond are all equatorial (see 48). A low-temperature crystallization raises the chemical and enantiomeric purity of isopulegol (43) close to 100%. Finally, hydrogenation of the double bond in 43 completes the synthesis of (-)-menthol (1). 

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