D-menthol

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. 

The resolution of DL-menthol is important industrially. L-Menthol has a mint taste and gives a cooling sensation. It finds use in a number of important products including toothpaste and confectionary. D-Menthol does not have the same taste nor the same cooling properties. DL-menthol can be produced relatively simply using a variety of chemical routes. 

Explain how this enzyme may be used to resolve a racemic mixture of DL-menthol. Assume you want to prepare both D-menthol and L-menthol. 

Figure 15.7 Response of the molecular imprinted polymer quartz crystal microbalance (MIP-QCM) sensor to monoterpene analogues ( ) L-menthol, (A) D-menthol, ( ) citronel-lol, (A) citronellal, and (O) menthone. Reprinted from Percival et al. (2001). Copyright 2001 American Chemical Society.

Alkylation of m-cresol with propene in the presence of an aluminium catalyst results in the formation of thymol, which upon hydrogenation gives a rnkture of all eight isomers of menthol, D-menthol, L-menthol, neomenthol, isomenthol and neoisomenthol (Scheme 13.3). The preferred isomer is L-menthol, because of its ability to induce physiologically the sense of cold which is desired in many products such as chewing gum and toothpaste L-menthol is about... 

All ( )-menthol is made by synthetic methods. One method involves the cydization of (+)-citronellal (68). Using a mild acid catalyst, (+)-citronellal [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 (zt)-menthol is obtained after efficient fractional distillation and the remaining isomers can be equilibrated, usually with sodium mentholate or aluminum isopropoxide. An equilibrium mixture is obtained, comprised of 62 wt % (d=)-menthol, 23 wt % (+)-neomenthol, 12 wt % ( )-isomenthol, and 3 wt % (+)-neoisomenthol. The equilibrium mixture can be distilled to recover additional ( )-menthol. 

B. (5S)-(d-Menthyloxy)-2(5H)-furanone. A 500-mL, round-bottomed flask equipped with a magnetic stirring bar, 10-mL Dean-Stark trap, and reflux condenser is charged with d-menthol (51.9 g, 0.330 mol), 5-hydroxy-2(5H)-furanone (37.3 g, 0.370 mol), D-(-i-)-camphorsulfonic acid (3.96 g, 0.170 mol), and 190 mL of dry benzene (Note 8). The stirred suspension is heated to reflux under argon with an oil bath preheated to 100°C (Note 9). After 1-2 hr, a total of 5.1 mL of water is collected and no residual menthol is apparent by TLC analysis (Note 10). The reaction mixture is cooled in an ice bath and treated carefully with 100 mL of saturated sodium bicarbonate solution. After completion of the addition, stirring is maintained for 90 min as the mixture is allowed to warm to room temperature. The... 

The submitters purchased d-menthol from TCI and the checkers obtained this compound (99%, 98% ee) from Aldrich Chemical Company, Inc. Menthol was used as received. D-(-i-)-camphorsulfonic acid (99%) was purchased from Avocado and used as received. Benzene was purchased from EM Science and used as received. 

The process uses cells of Rhodotorula minuta entrapped in pol)airethane. These cells selectively hydrolyse the L-ester. The remaining D-menthyl succinate is then hydrolysed and the D-menthol racemised via D-menthone and then recycled. We have represented this process in Figure 9.9. 

Menthol is widely used in pharmaceuticals, confectionery, and toiletry products as a flavoring agent or odor enhancer. In addition to its characteristic peppermint flavor, /-menthol, which occurs naturally, also exerts a cooling or refreshing sensation that is exploited in many topical preparations. Unlike mannitol, which exerts a similar effect due to a negative heat of solution, /-menthol interacts directly with the body s coldness receptors. d-Menthol has no cooling effect, while racemic menthol exerts an effect approximately half that of /-menthol. 

The esterase EPIO was highly selective for esterification of the L-isomer. Supercritical CO2 was the solvent for the reaction and for the postreaction separation of the acetate from the unreacted D-menthol. 

The essential oil of Eucalyptus dives contains L-piperitone and this provides a starting material for L-menthol using the process shown in Scheme 4.25. The L-piperitone is reduced to a mixture of piperitols, which are separated, and the major isomer, D-/ra j-piperitol, hydrogenated to give D-isomenthol containing a small amount of D-menthol. After purification, the former can be isomerized into L-menthol using aluminium isopropoxide as catalyst. About 30 tonnes per annum of l-menthol are produced by Keith Harris Co. in Australia using this route. 

Schmeltz, I. and W.S. Schlotzhauer Benzo[a]pyrene, phenols, and other products from pyrolysis of the cigarette additive, (d,/)-menthol Nature 219 (1968)... 

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

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