L-Menthol from

You probably came up with the suggestion that by using an esterase which selectively hydrolyses the succinate ester of L-menthol, you would be able to isolate L-menthol from the mixture. This is in essence the way the process is carried out commercially. We can represent this process by ... 

Before leaving asymmetric hydrogenation reactions, we should mention one other related process that has acquired immense importance, again because of its industrial application. You have come across cit-ronellol a couple of times in this chapter already the corresponding aldehyde citronellal is even more important because it is an intermediate in the a synthesis of L-menthol by the Japanese chemical company Takasago. Takasago manufacture about 30% of the 3500 ton annual worldwide demand for L-menthol from citronellal by using an intramolecular ene reaction (a cycloaddition you met in Chapter 35). 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

Asymmetric isomerization of allylamines is performed with high enantioselectivity [57]. This process is applied to the industrial production of L-menthol from diethylger-anylamine by the Takasago Perfumery Company (eq (48)). 

The synthesis of L-menthol from /3-pinene by homogeneous catalysis is an outstanding example of the application of enantioselective catalysis in the perfumery industry (Noyori and Takaya, 1990 Parshall and Ittel, 1992). The synthetic scheme for this process is included in Table 9.7. The key step is isomerization... 

Schlemenat, A., Langer, R Dreisbach, C Gross, H.-J., Prinz, T, Schulze-Tilling, A., Friederich, M Jentsch, J.D., and John, G. (2001) Isomerization process and supported mihenium catalysts for the preparation of D, L-menthol from menthol stereoisomers. DE10023283. 

Yoshida, T, Komatsu, A., and Indo, M. (1966) Isomerization and racemization of menthols. III. A new isolation procedure of (-l-)-menthol from isomeric mixture. Agric. Biol. Chem., 30, 68-72. 

The L-menthol could be recovered by hydrolysing the L-menthyl-5-phenylvalerate. You might anticipate using an esterase to carry out this hydrolysis such as the enzyme from Rhodotorula minuta described in the text. 

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.

D,L-Menthol is separated from the mixture by distillation, then converted into the benzoate which is resolved by crystallization with entrainment (see Section 2.1.). The mother liquor and the unnatural diastereomers are recycled by dehydrogenation3. 

Chiral crotonates derived from S-citroncllol, l-(—)-menthol, and S-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active hifluoromethylated a, /l-unsaturated aiyl sulfones (43) with nitrones yield the corresponding isoxazolidmes (44) and (45) with high regio- and... 

Terpenes continue to be a popular choice as experimental enhancers for delivering materials across skin membranes. For example, L-menthol facilitated in vitro permeation of morphine hydrochloride through hairless rat skin [37], imipramine hydrochloride across rat skin [59], and hydrocortisone through hairless mouse skin [60]. Recently, niaouli oil was found to be the most effective of six essential oils in promoting estradiol penetration through hairless mouse skin [61]. It is noteworthy that there is currently little control on the topical use of most terpenes, and many aromatherapy oils and formulations contain appreciable quantities of these chemicals. Their excessive use offers potential for permeation of hazardous compounds from the same formulations into the skin some terpenes also have pharmacological activity. 

To prepare the enantiomerically pure iron acyl complex (R)-(39), a precursor diastereomeric menthoxyaUcyl complex was resolved and then manipulated (Scheme 14). More recently resolution of the chiral-at-metal acyl complexes themselves was achieved, and this has become the basis for a commercial preparation of the iron acyl developed for use as a chiral auxiliary (see below). Cationic iron complex (43) was treated with potassium L-mentholate to produce diastereomeric esters (44) that were not isolated but were reacted with LiBr/MeLi (Scheme 15). After chromatography and recrystallization the enantiomerically pure ironacyl complex (5 )-(39a) was obtained. It was suggested that only one diastereomeric ester can react (with inversion of configuration at iron, as shown) with the methyl nucleophile the unreactive diastereomer suffers from severe steric congestion about the electrophilic CO ligand. 

The world s biggest application of asymmetric catalysis is Takasago Perfumery s synthesis of (-)-menthol from myrcene (see Sections 2.9 and 3.3.1) with about 1500 t/a (menthol and other chiral terpenic substances). The key step is the isomerization of geranyldiethylamine with an Rh -S-BINAP catalyst to citronellal ( )-enamine (eqs. (17)) (BINAP = 2,2 -bis(diphenylphosphine)-l,l -binaphthyl).The geometry of the double bond is 100% E. 

Dinuclear niobium sulfido and selenido dithiophosphates, Nb2Q4[S2P(OR)2]4,75,76 (Q = S, Se R = Et) (also xanthates and dithiocarbamates) have been prepared but no crystal structure was reported. Optically active chromium complexes, Cr[S2P(OR)2]3 derived from Z)-borneol and L-menthol, have been described.77... 

OH-groups in cyclic terpenes must contain oxygen from O2, introduced by a monooxygenase reaction, hence have 8 0-values near +5%o this is found for L-menthol [69[. Unexpectedly, also the natural cyclic ketones pulegone and menthone show relatively low 5 0-values [69], perhaps these compounds have not had the time for an equilibration with water. 

A mixture of Z- and -isomers was obtained the isomer ratio was not reported. The stereochemistry of the alkene is on comparative basis the reaction conditions were not optimized. Synthesized from L-menthol. Diastereomeric excess... 

Thymol, isopropyl meta-cresol, is a precursor of L-menthol. Meta-cresol with a purity of >98.5% must be used as the starting material for thymol production, because the isomer, 2-iso-propyl-4-methyl phenol derived from p-cresol is the main contaminant and cannot be easily separated from thymol. 

There are three major producers of L-menthol in the world, viz. The People s Republic of China. Haarmann Reimer and Takasago. Mint is grown in China and extracted to produce pure L-menthol. As a result 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... 

The other major producer of synthetic L-menthol is the Japanese company Takasago. They produce about 1000 tonnes per annum using elegant chemistry developed by Noyori (Scheme 4.22). Pyrolysis of / -pinene gives myrcene, to which diethylamine can be added in the presence of a catalytic amount of strong base. This produces N,N-diethylgeranylamine. Isomerization of this with the rhodium 2,2 -(diphenylphosphino)-1,1-binaphthyl (BINAP) complex produces the enamine of citronellal. The elegance of this route stems from the fact... 

Very high levels of diastereomeric and enantiomeric excess have been observed in the cycloadditions of (5R) and (5S)-5-menthyloxy-2(5H)-furanones 28 and 29 (Figure 2.2), readily available from furfural and d- and l-menthol [28]. 

Figure 1. Diagrammatic representation of olfactory receptor cell activity during odour stimulation. The spot size is roughly proportional to spike frequency (spike/min). Receptor cells taken at random from the epithelium of a frog are identified hy a serial number in the left column (60 in all). ACE - acetophenone, ANI - anisole, BUT - n-butanol, CAM - DL-camphor, CDN - cyclodecanone, CIN - cineole, CYM, p-cymene, DCT D-citronellol, HEP - n-heptanol, ISO - isoamylacetate, IVA - isovaleric acid, LIM -D-linonene, MAC - methyl-amylketone, MEN - L-menthol, PHE - phenol, PHO -thiophenol, PYR - pyridine, THY - thymol, XOL - cyclohexanol, XON - cyclohexanone. (From Sicard Holley [7]).

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