Menthol resolution

Combined thermoanalytical (TA,TGA and DSC) investigations of DBTA complexes of chiral alcohols may serve valuable data on the composition and stabilities of these solid supramolecular compounds. DSC monitoring of menthol resolution with DBTA in melt has already discussed in point 3.4. Thermal stability of further ten complexes of DBTA with alcohols 26, 29-31, 35-37 and 39-41 was also determined. [47] The melting points of the DBTA complexes (Table 11) increase in the 2-alkanol, 2-alkoxycyclohexanol, 2-halogenocyclohexanol order. 

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). 

Optical resolution is another method of producing (—)-mentho1 from racemic materials. (A)-Menthol is treated with optically active resolving agents to separate the (—)-mentho1 from the (+)-menthol, which is further processed by racemization over a nickel catalyst and recycled (156). 

Resolution methods using nonopticaHy active agents are also used by taking advantage of the fact that certain benzoic acid derivatives of (A)-menthol can be inoculated with crystals of one enantiomer to induce immediate crystallization of that enantiomer. Although repeated crystallizations and separations must be done, the technique has been successhil for (—)-mentho1 (157). 

Figure 9.9 Resolution of DL-menthol using an esterase from Rhodotorula minuta var texensis.

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. 

The way to achieve resolution is to use the lipase to selectively esterify the L-menthol. 

Scheme 2 Optical resolution with /-menthol and carane-3,4-diol...

Menthol ester (20) with (l/ S)-frans-2,2-dimethyl-3-(2,2-dichloroethenyl) cyclopropanecarboxylic acid (19) has been utilized to produce ( R)-trans-2, 2-dimethyl-3-(2,2-dichloroethenyl) cyclopropanecarboxylic acid (21), an acid moiety of transfluthrin (22) [9]. Matsuo et al. surveyed various optically active secondary alcohols for their potential in the optical resolution of (lRS)-trans-chrysanthemic acid [10] (Scheme 2). 

Wudl and Lee (96,97) reported the first preparation and resolution of the cyclic diastereomeric amidosulfites 58, which have been successfully used in the synthesis of chiral sulfoxides. A mixture of diastereomeric menthyl dimethylamidosulfites (100) was obtained in the reaction of racemic dimethylaminosulfinyl chloride (101) with menthol in the presence of pyridine (149). The degree of asymmetric... 

In contrast, electrophilic additions to the double bond of acetal 70 (derived from 64 ) gave adduct mixtures 71/72 with regioselectivities opposite to those of reactions 64 + EX — 68 + 69, 72 being the major adducts. Tests were carried out to confirm that adducts 68 + 69 and 71+72 were formed under conditions of kinetic control. Acetal 70 was obtained optically pure via resolution of lactol 73 by medium pressure chromatographic (silica gel) separation of the diastereomeric acetals 74 derived from (-)-menthol. ... 

In certain cases, especially for neutral substrates, the formation of covalent p,n-pairs, instead of salts, may be necessary to achieve optical resolution by crystallization. Suitable derivatives are esters of camphanic acid (1) or chrysanthemic acid (2) with racemic alcohols, or esters of menthol (3) and 1-phenylethanol (5) with racemic acids, or hydrazones of menthylhydrazine (4) with racemic aldehydes and ketones. 

Optical resolution of enantiomeric mixtures which have been obtained by short chemical syntheses continues to be the method of choice for a wide variety of compounds. For instance, the industrial synthesis of (-)-menthol starts from thymol which is catalytically hydrogenated to furnish all four diastereomers in racemic form. 

Hydrolysis of the enamine 14 furnishes citronellal (15) in high optical purity (ca. 99% ee) which gives 17 via ene cyclization with zinc bromide as catalyst. The diastereoselectivity of this step is the result of simple diastereoselection in a trans-decalin-like transition state 16. Catalytic hydrogenation converts the olefin 17 into (—)-menthol (18). Despite its elegance this novel route has not been able to replace the older resolution-based procedure described earlier in this section. 

Chemical Properties. Hydrogenation of menthols yields / -menthane oxidation with chromic acid or catalytic dehydrogenation yields menthones. Dehydration under mild conditions yields 3-/ -menthene as the main product. Reaction with carboxylic acids or their derivatives yields menthyl esters, which are used mainly as aroma substances and in pharmaceutical preparations and formulations. The esterification of menthols with benzoic acid is used on an industrial scale in the resolution of racemic menthol. 

Production. Many industrial processes exist for the production of menthols. For (—)-menthol, isolation from peppermint oil (see Mint Oils) competes with partial and total syntheses. When an optically active compound is used as a starting material, optical activity must be retained throughout the synthesis, which generally consists of several steps. Total syntheses or syntheses starting from optically inactive materials require either resolution of racemic mixtures or asymmetric synthesis of an intermediate. Recently used processes are the following ... 

However, the isopulegol mixture can also be hydrogenated to produce a mixture of menthols the individual stereoisomers are then separated by distillation. To obtain optically pure (-)-menthol, a resolution step involving a suitable crystalline derivative (such as the benzoate) is required. The undesired stereoisomeric menthols mainly (+)-neomenthol and (+)-isomenthol, are epimerized to an equilibrium mixture (e.g., by heating in the presence of sodium menthylate). (-)-Menthol is then again separated from the mixture. 

There are several biochemical and chemical processes for the resolution of a racemic mixture of menthol. Many microbiological lipases hydrolyse men-... 

The synthesis of racemic Tic (rac-33) can be accomplished by alkylation of acet-amidomalonates in a reasonable yield (Scheme 15). Racemic Tic can then be subjected to resolution using menthol.1[7 ] This route is a good alternative for synthesizing both enantiomers of Tic. 

Three processes have been developed for L-(-)-menthol, which has three asymmetric centers (i) separation of diastereomeric salt pairs (ii) homogeneous catalysis with Rh-BINAP and (iii) lipase resolution of menthol benzoates. 

Lipase-Catalyzed Resolution of Racemic Menthol Esters... 

Haarmann Reimer (Holzminden, Germany) in collaboration with Rolf Schmid s group at the University of Stuttgart developed a process based on the resolution of racemic menthol esters, such as acetate or benzoate esters. The team employed several lipases such as Candida cyclindracea which resulted in enantio-selectivities up to 100% e.e. (Bomscheuer, 2002). 

Fontes et al. (1998b) studied the enantioselectivity of cutinase and found that it was very selective toward one enantiomer with an enantiomeric excess of almost 100%. They found that the enantioselectivity was very sensitive to changes in water content. Bornscheuer et al. (1992) studied hydrolysis, esterification, and transesterification in carbon dioxide to try to find the best method for producing enantiomerically pure substances in carbon dioxide. They found that the thermodynamically favored hydrolysis led to higher enantiomeric excess with less enzyme in the shortest time. Michor et al. (1996b) also examined more than one system to determine a better route to product and found that while the transesterification of -menthol was fast and resulted in high enantiomeric excess, resolution of -citronellol was not feasible. The reaction rate for the reaction of -citronellol was 10-20 times of that of -menthol, but was not selective. 

Authenticity evaluation has recently received increased attention in a number of industries. The complex mixtures involved often require very high resolution analyses and, in the case of determining the authenticity of natural products, very accurate determination of enantiomeric purity. Juchelka et al. have described a method for the authenticity determination of natural products which uses a combination of enantioselective multidimensional gas chromatography with isotope ratio mass spectrometry (28). In isotope ratio mass spectrometry, combustion analysis is combined with mass spectrometry, and the 13C/12C ratio of the analyte is measured versus a C02 reference standard. A special interface, employing the necessary oxidation and reduction reaction chambers and a water separator, was used employed. For standards of 5-nonanone, menthol and (R)-y-decalactone, they were able to determine the correct 12C/13C ratios, with relatively little sample preparation. The technical details of multidimensional GC-isotope ratio MS have been described fully by Nitz et al. (29). A MDGC-IRMS separation of a natural ds-3-hexen-l-ol fraction is... 

Data from the literature show that even if new convenient preparative methods are being developed for the resolution of l,l/-binaphthyl-2,2/-diol (17) via a phosphite using (—)-menthol as a resolving agent [39], the inclusion complexation method can still compete with these, owing to its simplicity, efficiency, and low cost. 

Among the preparative methods used for obtaining P-chiral phosphorus compounds, there are procedures involving the use of optically pure auxiliaries like (—)-menthol [40], (—)-ephedrin [41,42], or more recently, the kinetic resolution of 1-hydroxymethylalkylphenylphosphine oxides using Pseudomonas or Candida antarctica lipases [43], It has been found that some [(alkyl-substituted)arene] phosphinates and phosphine oxides can also be resolved efficiently by inclusion complexation with optically active 2,2 -dihydroxy-1, 1 -binaphthyl (17) [44],... 

Efficiency of the above discussed resolutions changed in a wide range 0 < S < 0.433 (Table 5). Menthol (28) and 2-halogenocyclohexanol (35, 36, 37) enantiomers were the best ligands of DBTA for chiral recognition during host-guest complex formation, therefore these model compounds were used for further elaboration of the resolution processes (point 3.4.). 

Optical resolution of menthol (28) with DBTA in hexane suspension is quite efficient (S = 0.374, Table 5 [38]) but complex formation is slow. In order to increase the reaction rate, the highest possible concentrations of the reactants were reached by solving DBTA monohydrate in the melt of racemic menthol. [41]... 

The melting point of racemic 28 is 33 °C therefore clean liquid could be obtained by gentle heating of the mixture. As far as the stirred reaction mixture cooled down to 25 °C, the unreacted optically active menthol could be withdrawn from the solid by simple extraction [41] (Scheme 15). The yield and enantiomeric enrichment depends on the molar ratio of the racemate and DBTA (Table 8). The most efficient resolution of 28 was accomplished with half an equivalent DBTA (S = 0,456) and this result is significantly better then the selectivity of the original resolution in hexan (S = 0,37). 

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