Menthol enantiomer

Emberger R, Hopp R, Synthesis and sensory characterization of menthol enantiomers and their derivatives for the use in nature identical peppermint oils, in Berger RG, Nitz N, Schreier P, (eds.). Topics in Flavour Research, H. Eichhorn, Marzling-Hangenham, Germany, pp. 201-218, 1985. 

A non-covalent sensory system based on phosphorescence was also described recently. The inclusion complex of 1-bromonaphthalene with p-cyclodextrin (58) shows room temperature phosphorescence in the presence of menthol enantiomers, due to the formatiOTi of ternary complexes with both menthol and 1-bromonaphthalene included. The phosphorescence lifetime was found to be different for the two enantiomers (4.28 0.06 and 3.71 0.06 ms for (—)-menthol and (-F)-menthol, respectively) due to the higher exposure to dissolved oxygen of the latter complex [123]. 

Humans were able to differentiate the odors of the (-I-) and (—) enantiomers of a-pinene, carvone and limonene but failed to differentiate between (-1-)- and (—)-menthol. Both menthol enantiomers have a peppermint odor quality but (—)-menthol has a much stronger cooling effect than (-i-)-menthol [25]. S-(—)-limonene has a turpentine odor impact and R-(-i-)-limonene an orange odor impact [25]. Neomenthol, isomenthol, and neoisomenthol do not present a cooling effect. 

Menthol is widely used in pharmaceuticals, agrochemicals, cosmetics, and flavoring applications [128]. Among the four diastereomeric pairs of the eight menthol enantiomers, only (-)-menthol exerts a unique cooling sensation on the skin and mucous membranes and exhibits the characteristic peppermint odor. 

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). 

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). 

BINAP is a versatile ligand the S-enantiomer, complexed with rhodium, is used in the commercial production of 1-menthol (Scheme 4.23). In this case the reaction involves isomerization of diethylgeranylamine to R)-citronellal enamine, which proceeds to approximately 99% ee. 

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin starting from the Diels-Alder reaction of methyl 3-nitro-propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (-)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55... 

Cervinka has employed these reagents in the asymmetric reduction of im-monium salts (49,50) and imines (51). The reduction of 2-substituted jV-methyl-A -tetrahydropyridinium perchlorates (10) with (— )-menthol-LAH in ether or THF led to optically active piperidine derivatives (eq. [10]). The optical purity obtained for the Pr" derivative was 12%. In the case of R = Me and Pr" the configuration of the predominant enantiomer was shown to be S. The (-)-menthol-LAH reagent was similarly shown to reduce l-methyl-2-alkyl-A -di-hydropyrrolinium perchlorates (11) to optically active pyrrolidine derivatives (eq. [11]). The optical yield could be calculated only for R = CH2Ph, and was only 6% (/ enantiomer) obtained with a 1 1 (— )-menthoi-LAH reagent. With 2 1 or 3 1 molar ratios of menthol LAH, the optical yield decreased. The... 

For these and similar reactions recently a variety of Lewis acidic aluminium, rare earth metals, and titanium alkoxides have been applied. Alkoxides have the additional advantage that they can be made as enantiomers using asymmetric alcohols which opens the possibility of asymmetric catalysis. Examples of asymmetric alcohols are bis-naphtols, menthol, tartaric acid derivatives [28], Other reactions comprise activation of aldehydes towards a large number of nucleophiles, addition of nucleophiles to enones, ketones, etc. 

Fig. 20 MIKE/CID spectra of the substituted m/z228 ions from the enantiomers of menthol ((7/ ,25,5R)-(— )-14 (A) and (75,27 ,55)-(+)-14 (B)) formed under CE(5)-2-amino-l-butanol (As) conditions (the m/z2 0 and mlz90 daugther ions are also produced during unimolecular decomposition of the m/z228 ions) (reprinted from ref. 472, with permission from Elsevier).

Emberger and ITopp and Werkhoff and ITopp reported that there are significant sensory differences between the eight menthol and the four menthone enantiomers. (5)(-)-7-Hydroxy-6, 7-dihydrocitronellal has a lily-of-the-valley odor, while the odor of its enantiomer is weaker and has green, leaf like and minty notes.The enantiomers of cis- and trans-Tose oxide have closely similar odors with slight but detectable quality differences. ... 

Werkhoff P, Hopp R, Isolation and gas chromatographic separation of menthol and menthone enantiomers from natural peppermint oils, in Brunke EJ (ed.). Progress in Essential Oil Research, Walter de Gruyter, Berlin, Germany, pp. 529— 549, 1986. 

An early example of an MIP-QCM sensor was a glucose monitoring system by Malitesta et al. (1999). A glucose imprinted poly(o-phenylenediamine) polymer was electrosynthesized on the sensor surface. This QCM sensor showed selectivity for glucose over other compounds such as ascorbic acid, paracetamol, cysteine, and fructose at physiologically relevant millimolar concentrations. A unique QCM sensor for detection of yeast was reported by Dickert and coworkers (Dickert et al. 2001 Dickert and Hayden 2002). Yeast cells were imprinted in a sol-gel matrix on the surface of the transducer. The MIP-coated sensor was able to measure yeast cell concentrations in situ and in complex media. A QCM sensor coated with a thin permeable MIP film was developed for the determination of L-menthol in the liquid phase (Percival et al. 2001). The MIP-QCM sensor displayed good selectivity and good sensitivity with a detection limit of 200 ppb (Fig. 15.7). The sensor also displayed excellent enantioselectivity and was able to easily differentiate the l- and D-enantiomers of menthol. 

Mandelic acid sublimation, 280 Mandelonitrile, 233, 330 Melting point, enantiomers, 279 Menthol, 9... 

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. 

The first enantiomer-selective polymerization was performed with propylene oxide (172) as a monomer [245], The polymerization was carried out with a ZnEt2/(+)-bor-neol or ZnEt2/(-)-menthol initiator system. The obtained polymer was optically active and the unreacted monomer was rich in (S)-isomer. Various examples are known concerning the polymerization and copolymerization of 172 [246-251 ]. A Schiff base complex 173 has been shown to be an effective catalyst In the polymerization at 60°C, the enantiopurity of the remaining monomer was 9% ee at 50% monomer conversion [250],... 

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. 

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.). 

Supercritical carbon dioxide is an apolar solvent, thus it is able to replace hexane during separation of the unreacted enantiomer from the diastereoisomeric complex containing reaction mixture. This idea was successfully applied in the complex forming resolution of tram-2-halogenocyclohexanols (35, 36, 37) and menthol (28). [42, 43] Diastereo-isomeric complex formation reaction was carried out in the mixture of the hexane solution of the racemic ligand and less then an equivalent amount of pulverised DBTA monohydrate. 

After a long incubation time the unreacted menthol (28) was withdrawn from the solid material in good yields but low ee values. In another experiment two consecutive extractions were accomplished at 32 °C and then at 50 °C after three hours reaction time. The first extract contained (IS, 2R, 5.S)-28 in 24 % ee but the second fraction was practically racemic because the (1R,2S,5R)-2S enantiomer partially escaped from the complex at 50 °C. 

In the case of lipases and esterases, chiral recognitions are not so strict. Both enantiomers were incorporated to the enzyme to form the substrate-enzyme complex. However, the slow reacting enantiomer lacked the necessary hydrogen-bonding interaction, for example in the hydrolysis of menthol acetate, between the substrate menthol and the enzyme histidine group for the reaction to proceed further (Figure 3(b)).2 3 The explanation was also supported by the observation in the esterification reaction of 1-phenylethanol by lipases.4 Km values of the slow and fast reacting... 

---