Menthol esters

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). 

S,3//,4/C6//)-carane-3,4-diol with (l/ )-tra s-chrysanthemic acid is 0.62, and the Rf. value of the corresponding ( l,S )-/ra .v-chrysanthemic acid ester is 0.65 (toluene ethyl acetate = 3 1). However, the /-menthol ester of (1 /. S )-/ra .v-chrysanthemic acid could not easily be separated by silica gel column chromatography to obtain (1 AfWran.v-chrysanthemic acid /-menthol ester. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

The use of Lewis acids in controlling the stereoselective outcome of radical cyclization reactions has been explored, in particular the effect of aluminium-based Lewis acids using low temperature Et3B/Bu3SnH-initiated procedures.171,172 For example, cyclization of propargyl ether (78) or allyl ether (79) in the presence of Lewis acid (80) can completely reverse the normal selectivity (Scheme 34).171 The effect of aluminium Lewis acids on the diastereoselectivity of 6-exo cyclization of unsaturated chiral menthol esters has been studied.172 Cyclization at low temperature in the presence of the Lewis acid MAD modified the de of the reaction from 31 to 98%. 

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). 

The best results can be obtained considering the energy of the triplet biradical intermediates (Fig. 3.19). Calculations on these biradical intermediates showed that the first (the precursor of the observed product) was more stable than the other by 0.73 kcal mol-1. Furthermore, the first and the second possible biradical intermediate in the reaction of the ester of (S)-2-methyl-l-butanol and differed by only 0.02 kcal mol-1, in agreement with the observed no stereoselectivity of the reaction. Finally, the first biradical intermediate in the reaction of 8-phenyl-menthol ester proved to be more stable than the other one by 21.9 kcal mol-1. This result is also in agreement with the observed high diastereoisomeric excess. 

Hamon and co-workers disclosed the asymmetric synthesis of non-proteinogenic a-amino acids [27], The authors used A -protected imino menthol esters as the building blocks (see Table 3, entry 3). They expected that 1,2-addition to the imine would take place, rather than attack at the nitrogen, because of the presence of the acyl group. The... 

Fig. 9.10 HPLC separation of MaNP acid menthol esters (S)-(-)-47a and (R)-(-)-47b [50].

Fig. 9.13 Comparison ofthe NMR A(5 values of menthol esters formed with chiral carboxylic acids [42].

It is interesting to note that for the assymmetric formation of cyclopropanes of high enantioselectivity, the use of ketocarbenoids with chiral auxiliaries, e. g., diazoacetates as borneol or menthol esters, has been fairly common for a long time. 

Terpenoids are frequently used to introduce asymmetry into molecules (a classic example is isopinocamphenylborane), and the use of camphor to introduce chirality into lanthanide shift reagents is now established (see also the section on bicyclo[2,2,l]heptanes below). The difference in geminal nonequivalence of methylene hydrogens of diastereomeric ( —)-menthoxyacetamides has been used as a monitor for the optical resolution of amines, this being a development of earlier work using menthoxyacetates for diastereomeric alcohols. The optical purity of chiral amines can also be checked from the n.m.r. spectrum of the amides obtained with (-t-)-(lR,4R)-camphor-10-sulphonic acid. Use of a menthol ester to separate pseudoasymmetric ferrocenes has been described. ... 

Evidence for conjugate reduction as a key step in monot-erpene biosynthesis has been obtained from studies of the oxygenated monoterpenes of Mentha piperita (Fig. 19.10) (Croteau, 1984). The pathway from isopiperitenone to the menthol esters was deduced largely by time-course studies and direct feeding experiments. Other evidence supports the intermediacy of /-limonene (11) as the first cyclization product of GPP in this plant. This is followed by the adlylic oxidation of the olefin and subsequent isomerization and reduction of the double bonds of isopiperitenone to the men-thones (such as 26). Furthermore, stereospecific dehydrogenases responsible for the synthesis of /-menthol (27) and d-neomenthol (28) have been isolated (Croteau, 1984). 

Peppermint oil is derived from the dried leaves and flowering tops of Mentha piperita (Lamiaceae). The oil consists of about 50% menthol. The taste and odour of peppermint oil are also influenced by some of its minor components, notably the menthol esters... 

In an analogous series, surfactants derived from 6-aminopenicillanic acid but bearing only hydrogenated substituents [98] have been synthesized, with yields of ca. 50%. One of the aims of these preparations is to access amphiphilic substances useful for chiral recognition [99,100], We have recently attempted the enantioselective synthesis of the p-perfiuoroalkyl-P-alanines (42). The enantiomeric excess achieved is rather modest for the moment. The approach is described in Scheme 36, with the enantioselective step being the hydrogenation of the chiral menthol ester. 

Good to excellent diastereoselectivities are also obtained with chiral enolates derived from menthol ester 88 [69], Schiffbase of 2-hydroxypinan-3-one 89 [70], bicyclic lactam 90 [71], 2-phenyloxazoline 91 [72], (25,55)-cw-l,3-dioxolan-4-one 92 [73], and imidazolidinone 93 [74, 75] (Fig. 8.4)... 

In one approach, an ester of one chiral isomer (e.g., L-menthol) may preferentially be formed via enzymatic action [78]. Then one only has to separate the initial alcohol form (e.g., D-menthol — not esterified) of the target compound from its ester form (L-menthol ester), which is reasonably easy. The alternative approach is to chemically form esters of both enantiomers and use an enzyme to cleave the ester from one chiral form. This again leaves a mixture that is an ester and an alcohol that are readily separated. Berger et al. [42] have illustrated this process for the separation of enantiomers of karahanaenol (Figure 9.10). Gatfield et al. [79] have a recent patent on this method for the isolation of pure L-menthol. 

In this example, synthetic DJ.-menthol racemate is initially chemically esterified with acetate, formate, propionate, myristate, benzoate, or succinate. The ester is then selectively hydrolyzed by steriospecilic microbial enzymes to produce L-menthol that is readily isolated from the D-menthol ester. The low water solubility of the menthyl esters and L-menthol has made this process particularly suitable to non-aqueous systems. Omata et al. [90] immobilized cells of Rhodotorula minuta in photo-cross-linked or polyurethane resin gels and used a water saturated hexane eluant to obtain a product of 100% optical purity. The immobilized cells had an estimated half-life of 55 to 63 days in this solvent. 

---