Menthol diastereomers

Scheme 6.17.1 Reaction scheme of epimerization of menthol diastereomers (Etzold, 2007 Etzold and Jess, 2008 and 2009).

Reaction mechanisms of epimerization of menthol diastereomers (Etzold, 2007). 

Kinetic studies on the epimerization of menthol diastereomers have been conducted in a laboratory-scale semi-batch reactor (Figure 6.17.3) as well as in a continuous fixed bed reactor (Figure 6.17.4). In the latter case, the liquid feed was externally saturated with Hz to suppress dehydrogenation to menthone [presaturated one-liquid flow (POLF) reactor]. 

Figure 6.17.6 Equilibrium concentrations of menthol diastereomers. Data from Etzold (2007) Etzold and jess (2008) Bedoukian (1970) Yoshida, Komatsu, and Indo (1966) Schlemenat et al. (2001) and Stolow and Groom (1968).

For several combined reversible reactions, as in the case of the epimerization (Scheme 6.17.1), we have an analytically unsolvable reaction network with respect to the influence of internal mass transfer. In the following, a numerical method developed by Etzold (Etzold, 2007) is presented, which allows the fast and accurate simultaneous calculation of the change of the concentrations in the bulk phase as well as within the porous particles with time (batch reactor) or local position (tubular flxed bed reactor). This method may also be used for other reaction systems beyond the special case of epimerization of menthol diastereomers. 

Figure 6.17.11 Experimental and calculated data of the epimerization of menthol diastereomers for small particles (intrinsic kinetics) and large particles (pore diffusion). The gray symbols represent three reference values that are also used and indicated in Figure 6.17.12. Adapted from Etzold and Jess (2008).

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). 

As an alternative, Harpp and coworkers reacted benzenesulfinyl chloride with the trimethylsilyl derivative of menthol to form the diastereomeric esters in 91% yield the epimer of configuration R could be isolated by crystallization in unspecified yield. Grossert and coworkers prepared ester 19 in 51% yield as a mixture of diastereomers by treating p-toluenesulfonyl chloride with sodium p-toluenesulfinate in DMF containing menthol. It was postulated that initial nucleophilic attack by the sulfinate oxygen on the sulfonyl sulfur atom gave the mixed sulfonate-sulfinate anhydride 21, which then reacted... 

Although menthyl esters, especially 19, are most often used to prepare sulfoxides, esters derived from optically active alcohols other than menthol have been prepared . Ridley and Smal prepared arenesulfmic esters of 1,2 5,6-di-O-cyclohexylidene-a-D-glucofuranose. Unfortunately, these diastereomers were oils, except for the mesityl derivative, with the major epimer having configuration R at sulfur and so they offered no advantage over the menthyl esters. Separation of the epimers by chromatography failed. 

Esterification of p-toluenesulfinic acid with (- )-menthol gives a mixture of two diastereomers, which equilibrate to the pure (-)-menthyl (S)-p-toluenesulfinate diastereomer in the presence of hydrochloric acid (80% yield). The report includes an improved procedure for reaction of 1 with CH,MgI to give (R)-( + )-methyl p-tolyl sulfoxide.1... 

Brimble and coworkers172 reported the asymmetric Diels-Alder reactions between quinones 265 bearing a menthol chiral auxiliary and cyclopentadiene (equation 73). When zinc dichloride or zinc dibromide was employed as the Lewis acid catalyst, the reaction proceeded with complete endo selectivity, but with only moderate diastereofacial selectivity affording 3 1 and 2 1 mixtures of 266 and 267 (dominant diastereomer unknown), respectively. The use of stronger Lewis acids, such as titanium tetrachloride, led to the formation of fragmentation products. Due to the inseparability of the two diastereomeric adducts, it proved impossible to determine which one had been formed in excess. 

In addition to sulfimides, the nitrogen analogs of sulfinates and sulfinamides are chiral and have been obtained as optically active compounds. For instance, the synthesis of diastereomeric menthyl p-toluenesulfinimidoates 90 mentioned above was effected by Cram and his collaborators (18,137) on two ways. The first comprised the reaction of racemic A -tosyl-p-tolueneiminosulfinyl chloride 92 with menthol, followed by separation of the diastereomers of 90, whereas in the second method the reaction of the ester (->45 with chloramine T was utilized. 

The addition of different organometallics to the aldehyde function of 231, obtained by the regio- and diastereo-selective ring closure of (—)-8-(benzylamino)menthol 234 and 2-(t>-formylphenyl)acetaldehyde, resulted in formation of a mixture of diastereomeric secondary alcohols 232 and 233. The formation of the major diastereomers 232 was... 

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... 

Chiral furanones (butanolides) such as 191 have been used as dipolarophUes in various 1,3-dipolar cycloadditions. The chiral 4-substituted butanolide 190 was prepared from 191 and the chiral auxiliary menthol (Scheme 12.55) (310,311). The single diastereomer 191 is obtained by crystallization and epimerization of the other diastereomer, as the amount of 191 in solution decreases. 1,3-Dipolar... 

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. 

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. 

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. 

Thermal cyclization of chiral. V-sulfinyl carbamate 7, prepared from optically active 8-phenyl-menthol, with ( , >2,4-hexadicne affords a mixture of all four possible diastereomeric cycloadducts 8 A-D (d.r. 7 14 17 62)". However, when the reaction is carried out in the presence of tin(lV) chloride, diastereomer 8B (yield 42%) only is obtained. 

The use of the corresponding thiourea in this reaction leads to equal amounts of both diastereomers, that is, no stereoselectivity is observed48. Chiral carbamates, derived from (-)-menthol and (+ )-camphor, give, in a similar reaction, a-aminoalkanephosphonic acids with optical purity up to 42 %71. 

Preparative Methods obtained by reaction of (—)-menthol with p-toluenesulfinyl chloride. This esterification showed no particular stereoselectivity, giving an equal amount of the two sulfinate diastereomers. In order to avoid a chromatographic separation, it is possible to epimerize these sulfinate esters in acidic medium and displace the resulting equilibrium towards the less soluble isomer, (—)-menthyl (5)-p-toluenesulfinate, in 80% yield (eq 1). This procedure was later extended to large scale preparation. ... 

Poor (<4% de) to modest (56% de) amounts of diastereofacial selection is observed in the cycloaddition of nitrile oxides to optically active acrylates. The plan in each case, of course, was to use a chiral auxiliary which would preferentially shield one of the two ir-faces of the dipolarophile. Of the auxiliaries used, the sulfonamide esters derived from (+)-camphorsulfonyl chloride worked best, the menthyl esters derived from (-)-menthol the poorest (<4% de). As illustrated in Table 19, changes in both temperature and solvent had either no or little affect on the product ratios. Unlike Diels-Alder reactions, the addition of Lewis acids, specifically Et2AlCl, EtAlCh and TiCL, resulted in significant decreases in both the rate of cycloaddition and isolated yield, without an appreciable change in diastereomer ratio. ... 

The first examples of an asymmetric Diels-Alder reaction of a non-chiral diene and a dienophile catalyzed by a chiral Lewis acid were reported by Koga and coworkers in 1979 (Sch. 1 and 16) [3]. The catalysts 4,142 and 143 were prepared from (-)-menthol, (+)-neomenthol and (+)-borneol. The reaction of methacrolein and cyclopentadiene mediated by catalyst 4 gave a 98 2 mixture of exo to endo products and upon separation of these diastereomers by chromatography the exo product 3 was obtained in 69 % yield and 72 % ee. The exo .endo ratios for the other reactions in Sch. 16 were not reported. Low asymmetric induction was observed for acrolein and methyl acrylate with all three catalysts. Moderate induction was observed in the reaction of methacrolein with catalyst 4, and with catalyst 142, but in the latter the enantiomer of 3 was the predominant product. The reaction of methyl acrylate with cyclopentadiene mediated by 10 mol % catalyst 4 was also reported by Kobayashi, Matsumura and Furukawa to give the cycloadduct 141 in 2.9 % ee at 30 °C [37]. These workers also reported that catalyst 4 will give optically active product from the reaction of cyclopentadiene and acrylonitrile, although the optical yield was not determined. 

Interesting examples of diastereomers and enantiomers of monoterpenoids are menthones and menthols. 

The thermally promoted reaction of an enantiomerically pure a-alkoxyallylstan-nane with achiral aldehydes was first reported by Thomas in 1984 [100]. The a-alkoxyallylstannane 145 (prepared from menthol and a racemic stannol) is heated with the aldehyde at 130°C to produce the homoallylic alcohol 146 as a single diastereomer in good yield (Scheme 10-62). Chairlike, six-membered transition structures can account for the observed diastereoseleetivity in these reactions. The a-alkoxy group prefers to adopt an axial position in the transition structure, ensuring that the diastereomers 145 and 147 react selectively with the aldehyde from only one face of the carbonyl group. 

---