Menthol diastereoisomers

Menthol can also be synthesized from optically active terpenoids such as (+)-citroneUal, (-)- P-pheUandrene, and (+)-3-carene. The synthesis from (+)-3-carene has already been discussed in the section on hydrocarbons. Such methods must avoid any racemization during the course of a usually multiple-step synthesis. One disadvantage of such methods is that the other menthol diastereoisomers must be equilibrated and recycled. 

Neomenthol differs from menthol in having different stereochemistry at a single position. This makes it a configurational isomer, a diastereoisomer (there are two other chiral centres that are unchanged), and an epimer. The other terms are not applicable. 

Determine the absolute configurations of the chiral centres in menthol and phenbutrazate. List the configurations of the pairs of enantiomeric diastereoisomers of menthol (Fig. 2.24). 

It can be seen in Figure 11.13 that, although the menthol portions of the esters are mirror images, addition of the chiral acylating reagent generates esters which are not mirror images but are diastereoisomers and thus have different physical properties. 

To our knowledge, the first examples of asymmetrically substituted monocyclic phosphoranes are 60 and 61, described by Moriarty et al.135 and involving the reaction of a substituted o-benzoquinone136,137 (Scheme 6) on an aminophosphine (59), itself obtained by alcoholysis of 58 with l-( — )-menthol. In contrast to the amino phosphine 53 (Scheme 5), 59 is a mixture of the diastereoisomers 59a and b, and its reaction with 3,5-di-tert-butyl-l,2-benzoquinone yields two diastereoisomeric phosphoranes, 60a and b. Finally, alcoholysis of the P(V)—NR2 bond138 in 60a and b leads to 61a and b or 62. 

In other systems, a particular structure may be found as a mixture of diastereoisomers. Peppermint (Mentha x piperita Labiatae/Lamiaceae) typically produces (—)-menthol, with smaller amounts of the stereoisomers (+)-neomenthol, (+)-isomenthol, and (+)-neoisomenthol, covering four of the possible eight stereoisomers (Figure 5.16). Oils from various Mentha species also contain significant amounts of ketones, e.g. (—)-menthone, (+)-isomenthone, (—)-piperitone, or (+)-pulegone. The metabolic relationship of... 

Enantiomers of carboxylic acids may sometimes be separated by GC as methyl esters, but special derivatives are mostly prepared for this purpose. Ackman et al. [188] resolved enantiomers of isoprenoid fatty acids after their conversion into L-menthyl esters. The acids under analysis were chlorinated by refluxing with distilled freshly prepared thionyl chloride and the chlorides produced were treated with L-menthol in the presence of pyridine under strictly anhydrous conditions. GC separation was carried out in a capillary column coated with butanediol succinate polyester. Annett and Stumpf [189] made use of L-menthyloxycarbonyl derivatives for the separation of enantiomers of methyl esters of hydroxy acids. The derivatization reagent, L-menthyl chloroformate, was prepared by the reaction of L-menthol with phosgene, with cooling with ice. Diastereoisomers of different hydroxy acids were thus separated on 1.5% OV-210. 

N-methyl derivative resulted in oxidation of the ligand with concomitant reduction of Co (III) to Co (II). The preparation of tris (benzohydroxa-mato) chromium (III), Cr(benz)3, was successful and resulted in the separation and characterization of its two geometric isomers (2). The half-lives for isomerization of these complexes near physiological conditions is on the order of hours. To facilitate the separation of all four optical isomers of a simple model tris (hydroxamate) chromium (III) complex, we prepared (using Z-menthol as a substituent) the optically active hydroxamic acid, N-methyl-Z-menthoxyacethydroxamic acid (men). This resulted in the separation of the two cis diastereoisomers of tris(N-methyl-Z-menthoxyacethydroxamato) chromium (III) from the trans diastereoisomers and their characterization by electronic absorption and circular dichroism spectra. 

They made a racemic sample using the Strecker synthesis of amino acids that you met in Chapter 12. The racemic amino acid was reacted with acetic anhydride to make the mixed anhydride and then with the sodium salt of naturally derived, enantiomerically pure alcohol menthol to give two diastereoisomers of the ester (see top of facing page). 

These two diastereoisomeric cyclohexyl chlorides derived from menthol react very differently under the same conditions with sodium ethoxide as base. Both eliminate HC1 but diastereoisomer A reacts rapidly to give a mixture of products, while diastereoisomer B (which differs only in the configuration of the carbon atom bearing chlorine) gives a single alkene product but very much more slowly. We can safely exclude El as a mechanism because the same cation would be formed from both diastereoisomers, and this would mean the ratio of products (though not necssarily the rate) would be the same for both. 

Sulfinate esters, like sulfoxides, are chiral at sulfur and, if the ester is formed from a chiral alcohol i (menthol is best), they can be separated into two diastereoisomers by crystallization—this is really a j resolution of the type you first met in Chapter 16. Attack by the Grignard reagent takes place with i inversion of configuration at sulfur, giving a single enantiomer of the sulfoxide. i... 

The whole process is a resolution with the difference that the resolving agent (menthol) becomes the leaving group in a constructive nucleophilic displacement that builds an essential C-P bond. Racemic phosphinoyl chloride combines with a single enantiomer of rnenthol to give a separable mixture of diastereoisomers. 

The best way to prepare large quantities of optically active sulfoxides makes use of optically active menthyl sulfinate. By esterification of p-toluenesulflnic acid with 1-menthol, a mixture of dia-stereoisomeric menthyl sulfinates is obtained. This esterification reaction shows no particular stereoselectivity and therefore a mixture of the two diastereoisomeric esters was obtained. However, it is possible to equilibrate these diastereoisomers in acidic media and to shift the equilibrium towards the... 

Hudlicky et al. created a chiral version of the Burgess reagent (63), that was exposed to meso-aliphatic epoxides, to afford a 1 1 mixture of cts-fused sulfamidate diastereoisomers (64, 65, M = menthol chiral auxiliary) in modest yield.18... 

Unlike enantiomers, diastereoisomers have different physical properties, including boiling points. At atmospheric pressure, d,/-menthol boils... 

More reeently, Whitesell has recently reported an improved method for the preparation of enantiomerically pure sulfinate esters (Scheme 2.11) [19]. As previously described, the (5)-(-)-menthyl p-toluene sulfinate diastereoisomer only is readily available in a pure, crystalline form using the Andersen procedure. Whitesell discovered that reaction of the ehiral auxiliary trans-2-phenylcyclohexanol (8) with an excess of alkyl or arene sulfinyl chloride afforded the appropriate sulfinate esters (9) and (10) in good yield and with better selectivities (up to 10 1) than those observed with (lf ,25,5f )-(-)-menthol ( 2 1). These diastereoisomers can be readily separated (R p-Tol (9a) = 62% yield, 98% de) by either crystallization or by chromatography, in contrast to the Andersen procedure. 

In this case the resolving agent should be added to the racemic compound and the mixture should be warmed until it melted then is should be cooled while one of the diastereoisomers crystallizes from the melt. The ciystalline material can be separated by filtration from the residue of the melt (as in case of enantiomeric mixtures). An example for this method is the resolution of racemic menthol (MEN) with 0,0 -dibenzoyl-(J ,J )-tartaric acid ((R,R)-DBTA). The crystalline molecular complex (diastereoisomer) contains the (lJ ,2S,5J )-menthol (the L-menthol (L-MEN)), while the remained melt is enriched in the other enantiomer ... 

Chiral oxazaphosphorinanes, derived from (-)-8-amino menthol are alkylated with good to excellent diastereoselectivities. The regioselectivity in the alkylation is dependent on the base used for protonation.Both enantiomers of the major diastereoisomer of 2-(l-phenyl)ethylamino-4-thioxo-4-phenoxy-l,3,4-thiazaphos-phol-2-ine were obtained in optically pure form by the reaction of 0-phenyl(chloro-methyljisothiophosphonate with (i )-(-l-)- and (5)-(—)-(l-phenyl)ethylamine. Phase-transfer 7V-allylation and A7-propargylation of (bicyclo[1.1.0]butylmethyl)-amines initiate diastereoselective pericyclic cascade reactions that culminate in novel spirocyclic (206) and tricyclic pyrrolidine (207) heterocycles through formal ene or [2 + 2] pathways (Scheme 76). ... 

Most terpenes contain one or more chiral centers. Of several terpenes, the optically inactive form and the 1- and d-form occur in different plants. The enantiomers and diastereoisomers differ regularly in their odor characteristics. For example, menthol (XIV in Table 5.33) in the 1-form... 

FIGURE 8.10 Chromatographic behavior of some diastereoisomers of menthols on silica gel. Mobile phases (v/v) 1, benzene 2, benzene-methanol (95 + 5) 3, benzene-methanol (75 + 25) 4, methanol. (Data from Petrowitz, H.-J., Angew. Chem., 23, 921,1960.)... 

The studied diastereoisomers have been separated by adsorption TLC on silica gel plates activated 30 min at 120 C before use. The spotted plates were developed three times, for menthols with the binary mixture n-hexane-ethanol (85 +15, v/v) and for thujols with benzene. The experimental Rp and Rm values of investigated diastereoisomers and the numerical values of the proposed stereoisomeric topological indexes (/sn) and the modified version of the index Bsti are given by the author [43]. The data demonstrate close correlation between Rp and Rm values and the numerical values of the topological indexes. 

The calculated Rp ( 0.030 deviation) and Rm values for the diastereoisomers of menthol and thujol are in good agreement with the experimental data that attest the physicochemical significance of the topological indexes proposed by the author. Such indexes can be used for analytical identification of diastereoisomers separated by TLC. 

General Correlations on the Chromatographic Behavior of Menthol and Thujol Diastereoisomers with Hydroxyl Group in Axial or Equatorial Position... 

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