Menthol stereochemistry

Reaction with the hindered secondary alcohol menthol stops at the dialkyl sulfite ester. The examples reported do not establish the stereochemistry of the reaction. 

The first organoaluminium complex that catalysed a Diels Alder reaction was formed from menthol and ethylaluminium dichloride. This finding was complemented by work of Corey who showed that the aluminium diamine complex (49) was effective for controlling the stereochemistry of Diels-Alder reactions involving cyclopentadiene and acryloyl and crotonyl amides (e.g. 

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. 

Allylic double bonds can be isomerized by some transition metal complexes. Isomerization of alkyl allyl ethers 480 to vinyl ethers 481 is catalysed by Pd on carbon [205] and the Wilkinson complex [206], and the vinyl ethers are hydrolysed to aldehydes. Isomerization of the allylic amines to enamines is catalysed by Rh complexes [207]. The asymmetric isomerization of A jV-diethylgeranylamine (483), catalysed by Rh-(5)-BINAP (XXXI) complex to produce the (f )-enaminc 484 with high optical purity, has been achieved with a 300 000 turnover of the Rh catalyst, and citronellal (485) with nearly 100% ee is obtained by the hydrolysis of the enamine 484 [208]. Now optically pure /-menthol (486) is commerically produced in five steps from myrcene (482) via citronellal (485) by Takasago International Corporation. This is the largest industrial process of asymmetric synthesis in the world [209]. The following stereochemical corelation between the stereochemistries of the chiral Rh catalysts, diethylgeranylamine (483), diethylnerylamine (487) and the (R)- and (5)-enamines 484... 

All that remains is to establish the relative stereochemistry of the three substituents, which could be accomplished by NOESY. The compound is our old friend menthol. ... 

Previously documented methods for menthol inversion under standard Mitsunobu conditions (benzoic acid, PPha, diethyl azodicarboxylate) result in low yields4 (27%). More effective methods have been reported using extended reaction periods in refluxing toluene via a formic acid/N,N -dicyclohexylcarbodiimide-mediated transformation5 (20-92 hr, 80%). For hindered alcohols in general, representative methods for inverting alcohol stereochemistry necessitate conversion of the alcohol to... 

The isomerization of the double bond in the synthesis of (-)-menthol is stereospecific. Evidence obtained using vinyl amine specifically deuterated at C-l indicates that the transfer of a proton from C-l to C-3 is suprafacial,118 as indicated by equation 9.46. Equation 9.47 illustrates how the chirality of the BINAP ligand and the stereochemistry of the trisubstituted double bond in 86 control the stereochemistry of the methyl group at C-3 in 87 upon double bond migration. 

A mixture of Z- and -isomers was obtained the isomer ratio was not reported. The stereochemistry of the alkene is on comparative basis the reaction conditions were not optimized. Synthesized from L-menthol. Diastereomeric excess... 

Important information about the stereochemistry of dehydration has been obtained by studying the transformation of cyclic alcohols many of these reactions have proved suitable for the selective synthesis of alkenes [2]. The dehydration of menthol (5) and neomenthol (6) illustrates the usefulness of such processes (Scheme 3 axial hydrogens participating in water loss to form the major menthene isomers are shown) [55]. The regioselectivity observed points to an anti elimination mechanism. Isomer 6, with a trans OH/H configuration in the most stable conformation, reacts faster than compound 5. 

Having reviewed the principles of stereochemistry, we are now in a position to investigate the chemistry of mint. There are many species and sub-species of mint and their chemistry is dominated by monocyclic monoterpenoids, mostly alcohols and ketones. Some of the more important ones are shown in Figure 4.9. By far the most important of these are carvone and menthol, both of which will be discussed in more detail later. 

All eight isomers possess characteristic minty odours. The reason for the importance of /-menthol is its ability to interact, not only with odour receptors, but also with the receptors which sense cold. The presence of menthol will induce cold receptors to respond as if they had sensed a drop in temperature. This physiologically induced sensation of cold is used in many products from foodstuffs, such as confectionery, chewing gum, through oral care products such as toothpaste to cosmetic preparations such as shaving products. There is therefore a large market for menthol and, since not all of it can be met from natural mint oils, a demand for synthetic material. Consequently, there has been a lot of work on the synthesis of menthol and all of the synthetic routes considered must take stereochemistry into account as /-menthol is always the preferred target. 

The other two chiral centres of menthol are formed in the ene reaction when citronellal is cyclised to isopulegol in the presence of zinc chloride. The ene reaction is a 6-centre reaction. As the reaction starts, the six atoms involved come together in a ring and the shape of this ring determines the stereochemistry of the product. This is shown in Figure... 

With the above information in mind, we can proceed to deduce the stereochemistry of menthol aind neomenthol,... 

It has been shown by Griesinger and co-workers that it is possible to measure long-range H-C dipolar couplings for the water insoluble compounds in orienting media. The measurements have been performed for menthol dissolved in solution of poly-y-benzyl-glutamate in chloroform. The results have been used to check the usefulness of the method for elucidation of the stereochemistry of the studied compound. 

The stereochemistry of menthol results ultimately from a transition state in the chair conformation, in which aU the substituents are arranged equatorially the diastereoselectivity is greater than 98 %. 

Pickard and Littleburyi have isolated from the oil an isomer of menthol, which occurs in small quantity, and which they have named neomenthol. This body is of particular interest in regard to the stereochemistry of this important body. 

Fig. 8.36. As the asymmetric center of citronellal is unaffected by the reactions, all of the isopulegol and menthol isomers formed have the correct stereochemistry at Cl of the /i-menthane skeleton. There are therefore two strategies for recycling unwanted isomers. The first is to purify the ( )-isopulegol (172) by crystallization and recycle (178-180) back to citronellal by pyrolysis [221, 223, 224]. The second is to hydrogenate the mixture, separate the (—)-menthol by crystallization and treat the remainder with aluminium isopropoxide, which converts all of them, by Oppenauer oxidation, enoliza-tion, reketonization and Meerwein-Ponndorf-Verley reduction, to (—)-menthol, which is the thermodynamically most stable isomer (225).

The molecule below is menthol, with the stereochemistry omitted (see Section 4-7). (a) Identify all stereocenters in menthol, (b) How many stereoisomers exist for the menthol structure (c) Draw aU the stereoisomers of menthol, and identify all pairs of enantiomers. 

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