Synthesis of menthol

Perhaps the most successful industrial process for the synthesis of menthol is employed by the Takasago Corporation in Japan.4 The elegant Takasago Process uses a most effective catalytic asymmetric reaction - the (S)-BINAP-Rh(i)-catalyzed asymmetric isomerization of an allylic amine to an enamine - and furnishes approximately 30% of the annual world supply of menthol. The asymmetric isomerization of an allylic amine is one of a large and growing number of catalytic asymmetric processes. Collectively, these catalytic asymmetric reactions have dramatically increased the power and scope of organic synthesis. Indeed, the discovery that certain chiral transition metal catalysts can dictate the stereo-... 

We now turn to the Takasago Process for the commercial synthesis of (-)-menthol (1),4 one of the most successful industrial applications of catalytic asymmetric synthesis. This exquisite synthesis is based on the BINAP-Rh(i)-catalyzed enantioselecdve isomerization of allylic amines, and has been in operation for the commercial production of (-)-menthol since 1984. 

Scheme 12. The Takasago process for the asymmetric synthesis of (-)-menthol (1).

Lewis acids, results in the formation of isopulegol (43) with greater than 98% diastereoselectivity isopulegol (43), wherein all of the ring substituents are equatorially oriented, arises naturally from a chairlike transition state structure in which the C-3 methyl group, the coordinated C-l aldehyde carbonyl, and the A6,7 double bond are all equatorial (see 48). A low-temperature crystallization raises the chemical and enantiomeric purity of isopulegol (43) close to 100%. Finally, hydrogenation of the double bond in 43 completes the synthesis of (-)-menthol (1). 

Metal-catalyzed C-H bond formation through isomerization, especially asymmetric variant of that, is highly useful in organic synthesis. The most successful example is no doubt the enantioselective isomerization of allylamines catalyzed by Rh(i)/TolBINAP complex, which was applied to the industrial synthesis of (—)-menthol. A highly enantioselective isomerization of allylic alcohols was also developed using Rh(l)/phosphaferrocene complex. Despite these successful examples, an enantioselective isomerization of unfunctionalized alkenes and metal-catalyzed isomerization of acetylenic triple bonds has not been extensively studied. Future developments of new catalysts and ligands for these reactions will enhance the synthetic utility of the metal-catalyzed isomerization reaction. 

Isomerization of allylic amines is another example of the application of the BINAP complex. Rh BINAP complex catalyzes the isomerization of N,N-diethylnerylamine 40 generated from myrcene 39 with 76-96% optical yield. Compound (R)-citronellal (R)-42. prepared through hydrolysis of (R)-41, is then cyclized by zinc bromide treatment.49 Catalytic hydrogenation then completes the synthesis of (—)-menthol. This enantioselective catalysis allows the annual production of about 1500 tons of menthol and other terpenic substances by Takasago International Corporation.50... 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

The synthesis of menthol is given in the reaction scheme, Figure 5. 6. The key reaction [2] is the enantioselective isomerisation of the allylamine to the asymmetric enamine. It is proposed that this reaction proceeds via an allylic intermediate, but it is not known whether the allyl formation is accompanied by a base-mediated proton abstraction or hydride formation. 

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. 

Recently, a striking synthesis of (—)-menthol (18) has been introduced8, based on chiral catalysis in the isomerization of 13 to the enamine 14 ... 

Pure citronellal is a colorless liquid with a refreshing odor, reminiscent of balm mint. Upon catalytic hydrogenation, citronellal yields dihydrocitronellal, citro-nellol, or dihydrocitronellol, depending on the reaction conditions. Protection of the aldehyde group, followed by addition of water to the double bond in the presence of mineral acids or ion-exchange resins results in formation of 3,7-dimethyl-7-hydroxyoctan-l-al (hydroxydihydrocitronellal). Acid-catalyzed cycli-zation to isopulegol is an important step in the synthesis of (-)-menthol. 

Most menthol is isolated from peppermint oils, especially from crude oil from Mentha arvensis from India. But menthol can also be prepared by chemical synthesis. There are two important commercial processes for the synthesis of menthol. One is based on a renewable resource, /1-pinene from turpentine, and the other on m-cresol from petrochemical origin (Scheme 13.3). 

Scheme 13.3 Chemical synthesis of menthol from m-cresol and from -pinene...

Noyori s BINAP catalysts deserve special attention because their chirality is based on the bulkiness of the naphthalene groups, rather than on carbon or phosphorus asymmetric centers (Figure 3.28, inset) [77]. One of the many examples of asymmetric catalysis using BINAP is the synthesis of (—)-menthol, an important additive for flavors, fragrances, and pharmaceuticals. Starting from myrcene, the process is carried out by Takasago International on a multi-ton scale. The key step is the isomerization of geranyldiethylamine to (R)-citronellal enamine [78], which is then hydrolyzed to (R)-citronellal with nearly 99% ee. 

R-citronellal (69). This isomerization is a crucial step in the synthesis of ( — )-menthol. Enantioselectivity in this isomerization exceeds 96%. 

Significantly, the previously developed chiral amine based catalysts that we and MacMillan and co-workers have studied have not been of use for sterically nonhindered aliphatic substrates. For example, citral (29), of which the hydrogenation product citronellal (30) is an intermediate in the industrial synthesis of menthol and used as a perfume ingredient, could not readily be used (Scheme 26, Eq. 41). We could... 

The use of chiral rhodium-BINAP complexes for the asymmetric isomerization of alkenes has been utilized in the industrial synthesis of menthol by Ryoji Noyori (winner of the 2001 Nobel Prize in Chemistry). This synthetic method was industrialized by Takasago International Corporation and provides (—)-menthol to pharmaceutical and food companies worldwide. In this case the catalyst [(S-BINAP)-Rh(COD)] or [(S-BINAP)2-RuC104 ] is used for the asymmetric isomerization of diethylgeranylamine (1.62) to 3-(R)-citronellalenamine (1.63) (Scheme 1.13). 

Scheme 1.13 Asymmetric synthesis of menthol by Takasago International Corporation...

The world s biggest application of asymmetric catalysis is Takasago Perfumery s synthesis of (-)-menthol from myrcene (see Sections 2.9 and 3.3.1) with about 1500 t/a (menthol and other chiral terpenic substances). The key step is the isomerization of geranyldiethylamine with an Rh -S-BINAP catalyst to citronellal ( )-enamine (eqs. (17)) (BINAP = 2,2 -bis(diphenylphosphine)-l,l -binaphthyl).The geometry of the double bond is 100% E. 

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. 

The Rh-catalyzed isomerization step of the Takasago synthesis of (-)-menthol is highly efficient. With modification of the catalyst precursor (still based on BINAP and its derivatives), the % ee has risen to 99% with a TON of up to 400,000 (if catalyst recycling occurs). The isomerization step is also useful in producing precursors to (+)-d,v-p-mcnthanc-3,8-diol (94), which shows promise as an insect repellant that could replace DEET, the most common repellant sold today.120... 

The synthesis of menthol makes an interesting study since it neatly illustrates the balance of economic and technological factors governing the range of production methods that can be employed commercially. 

Reduction of 2-acylamino acrylates to give aminoacids Hydrogenation with C2-Symmetrical BINAP Rh and Ru Complexes Asymmetric Hydrogenation of Carbonyl Groups Regioselective asymmetric hydrogenation ofenones Asymmetric reduction of ketones with kinetic resolution A Commercial Synthesis of Menthol... 

Noyori s synthesis of menthol by Rh+-catalysed [1,3]H shifts Corey s CBS Reduction of Ketones A synthesis of the H1 blocker cetirizine Part II - Asymmetric Formation of C-C Bonds Organic Catalysis... 

One of Noyori s most remarkable achievements is a commercial synthesis of (-)-menthol 51 used since 1983 by the Takasago International Corporation on a scale of thousands of tonnes a year. This and related processes are discussed in detail by S. Akutagawa and K. Tani in chapter 3 of Ojima s Catalytic Asymmetric Synthesis. The process is summarised here ... 

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