Menthol Takasago process

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).

An important application of an isomerisation is found in the Takasago process for the commercial production of (-)menthol from myreene. The catalyst used is a rhodium complex of BINAP, an asymmetric ligand based on the atropisomerism of substituted dinaphthyl (Figure 5.5). It was introduced by Noyori [1],... 

Enantiomerically pure citronellal in both of its antipodal forms has outstanding importance as a key intermediate for the production of fine chemicals, especially for the production of fragrances and flavors. In this respect the isomerization of diethylgeranylamine to R) -citronellal enamine in the presence of Rh /(S) -BINAP is an exceptional industrial process, for instance as one of the key steps of the Takasago process for the production of (-) -menthol [22]. In the search for alternatives for this process, both Josiphos and Daniphos derivatives were evaluated (Scheme 1.4.5) [23]. 

An elegant example of a highly efficient catalytic asymmetric synthesis is the Takasago process [128] for the manufacture of 1-menthol, an important flavour and fragrance product. The key step is an enantioselective catalytic isomerisation of a prochiral enamine to a chiral imine (Fig. 1.44). The catalyst is a Rh-Binap complex (see Fig. 1.44) and the product is obtained in 99% ee using a sub-strate/catalyst ratio of 8000 recycling of the catalyst affords total turnover numbers of up to 300000. The Takasago process is used to produce several thousand tons of 1-menthol on an annual basis. 

Thermal rearrangement of / -pinene affords myrcene (Fig. 8.43) which is the raw material for a variety of flavor and fragrance compounds, e.g. the Takasago process for the production of optically pure L-menthol (see Chapter 1). Dehydro-... 

Since several decades, for the manufacturing of synthetic menthol, two industrial processes are employed the Haarmann-Reimer Process and the Takasago Process. BASF has developed a third one, which has recently gone into use. 

From a historical perspective, the Monsanto process for the preparation of (l.)-DOPA in 1974 laid the foundation stone for industrial enantioselective catalysis. Since then it has been joined by a number of other asymmetric methods, such as enantioselective Sharpless epoxidation (glycidol (ARCO) and disparlure (Baker)), and cyclopropanation (cilastatin (Merck, Sumitomo) and pyre-throids (Sumitomo)). Nevertheless, besides the enantioselective hydrogenation of an imine for the production of (S)-metolachlor(a herbicide from Syngenta), the Takasago process for the production of (-)-menthol remains since 1984 as the largest worldwide industrial application of homogeneous asymmetric catalysis. [124]... 

A very efficient asymmetric synthesis occurs in the Takasago process [57] for making 1-menthol, an important flavouring and fragrance compound. This process (12.377) employs the catalyst Rh-(s) BINAP (12.373) which yields a product of 99% ee purity. 

The inexpensive natural alcohol ( )-menthol is obtained from the natural souree, Mentha arvensis, or from myreene via a homogenously eatalysed route (Takasago process) in multi-tonne quantities (Scheme 2.8). 

From the viewpoint of industrial utilisation, a major breakthrough in catalytic asymmetric synthesis was the discovery of the BINAP-Rh catalysed enantioselective isomerisation of prochiral allylic amines [35, 36], which led to the Takasago process for production of 1-menthol (Scheme 7.7). An annual production of over 1500 tonnes makes this by far the world s largest scale and most important example of asymmetric synthesis. 

One of the major industrial routes to (-)-menthol is the Takasago process that involves, as one of the key steps, the diastereoselective isomerization of (-i-)-citronellal to (-)-isopulegol with an aqueous ZnBrj catalyst [129]. 

Takasago A catalytic process for the enantioselective isomerization of allylic amines. The catalyst is a chiral rhodium complex. Used in the manufacture of (-)menthol. Named after Takasago International Corporation, the Japanese company which commercialized the process in 1983. 

In the Rh-BINAP-catalyzed allyl amine isomerization step used in Takasago s Menthol process, the catalyst is inhibited by water through the formation of a hydroxyl-bridged rhodium trinuclear complex [ Rh(BINAP) i(/<2-0H)2]C104 [61]. 

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 synthetic process starts with the isopropylation of m-cresol to yield thymol. After catalytic hydrogenation a mixture of stereoisomers is obtained from which (+)-menthol is isolated. The process requires much separation and recycling work. In contrast, the semi-synthetic process of Takasago (Scheme 5.5) leads essentially to stereopure (—)-menthol [19]. 

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