Takasago process for -menthol

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]. 

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-... 

One of the most important examples reported in Table 2.14 is the Takasago process for the manufacture of L-menthol, an important flavor and fragrance product. The key step is an enantioselective catalytic isomerization of a prochiral enamine to a chiral imine. The catalyst is a Rh-binap complex (developed by the vdnner of the 2001 Nobel Prize in Chemistry R. Noyori) and the product is obtained in 99% e.e. using a substrate/catalyst ratio of 8000 recycling of the catalyst affords total turnover numbers of up to 300 000. The Takasago process is used to produce several thousand tons of L-menthol on an annual basis. 

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]... 

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. 

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-... 

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. 

Menthol can be extracted from various species of mint. Commint (Mentha arvensis) contains the highest levels of 1-menthol and therefore is the major variety cultivated for menthol production. Mint is grown in China, India, Brazil and the United States. Because of the vagaries of climate and competition for land from other agricultural products, the supply of natural menthol is not stable. Price and availability fluctuate and these movements have a major impact on the economics of the various synthetic processes for 1-menthol. When natural menthol is scarce, the synthetic materials command a high price and marginal processes become economically attractive. When the natural material is in abundant supply, only the more efficient of the synthetic processes will compete. The most competitive synthetic processes are those of Symrise and Takasago hence their market domination. 

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. 

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. 

Reagents and conditions /. NHEt2-LiNEt2 //. Rh(l)-BINAP Hi. H2SO4 iv. ZnBr2 v. H2-catal. Scheme 9.2 Takasago Co. process for production of (—)-menthol... 

All the knowledge accumulated over the years at Takasago Research Institute, Tokyo, headed by S. Akutagawa, and by the research team of R. Noyori, Nobel Laureate for chemistry in 2001, prompted the development of an industrial process for the production of (—)-menthol by this method. Superficial observation of this scheme, and the list of reagents cited for the steps i-v, do not reveal the impressive mechanistic knowledge which has been gained on nearly all steps on this route to (—)-menthol. Already in the first step (/), reaction conditions in the alkylation of... 

Takasago have patented a process for the preparation of (—)-menthol from mesityl oxide and methyl vinyl ketone (231). The key step, hydrogenation of piperitenone (186) to (-l-)-pulegone (187), uses their chiral hydrogenation technology. The process, shown in Fig. 8.38, will provide a useful alternative to their process described above, when myrcene is in short supply. 

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. 

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. 

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