Takasago - -menthol synthesis

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... 

Find out how the catalyst efficiency of the Takasago synthesis of menthol was developed. 

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).

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. 

Isomerization is a frequent side-reaction of catalytic transformations of olefins, however, it can be a very useful synthetic method, as well. One of the best-known examples is the enantioselective allylamine enamine isomerization catalyzed by [Rh (jR)-or(S)-BINAP (COD)] which is the crucial step in the industrial synthesis of L-menthol by Takasago [42]... 

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... 

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. 

Although menthol (23) is a terpene available from natural sources (Chapter 5), asymmetric synthesis by the Takasago method now accounts for a substantial portion of the market. This synthesis is discussed in detail in Chapter 12. The key step is the asymmetric isomerization of an imine to an allyl amine (Scheme 31.18 ).224-225... 

Before leaving asymmetric hydrogenation reactions, we should mention one other related process that has acquired immense importance, again because of its industrial application. You have come across cit-ronellol a couple of times in this chapter already the corresponding aldehyde citronellal is even more important because it is an intermediate in the a synthesis of L-menthol by the Japanese chemical company Takasago. Takasago manufacture about 30% of the 3500 ton annual worldwide demand for L-menthol from citronellal by using an intramolecular ene reaction (a cycloaddition you met in Chapter 35). 

But it is not this step that makes the synthesis remarkable, but rather Takasago s route focitronel lal. Pinene is another terpene that is produced in only low enantiomeric excess by pine trees (and indeed, which is the major enantiomer depends on whether it is a European or a North Americar pine tree). But in the menthol process none of this matters, and cheap, enantiomerically impure pinene can be used, because the first step is to convert it to an achiral terpene, myrcene. Lithium diethylamide adds to this diene to give an allylic amine. 

Like the synthesis of L-DOPA by asymmetric hydrogenation, the manufacture of L-menthol hy Takasago Company is also one of the early examples of an industrial process where asymmetric isomerization is a key step. The desired isomerization reaction is one of the steps of the overall synthetic scheme. The synthesis of L-menthol from diethyl geranylamine is shown by 9.2. The formal electron pair pushing mechanism for the isomerization of the allylic amine to the enamine proceeds according to reaction 9.3. 

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. 

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...

A further highlight was introduced by R. Noyori in the 1980s when an efficient stereoselective hydrogen migration (allylamine —> enamine) was found to occur with Rh catalysts containing the BINAP diphosphine ligand of axial chirality (see Scheme 3 and Section 2.9). An L-menthol synthesis with an annual production of 2000 tons was the first commercial result of this development at Takasago Perfumery Co. Ltd. in Japan [66]. 

Scheme 3. The L-menthol synthesis of Takasago Perfumery, exploiting an axially chiral ligand to generate the first chiral environment (cat. = [Rh (-)-BlNAP COD]+).

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. 

For more information on the Takasago (-)-menthol synthesis, see H. Kumobayashi, Reel. Trav. Chim. Pays-Bas, 1996,115, 201 C. Chapuis and D. Jacoby, Appl. Catal. A, 2001, 221, 93 and G. P. Chiusoli and P. M. Maitlis, Metal-Catalysis in Industrial Organic Processes, RSC Publishing Cambridge, 2006, pp. 103-107. 

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 ... 

Asymmetric hydrogenation was boosted towards synthetic applications with the preparation of binap 15 by Noyori et al. [55] (Scheme 10). This diphosphine is a good ligand of rhodium, but it was some ruthenium/binap complexes which have found spectacular applications (from 1986 up to now) in asymmetric hydrogenation of many types of unsaturated substrates (C=C or C=0 double bonds). Some examples are listed in Scheme 10. Another important development generated by binap was the isomerization of allylamines into enamines catalyzed by cationic rhodium/binap complexes [57]. This reaction has been applied since 1985 in Japan at the Takasago Company for the synthesis of (-)-menthol (Scheme 10). 

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