Takasago Company

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. 

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). 

This type of dynamic kinetic resolution has been conducted on a production scale by the Takasago Company. - [Ru(cymene)yj, in combination with Tol-BINAP, generates a catalyst for the hydrogenation of a p-keto ester containing an amidomethyl group on the central carbon (Equation 15.58). The product of this reaction is used for the synthesis of carbapanen antibiotics. This hydrogenation has been reported to be conducted on the scale of 50-120 tons per year. 

R)-Citronellal purchased from Aldrich Chemical Company, Inc., Dragoco, Holzmlnden, or Takasago, Perfumery Co., Ltd., Tokyo was used as received. (R)-Citronellal can also be synthesized from pulegone with ee > 99%.3 The optical purity... 

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. 

The hydrogenation of a number of aromatic ketones is shown in Figure 37.30. Noyori s very effective Ru-diphosphine-diamine technology was developed by several companies. It is not clear on which scale the processes developed by Takasago (dm-binap = 3,5-xylyl-binap) [16] and Dow/Chirotech [109-111] for the reduction of substituted acetophenones are actually applied commercially. Using the Xyl-PhanePhos-dpen catalyst, a highly efficient bench-scale process was developed for the hydrogenation of p-fluoroacetophenone (ee 98%, TON 100000, TOF 50000 IT1 at r.t., 8 bar) [109]. Ru-P-Phos (licensed to Johnson Matthey [112]) achieved ee-values >99.9% and TON up to 100000 for sev-... 

Financial resources for the colloquium were provided by the Academy and supplemented by contributions from a number of industries (American Cyana-mid Company, E. I. DuPont de Nemours Co., Givaudan-Roure Corporation, Merck Co., Monsanto, Rohm and Haas Company, Schering-Plough Research Institute, Sterling-Winthrop Inc., Syntex, Takasago International Corporation, Zeneca Inc.), to which we are much indebted. 

The commercialization in 1983 of the process illustrated in Eq. (1) is undoubtedly one of the most significant triumphs of asymmetric catalysis to date [2]. Takasago Chemical Company produced more than 22 000 tons of menthol by this route during the period 1983-1996, consuming only 125 kg of the chiral Hgand in the process. Rh(I)/Tol-BINAP-catalyzed isomerizations of allylic amines are beheved to proceed through the pathway outlined in Eq. (2) [3]. 

Research Laboratories, Nippon Fine Chemical Company, Ltd., 5-1-1 Umei, Takasago-cily, Hyogo 676, Japan... 

Osaka Research Laboratory, Koa Oil Company, 2-1, Takasago, Takaishi-shi, Osaka 92, Japan... 

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). 

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). 

In response to the DC1, the manufacturers and sellers of PBO technical advised the USF.PA that they would develop the necessary data. These companies were Endura Spa, Takasago USA. Inc., Hard wi eke Chemical Company Division of Ethyl Corporation, McLaughlin GormLey King Company, Fairlield American Company and its parent. Wellcome Foundation, Prentiss Drug. Chemical Company. Inc. and Penick Corporation. The companies formed the PBO Task Force (PBTF), a joint venture under US Law, to produce the data. The PBTF is the owner of the data and all rights in the data, worldwide. 

CCCs may be companies that specialize in chiral compounds, such as Celgene, Chiroscience, and Oxford Asymmetry, or may have developed into a chiral raw material supplier to an industry other than its original main customer base [e.g., Takasago, a flavor manufacturer, who developed a catalytic route to (-)-menthol, and used related technology to make beta-lactam intermediates]. 

Asymmetric isomerization of allylamines is performed with high enantioselectivity [57]. This process is applied to the industrial production of L-menthol from diethylger-anylamine by the Takasago Perfumery Company (eq (48)). 

The other major producer of synthetic L-menthol is the Japanese company Takasago. They produce about 1000 tonnes per annum using elegant chemistry developed by Noyori (Scheme 4.22). Pyrolysis of / -pinene gives myrcene, to which diethylamine can be added in the presence of a catalytic amount of strong base. This produces N,N-diethylgeranylamine. Isomerization of this with the rhodium 2,2 -(diphenylphosphino)-1,1-binaphthyl (BINAP) complex produces the enamine of citronellal. The elegance of this route stems from the fact... 

The symposium and book would not have been possible without the financial assistance of Ajinomoto Company, Inc. Hasegawa Company, Ltd. Kirin Brewery Company, Ltd. Ogawa Company, Ltd. and Takasago International Corporation. We are grateful for their generous contributions. 

T. Hasegawa Company, Limited, 167 Takasago International Corporation, 188 Technische Universitat Miinchen,... 

The other menthol synthesis which is of major commercial importance is the one used by the Japanese company Takasago. The synthesis was devised by Professor Noyori of Nagoya University and is part of the work for which he was awarded the Nobel Prize for chemistry in 2002. The basic scheme is shown in Figure 4.20. 

Myrcene, obtained from SCM Organic Chemicals (also available from Takasago Perfumery Company, Ltd., in Japan), was distilled (bp 69-70°C, 20 mm) prior to use, GLC analysis (Triton X-305, 0,28 mm x 30 m, 80-120°C) showed that the fraction contained 74% nyrcene. The submitters used 80% pure myrcene. 

In the last 25 years or so, this subject has occupied more organic chemists than possibly any other, and we are now at a point where it is not only possible (and in fact essential because of strict regulatory rules) to make many drug molecules as single enantiomers, but it is also even possible to make many chiral molecules that are indigenous to nature more cheaply in the laboratory. By 2007, for example, at least 30% of the world s supply of menthol was not extracted from plants but made synthetically. A thousand tonnes of (-)-menthol a year is made by the company Takasago in Japan using the techniques of asymmetric synthesis that you will meet later in this chapter. 

It is the existence of the eight menthol isomers that makes the chemical synthesis onerous. In many procedures, more than one isomers form as a final product, and needs to be separated out at the end. These byproducts, the isomers of (-)-menthol, all have cooling and refreshing effects, but none of them is as potent as menthol itself. So the presence of these isomers lowers the quality of the final product. Another option is to look for a chemical reaction that produces (-)-menthol exclusively. This was achieved from meta-cresol by the company Haarman and Reimer, which is also a major vanillin producer, whereas a Japanese chemical company, Takasago,... 

Limonin has recently become commercially available from several chemical companies including Aldrich and Sigma. Nomilin is also available from Takasago (Toyko, Japan). Other limonoid aglycones and limonoid glucosides are currently only obtained by isolation from citrus seeds. See Herman et al. (1992) for extraction and isolation methods. 

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