Menthol process

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]. 

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. 

This selection of menthol processes shows how the major producers are those with the most cost-effective processes, but that local economic conditions or feedstock availability can provide niche opportunities for less efficient processes. 

Using chemistry based on their menthol process (as described above), Takasago can produce optically pure ( )-hydroxycitronellal and they claim that this enantiomer has a preferable odor and is a weaker skin sensitizer than the racemate [168, 297]. 

Natural menthol is obtained by freezing the essential oU, eg, Mentha arvensis and the menthol crystals ate separated by centrifuging the supernatant hquid away from the crystals. The supernatant oU is then caUed dementholized cornmint oU. Impurities in the crystals come from the essential oU and usuaUy give a slight peppermint aroma to the crystallized menthol. The cornmint oU, rich in (—)-menthone (- 28%) and (—)-menthol (- 32%), can be further processed to give additional natural menthol. 

Optical resolution is another method of producing (—)-mentho1 from racemic materials. (A)-Menthol is treated with optically active resolving agents to separate the (—)-mentho1 from the (+)-menthol, which is further processed by racemization over a nickel catalyst and recycled (156). 

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).

You probably came up with the suggestion that by using an esterase which selectively hydrolyses the succinate ester of L-menthol, you would be able to isolate L-menthol from the mixture. This is in essence the way the process is carried out commercially. We can represent this process by ... 

The process uses cells of Rhodotorula minuta entrapped in polyurethane. These cells selectively hydrolyse the L-ester. The remaining D-menthyl succinate is then hydrolysed and the 15-menthol racemised via D-menthone and then recycled. We have represented this process in Figure 9.9. 

Fischer alkenylcarbene complexes undergo cyclopentannulation to alkenyl AT,AT-dimethylhydrazones (1-amino-1-azadienes) to furnish [3C+2S] substituted cyclopentenes in a regio- and diastereoselective way along with minor amounts of [4S+1C] pyrrole derivatives. Enantiopure carbene complexes derived from (-)-8-(2-naphthyl)menthol afford mixtures of trans,trans-cycloipentenes and ds,ds-cyclopentenes with excellent face selectivity [75]. The mechanism proposed for the formation of these cyclopentene derivatives is outlined in Scheme 28. The process is initiated by nucleophilic 1,2-attack of the carbon... 

Liquids with high vapor pressures at ordinary temperatures are said to be volatile. Methanol (vapor pressure 98 Torr at 20°C) is highly volatile mercury (1.4 mTorr) is not. Solids also exert a vapor pressure, but their vapor pressures are usually much lower than those of liquids because the molecules arc gripped more tightly in a solid than they are in a liquid. Nevertheless, solids vaporize in the process called sublimation (Section 6.11), which we can observe in the presence of some pungent solids—such as menthol and mothballs. 

The above system has been used for the reaction of EtjNH with myrcene to give a mixture of hydroamination products (53% yield) containing 80% of N,N-diethylgeranylamine [208], a key intermediate for the synthesis of industrially important monoterpenes [208, 209-211], including (-)-menthol (Tagasako process) [212]. 

Determination of the acidic sites through IR spectroscopy of adsorbed CO is a valuable tool for the choice of the support when selective or multifunctional processes are to be set up. This technique allowed to identify a particular kind of silica as the support of choice for the selective hydrogenation of citral to citronellal and sepiolite as a Lewis acid support able to promote the one-step transformation of citral into menthol. 

Geraniol can be converted into citronellol and menthol over Cu/A1203 under catalytic hydrogenation conditions owing to chemoselective hydrogenation and a three-functional process taking place on the catalyst surface. 

Citronellol is formed through selective hydrogenation of the C=C bond activated by the presence of the OH group, whereas menthol 3 is the product of a three-functional process involving isomerization of the allylic alcohol 1 to citronellal 4, ene reaction to isopulegol 5 and final hydrogenation (Scheme 2). 

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. 

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. 

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