Menthol synthesis

The enantioselective hydrolysis of racemic menthyl benzoate (industrially key compound) by recombinant Candida rugosa lipase LIPl leads to optically pure l-(-)-menthol ee>99% [21]. This pathway is part of a menthol synthesis developed by the flavour industry. 

LefSngwell, J-C. Shakelford, R-E. Laevo menthol synthesis and organoleptric properties. Cosmetic and perfumery 1974, 89 (6), 69-89. 

In the fine chemicals industry, (-l-)-citronellol for use in L-menthol synthesis has been prepared by hydroalumination... 

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]+).

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. 

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. 

The menthol synthesis is all the more remarkable because three chiral centers are created, all of which are necessary to produce the characteristic menthol odour and local anaesthetic action. 

The rhodium-catalysed enantioselective double bond migration has found further interesting appiications apart from menthol synthesis. (/ )-7-Hydroxydlhydrocitronellal, which provides the scent in lily of the valley Convallaria majalis) is accessible in this way. When combined with an enantioselective hydrogenation, this catalyst can also be used to build up the side-chain of a-tocopherol (Vitamin E). 

Phellandrenes Both a-phellandrene [99-83-2] (106) and 3-phellandrene [555-10-2] (107) occur widely in essential oils. (—)-a-Phellandrene can be isolated from Eucalyptus dives oil. A particularly rich source of (S)-(—)- 3-phellandrene is the lodgepole pine, Pinus contorta. (5)-(—)-(3-Phellandrene [6153-17-9] (110) is found at a level of 2% in the southeastern United States turpentine and processing the turpentine gives a fraction containing 28% (—)-(3-phellandrene and 62% (—)-limonene [5989-54-8] (111). The (—)- (3-phellandrene in the fraction can be selectively hydrochlorinated to piperityl chloride (116) as the first step in an 1-menthol synthesis, details are given below in the entry on menthol. 

Like (- -)-3-carene, (+)-limonene (11) is a readily available natural homochiral feedstock and so, in principle, could be a useful starting material for ( )-menthol synthesis. At least one route has been reported [206, 230]. As shown in Fig. 8.37, the synthesis starts with selective hydrogenation of the disubstituted double bond and epoxidation of the trisubstituted one to give the epoxide (181). Hydrolysis and selective acylation of the... 

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