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Menthol via Lipase Resolution
Researchers at CSIR Bio/Chemtek have developed a process to produce l-menthol from the readily available raw material m-cresol.
Alkylation of m-cresol generates thymol. Hydrogenation of thymol yields four pairs of racemic diastereomers: menthol, isomenthol, neomenthol, and neoisomenthol. Acylation of this mixture using a stereoselective lipase yields l-menthyl acetate in at least 96% enantiomeric excess (ee). l-Menthyl acetate is separated from the unreacted isomers by distillation. Hydrolysis yields (-)-menthol. The enzymatic resolution has been demonstrated in a continuous process at 1 kg per hour. Enzyme activity is retained even after 2,000 hours of operation. Furthermore, isomerization/racemization of the unreacted isomers regenerates the original mixture of diastereomers, which is routed again to enzyme resolution. Over several cycles, thymol is almost fully converted to l-menthol. This process is the subject of a 2002 patent assigned to AECI which is available for download below.
Similarly, Haarmaan & Reimer was recently (July 17, 2002) issued a patent for the resolution of racemic menthol esters (Benzoate, acetate, etc.) using lipases (e.g., Candida rugosa) that provides (-)-menthol with essentially 100% enantioselectivity. This patent is also available for download below.
While neither the AECI or H&R process have yet been commercialized, these routes are certainly of high interest.
It should be noted that as early as 1968, workers at Takasago had shown that (-)-menthol could be selectively produced by the hydrolysis of racemic esters of menthol using an enzyme carboxylic acid hydrolase.7
1. CHAPLIN, JENNIFER ANN; DICKSON, MELANIE DARYL EVANS; MARAIS, STEPHANUS FRANCOIS; MITRA, ROBIN KUMAR; REDDY, SHAVANI; BRADY, DEAN; PORTWIG, MADRIE; GARDINER, NEIL STOCKENSTROM; MBONISWA, BUTANA ANDREW; PARKINSON, CHRISTOPHER JOHN, PROCESS FOR PREPARING (-)- MENTHOL AND SIMILAR COMPOUNDS, PATENT NO. WO 02/36795 A2 (MAY 10, 2002)
2. BORNSCHEUER, UWE PROF DR; GATFIELD, IAN-LUCAS DR; HILMER, ENS-MICHAEL DR; VORLOVA, SANDRA; SCHMIDT, ROLF PROF DR, Method for preparing D- or L-menthol, Pantent No. EP1223223 (July 17, 2002)
3. Rabiller, C. G.; Koenigsberger, .; Faber, K.; Griengl, H., ENZYMATIC RECOGNITION OF DIASTEREOMERIC ESTERS, Tetrahedron 1990, 46: 12 4231-4240
4. Langrand, Georges; Baratti, Jaquess; Buono, Gerard; Triantaphylides, Christian, LIPASE CATALYZED REACTIONS AND STRATEGY FOR ALCOHOL RESOLUTION, Tetrahedron Lett. 1986, 27: 1 29-32
5. Langrand, Georges; Secchi, Michel; Buono, Gerard; Baratti, Jacques; Triantaphylides, Christian, LIPASE-CATALYZED ESTER FORMATION IN ORGANIC SOLVENTS. AN EASY PREPARATIVE RESOLUTION OF a-SUBSTITUTED CYCLOHEXANOLS, Tetrahedron Lett. 1985, 26: 15 1857-1860
6. Cygler, Miroslaw; Grochulski, Pawel; Kazlauskas, Romas J.; Schrag, Joseph D.; Bouthillier, Francois; et al., A Structural Basis for the Chiral Preferences of Lipases, J.Amer.Chem.Soc. 1994, 116: 8 3180-3186
7. Moroe, T.; Hattori, S; Komatsu, A; Yuzo, Y., Method for the Biochemical Isolation of l-Menthol, U.S. Patent No. 3,607,651 (Sept. 21, 1971) assigne to Takasago Perfumery Co.
AECI & Haarmann & Reimer Processes
The AECI Process
The H&R Lipase Resolution of Menthyl Esters Process
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