What is (R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol?

(R)-[3,5-bis (trifluoromethyl) phenyl] ethanol is an important chiral intermediate for the synthesis of novel chemotherapeutic and antiemetic drugs NK-1 receptor antagonists. Antidepressants have good potential efficacy in treating a range of central and peripheral nervous system depressions. At present, the methods for preparing optically pure (R)-[3,5-bis (trifluoromethyl) phenyl] ethanol include chemical methods and biological methods. Chemical synthesis requires the use of expensive transition metal Ru and other chemical catalysts, complicated steps, harsh reaction conditions, high energy consumption, large pollution, and low yield. Biological law is the use of free enzymes or whole cells for catalytic preparation. It has the characteristics of mild reaction conditions, high catalytic efficiency, and strong specificity. In this paper, an asymmetric reduction of [3,5-bis (trifluoromethyl) phenyl] ethanone with microbial whole cells to prepare an important chiral intermediate (R)- [3,5-bis (trifluoromethyl) phenyl] ethanol was used as the research model. New and efficient biocatalysts were screened from the natural environment, and analyzed and identified. In addition, The biocatalytic process is optimized. To screen for microbial strains capable of efficiently and asymmetrically reducing [3,5-bis (trifluoromethyl) phenyl] ethanone to produce (R)-[3,5-bis (trifluoromethyl) phenyl] ethanol, Bio-efficient preparation of (R)-[3,5-bis (trifluoromethyl) phenyl] ethanol, an important chiral intermediate for NK-1 receptor antagonists[1-3].

Fig 1. Chemical structure formula and three-dimensional structure of  (R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethanol

(R)-[3,5-Bis(trifluoromethyl)phenyl] ethanol is a crucial intermediate for the synthesis of aprepitant (Emend),which was developed by Merck Corporation and used for the treatment of chemotherapy-induced emesis[4,5]. The synthesis of (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol via the asymmetrically biocatalytic reduction of 3,5-bis(trifluoromethyl) acetophenone has been established, which is highly enantioselective and environmentally friendly. This approach avoids the usage

of expensive heavy-metal catalysts such as Ru and Rh, which are usually applied in chemical catalytic processes[6-9]. As listed in Table 1, a number of microorganisms capable of catalyzing the bioreduction of 3,5-bis(trifluoromethyl)acetophenone to (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol have been investigated. Among them, Candida tropicalis, Lactobacillus kefir, Penicillium expansum, and Leifsonia xyli were identified as the positive reduction microbes with high enantioselectivity. However, like most whole-cell biocatalysts, these microbes could only perform the expected reduction at a relatively low substrate concentration. The presence of excess ketone will inhibit the oxidoreductases[10] and decrease the yield. The usage of a high content of non-natural substrates on the industrial scale with the desired high yield of products via biocatalytic processes could not be handled by such microorganisms. Therefore, a competent whole-cell reaction system has to be developed to conquer this challenge and attain a satisfactory process yield and excellent enantioselectivity at high substrate concentrations.Adding isopropanol as the hydrogen donor efficiently regenerates NADH during the bioreduction. Furthermore, both the substrate and product solubility and cell permeability of the microorganism were enhanced. This potent process provided an alternative to prepare (R)-[3,5-bis(trifluoromethyl)phenyl] ethanol with good product yield and excellent e.e. value using a biocatalysis approach.

References

[1]  Hansen, K.B., Chilenski, J.R., Desmond, R., et al. (2003) Scalable, Efficient Process for the Synthesis of (R)-3,5-Bistrifluoromethylphenyl Ethanol via Catalytic Asymmetric Transfer Hydrogenation and Isolation as a DABCO Inclusion Complex. Tetrahedron: Asymmetry, 14, 3581-3587.

[2] Brands, K.M.J., Payack, J.F., Rosen, J.D., et al. (2003) Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization-Induced Diastereoselective Transformation. Journal of the American Chemical Society, 125, 2129-2135.

[3]  Naud, F., Malan, C., Spindler, F., et al. (2006) Ru-(Phosphine-Oxazoline) Complexes as Effective, Industrially Viable Catalysts for the Enantioselective Hydrogenation of Aryl Ketones. Advanced Synthesis & Catalysis, 348, 47-50.

[4] Hansen, K. B., J. R. Chilenski, R. Desmond, P. N. Devine, E. J.J. Grabowski, R. Heid, et al. 2003. Scalable, efficient process for the synthesis of (R)-3,5-bistrifluoromethylphenyl ethanol via catalytic asymmetric transfer hydrogenation and isolation as a DABCO inclusion complex. Tetrahedron Asymmetry 14:3581-3587.

[5]  Vankawala, P. J., N. Kolla, C. R. Elati, M. Sreenivasulu, K. A.Kumar, Y. Anjaneyulu, et al. 2007. Efficient synthesis of (1R)-[3,5-bis(trifluoromethyl)phenyl] ethanol, a key intermediate for aprepitant, an NK-1 receptor antagonist. Synth. Commun. 37:3439-3446.

[6] Gelo-Pujic, M., F. Le Guyader, and T. Schlama. 2006. Microbial.and homogenous asymmetric catalysis in the reduction of 1-[3,5-bis(trifluoromethyl)phenyl]ethanone. Tetrahedron Asymmetry 17: 2000-2005.

[7] Homann, M. J., R. B. Vail, E. Previte, M. Tamarez, B. Morgan,D. R. Dodds, and A. Zaks. 2004. Rapid identification of enantioselective ketone reductions using targeted microbial libraries. Tetrahedron. 60: 789-797.

You may like