Asymmetric Routes to Chiral Secondary Alcohols - Pharmaceutical Technology

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Asymmetric Routes to Chiral Secondary Alcohols
The authors describe several examples of using asymmetric hydrogenation and biocatalysis for synthesizing several secondary alcohol compounds.


Pharmaceutical Technology
pp. s6-s13

Lipase-catalyzed resolution

Lipase-catalyzed production of chiral secondary alcohols via transesterification of the racemic alcohol or hydrolysis of the ester are well-known methods frequently run at large scale. This route has the disadvantage that the yield of the desired isomer is a maximum of 50%; however, in many cases this approach is still the method of choice. Lipases are industrially suitable enzymes due to their stability, tolerance of organic solvents and high temperatures, low price, and availability. In addition, the off-isomer can sometimes be racemized and recycled to increase efficiency.

Propylene glycol alkyl or aryl ethers


Figure 5: Lipase-catalyzed production of propylene glycol ethers. CAL-B is Candida antarctica lipase B, and ee is enantiomeric excess. (FIGURE IS COURTESY OF THE AUTHOR)
Chiral 1,2-propanediols are useful synthons for preparing cardiovascular drugs, antiviral drugs, and enantiomerically pure crown ethers (6). Propylene oxide-derived racemic glycol ethers are readily available at large scale and low cost. A viable approach for synthesizing single isomers is through lipase-catalyzed resolution of these racemates (7). A screen of hydrolases for their ability to catalyze enantioselective hydrolysis of an aqueous solution of a racemic mixture of test glycol alkyl ether acetates revealed Candida antarctica lipase B (CAL-B) to be the most enantioselective enzyme for all substrates screened (all E > 50, where E is the enantioselectivity constant). Moreover, immobilized CAL-B was the best catalyst for transesterification-based resolution in organic solvent with various acyl donors, for example, ethyl acetate and vinyl acetate. For large-scale manufacture, the transesterification reaction using an immobilized lipase (see Figure 5) was favored for several reasons. No additional ester-formation step is necessary. The reaction can be run with much higher substrate loadings. The work-up is easier as it is possible to directly recover products by distillation following bioresolution, and the enzyme can be easily recycled without loss of activity either in batch mode or in a continuous process with enzyme packed in a column. As an example, the resolution of 1-n-propoxy-2-propanol was conducted in batch mode at a 1-L scale giving (S)-alcohol in 99% ee; more than 20 consistent recycles of the enzyme were obtained. These reactions have been scaled to several 100-kg scale in an economic process made possible via the short-reaction sequence, effective recycling of enzyme, the low-cost starting material, and straightforward isolation of the reaction products.

Conclusion

Chiral secondary alcohols are important intermediates and starting materials for pharmaceutical compounds. Examples cited in this article describe biocatalytic asymmetric reduction and catalytic hydrogenation of prochiral ketones as well as the resolution of racemates using enzymes such as lipases as efficient methods to make various aryl and alkyl secondary alcohols.

Christopher J. Cobley, PhD, is head of chemocatalysis, and Karen E. Holt-Tiffin,* PhD, is head of biocatalysis, both at Chirotech Technology, Dr. Reddy's Custom Pharmaceutical Services, 162 Cambridge Science Park, Cambridge, CB4 0GH, UK, tel. +44 (0) 1223 728010,
.

*To whom all correspondence should be addressed.

References

1. C. H. Squires et al., BioProcess Intl., 2 (11) 54–59, 2004.

2. R. Noyori and T. Ohkuma, Angew. Chem. Int. Ed. 40 (1), 40–73, 2001.

3. Noyori and S. Hashiguchi, Acc. Chem. Res. 30 (2), 97–102, 1997.

4. D. Chaplin et al., Org, Process Res. Dev. 7 (1), 89–94 (2003).

5. I.C. Lennon and J.A. Ramsden, Org. Process Res. Dev. 9 (1), 110–112 (2005).

6. B.H. Hoff et al., Tetrahedron: Asymmetry, 7 (11), 3181–3186 (1996).

7. S.M. Resnick et al., "Enzymatic Resolution of Propylene Glycol Alkyl (or Aryl) Ethers and Ether Acetates," WO 2003083126, March 2003.


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