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
Propylene glycol alkyl or aryl ethers
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.
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 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, firstname.lastname@example.org
*To whom all correspondence should be addressed.
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,