Achieving Enantioselectivity - Pharmaceutical Technology

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Achieving Enantioselectivity
Carbon–hydrogen functionalization, ketone α-alkylation, and biocatalysis are some recent advances in asymmetric synthesis.


Pharmaceutical Technology
Volume 9, Issue 32, pp. 60-64

Using another approach, Codexis developed a biocatalytic reduction for MLK-III using a ketoreductase biocatalyst evolved to reduce MLK-II. Codexis evolved the ketoreductase to increase its activity and stability by more than 2000-fold, replacing one-third of the amino acids in its active site in the process and under improved reaction conditions: 100 g/L in isopropanol–water–toluene at 45 C. Isopropanol is the reductant, which the ketoreductase uses to regenerate its catalytic cofactor, NADPH, producing acetone as the coproduct. The process runs as a slurry-to-slurry conversion with product precipitation driving the reaction to completion. The precipitated chiral alcohol is of high chemical purity and stereopurity. Codexis has scaled up the manufacture of MLK-III using this biocatalytic reduction and has provided samples of MLK-IV to manufacturers of generic montelukast. The company is planning commercial-scale manufacture on a multiton scale in 2008 (8).

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,
.

For insight on chiral separations, see Chiral Separations.




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References

1. I. Lennon, N.B. Johnson, and P.H. Moran, "Manufacture of Asymmetric Hydrogenation Catalysts," Pharm. Technol. 31 (9) supplement Pharm. Ingredients, s6–s13 (2008).

2. H. Davies and J.R. Manning, "Catalytic C–H Functionalization by Metal Carbenoid and Nitrenoid Insertion," Nature 451, 417–424 (2008).

3. D. Lim and D. Coltart, "Simple and Efficient Asymmetric α-Alkylation and α,α-Bisalkylation of Acyclic Ketones by Using Chiral N-Amino Cyclic Carbamate Hydrazones," Angew. Chem. Int. Ed. 47 (28), 5207–5210 (2008).

4. M.M. Biddle, K. Lin, and K.A. Scheidt, "Catalytic Enantioselective Synthesis of Flavanones and Chromanones," J. Am. Chem. Soc. 129 (13), 3830–3831 (2007).

5. K.A. Scheidt, "New Discoveries with Carbene Catalysis," presented at Vision of Chemistry Symposium (North Branch, NJ, May 2008).

6 E. Balskus and E. Jacobsen, "Asymmetric Catalysis of the Transannular Diels–Alder Reaction," Science 317 (5845), 1736–1740 (2007).

7. B Hauer et al., "Asymmetric Bioreduction of C=C Bonds Using Enoate Reductases OPR1, OPR3 and YqjM: Enzyme-Based Stereocontrol," Adv. Syn. Catal. 350 (3), 411–418 (2008).

8. EPA, "The Presidential Green Chemistry Challenge Awards Program: Summary of 2008 Award Entries and Recipients" (Washington, DC, 2008).


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