Achieving Enantioselectivity - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

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.




What would you do differently? Email your thoughts about this paper to
and we may post them to the site.

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).


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
What role should the US government play in the current Ebola outbreak?
Finance development of drugs to treat/prevent disease.
Oversee medical treatment of patients in the US.
Provide treatment for patients globally.
All of the above.
No government involvement in patient treatment or drug development.
Finance development of drugs to treat/prevent disease.
28%
Oversee medical treatment of patients in the US.
12%
Provide treatment for patients globally.
9%
All of the above.
45%
No government involvement in patient treatment or drug development.
7%
Jim Miller Outsourcing Outlook Jim MillerCMO Industry Thins Out
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerFluorination Remains Key Challenge in API Synthesis
Marilyn E. Morris Guest EditorialMarilyn E. MorrisBolstering Graduate Education and Research Programs
Jill Wechsler Regulatory Watch Jill Wechsler Biopharma Manufacturers Respond to Ebola Crisis
Sean Milmo European Regulatory WatchSean MilmoHarmonizing Marketing Approval of Generic Drugs in Europe
Seven Steps to Solving Tabletting and Tooling ProblemsStep 1: Clean
Legislators Urge Added Incentives for Ebola Drug Development
FDA Reorganization to Promote Drug Quality
FDA Readies Quality Metrics Measures
New FDA Team to Spur Modern Drug Manufacturing
Source: Pharmaceutical Technology,
Click here