1. A Greener Simvastatin Abstract Action project Introduction Discussion
Juan Posada,
University of New Hampshire
Manchester, NH 03101
Abstract
Dr. Tang of UCLA designed a greener synthetic pathway to manufacture simvastatin. What’s different? He identified LovD, an acyltransferase, as biocatalyst to synthetize simvastatin. Through this, a reduction in waste and an increase in yield was achieved. This process was optimized by Codexis, Inc.
Introduction
Action project
Great way to learn about the importance of green chemistry and how it has impacted the manufacturing industry.
Chose this project due to the relevance of this research conducted by Dr. Tang of UCLA and Codexis.
Dr Tang’s research was recognized by the EPA and awarded with the Presidential Green Chemistry Challenge in 2012.
I started this project in September. I recorded a lecture-cast with specifics Dr Tang’s research and principles of green chemistry. Lecture made available to the public on Tegrity.
I did a wikisite, with images and user friendly navigation features, and a poster.
Simvastatin one of the largest selling drugs to lower cholesterol. Also known as Zocor.
Statins are important drugs for treating cardiovascular disease. Simvastatin is a statin and a semi-synthetic derivative of lovastatin.
Simvastatin has an additional methyl group at the C2' position of the side chain that makes it more efficient in the reduction cholesterol.
Traditional pathway to synthetize Simvastatin demanded various chemical steps to protect and deprotect some of the functionalities in the lovastatin molecule.
This green pathway clear example of benefits of applying green chemistry.
The question posed at the outset of this project were:
What is it that makes this manufacturing process greener than the traditional one?
Has this relatively new way of manufacturing Simvastatin been adopted at a commercial level in the US or any other country in the world?
Discussion
This projects follows the following to green chemistry principles:
Waste prevention & atom economy: Biocatalytic provides product in higher yield and bypass protection/deprotection processes in the reaction. Reduced use of extraction solvents and its high yield and purity.
Less hazardous chemical syntheses: Avoid using dangerous chemicals such as MeI and TBDMS.
Design safer chemicals: Acyl donor is safer than traditional chemistries.
Safer solvent and auxiliaries: Water is used as safe and recyclable solvent.
Design for energy efficiency and Use of renewable feedstock: Reaction runs at or near room temperature and atmospheric pressure. The catalyst is produced from renewable resources.
Reduce derivatives and Catalysis : No protection/deprotection required due to the regioselective catalyst.
Project relates to organic chemistry because it deals with organic molecules such as cholesterol, lovastatin, and simvastatin, and with enzymes such as LovD (biocatalyst). Project highlights structures, properties and reactions of organic material. Modification to organic molecules ultimately rendered a greener pathway to synthetize simvastatin.
Outcomes
References
Gao, X., Xie, X., Pashkov, I., Sawaya, M.,Laidman, J., Zhang, W.,…Tang, Y. (2009) Directed evolution and structural characterization of Simvatatin Synthase. Chemistry & Biology, 16(10), doi: /j.chembiol
Jiménez-Osés, G., Osuna, S., Gao, X., Sawaya, M. R., Gilson, L., Collier, S. J., Houk, K. N. (2014). The role of distant mutations and allosteric regulation on LovD active site dynamics. Nature Chemical Biology Nat Chem Biol, 10(6), doi: /nchembio.1503
Barrios-González, J., & Miranda, R. U. (2009). Biotechnological production and applications of statins. Applied Microbiology and Biotechnology, 85(4), doi: /s
This project provides the audience a great deal of information that might be helpful in future research and lay out principles of green chemistry so they can assess how the current manufacturing industry is applying them.
Since the lecturecast is available to the public, I expect to reach a variety of audiences, among those healthcare workers, students and environmentalist.
Takeaways:
Green chemistry essential for sustainability of our planet. We are headed to a greener future.
Enzyme LovD transfers the 2-methylbutyryl side from lovF to the C8 alcohol of monacolin J sodium. This reaction proved to be regioselective, demonstrated protection chemistry was not required and represented the first enzymatic synthesis of Simvastatin.