L-DOPA

          This upcoming fall I will be applying for pharmacy school in hopes of starting July 2015.  During this time my brain will be in overload of learning drugs names, how they are synthesized, and how they affect the body.  Even though I am not to that point yet, I have already taken a few steps in my organic class.  For this blog I was asked to look at the Chemistry By Design webpage (1) and choose one of the 52 pharmaceutical drugs listed.

          The drug I chose was L-dopa.  Also known as Levadopa, this drug is used for treating Parkinson's Disease.  Parkinson's disease is a neurological disorder that affects balance, movement, and muscle control.  It is a result of having a deficiency of dopamine in the brain.  Dopamine is one of the main neurotransmitters that helps the body respond to stress and the fight or flight response (2).  The structure of L-dopa is shown in Figure 1 (3).

                                                       Figure 1: L-dopa

           On the Chemistry by Design webpage the synthesis of L-dopa is shown.  However; after researching the drug, I noticed a few steps were left out of the synthesis.  The synthesis shown on the webpage only includes 3 steps.  On the webpage, it gives the name Monsanto, however there is not a link at the end of the synthesis in order to pull up a publication.  Monsanto is an agricultural company headquartered in St. Louis, Missouri (4).  They are given credit for synthesizing L-dopa from vanillin.  However, their process created two forms.  One form, L-dopa is used for the treatment of Parkinson's disease.  Another form, D-dopa is toxic.  In the 1960's, the process yielded equal amounts of the two forms.  Separating the two forms was expensive and time-consuming (5).
        
          William S. Knowles worked at Monsanto Company and lead a team (Dr. Billy Vineyard and Dr. Jerry Sabacky) during 1968-1972 to find a solution to this problem (4).  He developed a process called asymmetric hydrogenation which used a catalyst.  This catalyst sped up the process, but most importantly produced 97.5% L-dopa and 2.5% D-dopa.  This lead to the commercialization breakthrough of L-dopa (5).  Dr. Knowles was one of three guys who received the Nobel Prize for chemistry in 2001 for his work on L-dopa.  I was also able to find a formal publication by Dr. Knowles on asymmetric hydrogenation (6).  

         During my research, I found a lecture given by Dr. Knowles which was posted on the Nobel Prize website.  This paper showed the Monsanto synthesis, including the catalyst, which is four steps.  The four step-synthesis is shown below in steps 1-4 (3).
 

 

          All of the reagents used for this synthesis are commercially available, however some of them only come in small quantities at a time such as the catalyst used in Step 3.  In my organic chemistry class we have talked about each of these type of reactions.  For example, Step 2 is an acid-catalyzed hydrolysis of an ester, where an ester is converted into a carboxylic acid.  Step 3 is a reduction reaction, we just have not talked about the specific catalyst that is used in that reaction scheme.  Step 4 is a simply an acid-catalysted reaction (7).   

The mechanism of Step 2 is shown and easily followed in Figure 2, shown below.  It shows the general mechanism of an ester being converted to a carboxylic acid via acid-catalyzed hydrolysis.  This is an important step during the synthesis, because L-dopa contains a COOH group.  If this step did not take place, then the COOH group may not be made therefore effecting the final product.   

 
                              Figure 2: General Mechanism of Acid-Catalyzed Hydrolysis

         If you ever get curious about how some drugs are synthesized, or just want to test your knowledge then visit the Chemistry by Design webpage.  You are sure to learn something just like I did.  Even as a sophomore in college I am being challenged to use different resources such as this webpage.  As the next couple years of my life start to approach, who knows I may be revisiting that webpage again once I am in pharmacy school. 

References

1) Njadrarson, J. T. Chemistry By Design. http://chemistrybydesign.oia.arizona.edu/(accessed April 16, 2014)

2) University of Maryland Medical Center. Parkinson's disease. http://umm.edu/health/medical/reports/articles/parkinsons-disease (accessed April 16, 2014)

3) Knowles, W. S. Asymmetric Hydrogenation.  http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2001/knowles-lecture.pdf (accessed April 16, 2014)

4) Monsanto. William S. Knowles 1917-2012. http://monsantoblog.com/2012/06/18/william-s-knowles-1917-2012/ (accessed April 16, 2014

5) Chang, Kenneth. William Knowles, Nobel Winner in Chemistry, Dies at 95. New York Times, July 15, 2012, [Online]

6) Knowles, W. S. Asymmetric Hydrogenation. Acc. Chem. Res. [Online] 1983, 16 (3), pp106-112

7) Smith, J. Organic Chemistry, 3rd ed.; McGraw-Hill: New York, 2011.