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. 

Amino Acids: Creating Your Own

When someone hears the words amino acid, one of their first thoughts is biology.  Throughout high school and during my first college science class I remember discussing how amino acids are important biologically because they make up the proteins in our bodies.  In organic chemistry I am looking at amino acids in a totally new way.  Now, I do not study how they effect me biologically, but rather I have to look at there nomenclature, how they are synthesized, and how they bond together with other amino acids.

Naturally occurring amino acids have an amino group bonded to an alpha carbon of a carboxy group.  Therefore, they take on the name alpha-amino acids.  There are 20 naturally occurring amino acids that make up different proteins.  They all differ in the R group (side chain) that is bonded to the alpha carbon.  All amino acids, except glycine, have a stereogenic center on the alpha carbon.  A general alpha amino acid is shown below in Figure 1 (1).

                                                  Figure 1: Alpha-Amino Acid

There are three classifications of amino acids.  Acidic amino acids are any amino acids with an additional COOH group in the side chain.  Basic amino acids are those with an additional basic N atom on the side chain, and all other amino acids are considered neutral (1).     

For this blog, I was asked to think outside of the box.  I was asked to create an artificial amino acid that contained at least six carbons.  For me, personally, this was a hard task.  I am a very structured person so I lack creativity.  First I looked at the 20 naturally occurring amino acids to make sure I did not duplicate an already existing amino acid.  With the help of ChemSketch, I finally came up with the neutral amino shown in Figure 2.

 

(2S,5R)-2-amino-5-methyl-6-phenylhexanoic acid

  

Figure 2: Artificial Amino Acid

My next task was to figure out a synthesis for the artificial amino acid I created.  I used my organic chemistry textbook (1) as my main resource.  It describes three different methods but states there are other various ways to prepare amino acids in a laboratory.  The method that I chose to "hypothetically" synthesize my artificial amino acid was the Strecker Synthesis.  This synthesis converts an aldehyde into an amino acid by adding one carbon atom to the aldehyde carbonyl via a two-step sequence.  The aldehyde is treated with NH4Cl and then NaCN which forms an alpha-amino nitrile.  The mechanism of this reaction is shown in Figure 3.  Then the alpha-amino nitrile is hydrolyzed in aqueous acid to the amino acid (1).  The synthesis reaction of (2S,5R)-2-amino-5-methyl-6-phenylhexanoic acid is shown in Figure 4.  A "CN" (cyanide) should be where the "A" atom, for lack of knowledge using ChemSketch to draw the structures.  

                                           Figure 3: Mechanism of Alpha- Amino Nitrile

                              Figure 4: Synthesis of (2S,5R)-2-amino-5-methyl-6-phenylhexanoic acid
                                                       

Peptides are larger molecules that are formed by joining amino acids together with amide bonds (1).  My last challenge was creating a pentapeptide structure with the form of CGXHA.  For those people unfamiliar with abbreviations a key is below, followed by the pentapeptide structure I created. 

Key:
C-Cysteine
G-Glycine
X-Artificial Amino Acid Created
H-Histidine
A-Alanine

   

                                            Figure 5: Pentapeptide Structure

I am sure the next time I hear the words amino acids I will have a flashback to my high school biology class.  However; I will also have deeper understanding of amino acids overall instead of just knowing they form the proteins in my body.  Even though this blog was somewhat of a challenge making me step outside of my comfort zone, I believe it was beneficial in helping me learn and grow as an individual and as a student. 

    References:

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

Electrophilic Aromatic Substitution: From a Biological Standpoint

          In an electrophilic aromatic substitution reaction, an electrophile attacks the aromatic ring and replaces one of the hydrogen atoms.  All reactions occur via a two-step mechanism, regardless of the electrophile.  The first step a carbocation is formed by the addition of the electrophile.  In the second step, the aromatic ring is re-formed when there is a loss of a proton.  The general mechanism is shown in Figure 1 (1). 

     



                              Figure 1

Five examples of electrophilic aromatic substitutions is shown in Figure 2 (1).
 

                   Figure 2


A substituent group affects the electrophilic aromatic substitution in two ways: the rate of the reaction and the orientation.  If a substituent activates a benzene ring, such as an alkyl group, then substitution is directed ortho and para.  If a substituent deactivates a benzene ring, such as a nitro group, then substitution is directed meta (1).     

The purpose of this blog post was to research and find out how electrophilic aromatic substitutions are used in a biological sense.  After searching the internet, it was quickly noted that many of these reactions take place in enzyme pathways.  However, they are also used in synthesis of many different drugs. 

An example of a drug synthesized using electrophilic aromatic substitution is 2-(4-isobutylphenyl)propanoic acid, most commonly known as ibuprofen (2).  Isobutylbenzene first undergoes a Friedel-Crafts acylation to produce a ketone.  The alkyl group directs the substitution to ortho and para positions; para dominates because of the size of the electrophile.  This ketone is then reduced using borohydride, which creates an alcohol.  Nucleophilic substitution then takes place using HBr, replacing the OH group with Br.  This product then reacts with NaCN in a nucleophilic substitution reaction to replace the Br with CN.  Finally, an acid-cataylized reaction using sulfuric acid hydrolyzes the nitrile group to a carboxylic acid.  Thus the final product of ibuprofen is formed.  The mechanism of this synthesis is shown in Figure 3 (3).

   















                                Figure 3


In conclusion, electrophilic aromatic substitutions are common in laboratory synthesis and within biological pathways.  They have a profound impact within everyday use, even though one might not realize it.  In the synthesis of ibuprofen, the very first step is an electrophilic aromatic substitution.  These reactions are important because they produce products that can then undergo other substitutions that will yield the desired compound.  As technology advances scientists will be able to learn even more knowledge about these type of reactions, specifically in these two areas.               

References

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

2) Sigma Aldrich. Ibuprofen. http://www.sigmaaldrich.com/catalog/product/sigma/i4883?lang=en&  
 region=US (accessed Mar 12, 2014)

3) Dewick P. Essentials of Organic Chemistry: For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry. John Wiley & Sons Ltd: West Sussex, 2006