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Unit 6 Stereochemistry Stereoisomers & Chirality

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Stereoisomers

Stereochemistry is the study of the 3-dimensional structure of molecules. Isomers are molecules with the same chemical formula and often with the same kinds of bonds between atoms, but in which the spatial arrangement of atoms differs. Isomers are grouped into two broad classes. (Most of the non-substituted cycloalkanes have conformational isomers, or diastereomers also known as conformers.)

 1) Constitutional isomers (structural isomers) differ in their bonding sequence. Thus their atoms and constituents (or functional groups) are connected differently.

 2) Stereoisomers have the same bonding sequence, but they differ in the spatial orientation or geometric relationships between their atoms and groups. 

The concept of chirality is essential for understanding stereoisomers and optically active enantiomers. We can tell whether an object is chiral by looking at its mirror image. Every physical object has a mirror image. Objects with mirror images which are identical to themselves are achiral. But a chiral object has a mirror image different from the original object. This is due to its lack of symmetry along a given plane. I.E. There is something on one side of the object which differs from that on the other side of the object (e.g. the thumb of a hand, the pocket on a shirt, the heart in the chest, the steering wheel of a car, etc.). These objects all have chirality.      

If molecules contain internal planes of symmetry, then their mirror images can be superimposed, and they are achiral. However, just because we cannot find an internal plane of symmetry does not mean that molecule must be chiral (typical examples are aromatic compounds). If two of the four groups on a carbon atom are the same, then the molecule is not chiral. A carbon atom with two identical constituents usually has an internal plane of symmetry which splits the molecule down the middle along the plane between the 2 common constituents. When rotated by 180 degrees, the mirror images of such structures can be superimposed on each other. Thus, these type of molecules are achiral.

The most common feature that lends the property of chirality to an organic molecule is a carbon atom that is bonded to four different groups. Such a carbon atom is called an asymmetric carbon atom or a chiral carbon atom, and is often designated by an asterisk. An asymmetric carbon atom is the most common example of a chirality center. Chirality centers belong to an even broader group called stereocenters.  A stereocenter is any atom at which the interchange of 2 groups gives a stereoisomer.

Thus, if a compound has no asymmetric carbon, it is usually achiral. If a compound has just one symmetric compound, it is chiral. If a compound has more than one asymmetric carbon, it may or may not be chiral. 

Stereoisomers have the same bonding sequence, but they differ in the spatial orientation or geometric relationships between their atoms and groups. 

This class includes chiral enantiomers which are non-superimposable mirror-images of each other, as well as diastereomers which are not mirror images. Thus, diastereomers are stereoisomers that are not mirror images. This group can be subdivided into conformational isomerism (conformers) when isomers can interconvert by chemical bond rotations and cis-trans isomerism when this is not possible. (Note: Although conformers can be referred to as having a diastereomeric relationship, these isomers over all are not diastereomers, since bonds in conformers can be rotated to make them mirror images.)  Most diastereomers contain 2 or more chirality centers.

Fischer projections are used to visually describe various isomers of the same compound in two dimensions. They are also used as a basic test for optical activity (or chirality). The Fischer projection looks like a cross, with the (invisible) asymmetric carbon located at the points where the lines cross. The horizontal lines are taken to be wedges, or bonds that project out of the plane of the paper. The vertical lines are taken to project away form the viewer, or back below the plane of the paper, as dashed lines.

Fischer projections that differ by a 180 degree rotation are the same. This is due to the fact that the vertical lines remain forward, and the horizontal lines remain recessed into the page. Alternatively, 90 degree rotations change the spatial characteristics of the molecule by switching the forward and reverse arrangements of the chiral center. This typically results in a chiral enantiomer of the original configuration. (Flipping them over has a similar effect).

The mirror image of a Fischer projection is created simply by interchanging the groups on the horizontal part of the cross. This effectively reverses left and right, while leaving the vertical portion of the configuration unchanged.
 

"Enantiomers are conformations of the same molecule whose mirror images cannot be superimposed on one another."

Testing for chirality (and thus enantiomerism) is particularly simple using Fischer projections. If the mirror image cannot be made to look the same as the original structure with a 180 degree rotation in the plane of the paper, the two mirror images are enantiomers. If the original structure can be obtained using a 180 degree rotation of the mirror image, then the structure is achiral.  

Mirror planes of symmetry are particularly easy to identify using Fischer projections. Molecules with symmetry planes cannot be chiral.

Diastereomers are stereoisomers not related through a reflection operation. These often have multiple chiral centers, and include meso compounds, cis-trans (E-Z) isomers, and non-enantiomeric optical isomers. Diastereomers seldom have the same physical properties. In the example shown below, the meso form of tartaric acid (on the right) forms a diastereomeric pair with both levo and dextro tartaric acids (on the left) , which form an enantiomeric pair.

Applications I: Biochemistry

Stereochemistry is an excellent example of the importance of structural symmetry in nature. Some 50 % of all organic compounds have chiral centers. E.G. When the amino acid alanine is synthesized in the laboratory, a mixture of the two possible structures is formed. However, when alanine is produced in a living cell, only one of the two forms is seen. The naturally occurring form of alanine is called L-alanine, and its mirror image is called D-alanine. Comparison of the 20 common amino acids will show that only the "L" form is used in protein synthesis.

http://web.mit.edu/esgbio/www/chem/stereo.html

Receptors have a distinct three-dimensional structure whose surface consists of grooves and cavities. They can interact only with three-dimensional molecules which have a complementary structure. Depending on the form of the molecule that links to the receptor, the biological results may vary significantly.

Thus, receptors usually display of preference for binding a specific structure. Through selective metabolism, a membrane can also displace selective intake by providing a specific transport mechanism that only recognizes only a single enantiomer. Toxic effects include non-specific receptors that can bind the drug, thus lowering the available concentration for specific receptors.

The enzymatic machinery used in protein synthesis has an asymmetric binding site the amino acids must fit into. Your right hand won't fit properly into a left handed glove, and an amino acid of the wrong shape won't fit into an enzyme. Of all the naturally occurring amino acids in proteins, only Glycine (NH2-CH2-COOH) has a plane of symmetry (along its "spine").

Our bodies only create and digest carbohydrates and amino acids of a certain stereochemistry. Thus, all the proteins that make up our hair, skin, organs, brain, and tissues, are composed of a single stereoisomer of amino acids. We can synthesize and digest starch (e.g. bread & potatoes) but not wood pulp or cellulose (plant fibers) even though both are stereoisomers of polymerized glucose.

Stereochemistry is also very important from the point of view of synthetic pharmaceuticals and their mechanism of action in the body. Since so many biochemical compounds consist of stereoisomers (e.g. amino acids, nucleotides, carbohydrates & phospholipids) it makes sense that synthetic drugs also have chiral centers. But while one stereoisomer may have positive effects on the body, another stereoisomer may be toxic -- or even lethal.

Thus, a drug upon administration undergoes a series of steps (aside form official FDA approval) before exerting its activity. At each step the molecular structure of the compound and hence its chirality influences the further metabolism. Because of this, a great deal of work done by synthetic organic chemists today is in devising methods to synthesize compounds that are purely one stereoisomer.

http://tigger.uic.edu/~kbruzik/text/chapter4.htm

E.G. Thalidomide was a drug used during the 1950s to suppress morning sickness. The drug was prescribed as a racemic mixture -- that is, it contained a 50:50 mixture of its mirror images -- and while one stereoisomer of the drug actively worked on controlling morning sickness, the other stereoisomer caused serious birth defects. Ultimately the FDA pulled it from the marketplace.

E.G. The binding of Ibuprofin, a common pain reliever. While one stereoisomer of the compound has the right three-dimensional shape to bind to the protein receptor, the other does not and can not bind, and is therefore ineffective as a pain reliever.

http://www.chemhelper.com/biostereo.html

Another example is Vitamin E (an essential component in our immune system) which contains three asymmetric carbons. This allows for up to eight possible isomeric structures to be formed. In nature, due to unique specificity, only one form is produced. In the synthetic formulation, however, all eight forms are created, thus diluting the natural form to only 12.5% of the vitamin added.

http://www.mazuri.com/Llama-VitaminE.htm?Animal=Llama

The current policies of FDA in drug approval is that the inactive stereoisomer (or enantiomer) in the racemic drug has to be shown to be devoid of any toxicity or undesired side-effects.

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Eliel, E.E. and Wilen, S.H.
Stereochemistry of Organic Compounds
John Wiley & Sons: NY, NY (1994)
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Applications II: Pharmaceuticals

This note is regarding the ramifications of racemic mixtures in synthetic pharmaceuticals. According to the article referenced below (which can be downloaded in PDF format) the 2 enantiomers of a chiral drug may differ significantly in their bioavailability, rate of metabolism, excretion, potency and selectivity for receptors, transporters and/or enzymes, and toxicity.

Single-enantiomer formulations of (S)-albuterol (asthma inhibitor: Ventalin, Proventil) and (S)-omeprazole (acid reflux inhibitor: Prilosec) have both exhibited superiority to their racemic formulations in clinical trials.

Alternatively, one enantiomer of Sotalol has both beta-blocker and antiarrhythmic activity, while the other enantiomer has antiarrythmic properties but lacks beta-adranergic antagonism. In addition, one enantiomer of fluoxetine (Prozac), at its highest dosage, let to statistically significant prolongation of cardiac repolarization.

Although many psychotropic drugs are either achiral
[fluvoxamine (Luvox) and nefazodone]
or are already marketed as single enantiomers
[sertraline (Zoloft), paroxetine (Paxil), escitalopram (Lexapro)]
several antidepressants have been marketed as racemates:
[bupropion (Wellbutrin), citalopram (Celexa), fluoxetine (Prozac), tranylcypromine (Parmate), trimipramine (Surmontil), and vanlafaxine (Effexor)].

Other drugs often used in psychiatric practice (zopiclone, methylphenndate, and some phenothiazines) are also available as racemates. Of these, single-enantiomer formulations are being developed for buproprion (Wellbutrin) and zopiclone, as well as methylphenidate (Ritalin, Concerta) or d-methylphenidate (Focalin).

In both citalopram and fluoxetine, one enantiomer appeared to have superior in vivo properties.

In the case of citalopram, the -enantiomer is primarily responsible for antagonism of seratonin uptake, while the (S)-enantiomer is 30 time less potent. In clinical trials, both racemic (R,S)-citalopram (Celexa) and the (S)-enantiomer version (Lexapro) were significantly better than placebo for improving depression.

In the case of fluoxetine (Prozac), the attempt to develop a single-enantiomer formulation for the treatment of depression was unsuccessful. While the R and S enantiomers of fluoxetine are are similarly effective at blocking the uptake of seratonin, they are metabolized differently. The use of the R enantiomer was expected to result in less variable plasma levels of fouxetine and its active metabolites than observed with racemic fluoxetine. In addition, the -fluoxetine and its metabolites inhibit certain target enzymes to a lesser extent than (S)-fluoxetine and its metabolites.

As previously mentioned, one enantiomer of fluoxetine, at its highest dosage, let to statistically significant prolongation of cardiac repolarization (but studies were terminated). Although racemic fluoxetine has proven to be both safe and effective for over 15 years, the -enantiomer formulation was not viable due to safety concerns.

It would appear obvious now that when both a single-enantiomer and a racemic formulation of a drug are available, the information from both trial and experience should be used to decide which formulation is most appropriate on a case-by-case basis.

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McConathy, J. and Owens, M.
"Stereochemistry in Drug Action"
J. Clinical Psychiatry / Primary Care Companion
Vol 5, p.70 (2003)
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