Chiral molecules of "Thalidomide" Until "L-DOPA"

What is chiral? The word "chiral" comes from the Greek "cheir" meaning hand. Try to imagine the left hand in front of the mirror, her reflection is of course the right hand. Now position the left hand and right hand facing down or toward the floor. Then put your left hand on your right hand. Look, the right hand could not diimpitkan with our left hand.
The same is true of certain organic molecules. In Figure 1, can be Alanine compound has two different structures. Assume that A and B are analogous to the left hand and right hand us. A and B are often referred to as stereoisomers (isomer of space) or optical isomers. It must be remembered, an organic molecule is called chiral molecules if there is at least one C atom that binds to four different groups such as Alanine compounds in Figure 1. Chiral molecules have very unique properties, namely optical properties. This means that a chiral molecule has the ability to rotate the plane of polarized light in a device called a polarimeter.
Optical isomer nomenclature system was introduced Chan-Ingold-Prelog who menglasifikasikan chiral C atom as R or S. This nomenclature system is often called the absolute configuration / absolute. For example (2R, 3S) -2.3 dibromo pentane. In this paper will not explain the rules of naming R and S, but the reader can read them at the organic level literature courses. With this nomenclature system of classification introduced two stereoisomers, namely enantiomers and diastereoisomers. Definition of enantiomers and diastereoisomers bit tricky but it will be explained in simple.

    (2R, 3S) -2.3 dibromo pentane and (2S, 3R) -2.3 dibromo pentane
    (2R, 3S) -2.3 dibromo pentane and (2R, 3R) -2.3 dibromo pentane
Now the following explanation:

    If in between a pair of stereoisomers no chiral C atom has the same configuration, the stereoisomers are enantiomers. As the first example of (2R, 3S) -2.3 dibromo pentane and (2S, 3R) -2.3 dibromo pentane.
    If in between a pair of stereoisomers there are at least one chiral C atoms having the same configuration, the stereoisomers are diastereoisomers. As a second example (2R, 3S) -2.3 dibromo pentane and (2R, 3R) -2.3 dibromo pentane.
Some communities may be less attention to the optical properties of an organic compound, whereas the chemical reactions in living biological systems are very stereospecific. This means that a stereoisomer would undergo different reactions with her partner stereoisomer in biological systems of living things. In fact, sometimes a stereoisomer will produce different products with stereoisomer partner in living biological systems. Examples are:

    Thalidomide drug
    This drug is marketed in Europe around the year 1959-1962 as a sedative. This drug has two enantiomers, where the enantiomers are useful as a sedative is (R)-Thalidomide. But pregnant women who consume enantiomernya namely (S)-Thalidomide experienced a problem with fetal limb growth. Occurred at least 2000 cases of birth defects in the 1960s. This is a great tragedy that can not be forgotten in the history of chiral drugs.
    Nicotine
    (-) Nicotine is reported to be more toxic and dangerous than the (+) Nicotine. Sign "+" direction of rotation of the polarimeter according to state-clockwise, while the sign "-" states the direction of rotation counter-clockwise polarimeter.
    Thyroxine
    Thyroxine is a hormone produced by the thyroid gland. (-) Thyroxine regulates the body's metabolism, whereas (+) Thyroxine regulation does not produce any effect.
Looking at the facts on the stereochemistry (spatial structure) of an organic compound absolutely must be taken into account in biological reactions of living things. Unfortunately very difficult to produce a pure enantiomers or diastereoisomers. Even 90 percent of synthetic drugs containing chiral compounds are marketed under rasemik until the early 1990s.
Rasemik mixture means a mixture containing a pair of enantiomers in equal amounts. So how do I obtain an enantiomer with enantiomeric excess (EE) is high? Enantiomeric excess means that the configured percentage of the R enantiomer reduced the percentage of spouses who berkonfigurasi S enantiomer in a mixture or vice versa. Before answering that question, keep in mind two basic principles of optical isomers, namely:

    A pair of enantiomers having the physical properties (boiling point, solubility, etc.) are similar but differ in the direction of rotation of the polarimeter and interaction with other chiral substances.
    A pair of diastereoisomers having the physical properties and the rotation angle polarimeter which differ from each other. In fact often the reaction takes a different way. This means that we can separate a mixture of two diastereoisomers by means of physics (distillation, crystallization, etc.). But can not separate a mixture of two enantiomers by means of physics, for a pair of enantiomers have the same physical properties. In conclusion, we can easily separate a mixture of two diastereoisomers, but it will be difficult to separate a mixture of two enantiomers.
Then how to obtain an enantiomer with high ee? Louis Pasteur is said never to separate the two enantiomers of tartaric Sodium Amoium using tweezers. This can happen because the two enantiomers crystallize separately. This method is often referred to the resolution. This is less effective because not all enantiomers crystallize separately.
So the resolution can not be regarded as a common technique. Another way that is often taken by the chemists is a biochemical route by using enzymes or microorganisms to produce the pure enantiomer. For example, (R)-Nikotina can be obtained by incubating the mixture rasemik (R)-Nikotina and (S)-Nikotina in a container of the bacteria Pseudomonas putida. The bacteria will only oxidize (S)-Nikotina, whereas (R)-Nikotina will remain in the container. Some other products of the biochemical route is Monosodium L-glutamate, L-Lysine and L-Menthol. Nomenclature system of D and L is called the relative configuration. This system is often used in naming the amino acids and carbohydrates.
Unfortunately not all of enantiomers can be produced with high ee through this biochemical route. This is because the specificities of the enzymes and microorganisms. For example, the bacteria Pseudomonas putida can not be used to separate the (+)-Menthol with (-)-Menthol.
The organic chemists such as Ryoji Noyori and William S. Knowles did not lose the sense in solving this problem. William S. Knowles managed to synthesize a compound called (R, R)-DiPAMP (Fig. 2.). It uses the (R, R)-DiPAMP as a ligand to form complex compounds with Rh metal. These complex compounds are very useful in asymmetric hydrogenation processes enamida group. With this complex compound, he managed to synthesize L-DOPA which is very useful in the treatment of Parkinson's disease with a purity of 95 percent ee.
In addition to L-DOPA, the complex compound is also often used to synthesize the acid? alpha-amino acids with high ee, L-Phenilalanin example, L-tryptophan, L-Alanine, L-lysine, etc., except for aspartic acid because it has two adjacent carboxylate groups.
On the other hand, Ryoji Noyori synthesize compounds that are named BINAP (Figure 3.). He used BINAP as a ligand to form complex compounds with metal Ru. These complex compounds are very flexible, because it can be used for asymmetric hydrogenation of alkenes, and enantioselective reduction of ketones are. Actually, the enantioselective reduction of ketones is not new, but the use of transition metals as catalysts for the reduction of ketones is usually difficult and is not enantioselective. Enantioselective means a reaction that produces two enantiomers, in which one enantiomer is produced in greater numbers than the enantiomer partner.
Especially for the reduction of ketones, Ryoji Noyori synthesize (S)-BINAP / (S)-diamine Ru (II) catalyst. With these complex compounds are widely produced chiral drugs with low production costs and high purity. For example, L-DOPS, Levofloxacin, Neobenodine, Fosfomycin, fluoxetine hydrochloride, naproxen, and others. For the record L-DOPS is a precursor of Norepinephrine. Norepinephrine is a neurotransmitter to send signals to the heart and blood vessels.
Both of these discoveries have opened new horizons in science and technology. According to reports, until 2000, sales of chiral drugs in enantiomerically pure form in the world has reached 123 billion U.S. dollars. It is also possible the realization of new discoveries, it is even possible that the Indonesian people will make new breakthroughs. Remember, this story is not over, because science is never dead. Finally, science continues to advance Indonesia.

Stereochemistry

Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules.^[1]
Stereochemistry is also known as 3D chemistry because the prefix "stereo-" means "three-dimensionality".^[2]
The study of stereochemical problems spans the entire range of organic, inorganic, biological, physical and supramolecular chemistries. Stereochemistry includes methods for determining and describing these relationships; the effect on the physical or biological properties these relationships impart upon the molecules in question, and the manner in which these relationships influence the reactivity of the molecules in question (dynamic stereochemistry).

History and significance

Louis Pasteur could rightly be described as the first stereochemist, having observed in 1849 that salts of tartaric acid collected from wine production vessels could rotate plane polarized light, but that salts from other sources did not. This property, the only physical property in which the two types of tartrate salts differed, is due to optical isomerism. In 1874, Jacobus Henricus van 't Hoff and Joseph Le Bel explained optical activity in terms of the tetrahedral arrangement of the atoms bound to carbon.

Cahn-Ingold-Prelog priority rules are part of a system for describing a molecule's stereochemistry. They rank the atoms around a stereocenter in a standard way, allowing the relative position of these atoms in the molecule to be described unambiguously. A Fischer projection is a simplified way to depict the stereochemistry around a stereocenter.

Thalidomide example

An oft cited example of the importance of stereochemistry relates to the thalidomide disaster. Thalidomide is a drug, first prepared in 1957 in Germany, prescribed for treating morning sickness in pregnant women. The drug was discovered to be teratogenic, causing serious genetic damage to early embryonic growth and development, leading to limb deformation in babies. Some of the several proposed mechanisms of teratogenecity involve a different biological function for the (R)- and the (S)-thalidomide enantiomers^[3]. In the human body however, thalidomide undergoes racemization: even if only one of the two enantiomers is administered as a drug, the other enantiomer is produced as a result of metabolism^[4]. Accordingly, it is incorrect to state that one of the stereoisomer is safe while the other is teratogenic^[5]. Thalidomide is currently used for the treatment of other diseases, notably cancer and leprosy. Strict regulations and controls have been enabled to avoid its use by pregnant women and prevent developmental deformations. This disaster was a driving force behind requiring strict testing of drugs before making them available to the public.

HYDROLYSING NITRILES

The hydrolysis of nitriles
Introduction
When nitriles are hydrolysed you can think of them reacting with water in two stages - first to produce an amide, and then the ammonium salt of a carboxylic acid.
For example, ethanenitrile would end up as ammonium ethanoate going via ethanamide.

In practice, the reaction between nitriles and water would be so slow as to be completely negligible. The nitrile is instead heated with either a dilute acid such as dilute hydrochloric acid, or with an alkali such as sodium hydroxide solution.
The end result is similar in all the cases, but the exact nature of the final product varies depending on the conditions you use for the reaction.
Acidic hydrolysis of nitriles
The nitrile is heated under reflux with dilute hydrochloric acid. Instead of getting an ammonium salt as you would do if the reaction only involved water, you produce the free carboxylic acid.
For example, with ethanenitrile and hydrochloric acid you would get ethanoic acid and ammonium chloride.

Why is the free acid formed rather than the ammonium salt? The ethanoate ions in the ammonium ethanoate react with hydrogen ions from the hydrochloric acid to produce ethanoic acid. Ethanoic acid is only a weak acid and so once it has got the hydrogen ion, it tends to hang on to it.
Alkaline hydrolysis of nitriles
The nitrile is heated under reflux with sodium hydroxide solution. This time, instead of getting an ammonium salt as you would do if the reaction only involved water, you get the sodium salt. Ammonia gas is given off as well.
For example, with ethanenitrile and sodium hydroxide solution you would get sodium ethanoate and ammonia.

The ammonia is formed from reaction between ammonium ions and hydroxide ions.
If you wanted the free carboxylic acid in this case, you would have to acidify the final solution with a strong acid such as dilute hydrochloric acid or dilute sulphuric acid. The ethanoate ion in the sodium ethanoate will react with hydrogen ions as mentioned above.

LACTAM

A lactam (the noun is a portmanteau of the words lactone + amide) is a cyclic amide. Prefixes indicate how many carbon atoms (apart from the carbonyl moiety) are present in the ring: β-lactam (2 carbon atoms outside the carbonyl, 4 ring atoms in total), γ-lactam (3 and 5 total), δ-lactam (4 and 6 total). Beta β, gamma γ and delta δ are the second, third and fourth letters in the alphabetical order of the Greek alphabet, respectively.
Contents

    1 Synthesis
    2 Tautomerization to Lactim
    3 Reactions
    4 See also
    5 References

Synthesis

General synthetic methods exist for the organic synthesis of lactams.

    Lactams form by the acid-catalyzed rearrangement of oximes in the Beckmann rearrangement.
    Lactams form from cyclic ketones and hydrazoic acid in the Schmidt reaction.
    Lactams form from cyclisation of amino acids.
    Lactams form from intramolecular attack of linear acyl derivatives from the nucleophilic abstraction reaction.
    In iodolactamization [1] an iminium ion reacts with an halonium ion formed in situ by reaction of an alkene with iodine.

    Iodolactamization reaction

    Lactams form by copper catalyzed 1,3-dipolar cycloaddition of alkynes and nitrones in the Kinugasa reaction
    Diels-Alder reaction between cyclopentadiene and chlorosulfonyl isocyanate (CSI) can be utilized to obtain both β- as well as γ-lactam. At lower temp (−78 °C) β-lactam is the preferred product. At optimum temperatures, a highly useful γ-lactam known as Vince Lactam is obtained.[2]

Preparation of VL and beta lactam
Tautomerization to Lactim

Lactim is a cyclic carboximidic acid compound characterized by an endocyclic carbon-nitrogen double bond. It is formed when lactam undergoes tautomerization.
Reactions

    Lactams can polymerize to polyamides.

    β-lactam with a four-membered ring found in beta-lactam antibiotics. Penicillin, considered the most famous antibiotic, is a β-lactam antibiotic.
   

HYDROLYSING AMIDES

This page describes the hydrolysis of amides under both acidic and alkaline conditions. It also describes the use of alkaline hydrolysis in testing for amides. The hydrolysis of amides What is hydrolysis? Technically, hydrolysis is a reaction with water. That is exactly what happens when amides are hydrolysed in the presence of dilute acids such as dilute hydrochloric acid. The acid acts as a catalyst for the reaction between the amide and water. The alkaline hydrolysis of amides actually involves reaction with hydroxide ions, but the result is similar enough that it is still classed as hydrolysis. Hydrolysis under acidic conditions Taking ethanamide as a typical amide: If ethanamide is heated with a dilute acid (such as dilute hydrochloric acid), ethanoic acid is formed together with ammonium ions. So, if you were using hydrochloric acid, the final solution would contain ammonium chloride and ethanoic acid.
	Note:  You might argue that because the hydrochloric acid is changed during the reaction, it isn't acting as a catalyst. In fact, it is doing two things. It is acting as a catalyst in a reaction between the amide and water which would produce ammonium ethanoate (containing ammonium ions and ethanoate ions). It is secondly reacting with those ethanoate ions to make ethanoic acid.
Hydrolysis under alkaline conditions Again, taking ethanamide as a typical amide: If ethanamide is heated with sodium hydroxide solution, ammonia gas is given off and you are left with a solution containing sodium ethanoate. Using alkaline hydrolysis to test for an amide If you add sodium hydroxide solution to an unknown organic compound, and it gives off ammonia on heating (but not immediately in the cold), then it is an amide. You can recognise the ammonia by smell and because it turns red litmus paper blue. The possible confusion using this test is with ammonium salts. Ammonium salts also produce ammonia with sodium hydroxide solution, but in this case there is always enough ammonia produced in the cold for the smell to be immediately obvious.
	Note:  This test is OK for UK A level purposes, but there are other things which also give off ammonia on heating with sodium hydroxide solution - for example, nitriles (but you won't come across them in a practical situation at this level) and imides (but they are beyond the scope of courses at this level).