Chirality in Pharmaceutical Synthesis

Chirality in Pharmaceutical  synthesis

Chiral molecule: Lacks an internal plane of symmetry Has a non-super imposable mirror image  Asymmetric Carbon atom present: having 4 different atoms or groups of atoms attached    

T he

term chirality is derived from the Greek word for hand,  (cheir)

Images of: S-Alanine and

R-Alanine

I n

chemistry, chirality gives rise to optical isomers (enantiomers) Enantiomers are common and find many uses in pharmaceutical industry due to the specificity of their shape and function. Generally n = 2 x 

T   ypes

of enantiomers: R/S isomers : R- priority of substituents on the Carbon atom decreases in clockwise direction S-priority of substituents decreases in anticlockwise direction. d/l isomers (also +/-) : d-dextrarotatory; rotates plane polarised  light in clockwise direction l-levorotatory; rotates the plane polarised light in anticlockwise direction D/L isomers: spatial configuration of groups in relation to Glyceraldehyde (has 2 optical isomers). CORN (COOH > R>NH2) Clockwise arrangement gives rise to L-form, anticlockwise produces D-form. Levorotatory isomers are most abundant in nature. I n chemical synthesis a RACEM I C M IXTU RE 50:50 ratio of both isomers is occurring. T his can potentially cause problems.

Chiral compounds in Medicine Pharmacological activity- the beneficial or adverse effects of drug on living matter  On our cell membranes there are many receptors involved in cell signalling. These include proteins, glycoproteins and other sugars. These have a specific shape (many of the constituent molecules that make up receptors are enantiomers). Only a specific shape of the pharmaceutical /drug will bind with a particular receptor in order for it to be recognised by the cell. Hence the effectiveness of  the drug will greatly depend upon the type of  enantiomer produced.

U ndesired

enantiomer is either disposed of by the body or it may interact with cell resulting in harm (possible side effects of using the drug). Structure of a

glycoprotein receptor. It has a specific shape.

Two optical isomers cannot form enzyme-substrate complex. Only the isomer  with correct complementary shape will have pharmacological significance.

Problems with pharmaceutical  synthesis of chiral compounds In organic chemistry there is always a mixture of products present. In pharmaceutical industry this may be a problem because: side effects can result from the undesirable form of the enantiomer drug production of the desired enantiomer is not cost-effective and is energy  inefficient as percentage yield is low separation of products is required to make use of synthetic forms of  pharmacologically active product Products separated using enzymes, electrophoresis ,chromatography and other routes the by-product isomer has to be disposed of as it has no commercial use  money and energy wasted  

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Examples of Chiral Compounds in Pharmaceutical I ndustry

Things to consider when designing a drug: -atom economy: Are by products useful? Are there alternative routes? 50:50 in lab - racemic mixture -percentage yield -many to few step processes -possible side effects -costs of production : profit ratio - methods of purification of the product -compromises often have to be made to achieve safe, profitable product

 Modern chiral synthesis Single optical isomer can be produced by the aid of enzyme similarly to the action shown above, this is called  Biocatalysis & organocatalysis Biocatalysis makes use of enzymes to effect chemical reagents stereoselectively. Some small organic molecules can also be used to help accelerate the desired  reaction; this method is known as organocatalysis. I  f the organic molecule is chiral, it may react preferentially with the substrate of a certain chirality. Disadvantages: -time consuming, can be expensive as specific enzymes need to be used  Chiral pool synthesis  A chiral starting material is manipulated through successive reactions using achiral reagents that retain its chirality to obtain the desired target molecule. Often naturally occurring sugars and amino acids are used as these are enantiopure. Disadvantages: limited number of reactions possible, hence not all desired   products can be synthesised 

symmetric Catalysis U ses chiral ligands as catalysts, these can be metal complexes using e.g. Rhodium or Ruthenium, using chiral phosphine ligands in hydrocyanation reaction. T hese complexes produce chiral crystals which can be further used  to produce single product optical isomers. Disadvantages: quite low yield is achieved with these methods Chiral auxiliary T his physically blocks the other trajectory for attack, leaving only the desired trajectory open. Assuming the chiral auxiliary is enantiopure, the different trajectories are not equivalent, but diastereomeric. Similar to nucleophilic attack which can occur from top or bottom  forming 2 enantiomers (nucleophilic addition e.g. Aldehyde+ ammonia)

 An alternative to Synthesis of desired optical isomer is Chiral Resolution

Separation methods of racemic compounds into their  enantiomers Resolution by crystallisation First achieved by Louis Pasteur (discovered the concept of optical  activity). Here racemic mixture will crystalise as enantiopure compounds after saturation in Sodium Ammonium T artrate  Na+OOC-CH(OH)-CH(OH)-COO  NH3+ Chiral resolving agents T o

the racemic mixture optically pure reagents are added.Diesteromers are formed often as salts, which can be separated. Deprotonation then  follows. Reagents used  include tartaric acid and  brucine.

Chiral column chromatography T he two enantiomers in the racemic mixture will have different affinities for a particular other enantiomer in its stationary  phase. T hey will therefore exit the column at different times. Simplified column chromatography apparatus

Electrophoresis apparatus

Electrophoresis T his is also used in DNA analysis. I t involves a use of electrically charged isomers, which will  move through a conductive buffer solution  from one node to another depending on the charge they carry. T his will vary between the enantiomers. DNA fragments as bands obtained by gel  electrophoresis