Chirality in Pharmaceutical Synthesis

Chirality in

Chirality in

Pharmaceutical 

Pharmaceutical 

synthesis

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 

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 

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).

S_{tructure 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

Examples of Chiral Compounds in

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

 Modern chiral synthesis

Single optical isomer can be produced by the aid of enzyme similarly to the action shown above, this is called 

B_{iocatalysis & 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

 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

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 Electrophoresis apparatus