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

Images of: S-Alanine and R-Alanine

The term chirality is derived from the Greek word for hand, χειρ (cheir)

In 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 = 2xTypes of enantiomers:R/S isomers : R- priority of substituents on the Carbon atom decreases in clockwise directionS-priority of substituents decreases in anticlockwise direction.d/l isomers (also +/-) : d-dextrarotatory; rotates plane polarised light in clockwise directionl-levorotatory; rotates the plane polarised light in anticlockwise directionD/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. In chemical synthesis a RACEMIC MIXTURE 50:50 ratio of both isomers is occurring.This can potentially cause problems.

Chiral compounds in MedicinePharmacological 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.

Undesired 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 compoundsIn 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 Pharmaceutical Industry

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 synthesisSingle optical isomer can be produced by the aid of enzyme similarly to the action shown above, this is calledBiocatalysis & organocatalysisBiocatalysis 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. If 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 synthesisA 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

Asymmetric CatalysisUses chiral ligands as catalysts, these can be metal complexes using e.g. Rhodium or Ruthenium, using chiral phosphine ligands in hydrocyanation reaction. These complexes produce chiral crystals which can be further used to produce single product optical isomers.Disadvantages: quite low yield is achieved with these methodsChiral auxiliaryThis 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 crystallisationFirst achieved by Louis Pasteur (discovered the concept of optical activity). Here racemic mixture will crystalise as enantiopure compounds after saturation in Sodium Ammonium Tartrate Na+O−OC-CH(OH)-CH(OH)-COO−NH3+Chiral resolving agents

To 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 chromatographyThe two enantiomers in the racemic mixture will have different affinities for a particular other enantiomer in its stationary phase. They will therefore exit the column at different times.

Simplified column chromatography apparatus

ElectrophoresisThis is also used in DNA analysis. It 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. This will vary between the enantiomers.

DNA fragments as bands obtained by gel electrophoresis

Electrophoresis apparatus