30. Organic Synthesis Flashcards
Which structural features should be assessed when designing drugs?
Sites with specificity like active sites on enzymes in bacteria. This allows shape prediction to block the specific sites.
Functional groups are important for effective binding (H-bonding, ionic attraction, VDWs, dipole-dipoles).
What is molecular modelling and how has it been used in the past?
Using computers to predict the fit between a drug and a receptor site. It has been used against AIDS - finding the shape of HIV protease using X-ray crystallography. An antiviral drug which was water-soluble was discovered, but as it mutated, new strains were created and the drugs did not work.
How can NMR be used to identify molecules?
Finding the environment of each H atom as well as the distance between atoms in macromolecules. Occurs in solution (mimics conditions in cells / blood), produces ribbon diagrams.
Describe the role of chirality in drug molecules.
The molecule exists as two non-superimposable mirror images (entaniomers) which differ in their ability to rotate a plane of polarised light to the left or right. A 1:1 mixture of the two is produced (racemic mixture). The physical properties are the same but their pharmaceutical properties differ greatly.
Why do drugs need to contain only one entaniomer?
The required dosage is reduced by half, and the costs (both financial and physical) are less. Eg. the wrong naproxen entaniomer (arthritis) can cause liver damage, and the wrong one for TB can cause blindness.
Describe the ‘optical resolution’ method of separating entaniomers.
A chiral auxiliary (different pure entaniomer) reacts with one entaniomer to produce a compound with different physical properties (eg. different solubility, fractional crystallisation).
The new product is converted to the desired entaniomer by eg. adding dilute alkali. The process is repeated many times.
Describe the disadvantages of optical resolution.
- Uses large volumes of reagent
- Organic solvents often harmful
- Half original mixture is discarded
Describe better alternatives to optical resolution.
Using supercritical CO2 as a solvent - at 31°C and 73ATM, it is a good non-polar solvent. The solubility of the drug derivatives can be varied by changing the solvent density. It is non-toxic and can be removed + recycled by changing the pressure.
HPLC can also be used as long as the stationary medium is optically active.
Describe the ‘starting materials’ method of asymmetric synthesis.
The materials are optically active and in the same orientation as the produce, so that the intermediates and product are in the same entaniomeric form. Examples are natural, like L-amino acids and carboxylic acids (these are selected from a ‘chiral pool’.
Describe the ‘chiral catalyst’ method of asymmetric synthesis.
Eg. Ru organometallic catalyst used to produce naproxen.
Enzymes can also be used for stereoselectivity due to their specific active site. Different arrangements around a chiral centre yield different shapes, which won’t fit the active site.
- immobilised to avoid need for separation
- can be reused and recycled
- fewer steps and reactants required
- expensive to extract - synthetic enzymes / whole organisms used instead.
How can carbon atoms be added to organic compounds?
- Adding the nitrile group to a haloaklane, reflux with ethanolic KCN.
RBr + HCN -> RCN + HBr (R = alkyl group) - RCN can be hydrolysed (reflux with dilute HCl) to a carboxylic acid or reduced (LiAlH4 in dry ether) to an amine.
- Adding an alkyl/acyl side chain to a benzene ring using a Friedel-Crafts reaction.
