Chiral chemistry

Question 1

Why chrial chemistry

Answer 1

• FDA policy Development of new stereoisomeric drugs”
• Does not restrict useof racemates but requires ensntiomers of new drugs to be evaluated separately

Question 2

Top 10 best selling drugs

Answer 2

• 70% of top 10 drugs have a chiral centre

Question 3

Enantiomers

Answer 3

• The C atom is chiral because it is attached to four different groups
• Enantiomers are non-superimposable mirror images
• Same physical properties but differ in their interaction rotation of plane-polarised light
• Different enantiomers of the same drug often show very different pharmacological properties
• A racemate is a 50:50 mix of enantiomers

Question 4

Cahn-Inglod-Prelog (CIP) rules

Answer 4

• Chiral centres are assigned R or S according to
  
  • Step 1: prioritise each atom directly connected according to highest 1 with the highest atomic number and 4 lowest
  • Step 2: Link up highest three priority atoms 1,2 and 3
  • Step 3: Orientation 1-2-3 as you look down the carbon-lowest priority atom bond: R= clockwise, S= anticlockwise

Question 5

Ibuprofen

Answer 5

• An analgesic drug that inhibits cyclo-oxygenases (COX-1 and COX-2) during prostaglandin synthesis
• Sold as a racemate but R enantiomer is inactive as an analgesic but has some teratogenicity
• Not recommended during pregnancy especially 1^st trimester
• When the racemate is given the R enantiomer converted enzymatically to the more active S enantiomer

Question 6

Salbutamol

Answer 6

• Salbutamol is a reliever of the symptoms of asthma
• Selective agonist of B₂Receptor in the lung
• Potent bronchodilator reversing constriction of airways
• Sold as a racemate but R enatiomer 68X more active
• No proven clinical benefit from R isomer over the racemate
• When R enatiomer given, S enantiomer found in the urine

Question 7

Thalidomide

Answer 7

• Prescribed as a racemate in 1959 for women in pregnancy but resulted in severe birth defects in new born babies
• R enantiomer responsible for its anti-inflammatory activity
• S enantiomer responsible for teratogenic activity
• Not possible to give thalidomide as the R enantiomer as it is converted to the S enantiomer eenzymatically in the liver

Question 8

Omeprazole

Answer 8

• AZ omeprazole is a PPI used to reatdyspepsia/peptic ulcer disease (PUD)
• Esomeprazole (aka Losec) is the S enantiomer that AZ claims improved efficacy over the racemate
• AZ claims have been disputed but nevertheless
• What commercial benefits of S enantiomer vs racemate

Question 9

Aspartame

Answer 9

• 2S, 5S isomer is 180x sweeter than sucrose
• The other three diasteroisomers are all bitter tasting

Question 10

Isotopes

Answer 10

• Assign the configurations R and S to the following pair of enantiomers
• Atomic number determines the priority of each atom
• Atomic mass determines the priority of isotopes
• Tritium (³H) > Deuterium (²H) > Hydrogen (¹H)

Question 11

Prochirality

Answer 11

• C5 prochiral so H are diastereotopic
• Dihydro-orotate dehydrogenase (DHOD) catalyses trans oxidation of DOA
• Basic group: -enz DHOD removes pro-S proton from C5 to give resonance stabilised anion
• Transfer of hydride (H^-) from C6 to FMN⁺

Question 12

Exam question

Answer 12

Question 13

Re and Si faces

Answer 13

• Prioritise the atoms
• Link 1-2-3
• Re if clockwise
• Si if anticlockwise

Question 14

Enolates

Answer 14

1. Add base to ketone or aldehyde
2. Acidic a hydrogen removed
3. Oxygen can share -ve charge
4. Lithium helps stabilise -ve charge

Question 15

Chiral enolates: iron acyl complexes

Answer 15

Question 16

Captopril

Answer 16