Home'Lock and key' hypothesis). ## Chiral Recognition * **Glycerol kinase**: An enzyme that catalyzes the reaction of L-glyceraldehyde to form L-glycerol-3P. * The enzyme can distinguish between different enantiomers of glyceraldehyde (chiral recognition)! ## Poison Birds and Frogs * South American Poison dart frogs & Hooded Pitohui birds use Batrachotoxin. * $$200 \,mu g$$ is fatal to humans (0.0002 g!). * They obtain it from Choresine beetles, which have invested a lot in functional group and chiral chemistry.

'Lock and key' hypothesis). ## Chiral Recognition * Glycerol kinase: An enzyme that catalyzes the reaction of L-glyceraldehyde to form L-glycerol-3P. * The enzyme can distinguish between different enantiomers of glyceraldehyde (chiral recognition)! ## Poison Birds and Frogs * South American Poison dart frogs & Hooded Pitohui birds use Batrachotoxin. * $$200 \,mu g$$ is fatal to humans (0.0002 g!). * They obtain it from Choresine beetles, which have invested a lot in functional group and chiral chemistry.

Stereoisomers Part II

Stereoisomers

Stereoisomers are molecules that have the same number and kinds of atoms bonded to each other in the same order, but with different arrangements of atoms/groups in space.
- Mirror images: Enantiomers
- Non-mirror images: Diastereomers

Enantiomers or Chiral Molecules

Polarimeter: An instrument used to measure the rotation of plane-polarized light by a chiral molecule in solution.
When plane-polarized light is shined through a solution of a chiral molecule, the light is rotated by a specific rotation, denoted as $\,alpha_r$ .
One enantiomer rotates the light by $+\,alphar$ , while the other rotates it by $-\,alphar$ .
The specific rotation is the only physical property that differs between enantiomers.
Only the S form of amino acids is observed in natural amino acids (20 AAs).

Enantiomerism

Enantiomers: Stereoisomers that are non-superimposable mirror images.
Chirality: Refers to the 'handedness' of isomers.
Example: butan-2-ol ( $CH3CH2CHOHCH_3$ ).

Chirality

If the mirror image of a molecule (e.g., butan-2-ol) cannot be superimposed on the original structure, the molecule is chiral, and the mirror images are enantiomers.
Racemate or Racemic Mixture: An equal (50:50) mixture of enantiomers.

Stereocentres

Stereocenters: Points in a molecule where changing the spatial orientation of atoms or groups generates a different stereoisomer.
- Example 1: $sp^2$ carbons (defining E/Z isomerism).
- Example 2: $sp^3$ carbons in enantiomers.
Chiral Centre: A type of stereocenter, specifically an $sp^3$ carbon atom with four different atoms/groups bonded to it.
- This is the most common cause of enantiomerism in organic molecules.
- The symbol * (asterisk) is commonly used to indicate a chiral center (C*).

Achiral

Achiral: A molecule that is superimposable on its mirror image.
Most achiral molecules have a plane of symmetry or a center of symmetry.

Diastereomers

Diastereomers: Stereoisomers that are not mirror images and are not superimposable.
- Examples: cis/trans isomers of disubstituted cycloalkanes, E/Z isomers.
Stereoisomers: Molecules with the same numbers and kinds of atoms, all bonded to each other in the same order, but which have different arrangements of atoms/groups in space.

Representing Enantiomers

To represent enantiomers:
- Place the chiral center and two atoms/groups of the carbon framework in the plane of the paper.
- Place one atom/group coming out of the plane ('wedged' bond) and the other atom/group behind the plane ('dotted wedged' bond).
- Example: an enantiomer of butan-2-ol, glucose.

Cahn-Ingold-Prelog (CIP) Rules

CIP Rules: A set of rules used to specify the configuration around a chiral stereocenter (C*).
- To assign configuration:
  1. Locate the chiral stereocenter (C*).
  2. Identify substituents and assign priority from 1 (highest) to 4 (lowest, generally H). (same rules as E/Z based on atomic number)
  3. Move the molecule so the group of lowest priority (4) is pointing into the page (i.e., it will be a 'dotted wedged' bond).
  4. Read the groups projecting out of the page in order from 1 to 3.

CIP Rules and R/S Naming

R Configuration (Rectus): Groups (1-3) rotate in a clockwise direction.
S Configuration (Sinister): Groups (1-3) rotate in an anti-clockwise direction.
Example: 2-bromobutane ( $CH3CH2CHBrCH_3$ )
- (R)-2-bromobutane
- (S)-2-bromobutane

Worked Examples

General Steps:
1. Determine chiral carbon(s).
2. Assign priority.
3. Lowest priority group pointing back.
4. Assign R/S configuration.
May require re-drawing or rotating the molecule to view from directly opposite the No. 4 group.

Drug Examples

Oseltamivir (Tamiflu): ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3-yloxy)-cyclohex-1-ene-1-carboxylate
- Has three chiral centers (3R, 4R, 5S).
- The steps to determine R/S configuration are the same as in previous examples.

The Relevance

Thalidomide Tragedy: Sold between 1959-1962 as a racemic mixture to treat morning sickness.
- Only the R-enantiomer was effective; the S-enantiomer was teratogenic.
- Teratogenic chemicals: Damage germ and fetal cells, causing birth defects.
- Thalidomide caused approximately 10,000 infants to be born with deformities (phocomelia).

Chirality in Enzymes

Enzymes: Proteins that catalyze (speed up) biological reactions.
- For the reaction to occur, the molecule involved must fit into the enzyme's binding site.
- Often, the binding site is chiral and accepts only chiral molecules.
- Enzymes are chiral substances that only produce or react with substances matching their specific stereochemical requirements (