Chirality

MPharm Programme: Chirality

• This programme covers the topic of chirality, specifically focusing on constitutional isomerism, geometric isomerism, and conformational isomerism.
• The lecture discusses different types of isomers and their significance, including examples of molecules with specific properties.
• The material also covers the IUPAC nomenclature for alkenes, particularly utilizing the Cahn-Ingold-Prelog (CIP) rules.
•  The presentation includes examples such as Aspirin, caffeic acid, and 4-hydroxyphenyl-pyruvic acid with their physical properties and biological activities.

Constitutional Isomerism

• Constitutional isomers, also known as structural isomers, are molecules with the same molecular formula but different bonding arrangements of their constituent atoms.
• These isomers have diverse physical and pharmaceutical properties, including differences in melting point, boiling point, solubility, and density.
• Constitutional isomers cannot interconvert.

Geometric Isomerism (cis-trans)

• Geometric isomerism involves molecules with the same molecular formula but different spatial arrangements of substituents around a double bond.
• This type of isomerism is illustrated by cis and trans isomers.
• There is no interconversion between cis and trans forms at ambient or body temperatures.
• Examples include maleic acid and fumaric acid isomers, exhibiting different physical properties like melting points.

IUPAC Nomenclature for Alkenes: Cahn-Ingold-Prelog (CIP) Rules

• The CIP rules provide a system for assigning priorities to substituents on alkenes to unambiguously name Z (same side) and E (opposite side) isomers.

Conformational Isomerism

• Conformational isomers, or conformers, are different spatial arrangements of a molecule that can be interconverted by rotation around single bonds.
• Conformational changes significantly influence the shape of a molecule.
• These changes affect how molecules interact and bind to their target molecules (e.g., receptors).
• Strain in molecules (steric, torsional, and angle strain) plays a vital role in determining the preferred conformations.
• The principle of minimizing strain and achieving lowest energy dictates the preferred conformations.

Example Exercises: Geometry Assignment

• Example exercises are presented to illustrate the principles of assigning alkene geometry (Z or E) based on molecular structures in specific examples like acrivastine and fusidic acid.

Why is Geometry Important?

• Molecular shape is critical for proper binding and function.
• The Z (trans) geometry of tamoxifen is crucial for its ability to bind effectively to receptors.
• Correct geometry facilitates interactions with target molecules, leading to more potent effects.

Key Messages: Alkene Geometry

• Using Z and E for alkenes avoids ambiguity, resulting in precise naming.
• Prioritising substituents correctly is essential.
• This feature is vital in pharmaceuticals, as geometry significantly impacts binding to targets.

Acyclic Molecules

• Acyclic molecules, like cysteamine, can adopt different spatial orientations and conformations due to rotation around their single bonds.
• Newman projections aid in visualizing these arrangements.
• Eclipsed and staggered conformations differ in their relative positions of substituents, impacting properties.
• An important consideration is energy minimization.

Conformational analysis of Cysteamin

• Eclipsed conformations of cysteamin are found to be less stable
• Staggered conformations are considered more stable or at lower energy
• Synperiplanar conformations are found to carry more energy than antiperiplanar conformations

Cyclohexane Conformations

• Cyclohexane adopts chair conformations due to reduced strain compared to boat conformation.
• Chair conformations have all staggered bonds and minimised strain.
• The stability preference is explained by the steric and torsional strain minimised.

Chair Form: Drawing the Bonds

• Axial substituents are located on vertical bonds, while equatorial substituents circle the equator of the ring.
• Equatorial bonds are parallel to the ring's C-C bonds two carbons away.

Ring Flip

• Ring flips involve axial bonds becoming equatorial and vice versa.
• The ability of ring flips between various conformations is essential for the adoption of the most stable shapes and interactions with receptors.
• The ring flips via passing through a boat form.

Tranexamic Acid: Preferred Chair Form

• Tranexamic acid's efficacy is linked to its preferred chair conformation where substituents are equatorial, thus minimizing steric strain.
• Substituents in equatorial positions point away from the ring minimizing steric strain. This conformation often leads to greater stability and activity.

Numerous Pharmaceutical Examples

• Various pharmaceuticals, including cetrizine, ropivacaine and Lactulose, Streptomycin, are presented, highlighting examples that utilize either piperazine, piperidine, Pyranose rings, demonstrating the presence of cyclic rings in their structures.

Five-Membered Ring Systems

• Five-membered rings are common in pharmaceuticals and frequently appear in sugars, pyrrolidines (such as in sulpiride), and tetrahydrofurans (like in furethidine).
• These rings exhibit twists or envelope conformations to minimize strain, and sometimes have eclipsing and torsional/steric strain remaining, even in these conformations.

Four-Membered Ring Systems

• Four-membered ring systems, particularly saturated cyclobutanes, tend to adopt a V-shape due to high steric, angle, and torsional strain.
• This structural feature influences how the molecule interacts with other molecules, in this case, the molecular interaction or shape is less consistent. 

Key Messages: Cyclic Conformations

• Saturated cyclohexane rings are not planar but adopt conformations that minimise strain. Chair conformations are preferred since angle strain, steric strain and torsional strain are minimised.
• For six-membered rings, chair conformations are preferred, with the largest groups positioned in equatorial positions to minimise steric hindrance. Envelope conformations are common for five-membered rings.

Stereoisomerism

• Stereoisomers (optical or conformational isomers) result from the spatial arrangement of atoms around chiral centres. Asymmetry around a saturated carbon atom with four different atoms or groups attached is a source of stereoisomerism.
• Stereoisomers are crucial in pharmaceuticals, with adverse effects observed in cases exhibiting non-stereospecificity.
• These adverse effects necessitate greater scrutiny and considerations in the registration and licensing procedures of pharmaceuticals.

Terminology

• Stereoisomerism, often referred to as chirality, is a crucial concept involving spatial arrangement.
• Chiral carbon (or stereocentre, or stereogenic carbon) is a critical element in determining the three-dimensional structure.
• Racemic mixtures are defined as equal mixtures of enantiomers, and Optically inactive compounds don´t rotate polarized light, and can either lack a chiral centre or consist of a racemic mix of enantiomers.
• Enantiomers denote non-superimposable mirror images, and diastereoisomers refer to non-superimposable non-mirror-image stereoisomers.

What is a Chiral Carbon?

• A chiral carbon has four different atoms or groups attached to it.
• The mirror image of a chiral molecule is non-superimposable.
• Non-superimposable mirror images are called enantiomers.

Practice: Identify the Chiral Carbons

• Examples like Amikacin, Latanoprost, and other structures are presented for the practice of identifying chiral carbons in various molecular compounds.

Nomenclature (CIP Rules)

• The CIP rules establish a systematic approach for determining priorities of atoms around a chiral centre (or carbon), facilitating unambiguous naming of stereoisomers (R or S configuration).

Steps to Classify Chirality

• The process for classifying molecules as R or S is described, emphasizing creating a 3-D representation, prioritizing atoms connected to the chiral center using atomic numbers, ensuring the fourth priority group is in the rear of the molecule, and evaluating the spatial arrangement for R or S configuration.

Worked Examples: Acebutolol and Rivastigmine

• Worked examples of chiral carbon assignment are shown in molecules acebutolol and rivastigmine using Fischer projections and prioritizing atoms surrounding the chiral centre.

What do we do if Priority 4 Atom At Front?

• Reversing the rotation direction will give the correct answer, since sometimes the structure is viewed from the opposite face, and this must be considered to apply the rules properly.

Worked Example: R vs S

• Examples help illustrate how to apply the CIP rules to assign R or S configurations to specific chiral centres or carbons.

Properties of Enantiomers

• Enantiomers possess identical physical and chemical properties, with exceptions, (except for optical activity)

Plane Polarized Light (PPL)

• Plane polarized light can be used to differentiate enantiomers.
• Specific rotation ([a]) values are used to describe the rotational ability of a chiral compound with plane polarized light.

Rotation of PPL by Enantiomers

• Enantiomers rotate polarized light by equal amounts but in opposite directions.

Interactions with Other Enantiomers

• The shape of the molecule is critical in its interaction with the receptor influencing its activity or its interaction with a chiral biological target, (enzyme, receptor, etc).
• Often one enantiomer only displays desired properties, whilst the other might exert adverse or no activity at all.

Compounds Showing different activities

• Several examples (e.g., Ibuprofen, Warfarin) are presented where the different configurations of a compound can lead to considerable differences in their activity, or their interaction with the biological system.

Carvone

• Enantiomers of carvone, with differing stereochemistry, display marked variations in odors, demonstrating how minute structural differences can influence perceptions (smell and aroma).

Vigabatrin (Sabril®)

• The S enantiomer of Vigabatrin is the active component of this anti-epileptic drug, while the R enantiomer has no activity. 

Fluoxetine (Prozac®)

• The S-enantiomer of Fluoxetine demonstrates higher activity in its role as a serotonin reuptake inhibitor.

Warfarin

• Both enantiomers of Warfarin are active in antagonizing Vitamin K epoxide reductase. However, the S-enantiomer demonstrates four times greater activity and faster action.

Why are Amines Rarely Chiral?

• Amines can sometimes invert due to protonation/deprotonation processes.
•  Amines may adopt conformations influenced by resonance interactions, preventing formation of chiral centers due to partial double bonds.

L and D: Fischer Notation

• The D/L notation is an alternative stereochemical convention for chiral molecules, developed by Emil Fischer and grounded in the structure of D-glyceraldehyde.

Fischer Projections

• Fischer projections are two-dimensional representations of three-dimensional organic molecules used in the D and L conventions.

Example Exercise

• Examples of glyceraldehyde and its D and L form are provided for the purpose of illustrating assignment of a chiral form.

Key Messages: 2 or more Chiral Centres

• The presence of two or more chiral centers in a molecule results in the potential for numerous stereoisomers and can exhibit varying physical and chemical characteristics.
• Separating these isomers can present a significant challenge.

Selectivity in Reactions

• Reactions involving chiral reactants or products can exhibit selectivity given the existence of different mechanisms of action in stereo-isomers, exhibiting various outcomes (no stereoselectivity, or stereoselectivity, racemisation, or inversion/conservation of stereochemistry).

Concerted vs Non-concerted Reactions

• Non-concerted reactions involve separate steps, potentially leading to intermediate formation, which is dependent on the mechanism involved.
• Concerted reactions happen in a single step, often preserving or inverting stereochemistry. This is important in biological systems if stereochemistry must be conserved in order to properly interact with the biological system.

Non-concerted Reaction: SN1

• SN1 reactions proceed via a carbocation intermediate, resulting in a loss of stereochemical information.
• The reaction's outcome (products) depends on the planar intermediate that is accessible from either side. No stereoselectivity is demonstrated.

Concerted Reaction: SN2

• SN2 reactions proceed in a single concerted step with an inversion of configuration at the reaction center.

Reduction of Carbonyl Compound

• This reaction involves adding a hydrogen atom to a carbonyl group, and this can cause a result in enantiomers being formed.
• Stereochemistry can be maintained depending on the mechanism of action, either a concerted or non-concerted mechanism, which will determine if the reaction or the product has stereochemistry that is inverted or conserved.

Identifying Stereoisomers with 2 Chiral Carbons

• Enantiomers are non-superimposable mirror images, whilst diastereoisomers are non-superimposable and non-mirror images. Meso compounds are superimposable and have an internal mirror plane.

Properties of Diastereoisomers

• Diastereomers have distinct physical properties (like melting points, solubilities) that can be exploited for their separation.

Separation of Diastereoisomers

• Separation techniques capitalize on the differing physical properties of diastereoisomers to isolate them from a mixture.

Classical Resolution Example

• This provides an example of resolving enantiomers by forming diastereomeric salts, exploiting their different physical properties for separation.

Resolution by Esterification

• A resolution method using esterification is provided as an example for resolving a mixture, where the separation methodology of diastereoisomers is applied for the resolution of enantiomers.

Example: Racemic Ibuprofen

• A worked example of a reaction demonstrating different solubilities and subsequent separation of diastereoisomers based on their diverse solubilities. This is used to derive an enantiomer.

Consequences of Chirality: Pharmacological Effects

• Appropriate binding to targets results in desired pharmacological activity.
• If only one enantiomer is active, the inactive or inactive enantiomers may lead to adverse effects.

Key Messages: 2 or more Chiral Centres

• The presence of two or more chiral centres in molecules significantly increases the possible stereoisomers.
• Diastereoisomers exhibit varying physical properties, which facilitate their separation.
• Meso compounds, despite having chiral centers, are achiral due to internal symmetry. 

Selectivity in Reactions

• Stereoselective reactions proceed with a preference for a specific stereochemical outcome based on the reaction mechanism.

Concerted vs Non-concerted Reactions

• Non-concerted reactions proceed through multiple steps, potentially leading to loss of stereochemistry or to racemization.
• Concerted reactions, on the other hand, occur in a single step, minimizing changes to the stereochemistry.

Non-concerted Reaction SN1

• Non-concerted nucleophilic substitution (SN1) reactions result in loss of stereochemistry at the carbon center, with equally probable attack from either side of the reaction interface.
• A racemic mixture results, illustrating the lack of stereoselectivity in this non-concerted reaction.

Concerted Reaction SN2

• Concerted substitution (SN2) reactions exhibit stereoselectivity with an inversion of configuration due to the simultaneous bond-breaking and bond-forming in one step.

Reduction of Carbonyl Compound

• Reduction of carbonyl compounds with a chiral reducing agent can yield enantiomers or racemic mixtures dependent on the mechanism involved (concerted, or non-concerted). Stereoselectivity is only present when a chiral nucleophile is involved.