MEDCHEM.03

Page 1: Introduction

• Medicinal and Pharmaceutical Chemistry (MEDCHEM.3) focuses on the Applications of Chirality.

• Presented by Dr. Marco Monopoli.

• Date: 21st of January 2025.

Page 2: Learning Outcomes

• Chirality Fundamentals:

  • If a molecule has ‘n’ chiral centers, it can exhibit ‘2n’ stereoisomers.

  • Ability to assign absolute configurations to molecules with 2 chiral centers.

  • Definitions:

    • Diastereomers

    • Meso compounds

  • Explore biochemical and therapeutic applications of chirality, including:

    • Enzymes

    • Chiral drugs

    • Amino acids

  • Discuss medicinal and pharmaceutical applications of chirality.

Page 3: Summary of Isomerism

• Isomerism: Molecules with the same molecular formula exhibit variations.

  • Types of Isomers:

    • Constitutional (Structural) Isomers: Different bond patterns (e.g., C2H6O as alcohol/ether).

    • Stereoisomers: Same molecular formula but different arrangement in space.

      • Conformational Isomers: Differ by single bond rotations.

      • Configurational Isomers: Require bond changes to interconvert.

Page 4: Assigning Configuration to 3-D Chiral Molecules

• Cahn-Ingold-Prelog Rules for Configuration:

  • Align molecule so lowest priority group is at the back.

  • Draw an arrow from highest to lowest priority groups.

    • Clockwise = (R) configuration.

    • Anti-clockwise = (S) configuration.

Page 5: Assigning Absolute Configuration (R or S)

• Procedure:

  1. Identify priorities for substituents as per Cahn-Ingold-Prelog rules.

  2. Orient the molecule with the lowest priority at the back.

  3. Determine (R) or (S) based on clockwise/counterclockwise direction.

Page 6: Double-Switch

• More than one way to determine R or S configuration.

Page 7: Fischer Projections

• Visualization of 3D Molecules in 2D:

  • Tetrahedral chiral carbon depicted with crossed lines;

    • Horizontal line: Out of the plane (toward viewer).

    • Vertical line: Into the plane (away from viewer).

Page 8: Fischer Projections Examples

• Different representations and manipulations of Fischer projections.

Page 9: Manipulation of Fischer Projections

• Rotation Rules:

  • Rotations of Fischer projections: Only 180° rotation permissible.

  • A 90° rotation inverts stereochemistry (illegal).

  • Positioning hydrogen in vertical position is necessary to confirm R/S configurations.

Page 10: Manipulation of Fischer Projections Continued

• Holding one group fixed allows the remaining groups to rotate either direction.

Page 11: Assigning R and S Configuration

• Steps to assign R and S from Fischer projections:

  1. Assign priority based on Cahn-Ingold-Prelog rules.

  2. Manipulate the projection for placing the lowest priority group correctly.

  3. Determine clockwise (R) or counterclockwise (S) for configuration.

Page 12: Multiple Chiral Centres

• Example scenarios:

  • 1 chiral center = 2 stereoisomers (R/S).

  • 2 chiral centers = 4 stereoisomers (RR, SS, RS, SR).

  • General rule: n chiral centers = 2^n stereoisomers.

  • Fischer projections effectively illustrate more than two chiral centers.

Page 13: Compounds with More Than One Chiral Centre

• Compounds exhibiting multiple chiral centers can possess diverse stereoisomers.

Page 14: Continued Discussion on Multiple Chiral Centres

• Visual representations showing configurations and their implications.

Page 15-16: Non-Superimposable Mirror Images (Enantiomers)

• Enantiomers: Non-superimposable mirror images demonstrate different arrangements leading to distinct compounds.

Page 17: Comparing Stereoisomers

• Key characteristics of stereoisomers shown through illustrated comparisons.

  • Difference in configuration of chiral centers introduces diastereomers.

Page 18: Diastereomers

• Definition: Stereoisomers that are not mirror images.

  • Criteria:

    • Same configuration at one center, different at another.

    • Distinct physical and chemical properties, such as melting and boiling points.

    • Non-identical effects on polarized light.

Page 19: Further Comparison of Diastereomers

• Illustrations demonstrate the unique features of diastereomers.

Page 20: More Than One Chiral Centre Example

• Tartaric Acid:

  • Illustrates exceptions with chiral centers leading to non-optically active structures due to symmetry.

Page 21: Specific Tartaric Acid Configuration

• Representation of tartaric acid's configurations and their implications on chirality.

Page 22: Meso Compounds

• Identical configurations leading to achiral properties.

  • Importance of a plane of symmetry in identifying meso compounds.

Page 23: Tartaric Acid Summary

• Summary of relationships between isomers

  • Enantiomers, diastereomers, and the unique characteristics of meso compounds.

Page 24: Example: 2,3-Dichlorobutane

• Discusses the stereoisomers and chirality involved in 2,3-Dichlorobutane.

Page 25: Applications of Chirality

• Biological Relevance:

  • Molecules with different shapes interact uniquely with receptors, leading to varied biological effects.

  • Example: Limonene variants demonstrate different scents based on chirality.

Page 26: Drug Design & Chirality

• Chiral drugs often present only one therapeutically active enantiomer;

  • Other forms could be inactive or introduce side effects.

Page 27-28: Case Studies: Adrenaline and Thalidomide

• Thalidomide Case Study:

  • History and implications of chiral drug use in healthcare, emphasizing the importance of chirality in pharmacology.

Page 29: Summary of Terms

• Overview of key terms and definitions regarding chirality and isomerism.

Page 30: Chirality Effects on Optical Activity

• Detailed explanation of how chirality influences optical properties and activities.

Page 31: Non-Superimposable Stereoisomers

• Clarification of terms and procedures regarding diastereomers and meso structures.

Page 32: Summary of Isomerism

• General outline of isomer types and characteristics, including structural and configurational isomers.

Page 33: Conclusion

• For further information, contact Dr. Marco Monopoli via email.