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:
Identify priorities for substituents as per Cahn-Ingold-Prelog rules.
Orient the molecule with the lowest priority at the back.
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:
Assign priority based on Cahn-Ingold-Prelog rules.
Manipulate the projection for placing the lowest priority group correctly.
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.