stereoselective synthesis presentation .

PHM-312
PHARMACEUTICAL CHEMISTRY
STEREOSELECTIVE SYNTHESIS
PRESENTED BY GROUP 4
MARYAM IRSHAD
MUHAMMAD AHMAD
MARYAM MUNIR
TO
Dr. MUHAMMAD TARIQ KHAN

CONTENTS
OVERVIEW
CATEGORIES
TECHNIQUES
PROCEDURES AND GEARS
DRUGS MANUFACTURED
DEDUCTIONS

STEREOISOMERS
 Stereoisomers are molecules that have the same molecular formula and sequence of bonded
atoms, but differ in the three-dimensional orientations of their atoms in space.
 There are two main types of stereoisomers:
 Enantiomers:
 These are stereoisomers that are mirror images of each other and are non-
superimposable. This means that they cannot be rotated or flipped to become identical.
Enantiomers are often referred to as "optical isomers" because they can rotate the plane of
polarized light in opposite directions.
 Diastereomers:
 These are stereoisomers that are not mirror images of each other. They can have
different physical and chemical properties, such as boiling point, melting point, and reactivity.

STEREOSELECTIVE SYNTHESIS
OVERVIEW
The mechanism of shaping one particular stereoisomer over others in a chemical
reaction is known as Stereoselective synthesis.
The primary objective is to manipulate the three-dimensional configuration of atoms
in molecules.
Favoring the formation of a particular stereoisomer with unique characteristics is the
goal.
In order to create compounds with accurate structures, this synthesis is essential.
It is extensively utilized in domains such as drug design.
To guarantee selective isomer formation, several tactics are used.

CATEGORIES
DIASTEREOSELECTIVE SYNTHESIS ENANTIOSELECTIVE SYNTHESIS
 Yields a higher quantity of
one diastereomers than
others.
 Emphasizes particularly
producing one enantiomer,
compounds with a particular
chirality are obtained using it.
 Focuses on isomers that
are not mirror images.
 Crucial for the production
of chiral molecules, such as
in Michael addition
reactions or Diels-Alder
reactions.
 Focuses on isomers of
mirror images.
 Asymmetric reactions such
as enzymatic catalysis and
sharpless oxidation are
instances.
DIASTEREOSELECTIVE SYNTHESIS ENANTIOSELECTIVE SYNTHESIS

Techniques of Stereoselective Synthesis
Chiral Pool Strategy
Highly selective reactions are produced
when catalysts with an identified chirality
orient the emergence of a particular
stereoisomer.
Simplifies the production of
complex chiral compounds by
using naturally existing chiral
molecules as base substances.
Chiral Catalysts

Kinetic Resolution
Produces an improved mixture of the
target enantiomer by selectively
reacting with one enantiomer more
quickly than the other.
Asymmetric Hydrogenation
Stereoselectivity incorporates hydrogen to a
molecule, which is essential for the synthesis of
numerous medications.
Chiral Auxiliaries
Short-term chiral groups that
are affixed to a molecule
and that guide the
development of a particular
stereoisomer.

Procedures and Gears
Chromatography NMR Spectroscopy
X-ray Crystallography
Enantiomers are separated
via chromatography,
guaranteeing the ultimate
product's quality and the
appropriate stereochemistry.
Confirms the intended
configuration by offering
comprehensive details
regarding molecular structure,
which involves
stereochemistry.
Provides comprehensive
structural details by precisely
determining the
stereochemistry and three-
dimensional configuration of
molecules.
Computational Modeling
Helps create effective
Stereoselective reactions by
simulating reaction processes
and forecasting the
stereochemical result.

DRUGSMANUFACTURED
BYSTEREOSELECTIVESYNTHESIS

CLOPIDOGREL
 What is it?
 An antiplatelet drug that prevents blood clots and reduces the risk of heart attacks or
strokes.
 How it works?
 It blocks a receptor on platelets P2Y12, stopping them from sticking together and forming
clots.
 Prodrug:
 Clopidogrel is inactive initially and is converted to its active (S)-form in the body.
 Chiral Center:
 The active form is the (S)-enantiomer, which is responsible for its antiplatelet effect. The (R)-
enantiomer is inactive.
USES:
It is used in the prevention of Heart attacks , strokes and Peripheral Artery Diseases[PAD] ,
etc.

CLOPIDOGREL
SYNTHESIS BY ASSYMMETRIC CATALYSIS
1. Starting Material:
Methyl α-(2-chlorophenyl)acetate (prochiral compound).It doesn’t have chirality initially but can be made
chiral.
2. Catalyst:
A chiral catalyst like Rhodium (Rh) or Ruthenium (Ru) with a BINAP ligand. This catalyst helps control the
stereochemistry of the reaction.
3. Reaction:
The prochiral compound undergoes hydrogenation in the presence of H under the chiral catalyst. The catalyst
₂
selectively adds hydrogen to one face of the molecule, forming the (S)-enantiomer, which is the active form of
clopidogrel.
4. Outcome:
The reaction results in the (S)-Clopidogrel (active form), which is used to prevent blood clots.
Methyl α-(2-chlorophenyl)acetate + H2 Chiral Rh or Ru S-Clopidogrel

ESOMEPRAZOLE
 What is it?
 Esomeprazole is a proton pump inhibitor (PPI) used for treating acid reflux and
stomach ulcers by reducing stomach acid.
 How it works?
 It blocks the proton pump (H+/K+ ATPase), reducing acid production in the
stomach.
 Chirality:
 Esomeprazole is the (S)-enantiomer of Omeprazole and is more effective at
inhibiting stomach acid production.
 Uses:
 Used to treat GERD, Stomach ulcers, and H.Pylori infections, etc.

ESOMEPRAZOLE
 1. Starting Material:
 The process begins with (S)-pantothenic acid, a naturally chiral compound.
 2. Cyclization:
 (S)-pantothenic acid undergoes cyclization to form a pyridine ring, a crucial part of the
Esomeprazole structure.
 3. Sulfoxidation:
 The intermediate undergoes sulfoxidation, where an oxidizing agent (e.g., m-
chloroperbenzoic acid) adds a sulfoxide group to the structure.
 4. Functional Group Addition:
 Additional groups like methyl are introduced in the final steps to complete the structure.
 5. Final Product:
 The result is (S)-Esomeprazole, the active enantiomer used to treat conditions like GERD.
SYNTHESIS BY CHIRAL POOL PRODUCTION

LEVO DOPA
 1. What is it?
 L-Dopa (Levodopa) is a precursor to the neurotransmitter dopamine, which is vital for
movement and coordination.
 2. How it works:
 Once L-Dopa crosses the blood-brain barrier, it is converted into dopamine in the brain,
helping to restore the dopamine levels that are low in people with Parkinson's disease.
 3. Chirality:
 L-Dopa is chiral, with an L-configuration at the alpha-carbon. This specific chirality is
important for its biological effectiveness in the brain.
 4. Uses:
 It is primarily used to treat Parkinson’s disease, improving motor function, and reducing
symptoms like tremors, stiffness, and slowness in movement.

LEVO DOPA
 The process starts with an achiral precursor like phenylalanine or a similar aromatic amino
acid.
 2. Chiral Auxiliary Addition:
 A chiral auxiliary, like (S)-Mandelic acid, is added to the precursor. The auxiliary helps
introduce a specific chirality to the reaction, ensuring the desired stereochemistry is
achieved.
 3. Reaction:
 The chiral auxiliary creates a chiral environment for the reaction, directing the formation of
the (S)-enantiomer of L-Dopa in a stereoselective manner.
 4. Removal of Chiral Auxiliary:
 Once the reaction is complete, the chiral auxiliary is removed using a mild chemical
procedure, leaving behind L-Dopa.
SYNTHESIS BY CHIRAL AUXILIARIES

ATROVASTATIN
 1. What is it?
 Atorvastatin is a statin drug used to lower cholesterol and reduce the risk of heart disease,
stroke, and other cardiovascular issues.
 It works by inhibiting HMG-CoA reductase, an enzyme involved in the production of
cholesterol in the liver, leading to a decrease in blood cholesterol levels, especially LDL
(bad cholesterol).
 3. Chirality:
 Atorvastatin has chiral centers in its structure, and its effectiveness depends on the
specific stereochemistry of the molecule.
 4. Uses:
 It is primarily used to treat high cholesterol, high triglycerides, and to prevent
cardiovascular diseases. It helps lower LDL cholesterol and raises HDL cholesterol (the
"good" cholesterol).

ATROVASTATIN
 Starting Material:
 Use a prochiral β-keto ester as the precursor, which can develop chirality during
hydrogenation.
 2. Asymmetric Hydrogenation:
 Perform hydrogenation with a chiral catalyst, such as Rhodium-BINAP. This ensures
selective hydrogen addition to one side of the prochiral molecule, forming a chiral
alcohol with the desired stereochemistry.
 3. Intermediate Formation:
 The chiral alcohol is converted into a lactone ring, a vital part of the Atorvastatin
structure, through a cyclization reaction.
 4. Functional Group Introduction:
 Introduce additional groups like the fluorophenyl group, carboxylic acid, and hydroxyl
groups to finalize the structure of Atorvastatin.
 The resulting compound is Atorvastatin, with the correct stereochemistry required for its
cholesterol-lowering activity.
SYNTHESIS BY ASSYMMETRIC HYDROGENATION

PREGABALIN
 1. What is it?
 An anticonvulsant and neuropathic pain reliever, derived from GABA, but it does not act
on GABA receptors.
 Binds to the α2δ subunit of calcium channels, reducing neurotransmitter release, nerve
signals, and pain perception.
 3. Chirality:
 Has a chiral center; the (S)-enantiomer is biologically active and responsible for its
therapeutic effects.
 4. Uses:
 Treats neuropathic pain, partial seizures, and sometimes generalized anxiety disorder
(GAD), depending on the region.

PREGABALIN
 Choose a compound with a double bond or imine group (like a special amino acid).
 2. Chiral Catalyst:
 Add a chiral catalyst (like rhodium or ruthenium) to control the reaction and make only
the desired (S)-pregabalin.
 3. Hydrogenation:
 Add hydrogen (H ) under mild conditions to change the double bond into a single bond,
₂
forming (S)-pregabalin.
 4. Purification:
 Clean the product using methods like crystallization or chromatography.
 Get the pure (S)-pregabalin, which is ready for use.
SYNTHESIS BY ASSYMMETRIC HYDROGENATION

Deductions
Modern chemistry depends on Stereoselective
manufacturing, which regulates stereochemistry
to create safer, more potent medications. Its
effectiveness and sustainability will be further
improved by the creation of innovative
catalysts, AI-driven layouts, and environmentally
friendly techniques, making it a promising area
for future advancement in the pharmaceutical
industry as well as thereafter.

REFERENCE
 FRANCIS A. CAREY ; ROBERT M. GIULIANO’s organic chemistry.
 VASYL ANDRUSHKO,NATALIA ANDRUKSHO-Stereoselective synthesis.

stereoselective synthesis presentation .

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