This PPT consists of types of asymmetric synthesis with examples. It consists of absolute asymmetric synthesis and partial asymmetric synthesis. The partial absolute synthesis consists of chiral pool, chiral catalyst, chiral reagent.

1. METHODS OF ASYMMETRIC
SYNTHESIS
PRESENTED BY
A.S Madhu Prasanth
M. Pharmacy, 1st Year
Pharmaceutical Chemistry
JSS College Of Pharmacy,

2. CONTENTS
• Introduction
• Stereoselectivity and Stereospecificity
• Mechanism of asymmetric synthesis
• Generations
• Approaches
• Advantages and disadvantages

3. INTRODUCTION
• Asymmetric synthesis is a reaction in which an achiral unit in a substrate molecule is converted
into a chiral unit in such a manner that unequal amounts of stereoisomers (enantiomers or
diastereomers) are produced.
• When a compound containing an asymmetric carbon (CHIRAL) is synthesized by conventional
laboratory methods from an achiral compound the product is a racemic mixture.
• If such a synthesis carried out under chiral influence, only one of optically active isomer will
form preferentially over the other.

4. • Asymmetric synthesis refers to the selective synthesis of one of the isomer of the chiral product.
• The enantiomers can be separated by the methods includes
-Chiral chromatography
-Enzymes
-Asymmetric synthesis.
• The asymmetric synthesis is also called as enantioselective synthesis.
A
B + BI
B

5. STEREOSPECIFIC REACTIONS STEREOSELECTIVE REACTIONS
A stereospecific reaction is a rection in
which the stereochemistry of the reactant
completely determines the stereochemistry
of the product without any other option.
A stereoselective reaction is a rection in
which there is a choice of pathway, but the
product stereoisomer is formed due to its
reaction pathway being more favorable than
the others available.
Gives a specific product from a certain
reactant.
Can result in multiple products.
Final product depends on the
stereochemistry of the reactant
Selectivity of the reaction pathway depends
on differences in steric effects an electronic
effects
SN2 reaction is an example for the
stereospecific reaction.
Dehydrohalogenation of 2-iodo butane
which yields 60% trans and 20% cis

6. MECHANISM
• The aim is to make enantiomers into diastereomers . To make this possible ,we need to incorporate
reagents or catalysts having chirality.
• The reaction will now proceed differently for different enantiomers because of the difference in
energy of transition state.
• In the absence of chiral influence, reaction producing enantiomers in equal amounts via transition
states of identical energies (enantiomeric transition state) . These reactions therefore takes place at
identical rates to give equal amounts of enantiomers
• If we are using chiral components , then we could make the possible enantiomeric transition state,
diastereomeric transition state with different activation energy which results in unequal amounts of
isomers

8. GENERATIONS
• There are total four generations of asymmetric synthesis, those are
1st Generation – Substrate controlled asymmetric synthesis
Diastereoselective reactions where the formation of chiral centre is controlled by another chiral
centre already present in the substrate.
2nd Generation – Auxiliary controlled asymmetric synthesis
In this method a chiral auxiliary is covalently attached to the substrate and, through that controls the
asymmetric synthesis
3rd Generation – Reagent controlled asymmetric synthesis
The formation of a new chiral centre is induced by a chiral reagent, intramolecularly.
4th Generation – Catalyst controlled asymmetric synthesis
One general procedure involves a reaction of a chiral substrate with a chiral reagent, and is
especially useful in reactions where two new stereogenic units are formed stereo selectively in one

9. 1st Generation
Substrate* Product*
2nd Generation
Substrate + Auxiliary S-A P-A* Product*
3rd Generation
Substrate Product*
4th Generation
Substrate* Product*
Reagen
t
Reagen
t
Reagent
*
Catalyst
*
Auxiliary*

10. APPROACHES
Asymmetric synthesis are of 2 types
1.Partial asymmetric synthesis
2.Absolute asymmetric synthesis
Partial Asymmetric Synthesis-
Synthesis of new chiral center from an achiral center by using optically active reagents.
1.Use of chiral substrate-
• It uses natures ready-made chiral centers as starting materials
• It is more economical way of making compounds in enantiopure form.
• Eg. – Conversion L-tyrosine into L-DOPA.
• In this conversion starting material L-tyrosine is a naturally occurring chiral molecule.
• This conversion doesn’t affect the existing stereocenter.

11. • This method is also known as “ CHIRAL POOL” strategy.
• Pure natural products, usually amino acids or sugars, from which pieces containing the required
chiral centres can be taken and incorporated into product.
• It is an internal asymmetric induction – refers to the control of stereoselectivity exerted by an
existing chiral centre on the formation of new chiral centre.
• Chiral pool is the collection of cheap , readily available natural products .
• Eg:(+)nicotine, (+)tartaric acid, D-glyceraldehyde etc .

12. II Use of chiral auxiliary
• In this approach a prochiral substrate attach with a chiral auxiliary to give a chiral intermediate.
• During which auxiliary directs the preferred stereochemistry.
• Finally we can remove the auxiliary from product to use it again.
• It is an relayed asymmetric induction – refers to the control of stereoselectivity exerted by
chiral auxiliary on the formation of new chiral center
Eg- Asymmetric alkylation of cyclohexanone using SAMP

13. III Use of chiral reagents
• In this method an inactive substrate converted selectively into one of the enantiomer
(enantiospecific).
• In this type of synthesis chiral reagent turns achiral by transforming an achiral substrate to chiral.
• Thus the reagent is “self- immolative”

14. IV Use of chiral catalyst
• In this the chiral catalyst directs the formation of a chiral compound such that formation of one
stereoisomer is favored.
• Effective optically pure catalysts are much more promising , because reagents are required in
stoichiometric amounts ,while catalysts are required only in very small amounts.
• Eg: Catalytic asymmetric reduction of ketones
Catalytic asymmetric hydrogenation of alkenes
Asymmetric epoxidation.
Ru-catalysed asymmetric hydrogenation of unsaturated carboxylic acids

15. Ru-catalysed asymmetric hydrogenation of allylic alcohols
The industrial application for the catalytic asymmetric synthesis is the production of the
painkiller
(S)-naproxen

16. METHODS ADVANTAGES DISADVANTAGES
Chiral Pool 100% ee is guaranteed Often only 1 enantiomer available
Chiral Auxiliary
Often excellent ee & can
recrystallize to purify to high ee
Extra steps to introduce and
remove auxiliary
Chiral Reagent
Often excellent ee & can
recrystallize to purify to high ee
Only few reagents are successful
and often for few substrates
Chiral Catalyst
Economical, only small amounts
are recyclable material used
Only few reactions are really
successful

17. Absolute Asymmetric Synthesis
• It is the synthesis of optically active products from achiral substrate without the use of optically
active reagents.
• In this type of synthesis a physical presence of chirality is necessary.
• Eg: Addition of bromine to 2,4,6-trinitrostilbene give a dextrorotatory product.
• Here we are using circularly polarized light for the induction of chirality.
• The role of circularly polarized light is reminiscent of an optically active compound in
conventional resolution.

18. REFERENCES
1. Stereochemistry CONFORMATION AND MECHANISM – P S Kalsi
2. BASIC ORGANIC CHEMISTRY : Ernest L Eliel
3. Clayden, Jonathan, Nick Greeves and Stuart Warren. Organic Chemistry, 2nd Edition. Oxford.
2012.

19. Thank you
Any Questions?