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ASYMMETRIC SYNTHESIS

ALI HAMZA
8TH SEMESTER ORGANIC CHEMISTRY
PAPER CODE: CHEM-459
Asymmetric synthesis 2
 Asymmetric synthesis is a reaction in which an achiral unit in a substrate a
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.
EXAMPLE :reduction of pyruvic acid.
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Chiral environment is the necessary condition for asymmetric synthesis.

DEPENDING ON THE RELATIONSHIP BETWEEN PRODUCTS FORMED DURING
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ASYMMETRIC SYNTHESIS ,REACTION MAY BE ENANTIOSELECTIVE OR
DIASTEREOSELECTIVE .

A+B C + D
STEREOISOMERS

C and D formed in unequal amounts

STEREOSELECTIVE

C and D are

diastereomers C and D are enantiomers

DIASTEREOSELECTIVE ENANTIOSELECTIVE
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FUNDAMENTALS
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One of the two conditions need to be met for successful asymmetric synthesis.

A) PROCHIRALITY

A tetrahedrally bonded achiral atom have general formula

Cabc2 will become a chiral center Cabcd on
replacement of one of the identical ligand c with a
different ligand d is called a prochiral centre and the
molecule is said to be prochiral.
DEPENDING ON THE PRODUCT FORMED FROM A PROCHIRAL CENTRE, THE MOLECULE WILL BE
ENANTIOTOPIC OR DIASTEREOTOPIC . 7
Eg:Enantiotopic

Eg:Diastereotopic
B) ASYMMETRIC INDUCTION 8

The second condition of asymmetric synthesis is brought about in the reaction

pathway by the presence of an element of chirality, which plays an active role
in the reaction.
Property of chirality is induced by chiral reagent,solvent,catalyst or circularly
polarized light
WHY ASYMMETRIC SYNTHESIS IMPORTANT
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 Before 1940 optically pure compound is obtained by isolation from natural
products, resolution of racemic mixture and by laboratory controlled
enzymatic reactions, but the yield of optically pure compound was very less.
 All natural or biologically occurring molecules are chiral . Because nature
uses enzymes ,these are biological catalysts.
 Synthesis of optically pure substance are important because different
enantiomers or diasteroemers of a compound have different biological
activity. Eg:+ and – thalidomide have different action with biological
receptors.
MECHANISM OF ASYMMETRIC SYNTHESIS
 10 to
The aim is to make enantiomers into diastereomers . To make this possible ,we need
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
enantomeric transition state , diastereomeric transition state with different
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activation energy which results in unequal amounts of isomers.
 We have to go through a diastereomeric transition state to achieve
asymmetric synthesis.
MAJOR APPROACHES IN ASYMMETRIC SYNTHESIS
 Asymmetric synthesis are of two types
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A) PARTIAL ASYMMETRIC SYNTHESIS
synthesis of a new chiral center from an achiral center by using optically
active reagents .
 Different methods of partial asymmetric synthesis are:
1) Use of chiral substrate (first generation method)
 It uses natures ready-made chiral centers as starting materials .
 More economical way of making compounds in enantiopure form.
Eg: Conversion of L-tyrosine into L-DOPA
 In this conversion starting material L-tyrosine is a naturally occurring13
chiral
molecule .
 This conversion doesn’t affect the existing stereocenter .
 This method is also known as “ CHIRAL POOL” STRATEGY.
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 Chiral pool is the collection of cheap , readily available natural products .
Eg:(+)nicotine, (+)tartaric acid, D-glyceraldehyde etc .
 Nucleophilic attack on acyclic carbonyl compounds :
 For certain additions to c=o groups of chiral aldehyde or ketones CRAM’S
RULE is useful to predict which diastereomer will predominate .
 2) Use of chiral auxiliary (second generation method)
 15give a
In this approach a prochiral substrate attach with a chiral auxiliary to
chiral intermediate.
 During which auxiliary dictates the preferred stereochemistry.
 Finally we can remove the auxiliary from product to use it again .
 Eg: asymmetric alkylation of cyclohexanone using SAMP .
Eg: Asymmetric halolactonization – Synthesis of α-hydroxyl acid
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3)Use of chiral reagents (third generation methods)
 In this method an inactive substrate converted selectively17
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”
eg:
Eg: Reduction of a prochiral carbonyl group enantioselectively by
a chiral reducing agent 18
4)Use of chiral catalyst
 Effective optically pure catalysts are much more promising , because
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reagents are required in stoichiometric amounts ,while catalysts are
required only in very small amounts.
 Eg: Sharpless asymmetric epoxidation- It is an enantioselective reaction that
oxidises alkenes to epoxides.
The mechanism of Sharpless asymmetric epoxidation involves
following steps . 20
B) ABSOLUTE ASYMMETRIC SYNTHESIS 21
 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.
Eg: Light induced cyclisation of 1,2 –diarylethylenes to
dihydrophenanthrene derivatives 22

 The role of circularly polarized light is reminiscent of an optically active compound in

conventional resolution.
 It combines with individual enantiomers of diarylethylene , forming a pair of excited
states which are diastereomerically related and thus formed and decomposed at
different rates .
Advantages and disadvantages of different methods
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METHODS ADVANTAGES DISADVANTAGES

RESOLUTION Both enantiomers are Maximum 50% yield

available

CHIRAL POOL 100 % ee is guaranteed Often only 1 enantiomer

available
Often excellent ee & can Extra steps to introduce and
CHIRAL AUXILIARY recrystallize to purify to high ee remove auxiliary

Often excellent ee & can Only few reagents are successful

CHIRAL REAGENT recrystallize to purify to high ee and often for few substrates

Economical, only small amounts Only few reactions are really

CHIRAL CATALYST of recyclable material used successful.
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 REFERENCES
1. STEREOCHEMISTRY :CONFORMATION AND MECHANISM – P S
Kalsi
2. BASIC ORGANIC CHEMISTRY : Ernest L Eliel