Asymmetric synthesis

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© Dr. Atul R. Bendale

Asymmetric synthesis, also known as Enantioselective synthesis.
It is defined by IUPAC as: a chemical reaction (or reaction sequence) in
which one or more new elements of chirality are formed in a substrate
molecule and which produces the stereoisomeric (enantiomeric or
diastereoisomeric) products in unequal amounts.
More simply: The synthesis of an asymmetric compound carried with the
help of an optically active molecule or group is termed asymmetric
synthesis.
[Enantiomers are stereoisomers that have opposite configurations at every
chiral center.
Diastereomers are stereoisomers that differ at one or more chiral centers.]

In such synthesis the two d and l forms are not produced in equal quantities.
For example, pyruvic acid on reduction yields a dl mixture of lactic acid
But if it is esterified with some optically active alcohol (ROH*) and then
reduced, the resulting ester on hydrolysis yields an optically active lactic
acid.

The asymmetric synthesis explains why most asymmetric compounds
obtained from natural sources are optically active.
In nature, the syntheses are carried out under the influence of optically
active enzymes.
The enzymes unite with the substance and when the synthesis is complete,
they separate from the product and are again free to combine with fresh
molecules of the original substance.
Thus there exists a radical difference between the reactions that go on in
the animal and vegetable world on the one hand and those in the
laboratory on the other.
Enantioselective synthesis is a key process in modern chemistry and is
particularly important in the field of pharmaceuticals, as the different
enantiomers or diastereomers of a molecule often have different biological
activity.

Many of the building blocks of biological systems such as sugars and amino
acids are produced exclusively as one enantiomer.
As a result, living systems possess a high degree of chemical chirality and
will often react differently with the various enantiomers of a given
compound.
Examples of this selectivity include:
Flavour: the artificial sweetener aspartame has two enantiomers. L-
aspartame tastes sweet whereas D-aspartame is tasteless.
Odor: R-(–)-carvone smells like spearmint whereas S-(+)-carvone smells like
caraway.
Drug effectiveness: the antidepressant drug Citalopram, only the (S)-(+)
enantiomer is responsible for the drug's beneficial effects
Drug safety: D-penicillamine is used in chelation therapy and for the
treatment of rheumatoid arthritis whereas L-penicillamine is toxic.
As such enantioselective synthesis is of great importance but it can also be
difficult to achieve.
OVERVIEW Of ASYMMETRIC SYNTHESIS

Why we always need a chiral component to achieve asymmetric
synthesis?
The answer is if both reactant and reagent are achiral resulting transition
state is enantiomeric and results in racemic products.

TYPES Of ASYMMETRIC SYNTHESIS
1. Partial asymmetric synthesis
2. Absolute asymmetric synthesis

1. Partial asymmetric synthesis
Defined as a method for preparing optically active compound from
optically inactive substance by the use of optically active reagent but
without the requirement of resolution (without separation).
Principle
1. For preferential formation of one stereoisomer over the other, the
reagent must be in pure enantiomeric form.
2. The chiral reagent must play active role in the reaction (transition state)
3. Chiral reagent react with enantiomer at different rates.
So chiral reagent involved in asymmetric synthesis should lead to rapid
completion to produce pure stereo isomeric product (pure enantiomer).

For Example
Direct reduction of pyruvic acid yield racemic mixture of lactic acid
Here, in this reaction neither pyruvic acid nor hydrogen are chiral but the
product lactic acid is chiral. However it is produced in racemic form i.e.
equimolar mixture of (+) and (–) enantiomer. It becomes stereo-selective
reaction.
So, how one can prepare pure enantiomer that we will see ahead…

Modification in Reaction
• If pyruvic acid is pre-esterified with optically active alcohol (-) menthol
and thereafter reduced and subsequently hydrolysed, the resultant
product formed exclusively pure enantiomer (-) lactic acid
(enantioselective reaction)
• If reaction leads to formation of enantiomer produces majority of one
enantiomer over its mirror image (other enantiomer) the reaction is
said to be Enantioselective.
• In this chiral reagent must assert an influence on the course of reaction.
• In this reaction preferred enantiomer is formed along with small
amount of un-preferred enantiomer and hence it is called as partial
asymmetric synthesis.

For example (-) menthol utilized for asymmetric synthesis of (+) tartaric
acid, (+) maleic acid, (-) nicotine etc.

2. Absolute asymmetric synthesis
Preparation of optically active compound from optically inactive substance
without the use of chiral reagent but just irradiating it by right or left
circularly polarised light is called absolute (total) asymmetric synthesis.
Here one of the enantiomer is selectively or preferentially decomposed by
the light irradiated.

For Example
A racemic mixture of (±) azidopropionic acid dimethyl amide when
irradiated separately by right and left circularly polarized light yielded the
corresponding un-decomposed products with corresponding (+) and (-)
rotation.

Asymmetric induction Approaches
1. Enantioselective catalysis
They are chiral coordination complexes.
Catalysis is effective for a broader range of transformations than any other
method of enantioselective synthesis.
The catalysts are almost invariably rendered chiral by using chiral ligands.
Most enantioselective catalysts are effective at low substrate/catalyst
ratios.
Given their high efficiencies, they are often suitable for industrial scale
synthesis.
A versatile example of enantioselective synthesis is asymmetric
hydrogenation, which is used to reduce a wide variety of functional groups

2. Chiral auxiliaries
A chiral auxiliary is an organic compound which couples to the starting
material to form a new compound which can then undergo
enantioselective reactions via intramolecular asymmetric induction.
At the end of the reaction the auxiliary is removed, under conditions that
will not cause racemization of the product. It is typically then recovered for
future use.

Advantages of Using Chiral Auxiliaries
(a) high levels of diastereofacial control in the reactions
(b) The diastereomers generated from the use of chiral auxiliaries
can be separated by the use of simple methods (such as chromatography
and crystallization).
(c) Chiral auxiliaries can be recycled (re-used)
Disadvantages of Using Chiral Auxiliaries
(a) Both enantiomers of a chiral auxiliary are usually not readily available.
More often, one enantiomer may be far more expensive than the other.
(b) Chiral auxiliaries need to be synthesized.
(c) As with protecting groups, there are extra steps associated with the use
of chiral auxiliaries. The chiral auxiliary has to be introduced and then
removed once it purpose has been accomplished.

Qualities of a Good Chiral Auxiliary
(a) Needs to be available in both enantiomeric forms
(b) Needs to be easy and quick to synthesize
(c) Must be readily incorporated onto an achiral substrate
(d) It should provide good levels of asymmetric induction leading to
high enantiomeric excess .
(e) Needs to be selectively cleaved from the substrate under mild
conditions
(f) Must be recoverable and re-useable

3. Biocatalysis
Biocatalysis makes use of biological compounds, ranging from isolated
enzymes to living cells, to perform chemical transformations.
The advantages of these reagents include very high reagent specificity, as
well as mild operating conditions and low environmental impact.
Biocatalysts are more commonly used in industry for example in the
production of statins.

4. Chiral pool synthesis
Chiral pool synthesis is one of the simplest and oldest approaches for
enantioselective synthesis.
A readily available chiral starting material is manipulated through
successive reactions, often using achiral reagents, to obtain the desired
target molecule. This can meet the criteria for enantioselective synthesis
when a new chiral species is created, such as in an SN2 reaction.
Chiral pool synthesis is especially attractive for target molecules having
similar chirality to a relatively inexpensive naturally occurring building-
block such as a sugar or amino acid.
However, the number of possible reactions the molecule can undergo is
restricted and indirect synthetic routes may be required (e.g. Oseltamivir
total synthesis).

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