Subject Chemistry

Paper No and Title 1; Organic Chemistry-I (Nature of Bonding and

Stereochemistry)
Module No and 27; Asymmetric Synthesis
Title
Module Tag CHE_P1_M27

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 TABLE OF CONTENTS

1. Learning Outcomes

2. Introduction

3. Asymmetric Synthesis
3.1 Asymmetric Synthesis: Borrowing From Nature’s Chiral Pool
3.2 The Chiral Auxiliary strategy
3.3 Chiral reagents and chiral catalysts

4. Summary

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 1. Learning Outcomes

After studying this module, you shall be able to

 Know what is the meaning of asymmetric synthesis

 Understand various aspects and definitions of asymmetric synthesis
 Learn about nature’s chiral pool and its importance in asymmetric synthesis
 Analyse various examples based on nature’s chiral pool serving as precursors for
asymmetric synthesis
 Study other examples and case studies relating to asymmetric synthesis

2. Introduction

Absolute asymmetric synthesis or asymmetric induction is the synthesis of optically active

products from achiral or racemic precursors without employing optically active catalysts or
auxiliaries. The synthesis of a racemic (50:50 mixture of both enantiomers) version was
historically accepted as a successful outcome but that is no longer the case. Synthetic organic
chemists remain interested not only in mimicking nature but also in synthesising totally novel
chiral structures.
If organic chemists wish to synthesise the molecules produced by nature, then they must be
able to prepare the same enantiomer which occurs naturally. For example, for a perfumer or
flavour and fragrance manufacturer, the distinction between enantiomers of the same
molecule is clearly of great importance. In this module, we shall learn about different aspects
and some very fascinating aspects about asymmetric synthesis, which will help in kindling a
new enthusiasm about this topic.

3. Asymmetric Synthesis

In actual words asymmetric synthesis means:

"A reaction that uses optically inactive reactants and catalysts cannot produce a product
that is optically active. Any chiral product must be formed as a racemic mixture because

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 the transition states leading to the two enantiomers are themselves enantiomeric and
therefore equal in energy." Or

"Reaction between two optically inactive (achiral) partners always leads to an optically
inactive product– either racemic or meso.”

“Also optical activity does not occur from optically inactive products; optically active
products can't be produced from optically inactive reactants."

Fig. 1: Asymmetric synthesis

Asymmetric synthesis or asymmetric induction is only tenuously different from kinetic
resolution. The difference is that the asymmetric atom instead of being in the molecule to
begin with, is introduced in the course of the reaction.
A fine example is the synthesis of glucononitrile and mannononitrile from (+)-arabinose.
Since the two products are diastereoisomeric, thus the transition states leading to them would
also be expected to be diastereoisomeric. This makes them different in their respective free
energies. Since the starting state [(+)-arabinose] is the same for the two reactions, the
activation energies are expected to differ, and the rate at which the two products are formed
will also be different. In fact, before the actual findings, it was believed that the mannonic
acid nitrile predominated to such an extent that it was believed to be the product of this
reaction.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 3.1 Asymmetric Synthesis: Borrowing From Nature’s Chiral Pool
Most asymmetric syntheses generally require more than one or two steps from chiral pool
constituents. If there happens to be an existing chiral centre, the two possible TS’s are
diastereomeric and can be of different energy. Thus one isomer of the new stereogenic centre
can be produced in a larger amount.

Fig. 2: Production of one stereoisomer in larger quantity

CASE STUDIES:
Case 1: Male bark beetles belonging to the genus Ips produces a pheromone that is a mixture
of several enantiomerically pure compounds. One of them being a simple diene alcohol (S)-(–
)-ipsenol. In the 1970s, Japanese chemists noted the similarity of part of the structure of
ipsenol (in black) to the widely available amino acid (S)-leucine and decided to exploit this in

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 a chiral pool synthesis, using the stereogenic centre (green ring) of leucine to provide the
stereogenic centre of ipsenol.

Fig. 3: Possible retrosynthesis of (S)-(-)-ipsenol

The amino group needs to be converted to a hydroxyl group with retention of configuration.
The process of diazotization followed by hydrolysis performs the same reactions because of
neighbouring group participation from the carboxylic acid.

Fig. 4: NGP by carboxylic acid group

THP derivative was prepared for the protection of the alcohol. Reduction of the acid, via the
ester, allows the introduction of the tosyl leaving group, which was displaced to make an
epoxide. The epoxide reacted with a Grignard reagent carrying the diene portion of the target
molecule.

Fig. 5: Preparative reactions of the target molecule

Case 2: Another insect pheromone synthesis illustrates one of the drawbacks of chiral pool
approaches. The ambrosia beetle aggregation pheromone is called sulcatol and is chemically
a simple secondary alcohol. This pheromone poses a rather unusual synthetic problem: the
beetles produces it as a 65:35 mixture of enantiomers so, in order to mimic the pheromone’s
effect. Thus, the challenge for the chemist remains to synthesize both enantiomers separately
and mix them together in the right proportion.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 Fig. 6: (R)-sulcatol and (S)-sulcatol

One approach to the (R)-enantiomer employs the sugar found in DNA, 2-deoxy-D-ribose, as
a source of chirality.

Fig. 7: 2-deoxy-D-ribose, as a source of chirality

Only one (ringed with green again) of the two defined chiral centres in the sugar appears in
the product so, after protecting the hemiacetal, the two free hydroxyl groups were removed
by mesylation, substitution by iodide, and reduction. A simple olefination gave (R)-sulcatol.
Sugars often need simplifying in this way, because only rarely are all their chiral centres
needed in the final product.

Fig. 8: Rarely are all chiral centres present in sugars needed in the final product
Since the L-sugar is unavailable (even D-deoxyribose is quite expensive), thus, (S)-Sulcatol
cannot be made by this route, So an alternative synthesis was needed that could be adapted to
give either isomer. The solution is to go back to another hydroxy-acid, ethyl lactate, which is
more widely available as its (S)-enantiomer, but which can be converted simply to either
enantiomer of a key epoxide intermediate. From (S)-ethyl lactate, protection of the alcohol,
reduction of the ester, and tosylation allows ring closure to one enantiomer of the epoxide;
tosylation of the secondary hydroxyl group followed by reduction and ring closure gives the
other enantiomer.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 Fig. 9: Two enantiomers are possible to be made from (S)-ethyl acetate
For this reason, the two enantiomers of propylene oxide are commonly used as ‘chiral pool’
starting materials. These epoxides react with the appropriate Grignard reagent to give either
enantiomer of the sulcatol.

Fig. 10: ‘chiral pool’ starting materials

For target molecules having more than one stereogenic centre, only one needs to be borrowed
from the chiral pool, provided diastereoselective reactions can be employed to introduce the
others with control over relative stereochemistry. Since the first chiral centre has defined
absolute configuration, any diastereoselective reaction that controls the relative
stereochemistry of a new chiral centre also defines its absolute configuration. In this synthesis
of the rare amino sugar methyl mycamino- side, only one chiral centre comes directly from
the chiral pool—the rest are introduced diastereoselectively.

Fig. 11: In this synthesis only one chiral centre comes directly from the chiral pool—the
rest are introduced diastereoselectively.

The ring was built up from acetylated (S)-lactic acid, and a cyclization step introduced the
second chiral centre—the methyl group goes pseudoequatorial while the pseudoaxial position
is preferred by the methoxy group because of the anomeric effect.
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and
Stereochemistry
Module No. 27: Asymmetric Synthesis
 Fig. 12: Note that the pseudoaxial position is preferred by the methoxy group because of
the anomeric effect.
The third stereogenic centre was controlled by axial reduction of the ketone to give the
equatorial alcohol, which then directed introduction of the fourth and fifth stereogenic centres
by epoxidation.

Fig. 13: Axial reduction of the ketone

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 Finally, the simple nucleophilic amine Me2NH attacks the epoxide with inversion of
configuration to give methyl mycaminoside. The conformational drawing shows that all
substituents are equatorial except the MeO group, which prefers to be axial because of the
anomeric effect.

Fig. 14: Observation of anomeric effect again

The disadvantage with chiral pool approaches is that the compound you make has to be quite
close in structure to one of the natural products that are readily available. Otherwise, if this is
not the case, the synthetic route becomes so strenuous that it’s even more wasteful than
resolution. The second major disadvantage is the lack of availability of both enantiomers of
most natural products, especially useful starting materials like amino acids and sugars—we
have just confronted this problem with the synthesis of sulcatol from deoxyribose. As a
further example, we can return again to our Japanese beetles. Their pheromone can be made
from glutamic acid by a short route. Unfortunately, when widely available (S)-(+)-glutamic
acid is used, the product is the enantiomer of the active pheromone, which you will
remember is a powerful inhibitor of the natural pheromone. Making the right enantiomer is
not economical for a chemist, because (R)-(–)-glutamic acid is about 40 times more
expensive than (S)-(+)-glutamic acid.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 Fig. 15: Uneconomical isomer synthesized

3.2 The Chiral Auxiliary Strategy

This strategy involves these steps:
 An enantiomerically pure compound (usually derived from a simple natural product
like an amino acid), called a chiral auxiliary, is attached to the starting material.
 A diastereoselective reaction is carried out, which, because of the enantiomeric purity
of the chiral auxiliary, gives only one enantiomer of the product.
 The chiral auxiliary is removed by, for example, hydrolysis, leaving the product of the
reaction as a single enantiomer. The best chiral auxiliaries (of which the example
above is one) can be recycled, so although stoichiometric quantities are needed, there
is no waste.
Racemic mixture is the product of a normal Diels Alder reaction, however, if we replace the
achiral benzyl ester group with an amide derived from the natural amino acid valine. The
diastereoselectivity remains the same but the chiral environment created by the single
enantiomer covalently bonded to the dienophile has a remarkable effect: only one enantiomer
of the product is formed.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 Fig. 16: Chiral auxiliary strategy

3.3 Chiral reagents and chiral catalysts

If we want to create a new chiral centre in a molecule, our starting material must have
prochirality—the ability to become chiral in one simple transformation. The most common
prochiral units that give rise to new chiral centres are the trigonal carbon atoms of alkenes
and carbonyl groups, which become tetrahedral by addition reactions. A prochiral alkene (we
CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and
Stereochemistry
Module No. 27: Asymmetric Synthesis
 can count enolates as alkenes for this purpose) reacted selectively on one face because of the
influence of the chiral auxiliary, which made the faces of the alkene diastereotopic.
One of the simplest transformations you could imagine of a prochiral unit into a chiral one is
the reduction of a ketone. Although chiral auxiliary strategies have been used to make this
type of reaction asymmetric, you will appreciate that, conceptually, the simplest way of
getting the product as a single enantiomer would be to use a chiral reducing agent—in other
words, to attach the chiral influence not to the substrate (as we did with chiral auxiliaries) but
to the reagent.

Fig. 17: Reduction of ketone to for introduction of a prochiral unit

The following table discusses the comparison of all the methods studied in this module to
achieve asymmetric synthesis.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis
 4. Summary
In this module, we have taught you that:
 Absolute asymmetric synthesis or asymmetric induction is the synthesis of optically
active products from achiral or racemic precursors without employing optically active
catalysts or auxiliaries.
 Any chiral product must be formed as a racemic mixture because the transition states
leading to the two enantiomers are themselves enantiomeric and therefore equal in
energy.
 Asymmetric synthesis or asymmetric induction is only tenuously different from
kinetic resolution. The difference is that the asymmetric atom instead of being in the
molecule to begin with, is introduced in the course of the reaction.
 Most asymmetric syntheses require rather more than one or two steps from chiral pool
constituents. When there is an existing chiral centre, the two possible TS’s are
diastereomeric and can be of different energy. Thus one isomer of the new
stereogenic centre can be produced in a larger amount.
 Various methods for carrying out asymmetric synthesis and their pros and cons are
discussed in the module.

CHEMISTRY Paper No. 1: Organic Chemistry-I (Nature of bonding and

Stereochemistry
Module No. 27: Asymmetric Synthesis