ASYMMETRIC SYNTHESIS

PRESENTED BY : FAIZAN AHMED M.SC(F)

PRESENTED TO : DR. IMRAN ALI HASHMI
CONTENTS

1. INTRODUCTION TO ORGANIC SYNTHESIS.

2. RETRO AND ASYMMETRIC SYNTHESIS.

3. WHY ASYMMETRIC SYNTHESIS?

4. OVERVIEWS.
INTRODUCTION OF ORGANIC SYNTHESIS
• ORGANIC COMPOUNDS AND MANY OTHER COMPOUNDS
THAT ARE PHYSIOLOGICALLY ACTIVE ARE SYNTHESIZED
IN PAST CENTURY.
• A NUMBER OF COMPOUNDS SYNTHESIZED LIKE
VITAMINS, ARTIFICIAL FLAVORS AND MANY
PHARMACEUTICALS DRUGS.
• SMALL AMOUNTS OF MANY DRUGS CAN BE ISOLATED
FROM PLANTS OR MARINE ANIMALS; MUCH GREATER
QUANTITIES ARE MADE BY CHEMISTS IN LABORATORIES.
• A PROPOSAL FOR THE SYNTHESIS OF THE TARGET
MOLECULE, IRRESPECTIVE OF ITS COMPLEXITY, CAN BE
Retro Synthesis
Guide lines for Organic Synthesis
• Disconnections must correspond to known, reliable
reactions.
• Synthons are idealized reagents.
• For compounds consisting of two parts joined by a
heteroatom, disconnect next to the heteroatom.
• Multiple step syntheses, avoid Chemoselectivity problems.
• Consider alternative disconnections and choose routes that
avoid Chemoselectivity
• problems—often this means disconnecting reactive groups
first.
Disconnections must correspond to
known, reliable reactions
• Paracetamol, for example, is an amide that can be disconnected
either
• To amine + acyl chloride Synthon =
OR
• To amine + anhydride
Equivelents
Synthons are idealized reagents.
• Synthons are fragments of molecules, that can be used in the forward
synthesis.
• It has an associated polarity (represented by a ‘ + ‘ or ‘–’) which stand
for the reagents.
Example: The herbicide 2,4-D (2,4-dichlorophenoxyacetic acid).
Synthons are idealized reagents.
For compounds consisting of two parts
joined by a heteroatom, disconnect
next to the heteroatom.
Multiple step syntheses, avoid
Chemoselectivity problems—often this
means disconnecting reactive groups first.
• The next compound was an intermediate in the synthesis of the
potential anti-obesity drug ICI-D7114.
• It has two ethers and an amine functional group.
• it requires several disconnections to take it back to simple
compounds.
• Both (a) and (b) pose problems of chemoselectivity as it
would be hard to alkylate the phenol in the presence of the
basic nitrogen atom.
• Between (c) and (d), (c) appears to be the better choice
because the next disconnection after (d) will have to be an
alkylation of O in the presence of an NH2 group.
• To avoid chemoselectivity problems like this, we want to try to
introduce reactive groups late in the synthesis.
Consider alternative disconnections
and choose routes that avoid
Chemoselectivity.
• This guideline helps us in the next retrosynthetic step for the ICI-
D7114 intermediate.
• Disconnection (c) gave us a compound with two ethers that might be
disconnected further by disconnection (e) or (f ).
Functional Group Interconversion
• Chemoselectivity problems are also avoided by FGI.
• As the two different Functional group effect different during the
reaction.
• Drug ofornine contains an amide and an amine functional group.
• (a) seems to pose a problem because we now have to construct an
amine in the presence of an acyl chloride.
• Using FGI the acyl chloride from the carboxylic acid, which can then
easily be disconnected to 2-aminobenzoic acid (anthranilic acid) and
4-chloropyridine.
• If disconnect the secondary amine first (b), we have chemoselectivity
problem constructing the amide in the presence of the resulting NH2
group.
Functional Group Interconversion
Functional Group Interconversion
• The synthesis of amines poses a special problem.
• The problem is that the product is usually more reactive than the
starting material and multiple alkylation will take place.
• Further alkylation is made unfavourable by
a) Increased Steric hindrance
b) Functional group interconversion.
Functional Group Interconversion
• Further alkylation is made unfavourable by
a) Increased Steric hindrance
b) Functional group interconversion.
Two-group disconnections are better
than one-group disconnections
• it might be hard to control selective alkylation of the primary hydroxyl
group in the presence of the secondary one.
• We have used one functional group to help disconnect another—in
other words, we noticed the alcohol adjacent to the ether we wanted
to disconnect and managed to involve them both in the
disconnection.
• Such disconnections are known as two-group disconnections.
Two-group disconnections are better
than one-group disconnections
WHY ASYMMETRIC SYNTHESIS?
• In a chiral molecule, From diastereomers, the preparation of one
enantiomer is called asymmetric synthesis or enantioselective.
• Asymmetric synthesis is synthesis of an enantiomerically pure
compound.
• When more stereogenic centers are present, asymmetric
synthesis of an optically pure compound is preferred.
• The painkiller naproxen marketed only as their S-enantiomer
because the R-enantiomer is essentially inactive.
WHY ASYMMETRIC SYNTHESIS?
• As you read the book you are probably turning the pages with your
right hand and processing the information with the left side of your
brain.
• The smells of orange and lemon differ in being the left- and right-
handed versions of the same molecule,
• Limonene. (R)-(+)-Limonene smells rounded and orangey whereas
(S)-(–)-limonene is sharp and lemony.
• Similarly, spearmint and caraway seeds smell quite different,again this
pair of aromas differs only in being the enantiomeric forms of the
ketone carvone.
SOME ASYMMETRIC COMPOUNDS
ASYMMETRIC SYNTHESIS
• A laboratory synthesis of a chiral compound from achiral or
racemic starting materials alone always gives a racemic mixture
of enantiomers.
• If you want to make just one enantiomer, you have to use a
starting material or reagent which is also just one enantiomer.
• Chiral Pool: Nature provides a collection of enantiomerically pure
compounds that we can exploit in various ways.
• The collection of natural, enantiomerically pure compounds is
called the chiral pool.
EXAMPLES OF CHIRAL POOLS
• The amino acids.

• Simple derivatives of the amino acids: amino alcohols and

hydroxy acids.

• Carbohydrates and their derivatives.

RESOLUTION CAN BE USED TO
SEPARATE ENANTIOMERS
• Resolution as a means of separating enantiomers.
• Resolution requires an enantiomerically pure resolving agent, which
must be a compound from the chiral pool or a simple derivative of
that compound. It give maximum 50% yield as 50% wasted.
CHIRAL AUXILIARIES
• Diastereoselective reactions work just as well whether the starting
material is racemic or enantiomerically pure.
• Chiral Auxiliary assists the substrate to react in a diastereoselective
way such that only one of the two possible products is allowed to
form.
• The chiral auxiliary is enantiomerically pure to start with, so the
product must be diastereoisomerically and enantiomerically pure.
• Start with enantiomerically pure material you get enantiomerically
pure product.
COMMON CHIRAL AUXILIARY

• Valine is the chiral auxiliary.

• It is a member of the oxazolidinone (the name of the heterocyclic
ring) family of auxiliaries developed by David Evans at Harvard
University.
• It is easily and cheaply made from the amino acid (S)-valine. It can be
recycled.
• The last step of the route, regenerates the auxiliary ready for re-use.
CHIRAL AUXILIARY STRATEGY
• 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 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.
ASYMMETRIC SYNTHESIS USING
CHIRAL AUXILIARY
• The product of a Diels–Alder reaction between cyclopentadiene and
benzyl acrylate must racemic as both reagents are achiral.
• one diastereoisomer—the endo product—is formed, with an exactly
50:50 mixture of enantiomers.
 USING CHIRAL AUXILIARY
• Finally comes the step which shows the power of chiral auxiliary strategy.
• Remove the chiral auxiliary from the product by treating with a
nucleophile.
USING CHIRAL AUXILIARY
CHIRAL AUXILIARY (ALKYLATION
OF ENOLATES)
• Treatment with base (usually LDA) at low temperature produces an
enolate.
• The bulky auxiliary means that only the cis enolate forms and the
trans enolate is too hindered.
CHIRAL AUXILIARY (ALKYLATION
OF ENOLATES)
• Electrophiles have little choice but to attack the enolate from the
front.
• The table shows the ratio of diastereoisomers (the diastereoisomeric
ratio, abbreviated to d.r.) produced for a selection of alkylating
agents.
RETRO AND ASYMMETRIC
SYNTHESIS OF (S)-1-(PYRIDINE-3-
YL) PROPAN-1-OL
ASYMMETRIC SYNTHESIS OF (S)-1-
(PYRIDINE-3-YL) PROPAN-1-OL

• we completely neglected the stereochemistry.

• This is chiral molecule, and in praxis usually preparation of one
enantiomer.
• The asymmetric synthesis of an optically pure compound is preferred.
Let as now assume that our target is (S)-TM.
• When performed in the presence of a chiral catalyst with a defined
absolute configuration.
• The catalyst induces an S-configuration in the enantiomer of TM.
ASYMMETRIC SYNTHESIS OF (S)-1-
(PYRIDINE-3-YL) PROPAN-1-OL
MECHANISM
REFERENCES
• Organic Chemistry 2nd edition Jonathan Clayden, Nick Greeves, and
Stuart Warren
• Organic Chemistry from Retrosynthesis to Asymmetric Synthesis
Author: Vitomir Šunjić • Vesna Petrović Peroković Springer.
• Organic Synthesis 2nd edition Stuart Warren.