Asymmetric Synthesis. PPT

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Lecture No. 05

Asymmetric Synthesis

 

Session Objectives

By the end of this session, students will be able to:

➢ Define Asymmetric synthesis

➢ Define Chiral pool strategy and chiral auxiliary with examples

➢ Define Enantiomeric excess

➢ Define chiral reagents and chiral catalysts

➢ Discuss its application with examples

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Asymmetric synthesis
• we could distinguish the smell of oranges from the smell of lemons
• Its just because of right and left handed versions of the same molecule
• Same way spearmint and caraway seeds smell quite differently

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Asymmetric synthesis

• All living systems are chiral environment
• Nature has chosen to make all its living structures from chiral

molecules (amino acids, sugars), and has selected a single
enantiomeric form of each

• Every amino acid in your body has the S and not the R configuration
• Chirality is seen in all living structures from the DNA double helix to

a blue whale’s internal architecture
• The proteins which will be made of S-amino acids and L-lactose will

be quite indigestible

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Asymmetric synthesis
• Coming to drug molecules, making the right enantiomer can be a matter of life

and death
• Parkinson’s disease sufferers are treated with the non-proteinogenic amino acid

dopa (3-(3,4-dihydroxyphenyl)alanine)
• Dopa is chiral, and only (S)-dopa (known as L-dopa) is effective in restoring nerve

function
• (R)-dopa is not only ineffective; it is, in fact, quite toxic, so the drug must be

marketed as a single enantiomer

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Chiral pool strategy

• Use of chiral substrates (First generation methods)
• More economical way of making compounds in single enantiomers is to

manufacture them using enantiomerically pure starting materials
• This method is known as chiral pool strategy
• Relies on finding a suitable enantiomerically pure natural product that can be

easily transformed to target molecule
• The chiral pool is that collection of cheap, readily available pure natural

products, usually amino acids or sugars, from which required chiral centers can
be taken and incorporated into the product

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Chiral pool strategy

• For example, synthesis of artificial sweetener aspartame
• Asymmetric synthesis of this compound involves (S)-amino acids, aspartic acid

and phenylalanine

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Chiral pool strategy
• Conversion of L-tyrosine into L-DOPA
• It’s a method of synthesis which doesn’t effect existing stereocentre

already present in the reactant
• Its similar to stereospecific pathway to give enantiomerically pure

product

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Chiral pool strategy

2) Use of chiral auxiliaries (Second generation methods)
• Here chiral auxiliary is attached chemically to the achiral substrate to give a chiral

intermediate
• And auxiliary dictates the preferred stereochemistry
• At the end of synthesis, chiral auxiliary is removed

A) alkylation of chiral enolates
• Most commonly reported reaction is alkylation of enolates
• Evans’s oxazolidinone auxiliaries are particularly appropriate here because they

are readily turned into enolizable carboxylic acid derivatives
• Treatment with base (usually LDA) at low temperature produces an enolate

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Chiral auxiliary
• Here auxiliary has been designed to favour attack by electrophiles

on only one face of that enolate
• Coordination of the lithium ion to the other carbonyl oxygen makes

the whole structure rigid, fixing the isopropyl group where it can
provide maximum hindrance to attack on the ‘wrong’ face

• On hydrolysis gives >98% of pure enantiomer ee

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Chiral auxiliary

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Chiral auxiliary

Enantiomeric excess
• Compounds that are neither racemic nor enantiomerically pure, chemists will

not describe it as enantiomeric ratios, call it as enantiomeric excess
• Enantiomeric excess (or ee) is defined as the excess of one enantiomer over the

other, expressed as a percentage of the whole
• For example, a mixture contains 98:2 of enantiomers- we call it as 96% ee
• The 2% of the wrong enantiomer makes a racemate of 2% of the right isomer so

the mixture contains 4% racemate and 96% of one enantiomer that is 96% ee
• So by using different chiral auxiliaries, we can increase the ee of reaction

products

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Enantiomeric excess
How to measure ee?
• One way is simply to measure the angle through which sample rotates plane polarized

light
• Angle of rotation is proportional to enantiomeric excess of sample
• For that we need to know what rotation a sample of 100% ee gives and that is not

always practically possible
• Polarimeter results depends on temperature, solvent and concentration and subject to

massive error due to presence of highly optically active impurities
• Modern chemists use either chromatography to tell the difference between

enantiomers
• Enantiomers are always identical unless they are in chiral environment
• Passing through chiral stationary phase of preparative HPLC or Gas chromatography

and determine the ee
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Chiral reagents and chiral catalysts

• Its third generation methods
• To create a chiral center in a molecule, starting material must have prochirality-

the ability to become chiral in one simple transformation
• Most prochiral units are trigonal carbon atoms of alkenes and carbonyl groups

which become tetrahedral by addition reactions
• Simple transformation using prochiral unit is reduction of a ketone

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Chiral reagents and chiral catalysts
• More effective is the chiral borohydride analogue developed by Corey, Bakshi,

and Shibita
• It is based upon a stable boron heterocycle made from an amino alcohol derived

from proline, and is known as the CBS reagent after its developers
• CBS reagent is activated by complexing with borane
• Catalytic amounts of borane (usually less than 10%) is used, because borane is

reactive to ketones
• CBS reductions are best when ketones are the substituents

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Chiral catalysts

• BINAP is a chelating diphosphine: the metal sits between the two
phosphorus atoms firmly anchored in a chiral environment

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Summary

• More economical way of making compounds in single enantiomers is to

manufacture them using enantiomerically pure starting materials

• Enantiomeric excess (or ee) is defined as the excess of one enantiomer over the

other, expressed as a percentage of the whole

• Angle of rotation is proportional to enantiomeric excess of sample

• To create a chiral center in a molecule, starting material must have prochirality-

the ability to become chiral in one simple transformation

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Thank You
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