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

Asymmetric synthesis

• We could distinguish the smell of oranges from the smell of lemons

• It’s just because of right and left handed versions of the same molecule

• Same way spearmint and caraway seeds smell quite differently

• 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

• 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

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

• For example, synthesis of artificial sweetener aspartame

• Asymmetric synthesis of this compound involves (S)-amino acids, aspartic acid and phenylalanine

• Conversion of L-tyrosine into L-DOPA

• It’s a method of synthesis which doesn’t affect existing stereocentre already present in the reactant

• It’s similar to stereospecific pathway to give enantiomerically pure product

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

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

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

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

How to measure Enantiomeric excess (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 

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

• 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 

Chiral catalysts

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

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