In Asymmetric synthesis, Enantiomeric Excess and ...

In Asymmetric synthesis, Enantiomeric Excess and Diastereomeric Excess

are commonly encountered.

The composition of non-racemic mixtures is described by the enantiomeric

excess, which is the difference between the relative abundance of the two

enantiomers.

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The fraction of the main isomer and minor isomer can be calculated

by using the following formula

Optical Purity = Enantiomeric Excess

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Diastereomeric Excess: the ratio of the percentage of one diastereoisomer in a

mixture to that of the other.

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Many of the transformations encountered in asymmetric synthesis have the

potential to create multiple products –isomers –from a single starting

material.

The reactions could form a mixture of constitutional isomers

(i.e. regioisomers),

diastereomers,

or enantiomers.

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“Selective” means that there are factors which favor one product over the other, while

“specific” is usually a sign that there’s something intrinsic to the mechanism that leads to

only one product. 5

Regioselective reactions –Reaction where a starting material forms two (or more)

structural isomers, and one predominates.

A good example is Markovnikoff addition of water.

This a reaction where one stereoisomer of a product is formed preferentially over another.

The mechanism does not prevent the formation of two or more stereoisomers but one does

predominate.

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When a stereogenic centre is introduced into a molecule in a way that

diastereoisomers are produced in unequal amounts the reaction is

Diastereoselective.

Stereospecific reactions- is one which, when carried out with stereoisomeric

starting materials, gives a product from one reactant that is a stereoisomer of the

product from the other.

'Stereospecific' relates to the mechanism of a reaction, SN2 reaction being a

good example.

It proceeds always with inversion of stereochemistry at the reacting centre. 7

If the reaction starts with a chiral material the reaction will be enantiospecific.

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If the reaction forms only one diastereoisomer it is diastereospecific.

ALL stereo selective reactions are stereo specific but All stereo specific

reaction are not stereo selective.

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Why is a chiral component needed to achieve asymmetric synthesis?

Answer: if both reactant and reagent are achiral, the resulting

transition state is enantiomeric and thus racemic products obtained.

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Achiral carbonyl compound in the presence of an achiral nucleophile:

The two faces (Re and Si) of the achiral compound are enantiotopic.

Nucleophile can attack either face leading to two possible transition states.

If the nucleophile is itself achiral then the two transition states are

enantiomeric and thus equal in energy.

The two enantiomeric transition states lead to the formation of the two

enantiomeric products in equal amount, this produces a racemic mixture.

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Chiral carbonyl compound in the presence of an achiral nucleophile:

If the carbonyl compound is included within the structure of a stereogenic

centre, the two faces of the carbonyl group are now diastereotopic.

Hence the two transition states are different in energy and thus one of the

two diastereomers will be formed preferentially.

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Achiral carbonyl compound with a chiral nucleophile:

The two faces of the carbonyl compound are enantiotopic and the

nucleophile can attack either one.

However since the nucleophile is chiral, the two transition states for the

two reactions must be diastereomeric.

Thus the reaction leads to the preferential formation of one diastereomer

as the two diastereomeric transition states are not equal in energy.

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Hence, asymmetric synthesis takes place via diastereomeric transition states

and takes advantage of the difference in energy between the two transition

states in order to obtain predominantly one product.

All asymmetric reactions are stereoselective reactions but stereoselective

reactions where products are achiral are not asymmetric reactions

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Asymmetric synthesis is further classified into:

Enantioselective asymmetric synthesis

A reaction step in which one chiral center is generated predominantly is

said to be enantioselective asymmetric synthesis.

An essential feature of an enantioselective synthesis is that the reactant

must be prochiral with one or more Sp3 or Sp2 prochiral centres.

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Key: RL = Largest substituent; RM = Medium-sized substituent; RS = Smallest substituent

Example of enantioselective synthesis using asymmetric induction is the

Sharpless dihydroxylation reaction where the chirality of the product can be

controlled by the "AD-mix".

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Diastereoselective asymmetric synthesis

A reaction in which two chiral centres are generated in a single step, four

possible isomers are formed i.e. RR, SS, RS & SR out of which exclusive

formation of one isomer takes place is said to be Diastereoselective

asymmetric synthesis.

An essential feature of Diastereoselective synthesis is that the reactant/s is

chiral and enantiopure with one or more prochiral units.

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Some Examples of asymmetric synthesis

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Sharpless Asymmetric Epoxidation

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Generally, Sharpless asymmetric dihydroxylation favors oxidation of the more electron-rich alkene.

Sharpless Asymmetric Dihydroxylation

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Asymmetric Hydrogenation of Alkenes

Reduction of an alkene by addition of hydrogen to one of its two enantiotopic

faces can give all sorts of products creating either one or two chiral centres

depending on the substituents on the alkene.

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Using Ru metal instead of Rh broadens the scope of the substrate that will

undergo asymmetric hydrogenation, this was discovered by Noyori.

They still need a functional group usually the –OH group of an alcohol (or) a

carboxylic acid.

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Two important industrial asymmetric hydrogenation syntheses are the

production of the pain killer (S)-Naproxen and the synthetic intermediate

and perfumery compound (R)-Citronellol.

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Chiral auxiliaries

By Jammercer - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=23264169 32

Some Examples of Enantiomers

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References1. www.slideshare.net<krishnaSwamy20<asymmetric synthesis.

2. IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997).3. Organic Chemistry, 2nd ed - Joseph Hornback

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