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Asymmetric Synthesis Lecture Notes 1

The document discusses several key topics in asymmetric synthesis and chirality: 1) Chirality is important in nature and pharmaceuticals, with different enantiomers often having very different biological effects. 2) There are various types of stereogenic elements and forms of chirality, including central, axial, and planar chirality. 3) Enantiomers have identical physical properties but differ in how they rotate plane-polarized light, while diastereomers have different physical properties and can thus be separated.

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Sankar Adhikari
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339 views

Asymmetric Synthesis Lecture Notes 1

The document discusses several key topics in asymmetric synthesis and chirality: 1) Chirality is important in nature and pharmaceuticals, with different enantiomers often having very different biological effects. 2) There are various types of stereogenic elements and forms of chirality, including central, axial, and planar chirality. 3) Enantiomers have identical physical properties but differ in how they rotate plane-polarized light, while diastereomers have different physical properties and can thus be separated.

Uploaded by

Sankar Adhikari
Copyright
© © All Rights Reserved
Available Formats
Download as PDF, TXT or read online on Scribd
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Asymmetric Synthesis
The importance of chirality
 Nature
yields an
enormous
variety of
chiral

compounds
 Each antiomer can have very different effects.
 As a result we must have methods to control stereochemistry.

 Roughly 1/3 of pharmaceuticals are chiral – 90% of thet op selling drugs have a
chiral active ingredient.

 Stereoisomers – isomers that differ only by the arrangement of substituents in


space
 Stereogenic element – the focus of stereoisomerism, be it a stereogenic centre,
axis or plane, within the molecule such that the change of two substituents about this
element leads to different stereoisomers.
 Chiral compound – a molecule/object that cannot be superimposed upon its mirror
image.

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 Chiral centre – in a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure, the


atom X to which the four or three substituents abc(d) are attached,

One stereogenic centre:


chirality on an atom

Chiral
 Mirror images are non-superimposable
 Each mirror image is an enantiomer
 Only differ by their absolute configuration or
actual 3D shape
 Simplistically – 4 different groups
 Do no have plane of symmetry

Achiral
 Mirror images are superimposable
 Compound has a plane of symmetry

Defining absolute configuration

 Need to be able to define the absolute configuration of a chiral centre


 First assign priorities according to Cahn-Ingold-Prelog rules (highest atomic
number)

 Next rotate molecule until lowest priority (4) is pointing away from viewer
 Draw a line connecting 1 to 3
 If line clockwise (right), R
 If line anticlockwise (left), S
 Define priorities according to CIP
 Point lowest priority (4) away from viewer.
 Draw line from 1-3.
 Line is anticlockwise so (S).
Central chirality at elements other than Carbon
 Any tetrahedral or pyramidal atom with four (three)
different substituents can be chiral
 Nitrogen/amines have the potential to be chiral – but rapid pyramidal inversion
normally prevents isolation of either enantiomer.
 If substituents are constrained in a ring then rigid structure prevents inversion.

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 Trigonal pyramidal phosphorus (III) is configurationally stable below 200˚c


 Tetrahedral phosphorus (V) is configurationally stable.

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 Sulfoxides are tetrahedral: have a lone pair.


 Configurationally stable at room temperature.
 Certain anions can cause racemisation (interconversion of the enantiomers)


Stereogenic centre (central chirality) is not a requirement for the existence of chirality,
but is sufficient.
 Compound can have a stereogenic centre BUT be achiral.
Axial Chirality
 Axial chirality – nonplanar arrangement of four groups about an axis.

Other forms of chirality


 Helical chirality – molecules that twist
 Right-handed helix is denoted P (clockwise as you travel
away from the viewer)
 Planar chirality – chirality resulting from the arrangement of out
of plane-groups.
Enantiomers & Optical Rotation
 Each enantiomer has identical physical and chemical
properties (in an achiral environment)
 Only differ by how they rotate plane polarised light
 Enantiomers are said to be optically active.

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 Not very useful as value is very unreliable (dependent on solvent, all factors listed
above)
 Even sign (+/-) can change depending on concentration of solvent.

Enantiomeric excess
 Optical purity – an outdated measurement of enantiomeric excess in a
solution/mixture
 If a solution contains only one enantiomer, the maximum rotation is obserbed
 The observed rotation is proportional to the amount of each enantiomer present.

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 Racemate (racemic mixture) 1:1 Mixture of enantiomers (50% of each)

 Racemisation – converting 1 enantiomer to a 1:1 mixture of enantiomers.

 Polarimeter measures difference in the amount of each enantiomer

 New methods more reliable and purity measured in terms of enantiomeric excess
(e.e.)

Two chiral centres

 A molecule with 1 stereogenic centre exists as 2 stereoisomers or enantiomers


 Enantiomers have identical physical properties in an achiral environment
 A molecule with 2 stereogenic centres can exist as 4 stereoisomers
 Eanantiomers still have identical physical properties
 Diastereoisomers (non-mirror images) have different properties.

Diastereoisomers
 Enantiomers differ only by their absolute stereochemistry (R or S etc)
 Diastereoisomers differ by their relative stereochemistry.
 Relative stereochemistry – defines configuration with respect to any other
stereogenic element within a molecule but does not differentiate enantiomers.
 A molecule can only have one enantiomer but any number of diastereoisomers
 The different physical properties of diastereoisomers allow us to purify them

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