1

Importance of stereochemistry
Enantiomers have identical chemical and physical properties
Differ - rotating polarised light
R

R
Me
Me2N

....... ..- interaction with other chiral molecules

Important in biology...

enzyme

only one enantiomer matches

chiral enzyme

Ph O
O
Et
darvon

Darvon is a
painkiller.
Its enantiomer is an
anticough agent.

Polarised light
Ordinary light has EM radiation oscillating in all possible planes (3 shown)
Polarised light is in a single plane

ordinary light

polarised light
Chiral

H NH2
CO2H

measure rotation
derive []D = +14

H2N H
CO2H

measure rotation
derive []D = -14

compounds rotate
polarised
light
.
A pair of enantiomers rotate
the plane of polarised light by
equal amounts in opposite
directions
.
A 1:1 mixture of enantiomers
does not rotate light and is
called a racemate

Diastereoisomers I

Cyclic compounds can exist as diastereoisomers

Diastereoisomers differ by the spatial orientation of atoms
Can have very different physical properties
Do NOT have to be chiral (if they have a plane of symmetry)
OH

OH
diastereoisomers

identical

identical

OH

OH

molecule has a
plane of symmetry

OH

Diastereoisomers II
O2N

O2N
CO2Me

CO2Me

O
enantiomers

trans
epoxide
mp = 141C

O2N

diastereoisomers

cis
epoxide
mp = 98C

enantiomers

O2N
CO2Me
O

CO2Me
O

2 stereocentres can result in FOUR compounds (4 diastereoisomers)

No plane of symmetry chiral & 2 pairs of enantiomers (mirror images)
2 enantiomeric pairs - each enantiomer has identical physcial properties
But diastereoisomers have different physical properties
Enantiomers have same relative stereochemistry but different absolute
stereochemistry

Diastereoisomers III
OH
CHO

HO

OH OH
ribose
(2R,3R,4R)-2,3,4,5-tetrahydroxypentanal
OH

OH
CHO

HO

OH OH
(2R,3R,4R)-ribose

CHO

HO

OH OH
(2R,3R,4S)-arabinose

OH
HO

OH

OH OH
(2S,3S,4S)-ribose

HO

CHO

HO

OH OH
(2R,3S,4R)-xylose

OH
CHO

OH

OH OH
(2R,3S,4S)-lyxose

OH
CHO

OH OH
(2S,3S,4R)-arabinose

HO

CHO

HO

four
diastereomers

OH
CHO

OH OH
(2S,3R,4S)-xylose

HO

CHO

OH OH
(2S,3R,4R)-lyxose

and their 4
enantiomers

If a molecule has 3 stereocentres then it has potentially 8

stereoisomers (4 diastereoisomers & their enantiomers)

If a molecule has n stereocentres then potentially 2n stereoisomers
But if a molecule has a plane of symmetry it wil be less...

Meso compounds I
OH
HO2C

OH
HO2C

CO2H

OH
tartaric acid

OH
HO2C

CO2H
OH

OH
diastereoisomers

enantiomers

identical

OH
HO2C

CO2H
OH

CO2H

OH
HO2C

CO2H
OH

2 stereocentres so 4 stereoisomers?
There are 2 diastereoisomers - one has an enantiomer
...................................na......... - the other does NOT

Meso compounds II
Two compound on previous slide identical as rotation below shows...
OH
HO2C

CO2H
OH

OH
HO2C

CO2H

OH
HO2C
CO2H

HO
CO2H

OH
HO2C

OH
rotate around
central axis

OH

Even though compound has TWO stereocentres it

It is achiral because it has a plane of symmtery...
HO2C

OH

HO
CO2H
rotate LHS

HO
HO2C

OH
HO2C

CO2H
OH

is ACHIRAL

OH
CO2H

mirror
plane

Meso compounds - compounds containing stereocentres but are

still achiral
Meso compounds have a plane of symmetry with (R) configuration
on one side and (S) on the other

Resolution
O
H OH

HO2C

Ph

OMe

O
Ph

Ph

OMe

OMe

2 diastereoisomers
(hopefully
separable)

() or (R) / (S)
racemate
NaOH
H2O

NaOH
H2O

need enantiomerically pure

..compounds
OH
OH
If you can't synthesise it pure
..how do you purify enantiomers?
Separation of enantiomers is
pure (S)
pure (R)
..called resolution
Enantiomers physically the same - diastereoisomers are not!
React 2 chiral compounds to form diastereoisomers
Separate these (if possible)
Regenerate required compound
We

Chirality in nature I
Natural amino acids are enantiomerically pure
These are the building blocks of proteins and enzymes
HO2C

Me
NH2

alanine

HO2C

H
N

HO2C
NH2

phenylalanine

NH2

histidine

Why this enantiomer? Who knows...

But why just one enantiomer is more obvious...

Insulin is made of 2 peptide chains - 1x30 amino acids & 1x21 amino acids
Potentially 2.25 x 1015 diastereoisomers
A relatively small protein is ribonuclease at 124 amino acids or
Potentially 2.13 x 1037 diastereoisomers

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Chirality in nature II
O

NH2
N
HO

HO O HO O HO O

O
O

HO
O

HO
OH
adenosine triphosphate ATP

NH

N
N

HO
thymine derivative of
deoxyribonucleic acid
(DNA)

HO
O

NH
N

NH2

HO
OH
guanine derivative of
ribonucleic acid (RNA)

Nucleosides are enantiomerically pure

These are the basis of all life via DNA and / or RNA
Also ATP which is the main sourse of energy in our cells
O

H
(R)-carvone
spearmint
(R)-2-methyl-5-(prop-1-en-2yl)cyclohex-2-enone

H
(S)-carvone
caraway
(S)-2-methyl-5-(prop-1-en-2yl)cyclohex-2-enone

H
(S)-limonene
lemons
(S)-1-methyl-4-(prop-1en-2-yl)cyclohex-1-ene

H
(R)-limonene
oranges
(R)-1-methyl-4-(prop-1en-2-yl)cyclohex-1-ene

Enantiomers are identical except their interaction with polarised light and other
chiral molecules (like our bodies)
This can have trivial effects...like smell / taste

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Chirality in nature III

O
H H H
N
S

HO
O

N
O

penicillin skeleton

N
O

CO2H

N
N

NH

AZT
azidothymidine

N
H

(R)-thalidomide

OMe
dextromethorphan

Drugs frequently need to be optically pure

(R)-Thalidomide is a sedative - (S) isomer cause birth defects
Dextromethorphan is a cough suppresant
Levomethorphan (its enantiomer) is a narcotic
Top two drugs were Lipitor and Zucor and are single enantiomers
They generated $14 billion in 2002
Single enantiomer drugs worth $159 billion in 2002
Big buisiness!

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Other forms of chirality

axial
chirality

PPh2

Ph2P

PPh2

Ph2P

full rotation
impossible

(S)-BINAP
(R)-BINAP
2-(diphenylphosphino)-1-((R)-22-(diphenylphosphino)-1-((S)-2(diphenylphosphino)naphthalen-1(diphenylphosphino)naphthalen-1yl)naphthalene
yl)naphthalene
mirror
plane

planar
chirality

NH2

(Rp)-4amino[2.2]paracyclophane

H2N

mirror
plane

(Sp)-4amino[2.2]paracyclophane

It is not necessary for a compound to have a tetrahedral

stereocentre to be a chiral compound!!