1

Importance of stereochemistry
• Enantiomers have identical chemical and physical properties
• Differ - rotating polarised light
....... ..- interaction with other chiral molecules
• Important in biology...
R R
Me
Me2N

Ph O
O
X

Et
darvon
enzyme Darvon is a
painkiller.
Its enantiomer is an
anticough agent.
only one enantiomer matches
chiral enzyme
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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

H NH2 • Chiral compounds rotate

CO2H polarised
.
light
• A pair of enantiomers rotate
measure rotation
derive [α]D = +14 the plane of polarised light by
equal amounts in opposite
directions
H2N H

CO2H .
• A 1:1 mixture of enantiomers
measure rotation does not rotate light and is
derive [α]D = -14
called a racemate
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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
OH

molecule has a
plane of symmetry
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Diastereoisomers II
O2N O2N

CO2Me CO2Me

O O
trans diastereoisomers cis
enantiomers epoxide epoxide enantiomers
mp = 141˚C mp = 98˚C

O2N O2N

CO2Me CO2Me

O 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
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Diastereoisomers III
OH
CHO
HO
OH OH
ribose
(2R,3R,4R)-2,3,4,5-tetrahydroxypentanal

OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO four
diastereomers
OH OH OH OH OH OH OH OH
(2R,3R,4R)-ribose (2R,3R,4S)-arabinose (2R,3S,4R)-xylose (2R,3S,4S)-lyxose
OH OH OH OH
CHO CHO CHO CHO
HO HO HO HO and their 4
enantiomers
OH OH OH OH OH OH OH OH
(2S,3S,4S)-ribose (2S,3S,4R)-arabinose (2S,3R,4S)-xylose (2S,3R,4R)-lyxose

• 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...
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Meso compounds I
OH
HO2C
CO2H
OH
tartaric acid
OH OH
HO2C HO2C
CO2H CO2H
OH OH
diastereoisomers
enantiomers identical

OH OH
HO2C HO2C
CO2H CO2H
OH OH

• 2 stereocentres so 4 stereoisomers?
• There are 2 diastereoisomers - one has an enantiomer
...................................na......... - the other does NOT
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Meso compounds II
Two compound on previous slide identical as rotation below shows...
OH CO2H OH
OH OH HO
HO2C HO2C
HO2C
CO2H ≡ HO2C
CO2H
OH
CO2H
HO2C
OH
OH
CO2H

OH OH rotate around
central axis

• Even though compound has TWO stereocentres it is ACHIRAL

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

HO2C OH HO OH

HO CO2H HO2C CO2H

rotate LHS
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
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Resolution
O O
H OH HO2C Ph
H Ph Ph
+ O + O
OMe
OMe OMe
(±) or (R) / (S) 2 diastereoisomers
racemate (hopefully
separable)

NaOH NaOH
• We need enantiomerically pure H2O H2O
..compounds
• If you can't synthesise it pure OH OH
..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
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Chirality in nature I
Natural amino acids are enantiomerically pure
These are the building blocks of proteins and enzymes
HO2C Me HO2C H
HO2C N

NH2 NH2 NH2

N
alanine phenylalanine 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
NH2 O O

N N NH N NH
HO O O O HO HO
P P P N N N O N N NH2
O O O
HO O HO O HO O

HO OH HO HO OH
adenosine triphosphate ATP thymine derivative of guanine derivative of
deoxyribonucleic acid ribonucleic acid (RNA)
(DNA)

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 O

H H H H

(R)-carvone (S)-carvone (S)-limonene (R)-limonene

spearmint caraway lemons oranges
(R)-2-methyl-5-(prop-1-en-2- (S)-2-methyl-5-(prop-1-en-2- (S)-1-methyl-4-(prop-1- (R)-1-methyl-4-(prop-1-
yl)cyclohex-2-enone yl)cyclohex-2-enone en-2-yl)cyclohex-1-ene en-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

NH N
H H H O H
R N S HO
N O H
O N
O N
O O
CO2H O N O
N
H
N OMe
penicillin skeleton N (R)-thalidomide dextromethorphan
AZT
azidothymidine

• 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

PPh2 Ph2P full rotation
impossible
axial PPh2 Ph2P

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

NH2 H2N
planar
chirality
(Rp)-4- (Sp)-4-
amino[2.2]para- mirror amino[2.2]para-
cyclophane plane cyclophane

• It is not necessary for a compound to have a tetrahedral

stereocentre to be a chiral compound!!