Chiral

1
Asymmetric
Synthesis
Gareth
Rowlands
Gareth J. Rowlands
123.702 Organic Chemistry
2
The importance of chirality
Me
H
CO2H
Me
CO2H
N
NH2
NH2
L-alanine
mammalian amino acid
D-alanine
bacterial cell wall
Me
N
nicotine
toxin / stimulant
• Nature yields an enormous variety of chiral compounds
• Each enantiomer can have very different effects as highlighted below
• As a result we must have methods to control stereochemistry
NH
OH
Me
Me
Et
HN
Me
Me
OH
OH
(–)-propanolol
β-blocker for heart disease
(+)-propanolol
contraceptive
N
H
OH
H
N
Et
Ethambutol
tuberculostatic (anti-TB)
OH
H
N
Et
Et
N
H
OH
(R,R)-enantiomer
causes blindness
123.702 Organic Chemistry
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The importance of chirality
NAME
GLOBAL SALES
2003 (BILLION $)
ACTIVE
INGREDIENT
FORM OF ACTIVE
INGREDIENTS
THERAPEUTIC EFFECT
LIPITOR
10.3
ATROVASTATIN
Single Enantiomer
Lipid-Lowering agent
ZOCOR
6.1
SIMVASTATIN
Single Enantiomer
Lipid-Lowering agent
ZYPREXA
4.8
OLANZAPINE
Achiral
Psychotropic agent
NORVASC
4.5
AMLODIPINE
Racemate
Calcium channel blocker
PROCRIT
4.0
EPOETIN A
Protein
Stimulant of blood cells production
PREVACID
4.0
LANSOPRAZOLE
Racemate
Inhibitor of gastric acid secretion
NEXIUM
3.8
ESOMEPRAZOLE
Single Enantiomer
Inhibitor of gastric acid secretion
PLAVIX
3.7
CLOPIDOGREL
Single Enantiomer
Inhibitor of platelet aggregation
ADVAIR
3.7
SALMETEROL
Racemate
β2-Adrenergic bronchodilator
FLUTICASONE
Single Enantiomer
Anti-inflammatory agent
SERTALINE
Single Enantiomer
Inhibitor of serotonin re-uptake
ZOLOFT
3.4
TOTAL
48.3
• Roughly 1/3 of pharmaceuticals are chiral
• 90% of the top 10 selling drugs the active ingredient is chiral
• A. M. Rouhi, Chem. Eng. News. 2004, June 14, 47 & Sept. 6, 41
123.702 Organic Chemistry
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Terminology
• 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 - simply a molecule (or object) that cannot be superimposed upon
its mirror image
Most obvious example is our hands...
Mirror image
Left & right hands
Non-superimposable
• Chiral centre - In a tetrahedral (Xabcd) or trigonal pyramidal (Xabc) structure, the
...atom X to which the four (or three, respectively) substituents abc(d) are attached
a
c
H OH
b
X
d
a
X
c
b
chiral centre
Ph
Me
Ph
P H
Me
123.702 Organic Chemistry
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One stereogenic centre: chirality on an atom
Mirror
plane
Mirror
plane
rotate
rotate
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 not have a plane of symmetry
Achiral
• Mirror images are superimposable
• Compound has a plane of symmetry
R1
R1
R2
R4
R3
chiral
1
R ≠R2≠R3≠R4
H OH
R1
R4
R3
achiral
1
R =R1≠R3≠R4
Me
Me
plane of symmetry
running through central
carbon, hydrogen and OH
ACHIRAL
123.702 Organic Chemistry
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Defining absolute configuration
H
Me
NH2
CO2H
alanine
• 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)
rotate around axis until
lowest priority points
away from you
4
H
Me
3
1
NH2
CO2H
2
2
H
Me
HO2C
NH2
CO2H
Me
H
NH2
≡
3
H
Me
CO2H
NH2
1
• Next rotate molecule until lowest priority (4) is pointing away from viewer
• Draw a line connecting 1 to 3
• If line clockwise (right) the (R)
• If line anti-clockwise (left) the (S)
H
Me
NH2
CO2H
(S)-alanine
(S)-2-aminopropanoic acid
123.702 Organic Chemistry
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Defining absolute configuration II
O1
O1
2
3 P
Me
4
OMe
MeO
4
2 P Me
Ph
3
• Define priorities according to CIP
• Point lowest priority (4) away from viewer
• Draw line from 1 to 3
• Line is anti-clockwise so (S)
1
Me
2 Ar
O
P
Ph 3
O
P
Me
OMe
(S)-(4methoxyphenyl)methylphenyl
phosphine oxide
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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
N
R1
N R3
R1
R2
Me
R2
3
N R
Me
N
Tröger's base
• Trigonal pyramidal phosphorus(III) is configurationally
• Tetrahedral phosphorus (V) is configurationally stable
P
Me
X
stable below 200°C
MeO
O
P Me
O
P
t-Bu
Ph
MeO
(S)-cyclohexyl(4methoxyphenyl)(methyl)
phosphine
(S)-naphthalen-1-yl tertbutyl(phenyl)phosphinate
123.702 Organic Chemistry
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Central chirality at elements other than carbon II
• Sulfoxides are tetrahedral; remember they have a lone pair!
• Configurationally stable at room temperature
• Certain anions (Cl ) can cause racemisation (interconversion of the enantiomers)
Me Me
O
Me
S
Me
Me
(R)-1-methyl-4(methylsulfinyl)benzene
O
O
S S
Me
Me Me
(R)-S-tert-butyl 2methylpropane-2sulfinothioate
t-Bu
S
H
N
Ph
(S)-N-benzylidene-2methylpropane-2-sulfinamide
• It should be stressed that the definition of a chiral compound is that it
...cannot be superimposed upon its mirror image
• A stereogenic centre (central chirality) is sufficient for the existence of
...chirality BUT it is not a requirement
• Furthermore, as we shall see, a compound can have a stereogenic
...centre BUT be achiral
123.702 Organic Chemistry
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Axial chirality
Axial chirality - Nonplanar arrangement of four groups about an axis
Spiro-compounds
Mirror
axis of
chirality
O
O
O
O
O
(R)-olean
O
olean
(R)-1,7dioxaspiro[5.5]undecane
attracts male olive flies
olean
(S)-1,7dioxaspiro[5.5]undecane
attracts female olive flies
Axial chirality and atropisomerism
Atropisomers - stereoisomers resulting from restricted rotation about a single bond
axis of
chirality
Mirror
PPh2
Ph2P
PPh2
Ph2P
(R)-(+)-BINAP
(R)-2-(diphenylphosphino)-1-(2-(diphenyl
phosphino)naphthalen-1-yl)naphthalene
(S)-(-)-BINAP
(S)-2-(diphenylphosphino)-1-(2-(diphenyl
phosphino)naphthalen-1-yl)naphthalene
123.702 Organic Chemistry
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Other forms of chirality
• Helical chirality - molecules that twist (like a cork-screw)
• Right-handed helix is denoted P (clockwise as you travel away from viewer)
Mirror
P-[8]helicene
M-[8]helicene
• Planar
chirality - chirality resulting from the arrangement of out-of-plane groups
...with respect to a plane
Mirror
Ph
Fe
PPh2
(S)-2-phenyl-1(diphenylphosphanyl)
ferrocene
Ph
Ph2P
Fe
(R)-2-phenyl-1(diphenylphosphanyl)
ferrocene
123.702 Organic Chemistry
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Enantiomers & optical rotation
H
Ph
• Each enantiomer has identical physical &
OH
HO
H
CO2H
Ph
CO2H
(R)-(-)-mandelic acid
131-133°C
23 –153
[α]D
(S)-(+)-mandelic acid
131-134°C
20 +154
[α]D
•
•
chemical properties (in an achiral environment)
Only differ by how they rotate plane polarised light
(rotate in opposite directions)
Enantiomers are said to be optically active
α
Optical rotation
[α]Dt =
light
source
light (λ)
polariser
plane
polarised light
sample
cell length l (dm)
reading
α
lxc
α = observed rotation
l ..= cell path (dm)
c .= concentration
.(g/ml [or g/100ml])
t .= temperature
• Not very useful as value is very unreliable (dependent on solvent, all factors listed
...above and more besides)
• Even sign (+/–) can change depending on concentration!!
123.702 Organic Chemistry
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Enantiomeric excess
• Optical purity - an outdated measurement of the enantiomeric excess (amount of
two enantiomers) in a solution / mixture
• If a solution contains only one enantiomer, the maximum rotation is observed...
H NH2
CO2H
measure rotation
derive [α]D = +14
100% (+) enantiomer
100% of maximum
observed rotation
100% enantiomer
excess
measure rotation
derive [α]D = -14
100% (–) enantiomer
100% of maximum
observed rotation
100% enantiomer
excess
H2N H
CO2H
• The observed rotation is proportional to the amount of each enantiomer present...
123.702 Organic Chemistry
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Enantiomeric excess II
=
90% (+) enantiomer
10% (–) enantiomer
+
10% anticlockwise
10% of major
enantiomer is
‘cancelled out’
80% of maximum
rotation observed
80% e.e.
50% clockwise
50% of major
enantiomer is
‘cancelled out’
0% of maximum
rotation observed
0% e.e.
+
=
50% (+) enantiomer
50% (–) enantiomer
90% clockwise
50% anticlockwise
• Racemate (racemic mixture) - 1 to 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 & purity measured in terms of enantiomeric excess (e.e.)
•
Enantiomeric excess (% ee) = [R] – [S] = %R – %S
[R] + [S]
How do we measure enantiomeric excess?
123.702 Organic Chemistry