asymmetric synthesis - massey universitygjrowlan/stereo2/lecture1.pdf · 2007. 5. 1. · asymmetric...
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GarethRowlandsGareth J. Rowlands
Asymmetric Synthesis
123.702 Organic Chemistry
1
123.702 Organic Chemistry
The importance of chirality
• 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
2
NHMeN
nicotinetoxin / stimulant
Me CO2H
NH2
L-alaninemammalian amino acid
Me CO2H
NH2
D-alaninebacterial cell wall
OHNH
Me Me
(–)-propanololβ-blocker for heart disease
(+)-propanololcontraceptive
OHHN
MeMe NH
HN
OH
Et OH
Et
Ethambutoltuberculostatic (anti-TB)
NH
HN
OH
EtOH
Et
(R,R)-enantiomercauses blindness
123.702 Organic Chemistry
The importance of chirality
• 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
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NAME GLOBAL SALES2003 (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
ZOLOFT 3.4 SERTALINE Single Enantiomer Inhibitor of serotonin re-uptake
TOTAL 48.3
123.702 Organic Chemistry
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...
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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
Ph Me
OHHP
Ph MeHc
Xd
baX
a bc
chiral centre
123.702 Organic Chemistry
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 not have a plane of symmetry
5
Mirror plane
Mirror plane
rotaterotaterotate rotaterotate
Achiral• Mirror images are superimposable• Compound has a plane of symmetry
R4 R3chiral
R1≠R2≠R3≠R4
R2R1R4 R3achiral
R1=R1≠R3≠R4
R1R1
plane of symmetry running through central
carbon, hydrogen and OHACHIRAL
Me Me
H OH
123.702 Organic Chemistry
Me CO2H
H NH21
2Me CO2H
H NH21
Me CO2H
H NH2
Me NH2
CO2HH
1
2
3Me
H
CO2HNH2 Me NH2
HO2C H ≡
rotate around axis until lowest priority points
away from you
Me CO2H
H NH21
23
4
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)
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• 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)
Me CO2H
H NH2
alanine
Me CO2H
H NH2
(S)-alanine(S)-2-aminopropanoic acid
123.702 Organic Chemistry
PAr Ph
OMe
1
2 3
PO
MePh
12
3
4
MeO
PO
OMeMe
123
4
PO
OMeMe
12P
O
OMeMe
1
Defining absolute configuration II
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• Define priorities according to CIP
• Point lowest priority (4) away from viewer
• Draw line from 1 to 3
• Line is anti-clockwise so (S)
PO
OMeMe
(S)-(4-methoxyphenyl)methylphenyl
phosphine oxide
PO
OMeMe
123.702 Organic Chemistry
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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R1N R3R2
R1N R3R2
N
N
Me
Me
Tröger's base
• Trigonal pyramidal phosphorus(III) is configurationally stable below 200°C• Tetrahedral phosphorus (V) is configurationally stable
PMe
MeOP Me
MeO
X(S)-cyclohexyl(4-
methoxyphenyl)(methyl)phosphine
PO
O
Pht-Bu
(S)-naphthalen-1-yl tert-butyl(phenyl)phosphinate
123.702 Organic Chemistry
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)
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SMe
O
Me
(R)-1-methyl-4-(methylsulfinyl)benzene
OSS
Me
MeMe
MeMe
Me(R)-S-tert-butyl 2-methylpropane-2-
sulfinothioate
H Ph
NSO
t-Bu
(S)-N-benzylidene-2-methylpropane-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
Axial chiralityAxial chirality - Nonplanar arrangement of four groups about an axis
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Spiro-compoundsMirror
O
O
O
O
olean(R)-1,7-
dioxaspiro[5.5]undecaneattracts male olive flies
olean(S)-1,7-
dioxaspiro[5.5]undecaneattracts female olive flies
OO
axis of chirality
(R)-olean
Axial chirality and atropisomerismAtropisomers - stereoisomers resulting from restricted rotation about a single bond
Mirror
PPh2
PPh2
(R)-(+)-BINAP(R)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene
Ph2PPh2P
(S)-(-)-BINAP(S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)naphthalen-1-yl)naphthalene
axis of chirality
123.702 Organic Chemistry
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)
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• Planar chirality - chirality resulting from the arrangement of out-of-plane groups...with respect to a plane
P-[8]helicene M-[8]helicene
Mirror
Fe PPh2
PhFePh2P
Ph
(S)-2-phenyl-1-(diphenylphosphanyl)
ferrocene
(R)-2-phenyl-1-(diphenylphosphanyl)
ferrocene
Mirror
123.702 Organic Chemistry
Ph CO2H
OHH
(R)-(-)-mandelic acid131-133°C[α]23 –153D
Ph CO2H
HHO
(S)-(+)-mandelic acid131-134°C[α]20 +154D
Enantiomers & optical rotation
• Each enantiomer has identical physical & 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
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α
light source
polariser plane polarised light
samplecell length l (dm)
readinglight (λ)
[α]t = αDl x c
Optical rotation
α = observed rotationl ..= 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
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...
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CO2H
H NH2
measure rotationderive [α]D = +14
100% (+) enantiomer100% of maximum observed rotation 100% enantiomer excess
CO2H
H2N H
measure rotationderive [α]D = -14
100% (–) enantiomer100% of maximum observed rotation100% enantiomer excess
• The observed rotation is proportional to the amount of each enantiomer present...
123.702 Organic Chemistry
Enantiomeric excess II
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90% (+) enantiomer10% (–) enantiomer
= +90% clockwise10% anti-
clockwise80% of maximum rotation observed
80% e.e.
= +
50% (+) enantiomer50% (–) enantiomer
50% clockwise50% anti-clockwise
10% of major enantiomer is ‘cancelled out’
50% of major enantiomer is ‘cancelled out’
0% of maximum rotation observed
0% e.e.
• 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.)
• How do we measure enantiomeric excess?
Enantiomeric excess (% ee) = [R] – [S][R] + [S]
= %R – %S
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