advanced organic chemistry - massey universitygjrowlan/stereo/lecture1.pdfadvanced organic chirality...
TRANSCRIPT
Gareth J. Rowlands
Advanced Organic Chemistry
Advanced organic
1
Advanced organic
Enantioselective synthesis
• Nature yields an enormous variety of chiral compounds• A change in stereochemistry can have profound effects
2
Why is enantioselective synthesis important?
NMe
O HO
H O
(1R,2R,3S,5S)-2-acetyl-8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl benzoate
cocainestimulant
NHN
(S)-3-(1-methylpyrrolidin-2-yl)pyridine
nicotinetoxin / stimulant
OH
O
O
O
AcOMeO2C H
OH
O OHCO2Me
OO O
O
azadiractinanti-feedant
Me CO2H
NH2
(S)-2-aminopropanoic acidL-alanine
mammalian amino acid
Me CO2H
NH2
(R)-2-aminopropanoic acidD-alanine
bacterial cell wall
N
O
O
NHO
OH
(S)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
(S)-thalidomideteratogen (birth defects)
Advanced organic
Chirality and biology
• Enzymes & receptors are invariably chiral• Chiral drugs can interact with these to give two diastereomeric complexes• Imagine the hand below is the enzyme, it can form two very different complexes
depending on the chirality or “handness” of the drug it interacts with...
3
HIV protease + inhibitor Nicotinic receptor
Advanced organic
Chirality and biology II
• As you can imagine, these two complexes can have very different effects• The three drugs above highlight the possible effects of using the “wrong” compound• As a result we must have methods to prepare the correct enantiomers
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OHNH
OHHN
(R)-1-(isopropylamino)-4-(naphthalen-1-yl)butan-2-ol
(–)-propanololβ-blocker for heart disease
(S)-1-(isopropylamino)-4-(naphthalen-1-yl)butan-2-ol
(+)-propanololcontraceptive
CO2H
NH2
HS
(S)-2-amino-3-mercapto-3-methylbutanoic acid
D-penicillaminetreats chronic arthritus
CO2H
NH2
HS
(R)-2-amino-3-mercapto-3-methylbutanoic acid
L-penicillaminetoxic
NH
HN
OH
Et OH
Et(S,S)-2-[2-(1-Hydroxymethyl-
propylamino)-ethylamino]-butan-1-olEthambutol
tuberculostatic (anti-TB)
NH
HN
OH
EtOH
Et(R,R)-2-[2-(1-Hydroxymethyl-
propylamino)-ethylamino]-butan-1-olcauses blindness
Advanced organic
Revision: 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
• The easiest to identify are the cis-trans isomers found with sp2 systems• Alkenes should be assigned E or Z using Cahn-Ingold-Prelog rules• We are not going to look at these BUT will see their effects in enolate chemistry
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B
A C
DA & C have highest priority
alkene = Z
B
A C
DA & D have highest priority
alkene = E
• Imines are treated in a similar manner
NB
A C
A has highest priorityimine = Z or cis
B has highest priorityimine = E or trans
NB
A C
Advanced organic
One stereogenic centre: chirality on an atom• Chiral compounds - 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 MeH
chiral centre
Advanced organic
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
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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
Advanced organic
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• Not very useful as value is very unreliable (dependent on solvent & all factors below)• Even sign (+/–) can change depending on concentration!!
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α
light source
polariser plane polarised light
samplecell length l (dm)
readinglight (λ)
Ph CO2H
OHH
(R)-(-)-mandelic acid131-133°C[α]23 –153D
Ph CO2H
HHO
(S)-(+)-mandelic acid131-134°C[α]20 +154D
[α]t = αDl x c
optical rotation
α = observed rotation; l = cell path (dm); c = concentration g/ml (or g/100ml); t = temperature
Advanced organic
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
Advanced organic
PAr Ph
OMe
1
2 3S
Me Tol
O
1
23
SMe
O
Me
1
23
4SMe
O
Me
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
• Define priorities according to CIP
• Point lowest priority (4) away from viewer
• Draw line from 1 to 3
• Line is anti-clockwise so (R)
SMe
O
Me(R)-methyl-4-
methylphenylsulfoxide
Advanced organic
Central chirality at elements other than carbon
• As last two examples indicated it is not just carbon that can have central chirality• Any tetrahedral or pyramidal atom with four (three) different substituents can be chiral• Nitrogen / amines have the potential to be chiral...
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Chiral Nitrogen compounds
• But rapid pyramidal inversion normally prevents isolation of either enantiomer• If substituents are constrained in a ring then rigid structure prevents inversion• Quaternary ammonium salts (below) can be isolated enantiomerically pure• Racemisation has been observed, presumably via dissociation...
N
N
Me
Me
Tröger's base(5S)-2,8-Dimethyl-6H,12H-5,11-
methano-dibenzo[b,f][1,5]diazocine
R1N R3R2
R1N R3R2
EtNi-PrMe
Ph
Cl
Advanced organic
Central chirality at phosphorus
• Trigonal pyramidal phosphorus (III) is configurationally stable below 200°C• P-chiral phosphines have a rich history as chiral ligands
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PMe
MeOP Me
MeO
X(S)-cyclohexyl(4-
methoxyphenyl)(methyl)phosphine
• Tetrahedral phosphorus (V) is configurationally stable
PO
O
Pht-Bu
(S)-naphthalen-1-yl tert-butyl(phenyl)phosphinate
Advanced organic
Central chirality at sulfur
• 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
(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 it is not a requirement• Furthermore, as we shall see, not all compounds with a stereogenic centre are chiral!!
Advanced organic
HO2C
H
CO2H
HD-Fecht acid
(S)-spiro[3.3]heptane-2,6-dicarboxylic acid
Axial chiralityAxial chirality - Nonplanar arrangement of four groups about an axis
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Spiro-compounds
CO2H
H
HO2C
HL-Fecht acid
(R)-spiro[3.3]heptane-2,6-dicarboxylic acid
Mirror
axis of chirality
CO2H
H
H CO2H
CO2H
H
HHO2C
Mirror
Viewed along axis
OO
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
Mirror
axis of chirality
RH2C OR
CH2R
OR1
2
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anti-clockwise = (S)
Advanced organic
Axial chirality II
Axial chirality and atropisomerismAtropisomers - stereoisomers resulting from restricted rotation about a single bondMostly commonly found in hindered biaryls
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AllenesMirror
CCl
H Cl
HC
Cl
HCl
H(R)-1,3-dichloropropa-
1,2-diene(S)-1,3-dichloropropa-
1,2-diene
axis of chirality
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
Advanced organic
Axial chirality III• Atropisomerism is not just found in biaryl compounds• Any molecule in which rotation is restricted sufficiently to allow isolation of each
isomer can be chiral...
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MeOCHO
NOMeO
CHO
NO
Xrotation around
central bond
• Atropisomerism is found in nature• Vancomycin is an anti-bacterial• Kotanin is from rice mold
OO
MeO
Me
MeO
Me OMe
O
OMe
O
kotanin
NH
HN
HN
NH
HN
NH
NHMe
Me
Me
OO
O
O
O
HO OHOH
O O
O
NH2
OHHO
O
Cl
Cl
O
HOHO
OH
OOMe
NH2OH
Me
HO2CO
Vancomycin
Advanced organic
Helicity
• Molecules that twist like a helix, propeller or screw• Right-handed helix is denoted P (clockwise as you travel away from viewer)• Interestingly, [8]helicene racemises (1:1 mixture of enantiomers) readily at 293°C!
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P [8]helicene M [8]helicene
Mirror
Advanced organic
Planar chirality• Planar chirality - chirality resulting from the arrangement of out-of-plane groups
with respect to a plane, called the chiral plane• In [2.2]paracyclophane the more substituted benzene ring is considered the chiral
plane
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NH2
(R)-4-amino[2.2]para-cyclophane
H2N
(S)-4-amino[2.2]para-cyclophane
Mirror
NH2
plane of chirality
Advanced organic
Planar chirality II• Probably the most important planar chiral compounds are ferrocene derivatives• These have found considerable use in enantioselective catalysis
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Fe PPh2
PhFePh2P
Ph
(S)-2-phenyl-1-(diphenylphosphanyl)
ferrocene
(R)-2-phenyl-1-(diphenylphosphanyl)
ferrocene
Mirror
• An interesting example of planar chirality is found in some (E)-cycloalkenes
H
H
(R)-(E)-cyclooctene
H
H
(S)-(E)-cyclooctene
Mirror