asymmetric synthesis introduction. outline introduction introduction principles principles addition...
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Asymmetric SynthesisAsymmetric Synthesis
IntroductionIntroduction
Outline
IntroductionIntroduction PrinciplesPrinciples Addition to carbonyl compoundsAddition to carbonyl compounds α-Substitution using chiral enolatesα-Substitution using chiral enolates Asymmetric aldol reactionsAsymmetric aldol reactions Additions to C=C bondsAdditions to C=C bonds Reduction and oxidationReduction and oxidation RearrangementsRearrangements Hydrolysis and esterificationHydrolysis and esterification
VancomycinVancomycin
CH3
O
OH
HOHO
O
H3C
HO
NH2
O Cl
OHOH
-O2C
HO
O
NH
Cl
+NH2Me
H3C
CH3
OO
NH2
OH
NH
H
NHNHNH
HNH
OO
O
OO
OHO
Vancomycin modelsVancomycin models
NHNH peptide
O
O
HO2C
Me
Me
D-Ala-D-Ala terminus
NHNH Ph
O
O
HO2C
Me
Me
D-Ala-D-Ala model L-Ala-D-Ala model
NHNH Ph
O
O
HO2C
Me
Me
DefinitionsDefinitions Stereospecific reactionStereospecific reaction
• A reaction in which the configuration of the substrate A reaction in which the configuration of the substrate influences the configuration of the product, orinfluences the configuration of the product, or
• A reaction in which only a specific isomer reacts, in such A reaction in which only a specific isomer reacts, in such a way that its configuration influences the configuration a way that its configuration influences the configuration of the product.of the product.
Stereoselective reactionStereoselective reaction• A reaction in which one specific isomer is formed to a A reaction in which one specific isomer is formed to a
greater extent than any other.greater extent than any other. Asymmetric synthesisAsymmetric synthesis
• A synthesis in which the stereoisomers of a chiral A synthesis in which the stereoisomers of a chiral molecule are formed in unequal quantities.molecule are formed in unequal quantities.
StereodifferentiationStereodifferentiation
Enantiodifferentiating reactionEnantiodifferentiating reaction• Differentiation is provided by the reagent or Differentiation is provided by the reagent or
reaction environment, and refers to the reaction environment, and refers to the reagent’s ability to differentiate between reagent’s ability to differentiate between enantiofaces, enantiotopes, or enantiomers.enantiofaces, enantiotopes, or enantiomers.
Diastereodifferentiating reactionDiastereodifferentiating reaction• Reactions are influenced by chirality in the Reactions are influenced by chirality in the
substrate and form diastereomers in unequal substrate and form diastereomers in unequal quantities. May differentiate between quantities. May differentiate between diastereofaces, diastereotopes, or diastereofaces, diastereotopes, or diastereomers.diastereomers.
Introduction Biologically active molecules are also Biologically active molecules are also
chiralchiral Enantiomers possess different types of Enantiomers possess different types of
activityactivity• Both are active, have different potenciesBoth are active, have different potencies• Both have similar activityBoth have similar activity• Both are active but type of activity is different.Both are active but type of activity is different.• Only one enantiomer is active, other is devoid Only one enantiomer is active, other is devoid
of activityof activity
Examples
Hypertensive agent L-Hypertensive agent L-MethyldopaMethyldopa
Propoxyphene – both Propoxyphene – both enantiomers are enantiomers are biologically active. D biologically active. D isomer is an isomer is an analgesic while L analgesic while L isomer has isomer has antitussive propertyantitussive property
NMe2
Ph
OCOEt
Ph
Ph
OCOEt
Ph
NMe2
Ph
Ph
Darvon Novrad
HO
HO
NH3+
CO2-
Me
Potential Problems of Enantiomers & their Solution
In the racemic mixtureIn the racemic mixture • only half may have beneficial result so the dosage must only half may have beneficial result so the dosage must
be increased to reach the therapeutic windowbe increased to reach the therapeutic window• one enantiomer may have adverse effect when takenone enantiomer may have adverse effect when taken
To get pure enantiomersTo get pure enantiomers• Resolution of the racemate or intermediate in the Resolution of the racemate or intermediate in the
synthetic route – expensive & introduces disposal of synthetic route – expensive & introduces disposal of other enantiomerother enantiomer
• Use of enantiomerically pure starting material – must be Use of enantiomerically pure starting material – must be readily availablereadily available
Asymmetric Synthesis An array of synthetic methods which result in the An array of synthetic methods which result in the
desired transformation and control the absolute desired transformation and control the absolute stereochemistry of chiral centres created as a stereochemistry of chiral centres created as a result of the synthetic operations is called result of the synthetic operations is called asymmetric synthesisasymmetric synthesis
In order to achieve asymmetric synthesis one or In order to achieve asymmetric synthesis one or more components of the reaction must be chiral, more components of the reaction must be chiral, or chiral auxiliaries (stoichiometric or catalytic or chiral auxiliaries (stoichiometric or catalytic amounts) or catalysts can be usedamounts) or catalysts can be used
Chiral components could make the possible Chiral components could make the possible enantiomeric transition states diastereomeric, enantiomeric transition states diastereomeric, different energiesdifferent energies
Enantiomeric Transition States
Energy
mirror
Enantiomeric transition states
O O
Me MePh PhH-
OH
H
Ph
Me
OH
H Me
Ph
R S
Diastereomeric Transition States
Energy
O O
Me MePh PhAl(L*)2H2-
Diastereoisomeric transition states
PhMe2N
Me
PhHO
OH
H
Ph
Me
OH
H Me
Ph
R S
L* =
Example
ON
O O
ON
O OLi
LiN(iso-prop)2
ON
O O
Ph
ON
O O
Ph
a
b
Diastereomeric excess (d.e.) = (major diastereomer(%) – minor diastereomer (%))
= (% a - % b) = 99-1 = 98%
1 2
Use of Chiral Auxiliary
Prochiralsubstrate
+ Chiralauxiliary
Join substrate and
Chiral auxiliary
Prochiralsubstrate
Chiralauxiliary
Chiralauxiliary
Remove chiral
auxiliary and isolatemodified substrate
Modifiedsubstrate
Modifiedsubstrate
Chiralauxiliary
+
React at prochiral substrate to produce chiral center(s)
Cycle starts
Example of chiral auxiliary
OHN
O
BuLi
EtCOClProchiralsubstrate
ON
OO
LiN(iso-prop)2
PhCH2Br
ON
OO
Ph
LiOH
OHN
O
+OH
O
Ph Chiral, non-racemic product
Recovered chiral auxiliary
Chiralauxiliary
Evans AuxiliaryEvans Auxiliary
(S)-Valine
OH
O
SMe
OEtO OEt
O OHN
ONH2 NH2
Me2S.BH3 +K2CO3
Ph
H2N OH
EtO OEt
OK2CO3
Norephedrine Norephedrine-derived auxiliary
OHN
O
Ph
Why does it work?Why does it work?
ON
OO
Et2Als-cis
ON
OO
Et2Al
H
s-cis
ON
OO
Et2Al
H
s-trans
disfavoured by steric crowding
Requirements for Chiral AuxiliariesRequirements for Chiral Auxiliaries
Enantiomerically pureEnantiomerically pure Cheap and easy to obtain in quantityCheap and easy to obtain in quantity Easy to attach to substrateEasy to attach to substrate High and predictable control of High and predictable control of
stereoselectivitystereoselectivity Easy purification of diastereomersEasy purification of diastereomers Easy removal without loss of purityEasy removal without loss of purity Easy separation and recoveryEasy separation and recovery
Two chiral components (1)Two chiral components (1)
ON
OO
CHO
OH
N
O
O
O
+ Aldolreaction
> 400 : 1
Two chiral components (2)Two chiral components (2)
PhO
O
O
H
OMeO
CHO
O
CHO
O
Ph
O
Ph
OMe OMe+
+
4.5 : 1
PhO
O
OO O
O
Ph
O
Ph
++
8 : 1
OH
Ph
O
OH
O
OH
Ph Ph
Two chiral components (3)Two chiral components (3)Ph
O
O
OMeO O
O
Ph
O
Ph
OMe OMe+
+
O
OH
Ph
O
OH
O
OH
Ph Ph
40 : 1Matched pair
PhO
O
OMeO O
O
Ph
O
Ph
OMe OMe+
+
O
OH
Ph
O
OH
O
OH
Ph Ph
1 : 2Mismatched pair
Double asymmetric induction
Schematic Representation of Asymmetric Catalysis
Prochiralsubstrate
+ ChiralCatalyst
Catalyst-substrate
Complex forms
Prochiralsubstrate
ChiralCatalyst
Reaction occurs Under the control Of chiral catalyst
ChiralCatalyst
Modified substratedecomplexes from catalyst
Modifiedsubstrate
Modifiedsubstrate
ChiralCatalyst
+
Another catalyticcycle starts
Example of chiral catalyst
H
O
H
Et OH
Et2Zn +
98% ee
(Catalyst)
Me
NMe2
OH
MeMe
Methods for asymmetric synthesisMethods for asymmetric synthesis
Chiral reagent:Chiral reagent: No manipulations required, No manipulations required, but lacks generality.but lacks generality.
Chiral solvent:Chiral solvent: No practically useful No practically useful procedures.procedures.
Chiral solvating agent:Chiral solvating agent: As chiral reagent. As chiral reagent. Chiral auxiliary:Chiral auxiliary: Predictable, reliable, Predictable, reliable,
recycled.recycled. Chiral catalyst:Chiral catalyst: Ideal, but few catalysts Ideal, but few catalysts
give high ee and accept wide substrate give high ee and accept wide substrate range, and enantiomer mixtures are range, and enantiomer mixtures are obtained.obtained.
Update: Jones, J Chem Soc, Perkin 1 2002, 1-21
Questions ?