sintesis asimetri (ngajar)
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Asymmetric synthesis
Asymmetric synthesis
Asymmetric synthesis, also called chiralsynthesis, enantioselective synthesis or
stereoselective synthesis, is organic synthesis
which introduces one or more new and desired
elements of chirality. elements of chirality.
This is important in the field of pharmaceuticals
because the different enantiomers or
diastereomers of a molecule often have
different biological activity.
Introduction
• Biologically active molecules are also chiral
• Enantiomers possess different types of activityactivity– Both are active, have different potencies
– Both have similar activity
– Both are active but type of activity is different.
– Only one enantiomer is active, other is devoid of activity
Examples
Hypertensive agent L-Methyldopa
HO
HO
NH3+
CO2-
Me
NMe2
Ph
OCOEt
Ph
Ph
OCOEt
Ph
NMe2
Ph
Ph
DarvonNovrad
Propoxyphene – both enantiomers are biologically active. D isomer is an analgesic while L isomer has antitussive property
Chiral Catalysis for Therapeutic Drugs
• Organisms sense the chirality of bioactive
compounds– Carvone enantiomers bind different chiral taste and odor sensors:
• (S)-Carvone is a component of Dill and Caraway flavor
• (R)-Carvone is a component of Spearmint flavor• (R)-Carvone is a component of Spearmint flavor
Limonene enantiomers bind different chiral
taste and odor sensors:
• (R)-Limonene is a component of Orange flavor
• (S)-Limonene is a component of Lemon flavor
Aspartame enantiomers bind different chiral taste and
odor sensors:
• One enantiomer of Aspartame is 160 times sweeter than
sugar
• The other enatiomer tastes bitter
Chiral Drugs
• Drugs are (or have been) frequently prepared as RacemicMixtures– Usually, only one enantiomer is biologically active
– The other was generally assumed to be completely inactive
• Thalidomide is an example where the “silent” enantiomerwas actually deadly
Other Examples
(S)-asparagine (R)-asparagine
H2N
O
OH
NH2
O
O
OH
H2N H
HO
OH NH2
pahit manis
Estrone
(+)-Estrone (-)-Estrone
O O
Sexual hormone inactives
HO
HH
OH
HH
1-chloro-2,3-propanediol
(R)-1-chloro-2,3-propanediol (S)-1-chloro-2,3-propanediol
Cl OH HO Cl
poison medicinal drug
Cl OH
HO H
HO Cl
H OH
All of our proteins are made from single enantiomer amino acids
– Organisms only use L-amino acids
Organisms primarily use D-sugars
L-amino acid D-amino acid
Organisms’ responses to enantiomers
• Drug receptor sites (usually proteins) are themselves chiral
• Chiral drugs may not be able to bind effectively to elicit the
correct response
Enantiomeric Transition States
Energy
O O
Me MePh PhH-
H
Ph
Me H Me
Ph
mirror
Enantiomeric transition states
OH OH
R S
Examples of reactions which form chiral centres
Hydrogenation of C=C, C=O, C=N bonds:
R2R1
R3R4
R2R1
R3R4
H
H
H2 gas
catalyst
O
R2R1
OH
R2R1
H
reducingagent
NR NHRreducingagent
16
R2R1 R2R1
H
agent
Hydroboration of C=C bonds:
R2R1
R3R4
R2R1
R3R4
OH
H
i) BH3
ii) H2O2
Epoxidation of C=C bonds:
R2R1
R3R4
R2R1
R3R4
ORCO3H
Examples of reactions which form chiral centres, cont…
Dihydroxylation of C=C bonds:
R2R1
R3R4
R2R1
R3R4
OH
i) OsO4
ii) hydrolysis
OH
Hydrocyanation of C=O bonds:
O
R2R1
OH
R2R1
HCN
CN
17
Hydrovinylation of C=C bonds: Addition of Grignard reagent
to C=O bonds:
R2R1
R3R4
R2R1
R3R4CH2=CH2
catalyst
H
O
R2R1
OH
R2R1
i) RMgBr
Rii) acid workup
Examples of reactions which form chiral centres, cont. 2…
Enolate alkylation: Aldol reaction:
R2R1
R3O
R2R1
R3
R-X
Enolate(formed by ketone deprotonation)
R
O
R2R1
R3O
R1
R3
RCHO
EnolateR2
O
(aldehyde) OH
R
H
(three chiralcentres)
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Diels-Alder (cycloaddition):
And many, many more….
Hydroformylation of C=C bonds:
R2R1
R3R4
R5
R7
R6
R8
R2
R1
R3R4R5
R7
R6
R8
Fourchiral centres
R2R1
R3R4
R2R1
R3R4CO, H2
catalyst
H
OH
Asymmetric epoxidation of alkenes (1980s)
R2R1
R3R4
R2R1
R3R4
ORCO3H
Sharpless discovered that a combination of diethyl tartrate, titanium isopropoxide and a peroxide.
But it requires an allylic alcohol as substrate. The oxidant is used stoichiometrically (i.e. you need one
equivalent), but the titanium and tartrate are used in catalytic amounts (ca. 5 mol%).
Mechanism? Could you modify this in
an asymmetric manner?
t-butyl peroxide
19
The (-)-diethyl tartrate gives the
opposite enantiomer.
OOH
OO
H
t-butyl peroxide(oxygen source)
Ti(OiPr)4 (metal for complex formation)
OH
CO2EtHO
HO CO2Et(+)-diethyl tartrate (source of chirality)
70-90% yield, >90% e.e.
How the Sharpless epoxidation (of allylic alcohols) works (catalytic cycle):
EtO2C O
OEtO2C
CO2EtO
O CO2Et
Ti
Ti
OiPr
PrOi
OiPr
OiPr
The tartrate and metal form a complex:
O
CO2EtO
O CO2Et
Ti
Ti
O O
OOH
OH
O
The substrateand oxidant
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O
CO2EtO
O CO2Et
Ti
Ti
OO
O
O OH
OH
2 x iPrO ligandsreplace the departing producthence the catalyst is regenerated.
and oxidantreplace twoOiPr ligands.
product
side-product
The oxygen atom isdirected to the alkene.The alkene is above the peroxide.
Asymmetric epoxidation of alkenes using Mn/Salen
complexes (Jacobsen epoxidation):
N N
H H
catalyst -5 mol%
The iodine reagent transfers its oxygen atom to Mn, then the Mn tranfers in to the alkene
in a second step. The chirality of the catalyst controls the absolute configuration.
Advantage? You are not limited to allylic alcohols.
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O
O
N
O
N
Mn
tBu
ButtBu
But
I
O
(hypervalnet iodinereagent)Source of oxygen.
Asymmetric hydrogenation for the synthesis of amino acids:
Addition of hydrogen to an acylamino acrylate results in formation of an amine acid
precursor.
Ph
HO2C NH
O
N-acylated amine acid.
H2
Rh. catalyst
Ph
HO2C NH
O
αααα-acylamino acrylate
H
S
<1 mol%
22
The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I)
results in formation of a catalyst for asymmetric reactions.
P P P RhP
S S.. ..
RR-DiPAMP = a homochiral ligand DiPAMP coordinated to Rh(I)
OMe
MeOOMe
MeO
Asymmetric catalysis - hydrogenation
Rh-diphosphine complexes control asymmetric induction by controlling the face of the alkene
which attaches to the Rh. Hydrogen is transferred, in a stepwise manner, from the metal to
the alkene. The intermediate complexes are diastereoisomers of different energy.
Rh/DiPAMP
P Rh P
OMe
OMe
Ph
HO C N
OP Rh P
OMe
OMe
Ph
CO HN
O
Less stable, but more reactive - leads to product
23
Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high
enantioselectivity.
HO2C NH
CO2HNH
More stable,but less reactivecomplex
Ph
CO2HNH
O
H2
HH
H
S
Asymmetric catalysis – Ketone reduction
The reduction of a ketone to a secondary alcohol is a perfect reaction for
asymmetric catalysis:
OHO H
i) Borane (BH3),
oxazaborolidine catalyst
ii) hydrolysis (work up)
24
NB
O
PhPhH
Me
Oxazaborolidinecatalyst:
How it works:O
B
H
Ph
PhN
B
O
Me
HHH
Concave moleculehydride directed to one face.
Asymmetric catalysis – Ketone reduction by pressure
hydrogenation (i.e. hydrogen gas)
OHO H
H2 , solvent
Ph2P
PPh2
Ru
H2N
NH2
Ph
Ph
H
H
Very high e.e.from very lowcatalyst loadings
25
Ph2P
PPh2
RuN
NH2
Ph
Ph
H
H
Mechanism
H
H
OMe
Ph
Ph2P
PPh2
RuN
NH2
Ph
PhH
H
H
OHMe
Ph
H2
H2 , solvent
Asymmetric catalysis – Isomerisation
Ph2P
PPh2
[Rh/S-BINAP]
Rh
NMe2 NMe2
Isomerisation (not a reduction!)
H
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Isomerisation (not a reduction!)
O
H H
R-citro-nellal, 96-99% e.e.
ZnBr2
then H2, Ni cat (to reduce alkene)
H
OH
(-)-menthol
Asymmetric catalysis – Organocatalysis (no metals)
10 mol%:
Some time ago, it was found that proline catalyses the asymmetric cyclisation of a diketone (known as the Robinson annelation reaction).
O O
O
this is not a chiral centre
NH
CO2H
L-proline
O
Now this IS a chiral centre-S configuration
O
Major product
27
O
The enantiomericcompound is:
O
Mechanism is via: O
N
O
HO2C
Asymmetric catalysis – Organocatalysis (no metals)
10 mol%:
This is now the basis for many other reactions e.g.:
H
O O
Aldols:
NH
CO2H
L-proline
Me
H
Me DMF
H
O OH
Me Me
90% yield
4:1 anti:syn
anti product e.e.: 99%
and even more complex ones:
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and even more complex ones:
20 mol%O O
OTBS
H
O3 mol% water, rt 2 days.TBSO
O
OtBu
CO2HH2N
O OH
OTBS OTBSO
O
68%, major product: D-fructose precursor
(it turns out that most amines act as catalysts!)
Asymmetric catalysis – Organocatalysis
Other applications
catalysed by:
Other applications include:
Diels-Alder reactions:
H
O
NH
CO2H
L-proline
Asymmetric reductiions:
R
+
or pyrrolidines:O
+
O
H
R
H H
CO EtEtO C
O
catalyst
catalyst
29
and oxidations:
or pyrrolidines:
NH
PhNH
PhPh
or other N-heterocycles:
NH
NMe
CO2H
O
Ph
+
PhNH
CO2EtEtO2C
Ph
H
H
O
R
+ RO
OH
H
O
R
O
catalyst
catalyst
(Hantzsch ester-hydride source)
Can you work out the mechanisms?
Asymmetric catalysis – Enolate alkylation
OCl
Cl
MeO
10 mol% (i.e. 01 eq.) Catalyst
(below), 50% NaOH-toluene
CH3Cl
OCl
Cl
MeO
98% yield94% e.e.
several steps
The reaction proceeds via a complex in which the catalyst and the enolateare bound by a hydrogen bond (at least, that's the theory):
O HH
30
several steps
OCl
Cl
O
CO2H indacrinone
OCl
Cl
MeO
The enolate is formedby deprotonation by hydroxide.
N
O
N
HH
CF3
Catalyst:
Enolate is methylatedon the front face (as illustrated)
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