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CH402 Asymmetric catalytic reactions
Prof M. Wills
Think about chiral centres.How would you make these products?
H2N CO2H
Ph
H
PhNMe2
OHH
Ph
OHH
R2
R1H
O
EtO
O
Ph
H
Think about how you would make them in racemic form first, then worry about the asymmetric versions! What does a catalyst need to be able to provide in a catalytic version?
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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
R2R1H
reducingagent
NR
R2R1
NHR
R2R1H
reducingagent
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
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Examples of reactions which form chiral centres, cont…
Dihydroxylation of C=C bonds:
R2R1
R3R4
R2R1
R3R4
OHi) OsO4
ii) hydrolysis
OH
Hydrocyanation of C=O bonds:
O
R2R1
OH
R2R1
HCN
CN
Hydrovinylation of C=C bonds: Addition of Grignard reagent to C=O bonds:
R2R1
R3R4
R2R1
R3R4CH2=CH2
catalyst
H
O
R2R1
OH
R2R1i) RMgBr
Rii) acid workup
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Examples of reactions which form chiral centres, cont. 2…
Enolate alkylation: Aldol reaction:
Diels-Alder (cycloaddition):
And many, many more….
R2R1
R3O
R2R1
R3R-X
Enolate(formed by ketone deprotonation)
R
O
R2R1
R3O
R1
R3
RCHO
EnolateR2
O
(aldehyde) OH
R
H(three chiralcentres)
Hydroformylation of C=C bonds:
R2R1
R3R4
R5
R7
R6
R8R2
R1
R3R4R5
R7
R6
R8
Fourchiral centres
R2R1
R3R4
R2R1
R3R4CO, H2
catalyst
H
OH
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What properties are required of an asymmetric catalyst?
Turnover,
rate enhancement,
selectivity
The catalyst must recognise the reagents, accelerate the reaction, direct the reaction to one face of a substrate and release the product:
catalyst
substrate 1 substrate 2
+catalyst
+recognition
reaction
(a bond forms)
catalyst
+
release
Product!
Catalyst recycled
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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 inan asymmetric manner?
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.
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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
O
CO2EtO
O CO2Et
Ti
Ti
OO
O
O OH
OH
2 x iPrO ligandsreplace the departing producthence the catalyst is regenerated.
The substrateand oxidantreplace twoOiPr ligands.
product
side-product
The oxygen atom isdirected to the alkene.The alkene is above the peroxide.
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Asymmetric epoxidation of alkenes using Mn/Salen complexes(Jacobsen epoxidation):
OO
N
O
NMn
H H
tBu
ButtBu
But
catalyst -5 mol%
IO
(hypervalnet iodinereagent)Source of oxygen.
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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Asymmetric hydrogenation for the synthesis of amino acids:
Addition of hydrogen to an acylamino acrylate results in formation of an amine acid precursor.
The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I) results in formation of a catalyst for asymmetric reactions.
Ph
HO2C NH
O
N-acylated amine acid.
H2
Rh. catalystPh
HO2C NH
O
-acylamino acrylate
H
S
<1 mol%
P P P Rh PS S
.. ..
RR-DiPAMP = a homochiral ligand DiPAMP coordinated to Rh(I)
OMe
MeOOMe
MeO
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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.
Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high enantioselectivity.
Rh/DiPAMP
P Rh P
OMe
OMe
Ph
HO2C NH
O P Rh P
OMe
OMe
Ph
CO2HNH
O
More stable,but less reactivecomplex
Less stable, but more reactive - leads to product
Ph
CO2HNH
O
H2
HH
H
S
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Asymmetric catalysis - hydrogenation
Other chiral diphosphines are not chiral at P, but contain a chiral backbone which ‘relays’ chirality to conformation of the arene rings.
Rh/Diphosphine complex
P Rh P
face
face
edge
edge
PPh2
PPh2
O
O
PPh2
PPh2H
H
S-BINAP
PPh2
PPh2H
H
Chiraphos
DIOP
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Asymmetric catalysis – Ketone reduction
The reduction of a ketone to a secondary alcohol is a perfect reaction for asymmetric catalysis:
O HO Hi) Borane (BH3),oxazaborolidine catalyst
N BO
PhPhH
Me
ii) hydrolysis (work up)
Oxazaborolidinecatalyst:
How it works:O
BH
Ph
PhN
BO
Me
HHH
Concave moleculehydride directed to one face.
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Asymmetric catalysis – Ketone reduction by pressure hydrogenation (I.e. hydrogen gas)
Ph2P
PPh2
Ru NNH2
Ph
Ph
H
H
Mechanism
HH
OMe
Ph
Ph2P
PPh2
Ru NNH2
Ph
PhH
H
H
OHMe
Ph
H2
O HO H
H2 , solvent
Ph2P
PPh2
Ru
H2N
NH2
Ph
Ph
H
H
Very high e.e.from very lowcatalyst loadings
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Asymmetric catalysis – Isomerisation
Ph2P
PPh2
[Rh/S-BINAP]
Rh
NMe2 NMe2
Isomerisation (not a reduction!)
H
O
H H
R-citro-nellal, 96-99% e.e.
ZnBr2
then H2, Ni cat (to reduce alkene)
H
OH
(-)-menthol
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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-prolineO
Now this IS a chiral centre-S configuration
O
O
The enantiomericcompound is:
O
Major product
Mechanism is via: O
NO
HO2C
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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:
20 mol%O O
OTBS
H
O 3 mol% water, rt 2 days.TBSO
O
OtBu
CO2HH2N
O OH
OTBS OTBSOO
68%, major product: D-fructose precursor
(it turns out that most amines act as catalysts!)
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Asymmetric catalysis – Organocatalysis Other applications
catalysed by:
Other applications include:
Diels-Alder reactions:
H
O
NH
CO2H
L-proline
Asymmetric reductiions:
and oxidations:
R
+
or pyrrolidines:
NH
Ph NH
PhPh
or other N-heterocycles:
NH
NMe
CO2H
O
Ph
O+
OH
R
PhNH
H HCO2EtEtO2C
O
PhH
H
O
R
+ RO
OH H
O
R
O
catalyst
catalyst
catalyst
(Hantzsch ester-hydride source)
Can you work out the mechanisms?
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Asymmetric catalysis – Enolate alkylation
OClCl
MeO
10 mol% (i.e. 01 eq.) Catalyst(below), 50% NaOH-toluene
CH3Cl
OClCl
MeO
98% yield94% e.e.
several steps
OClCl
O
CO2H indacrinone
The reaction proceeds via a complex in which the catalyst and the enolateare bound by a hydrogen bond (at least, that's the theory):
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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Asymmetric catalysis – Enolate alkylation for synthesis of amino acids.
Ph N
10 mol% Catalyst (below),
50% NaOH - toluenePhCH2Br
full conversion90-95% e.e.
several steps
By using an amino acid precursor with a relatively low pKa, it is possible to alkylate under relatively mild conditions:
Think about the mechanismand the enantiocontrol.
N
O
N
HHCatalyst:
Ph
OtBu
O
Ph N
Ph
OtBu
O
Ph
H3NO
O
Ph
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Asymmetric catalysis – Addition to an aldehyde (C-C bond forming reaction) – for interest only.
H
O
H
HO Et
Et2Zn, toluene (solvent)
(-)-DAIB (see below)See table for results
NMe2
OH
NMe2
OH
(-)-DAIB
(two pictures of the same molecule)
Results:
mol% DAIB used(relative to aldehyde)
0 (i.e. none)
2 (0.02 eq.) 100 (1.0 eq.)
Yield
0%
97%
0%
E.e.
-
98
-
How come a little bit of amino alcoholcatalyses the reaction, but a lot of it doesn't?