ch402 asymmetric catalytic reactions prof m. wills
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CH402 Asymmetric catalytic reactions Prof M. Wills. Think about chiral centres. How would you make these products?. 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?. - PowerPoint PPT PresentationTRANSCRIPT
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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?