Transcript Handout

CH402
Asymmetric catalytic reactions
Prof M. Wills
Think about chiral centres.
How would you make these products?
H2N
H
H OH
CO2H
Ph
Ph
H OH
NMe2
H R1
O
H
Ph
EtO
R2
Ph
O
Think about how you would make them in racemic form first, then worry about the asymmetric
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versions! What does a catalyst need to be able to provide in a catalytic version?
Examples of reactions which form chiral centres
Hydrogenation of C=C, C=O, C=N bonds:
R
3
4
R
H2 gas
2
R1
R
catalyst
R
H
4
R3
2
R1
R
O
R2
R1
H
R2
R1
R
R1
R
i) BH3
2
R
ii) H2O2
R4
OH
R3
reducing
agent
NHR
R2
R1
H
Epoxidation of C=C bonds:
Hydroboration of C=C bonds:
3
R2
R1
H
NR
4
OH
reducing
agent
4
R
R3
RCO3H
R4
R3
O
R2
R1
H
R1
R2
R1
R2
2
Examples of reactions which form chiral centres, cont…
Hydrocyanation of C=O bonds:
Dihydroxylation of C=C bonds:
R
4
3
R
2
R1
R
i) OsO4
ii) hydrolysis
R4
OH
R3
R2
OH
R1
O
R1
R3
R2
CH2=CH2
catalyst
R2
R1
HCN
R2
CN
R1
Addition of Grignard reagent
to C=O bonds:
Hydrovinylation of C=C bonds:
R4
OH
R2
R1
OH
O
R3
R4
R1
R2
i) RMgBr
ii) acid workup
R2
R1
R
H
3
Examples of reactions which form chiral centres, cont. 2…
Enolate alkylation:
O
R3
R1
R2
R-X
Aldol reaction:
R3
O
R2
R1
R
O
R3
R1
R2
4
R6 R
R8
R7
R1
(three chiral
centres)
H
OH
(aldehyde)
R1
R2
R
Hydroformylation of C=C bonds:
Diels-Alder (cycloaddition):
R6 R5
R3
RCHO
Enolate
Enolate
(formed by ketone deprotonation)
R5
O
R3
R4
R3
R2
R2
R1
R8 R7
Four
chiral centres
H
R4
R1
And many, many more….
R3
R2
CO, H2
catalyst
O
R3
R4
R2
R1
H
4
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 recycled
catalyst
+
+
recognition
substrate 1
reaction
catalyst
(a bond forms)
substrate 2
catalyst
+
release
Product!
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Asymmetric epoxidation of alkenes (1980s)
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R
R3
R4
RCO3H
R3
Mechanism? Could you modify this in
an asymmetric manner?
O
R1
R1
R2
R2
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%).
t-butyl peroxide
(oxygen source)
O
O
H
Ti(OiPr)4
(metal for complex
formation)
OH
HO
HO
O
CO2Et (+)-diethyl
tartrate (source of
CO2Et chirality)
OH
70-90% yield, >90% e.e.
The (-)-diethyl tartrate gives
the opposite enantiomer.
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How the Sharpless epoxidation (of allylic alcohols) works
(catalytic cycle):
The tartrate and metal form a complex:
EtO2C
O
OiPr
OiPr
O
OH
Ti
EtO2C
O
Ti
O
CO2Et
OH
O
OH
product
O
OiPr
CO2Et
The substrate
and oxidant
replace two
OiPr ligands.
O
O
Ti
PrOi
O
2 x iPrO ligands
replace the departing product
hence the catalyst is regenerated.
CO2Et
O O
CO2Et
Ti
The oxygen atom is
directed to the alkene.
The alkene is above the peroxide.
Ti
O
O
OH
O
O
O
CO2Et
O O
CO2Et
Ti
side-product
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Asymmetric epoxidation of alkenes using Mn/Salen complexes
(Jacobsen epoxidation):
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.
catalyst 5 mol%
H
H
N
N
Mn
But
O
tBu
O
tBu
But
O
I
O
(hypervalnet iodine
reagent)
Source of oxygen.
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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.
<1 mol%
Ph
Rh. catalyst
O
HO2C
Ph
N
H
HO2C
H
H2
-acylamino acrylate
O
S
N
H
N-acylated amine acid.
The combination of an enantiomerically-pure (homochiral) ligand with rhodium(I) results
in formation of a catalyst for asymmetric reactions.
MeO
P
P
..
..
OMe
RR-DiPAMP = a homochiral ligand
OMe
P
S
Rh
P
S
MeO
DiPAMP coordinated to Rh(I)
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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.
Rh/DiPAMP
OMe
OMe
Ph
P
HO2C
Rh
Ph
P
O
OMe
P
O
Rh
N
H
P
CO2H
N
H
More stable,
but less reactive
complex
OMe
Less stable, but
more reactive leads to product
H2
Ph
O
H H
S
N
H
H
CO2H
Using Rh(DIPAMP) complexes, asymmetric reductions may be achieved in very high
enantioselectivity.
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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.
PPh2
Rh/Diphosphine complex
PPh2
H
PPh2
S-BINAP
P
PPh2
H
H
O
PPh2
O
PPh2
Chiraphos
face
edge
face
Rh
P
edge
H
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:
HO H
O
i) Borane (BH3),
oxazaborolidine catalyst
ii) hydrolysis (work up)
Ph
Oxazaborolidine
catalyst:
H
Ph
Ph
O
N
B
Concave molecule
hydride directed to one face.
O
How it works:
N
H Ph
B
Me
O
B
H
H
H
Me
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Asymmetric catalysis – Ketone reduction by
pressure hydrogenation (I.e. hydrogen gas)
Ph2
P
H
H2
N
Ph
N
H2
Ph
Ru
P
Ph2
O
H
Very high e.e.
from very low
catalyst loadings
H2 , solvent
Mechanism
Ph
O
Me
Ph2
P
P
Ph2
H
Ru
H
HO H
H
H
N
N
H2
Ph
OH
Me
H
Ph
Ph
H2
Ph2
P
P
Ph2
Ru
H
N
H
N
H2
Ph
Ph
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Asymmetric catalysis – Isomerisation
Ph2
P
Rh
PPh2
H
NMe2
NMe2
[Rh/S-BINAP]
Isomerisation (not a reduction!)
H
H
ZnBr2
OH
(-)-menthol
then H2, Ni cat (to reduce alkene)
H
O
R-citronellal, 96-99% e.e.
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Asymmetric catalysis – Organocatalysis (no metals)
Some time ago, it was found that proline catalyses the asymmetric cyclisation of a
diketone (known as the Robinson annelation reaction).
this is not a
chiral centre
O
Now this IS a chiral centreS configuration
L-proline
O
10 mol%:
N
H
CO2H
O
Major product
O
O
The enantiomeric
compound is:
Mechanism is via: O
O
N
O
HO2C
O
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Asymmetric catalysis – Organocatalysis (no metals)
This is now the basis for many other reactions e.g.:
L-proline
Aldols:
O
O
10 mol%:
N
H
H
H
Me
Me
90% yield
O
CO2H
OH
4:1 anti:syn
H
Me
DMF
Me
anti product e.e.: 99%
and even more complex ones:
OtBu
20 mol%
O
H2N
H
TBSO
O
O
OTBS
CO2H
O
O
O
OH
3 mol% water, rt 2 days.
TBSO
OTBS O
68%, major product: D-fructose
precursor
(it turns out that most amines act as catalysts!)
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Asymmetric catalysis – Organocatalysis
Other applications
Other applications include:
Diels-Alder reactions:
O
catalyst
catalysed by:
+
H
R
L-proline
O
R
H
Asymmetric reductiions:
O
H H
O
Ph
N
H
Ph
or pyrrolidines:
CO2Et catalyst
EtO
+ 2C
N
H
H
(Hantzsch esterhydride source)
H
O
catalyst
+
R
O
O
H
R
Can you work out the mechanisms?
Ph
Ph
N
H
or other N-heterocycles:
O
NMe
and oxidations:
O
CO2H
N
H
H
O
R
Ph
N
H
CO2H
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Ph
Asymmetric catalysis – Enolate alkylation
The reaction proceeds via a complex in which the catalyst and the enolate
are bound by a hydrogen bond (at least, that's the theory):
Cl
O
10 mol% (i.e. 01 eq.) Catalyst
(below), 50% NaOH-toluene
Cl
CH3Cl
MeO
Cl
O
Cl
98% yield
94% e.e.
MeO
H O H
several steps
N
Catalyst: N
Cl
Cl
MeO
The enolate is formed
by deprotonation by
hydroxide.
O
CF3
Cl
O
Cl
Enolate is methylated
on the front face
(as illustrated)
O
CO2H
indacrinone
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Asymmetric catalysis – Enolate alkylation for
synthesis of amino acids.
By using an amino acid precursor with a relatively low pKa, it is possible to alkylate
under relatively mild conditions:
Ph
Ph
OtBu
Ph
N
O
Ph
10 mol% Catalyst (below),
50% NaOH - toluene
PhCH2Br
Ph
full conversion
OtBu 90-95% e.e.
N
O
several steps
H O H
Catalyst:
N
N
Ph
O
Think about the mechanism
and the enantiocontrol.
H3N
O
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Asymmetric catalysis – Addition to an aldehyde (C-C
bond forming reaction) – for interest only.
HO Et
O
H
Et2Zn, toluene (solvent)
H
See table for results
(-)-DAIB (see below)
Results:
NMe2
mol% DAIB used
Yield
(relative to aldehyde)
E.e.
(-)-DAIB
0 (i.e. none)
0%
-
(two pictures
of the same
molecule)
2 (0.02 eq.)
97%
98
100 (1.0 eq.)
0%
-
OH
NMe2
OH
How come a little bit of amino alcohol
catalyses the reaction, but a lot of it doesn't?
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