Download TRANSITION METAL COMPLEXES AS

MASTER 2
Molecular Chemistry – Medicinal Chemistry
Université de Rennes 1 – Vietnam National University, Hanoi
CATALYSIS FOR THE SYNTHESIS
OF BIOACTIVE COMPOUNDS
Prof. Pierre van de Weghe
e-mail : [email protected]
2011-2012
INTRODUCTION TO CATALYSIS
An example
Synthesis of Losartan (marketed by Merck & Co), an angiotensin II receptor antagonist drug
used to treat high blood pressure (hypertension).
KEY STEP : A PALLADIUM-CATALYZED CROSS-COUPLING REACTION
catalytic amount !
Cl
N
Bu
Cl
N
CPh3
N N
N
N
OH
N
+
Bu
5 mol%
B(OH)2
Pd(PPh3)4, K2CO3
THF - H2O
OH
new
aryl-aryl bond
N
then H3O+
Br
N
HN
N N
losartan
What is the mechanism of this reaction ?
What is the role of the palladium and the base ?
2
INTRODUCTION TO CATALYSIS
Pro memoria
A catalyst accelerates the rate of a thermodynamically feasible reaction by opening a lower
activation energy pathway. It is added to the reaction mixture in quantities that are much lower
than stoichiometric ones and, in principle, it is found unchanged at the end of reaction. Thus it
does not appaer in the reaction balance, and is usually written on the reaction arrow in order to
emphasis this feature:
[cat]
A + B
C + D
A
activation
slow
A + B
[cat]
[cat]
A + B
1- transition metal complex
C + D
[cat]-A
[cat]
2- organic molecule
3- enzyme
C + D
reaction
C+D
B
3
INTRODUCTION TO CATALYSIS
The catalyst does not influence the thermodynamics of a reaction. It changes the reaction
pathways, i. e. the kinetics; in particular it lowers the energy of transition states.
Comparison of the profiles of the uncatalyzed and catalyzed reaction :
- the energy levels of the starting substrates and reaction products are the same
with or without catalyst (∆G° constant), but the activation energy ∆G‡ is much lower when the
reaction is catalyzed (∆G1‡ >> ∆G2‡).
- a catalyzed reaction can eventually involve one or several reaction intermediates
(for instance, one intermediate in the right figure above).
4
INTRODUCTION TO CATALYSIS
Three different modes of catalysis
transition metal complexes as catalysts
MeO
Mosanto's approach
CO2H
1 - H2, [cat]
NHAc
AcO
H
CO2
NH3
2- deprotection
HO
OMe
Ph
P
[cat] =
Rh(MeOH)2
P
Ph
OH
(S)-DOPA
treatment of Parkinson's disease
MeO
organic molecules as catalysts or organocatalysis
EtO2C
Me
O
CO2Et
N
H
Me
O
Bn2NH - TFA (cat.)
Lepidopteran sex pheromon
enzymes as catalysts
O
O
reductase in yeast
OEt
ethyl acetoacetate
OH O
OEt
S
major product
OH O
OEt
R
minor product
3-hydroxy-ethylbutanoate
5
PART 1
TRANSITION METAL COMPLEXES
AS CATALYSTS
6
TRANSITION METAL COMPLEXES AS CATALYSTS
Organic versus Organometallic reactivity
7
TRANSITION METAL COMPLEXES AS CATALYSTS
What is a transition metal ?
A transition metal = an element with valence of d- or f-electrons.
8
TRANSITION METAL COMPLEXES AS CATALYSTS
Transition metal valence electron count
Fe
4s2 3d6
=
3d8
CO
OC Fe CO
CO
CO
3d8
N
N
FeΙΙ
Cl
for free (gas phase)
transition metals: (n+1)s is
below (n)d in energy.
for complexed transition
metals: the (n)d levels are
below the (n+1)s and thus
get filled first.
N
3d6
Cl
for oxidized metals, substract the
oxidation from the group “8” .
9
TRANSITION METAL COMPLEXES AS CATALYSTS
Transition metal valence orbitals
10
TRANSITION METAL COMPLEXES AS CATALYSTS
The 18-electron rule
Recall : first row of elements have 4 valence orbitals (1 s + 3 p) so they can accomodate up to 8
valence electrons
the octet rule.
Transition metals have 9 valence orbitals (1 s + 3 p + 5 d). Upon bonding to a ligand set, there
will be a totyal of 9 low lying orbitals (bonding + non-bonding molecular orbitals). Therefore, wa
can expect that the low lying molecular orbitals can accommodate up to 18 valence electrons.
the 18-electron rule.
Organometallics complexes with 18 electrons are predicted to be a particularly stable because
they will have a closed shell of electrons. Complexes with 18 electrons are aften referred to as
being coordinatively saturated.
There are exceptions to this rule !
11
TRANSITION METAL COMPLEXES AS CATALYSTS
Electron counting
Two models for counting electrons: the colvalent and ionic models. Both give the same answer,
but offer different advantages and disavantages.
Example: CH4
covalent model: since C-H bond are covalent, assume that the electrons are shared
equally between carbon and hydrogen. To count the electrons, we dissect the molecule
giving each atom 1 electron of the bonding pair.
H
H C H
H
H
H
C
H
H : 4x1 e = 4
C:4e
Total = 8 electrons
H
ionic model: alternatively, we can treat the bonds as being ionic. This allow us to assign
a formal oxidation state to the carbon atom. This can be useful to determine whether a
particular transformation is an oxidation or a reduction. In this model, both electrons are
given to the atom with highe electronegativity. For C-H bond, this is the carbon.
H
H C H
H
H
4
H
C
H
H
H+ : 4x0 e = 0
C (-4): 8 e
Total = 8 electrons
Similarly for a transition metal complex, the electron count is the sum of the metal
valence electrons + the ligand centered electrons.
12
TRANSITION METAL COMPLEXES AS CATALYSTS
Covalent model :
NVE= nb metal electrons + nb ligand electrons – complex charge
(NVE = Number of Valence Electrons)
•Metal = the number of metal electrons equals it’s row number
examples: Ti = 4e, Fe = 8e, Pd = 10e
• Ligands = in general L donates 2 electrons, X donates 1 electron.
•Formal oxidation state of the metal = nb of ligands X + complex charge
(oxidation states in organometallic complexes are merely formalisms that may bear little resemblance to the actual
positive charge on the metal)
Ionic model :
NVE= nb metal electrons (dn) + nb ligands electrons
• Metal = you must first determine the formal oxidation state of the metal. The number of
electrons is the row number minus the charge on the metal. The formal oxidation state is
simply the charge on the complex minus the charges of the ligands.
• Ligands = in general L and X are both 2 electrons donors.
In my opinion the covalent model is easier. All discussions in this class will use the covalent model, so I would encourage
you to learn that one. You should also be aware of the ionic method, since you will encounter it from time to time.
13
TRANSITION METAL COMPLEXES AS CATALYSTS
Organometallic ligands :
© R. H. Crabtree, The Organometallic Chemistry of the Transition Metals (fourth edition), John Wiley & Sons, 2005
Most common ligands found in classical transition metal complexes in catalysis :
ligands type L (2 electrons in CM) : PR3, CO, NR3, alkenes, NHC, ROR1 …
ligands type X (1 electron in CM) : I, Br, Cl, OR, R, Ar, H …
Ar N C N Ar
NHC
14
TRANSITION METAL COMPLEXES AS CATALYSTS
Electron counting and oxidation state:
- procedure for a neutral complex MLlXx
NVE = n + 2l + x
oxidation state = x
n = nb electrons metal, l = nb of ligands L, x = nb of ligands X
- procedure for complex with charge [MLlXx]q
NVE = n + 2l + x – q
oxidation state = x + q
n = nb electrons metal, l = nb of ligands L, x = nb of ligands x, q = complex charge
covalent model
PPh3
Cl Rh PPh3
PPh3
d9
Rh :
ionic model
Rh+ : d8 = 8 e
=9e
3 x PPh3 : 3 x L = 6 e
1 x Cl : 1 x X = 1 e
total = 16 e, +I
3 x PPh3 : 3 x L = 6 e
1 x Cl- : 2 e
oxidation state : 1 x X = +ΙΙ
(L)
Cl
(L)
PPh3
Rh
(X, 1 e)
(L) PPh 3
PPh3
(L)
Cl
PPh3
Rh
(X, 2 e)
(L)
PPh3
(L) PPh3
15
TRANSITION METAL COMPLEXES AS CATALYSTS
Electron counting and oxidation state:
covalent model
Fe :
Fe
di(cyclopentadienyl)iron
(ferrocene)
CO
OC
CO
Cr
OC
CO
H
d8
ionic model
Fe2+ : d6 = 6 e
=8e
2 x Cp : 2 x (L2X) =
2 x (2 x 2 + 1) = 10 e
oxidation state : 2 ligands X, 0 charge
= +ΙΙΙ
2 x Cp- : 2 x 6 = 12 e
covalent model
ionic model
Cr : d6 = 6 e
Cr : d6 = 6 e
5 x CO : 5 x L = 10 e
1xH:5xX=1e
charge : -1 e
5 x CO : 5 x 2 = 10 e
1 x H- : 2 e
total = 18 e, +ΙΙΙ
total = 18 e, 0
oxidation state : 1 x X + 1 x (-1) = 0
PPh3
Ph3P Pd PPh3
covalent model
ionic model
Pd : d10 = 10 e
Pd : d10 = 10 e
NVE = 10 + 2 x 4 = 18 e
NVE = 10 + 2 x 4 = 18 e
total = 18 e, 0
PPh3
oxidation state : 0 x X = 0
training = PdCl2(PPh3)2, Mn(CO)5H, Au(Me)3(PMe3).
16
TRANSITION METAL COMPLEXES AS CATALYSTS
Common geometries for transition metal complexes
Two aspects to define the geometry of the complex : sterics and electronics.
- sterics : to a first approximation, geometries of complexes were determined bu
steric factors. The M-L bonds are arranged to have the maximum possible separation around
the metal.
- electronics : d electron count combined with the complex electron count must be
considered when predicting geometries for complexes with non-bonding d electrons. Often this
leads to sterically less favorable geometries for electronic reasons (e.g. CN = 4, d8, 16 e
complexes prefer a square planar geometry).
STERICS
L
CN = 2
L
CN = 3
L
M
L
L
M
linear
CN = 5
L
M
L
L
trigonal bipyramidal
L
trigonal planar
L
L
L
L
L
L
CN = 4
M
CN = 6
tetrahedral
L
L
M
L
octahedral
L
L
(CN = coordination number)
ELECTRONICS
L
L M
L
L
T-shaped
L M L
L
L
square planar
L
L
M
L
L
square pyramidal
17
TRANSITION METAL COMPLEXES AS CATALYSTS
Main classes of reactions around the transition metal
ligand substitution
+ L1
-L
MLl
[MLl-1]
ML l-1L1
oxidative addition & reductrice elimination
A B
[M]
[M]
A
B
NVE (M) < or = 16 e ; o.s.
insertion & elimination
[M] A
X C
[M]
H
-L
NVE (M) + 2 ; o.s. + 2
B
[M] A
+B
[M] B A
X C
[M]
H
A
B
[M]
X C
[M]
H
X C
[M] H
L
NVE
NVE - 2
NVE
18
TRANSITION METAL COMPLEXES AS CATALYSTS
Ligand substitution
Two limiting mechanisms for ligand substitution
- associative mechanism : bond making occurs before bond breaking.
This is the most common mechanism for coordinatively unsaturated metal complexes. The d8
square planar complexes are prototypical examples (Pt(II), Pd(II), Ir(I) and Rh(I)).
Y
L Pt X
L
L
slow
+ Y
L
L Pt X
L
L
L
Pt Y
X
L
fast
L Pt Y
L
L
X
L Pt Y
+ X
L
L
-dissociative mechanism : bond breaking occurs before bond making.
This is normally the preferred mechanism for coordinatively 18 e complexes. The rates of
ligand substitution for ccordinatively satured complexes are usually significantatly slower than
those for coordinatively unsaturated complexes.
L
L
1
L
L
M L
L
-L
1
L
L
L
L
M
L
+ L2
1
L
M
L
L
L
L
+
L2
L
1
L
L
L
M L
L2
+ L2
L2
L
1
L
L
L
M L2
L
1
L
L
L
M L
19
L
TRANSITION METAL COMPLEXES AS CATALYSTS
Oxidative addition – reductive elimination
- oxidative addition : addition of A-B to a metal center resulting in an increase in coordination
number by 2, an increase of oxidation state by 2 units, and an increase in the electron count by
2.
- reductive elimination : elimination of two ligands from a metal center to gice a new A-B
bond. The metal center is reduced by 2 units and has 2 fewer coordinated ligands. The complex
has 2 less electrons (concerted reductive elimination requires cis coordination of the ligands to
be eliminated).
LnM
NVE
m+
+
A
B
A
LnM
(m+2)+
B
NVE+2
Oxidative addition and reductive elimination are the microscopic reverse of each other. They
represent the foward and reverse reaction of an equilibrium. The position of the equilibrium
depends on the thermodynamics of the oxidative addition or reductive elimination process. For
example many metal complexes will oxidatively add CH3I, but few will reductively eliminate this
compound. In contrast, M(H)R usually undergo rapid reductive elimination, but oxidative
addition of alkanes is much less common.
20
TRANSITION METAL COMPLEXES AS CATALYSTS
Insertion – elimination
Features of this transformation :
- there is no change in the formal oxidation state of the metal unless AB is an alkalydene or an
alkylidyne.
- the groups undergoing migratory insertion must be cis to one another. In complexes where
the cis coordination sites are blocked by strongly coordinated ligands, insertion or elimination
processes are not possible.
- an open coordination site is created during migratory insertion. Therefore, for the reverse
reaction (elimination) to occur, an open coordination site must be generated by ligand
dissociation.
- in the case where C is a chiral center, the reaction usually occurs with retention of
configuration.
- cases where C migrates to AB followed by coordination of L in place of C, and where AB
migrates to C followed by coordination of L in place of AB are both known.
C
M
1,1-insertion
A
B
M
+L
B
-L
A
elimination
A
B
1,2-insertion
B
M
elimination
L
M
C
C
M
C
+L
A
-L
C
A
B
L
M
C
B
A
17
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : alkenes hydrogenation
H
[cat]
R
+
H2
H
R
The Wilkinson’s catalyst, a Rhodium complex : RhCl(PPh3)3
catalytic cycle
Ph3P
Ph3P
Rh
Cl
PPh3
= ML3X
Rh = d 9
NVE (Rh) = 9 + (3 x 2) + 1 = 16 e
o.s. = +ΙΙ
to have a good understanding of the
mechanism of the reaction, it is well to
determine the NVE and o.s. of the metal at
each stage of the catalytic cycle.
reactivity =
R
=
R
> R
R
> R
> R
R >
R
22
TRANSITION METAL COMPLEXES AS CATALYSTS
selective hydrogenation.
Me O
Me
Me O
Me
Rh(PPh3)3 Cl / H2
O
O
Hydrogenation of olefins (and alkynes) can be carried out in the presence of functional groups
such as RCHO, R2CO, OH, CN, NO2, Cl, ROR1, CO2R, CO2H.
stereoselective synthesis of (+)-biotin : an example of asymmetric hydrogenation.
O
Me
HO
steps Ph
O
O
Fe
NH
O
Me
[Rh] =
N
O
Me
H2 / [Rh]
Ph
N
NH
H
H
O
O
O
O
steps
HN
H
NH
H
CO2H
S
(+)-biotin
t-Bu2
P
Rh(COD)
P
Ph2
(Lonza industrial process)
COD = cyclooctadiene
= ligand L2
23
TRANSITION METAL COMPLEXES AS CATALYSTS
stereoselective synthesis of Naproxen : asymmetric hydrogenation.
Naproxen, a nonsteroidal anti-inflammatory drug
Me
CO2H H2 (100 atm)
MeO
Ru-BINAP MeO
(1 mol%)
CH2Cl2, 50 °C
CO2 H
97% e.e.
Ru-BINAP =
Me
PhPh
O
O
P
Ru
O
P
O
Ph Ph Me
(Noyori's catalyst, Nobel Prize 2001)
industrial synthesis (Synthex) : non catalyzed
synthesis (racemic approach)
24
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : alkenes reduction – hydride transfer
H
[cat] / base
+
R
H2
H
R
a Ruthenium complex : RuCl2(PPh3)3
generation of the Ruthenium active species
PPh3
Ru PPh3
Ph3P
Cl
H
δ
H
δ
PPh3
PPh 3
Ru
+
Ph3P
H
Cl
PPh3
Cl
PPh 3
+ B: +
Ru
Ph3P
Cl
+B:
Cl
HCl
B:H + Cl−
−
H2
δ+
PPh3
Ru PPh3
Ph3P
Cl
δ H
δ H
:B
Cl
−
- BH+
PPh3
Ru PPh3
Ph3P
Cl
H
Cl
-Cl−
PPh3
PPh 3
Ru
Ph3P
H
Cl
+
catalytic cycle
R
Cl
Ph3P
PPh3
PPh3
Cl
Ru PPh3
Ph3P
H
Ph3 P
R
PPh3
PPh 3
Ru
δ−
H
H
δ
Cl
PPh3
Ru PPh3
Ph3P
H
Cl
R
Ru
Cl
PPh3
= ML3X2
Ru = d8
NVE (Ru) = 8 + (3 x 2)
+ (2 x 1) = 16 e
o.s. = +ΙΙΙ
R
+
δ
Cl
Ph3P
PPh3
PPh 3
Ru
25
R
TRANSITION METAL COMPLEXES AS CATALYSTS
asymmetric hydrogenation transfer : the Noyori’s ruthenium catalyst.
in classical organic chemistry = Meerwein-Ponndorf-Verley / Oppenauer reaction
O
F3 C
OH
O
cat
NHMe
NHMe
NHMe
i-PrOH
fluoxetine
(antidepressant agent)
cat =
Ph Ph
Cl
P
Ru
P
Ph Ph Cl
H2
N
Ph
N
H2
Ru = d8
NVE (Ru) = 8 + (4 x 2)
+ (2 x 1) = 18 e
o.s. = +ΙΙ
= ML4X2
Ph
O
P
P
catalytic cycle
O
Me
Me
R
R1
R1 H
Ru
R
O
H
N
+ HCl
Me
OH
R
OH
Me
H H
H N
Ru
Cl N
H H
P
P
H H
Cl N
Ru
Cl N
H H
HCl
P
P
R1
H H
N
Ru
Cl N
H H
26
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : hydroboration of olefins
H
H
O
+
R
O
B
[cat]
B H
O
R
O
O
anti-Markovnikov
+
R
B
O
H H2O2 / OH
Markovnikov
OH
R
OH
R
H
Hydroboration of olefins with catecholborane : the reaction catalyzed by the Wilkinson’s
catalyst (Rh(PPh3)3Cl) gives the Markovnikov product.
catalytic cycle
classical hydroboration, recall :
9-BBN
H2O2 / NaOH
OH 99
OH
1
hex-1-ene
catalyzed hydroboration :
Ph
+
OH
RhCl(PPh3)3 H2O2 / NaOH
O
B H
Ph
O
application to
asymmetric synthesis
27
TRANSITION METAL COMPLEXES AS CATALYSTS
diastereoselective catalyzed hydroboration.
OPPh2
O
1- RhCl(PPh3)3
BH
OAc
O
2- H2O2, NaOH
85% yield
OAc
syn > 50:1
2-Ac2O, base
28
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : the palladium catalyzed reactions
Generalities
During the last decades, palladium-catalyzed reactions have emerged as versatile tools for the
formation of carbon-carbon bonds, hydrogenation and oxidation.
Pd
electronic configuration = 4d8 5s2 or 4d10 5s0
formal oxidation number = 0, +2, (+4)
review for fundamental transformations, see Tetrahedron 2000, 56, 5959.
Pd-cat cross-coupling in total synthesis, see Angew. Chem. Int. Ed. 2005, 44, 4442.
General principle
C-Pd
activation
modification(s) of the Pd
complexed organic fragments
Pd
A
A
C---Pd
cleavage
fundamental
"Pd" (recycling) + B
29
Nobel Prize of Chemistry 2010
Richard F. Heck
Ei-ichi Negishi
Akira Suzuki
for palladium-catalyzed cross couplings in organic synthesis
Nobel Prize 2010
Nobel Prize of Chemistry 2010
The Heck cross-coupling reaction
Br
+ H
Pd(0) cat.
R1
R1
(1968)
base
Nobel Prize 2010
Nobel Prize of Chemistry 2010
The Negishi cross-coupling reaction
X
+ R1
ZnY
Pd(0) cat.
R1
(1977)
base
The Suzuki-Miyaura cross-coupling reaction
X
+ R1
R
B
Pd(0) cat.
R
R1
(1979)
base
Nobel Prize 2010
Nobel Prize of Chemistry 2010
Heck reaction
Negishi and
Suzuki reactions
Nobel Prize 2010
TRANSITION METAL COMPLEXES AS CATALYSTS
Palladium-catalyzed cross-coupling reactions
The cross-coupling reactions have become powerful synthetic methods because they allow C-C
and C-heteroatom bonds to be formed under very mild conditions with high fucntional group
tolerance.
30
TRANSITION METAL COMPLEXES AS CATALYSTS
catalyst precursors.
metal sources : Palladium is the most widely used metal for cross-coupling reactions, although
there are examples of Nickel, Rhodium and Copper catalyzed cross-coupling reactions.
In general, the palladium is supported by a ligand and the catalyst can be derived
from a preformed palladium complex or formed in situ from combination of palladium sources
and a ligand. Both Pd(0) and Pd(II) sources can be used although the active species is Pd(0) in
all cases.
common sources of palladium
Pd/C
Pd(PPh3)4 = tetrakis(triphenylphosphine) palladium (most common complex)
Pd2(dba)3 or Pd(dba)2
dba = dibenzylideneacetone
PdCl2(PPh3)2
O
PdCl2(CH3CN)2
Pd(OAc)2
Ph
Ph
PdCl2
training = determine NVE and formal oxidation state (except Pd/C)
31
TRANSITION METAL COMPLEXES AS CATALYSTS
ligands.
Palladium alone can catalyze the reactions, but usually only with reactive Ar-I substrates
and/or high temperature.
Ligands necessary to - give more active catalyst system,
- stabilize the Pd(0) intermediate
- solubilize the catalyst
- increase the rate of oxidative addition.
The most ligands use in palladium chemistry = phosphine derivatives. In general arylphosphines
remain the most widely used.
CH3
P
PR2
P
3
P(t-Bu)3
triphenylphosphine tri-o-tolylphosphine
Ph 2P
PPh2
PPh2
PPh2
Ph2P
1,2-Bis(diphenylphosphino)ethane
BINAP
PPh2
1,3-Bis(diphenylphosphino)propane
PPh2
dppf
PPh2
1,1'-Bis(diphenylphosphino)ferrocene
Fe
2,2'-bis(diphenylphosphino)-1,1'-binaphthyle
monodentate phosphines
PMe3
R2 = Cy, t-Bu
3
chelating phosphines
32
TRANSITION METAL COMPLEXES AS CATALYSTS
A new generation of ligands = the N-heterocyclic carbenes (NHC)
NHC are stronger electron donors than phosphines and they tend to have stronger M-L bonds,
thus they may give more stable catalysts.
CH3
H3C
CH3
i-Pr
N
N
..
CH3
N
N
CH3
H3C
H3C
..
i-Pr
CH3
IMes
N
N
i-Pr
i-Pr
i-Pr
..
CH3
N
CH3
H3C
IPr
N
..
i-Pr
i-Pr
i-Pr
CH3
sIMes
sIPr
Review Pd complexes of NHC as catalysts : Angew. Chem. Int. Ed. 2007, 46, 2768.
33
TRANSITION METAL COMPLEXES AS CATALYSTS
The Heck reaction (Nobel Prize 2010).
The Heck reaction involves coupling of alkenyl or aryl halides with alkenes in the presence of
palladium complex and a base to furnish alkenyl- and aryl-substituted alkenes.
R1 -X
Pd(0)
+
R
R1
base
R
R1 =
or
R2
Pd sources : PdCl2, Pd(OAc)2, Pd(PPh3)4.
Bases : Et3N, CH3CO2Na, K2CO3, NaHCO3.
Solvents : THF, Toluène, DMF, DMA (in general under reflux).
reactivity order in oxidative addition
Ar-I > Ar-OTf > Ar-Br >> Ar-Cl
Catalytic cycle
Base : essential to capture
the formation of HX
Review : Angew. Chem. Int. Ed. 1994, 33, 2379,
and Chem. Rev. 2003, 103, 2945.
Pd
H
H
R1
R
H
only syn-β
β -H-elimination
34
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = regioselectivity.
Br
Pd cat. / base
Product
+ Alkene
100%
100%
100%
100%
80%
1%
21%
Me
Me
CO2Me
100%
Me
CN
CO2Me
20%
7%
OMe
Me
MeO
99%
79%
93%
Heck reaction = stereoselectivity.
In general, reactions of terminal olefins give a prepoderance of E product.
OTBS
I
Me
100% E
OTBS
+
Me
Me
cat. Pd(OAc)2, AgOAc
OH
DMF, rt
70%
Me
Me
Me
Chem. Eur. J. 2003, 9, 1129.
OH
L
Ar Pd X
R1
R2
syn-addition L(X)Pd
H
Ar
R1 R2
H
L(X)Pd
H
H
R1 Ar
R2
R2
β-H-elim
(syn)
R1
Ar
35
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = applications.
- UV-B sunscreen
O
Me
Br
O
+
MeO
Me
Pd/C, Na2CO3
NMP, 180 - 190 °C
O
O
MeO
Me
Me
pilot scale - several tons
- synthesis of Eleptritan or Relprax (Pfizer, for the treatment of migraine
headaches)
O O
S
1- cat. Pd(OAc)2, P(o-Tol)3
Et3N, CH3CN
N
Me
Br
+
O O
S
2- cat. Pd/C, H2
N
H
N
H
- synthesis of Naproxen (anti-inflammatory)
Br
MeO
CO2H
< 0.05 mol% PdCl2, L, Et3N
Me
30 bar pentan-3-one MeO
H2O, 95 °C
Me
pentan-3-one precursor of CH2=CH2
N
Me
MeO
500 tons/year
L=
PPh2
i-Pr
36
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = β-H-elimination – insertion - migration, case of cyclic ethers.
I
0.01 mol% Pd(OAc)2
+
+
Et3N, 100 °C
O
O
Ph
O
expected
L
Ph Pd I
+δ
-δ
δ
δ
syn addition
Ph
Pd(I)L2
H
H
O
O
β-H elim
Ph
obtained !
I
L
Pd
O
Ph
insertion
Ph
H
O
only syn
β-H elim
Ph
H
Ph
β-H elim
insertion
O
O
L
H
Pd
H
I
Pd(I)L2
L2Pd(I)H
Ph
Ph
O
Pd(I)L2
O
H Pd L
I
- synthesis of platelet activator factor antagonist
OMe
O
OMe
I
I
OMe
MeO
2.5 mol% Pd(OAc)2 / PPh3
AcOK, 80 °C
OMe
MeO
O
2.5 mol% Pd(OAc)2 / PPh3
AgCO3, CH3CN, 80 °C
O
OMe
MeO
H2 / PtO2
J. Org. Chem. 1990, 55, 407.
O
37
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = β-H-elimination – insertion - migration, case of allylic alcohols.
2 mol% Pd(OAc)2
Ar-I +
Me
PPh3, base
OH
L
Ar Pd I
Me
versus
OH
base = AgOAc
L
L
L Pd I
H Pd I
L Pd I
Ar
Me
OH
HO
Me
Ar
Me
O
base = NaOAc
L
Ar
Me
Ar
L
Ar
H Pd I
OH
Me
OH
HO
Ar
Me
kinetically favored
but reversibly formed
inclusion of Ag+ prevents reversibility
- synthesis of prostaglandin E2
HO
I
C5 H11
HO H
OTBS
HO
HO
Pd(H)(I)L
Pd(I)L2
5 mol% Pd(OAc)2
Bu4NCl, DMF, rt
R
HO
O
- L2 Pd(H)(I)
HO
R
HO
R
(Jeffery's conditions)
O
CO2H
Pure & Appl. Chem. 1990, 62, 653.
C5H11
HO
HO
38
TRANSITION METAL COMPLEXES AS CATALYSTS
The Palladium-catalyzed cross-coupling with organometallic reagent.
The palladium-catalyzed cross-coupling of alkenyl or aryl halides (and triflates) with
organometallics proceeds via sequential oxidative addition, transmetallation, (trans-cisisomerization), and reductive elimination processes.
R X +
R1 M
[Pd]
R R1 +
M X
reactivity order in oxidative addition
Ar-I > Ar-OTf > Ar-Br >> Ar-Cl
General catalytic cycle
39
TRANSITION METAL COMPLEXES AS CATALYSTS
the Suzuki-Miyaura reaction (Nobel Prize 2010).
The Suzuki-Miyaura reaction provides a versatile, general method for stereo- and regiospecific synthesis of
conjugated dienes, enynes, aryl substituted alkenes, and biaryl compounds. The wide use of this reaction
stems from the tolerance of functional groups, and the ready availability of the starting materials.
X
+ R1
R
B
R1
Pd(0) cat.
R
X
or
+
base
R1
R
B
Pd(0) cat.
R
R1
base
X = I, Br, Cl, OTf
Catalytic cycle
Pd sources : Pd(PPh3)4, PdCl2(PPh3)2.
L2Pd(0)
Bases : Na2CO3, EtONa, NaOH, KOH, K3PO4, Et3N.
Solvents : THF, toluene (presence of water possible).
Ar-X
oxidative
addition
Ar
Ar
L2Pd
R1
reductive
elimination
X
transmetallation
Ar
R Na
R B
OH
R
L2Pd
(II)
R1
NaOH
R1
R
B
+ NaX
OH
R
R
B
R1
Main sources of organoboron reagents
HO :
HO
Ar
RO
RO
Ar
B
OH
B
OH
boronic acids
B
RO
B
RO
boronic esters
Review : Chem. Rev. 1995, 95, 2457.
applications in total synthesis : Tetrahedron 2002, 58, 9633
40
TRANSITION METAL COMPLEXES AS CATALYSTS
- synthesis of Boscalid (polyvalent fongicide,
BASF, > 1000 tons/years)
N
Cl
O
B(OH)2
NO2
NO2
Pd(PPh3)4 cat.
+
NH
Bu 4NBr, K2 CO3
Toluene, H2O
Cl
Cl
Cl
Boscalid
- preparation of valuable intermediate
(GlaxoSmithKline, 20 L scale)
Cl
t-Bu
t-Bu
Br
Pd(OAc)2 cat.
CO2Et +
N
H
B(OH)2
CO2 Et
P(o-Tolyl)3
KHCO3, H2O, i-PrOH
N
H
- kg-scale manufacture of dibenzoxapine (cascade reaction, 2 kg scale)
(HO)2B
O
Br
NO2
Br
Br
O
O
I
Pd(OAc)2 cat.
Me
Na2 CO3
dioxane, H2O
Me
NO2
Me
NH2.HCl
41
TRANSITION METAL COMPLEXES AS CATALYSTS
- Suzuki coupling of sp3 nucleophiles (sp2 – sp3 bonds)
9-BBN
Br
9-BBN
Pd(0) cat., base
Br
application to the synthesis of epothilone A
TBSO
OTPS
OMe
N
TBSO
9-BBN
3
9-BBN
OMe
S
S
N
N
OAc
I
OTPS
CH(OMe)2
S
OAc
PdCl2 (dppf) cat
CsCO3, AsPh 3
H2O, DMF
O
O
OH
CH(OMe)2
71% yield
OTPS
OTBS
O
OH
epothilone A
Review Suzuki-Miyaura cross-coupling in natural product synthesis : Angew. Chem. Int. Ed. 2001, 40, 4545.
42
TRANSITION METAL COMPLEXES AS CATALYSTS
the Stille cross-coupling reaction.
The Stille reaction involves the palladium-catalyzed cross-coupling of organostannanes with electrophiles such
as organic halides, triflates, or acid chlorides. The coupling of the two carbon moieties is stereospecific and
regioselective, occurs under mild conditions, and tolerates a variety of functional groups (CHO, CO2R, CN,
OH) on either coupling partner. These properties make the Stille reaction frequently the method of choice in
syntheses of complex molecules. A problem of the Stille reaction is the toxicity of organotin reagents,
especially the lower-molecular weight alkyl derivatives.
R1
X +
R2
[Pd]
R1 R2 +
SnR3
R3Sn X
R1 = acyl, allyl, aryl, vinyl, benzyl
R2 = aryl, vinyl
Catalytic cycle
L2Pd(0)
Pd sources : Pd(PPh3)4, (MeCN)2PdCl2.
improved reactivity with CuI/CsF
Solvents : THF, DMF (anhydrous)
R1 -X
oxidative
addition
R2
R1
R1
reductive
elimination
L2Pd
transmetallation
R1
L2 Pd 2
(II) R
X
R2 SnR3
Best catalytic system : Pd2(dba)3, AsPh3, LiCl, THF
The most widely used groups in transmetalation from
tin to carbon are those with proximal π-bonds such as
alkenyl-, alkynyl-, and arylstannanes.
reactivity order in transmetallation (R2) :
RC≡C > RCH=CH > Ar > RCH=CHCH2 ≈ ArCH2 >> alkyl
X SnR3
Review : mechanisms of the Stille reaction: Angew. Chem. Int. Ed. 2004, 43, 4704.
short historical note : J. organometall. Chem. 2002, 653, 50.
43
TRANSITION METAL COMPLEXES AS CATALYSTS
Bu
I
CO2 Et PdCl (CH CN) cat
2
3
2
+
DMF, rt
Bu3Sn
65% yield
N
N
PdCl2 (PPh3 )2 cat
I + Bu3Sn
MeO2C
CO2Et
Bu
THF, 65 °C
MeO2C
95% yield
- short efficient synthesis of pleraplysillin-1 (isolated from a marine sponge)
TfO
SnBu3 +
Pd(PPh3)4 cat.
LiCl, THF, 70 °C
O
O
Me Me
Me Me
75% yield
- enediyne construction system for the dynemicin total synthesis
I
I
Me
TeocN
Me3Sn
OH
O
OH
Me
SnMe3
5 mol% Pd(PPh3)4
TeocN
OH
O
DMF, 75 °C
OH
O
NH
CO2H
O
OH
H
OTBS
Me
OH
H
OTBS
81% yield
H
OH
O
OH
44
TRANSITION METAL COMPLEXES AS CATALYSTS
- carbonylative Stille cross-coupling
When the Stille reaction is carried out under a CO atmosphere, the carbonylative coupling proceeds with
carbon monoxide insertion; namely, carbonyl insertion into the Pd–C bond of the oxidative addition
complex.transmetalation, followed by cis-trans-isomerization and reductive elimination, generates the ketone
product.
R1
R2
A similar carbonylation could be carried out in
O
reductive
elimination
the Suzuki-Miyaura cross-coupling reaction.
R -X
oxidative
addition
1
R1
O
C R1
L2Pd
R2
L2Pd
X SnR3
transmetallation
R2 SnR3
O
C R1
L2 Pd
(II) X
R
LnPd
X
X
+ CO
-L
CO
O
1
R
+L
L(n-1)Pd
R1
LnPd
X
X
CO
carbon monoxide
insertion
O
OTf
Me
1
L2Pd(0)
SnMe3
Pd(PPh3)4 cat.
LiCl / CO (1 atm)
I
Me
Bu
78% yield
+
Bu3Sn
Ph
O
PdCl2 (CH3CN)2 cat
CO, THF, 50 °C
Bu
Ph
65% yield
THF, 50 °C
45
TRANSITION METAL COMPLEXES AS CATALYSTS
the Sonogashira cross-coupling reaction.
The Sonogashira reaction has emerged as one of the most general, reliable, and effective methods for the
synthesis of substituted alkynes. In addition to Heck and Suzuki-Miyaura coupling reactions, Sonogashira
reactions have been realized on an industrial scale as well.
R1
X
R1
H
+
Pd(0) cat., CuI cat.
base
Catalytic cycle
L2Pd(0)
Ar-X
oxidative
addition
Ar
R1
Ar
L2Pd
reductive
elimination
X
Cu
R1
transmetallation
Ar
L2Pd
(II)
Pd sources : Pd(PPh3)4 or (PPh3)2PdCl2.
Solvents : without solvent (the amine was used as reagent
and as base) or THF or CH2Cl2
CuX
CuX
H
R1
Et3N
CuI / Et3N (or other amines)
to form the copper(I) alkynide
R1
Review : Chem. Rev., 2007, 107, 874.
46
TRANSITION METAL COMPLEXES AS CATALYSTS
- synthesis of Eniluracil (Glaxo SmithKline ; a chemotoxic agent enhancer used in
combination with 5-fluorouracil, one of the most widely used drugs in cancer chemotherapy.
O
O
I
HN
O
+
SiMe3
H
HN
0.5 mol% PdCl2(PPh 3)2
0.5 mol% CuI
Et3N, AcOEt
N
H
O
SiMe3
H
O
HN
NaOH
O
N
H
93% yield
O
F
HN
N
H
eniluracil
O
N
H
5-fluorouracil
- synthesis of lipoxin A4.
TBSO
OTBS
Me
Br
OTBS
CO2Me
+
1 mol% Pd(PPh 3)4
16 mol% CuI
PrNH2, benzene, rt
TBSO
OTBS
HO
CO2Me
96%
CO2H
Me
Me
OTBS
OH
- cascade reactions in the total synthesis of frondosin B.
OMe
CO2Me
I
OH
OMe
Me
CuI cat.
Et3N, DMF, rt
O
Me
Me
Me
Me
HO
50 °C
OH
(5S, 6S, 15S)-lipoxin A4
CO2Me
MeO
CO2Me
PdCl2(PPh3)2 cat.
+
OH
O
frondosin B
Me
47
TRANSITION METAL COMPLEXES AS CATALYSTS
the Negishi cross-coupling reactions (Nobel Prize 2010).
The Negishi palladium-catalyzed cross-coupling reaction of alkenyl, aryl, and alkynyl halides with unsaturated
organozinc, organoaluminium, and organozirconium reagents provides a versatile method for preparing
stereodefined arylalkenes, arylalkynes, conjugated dienes, and conjugated enynes.
R1 X + R2 M
[Pd] cat.
L2Pd(0)
Catalytic cycle
R1 R2 +
X M
M = ZnCl, AlR2, Zr(Cl)Cp2
R1 -X
oxidative
addition
R2
R1
R1
reductive
elimination
L2Pd
transmetallation
R1
L2 Pd 2
(II) R
X
R2 M
X M
Review : Bull. Chem. Soc. Jpn 2007, 80, 233.
48
TRANSITION METAL COMPLEXES AS CATALYSTS
- Negishi cross-coupling reaction : applications.
OMe
OMe
OAc
OHC
O
OMe
OAc
i-Pr2Zn (0.55 equiv)
Li(acac) (0.1 equiv)
NMP, rt
I
OHC
2 Zn
C6H11
OAc
Cl
O
OHC
2.5 mol% Pd2(dba)
5 mol% P(furyl)3
75% yield
I +
BrZn
Br
2 mol% Pd(PPh3 )4
SiMe3
THF, rt
Br
SiMe3
81% yield
O
O
MeO
Me
Cl
Me
+ Me2Al
MeO
Me
2
2 mol% Pd(PPh3 )4
Me
THF, 0 °C
Me
MeO
2
MeO
coenzyme Qs
O
OMe H
Cp2Zr(H)Cl
Ph
Me
Me
Ph
Zr(Cl)Cp2
THF, 50 °C
Me
Me
Me
O
OMe
Me
hydrozirconation
Cp 2Zr(H)Cl = Schwartz reagent
Me
NHBoc
I
OMe
OTBS
Me
NHBoc
Ph
OTBS
Pd(PPh3)4, dry ZnCl2
THF, rt
Me
Me
Me
49
TRANSITION METAL COMPLEXES AS CATALYSTS
Carbon-heteroatom cross-coupling reaction :
R1 NHR2
X
+
Y
Y = NR1R2, OR1, SR1
R1 OH
R1 SH
the example of the Buchwald-Hartwig coupling reaction (C-N bond formation).
X
+
R1 NHR2
[Pd] cat.
NR1R2
base
Best catalytic system
Pd2(dba)3 or Pd(OAc)2, Ligand, NaOt-Bu, Toluene rt to 100 °C
P(tBu)2
X
Catalytic cycle
Ligand =
P(Cy)2
dppf,
Review : Adv. Synth & Catal. 2004, 346, 1599.
50
TRANSITION METAL COMPLEXES AS CATALYSTS
- process scale synthesis of a pharmaceutical intermediate (Astra Zeneca)
Me
Me
Me
N
H
Br
H
N
+
Ph
N
Me
Me
0.5 mol% Pd 2(dba)3
N
H
N
1.5 mol% BINAP
NaOt-Bu, Tol, 100 °C
Ph
95% yield
125 kg scale
N
Me
- a cholesteryl ester transfer protein inhibitor, the Torcetrapib (Pfizer)
(abandoned, excessive mortality during clinical trials)
MeO2C
F3C
CN
+
Cl H2N
Me
F C
0.5 mol% Pd2(dba)3 3
CN
1.5 mol% BINAP
NaOt-Bu, Tol, 100 °C
N
H
CF 3
N
F 3C
Me
N
H
CF3
Me
- double N-arylation : synthesis of Mukonine
MeO2C
OMe
OTf
OTf
MeO2C
BocNH2
2 mol% Pd 2(dba)3
OMe
MeO2 C
OMe
Me Me
TFA
NBoc
NH
10 mol% XantPhos
K3PO4 , xylene, 100 °C
Mukonine
O
PPh2
PPh2
XantPhos
51
TRANSITION METAL COMPLEXES AS CATALYSTS
The Tsuji-Trost reaction : Palladium-catalyzed allylic substitution.
Allylic substrates with good leaving groups are excellent reagents for joining an allyl moiety with a nucleophile.
However, these reactions suffer from loss of regioselectivity because of competition between SN2 and SN2’
substitution reactions. Palladium-catalyzed nucleophilic substitution of allylic substrates allows the formation
of new carbon-carbon or carbon-hetero bonds with control of both regio and stereochemistry.
[Pd] cat.
R1
OAc
+
R2
R1
L 2Pd(0)
Catalytic cycle
R1
oxidative
addition
R2
M
R2 + AcOM
OAc
R1
L2Pd
AcO
R2 M
R1
AcOM
L2 Pd
R1
Pd source : Pd(PPh3)4.
Solvents : THF or DMF.
Other possible leaving groups : OC(O)OR,
OP(O)OR2, OPh, Cl, Br.
Nucleophiles : best results with malonate
type anions, other soft nucleophiles as
anions from nitromethane, enolates, and
enamines.
(M = Na, K, Li)
R2
The palladium-mediated allylation proceeds via an initial oxidative addition of an allylic substrate to Pd(0). The
resultant π-allylpalladium(II) complex is electrophilic and reacts with carbon nucleophiles generating the Pd(0)
complex, which undergoes ligand exchange to release the product and restart the cycle for palladium. With
substituted allylic compounds, the palladium-catalyzed nucleophilic addition usually occurs at the less
substituted side. The reaction is usually irreversible and thus proceeds under kinetic control.
52
TRANSITION METAL COMPLEXES AS CATALYSTS
- Tsuji-Trost reaction : the stereoselectivity.
Palladium-catalyzed displacement reactions with carbon nucleophiles are not only regioselective but also highly
stereoselective. In the first step, displacement of the leaving group by palladium to form the π-allylpalladium
complex occurs from the less hindered face with inversion. Subsequent nucleophilic substitution of the
intermediate π-allylpalladium complex with soft nucleophiles such as amines, phenols, or malonate-type anions
also proceeds with inversion of the stereochemistry. The overall process is a retention of configuration as
a result of the double inversion.
CO2Me
CO2Me
Pd(PPh3)4 cat.
OAc
CO2Me
Nu
CH2 (CO2 Me)2 / NaH
THF
CH(CO2Me)
PdL2
The mechanism of double
inversion operates with soft
stabilized nucleophiles. In the
presence of hard nucleophiles
the reaction occurs with
inversion of configuration.
53
TRANSITION METAL COMPLEXES AS CATALYSTS
- Tsuji-Trost reaction : examples.
Me
Me
Me
Me
geranyl acetate
OAc
+
Me
Me
neryl acetate
CO2Me
Me
Na
Me
Me
CO2Me
HC
SO2Ph
SO2Ph
Pd(PPh3)4 cat
Me
THF, 65 °C
Me
Me
CO2Me
OAc
SO2Ph
OAc
O
Me
CO2Me
E E
H
AcO
E = CO2Me
O
CO2R
7 mol% Pd(PPh3)4
O
Me
NaH, THF, 65 °C
99% yield CO2Me
Pd2(dba)3 / PPh3
E E
H
NaH, THF, 65 °C
H
only cis
O
CO2R
54
TRANSITION METAL COMPLEXES AS CATALYSTS
- π-trimethylene methane cyclization.
SiMe3
Me
CO2Me +
Pd(PPh3)4 / dppe
OAc
Me
O
SiMe3 L Pd(0)
2
SiMe3
CO2Me
THF
C6H11
H11C6
OMe
PdL2
C6H11
OMe
OAc
OAc
O
PdL2
PdL2
PdL2
CO2Me
Ph
SiMe3
+
O
OAc
O
Ph
H
Pd(PPh3 )4
Toluen, reflux
H
O
O
mixture of stereoisomers
55
TRANSITION METAL COMPLEXES AS CATALYSTS
The palladium-catalyzed oxidation reaction of terminal olefins : the Wacker reaction .
The Wacker process consists to oxidize selectively terminal olefins in the presence of palladium +2 as
catalyst. The most common palladium source used in this reaction id PdCl2.
R
[Pd(II)] cat, CuCl2 cat.
O2 atm, H2O, DMF
O2 + HCl
O
R
Cu(+1)
PdCl2
Cu(+2)
oxidation
Regioselectivity : Markonikov addition usually
observed.
R
O
Pd(0)
HCl
Me
R
PdCl2
nucleophilic
attack
β-H elimination
Catalytic cycle
Pd(H)Cl
R
O
H
PdCl2
H2O
Pd
OH
R
R
Me
R
H
O
PdCl2
anti
Cl
Cl
R
CHO
no formed
H2O
Pd
Cl
Cl
R
O
CH3
Anti-hydroxypalladation :
R
H
R
H2O
O
H
H
R
OH
HCl
reductrice elimination
56
TRANSITION METAL COMPLEXES AS CATALYSTS
- Wacker reaction: examples.
- The Wacker reaction could oxidize only the terminal olefin regioselective reaction.
O
PdCl2 cat, CuCl2 cat
O2, DMF / H2 O
O
O
- CuCl/O2 could replace CuCl2 to avoid chlorinated by-products.
H
H
O
PdCl2 cat, CuCl cat
O
O
OTBS
O2, DMF / H2O
O
O
OTBS
- Used also in intramolecular process.
[Pd(II)]
Pd(OAc)2
OH
Cu(OAc)2, O2
O
H
O
[Pd(II)]
O
O
57
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : the metathesis of olefins
R1
C
H
H
C
R2
+
R3
H
C
C
H
R4
M=CH2
R1
C
H
H
C
+
R3
R2
H
C
C
H
R4
most common catalysts in metathesis of olefins
i-Pr
Me
F3C
CF3
F3C
Me
N
i-Pr
O Mo
O Me
CF3
Ph
Me
Cl
Mes N
PCy3
Cl
Ru
Ph
Cl
PCy3
N Mes
Ru
Cl
Ph
PCy3
[Mo]
[Ru]-1
[Ru]-2
Schrock catalyst
first generation
Grubbs catalyst
second generation
Grubbs catalyst
Nobel Prize in Chemistry 2005
"for the development of the metathesis method in organic synthesis"
Y. Chauvin
R.H. Grubbs
R.R. Schrock
58
TRANSITION METAL COMPLEXES AS CATALYSTS
common metathesis olefins reactions and simplified catalytic cycle.
Metathesis = « change places »
X
RCM
- C2H4
RCM
( )n
ROM
+ C2H4
( )n
[M]
ADMET
- C2H4
R1
+
CM
R2
M=CH2
ROMP
( )n
R1
X
M=CH2
X
X
( )n
R2
[M]
+
[M]
C2H4
RCM = Ring Closing Metathesis
ROM = Ring Opening Metathesis
ROMP = Ring Opening Metathesis Polymerization
ADMET = Acyclic Diene Metathesis Polymerization
CM = Cross Metathesis
H2C CH2
X
[M]
All of the above reactions are reversible, so equilibrium mixtures are obtained. To produce high yields of a
given product a suitable driving force must be present.
• Cross metathesis: Mixtures of products are produced unless a volatile byproduct (ethylene) is produced that
can be removed from the reaction mixture.
• RCM is favored for the production of unstrained rings and is driven both entropically and by the elimination
of a volatile alkene.
• ROM is only favored at very high olefin concentrations, or more commonly with strained olefins.
59
TRANSITION METAL COMPLEXES AS CATALYSTS
- the RCM reaction : examples.
[Ru]-1 cat
+ C13H27
C8H17
C13H27
C8H17
+ H2C CH2 + other products
commercial synthesis of house fly pheromone
O
R
N
O
( )n
3 mol% [Ru]-1
R
N
( )n
PhH, rt, 1 h
N
S
n = 0, 78%
n = 1, 93%
N
H
S
O
OH
H
O
OH
[Ru]-1
81% yield, E / Z = 9 / 1
O
OH
O
OH
desoxyepothilone A
60
TRANSITION METAL COMPLEXES AS CATALYSTS
Metalloenzymes : examples
Metals play roles in approximately one-third of the known enzymes. Metals may be a co-factor
(prosthetic group), and these are known as metalloenzymes. Amino acids in peptide linkage
posses groups that can form coordinate-covalent bonds with the metal atom. The free amino
and carboxy group bind to the metal affecting the enzymes structure resulting in its active
conformation .
Metals main function is to serve in electron transfer. Many enzymes can serve as electrophiles
and some can serve as nucleophilic groups. This versatility explains metals frequent occurrence
in enzymes. Some metalloenzymes include hemoglobins, cytochromes, phosphotransferases,
alcohol dehydrogenase, arginase, ferredoxin, and cytochrome oxidase.
The Methionine Aminopeptidase 2 (MetAP2).
The Methionine aminopeptidase 2 (MetAP2) is a metalloenzyme, a
bifunctional protein that plays a critical role in the regulation of posttranslational processing and protein synthesis.The MetAP2 catalyzes
release of N-terminal amino acids, preferentially methionine, from peptides
and arylamides. Methionine aminopeptidases (MetAPs) are the enzymes
responsible for the removal of methionine from the amino-terminus of
newly synthesized. The removal of methionine is essential for further amino
terminal modifications (e.g., acetylation by N-alpha-acetyltransferase and
myristoylation of glycine by N-myristoyltransferase, NMT) and for protein
stability.
Me
Me
S
S
H2N
O
MetAP2
O
H
N
Pept
R1
OH
H2N
O
+
O
H2N
Pept
R1
61
TRANSITION METAL COMPLEXES AS CATALYSTS
Active site with an irreversible inhibitor (fumagilline)
The fumagillin was found to inhibit the
angiogenesis process (construction of new blood
vessels). The MetAP2 was identified as biological
target of the fumagillin. The formation of a
covalent bond between the fumagillin and the
MetAP2 was catalyzed by the presence of two
cations of Manganese (Mn2+) which act as Lewis
acids.
Glu 459
O
H
CH3
CH3
O
OCH3
CO2H
O
3
O
CH3
fumagillin
Asp 262
Glu 364
Asp 251
His 331
covalent bond
Fumagilline
His 231
mechanism of inhibition of MetAP2 with fumagillin
62
TRANSITION METAL COMPLEXES AS CATALYSTS
The Carbonic Anhydrases (CAs).
Carbonic anhydrases (CAs), a group of ubiquitouly expressed metalloenzymes
are involved in numerous physiological and pathological processes, including
gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and
virulence of various pathogens. Furthemore, recent studies suggest that CA
activation may provide a novel therapy for Alzheimer’s disease.
CAs catalyse the following reaction : CO2 + H2O
O
OH
O
Zn 2+
His94
+B
His94
C
CO2
His119
His96
O
HCO3
-
+ H
+
Active site
Zn2+
OH-
His119
His96
His94
- BH+
His94
OH2
- HCO3
Zn 2+
+ H2O
His119
His96
H
His119
O
O
Zn2+
His94
Zn2+
O
His119
His96
His96
63
PART 2
ORGANOCATALYSIS
64
ORGANOCATALYSIS
Definition : in organocatalysis, a purely organic and metal-free small molecule is used to
catalyze a chemical reaction.
This approach has some important advantages :
- small organic molecule catalysts are generally stable and fairly easy to design and
synthesize.
- often based on nontoxic compounds, such as sugars, peptides, or even amino acids,
and can easily be linked to a solid support, making them useful for industrial
applications.
Organocatalysts can be broadly classified as Lewis bases, Lewis acids, Brønsted bases, and
Brønsted acids.
Major reaction pathways :
- via covalent activation complexes as enamine and iminium ion
R1
O
N
H
R2
+ H+
R1
N
R2
- H+
R1
N
R2
- via noncovalent activation complexes as H-bonding or ion pairing
H A
O
Reviews : Angew. Chem. Int. Ed. 2004, 43, 5138 , Angew. Chem. Int. Ed. 2008, 47, 4638 and Drug Discovery Today, 2007, 12, 8.
65
ORGANOCATALYSIS
The most common system : Proline (and derivatives) as catalyst
Why Proline ?
Chiral center asymmetric synthesis
L-proline
Abundant end cheap material
Amine function to
active the carbonyl
group
O
N
H
O H
Proton delivery
Proline as catalyst for the aldol reaction – proposed mechanism
O
O
N
H
+
H
R
R = aryl or i-Pr
CO2 H
O
R
(30 mol%)
DMSO
OH
54 - 97% yield
60 - 96% ee
Seminal work : J. Org. Chem. 1974, 39, 1615 .
Mechanism : Science 2002, 298, 1904.
66
ORGANOCATALYSIS
Proline as catalyst for the aldol reaction – justification of the enantioselectivity
J. Am. Chem. Soc. 2000, 122, 2395.
67
ORGANOCATALYSIS
Proline as catalyst for the aldol reaction – comparaison with various organocatalyst
O
O
O
pyrrolidine derivatives
O
solvent, rt
O
OH
68
ORGANOCATALYSIS
Proline as catalyst : examples
O
Me
H
O
10 mol% L-Proline
DMF, 4 °C
Me
O
H
then TBSCl, base
Et2O/CH2Cl2
61% (two steps)
H
80% yield
TBSO
10 mol% L-Proline
DMF, 40 h, 5 °C
+
4 : 1 anti : syn
99% ee (anti)
Me
H
"2 equiv"
O
OH
O
OTBS
H
Me
O
OEt
OH OTBS
BF3.OEt2, CH2Cl2 EtO
-78 °C, 65%
Me
48% HF, H2O, CH3CN
4.5 h, rt, 55%
O
Tetrahedron Lett. 2003, 44, 7607
3 steps, 22% overall yield
(-) Prelactone B
O
HO
Me
OMe
NH2
O
O
+
OH
H
35 mol% L-Proline
+
DMSO, rt, 12 h
OMe
O
HN
OH
57% yield
69
ORGANOCATALYSIS
Proline and derivatives as catalysts
N
H
CO2H
N
H
OTMS
Ar
Ar
N
H
O
Me
CO2H
N
N
HN N
N
H
Me
O
O
Bn
Me
Me
N Me
H
.HCl
N
Bn
.HCl
N
H
Bn
Me
N
the MacMillan catalysts
Bn
N
H
Me
Me
Me
N
Bn
O
O
R1
Me
N Me
H
.HCl
(5 mol%)
THF, rt
O
O
R1
85-99% yield
80-97% ee
70
ORGANOCATALYSIS
MacMillan as catalysts : examples
71
ORGANOCATALYSIS
H-bonding catalysis : examples of the chiral phosphoric acid
Boc
N
R1
O
+
H Me
Boc
2 mol% cat
O
Me CH2Cl2, rt, 1 h
NH
O
R1
Me
Ar
O
Me
> 94% yield, > 92% ee
OH
OH
O
O
P
OH
O
OTMS
N
R1
+
H
10 mol% cat
H
OEt
2
R
Ar
NH O
Tol, -78 °C, 24 h
R1
OEt
R2
> 97% yield, > 88% ee
Bull. Chem. Soc. Jpn 2010, 83, 101.
72
PART 3
ENZYMES AS CATALYSTS
73
ENZYMES AS CATALYSTS
Typical enzyme-catalyzed transformations
Enzyme-catalyzed chemical transformations are now widely recognized as practical
alternatives to traditional organic synthesis, and as convenient solutions to certain intractable
synthetic problems.
Enzymes commonly used in organic synthesis
74
ENZYMES AS CATALYSTS
Enzymes commonly used in organic synthesis
75
ENZYMES AS CATALYSTS
Examples of applications
- resolution of racemic mixture of alcohols.
OH
R1
R2
O
+
O
OH
lipase or esterase
R1
Me
OAc
R2
+
R1
R2
- synthesis of a new [beta]-lactam.
O
O
CO 2Me
H2N
O
PhO
O
N
Penicillin G acylase
O
NH2
H
N
H
N
O
N
O
CO 2H
N
O
CO2 H
Loracarbef
(antibiotic)
Cl
CO2H
- a representative chemgenzymatic preparation of cyclic imine sugars.
N3
Me
O
CHO + HO
OPO3
2-
HCl.H2 N
O
OH OH
NaOH Me
OH O
Me
2- phosphatase
OH
H2, Pd/C, HCl
N3
1- aldolase
OH OH OH
N
OH
OH
OH
HO
Me
HO
OH
76