MASTER 2
Molecular Chemistry – Medicinal Chemistry
Université de Rennes 1 – Vietnam National University, Hanoi
CATALYSIS FOR THE SYNTHESIS
OF BIOACTIVE COMPOUNDSOF BIOACTIVE COMPOUNDS
Prof. Pierre van de Weghee-mail : [email protected] 2011-2012
INTRODUCTION TO CATALYSIS
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
An example
NOH
ClNN
CPh3N
NOH
Cl
Bu5 mol% Pd(PPh ) , K CO
newaryl-aryl bond
catalytic amount !
2
What is the mechanism of this reaction ?
What is the role of the palladium and the base ?
Br
NOH
Bu NNN
N
B(OH)2
N
NHN
N Nlosartan
+
5 mol% Pd(PPh3)4, K2CO3THF - H2O
then H 3O+
aryl-aryl bond
INTRODUCTION TO CATALYSIS
Pro memoria
A catalyst accelerates the rate of a thermodynamically feasible reaction by opening a loweractivation energy pathway. It is added to the reaction mixture in quantities that are much lowerthan stoichiometric ones and, in principle, it is found unchanged at the end of reaction. Thus itdoes not appaer in the reaction balance, and is usually written on the reaction arrow in order toemphasis this feature:
A + B[cat]
C + D
3
A + B C + D
A + B[cat]
C + D
[cat] [cat]-A
A
BC + D
activation
reaction
[cat]
1- transition metal complex
2- organic molecule
3- enzyme
slow
INTRODUCTION TO CATALYSIS
The catalyst does not influence the thermodynamics of a reaction. It changes the reactionpathways, i. e. the kinetics; in particular it lowers the energy of transition states.
4
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 thereaction is catalyzed (∆G1
‡ >> ∆G2‡).
- a catalyzed reaction can eventually involve one or several reaction intermediates(for instance, one intermediate in the right figure above).
INTRODUCTION TO CATALYSIS
Three different modes of catalysis
� transition metal complexes as catalysts
� organic molecules as catalysts or organocatalysis
AcO
CO2H
NHAc
OMe
1 - H2, [cat]
2- deprotection HONH3
OH
CO2
H
(S)-DOPAtreatment of Parkinson's disease
[cat] =P
Rh(MeOH)2
PPh
Ph
MeO
MeO
Mosanto's approach
5
� organic molecules as catalysts or organocatalysis
� enzymes as catalysts
O ONH
MeMe
EtO2C CO2Et
Bn2NH - TFA (cat.)Lepidopteran sex pheromon
O
OEt
O reductase in yeast OH
OEt
O OH
OEt
O
S Rmajor product minor product
ethyl acetoacetate 3-hydroxy-ethylbutanoate
TRANSITION METAL COMPLEXES
AS CATALYSTS
PART 1
6
AS CATALYSTS
TRANSITION METAL COMPLEXES AS CATALYSTS
Organic versus Organometallic reactivity
7
What is a transition metal ?
TRANSITION METAL COMPLEXES AS CATALYSTS
A transition metal = an element with valence of d- or f-electrons.
8
Transition metal valence electron count
TRANSITION METAL COMPLEXES AS CATALYSTS
9
for free (gas phase)transition metals: (n+1)s isbelow (n)d in energy.
Fe4s2 3d6
= 3d8OC Fe
COCO
CO
CO
3d8
for complexed transitionmetals: the (n)d levels arebelow the (n+1)s and thusget filled first.
NN N
FeΙΙΙΙΙΙΙΙ
Cl Cl
3d6
for oxidized metals, substract theoxidation from the group “8” .
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 8valence electrons the octet rule.
Transition metals have 9 valence orbitals (1 s + 3 p + 5 d). Upon bonding to a ligand set, therewill be a totyal of 9 low lying orbitals (bonding + non-bonding molecular orbitals). Therefore, wacan expect that the low lying molecular orbitals can accommodate up to 18 valence electrons.
the 18-electron rule.
11
Organometallics complexes with 18 electrons are predicted to be a particularly stable becausethey will have a closed shell of electrons. Complexes with 18 electrons are aften referred to asbeing coordinatively saturated.
There are exceptions to this rule !
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 sharedequally between carbon and hydrogen. To count the electrons, we dissect the moleculegiving each atom 1 electron of the bonding pair.
H CH
H H C
H
HH : 4x1 e = 4C : 4 e
12
� ionic model: alternatively, we can treat the bonds as being ionic. This allow us to assigna formal oxidation state to the carbon atom. This can be useful to determine whether aparticular transformation is an oxidation or a reduction. In this model, both electrons aregiven to the atom with highe electronegativity. For C-H bond, this is the carbon.
Similarly for a transition metal complex, the electron count is the sum of the metalvalence electrons + the ligand centered electrons.
H CH
H H C
H
H C : 4 eTotal = 8 electron s
H CH
HH H C
H
H
HH+ : 4x0 e = 0C (-4): 8 eTotal = 8 electron s
4
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 numberexamples: 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 actualpositive charge on the metal)
13
(oxidation states in organometallic complexes are merely formalisms that may bear little resemblance to the actualpositive 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 ofelectrons is the row number minus the charge on the metal. The formal oxidation state issimply 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 encourageyou to learn that one. You should also be aware of the ionic method, since you will encounter it from time to time.
TRANSITION METAL COMPLEXES AS CATALYSTS
Organometallic ligands :
14
© 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 …
NC
N ArAr
NHC
TRANSITION METAL COMPLEXES AS CATALYSTS
Electron counting and oxidation state:
- procedure for a neutral complex MLlXx NVE = n + 2l + xoxidation 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 – qoxidation state = x + q
n = nb electrons metal, l = nb of ligands L, x = nb of ligands x, q = complex charge
covalent model
Rh : d 9 = 9 e
3 x PPh3 : 3 x L = 6 e1 x Cl : 1 x X = 1 e
oxidation state : 1 x X = + ΙΙΙΙ
ionic model
Rh+ : d 8 = 8 e
3 x PPh3 : 3 x L = 6 e1 x Cl - : 2 e
total = 16 e, + IRh
PPh3
PPh3
Cl PPh3
Rh
PPh3
PPh3
Cl PPh 3 Rh
PPh3
PPh3
Cl PPh3
(L)
(L)
(L)
(L)
(L)
(L)
(X, 1 e) (X, 2 e)
15
TRANSITION METAL COMPLEXES AS CATALYSTS
Electron counting and oxidation state:
Fe
di(cyclopentadienyl)iron(ferrocene)
covalent model
Fe : d8 = 8 e
2 x Cp : 2 x (L 2X) = 2 x (2 x 2 + 1) = 10 eoxidation state : 2 ligands X, 0 charge = +ΙΙΙΙΙΙΙΙ
ionic model
Fe2+ : d 6 = 6 e
2 x Cp - : 2 x 6 = 12 e total = 18 e, + ΙΙΙΙΙΙΙΙ
covalent model
Cr : d6 = 6 e
ionic model
Cr : d6 = 6 e
16
CrOCOC CO
CO
CO
H
Cr : d6 = 6 e
5 x CO : 5 x L = 10 e1 x H : 5 x X = 1 e
oxidation state : 1 x X + 1 x (-1) = 0
Cr : d6 = 6 e
5 x CO : 5 x 2 = 10 e1 x H- : 2 e
total = 18 e, 0
charge : -1 e
Pd
PPh3
PPh3
Ph3P PPh3
covalent model
Pd : d 10 = 10 e
NVE = 10 + 2 x 4 = 18 e
oxidation state : 0 x X = 0000
ionic model
Pd : d10 = 10 e
NVE = 10 + 2 x 4 = 18 e total = 18 e, 0
training = PdCl2(PPh3)2, Mn(CO)5H, Au(Me)3(PMe3).
Common geometries for transition metal complexes
TRANSITION METAL COMPLEXES AS CATALYSTS
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 aroundthe metal.
- electronics : d electron count combined with the complex electron count must beconsidered when predicting geometries for complexes with non-bonding d electrons. Often thisleads to sterically less favorable geometries for electronic reasons (e.g. CN = 4, d8, 16 ecomplexes prefer a square planar geometry).
STERICSL
17
L M L
(CN = coordination number)
CN = 2 linear
L MCN = 3 trigonal planarL
L
CN = 4
L
ML L
Ltetrahedral
CN = 5 L ML
LL
L
trigonal bipyramidal
CN = 6 ML
L L
L
L
L
octahedral
ELECTRONICS
L M LL
T-shaped
MLL L
L
square planar
LL
M LL
L
square pyramidal
Main classes of reactions around the transition metal
TRANSITION METAL COMPLEXES AS CATALYSTS
� ligand substitution
� oxidative addition & reductrice elimination
MLl [ML l-1]- L
ML l-1L1+ L1
A B
[M][M] A
B[M]
BA
18
� insertion & elimination
NVE (M) < or = 16 e ; o.s. NVE (M) + 2 ; o.s. + 2
[M] A+ B
[M] AB
[M] B A
[M]
L
X C
H- L
NVE
[M]X C
H
NVE - 2
[M]X C
H [M]
X C
NVE
H
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 d8square planar complexes are prototypical examples (Pt(II), Pd(II), Ir(I) and Rh(I)).
PtLL X
L+ Y
slowPt
LL X
L
Y
Pt YX
L
L
L
PtLL Y
LX
fastPt
LL Y
L+ X
19
-dissociative mechanism : bond breaking occurs before bond making.This is normally the preferred mechanism for coordinatively 18 e complexes. The rates ofligand substitution for ccordinatively satured complexes are usually significantatly slower thanthose for coordinatively unsaturated complexes.
L
M
L
L1 LL
L
- LL
M
L
L1L
L
L
M
L
L1 L2L
L
+ L2
LM
LL1
L
L
L2
M
L
L1 LL
L
+ L2
+ L2L
M
L2
L1 LL
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 coordinationnumber by 2, an increase of oxidation state by 2 units, and an increase in the electron count by2.- reductive elimination : elimination of two ligands from a metal center to gice a new A-Bbond. The metal center is reduced by 2 units and has 2 fewer coordinated ligands. The complexhas 2 less electrons (concerted reductive elimination requires cis coordination of the ligands tobe eliminated).
m+ AA
20
Oxidative addition and reductive elimination are the microscopic reverse of each other. Theyrepresent the foward and reverse reaction of an equilibrium. The position of the equilibriumdepends on the thermodynamics of the oxidative addition or reductive elimination process. Forexample many metal complexes will oxidatively add CH3I, but few will reductively eliminate thiscompound. In contrast, M(H)R usually undergo rapid reductive elimination, but oxidativeaddition of alkanes is much less common.
LnMm+ +AB
LnM (m+2)+
B
NVE NVE+2
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 analkylidyne.- the groups undergoing migratory insertion must be cis to one another. In complexes wherethe cis coordination sites are blocked by strongly coordinated ligands, insertion or eliminationprocesses are not possible.- an open coordination site is created during migratory insertion. Therefore, for the reversereaction (elimination) to occur, an open coordination site must be generated by liganddissociation.
17
dissociation.- in the case where C is a chiral center, the reaction usually occurs with retention ofconfiguration.- cases where C migrates to AB followed by coordination of L in place of C, and where ABmigrates to C followed by coordination of L in place of AB are both known.
M A
C
B M AC
B
1,1-insertion
eliminationM
L+ L
- LA
C
B
M
C
M AB1,2-insertion
elimination
+ L
- L
A
B
C
M AB
CL
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : alkenes hydrogenation
The Wilkinson’s catalyst, a Rhodium complex : RhCl(PPh3)3
R + H2
[cat]R
HH
catalytic cycleRh
Ph3P
Ph3P Cl
PPh3
= ML3X
Rh = d 9
NVE (Rh) = 9 + (3 x 2) + 1 = 16 eo.s. = +ΙΙΙΙ
22
= ML3X o.s. = +ΙΙΙΙ
= R > R
R
> RR
> RR >
R
reactivity =
to have a good understanding of themechanism of the reaction, it is well todetermine the NVE and o.s. of the metal ateach stage of the catalytic cycle.
TRANSITION METAL COMPLEXES AS CATALYSTS
� stereoselective synthesis of (+)-biotin : an example of asymmetric hydrogenation.
� selective hydrogenation.
Me
Me
O
O
Rh(PPh3)3Cl / H2
Me
Me
O
O
Hydrogenation of olefins (and alkynes) can be carried out in the presence of functional groupssuch as RCHO, R2CO, OH, CN, NO2, Cl, ROR1, CO2R, CO2H.
23
� stereoselective synthesis of (+)-biotin : an example of asymmetric hydrogenation.
O
NHN
O
O
Ph
Me
O O
HO steps H2 / [Rh]
O
NHN
O
O
Ph
Me
HHsteps
S
NHHN
O
HHCO2H
(+)-biotin
[Rh] =Fe
PPh2
t-Bu 2P
Me
Rh(COD) COD = cyclooctadiene = ligand L 2
(Lonza industrial process)
� stereoselective synthesis of Naproxen : asymmetric hydrogenation.
Naproxen, a nonsteroidal anti-inflammatory drug
TRANSITION METAL COMPLEXES AS CATALYSTS
MeO
CO2H
Ru-BINAP
H2 (100 atm)
MeO
CO2H
Me
97% e.e.(1 mol%)CH2Cl2, 50 °C
Ru-BINAP =
(Noyori's catalyst, Nobel Prize 2001)
PP
RuO
O
OO
Me
MePhPh
PhPh
24
industrial synthesis (Synthex) : non catalyzedsynthesis (racemic approach)
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : alkenes reduction – hydride transfer
R + H2
[cat] / baseR
HH
a Ruthenium complex : RuCl2(PPh3)3
RuCl PPhPPh3
RuPh3P
Cl PPh3
Cl
PPh3
HHδδδδ−
RuPh3P
Cl PPh3
H
PPh3
+ HCl
+B:B:H+ Cl−
generation of the Ruthenium active species
25
RuPh3P
Cl PPh3
Cl+ B: + H2
HHδδδδ−
δδδδ+
RuPh3P
Cl PPh3
Cl
PPh3
HH
:B
δδδδ−
δδδδ+
RuPh3P
Cl PPh3
Cl
PPh3
H
- BH+ -Cl−
RuPh3P
Cl PPh3
H
PPh3
RuPh3P
Cl PPh3
H
PPh3
RuPh3P
Cl PPh3
H
PPh3
R
RuPh3P
Cl PPh3
PPh3
R
RuPh3P
Cl PPh3
PPh3
RHHδδδδ−
δδδδ+
R R
catalytic cycle
RuCl
Ph3P Cl
PPh3
= ML3X2
Ru = d 8
NVE (Ru) = 8 + (3 x 2) + (2 x 1) = 16 eo.s. = + ΙΙΙΙΙΙΙΙ
PPh3
TRANSITION METAL COMPLEXES AS CATALYSTS
� asymmetric hydrogenation transfer : the Noyori’s ruthenium catalyst.
PPhPh
RuCl Ph
H2N
O
NHMei-PrOH
catOH
NHMe
O
NHMe
F3C
fluoxetine(antidepressant agent )
cat = = ML4X2
Ru = d8
NVE (Ru) = 8 + (4 x 2)
in classical organic chemistry = Meerwein-Ponndorf-Verley / Oppenauer reaction
26
PPh Ph
RuCl PhN
H2
cat = = ML4X2 + (2 x 1) = 18 eo.s. = + ΙΙΙΙΙΙΙΙ
Me Me
OH
Me Me
O+ HCl
PP Ru
H
Cl
N
N
HH
H H
R R1
O
OH
N
RuHR1
R
R R1
OH
PP Ru
Cl
N
N
HH
H H
HClPP Ru
Cl
Cl
N
N
HH
H H
catalytic cycle
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : hydroboration of olefins
Hydroboration of olefins with catecholborane : the reaction catalyzed by the Wilkinson’scatalyst (Rh(PPh3)3Cl) gives the Markovnikov product.
R +[cat]
R
HB
OB
OH O
OH2O2 / OH-
R
HOH
R
BH
OO
R
OHH
+
anti-Markovnikov Markovnikov
catalytic cycle
27
catalytic cycleclassical hydroboration, recall :
hex-1-ene
9-BBN H2O2 / NaOHOH
OH
99
1
catalyzed hydroboration :
Ph +O
BO
HRhCl(PPh 3)3 H2O2 / NaOH
Ph
OH
application to asymmetric synthesis
TRANSITION METAL COMPLEXES AS CATALYSTS
� diastereoselective catalyzed hydroboration.
OPPh2 1- RhCl(PPh 3)3O
BHO
2- H2O2, NaOH
2-Ac2O, base
OAc
OAc
85% yield
syn > 50:1
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 theformation of carbon-carbon bonds, hydrogenation and oxidation.
Pd electronic configuration = 4d 8 5s2 or 4d 10 5s0
formal oxidation number = 0, +2, (+4)
29
A
Pd
"Pd" (recycling) + B
A fundamental
C-Pdactivation
modification(s) of the Pdcomplexed organic fragments
C---Pdcleavage
Pd formal oxidation number = 0, +2, (+4)
General principlereview for fundamental transformations, see Tetrahedron 2000, 56, 5959.Pd-cat cross-coupling in total synthesis, see Angew. Chem. Int. Ed. 2005, 44, 4442.
Nobel Prize of Chemistry 2010
Richard F. Heck Ei-ichi Negishi Akira SuzukiRichard F. Heck Ei-ichi Negishi Akira Suzuki
for palladium-catalyzed cross couplings in organic synthesis
Nobel Prize 2010
The Heck cross-coupling reaction
Br
+ R1HPd(0) cat.
base
R1
(1968)
Nobel Prize of Chemistry 2010
Nobel Prize 2010
The Negishi cross-coupling reaction
(1977)X
+ R1 ZnYPd(0) cat.
base
R1
Nobel Prize of Chemistry 2010
The Suzuki-Miyaura cross-coupling reaction
(1979)X
+ R1 BPd(0) cat.
base
R1
R
R
Nobel Prize 2010
Heck reaction
Nobel Prize of Chemistry 2010
Negishi andSuzuki 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-Cand C-heteroatom bonds to be formed under very mild conditions with high fucntional grouptolerance.
30
TRANSITION METAL COMPLEXES AS CATALYSTS
� catalyst precursors.
metal sources : Palladium is the most widely used metal for cross-coupling reactions, althoughthere 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 derivedfrom a preformed palladium complex or formed in situ from combination of palladium sourcesand a ligand. Both Pd(0) and Pd(II) sources can be used although the active species is Pd(0) inall cases.
common sources of palladium
Pd/CPd(PPh ) = tetrakis(triphenylphosphine) palladium (most common complex)
31
Pd/CPd(PPh3)4 = tetrakis(triphenylphosphine) palladium (most common complex)Pd2(dba)3 or Pd(dba)2
PdCl2(PPh3)2
PdCl2(CH3CN)2
Pd(OAc)2
PdCl2
dba = dibenzylideneacetone
O
Ph Ph
training = determine NVE and formal oxidation state (except Pd/C)
TRANSITION METAL COMPLEXES AS CATALYSTS
� ligands.
Palladium alone can catalyze the reactions, but usually only with reactive Ar-I substratesand/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 arylphosphinesremain the most widely used.
32
P
3
P
3
CH3
FePPh2
PPh2
PPh2
PPh2
triphenylphosphine tri- o-tolylphosphine
dppf
1,1'-Bis(diphenylphosphino)ferrocene
BINAP
2,2'-bis(diphenylphosphino)-1,1'-binaphthyle
PMe3
P(t-Bu)3
PR2
R2 = Cy, t-Bu
PPh2Ph2P Ph2P PPh2
1,2-Bis(diphenylphosphino)ethane 1,3-Bis(diphenylpho sphino)propan e
monodentate phosphines
chelating phosphines
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.
N
N
H3C
CH3
CH3
CH3
H3C
..N
N
i-Pr
i-Pr
i-Pr
i-Pr
..N
N
H3C
CH3
CH3
CH3
H3C
..N
N
i-Pr
i-Pr
i-Pr
i-Pr
..
33
CH3IMes IPr
CH3sIMes sIPr
Review Pd complexes of NHC as catalysts : Angew. Chem. Int. Ed. 2007, 46, 2768.
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 ofpalladium complex and a base to furnish alkenyl- and aryl-substituted alkenes.
Catalytic cycle
Pd sources : PdCl2, Pd(OAc)2, Pd(PPh3)4. Bases : Et3N, CH3CO2Na, K2CO3, NaHCO3.
Solvents : THF, Toluène, DMF, DMA (in general under reflux).
R1-X + RPd(0)
baseR1 R
R1 = R2or
reactivity order in oxidative addition
Ar-I > Ar-OTf > Ar-Br >> Ar-Cl
34
Base : essential to capturethe formation of HX
H
HR1
Pd
RHonly syn-ββββ-H-elimination
Review : Angew. Chem. Int. Ed. 1994, 33, 2379,and Chem. Rev. 2003, 103, 2945.
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = regioselectivity.
Br
+ AlkenePd cat. / base
Product
CO2Me
100%
CN
100% 100% 100%
Me
80%
20%
CO2Me
1%
Me
99%
100%
OMeMeO
21%
Me
79%
7%
93%
Me
35
Heck reaction = stereoselectivity.
In general, reactions of terminal olefins give a prepoderance of E product.
OTBS
Me
I
Me+
Me
OH
cat. Pd(OAc) 2, AgOAc
DMF, rt
OTBS
Me Me
Me
OH70%
100% E
Chem. Eur. J. 2003, 9, 1129.
R1 R2
PdAr X
L
syn-addition ArL(X)Pd
HR1 R2H
HL(X)Pd
HR1 Ar
R2
ββββ-H-elim
(syn) R1
R2
Ar
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = applications.
- UV-B sunscreen
Br
MeO+ O
O
MePd/C, Na2CO3
NMP, 180 - 190 °C MeO
Me
O
O
Me
Me
pilot scale - several tons
- synthesis of Eleptritan or Relprax (Pfizer, for the treatment of migraineheadaches)
OO 1- cat. Pd(OAc) , P(o-Tol) OO
36
SOO
+Br
NH
N1- cat. Pd(OAc)2, P(o-Tol)3 Et3N, CH3CN
2- cat. Pd/C, H 2
Me
NH
NMe
SOO
- synthesis of Naproxen (anti-inflammatory)
Br
MeO
< 0.05 mol% PdCl 2, L, Et3N
30 bar pentan-3-oneH2O, 95 °C
MeO MeO
Me
CO2H
500 tons/year
pentan-3-one precursor of CH 2=CH2 L =
Me
i-PrPPh2
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = β-H-elimination – insertion - migration, case of cyclic ethers.
O
+I 0.01 mol% Pd(OAc) 2
Et3N, 100 °C O Ph
+
O Ph
expected obtained !
Ph PdL
I
O
+δδδδ -δδδδ
syn addition
O
Ph Pd(I)L 2
HH
ββββ-H elim
only syn
O
PhPd
H
ILinsertion
O
Ph
Pd(I)L2
H
Ph Ph Ph L2Pd(I)H Ph
37
ββββ-H elimO
Ph
HPd
I
L
insertionO
Ph
Pd(I)L2H
ββββ-H elimO
Ph
H Pd LI
L2Pd(I)H
O
Ph
- synthesis of platelet activator factor antagonist
OMeOMe
I
O
2.5 mol% Pd(OAc) 2 / PPh3
AcOK, 80 °C
OMeMeO
O 2.5 mol% Pd(OAc) 2 / PPh3
AgCO3, CH3CN, 80 °C
OMeMeO
I
O
H2 / PtO2
OMeMeO
O
J. Org. Chem. 1990, 55, 407.
TRANSITION METAL COMPLEXES AS CATALYSTS
Heck reaction = β-H-elimination – insertion - migration, case of allylic alcohols.
Ar-I +
OHMe
2 mol% Pd(OAc)2
PPh3, baseOH
MeAr
OMe
Arversus
base = AgOAc base = NaOAc
Ar Pd
L
I
HO
Me
L Pd
L
IAr
OHMe
H Pd
L
I
HO
MeArL Pd
L
IAr
OHMe
H Pd
L
I
Me
OH
Ar
38
HO HO Me
kinetically favoredbut reversibly formed
inclusion of Ag+ prevents reversibility
- synthesis of prostaglandin E2
HO
HO
I C5H11
OTBS
5 mol% Pd(OAc) 2
Bu4NCl, DMF, rt
(Jeffery's conditions)
HO
HO
HPd(I)L2
R
HO
HOR
Pd(H)(I)L O
HOR
- L2Pd(H)(I)
O
HOC5H11
HO
CO2HPure & Appl. Chem. 1990, 62, 653.
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) withorganometallics proceeds via sequential oxidative addition, transmetallation, (trans-cis-isomerization), 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
39
General catalytic cycle
Ar-I > Ar-OTf > Ar-Br >> Ar-Cl
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 ofconjugated dienes, enynes, aryl substituted alkenes, and biaryl compounds. The wide use of this reactionstems from the tolerance of functional groups, and the ready availability of the starting materials.
Catalytic cycle Pd sources : Pd(PPh3)4, PdCl2(PPh3)2.
Bases : Na2CO3, EtONa, NaOH, KOH, K3PO4, Et3N.
Solvents : THF, toluene (presence of water possible).
X
+ R1 BPd(0) cat.
base
R1
orX
+ R1 BPd(0) cat.
base
R1
R
R
R
R
X = I, Br, Cl, OTf
L2Pd(0)Ar-X
40
Solvents : THF, toluene (presence of water possible).
Main sources of organoboron reagents
:B
HO
OHB
ArHO
OHB
RO
ROB
ArRO
RO
boronic acids boronic esters
Ar-X
L2PdAr
X
oxidative addition
L2PdAr
transmetallationreductiveelimination
(II)
R1
ArR1
R1BR
RNaOH
R1BR
ROH
Na
BRR
OH+ NaX
Review : Chem. Rev. 1995, 95, 2457.applications in total synthesis : Tetrahedron 2002, 58, 9633
TRANSITION METAL COMPLEXES AS CATALYSTS
- synthesis of Boscalid (polyvalent fongicide,BASF, > 1000 tons/years)
NO2
Cl+
Cl
B(OH)2
Pd(PPh 3)4 cat.
Bu 4NBr, K 2CO3Toluene, H 2O
NO2
Cl
NH
Cl
O
N Cl
Boscalid
- preparation of valuable intermediate(GlaxoSmithKline, 20 L scale) t-Bu
41
NH
CO2Et
Br
+
t-Bu
B(OH)2
Pd(OAc) 2 cat.
P(o-Tolyl) 3KHCO3, H2O, i-PrOH
NH
CO2Et
- kg-scale manufacture of dibenzoxapine (cascade reaction, 2 kg scale)
Br
Me
OI
NO2(HO)2B
Pd(OAc) 2 cat.
Na2CO3dioxane, H 2O
Br O
MeNO2
Br O
MeNH2.HCl
TRANSITION METAL COMPLEXES AS CATALYSTS
- Suzuki coupling of sp3 nucleophiles (sp2 – sp3 bonds)
Br
9-BBN
Br
9-BBN Pd(0) cat., base
OTPSTBSO
OMe
OMe 9-BBN9-BBN
OTPSTBSOCH(OMe)2
3
SN
IOAc
PdCl2(dppf) cat
application to the synthesis of epothilone A
42
PdCl2(dppf) catCsCO3, AsPh 3
H2O, DMFS
N
OAc
CH(OMe)2
OTBSOTPS
71% yield
S
N
O
OHO
OOH
epothilone A
Review Suzuki-Miyaura cross-coupling in natural product synthesis : Angew. Chem. Int. Ed. 2001, 40, 4545.
TRANSITION METAL COMPLEXES AS CATALYSTS
� the Stille cross-coupling reaction.
The Stille reaction involves the palladium-catalyzed cross-coupling of organostannanes with electrophiles suchas organic halides, triflates, or acid chlorides. The coupling of the two carbon moieties is stereospecific andregioselective, 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 insyntheses 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 SnR3
[Pd]R1 R2 + R3Sn X
R1 = acyl, allyl, aryl, vinyl, benzyl
R2 = aryl, vinyl Pd sources : Pd(PPh3)4, (MeCN)2PdCl2.
43
R = aryl, vinyl
L2Pd(0)R1-X
L2PdR1
X
oxidative addition
L2PdR1
R2
transmetallationreductiveelimination
(II)
R2R1
R2 SnR3
X SnR3
Catalytic cycle
Pd sources : Pd(PPh3)4, (MeCN)2PdCl2.
improved reactivity with CuI/CsF
Solvents : THF, DMF (anhydrous)
Best catalytic system : Pd2(dba)3, AsPh3, LiCl, THF
The most widely used groups in transmetalation fromtin to carbon are those with proximal π-bonds such asalkenyl-, alkynyl-, and arylstannanes.reactivity order in transmetallation (R2) :
RC≡C > RCH=CH > Ar > RCH=CHCH2 ≈ ArCH2 >> alkyl
Review : mechanisms of the Stille reaction: Angew. Chem. Int. Ed. 2004, 43, 4704.short historical note : J. organometall. Chem. 2002, 653, 50.
TRANSITION METAL COMPLEXES AS CATALYSTS
- short efficient synthesis of pleraplysillin-1 (isolated from a marine sponge)
TfOPd(PPh ) cat.
Bu I + CO2Et
Bu 3Sn
PdCl2(CH3CN)2 cat
DMF, rtBu
CO2Et
65% yield
IMeO2C +N
Bu3SnPdCl2(PPh3)2 cat
THF, 65 °CMeO2C
N
95% yield
44
SnBu 3
O+TfO
Me Me
Pd(PPh3)4 cat.
LiCl, THF, 70 °CMe Me
O
75% yield
- enediyne construction system for the dynemicin total synthesis
81% yield
TeocN
OTBS
O
I
H
OH
OH
Me
I
Me3Sn SnMe3
5 mol% Pd(PPh 3)4
DMF, 75 °C
TeocN
OTBS
O
H
OH
OH
Me
NH
OH
O
H
CO2H
OH
Me
OH O
OH O
TRANSITION METAL COMPLEXES AS CATALYSTS
- carbonylative Stille cross-coupling
When the Stille reaction is carried out under a CO atmosphere, the carbonylative coupling proceeds withcarbon monoxide insertion; namely, carbonyl insertion into the Pd–C bond of the oxidative additioncomplex.transmetalation, followed by cis-trans-isomerization and reductive elimination, generates the ketoneproduct.
L2Pd(0) R1-X
L2PdR1
X
oxidative addition
reductiveelimination
R2 R1
O
O
A similar carbonylation could be carried out inthe Suzuki-Miyaura cross-coupling reaction.
LnPdR1 + CO
L(n-1)PdR1CO
LnPd+ L
O
R1
45
L2PdX
L2PdC
Xtransmetallation (II)
CO
carbon monoxideinsertion
O
R1
R2 SnR3
X SnR3
L2PdC
R2
O
R1
MeOTf
SnMe3
Pd(PPh 3)4 cat.LiCl / CO (1 atm)
THF, 50 °C
Me
O
78% yiel d
XLnPd
XL(n-1)Pd
XLnPd
- L
I + Ph
Bu3Sn
PdCl2(CH3CN)2 cat
CO, THF, 50 °C65% yield
BuBu
O
Ph
TRANSITION METAL COMPLEXES AS CATALYSTS
� the Sonogashira cross-coupling reaction.
HR1 +X Pd(0) cat., CuI cat.
base
R1
The Sonogashira reaction has emerged as one of the most general, reliable, and effective methods for thesynthesis of substituted alkynes. In addition to Heck and Suzuki-Miyaura coupling reactions, Sonogashirareactions have been realized on an industrial scale as well.
L2Pd(0)Ar-X
Catalytic cyclePd sources : Pd(PPh3)4 or (PPh3)2PdCl2.Solvents : without solvent (the amine was used as reagent
46
Ar-X
L2PdAr
X
L2PdAr
H R1CuX
Cu R1
Et3N
R1
CuX
transmetallation
(II)
R1
Ar
oxidative addition
reductiveelimination
Pd sources : Pd(PPh3)4 or (PPh3)2PdCl2.Solvents : without solvent (the amine was used as reagentand as base) or THF or CH2Cl2
CuI / Et3N (or other amines) to form the copper(I) alkynide
Review : Chem. Rev., 2007, 107, 874.
TRANSITION METAL COMPLEXES AS CATALYSTS
- synthesis of Eniluracil (Glaxo SmithKline ; a chemotoxic agent enhancer used incombination with 5-fluorouracil, one of the most widely used drugs in cancer chemotherapy.
HN
NH
O
O
I
+ H SiMe30.5 mol% PdCl 2(PPh3)2
0.5 mol% CuIEt3N, AcOEt
HN
NH
O
O
SiMe3
93% yield
NaOH HN
NH
O
O
H
eniluracil
HN
NH
O
O
F
5-fluorouracil
- synthesis of lipoxin A4.
Me Br
OTBS
+CO2Me
OTBSTBSO
47
Me Br
1 mol% Pd(PPh 3)416 mol% CuI
PrNH2, benzene, rt
OTBS
Me
CO2MeOTBSTBSO
96%
OH
Me
CO2HOHHO
(5S, 6S, 15S)-lipoxin A 4- cascade reactions in the total synthesis of frondosin B.
OHI
OMe
+
CO2Me
Me
PdCl2(PPh3)2 cat.
CuI cat.Et3N, DMF, rt
OH
OMeCO2Me
Me
50 °C O
MeO CO2Me
Me O
HO
Me
MeMe
frondosin B
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 unsaturatedorganozinc, organoaluminium, and organozirconium reagents provides a versatile method for preparingstereodefined arylalkenes, arylalkynes, conjugated dienes, and conjugated enynes.
R1 X + R2 M[Pd] cat.
R1 R2 + X M M = ZnCl, AlR 2, Zr(Cl)Cp 2
L2Pd(0)R1-X
R1
oxidative addition
R2
Catalytic cycle
48
L2PdR1
X
L2PdR1
R2
transmetallationreductiveelimination
(II)
R2R1
R2 M
X M
Review : Bull. Chem. Soc. Jpn 2007, 80, 233.
TRANSITION METAL COMPLEXES AS CATALYSTS
OAcOMe
IOHC
i-Pr2Zn (0.55 equiv)
NMP, rtLi(acac) (0.1 equiv)
OAcOMe
ZnOHC 2
C6H11
O
Cl
2.5 mol% Pd 2(dba)5 mol% P(furyl) 3
OAcOMe
OHCO
75% yield
- Negishi cross-coupling reaction : applications.
IBr + BrZn SiMe3
2 mol% Pd(PPh 3)4
THF, rtSiMe3
Br
81% yield
49
O
OMeMeO
MeOCl
Me2AlMe
Me
Me
2+
2 mol% Pd(PPh 3)4
THF, 0 °C
O
OMeMeO
MeOMe
Me
Me
2
coenzyme Q s
MePh
OMe
Me
Cp2Zr(H)Cl
THF, 50 °C
PhOMe
Me
Zr(Cl)Cp 2
Me
Hhydrozirconation
Cp2Zr(H)Cl = Schwartz reagent
PhOMe
Me MeOTBS
Me
NHBocOTBSMe
NHBoc
I
Pd(PPh3)4, dry ZnCl 2
THF, rt
TRANSITION METAL COMPLEXES AS CATALYSTS
� Carbon-heteroatom cross-coupling reaction :
the example of the Buchwald-Hartwig coupling reaction (C-N bond formation).
X
+
R1NHR2
R1OH
R1SH
Y
Y = NR1R2, OR1, SR1
X
+ R1NHR2NR1R2
[Pd] cat.
base
50
base
X
Catalytic cycle
Best catalytic system
Pd2(dba)3 or Pd(OAc)2, Ligand, NaOt-Bu, Toluene rt to 100 °C
Ligand = dppf,
P(tBu)2 P(Cy)2
Review : Adv. Synth & Catal. 2004, 346, 1599.
TRANSITION METAL COMPLEXES AS CATALYSTS
- process scale synthesis of a pharmaceutical intermediate (Astra Zeneca)
NH
Ph
Me
Me
Br
+
N
HN
Me
0.5 mol% Pd 2(dba) 3
1.5 mol% BINAPNaOt-Bu, Tol, 100 °C
NH
Ph
Me
Me
N
NMe
95% yield125 kg scale
- a cholesteryl ester transfer protein inhibitor, the Torcetrapib (Pfizer)(abandoned, excessive mortality during clinical trials)
MeO2C CF3
51
Cl
F3C+
Me
CN
H2N
0.5 mol% Pd 2(dba)3
1.5 mol% BINAPNaOt-Bu, Tol, 100 °C
NH
F3C
Me
CN
NH
F3CN
Me
MeO2C
CF3
CF3
- double N-arylation : synthesis of Mukonine
MeO2C OMe
OTfOTf
2 mol% Pd 2(dba)3
10 mol% XantPhos
K3PO4, xylene, 100 °C
BocNH 2
NBoc
MeO2COMe
NH
MeO2COMe
TFA
Mukonine
O
MeMe
PPh2 PPh2XantPhos
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 formationof new carbon-carbon or carbon-hetero bonds with control of both regio and stereochemistry.
R1 OAc + R2 M[Pd] cat.
R1 R2 + AcOM
L2Pd(0)
oxidative
R1 OAc
R1Catalytic cycle
Pd source : Pd(PPh ) .
52
L2Pd
addition
L2Pd
R2 M
AcOM
R1
AcO
(M = Na, K, Li)
R1
R2
R1 R2
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 malonatetype anions, other soft nucleophiles asanions from nitromethane, enolates, andenamines.
The palladium-mediated allylation proceeds via an initial oxidative addition of an allylic substrate to Pd(0). Theresultant 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. Withsubstituted allylic compounds, the palladium-catalyzed nucleophilic addition usually occurs at the lesssubstituted side. The reaction is usually irreversible and thus proceeds under kinetic control.
TRANSITION METAL COMPLEXES AS CATALYSTS
- Tsuji-Trost reaction : the stereoselectivity.
Palladium-catalyzed displacement reactions with carbon nucleophiles are not only regioselective but also highlystereoselective. In the first step, displacement of the leaving group by palladium to form the π-allylpalladiumcomplex occurs from the less hindered face with inversion. Subsequent nucleophilic substitution of theintermediate π-allylpalladium complex with soft nucleophiles such as amines, phenols, or malonate-type anionsalso proceeds with inversion of the stereochemistry. The overall process is a retention of configuration asa result of the double inversion.
CO2Me
OAc
Pd(PPh3)4 cat.
CH2(CO2Me)2 / NaH
THF
CO2Me
PdL
Nu
CO2Me
CH(CO2Me)
53
THF PdL2
The mechanism of doubleinversion operates with softstabilized nucleophiles. In thepresence of hard nucleophilesthe reaction occurs withinversion of configuration.
TRANSITION METAL COMPLEXES AS CATALYSTS
- Tsuji-Trost reaction : examples.
Me
Me Me
OAcgeranyl acetate
Me
Me Me
neryl acetateOAc
+ HCCO2Me
SO2Ph
Na Pd(PPh3)4 cat
THF, 65 °C
Me
Me Me
Me
Me Me
CO2Me
SO2Ph
SO2Ph
CO2Me
OAc
54
OAc
CO2Me
O Me 7 mol% Pd(PPh 3)4
NaH, THF, 65 °C
OMe
CO2Me99% yield
AcO OCO2R
EE
E = CO2Me
Pd2(dba)3 / PPh3
NaH, THF, 65 °CO
CO2R
EEH
H
H
only cis
TRANSITION METAL COMPLEXES AS CATALYSTS
- π-trimethylene methane cyclization.
Me CO2Me +
SiMe3
OAc
Pd(PPh3)4 / dppe
THFMe
CO2Me
SiMe3
OAc
L2Pd(0) SiMe3
PdL 2
OAc
PdL2
C6H11
O
OMe
PdL2
H11C6
OMe
OC6H11
CO2MePdL 2
55
O O+
SiMe3
OAc
Ph
Pd(PPh3)4
Toluen, reflux O O
Ph
H
H
mixture of stereoisomers
TRANSITION METAL COMPLEXES AS CATALYSTS
� The palladium-catalyzed oxidation reaction of terminal olefins : the Wacker reaction .
R[Pd(II)] cat, CuCl2 cat.
O2 atm, H2O, DMFMeR
O
The Wacker process consists to oxidize selectively terminal olefins in the presence of palladium +2 ascatalyst. The most common palladium source used in this reaction id PdCl2.
R
Cu(+2)
Cu(+1)O2 + HCl
PdCl2
Regioselectivity : Markonikov addition usually
56
Catalytic cycle
R
PdCl2
H2O
O
RPdCl2
H
H
HClO
RPdCl2H
Pd(H)Cl
R
OHMe
R
O
HCl nucleophilicattackββββ-H elimination
reductrice elimination
oxidation
Cu(+2)
Pd(0)
Regioselectivity : Markonikov addition usuallyobserved.
Anti-hydroxypalladation :
R R CH3 R CHO
O
no formed
R
PdCl
ClH2O
OH
H
antiPd
Cl
ClH2O
ROH
TRANSITION METAL COMPLEXES AS CATALYSTS
- Wacker reaction: examples.
O
PdCl2 cat, CuCl 2 cat
O2, DMF / H2OO
O
- The Wacker reaction could oxidize only the terminal olefin ���� regioselective reaction.
H HO
- CuCl/O2 could replace CuCl2 to avoid chlorinated by-products.
57
OO OTBS
PdCl2 cat, CuCl cat
O2, DMF / H2OO
O OTBS
- Used also in intramolecular process.
OH O
Pd(OAc) 2
Cu(OAc) 2, O2
[Pd(II)]
H
O [Pd(II)] O O
TRANSITION METAL COMPLEXES AS CATALYSTS
Applications : the metathesis of olefins
CH
HCR1
CH
R4HC
R2 R3+CH
HCR1
CH
R4HC
R3 R2+M=CH2
most common catalysts in metathesis of olefins
PCy3
Ru
PCy3
PhCl
ClRu
PCy3
PhCl
Cl
N N MesMesN
MoPh
i-Pr
i-Pr
MeMe
O
O
F3C
CF3Me
F3C
58Y. Chauvin R.H. Grubbs R.R. Schrock
Nobel Prize in Chemistry 2005"for the development of the metathesis method in organic synthesis"
PCy3 PCy3
[Ru]-2[Ru]-1
first generationGrubbs catalyst
second generationGrubbs catalyst
MeMe
CF3
F3CMe
[Mo]
Schrock catalyst
TRANSITION METAL COMPLEXES AS CATALYSTS
( )n
( )n
( )n ( )n
[M]
RCM- C2H4
ROMP+ C2H4
ROM
ADMET- C2H4
� common metathesis olefins reactions and simplified catalytic cycle.
X M=CH2 X
RCM
M=CH2
X
X
Metathesis = « change places »
59
( )n ( )n
R1R2+ R1
R2 + C2H4CM
[M]
H2C CH2
[M]
X
[M]
RCM = Ring Closing MetathesisROM = Ring Opening MetathesisROMP = Ring Opening Metathesis PolymerizationADMET = Acyclic Diene Metathesis PolymerizationCM = Cross Metathesis
All of the above reactions are reversible, so equilibrium mixtures are obtained. To produce high yields of agiven product a suitable driving force must be present.• Cross metathesis: Mixtures of products are produced unless a volatile byproduct (ethylene) is produced thatcan be removed from the reaction mixture.• RCM is favored for the production of unstrained rings and is driven both entropically and by the eliminationof a volatile alkene.• ROM is only favored at very high olefin concentrations, or more commonly with strained olefins.
TRANSITION METAL COMPLEXES AS CATALYSTS
- the RCM reaction : examples.
C8H17 + C13H27[Ru]-1 cat
C8H17C13H27 + H2C CH2 + other products
commercial synthesis of house fly pheromone
N
OR
N
OR( )n ( )n
3 mol% [Ru]-1
PhH, rt, 1 hn = 0, 78%n = 1, 93%
60
O
OOH
N
SH
OH
[Ru]-1
O
OOH
N
SH
OH
desoxyepothilone A
81% yield, E / Z = 9 / 1
PhH, rt, 1 h n = 1, 93%
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 linkageposses groups that can form coordinate-covalent bonds with the metal atom. The free aminoand carboxy group bind to the metal affecting the enzymes structure resulting in its activeconformation .Metals main function is to serve in electron transfer. Many enzymes can serve as electrophilesand some can serve as nucleophilic groups. This versatility explains metals frequent occurrencein enzymes. Some metalloenzymes include hemoglobins, cytochromes, phosphotransferases,alcohol dehydrogenase, arginase, ferredoxin, and cytochrome oxidase.
61
� The Methionine Aminopeptidase 2 (MetAP2).
The Methionine aminopeptidase 2 (MetAP2) is a metalloenzyme, abifunctional protein that plays a critical role in the regulation of post-translational processing and protein synthesis.The MetAP2 catalyzesrelease of N-terminal amino acids, preferentially methionine, from peptidesand arylamides. Methionine aminopeptidases (MetAPs) are the enzymesresponsible for the removal of methionine from the amino-terminus ofnewly synthesized. The removal of methionine is essential for further aminoterminal modifications (e.g., acetylation by N-alpha-acetyltransferase andmyristoylation of glycine by N-myristoyltransferase, NMT) and for proteinstability.
H2N
HN
OPept
O
R1
SMe
MetAP2
H2NH2N
OPept
O
R1
SMe
OH+
TRANSITION METAL COMPLEXES AS CATALYSTS
Active site with an irreversible inhibitor (fumagilline)
His 231
Asp 251
Asp 262Glu 364
Glu 459
His 331
Fumagilline
covalent bond
O
OOCH3
CH3
O
HCH3
CH3
O
CO2H3
fumagillin
The fumagillin was found to inhibit theangiogenesis process (construction of new bloodvessels). The MetAP2 was identified as biologicaltarget of the fumagillin. The formation of acovalent bond between the fumagillin and theMetAP2 was catalyzed by the presence of twocations of Manganese (Mn2+) which act as Lewisacids.
62
mechanism of inhibition of MetAP2 with fumagillin
TRANSITION METAL COMPLEXES AS CATALYSTS
� The Carbonic Anhydrases (CAs).
Carbonic anhydrases (CAs), a group of ubiquitouly expressed metalloenzymesare involved in numerous physiological and pathological processes, includinggluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth andvirulence of various pathogens. Furthemore, recent studies suggest that CAactivation may provide a novel therapy for Alzheimer’s disease.
CAs catalyse the following reaction : CO2 + H2O ���� HCO3-
+ H+
OC
Zn2+
OH-
His94
His96
His119
Active site
63
OH
Zn2+
His94 His96
His119
CO2
O
Zn2+
His94 His96
His119
CO
O
Zn2+
His94 His96
His119
H O
O+ H2O
- HCO3OH2
Zn2+
His94 His96
His119
- BH++ B
ORGANOCATALYSIS
PART 2
64
ORGANOCATALYSIS
Definition : in organocatalysis, a purely organic and metal-free small molecule is used tocatalyze a chemical reaction.This approach has some important advantages :
- small organic molecule catalysts are generally stable and fairly easy to design andsynthesize.- 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 industrialapplications.
Organocatalysts can be broadly classified as Lewis bases, Lewis acids, Brønsted bases, andBrønsted acids.
Major reaction pathways :
65
Major reaction pathways :- via covalent activation complexes as enamine and iminium ion
- via noncovalent activation complexes as H-bonding or ion pairing
ONH
R2R1
+ H+N
R2R1- H+
NR2R1
OH A
Reviews : Angew. Chem. Int. Ed. 2004, 43, 5138 , Angew. Chem. Int. Ed. 2008, 47, 4638 and Drug Discovery Today, 2007, 12, 8.
ORGANOCATALYSIS
The most common system : Proline (and derivatives) as catalyst
Why Proline ?
NH O
O
H
L-proline
Proton deliveryAmine function toactive the carbonylgroup
Chiral center � asymmetric synthesis
Abundant end cheap material
Proline as catalyst for the aldol reaction – proposed mechanism
66
O+
H
O
R
NH
CO2H
(30 mol%)
DMSO
OH
R
O
54 - 97% yiel d60 - 96% ee
R = aryl or i-Pr
Seminal work : J. Org. Chem. 1974, 39, 1615 .
Mechanism : Science 2002, 298, 1904.
ORGANOCATALYSIS
Proline as catalyst for the aldol reaction – justification of the enantioselectivity
67
J. Am. Chem. Soc. 2000, 122, 2395.
ORGANOCATALYSIS
Proline as catalyst for the aldol reaction – comparaison with various organocatalyst
O O
O
pyrrolidine derivatives
solvent, rtOH
O
O
68
ORGANOCATALYSIS
Proline as catalyst : examples
HMe
O
"2 equiv"
10 mol% L-Proline
DMF, 4 °C H
O
Me
MeOH
80% yield
4 : 1 anti : syn99% ee (anti)
H
O+
H
O10 mol% L-Proline
DMF, 40 h, 5 °C
then TBSCl, base H
O OTBS
TBSO
OEt
BF3.OEt2, CH2Cl2
OH OTBS
EtO
O
69
Et2O/CH2Cl261% (two steps)
Me -78 °C, 65% Me
O
O
HOMe
48% HF, H2O, CH3CN4.5 h, rt, 55%
(-) Prelactone BTetrahedron Lett. 2003, 44, 7607
3 steps, 22% overall yield
O
OH
+ H
O
+
NH2
OMe
35 mol% L-Proline
DMSO, rt, 12 h
O
OH
HN
OMe
57% yiel d
ORGANOCATALYSIS
Proline and derivatives as catalysts
NH
CO2H NH
NH
BnBnAr
OTMSAr N
HCO2H
Me
NH HN N
NN
the MacMillan catalystsN
Bn
O Me
MeN
Bn
O Me
Me
70
the MacMillan catalystsNH
BnMeMe
.HCl
NH
Bn
.HClMe
Me
OO
R1
N
NH
Bn
O Me
MeMe
.HCl
(5 mol%)
THF, rt
O
R1
O
85-99% yield80-97% ee
ORGANOCATALYSIS
MacMillan as catalysts : examples
71
ORGANOCATALYSIS
H-bonding catalysis : examples of the chiral phosphoric acid
Ar
Ar
O
O
PO
OH
R1 H
NBoc 2 mol% cat
CH2Cl2, rt, 1 h+
Me Me
O O
R1
NHBoc
O Me
Me
O
> 94% yield, > 92% ee
N 10 mol% cat
Tol, -78 °C, 24 h+
NH O
OH
OEt
OTMSH
OH
72
R1 H Tol, -78 °C, 24 h R1 OEt
> 97% yield, > 88% ee
OEtR2
R2
Bull. Chem. Soc. Jpn 2010, 83, 101.
ENZYMES AS CATALYSTS
PART 3
73
ENZYMES AS CATALYSTS
Enzyme-catalyzed chemical transformations are now widely recognized as practicalalternatives to traditional organic synthesis, and as convenient solutions to certain intractablesynthetic problems.
Typical enzyme-catalyzed transformations
Enzymes commonly used in organic synthesis
74
ENZYMES AS CATALYSTS
Enzymes commonly used in organic synthesis
75
ENZYMES AS CATALYSTS
Examples of applications
- synthesis of a new [beta]-lactam.
H2N
OO CO2Me H
N
O
O
PhO HN
O
NH2
- resolution of racemic mixture of alcohols.
R1 R2
OH lipase or esterase+
O Me
O
R1 R2
OH+
R1 R2
OAc
76
NO
CO2H
Penicillin G acylaseN
OCO2H
ON
O
OCl
CO2HLoracarbef(antibiotic)
- a representative chemgenzymatic preparation of cyclic imine sugars.
MeCHO
N3
OH
+ OPO32-
OHO
1- aldolase
2- phosphataseMe
N3
OH
OH
OH
O
OH
H2, Pd/C, HCl
HO OH
OOHHCl.H2N
Me
OH NaOH NOHOH
OHHO
Me
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