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CH2 Catalyseur R1
R1 + HC H 2C CH2
2
R2 R2
Couplage croisé
(cross coupling : CM)
• .
• .
• .
• .
2
Metathesis and synthesis
H
[Met] H
H R1 H
R1 + R2 R2 + H
H
2 alcènes alcène éthylène
non cyclique
H H
[Met] H
H H
+ H
H H éthylène
diène alcène
cyclique
3
Metathesis and synthesis
Métathèse cyclisante ène-yne (Enyne metathesis): EYM
H
[Met]
H
R1 R1
alcène / alcyne 1,3-diène
[Met] R
+ R R
alcyne
R
R alcyne
cyclique
alcyne / alcyne
4
Metathesis and oligo-/polymerization
cata
H2C CH HC CH HC CH2
n
HC CH cata CH HC CH2
H2C HC CH
+ n
H2C CH2
5
Metathesis - Catalysts
6
Metathesis – Commercially available Catalysts
G-I
PCy3 PCy3 Actif en ROMP, éthanolyse,
Cl Cl CM et RCM
Ru Ph Ru
Cl Cl Ph des alcènes terminaux
PCy3 Ph PCy3
Grubbs (Caltech)
+
N
PF6-
F3C O Mo Ph
F3C O Cl Ru Ph
Cy3P
F3C Ph
CF3
Schrock (MIT) O Dixneuf (Rennes)
W Fürstner
ArO
OEt2 (Max Planck Inst.)
Cl
Ar=2,6-Ph2C6H3
Basset (CPE Lyon)
7
Metathesis – NHC Catalysts
MesN NMes
Plus actif que G-I,
Plus efficace en RCM Cl
Ru
G-II Et pour des CM stériquement
Encombrées ou avec alcènes désactivés
Cl
O
MesN MesN
HG
NMes NMes R N N R Hoveyda - Grubbs
Cl Cl Cl
Ru Ru Ru
Cl Ph Cl Ph Cl Ph Comparable à G-II
PCy3 PCy3 R N
N R Mais initiation plus rapide
À plus basse température
Efficace avec alcènes appauvris.
R=Cy
Nolan Grubbs
Fürstner
Grubbs (2nd génération)
Herrmann MesN NMes
Cl
Ru
Cl
O
Blechert 8
Métathèse – NHC Catalysts
Br MesN NMes
N N MesN NMes
Cl
N Ru . Cl Cl
Ru Ru
Cl Cl
Cl N Ph
PCy3 O NO 2
Br
Grubbs 3ème Stewart-Grubbs Grela
G-III
Plus efficace que G-II Utilisé pour la synthèse
Réaction à 0°C D’alcènes tétrasubstitués Initiation encore plus
Pb solub ilité Par RCM et CM Rapide que HG
Utilisé en ROMP
9
Metathesis – RCM
Chauvin’s mechanism
◼ Hérisson, J.L. ; Chauvin, Y. Makromol. Chem. 1970, 141, 161-176
R
[M] précatalyseur
.
[M] CH2
[M] [M]
[M]
H2C CH2
10
Nobel Prize 2005
11
Metathesis – Key steps
Mécanisme associatif
k1 R k2
L L L
Cl R' Cl -PCy3 Cl
Ru Ru R' Ru (eq 1)
Cl R Cl Cl R
PCy3
- R' PCy3
+PCy3
k-1 k-2 R'
Mécanisme dissociatif
L k1 L k2 L
Cl -PCy3 Cl R' Cl
Ru Ru Ru (eq 2)
Cl R Cl R Cl R
PCy3 +PCy3 - R'
k-1 espèce à 14 k-2 R'
électrons
GI GII
T (°C) 37 50
k-1/k2 15300 1,25
12
◼ R. H. Grubbs et al
J. Am. Chem. Soc.
2003, 125, 11360.
13
Metathesis and oligo-/polymerization
Norsorex process
[Mo]
Polychlorocyclopentadiene + +
R SHOP
10-20 [cat] R
+
R 9-13
2-7
14
Metathesis and Topology
15
Metathesis and Topology
16
RCM - Application : Sch 38516
AcO OAc
AcO OAc O
O NHCOCF 3
NHCOCF 3 O
O
Catalyseur
de Schrock O
O
HN
N
H 60%
HO OH
O
NH 2
O
O
Sch 38516
HN
◼ .
17
Epothilone synthesis : RCM
Z / E = 1.2 / 1
S S
HO N GBI HO N
O -3 O
6. 10 M, CH2Cl2
O O O
RCM O O O
TBS TBS 85%
O
S S
HO HO N
N
TFA, CH2Cl2 Dioxirane
O O
0°C, 3h O OH O
O OH O
98% 75%
Epothilone C Epothilone A
ratio : 4.8 / 1
18
RCM – Iejimalide B
MeO O CHO
O N
N H
O H
O-Sit-BuMe2
MeO
MeO O CHO
O N
N H
OMe O H
OH
72% Iejimalide
◼ J
19
RCM ene-diene
GBI (15mol%)
NH
DCM,
N OO HN
O
NH
O Ph
57%
NH
N OO HN
O O
NH
Ph
GBII (15mol%) NH
DCM, N OO HN O
NH
Ph
45%
20
Dimerization and métathèse
Réactif de Schrock
(30 mol%) MeO OMe
MeO OMe
MeO OMe +
PhH, 20°C MeO OMe
Cylindrophane
72%
21
Dimerisation and metathesis: reversibility
Réactif de Schrock
(32 mol%)
PhH, 20°C,
75min,
MeO OMe MeO OMe
75%
MeO OMe
MeO OMe
PhH, 20°C,
75min,
81%
MeO OMe
22
RCM versus oligomerization
C = 5 mM
23
Metathesis – purification/ catalyst recovery
Catalyseur
24
Supported catalyst
25
Influence of EWG
S S
N N
O O O
O OTES
OTES
GBII, DCM
F3C F3C
0,002M O
O
OTroc OTroc
2(
Dimère
S S
N N
O O O O
OTES OTES
GBII, DCM
F3C F3C
H2C 0,002M
O O
OTroc 57% OTroc
26
Scale up
O O O O
S S
O O
Br Br
N O N O
O NH O NH
Catalyseur d'Hoveyda (3%)
O O O O
O O
N Ph-Me, 80°C N
O H 6000 litres O H
400kg
83 %
27
RCM and steric hindrance
PCy3
Cl
Ru
Cl
G-I PCy3
Ph
R R
R R R R
E E E E
[Ru]
E E
E = CO2Me
R = alkyl
Grubbs-Stewart
PhMe, 60°C Conversion >95%
30 min.
N N
. Cl
Ru 5%
Cl Ph
PCy3
28
RCM and steric hindrance
RRCM relayed reactions
PCy3
Cl
Ru
Cl Ph R R
R R PCy3 R R
E E E E
[Ru]
E E
E = CO2Me
R = alkyl
PCy3
Cl
R R Ru R R
Cl Ph
E E PCy3 E E
[Ru]
29
RRCM : (-) - Archazolide B
MeO MeO
OTBS OH
1) GBII (20%)
O Ph-Me O
30
RRCM or not
Réactifs et conditions:
(a) n-BuLi, methyl propionate,
BF3·OEt2, THF, −78 °C, 92%; (b)
Pd(OAc)2, tris(2,6-
dimethoxyphenyl)phosphine, 20,
benzene, then Pd(O2CCF3)2, rt,
55%; (c) trifluoroperacetic acid,
Na2HPO4, CH2Cl2/CH3CN/CH3OH,
0 °C; (d) Dess−Martin oxidation;
(e) NaBH4, CeCl3·7H2O, −30 °C; (f)
Ac2O, pyridine, DMAP, CH2Cl2, rt,
45% over four steps; (g)
Et3N·3HF, THF, rt, 54−77%; (h)
Dess−Martin oxidation, 94%; (i)
CrCl2, CHI3, THF, rt, 26% (47%
BRSM); (j) Pd(PPh3)4, 22, THF, rt,
68%; (k) AcOH/H2O (3:1); (l)
TESCl, TEA, DMF, −35 to −15 °C,
60% over two steps; (m) Et3N,
DMAP, 2-methyl-6-nitrobenzoic
acid anhydride, CH2Cl2, 51%; (n)
benzene, 50−80 °C, 17 mol % of
Grubbs−Hoveyda catalyst, 80%,
1:1 E:Z mixture; (o) PPTS, MeOH,
rt, 36% of 1, 46% of 27.
métathèse
31
Stemoamide
H
MeO2C MgBr MeO2C
HO2C O N O O
N N
H CuBr, DMS
O H
GB II (6% mol) H NaOH I2
MeO2C N O
N O
MeOH O
CH2Cl2, reflux NaHCO3
H
95% 83% 91% I
NaBH4
O H O H
Bu3Sn-H LHMDS H2O2 NiCl2
O N O
N O
O Ph-Se-Br
AIBN, Ph-Me 76% H
H 81%
H3C
O H
CH3
O H N O
LHMDS
N O O
O
Me-I
H
H
70%
32
Enantioselective allylations and Metathesis
◼ Diospongine
O OH OTBS
H a b
1 2 3
TBSO OH
TBSO OH O
d
6 O 4
e
5
33
Tandem Metathesis / Hydrogenation
Cl Cl 90%
OH OH O O
GII NaOH H2
Muscone
56%
◼ Louie, J. ; Bielawski, C.W. ; Grubbs, R.H. J. Am. Chem. Soc. 2001, 123, 11312-11313.
◼ Autre ex: A.N. Whelan, J. Elaridi, R.J. Mulder, A.J. Robinson, W.R. Jackson Can. J. Med. 2005, 83, 875-881.
34
Cycloproparadicicol
H O OH
1)
O Br Zn, THF 1) n-BuLi, THF
H
2) TBS-Cl, CH2Cl2, imidazole OTBS
2) CO2
66% OTBS
(2 étapes)
H H
O O O O
HO
H (CO)3 Co H
Co2(CO)8
(CO)3 Co
DIAD, PPh3, THF PhMe
-20°C
OTBS OTBS
47% 100%
(3étapes)
H
O O O
H O
GBII I2 H
(CO)3 Co
H Z
CH2Cl2 (2. 10-4 M) (CO)3 Co THF, 0°C
TBSO
45°C OTBS
57% 69%
35
Cycloproparadicicol
H
H OTBS
O O O
O
TBSO H
H
TBSO
OTBS
140°C, neat
OTBS TBSO
75%
H
O O
HO H
O
HO
36
Tandem Metathesis – Migration of C=C
37
Tandem Cyclisation / Ring Opening / Ring
Closing (RCM/RO/RCM)
N
Boc
N
Ns
Ru CH2
CH2=CH2
Ru
N N Ru N
Boc Ru Boc Boc N
N N Ns
Ns Ns
Ru
Ru H
N N
N Boc
Boc N N
Boc N
Ns Ns
Ns
38
Tandem RCM/CM
O
O O
R O ( )n
O ( )n O ( )n
Catalyseur
CH2Cl2, R
+ (E)
40°C
[Ru]
R
39
Tandem RCM / CM
RO
B
RO
OR
excès O H
B H oxydation
RO
HG (10%)
benzène, 40°C O
O
O
51% (2 étapes)
◼ B.M. Stoltz
40
Spiranic derivatives
O
O O
HO O
R MgBr Cl
R R
( )n Et3N, THF, 0°C
( )n ( )n
49-83% 42-81%
Ru
R' R" O O
R' R" O
Ru
O R' O
O "R
"forme improductive"
TiL4
O
Ti(OiPr)4 Cyclisation
O
Ru
R'
"R
41
RCM and Téther : (-) Mucocin
HO OH
O
( )9 O O
O
OH OH
Mucocine (anti-cancéreux)
HO O
OHC
O
( )9 O
OH O
OH
O
O
OH
◼ P.A. Evans, J. Cui, S.J. Gharpure, A. Polosukhin, H-R. Zhang, J. Am. Chem. Soc. 2003, 125, 14702-14703.
42
RCM and Tether : (-) Mucocin
OH
O O
OHC
O 1) Et2Zn, PhMe O ( )3 O
O
OPMP
(R)-Binol + Ti(OiPr)4 OPMP 81%
PMP : p-méthoxyphényl THF, 0°C (ed > 20/1)
OTIPS
O
43
(-) Mucocin
OTIPS
O
( )9 O ( )3 O
O
OH OH
iPr2SiCl2, imidazole
CH2Cl2, 0°C
OTIPS
O
( )9 O ( )3 O ( )9 O R
O O
O O Grubbs type II O O
Si Si
1.8 equiv.
1,2-dichloroéthane
74% 83%
44
(-) Mucocin
9( )
O 9( )
O
O
Si HO
O
O Ts-NHNH2
HF, pyridine
HO
( )3 MeCN, CH2Cl2 NaOAc O
OH
OTIPS 1,2-DME ( )7
91%
95%
O
O O
O
◼ P.A. Evans, J. Cui, S.J. Gharpure, A. Polosukhin, H-R. Zhang, J. Am. Chem. Soc. 2003, 125, 14702-14703.
45
Cross coupling : Resvératrol
OH
OH
95
HO
Resvératrol
MesN NMes
Cl (3% mol)
Ru OH
Cl Ph
PCy3 -
HO OH
THF, reflux, 1h
OH HO
(94%)
10 eq. 1 eq. OH
HO 5
OH
OH
46
Gyrotope
47
Allylation / cross-metathesis
48
Ene-ynes metathesis - Principle
PCy3
R1 Cl Ru
Cl Ph R1
PCy3
R2 [Ru] R1
R1
R2
R2
R1 R1 CH2
R1 R1 CH2
[Ru]
Ru R1
R1 Ru
R1 R1
R2
49
Tandem Metathesis / Diels Alder
EtO2C CO2Et
N N
GI (2-6mol%) DEAD
Ph
O N O O
Ph
N
GII (10mol%) (10eq)
+ O
N DCM, 0,05M, , 3-5j
Ts (5eq) 3-5h N
Ts N
Ts
83%
50
Tandem Metathesis / Diels Alder
Ph [RuCl2 Ph Ph
EtO2C CO2Et
(p-Cymène)]2
O O O
Si Si Si
MesH2ImCl PhMe, CO2Et
H
Cs2CO3 CO2Et
79%
e.d. 72/28
O O O O
GI (5 mol%) O O O O O
CH2=CH2 HH HH
O
DCM, TA O O
O (2,2 eq)
2-6h
AcOEt O O
51
Metathesis Diene-Yne
CO2Me
O
CO2Me MeO2C
G-II (12%)
CH2Cl2, reflux
3h
82%
OHC
O OH
AcO
Guanacastepène A
52
53
Metathesis Diene-Yne
54
Metathesis of alkanes…
◼ .
55
◼ A. Fürstner, Chem Commun 2011, 6505-6511.
56