75
ALKENE METATHESIS BACKGROUND & CATALYST DEVELOPMENT
![Page 1: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/1.jpg)
ALKENE METATHESIS
BACKGROUND & CATALYST DEVELOPMENT
![Page 2: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/2.jpg)
OLEFIN METATHESIS
R2R1
R4R3
catalyst R1 R2
R4R3
+
Selected Reviews:
R. H. Grubbs et al., Acc. Chem. Res. 1995, 28, 446; ibid. 2001, 34, 18
S. Blechert et al., Angew. Chem. Int. Ed. 1997, 36, 2037; ibid. 2003, 42, 1900
R. R. Schrock, A. Hoveyda, Angew. Chem. Int. Ed. 2003, 42, 4592
A. Fürstner, Angew. Chem. Int. Ed. 2000, 39, 3012
S. F. Martin et al., Chem. Rev. 2004, 104, 2199
![Page 3: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/3.jpg)
MoO
O N
F3CF3C
F3CF3C R
R
Ph
PCy3
RuCl
ClPCy3
Ph
Schrock (1990) Grubbs (1992, 1995)
„Chauvin mechanism“
Chauvin, Katz, Casey, Grubbs
CH2
CH2CH2
H2C [M]
H2C
[M]
H2C [M]
[M] CH2 CH2H2C
H2C[M]
ADMET POLYMERRCM
![Page 4: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/4.jpg)
THE FUNCTIONAL GROUP AS AN ESSENTIAL RELAY
[Ru] O
R
[Ru] O
R
L
RuL
O
O
C43
C44
C53
C42
C54
Cl1
C55
C45
C52
C41
C51
C56
C46
C23
P1
Ru1
C9
O1
C22
C31
C2
C8
O2
C7
C3
C21
C36
C6
C4
C32
C5
Cl2
C35
C33
C34
A. Fürstner et al., J. Org. Chem. 1996, 61, 3942; Synthesis 1997, 792
structural investigation: A. Fürstner et al., Organometallics 2002, 21, 331
![Page 5: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/5.jpg)
A CHEAP AND STABLE CARBENE SOURCE
Ph
PCy3
Ru
PCy3
Cl
ClPh
PPh3
Ru
PPh3
Cl
Cl
PPh3
Ru
PPh3
Ph
PhCl
Cl
OH
PhPh
(PPh3)3RuCl2
THF, reflux
PCy3
CH2Cl2, r.t.
Synthesis and Proposal of the Allenylidene Structure: A. F. Hill et al., J. Chem. Soc. Dalton Trans. 1999, 285
Correct Structure, Optimized Synthesis and Applications: A. Fürstner et al., Chem. Eur. J., 2001, 7, 4811.
since 2005 commercially available: STREM (g-quantities), UMICORE, Hanau (kg-quantities)
![Page 6: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/6.jpg)
A. Fürstner et al, Chem. Eur. J. 2001, 7, 4811.
94%77%83%
82%
ON
O
Fmoc
O
BrE E
60%
N O
H
65%
N
N
N
MeO
H
HH
Cl
OHO
HO
O
69%
N
OBnOH
OOtBu
87%
74%
N
N
H
O
PMB
O
COOtBu
98%
O
O
O
OHHO
HO
O
O
O
OHO
HO
OH
HOHO
O
OO
OO
OH
O
O
O
O
OOHO
OO
94%
Ph
PCy3
Ru
PCy3
Cl
Cl
![Page 7: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/7.jpg)
SECOND GENERATION CATALYSTS
N NR R
RuCl
Cl
Ph
RR NN
N NR R
RuCl
Cl
Ph
RR NN
W. A. Herrmann et al., Angew. Chem. Int. Ed. 1998, 37, 2490;
corrigendum: Angew. Chem. Int. Ed. 1999, 38, 262.
Nolan et al. J. Am. Chem. Soc. 1999, 121, 2674
PCy3
RuCl
Cl
Ph
RR NNTetrahedron Lett. 1999, 4787Fürstner, Herrmann et al.
Grubbs et al. Tetrahedron Lett. 1999, 2247; Org. Lett. 1999, 1, 953
![Page 8: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/8.jpg)
C71 Cl1
C72
C37
C39
C61
C9
P
C10
C62
C17
Ru
C31
C8
C51
C5
N2
C1
C32
C4 C52
C7
C2
N1
Cl4
C6
C3
C11
Cl2
C38
Cl3
C12
C19
C18
A. Fürstner et al., Chem. Eur. J.
2001, 7, 3236
Ru
PCy3
PhCl
Cl
N N
Cl Cl
![Page 9: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/9.jpg)
PCy3
RuCl
Cl
Ph
PCy3
PCy3
RuCl
Cl
Ph
RR NN
N
TsN
Ts
E EE
E
E EE E
L. Ackermann, A. Fürstner, T. Weskamp, F. J. Kohl, W. A. Herrmann, Tetrahedron Lett 1999, 40, 4787.
0% 80%
0% 96%
0% 83%
![Page 10: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/10.jpg)
RUTHENIUM NHC COMPLEXES: RCM OF ACRYLATES
O
O
O
O
O
O
O
O
O O O O O O O O
N
O
Ph
OO
O
O
O
O
93% 92% 78% 63% 82%
89% 62%42%73%79%95%
A. Fürstner et al, J. Org. Chem. 2000, 65, 2204.
![Page 11: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/11.jpg)
RUTHENIUM-BASED “DESIGNER” CATALYSTS
C39
C133
C132
C131 C13
C31
Cl2
C6
C3
C7
C32
N2
C4
C2
Si
C12
C15
C1
C5
N1
C8
O
C38
Ru
C71
C14
C11
C10
C9
C72
C52
P
C51
C62
Cl1
C61
C37
Chem. Eur. J. 2001, 7, 3236;
for metathesis in scCO2 see: A. Fürstner et al. JACS 2001, 123, 9000
N NF3C(F2C)5
Ru
PCy3
Cl
Cl
Ru
PCy3
Cl
Cl
N NO
tBuMe2Si
![Page 12: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/12.jpg)
RUTHENIUM-BASED “DESIGNER” CATALYSTS
C18
C17
C9
C12
C8O1
Cl1/Br1
C11
C7
C3
N2C6
C20 C21
C2
C1
C31
C5
N1
Ru1
C19
C22
C32
C4
P1C52C51
Cl2/Br2
C41
C42
A. Fürstner et al., Organometallics 2004, 23, 280
Ru
PCy3
Cl
Cl
N NO
SiO
R
O
R = Me
R = Ph
ClSi
O
R
Osilica
Ru
PCy3
Cl
Cl
N NHO
RSiCl3
![Page 13: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/13.jpg)
UNUSUAL REORGANIZATIONS
C42
N41
O1
C5C17
Cl1
Ru1
C4
C12 C1
N1
C20
C2
N2
C32
C11
C3
N31
C21C18
C22
C19
Cl2
Ru
PCy3
Cl
Cl
N NMe3SiO
N
NCy3P
RuCl Cl
HO
HCl cat.
Ph
N NMes
ORu
ClPy
H
PyCl
pyridine
quant. 82%
C18C19
C52C42
C41
C51
C11 C12N2
C3
P1
C20
C21
C1
C2 C17
C31
Ru1
N1
C22
C32
C4
Cl1
Cl2
C5
C9 / O9C6
C8 / O8
C7 / O7
S. Prühs, C. W. Lehmann, A. Fürstner, Organometallics 2004, 23, 280
![Page 14: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/14.jpg)
RUTHENIUM-BASED “DESIGNER” CATALYSTS
C37
C39
C32
Cl2
C31
N2 C2
C6
C51
C61
C1 C3
C52
C62
Ru
C7
N1
P
C38
C5
C8 C4
C71 Cl1
C72
A. Fürstner et al., Chem. Commun. 2001, 2240; Chem. Eur. J. 2001, 7, 3236
Ru
PCy3
Cl
Cl
NN
Ru
PCy3
Cl
Cl
Ph
NN
toluene, 80°C
![Page 15: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/15.jpg)
RUTHENIUM-BASED “DESIGNER” CATALYSTS
Ru
PCy3
Cl
Cl
NN
Ru
PCy3
CH2Cl
Cl
NN
CH2 CH2
NN
X
Cl
ClRu
X
X
initiation
propagation
termination
![Page 16: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/16.jpg)
R. H. Grubbs et al., Science 2002, 297, 2041
Ru
PCy3
Cl
Cl
NN
3
NN
Ru
PCy3
Cl
Cln
n n
n
H2
cyclic polyoctenamer cyclic polyethylene
![Page 17: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/17.jpg)
ALTERNATIVE „HOVEYDA-TYPE“ CATALYSTS
via ENYNE METATHESIS
R
Ru
Cl
ClL
PCy3
O
R
CH2Cl2, AgCl
L
Ph
Ru
O
Cl
Cl R
A. Fürstner, P. W. Davies, C. W. Lehmann, Organometallics 2005, 24, 4065
![Page 18: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/18.jpg)
C52
C51
Cl1
C42
C41
C11
C12
P1
C29
C1
C27
C7
Ru1
C2
C31
C1A
C28
O1
C6
C3
C5A
C9
C32
C8
Cl2
C26
C4
C21
C25
C22
C24
C23
Ru
O
Cl
ClPhCy3P Cy3P
PhRu
O
Cl
Cl
Ru
O
Cl
ClPhNR N R
Ru
O
Cl
Cl
Ph
SiMe3
Cy3P
Ru
O
Cl
Cl
Ph
O
O
O
OMe
H
Cy3P
= 5.18 ppm
Cy3P
= 4.38 ppm
Ru
O
Me3Si
Cl
Cl
Ph
O H
C15
C6
Cl1
C5
C7
C42
C4
C8
C22
C23
C2
Si1
C9
C41
O1
C1
C14
C3
C20
C21
Ru1
C24
C13
P1
C26
C25
C51
C31
O2
Cl2
C32
C12
C52
C10
C11
A. Fürstner, P. W. Davies, C. W. Lehmann, Organometallics 2005, 24, 4065
![Page 19: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/19.jpg)
56
10
9
11
1
2
3
toluene
catalyst (0.6 mol%)O Ph
PhO Ph
Ph
321
Ru
PCy3
PhCl
Cl
PCy3 N N
Ru
PCy3
PhCl
Cl
N N
Ru
PCy3
PhCl
Cl
NN
N
Cl
Cl PhPCy3
RuRu
PCy3
PhCl
ClRu
PCy3
PhCl
Cl
N NN N
Cl Cl
9 10 1156
Ru
PCy3
Cl
Cl
PCy3 Ph
5 sec 51 sec 60 sec
A. Fürstner et al., Chem. Eur. J. 2001, 7, 3236, Angew. Chem. Int. Ed. 2000, 39, 1236
SCREENING BY
IR THERMOGRAPHY
![Page 20: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/20.jpg)
SEARCH FOR ALTERNATIVE CATALYSTS
RuPh
PCy3
PCy3
Cl
ClRu CH2
PCy3
L
Cl
Ru
R3P
ClPh
Ph
A. Fürstner, P. H. Dixneuf et al., Chem. Commun. 1998, 1315 and Chem. Eur. J. 2000, 6, 1847
![Page 21: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/21.jpg)
CATIONIC RUTHENIUM ALLENYLIDENE COMPLEXES
Ru
R3P
ClPh
Ph
R = Cy, i-Pr, Ph etc.
CH2Cl2, r.t., 4h
2 PR3[(p-cymene)RuCl 2]2
NaPF6 (1 eq.), MeOH, r.t., 3h
Ph
OH
Ph
Ru
R3P
ClCl
Ru
R3P Cl
AgX
X
Ph
OH
Ph
CH2Cl2, r.t., < 1h
X
A. Fürstner, M. Liebl, C. W. Lehmann, M. Picquet, R. Kunz, C. Bruneau, D. Touchard, P. H. Dixneuf,
Chem. Eur. J. 2000, 6, 1847.
![Page 22: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/22.jpg)
Ru
iPr3P
ClPh
Ph
PF6
N
Ts
O
Br
O
OPh
ON
Ts
NO
H
O
O
O
O
ON
O
Fmoc
O
O
OCH3
O
OO
OOO
OPh
OHO
O
83% 93% 88% 86% 75%
66% 40% 79% 90%
85%
![Page 23: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/23.jpg)
METATHESIS IN scCO2
0.55 0.60 0.65 0.70 0.75 0.80 0.85
0
20
40
60
80
100
RCM-product 9
oligomers
Yield
[%]
d [g/ml]
A. Fürstner, W. Leitner et al.,
JACS 2001, 123, 9000
O
O
O
O
RCMADMETO
O
+ ethene n
+ n ethene
![Page 24: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/24.jpg)
METATHESIS IN scCO2
Grubbs catalyst
nmono/ncat. = 5350
T = 34°C, p = 165 bar
polynorbornenamerA. Fürstner, W. Leitner et al.,
JACS 2001, 123, 9000
![Page 25: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/25.jpg)
applies to all kinds of metathetic conversions:
RCM, ROMP, ADMET, Enyne-metathesis, Cross-metathesis
the density of the medium gives hands on the reaction pathway
RCM: applies to all ring sizes 5
easy separation of the product (e.g. musk-odored macrolides)
the catalyst is reusable
the CO2 is reusable
compatible with free amines
subsequent transformations of the products possible
RCM IN SUPERCRITICAL OR LIQUID CO2
![Page 26: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/26.jpg)
ALKENE METATHESIS
APPLICATIONS
![Page 27: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/27.jpg)
MY PERSONAL INITIATION
HOMe3SiO 1. Mo(=NAr)(=CHCMe2Ph)[OCMe(CF3)2]2
(3 mol%)
2. TBAF 92%
"Dactylol"
A. Fürstner, K. Langemann, J. Org. Chem. 1996, 61, 3942
A. Fürstner, K. Langemann, J. Org. Chem. 1996, 61, 8746
H2, Pd/C(4 mol%)
(Cy3P)2Cl2Ru=CHCH=CPh2O
O
O
O
O
O
79%94%
E : Z = 46 : 54perfume ingredient
"Exaltolide"
![Page 28: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/28.jpg)
THE FUNCTIONAL GROUP AS AN ESSENTIAL RELAY
(4 mol%)
(Cy3P)2Cl2Ru=CHCH=CPh2O
O
O
O
79%
(4 mol%)
(Cy3P)2Cl2Ru=CHCH=CPh2
oligomers
![Page 29: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/29.jpg)
THE FUNCTIONAL GROUP AS AN ESSENTIAL RELAY
84%
[Ru] (5 mol%)no reaction
O
N
O
R
O
N
O
R
O
N
O
R
[Ru] (5 mol%)
A. F. and K. Langemann, Synthesis 1997, 792.
![Page 30: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/30.jpg)
THE FUNCTIONAL GROUP AS AN ESSENTIAL RELAY
[Ru] O
R
[Ru] O
R
L
RuL
O
O
C43
C44
C53
C42
C54
Cl1
C55
C45
C52
C41
C51
C56
C46
C23
P1
Ru1
C9
O1
C22
C31
C2
C8
O2
C7
C3
C21
C36
C6
C4
C32
C5
Cl2
C35
C33
C34
A. Fürstner et al., J. Org. Chem. 1996, 61, 3942; Synthesis 1997, 792
structural investigation: A. Fürstner et al., Organometallics 2002, 21, 331
![Page 31: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/31.jpg)
PREDICTIVE POWER: (R)-(+)-LASIODIPLODIN
Lasiodiplodin
[Ru]
MeO
MeO O
OO
MeO
MeO O
94%
[Ru]
MeO
MeO O
OO
MeO
MeO O
O
OMeO
HO
E : Z = 2.3 : 1
A. Fürstner, N. Kindler, Tetrahedron Lett. 1996, 37, 7005.
![Page 32: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/32.jpg)
RUTHENIUM NHC COMPLEXES: RCM OF STYRENES
A. Fürstner, O. R. Thiel, N. Kindler, B. Bartkowska J. Org. Chem. 2000, 65, 7990.
(E)-isomer only !
no reactionO
OMeO
MeOO
O
PCy3
Ru
PCy3
Cl
Cl Ph 5 mol%
N N
Ru
PCy3
Cl
Cl Ph
O
OHO
HO O
Zearalenone
O
OMeO
MeOO
O
91%
![Page 33: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/33.jpg)
(-)-GLOEOSPORONE: A FUNGAL GERMINATION
SELF INHIBITING MACROLIDE
OO
H
OH
H
O
O
correct structure: D. Seebach, S. L. Schreiber et al., Helv. Chim. Acta 1987, 70, 281.
other syntheses: D. Seebach et al. (1987); S. L. Schreiber et al. (1988), S. Takano et al. (1988),
A. B. Holmes et al. (1991), H. Irie et al. (1992), S. V. Ley et al. (2003)
![Page 34: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/34.jpg)
(-)-GLOEOSPORONE: RETROSYNTHETIC ANALYSIS
(R) (R)
O OORO
H
H
OOR
OO
H
H
O
OOROO
H
OH
H
O
O
![Page 35: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/35.jpg)
TOTAL SYNTHESIS OF (-)-GLOEOSPORONE
82%
91%
DMAP, pyridine
4-pentenoyl chloride
MeO
MeO O O
88%, ee > 98%
MeO
MeO OH
Ti(OiPr)4 (1.2 eq.)
(20 mol%)
Zn(pent)2
NHTf
NHTf
OMeO
MeO
NaHCO3, Me2S
MeOH, pTsOH
ozonolysis
![Page 36: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/36.jpg)
TOTAL SYNTHESIS OF (-)-GLOEOSPORONE
91%
TBDMSCl, imidazole77%, de > 98%
90%
R = SiMe2tBu
R = H
O OOR
molecular sieves
(S)-Binol (20 mol%), Ti(OiPr)4 (20 mol%)
SnBu3
O
O O
CH2Cl2:H2O (1:1)
CF3COOH
MeO
MeO O O
![Page 37: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/37.jpg)
TOTAL SYNTHESIS OF (-)-GLOEOSPORONE
54%
(-)-gloeosporone
MeCN
aq. HF
O OO
O
H
OH
KMnO4, Ac2O
O O
Me2tBuSiO
O
O
E : Z = 2.7 : 1
80%
O O
Me2tBuSiO
CH2Cl2, 40°C
Ti(OiPr)4 (30 mol%)
[Ru] (3 mol%)
O OtBuMe2SiO
A. Fürstner, K. Langemann, J. Am. Chem. Soc. 1997, 119, 9130
![Page 38: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/38.jpg)
FORMAL TOTAL SYNTHESIS OF (-)-BALANOL
A. Fürstner, O. R. Thiel, J. Org. Chem. 2000, 65, 1738
87%
Ph
PCy3
Ru
PCy3
Cl
Cl
55% (over both steps)
2. p-BnOC6H4COCl, Et3N
1. H2, Pd/C
91%
Mitsunobu
quant.
Boc2O, Et3N
94%
allylamine, 70°C
95%
NaH, BnBr
ee > 99%
Ti(OiPr)4 cat.
(D)-(-)-DET, tBuOOHOH OR
O
R = H
R = Bn
N
R
OH
BnO
R = H
R = Boc
N
Boc
OH
BnO
N
Boc
N3
BnO
OBn
OH
N
Boc
N
HO
![Page 39: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/39.jpg)
N
NH
N
MeO
H
H
Cl
ClCl
N
N
N
MeO
H
HH
N
NH
HO
HN
Me
N
N
N
MeO
H
HH
Ph
PCy3
Ru
PCy3
Cl
Clcat.
65%
RhCl(PPh3)3 cat., H2
73%
Cl
Nonylprodigiosin.HCl(E)-isomer only !
A. Fürstner et al., J. Org. Chem. 1999, 64, 8275; ChemBioChem 2001, 2, 60 and 706
TOTAL SYNTHESIS OF NONYLPRODIGIOSIN
![Page 40: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/40.jpg)
HO
HO
O
O
HO
HO
O
O
HO
O
O
HO
HO
O
O
H
O
O
OBnO
BnO
BnO
O
O
O
O
OPh
O
O
OO
Tricolorin G
Ph
O
O
O
O
O
O
O
O
OH
OO
OO
OH
O
O
O
O
O
O
O
PhH
O
O
O
HO
HO
OH
O
O
O
O
O
HOHO
O
O
O
O
O
HO
HOO
O
Tricolorin A
OO
OH
O
O
O
O
O
O
O
O
Ph
1. [Ru]
2. H2OO
OH
O
O
PhO
O
O
O
O
O
A. Fürstner, T. Müller, J. Am. Chem. Soc. 1999, 121, 7814; Review: Eur. J. Org. Chem. 2004, 943
OO
HO
O
HO
PhO
O
O
O
O
![Page 41: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/41.jpg)
K. Miyahara et al., Chem. Pharm. Bull. 1993, 41, 1925
review on the chemistry & biology of resin glycosides: A. Fürstner Eur. J. Org. Chem. 2004, 943
WOODROSIN I
Ipomoea tuberosa L.
O
O
O
OHHO
HO
O
O
O
OHO
HO
OH
HOHO
O
OO
OO
OH
O
O
O
O
OOHO
OO
![Page 42: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/42.jpg)
A. Fürstner, F. Jeanjean, P. Razon, Angew. Chem. Int. Ed. 2002, 41, 2097; Chem. Eur. J. 2003, 9, 307 and 320
for the ruthenium indenylidene catalyst see: A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811
cat.
Ph
Ru
PCy3
PCy3
Cl
Cl
OO O
O
O
O O
Cl
OBn
BnOBnO
O
OO
Ph
OHO
OOO
OBn
OBnO
BnO
O
O
O
94%
1.
O
O
O
OHHO
HO
O
O
O
OHO
HO
OH
HOHO
O
OO
OO
OH
O
O
O
O
OOHO
OO
O NHO
OBnO
O O
O CCl3
2. deprotection, 84%WOODROSIN I
O
O
O
BnO
BnO O
O O
O
O
O
O
OBn
O
Cl
OBn
BnOBnO
O
OO
Ph
OHO
OOO
E : Z = 9 : 1
60%
![Page 43: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/43.jpg)
IPOMOEASSIN
D. Kingston et al., J. Nat. Prod. 2005, 68, 487
Ipomoea squamosa
![Page 44: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/44.jpg)
![Page 45: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/45.jpg)
![Page 46: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/46.jpg)
REVISED RETROSYNTHETIC ANALYSIS
![Page 47: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/47.jpg)
A. F. with T. Nagano
J. Am. Chem. Soc. 2007, 129, 1906
![Page 48: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/48.jpg)
A. F. with T. Nagano, J. Pospisil, G. Chollet, S. Schulthoff, V. Hickmann, E. Moulin, J. Herrmann, R. Müller,
Chem. Eur. J. 2009, 15, 9697-9706.
![Page 49: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/49.jpg)
very scarce
mixed polyketide biosynthesis
(very) potent cytotoxicity
generally unknown mode of action
THE AMPHIDINOLIDES
![Page 50: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/50.jpg)
TOWARD AMPHIDINOLIDE H
![Page 51: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/51.jpg)
TOWARD AMPHIDINOLIDE H (II)
![Page 52: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/52.jpg)
A. F. with L. C. Bouchez, J.-A. Funel, V. Lipins, F.-H. Porée, R. Gilmour, F. Beaufils, D. Laurich, M. Tamiya
Angew. Chem. Int. Ed. 2007, 46, 9265; Chem. Eur. J. 2009, 15, 3983
![Page 53: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/53.jpg)
THE AMPHIDINOLIDE T FAMILY
J. Kobayashi et al., J. Org. Chem. 2000, 65, 1349 and 2001, 66, 134.
O
O
OH
O
O
O
O
O
HO
O
Amphidinolide T1 Amphidinolide T3
O
O
O
HO
O
Amphidinolide T4
O
O
O
HO
O
Amphidinolide T5
Review: J. Kobayashi et al., Nat. Prod. Rep. 2004, 77.
![Page 54: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/54.jpg)
RETROSYNTHETIC ANALYSIS
O
Y
Cl
O
O
O
X
R3SiO
OR2
A
B
C
O
O
OR2
R1O
O
45
12 14
syn syn
O
O
OR2
R1O
O
Amphidinolide T
family
![Page 55: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/55.jpg)
O
TBDPSO
OMOM
O
O
O
Ru
PCy3
PhCl
Cl
Mes MesNN
O
O
O
OMOM
TBDPSO
O
86%
O
O
HO
O
O
O
O
O
O
OH
Amphidinolide T4
Amphidinolide T1
E:Z = 6:1
A. Fürstner, C. Aissa, R. Riveiros, J. Ragot, Angew. Chem. Int. Ed. 2002, 41, 4763;
J. Am. Chem. Soc. 2003, 125, 15512
![Page 56: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/56.jpg)
O
TBDPSO
OMOM
O
O
O
Ru
PCy3
PhCl
Cl
Mes MesNN
O
O
O
OMOM
TBDPSO
O E:Z = 6:1
O
TBDPSO
OMOM
O
O
O
Ru
PCy3
PhCl
Cl
Mes MesNN
O
O
O
OMOM
TBDPSO
O E:Z = 2:1
toluene, 110°C
82%
CH2Cl2, 40°C
86%
![Page 57: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/57.jpg)
TOTAL SYNTHESIS OF AMPHIDINOLIDE T
OZnBr
Zn
BrZn
O
O
O
OMOM
TBDPSO
O
O
O
OMOM
TBDPSO
O
O
OMOM
TBDPSO
O
COOH
Ph3P=CH2
TiCl4
THF, reflux, 64%
![Page 58: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/58.jpg)
O
O
HO
O
O
Amphidinolide T4
O
O
O
O
OH
Amphidinolide T1
O
O
TBDPSO
O
OMOM
1. [(Me2N)3S][Me3SiF2], 84%
2. Dess-Martin periodinane, 93%
3. Dowex, 52%
1. TMSCl, Bu4NBr, 85%
3. HF.pyridine, 87%
2. Dess-Martin periodinane, 83%
A. Fürstner, C. Aissa, R. Riveiros, J. Ragot, ACIE 2002, 41, 4763; JACS 2003, 125, 15512
![Page 59: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/59.jpg)
V. Prelog et al., Helv. Chim. Acta 1946, 29, 1524
previous syntheses: G. Büchi (1957), M. Kumada (1975), H. Nozaki (1980), M. Hesse (1992), M. Ando (2000)
MUSCOPYRIDINE
N NM M
N XX
![Page 60: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/60.jpg)
NCl OTf
Cl N
N
BrMg
[Fe] cat.+ +
N6-heptenyl-MgBr
[Fe] cat.
![Page 61: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/61.jpg)
A. Fürstner, A. Leitner, Angew. Chem. Int. Ed. 2003, 42, 308
for the preparation of the ruthenium indenylidene catalyst see: A. Fürstner et al., Chem. Eur. J. 2001, 7, 4811
since 2005 commercially available: STREM (g-quantities), UMICORE, Hanau (kg-quantities)
N
N
PhPCy3
Ru
PCy3
Cl
Cl
HCl/Et2O
then
+
0.006 M N
H
Cl
H2 (50 atm)
then aq. NaHCO3
N
57% overall
0.13 M
ADMET
polymer
„INTEGRATED„ SYNTHESIS OF MUSCOPYRIDINE
![Page 62: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/62.jpg)
(-)-ISOONCINOTINE
NN
H
N O
HH
NN
H
N O
HHH
H
2 X
N
H
HN
Cl
X
N
OR1
Isolation from the stem bark of Oncinotis nitida by
M. Hesse et al., Helv. Chim. Acta 1968, 51, 1813
![Page 63: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/63.jpg)
ASYMMETRIC HYDROGENATION OF PYRIDINES
NO
N R
O
N
O
N R
OH
X
H2
Pd/CN
O
N R
O X
X
N R
X
N R N RPd/C
HX H2
NHO
O
H2
H H2 H
F. Glorius et al., Angew. Chem. Int. Ed. 2004, 43, 2850
![Page 64: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/64.jpg)
B. Scheiper, F. Glorius, A. Leitner, A. Fürstner, Proc. Natl. Acad. Sci. USA 2004, 101, 11960
NCl Cl
NHO
O
BrMgOBn
NCl OBn NO
N
O
OBn
N
H
OHN
N
H
N O
HNs
OH
NN
H
N O
HR
R = Ns
R = H
NN
H
N O
HH
Ph
Ru
PCy3
PCy3
Cl
Cl
ee = 94%
Fe(acac)3 cat.
83%
CuI cat.
90%
H2 (120 atm)
Pd(OH)2/C cat.
78%
NBr
N O
HNs
K2CO3, NaI, 73%
1. Swern, 81%
2. Ph3P=CH2, 82%
HSCH2COOH
LiOH, 84%
then H2
76%
(-)-Isooncinotine
![Page 65: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/65.jpg)
OH
O
MeO
NHO
MeO
O
NH
O H
OTBSH
O
O
MeO
MeO
N
O
NH
O H
OTBSH
N
N
DCC
O
O
MeO
MeO
RuCl
Cl
PCy3Ph
N NMes Mes
69%
N
O
NH
O H
ORH
R = TBS
R = HTBAF, 80%
A. F. with C. Nevado, M. Tremblay, C.
Chevrier, F. Teplý, C. Aissa, M. Waser
Angew. Chem. Int. Ed. 2006, 45, 5837
TOTAL SYNTHESIS
OF IEJIMALIDE B
![Page 66: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/66.jpg)
SCALE-UP AND MOLECULAR EDITING
> 1 g
submitted for publication
![Page 67: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/67.jpg)
THE ASPERCYCLIDES
A. F. with C. Müller, J. Pospisil, Chem.
Eur. J. 2009, 15, 5956
![Page 68: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/68.jpg)
SPIRASTRELLOLIDE
Isolation: R. J. Anderson et al., Org. Lett. 2004, 6, 2607; J. Org. Chem. 2007, 72, 9842
Review: I. Paterson et al., Nat. Prod. Rep. 2009, in press
![Page 69: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/69.jpg)
A. F. with B. Fasching, G. W. O‘Neil, M. D. B. Fenster, C. Godbout, J. Ceccon, Chem. Commun. 2007, 3045
for the development of the „relay strategy“ see: T. Hoye et al., J. Am. Chem. Soc. 2004, 126, 10210
![Page 70: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/70.jpg)
THE E/Z-PROBLEM
Chem. Eur. J. 2002, 8, 1856 Chem. Eur. J. 2001, 7, 5286
H 0 : 100
Me 66 : 34
R E : Z
E:Z = 1 : 1.1
OMe
OR
OR
OR
E:Z = 6.9 : 1
Turriane Salicylihalamide
O
O
O
OMOM
TBDPSO
O
E:Z = 6:1
O
O
O
OMOM
TBDPSO
O
E:Z = 2:1
Amphidinolide T
JACS 2003, 125, 15512
RO
O
O
OMOM
OPMB
![Page 71: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/71.jpg)
RCM APPROACH TO SALICYLIHALAMIDE
RO
O
O
OMOM
OPMB
RO
O
O
OMOM
OPMBRu
PCy3
Cl
Cl Ph
N N
5 mol%
toluene, 80°C
R Yield E : Z
H 69% 0 : 100
Me 93% 66 : 34
MOM 91% 68 : 32
SiMe2tBu 91% 40 : 60
Org. Lett. 2000, 2, 3731
![Page 72: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/72.jpg)
TOTAL SYNTHESIS OF SALICYLIHALAMIDE
HO
O
O
OH
NH
O
R1 = R2 = H
R1 = MOM, R2 = Me
R2O
O
O
OR1
I
MeO
O
O
OMOM
O
R = H
R = PMB
MeO
O
O
OMOM
OR
DDQ, 94%
Dess-Martin
87%
CHI3, CrCl2
87%
BBr3, 88%
H2N
O
Cu-thiophene carboxylate
Rb2CO3
57%
A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem. Eur. J. 2001, 7, 5286
![Page 73: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/73.jpg)
E/Z-CONTROL: PHYTOTOXIC LACTONES
Herbarumin: J. F. Rivero-Cruz et al., Tetrahedron 2000, 56, 5337; Lethaloxin: A. Arnone et al.,
Gazz. Chim. Ital. 1993, 123, 71; Pinolidoxin: A. Evidente et al., Phytochemistry 1993, 34, 999
PinolidoxinLethaloxinHerbarumin IIHerbarumin I
O
O
HO
HO O
O
O
O
HO
HO O
O
O
O
HO
HO OHO
O
HO
HO
![Page 74: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/74.jpg)
O
O
O
O
O
O
O
O
(Z)-isomer is ca. 3.5 kcal/mol more stable
CONCEPT
O
O
HO
HO
O
O
HO
HO
(Z)-isomer is ca. 1.5 kcal/mol more stable
![Page 75: ALKENE METATHESIS...METATHESIS IN scCO 2 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0 20 40 60 80 100 RCM-product 9 oligomers Yield [%] A. Fürstner, W. Leitner et al., d [g/ml] JACS 2001,](https://reader039.documents.pub/reader039/viewer/2022040306/5ec958720314b5791871cebd/html5/page/75.jpg)
HERBARUMIN: E/Z CONTROL BY CATALYST TUNING
O
O
O
O
N NMesMes
O
O
O
O
Ru
PCy3
PhCl
Cl
O
O
HO
HO
PCy3
Ru
PCy3
Cl
Cl Ph
O
O
O
O
cat.
cat.
86%only (Z)
E : Z = 7.6 : 1
78% aq. HCl
90%
Herbarumin I
A. Fürstner, et al., Chem. Commun. 2001, 671; J. Am. Chem. Soc. 2002, 124, 7061
for further applications of the concept of „catalyst tuning“ in synthesis see: A. Fürstner et al., Adv. Synth.
Catal. 2002, 344, 657; Chem. Commun. 2005, 5583; Chem. Eur. J. 2007, 13, 1452
