Review: B. D. Sherry, A. Fürstner, Acc. Chem. Res. 2008, 41, 1500
vinyl sulfones (Julia, 1982), vinyl halides (Hanack, 1974; Molander, 1983), acid chlorides (Marchese,
1984), allyl phosphates and halides (H. Yamamoto, 1991; Szeimies, 1994),
vinyl halides & phosphates (Cahiez, 1998)
J. Kochi et al., J. Am. Chem. Soc. 1971, 93, 1487
M. S. Kharasch et al. JACS 1941, 63, 2316; G. Vavon et al., Hebd. Sceances Acad. Sci. 1945, 220, 850;
W. C. Percival et al., JACS 1953, 75, 3731
Fe-II: [Ar] 3d8 4s2
Pd0: [Kr] 3d10 4s0
Cu+I: [Kr] 3d10 4s0
Fe0: [Ar] 3d6 4s2
Ni0: [Ar] 3d8 4s2
Ru0: [Kr] 3d6 4s2
RhI: [Kr] 3d8 4s0
IrI: [Xe] 3d8 4s0
A CHEAP METAL FOR A NOBLE TASK ?
X Cross coupling Reduction
I 27% 46%
Br 38% 50%
Cl > 95% ---
OTf > 95% ---
OTs > 95% ---
A. Fürstner et al. Angew. Chem. Int. Ed. 2002, 41, 609; JACS 2002, 124, 13856
for a larger scale application see: A. F. with A. Leitner, G. Seidel, Org. Synth. 2004, 81, 33
A. F. with A. Leitner, M. Méndez, H. Krause, J. Am. Chem. Soc. 2002, 124, 13856
alkyl-MgX >> aryl-MgX (homocoupling)
the reaction is sensitive to steric hindrance
H29C14
SN(iPr)2
O
O
C14H29MeO
OMeO
C14H29
N
N C14H29
NN
H
O
OAcAcO
NAcO
N
NN
C14H29
N
N
R
R = Ph (73%)
R = 2-pyridyl (82%)
94% 90% 81% 93%
67% 72%
R = C14H29 (95%)
for advances in Fe-catalyzed Ar-Ar cross coupling, see: M. Nakamura et al., JACS 2007, 129, 9844
A. F. with B. Scheiper, F. Glorius, A. Leitner, Proc. Natl. Acad. Sci. USA 2004, 101, 11960
F. Glorius et al., ACIE 2004, 43, 2850
A. F. et al., Chem. Eur. J. 2001, 7, 4811
commercially available (Umicore, Evonik)
NCl Cl
NHO
O
BrMgOBn
NCl OBn N
O O
N 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%
K2CO3, NaI, 73%
1. Swern, 81%
2. Ph3P=CH2, 82%
HSCH2COOH
LiOH, 84%
then H2
76%
(-)-Isooncinotine
NBr
N O
HNs
MeOH/HOAc
A. F. with G. Seidel, D. Laurich, J. Org. Chem. 2004, 69, 3950
ALTERNATIVE ROUTE TO FTY720
OAc
HO
C8H17MgBr
Fe(acac)3 cat.
OAc
OH
HO
NaHSO4/SiO2
EtOAc/hexane
98% (14 g scale)94% (23 g scale)
O
OTfO
Tf2O, pyridine
84% (9 g scale)
NH2
HO
OH
FTY720
(immunomodulatory, phase III clinical trials)
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
NCl OTf
Cl N
N
BrMg
[Fe] cat.+ +
N6-heptenyl-MgBr
[Fe] cat.
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
ENOL TRIFLATES
N
C14H29
BOCO
O
Ph O C14H29MeO
C14H29
Me73% 68% 67% 64% 91%
A. F. with B. Scheiper, M. Bonnekessel, H. Krause, J. Org. Chem. 2004, 69, 3943
O O
MeO
84%O O
TfO
MgBr
MeO
Fe(acac)3 (5 mol%)
APPLICATION IN TOTAL SYNTHESIS
A. Fürstner, P. Hannen, Chem. Eur. J. 2006, 12, 3006;
HAcOH
HTfOH
HMeH
O
O
PtCl2 cat.
MeMgBr
Fe(acac)3 cat.
90%
-cubebene
O
toluene, 80°C
92%
A. Fürstner, A. Schlecker, Chem. Eur. J. 2008, 14, 9181
ACID CHLORIDES
OAc
Cl
O
O
O MgBr
Fe(acac)3 (3 mol%)
OAc
O
O
O
78%ee > 99%
O
Cl OMe
96%
MeO
O O
MeO
O O
BnO
88%65%
OOO
O
O
59%
A. F. with B. Scheiper, M. Bonnekessel, H. Krause, J. Org. Chem. 2004, 69, 3943
see also: P. Knochel et al., Angew. Chem. Int. Ed. 2004, 43, 2968 (acyl cyanides)
for the synthesis, biological evaluation and computational analysis of the latrunculins and analogues, see:
A. Fürstner et al., Proc. Natl. Acad. Sci. USA 2005, 102, 8103;
Chem. Eur. J. 2007, 13, 115 and 135
O
OEt
MgBr
OEt
TfO
O
S
RN
O
O
S
PMBN
O Cl
O
Fe(acac)3 cat.
97%
MeMgBr
Fe(acac)3 cat.
80%
O
PMBN
S
O
O
OMeH
O
O
PMBN
S
O
O
OMeH
O
ring closing
alkyne metathesis
O
O
O
HN
S
OH
H
O
Latrunculin B
review: A. Fürstner et al.
Chem. Commun. 2005, 2307
B. D. Sherry, A. Fürstner, Chem. Commun. 2009, 7116
A. Fürstner, M. Méndez, Angew. Chem. Int. Ed. 2003, 42, 5355
A. F. with E. Kattnig, O. Lepage J. Am. Chem. Soc. 2006, 128, 9194
synthesis and biological assessment of a library of analogues: Chem. Eur. J. 2009, 15, 4030
CROSS COUPLING OF ALKYL HALIDES
Br BrMg
X
+
X
94% (X = H)
95% (X = OMe)
93% (X = Ph)
67% (X = Cl)
88% (X = NTMS2)
iron catalyst
R. Martin, A. Fürstner, Angew. Chem. Int. Ed. 2004, 43, 3955
E. Nakamura et al., JACS 2004, 126, 3686
T. Hayashi et al., Org. Lett. 2004, 6, 1297
R. B. Bedford et al., Chem. Commun. 2004, 2822
CHEMOSELECTIVITY
Br
O
OEtPhMgBr, 5 min, -20°C
O
OEt
Li2[Fe(C2H4)4] (5 mol%)
-II
87%
A. F. with R. Martin, Angew. Chem. Int. Ed. 2004, 43, 3955; J. Am. Chem. Soc. 2008, 130, 8773
PhPh
O
OEt
O
Ph
C NPh
Ph N C O
ClPh
PhN
O
87%
83%
91% 88% 90%
86%
PhOEt
O
94%
S. L. Buchwald, C. Bolm, Angew. Chem. Int. Ed. 2009, 48, 5586
ARE YOU SURE IT„S IRON?
Li LFeL LiO
O
LiFe
C. Bolm et al., Angew. Chem., Int. Ed. 2007, 46, 8862
PUZZLING OBSERVATIONS
Li1
C2*C2
C4
Fe1
C1
Li2*Li2
O7*
C9*
C6*
O7
C8*
C6
C3
C9
C8
C5*C5
Li Li
Fe
Li
OEt2
Et2O
Me
LiMe
Li
MeLi
Fe
Me
Me
OEt2
Et2O
MeLi (excess) + FeCl3
Et2O, < -30°C
1/2 ethane
[(Me4Fe) . (MeLi)] [Li(OEt2)]2 + 3 LiCl
A. F. with H. Krause, C. W. Lehmann, Angew. Chem. Int. Ed. 2006, 45, 440
„... the catalytic species produced from the reaction
of iron(III) complexes and methylmagnesium
bromide is highly labile and strongly discourage
attempts at isolation...“
J. Kochi et al., JOC 1975, 40, 599-606
methyl-, phenyl-, vinyl donors lead to
organoferrate complexes which react
with activated electrophiles only
A. Fürstner et al., JACS 2008, 130, 8773
the “Bogdanovic postulate“
(Angew. Chem. Int. Ed. 2000, 39, 4610)
C8*
C10
C7*
C3*C4*
N1*
C6A
N2
C5B*
C1*
C7
Li1*
C2*
Li1
C9
C5A
C6B*
Fe1
N1 C3
N2*
C4
C9*C2
C8
C1
C10*
more than one „active“ species?
ill defined intermetallic cluster
size distribution
extremely air and moisture sensitive
rapidly aging
paramagnetic
K. Jonas et al., Angew. Chem. Int. Ed. Engl.
1979, 18, 549 and 550
Cp2Fe
Li LFeL Li-2
0N
N
LiFe
0O
O
LiFe
0N
N
LiFe
L = TMEDA
formal oxidation states
N
N
LiFe
Br
Fe
C5
C4
C6
C3
C2
D3
C10
C7
D2
C12
Fe1
C13
C1
C9C8
D1
C11
C14C15
Fe
Cl
PMe3
Fe
PMe3
PMe3
C15
C4
C3
C14
N2
C9 C8
Fe1
C11
Li1
C2C1
C5C7
C10
C6
N1
C13
C12
C8
C9
C16
C15
C7
C10
P2
C6
C11
C17
C13
C1
Fe1
C2
C5
P1
D1
C3C4
C14
C12
A. F. with R. Martin, H. Krause, G. Seidel, R. Goddard,
C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773
Li LFeL Li
N
N
LiFe
Fe
Cl
FeFe
Me
FeL L
Cl
Fe
Cl
X-ray
X-ray
X-ray
X-ray
X-ray
isolated
SiMe3Me3Si
Br
X-ray
SiMe3Me3Si
Fe Li
SiMe3
Me3Si
SiMe3
Me3SiFe
X-ray
14-electron (!)
A. F. with R. Martin, H. Krause, G. Seidel, R. Goddard, C. W. Lehmann, J. Am. Chem. Soc. 2008, 130, 8773
C13
C23
C22
C3
Fe1
C24
C21
C14
C12
C4
C2
C5
C1
C15
C11
YET ANOTHER “NOBLE” TASK ?
LiFe L
[Fe]
product
0O
O
LiFe
ferrate catalyst
C15C14C16
C13C11 C12
C10
C4
C3
C5
C27
C3AC2
C25
C24
C6
C26
C23
C9A
N1
C21
C22
C7
C8
C9S1
O2
O1
FERRATE-CATALYZED ALDER-ENE REACTIONS
A. F. with R. Martin, K. Majima, J. Am. Chem. Soc. 2005, 127, 12236
N
Ph
Ts
[CpFe(C2H4)2]Li (5 mol%)
toluene
N
Ph
Ts
94%
ALDER-ENE REACTIONS
M
M
M
THOUGHT EXPERIMENT
N
N
LiFecatalyst:
J. Am. Chem. Soc. 2008, 130, 1992
FERRATE-CATALYZED [5+2] CYCLOADDITIONS
E E
R
R
E E76%, R = H
81%, R = Ph
70%, R = Me
95%, R = TMS
toluene, 80°C
FeN
N
Li
cat.
A. F. with K. Majima, R. Martin, H. Krause, E. Kattnig, R. Goddard, C. W. Lehmann,
J. Am. Chem. Soc. 2008, 130, 1992
OTHER FERRATE-CATALYZED CYCLOADDITIONS
EE
E E
cat.
toluene, 89%
EE
E
E
E E
R R
EE
67% (R = H)
66% (R = SiMe3)
O
O
LiFe
cat.
toluene, 80°C
O
O
LiFe
for early work on Fe(0)-catalyzed Diels-Alder reactions, see: H. tom Dieck, R. Diercks, Angew. Chem. 1983, 95, 801;
J. Fichini et al., Tetrahedron Lett. 1979, 20, 1499; G. dall‘Asta et al., JOC 1968, 33, 3948
C9
C8
C10
C13
C14
C7
C12
C15C5
C6
C16
C11
C1
C35
C2
C28
C4
C27
C3
C30
C34
Fe1
C23
C29 C36C31
C17
C26
C18
C22C24
C33
C32
C19
C25
C21
C20
C38
C37
J. Am. Chem. Soc. 2008, 130, 1992
FeFe
PhPh
Fe
PhPh
PhPh
tolane
pentane
-78°C to 0°C77%
stable 17e complex!
C13
C23
C22
C3
Fe1
C24
C21
C14
C12
C4
C2
C5
C1
C15
C11
0O
O
LiFe
X
RX
R
H
H
X
R
X
R
Alder-ene [5+2]
X
X
Diels-Alder
X
X
[2+2+2]
X
X
A. F. with K. Majima, R. Martin, H. Krause, E. Kattnig, R. Goddard, C. W. Lehmann,
J. Am. Chem. Soc. 2005, 127, 12236; J. Am. Chem. Soc. 2008, 130, 1992
tolerates esters, ketones, sulfonamides,
acetals, ethers, cyclopropanes, remote
alkenes, amines, aryl halides etc
A POOR MAN„S
CATALYST