Catalytic Alkane Metathesis by Tandem Alkane Dehydrogenation– Olefin Metathesis
ALKYNE METATHESIS - Startseite · ALKYNE METATHESIS CATALYSTS cheap air stable user friendly harsh...
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ALKYNE METATHESIS BACKGROUND AND CATALYST DEVELOPMENT
Transcript of ALKYNE METATHESIS - Startseite · ALKYNE METATHESIS CATALYSTS cheap air stable user friendly harsh...
ALKYNE METATHESIS
BACKGROUND AND CATALYST DEVELOPMENT
ALKYNE METATHESIS
F. Pennella et al., Chem. Commun. 1968, 1548
(supported tungsten oxide, 200-450°C)
A. Mortreux et al., Chem. Commun. 1974, 786
(Mo(CO)6 + phenol, > 130°C)
mechanism: T. J. Katz et al., JACS 1975, 97, 1592
first example of alkyne metathesis using defined
alkylidyne complexes, e. g. (tBuO)3WCCMe3:
R. R. Schrock et al., JACS 1981, 103, 3932
ALKYNE METATHESIS CATALYSTS
cheap
air stable
user friendly
harsh
slow
limited compatibility
expensive
laborious
(highly) sensitive (O2, H2O, N2)
short lifetimes
(highly) active: W > Mo
excellent compatibility: Mo > W
broad scope
MORTREUX SYSTEMS
SCHROCK ALKYLIDYNES
ALKYNE METATHESIS
140 °C
1,2-dichlorobenzene
Mo(CO)6 cat. + phenol (30%)
+ 2-butyne
MeO OMe2 MeO
2
equilibrium reached in < 5 min at ambient temperature!
(tBuO)3W cat.
+
R. R. Schrock et al., J. Am. Chem. Soc. 1981, 103, 3932; Organometallics 1984, 3, 1563.
original report: A. Mortreux et al., Chem. Commun. 1974, 786
optimizations: M. Mori et al., Chem. Lett. 1995, 627; U. H. W. Bunz et al., Tetrahedron Lett 1999, 40, 2481;
D. Villemin et al., Tetrahedron Lett. 2001, 42, 3701; K. Grela et al., Tetrahedron Lett. 2002, 4, 3747; R.
Chauvin et al., New J. Chem. 2003, 27, 1412;
RING CLOSING ALKYNE METATHESIS (RCAM)
A. Fürstner, G. Seidel, Angew. Chem. Int. Ed. 1998, 110, 1758
Lindlar Birch
(tBuO)3W R
Schrock-type alkylidyne
Review on alkyne metathesis: A. Fürstner, P. W. Davies, Chem. Commun. 2005, 2307
TOTAL SYNTHESIS OF TURRIANES
OMe
OR
OR
OROMe
OR
OR
ORRu
PCy3
PCy3
Cl
Cl
Ph
cat.
84%
E : Z = 6.9 : 1
but the natural product is (Z)-configured !
A. Fürstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.
turrianes are efficient DNA-cleaving agents under oxidative conditions;
for the total synthesis and biological evaluation see:
OMe
OR
OR
OR
76%
F3CC6H4OH
Mo(CO)6 cat.
OMe
OR
OR
OROMe
OR
OR
OR
Lindlar
96%
R = PMB
R = H
BF3, EtSH
54%
or:
(tBuO)3W CCMe3 cat.
61%
TOTAL SYNTHESIS OF TURRIANES
NN
N
Mo
C. C. Cummins et al., Chem. Commun. 1998, 1777
designed for the stoichiometric cleavage of N2
toluene, 80°COO
O OOO
O O
80%
NN
N
C
Mo
H
CH2Cl2
cat.
A. F. with C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 1999, 121, 9453;
Chem. Eur. J. 2001, 7, 5299
ALTERNATIVE
CATALYST
FURTHER DEVELOPMENT
W. Zhang, S. Kraft, J. S. Moore, Chem. Commun. 2003, 832; idem, J. Am. Chem. Soc. 2004, 126, 392;
See also: C. C. Cummins et al., Organometallics 2003, 22, 3351.
NN
N
Cl
MoN
NN
C
Mo
H
NN
N
Mo
CH2Cl2+
NN
N
Cl
MoN
NN
C
Mo
R
+
R-CHCl2
Mg
ArAr
OOO
C
Mo
Ar
R
ArOH
A. Fürstner et al.,
J. Am. Chem. Soc.
1999, 121, 9453
THE NEXT GENERATION OF ALKYNE METATHESIS CATALYSTS
0
10
20
30
40
50
0 10 20 30 40 50 60time [min]
yield [%]
0
20
40
60
80
100
0 10 20 30 40 50 60time [min]
yield [%]
in the presence of molecular sieves 5Å
much improved rate AND conversion !
air stable for weeksindefinitely air stable
superbly active & selective
STABLE, CHEAP, SCALEABLE VERSIONS
inactiveinactive
A. F. with J. Heppekausen, R. Stade, R. Goddard, J. Am. Chem. Soc. 2010, 132, 11045
SCOPE
ALKYNE METATHESIS
APPLICATIONS
AMPHIDINOLIDE V
O
OH H
O
OH
Amphidinolide V
Isolation: J.-I. Kobayashi et al., Tetrahedron Lett. 2000, 41, 713
TOTAL SYNTHESIS OF AMPHIDINOLIDE V
A. F. with O. Larionov, S. Flügge
Angew. Chem. Int. Ed. 2007, 46, 5545;
Chem. Eur. J. 2009, 15, 4011
30 mol%
80°C
With: A. F. with J. Heppekausen, R. Stade, R. Goddard,
J. Am. Chem. Soc.. 2010, 132, 11045
MARINE OXYLIPINS
M. Kurada et al., Chem. Lett. 1989, 267; W. H. Gerwick et al., J. Nat. Prod. 1994, 57, 171;
K. Kosuaka et al., J. Nat. Prod. 2003, 66, 1318
A. Fürstner et al. Chem. Eur. J. 2001, 7, 4811
now commercially available from Umicore and Evonik
PROTECTING GROUP FREE TOTAL SYNTHESIS OF ECKLONIALACTONE A
A. F. with V. Hickmann, M. Alcarazo, J. Am. Chem. Soc. 2010, 132, 11042
LACTIMIDOMYCIN: ANALYSIS
TOTAL SYNTHESIS OF LACTIMIDOMYCIN
A. F. with K. Micoine, J. Am. Chem. Soc. 2010, 132, 14064
A. F. with M. Bindl, L. Jean, Angew. Chem. Int. Ed. 2007, 46, 9275; Chem. Eur. J. 2009, 15, 12310
A. F. with L. Turet, Angew. Chem. Int. Ed. 2005, 44, 3462; Chem. Eur. J. 2007, 13, 115 and 135
A. F. with K. Radkowski, Chem. Commun. 2002, 2182; Tetrahedron 2004, 60, 7315
for the trans-hydrosilylation, see: B. M. Trost et al. J. Am. Chem. Soc. 2002, 124, 7922
A. F. with M. Bonnekessel, J. T. Blank, K. Radkowski, G. Seidel, F. Lacombe, B. Gabor, R. Mynott,
Chem. Eur. J. 2007, 13, 8762
A. F. with A.-S. Castanet, K. Radkowski, C. W. Lehmann, J. Org. Chem. 2003, 68, 1521.
Nysin-loop isostere: A. F. with R. M. J. Liskamp et al., Org Lett. 2005, 7, 2961
EPOTHILONES VIA RCAM
A. Fürstner, Ch. Mathes, K. Grela Chem. Commun. 2001, 1057; Chem. Eur. J. 2001, 7, 5299
O
OR
ORO
S
N
O
O
OR
ORO
S
N
O
O
OH
O
OHO
S
N
O
O
OR
ORO O
S
N
OH
S
N
O
OO O
R = TBS
[Mo] cat.
80%
Lindlar, H2
CH2Cl2
R = TBS
R = H
aq. HF
Epothilone C
OO
literature: 70%
Epothilone A79% over both steps
SOPHOROSE LIPID LACTONE
RORO
OROO
OO
O
RORO
OR
O
OO
O
RORO
OR
RO
ORO
OR
O
O
OO
O
RORO
OR
RO
ORO
OR
O
O
R = PMB
R = H
Mo[N(tBu)(Ar)]3 (10 mol%)
toluene/CH2Cl2
78%
Lindlar / H2
quant.DDQ
93%
A. Fürstner, K. Radkowski, J. Grabowski, C. Wirtz, R. Mynott J. Org. Chem. 2000, 65, 8758
A. Fürstner, F. Stelzer, A. Rumbo, H. Krause, Chem. Eur. J. 2002, 8, 1856.
turrianes are efficient DNA-cleaving agents under oxidative conditions;
for the total synthesis and biological evaluation see:
OMe
OR
OR
OR
76%
F3CC6H4OH
Mo(CO)6 cat.
OMe
OR
OR
OROMe
OR
OR
OR
Lindlar
96%
R = PMB
R = H
BF3, EtSH
54%
or:
(tBuO)3W CCMe3 cat.
61%
TOTAL SYNTHESIS OF TURRIANES
TOTAL SYNTHESIS OF PGE2-LACTONE
O
O
HO
O
O
TBSO
Bu3Sn OTES
1. BuLi
2. Me2Zn
3.
OTES
MO
TBSO
IOR
O
TBSO
R = TES
R = H
HOAc, aq. THF
80% over both steps
O
O
TBSO
O
5-heptynoic acid
DCC, DMAP cat.
94%
O
O
TBSO
O
[(tBu)(Ar)N]3Mo cat.
CH2Cl2 / toluene
70%
ee > 99% ee = 98%
1. H2, Lindlar, 86%
2. HF, MeCN, 88%
A. Fürstner, K. Grela, Angew. Chem. Int. Ed. Engl. 2000, 39, 1234.
A. Fürstner, K. Grela, C. Mathes, C. W. Lehmann, J. Am. Chem. Soc. 2000, 122, 11799.
ALKYNE CROSS METATHESIS
A. Fürstner, C. Mathes Org. Lett. 2001, 3, 221.
PGE2
COOH
OHHO
O
51%
COOMe
O
TBSO OTES[Mo] cat., CH2Cl2, toluene, 80°C
OMe
MeO O
O
OTES
O
TBSO
DEHYDROHOMOANCEPSENOLIDE
A. Fürstner, Th. Dierkes Org. Lett. 2000, 2, 2463.
96%
Lindlar
75%
cat.
(tBuO)3W
70%
[Ru] cat.
70%
1
3. ester 1
I2.
1. CuCN (1 eq.)
ZnX = ZnI
X = I
O
O
O
O
X X
O
OO
O O
OO
O
71%
DEAD, PPh3OHBrHO
O
+BrO
O
isolated from various marine organisms by Kashman (1980), Scheuer (1985), Crews (1987), Jefford (1996), Hoye (2002)
potent actin microfilament disrupting agents, cf. I. Spector et al., Science 1983, 219, 493.
total syntheses: A. B. Smith et al., J. Am. Chem. Soc. 1992, 114, 2995; J. D. White et al., J. Org. Chem. 1992, 57, 5292
O
O
O
HN
S
OHH
O
O
O
O
HN
S
OHH
O
OH
O
O
OH
HN
S
H
O
OMe
O
O
O
HN
S
H
O
Latrunculin A Latrunculin B
Latrunculin C Latrunculin D
Latrunculia magnifica
LATRUNCULIN B: RETROSYNTHETIC ANALYSIS
O
O
O
HN
S
OH
H
O
Latrunculin B
RCAM/Lindlar Fe-catalyzed cross coupling
aldol
Fe-catalyzed cross coupling
OR
O
S
RN
O
O
O
OH
TOTAL SYNTHESIS OF LATRUNCULIN B
O
OR
OEt
OO
OEt
OOTfMgBr
Fe(acac)3 cat.
97%
R = Et
R = H
NaOH, MeOH
92%
Ph-N(Tf)2
KHMDS
61%
for a comprehensive study on Fe-catalyzed cross coupling reactions of enol triflates see:
B. Scheiper, M. Bonnekessel, H. Krause, A. Fürstner, J. Org. Chem. 2004, 69, 3943
for a short review see: A. Fürstner, R. Martin Chem. Lett. 2005, 34, 624
TOTAL SYNTHESIS OF LATRUNCULIN B
in the absence of Fe cat.: < 30% yield
using Cu(I) in catalytic or stoichiometric amounts instead of Fe cat. leads to decomposition
O2S1
C2
O2'
N3
C30
C5
C2'
C4
C2"
C31
C32
C36
C33
C35
C34
O37
C38
S
RN
O
O
H2N
O OEt
SH S
PMBN
O OH
O
S
PMBN
O Cl
O
MeMgBr
Fe(acac)3 cat.
Cl
NMe23 steps
ee = 87%
ee = 99%recryst.
80%
for a short review on Fe-catalyzed cross coupling, see: A. Fürstner, R. Martin. Chem. Lett. 2005, 34, 624
OTBS
O
S
PMBN
O
O
TiCl4, iPrNEt2
73%
TBSO O
PMBNS
O
OH
dr = 2:1
1. HCl
2. CSA, MeOH
64%
O
PMBN
S
OH
O
OMeH
dr = 7:1
O
PMBN
S
O
O
OMeH
O1. Tf2O, pyridine
2. NaO
O
58%
citronellene
TOTAL SYNTHESIS OF LATRUNCULIN B
O2
S1
C2
C3'
C4'
N3
O4'
C30
C5
C5'
C4
C2'
C31
C32
O2'
O1'
C6'
C36
C33
C7'
C2"
C34
C12'
C35
C11'C8'
O37
C10'
C9'
C38
C9"
X-ray of minor isomer
TOTAL SYNTHESIS OF LATRUNCULIN B
C9"
C7'
C9'
C5'
C10'C11'
C8'
C12'
C2"
C4'
O4'
O1'
C16'
C13'
C3'
C15'
O16'
C14'
C14"
C30
C2'
O2
N3
C36
O2'
C31
C2
C4
C6'
C35
C32
S1
C5
C34
C33
C38
O37
O
PMBN
S
O
O
OMeH
O[Mo] cat.
CH2Cl2/toluene
70%O
PMBN
S
O
O
OMeH
O
O
O
O
HN
S
OHH
O
Latrunculin B
1. Lindlar, quant.
2. CAN, 78%
A. Fürstner, D. De Souza, L. Parra-Rapado, J. Jensen,
Angew. Chem. Int. Ed. 2003, 42, 5358
O
RN
S
OH
O
OMeH
O
TeocN
S
O
O
OMeH
O [Mo]
toluene/CH2Cl2
70%
O
O
O
HN
S
OHH
O
Latrunculin A
O
O
O
TeocN
S
OMeH
O
ENYNE-YNE METATHESIS: LATRUNCULIN A
L. Turet, A. Fürstner,
Angew. Chem. Int. Ed. 2005, 44, 3462;
Chem. Eur. J., 2007, 13, 115
O
RN
S
OH
O
OMeH
RN
S
O
H
O
OTBS
O
OTBS
O
HH
RN
S
O
H
O
RN
O
O
H
O
RN
O
O
H
O
O
RN
S
OH
O
OMeH
O
RN
O
OH
O
OMeH
O
RN
S
OH
O
OMeH
HH
O
RN
O
OH
O
OMeH
HH
O
RN
O
OH
O
OMeH
HH
O
OH
O
OH
O
OH
O
OH
O
OH
DIVERTED TOTAL SYNTHESIS
O
O
OH
HN
SO
H
O
O
O
OH
HN
OO
H
O
O
O
HN
S
O
OHH
O
H
O
O
HN
S
O
OHH
O
O
O
HN
S
O
OHH
O
H
HH
O
O
HN
O
O
OHH
O
O
O
HN
O
O
OHH
O
HH
O
O
HN
O
O
OHH
O
HH
H
O
O
NH
S
O
OHH
O
H
H
O
OO
HN
S
OHH
O
O
O
OH
O
N
S
O
HO
HH
H
O
O
O
HN
S
OHH
O LAT-B
O
O
O
HN
S
H
OHH
O
H
H
A. Fürstner, D. Kirk, M. Fenster, C. Aissa, D. De Souza, O. Müller, PNAS 2005, 102, 8103
QM/MM CALCULATIONS
Latrunculin A / Actin Complex
refined and corrected picture of H-bonding network
importance of hydrophopic interactions
“Lat 32” / Actin Complex
different but equally strong hydrogen bond network
hydrophobic interactions optimized
A. F. with D. Kirk, M. D. B. Fenster, C. Aissa, D. De
Souza, C. Nevado, T. Tuttle, W. Thiel, Chem. Eur. J.
2007, 13, 135
(E)-ALKENES FROM ALKYNES
Lindlar
method other
than Birch ?
(E)-ALKENES FROM ALKYNES
N
Ts
Si(OEt)3
N
Ts
[Cp*Ru(MeCN)3]PF6 cat.
(EtO)3SiH
80%
E : Z > 97 : 3
N
Ts
AgF
THF / MeOH
85%
E : Z > 97 : 3
A. Fürstner, K. Radkowski, Chem. Commun. 2002, 2182; idem, Tetrahedron 2004, 60, 7315
see also: B. M. Trost, Z. T. Ball and T. Jöge J. Am. Chem. Soc., 2002, 124, 7922
