Alkyne MetathesisCatalyst Development
and
Application in Total Synthesis
Meisam Nosrati
January 19th, 2011
Metathesis Reaction
Metathesis: Exchange of bonds between the two reacting chemicalspecies.
Mortimer, E. C.; General Chemistry, Sixth Edition 1986.
Ag NO3 (aq) + Na Cl (aq) Ag Cl (s) + Na NO3 (aq)
H Cl (aq) + Na OH (aq) H OH (l) + Na Cl (aq)
H3C
O
OH
+ O
O
ONa (aq)Na
+ O
O
OHH
H3C
O
ONa (aq)
2 2
(CO2 (g) + H2O (l))
Metathesis Reaction in Organic Chemistry
Alkene metathesis
Kürti, L. Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA 2005.
Alkyne metathesis
CatalystR1
R1R1
R1
R2
R2R2
R2
R2
R2R1
R12
R1 R1R1 R2
Catalyst
R2 R2
2
Enyne Metathesis
Nitrile Alkyne Cross Metathesis (NACM)
Kürti, L. Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA 2005.Geyer, A. M.; Gdula, R. L.; Wiedner, E. S.; Johnson J. A. M. J. Am. Chem. Soc. 2007, 129, 3800.
R2H2C
R1
CatalystR1 R2
CH2
R1 N R1N
R2R2
Catalyst
R2 N R2N
R1R1
Ring Closing Metathesis (RCM)
Hoveyda, H. A.; Cogen, A. D.; Xu, Z.; Houri, F. A.; J. Am. Chem. Soc. 1995, 117, 2943-2944.Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.
Ring Closing Alkyne Metathesis (RCAM)
C CH2
C CH2
C
C+ H2C CH2
Catalyst
C C
C C
C
C+ C C
Catalyst
Alkyne Metathesis Reaction Mechanism
Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592.
(RO)3M
R1
R1
R
(RO)3M
R
(RO)3M
R1
R1
R
R1
M(OR)3+ R1R
R1
R1
(RO)3M
R2
R2
R1
(RO)3M
R1
(RO)3M
R2
R2
R1
R2
M(OR)3+ R2R1
R2
R2
R1 R1
R1 R2
Catalyst
R2 R2
Catalyst:
2
Carbyne ComplexM = Mo, W R = Alkyl, Aryl(RO)3M
R
Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592.Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; and Schrock, R. R. Organometallics. 1984, 3, 1554.
Alkylidyne Mechanism Evidence
R
R(RO)3W
R
R
R
(RO)3W
(RO)3W
R
R
R
RR + (RO)3W RR +(RO)3W
W
Et
RORO OR
+ EtEt WRORO
ROEt
Et
Et R =
Crystals F3C
HF3C
RR
R
First Reports on Alkyne Metathesis
Pannella, F.; Banks, R. L.; Bailey, G. C.; Chem. Commun. 1968, 1548.A. Mortreux, M. Blanchard, J. Chem. Soc., Chem. Commun. 1974, 786.
Mortreux Catalyst
6.8 % WO3 on Silica
200 °C - 450 °C+
56% 23%
+ polymeric products
21%
Resorcinol : Mo(CO)66:1 10 mol %
160 °C+ Resorcinol:2
55% 23.5% 21.5%
OH
OH
Metallacycle Mechanism
Mortreux, A.; Coutelier, O. J. Mol. Catal. A. 2006, 254, 96.
Resorcinol : Mo(CO)66:1 10 mol %
160 °C+ Resorcinol:2
55% 23.5% 21.5%
OH
OH
R
R'
R
R'
M M
RR'
RR'
R
RR'
R'
RR'
R' R
M
M
R'
R'
R
R
MM
R
R
R'
R'
M = Active Metathesis Complex
In Situ Generation of Carbyne Complexes
Huc, V.; Weihofen, R.; Jimenez, M. I.; Oulié, P.; Lepetit, C.; Lavigne, G.; Chauvin, R. New J. Chem.2003, 27, 1412.
• No solid evidence to support the formation of carbyne complex
• No solid evidence to support metallacycle mechanism
Mo(CO)6 + ArOH Mo MoOAr
ArO
ArOArO
OArOAr
C6H5Cl, 135 °C
Mo(OAr)3Mo(OAr)3
Me
Ph
Mo(OAr)3
Mo(OAr)3Ph
Me
Ph
MeMo(OAr)3
Mo(OAr)3
Ph
Me
Mo(OAr)3
Mo(OAr)3
Ph Me21 , 25 - 50 °C
Ph Ph +
1MS 4 Å
+H3CO OCH3
First Step:
Second Step:
ArOH = Cl OH
Catalyst Development
Pschirer G. N.; Bunz, F. H. Tetrahedron Lett.1999, 40, 2481.Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.
MeO
OMe
NC
Catalyst
Catalyst
Catalyst
MeO
OMe
NC
OMe
MeO
CN15%
72%
0%
Catalyst: 5 mol % Mo(CO)6, 140 °C, 1,2-Dicholorobenzene, 12-16h Cl OH
OO
OO
OO
OOCatalyst
p-Chlorobenzene as solvent,140 °C, 64%
Catalyst Development
Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Stelzer, F.; Rumbo, A.; Krause, H. Chem. Euro. J. 2002, 8, 1856.
Catalyst: 5 mol % Mo(CO)6, 140 °C, Chlorobenzene Cl OH
O
O
O
O
NH
OSi
PhPh
O
O7
7
DecompositionStarting material recoveredStarting material recovered
Alcohol:
PMBO
PMBO OCH3
OPMB
PMBO
PMBO OCH3
OPMB
Chlorobenzene, microwave heating,
150 °C, 5 min
Mo(CO)6, 1
OH
CF3
1 =Cyclophaneintermediate
Fischer Type Catalysts
Cr COCOOC
OC
CO
H3CO Ph
W COCOOC
OC
Cl
Ph
Fischer CarbeneComplex
Fischer CarbyneComplex
Nobelprize.org/nobel_prizes/chemistry/laureates/1973/fischer-lecture.pdf Fischer, O. E.; Maasaböl, A. J. Organomet. Chem. 1968, 12, P15.
(CO)5WCH3
OCH3+
O
OCH3H2N
Ether, 20 °C CH3OH(CO)5WCH3
HN
O
OCH3
(CO)5CrCH2
OCH3 90 °C, 1.5 h
Pyridine
H
HH3CO
H+ (C5H5N)Cr(CO)5
+
H
Alkyne Metathesis with Fischer Carbynes
Fischer, E. O., Kreis, C., Kreiter, C. G., Müller, J., Huttner, G. and Lorenz, H., Angew. Chem.Int. Ed. 1973, 12, 564.Nobelprize.org/nobel_prizes/chemistry/laureates/1973/fischer-lecture.pdfFischer, O. E.; Ruhs, A.; Plabst, D. Naturforsch. Z. Teil B 32B 1977,7, 802.
Cr COCOOC
OC
Br
Ph
2Hexane, 30 °C
1.5 h
Cr COCOOC
OC
Br
Ph
m/z = 178
Cr COCOOC
OC
Br
Ph
+ Cr COCOOC
OC
Br
40 °C+ +
Schrock Catalyst Development
McLain, J. S.; Wood, D. C.; Schrock, R. R. J. Am. Chem. Soc. 1979, 101, 4558.Wengrovius, H. J.; Sancho, J.; Schrock, R. R. J. Am. Chem. Soc. 1981, 103, 3932.
, Aromatic AlcoholMo COCOOC
OC
CO
CO
Schrock Catalyst: First highly efficient CarbyneComplex in Alkyne Metathesis.
Ta
CMe3H
tBuH2CtBuH2C
CH2tBuTa
tBuH2CtBuH2C
CH2tBu
WtBuH2C
tBuH2CCH2tBu tBuO
WOtBu
tBuO
Metathesis inactive Metathesis inactive
Metathesis inactive Metathesis activeSchrock Catalyst
W COCOOC
OC
Cl
Ph
Fischer CarbyneLow Oxidation State MetalPositive Carbyne Carbon
The Role of the Alkoxide Ligand
Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; Schrock, R. R. Organometallics 1984, 3, 1554.Schrock, R. R. Polyhedron 1995, 14, 3177.
Inactive
Metathesis
Polymerization
Polymerization
MotBuOtBuO
OtBuMoiPrO
iPrOOiPr
MoMe3CCH2OMe3CCH2O
OCH2CMe3WtBuO
tBuOOtBu
+ R'R
MAr(R)OAr(R)O
Ar(R)OR
R'
M = Mo, WR = Me R' = MeR = Et R' = EtR = Et R' = PrR= Pr R' = Pr
rt
R' +
MAr(R)OAr(R)O
O(R)Ar
MAr(R)OAr(R)O
O(R)Ar
R
• Molybdenum complexes in general are less reactive than theirTungsten analogs.
• Molybdacyclobutadiene complexes are much prone to losealkyne than tungstacyclobutadiene complexes.
• Molybdenum catalysts are more likely to polymerize alkynes.Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; Schrock, R. R. Organometallics 1984, 3, 1554.Schrock, R. R. Polyhedron 1995, 14, 3177.
The Role of the Alkoxide Ligand
Metallayclobutadiene
MetathesisMetathesis
Metathesis
Mo(2,6-iPrC6H3)O(2,6-iPrC6H3)O
O(2,6-iPrC6H3)
W(2,6-iPrC6H3)O(2,6-iPrC6H3)O
O(2,6-iPrC6H3)W(CF3)2CH3CO
(CF3)2CH3COOCCH3(CF3)2
Mo(CF3)2CH3CO(CF3)2CH3CO
OCCH3(CF3)2
Theoretical Calculations of Alkyne Metathesis
Me
Me(R)3M
Me
Me
Me
(R)3M
(R)3M
Me
Me
Me
M = W R = OMe, NMe2
M = Mo R = OMe, CH2F
Me
Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.
• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.
MoMeOMeO
OMe
WMeOMeO
OMeWMe2N
Me2NNMe2
MoFCH2OFCH2O
OCH2F
Theoretical Calculations of W Carbyne Complexes
Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.
WMeOMeO
OMe
[W]
[W]
[W]
[W]
[W]
[W] [W]
0.0
22.3
10.3
9.1 9.1
22.3
0.0
[W] = W(OMe)3
WMe2NMe2N
NMe2
Free energies in kcal/mol
[W] = W(NMe2)3
[W]
[W]
[W]
0.0
33.4
18.5
• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.
Theoretical Calculations of Mo Carbyne Complexes
MoCH3OCH3O
OCH3
[Mo] = Mo(OMe)3
[Mo]
[Mo][Mo]
0.0
30.3
21.5
[Mo]23.9
[Mo]
16.9
[Mo]
30.3
[Mo]
0.0
MoFCH2OFCH2O
OCH2F
Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.
• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.
Free energies in kcal/mol
[Mo]
[Mo]
[Mo]
[Mo] [Mo]
0.0
15.9
5.5
15.9
0.0
[Mo] = Mo(OCH2F)3
Theoretical Calculations for W vs Mo Complexes
Zhu, J.; Gia, J.; Lin, Z. Organometallics 2006, 25, 1812.
[W]
[W]
[W]
[W]
[W]
[W] [W]
0.0
22.3
10.3
9.1 9.1
22.3
0.0
[W] = W(OMe)3
[Mo] = Mo(OMe)3
[Mo]
[Mo][Mo]
0.0
30.3
21.5
[Mo]23.9
[Mo]
16.9
[Mo]
30.3
[Mo]
0.0
Free energies in kcal/mol
MoCH3OCH3O
OCH3
WMeOMeO
OMe
• B3LYP level of Density Functional Theory, LanL2DZ basis set for W and Mo atoms , 6-31G basis setfor C, N, F, O and H.
Schrock Catalyst Scope
Vintonyak, V. V.; Maier, M. E. Org. Lett. 2007, 9, 655 –658.Funk, L. R.; Nilson, G. M. Org. Lett. 2010, 12, 4912.
PhCl, 80 °C, 3 h77%
N
N
O
OTIPS
Boc
HON
N
O
OTIPS
Boc
HO
25 mol %
OMe
MeO
TIPSO
O
O
ROODMB
WtBuO
tBuOtBuO
toluene, 85 °C91%
OMe
MeO
O
TIPSO
ODMB
O
TBSO
WtBuO
tBuOtBuO
20 mol %
Nakadomarin A intermediate
Cruentaren A intermediate
Schrock Catalyst Limitations
Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Muller, R.; Herrman, J.; Jean, L.; Bindl, M. Chem. Eur. J 2009, 15, 12310.Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.
OS
O
OO
NO
O
OO O
O
OO
O
OMe
MeO
TIPSO
O
O
OTHPTBSO
Thioethers
HeterocyclesUnsaturated Esters
Acetal Epoxide
Cruentaren A intermediate Ecklonialactone intermediate
tBuOW
OtButBuO
Schrock Catalyst
Trisamido Molybdenum Complexes
(tBuO)3W W(tBuO)3 + 2 (tBuO)3W
(tBuO)3W W(tBuO)3 + N (tBuO)3W + (tBuO)3W N
(tBuO)3W W(tBuO)3 + N N N.R.
Schrock, R. R.; Listemann, L. M.; Sturgeoff, G. L. J. Am. Chem. Soc. 1982, 104, 4291.Laplaza, C. E.; Cummins, C. C. Science 1995, 268, 861.Wu, X.; Tamm, M. Beilstein. J. Org. Chem. 2011, 7, 82.
MoN
NN
+ N N
MoN N
N
N
22
Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.
Akyne Metathesis With Molybdenum TrisamidoComplexes
R21 , 10 mol %
CH2Cl2 (25 eq) / tolueneR R
R = H 60%R = CN 58%
RO
1 , 10 mol %
CH2Cl2 (25 eq) / tolueneR
OO
R
R = Me 59%R = THP 55%
2
MoN N
N+ Small Acetylenic molecule N.R.
1
MoN N
NCH2Cl2
Strongly endothermic reaction
1
Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.
Active Metathesis Species in the Reaction
MoN N
N CH2Cl2Mo
N NN
Cl
+
MoN N
N
H
1 2 3
MoN N
Ntoluene/CH2Cl2
5 min 80 °CAbruptly -20 °C
OCH3
+ Prepare a sample for Crystallography
Mo Mo
Cl
Cl
(tBu)ArN(tBu)ArN
NAr(tBu)NAr(tBu) Mo N
Cl
Cl
Ar(tBu)N
Ar(tBu)N
4 5
OO
OO
OO
OOCatalyst
Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.Chisholm, H. M.; Folting, K.; Hoffman, M. D.; Huffman, C. J. J. Am. Chem. Soc. 1984, 106, 6794.
Active Metathesis Species in the Reaction
Mo
RO
RORO
R'2 Mo MoOR
OR
RO
ROOR
OR
R'R'
R = CH2t-Bu, R' = HR = i-Pr, R' = H, Me
MoN N
N
H
35 mol %, , toluene 80 °C, 38%
Catalyst Dimerization:
3
Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.
Active species in Catalysis
• Halogenated Molybdenum complexes at different oxidationstate are able to catalyze metathesis reactions
Mo Mo
Cl
Cl
(tBu)ArN(tBu)ArN
NAr(tBu)NAr(tBu)
10 mol % , toluene 80 °C, 0%
MoN N
N
Cl
10 mol % , toluene 80 °C, 70%
Mo N
Cl
Cl
Ar(tBu)N
Ar(tBu)N
5 mol %, toluene, rt, 90%
MoN
NN
Br
10 mol %, toluene 80 °C, 79%
4 2
5
Fürstner, A.; Mathes, C.; Lehmann, W. C. Chem. Euro. J. 2001, 7, 5299.
Substitution on the Aromatic Rings
MoN N
OMe
OMeN
MeO MeOOMeMeO
Cl
10 mol %, , toluene, 80 °C, 51%
MoN N
F
FN
F FFF
10mol%, 25 equiv CH2Cl2, toluene, 80 °C, 79%
MoN N
N
Cl
10 mol % , toluene, 80 °C, 70%
MoN N
N
10 mol % , 25 equiv CH2Cl2, toluene, 80 ˚C, 81%
OO
OO
OO
OOCatalyst
Schrock Catalyst Limitations
Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Muller, R.; Herrman, J.; Jean, L.; Bindl, M. Chem. Eur. J 2009, 15, 12310.Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.
OS
O
OO
NO
O
OO O
O
OO
O
OMe
MeO
TIPSO
O
O
OTHPTBSO
Thioethers
HeterocyclesUnsaturated Esters
Acetal Epoxide
Cruentaren A intermediate Ecklonialactone intermediate
tBuOW
OtButBuO
Schrock Catalyst
Trisamido Molybdenum Catalyst Scope
Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.
OS
O
OO
NO
O
OO
Thioethers
Unsaturated Esters
O
1, 10 mol %, CH2Cl2, Toluene, 80 °C, 84%
1, 10 mol %, CH2Cl2, Toluene, 80 °C, 88%
Heterocycles1, 10 mol%, CH2Cl2, Toluene, 80 °C, 83%
MoN N
N
Catalyst: 1
O8
Fürstner, A.; Muller, R.; Herrman, J.; Jean, L.; Bindl, M. Chem. Eur. J 2009, 15, 12310.Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.
Trisamido Molybdenum Catalyst Scope
O
O
O
1 , 20-40 mol %, CH2Cl2, toluene, 50-89%2 Unsuitable
Ecklonialactone total synthesis
OMe
MeOTIPSO
O
O
OTHPTBSO
1 10 mol %, CH2Cl2, toluene, 80 °C, 87%2 Unsuitable
Cruentaren A intermediate
MoN N
N
Catalyst: 1tBuO
WOtBu
tBuO
2
Trisamido Molybdenum Catalyst Scope
Fürstner, A.; .Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Flügge, S.; Larionov, O.; Takahashi, Y.; Kubota, T.; Kobayashi.; I. J. Chem. Eur. J. 2009, 15, 4011.Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.
N
O
R
1, 10 mol %, CH2Cl2, toluene, 80 °CR = H 0%, R=Me 72%2, 5 mol %, Chlorobenzene, 80 °CR = H 62%R = Me 72%
7RO
OOTBS
O O
1, 30 mol %, CH2Cl2, toluene, 80 °C, 84%
Amphidinolide V intermediate
MoN N
N
Catalyst: 1tBuO
WOtBu
tBuO
2
Silyloxy based Molybdenum Catalysts
Freudenberger, J. H.; Schrock, R. R. Organometallics 1986, 5, 398. Gdula, R. L.; Johnson, M. J. A. J. Am. Chem. Soc. 2006, 128, 9614.Wu, X.; Tamm, M. Beilstein. J. Org. Chem. 2011, 7, 82.
ROW
ORRO RO
WOR
RO
N
+
ROW
ORRO
N
ROW
ORRO
+
R =
R = C(CF3)(CH3)2
N
N
ROMo
ORRO
N
ROMo
ORRO + N
R = C(CF3)2Me, C(CF3)3
95 °C, 14.5 h
hexane
toluene
Metathesis inactive
Metathesis inactive
Metathesis active
Bindl, M.; Stade, R.; Heilmann, E. K.; Picot, A.; Goddard, R.; Fürstner, A. J. Am. Chem. Soc. 2009, 131, 9468.Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem Soc. 2010, 132, 11045.
Nitrido Molybdenum Silyloxy Based Catalysts
Mo
N
Ph3SiO
Ph3SiO
N
OSiPh3
Mo
NPh3SiO
Ph3SiO
OSiPh3
N
N
Air StableStable to be weighed in Air
Mo
N
NMe3SiO
Me3SiOSiMe3
SiMe3
1)Ph3SiOH (3 equiv), toluene, 80 °C
then Pyridine (5eq)81%
Mo
N
Ph3SiO
Ph3SiON
OSiPh3
1,10-Phenantroline, toluene/Et2O, 81%
Mo
NPh3SiO
Ph3SiO
OSiPh3
N
N
MnCl2, toluene, 80 °CAir Stable
Mo
N
Ph3SiO
Ph3SiOOSiPh3
Scope of Nitrido Silyloxy Based Catalysts
Smith, J. B.; Sulikowski, A. G.; Angew. Chem. Int. Ed 2010, 49, 1599.Funk, L. R.; Nilson, G. M. Org. Lett. 2010, 12, 4912.
20 mol %
PhMe, 80 °C, 16 h, 80%
N
N
O
OTIPS
Boc
HO
N
N
O
OTIPS
Boc
HOMo
N
Ph3SiO
Ph3SiO OSiPh3
N
Nakadomarin A intermediate
N
N
H
H
H
H
N
N
H
H H H
Ph3SiOH (3 equiv), toluene, 80 °C, 63%
Mo
N
NMe3SiO
Me3SiOSiMe3
SiMe3
Haliclonacyclamine CIntermediate
( 50 mol % Catalyst)
Scope of Silyloxy Based Carbyne Catalysts
Fürstner, A.; Micoine, K. J. Am. Chem. Soc. 2010, 132, 14064.Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem Soc. 2010, 132, 11045.
Mo
Ph
Ph3SiO
Ph3SiO
OSiPh3
OEt2
1,10-Phenantroline, toluene/Et2O, 81%
Mo
Ph
Ph3SiO
Ph3SiO
OSiPh3
N
N
MnCl2, toluene, 80 °CAir Stable
5 mol %
toluene, MS 5 Å, 80 °C, 95 %O
OTES OO O
OTESMo
Ph
Ph3SiO
Ph3SiO OSiPh3
OEt2
Lactimidomycin intermediate
Fürstner, A.; Alcarazo, M.; Hickmann, V. J. Am. Chem. Soc. 2010, 132, 11042.
Scope of Silyloxy Based Carbyne Catalysts
O
O
O
OO
O
Catalyst
Catalyst
WOtBu
OtBuOtBu
Mo
N
Ph3SiO
Ph3SiO OSiPh3
N
20-40 mol %, CH2Cl2/toluene, 50-89 %
Mo
Ph
Ph3SiO
Ph3SiO OSiPh3
OEt2
MoN N
N
Unsuitable
Unsuitable 5 mol %, toluene, 5Å ,80%
Ecklonialactone intermediate
Ring Closing Alkyne Metathesis (RCAM)in Natural Product total Synthesis
C CH2
C CH2
+ H2C CH2C
C H
HRCM C
C
H
H+
RCM
RCAM Z- selective olefin synthesis
C C
C C
C
C+ C C
RCAMLindlar
Reduction CC
H
H
Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.
E-Selective Olefin Synthesis
(EtO)3SiH
(Cp*Ru[MeCN)]PF6
C C
C C
C
C+ C C
RCAM
C
C Si(OEt)3
H AgF
THF/MeOH
C
C H
H
Lacombe, F. Radkowski, K.; Günter, S.; Fürstner, A. Tetrahedron 2004, 60, 7315.
Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 42, 2020.Funk, L. R.; Nilson, G. M. Org. Lett. 2010, 12, 4912.
RCM
RCAM
RuPhPCy3
PCy3Cl
Cl
20 mol %, CH2Cl2 reflux 24 h
N
N
O
H
O
ON
N
O
H
O
O
Z/E: 1:1.8 26%:46%
Nakadomarin A intermediate
Catalyst
PhCl, 80 °C, 3 h77%
20 mol %PhMe, 80 °C,
16 h, 80%
N
N
O
OTIPS
Boc
HON
N
O
OTIPS
Boc
HO
(tBuO)3W Mo
N
Ph3SiO
Ph3SiO OSiPh3
N
N
N
O
OH
Boc
HO
1) H2, Lindlar
2) TBAF, 80%Two steps
O
25 mol % OrCatalyst:
Nakadomarin Aintermediate
RCM
Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang,Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960.
O
O O
HO N
S
OTBSO
O
N
S
OTBS
O
HO
O
O O
HO N
S
OH
RuPhPCy3
PCy3Cl
Cl
0.1 equiv, CH2Cl2, 25 °C, 20 h
CatalystCatalyst:
46% 39%Epothilone C intermediate
RCAM
Fürstner, A.; Mathes, C.; Grela, K.; Chem. Commun. 2001, 1057.
O
O O
TBSON
S
OTBS O
TBSO
N
S
OTBS
O
NMo
NN
10 mol%
toluene/CH2Cl2, 80 °C8 h, 80 %
Lindlar, H2, CH2Cl2,
O
O O
TBSON
S
OTBS
O
Quant
Epothilone C intermediate
Alkyne Activity in Metathesis Reactions
RCAM in the presence of Alkene
RCM in the presence of triple bond
Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 42, 2020.Fürstner, A.; Micoine, K. J. Am. Chem. Soc. 2010, 132, 14064.
BocN
N
O
H
O
Co2(CO)8
RuPh
PCy3Cl
Cl
NMesMesN
CH2Cl2 (1mM)reflux, 1.5 h, 83 %
25 mol %BocN
N
O
H
O
Co2(CO)8
Nakadomarin A intermediate
5 mol %
toluene, MS 5 Å, 80 °C, 95 %O
OTES OO O
OTESMo
Ph
Ph3SiO
Ph3SiO OSiPh3
OEt2
Lactimidomycin intermediate
Summary
• High oxidation state Tungsten and Molybdenum Carbynes are thecatalysts that has been used so far for Alkyne metathesis in thenatural product total synthesis.
• Metathesis activity of a carbyne comlplex highly depends on thecontrol of the lewis acidity of the catalyst, which can be optimized bythe electronic effects of ligands.
• The choice of a catalyst for Alkyne metathesis depends on itsfunctional group tolerancy.
• However, Alkyne Metathesis is much less used than AlkeneMetathesis in natural product total synthesis, it can be acomplementary approach to selectivity control of RCM reactions.
Acknowledgement
AdvisorsProf.Geiger, Prof.Borhan
ProfessorsProf.Maleczka, Prof.Odom, Prof.Jackson
Dr.Vasileiou
Best LabmatesRoozbeh, Ipek, Arvind, Carmin, Wenjing,Atefeh, Sarah, Kumar, Tanya, Mercy, Calvin,Camille, Aman, Nastaran, Susan, Rafida,Remi.
And You
Chuck-Harrold Mechanism
Chung, W. L.; Wu, Y.; Trost, M.; B.; Ball, T. Z. J.Am.Chem.Soc. 2003, 125, 11578.
Reductive Recycle strategy for TrisamidoMolybdenum complexes
Zhang, W.; Kraft, S.; Moore S. J. Am. Chem. Soc. 2004, 126, 309.
New Class of Carbyne catalysts
MoN N
N
Cl
Mo(CO)6
Mo
Ph
Ph3SiOOSiPh3Ph3SiOOEt2
tBuOW
OtButBuO
1
2
3
4
OO
OO
OO
OOCatalyst
73%4, 2mol%, toluene, rt, MS 5Å
70%3, 10mol%, toluene, 80oC
73%2, 5mol%, Cholorobenzene, 80oC
64%1, 5mol%, p-Chlorophenol(1eq),Cholorobenzene, 140oC
YieldCatalyst
Fürstner, A.; Guth, O.; Rumbo, A.; Seidel, G. J. Am. Chem. Soc. 1999, 121, 11108.Fürstner, A.; Mathes, C.; Lehmann, W. C. J. Am. Chem. Soc. 1999, 121, 9453-9454.Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner, A. J. Am. Chem Soc. 2010, 132, 11045.
W NO
O
N
N
tBu
tBu
F3C
F3CF3C
F3C
Wu, X.; Tamm, M. Beilstein. J. Org. Chem. 2011, 7, 82.Lysenko, S.; Haberlag, B.; Daniliuc, G. C.; Jones, G. P.; Tamm, M. Chem. Cat. Chem. 2011, 3, 115.
Imidazoline-2-Iminato Tungsten Catalysts
Tri(tert-butoxy)silanolate-Supported TungstenBenzylidyne Complex
W OO
O
Si
Si
Ph
SiOtButBuO
OtButBuO
tBuO
tBuOtBuO OtBu
OtBu
Imidazoline iminato Tungsten vs Shrock catalyst
1
R = H
R = CH3
(tBuO)3W
W
CMe3
NO
O
NN
tBu
tBu
F3C
F3CF3C
F3C
R Hexane, rt350 mbar
R
RR = HR = CH3
Catalyst 1mol%
Beer, S.; Hrib, G. C.; Jones, G. P.; Brandhorst, K.; Grunenberg, J.; Tamm, M.Angew. Chem. Int. Ed. 2007, 46, 8890.