NEW CATALYST SYSTEMS
FOR Z-SELECTIVE OLEFIN
METATHESIS
Alicia Phelps
Schomaker Group
UW-Madison Literature Seminar
March 15, 2012
1
What is Olefin Metathesis?
2005 Nobel Prize in Chemistry
awarded for “the development
of the metathesis method in
organic synthesis".
Yves Chauvin
Robert Grubbs
Vougioukalakis, G.; Grubbs, R. Chem. Rev. 2010, 110, 1746.
Richard Schrock
2
Types of Olefin Metathesis
Ring Opening Metathesis Polymerization (ROMP)
Ring Closing Metathesis (RCM)
Cross Metathesis (CM)
3
Vougioukalakis, G.; Grubbs, R. Chem. Rev. 2010, 110, 1746.
Mechanism of Olefin Metathesis
• Reversible at each step
• Equilibrium mixture of
products
Thermodynamic
conditions favor E
product!
4
Vougioukalakis, G.; Grubbs, R. Chem. Rev. 2010, 110, 1746
Two Classes of Catalysts
Grubbs 1st Generation
Schrock Alkylidene
Hoveyda-Grubbs
2nd Generation
Grubbs 1st Generation
Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare, M.; O’Regan, M. B. J. Am. Chem. Soc. 1990, 112, 3875.
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
5
Other Approaches to Z Olefins
• Classic Olefinations
• Wittig Reaction (non-stabilized ylides)
• Cross-coupling reactions
• Peterson Olefination
• Partial Hydrogenation of Alkynes
• Removable directing groups
Fürstner, A.; Mathes, C.; Lehmann, C. Chem. Eur. J. 2001, 7, 5299.
Wang, Y.; Jimenez, M.; Hansen, A.; Raiber, E.; Schreiber, S.; Young, D. J. Am. Chem. Soc. 2011, 133, 9196.
6
Substrate Controlled Z Selectivity
Sattely, E.; Cortez, G.; Moebius, D.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2005, 127, 8526.
Crowe, W.; Goldberg, D. J. Am. Chem. Soc. 1995, 117, 5162.
Hansen, E.; Lee, D. Org. Lett. 2004, 6, 2035.
7
Catalyst Screening
X=
dr cat
A/B/C (%)
yield (%)
er
Z/E
Cl
3.0:1
56:22:22
80
95:5
>98:2
Br
2.2:1
62:08:30
85
98:2
>98:2
I
1.7:1
67:04:29
60
>98:2
95:5
F
N/A
07:47:46
57
95:5
80:20
Ibrahem, I; Yu, M.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 3844.
8
Mode of Selectivity
• Steric bulk of aryloxide as compared to imido forces
reaction to go through all-syn metallocyclobutane
Ibrahem, I.; Yu, M.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 3844.
9
Substrate Scope of ROCM
Ar
Olefin
equiv.
mol% cat
Time (h)
Yield (%)
er
Z/E
p-OMeC6H4
2
1
0.5
80
97:3
95:5
p-CF3C6H4
2
1
1
67
98:2
>98:2
o-BrC6H4
10
2
1
50
99:1
89:11
o-MeC6H4
10
2
1
54
99:1
88:12
10
Ibrahem, I; Yu, M.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 3844.
Z-Selective ROMP and CM
• Able to isolate 99% cis, 99% syndiotactic polymers of
dicarbomethoxynorbornadiene
• Catalyst screens showed “small” imido group is not required for terminal
substrates and W catalysts deliver higher % Z product compared to Mo
catalysts
Flook, M.; Jiang, A.; Schrock, R.; Müeller, P.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 7962.
Jiang, A.; Zhao, Y.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 16630.
11
Tungsten Catalysts
R
n
time
%conv
%cis
Me
3
4h
74
>99
Me
5
4d
89
>99
CO2Me
8
2d
45
>99
Ph
1
24 h
35
97
SiMe3
1
4h
45
81
1
2.5 h
6
92
First example of Z-selective metathesis in the presence of E olefins
12
Marinescu, S.; Schrock, R.; Müeller, P.; Takase, M.; Hoveyda, A. Organometallics 2011, 30, 1780.
Cross-Metathesis – Enol Ethers
Catalyst
Time
Conv (%)
Z:E
1a
2h
85
98:2
1b
2h
47
>98:2
2
2h
37
>98:2
3
2h
<2
NA
4
10 min
80
48:52
5
24 h
<2
NA
• No previous CM of enol ethers reported
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
13
Cross Metathesis System Design
VS.
• Mo-methylidene can cause equilibration
• Alkoxy-substituted alkylidene is less reactive
• Conclusion: use excess enol ether
14
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
Cross-Metathesis – Enol Ethers
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
15
Ring Closing Metathesis
Cat
Mol%
cat
Conc.
Pressure
Time
(h)
Yield
(%)
Z:E
1
5.0
1.0 mM
ambient
16
96
34:66
2
10.0
1.0 mM
1.0 torr
3.0
57
64:36
3
10.0
1.0 mM
ambient
1.5
87
85:15
3
10.0
1.0 mM
1.0 torr
1.5
91
90:10
4
10.0
1.0 mM
1.0 torr
2.5
97
96:4
4
3.0
0.05 M
1.0 torr
3.0
97
97:3
4
7.5*
6.0 mM
0.02 torr
4.0
96
94:6
* Catalyst weighed out in air
Yu, M.; Wang, C.; Kyle, A.; Jakubec, P.; Dixon, D.; Schrock, R.; Hoveyda, A. Nature 2011, 479, 88.
16
Enol Ethers in ROCM
• Enol ethers formed are electronically differentiated, unlike
previous reactions with aryl substrates
Yu, M.; Ibrahem, I.; Hasegawa, M.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2012, 134, 2788.
17
Summary of Mo/W Catalysis
• Molybdenum and tungsten catalysts can perform
olefin metathesis with very high Z selectivity
• Ring opening cross metathesis
• Ring opening metathesis polymerization
• Ring closing metathesis
• Cross metathesis
• Z-selectivity controlled by steric interaction with
aryloxide ligand
18
Ruthenium Catalysis – Catalyst Design
• Intramolecular C-H activation of NHC ligand yields Z-
selective catalysts
Endo, K.; Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525.
19
Ruthenium Catalyst - Results
Cat
mol% cat
Solvent
Temp (°C)
Time (min)
Yield 1 (%)
Z/E 1
Yield 2 (%)
Z/E 2
A
2.5
C6H6
23
60
57
31:69
3
17:83
B
5.0
C6H6
70
120
36
88:12
26
94:6
B
5.0
THF
Reflux
240
60
81:19
31
96:4
B
5.0
THF/H2O
Reflux
240
64
86:14
29
97:3
C
2.5
C6H6
23
30
66
9:91
10
15:85
D
2.5
C6H6
23
30
<1
34:66
NA
NA
Endo, K.; Grubbs, R. J. Am. Chem. Soc. 2011, 133, 8525.
20
Homodimerization with Ruthenium
Substrate
Time (h)
Yield (%)
Z:E
Allylbenzene
1
81
92:8
Methyl undecenoate
5.5
>95
73:27
Allyl acetate
4
62
89:11
1-octene
4
79
83:17
Allyl trimethylsilane
3
54
>95:5
Allyl pinacol borane
4
74
>95:5
4-penten-1-ol
1
72
72:28
2-(allyloxy)ethanol
1
73
66:34
N-allylaniline
2
67
71:29
21
Keitz, B.; Endo, K.; Herbert, M.; Grubbs, R. J. Am. Chem. Soc. 2011, 133, 9686.
Screening for Improved Ru Catalysts
• Adamantyl group is critical for selectivity
• Monodentate ligands have no CM reactivity
• Nitrato groups were more active than carboxylate groups
• Changes to aryl group on NHC did not affect reactivity
22
Keitz, B.; Endo, K.; Patel, P.; Herbert, M; Grubbs, R. J. Am. Chem. Soc. 2012, 134, 693.
Improved Ru Catalysts
Substrate
Time (h)
%Z
Yield (%)
Methyl undecenoate
12
91
85
1-octene
12
92
83
4-penten-1-ol
12
81
67
Allyl trimethylsilane
9
>95
14
Allyl pinacol borane
3
>95
36
Allyl acetate
12
>95
8
2-(allyloxy)ethanol
12
67
30
N-allylaniline
12
90
12
• Z selectivity highest at
low conversions
• Yield poor in
comparison to
previous catalyst
Keitz, B.; Endo, K.; Patel, P.; Herbert, M; Grubbs, R. J. Am. Chem. Soc. 2012, 134, 693.
23
Ruthenium Catalysis in ROMP
Monomer
Catalyst
% cis
Yield (%)
1
2
58
88
88
94
1
2
<5
75
93
88
1
2
81
91
95
78
1
2
78
61
95
40
• High cis selectivity, but no long-range tacticity
24
Keitz, B.; Federov, A.; Grubbs, R. J. Am. Chem. Soc. 2012, 134, 2040.
Selectivity of Ruthenium Catalysts
• Free energy calculations show side-bound pathway favored with Z-
selective catalysts by 3.1 kcal/mol (B3LYP/LANL2DZ-6-31G(d))
25
Liu, P.; Xu, X.; Dong, X.; Keitz, B.; Herbert, M.; Grubbs, R.; Houk, K. J. Am. Chem. Soc. 2012, 134, 1464.
Transition States
26
Liu, P.; Xu, X.; Dong, X.; Keitz, B.; Herbert, M.; Grubbs, R.; Houk, K. J. Am. Chem. Soc. 2012, 134, 1464.
Transition States
Side-bound transition state
d → π* (NHC)
d → π* (alkylidene)
Bottom-bound transition state
Backdonation to NHC and alkylidene involves same Ru d orbital
27
Liu, P.; Xu, X.; Dong, X.; Keitz, B.; Herbert, M.; Grubbs, R.; Houk, K. J. Am. Chem. Soc. 2012, 134, 1464.
Transition States – E/Z Selectivity
ΔG‡ = 16.1 kcal/mol
ΔG‡ = 14.6 kcal/mol
ΔG‡ = 18.8 kcal/mol
ΔG‡ = 14.4 kcal/mol
• Steric interaction favors Z selectivity (B3LYP/LANL2DZ-6-
31G(d))
Liu, P.; Xu, X.; Dong, X.; Keitz, B.; Herbert, M.; Grubbs, R.; Houk, K. J. Am. Chem. Soc. 2012, 134, 1464.
28
Summary of Ru Catalysis
• Ru catalysts perform homodimerization and
ROMP with comparable selectivity to Mo/W
catalysts
• Catalyst system is more functional group and
moisture tolerant than Mo/W systems
• Z-selectivity controlled by side bound
metallocyclobutane transition state
29
Nakadomarin A
Nilson, M.; Funk, R. Org. Lett. 2010, 12, 4912.
Yu, M.; Wang, C.; Kyle, A.; Jakubec, P.; Dixon, D.; Schrock, R.; Hoveyda, A. Nature 2011, 479, 88.
30
Conclusions
• High Z selectivity in olefin metathesis, previously
unattainable, has been observed
• Both molybdenum/tungsten and ruthenium catalyst
systems have been developed to accomplish major
classes of olefin metathesis
• Methods have already been applied to total synthesis of
epothilone C and nakadomarin A
Future Work:
Metathesis of tri-and tetra-substituted alkenes
Moisture and air tolerant catalyst systems
31
Acknowledgements
• Prof. Jennifer Schomaker
• Kat Myhre
• Schomaker Group
• Practice Talk Attendees
• Rob Risi
• Alex Clemens
• Jackie Brown
• Dr. Doris Pun
• Janelle Steves
• Megan Cismesia
• Dr. Dan Wherritt
32
Synthesis of C18(plasm)-16:0(PC)
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
33
Synthesis of KRN7000
34
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
Mechanism of Ruthenium Catalysts
• Side bound pathway (blue) is energetically favored over
bottom bound pathway (green)
35
Transition State Computational Models
36
NBO Models
37
NBO Models
38
Mechanism of Mo Catalysts
• Both diastereomers of catalyst 1 were isolated and crystal
structures obtained
39
Meek, S.; Malcomson, S.; Li, B.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 16407.
Mechanism of Schrock Catalysts
Mechanistic
Observations:
• R-cat promotes
reaction slowly,
but with same
sense of
enantioinduction
• Initial
enantioselectivity
is low but
increases during
the reaction
Cat.
Time (min)
Conv (%)
er (S:R)
S-1
2
4
76:24
S-1
2.5
7
87.5:12.5
S-1
3
13
93.5:6.5
S-1
30
>98
96.5:3.5
R-1
30
5
85.5:14.5
R-1
45
15
94:6
R-1
60
23
95:5
R-1
180
>98
96:4
40
Meek, S.; Malcomson, S.; Li, B.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 16407
Mechanism of Schrock Catalysts
• Reaction requires 3 metathesis steps to get to product
• Should give net inversion of Mo, lowering er
41
Meek, S.; Malcomson, S.; Li, B.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 16407
Mechanism of Schrock Catalysts
• Mechanism without off-cycle isomerization
Problems:
• R center in 2nd step should react slowly
• Other enantiomer of product is observed
Meek, S.; Malcomson, S.; Li, B.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 16407
42
Mechanism of Mo Catalysts
Mechanism of degenerate ethylene isomerization
• Under steady-state conditions, inversion of metal center via
degenerate metathesis with ethylene is faster than product
conversion
• Stereochemistry is independent of the starting alkylidene
Meek, S.; Malcomson, S.; Li, B.; Schrock, R.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 16407.
43
Synthesis of Natural Products - CM
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
44
Cross-Metathesis – Allylic Amides
Meek, S.; O’Brien, R.; Llaveria, J.; Schrock, R.; Hoveyda, A. Nature 2011, 471, 461.
45