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Macrocyclization via ruthenium-
catalyzed ring-closing metathesis:
strategies and limitations
Joseph Grim
Kiessling Research Group
October 8, 2009
The Chauvin mechanism for RCM
n, P. and coworkers. J. Am. Chem. Soc. 2004, 126, 3496. 4
2005 Nobel Prize in Chemistry
“for the development of the metathesis method in organic
synthesis”
Yves Chauvin Robert Grubbs Richard Schrock
Institut Français du Pétrole California Institute of Technology Massachusetts Institute
of Technology
/nobelprize.org/nobel_prizes/chemistry/laureates/2005/index.html 10
Ring closing metathesis exists in an
equilibrium
• RCM efficiency limited by competition between
pathways
• fully reversible
• product distribution is “living” -- known as
equilibrium ring closing metathesis (ERCM)
Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, 1024. 12
Methods to perturb equilibrium
Which product is the kinetic/thermodynamic?
Reaction time
Temperature
Dilution factor
Reactivity of catalyst
15
Increasing reaction temperature
promotes ERCM
• isolated from Monocillium nordinii
• exhibits a wide variety of antifungal and
antibiotic properties
• has high affinity for heat shock protein
90 (Hsp 90), which stimulates depletion
of oncogenic proteins
Danishefsky, S. J. and coworkers. J. Am. Chem. Soc. 2001, 123, 10903. 17
Decreasing concentration increases
the effective molarity
• ansaymycin antiobiotic isolated
from Streptomyces
hygroscopicus
• shown to have anticancer activity
due to its binding of Hsp 90
Bach, T.; Lemarchand, A. Synlett 2002, 1302.
Lemarchand, A.; Bach, T. Tetrahedron 2004, 60, 9659.
19
Decreasing diene concentration
increases the effective molarity
entry n= ring size conc. [mM] catalyst time [h] yield [%]
1 3 20 6 Grubbs I 20 14
2 3 20 2 Grubbs I 20 44
3 3 20 0.5 Grubbs I 20 66
Decreasing diene concentration promotes RCM
Bach, T. et al. Synlett 2002, 1302. 20
Increasing ring size increases the
formation of RCM product
entry n= ring size conc. [mM] catalyst time [h] yield [%]
4 4 21 0.5 Grubbs I 36 77
5 4 21 0.5 Grubbs II 36 85
6 5 22 0.5 Grubbs I 36 77
7 5 22 0.5 Grubbs II 36 91
8 2 19 0.5 Grubbs I 60 0
9 1 18 0.5 Grubbs I 40 0
increasing ring size increases the yield of RCM product
Bach, T. et al. Synlett 2002, 1302. 21
Addition of reactive catalyst promotes
ERCM
not observed
Addition of a more reactive
catalyst can promote ERCM
ermann, L. and coworkers. Org. Lett. 2001, 3, 449. 22
Thermodynamic vs. Kinetic ERCM
Favoring thermodynamic ERCM:
• ↑ reaction time
• ↑ temperature
• ↓ concentration
• try more reactive catalyst
Favoring kinetic ERCM:
• ↓ reaction time
• ↓ temperature
• ↓ concentration
• use less reactive catalyst
23
Olefin geometry is difficult to control
Thermodynamic product determines E/Z selectivity.
ubbs, R. and coworkers. Org. Lett. 2000, 2, 2145.
24
Applications in Process Chemistry:
BILN 2061
• developed by Boehringer Ingelheim
Pharmaceuticals
• blocks replication of hepatitis C virus
(HCV)
• binds HCV NS3 protease
• discontinued due to cardiotoxicity reported
in testing on rhesus monkeys
• demonstrated utility of macrocyclization via
RCM in industrial setting
agopalan, R. et al. Biochemistry 2009, 48, 2559.
25
BILN 2061: Retrosynthetic analysis
, N. et al. J. Org. Chem. 2006, 71, 7133. 26
BILN 2061: Initial macrocyclization
had many issues
• Four issues in industrial application:
1. high catalyst loading
2. long reaction time
3. dilution factor
4. RCM is reversible (lead to decomposition upon
concentration of crude reaction)
Yee, N. et al. J. Org. Chem. 2006, 71, 7133. 27
BILN 2061: Catalyst chelates to
amide?
resting state of catalyst as determined by
1H NMR
• observed carbene transfer of catalyst at the vinylcyclopropane
• chelation to ester ties up active catalyst?
• protecting the amide with a bulky group will disfavor chelation
Zeng, X. et al. J. Org. Chem. 2006, 71, 7133.
28
BILN 2061: Amide protection
R = H, 96%
R = Boc, 100%
Shu, C. et al. Org. Lett. 2008, 10, 1303. 29
BILN 2061: Amide protection
entry R= conc. [M] cat. mol % temp [oC] yield [%]
1 H 0.01 1 60 82
2 H 0.02 1 60 70
3 H 0.05 1 60 52
4 H 0.10 1 60 35
Shu, C. et al. Org. Lett. 2008, 10, 1303. 30
BILN 2061: Amide protection
entry R= conc. [M] cat. mol % temp [oC] yield [%]
1 Boc 0.01 1 60 98
2 Boc 0.05 1 60 87
3 Boc 0.10 1 60 80
4 Boc 0.10 0.1 110 97
5 Boc 0.20 0.1 110 93
6 Boc 0.40 0.1 110 80
7 H 0.01 1 60 82
Shu, C. et al. Org. Lett. 2008, 10, 1303.
31
BILN 2061: A computational study on
the effect of Boc protection
vs.
Does Boc protection stabilize the diene and product?
ΔΔE was calculated (change in energy of open chain molecules with
and without Boc substitution subtracted from change in energy of ring
molecules with and without Boc substitution)
method OPLS01 MM3 MMFFs DFT/B3LYP
ΔΔE [kcal/mol] -3.33 -1.99 -1.10 -2.18
Boc substitution reduces strain energy on ring molecule
by ~2 kcal/mol
Shu, C. et al. Org. Lett. 2008, 10, 1303. 32
BILN 2061: Amide protection appears
to effect the reaction two ways
Effect of Boc protection appears two-fold:
•induces allylic strain for coordination of catalyst to ester
•relieves forced planarity of both diene and product
Shu, C. et al. Org. Lett. 2008, 10, 1303.
33
BILN 2061: Results of optimization
Addressed all four initial issues with RCM in industrial setting:
1. high catalyst loading (from 5 mol% to 0.05 mol%)
2. long reaction time (from 40 hrs. to 30 min)
3. dilution factor (from 150,000L solvent to process 1 MT of
diene to 7,500L!)
4. RCM is reversible (2-mercaptonicotinic acid quench affords
<50 ppm Ru, no filtrations necessary)
a, V. et al. Org. Process Res. Dev. 2009, 13, 250. 35
Conclusions: The utility of
macrocyclizations via RCM
Pros Cons
• simple reaction conditions • oligomerization side-reactions
• simple work up • often requires very dilute
• functional group tolerance conditions
• many catalysts • difficult to control E/Z selectivity
• often requires optimization
Future Directions
• develop longer lasting catalysts
• develop a catalyst selective for E/Z
36
Acknowledgements
Laura Kiessling
Kiessling Research Group
Practice Talk Attendees
Chris Brown
Becca Splain
Shane Mangold
Aaron Smith
Katie Garber
Paul White
Teresa Beary
Aaron McCoy
Kelsey Mayer
Mario Martinez
Margaret Wong
Rick McDonald
` Raja Annamalai 37
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