Transcript Macrocyclization via ruthenium-catalyzed ring

Macrocyclization via rutheniumcatalyzed ring-closing metathesis:
strategies and limitations
Joseph Grim
Kiessling Research Group
October 8, 2009
Various methods for macrocyclization
Macrolactonization:
Macrolactamization:
Nozaki-Hiyama-Kishi
C-H oxidation
Enyne metathesis
Ring-closing metathesis
g, E.; Christina White, M. Nat. Chem. 2009, 1, 547.
, L, Czako, B. Strategic Applications of Named Reactions in Organic Synthesis, 1st ed,; Elsevier: Amsterdam, 2005.
2
A brief history of ruthenium-catalyzed
RCM
representative ring closing
metathesis (RCM)
• Ru reacts with soft Lewis
• highly active toward metathesis
• highly oxophilic (low functional
group tolerance)
bbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760.
bases and π-olefins
• more functional group
tolerant
• very low reactivity
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The Chauvin mechanism for RCM
n, P. and coworkers. J. Am. Chem. Soc. 2004, 126, 3496.
4
First generation catalysts
SonBihn
Grubbs I
Hoveyda-Grubbs I
• more donating phosphine
• dative bond replaces one
stabilizes metallacyclobutane
• favors electron rich,
monosubtituted olefins
• decomposes quickly
phosphine
• more thermally stable than
Grubbs I
Nolan, S. P. and coworkers. Organometallics 2003, 22, 4322.
Nolan, S. P. and coworkers. Chem.--Eur. J. 2007, 13, 8029.
RDS is metallacyclobutane
formation
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Second generation catalysts
contain an N-heterocyclic carbene (NHC)
IMes Grubbs II
H2IMes Grubbs II
Hoveyda-Grubbs II
• strong σ-donor with slight • better σ-donors than IMes • phosphine free
π-back bonding
•
approaches reactivity of • slower initiation
• stable at high
• improved activity toward
Schrock catalysts
•
temperatures
reactive with electron
deficient, substituted
olefins
electron deficient alkenes
RDS is dissociation step
n, S. P. and coworkers. Organometallics 2003, 22, 4322.
n, S. P. and coworkers. Chem.--Eur. J. 2007, 13, 8029.
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Third generation catalysts
Initiation rate increase by modification of aryl moieties
Blechert
• initiation rate promoted
by relief of sterics
Grela
• initiation rate promoted
by decrease in electron
density on oxygen
Fine-tuning of sterics and electronics of catalysts
a, K. and coworkers. Angew. Chem., Int. Ed. 2002, 41,114.
hert, S. and coworkers. Angew. Chem., Int. Ed. 2002, 41, 2403.
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Many catalysts exist for olefin metathesis
Non-ruthenium based catalysts:
1st generation catalysts:
2nd generation catalysts:
3rd generation catalysts:
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RCM macrocyclizations are useful in
many areas of synthetic chemistry
Natural product synthesis:
Nicolaou, K. and coworkers. J. Am. Chem. Soc. 2005, 127, 8872.
Carbohydrate vaccines:
shefsky, S. and coworkers. J. Am. Chem. Soc. 2009, ASAP
Peptide chemistry:
Blackwell, H. et. al. J. Org. Chem. 2001, 66, 5291.
Crown ether analogs:
Grubbs, R. H and coworkers. Angew. Chem., Int. Ed. 2003, 42, 3281.
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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
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Representitive olefin metathesis
transformations
Ring closing metathesis (RCM)
Acyclic diene metathesis
polymerization
(ADMET)
Ring opening metathesis
polymerization
(ROMP)
Cyclodepolymerization metathesis
(CDP)
Monfette, S.; Fogg, D. Chem. Rev. 2009, 109, 3783.
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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.
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Loss of ethylene simplifies equilibrium
• loss of ethylene in monosubstituted olefins drives equilibrium
• important equilibrium is between ROMP and CPD
1,2-disubstituted
1,1,2-trisubstituted
Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, 1024.
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Why is macrocyclization difficult?
Kintra
effective molarity (EM) = Kinter
Shorter length dienes have greater torsional mobility
Higher probability for reactive ends to meet
Ring Strain of Cycloalkanes
30
25
20
15
10
15
13
11
9
7
5
5
0
3
strain energy
(kcal/mol)
ring size
yn, E., Dougherty, D. Modern Physical Organic Chemistry. University Science: Sausulito, 2005.
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Methods to perturb equilibrium
Which product is the kinetic/thermodynamic?
Reaction time
Temperature
Dilution factor
Reactivity of catalyst
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Increasing reaction time promotes ERCM
diene
product
oligomer
diene
product
Increasing reaction time allows for
oligomer equilibration to occur
Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, 1024.
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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.
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Increasing reaction temperature
promotes RCM
entry
conditions
yield
concentration
mono : dimer
1
PhMe, 42 oC, 19 h
0.5 mM
27% : 48%
2
PhH, 80 oC, 35 min
0.5 mM
33% : 36%
3
PhMe, 110 oC, 10 min
0.2 mM
55% : 0 %
Danishefsky, S. J. and coworkers. Tetrahedron Lett. 2003, 44, 3297.
Increasing the
temperature favors the
formation of the kinetic
RCM product.
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Decreasing concentration increases
the effective molarity
Bach, T.; Lemarchand, A. Synlett 2002, 1302.
Lemarchand, A.; Bach, T. Tetrahedron 2004, 60, 9659.
• ansaymycin antiobiotic isolated
from Streptomyces
hygroscopicus
• shown to have anticancer activity
due to its binding of Hsp 90
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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.
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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.
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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.
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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
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Olefin geometry is difficult to control
Thermodynamic product determines E/Z selectivity.
ubbs, R. and coworkers. Org. Lett. 2000, 2, 2145.
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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.
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BILN 2061: Retrosynthetic analysis
, N. et al. J. Org. Chem. 2006, 71, 7133.
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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.
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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.
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BILN 2061: Amide protection
R = H, 96%
R = Boc, 100%
Shu, C. et al. Org. Lett. 2008, 10, 1303.
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BILN 2061: Amide protection
conc. [M] cat. mol % temp [oC]
entry
R=
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.
yield [%]
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BILN 2061: Amide protection
conc. [M] cat. mol % temp [oC]
entry
R=
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.
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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.
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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.
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BILN 2061: Results of optimization
Initial process:
Optimized process:
arina, V. et al. Org. Process Res. Dev. 2009, 13, 250.
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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.
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Conclusions: The utility of
macrocyclizations via RCM
Pros
• simple reaction conditions
• simple work up
• functional group tolerance
• many catalysts
Cons
• oligomerization side-reactions
• often requires very dilute
conditions
• difficult to control E/Z selectivity
• often requires optimization
Future Directions
• develop longer lasting catalysts
• develop a catalyst selective for E/Z
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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
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