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.

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) bases and -olefins more functional group tolerant very low reactivity
3

bbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760.

The Chauvin mechanism for RCM

n, P. and coworkers. J. Am. Chem. Soc. 2004, 126, 3496.

First generation catalysts

SonBihn

Grubbs I

Hoveyda-Grubbs I

more donating phosphine

stabilizes metallacyclobutane favors electron rich, monosubtituted olefins decomposes quickly
Nolan, S. P. and coworkers. Organometallics 2003, 22, 4322. Nolan, S. P. and coworkers. Chem.--Eur. J. 2007, 13, 8029.

dative bond replaces one

phosphine more thermally stable than Grubbs I RDS is metallacyclobutane formation

Second generation catalysts

contain an N-heterocyclic carbene (NHC)

IMes Grubbs II

H2IMes Grubbs II

Hoveyda-Grubbs II

strong -donor with slight better -donors than IMes phosphine free -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

6

n, S. P. and coworkers. Organometallics 2003, 22, 4322.

n, S. P. and coworkers. Chem.--Eur. J. 2007, 13, 8029.

Third generation catalysts

Initiation rate increase by modification of aryl moieties

Blechert

Grela

initiation rate promoted

by relief of sterics

initiation rate promoted

by decrease in electron density on oxygen

Fine-tuning of sterics and electronics of catalysts

7

a, K. and coworkers. Angew. Chem., Int. Ed. 2002, 41,114.

hert, S. and coworkers. Angew. Chem., Int. Ed. 2002, 41, 2403.

Many catalysts exist for olefin metathesis

Non-ruthenium based catalysts: 1st generation catalysts:

2nd generation catalysts:

3rd generation catalysts:

RCM macrocyclizations are useful in many areas of synthetic chemistry

Natural product synthesis: Peptide chemistry:

Nicolaou, K. and coworkers. J. Am. Chem. Soc. 2005, 127, 8872.

Blackwell, H. et. al. J. Org. Chem. 2001, 66, 5291.

Carbohydrate vaccines:

Crown ether analogs:

shefsky, S. and coworkers. J. Am. Chem. Soc. 2009, ASAP

Grubbs, R. H and coworkers. Angew. Chem., Int. Ed. 2003, 42, 3281.

2005 Nobel Prize in Chemistry

for the development of the metathesis method in organic synthesis

Yves Chauvin
Institut Franais du Ptrole

Robert Grubbs
California Institute of Technology

Richard Schrock
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.

11

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

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

strain energy (kcal/mol)

15 10 5 0

11

13

ring size
14

yn, E., Dougherty, D. Modern Physical Organic Chemistry. University Science: Sausulito, 2005.

15

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

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Fogg, D. and coworkers. J. Am. Chem. Soc. 2007, 129, 1024.

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

Increasing reaction temperature promotes RCM

entry

conditions

yield concentration mono : dimer

1
2 3

PhMe, 42 oC, 19 h
PhH, 80 oC, 35 min PhMe, 110 oC, 10 min

0.5 mM
0.5 mM 0.2 mM

27% : 48%
33% : 36% 55% : 0 %

Increasing the temperature favors the formation of the kinetic RCM product.
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Danishefsky, S. J. and coworkers. Tetrahedron Lett. 2003, 44, 3297.

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.

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Decreasing diene concentration increases the effective molarity

entry 1 2 3

n= 3 3 3

ring size 20 20 20

conc. [mM] 6 2 0.5

catalyst Grubbs I Grubbs I Grubbs I

time [h] 20 20 20

yield [%] 14 44 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
5 6 7 8 9

4
4 5 5 2 1

21
21 22 22 19 18

0.5
0.5 0.5 0.5 0.5 0.5

Grubbs I
Grubbs II Grubbs I Grubbs II Grubbs I Grubbs I

36
36 36 36 60 40

77
85 77 91 0 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.

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Applications in Process Chemistry: BILN 2061

developed by Boehringer Ingelheim
Pharmaceuticals
(HCV)

blocks replication of hepatitis C virus 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.

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.

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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.

29

BILN 2061: Amide protection

entry

R=

conc. [M] cat. mol % temp [oC]

yield [%]

1
2

H
H

0.01
0.02

1
1

60
60

82
70

3
4

H
H

0.05
0.10

1
1

60
60

52
35

Shu, C. et al. Org. Lett. 2008, 10, 1303.

30

BILN 2061: Amide protection

entry
1 2 3 4 5 6

R=
Boc Boc Boc Boc Boc Boc

conc. [M] cat. mol % temp [oC]

0.01 0.05 0.10 0.10 0.20 0.40 1 1 1 0.1 0.1 0.1 60 60 60 110 110 110

yield [%]
98 87 80 97 93 80

7
Shu, C. et al. Org. Lett. 2008, 10, 1303.

0.01

60

82
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BILN 2061: A computational study on the effect of Boc protection

vs.

Does Boc protection stabilize the diene and product?

E 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 E [kcal/mol] OPLS01 -3.33 MM3 -1.99 MMFFs -1.10 DFT/B3LYP -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.

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BILN 2061: Results of optimization

Initial process:

Optimized process:

arina, V. et al. Org. Process Res. Dev. 2009, 13, 250.

34

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)
35

a, V. et al. Org. Process Res. Dev. 2009, 13, 250.

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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