Macrocyclization via ruthenium-Macrocyclization via ruthenium-catalyzed ring-closing metathesis: catalyzed ring-closing metathesis:

strategies and limitationsstrategies and limitationsJoseph Grim

Kiessling Research GroupOctober 8, 2009

2

Various methods for macrocyclization

Stang, E.; Christina White, M. Nat. Chem. 2009, 1, 547.

Kurti, L, Czako, B. Strategic Applications of Named Reactions in Organic Synthesis, 1st ed,; Elsevier: Amsterdam, 2005.

Macrolactonization:

Nozaki-Hiyama-KishiNozaki-Hiyama-Kishi

Macrolactamization:

Nozaki-Hiyama-Kishi C-H oxidation

Enyne metathesis Ring-closing metathesis

3

A brief history of ruthenium-catalyzed RCM

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

representative ring closing metathesis (RCM)

• Ru reacts with soft Lewis bases and π-olefins

• more functional group tolerant

• very low reactivity

• highly active toward metathesis

• highly oxophilic (low functional group tolerance)

4

The Chauvin mechanism for RCM

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

5

First generation catalysts

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

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

SonBihn

Hoveyda-Grubbs I

• dative bond replaces one phosphine

• more thermally stable than Grubbs I

Grubbs I

• more donating phosphine stabilizes metallacyclobutane

• favors electron rich, monosubtituted olefins

• decomposes quicklyRDS is metallacyclobutane

formation

6

Second generation catalysts

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

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

contain an N-heterocyclic carbene (NHC)

H2IMes Grubbs II

• better σ-donors than IMes• approaches reactivity of

Schrock catalysts

Hoveyda-Grubbs II

• phosphine free

• slower initiation

• improved activity toward electron deficient alkenes

RDS is dissociation step

IMes Grubbs II

• strong σ-donor with slight π-back bonding

• stable at high temperatures

• reactive with electron deficient, substituted olefins

7

Third generation catalysts

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

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

Blechert

• initiation rate promoted by relief of sterics

Initiation rate increase by modification of aryl moieties

Grela

• initiation rate promoted by decrease in electron density on oxygen

Fine-tuning of sterics and electronics of catalysts

8

Many catalysts exist for olefin metathesis

1st generation catalysts:

2nd generation catalysts: 3rd generation catalysts:

Non-ruthenium based catalysts:

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RCM macrocyclizations are useful in many areas of synthetic chemistry

Peptide chemistry:

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

Natural product synthesis:

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

Crown ether analogs:

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

Carbohydrate vaccines:

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

10

2005 Nobel Prize in Chemistry

http://nobelprize.org/nobel_prizes/chemistry/laureates/2005/index.html

“for the development of the metathesis method in organic synthesis”

Yves ChauvinInstitut Français du Pétrole

Robert GrubbsCalifornia Institute of Technology

Richard SchrockMassachusetts Institute

of Technology

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Representitive olefin metathesis transformations

Ring closing metathesis (RCM) Acyclic diene metathesis polymerization

(ADMET)

Cyclodepolymerization metathesis (CDP)

Ring opening metathesis polymerization

(ROMP)

Monfette, S.; Fogg, D. Chem. Rev. 2009, 109, 3783.

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Ring closing metathesis exists in an equilibrium

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

• RCM efficiency limited by competition between pathways

• fully reversible

• product distribution is “living” -- known as equilibrium ring closing metathesis (ERCM)

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

• loss of ethylene in monosubstituted olefins drives equilibrium

• important equilibrium is between ROMP and CPD

Loss of ethylene simplifies equilibrium

1,2-disubstituted 1,1,2-trisubstituted

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Why is macrocyclization difficult?

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

Shorter length dienes have greater torsional mobilityHigher probability for reactive ends to meet

ring size

0

5

10

15

20

25

30

3 5 7 9 11 13 15

strain energy(kcal/mol)

Ring Strain of Cycloalkanes

effective molarity (EM) = Kintra

Kinter

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

Increasing reaction time allows for equilibration to occur

oligomer

product

diene

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

diene

productoligomer

17

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.

18

Increasing reaction temperature promotes RCM

Increasing the temperature favors the formation of the kinetic

RCM product.

Danishefsky, S. J. and coworkers. Tetrahedron Lett. 2003, 44, 3297.

entry conditions concentrationyield

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 %

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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.

20

Decreasing diene concentration increases the effective molarity

Bach, T. et al. Synlett 2002, 1302.

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

21

Increasing ring size increases the formation of RCM product

Bach, T. et al. Synlett 2002, 1302.

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

22

Addition of reactive catalyst promotes ERCM

Ackermann, L. and coworkers. Org. Lett. 2001, 3, 449.

Addition of a more reactive catalyst can promote ERCM

not observed

23

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

24

Olefin geometry is difficult to control

Grubbs, R. and coworkers. Org. Lett. 2000, 2, 2145.

Thermodynamic product determines E/Z selectivity.

25

Applications in Process Chemistry: BILN 2061

Rajagopalan, R. et al. Biochemistry 2009, 48, 2559.

• 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

26

BILN 2061: Retrosynthetic analysis

Yee, N. et al. J. Org. Chem. 2006, 71, 7133.

27

BILN 2061: Initial macrocyclization had many issues

Yee, N. et al. J. Org. Chem. 2006, 71, 7133.

• 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)

28

BILN 2061: Catalyst chelates to amide?

Zeng, X. et al. J. Org. Chem. 2006, 71, 7133.

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

• 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

resting state of catalyst as determined by 1H NMR

29

BILN 2061: Amide protection

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

R = H, 96%

R = Boc, 100%

30

BILN 2061: Amide protection

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

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

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BILN 2061: Amide protection

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

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

32

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

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

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

33

BILN 2061: Amide protection appears to effect the reaction two ways

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

•induces allylic strain for coordination of catalyst to ester

•relieves forced planarity of both diene and product

Effect of Boc protection appears two-fold:

34

BILN 2061: Results of optimization

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

Initial process:

Optimized process:

35

BILN 2061: Results of optimization

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

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)

36

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

37

Acknowledgements

`

Laura Kiessling

Kiessling Research Group

Practice Talk AttendeesChris BrownBecca SplainShane MangoldAaron SmithKatie GarberPaul WhiteTeresa BearyAaron McCoyKelsey MayerMario MartinezMargaret WongRick McDonaldRaja Annamalai