32 the olefin metathesis reaction

Myers

Chem 115

The Olefin Metathesis Reaction
Cross Metathesis (CM):

Reviews:
Hoveyda, A. H.; Khan, R. K. M.; Torker, S.; Malcolmson, S. J. 2013 (We gratefully acknowledge
Professor Hoveyda and co-workers for making this review available to us ahead of print).
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 4490–4527.

CM
R2

R1

+

R4

R3

R1

R3

+

R4

R2

Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
• Self-dimerization reactions of the more valuable alkene may be minimized by the use of
an excess of the more readily available alkene.

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592–4633.

Catalysts

Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 1900–1923.
Fürstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3012–3043.
i-Pr

Ring-Opening Metathesis Polymerization (ROMP):
F3C
ROMP

F3C

n

O

MesN

i-Pr
N

Mo

CH3
Ph
CH3

CH3 O
H
F3C
CH
3
1-Mo
F3C

Cl
Cl

P(c-Hex)3
Ru
H
P(c-Hex)3
2-Ru

Ph
Ph

P(c-Hex)3
Cl
Ph
Ru

H
Cl
P(c-Hex)3

3-Ru
(Grubbs' 1st
Generation Catalyst)

NMes

Cl
Cl

Ru

Ph

H
P(c-Hex)3

4-Ru
(Grubbs' 2nd
Generation Catalyst)

• ROMP is thermodynamically favored for strained ring systems, such as 3-, 4-, 8- and largermembered compounds.
• When bridging groups are present (bicyclic olefins) the !G of polymerization is typically
more negative as a result of increased strain energy in the monomer.

• The well-defined catalysts shown above have been used widely for the olefin metathesis
reaction. Titanium- and tungsten-based catalysts have also been developed but are less used.

• Block copolymers can be made by sequential addition of different monomers (a
consequence of the "living" nature of the polymerization).

• Schrock's alkoxy imidomolybdenum complex 1-Mo is highly reactive toward a broad range of
substrates; however, this Mo-based catalyst has moderate to poor functional group tolerance,
high sensitivity to air, moisture or even to trace impurities present in solvents, and exhibits
thermal instability.

Ring-Closing Metathesis (RCM):

• Grubbs' Ru-based catalysts exhibit high reactivity in a variety of ROMP, RCM, and CM
processes and show remarkable tolerance toward many different organic functional groups.

RCM

+

H2C

CH2

• The reaction can be driven to the right by the loss of ethylene.
• The development of well-defined metathesis catalysts that are tolerant of many functional groups
yet reactive toward a diverse array of olefinic substrates has led to the rapid acceptance of the
RCM reaction as a powerful method for forming carbon-carbon double bonds and for
macrocyclizations.
• Where the thermodynamics of the closure reaction are unfavorable, polymerization of the
substrate can occur. This partitioning is sensitive to substrate, catalyst, and reaction conditions.

• The electron-rich tricyclohexyl phosphine ligands of the d6 Ru(II) metal center in alkylidenes 2Ru and 3-Ru leads to increased metathesis activity. The NHC ligand in 4-Ru is a strong "-donor
and a poor #-acceptor and stabilizes a 14 e– Ru intermediate in the catalytic cycle, making this
catalyst more effective than 2-Ru or 3-Ru.
• Ru-based catalysts show little sensitivity to air, moisture, or minor impurities in solvents. These
catalysts can be conveniently stored in the air for several weeks without decomposition. All of
the catalysts above are commercially available, but 1-Mo is significantly more expensive.

Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed Engl. 1995,
34, 2039–2041.
Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9858–9859.
M. Movassaghi, L. Blasdel

1


Myers

Chem 115

The Olefin Metathesis Reaction

Mechanism:

Dissociative:
P = P(c-Hex)3

EtO2C CO2Et

• The olefin metathesis reaction was reported as early as 1955 in a Ti(II)-catalyzed

polymerization of norbornene: Anderson, A. W.; Merckling, M. G. Chem. Abstr. 1955, 50,
3008i.

P

• 15 years later, Chauvin first proposed that olefin metathesis proceeds via
metallacyclobutanes: Herisson, P. J.-L.; Chauvin, Y. Makromol. Chem. 1970, 141, 161–176.
• It is now generally accepted that both cyclic and acyclic olefin metathesis reactions proceed
via metallacyclobutane and metal-carbene intermediates: Grubbs, R. H.; Burk, P. L.; Carr, D.
D. J. Am. Chem. Soc. 1975, 97, 3265–3266.

=

R

Cl

Ru

P

Cl H

–P

Cl

Cl Ru
H

Ru

H

P

P

Cl H
H

H

H

R

R

R

P

Cl H

Cl

Cl Ru
R

R
P

Cl
Cl

P(c-Hex)3
H
Ru
H
Cl
P(c-Hex)3

Cl

EtO2C CO2Et

– C2H4

H

P

c-C5H6(CO2Et)2

5 mol%
CD2Cl2, 25 ºC

H

Ru

P
EtO2C CO2Et

Cl

Ru

P

Cl H

Cl

Ru

H

P

P

Cl H

P

Cl H

Cl Ru

H

Cl

Ru

Cl
H

+P
• A kinetic study of the RCM of diethyl diallylmalonate using a Ru-methylidene describes two
possible mechanisms for olefin metathesis:

EtO2C CO2Et

EtO2C CO2Et

EtO2C CO2Et

EtO2C CO2Et

P

P

Associative:
• The "dissociative" mechanism assumes that upon binding of the olefin a phosphine is
displaced from the metal center to form a 16-electron olefin complex, which undergoes
metathesis to form the cyclized product, regenerating the catalyst upon recoordination of the
phosphine.

Cl

P
Ru

• The "associative" mechanism assumes that an 18-electron olefin complex is formed which
undergoes metathesis to form the cyclized product.
• Addition of 1 equivalent of phosphine (with respect to catalyst) decreases the rate of the
reaction by as much as 20 times, supporting the dissociative mechanism.

Cl

P

H

Cl

H

R

Cl

Ru

Cl H

P

Dias, E. L.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897.

Ru
P

Cl H

Cl Ru
H

H

R

Cl H
Cl
H

H

EtO2C CO2Et

Cl

Ru
P

P

R

c-C5H6(CO2Et)2

P
• It was concluded in this study that the "dissociative" pathway is the dominant reaction
manifold (>95%).

P

R

– C2H4

P
Cl

Ru

H

Cl H

P
Cl

H

P

P

EtO2C CO2Et

Cl

Ru

EtO2C

CO2Et

M. Movassaghi

2


Myers

Chem 115

The Olefin Metathesis Reaction

Catalytic RCM of Dienes:

Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM

substrate

product

O

N

time (h)

yield (%)a
substratea

O
X

X = CF3

N

X = O t-Bu

X

1

93

1

91

E E

R

R = CH3

yield
with 3-Ru (%)b

E E

93

100

98

100

NR

96

i-Pr
t-Bu
Ph

O

O

Ph

O

Ph

2

25

97

Br

NR

NR

CH2OH

98

decomp

97

100

96

100

E E

Ph

O

R

Ph

84

5

E E

86

CH3
O

CH3

O
Ph

Ph

8

E E

72

E E
CH3

O

1

O

O

CH3

Ph

O

Ph

yield
with 1-Mo (%)c

product

87

E E

–

No RCMd

No RCMd

CH3
R

a2-4

R = CO2H

1

87

CH2OH

1

88

CHO

1

82

R

E E
H3C

E E

CH3

mol% 2-Ru, C6H6, 20 ºC

H3C

• Five-, six-, and seven-membered oxygen and nitrogen heterocycles and cycloalkanes are formed
efficiently.

H3C

H
N

Cl–

4 mol% 2-Ru

CH2Ph
N

20 ºC, 36 h
CH2Cl2; NaOH
79%

Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856–9857.

NR

61

96e

100e

E E
E E
CH3

• In contrast to the molybdenum catalyst 1-Mo, which is known to react with acids, alcohols, and
aldehydes, the ruthenium catalyst 2-Ru is stable to these functionalities.

PhCH2

93

CH3

• Catalyst 2-Ru can be used in the air, in reagent-grade solvents (C6H6, CH2Cl2, THF, t-BuOH).

• Free amines are not tolerated by the ruthenium catalyst; the corresponding hydrochloride salts
undergo efficient RCM with catalyst 2-Ru.

NR

E E

H3C
CH3
E

E

aE

= CO2Et. b0.01 M, CH2Cl2, 5 mol%. c0.1 M, C6H6, 5 mol%. dOnly recovered starting material
and an acyclic dimer were observed. eThe isomeric cyclopentene product is not observed.

• Functional group compatibility permitting, the Mo-alkylidene catalyst is typically more effective for
RCM of substituted olefins.

Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310–7318.

M. Movassaghi

3


Myers

Chem 115

The Olefin Metathesis Reaction
Recyclable Ru-Based Metathesis Catalysts

Geminal Substitution

MesN
O

R

<1 mol% 1-Mo

R RR R

O

R

P(c-Hex)3
H
Cl
Cl Ru

R
R

25 ºC, 0.5-1 h
neat

Cl
Cl Ru

O

H3C
CH3

CH3

5a-Ru

5b-Ru

0%; (polymerization)
95%

CH3

substratea

product

• Standard "Thorpe-Ingold" effects favor cyclization with gem-disubstituted substrates.

cat

Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R., Jr.;
Wagener, K. B. J. Am. Chem. Soc. 1992, 114, 10978-10980.

H3C CH3

2-5 mol%
1-Mo or 3-Ru

Si
n O
R
m

C6H6, CH2Cl2
23 ºC, 0.5-5 h

Si
O
n
m

KF
R

H2O2

Ts
N

OH
n

22

99

75

5a-Ru

2.0

22

95

89

NTs

5a-Ru

1.0

40

99

88

5b-Ruc

0.3

22

87

98

5b-Ru

2

22

75

95

m
CH3

CH3

CH3

m = 1-3, n = 0-2
O

CH3

CH3

OH

OH
H3C

• RCM of allyl- or 3-butenylsilyloxy dienes (n≥1) proceeded efficiently with alkylidene 3-Ru,
while the more sterically hindered vinylsilyl substrates (n=0) required the use of alkylidene
1-Mo.

CH3
a5

• RCM of silicon-tethered alkenes is very efficient even at higher concentrations (0.15 M with
catalyst 3-Ru).

CH3

O

CH3

Chang. S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757–4760.

0.5

R

HO

80-93%

73–76%

5a-Ru

BnO H

BnO H

H3C CH3

recovered
time (h) temp (ºC) yield (%)b catalyst (%)b

TBSO H

TBSO H

RCM of Temporarily Connected Dienes

H

O

H3C
R=H

NMe

mol% catalyst, CH2Cl2. bIsolated yield after silica gel chromatography. c1 mol% of 5b-Ru was used.

• Catalysts 5a-Ru and 5b-Ru offer excellent stability to air and moisture and can be recycled in
high yield by chromatography on silica gel. 5a-Ru is effective for metathesis of terminal alkenes
while 5b-Ru offers enhanced catalytic activity toward substituted alkenes.

Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999,
121, 791–799.
Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168–
M. Movassaghi, Fan Liu
8179.

4


Myers

Chem 115

The Olefin Metathesis Reaction

RCM in Methanol and Water

H3C

CH3

solvent

productb

substratea

N Cl–

E E

E E

methanol

Ph
P(c-Hex)3
Ph
Ru
H
Cl
P(c-Hex)3
3-Ru
Cl

N(CH3)3

P

Cl
Cl

Cl

Ph

Ru
P

+Cl–

Cl

H

Ph

P

methanol

Ph

E E CH3

methanol

Ph

7-Ru

EtO2C CO2Et

Boc
N

Boc
N

Ph

6-Ru

45d

7-Ru

55d

methanol

Boc
N

100%
<5%

N(CH3)3+Cl–

N(CH3)3+Cl–

Stabilization of Ru-Carbene Intermediates by Phenyl Substitution

Ph

• first turnover step of RCM:

methylidene, R = H
benzylidene, R = Ph

R
Ph

R

LnRu

H

6-Ru

40
90e

6-Ru

30

7-Ru

>95f

methanol

7-Ru

90

water

7-Ru

60

water

7-Ru

90g

methanol

Ph

H

>95

7-Ru

7-Ru

Boc
N

23 ºC

LnRu

95

CH3

• Although benzylidene 3-Ru is highly active in RCM of dienes in organic solvents, it has no catalytic
acitivity in protic media.

solvent: CH2Cl2
CH3OH

80

7-Ru

E E

N Cl–
H3C CH3

5 mol% 3-Ru

6-Ru

E E
E E

H

• Alkylidenes 5-Ru and 6-Ru are well-defined, water-soluble Ru-based metathesis catalysts
that are stable for days in methanol or water at 45 °C.

EtO2C CO2Et

conversionc

P
Ru

N(CH3)3+Cl–

6-Ru

catalyst

aE = CO Et. b5 mol% catalyst (5- or 6-Ru), 0.37 M substrate, 45 °C. cConversions were
2
determined by 1H NMR. dSubstrate conc. = 0.1 M. e30 h. f2 h. g10 mol% 6-Ru used.

• Alkylidene 7-Ru is a significantly more active catalyst than alkylidene 6-Ru in these cyclizations;
this higher reactivity is attributed to the more electron-rich phosphines in 7-Ru.
• Cis-olefins are more reactive in RCM than the corresponding trans-olefins.

R

Ph

LnRu

RuLn

• Phenyl substitution within the starting material can also greatly increase the yield of RCM in

organic solvents.

R
LnRu

R

H
N

Ph
• Substitution of one of the two terminal olefins of the substrate with a phenyl group leads to
regeneration of benzylidene catalyst, which is far more stable than the corresponding
methylidene catalyst in methanol.

H H

H Cl–

5 mol% 3-Ru
R

N

Cl–

CH2Cl2
R=H
R = Ph

60%
100%

Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904–9909.

M. Movassaghi

5


Myers

Chem 115

The Olefin Metathesis Reaction

NHC Ruthenium Catalysts:

RCM of functionalized dienes

substratea
N Mes

Mes N
Cl

Ph

Ru

H

Cl

N Mes

Mes N
Cl

Mes N
Cl

Ph

Ru

Ru

CH3
CH3

Cl
Ru
H
P(c-Hex)3

Cl

9-Ru

4-Ru

substratea

product

1-Mo

O

8-Ru

4-Ru

O

O

CH2

O
O

CH2
O

97

CH2
1

37

0

100

100

100
O

t-Bu

24

93

0

40c

31

O

CH3

O

CH3 E E CH3

CH2

55

CH3

O

86

CH2

CH3
E E

CH3 E E

O
1.5
CH3

aE

CH2

O

9-Ru

E E

H OH

O

O

O

t-Bu

H3C

49

0

E E
E E

O
CH2

10-Ru

3-Ru

yield (%)

CH2

O

yield of product (%) using catalyst:b
time
(h)

product

N Mes

Mes N

P(c-Hex)3

P(c-Hex)3

8-Ru

Ph
H

Cl

H

Cl

P(c-Hex)3

N Mes

52

0

1.5

90

87

O
CH2

93

H3C
CH3

CH2

H OH
0.2

0

0

0.2

100

100

= CO2Et. b5 mol% of catalyst, CD2Cl2, reflux. c1.5 h.

aReactions

conducted with 5 mol% 10-Ru.

• Substrates containing both allyl and vinyl ethers provide RCM products while no RCM products
are observed if vinyl ethers alone are present.

• Alkylidenes 4- and 9-Ru are the most reactive Ru-based catalysts.
• In the case of 4- and 9-Ru as little as 0.05 mol% is sufficient for efficient RCM.

Scholl, M.; Ding, S.; Lee, C.-W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247–2250.
For the first Ru-based metathesis catalyst employing the Arduengo carbene ligand, see: Weskamp,
T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 1998, 37,
2490–2493.

• !,"-Unsaturated lactones and enones of various ring sizes are produced in good to excellent
yields.

Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783–
3784.

M. Movassaghi

6


Myers

Chem 115

The Olefin Metathesis Reaction

RCM Applications in Synthesis:
OH O
Bn

1. n-Bu2BOTf, Et3N
CH2Cl2, 0 ºC

O

N
O

Bn

OH

O

N

Cl

O

1 mol% 3-Ru
CH2Cl2

82%, >99% de
Bn

HO

HO

O

2. CH2=CHCHO
–78 ! 0 ºC

O

O

O

CH3

97%

OH

Cl

O

Pochonin C
trans epoxide

N
O

MOMO

O

O
O

Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192–4193.

MOMO

CH3
O
H

MOMO

5 mol% 4-Ru

H

toluene, 120 ºC
10 min

O
BnO
BnO

H

BnO
CO2CH3

N

BnO
O

5 mol% 2-Ru

BnO

110 ºC, 48 h

BnO

H

HO

HO

N
HO

O

70%

H

O

H3C

O

3

TBSO

O

OPMB
O

H3C

O

CH3 H
O

MOMO
O

O

O

MOMO
H

5 mol% 4-Ru
toluene, 120 ºC
10 min

O

CH3 H

O

O
MOMO

H

O

21%

71%
• Pre-organization of the substrate can have a dramatic effect upon the reaction efficiency.

O

• Both epoxide substrates produce macrocycles with good regioselectivity (i.e., the 14-membered
ring rather than the 12-membered ring) and E/Z selectivity. However, the trans epoxide
macrocycle is formed in a much higher yield.

RuLn

TBSO

Cl

H

cis epoxide
MOMO

Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126,
10210–10211.
10 mol% 5-Ru
CH2Cl2, 40 ºC

O
H

MOMO

N

• Particularly difficult cyclizations (due to steric congestion or electronic deactivation) can be
achieved by relay ring closing metathesis, which initiates catalysis at an isolated terminal
olefin. The reaction is driven by release of cyclopentene.

OPMB

O

OH

Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547–550.

O

CH3

87%

Castanospermine

TBSO

O

O

OPMB
O

O

Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Angew. Chem. Int. Ed. 2004, 43, 3601–
3605.

Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem. Int. Ed. 2004, 43,
2367–2370.
L. Blasdel and M. Movassaghi

7


Myers

Chem 115

The Olefin Metathesis Reaction
CH3

CH3
N
H

N
H

NHCOCF3

22 ºC, 10 h
C6H6
91%

OAc

H

H3C

O

H

NHCOCF3

H

O

CH3

OAc

O

N

OAc

CH3

• Before the advent of NHC ligands, 1-Mo was used more frequently than the Ru catalysts for
macrocyclization of trisubstituted olefins. The latter catalysts are typically less reactive with
sterically hindered substrates.

N

E

O
H

N

H
O

O

O

H3C

OH

N
D

H

CH3

CH3

20 mol% 1-Mo
OAc

Manzamine A

• The use of RCM in construction of both the D and the E rings of Manzamine A has been reported:

Zhongmin, X.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.;
Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302–10316.
Slight changes in substrate structure can control whether the E- or Z-olefin is formed:

H

H3C

CH2OTDS
H

O

N

O

23 ºC, 5 d
C6D6

O

30%

CH3

N
O

N

O

O

CH3

CO2CH3

H

O

N
H

O

50 ºC, 4 h
C6D6

Ph

CO2CH3
PO

CH3O

CH3

80%
Z-olefin only

10 mol% 4-Ru
CH2Cl2, 40%

CH3

H3C

O

5 mol% 2-Ru

CH3

O

O

OCH3
OP

P = p-BrBz

CH3

O

N

CH3

CH3

CH3

OP

Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35, 3191–3194.

Ph

O

H3C

CH3
O

86%
E-olefin only

H

H3C

CH3

OCH3 O

O

100 mol% 2-Ru
N

H3C

CH2OTDS

H3C
CH3

O

CH3

O

O
PO

O

CH3

OCH3

N
O

N

O

CH3

CH3

63%

H3C

O
O

Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691–694.

OHC

H3C

CH3

O
O

CH3

OH
Coleophomone B

OHC

O

CH3
CH3

OCH3

Coleophomone C

Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc. 2005,
M. Movassaghi and L. Blasdel
127, 8872–8888.

8


Myers

Chem 115

The Olefin Metathesis Reaction
Solid-Phase Synthesis of Epothilone A:

Synthesis of Epothilone C:
• Small changes can drastically affect reaction outcome. In the example below, TBS protective
groups changes the E/Z selectivity.

O

HO

CH3
CH3
H3C CH3

R1O

O

R1

CH3
N

O

H3C

S

CH3
R1O

H

O

Catalyst

Conditions

CH3

O
O

= Merrifield resin

CH3
N

H3C

S
N

O

H3C

OR2 O

R2

CH3
H3C CH3

S

CH3
CH3
H3C CH3

H

O
OTBS

H
3-Ru (0.75 equiv)
25 ºC, 48 h
CH2Cl2

OR2 O

Yield

HO

E/Z

H

H

1-Mo

50 mol%, PhH, 55 ºC

65%

2:1

H

TBS

3-Ru

10 mol%, CH2Cl2, 25 ºC

85%

1 : 1.2

TBS

TBS

8-Ru

6 mol%, CH2Cl2, 25 ºC

94%

1 : 1.7

TBS

TBS

4-Ru

50 mol%, PhH, 55 ºC

86%

1 : 1.7

CH3
O

H3C

H3C
H3C
TBSO

CH3

HO

S

CH3
O

CH3
N

H3C
H3C
H3C
TBSO

O
O

O

O
Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic,
S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973.
Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.;

Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 11073–11092.
Schinzer, D.; Bauer, A.; Bohm, O. M.; Limberg, A.; Cordes, M. Chem. Eur. J. 1999, 5, 2483–
2491.

O
OTBS
5.2%

S
CH3
N

O

H3C

CH3
N

15.6%

CH3
CH3
H3C CH3

S

O

15.6%

HO

CH3

CH3
HO

H

CH3
H3C CH3

CH3
N

O

H3C
O

S

H

O
OTBS
15.6%

• The amount of alkylidene 3-Ru (75%) used was greater than the total yield of product (52%),

perhaps reflecting the generation of a resin-bound Ru intermediate.
• Addition of n-octene or ethylene has been documented to provide a catalytic cycle; see:
Maarseveen, J. H.; Hartog, J. A. J.; Engelen, V.; Finner, E.; Visser, G.; Kruse, C. G.
Tetrahedron Lett. 1996, 37, 8249.

Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang,
Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387, 268–272.
M. Movassaghi and L. Blasdel

9


Myers

Chem 115

The Olefin Metathesis Reaction

Applications of Olefin Metathesis in Industry
• BILN 2061 ZW was investigated as a potential medication for the treatment of hepatitis C:

• A second-generation route was developed, which permitted higher reaction concentrations and
lower catalyst loading:

• First-generation route:

MesN

O O
S

O
H
N

N
O
O
O

PNBO

Br

O
N
H

CO2Me

5a-Ru (3 mol %)

O
H3C

O

toluene (0.01 M)
80 ºC, 83%
Z:E >99:1
O O

S
O

O
O

O
CH3

NO2
(0.1 mol %)

toluene (0.2 M), 110 ºC,
95%, Z:E >99:1

PNBO
CO2CH3

OCH3

O
H

N

O

5a-Ru

H

N

N
O
O

• During the reaction, nitrogen was bubbled through the reaction solution to remove ethylene.

O

Boc
N
CO2CH3

N
O

O

O

N

CH3

• 400 kg of the RCM product has been prepared using the first-generation route.

H
N

O

N
O

H

Br
H
N

N

Cl
Cl Ru
H3C

O

O

20.2-kg scale

P(c-Hex)3
H
Cl
Cl Ru

N

H
N

O

Boc
N
CO2CH3

NMe

H3C

S
CO2H

N
H

CH3
steps

O
N
H
BILN 2061 ZW

• 5-Ru was not stable at 80 ºC for the duration of the reaction so the catalyst was added in several
portions over 2 h.
• A dilute concentration (0.01 M) was used to minimize dimerization.

• Because traces of morpholine in the toluene led to catalyst inhibition, all toluene used was washed
with HCl prior to use.

Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. H. Org. Process Res.
Dev. 2009, 13, 250–254.

Nicola,T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, 9, 513–515.
Yee, N. K.; et al. J. Org. Chem. 2006, 71, 7133–7145.
Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. H. Org. Process Res.
Dev. 2009, 13, 250–254.

David W. Lin, Fan Liu

10


Myers

• Synthesis of MK-7009 (vaneprevir), now in clinical trials for the treatment of hepatitis C:

• SB-462795 is under development as a cathepsin K inhibitor for the treatment of osteoporosis:

O
O
N
O

O
O

OCH3

N

H
N

O
t-Bu

O

2,6-dichloroquinone
toluene (0.13 M)
100 ºC, 91%

O

H3C
H3C

O

OCH3

N

H
N

O

N

N
S
O
CH3 O

OH

N

5b-Ru (0.5 mol%)

O

O

5b-Ru (0.2 mol%)

O

OH

N

O

N

H3C
H3C

Chem 115

The Olefin Metathesis Reaction

O

toluene
110 ºC, 96%

N

N
S
O
O
CH3

80-kg scale

O

t-Bu

CH3
MesN
Cl

Cl Ru

O

H

N
H
N

O

5b-Ru

H3C
H3C

H
N

O
O

N
H

O

O

H3C
CH3

CH3 OH
H
N

O

NMe

N
O

O

t-Bu

O O O
S
N
H

O

SB-462795

N

N

S
O
O
CH3

• The choice of RCM substrate was crucial. Alternative substrates required higher catalyst loadings:

CH3

vaneprevir (MK-7009)

O
O
• The catalyst was added over 1h to minimize decomposition and mimic high dilution, which allows the
reaction to be run at higher concentrations.
• The reaction yield increased when nitrogen was bubbled through the reaction solution to remove
ethylene and adventitious oxygen.
• Trace Ru–H intermediates were trapped using 2,6-dichloroquinone, which also allowed the catalyst
loading to be lowered.

O

O

OH

HN

N
N

Ph

N
S
O
O
CH3

5b-Ru (10 mol%): 100%
5b-Ru (5 mol%): 60%

O
N

N
S
O
O
CH3
5b-Ru (11 mol%): 90%

• It was necessary to recrystallize the starting material to avoid poisoning the catalyst with trace
impurities.

• The diene substrate was required to be of high purity in order to achieve full conversion. Minor
urea or amide contaminants inhibited RCM.

Kong, J.; Chen, C.-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.;
Zacuto, M. J. J. Org. Chem. 2012, 77, 3820–3828.

Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M., Jr. Org. Process Res. Dev. 2008,
12, 226–234.
Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M., Jr. Tetrahedron
2009, 65, 6291–6303.
David W. Lin, Fan Liu

11


Myers

Chem 115

The Olefin Metathesis Reaction

Catalytic RCM of Olefinic Enol Ethers:

Tandem Ring Opening-Ring Closing Metathesis of Cyclic Olefins:
H3C

CH3CHBr2, TiCl4

O

Ph Zn, TMEDA,
cat. PbCl2
20 ºC, 11 h
THF

O

12 mol% 1-Mo
substrate

Ph 20 ºC, 3.5 h
n-pentane

O

O
Ph

88%

O

H H

yield catalyst 3-Ru
(%)
(mol%)

product
O

O

H H

conc.
(M)

time
(h)

temp.
(ºC)

O
82

3

0.1

1.5

45

90

5

0.1

2

60

70

3

0.07

6

45

68

6

0.04

2

45

92

5

0.04

3

60

55%
H3C

H3C

O
Ph

H3C

CH3CHBr2, TiCl4

Ph

Zn, TMEDA,
cat. PbCl2
20 ºC, 5 h
THF

O

H

O

H

H

O

O

H

O

12 mol% 1-Mo
O

20 ºC, 3.5 h
n-pentane

Ph

O

88%

O

H H

OHHO
O

79%
H

H

• Only catalyst 1-Mo is effective for RCM of these substrates.

Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029–4031.

Ti

O
O

H2
C
Al CH3
CH3
Cl

O

H

O
O

O

H H

O

H H

O

H
Tebbe reagent

Tandem Olefination-Metathesis

H
BnO
H
O
O

O
R

H

O

CH3

Tebbe reagent
(4.0 equiv)
THF, 25 ºC, 0.5 h;
reflux, 4h

R=H
CH3

• Without sufficient ring strain in the starting cyclic olefin, competing oligomerization (via CM) can
occur.

H
BnO
H
O

• Higher dilution favors intramolecular reaction:

H
O

O

R

R
50%
54%

O

O

H

H

mixture of E/Z isomers
R=H
H
CH3

R

6 mol% 3-Ru

O

H
H

C6H6, 45 ºC
6h
0.12 M
0.008 M
0.2 M

O

16%
73%
42%

• Here, a Ti-alkylidene is used in RCM.

Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118,
10335-10336.

• The relative rate of intramolecular metathesis versus CM may be further increased by
substitution of the acyclic olefin.

M. Movassaghi

12


Myers

Chem 115

The Olefin Metathesis Reaction
Examples in Complex Synthesis:

Proposed Mechanism for Ring Opening-Ring Closing Metathesis
LnRu CHPh

H

O

H

O
H3C

ethylene
O

H2C CH2 LnRu
O

H

H

H

CH3

H3C

O

CH3

H3C
O

2 mol% 3-Ru

Ph
H

CH3

CH3

CH3
CH3

O

O

O

OPMB

95%

O

O
CH3
H

H

O

O

LnRu CH2
Ru Ln
O

H H

O

O

H

H

H3C

CH3

O
H

H3C

O H3C

CH3

O

76%
H

O
H

HO HO
HO
O

25 mol% 5-Ru
toluene, !

CH3

OH

OPMB

Ingenol

RuLn
• Initial metathesis of the acyclic olefin is supported by the fact that substitution of this olefin
decreases the rate of metathesis.
• Subtle conformational preferences within the substrate are key to the success of these
transformations; as shown, trans-1,4-dihydronaphthalene diamide undergoes efficient ring
opening-ring closing metathesis while the corresponding diester and diether derivatives do not.

O

CH3
N

O

CH3

N

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am.
Chem. Soc. 2004, 126, 16300–16301.

O
O

O

20 mol% 4-Ru

O

HH

ethylene, toluene
H3C

CH3

43% (3 steps)

H3C

CH3

10 mol% 3-Ru
0.1 M, C6D6
40 ºC, 8 h

O

N
CH3

O
95%

N
CH3

H3C

CH3

OH

HH

CH3

unreactive substrates:
O

O

O

O

H3C

CH3

Cyanthiwigin U

O

O

O

Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634–6640.

Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–5335.
M. Movassaghi and L. Blasdel

13


Myers

Template-Directed RCM

Synthesis of Cyclic !-Turn Analogs by RCM
O H3C

H

O

H

CH3
O

N
H

N
H

Chem 115

The Olefin Metathesis Reaction

20 mol% 2-Ru

H N

O

N
Boc

N Bn
H

O H3C
N

H

N
O

H

CH2Cl2, 40 °C

CH3
O

H N

n

O

N
Boc

60%

O

O

O

substrate (n)

• The presence of the Pro-Aib sequence in the tetrapeptide induces a ß-turn conformation
which was covalently captured by RCM, yielding a 14-membered macrocycle.

"template" (equiv)

O
n
n = 1, 2

yield (%)

1

none

1

LiClO4 (5)

>95

O

O

CH2Cl2, THF
45 °C, 1 h
0.02 M

n = 1, 2

N Bn
H

Miller, S. J.; Kim, S. H.; Chen, Z. R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 2108–2109.
Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855-5856.

O

O

5 mol% 3-Ru
"template"

cis:trans

39

38 : 62
100 : 0

1

NaClO4 (5)

42

62 : 38

2

none

57

26 : 74

2

LiClO4 (5)

89

61 : 39

• Preorganization of the linear polyether about a complementary metal ion can enhance RCM.
• In general, ions that function best as templates also favor the formation of the cis isomer.

CH3

H3C
H3C

O
H N

H

N

Boc

O

CH3
N
H

O
H N

30 mol% 3-Ru
O
OBn

CH3

H3C

0.004 M, 21 h
CH2Cl2, 40 °C

H3C

O
H N

H

O

CH3
N
H

5 mol% 3-Ru

O
H N

CH2Cl2
1.2 M, 23 °C

O

N
Boc

OBn

60%

O
O

>95%
O

O

O

O
m

O

• Although interactions that increase the rigidity of the substrate and reduce the entropic
cost of cyclization can be beneficial in RCM, it is not a strict requirement for
macrocyclization by RCM.

O

5 mol% 3-Ru
LiClO4

Mn = 65900
cis : trans, 1 : 3.7

CH2Cl2
0.02 M, 50 °C
>95% (cis)

• Polymer degradation in the absence of a Li+ template produced the corresponding
crown ether as a mixture of cis- and trans-olefins (20% combined yield) along with
other low molecular weight polymers.

Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606–9614.

Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101–

1103.
M. Movassaghi

14


Myers

Chem 115

The Olefin Metathesis Reaction

3,727&8(-$&8),*9-:&#$),-;$4<&

!"#$%&'(')*+),-$&#-#&'
U $&

\++]%7+710%G=27/1I;7+8_8J18+`7`G1I7+8_8J,f=Pd=$%7=b=)7!=AJ.=d=#,E,.JJ_J>J_=b=)7!=AJ.QO=g
+++/7J^=.//7E?J7/+G,+^,2E+GC,+/J,C=7e8%.B01B0+.BG1`.2.JJ7J+=/%77G=J197+%_I2,07B+?,BI7I+
+++8_J1BI72/+PZ.PDbDJKQ+T+XX+)(L3+,BJ_+G%7+27.8G1-7+1/,E72+1/+/%,CBQ*

"

!
"

$%
"

!!

#
"
"
#
! !
"

!
!
!
!
" #
#
"
"

!
"

# "
#
!
!
!
"

$% $%

!
"

#
"

#
!

"

"

"
!

D;PD#KD!QR$&'

O

"!

"

"

!

$%
"

"

"

"

"

D#ODJO3+D#KD!
LMMS

"

"

!

!
!
"

"

"

"
"

"

!
"

T+D;U
V+E,JS+1234
OK+WD3+'+%
M*ML+)3+D#ODJO

OM=OV+E,JS+5234
DbDJK3+OK+WD3+RN+%

XOS

'VS

U $&
"
!!
#
"
"
#
! !
"

$%
"

"

$%
"

!
!
!
!
" #
#
"
"

!
"

# "
#
!
!
!

$% $%

"

(
'

"

"

(
'

"

"

"

"

"

"

"

"

"

"!
!
"
#
"

!

#

!

!
"

\++]%7+%_I2,07B=?,BI7I+7B/7E?J7+`,/1G1,B/+G%7+G72E1B.J+,J7^1B/+,^+G%7+^,;2
+++d=%,E,.JJ_J0J_81B7+27/1I;7/+1B+/;^^1817BGJ_+8J,/7+`2,e1E1G_+G%.G+7.8%+`.12+;BI720,7/+@D)+
+++1B+G%7+`27/7B87+,^+.J9_J1I7B7+5234+G,+01-7+.+G218_8J18+8_J1BI218.J+`2,I;8G+8,BG.1B1B0+.+KN=
+++E7E?727I+21B0+./+.+E1eG;27+,^+G%277+P81/=81/3+81/=G2.B/3+G2.B/=G2.B/Q+,J7^1B+1/,E72/*
\++]%1/+8,-.J7BG+8.`G;27+/G2.G70_+E._+?7+;/7^;J+1B+/G.?1J1a1B0+91B7G18.JJ_+J.?1J7+
=%7J18.J+.BI+
+++=/%77G+`7`G1I7+/78,BI.2_+/G2;8G;27/*

DJ.293+]*+b*5+>%.I1213+)*+@*+<*+AE*+D%7E*+:,8*+.//63+LLc3+LOK'R(LOK'V*

!

ZD!3+#O"

!

D#KD!

!
"

"
"

"
"

!

"

KO=E7E?727I+8.G7B.B7

[LMMS

!

!
!

"

"

"

"
"

"

G2.B/Y81/3+XNYO

\++]%7+27E.29.?J7+7^^1817B8_+,^+G%1/+@D)+1/+`2,`,/7I+G,+?7+I;7+G,+`27,20.B1a.G1,B+,^+G%7+
+++/;?/G2.G7*
),%23+4*5+67893+)*5+:.;-.073+<*=$*5+>2;??/3+@*+#*+AB07C*+D%7E*3+FBG*+HI*+HB0J*+.//03+K'3+

LKMN(LKLM*
)*+),-.//.0%1
15


Myers

Chem 115

The Olefin Metathesis Reaction

Cross Metathesis
Olefin categorization and rules for selectivity
Type I – Rapid homodimerization, homodimers reactive
Reaction between two olefins of Type I................................... Statistical CM

Type II – Slow homodimerization, homodimers largely unreactive

Reaction between two olefins of same type (non-Type I)........ Non-selective CM

Type III – No homodimerization

Reaction beween olefins of two different types....................... Selective CM

Type IV – Olefins inert to CM, but do not deactivate catalyst (spectator)

Selective Cross-Metathesis Reactions as a Function of Catalyst Structure:

MesN

NMes
P(c-Hex)3
Cl
Ph
Ru
H
Cl
P(c-Hex)3

Cl

Ph
Ru
H
Cl
P(c-Hex)3

3-Ru

4-Ru

i-Pr
F3C
F3C

i-Pr
N

O Mo

CH3 O
H
F3C
CH
3
F3C

CH3
Ph
CH3
1-Mo

Olefin type

Type I
(fast homodimerization)

terminal olefins, 1° allylic alcohols, esters, allyl
boronate esters, allyl halides, styrenes (no large
ortho substit.), allyl phosphonates, allyl silanes,
allyl phosphine oxides, allyl sulfides, protected
allyl amines

terminal olefins, allyl silanes, 1° allylic alcohols,
ethers, esters, allyl boronate esters, allyl halides

terminal olefins, allyl silanes

Type II
(slow homodimerization)

styrenes (large ortho substit.), acrylates,
acrylamides, acrylic acid, acrolein, vinyl ketones,
unprotected 3° allylic alcohols, vinyl epoxides, 2°
allylic alcohols, perfluoalkyl substituted olefins

styrene, 2° allylic alcohols, vinyl dioxolanes,
vinyl boronate

styrene, allyl stannanes

1,1-disubstituted olefins, non-bulky trisub. olefins,
vinyl phosphonates, phenyl vinyl sulfone, 4° allylic
carbons (all alkyl substituents), 3° allylic alcohols
(protected)

vinyl siloxanes

3° allyl amines, acrylonitrile

vinyl nitro olefins, trisubstituted allyl alcohols
(protected)

1,1-disubstituted olefins, disub a,b-unsaturated
carbonyls, 4° allylic carbon-containing olefins,
perfluorinated alkane olefins, 3° allyl amines
(protected)

1,1-disubstituted olefins

Type III
(no homodimerization)

Type IV
(spectators to CM)

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370.

L. Blasdel

16


Myers

Chem 115

The Olefin Metathesis Reaction

Non-selective Cross Metathesis: Two Type I Olefins

Olefin 1

producta,b

Olefin 2

Isolated Yield (%)

E/Z

82

10 : 1

50c (62)d

14 : 1

53

6.7 : 1

93

>20 : 1

91

>20 : 1

80

4:1

OTBS

71

>20 : 1

CH3

23

4:1

97

>20 : 1

Secondary allylic alcohols (Type II with Type I)
+

OAc

3 mol% catalyst
OAc

AcO
2 equiv.

CH3

CH2Cl2, 40 °C, 12 h

3

BzO

2 equiv.

BzO

CH3

OAc

OAc

3

80 %
CH3

E/Z

catalyst

3

3-Ru

3.2 : 1

4-Ru

7:1

CH3

3

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.

3

OAc

CH3

OAc
TBDPSO

2 equiv.

TBDPSO
• The difference in E/Z ratios reflects the enhanced activity of 4-Ru relative to 3-Ru. Because it is
more active, 4-Ru can catalyze secondary metathesis of the product, allowing equilibration of the
olefin to the more thermodynamically stable trans isomer.

HO

1 equiv.

HO

CH3

OAc

3

OAc

Quaternary allylic olefins (Type III with Type I)
H3C

CH3

HO
2 equiv.

3

OAc

CH3

H3C
HO

3

OAc

• Selectivity for the trans olefin can also be enhanced using sterically hindered substrates:

SiR3

+

PhO
3

O

2 mol% 1-Mo

PhO

DME, 23 °C, 4 h

SiR3
3

R

Yield

E/Z

CH3

72%

2.6 : 1

Ph

77%

7.6 : 1

O

BzO

3

CH3

AcO

+
3

CH2Cl2, 40 °C, 12 h

R=H
R = TBS

AcO

7

H2N

O

OR

3

58% yield
97% yield

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–
11370.

8

HO

O
3

O

OAc

CH3
a3–5

H2N
CH3

CH3

3

CH3
1.0 equiv.

3

OAc

O

OTBS

H3C

H

BzO
CH3

1.1 equiv.

CH3

H3C CH3

OAc

1.2 equiv.

CH3

• The lower yield obtained with the unprotected alcohol is a result of homodimerization of
the tertiary allylic alcohol. Subjecting this dimer to the reaction conditions results in no
CM product, indicating that the dimer cannot undergo a secondary metathesis reaction.

6 mol% 4-Ru

O
H3C

2 equiv.

O

• In addition, steric bulk can assist in favoring the cross metathesis reaction over
homodimerization pathways.

OAc

1,1-Disubstituted olefins (Type III with Type I)

Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 2117–2120.

OR
CH3
CH3

3

H3C

1 equiv.

7

O
HO
CH3

8

O

OAc
H

3

OAc

CH3

mol% 4-Ru, CH2Cl2, 40 °C. b See last reference on left half of this page.
2 equiv Olefin 2, the yield was 92%. dReaction was performed at 23 °C

cWith

L. Blasdel

17

Myers
Olefin 1

producta,b

Olefin 2

Isolated Yield (%)

E/Z

Selective Cross-Metathesis Reactions:

O

C(CH3)3
neat

HO
O

C(CH3)3
neat

t-BuO

O

CH3

4.0 equiv.

F

3

O
3

R

CH3

HO

CH3

O

C(CH3)3

t-BuO
O

3

HO

C(CH3)3

HO

CH3

4.0 equiv.

3

AcO

OAc

OAc

a1–5

+

CH2Cl2, 40 °C, 16 h

OTr

O
Cl3C

Si(CH3)3

N
H

98% isolated yield
>20 : 1 E/Z

Si(CH3)3

OEt
1.5–2.0 equiv.

OEt
1.5–2.0 equiv.

98

>20 : 1

(H3C)3Si

50

>20 : 1

CbzHN

+

Si(CH3)3

CO2CH3

10 mol% 1-Mo
H

CH2Cl2, 40 °C, 8 h

CbzHN

CO2CH3

95%
92% ee
92

>20 : 1

87
H3C
CH3
5

5 mol% 1-Mo

+

R

>20 : 1

CH3

CO2CH3

Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446.

NC

CO2CH3

H3C

Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446

97% ee

CO2CH3

O

CH3

10 mol% 1-Mo

2:1
2:1

F

O

CH3

Type III
N
H

H

OCH3
1.5–2.0 equiv.

CH3

55 R = H
83 R = CH3

N
H

OTr

O
Cl3C

F

OAc

O

H3C

1.5 equiv

2:1

O

50% isolated yield
1.5 : 1 E/Z

Si(CH3)3

F

2.0 equiv.

F

CH3

(H3C)3Si

CH2Cl2, 40 °C, 4 h

+

73

83

10 mol% 4-Ru

OTr

O

1.5 equiv

2.0 equiv.
F

Type I

Type I

CH3

EtO

OAc

AcO

CH3

73

Type IV
N
H

O

O

CH3

O

EtO

OTr

O

Type II and Type III

H3C

Chem 115

The Olefin Metathesis Reaction

>20 : 1

CH3

mol% 4-Ru, CH2Cl2, 40 °C.

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–

11370.

NC

CH2Cl2, 23 °C, 3 h

R

E/Z

R

yield (%)

CH2Si(CH3)3

76

1:3

(CH3)3OBn

60

1 : 7.6

(CH2)2CO2Bn

44

1 : 5.6

• The basis for the high cis-selectivity with acrylonitrile as substrate is not known.
Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162–5163.
L. Blasdel and M. Movassaghi

18


Myers

Chem 115

The Olefin Metathesis Reaction

Reagent preparation

Examples in synthesis

A Horner-Wadsworth-Emmons reagent:

• En route to the ABS ring fragment of thyrsiferol:

O
EtO P
EtO

+

O

EtO P
EtO

4 mol% 4-Ru

O
OEt

CH2Cl2, 40 °C, 12 h

O
OEt

H3C
H3C

87%
>20 : 1 E/Z

CH3
O

H3C
O

CH2Cl2, 45 °C

O

OAc

Br

Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7–10.
H3C
H3C

A Suzuki reagent:

CH3

H3C
O

H3C
H3C

O
OAc

2

H3C
AcO

+
3

CH3
CH3

O CH3

CH3
2.0 equiv

H3C
O
B

5 mol% 4-Ru
CH2Cl2, 40 °C, 12 h

AcO

58%
>20 : 1 E/Z

3

CH3
CH3
CH3

O

CH3

CH3

H3C

O

O

starting material homodimer

McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593–595.
• CM can be difficult in the presence of strained olefins, as was found in the preparation of the
AB ring fragment of ciguatoxin:

H

O
One-pot CM and allylboration reactions:

OBn

O

OBn

5 mol% 3-Ru
CH2Cl2, 23 °C, 30 min

OBn

H

O

H

H3C
H3C
H3C

O

O
B

+

2. PhCHO (2 equiv.), 23 °C
2.0 equiv

OBn
OBn

OBn
40 mol% 3-Ru
CH2Cl2, 40 °C

AcO

OH

OAc

33 h

Ph
Ph
H

88%
91 : 1 anti:syn
AcO
OAc

Yamamoto, Y.; Takahashi, M.; Miyaura, N. Synlett 2002, 128–130.

O

95%

compound A
1. 3 mol% 3-Ru
CH2Cl2 40 °C, 24 h

O

44% E-isomer
64% after recycling the homodimer

Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733–7736.

CH3

OTBS

OAc

Br

Br
O
B

10 mol% 4-Ru

OTBS

+

H

O

H

O

H
OBn
OBn

OBn

19%

via ring opening to compound A

+

AcO
OAc

H

O

H

O

OBn
OBn

OBn

8%
AB ring fragment of ciguatoxin

Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405–5408

L. Blasdel

19

Myers
Ring Opening Cross-Metathesis

Metathesis of Enyne Substrates
alkenea

product

substrate

CH3OH2C
H3CO2C

CO2CH3

CH2OCH3

A

O

O

O

n

2

14

85

R

R

H3C

8c

3

73

1.5 :1

CH3

3 mol% 2-Ru
25 °C, 8 h
0.06 M
CH2Cl2

Et3SiO

OSiEt3
+
CH3

dienyne
RCM
95%

diene
RCM
<3%

• The dienyne RCM is largely favored over the competing diene RCM.

A
O

m

n

[M]Ln

2:1

CH2OCH3
O

m

n

R

OSiEt3

NBoc

O

m

[M]Ln

2:1

O

CH3OH2C
O

m

Et

NBoc

O

94

n

• Fused [5.6.0], [5.7.0], [6.6.0], and [6.7.0] bicyclic rings have been successfully constructed

by RCM of dienynes.

C

O

96

Et

Et

O

6

Catalytic RCM of Dienynes: Construction of Fused Bicyclic Rings
time yield E,E;E,Z

R

B
O

mol%
cat.b

CO2CH3

H3CO2C

Et
O

Chem 115

The Olefin Metathesis Reaction

2

89

15

O

NA
OSiEt3

0.05-0.1 M
C6D6

a25

°C; 1.5 Equivalents of alkene used: A = trans-1,4-dimethoxybut-2-ene;
B = trans-hex-3-ene; C = cis-hex-3-ene. Solvent: C6H6 (entries 1 and 2) or
CH2Cl2 (entries 3 and 4). bCat. = 2-Ru. cCat. = 3-Ru.

• In these cases a preference for the E-olefin geometry is observed in ring opening
metathesis.

• Higher yields were achieved by slow addition of the cyclic alkene to a solution of
the 1,2-disubstituted alkene.
• Faster and more efficient ring opening cross metathesis was observed using
cis-hex-3-ene vs. trans-hex-3-ene.

Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 411–412.
Enantioselective ROM–CM reactions have been described: La, D. S.; Ford, J. F.; Sattely,
E. S.; Bonitatebus, P. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121,
11603–11604.

OSiEt3

3-5 mol% 2-Ru

R

R

R

yield (%)

conditions

H
CH3
i-Pr
t-Bu
Ph
CO2CH3

Si(CH3)3
Sn(n-Bu)3
Cl, Br, I

>98
95
78
NR
96
82
NR
NR
NR

23 °C, 15 min
23 °C, 8 h
60 °C, 4 h
60 °C, 3 h
60 °C, 4h

• Mo-, W- or Ti-based catalysts are not effective for the above transformations.
• Reaction rates decrease as the size of the acetylenic substituent increases.
• Substrates containing heteroatoms directly attached to the acetylene do not cyclize.

M. Movassaghi

20


Myers

Chem 115

The Olefin Metathesis Reaction

substrate

product

OSiEt3

yield
(%)

mol%
2-Ru

time
(h)

conc.
(M)

temp
(°C)

88

6

8

0.06

65

Enyne Metathesis Reactions Catalyzed by PtCl2

OSiEt3
substrate
PhO2S SO2Ph

H3C

CH3

yield

PhO2S SO2Ph
96%

OSiEt3
CH3

OSiEt3
83

3

6

0.03

65

CH3

CH3
OSiEt3

O

CH3
OSiEt3

H
OCH3

O H
70%

O

OSiEt3
78

H3C

product

15

1.5

0.01

100

O

OCH3

CH3
O

OSiEt3

H

H

O
54%

CH3

15

12

0.05

65

88

3

6

0.05

65

CH3

CH3
CH3
O

CH3

CH3

89

H3C

CH3

O

aReactions

CH3

OSiEt3

OSiEt3

• A pathway involving complexation of cationic Pt(II) with the alkyne has been proposed.

OSiEt3
Fürstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785–6786.

LnRu
CH3
CH3
86%, 1:1

conducted in toluene at 80 °C using 4-10 mol% of PtCl2

• Remote alkenes are unaffected.

CH3

CH3

RuLn
CH3

80%

• In most cases commercial PtCl2 was used as received.

RuLn

OSiEt3

H
TsN

CH3

• Regiochemical control within unsymmetrical substrates is achieved by substitution of the
olefin required to undergo metathesis last.
• Unsymmetrical substrates containing equally reactive olefins produce a mixture of bicyclic
products:
OSiEt3
OSiEt3
OSiEt3
RuLn
RuLn

RuLn

Ts H
N

CH3

Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073–1081.

M. Movassaghi, L. Blasdel

21


Myers

Chem 115

The Olefin Metathesis Reaction
Enyne Cross-Metathesis

Enyne Metathesis in Synthesis
CH3
TBSO

TBSO

• 4-Ru outperforms 3-Ru in both rate and overall conversion in the cross-metathesis of ethylene
and alkynes.

CH3
TBSO

substrate (+ethylene)

OCH3

product

OR

OTBS

OR

R=H
R = Ac
R = TBS

CH3 OTBS
1. 50 mol% 3-Ru
ethylene, CH2Cl2, 40 °C
2. TBAF, THF, 0 to 23 °C

40 mol% 3-Ru
ethylene, toluene, 45 °C
31 %
H3CO

CH3

OTBS
H

TBSO

OAc

42% (two steps)

H3C

TBSO

73
92
91

16

77

4.0

69

4.0

91

6.0

72

OCH3
AcO

H3 C

H3C
OH

2.0
2.0
8.5

H3C

AcO
OAc

OAc

O

yield (%)

OAc
CH3

CH3 OTBS

TBSO

time (h)

NTs

H3C

NTs

CH3
(–)-Longithorone A
O
O

CH3

aReactions

conducted in CH2Cl2 at 23 °C using 5 mol% of 4-Ru at 60 psi of
ethylene pressure.

Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775.
CO2CH3
H3C
H3C

CH3

H3CO2C
12 mol% 4-Ru

CH3
CH3

CH2Cl2, reflux, 3 h

H3C

CH3
O

BnO

BnO

H OHC

OHC

H3C
CH3

CH3

• Reactions conducted at 1 atm of ethylene pressure typically gave low conversions even after
extended reaction times.
• The more reactive imidazolylidene 4-Ru can tolerate free hydroxyl groups and coordinating
functionality at the propargylic and homopropargylic positions.
• Chiral propargylic alcohols afford chiral diene products without loss of optical purity:

OH
OH

AcO
H3C

H3C
CH3

CH3

Guanacastepene A
Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817–1820.

Ph

4-Ru (5 mol%)
ethylene (60 psi)
CH2Cl2, , 23 °C

99% ee
Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271–2274

OH
Ph
99% ee
L. Blasdel and M. Movassaghi

22


Myers

Chem 115

The Olefin Metathesis Reaction
Catalytic, Enantioselective RCM

Kinetic Resolution via Asymmetric RCM
R1
N
i-Pr

i-Pr
N

F3C
F3C

Mo

O

t-Bu

CH3
CH3

O

H3C

H

CF3
CF3

CH3
CH3

R2
CH3

H
t-Bu

CH3

22 ºC, 10 min
C6H6

CH3

R2 = Ph
R2 = Ph
R2 = Ph
R2 = CH3

Et3SiO
CH3

CH3
38%, 48% ee

H
OSiEt3

22 ºC, 2 min
C6H6

Ar

O
CF3
CF3
DISFAVORED

H

OSiEt3
H
CH3

F3C
F3C

H

N
H3C
O Mo
O

OSiEt3

CH3

CF3
CF3
DISFAVORED

Ar = 2,6-(i-Pr)2C6H3

40%, <5% ee

Mo-alkylidene Catalyzed Kinetic Resolution and Enantioselective Desymmetrization
via RCM
5 mol% 12-Mo
H

H3C

C6H5CH3

R

H3C

O
H

H3C

+
R

R

H

O

conv. (%)

recovered
SM ee (%)

krel

6

63

92

10

–25

10

56

95

23

c-C6H11

–25

7

62

98

17

c-C6H11

22

0.1

64

97

13

–25

6

56

75

8

R

temp. (ºC)

n-C5H11

–25

i-C4H9

C6H5

time (h)

• Increasing the size of the !-substituent can lead to greater selectivity.
• 1,2-disubstituted alkenes and tertiary ethers are not effectively resolved by either alkylidene 12Mo or 13-Mo.

O
Fujimura, O.; Grubbs, R. H. J. Org. Chem. 1998, 63, 824–832.
Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499–2500.

H
OSiEt3

• Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutane
intermediates and not during the initial metathesis step.

62%

Proposed Transition State Models for the Observed Selectivity

N
H3C
O Mo

H
OSiEt3

CH3

50%, <5% ee

• The first catalytic, asymmetric kinetic resolution via RCM was achieved, with low selectivity, using
the chiral alkylidene 11-Mo.

F3C
F3C

H3C

+

O

H

43%, 93% ee

Alexander, J. B.; La, D. S.; Cefalo, D. R. Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998,
120, 4041–4042.

CH3

Ar

H3C

CH3

5 mol% 12-Mo

CH3

+
Et3SiO

CH3

H OSiEt3

19%, >99% ee

12-Mo: R1 = i-Pr
13-Mo: R1 = CH3

14-Mo: R1 = Cl
15-Mo: R1 = Cl

–20 ºC, 660 min
toluene

CH3

CH3

H3C

2 mol% 11-Mo
Et3SiO

5 mol% 12-Mo

+

H3C

11-Mo

H OSiEt3

CH3

CH3

Mo

O
O

Ph

H OSiEt3

R1

O
H
n-C5H11

H3C

H3C

CH3
C6H5
M. Movassaghi

23


Myers

Chem 115

The Olefin Metathesis Reaction

• The alkylidene catalysts 12-Mo and 13-Mo are very effective in catalytic, enantioselective
desymmetrization processes, especially in the case of secondary allylic ethers.

H3C

O
H3C

CH3

R

• Desymmetrization metathesis reactions have been used to make a variety of heteroatomcontaining products:

R

1-2 mol% 13-Mo
22 °C, 5 min
neat

H3C CH3
Si
O

H
H3C

5 mol% 12-Mo

O

R

H 3C

R=H
R = CH3

Ph O Si CH3
CH3

H3C

CH2Cl2, 22 °C, 6 h

Ph

92%
93% ee

1. m-CPBA
2. n-Bu4NF

CH3 CH3

HO
Ph OH CH3

• Remarkably, this catalytic, asymmetric RCM can be carried out in the absence of solvent,

with <5% dimer formation.

H3C

• The catalytic, enantioselective desymmetrization of tertiary allylic ethers requires the use of
alkylidene 13-Mo.

86% two steps
93% ee
>20:1 de

Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868.
5 mol% 13-Mo
O
-–20 °C, 18 h
toluene

O
CH3

5 mol% 14-Mo
PhH, 22 °C, 12 h

O

41%, >98% conv.
83% ee

H3C

84%, 73% ee

O

CH3
O

O

5 mol% 13-Mo
O
-–20 °C, 18 h
toluene

O

91%, 82% ee

• Only 29% ee was observed using 12-Mo. 14-Mo is the catalyst of choice for synthesizing
non-racemic acetals.

Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H.
Tetrahedron Lett. 2000, 41, 9553–9559.
• It is believed that the stereodifferentiating step is the formation of the metallabicyclobutane
intermediate; see: Alexander, J. B.; La, D. S.; Cefalo, D. R. Hoveyda, A. H.; Schrock, R. R.
J. Am. Chem. Soc. 1998, 120, 4041–4042.

La, D. S.; Alexander, J. B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock R. R. J. Am.
Chem. Soc. 1998, 120, 9720–9721.

M. Movassaghi and L. Blasdel

24


Myers

Chem 115

The Olefin Metathesis Reaction

• Ruthenium based catalysts can also be used for enantioselective desymmetrizing RCM for the
preparation of allyl ethers:

i-Pr

i-Pr
C6H2(i-Pr)3 N

Ph

O

CH3
O Mo
Ph
O
CH3
C6H2(i-Pr)3

N
i-Pr
X

R

Ph

Ph
N
Ru

i-Pr

R

substrate

product

H3C

PCy3

temp
(ºC)

ee
(%)

64

17-Ru
(4)

40

90

77

18-Ru
(0.8)

40

92

H3C

CH3

H3C

catalyst
(mol%)

O

O

X

yield
(%)

H

CH3

H3C

CH3

17-Ru: R = H, X = I
18-Ru: R = i-Pr, X = Cl

16-Mo

• Catalyst 16-Mo was found to be effecive for the synthesis of cyclic enol ethers by an
enantioselective desymmetrizing RCM:

H3C

H3C CH3
Si
O

H3C CH3
Si

O
CH3

H3C
H

H3C
substrate

yield
(%)

product

16-Mo
(mol%)

time
(h)

temp
(ºC)

CH3

H3C

CH3

ee

(%)

Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840–1846.
CH3 O

O
H3C

10

6

22

90

Ph

• Arylamines are compatible with Mo catalysts:

CH3

H3C

CH3
CO2CH3

Ph

CH3

96

15

20

22

CO2Me

CH3

15

17

22

94

PhH, 22 °C

N n
Ph

H3C

94

catalyst

87

O
H3C

CH3

CH3

O

O
H3C

• Synthesis of azaheterocycles

70

CH3

O
H3C

CH3

N n
Ph

H3C

n

catalyst

%mol
catalyst

time

yield

ee

1

12-Mo

5

20 min

78%

98%

2

12-Mo

2

7h

90%

95%

3

15-Mo

5

20 min

93%

>98%

*The absolute stereochemistry of the RCM products was not reported.
*The absolute stereochemistry of the RCM products was not reported.
Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2006,
128, 5153–5157.

Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J Am. Chem. Soc. 2002, 124, 6991–
6997.
David W. Lin, Fan Liu

25