Olefin Metathesis

2005 Nobel Prize in Chemistry awarded jointly to Yves Chauvin, Robert Grubbs, and Richard Schrock "for
the development of the metathesis method in organic synthesis"

Chauvin

Hoveyda

Grubbs

Cossy

Schrock

Blechert

Frstner

Myers

Chem 215

The Olefin Metathesis Reaction

Cross Metathesis (CM):

Reviews:
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 44904527.

R2 +

R1

CM

R4

R3

R1

R3

R4

R2

Grubbs, R. H. Tetrahedron 2004, 60, 71177140.

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, 1136011370.
Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 19001923.

Catalysts

Frstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 30133043.

Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 44134450.

i-Pr

Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371388.

F3C
F3C

Ring-Opening Metathesis Polymerization (ROMP):

ROMP

ROMP is thermodynamically favored for strained ring systems, such as 3-, 4-, 8- and
larger-membered 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.
Block copolymers can be made by sequential addition of different monomers (a
consequence of the "living" nature of the polymerization).

N
O 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
Cl
H
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)

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.
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.
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.

Ring-Closing Metathesis (RCM):

RCM

MesN

i-Pr

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 2-Ru 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 commerically available, but 1-Mo is
significantly more expensive.
Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953956.
Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed Engl. 1995,
34, 20392041.
Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 98589859.
M. Movassaghi and L. Blasdel

Mechanism:

P = P(c-Hex)3

Dissociative:

EtO2C CO2Et
=

R
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.
15 years later, Chauvin first proposed that olefin metathesis proceeds via
metallacyclobutanes: Herisson, P. J.-L.; Chauvin, Y. Makromol. Chem. 1970, 141,
161176.

P
Cl

Ru

Cl

Cl H

Ru

Cl H

Cl Ru

Cl H
H

Cl

Cl Ru

R
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, 32653266.

Cl

P
H

Ru
Cl

C2H4

c-C5H6(CO2Et)2

P(c-Hex)3
H
Ru
H
Cl
P(c-Hex)3
5 mol%
Cl

EtO2C CO2Et

CD2Cl2, 25 C

P
Cl

Ru

Cl H

Cl

A kinetic study of the RCM of diethyl diallylmalonate using a Ru-methylidene describes

two possible mechanisms for olefin metathesis:

Associative:

The "dissociative" mechanism assumes that upon binding of the olefin a phosphine is
diplaced 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

Cl

Cl Ru

EtO2C CO2Et

R
Cl

Cl

Cl

Ru

Ru
P

Cl H

EtO2C CO2Et

EtO2C CO2Et

Cl
H

Cl H

Ru

Cl
H

P
Cl

Ru

Cl H

P
EtO2C CO2Et

Cl

Ru
P

c-C5H6(CO2Et)2

Addition of 1 equivalent of phosphine (with respect to catalyst) decreases the rate of the
reaction by as much 20 times, supporting the dissociative mechanism.

Dias, E. L.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 38873897.

Cl H

+P
EtO2C CO2Et

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

Ru
H

EtO2C CO2Et

The "associative" mechanism assumes that an 18-electron olefin complex is formed

which undergoes metathesis to form the cyclized product.

Cl H

C2H4
P
Cl

Ru

Cl H

P
Cl

P
EtO2C CO2Et

Cl

Ru

EtO2C

CO2Et

M. Movassaghi

Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM

Catalytic RCM of Dienes:

substrate

product

O
N

X = CF3
X

time (h)

X = Ot-Bu

Ph

yield

(%)a

93

91

substratea
E E

E E

R = CH3

i-Pr
t-Bu

Ph

yield
yield
with 3-Ru (%)b with 1-Mo (%)c

product

84

Ph
Br

Ph

CH2OH

Ph
5

86

CH3

Ph

Ph
O

Ph

98

100

NR

96

25

97

NR

NR

98

decomp

97

100

96

100

CH3

72

E E
E E

Ph
1

100

E E

E E

93

CH3

87

CH3

E E
R

R = CO2H

87

CH2OH

88

CHO

82

No RCMd

No RCMd

CH3
E E

a2-4

mol% 2-Ru, C6H6, 20 C.

CH3 E E

CH3

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

H3C

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 functional groups.

93

NR

61

CH3
E E

CH3 E E

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

NR

H3C
CH3
E

E E

Free amines are not tolerated by the ruthenium catalyst; the corresponding hydrochloride
salts undergo efficient RCM with catalyst 2-Ru.
PhCH2

+
N

H
Cl

4 mol% 2-Ru

CH2Ph
N

20 C, 36 h
CH2Cl2; NaOH
79%
Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 98569857.

96e

100e

E = 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, 73107318.

M. Movassaghi

Geminal Substitution

A Recyclable Ru-Based Metathesis Catalyst

O
<1 mol% 1-Mo

R
H3C

25 C, 0.5-1 h
neat

R RR R

CH3
O
N2

R=

H3C

CH2Cl2, 78 C

0%; (polymerization)
95%

H
CH3

P(c-Hex)3
Cl
(2 equiv)
Ru PPh3
CH2Cl2
H
75%

CH3

CH3 Cl
RuCl2(PPh3)3

90%

H3C

Cl

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

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

substrate
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, 1097810980.

Si
n O
m

R
C6H6, CH2Cl2
23 C, 0.5-5 h
73-96%

Si
O
n

Ts
N

KF
R
H2O2

OH
HO

R
n

recovered
catalyst (%)b

NTs

Ts
N

0.5

22

90

75

2.0

22

95

89

1.0

40

99

88

1.0

40

72

88

BnO H

BnO H

H3C CH3
2-5 mol%
1-Mo or 3-Ru

time (h) temp. (C) yield (%)b

TBSO H
TBSO H

RCM of Temporarily Connected Dienes

H3C CH3

producta

NTs

80-93 %
m = 1-3, n = 0-2

RCM of allyl- or 3-butenylsilyloxy dienes (n1) proceeded efficiently with alkylidene 3-Ru,
while the more sterically hindered vinylsilyl substrates (n=0) required the use of alkylidene
1-Mo.

5 mol% 5-Ru, CH2Cl2, Ar Atm. bIsolated yield after chromatography on silica gel.

Catalyst 5-Ru exhibitsexcellent stability toward air and moisture and can be recycled
in high yield by chromatography on silica gel.

RCM of silicon-tethered alkenes is very efficient even at higher concentrations (0.15 M with
catalyst 3-Ru).
Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. J. Am. Chem. Soc.
1999, 121, 791799.
Chang. S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 47574760.
M. Movassaghi

RCM in Methanol and Water

H3C

CH3
N + Cl

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

Cl
Cl

Ru

Cl

Ph

Cl

H
N(CH3)3+Cl

solvent

Ph

6-Ru
7-Ru

80
95

methanol

6-Ru
7-Ru

45d
55d

methanol

7-Ru

methanol

6-Ru
7-Ru

40
90e

methanol

6-Ru
7-Ru

30
>95f

methanol
water
water

7-Ru
7-Ru
7-Ru

90
60
90g

Ph

3-Ru
E

+
N Cl

Ph

Boc
N

Although benzylidene 3-Ru is highly active in RCM of dienes in organic solvents, it has no
catalytic acitivity in protic media.
EtO2C

CO2Et

Boc
N

Ph

Boc
N

CO2Et

5 mol% 3-Ru

Boc
N
Ph
N(CH3)3+Cl

23 C
solvent: CH2Cl2
CH3OH

>95

CH3

7-Ru
Alkylidenes 6-Ru and 7-Ru are well-defined, water-soluble Ru-based metathesis catalysts
that are stable for days in methanol or water at 45 C.

EtO2C

E E CH3

H3C CH3

6-Ru

conversionc

methanol

P
Ru

catalyst

Ph

N(CH3)3+Cl

productb

substratea

N(CH3)3+Cl

100%
<5%

Ph

Stabilization of Ru-Carbene Intermediates by Phenyl Substitution

aE

= CO2Et. b5 mol% catalyst (6- or 7-Ru), 0.37 M substrate, 45 C. cConversions were

determined by 1H NMR. dSubstrate conc. = 0.1 M. e30 h. f2 h. g10 mol% 7-Ru used.

first turnover step of RCM:

methylidene, R = H
benzylidene, R = Ph

R
LnRu

Ph
H

LnRu

R
H

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.
Phenyl substitution within the starting material can also greatly increase the yield of RCM in
organic solvents.

Ph

LnRu

RuLn
LnRu

R
R

H Cl
N+

5 mol% 3-Ru

H H

N + Cl

CH2Cl2
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.

R=H
R = Ph

60%
100%

Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 99049909.
M. Movassaghi

NHC Ruthenium Catalysts:

Mes N

N Mes

Cl

Mes N

Ph

Ru

Cl

RCM of functionalized dienes

Cl
Ru
Cl

P(c-Hex)3

Mes N

N Mes

N Mes

Cl

Ph

diene
CH3
CH3

Ru

Cl

N Mes

Cl

Ph

Ru

H
P(c-Hex)3

Mes N

Cl

P(c-Hex)3

H
P(c-Hex)3

CH2

9-Ru

4-Ru
a

substrate

product

time
(h)

3-Ru

8-Ru

4-Ru

CH2

0
O

t-Bu

37

100

100

O
CH2

24
H3C

93

40c

31

55

CH3

97

O
CH3

E E

CH3

86

CH2

CH3 E E
1.5
CH3

CH2

E E
CH3

CH2

100

t-Bu
CH3 E E

9-Ru

E E
E E

49
O

10-Ru

yield of product (%) using catalyst:b

1-Mo

CH2

O
8-Ru

yield (%)

product

52

95

90

87

CH2

H3C

CH3

O
93

H OH

H OH

0.2

NA

100

100
a

Reactions conducted with 5 mol% 10-Ru.

aE

= CO2Et.

b5

mol% of catalyst, CD2Cl2, reflux.

c1.5

h.

Alkylidenes 4- and 9-Ru are the most reactive Ru-based catalysts.

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

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, 22472250.
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, 24902493.

,-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,
37833784.

M. Movassaghi

Formation of Tri- and Tetrasubstituted Olefins

Me
N
Me

N
Cl

Modified NHC ligand

allows 1,1-disubstituted
olefins to bind easier

Sterically Crowded Cross-Metathesis: Stewart, I. C.; Douglas, C. J.;

Grubbs, R. H. Org. Lett. 2008, 10, 441444.

Ru

Cl
i-PrO

No phosphine ligand gives

longer catalyst lifetime. No
phosphine-mediated decomposition
(J. Am. Chem. Soc. 2007, 129, 7961).

RCM to tetrasubstituted: Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin,

J. M.; Grubbs, R. H.; Schrodi, Y. Org. Lett. 2007, 9, 15891592.

cat 2 = Hoveyda-Grubbs II, cat 3 = above

cat 3 = Grubbs II, cat 6a = above

Attempted cross metathesis to trisubstituted olefins reveals an

unexpected steric bias

This implies a more sterically crowded catalyst will increase the yield of
trisubstituted cross products.

The more sterically crowded catalyst gives higher yields!!

Two pathways are possible. One leads to productive metathesis,
one leads to unproductive metathesis.
Use in natural product synthesis: White, D. E.; Stewart, I. C.; Grubbs, R. H.;
Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810811.

RCM Applications in Synthesis:

Bn

Bn

1. n-Bu2BOTf, Et3N
CH2Cl2, 0 C

2. CH2=CHCHO
78 0 C

O
O

OH O

OH

N
O
O

HO

1 mol% 3-Ru
CH2Cl2

82%, >99% de
Bn

MOMO

CH3

BnO

BnO

110 C, 48 h

BnO

HO

HO

BnO

OH

O
H

MOMO
5 mol% 2-Ru

MOMO

5 mol% 4-Ru

Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 41924193.

CO2CH3

Pochonin C

Cl

trans epoxide

BnO

HO
Cl

97%

OH

BnO

CH3

toluene, 120 C
10 min

CH3
O

O
H

MOMO

87%

HO

70%

Castanospermine

cis epoxide
MOMO

Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547550.

CH3 H

O
O

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.

MOMO

O
H

5 mol% 4-Ru
toluene, 120 C
10 min

MOMO
O

CH3 H

O
MOMO

21%

Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 1021010211.

TBSO

OPMB

O
O

H3 C

10 mol% 5-Ru
CH2Cl2, 40 C

TBSO

OPMB

O
O

H3C

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

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.

O
RuLn
TBSO

OPMB

O
O

Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem. Int. Ed. 2004, 43,
23672370.
O

Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Angew. Chem. Int. Ed. 2004, 43,
36013605.

L. Blasdel and M. Movassaghi

CH3
N
H

N
H
H3C

OH

O
H

N
E

CH3

CH3

20 mol% 1-Mo

OAc

22 C, 10 h
O
NHCOCF3 C6H6
H
OAc
H3C
91%
CH3

CH3
H

O
H

O
N

OAc

NHCOCF3
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.

Manzamine A

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, 1030210316.

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

Slight changes in substrate structure can control whether the E- or Z-olefin is formed:
H

CH2OTDS

CH2OTDS

100 mol% 2-Ru

N
O

O
O

23 C, 5 d
C6D6

H3C

H3C

CH3

OCH3O

Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35,
31913194.

Ph

H
5 mol% 1-Mo

N
O

N
H

50 C, 4 h
C6H6

Ph

N
H

CH3
CH3

PO CH3O

CH3

CO2CH3

CH3

CH3
PO

CH3

CH3

OCH3

O
CH3

CH3

63%
O

CH3

CH3
OHC
Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691694.

CH3

80%
Z-olefin only

10 mol% 4-Ru
CH2Cl2, 40 C

CH3
O

CO2CH3

CH3

OCH3
OP

P = p-BrBz

86%
E-olefin only

CH2

CH3

CH3

O
OP

30%

H3C

CH3

H3C

CH2

HO
Coleophomone B

CH3

CH3

CH3
OHC

CH3

HO

Coleophomone C

Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc.
2005, 127, 88728888.
M. Movassaghi and L. Blasdel

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.
HO

R1O

CH3
CH3
H3C CH3

H3C
O

CH3

CH3

R1 O

CH3
H3C CH3

= Merrifield resin

CH3

O
OTBS
3-Ru (0.75 equiv)
25 C, 48 h
CH2Cl2

H3C

OR2 O

CH3

H3C
S

CH3

CH3
H3C CH3

OR2 O

HO
R1

R2

Catalyst

Conditions

Yield

E/Z

1-Mo

50 mol%, PhH, 55 C

65 %

2:1

TBS

3-Ru

10 mol%, CH2Cl2, 25 C

85%

1 : 1.2

TBS

TBS

3-Ru

6 mol%, CH2Cl2, 25 C

94%

1 : 1.7

TBS

TBS

1-Mo

50 mol%, PhH, 55 C

86%

1 : 1.7

CH3
O

H3C
H3C
H3C
TBSO

CH3

HO

CH3
O

CH3

H3C
H3C
H3C
TBSO

O
O

CH3
CH3
H3C CH3

O
OTBS
5.2%

CH3

N
O
O

S
N

H3C

15.6%

15.6%

HO

CH3

CH3

CH3
HO

CH3
H3C CH3

H3C
O

S
N

CH3

O
OTBS
15.6%

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, 79607973.
Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.;
Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 1107311092.
Schinzer, D.; Bauer, A.; Bohm, O. M.; Limberg, A.; Cordes, M. Chem. Eur. J. 1999, 5,
24832491.

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, 268272.

M. Movassaghi and L. Blasdel

Tandem Ring Opening-Ring Closing Metathesis of Cyclic Olefins

Catalytic RCM of Olefinic Enol Ethers:

CH3

CH3CHBr2, TiCl4

Ph

12 mol% 1-Mo

Zn, TMEDA,
cat. PbCl2,
20 C, 11 h
THF

substrate

Ph 20 C, 3.5 h
n-pentane

product

yield catalyst 3-Ru conc.

(%)
(mol %)
(M)

time
(h)

temp.
(C)

82

0.1

1.5

45

90

0.1

60

70

0.07

45

68

0.04

45

92

0.04

60

O
Ph

88%

H H

H H

55%

CH3

CH3
CH3CHBr2, TiCl4

O
Ph

Zn, TMEDA,
cat. PbCl2,
20 C, 5 h
THF

CH3
Ph

12 mol% 1-Mo
O

20 C, 7 h
n-pentane

Ph

H H

O HH O

87%
H

79%
O
O

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

H

Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 40294031.

O
O

H H
O

H H

Ti

CH2

Al

Cl

CH3
CH3

Tandem Olefination-Metathesis
Tebbe reagent
H
BnO
H
O
O

O
R

Without sufficient ring strain in the starting cyclic olefin, competing oligomerization (via CM)
can occur.
Higher dilution favors intramolecular reaction:

H
Tebbe reagent
(4.0 equiv)

CH3

BnO
H
O

THF, 25 C, 0.5 h;
reflux, 4h

R= H
CH3

H
O

O
H

O
H

R
50%
54%

R =H
H
CH3

6 mol% 3-Ru

H
H

C6H6, 45 C
6h
0.12 M
0.008 M
0.2 M

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

Proposed Mechanism for Ring Opening-Ring Closing Metathesis:

Examples in Complex Synthesis:

CH3

CH3

LnRu CHPh
O

CH3

H3C

2 mol% 3-Ru

CH3

CH3

H3C

ethylene
O

Ph

H2C CH2
O

LnRu

98%

LnRu CH2

H3C

CH3

O
H

H3C
RuLn

OPMB

CH3

CH3

H3C

HO HO
HO
O

25 mol% 5-Ru
toluene,

CH3
O H3 C

76%

CH3

O
H

O
H

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 and by the beneficial effects of dilution upon the
intramolecular manifold.
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.
CH3
CH3
O
N
O
N

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am.
Chem. Soc. 2004, 126, 1630016301.

O
O
O

20 mol% 4-Ru

HH

ethylene, toluene
H3 C

CH3

43% (3 steps)

H3 C

CH3

10 mol% 3-Ru
H3C

0.1 M, C6D6
40 C, 8 h
O

unreactive substrates:

N
CH3
O

O
95%
O

N
CH3

H3 C

CH3
HH

OH
CH3
CH3

Cyanthiwigin U
Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 53345335.

Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 66346640.

M. Movassaghi and L. Blasdel

Kinetic Resolution via Asymmetric RCM

Catalytic, Enantioselective RCM

R1
N

i-Pr

i-Pr
N

F3C
F3C

t-Bu
O
O

Ph

Mo

CH3
CH3

H3C

H
CF3
CF3

CH3

H
t-Bu

12-Mo:
13-Mo:
14-Mo:
15-Mo:

20 C, 660 min
toluene

Et3SiO

H OSiEt3

CH3

5 mol% 12-Mo

CH3

CH3

22 C, 10 min
C6H6

CH3

CH3

R1 = i-Pr
R1 = CH3
R1 = Cl
R1 = Cl

H
OSiEt3

5 mol% 12-Mo

CH3

22 C, 2 h
C6H6

CH3

H
OSiEt3

40%, <5% ee

62%

Mo-alkylidene Catalyzed Kinetic Resolution and Enantioselective

Desymmetrization via RCM
O
H
R

C6H5CH3

H3C

5 mol% 12-Mo

H +
R

H3C

Proposed Transition State Models for the Observed Selectivity

R

N
H3C
O Mo
O
CF3
CF3

DISFAVORED

Ar
OSiEt3
H
CH3

F3C
F3C

H
OSiEt3

Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutane

intermediates and not during the initial metathesis step.

H3C

F3C
F3C

CH3

50%, <5% ee

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

43%, 93% ee

CH3

CH3
38%, 48% ee

Ar

CH3

Alexander, J. B.; La, D. S.; Cefalo, D. R. Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc.
1998, 120, 40414042.

Et3SiO

CH3

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

H OSiEt3

19%, >99% ee
CH3

CH3
H3C

2 mol% 11-Mo
CH3

Mo

CH3
R2
CH3

CH3

11-Mo

Et3SiO

H OSiEt3

R1

N
H3C
O Mo
O

H
OSiEt3

CH3

CF3
CF3

FAVORED

temp. (C)

time (h)

R
H

conv. (%)

recovered
SM ee (%)

krel

n-C5H11

25

63

92

10

i-C4H9

25

10

56

95

23

c-C6H11

25

62

98

17

c-C6H11

22

0.1

64

97

13

25

56

75

C6H5

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
12-Mo or 13-Mo.

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

O
H
n-C5H11

Fujimura, O.; Grubbs, R. H. J. Org. Chem. 1998, 63, 824832.

Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 24992500.

O
H3C

CH3
C6H5

H3C
M. Movassaghi

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

CH3 1-2 mol% 13-Mo

5 mol% 12-Mo

H3C

O
H3C

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

22 C, 5 min
neat

R=H
R = CH3

H
H3C

Ph O Si CH
3
CH3

H3C

92%
93% ee

H3C

Ph

CH2Cl2, 22 C, 6 h

H3C CH3
Si
O

H3 C

1. m-CPBA
2. n-Bu4NF

CH3

85%, 93% ee
93%, 99% ee

OH
Ph OH
CH3
H3C
86% two steps
93% ee
>20:1 de

Remarkably, this catalytic, asymmetric RCM can be carried out in the absence of solvent,
with <5% dimer formation.
The catalytic, enantioselective desymmetrization of tertiary allylic ethers requires the use of
alkylidene 13-Mo.

Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124,
2868.
CH3

5 mol% 13-Mo
O
20 C, 18 h
C6H5CH3

H3 C

5 mol% 14-Mo
PhH, 22 C, 12 h

41%, >98% conv.

83% ee

CH3
O

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

84%, 73% ee

Weatherhead, G. S.; Houser, J. H.; Ford, J. G.; Jamieson, J. Y.; Schrock, R. R.;
Hoveyda, A. H. Tetrahedron Lett. 2000, 41, 9553-9559.

5 mol% 13-Mo
O
20 C, 18 h
C6H5CH3

91%, 82% ee

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, 40414042.

La, D. S.; Alexander, J. B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock R. R. J. Am.
Chem. Soc. 1998, 120, 97209721.

CH3

CH3
catalyst

H3 C

N
Ph

PhH, 22 C

H3 C

N
Ph

catalyst

%mol
catalyst

time

yield

ee

12-Mo

20 min

78%

98%

12-Mo

7h

90%

95%

15-Mo

20 min

93%

>98%

Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J Am. Chem. Soc. 2002, 124,
69916997.
M. Movassaghi and L. Blasdel

Enantioselective Olefin Metathesis: More Recent DevelopmentsMo

Malcomson, S. J.; Meek, S. J.; Sattely, E. S.; Schrock, R. S.;
Hoveyda, A. H. Nature 2008, 456, 933.

Enantioselective Olefin Metathesis: More Recent DevelopmentsRu

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

See also:
Berlin, J. M.; Goldberg, S. D.; Grubbs, R. H. Angew. Chem. Int. Ed.
2006, 45, 7591.
Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org. Lett. 2001, 3, 3225.

Enantioselective Olefin Metathesis: More Recent DevelopmentsRu

Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.; Hoveyda, A. H.
J. Am. Chem. Soc. 2002, 124, 4954.

AROM/CM of less-strained bicycles

Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H.
J. Am. Chem. Soc. 2004, 126, 12288.

Catalytic RCM of Dienynes: Construction of Fused Bicyclic Rings

substrate

product

[M]Ln

Ln[M]
R

CH3

H3C
OSiEt3

25 C, 8 h
0.06 M
CH2Cl2

H3C

CH3
dienyne
RCM
95%

0.06

65

83

0.03

65

78

15

1.5

0.01

100

89

15

12

0.05

65

88

0.05

65

OSiEt3

CH3

CH3
OSiEt3

diene
RCM
<3%

OSiEt3

CH3

CH3
CH3

CH3

The dienyne RCM is largely favored over the competing diene RCM.
OSiEt3

88

CH3
OSiEt3

3 mol% 2-Ru

CH3

temp.
(C)

OSiEt3

OSiEt3
+

conc.
(M)

CH3

Fused [5.6.0], [5.7.0], [6.6.0], and [6.7.0] bicyclic rings have been successfully constructed
by RCM of dienynes.

OSiEt3

time
(h)

CH3

CH3
OSiEt3

mol%
2-Ru

OSiEt3

OSiEt3
n

yield
(%)

CH3
O

CH3
O

OSiEt3
3-5 mol% 2-Ru

R
R
H
CH3
i-Pr
t-Bu
Ph
CO2CH3
Si(CH3)3
Sn(n-Bu)3
Cl, Br, I

0.05-0.1 M
C6D6
yield (%)
>98
95
78
NR
96
82
NR
NR
NR

CH3
R

conditions

Reaction rates decrease as the size of the acetylene substituent increases.

Substrates containing heteroatoms directly attached to the acetylene do not cyclize.

OSiEt3

OSiEt3

OSiEt3

LnRu

LnRu
RuLn

RuLn

CH3

CH3
OSiEt3

Mo-, W- or Ti-based catalysts are not effective for the above transformations.

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:

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

CH3

OSiEt3

CH3

RuLn
CH3

OSiEt3

OSiEt3
LnRu

CH3

CH3

CH3

86%, 1:1
Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61,
10731081.
M. Movassaghi

Enyne Metathesis Reactions Catalyzed by PtCl2

Enyne Metathesis in Synthesis

CH3

substrate

product

PhO2S SO2Ph

PhO2S SO2Ph

yield

TBSO

TBSO

CH3 OTBS

40 mol% 3-Ru
ethylene, toluene, 45 C

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

31%

42% (two steps)

H3C
O

O H

CH3

H3CO

70%

CH3O

OCH3

OTBS

TBSO
OCH3

96%

CH3

TBSO

OTBS
H

TBSO

OCH3

CH3 OTBS

H
H

OCH3

TBSO

O
54%

H3 C
O
O

CH3
()-Longithorone A

Ts H
N

aReactions

H OHC
H
TsN

80%
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773775.
H3CO2C

CO2CH3

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

H3C

CH3

12 mol% 4-Ru

CH3
In most cases commercial PtCl2 was used as received.
A cationic reaction pathway, involving the complexation of cationic Pt(II) with the
alkyne, has been proposed.

H3C

CH2Cl2, reflux, 3 h

CH3

OHC

CH3

CH3

OH

Remote alkenes are unaffected.

AcO
Frstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 67856786.

H3C

82%

CH3

CH3

H3 C

CH3
CH3

CH3

Guanacastepene A
Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 18171820.
L. Blasdel and M. Movassaghi

Cross Metathesis
Olefin categorization and rules for selectivity
Type I Rapid homodimerization, homodimers consumable
Reaction between two olefins of Type I................................... Statistical CM
Type II Slow homodimerization, homodimers sparingly consumable
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

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

Cl

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

Type I
(fast homodimerization)

Type II
(slow homodimerization)

Type III
(no homodimerization)

Type IV
(spectators to CM)

4-Ru

3-Ru

i-Pr
N

F3C
F3C

Mo

CH3
Ph

CH3
CH3 O
H
F3C
F3C CH3 1-Mo

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

styrenes (large ortho substit.), acrylates,

acrylamides, acrylic acid, acrolein, vinyl keones,
unprotected 3 allylic alcohols, vinyl epoxides, 2
allylic alcohols, perfluoalkyl substituted olefins

styrene, 2 allylic alcohols, vinyl dioxolanes,

vinyl boronates

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

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 1136011370.

L. Blasdel

Non-selective Cross Metathesis: Two Type I Olefins

Olefin 1
OAc

3 mol% catalyst
+

OAc

AcO
2 equiv

E/Z

3-Ru

3.2 : 1

4-Ru

7:1

OAc
3
2.0 equiv

BzO

CH3

CH3
3

TBDPSO

2.0 equiv

SiR3

2 mol% 1-Mo

PhO

DME, 23 C, 4 h

10 : 1

50c (62)d

14 : 1

53

6.7 : 1

93

>20 : 1

91

>20 : 1

OAc

80

4:1

OTBS

71

> 20 : 1

CH3

23

4:1

(OAc)

97

> 20 : 1

OAc

HO

OAc

CH3
TBDPSO

OAc

Quaternary allylic olefins (Type I with Type III)

H3C

CH3
3

HO
+

OAc

CH3

OAc
1.0 equiv

HO

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

BzO

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.
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 1136011370.

82

CH3

CH3
catalyst

E/Z

Secondary allylic alcohols (Type I with Type II)

CH2Cl2, 40 C, 12 h
80%

Isolated
Yield (%)

producta,b

Olefin 2

OAc

H3 C

CH3

HO

OAc

2.0 equiv

SiR3
3

O
R

E/Z

Yield

CH3

72%

2.6 : 1

Ph

77%

7.6 : 1

O
3

H3C

OAc

H3C

OAc

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

Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 21172120.
BzO
3

CH3
In addition, steric bulk can assist in favoring the cross metathesis reaction over
homodimerization pathways.

OAc

BzO

2.0 equiv

H2 N

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.

CH3

OTBS

H2 N

1.2 equiv

CH3

CH3

O
AcO

CH3
OR
CH3

6 mol% 4-Ru
CH2Cl2, 40 C, 12 h
80%

AcO

CH3
OR
CH3

HO

CH3

R=H
58% yield
R = TBS 97% yield

HO

CH3

1.1 equiv
O
3

CH3
a

CH3

H3C

H
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 1136011370.

CH3
1.0 equiv

OAc

H
CH3

35 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.

c With

L. Blasdel

Olefin 1

Isolated
Yield (%)

producta

Olefin 2

E/Z

Selective Cross-Metathesis Reactions:

Type II and Type III

O
C(CH3)3
neat

HO

HO

C(CH3)3

73

O
C(CH3)3
neat

t-BuO

HO

C(CH3)3

N
H

73

CH3

HO

CH3

HO

C(CH3)3

83

2:1

4.0 equiv

EtO

Cl3C

CH3

HO

C(CH3)3

55 R = H
83 R = CH3

2:1
2:1

N
H
50% isolated yield
1.5 : 1 E/Z

Type III
N
H

OTr

10 mol% 1-Mo
Cl3C

CH2Cl2, 40 C, 16 h

Si(CH3)3
O

OTr

OTr

Type I

CH3

(H3C)3Si

CH2Cl2, 40 C, 4 h

1.5 equiv

O
3

10 mol% 4-Ru

Si(CH3)3

O
O

Type IV

Type I

OTr

1.5 equiv

Si(CH3)3
N
H
98% isolated yield
>20 : 1 E/Z

4.0 equiv
Brmmer, O; Rckert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441446.
F

OAc

AcO

98
OAc

2.0 equiv
F

H
CbzHN

OAc

AcO

OAc

2.0 equiv
F

>20 : 1

92

>20 : 1

CO2CH3

OCH3
1.52.0 equiv

Si(CH3)3

CbzHN
CH2Cl2, 8 h
reflux

97% ee

CO2CH3

95%, 92% ee

H3 C

CH3

OEt
1.52.0 equiv

Brmmer, O; Rckert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441446.

NC
87
H3C

5
H3C

CH3

15 mol% 4-Ru, CH2Cl2, 40 C.

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 1136011370.

NC

23 C, 3h
CH2Cl2
yield (%)

E:Z

CH2Si(CH3)3

76

1:3

(CH2)3OBn

60

1:7.6

(CH2)2CO2Bn

44

1:5.6

CO2Et

O
OEt
1.52.0 equiv

>20 : 1

CH3
CH3

CH3

CH3

5 mol% 1-Mo

CO2Et

50

CO2CH3

10 mol% 1-Mo

F
O

H3 C

(H3C)3Si

>20 : 1

>20 : 1

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, 51625163.
L. Blasdel and M. Movassaghi

Reagent preparation

Examples in synthesis
En route to the ABS ring fragment of thyrsiferol:

A HornerWadsworthEmmons reagent:
O
EtO P
EtO

4 mol% 4-Ru
OEt

CH2Cl2 40 C, 12 h

O
EtO P
EtO

H3C
H3C

O
OEt

CH3
O

OAc

10 mol% 4-Ru

OTBS

CH2Cl2, 45 C

3.0 equiv

Br

87%
> 20 : 1 E/Z

H3C
H3C

Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 710.

CH3
O

CH3
OAc

H3 C
H3C

CH3
O

CH3

OTBS

OAc

Br

Br

44% E-isomer
64% after recycling the homodimer

starting material homodimer

A Suzuki reagent:

H3C
AcO

O
B

5 mol% 4-Ru

CH3

CH2Cl2 40 C, 12 h

CH3
2.0 equiv

McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593595.

H3C

CH3
CH3

AcO

O
B

CH3
CH3
CH3

CH3

58%,
>20 : 1 E/Z

CM can be difficult in the presence of strained olefins, as was found in the preparation of the
AB ring fragment of ciguatoxin:
H

5 mol% 3-Ru
CH2Cl2, 23 C, 30 min

OBn

Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 77337736.

OBn

OBn

O
H

95%

compound A
One-pot CM and allylboration reactions:

OBn
OBn

OBn
40 mol% 3-Ru
CH2Cl2, 40 C

AcO
OAc

33 h

5.0 equiv
H3C
H3C
H3C

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

CH3
O

O
B

2. PhCHO (2 equiv), 23 C
2.0 equiv

Yamamoto, Y.; Takahashi, M.; Miyaura, N. Synlett 2002, 128130.

OH
H

Ph

H
OBn

Ph
88 %
91 : 9 anti/syn

AcO
OAc

OBn
OBn

19%
via ring opening to compound A

AcO
OAc

OBn
OBn

OBn

8%
AB ring fragment of ciguatoxin

Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 54055408.
L. Blasdel

Ring Opening Cross-Metathesis:

substrate

Enyne Cross-Metathesis
mol %
alkenea cat.b

product

time yield E,E:E,Z

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

CH2OCH3

CH3OCH2

A
CH3O2C

CO2CH3

CH3O2C

O
CH3OCH2

14

85

2:1

2.0
2.0
8.5

73
92
91

16

77

4.0

69

4.0

91

6.0

72

OAc

CH3
8c

73

AcO

1.5:1

CH3
AcO

OAc
CH2OCH3

CH3
A

yield (%)

OR

OAc

NBoc

time (h)

O
O

Et

NBoc

product

R=H
R = Ac
R = TBS

substrate

2:1

Et

Et

94

OR

B
O

96

CO2CH3

Et

89

15

NTs

OAc
NTs

CH3

NA

O
BnO

BnO
a 25

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. c Cat. = 3-Ru.

Reactions conducted in CH2Cl2 at 23 C using 5 mol% of 4-Ru at 60 psi of

ethylene pressure.

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

Reactions conducted at 1 atm of ethylene pressure typically gave low conversions even
after extended reaction times.

Higher yields were achieved by the slow addition of the cyclic alkene to a solution of
the 1,2-disubstituted alkene.

The more reactive imidazolylidene 4-Ru can tolerate free hydroxyl groups and
coordinatingfunctionality at the propargylic and homopropargylic positions.

Faster and more efficient ring opening cross metathesis was observed using
cis-hex-3-ene vs. trans-hex-3-ene.

Chiral propargylic alcohols afford chiral diene products without loss of optical purity:

Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 411-412.
Enantioselective ROMCM 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,
1160311604.

OH
Ph

OH

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

99% ee
Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 22712274.

Ph
99% ee

M. Movassaghi

cis-Selective Cross Metathesis: Molybdenum catalysts

cis-Selective Ring-Closing Metathesis: Mo & W catalysts

Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.
Hoveyda, A. H. Nature 2011, 479, 88.

Meek, S. J.; OBrien, R. V.; Llaveria,

J.; Schrock, R. R.; Hoveyda, A. H.
Nature 2011, 471, 461.

cat 9: 80% conv., 62% yield, 91:9 Z:E selectivity, 7.0 torr

cat 10: 97% conv., 63% yield, 97:3 Z:E selectivity, 1.0 torr

cis-Selective Cross Metathesis: Ruthenium catalysts

N
Ru

Me
N
Cl
Me

Me
N
Me

3 equiv AgOPiv
THF, rt, 10 min
59% yield

Cl

N
Ru

Me

t-BuCO2

i-PrO

i-PrO

Cat A

Cat B
OAc

+
1 equiv

AcO

OAc

2 equiv

Hoveyda-Grubbs II
solvent:
C6H6 (THF/H2O)

time

temp

conv %

E/Z

30 min

23

66.3

10.7

0.23
36.4 (64.4)

2.9
0.12 (0.14)

Cat A
30 min
23
Cat B 240 (120) min reflux

Me

Metathesis of Alkynes and Diynes

RCM of Diynes

Inspired by the activation of the triple bond of molecular nitrogen with molybdenum
complexes of the general type Mo[N(t-Bu)Ar]3 (see: Laplaza, C. E.; Cummins, C. C.
Science, 1995, 268, 861), the reactivity of this class of molybdenum catalysts toward
alkynes was explored.

Efficient synthesis of 12-membered rings containing internal alkynes can be

achieved with 17-Mo.

t-Bu

t-Bu
N
t-Bu
N Mo
N

CH3
CH3
CH3

t-Bu
CH3

RX

t-Bu
N
t-Bu
N Mo
N
CH3
CH3

CH3

O
CH3

O
O

CH3
CH3

CH3

17-Mo, X = Cl
18-Mo, X = Br

16-Mo

yield (%)

Cl

CH3

CH3

producta

substrate

CH3
O

Oxidation of the Mo(III)-precatalyst 16-Mo occurs in situ upon addition of ~25 equivalents of
additives such as CH2Cl2, CH2Br2, CH2I2, and BnCl.

CH3
O
O

O
88

Alkyne metathesis may be achieved with equal efficiency either by in situ oxidation of
precatalyst 16-Mo or by use of pure Mo(IV)-catalysts 17-Mo and 18-Mo.

91

CH3

O(CH2)10

CH3

O
82

16-Mo (10 mol%)

R

CH3

R
R = H,
R = CN,

CH3
RO

O(CH2)10

CH2Cl2, Toluene
60%
58%

17-Mo (10 mol%)

CH2Cl2, Toluene

CH3

O(CH2)10

Ph

OR

Ph

RO

CH3

Si

Ph
O(CH2)10

Ph

CH3

74

Si
O

R = CH3, 59%
R = THP, 55%
O(CH2)10

CH3
Catalyst 17-Mo is sensitive to acidic protons such as those of secondary amides.

Catalysts 17-Mo and 18-Mo tolerate functional groups such as esters, amides,
thioethers, basic nitrogen atoms, and polyether chains, many of which are
incompatible with the tungsten alkylidyne catalysts previously used.

83
O

Terminal alkynes are incompatible with the catalysts.

Use of CH2Cl2 as the reaction solvent or the addition of ~25 equivalents of CH2Cl2
per mol of 16-Mo in toluene are equally effective.

CH3

aReactions

conducted in toluene at 80 C for 20-48h; 17-Mo was generated in situ

from 16-Mo and CH2Cl2 (~25 equiv).
Frstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 94539454.

M. Movassaghi

Template-Directed RCM

Synthesis of Cyclic -Turn Analogs by RCM

H O H3C CH3
N
O
N
H
O H N
O

20 mol% 2-Ru

H
CH2Cl2, 40 C N
N Bn
Boc
H
60%

N
Boc

H O H3C CH3
N
O
N
H
O H N
O

substrate (n)

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

Miller, S. J.; Kim, S. H.; Chen, Z. R.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 21082109.
Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855-5856.

H3C
H3C

O
H N

H
N
Boc

N
H

O
H N

H3C
30 mol% 3-Ru
0.004 M, 21 h
CH2Cl2, 40 C

OBn
60%

H3C

O
H N

H
N
Boc

n = 1, 2

yield (%) cis:trans

none

39

LiClO4 (5)

>95

NaClO4 (5)

42

62:38

none

57

26:74

LiClO4 (5)

89

61:39

38:62
100:0

5 mol% 3-Ru
CH2Cl2
1.2 M, 23 C

O
H N

CH2Cl2, THF
45 C, 1 h
0.02 M
"template" (equiv)

In general, ions that function best as templates also favor the formation of the cis isomer.

CH3
N
H

Preorganization of the linear polyether about a complementary metal ion can enhance RCM.

CH3

CH3

n O

n = 1, 2

N Bn
H

CH3

5 mol% 3-Ru
"template"

O
OBn

>95%

O
5 mol% 3-Ru
LiClO4

Mn = 65900
cis : trans, 1 : 3.7

CH2Cl2, THF
0.02 M, 50 C
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 byRCM.

Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 96069614.

>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.
Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101
1103.

M. Movassaghi

RCM-Mediated Covalent Capture

Synthesis of Catenanes
+ PF

The eight-residue cyclic peptide cyclo[-(L-Phe-D-MeN-Ala-L-HomoallylGly-D-MeN-Ala)2-]

self-assembles to form two slow-exchanging antiparallel -sheet-like hydrogen bonded
cylinders (Ka(CDCl3) = 99 M1, only the reactive isomer is shown).

N
O

Ph
O

NN
H
O
O
H
N N
O

N
N
N
N
O H
H
O
O

N
O

H O
H
N
N
N

Ph Ph

N
O
H
O

H
N

O
N

Cu(CH3CN)4PF6

ON

Ph
O

CH2Cl2, CH3CN
100%

N
N

O
O

N
O

= Cu+
5 mol% 3-Ru
23 C, 6 h
0.01 M, CH2Cl2

20-25 mol% 2-Ru

CDCl3, 23 C, 48 h

92%

65%

+ PF
O
NN
H
O
O
H
N N
O

Ph
O

Ph
O

N
N
N
N
O H
H
O

ON
N
O
H

H
H O
O H
O
N
N
N
N
N
N
O
O
O
Ph
Ph

The hydrogen-bonded ensemble positions the terminal olefins of the four

L-homoallylglycine residues in sufficiently close proximity that each pair undergoes RCM
in the presence of alkylidene 2-Ru to give a tricyclic cylindrical product containing a 38membered ring as a mixture of three (cis-cis, cis-trans, trans-trans) olefin isomers.
This covalent capture strategy may be useful in stabilizing kinetically labile -helical and
-sheet peptide secondary structures.

Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 1236412365.

N
N

KCN, H2O

CH3CN

O
O

32-membered catenane

~100%

N
N

O
O

trans:cis, 98:2

The remarkable efficiency of this RCM is proposed to be due to preorganization of the

substrate.
Mohr, B.; Weck, M.; Sauvage, J.-P.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
13081310.
M. Movassaghi