The Olefin Metathesis Reaction

Myers
Reviews:
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 4490–4527.
Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140.
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H.
J. Am. Chem. Soc. 2003, 125, 11360–11370.
Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 1900–1923.
Fürstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3013–3043.
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413–4450.
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371–388.
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 ΔG 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).
Ring-Closing Metathesis (RCM):
RCM
• The reaction can be driven to the right by the loss of ethylene.
n
H 2C CH 2
• 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 Olefin Metathesis Reaction Chem 215
Cross Metathesis (CM):
R 1
R 2
R3 R4 R1 R3 CM
+ +
• Self-dimerization reactions of the more valuable alkene may be minimized by the use of
an excess of the more readily available alkene.
Catalysts
i-Pr i-Pr
N
F3C CH3 O Mo Ph
F3C CH O CH3 3
H
F3C F
CH3 3C 1-Mo
Cl
Cl
P(c-Hex) 3
Ru
H
P(c-Hex) 3
2-Ru
Cl
Cl
P(c-Hex) 3
Ru
Ph
H
P(c-Hex) 3
3-Ru
(Grubbs' 1st
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.
Ph
Ph
• 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 – σ π
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.
R 2
MesN
Cl
Cl
R 4
NMes
Ph
Ru
H
P(c-Hex) 3
4-Ru
(Grubbs' 2nd
Generation Catalyst)
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 and L. Blasdel

Mechanism:
• 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,
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.
EtO 2C
CO 2Et
Cl
P(c-Hex) 3
H
Ru
Cl H
P(c-Hex) 3
5 mol%
CD 2Cl 2, 25 °C
EtO 2C CO 2Et
• A kinetic study of the RCM of diethyl diallylmalonate using a Ru-methylidene describes
two possible mechanisms for olefin metathesis:
• 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.
• 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 20 times, supporting the dissociative mechanism.
• It was concluded in this study that the "dissociative" pathway is the dominant reaction
manifold (>95%).
Dias, E. L.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897.
Dissociative:
Cl
Cl
R
Cl
R
Cl
Cl
Cl
P
Ru
P
P
Cl H
Ru
H
P
P
Ru
P
H
H
P
Cl H
Ru
H
P
EtO 2C CO 2Et
Associative:
H
H
Cl
R
R
c-C 5H 6(CO 2Et) 2
R
P
Cl H
Ru
H
P
EtO 2C CO 2Et
–P
+P
Cl
c-C 5H 6(CO 2Et) 2
Cl
P
Cl H
Ru
H
Cl
P
Cl H
Ru
H
P
P
Cl H
Ru
H
EtO 2C CO 2Et
Cl
P = P(c-Hex) 3
EtO2C R
Cl
H
R
Cl
H
R
P
Cl H
Ru
H
P
EtO 2C CO 2Et
Cl
=
P
Cl H
Ru
H
P
Cl H
Ru
H
EtO 2C CO 2Et
P
Cl H
Ru
H
P
Cl
CO 2Et
Cl
H
Cl
R
Cl
H
R
P
Cl
Ru
P
Cl
Ru
EtO 2C CO 2Et
P
Cl
Ru
P
EtO 2C CO 2Et
P
Cl
Ru
P
– C 2H 4
– C 2H 4
M. Movassaghi

Catalytic RCM of Dienes:
substrate product time (h)
O
N X
O Ph
O Ph
O
O
O
R
Ph
Ph
X = CF 3
X = Ot-Bu
R = CO 2H
CH 2OH
CHO
a 2-4 mol% 2-Ru, C6H 6, 20 °C.
O
O Ph
O
O
O
N X
O
Ph
Ph
PhCH2 H
N Cl –
+ 4 mol% 2-Ru
R
Ph
20 °C, 36 h
CH 2Cl 2; NaOH
79%
1
1
CH2Ph N
yield (%) a
93
91
2 84
5 86
8 72
1 87
• Five-, six-, and seven-membered oxygen and nitrogen heterocycles and cycloalkanes are
formed efficiently.
• Catalyst 2-Ru can be used in the air, in reagent-grade solvents (C 6H 6, CH 2Cl 2, THF,
t-BuOH).
• 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.
• Free amines are not tolerated by the ruthenium catalyst; the corresponding hydrochloride
salts undergo efficient RCM with catalyst 2-Ru.
Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856–9857.
1
1
1
87
88
82
Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM
substrate a
E E R
E E
E E
E E
CH 3
E E CH 3
CH 3
CH3E E
E E
R = CH
E E
3
93
CH 3
CH 3
i-Pr
CH 3
t-Bu
Ph
Br
CH 2OH
H 3C
product
H 3C
E
R
E E
CH3 E E
E E
E E
E
CH 3
CH 3
CH 3
yield
with 3-Ru (%) b
98
NR
25
NR
98
No RCM d
NR
NR
yield
with 1-Mo (%) c
100
100
96
97
NR
decomp
97 100
96 100
No RCM d
a E = CO2Et. b 0.01 M, CH 2Cl 2, 5 mol%. c 0.1 M, C 6H 6, 5 mol%. d Only
recovered starting material and an acyclic dimer were observed. e The
isomeric cyclopentene product is not observed.
93
61
96 e 100 e
• 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

Geminal Substitution
H3C CH3 Si
n
O
R
O
R R
R R

RCM in Methanol and Water
Ph
Cl
Cl
P(c-Hex) 3
Ph
Ru
H
P(c-Hex) 3
3-Ru
RuL n
R
Cl
Cl
R
P
Ru
P
6-Ru
L nRu
N(CH 3) 3 + Cl –
Ph
H
N(CH +
3) 3 Cl –
R
Cl –
H3C CH3 N
+
Cl
Cl
H 3C
P
Ru
P
N Cl –
+
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.
• Although benzylidene 3-Ru is highly active in RCM of dienes in organic solvents, it has no
catalytic acitivity in protic media.
L nRu
Ph
H
EtO 2C
CO 2Et
Ph
solvent:
5 mol% 3-Ru
23 °C
CH 2Cl 2
CH 3OH
EtO 2C
100%
95
methanol
methanol
methanol
water
water
6-Ru
7-Ru
6-Ru
7-Ru
7-Ru
7-Ru
7-Ru
a E = CO2Et. b 5 mol% catalyst (6- or 7-Ru), 0.37 M substrate, 45 °C. c Conversions were
determined by 1 H NMR. d Substrate conc. = 0.1 M. e 30 h. f 2 h. g 10 mol% 7-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.
• Phenyl substitution within the starting material can also greatly increase the yield of RCM in
organic solvents.
5 mol% 3-Ru
CH 2Cl 2
R = H
R = Ph
H H
N +
60%
100%
Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904–9909.
M. Movassaghi
Cl –
conversion c
80
95
40
90 e
30
>95 f
90
60
90 g

NHC Ruthenium Catalysts:
Mes N N Mes Mes N N Mes
Cl
Cl
Ru
Ph
H
P(c-Hex) 3
Cl
Cl
Ru
Ph
H
P(c-Hex) 3
Mes N N Mes
Cl
Cl
Ru
8-Ru 4-Ru 9-Ru
substrate a
E E t-Bu
E E CH 3
CH 3
CH3E E
H OH
CH 3
H 3C
H 3C
product
E E
E E
E E
H OH
t-Bu
CH 3
CH 3
time
(h)
1 37
Ph
H
P(c-Hex) 3
a E = CO2Et. b 5 mol% of catalyst, CD 2Cl 2, reflux. c 1.5 h.
yield of product (%) using catalyst: b
1-Mo 3-Ru 8-Ru 4-Ru 9-Ru
0 100 100 100
24 93 0 40 31 55
c
1.5 52 0 95 90 87
0.2 0 0 NA 100 100
• 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.
Mes
Cl
Cl
N N Mes
Ru
P(c-Hex) 3
10-Ru
H
CH 3
CH 3
RCM of functionalized dienes
O
O
O
O
O
O
O
diene product yield (%)
O
O
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 2
CH 3
a Reactions conducted with 5 mol% 10-Ru.
O
O
O
• Substrates containing both allyl and vinyl ethers provide RCM products while no RCM
• α,β-Unsaturated lactones and enones of various ring sizes are produced in good to
Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122,
3783–3784.
O
O
O
O
O
O
CH 3
products are observed if vinyl ethers alone are present.
excellent yields.
49
0
97
86
93
M. Movassaghi

O
Bn
BnO
RCM Applications in Synthesis:
N
O
O
BnO
H
BnO CO2CH3 O
N
1. n-Bu 2BOTf, Et 3N
CH 2Cl 2, 0 °C
2. CH 2=CHCHO
–78 → 0 °C
82%, >99% de
5 mol% 2-Ru
110 °C, 48 h
70%
BnO
H
BnO
BnO
O
O
Bn
N
Bn
O
O
N
O
O OH
Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192–4193.
Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547–550.
O
N
OH
HO
HO
1 mol% 3-Ru
CH 2Cl 2
97%
HO
H OH
N
Castanospermine
• 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.
Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc.
2004, 126, 10210–10211.
TBSO
O
H 3C
O
OPMB
O
3
10 mol% 5-Ru
CH 2Cl 2, 40 °C
TBSO
O
H 3C
O
OPMB
O
RuL n
TBSO
O
O
OPMB
Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Angew. Chem. Int. Ed. 2004, 43,
3601–3605.
71%
O
trans epoxide
MOMO
MOMO
MOMO
cis epoxide
MOMO
O
O
O CH 3
O
O
H
O CH3 H
O
H
O
HO
H
OH
Cl
O
O CH 3
O
HO
Pochonin C
5 mol% 4-Ru
toluene, 120 °C
10 min
87%
5 mol% 4-Ru
toluene, 120 °C
10 min
21%
Cl
MOMO
MOMO
MOMO
MOMO
O
O CH 3
O
O
H
O CH3 H
O
O
H
• Pre-organization of the substrate can have a dramatic effect upon the reaction efficiency.
• 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.
Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem. Int. Ed. 2004, 43,
2367–2370.
O
H
L. Blasdel and M. Movassaghi

Ph
N
O
N
O
CO
H
2CH3 H
N
H CH 2OTDS
N O
O
D
O
N
O
N
H
N
N
H
OH
100 mol% 2-Ru
23 °C, 5 d
C 6D 6
30%
Ph
N
O
N
O
H CH 2OTDS
N O
Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35,
3191–3194.
5 mol% 1-Mo
50 °C, 4 h
C 6H 6
63%
CO
H
2CH3 N
H
Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691–694.
E
Manzamine A
• The use of RCM in construction of both the D and the E rings of Manzamine A
has been reported:
O
O
H 3C
CH3 CH3 20 mol% 1-Mo
OAc
O
H
O
22 °C, 10 h
NHCOCF3 C6H6 H
O
OAc
H3C 91%
N CH3 H
N
H
CH 3
O
H
O
CH 3
CH3 OAc
O
NHCOCF3 H
OAc
• 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.
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 3C
O
OCH 3 O
O
OP
H 3C
CH 3
CH 2
CH 3
CH 3
H 3C
O
O
O
OCH3 OP
H 3C
CH 3
CH 2
86% 10 mol% 4-Ru
80%
E-olefin only CH2Cl2, 40 °C
Z-olefin only
O
O
PO CH 3O O
O
O
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
P = p-BrBz
O
CH 3
O
PO O OCH3
OHC O
HO
OHC O
HO
Coleophomone B Coleophomone C
Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc.
2005, 127, 8872–8888.
O
CH 3
O
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
M. Movassaghi and L. Blasdel

Synthesis of Epothilone C:
• Small changes can drastically affect reaction outcome. In the example below, TBS
protective groups changes the E/Z selectivity.
R1O CH3 H3C CH3 H 3C
O
OR 2
O
CH 3
H
O
S
N
CH 3
R1O CH3 H3C CH3 H 3C
O
OR 2
O
CH 3
H
O
R 1 R 2 Catalyst Conditions Yield E/Z
H
H
TBS
TBS
H
TBS
TBS
TBS
1-Mo
3-Ru
3-Ru
1-Mo
50 mol%, PhH, 55 °C
10 mol%, CH 2Cl 2, 25 °C
6 mol%, CH 2Cl 2, 25 °C
50 mol%, PhH, 55 °C
65 %
85%
94%
86%
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.
S
N
2 : 1
1 : 1.2
1 : 1.7
1 : 1.7
CH 3
Solid-Phase Synthesis of Epothilone A:
HO
CH3 CH3 H3C O
H3C O
H3C TBSO
O
HO CH3 H3C CH3 H 3C
= Merrifield resin
O
O
OTBS
O
H 3C
CH 3
O
HO CH3 H3C CH3 S
N
S
N
O
CH 3
O
OTBS
CH 3
O
CH 3
S
N
3-Ru (0.75 equiv)
25 °C, 48 h
CH 2Cl 2
CH 3
HO
CH3 CH3 H3C O
H3C O
H3C TBSO
O
15.6% 15.6%
5.2%
HO CH3 H3C CH3 H 3C
O
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.
O
CH 3
S
N
S
N
CH 3
CH 3
M. Movassaghi and L. Blasdel

Catalytic RCM of Olefinic Enol Ethers:
Ph
CH 3
O
O
O
O Ph
CH 3CHBr 2, TiCl 4
Zn, TMEDA,
cat. PbCl 2,
20 °C, 11 h
THF
55%
CH 3CHBr 2, TiCl 4
Zn, TMEDA,
cat. PbCl 2,
20 °C, 5 h
THF
79%
Tandem Olefination-Metathesis
H
BnO
H
O
O
H
O
O
R
CH3 CH 3
Ph
CH 3
CH 3
O
Tebbe reagent
(4.0 equiv)
THF, 25 °C, 0.5 h;
reflux, 4h
O Ph
• 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 CH 2
Cl
H
BnO
H
O
O
H
O
R
R = H
50%
CH3 54%
• Here, a Ti-alkylidene is used in RCM.
12 mol% 1-Mo
20 °C, 3.5 h
n-pentane
Ph
O
O
Al CH 3
CH 3
Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118,
10335-10336.
88%
12 mol% 1-Mo
20 °C, 7 h
n-pentane
87%
Tebbe reagent
Ph
Tandem Ring Opening-Ring Closing Metathesis of Cyclic Olefins
substrate product
H H
O O
H H
O
O
H H
O O
H H
O O
O O
H H O H H O
O
O
H
O
O
H
O
H H
H H
H H
O O
R O O R 6 mol% 3-Ru
H
O
H H
C6H6, 45 °C
6 h
R = H
H
CH3 O
• Without sufficient ring strain in the starting cyclic olefin, competing oligomerization (via CM)
can occur.
• Higher dilution favors intramolecular reaction:
yield
(%)
82
90
70
68
92
0.12 M
0.008 M
0.2 M
catalyst 3-Ru
(mol %)
16%
73%
42%
O
H
• The relative rate of intramolecular metathesis versus CM may be further increased
by substitution of the acyclic olefin.
3
5
3
6
5
conc.
(M)
0.1
0.1
0.07
0.04
0.04
time
(h)
1.5
2
6
2
3
temp.
(°C)
45
60
45
45
60
M. Movassaghi

Proposed Mechanism for Ring Opening-Ring Closing Metathesis:
H H
O O
H H
O O
H 2C CH 2
L nRu CH 2
L nRu
L nRu CHPh
Ph
H H
O O
H H
O O
RuL n
H H
O O
O
H
RuL n
H
O
• 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
unreactive substrates:
O N
CH3 O O
O O
10 mol% 3-Ru
0.1 M, C 6D 6
40 °C, 8 h
95%
O
O
O
N
CH3 Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634–6640.
H 3C
Examples in Complex Synthesis:
O
CH 3
CH3 2 mol% 3-Ru
H 3C
ethylene
O
98%
H 3C H
HO HO
HO
Ingenol
CH 3
OH
CH 3
H 3C
O
O
O
CH 3
H 3C
CH 3
H
O
O
O
CH 3
H
H 3C
CH 3
OPMB
O
CH 3
CH 3
OPMB
25 mol% 5-Ru
toluene, Δ
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
H 3C
CH 3
O
20 mol% 4-Ru
ethylene, toluene
43% (3 steps)
O
H H
H 3C CH 3
H 3C
O
H3C CH3 H H
CH 3
Cyanthiwigin U
Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–5335.
O
OH
CH3 76%
M. Movassaghi and L. Blasdel

Kinetic Resolution via Asymmetric RCM
Et 3SiO
F3C F3C CH 3
Ar = 2,6-(i-Pr) 2C 6H 3
i-Pr i-Pr
F3C F3C N
Ph
O Mo CH3 O CH3 H
CF3 CF3 CH 3
N
H3C O Mo
O
Ar
CF 3
CF 3
11-Mo
H
DISFAVORED
2 mol% 11-Mo
–20 °C, 660 min
toluene
CH 3
OSiEt 3
H
Et 3SiO
CH 3
F3C F3C CH 3
Proposed Transition State Models for the Observed Selectivity
N
H3C O Mo
O
Ar
+
CF 3
CF 3
H
FAVORED
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.
Et 3SiO
38%, 48% ee 62%
• The first catalytic, asymmetric kinetic resolution via RCM was achieved, with low selectivity,
using the chiral alkylidene 11-Mo.
H 3C
t-Bu
CH3 H3C R 1
O
O
CH 3
CH 3
R 1
N
Mo
H
CH3 R2 CH3 t-Bu
12-Mo: R 1 = i-Pr
13-Mo: R 1 = CH 3
14-Mo: R 1 = Cl
15-Mo: R 1 = Cl
H
R 2 = Ph
R 2 = Ph
R 2 = Ph
R 2 = CH 3
CH 3
OSiEt 3
Catalytic, Enantioselective RCM
CH 3
CH 3
CH 3
H OSiEt 3
H
CH3 OSiEt3 5 mol% 12-Mo
22 °C, 10 min
C 6H 6
5 mol% 12-Mo
22 °C, 2 h
C 6H 6
CH 3
CH 3
CH 3
H OSiEt 3
19%, >99% ee
H
CH3 OSiEt3 50%,

• The alkylidene catalysts 12-Mo and 13-Mo are very effective in catalytic, enantioselective
desymmetrization processes, especially in the case of secondary allylic ethers.
H 3C
O
R R
R = H
R = CH 3
O
O
CH 1-2 mol% 13-Mo
3
22 °C, 5 min
neat
H
H 3C
R
H 3C
O
85%, 93% ee
93%, 99% ee
• Remarkably, this catalytic, asymmetric RCM can be carried out in the absence of solvent,
with 20:1 de
Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124,
2868.
CH 3
catalyst
CH 3
H3C N
Ph
n
PhH, 22 °C
%mol
H3C N
Ph
n
n catalyst catalyst time yield ee
1
2
3
H 3C
O O
CH 3
12-Mo
12-Mo
15-Mo
5 mol% 14-Mo
PhH, 22 °C, 12 h
5
2
5
20 min
7 h
20 min
CH 3
41%, >98% conv.
83% ee O O
• 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.
78%
90%
93%
98%
95%
>98%
Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J Am. Chem. Soc. 2002, 124,
6991–6997.
M. Movassaghi and L. Blasdel

Catalytic RCM of Dienynes: Construction of Fused Bicyclic Rings
n m n m n m
L n[M]
R R
OSiEt 3
CH 3
OSiEt 3
R
R
H
CH 3
i-Pr
t-Bu
Ph
CO 2CH 3
Si(CH 3) 3
Sn(n-Bu) 3
Cl, Br, I
OSiEt 3
CH3 dienyne
RCM
95%
[M]L n
R R
• Fused [5.6.0], [5.7.0], [6.6.0], and [6.7.0] bicyclic rings have been successfully constructed
by RCM of dienynes.
3 mol% 2-Ru
25 °C, 8 h
0.06 M
CH 2Cl 2
• The dienyne RCM is largely favored over the competing diene RCM.
3-5 mol% 2-Ru
0.05-0.1 M
C 6D 6
yield (%) conditions
>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, 4 h
H 3C
OSiEt 3
R
diene
RCM

Enyne Metathesis Reactions Catalyzed by PtCl 2
PhO 2S
H
O
substrate product yield
Ts H
N
H
O
O OCH 3
SO 2Ph
CH 3O
O O H
H
TsN
PhO 2S
H
O
SO 2Ph
70%
54%
80%
a Reactions conducted in toluene at 80 °C using 4-10 mol% of PtCl2
• In most cases commercial PtCl 2 was used as received.
• A cationic reaction pathway, involving the complexation of cationic Pt(II) with the
alkyne, has been proposed.
• Remote alkenes are unaffected.
Fürstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785–6786.
96%
Enyne Metathesis in Synthesis
TBSO
H 3C
TBSO
H 3CO
OTBS
TBSO
OCH 3
40 mol% 3-Ru
ethylene, toluene, 45 °C
TBSO
H 3C
CH 3
31%
OTBS
H
O
H
O
H OHC
O
TBSO
CH 3
TBSO
OTBS
CH 3 OTBS
CH 3
O
CH 3
OCH 3
1. 50 mol% 3-Ru
ethylene, CH 2Cl 2, 40 °C
2. TBAF, THF, 0 → 23 °C
42% (two steps)
CH 3
OCH 3
(–)-Longithorone A
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775.
H 3C
CH 3
CH 3
H 3C
CO 2CH 3
CH 3
CH 3
12 mol% 4-Ru
H 3CO 2C
CH2Cl2, reflux, 3 h
CH3 82% H3C CH3 O
OHC
OH
AcO
H3C CH3 CH3 CH3 Guanacastepene A
Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817–1820.
CH 3
L. Blasdel and M. Movassaghi

Cross Metathesis
Olefin categorization and rules for selectivity
Selective Cross-Metathesis Reactions as a Function of Catalyst Structure:
Olefin type
Type I
(fast homodimerization)
Type II
(slow homodimerization)
Type III
(no homodimerization)
Type IV
(spectators to CM)
Type I – Rapid homodimerization, homodimers consumable
Type II – Slow homodimerization, homodimers sparingly consumable
Type III – No homodimerization
Type IV – Olefins inert to CM, but do not deactivate catalyst (spectator)
MesN
Cl
Cl
NMes
Ph
Ru
H
P(c-Hex) 3
Cl
Cl
P(c-Hex) 3
Ru
Ph
H
P(c-Hex) 3
4-Ru 3-Ru
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
styrenes (large ortho substit.), acrylates,
acrylamides, acrylic acid, acrolein, vinyl keones,
unprotected 3° allylic alcohols, vinyl epoxides, 2°
allylic alcohols, perfluoalkyl substituted olefins
1,1-disubstituted olefins, non-bulky trisub. olefins,
vinyl phosphonates, phenyl vinyl sulfone, 4° allylic
carbons (all alkyl substituents), 3° allylic alcohols
(protected)
vinyl nitro olefins, trisubstituted allyl alcohols
(protected)
terminal olefins, allyl silanes, 1° allylic alcohols,
ethers, esters, allyl boronate esters, allyl halides
styrene, 2° allylic alcohols, vinyl dioxolanes,
vinyl boronates
vinyl siloxanes
Reaction between two olefins of Type I................................... Statistical CM
Reaction between two olefins of same type (non-Type I)........ Non-selective CM
Reaction beween olefins of two different types....................... Selective CM
1,1-disubstituted olefins, disub a,b-unsaturated
carbonyls, 4° allylic carbon-containing olefins,
perfluorinated alkane olefins, 3° allyl amines
(protected)
i-Pr i-Pr
F3C O
F3C CH3 N
Mo
O
CH3 Ph
CH3 H
F3C F3C CH3 1-Mo
terminal olefins, allyl silanes
styrene, allyl stannanes
3° allyl amines, acrylonitrile
1,1-disubstituted olefins
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370. L. Blasdel

Non-selective Cross Metathesis: Two Type I Olefins
3
+
AcO
2 equiv
OAc
3 mol% catalyst
CH 2Cl 2, 40 °C, 12 h
80%
catalyst
3-Ru
4-Ru
• 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, 11360–11370.
E/Z
3.2 : 1
• Selectivity for the trans olefin can also be enhanced using sterically hindered substrates:
PhO
7 : 1
+ SiR3 2 mol% 1-Mo
PhO SiR3 3 DME, 23 °C, 4 h
3
R Yield E/Z
CH 3
Ph
72%
77%
Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 2117–2120.
• In addition, steric bulk can assist in favoring the cross metathesis reaction over
homodimerization pathways.
• 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.
AcO
+
CH3 OR
CH3 6 mol% 4-Ru
CH 2Cl 2, 40 °C, 12 h
80%
AcO
3
2.6 : 1
7.6 : 1
OAc
CH3 OR
CH3 R = H 58% yield
R = TBS 97% yield
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
Olefin 1 Olefin 2 product a,b
Secondary allylic alcohols (Type I with Type II)
BzO
HO
TBDPSO
CH 3
CH 3
3
3
OAc
OAc
Quaternary allylic olefins (Type I with Type III)
H 3C
HO
CH 3
2.0 equiv
O
H 3C
CH 3
O
1.0 equiv
3
3
3
OAc
OAc
OAc
1,1-Disubstituted olefins (Type I with Type III)
BzO
H 2N
HO
H
O
O
O
CH 3
CH 3
CH 3
CH 3
2.0 equiv
1.0 equiv
2.0 equiv
7
3
8
OAc
2.0 equiv
OTBS
1.2 equiv
CH 3
1.1 equiv
BzO
HO
TBDPSO
CH 3
CH 3
CH 3
H 3C CH 3
HO
O
H 3C
BzO
H 2N
HO
O
O
O
CH 3
CH 3
CH 3
OAc
Isolated
Yield (%) E/Z
82 10 : 1
50 c (62) d 14 : 1
53 6.7 : 1
93 >20 : 1
91 >20 : 1
80 4 : 1
71 > 20 : 1
23 4 : 1
O
H3C OAc
3 H
(OAc) 97 > 20 : 1
CH 3
3
CH3 1.0 equiv
7
3
3
3
3
8
3
OAc
3
OAc
OAc
OAc
OAc
OTBS
CH 3
a 3–5 mol% 4-Ru, CH2Cl 2, 40 °C. b See last reference on left half of this page.
c With 2 equiv Olefin 2, the yield was 92%. d Reaction was performed at 23 °C.
L. Blasdel

Olefin 1 Olefin 2 product a
Type II and Type III
HO
t-BuO
HO
EtO
H 3C
H 3C
F
O
O
O
O
F
F
CH 3
R
CH 3
CH 3
CH 3
CH 3
C(CH3) 3 HO
neat
C(CH3) 3 HO
neat
3
4.0 equiv
3
4.0 equiv
CH 3
CH 3
HO
HO
O
O
O
O
AcO OAc F
2.0 equiv
AcO OAc
2.0 equiv
O
OCH3 1.5–2.0 equiv
O
OEt
1.5–2.0 equiv
O
OEt
1.5–2.0 equiv
a 1–5 mol% 4-Ru, CH2Cl 2, 40 °C.
H 3C
F
C(CH 3) 3
C(CH 3) 3
C(CH 3) 3
C(CH 3) 3
OAc
OAc
CO 2CH 3
CH 3
CO 2Et
CO 2Et
Isolated
Yield (%) E/Z
73
73
83
55 R = H
83 R = CH 3
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
H 3C
F
CH 3
CH 3
98
50
92
87
5
2 : 1
2 : 1
2 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
>20 : 1
Selective Cross-Metathesis Reactions:
Type I
Type I
O
O N H
+
Si(CH 3) 3
1.5 equiv
O
Cl 3C N H
+
OTr
Si(CH 3) 3
1.5 equiv
OTr
Type IV
Type III
10 mol% 4-Ru
CH 2Cl 2, 40 °C, 4 h
10 mol% 1-Mo
CH 2Cl 2, 40 °C, 16 h
(H 3C) 3Si
Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446.
H
CbzHN CO 2CH 3
97% ee
+
+
NC R
R
CH 2Si(CH 3) 3
(CH 2) 3OBn
(CH 2) 2CO 2Bn
O
OTr
O
O N H
50% isolated yield
1.5 : 1 E/Z
OTr
Si(CH
Cl3C N
3) 3
H
98% isolated yield
>20 : 1 E/Z
(H 3C) 3Si
H
10 mol% 1-Mo
Si(CH3) 3 CbzHN CO2CH3 CH2Cl2, 8 h
reflux
95%, 92% ee
Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446.
5 mol% 1-Mo
23 °C, 3h
CH 2Cl 2
yield (%) E:Z
76
60
44
1:3
1:7.6
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.
NC
R
L. Blasdel and M. Movassaghi

Reagent preparation
A Horner–Wadsworth–Emmons reagent:
O
P
EtO EtO
A Suzuki reagent:
+
O
OEt
H 3C CH3
AcO
3
+
O
B
O
CH3 CH3 CH3 One-pot CM and allylboration reactions:
CH3 H3C H3C O
B
H3C O
2.0 equiv
+
2.0 equiv
4 mol% 4-Ru
CH 2Cl 2 40 °C, 12 h
87%
> 20 : 1 E/Z
5 mol% 4-Ru
CH 2Cl 2 40 °C, 12 h
58%,
>20 : 1 E/Z
1. 3 mol% 3-Ru
CH 2Cl 2 40 °C, 24 h
O
P
EtO EtO
Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7–10.
AcO 3
Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733–7736.
2. PhCHO (2 equiv), 23 °C
Yamamoto, Y.; Takahashi, M.; Miyaura, N. Synlett 2002, 128–130.
O
CH 3
OEt
H 3C CH3
O CH3 B
O CH3 Ph
OH
Ph
88 %
91 : 9 anti/syn
Examples in synthesis
• En route to the ABS ring fragment of thyrsiferol:
H 3C
H 3C
Br
O
H 3C
H 3C
Br
OAc
CH3 O
+
CH3 CH3 O
O
OAc
starting material homodimer
O
O
OBn
OBn
OBn
2
O
3.0 equiv
OTBS
McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593–595.
H
O
5 mol% 3-Ru
H 3C
H 3C
Br
CH 2Cl 2, 23 °C, 30 min
OBn
O OBn
H
OBn
95%
10 mol% 4-Ru
CH 2Cl 2, 45 °C
CH3 O
OAc
CH3 O
44% E-isomer
64% after recycling the homodimer
AcO
AcO
H
OAc
5.0 equiv
OAc
H
O
O
OBn
O OBn
H
OBn
H
H
O
OTBS
• CM can be difficult in the presence of strained olefins, as was found in the preparation of the
AB ring fragment of ciguatoxin:
AcO
compound A
OAc
H
19%
via ring opening to compound A
+
40 mol% 3-Ru
CH 2Cl 2, 40 °C
33 h
OBn
O OBn
H
OBn
8%
AB ring fragment of ciguatoxin
Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405–5408.
L. Blasdel

Ring Opening Cross-Metathesis:
CH 3O 2C
O
O
substrate product alkene a
O
O
CO 2CH 3
NBoc
O
O
CH 3OCH 2
O
Et
Et
CH 3OCH 2
O
CH 3O 2C
O
O
O
O
O
O
CO 2CH 3
O
NBoc
CH 2OCH 3
Et
Et
CH 2OCH 3
A
B
C
A 2 89 15 NA
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: C 6H 6 (entries 1 and 2) or
CH 2Cl 2 (entries 3 and 4). b Cat. = 2-Ru. c Cat. = 3-Ru.
O
mol %
cat. b time yield E,E:E,Z
6 96 94 2:1
2 14 85 2:1
8 c
3 73 1.5:1
• In these cases a preference for the E-olefin geometry is observed in ring opening
metathesis.
• Higher yields were achieved by the 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.
Enyne Cross-Metathesis
• 4-Ru outperforms 3-Ru in both rate and overall conversion in the cross-metathesis of
ethylene and alkynes.
AcO
CH 3
substrate product time (h) yield (%)
BnO
OAc
OR
Ph
CH 3
OAc
NTs
OH
AcO
CH 3
BnO
CH 3
OR
OAc
OAc
NTs
a Reactions conducted in CH2Cl 2 at 23 °C using 5 mol% of 4-Ru at 60 psi of
ethylene pressure.
Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271–2274.
R = H
R = Ac
R = TBS
Ph
2.0
2.0
8.5
16 77
4.0 69
4.0 91
OH
73
92
91
6.0 72
• 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
coordinatingfunctionality at the propargylic and homopropargylic positions.
• Chiral propargylic alcohols afford chiral diene products without loss of optical purity:
4-Ru (5 mol%)
ethylene (60 psi)
CH 2Cl 2, 23 °C
99% ee 99% ee
M. Movassaghi

Metathesis of Alkynes and 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.
RO
CH 3
t-Bu
N
CH3 CH3 t-Bu
Mo N
t-Bu
N
16-Mo
CH 3
CH 3
R CH 3
CH 3
CH 3
RX
CH 3
t-Bu
RO
N
CH3 CH3 Cl
t-Bu
Mo
N
N
t-Bu
CH 3
CH 3
X = Cl
X = Br
• Oxidation of the Mo(III)-precatalyst 16-Mo occurs in situ upon addition of ~25 equivalents of
additives such as CH 2Cl 2, CH 2Br 2, CH 2I 2, and BnCl.
• 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.
16-Mo (10 mol%)
CH 2Cl 2, Toluene
17-Mo (10 mol%)
CH 2Cl 2, Toluene
17-Mo,
18-Mo,
CH 3
R R
• Catalyst 17-Mo is sensitive to acidic protons such as those of secondary amides.
• Terminal alkynes are incompatible with the catalysts.
R = H,
R = CN,
R = CH 3,
R = THP,
60%
58%
59%
55%
• Use of CH 2Cl 2 as the reaction solvent or the addition of ~25 equivalents of CH 2Cl 2
per mol of 16-Mo in toluene are equally effective.
• 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.
OR
CH 3
RCM of Diynes
• Efficient synthesis of ≥12-membered rings containing internal alkynes can be
achieved with 17-Mo.
O
Ph
Ph
Si
CH 3
N
O
substrate
O
O
O
O
O(CH 2) 10
O(CH 2) 10
O(CH 2) 10
O(CH 2) 10
O O
O O
O(CH 2) 10
O
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
CH 3
Ph
Ph
CH 3
O
Si
O
O
O O
O O
O
O
O
product a
Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 9453–9454.
N
O
O
O
O
O
O
yield (%)
a Reactions conducted in toluene at 80 °C for 20-48h; 17-Mo was generated in situ
from 16-Mo and CH 2Cl 2 (~25 equiv).
88
82
74
83
91
M. Movassaghi

Synthesis of Cyclic β-Turn Analogs by RCM
H 3C
H
N
Boc
H3C H
H
N
Boc
H
O H3C CH3 N O
N H
O H N O
20 mol% 2-Ru
H
H
O H3C CH3 N O
N H
O H N O
N
H
CH2Cl2, 40 °C N
Bn
Boc
60%
N
H
Bn
• The presence of the Pro-Aib sequence in the tetrapeptide induces a β-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, 2108–2109.
Miller, S. J.; Grubbs, R. H. J. Am. Chem. Soc. 1995, 117, 5855-5856.
N
O
CH 3
CH 3
N O
H
O H N O
OBn
30 mol% 3-Ru
0.004 M, 21 h
CH 2Cl 2, 40 °C
60%
H 3C
H3C H
H
N
Boc
N
O
CH 3
CH 3
N O
H
O H N 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 byRCM.
Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606–9614.
OBn
Template-Directed RCM
O
O O
O
O
O
n
n = 1, 2
O
O
5 mol% 3-Ru
"template"
CH 2Cl 2, THF
45 °C, 1 h
0.02 M
substrate (n) "template" (equiv) yield (%) cis:trans
1
1
1
2
2
none
LiClO 4 (5)
NaClO 4 (5)
none
LiClO 4 (5)
39
>95
42
57
89
O
38:62
100:0
62:38
26:74
61:39
O
O
O O
O
n = 1, 2
• 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.
5 mol% 3-Ru
CH 2Cl 2
1.2 M, 23 °C
>95%
5 mol% 3-Ru
LiClO 4
CH 2Cl 2, THF
0.02 M, 50 °C
>95% (cis)
O
M n = 65900
n
cis : trans, 1 : 3.7
• 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.
O
m
M. Movassaghi

RCM-Mediated Covalent Capture
• The eight-residue cyclic peptide cyclo[-(L-Phe-D- Me N-Ala-L-HomoallylGly-D- Me N-Ala) 2 - ]
self-assembles to form two slow-exchanging antiparallel β-sheet-like hydrogen bonded
cylinders (K a(CDCl 3) = 99 M –1 , only the reactive isomer is shown).
Ph
O O
O
N
N
O
N
N
N
H
N
N
N
O H O
O H O H
Ph
O H O H
H O H O
N
N
N
N
N
N
N
N
O
O
O O
Ph Ph
20-25 mol% 2-Ru
CDCl 3, 23 °C, 48 h
65%
Ph
O O
O
N
N
O
N
N
N
H
N
N
N
O H O
O H O H
Ph
O H O H
H O H O
N
N
N
N
N
N
N
N
O
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 α-helical and
β-sheet peptide secondary structures.
Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12364–12365.
Synthesis of Catenanes
2
O
O
O
O
O
O
N
N
O O
O
N
N
N
N
O
O O
O
O
32-membered catenane
O
O
O
O
Cu(CH 3CN) 4PF 6
CH 2Cl 2, CH 3CN
100%
KCN, H 2O
CH 3CN
~100%
O
O
O
O
O
O
= Cu +
O
O
O
O
O
N
N
N
N
N
N
N
N
O
O
O
O O
trans:cis, 98:2
O
O
O
O
O
O
5 mol% 3-Ru
23 °C, 6 h
0.01 M, CH 2Cl 2
92%
• The remarkable efficiency of this RCM is proposed to be due to preorganization of the
substrate.
O
O
+ –
PF6 + PF –
6
Mohr, B.; Weck, M.; Sauvage, J.-P.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36,
1308–1310.
M. Movassaghi