Download - 24 Olefin Metathesis
The Olefin Metathesis Reaction Chem 215MyersReviews:
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.
nROMP
Ring-Opening Metathesis Polymerization (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).
H2C CH2RCM
Ring-Closing Metathesis (RCM):
• 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.
+
R1 R2R3 R4
R1 R3R2 R4
Cross Metathesis (CM):
+ +CM
• Self-dimerization reactions of the more valuable alkene may be minimized by the use of an excess of the more readily available alkene.
3-Ru (Grubbs' 1st
Generation Catalyst)
NMoO
O
i-Pr i-Pr
CH3
CH3Ph
H
F3C
CH3F3C
F3CCH3F3C 1-Mo
P(c-Hex)3Ru
P(c-Hex)3HCl
Cl
2-Ru
P(c-Hex)3Ru
P(c-Hex)3HClPhCl
Catalysts
• 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. • 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.
Ru
P(c-Hex)3HClPhCl
NMesMesN
4-Ru(Grubbs' 2nd
Generation Catalyst)
PhPh
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
σ π
M. Movassaghi
• 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.
Mechanism:
P
P
Ru
PHCl
HCl
CO2EtEtO2C
P
Ru
PHHCl
Cl
R
P
RuCl
Cl
R
H
H
P
RuCl
ClH
HR
H
P
RuCl
ClH
R
P
RuCl
ClH
H
P
Ru
PHHCl
Cl
R
P
RuCl
ClH
HR
H
P
Ru
PHCl
HClP
Ru
PHHCl
Cl
R
P
RuCl
ClH
RP
P
RuCl
ClH
H
EtO2C CO2Et
P
RuCl
Cl
EtO2C CO2Et
P
RuCl
Cl
EtO2C CO2Et
P
P
RuCl
ClH
H
EtO2C CO2Et
P
EtO2C CO2EtEtO2C CO2Et
P
Ru
PHHCl
Cl
EtO2C CO2Et
P = P(c-Hex)3
=
Dissociative:
Associative:
– C2H4
R
c-C5H6(CO2Et)2
R
– C2H4c-C5H6(CO2Et)2
P(c-Hex)3Ru
P(c-Hex)3HClHCl
CO2EtEtO2C
EtO2C CO2Et
5 mol%
CD2Cl2, 25 °C
Dias, E. L.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897.
• 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%).
–P
+P
N X
O
R
O Ph
O Ph
O
O Ph
O
Ph
NPhCH2 H
Cl–
O Ph
O
Ph
R
N X
O
O Ph
O
OPh
NCH2Ph
X = CF3
X = Ot-Bu9391
yield (%)aproductsubstrate time (h)
11
2 84
5 86
8 72
1 87
R = CO2H CH2OH CHO
878882
+ 4 mol% 2-Ru
20 °C, 36 hCH2Cl2; NaOH
79%
111
a2-4 mol% 2-Ru, C6H6, 20 °C.
• 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 (C6H6, CH2Cl2, 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.
Catalytic RCM of Dienes:
Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856–9857.
E E R
E E
CH3
E E
CH3
E E CH3CH3
E E
E E
CH3
CH3
E E
CH3
CH3
i-Prt-BuPhBrCH2OH
E E
CH3
H3C
E E
R
E E
CH3H3C
E E
CH3
EE
EE
CH3
No RCMd
NR
NR
No RCMd
M. Movassaghi
R = 9398
NR25
NR98
100 100 96 97
NRdecomp
yieldwith 3-Ru (%)b
yieldwith 1-Mo (%)cproductsubstratea
97 100
96 100
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.
93
61
96e 100e
Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM
Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310–7318.
• Functional group compatibility permitting, the Mo-alkylidene catalyst is typically more effective for RCM of substituted olefins.
–
OSi
R
H3C CH3
R RR R
O
OSiH3C CH3
R
CH3
H
O RRR R
ROH
HO
Geminal Substitution
<1 mol% 1-Mo
25 °C, 0.5-1 hneat
R = 0%; (polymerization)95%
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.
• "Thorpe-Ingold" effects favor cyclization with gem-disubstituted substrates.
n
m
n
m
2-5 mol% 1-Mo or 3-Ru
C6H6, CH2Cl223 °C, 0.5-5 h
73-96%
mnKF
H2O2
80-93 %
RCM of Temporarily Connected Dienes
m = 1-3, n = 0-2
• 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.
• RCM of silicon-tethered alkenes is very efficient even at higher concentrations (0.15 M with catalyst 3-Ru).
Chang. S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757–4760.
O
N2
H3C CH3
BnO H
TBSO H
TsN
TsN
TBSO H
BnO H
NTs
NTs
O Ru
CH3
H3C
H
PPh3
Cl ClO Ru
CH3
H3C
H
P(c-Hex)3
Cl Cl
5-Ru
M. Movassaghi
A Recyclable Ru-Based Metathesis Catalyst
RuCl2(PPh3)3
CH2Cl2, –78 °C
90%
P(c-Hex)3 (2 equiv)
CH2Cl2
75%
substrate producta time (h) yield (%)brecovered
catalyst (%)b
0.5 90 75
2.0 95 89
1.0 72 88
1.0 99 88
a5 mol% 5-Ru, CH2Cl2, Ar Atm. bIsolated yield after chromatography on silica gel.
temp. (°C)
22
22
40
40
• Catalyst 5-Ru exhibitsexcellent stability toward air and moisture and can be recycled in high yield by chromatography on silica gel.
Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799.
RLnRu
R
R
LnRuR
RuLnPh
6-Ru7-Ru
6-Ru7-Ru
EE
7-Ru
EE
PhEE
6-Ru7-Ru
Cl–
EE
CH3
PhEE
6-Ru7-Ru
PhEE CH3
NBoc
PRuP
HClPhCl
N
N
H3C
CH3
CH3
H3C
7-Ru7-Ru7-Ru
NBoc
N PhBoc
Cl–
PRuP
HClPhClN(CH3)3+Cl–
N(CH3)3+Cl–
N(CH3)3+Cl–
NBoc
Ph
7-Ru
Ph
N(CH3)3+Cl–
P(c-Hex)3Ru
P(c-Hex)3HCl
PhCl
6-Ru
3-Ru
Cl–
CO2EtEtO2C
NHH
Cl–
CH2Cl2CH3OH
N RHH
CO2EtEtO2C
LnRu RHLnRu Ph
H
Ph
M. Movassaghi
RCM in Methanol and Water
+
+
5 mol% 3-Ru
23 °C
100%<5%
methylidene,benzylidene,
R = HR = Ph
• 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.
• 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.
++
substratea productb solvent catalyst
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.
• 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.
methanol
conversionc
8095
methanol 45d
55d
methanol >95
methanol
methanol
4090e
30>95f
methanolwaterwater
906090g
Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904–9909.
5 mol% 3-Ru
CH2Cl2R = HR = Ph
60%100%
solvent:
Stabilization of Ru-Carbene Intermediates by Phenyl Substitution
• first turnover step of RCM:
NNMes MesNN MesMes NN MesMes
Ru
P(c-Hex)3HClPhCl
Ru
P(c-Hex)3HClPhCl
Ru
P(c-Hex)3HClPhCl
8-Ru 4-Ru 9-Ru
3-Ru 8-Ru1-Mo 4-Ru 9-Ru
E E
t-Bu
E E t-Bu
E E
CH3H3C
E E CH3CH3
E E
CH3
H3C
E E
CH3
CH3
NAH OHH OH
M. Movassaghi
substratea producttime(h)
1 37
yield of product (%) using catalyst:b
0 100 100 100
1.5 52 0 95 90 87
0.2 0 0 100 100
24 93 0 31 5540c
aE = CO2Et. b5 mol% of catalyst, CD2Cl2, reflux. c1.5 h.
• 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.
NHC Ruthenium Catalysts:
O
O
O
O
CH2
CH2
O
O CH2
CH2 O
O
O
O
O
OCH2
CH2
O
OCH3O CH3
O
CH2
CH2
OO
RCM of functionalized dienes
49
0
97
86
Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783–3784.
diene product yield (%)
• 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
aReactions conducted with 5 mol% 10-Ru.
93
products are observed if vinyl ethers alone are present.
excellent yields.
NN MesMes
Ru
P(c-Hex)3HCl
Cl
10-Ru
CH3CH3
ON
Bn
O
O
N
OBnO
BnOBnO CO2CH3
H
N
OBnO
BnOBnO H
ON
Bn
O
O OH
NHO
HOHO H OH
ON
Bn
O
O OH
Castanospermine
5 mol% 2-Ru
110 °C, 48 h
70%
Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547–550.
1. n-Bu2BOTf, Et3N CH2Cl2, 0 °C
2. CH2=CHCHO –78 → 0 °C
82%, >99% de
1 mol% 3-RuCH2Cl2
97%
Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192–4193.
RCM Applications in Synthesis:
O
O CH3
HH
MOMO
MOMO
O
O O
O CH3
HH
MOMO
MOMO
O
O
O
O CH3
ClHO
OH
HO
OCl
Pochonin C
5 mol% 4-Ru
toluene, 120 °C10 min
87%
O
O CH3MOMO
MOMO
O
O
O CH3MOMO
MOMO
5 mol% 4-Ru
toluene, 120 °C10 min
21%
HH
O
O
HH
O
• 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
O
3
TBSO
H3C
OPMB
O O
O
RuLn
TBSO
H3C
OPMB
O
O
OTBSO OPMB
O
10 mol% 5-RuCH2Cl2, 40 °C
• 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.
Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Angew. Chem. Int. Ed. 2004, 43, 3601–3605.
71%
trans epoxide
cis epoxide
L. Blasdel and M. Movassaghi
Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210–10211.
N
N
H
O
Ph
CO2CH3
OH
N
NO
H CH2OTDS
OO
DN
N
H
O
N NH
OH
N
N
H
O
Ph
CO2CH3
OH
N
NO
H CH2OTDS
OO
100 mol% 2-Ru
23 °C, 5 dC6D6
30%
Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35, 3191–3194.
5 mol% 1-Mo
50 °C, 4 hC6H6
63%
Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691–694.
EManzamine A
• The use of RCM in construction of both the D and the E rings of Manzamine A has been reported:
N
OH3C
H
O
CH3
CH3
O
CH3OAc
NHCOCF3OAcH
H
N
OH3C
H
O
CH3
CH3
O
CH3OAc
NHCOCF3OAcH
H
20 mol% 1-Mo
22 °C, 10 hC6H6
91%
• 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.
O
H3C
OP
OCH3O
O CH3
CH3
CH3
CH2H3C
O
H3C
OP
O O
OCH3CH3
CH3
CH3
CH2H3C
86% 10 mol% 4-RuCH2Cl2, 40 °C
80%
O
CH3
PO CH3OO
OCH3
CH3
CH3
O
PO OOCH3
OCH3
CH3
CH3
CH3
P = p-BrBz
O
CH3
OHC OHO
OCH3
CH3
CH3
O
OHC OHO
OCH3
CH3
CH3
CH3
Coleophomone B Coleophomone C
Slight changes in substrate structure can control whether the E- or Z-olefin is formed:
E-olefin only Z-olefin only
Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872–8888.
M. Movassaghi and L. Blasdel
H3CO
CH3H3C
OR2
R1O CH3
O
CH3
O
N
SCH3
H
H3CO
CH3H3C
OR2
R1O CH3
O
CH3
O
N
SCH3
H
Synthesis of Epothilone C:
R1 R2 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
50 mol%, PhH, 55 °C
6 mol%, CH2Cl2, 25 °C
10 mol%, CH2Cl2, 25 °C
65 %
85%
94%
86%
2 : 1
1 : 1.2
1 : 1.7
1 : 1.7
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.
H3CO
CH3H3C
OTBS
HO CH3
O
CH3
O
N
SCH3
O
CH3HO
H3C O
TBSO
H3CH3C O
CH3
N
SCH3
H3CO
CH3H3C
OTBS
HO CH3
O
CH3
O
N
SCH3
O
O
CH3HO
H3C O
TBSO
H3CH3C
O
CH3
N
SCH3
H3CO
CH3H3C
OTBS
HO CH3
O
CH3
O
N
SCH3
M. Movassaghi and L. Blasdel
Solid-Phase Synthesis of Epothilone A:
= Merrifield resin
3-Ru (0.75 equiv)25 °C, 48 h
CH2Cl2
15.6% 15.6%
15.6%5.2%
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.
• 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.
• Small changes can drastically affect reaction outcome. In the example below, TBS protective groups changes the E/Z selectivity.
O Ph
O
CH3
O
OPh
O O
O
CH3
O
BnOH
H
R
H
CH3
OPh
CH3
O Ph
CH3
HCH3
O
O O
BnOH
H
R
H
TiCH2
ClAl
CH3
CH3
OPh
OPh
R = 50%54%
Tebbe reagent(4.0 equiv)
THF, 25 °C, 0.5 h;reflux, 4h
Tandem Olefination-Metathesis
Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335-10336.
• Here, a Ti-alkylidene is used in RCM.
Catalytic RCM of Olefinic Enol Ethers:
• 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.
12 mol% 1-Mo
20 °C, 3.5 hn-pentane
88%
12 mol% 1-Mo
20 °C, 7 hn-pentane
87%
CH3CHBr2, TiCl4
Zn, TMEDA,cat. PbCl2, 20 °C, 11 h
THF
55%
CH3CHBr2, TiCl4
Zn, TMEDA,cat. PbCl2, 20 °C, 5 h
THF
79%
Tebbe reagent
OO H H OO H H
OO H H OO H H
OO H H OO H H
OO
OO
H H
H H
OO
H
HOO H H
OOH H
R R OO
H
H
HH
CH3
substrate productyield(%)
82
90
6 mol% 3-Ru
C6H6, 45 °C6 h
70
68
92
Tandem Ring Opening-Ring Closing Metathesis of Cyclic Olefins
• Without sufficient ring strain in the starting cyclic olefin, competing oligomerization (via CM) can occur.
• Higher dilution favors intramolecular reaction:
0.12 M0.008 M
0.2 M
16%73%42%
• The relative rate of intramolecular metathesis versus CM may be further increased by substitution of the acyclic olefin.
R =
3
5
3
6
5
1.5
2
6
2
3
45
60
45
45
60
0.1
0.1
0.07
0.04
0.04
catalyst 3-Ru(mol %)
conc.(M)
time(h)
temp.(°C)
M. Movassaghi
LnRu CHPh
OO H H
Ph
H2C CH2OO
LnRuH H
OO H H
OHO
RuLn
H
LnRu CH2
OO H H O H H
RuLn
O
O N
O N
CH3
CH3
N
NO
O
CH3
CH3
O O
O O
O
O
10 mol% 3-Ru
0.1 M, C6D640 °C, 8 h
95%
unreactive substrates:
Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634–6640.
Proposed Mechanism for Ring Opening-Ring Closing Metathesis:
• 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.
Examples in Complex Synthesis:
CH3
CH3H3C
O
2 mol% 3-Ruethylene
98%
CH3
CH3H3C
O
CH3
CH3H3C
O
O
O OPMB
O
OPMBH
O
OH
CH3
CH3H3C
25 mol% 5-Rutoluene, Δ
76%O
OHHO
H3C H
CH3
CH3H3C
HOHO
Ingenol
Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc. 2004, 126, 16300–16301.
H3C
OO
CH3
OH
H3C CH3
OH20 mol% 4-Ru
ethylene, toluene
43% (3 steps)
H
H3C CH3
OHHH3C CH3
O
CH3
Cyanthiwigin U
Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–5335.
M. Movassaghi and L. Blasdel
CH3CH3
Et3SiO
CH3
N
MoOO
CF3CF3
F3CF3C
ArOSiEt3
HH3C
H
CH3CH3
Et3SiO
CH3
N
MoOO
CF3CF3
F3CF3C
ArH
OSiEt3H3C
H
NMoO
O
i-Pr i-Pr
Ph
CH3CH3
HCF3
CF3
F3CF3C
11-Mo
Et3SiOCH3
+
Ar = 2,6-(i-Pr)2C6H3
FAVOREDDISFAVORED
Proposed Transition State Models for the Observed Selectivity
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.
Kinetic Resolution via Asymmetric RCM
2 mol% 11-Mo
–20 °C, 660 mintoluene
38%, 48% ee 62%
• The first catalytic, asymmetric kinetic resolution via RCM was achieved, with low selectivity, using the chiral alkylidene 11-Mo.
CH3
CH3
H OSiEt3
CH3
CH3 OSiEt3H
CH3
CH3
H OSiEt3
CH3
CH3 OSiEt3H
CH3
H OSiEt3
CH3
HOSiEt3
NMo
OO
R1 R1
CH3
CH3R2
H
t-Bu
t-BuCH3
CH3
H3C
H3C
Catalytic, Enantioselective RCM
Alexander, J. B.; La, D. S.; Cefalo, D. R. Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 4041–4042.
+5 mol% 12-Mo
22 °C, 10 minC6H6
+5 mol% 12-Mo
22 °C, 2 hC6H6
43%, 93% ee19%, >99% ee
40%, <5% ee50%, <5% ee
• Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutane intermediates and not during the initial metathesis step.
12-Mo: R1 = i-Pr 13-Mo: R1 = CH3 14-Mo: R1 = Cl15-Mo: R1 = Cl
Mo-alkylidene Catalyzed Kinetic Resolution and Enantioselective Desymmetrization via RCM
H3CO
RH H3C
O
RH
O
H3C
HR
R
n-C5H11
i-C4H9
c-C6H11
c-C6H11
C6H5
+5 mol% 12-Mo
C6H5CH3
temp. (°C) time (h) conv. (%)recovered SM ee (%) krel
–25
–25
–25
22
–25
6
10
7
0.1
6
63
56
62
64
56
92
95
98
97
75
10
23
17
13
8
O
n-C5H11
H
H3C
H3CO
C6H5
CH3
• Increasing the size of the α-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.
M. Movassaghi
R2 = PhR2 = PhR2 = PhR2 = CH3
CH3H3CO
R R
O
O
O
H3CH
H3C
R
O
O
1-2 mol% 13-Mo
22 °C, 5 minneat
R = H R = CH3
85%, 93% ee93%, 99% ee
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.
• 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.
• The alkylidene catalysts 12-Mo and 13-Mo are very effective in catalytic, enantioselective desymmetrization processes, especially in the case of secondary allylic ethers.
5 mol% 13-Mo
–20 °C, 18 hC6H5CH3
91%, 82% ee
5 mol% 13-Mo
–20 °C, 18 hC6H5CH3
84%, 73% 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, 4041–4042.
• Desymmetrization metathesis reactions have been used to make a variety of heteroatom- containing products:
H3C
Ph O Si CH3CH3
H3C
5 mol% 12-Mo
CH2Cl2, 22 °C, 6 h
92%93% ee
O Si
H3C
Ph
H3C CH3
CH3
H3C
Ph OH CH3OH
1. m-CPBA2. n-Bu4NF
86% two steps93% ee
>20:1 de
Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868.
H3C NPh
CH3
n
catalyst
PhH, 22 °CH3C N
Ph
CH3
n
n catalyst time yield ee
1
2
3
12-Mo
12-Mo
15-Mo
20 min
7 h
20 min
78%
90%
93%
98%
95%
>98%
%molcatalyst
5
2
5
O O
H3CCH3 5 mol% 14-Mo
PhH, 22 °C, 12 h
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.
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
CH3
R R
Ln[M] [M]Ln
R R
n m n m n m n m
CH3
OSiEt3
R
OSiEt3
CH3
OSiEt3
HCH3i-Prt-BuPhCO2CH3Si(CH3)3Sn(n-Bu)3Cl, Br, I
R
R
OSiEt3
OSiEt3
H3C
Catalytic RCM of Dienynes: Construction of Fused Bicyclic Rings
diene RCM<3%
dienyne RCM95%
3 mol% 2-Ru
25 °C, 8 h0.06 MCH2Cl2
+
• Fused [5.6.0], [5.7.0], [6.6.0], and [6.7.0] bicyclic rings have been successfully constructed by RCM of dienynes.
• The dienyne RCM is largely favored over the competing diene RCM.
3-5 mol% 2-Ru
0.05-0.1 M C6D6
yield (%) conditions
>98 95 78 NR 96 82 NR NR NR
23 °C, 15 min23 °C, 8 h60 °C, 4 h
60 °C, 3 h60 °C, 4 h
• Mo-, W- or Ti-based catalysts are not effective for the above transformations.
• Reaction rates decrease as the size of the acetylene substituent increases.
• Substrates containing heteroatoms directly attached to the acetylene do not cyclize.
CH3
OSiEt3
RuLn
RuLn
CH3
OSiEt3
CH3
OSiEt3
CH3
OSiEt3
CH3
O
CH3
CH3
CH3
CH3
OSiEt3
CH3
CH3
OSiEt3
H3C
LnRu
OSiEt3
CH3
CH3
OSiEt3
O
CH3
CH3
OSiEt3
CH3
CH3
OSiEt3
CH3
CH3
OSiEt3
CH3
OSiEt3
OSiEt3
CH3
LnRu
CH3
OSiEt3
RuLn
LnRu
OSiEt3
CH3
M. Movassaghi
substrate productyield (%)
88
83
78
89
88
• 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:
86%, 1:1Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073–1081.
mol% 2-Ru
time (h)
conc. (M)
6
3
15
15
3
8
6
1.5
12
6
0.06
0.03
0.01
0.05
0.05
temp.(°C)
65
65
100
65
65
Enyne Metathesis in Synthesis
TBSO
OCH3OTBS
TBSO
40 mol% 3-Ruethylene, toluene, 45 °C
OTBSH3COHTBSO
TBSO
H3C
CH3
TBSO
OCH3OTBSCH3
CH3
OCH3TBSO
CH3
CH3 OTBS
1. 50 mol% 3-Ru ethylene, CH2Cl2, 40 °C2. TBAF, THF, 0 → 23 °C
42% (two steps)31%
OO
CH3
OHCH
HOO
H3C
(–)-Longithorone A
Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775.
CH3
CH3
CO2CH3
H3C
CH3CH3
H3C
12 mol% 4-Ru
CH2Cl2, reflux, 3 h
82% CH3H3C
CH3
H3CO2C
CH3
CH3H3C
CH3
OHC
CH3
OHO
AcO
Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817–1820.
Guanacastepene A
OH
SO2PhPhO2S
OH
TsN
H
OH
O OCH3
O
CH3O
O H
TsNH
SO2PhPhO2S
Enyne Metathesis Reactions Catalyzed by PtCl2
70%
54%
80%
substrate product yield
• 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.
• Remote alkenes are unaffected.
aReactions conducted in toluene at 80 °C using 4-10 mol% of PtCl2
96%
Fürstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785–6786.
L. Blasdel and M. Movassaghi
Cross Metathesis
Selective Cross-Metathesis Reactions as a Function of Catalyst Structure:
Olefin type
RuP(c-Hex)3
HClPhCl
NMesMesNP(c-Hex)3
RuP(c-Hex)3
HClPhCl N
MoO
O
i-Pr i-Pr
CH3
CH3
Ph
H
F3C
CH3F3C
F3CCH3F3C 1-Mo4-Ru 3-Ru
Type I(fast homodimerization)
Type II(slow homodimerization)
Type III(no homodimerization)
Type IV(spectators to CM)
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
1,1-disubstituted olefins, disub a,b-unsaturated carbonyls, 4° allylic carbon-containing olefins, perfluorinated alkane olefins, 3° allyl amines (protected)
terminal olefins, allyl silanes
styrene, allyl stannanes
3° allyl amines, acrylonitrile
1,1-disubstituted olefins
Olefin categorization and rules for selectivity
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)
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
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370. L. Blasdel
3
Non-selective Cross Metathesis: Two Type I Olefins
OAcAcO3 mol% catalyst
CH2Cl2, 40 °C, 12 h
80%
OAc+
2 equivE/Z
3.2 : 1
7 : 1
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.
catalyst
• Selectivity for the trans olefin can also be enhanced using sterically hindered substrates:
PhO SiR32 mol% 1-Mo
DME, 23 °C, 4 hPhO SiR3+
R Yield E/ZCH3
Ph
72%
77%
2.6 : 1
7.6 : 1
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370.
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
3 3
CH3
CH3OR+
6 mol% 4-Ru
CH2Cl2, 40 °C, 12 h
80%
3AcO
CH3
CH3OR
R = H 58% yieldR = TBS 97% yield
Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370.
Secondary allylic alcohols (Type I with Type II)
Olefin 1 Olefin 2 producta,bIsolated Yield (%) E/Z
BzO
CH3 OAc3
82 10 : 1
TBDPSO
CH3 OAc3 53 6.7 : 1
Quaternary allylic olefins (Type I with Type III)
HO
H3COAc
3 93 >20 : 1
HO
CH3 OAc3
50c (62)d 14 : 1
CH3
H3COAc
391 >20 : 1OO
1,1-Disubstituted olefins (Type I with Type III)
H2N
O
CH3
OTBS7
71 > 20 : 1
HO
O
CH3
CH3823 4 : 1
H
O
CH3
OAc3 97 > 20 : 1
H3C
CH3
BzO OAc3 80 4 : 1
CH3
2.0 equiv
1.0 equiv
2.0 equiv
2.0 equiv
1.0 equiv
2.0 equiv
1.2 equiv
1.1 equiv
1.0 equiv
OAc3
BzO
CH3
OAc3
HO
CH3
OAc3
TBDPSO
CH3
HO
H3C CH3
OAc
H3COO
OAc
H2N
O
CH3
HO
O
CH3
H
O
CH3
BzOCH3
OAc
OTBS
CH3
(OAc)
3
3
3
7
8
3
a 3–5 mol% 4-Ru, CH2Cl2, 40 °C. b See last reference on left half of this page. c With 2 equiv Olefin 2, the yield was 92%. dReaction was performed at 23 °C. L. Blasdel
Olefin 1 Olefin 2 productaIsolated Yield (%) E/Z
Type II and Type III
HO
OC(CH3)3 HO
O
C(CH3)373
t-BuO
OC(CH3)3 HO
O
C(CH3)373
neat
neat
HO
O
HO
O
C(CH3)383
CH3
CH33 2 : 1
EtO
O
HO
O
C(CH3)355 R = H83 R = CH3
CH3
R CH332 : 12 : 1
4.0 equiv
4.0 equiv
FAcO OAc F
OAc2.0 equiv98 >20 : 1
FAcO OAc
F
OAc2.0 equiv
50 >20 : 1
F
CO2CH3
1.5–2.0 equiv
92 >20 : 1OCH3
O
CO2Et
1.5–2.0 equiv
87 >20 : 1OEt
O
CH3H3C CH3H3C
CO2Et
1.5–2.0 equiv
5 >20 : 1OEt
O
CH3H3C CH3H3C
CH3CH3
a 1–5 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.
O NH
O OTr
Si(CH3)3
Selective Cross-Metathesis Reactions:
O NH
O OTr
(H3C)3Si
Cl3C NH
O OTr
Si(CH3)3
+
10 mol% 1-Mo
CH2Cl2, 40 °C, 16 h
10 mol% 4-Ru
CH2Cl2, 40 °C, 4 h
50% isolated yield1.5 : 1 E/Z
98% isolated yield>20 : 1 E/Z
Cl3C NH
O OTr
Si(CH3)3
+
Type IV
Type I
Type I
Type III
1.5 equiv
1.5 equiv
Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446.
CbzHN CO2CH3
HSi(CH3)3 CbzHN CO2CH3
H
(H3C)3Si
10 mol% 1-Mo
CH2Cl2, 8 hreflux
+
95%, 92% ee97% ee
NC R
R
CH2Si(CH3)3(CH2)3OBn(CH2)2CO2Bn
NC R+5 mol% 1-Mo
23 °C, 3hCH2Cl2
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.
Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446.
L. Blasdel and M. Movassaghi
F
Reagent preparation
OPEtO
EtO OEt
O+
4 mol% 4-Ru
CH2Cl2 40 °C, 12 h
87%> 20 : 1 E/Z
OPEtO
EtO OEt
O
AcO B
CH3
O
O CH3
CH3
H3C CH3
+3
5 mol% 4-RuCH2Cl2 40 °C, 12 h
58%, >20 : 1 E/Z
B
CH3
O
O CH3
CH3
H3C CH3
AcO 3
BO
OH3CH3C
CH3H3C+
1. 3 mol% 3-Ru CH2Cl2 40 °C, 24 h
2. PhCHO (2 equiv), 23 °C PhPh
OH
A Horner–Wadsworth–Emmons reagent:
A Suzuki reagent:
One-pot CM and allylboration reactions:
88 %91 : 9 anti/syn
2.0 equiv
Yamamoto, Y.; Takahashi, M.; Miyaura, N. Synlett 2002, 128–130.
2.0 equiv
Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733–7736.
Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7–10.
Examples in synthesis
OOAc
OH3CH3C
Br
CH3
AcOOAc
10 mol% 4-RuCH2Cl2, 45 °C
3.0 equiv
OTBSO
+
OOAc
OH3CH3C
Br
CH3
CH3
OTBSOO
OAcOH3C
H3C
Br
CH3
CH3
2
44% E-isomer64% after recycling the homodimerstarting material homodimer
L. Blasdel
O
O
OBn
OBnOBn
O
O
OBn
OBnOBnH
H5 mol% 3-Ru
CH2Cl2, 23 °C, 30 min
95%H
O
O
OBn
OBnOBnH
H
HOAc
AcO
5.0 equiv
40 mol% 3-RuCH2Cl2, 40 °C
33 h
O
O
OBn
OBnOBnH
H
HOAcAcO
+
8%19%via ring opening to compound A
compound A
• CM can be difficult in the presence of strained olefins, as was found in the preparation of the AB ring fragment of ciguatoxin:
Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405–5408.
McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593–595.
AB ring fragment of ciguatoxin
• En route to the ABS ring fragment of thyrsiferol:
CH3
OAc
CH3 NTs
AcO
OAc
OR
BnO
Ph
OH
OAc
AcO
CH3 NTs
CH3
OAc
OR
BnO
Ph
OH
Enyne Cross-Metathesis
substrate product yield (%)
Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271–2274.
aReactions conducted in CH2Cl2 at 23 °C using 5 mol% of 4-Ru at 60 psi of ethylene pressure.
16 77
4.0 69
4.0 91
R = HR = AcR = TBS
2.02.08.5
739291
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 outperforms 3-Ru in both rate and overall conversion in the cross-metathesis of
time (h)
4-Ru (5 mol%)
ethylene (60 psi)CH2Cl2, 23 °C
99% ee 99% ee
ethylene and alkynes.
CO2CH3CH3O2CA
CH2OCH3CH3OCH2
CO2CH3CH3O2C
O OO
B
EtEt
O OO
NBocO
C
EtEt
NBocO
O
O OO
A NAO CH2OCH3CH3OCH2
O OO
6 9496 2:1
2 8514 2:1
8c 733 1.5:1
2 89 15
substrate product alkeneamol % cat.b yieldtime E,E:E,Z
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.
• 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.
Ring Opening Cross-Metathesis:
M. Movassaghi
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.
RO
CH3
R CH3
N Mo N
N
t-Bu
CH3
CH3
CH3CH3
CH3
t-But-Bu
CH3
16-Mo
RXN Mo N
N
t-Bu
CH3
CH3
CH3CH3
CH3
t-But-Bu
CH3
Cl
RO
OR
R R
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.
X = ClX = Br
• 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.
• 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.
17-Mo,18-Mo,
• Catalyst 17-Mo is sensitive to acidic protons such as those of secondary amides.
• 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.
• 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.
16-Mo (10 mol%)
CH2Cl2, TolueneR = H, R = CN,
17-Mo (10 mol%)
CH2Cl2, Toluene
R = CH3, R = THP,
60%58%
59%55%
O(CH2)10
O(CH2)10
SiPh
Ph
O(CH2)10
O(CH2)10
O
O
O
O(CH2)10CH3
N
O
O
O
O
CH3
CH3
O O
O O
CH3 CH3
CH3
CH3
CH3
CH3
CH3
O O
O O
O
O
SiPh
Ph
O
O
N
O
O
O
O
O
O
O
O
Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 9453–9454.
RCM of Diynes
• Efficient synthesis of ≥12-membered rings containing internal alkynes can be
yield (%)productasubstrate
88
82
91
74
83
aReactions conducted in toluene at 80 °C for 20-48h; 17-Mo was generated in situ from 16-Mo and CH2Cl2 (~25 equiv).
achieved with 17-Mo.
M. Movassaghi
ON
N O
N OH
O
HH
NH
Boc
CH3
CH3H3C
H3C
OBn
ON
NH O
N O
N
O
H
HBn
NH
Boc
H CH3H3C
ON
NH O
N O
N
O
H
HBn
NH
Boc
H CH3H3C
ON
N O
N OH
O
HH
NH
Boc
CH3
CH3H3C
H3C
OBn
20 mol% 2-Ru
CH2Cl2, 40 °C
60%
30 mol% 3-Ru
0.004 M, 21 hCH2Cl2, 40 °C
60%
Synthesis of Cyclic β-Turn Analogs by RCM
• 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.
• 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.; 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.
Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606–9614.
O
O O
O
O O O O
O O O O
OO O
O
M. Movassaghi
n = 1, 2n = 1, 2
nn
5 mol% 3-Ru"template"
CH2Cl2, THF45 °C, 1 h
0.02 M
substrate (n) "template" (equiv) yield (%) cis:trans
11122
noneLiClO4 (5)NaClO4 (5)none LiClO4 (5)
39>95 42 57 89
38:62100:0 62:38 26:74 61:39
Template-Directed RCM
• 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.
m
5 mol% 3-Ru
CH2Cl21.2 M, 23 °C
>95%
Mn = 65900
cis : trans, 1 : 3.7
5 mol% 3-RuLiClO4
CH2Cl2, THF0.02 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.
Marsella, M. J.; Maynard, H. D.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1101–1103.
N N N NO H O H
O O
ONHOH
NN N N NN N
O H O H
O OO OPh Ph
ONHOH
N N NO O
Ph Ph
NN
OO
OOO O
NN
OO
OOO O
NN
O
OO
O
OO
N N N NO H O H
O O
ONHOH
NN N N NN N
O H O H
O OO OPh Ph
ONHOH
N N NO O
Ph Ph
NN
O
OO
NN
O
OO
O
OO
NN
OO
OOO O
NN
O
OO
O
OO
O
OO
PF6–
PF6–
M. Movassaghi
Synthesis of Catenanes
Mohr, B.; Weck, M.; Sauvage, J.-P.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1308–1310.
2Cu(CH3CN)4PF6
CH2Cl2, CH3CN
100%
= Cu+
5 mol% 3-Ru23 °C, 6 h
0.01 M, CH2Cl2
92%
trans:cis, 98:2
KCN, H2O
CH3CN
~100%
• The remarkable efficiency of this RCM is proposed to be due to preorganization of the substrate.
32-membered catenane
+
+
20-25 mol% 2-RuCDCl3, 23 °C, 48 h
65%
Clark, T. D.; Ghadiri, M. R. J. Am. Chem. Soc. 1995, 117, 12364–12365.
RCM-Mediated Covalent Capture
• 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 38- membered 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.
• 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 β-sheet-like hydrogen bonded cylinders (Ka(CDCl3) = 99 M–1, only the reactive isomer is shown).