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.


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


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.


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.


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.


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.


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


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


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).

24 olefin metathesis

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