Myers

Reviews:

The Olefin Metathesis Reaction

Cross Metathesis (CM): R1 R2 + R3 R4 CM R1 R3 +

Chem 215
R4

Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 44904527. Grubbs, R. H. Tetrahedron 2004, 60, 71177140. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 1136011370. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 19001923. Frstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 30133043. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 44134450. Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371388.

R2

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
F3C F3C N O Mo

i-Pr
CH3 Ph CH3 Cl Cl

MesN P(c-Hex)3 Ru H P(c-Hex)3 2-Ru Ph Ph P(c-Hex)3 Cl Ph Ru Cl H P(c-Hex)3 Cl Cl Ru

NMes Ph

Ring-Opening Metathesis Polymerization (ROMP): ROMP

CH3 O H F3C CH 3 1-Mo F3C

H P(c-Hex)3

3-Ru (Grubbs' 1st Generation Catalyst)

4-Ru (Grubbs' 2nd Generation Catalyst)

ROMP is thermodynamically favored for strained ring systems, such as 3-, 4-, 8- and larger-membered compounds. When bridging groups are present (bicyclic olefins) the !G of polymerization is typically more negative as a result of increased strain energy in the monomer. Block copolymers can be made by sequential addition of different monomers (a consequence of the "living" nature of the polymerization).

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

Ring-Closing Metathesis (RCM): RCM

H2C

CH2

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

Mechanism:

Dissociative:

P = P(c-Hex)3 EtO2C CO2Et R = P H Cl Ru R Cl H H H R P Cl Ru

The olefin metathesis reaction was reported as early as 1955 in a Ti(II)-catalyzed polymerization of norbornene: Anderson, A. W.; Merckling, M. G. Chem. Abstr. 1955, 50, 3008i. 15 years later, Chauvin first proposed that olefin metathesis proceeds via metallacyclobutanes: Herisson, P. J.-L.; Chauvin, Y. Makromol. Chem. 1970, 141, 161176. It is now generally accepted that both cyclic and acyclic olefin metathesis reactions proceed via metallacyclobutane and metal-carbene intermediates: Grubbs, R. H.; Burk, P. L.; Carr, D. D. J. Am. Chem. Soc. 1975, 97, 32653266.

P Cl R R Cl Cl P Ru P Ru P

Cl H H

P P Cl R Ru

Cl H H

Cl

H H C2H4

EtO2C CO2Et

P(c-Hex)3 H Ru H Cl P(c-Hex)3 5 mol% Cl CD2Cl2, 25 C EtO2C CO2Et

c-C5H6(CO2Et)2
P Cl Ru P P Cl +P EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et Ru H P Cl Ru H P Cl Ru

Cl H H

Cl H

Cl H

Cl

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%).

Associative:
P Ru Cl P H H P Cl R Ru P P Cl H R Ru H P P Cl H R C2H4 P Cl Ru P EtO2C CO2Et EtO2C Cl H H P Cl Ru P CO2Et Cl Ru P

Cl

Cl H H

Cl H

Cl

c-C5H6(CO2Et)2
P Cl Ru P EtO2C CO2Et

Cl H H

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

M. Movassaghi

Catalytic RCM of Dienes: substrate O N X X = CF3 X = Ot-Bu N product O X time (h) 1 1 yield (%)a

Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM substratea E E R R = CH3 product E E yield yield with 3-Ru (%)b with 1-Mo (%)c 93 98 R NR 25 NR E E 98 100 100 96 97 NR decomp

93 91

i-Pr t-Bu
Ph Br CH2OH

Ph

Ph

84

Ph

Ph 5 86 E E

97 O Ph O Ph O O R R = CO2H CH2OH CHO

a2-4

100

CH3 8 72 E E

CH3 E E 96 100

O O

Ph

Ph 1 87 E E R 1 1 1 87 88 82

CH3

CH3 No RCMd No RCMd

CH3 E E

mol% 2-Ru, C6H6, 20 C.

CH3 E E

CH3 H3C CH3 E E

NR

93

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. PhCH2 + N H Cl 4 mol% 2-Ru 20 C, 36 h CH2Cl2; NaOH 79% Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 98569857. CH2Ph N
a

CH3 E E CH3 H3C

NR CH3 E E E E 96e

61

100e

E = CO2Et. b0.01 M, CH2Cl2, 5 mol%. c0.1 M, C6H6, 5 mol%. dOnly recovered starting material and an acyclic dimer were observed. eThe isomeric cyclopentene product is not observed. Functional group compatibility permitting, the Mo-alkylidene catalyst is typically more effective for RCM of substituted olefins. Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 73107318. M. Movassaghi

Geminal Substitution

A Recyclable Ru-Based Metathesis Catalyst

O <1 mol% 1-Mo R RR R 25 C, 0.5-1 h neat R= H CH3 R

R H3C O N2 CH3
RuCl2(PPh3)3

CH3 Cl H3C O

CH2Cl2, 78 C 90%

0%; (polymerization) 95%

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

CH3 H3C O

Cl

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

"Thorpe-Ingold" effects favor cyclization with gem-disubstituted substrates. substrate Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R., Jr.; Wagener, K. B. J. Am. Chem. Soc. 1992, 114, 1097810980. producta TBSO H TBSO H 0.5 BnO H 2.0 22 95 89 22 90 75 time (h) temp. (C) yield (%)b recovered catalyst (%)b

RCM of Temporarily Connected Dienes

BnO H

H3C CH3 Si n O m R C6H6, CH2Cl2 23 C, 0.5-5 h 73-96% 2-5 mol% 1-Mo or 3-Ru

H3C CH3 Si O n m KF R H2O2 80-93 % m = 1-3, n = 0-2

a

Ts N OH HO n m R Ts N

NTs

1.0

40

99

88

1.0 NTs

40

72

88

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

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).

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, 791799. Chang. S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 47574760. M. Movassaghi

RCM in Methanol and Water

H3C

CH3 N + Cl

substratea E E Ph

productb E E

solvent

catalyst

conversionc

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

Cl Cl

P Ru P

N(CH3)3+Cl Ph H N(CH3)3+Cl Cl Cl

methanol E E methanol E E methanol CH3

P Ru P Ph H E E Ph

6-Ru 7-Ru

80 95 45d 55d

6-Ru 7-Ru

+ N Cl 6-Ru H3C CH3 7-Ru Alkylidenes 6-Ru and 7-Ru are well-defined, water-soluble Ru-based metathesis catalysts that are stable for days in methanol or water at 45 C. Although benzylidene 3-Ru is highly active in RCM of dienes in organic solvents, it has no catalytic acitivity in protic media. EtO2C CO2Et EtO2C 5 mol% 3-Ru 23 C solvent: CH2Cl2 CH3OH 100% <5% CO2Et

E E CH3 Ph 7-Ru >95

Boc N Boc N

Ph

Boc N

methanol

6-Ru 7-Ru

40 90e

Boc N Ph

methanol

6-Ru 7-Ru 7-Ru 7-Ru 7-Ru

30 >95f 90 60 90g

N(CH3)3+Cl Ph

N(CH3)3+Cl methanol water water

Stabilization of Ru-Carbene Intermediates by Phenyl Substitution first turnover step of RCM: methylidene, R = H benzylidene, R = Ph LnRu R H
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. R 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.

LnRu

Ph H

Ph

RuLn R Ph LnRu

LnRu R

R H H Cl N+ 5 mol% 3-Ru CH2Cl2 R=H R = Ph

H H N + Cl

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.

60% 100%

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

NHC Ruthenium Catalysts:

RCM of functionalized dienes

Mes N Cl Ru Cl

N Mes

Mes N Cl Ru Cl

N Mes

Mes N Cl Ru Cl

N Mes

Mes N Cl Ru Cl

N Mes CH3 CH3

diene

product

yield (%)

Ph H

Ph

Ph H

P(c-Hex)3 8-Ru
a

H P(c-Hex)3 4-Ru time (h)

P(c-Hex)3 9-Ru

H P(c-Hex)3 10-Ru

O O

CH2 CH2

O 49 O

yield of product (%) using catalyst:b substrate product E E E E 1-Mo 3-Ru 8-Ru 4-Ru 9-Ru

O O

CH2 CH2

O 0 O O

t-Bu t-Bu
E E

37

100

100

100 O

O CH2 CH2 O

97

CH3 E E

CH3 H3C CH3 E E

24

93

40c

31

55 O

O CH3 CH2 O

O CH3 86

CH3 E E 1.5 CH3 H3C CH3 H OH 0.2 0 0 NA 100 100

a aE

52

95

90

87

CH2 O O 93

H OH

Reactions conducted with 5 mol% 10-Ru.

= CO2Et.

b5

mol% of catalyst, CD2Cl2, reflux.

c1.5

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

Alkylidenes 4- and 9-Ru are the most reactive Ru-based catalysts. In the case of 4- and 9-Ru as little as 0.05 mol% is sufficient for efficient RCM. Scholl, M.; Ding, S.; Lee, C.-W.; Grubbs, R. H. Org. Lett. 1999,1, 953-956. Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 22472250. For the first Ru-based metathesis catalyst employing the Arduengo carbene ligand, see: Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 24902493.

!,"-Unsaturated lactones and enones of various ring sizes are produced in good to excellent yields. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 37833784.

M. Movassaghi

RCM Applications in Synthesis: Bn N O O O 1. n-Bu2BOTf, Et3N CH2Cl2, 0 C 2. CH2=CHCHO 78 ! 0 C 82%, >99% de Bn N O O Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 41924193. MOMO BnO BnO BnO O H N BnO CO2CH3 5 mol% 2-Ru 110 C, 48 h 70% BnO BnO O Castanospermine Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547550. 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, 1021010211. OPMB O 10 mol% 5-Ru CH2Cl2, 40 C TBSO O O O 3 H3C RuLn TBSO O O OPMB Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem. Int. Ed. 2004, 43, 23672370. O H N HO HO HO H N OH O O OH O O 1 mol% 3-Ru CH2Cl2 97% Bn N HO Cl O O OH OH O O HO Cl CH3

Pochonin C

trans epoxide
MOMO O O H CH3 5 mol% 4-Ru O H toluene, 120 C 10 min 87% MOMO O MOMO O O H CH3 O H

cis epoxide
MOMO O O MOMO O CH3 H MOMO H 5 mol% 4-Ru toluene, 120 C 10 min 21% MOMO O O O CH3 H

O H

TBSO

OPMB 71%

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.

H3 C

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

L. Blasdel and M. Movassaghi

CH3 N H N D O N E Manzamine A N H OH H3C H N O H O

CH3 OAc

20 mol% 1-Mo

CH3 H O H N O O H CH3

CH3 OAc NHCOCF3 OAc

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

Before the advent of NHC ligands, 1-Mo was used more frequently than the Ru catalysts for macrocyclization of trisubstituted olefins. The latter catalysts are typically less reactive with sterically hindered substrates. Zhongmin, X.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.; Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 1030210316. Slight changes in substrate structure can control whether the E- or Z-olefin is formed:

The use of RCM in construction of both the D and the E rings of Manzamine A has been reported: CH2OTDS

H N O

CH2OTDS 100 mol% 2-Ru O O 23 C, 5 d C6D6 30% N O

H3C O

H3C OCH3O

CH2 CH3 CH3

H3C O O

H3C O

CH2 CH3 CH3

O O O OP 86% E-olefin only CH3

P = p-BrBz 10 mol% 4-Ru CH2Cl2, 40 C

OCH3 OP

CH3

80% Z-olefin only CH3

Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35, 31913194. O H Ph N O N H O CO2CH3 5 mol% 1-Mo 50 C, 4 h C6H6 63% O H Ph N O H N O CO2CH3 PO CH3O O

CH3 O CH3 CH3 CH3 PO O O

CH3 CH3 CH3

OCH3

CH3 O CH3 CH3 OHC CH3 OHC O O

CH3 O CH3 CH3 HO CH3

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

HO Coleophomone B

Coleophomone C

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

Synthesis of Epothilone C:

Solid-Phase Synthesis of Epothilone A: O CH3 O O O OTBS 3-Ru (0.75 equiv) 25 C, 48 h CH2Cl2 S N CH3

Small changes can drastically affect reaction outcome. In the example below, TBS protective groups changes the E/Z selectivity. HO H3C CH3 CH3 H3C CH3 O OR2 O O H S N CH3 CH3 R1 O H3C O OR2 O CH3 H3C CH3 H O S N CH3 = Merrifield resin

CH3 H3C CH3

R1O H3C

HO R1 H H TBS TBS R2 H TBS TBS TBS Catalyst 1-Mo 3-Ru 3-Ru 1-Mo Conditions 50 mol%, PhH, 55 C 10 mol%, CH2Cl2, 25 C 6 mol%, CH2Cl2, 25 C 50 mol%, PhH, 55 C Yield 65 % 85% 94% 86%

E/Z
2:1 1 : 1.2 1 : 1.7 1 : 1.7

H3C H3C H3C TBSO

CH3 O O O 15.6%

CH3

S N CH3

HO

H3C H3C H3C TBSO

CH3 O O O 15.6%

CH3

S N CH3

CH3 HO H3C O O OTBS 5.2% Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 79607973. Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 1107311092. Schinzer, D.; Bauer, A.; Bohm, O. M.; Limberg, A.; Cordes, M. Chem. Eur. J. 1999, 5, 24832491. CH3 H3C CH3

S N CH3 HO H3C O O OTBS 15.6% CH3 H3C CH3

CH3

S N CH3

The amount of alkylidene 3-Ru (75%) used was greater than the total yield of product (52%), perhaps reflecting the generation of a resin-bound Ru intermediate. Addition of n-octene or ethylene has been documented to provide a catalytic cycle; see: Maarseveen, J. H.; Hartog, J. A. J.; Engelen, V.; Finner, E.; Visser, G.; Kruse, C. G. Tetrahedron Lett. 1996, 37, 8249.

Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387, 268272.

M. Movassaghi and L. Blasdel

Catalytic RCM of Olefinic Enol Ethers: CH3 O

Tandem Ring Opening-Ring Closing Metathesis of Cyclic Olefins

O O Ph

CH3CHBr2, TiCl4 Zn, TMEDA, cat. PbCl2, 20 C, 11 h THF 55%

12 mol% 1-Mo

Ph 20 C, 3.5 h n-pentane
88%

substrate O Ph O H H O

product O H H O

yield catalyst 3-Ru conc. (%) (mol %) (M)

time (h)

temp. (C)

82 CH3 O Ph O CH3CHBr2, TiCl4 Zn, TMEDA, cat. PbCl2, 20 C, 5 h THF 79% O O H O O 68 O O H H H H O 92 O CH3 CH3 Ph O 12 mol% 1-Mo 20 C, 7 h n-pentane 87% H H Ph O O H H O O HH O 70 O H H O O H H O 90

0.1

1.5

45

0.1

60

0.07

45

0.04

45

Only catalyst 1-Mo is effective for RCM of these substrates. Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 40294031.

0.04

60

Ti Tandem Olefination-Metathesis

CH2 Cl

Al

CH3 CH3 Without sufficient ring strain in the starting cyclic olefin, competing oligomerization (via CM) can occur. Higher dilution favors intramolecular reaction:

Tebbe reagent H BnO H O O O R H O Tebbe reagent (4.0 equiv) THF, 25 C, 0.5 h; reflux, 4h O BnO H O H R 50% 54% H O

O H

O H

6 mol% 3-Ru C6H6, 45 C 6h 0.12 M 0.008 M 0.2 M

H H O

CH3

R= H CH3 Here, a Ti-alkylidene is used in RCM.

R =H H CH3

16% 73% 42%

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

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

Proposed Mechanism for Ring Opening-Ring Closing Metathesis:

Examples in Complex Synthesis: CH3 CH3 2 mol% 3-Ru ethylene H3C CH3 O O O O OPMB H3C CH3 CH3

LnRu CHPh O H H O H3C

CH3

Ph H H H2C CH2 O LnRu O H H

98%

O CH3 H H CH3 O H3 C O H OH OPMB O H CH3 25 mol% 5-Ru toluene, ! 76%

LnRu CH2

O RuLn

O H3C

H3C

O H

CH3

HO HO HO O RuLn Ingenol

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 10 mol% 3-Ru 0.1 M, C6D6 40 C, 8 h O N CH3 O O O 95% O N CH3

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

O O O H3 C CH3 20 mol% 4-Ru ethylene, toluene 43% (3 steps) H3 C

HH

CH3

H3C

CH3 HH

OH CH3 CH3

unreactive substrates:

H3 C

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

O M. Movassaghi and L. Blasdel

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

Kinetic Resolution via Asymmetric RCM R1 N R1 Mo H t-Bu CH3 R2 CH3

Catalytic, Enantioselective RCM H OSiEt3 CH3 CH3 5 mol% 12-Mo 22 C, 10 min C6H6 CH3 + CH3 19%, >99% ee CH3 CH3 12-Mo: 13-Mo: 14-Mo: 15-Mo: R1 = i-Pr R1 = CH3 R1 = Cl R1 = Cl R2 = Ph R2 = Ph R2 = Ph R2 = CH3 CH3 H OSiEt3 5 mol% 12-Mo 22 C, 2 h C6H6 CH3 CH3 H OSiEt3 + CH3 H OSiEt3 40%, <5% ee 43%, 93% ee H OSiEt3 CH3 H OSiEt3

i-Pr
F3C F3C N O Mo O H CF3 CF3

i-Pr
Ph CH3 CH3 H3C

t-Bu
O O CH3 H3C

11-Mo

50%, <5% ee

Diastereodifferentiation occurs during formation or breakdown of the metallabicyclobutane intermediates and not during the initial metathesis step. Alexander, J. B.; La, D. S.; Cefalo, D. R. Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc. 1998, 120, 40414042.

2 mol% 11-Mo Et3SiO CH3 CH3 20 C, 660 min toluene Et3SiO CH3 38%, 48% ee CH3

Et3SiO CH3 62%

Mo-alkylidene Catalyzed Kinetic Resolution and Enantioselective Desymmetrization via RCM O H3C H R 5 mol% 12-Mo C6H5CH3 H3C O H + R H3C R H O

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

Proposed Transition State Models for the Observed Selectivity R Ar F3C F3C N H3C O Mo O CF3 CF3 H Ar OSiEt3 H CH3 F3C F3C N H3C O Mo O CF3 CF3 H temp. (C) 25 25 25 22 25 time (h) 6 10 7 0.1 6 conv. (%) 63 56 62 64 56

recovered SM ee (%) 92 95 98 97 75

krel
10 23 17 13 8

n-C5H11
H OSiEt3

i-C4H9 c-C6H11 c-C6H11

C6H5

CH3

DISFAVORED

FAVORED

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

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

O H n-C5H11 H3C

O CH3 C6H5

Fujimura, O.; Grubbs, R. H. J. Org. Chem. 1998, 63, 824832. Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 24992500.

H3C M. Movassaghi

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

Desymmetrization metathesis reactions have been used to make a variety of heteroatomcontaining products: 5 mol% 12-Mo H3C Ph O Si CH 3 CH3 H3C CH2Cl2, 22 C, 6 h 92% 93% ee H3 C Ph H3C CH3 Si O 1. m-CPBA 2. n-Bu4NF

O H3C R CH3 1-2 mol% 13-Mo R R=H R = CH3 22 C, 5 min neat H3C R

H3C H O

CH3

85%, 93% ee 93%, 99% ee H3C

OH Ph OH CH3

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.

86% two steps 93% ee >20:1 de Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868. CH3 H3 C 5 mol% 14-Mo PhH, 22 C, 12 h 41%, >98% conv. 83% ee O

CH3 O

5 mol% 13-Mo O 20 C, 18 h C6H5CH3 84%, 73% ee 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. O CH3 catalyst H3 C n 1 2 3 N Ph PhH, 22 C
n

5 mol% 13-Mo O 20 C, 18 h C6H5CH3 91%, 82% ee

CH3

H3 C time 20 min 7h 20 min yield 78% 90% 93%

N Ph

It is believed that the stereodifferentiating step is the formation of the metallabicyclobutane intermediate; see: Alexander, J. B.; La, D. S.; Cefalo, D. R. Hoveyda, A. H.; Schrock, R. R. J. Am. Chem. Soc.1998, 120, 40414042.

catalyst 12-Mo 12-Mo 15-Mo

%mol catalyst 5 2 5

ee 98% 95% >98%

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

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

Catalytic RCM of Dienynes: Construction of Fused Bicyclic Rings

substrate OSiEt3

product OSiEt3

yield (%)

mol% 2-Ru

time (h)

conc. (M)

temp. (C)

m Ln[M]

m [M]Ln

m CH3 OSiEt3 CH3 CH3 CH3 OSiEt3 OSiEt3 CH3 OSiEt3

88

0.06

65

83 Fused [5.6.0], [5.7.0], [6.6.0], and [6.7.0] bicyclic rings have been successfully constructed by RCM of dienynes. H3C OSiEt3 3 mol% 2-Ru + CH3 25 C, 8 h 0.06 M CH2Cl2 CH3 dienyne RCM 95% H3C diene RCM <3% CH3 CH3 O CH3 OSiEt3 CH3 CH3 CH3 O 88 CH3 CH3 OSiEt3 OSiEt3 CH3 OSiEt3 89 CH3

0.03

65

78

15

1.5

0.01

100

15

12

0.05

65

The dienyne RCM is largely favored over the competing diene RCM. OSiEt3 3-5 mol% 2-Ru 0.05-0.1 M C6D6 yield (%) >98 95 78 NR 96 82 NR NR NR conditions 23 C, 15 min 23 C, 8 h 60 C, 4 h 60 C, 3 h 60 C, 4 h OSiEt3

0.05

65

CH3 R

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

Regiochemical control within unsymmetrical substrates is achieved by substitution of the olefin required to undergo metathesis last. Unsymmetrical substrates containing equally reactive olefins produce a mixture of bicyclic products: OSiEt3 LnRu RuLn OSiEt3 LnRu RuLn CH3 OSiEt3 OSiEt3 CH3 OSiEt3 LnRu CH3 CH3 CH3 CH3 OSiEt3 OSiEt3

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.

RuLn CH3

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

Enyne Metathesis Reactions Catalyzed by PtCl2

Enyne Metathesis in Synthesis CH3 CH3 TBSO OCH3 OTBS 96% 40 mol% 3-Ru ethylene, toluene, 45 C H3C 31% OTBS H CH3 OTBS 1. 50 mol% 3-Ru ethylene, CH2Cl2, 40 C 2. TBAF, THF, 0 ! 23 C 42% (two steps) CH3 TBSO TBSO CH3 OTBS TBSO 54% OCH3

substrate

product

yield

TBSO

TBSO

PhO2S SO2Ph

PhO2S SO2Ph

H O CH3O O OCH3 H H O O O O H 70%

H3CO

OCH3

H3 C O O H CH3 ()-Longithorone A

Ts H N

H OHC H TsN 80%

Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773775. CO2CH3 H3C CH3 CH3 CH3 CH3 12 mol% 4-Ru CH2Cl2, reflux, 3 h 82% OHC O AcO OH H3C CH3 CH3 CH3 H3CO2C

aReactions

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

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.

H3C

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

H3 C

CH3 CH3

CH3

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

Cross Metathesis Olefin categorization and rules for selectivity Type I Rapid homodimerization, homodimers consumable Reaction between two olefins of Type I................................... Statistical CM Type II Slow homodimerization, homodimers sparingly consumable Reaction between two olefins of same type (non-Type I)........ Non-selective CM Type III No homodimerization Reaction beween olefins of two different types....................... Selective CM Type IV Olefins inert to CM, but do not deactivate catalyst (spectator)

Selective Cross-Metathesis Reactions as a Function of Catalyst Structure: MesN Cl NMes P(c-Hex)3 Cl Ph Ru H Cl P(c-Hex)3 3-Ru F3C F3C

i-Pr
N O Mo

i-Pr
CH3 Ph

Ph Ru H Cl P(c-Hex)3 Olefin type 4-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

CH3 CH3 O H F3C F3C CH3 1-Mo

Type I (fast homodimerization)

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

terminal olefins, allyl silanes

Type II (slow homodimerization)

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

styrene, 2 allylic alcohols, vinyl dioxolanes, vinyl boronates

styrene, allyl stannanes

Type III (no homodimerization)

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

vinyl siloxanes

3 allyl amines, acrylonitrile

Type IV (spectators to CM)

vinyl nitro olefins, trisubstituted allyl alcohols (protected)

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

1,1-disubstituted olefins

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

L. Blasdel

Non-selective Cross Metathesis: Two Type I Olefins 3 mol% catalyst + AcO 2 equiv OAc CH2Cl2, 40 C, 12 h 80% catalyst 3-Ru 4-Ru OAc

Olefin 1

Olefin 2

producta,b

Isolated Yield (%)

E/Z

Secondary allylic alcohols (Type I with Type II) CH3 CH3 OAc 3 2.0 equiv BzO
3

E/Z
3.2 : 1 7:1

BzO

OAc

82

10 : 1

CH3 HO

OAc 1.0 equiv

3

CH3 HO
3

OAc

50c (62)d

14 : 1

The difference in E/Z ratios reflects the enhanced activity of 4-Ru relative to 3-Ru. Because it is more active, 4-Ru can catalyze secondary metathesis of the product, allowing equilibration of the olefin to the more thermodynamically stable trans isomer. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 1136011370. TBDPSO

CH3
3

OAc

CH3 TBDPSO
3

2.0 equiv

OAc

53

6.7 : 1

Quaternary allylic olefins (Type I with Type III) H3C HO CH3

3

Selectivity for the trans olefin can also be enhanced using sterically hindered substrates: PhO
3

OAc

H3 C HO

CH3
3

93 OAc

>20 : 1

SiR3

2 mol% 1-Mo DME, 23 C, 4 h

PhO
3

SiR3

2.0 equiv O O
3

R CH3 Ph

Yield 72% 77%

E/Z
2.6 : 1 7.6 : 1

OAc

O H3C

O
3

91 OAc

>20 : 1

H3C 1.0 equiv

1,1-Disubstituted olefins (Type I with Type III) Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett. 1996, 37, 21172120. BzO CH3 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. CH3 OR CH3 6 mol% 4-Ru CH2Cl2, 40 C, 12 h 80% CH3 OR CH3 H2 N CH3 O AcO + AcO HO CH3 O H Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 1136011370. CH3
a
8 3

OAc

BzO CH3 O

OAc

80

4:1

2.0 equiv OTBS

O
7

H2 N CH3 O

1.2 equiv

OTBS

71

> 20 : 1

CH3

HO CH3 O

CH3

23

4:1

1.1 equiv H3C CH3 1.0 equiv

3

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

OAc

H CH3

(OAc)

97

> 20 : 1

c With

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

L. Blasdel

Olefin 1 Type II and Type III O HO O

Olefin 2

producta

Isolated Yield (%)

E/Z

Selective Cross-Metathesis Reactions: O OTr Type IV N H 10 mol% 4-Ru CH2Cl2, 40 C, 4 h (H3C)3Si O O N H 50% isolated yield 1.5 : 1 E/Z OTr

O C(CH3)3 neat HO O C(CH3)3 neat CH3

3

C(CH3)3

73 Type I 73

O +

Si(CH3)3 1.5 equiv O OTr Type III N H + Si(CH3)3

t-BuO

HO

C(CH3)3

O HO

O CH3 HO C(CH3)3 83 2:1

Cl3C Type I

10 mol% 1-Mo CH2Cl2, 40 C, 16 h Cl3C

OTr

4.0 equiv O EtO R CH3

3

O CH3 HO C(CH3)3

55 R = H 83 R = CH3

2:1 2:1

1.5 equiv

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

4.0 equiv Brmmer, O; Rckert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441446. F AcO 2.0 equiv F F OAc F O OCH3 1.52.0 equiv O H3 C CH3 O H3 C
a

OAc

F 98 OAc

>20 : 1 H CbzHN 10 mol% 1-Mo CH2Cl2, 8 h reflux

(H3C)3Si H CbzHN CO2CH3

AcO 2.0 equiv

OAc

CO2CH3

Si(CH3)3

50

>20 : 1

97% ee

95%, 92% ee

CO2CH3 92 >20 : 1

Brmmer, O; Rckert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441446. 5 mol% 1-Mo R NC 23 C, 3h CH2Cl2 yield (%) 76 60 44 R

NC CO2Et 87 H3C CH3 CO2Et 5 H3C CH3 >20 : 1 CH3 >20 : 1

CH3

OEt 1.52.0 equiv

R CH2Si(CH3)3 (CH2)3OBn (CH2)2CO2Bn

E:Z
1:3 1:7.6 1:5.6

CH3

OEt 1.52.0 equiv

The basis for the high cis-selectivity with acrylonitrile as substrate is not known. Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 51625163. L. Blasdel and M. Movassaghi

15 mol% 4-Ru, CH2Cl2, 40 C. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 1136011370.

Reagent preparation

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

A HornerWadsworthEmmons reagent: O EtO P EtO O EtO P EtO O OEt H3C H3C Br O CH3 O OAc OTBS O 3.0 equiv 10 mol% 4-Ru CH2Cl2, 45 C

O OEt

4 mol% 4-Ru CH2Cl2 40 C, 12 h 87% > 20 : 1 E/Z

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

H3C H3C Br

CH3 OAc

CH3 O
2

H3 C H3C Br

CH3 OAc

CH3 O O

OTBS

starting material homodimer A Suzuki reagent:

44% E-isomer 64% after recycling the homodimer

H3C AcO
3

O B CH3

CH3 CH3 CH3

H3C 5 mol% 4-Ru CH2Cl2 40 C, 12 h 58%, >20 : 1 E/Z AcO

3

McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593595. CH3 CH3 CH3 CM can be difficult in the presence of strained olefins, as was found in the preparation of the AB ring fragment of ciguatoxin: O O OBn compound A H OBn OBn 5 mol% 3-Ru CH2Cl2, 23 C, 30 min 95% AcO OAc 5.0 equiv H O H O

O B CH3

2.0 equiv

OBn OBn

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

OBn 40 mol% 3-Ru CH2Cl2, 40 C 33 h

One-pot CM and allylboration reactions:

H3C H3C H3C

CH3 O O B + 2.0 equiv

1. 3 mol% 3-Ru CH2Cl2 40 C, 24 h 2. PhCHO (2 equiv), 23 C

OH Ph Ph 88 % 91 : 9 anti/syn AcO OAc O H H OBn OBn H O H OBn + AcO OAc H O H O OBn OBn OBn

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

19% via ring opening to compound A

8% AB ring fragment of ciguatoxin

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

Ring Opening Cross-Metathesis: substrate product mol % alkenea cat.b time yield E,E:E,Z

Enyne Cross-Metathesis

4-Ru outperforms 3-Ru in both rate and overall conversion in the cross-metathesis of ethylene and alkynes. CH3OCH2 CH2OCH3 A CH3O2C CO2CH3 CH3O2C Et CO2CH3 Et B O O O Et O O O Et C O CH3OCH2 O O O O O O O BnO
a 25

96

94

2:1

substrate OR

product OR R=H R = Ac R = TBS

time (h)

yield (%)

2.0 2.0 8.5

73 92 91

14

85

2:1

OAc CH3

OAc 16 CH3 AcO 4.0 OAc OAc CH3 NTs 4.0 91 69 77

8c

73

1.5:1

AcO

NBoc O

NBoc CH2OCH3 A 2 89 15 NA

CH3

NTs

BnO

6.0

72

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. Enantioselective ROMCM reactions have been described: La, D. S.; Ford, J. F.; Sattely, E. S.; Bonitatebus, P. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 1160311604.

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

OH Ph 99% ee

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

OH

99% ee

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

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.

RCM of Diynes

Efficient synthesis of !12-membered rings containing internal alkynes can be achieved with 17-Mo. substrate O O O O CH3 O O O O O O(CH2)10 CH3 CH3 O O 82 CH3 CH3 O O 88 N O O O O O 91 producta yield (%)

t-Bu

t-Bu N t-Bu N Mo N
CH3 CH3 CH3 CH3 16-Mo

t-Bu
CH3 RX CH3

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

Cl

CH3

CH3

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

16-Mo (10 mol%) R CH3 R CH2Cl2, Toluene R = H, R = CN, CH3 RO 17-Mo (10 mol%) CH2Cl2, Toluene RO R = CH3, 59% R = THP, 55% CH3 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.
aReactions

R 60% 58% OR O

O(CH2)10

CH3 O

Ph Ph Si

O(CH2)10

CH3

Ph Ph Si

O 74

O(CH2)10

CH3

O(CH2)10 O

CH3 O O 83

conducted in toluene at 80 C for 20-48h; 17-Mo was generated in situ from 16-Mo and CH2Cl2 (~25 equiv). Frstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 94539454.

M. Movassaghi

Synthesis of Cyclic !-Turn Analogs by RCM

Template-Directed RCM 5 mol% 3-Ru "template" CH2Cl2, THF 45 C, 1 h 0.02 M "template" (equiv) none LiClO4 (5) NaClO4 (5) none LiClO4 (5) yield (%) cis:trans 39 >95 42 57 89 38:62 100:0 62:38 26:74 61:39 O O O O n

H N Boc

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

20 mol% 2-Ru

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

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

n O

n = 1, 2 substrate (n) 1 1 1

n = 1, 2

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

2 2

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

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

CH3 H3C H3C H N O O N H O H N O OBn 60% CH3 H3C 30 mol% 3-Ru 0.004 M, 21 h CH2Cl2, 40 C H3C H N O O N H

CH3 CH3 O H N O OBn O O O O

5 mol% 3-Ru CH2Cl2 1.2 M, 23 C >95% 5 mol% 3-Ru LiClO4 CH2Cl2, THF 0.02 M, 50 C O O O O m

H N Boc

H N Boc

Mn = 65900
cis : trans, 1 : 3.7

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.

>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.

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

M. Movassaghi

RCM-Mediated Covalent Capture

Synthesis of Catenanes + PF
6

The eight-residue cyclic peptide cyclo[-(L-Phe-D-MeN-Ala-L-HomoallylGly-D-MeN-Ala)2-] self-assembles to form two slow-exchanging antiparallel "-sheet-like hydrogen bonded cylinders (Ka(CDCl3) = 99 M1, only the reactive isomer is shown). N O NN H O O H N N O Ph O Ph O ON N O H O N O H N 2 O O O O O O O N Cu(CH3CN)4PF6 CH2Cl2, CH3CN 100% O

O O O N N N N

O O O

N N N N O H H O O H O H N N N O

O O O O

N O

Ph Ph

= Cu+ 5 mol% 3-Ru 23 C, 6 h 0.01 M, CH2Cl2 92% + PF

6

20-25 mol% 2-Ru CDCl3, 23 C, 48 h 65% O O O ON N O H O N N O O O O N N O O O KCN, H2O CH3CN ~100% O O O O N N O O O O

O NN H O O H N N O

Ph O

Ph

O O O N N O O O

N N N N O H H O

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

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

32-membered catenane

trans:cis, 98:2

The remarkable efficiency of this RCM is proposed to be due to preorganization of the substrate. Mohr, B.; Weck, M.; Sauvage, J.-P.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 13081310. M. Movassaghi

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