The Olefin Metathesis Reaction

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Myers The Oleﬁn Metathesis Reaction Chem 115 Reviews: Cross Metathesis (CM):

Hoveyda, A. H.; Khan, R. K. M.; Torker, S.; Malcolmson, S. J. 2013 (We gratefully acknowledge Professor Hoveyda and co-workers for making this review available to us ahead of print). CM R2 + R4 R3 + R4 Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 4490–4527. R1 R3 R1 R2

Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. • Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. Self-dimerization reactions of the more valuable alkene may be minimized by the use of J. Am. Chem. Soc. 2003, 125, 11360–11370. an excess of the more readily available alkene.

Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592–4633. Catalysts Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 1900–1923.

Fürstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3012–3043.

i-Pr i-Pr MesN NMes Ring-Opening Metathesis Polymerization (ROMP): P(c-Hex) P(c-Hex) N 3 3 CH Cl Ph Cl F3C 3 Ph Cl O Mo Ru Ph Ru Ph Ph Cl H Cl H Ru F3C CH3 P(c-Hex) P(c-Hex) Cl H ROMP n CH3 O 3 3 H P(c-Hex)3 F3C CH3 F3C 1-Mo 2-Ru 3-Ru 4-Ru (Grubbs' 1st (Grubbs' 2nd Generation Catalyst) 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 • The well-defined catalysts shown above have been used widely for the olefin metathesis more negative as a result of increased strain energy in the monomer. reaction. Titanium- and tungsten-based catalysts have also been developed but are less used.

• Block copolymers can be made by sequential addition of different monomers (a • Schrock's alkoxy imidomolybdenum complex 1-Mo is highly reactive toward a broad range of consequence of the "living" nature of the polymerization). 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. Ring-Closing Metathesis (RCM): • 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.

6 RCM • The electron-rich tricyclohexyl phosphine ligands of the d Ru(II) metal center in alkylidenes 2- + H2C CH2 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 • The reaction can be driven to the right by the loss of ethylene. catalysts can be conveniently stored in the air for several weeks without decomposition. All of the catalysts above are commercially available, but 1-Mo is significantly more expensive. • 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. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956. • Where the thermodynamics of the closure reaction are unfavorable, polymerization of the Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed Engl. 1995, substrate can occur. This partitioning is sensitive to substrate, catalyst, and reaction conditions. 34, 2039–2041. Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9858–9859. M. Movassaghi, L. Blasdel

1 Myers The Oleﬁn Metathesis Reaction Chem 115

Mechanism: Dissociative: P = P(c-Hex)3 EtO C CO Et • The oleﬁn metathesis reaction was reported as early as 1955 in a Ti(II)-catalyzed 2 2 polymerization of norbornene: Anderson, A. W.; Merckling, M. G. Chem. Abstr. 1955, 50, R = 3008i.

• 15 years later, Chauvin first proposed that olefin metathesis proceeds via P P P P metallacyclobutanes: Herisson, P. J.-L.; Chauvin, Y. Makromol. Chem. 1970, 141, 161–176. Cl H –P Cl H Cl H Cl Cl Ru Cl Ru Cl Ru Cl Ru H H H H H • It is now generally accepted that both cyclic and acyclic olefin metathesis reactions proceed P via metallacyclobutane and metal-carbene intermediates: Grubbs, R. H.; Burk, P. L.; Carr, D. R R R D. J. Am. Chem. Soc. 1975, 97, 3265–3266. R R P Cl H Ru – C2H4 P(c-Hex)3 Cl H Cl H P Ru H Cl c-C5H6(CO2Et)2 P(c-Hex)3 EtO2C CO2Et 5 mol% P P P P Cl Cl H Cl H Cl CD Cl , 25 ºC H 2 2 EtO2C CO2Et Cl Ru Cl Ru Cl Ru Cl Ru H H H P +P

EtO C CO Et EtO2C CO2Et EtO C CO Et EtO2C CO2Et 2 2 • A kinetic study of the RCM of diethyl diallylmalonate using a Ru-methylidene describes two 2 2 possible mechanisms for olefin metathesis: Associative: • The "dissociative" mechanism assumes that upon binding of the olefin a phosphine is displaced 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. P R P P P Cl H Cl H Cl H Cl Ru Cl Ru Cl Ru Cl Ru H • The "associative" mechanism assumes that an 18-electron olefin complex is formed which Cl H H H H undergoes metathesis to form the cyclized product. P P P P R R R

c-C5H6(CO2Et)2 • Addition of 1 equivalent of phosphine (with respect to catalyst) decreases the rate of the – C2H4 reaction by as much as 20 times, supporting the dissociative mechanism. P P P Cl H Cl H Cl • It was concluded in this study that the "dissociative" pathway is the dominant reaction Cl Ru Cl Ru Cl Ru manifold (>95%). H H P P P

Dias, E. L.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897. EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et

M. Movassaghi

2 Myers The Oleﬁn Metathesis Reaction Chem 115 Catalytic RCM of Dienes: Synthesis of Tri- and Tetrasubstituted Cyclic Oleﬁns via RCM substrate product time (h) yield (%)a yield yield substratea product with 3-Ru (%)b with 1-Mo (%)c O O X = CF3 1 93 N X N X R R = CH E E 93 100 X = O t-Bu 1 91 E E 3 i-Pr 98 100 t-Bu NR 96 O Ph O Ph R 25 97 Ph 2 84 Br NR NR

CH2OH 98 decomp O Ph O Ph E E 5 86 E E 97 100

CH3 CH O 3 O E E 8 72 E E Ph Ph 96 100

CH3 CH O O Ph 3 Ph 1 87 E E O O – No RCMd No RCMd

CH3 R R = CO2H R 1 87 E E CH2OH 1 88 H3C E E CH3 CHO 1 82 NR 93

a 2-4 mol% 2-Ru, C6H6, 20 ºC H3C CH3 • Five-, six-, and seven-membered oxygen and nitrogen heterocycles and cycloalkanes are formed E E efﬁciently. H3C E E

• Catalyst 2-Ru can be used in the air, in reagent-grade solvents (C6H6, CH2Cl2, THF, t-BuOH). NR 61 H3C In contrast to the molybdenum catalyst 1-Mo, which is known to react with acids, alcohols, and CH3 • CH aldehydes, the ruthenium catalyst 2-Ru is stable to these functionalities. 3 E • Free amines are not tolerated by the ruthenium catalyst; the corresponding hydrochloride salts E E E undergo efﬁcient RCM with catalyst 2-Ru. 96e 100e

PhCH2 H CH2Ph – 4 mol% 2-Ru N Cl a b c d N E = CO2Et. 0.01 M, CH2Cl2, 5 mol%. 0.1 M, C6H6, 5 mol%. Only recovered starting material 20 ºC, 36 h and an acyclic dimer were observed. eThe isomeric cyclopentene product is not observed. CH2Cl2; NaOH • Functional group compatibility permitting, the Mo-alkylidene catalyst is typically more effective for 79% RCM of substituted oleﬁns. Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856–9857. Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310–7318. M. Movassaghi

3 Myers The Oleﬁn Metathesis Reaction Chem 115

Geminal Substitution Recyclable Ru-Based Metathesis Catalysts MesN NMe O P(c-Hex)3 O R R <1 mol% 1-Mo Cl H Cl H R R Ru Ru 25 ºC, 0.5-1 h Cl Cl R R R R neat O O H3C H3C R = H 0%; (polymerization) CH3 CH3

CH3 95% 5a-Ru 5b-Ru recovered substratea product cat time (h) temp (ºC) yield (%)b catalyst (%)b • Standard "Thorpe-Ingold" effects favor cyclization with gem-disubstituted substrates. TBSO H TBSO H 5a-Ru 0.5 22 99 75 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.

BnO H RCM of Temporarily Connected Dienes BnO H 5a-Ru 2.0 22 95 89

Ts H3C CH3 H3C CH3 2-5 mol% OH N NTs 5a-Ru 1.0 40 99 88 Si 1-Mo or 3-Ru Si KF O O HO R n n R R C6H6, CH2Cl2 H2O2 n m m 23 ºC, 0.5-5 h m CH3 80-93% CH3 73–76% CH3 m = 1-3, n = 0-2 5b-Ruc 0.3 22 87 98 O CH3 O CH3 CH3 CH3

OH OH H C • RCM of allyl- or 3-butenylsilyloxy dienes (n≥1) proceeded efﬁciently with alkylidene 3-Ru, 3 5b-Ru 2 22 75 95 while the more sterically hindered vinylsilyl substrates (n=0) required the use of alkylidene CH3 1-Mo. a b c 5 mol% catalyst, CH2Cl2. Isolated yield after silica gel chromatography. 1 mol% of 5b-Ru was used.

• RCM of silicon-tethered alkenes is very efﬁcient even at higher concentrations (0.15 M with • Catalysts 5a-Ru and 5b-Ru offer excellent stability to air and moisture and can be recycled in catalyst 3-Ru). high yield by chromatography on silica gel. 5a-Ru is effective for metathesis of terminal alkenes while 5b-Ru offers enhanced catalytic activity toward substituted alkenes.

Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791–799. Chang. S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757–4760. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168– 8179. M. Movassaghi, Fan Liu

4 Myers The Oleﬁn Metathesis Reaction Chem 115

a b c RCM in Methanol and Water H3C CH3 substrate product solvent catalyst conversion N Cl– E E E E 6-Ru 80 Ph methanol 7-Ru 95 + – P(c-Hex)3 N(CH3)3 Cl P P Cl Cl Ph Ph E E Cl Ph Ru Ru Ru Cl E E 6-Ru 45d H H Cl Cl H P Ph methanol P(c-Hex) P 7-Ru 55d 3 + – 3-Ru N(CH3)3 Cl

E E N Cl– E E CH3 H3C CH3 methanol 7-Ru >95 6-Ru Ph 7-Ru CH3 • Alkylidenes 5-Ru and 6-Ru are well-deﬁned, water-soluble Ru-based metathesis catalysts that are stable for days in methanol or water at 45 °C. Boc Boc 6-Ru 40 N methanol • Although benzylidene 3-Ru is highly active in RCM of dienes in organic solvents, it has no catalytic N Ph e 7-Ru 90 acitivity in protic media.

EtO C CO Et 5 mol% 3-Ru EtO2C CO2Et 2 2 Boc Boc 6-Ru 30 23 ºC N N methanol 7-Ru >95f Ph solvent: CH2Cl2 100% CH3OH <5% + – + – N(CH3)3 Cl N(CH3)3 Cl methanol 7-Ru 90 Stabilization of Ru-Carbene Intermediates by Phenyl Substitution water 7-Ru 60 • Ph ﬁrst turnover step of RCM: water 7-Ru 90g methylidene, R = H benzylidene, R = Ph a b c R E = CO2Et. 5 mol% catalyst (5- or 6-Ru), 0.37 M substrate, 45 °C. Conversions were determined by 1H NMR. dSubstrate conc. = 0.1 M. e30 h. f2 h. g10 mol% 6-Ru used. Ph R LnRu LnRu • Alkylidene 7-Ru is a signiﬁcantly more active catalyst than alkylidene 6-Ru in these cyclizations; H H 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 Ph R organic solvents. RuLn LnRu R H H L Ru n H H Cl– 5 mol% 3-Ru R N Cl– N R Ph CH2Cl2 R = H 60% • Substitution of one of the two terminal oleﬁns of the substrate with a phenyl group leads to R = Ph 100% regeneration of benzylidene catalyst, which is far more stable than the corresponding methylidene catalyst in methanol. Kirkland, T. A.; Lynn, D. M.; Grubbs, R. H. J. Org. Chem. 1998, 63, 9904–9909. M. Movassaghi

5 Myers The Oleﬁn Metathesis Reaction Chem 115 NHC Ruthenium Catalysts: RCM of functionalized dienes

substratea product yield (%) Mes N N Mes Mes N N Mes Mes N N Mes Mes N N Mes

CH2 O O Cl Cl Cl Cl CH 49 Ph Ph Ph 3 CH Ru Ru Ru Ru 2 CH3 O Cl H Cl H Cl H Cl H O

P(c-Hex)3 P(c-Hex)3 P(c-Hex)3 P(c-Hex)3 O CH2 O 8-Ru 4-Ru 9-Ru 10-Ru 0

O CH2 O yield of product (%) using catalyst:b time substratea product (h) 1-Mo 3-Ru 8-Ru 4-Ru 9-Ru O O CH2 O E E O CH 97 E E t-Bu 2 1 37 0 100 100 100

t-Bu O CH O E E O 3 CH3 CH3 E E CH3 CH O 24 93 0 40c 31 55 2 86

CH H3C CH3 2

E E CH3 E E O O

1.5 52 0 1.5 90 87 CH2 93 H3C CH3 CH3 CH2

H OH H OH 0.2 0 0 0.2 100 100 aReactions conducted with 5 mol% 10-Ru.

• Substrates containing both allyl and vinyl ethers provide RCM products while no RCM products a b c are observed if vinyl ethers alone are present. E = CO2Et. 5 mol% of catalyst, CD2Cl2, reﬂux. 1.5 h.

• Alkylidenes 4- and 9-Ru are the most reactive Ru-based catalysts. • !,"-Unsaturated lactones and enones of various ring sizes are produced in good to excellent • In the case of 4- and 9-Ru as little as 0.05 mol% is sufficient for efficient RCM. yields. 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. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 3783– For the first Ru-based metathesis catalyst employing the Arduengo carbene ligand, see: Weskamp, 3784. T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 2490–2493. M. Movassaghi

6 Myers The Oleﬁn Metathesis Reaction Chem 115 RCM Applications in Synthesis:

OH O CH3

Bn O 1. n-Bu2BOTf, Et3N Bn O OH O CH2Cl2, 0 ºC Cl N N HO HO O 2. CH =CHCHO O Cl 2 O O –78 ! 0 ºC O 1 mol% 3-Ru CH2Cl2 Pochonin C 82%, >99% de Bn O OH 97% trans epoxide

O MOMO O CH3 MOMO O CH3 O O 5 mol% 4-Ru O O O H H Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192–4193. MOMO H toluene, 120 ºC MOMO H 10 min Cl O O BnO BnO 87% H H HO BnO CO CH BnO H OH 2 3 5 mol% 2-Ru HO N N BnO 110 ºC, 48 h BnO N HO O 70% O Castanospermine cis epoxide

Overkleeft, H. S.; Pandit, U. K. Tetrahedron Lett. 1996, 37, 547–550. MOMO O CH3 H MOMO O CH H O 3 O H 5 mol% 4-Ru H • Particularly difficult cyclizations (due to steric congestion or electronic deactivation) can be O O achieved by relay ring closing metathesis, which initiates catalysis at an isolated terminal MOMO toluene, 120 ºC MOMO olefin. The reaction is driven by release of cyclopentene. O 10 min Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, O 10210–10211. 21%

10 mol% 5-Ru TBSO O OPMB TBSO O OPMB CH2Cl2, 40 ºC 71% O O • Pre-organization of the substrate can have a dramatic effect upon the reaction efficiency. O O • 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 H3C H3C RuLn 3 macrocycle is formed in a much higher yield.

TBSO O OPMB

O O Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N. Angew. Chem. Int. Ed. 2004, 43, 2367–2370. Wang, X.; Bowman, E. J.; Bowman, B. J.; Porco, J. A., Jr. Angew. Chem. Int. Ed. 2004, 43, 3601– 3605. L. Blasdel and M. Movassaghi

7 Myers The Oleﬁn Metathesis Reaction Chem 115

CH3 CH3 20 mol% 1-Mo CH3 CH3 OAc OAc O 22 ºC, 10 h O N H H N O C6H6 O H NHCOCF NHCOCF H H 3 H 3 H3C O OAc 91% H3C O OAc OH N N CH N CH H 3 H 3 D O N • 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 E Manzamine A sterically hindered substrates. Zhongmin, X.; Johannes, C. W.; Houri, A. F.; La, D. S.; Cogan, D. A.; Hofilena, G. E.; • The use of RCM in construction of both the D and the E rings of Manzamine A has been reported: Hoveyda, A. H. J. Am. Chem. Soc. 1997, 119, 10302–10316. Slight changes in substrate structure can control whether the E- or Z-olefin is formed:

H3C H3C CH2OTDS H3C CH3 H3C CH3 H CH2OTDS H CH3 CH3 100 mol% 2-Ru O OCH3 O O O O N 23 ºC, 5 d N CH3 CH3 O O N C6D6 O O N O CH3 CH3 O OCH3 30% O OP P = p-BrBz OP

86% 10 mol% 4-Ru 80% E-oleﬁn only Z-oleﬁn only CH2Cl2, 40% CH H C CH3 3 3 H C Borer, B. C.; Deerenberg, S.; Bieraugel, H.; Pandit, U. K. Tetrahedron Lett. 1994, 35, 3191–3194. CH 3 3 CH O 3 O O CH3 O CH3

CO CH 2 3 CO2CH3 H H CH O O PO 3 O OCH PO 3 5 mol% 2-Ru Ph N Ph N 50 ºC, 4 h O N O O C6D6 N O H CH3 63% CH3 H3C H3C CH3 CH3 O O O CH3 O CH3

Martin, S. F.; Liao, Y.; Wong, Y.; Rein, T. Tetrahedron Lett. 1994, 35, 691–694. OH O OCH OHC OHC 3 Coleophomone B Coleophomone C Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc. 2005, 127, 8872–8888. M. Movassaghi and L. Blasdel

8 Myers The Oleﬁn Metathesis Reaction Chem 115 Synthesis of Epothilone C: Solid-Phase Synthesis of Epothilone A:

• Small changes can drastically affect reaction outcome. In the example below, TBS protective O groups changes the E/Z selectivity. S CH 3 CH CH 3 HO 3 N H C CH 3 3 H O S S H3C CH CH 3 CH 3 CH O O CH 3 CH 3 = Merriﬁeld resin R1O 3 N R1O 3 N OTBS H C CH H C CH 3 3 H 3 3 H O O H C H C 3-Ru (0.75 equiv) 3 3 25 ºC, 48 h O OR O O OR O 2 2 CH2Cl2

HO S HO S R Catalyst Conditions Yield E/Z CH3 CH3 CH3 CH3 1 R2 CH3 CH3 O O H C N H C N H H 1-Mo 50 mol%, PhH, 55 ºC 65% 2 : 1 3 3 H3C O H3C O H TBS 3-Ru 10 mol%, CH2Cl2, 25 ºC 85% 1 : 1.2 H3C H3C TBSO O TBSO O TBS TBS 8-Ru 6 mol%, CH2Cl2, 25 ºC 94% 1 : 1.7 15.6% 15.6% TBS TBS 4-Ru 50 mol%, PhH, 55 ºC 86% 1 : 1.7

S S CH CH 3 CH 3 CH CH 3 CH 3 HO 3 N HO 3 N H C CH H C CH 3 3 H 3 3 H O O H3C H3C O O O O OTBS OTBS

Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, 5.2% 15.6% 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. • 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. Schinzer, D.; Bauer, A.; Bohm, O. M.; Limberg, A.; Cordes, M. Chem. Eur. J. 1999, 5, 2483– 2491. • Addition of n-octene or ethylene has been documented to provide a catalytic cycle; see: Maarseveen, J. H.; Hartog, J. A. J.; Engelen, V.; Finner, E.; Visser, G.; Kruse, C. G. Tetrahedron Lett. 1996, 37, 8249.

Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E. Nature 1997, 387, 268–272. M. Movassaghi and L. Blasdel

9 Myers The Oleﬁn Metathesis Reaction Chem 115 Applications of Olefin Metathesis in Industry • A second-generation route was developed, which permitted higher reaction concentrations and • BILN 2061 ZW was investigated as a potential medication for the treatment of hepatitis C: lower catalyst loading: • First-generation route: MesN NMe

O O PNBO Cl H S Br Boc Cl Ru O N CO2CH3 N O NO H 2 H H C 5a-Ru (3 mol %) O N O 3 N N CO2Me O CH3 (0.1 mol %) O O toluene (0.01 M) O O toluene (0.2 M), 110 ºC, 80 ºC, 83% N 95%, Z:E >99:1 O H Z:E >99:1

O 20.2-kg scale O S Br O PNBO H Boc P(c-Hex)3 N N CO CH N CO CH H 2 3 2 3 Cl OCH3 N Ru O H Cl O O N O O O N O O O H N H3C H3C CH 3 O N CH3 N 5a-Ru H S H steps N N CO2H O O O • 400 kg of the RCM product has been prepared using the first-generation route. N O H BILN 2061 ZW • During the reaction, nitrogen was bubbled through the reaction solution to remove ethylene.

• 5-Ru was not stable at 80 ºC for the duration of the reaction so the catalyst was added in several portions over 2 h.

• A dilute concentration (0.01 M) was used to minimize dimerization.

• Because traces of morpholine in the toluene led to catalyst inhibition, all toluene used was washed Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. H. Org. Process Res. with HCl prior to use. Dev. 2009, 13, 250–254.

Nicola,T.; Brenner, M.; Donsbach, K.; Kreye, P. Org. Process Res. Dev. 2005, 9, 513–515. Yee, N. K.; et al. J. Org. Chem. 2006, 71, 7133–7145. Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N. K.; Senanayake, C. H. Org. Process Res. Dev. 2009, 13, 250–254. David W. Lin, Fan Liu

10 Myers The Oleﬁn Metathesis Reaction Chem 115

• Synthesis of MK-7009 (vaneprevir), now in clinical trials for the treatment of hepatitis C: • SB-462795 is under development as a cathepsin K inhibitor for the treatment of osteoporosis:

O OH O OH O O N 5b-Ru (0.5 mol%) N N N O N O O S N O N 5b-Ru (0.2 mol%) O toluene S N O O CH3 110 ºC, 96% O OCH3 OCH3 CH3 N 2,6-dichloroquinone N H H 80-kg scale H C O N O toluene (0.13 M) H C O N O 3 O 3 O H3C 100 ºC, 91% H3C O t-Bu O t-Bu

CH3

O CH3 MesN NMe H OH N O N Cl H H N O O N Cl Ru S N O O O O O H O O CH3 N S SB-462795 H3C N N H CH3 H H3C O N O O • The choice of RCM substrate was crucial. Alternative substrates required higher catalyst loadings: 5b-Ru H3C O t-Bu CH3

vaneprevir (MK-7009) O O O OH O HN O N N • The catalyst was added over 1h to minimize decomposition and mimic high dilution, which allows the S N N O S N reaction to be run at higher concentrations. O O Ph CH3 O CH3 • The reaction yield increased when nitrogen was bubbled through the reaction solution to remove ethylene and adventitious oxygen. 5b-Ru (10 mol%): 100% 5b-Ru (11 mol%): 90% 5b-Ru (5 mol%): 60% • Trace Ru–H intermediates were trapped using 2,6-dichloroquinone, which also allowed the catalyst loading to be lowered. The diene substrate was required to be of high purity in order to achieve full conversion. Minor • It was necessary to recrystallize the starting material to avoid poisoning the catalyst with trace • impurities. urea or amide contaminants inhibited RCM.

Wang, H.; Goodman, S. N.; Dai, Q.; Stockdale, G. W.; Clark, W. M., Jr. Org. Process Res. Dev. 2008, 12, 226–234. Kong, J.; Chen, C.-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.; Dolman, S. J.; Janey, J.; Li, H.; Wang, H.; Matsuhashi, H.; Doan, B. D.; Goodman, S. N.; Ouyang, X.; Clark, W. M., Jr. Tetrahedron Zacuto, M. J. J. Org. Chem. 2012, 77, 3820–3828. 2009, 65, 6291–6303. David W. Lin, Fan Liu

11 Myers The Olefin Metathesis Reaction Chem 115 Catalytic RCM of Olefinic Enol Ethers: Tandem Ring Opening-Ring Closing Metathesis of Cyclic Olefins:

H3C O CH3CHBr2, TiCl4 12 mol% 1-Mo yield catalyst 3-Ru conc. time temp. substrate product (%) (mol%) (M) (h) (ºC) O Ph Zn, TMEDA, O Ph 20 ºC, 3.5 h cat. PbCl n-pentane O 2 H H 20 ºC, 11 h Ph H H O 88% O O O THF 82 3 0.1 1.5 45 55%

H C H C H H 3 3 H H O O O O 90 5 0.1 2 60 H C O CH3CHBr2, TiCl4 3 12 mol% 1-Mo Ph Zn, TMEDA, Ph 20 ºC, 3.5 h Ph O O O n-pentane cat. PbCl2 20 ºC, 5 h H H 88% H H O O THF O O 70 3 0.07 6 45 79%

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

Fujimura, O.; Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029–4031. O 68 6 0.04 2 45 O O H H O

H 2 H C CH O H H Ti Al 3 O O Cl CH3 O 92 5 0.04 3 60 H Tebbe reagent Tandem Olefination-Metathesis • Without sufficient ring strain in the starting cyclic olefin, competing oligomerization (via CM) can occur. H H BnO BnO • Higher dilution favors intramolecular reaction: H Tebbe reagent H O O O (4.0 equiv) O H H O THF, 25 ºC, 0.5 h; O O H R reflux, 4h R R O O R 6 mol% 3-Ru O CH3 O H H H C6H6, 45 ºC R = H 50% mixture of E/Z isomers 6 h CH3 54% R = H 0.12 M 16% H 0.008 M 73% CH3 0.2 M 42% • Here, a Ti-alkylidene is used in RCM. • The relative rate of intramolecular metathesis versus CM may be further increased by Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc. 1996, 118, substitution of the acyclic olefin. 10335-10336. M. Movassaghi

12 Myers The Oleﬁn Metathesis Reaction Chem 115 Proposed Mechanism for Ring Opening-Ring Closing Metathesis Examples in Complex Synthesis:

LnRu CHPh H H CH CH O O 3 3 CH3 CH3 CH3 CH3 H3C H3C H C 3 2 mol% 3-Ru O Ph ethylene O O O OPMB O H H 95% O O LnRu H2C CH2 H H O O CH3 CH3 25 mol% 5-Ru toluene, ! H H CH3 CH3 O H C H C O 3 O O 3 O 76% LnRu CH2 H C H H 3 O RuLn HO HO H H H HO OH OPMB O O H H O O Ingenol

RuLn

Nickel, A.; Maruyama, T.; Tang, H.; Murphy, P. D.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. • Initial metathesis of the acyclic oleﬁn is supported by the fact that substitution of this oleﬁn Chem. Soc. 2004, 126, 16300–16301. decreases the rate of metathesis.

• Subtle conformational preferences within the substrate are key to the success of these O transformations; as shown, trans-1,4-dihydronaphthalene diamide undergoes efﬁcient ring O 20 mol% 4-Ru H H O opening-ring closing metathesis while the corresponding diester and diether derivatives do not. O ethylene, toluene CH CH H C CH 3 3 3 3 43% (3 steps) H C CH O N O N 3 3

10 mol% 3-Ru

0.1 M, C6D6 40 ºC, 8 h H C 3 CH O N O N 3 OH 95% CH3 CH3 H H CH3 unreactive substrates: O O O O H3C CH3

Cyanthiwigin U

O O O Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334–5335. Zuercher, W. J.; Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634–6640. M. Movassaghi and L. Blasdel

13 Myers The Oleﬁn Metathesis Reaction Chem 115 Synthesis of Cyclic !-Turn Analogs by RCM Template-Directed RCM

O 5 mol% 3-Ru O H C O H C H 3 CH H 3 CH 3 3 O O "template" N O N O O O O O N H 20 mol% 2-Ru N H n CH2Cl2, THF O O H N H O H N O H O 45 °C, 1 h CH2Cl2, 40 °C n = 1, 2 n N N 0.02 M n = 1, 2 N Bn N Bn Boc 60% Boc H H substrate (n) "template" (equiv) yield (%) cis:trans

1 none 39 38 : 62 1 LiClO (5) >95 100 : 0 • The presence of the Pro-Aib sequence in the tetrapeptide induces a ß-turn conformation 4 which was covalently captured by RCM, yielding a 14-membered macrocycle. 1 NaClO4 (5) 42 62 : 38 2 none 57 26 : 74

2 LiClO4 (5) 89 61 : 39 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. • 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 CH3 H3C O H3C O CH3 CH3 5 mol% 3-Ru H C H C 3 N O 30 mol% 3-Ru 3 N O H N H H N H O H N O O H N O CH2Cl2 H 0.004 M, 21 h H N N 1.2 M, 23 °C OBn CH2Cl2, 40 °C OBn Boc Boc O >95% O O 60% O O O O m O M = 65900 5 mol% 3-Ru n LiClO4 • Although interactions that increase the rigidity of the substrate and reduce the entropic cis : trans, 1 : 3.7 cost of cyclization can be beneficial in RCM, it is not a strict requirement for CH2Cl2 0.02 M, 50 °C macrocyclization by RCM. >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. Miller, S. J.; Blackwell, H. E.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 9606–9614.

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

14 Myers The Oleﬁn Metathesis Reaction Chem 115

3,727&8(-$&8),*9-:&#$),-;$4<& !"#$%&'(')*+),-$&#-#&' U ( $&' )7 )7 = \++]%7+710%G=27/1I;7+8_8J18+`7`G1I7+8_8J,f=Pd=$%7=b= !=AJ.=d=#,E,.JJ_J>J_=b= !=AJ.QO g " " +++/7J^=.//7E?J7/+G,+^,2E+GC,+/J,C=7e8%.B01B0+.BG1`.2.JJ7J+=/%77G=J197+%_I2,07B+?,BI7I+ " " (L +++8_J1BI72/+PZ.PDbDJKQ+T+XX+) 3+,BJ_+G%7+27.8G1-7+1/,E72+1/+/%,CBQ* " " ! ! $% $% D;PD#KD!QR$&' ! ! "" O " " ! ! D# DJ 3+D# D! !! ! O O K ! ! ! ! ! " " # " # " " #" # LMMS " " " " " # " # " " "" " " # # ! ! ! ! ! " " ! ! ! " " "" T+D;U $% $% V+E,JS+1234 OK+WD3+'+% OM=OV+E,JS+5234 M*ML+)3+D#ODJO DbDJK3+OK+WD3+RN+% XOS 'VS U ( $&' " " " " $% $% "" " " " " " !!" !! ! ! ! ! " " " " # " # " " #" # ! ! ZD!3+#O" ! ! " # " # " " # # ! ! ! ! ! D#KD! ! ! ! ! ! ! ! " " [LMMS "" " " " " $% $% " " " " \++]%7+%_I2,07B=?,BI7I+7B/7E?J7+`,/1G1,B/+G%7+G72E1B.J+,J7^1B/+,^+G%7+^,;2 "" +++d=%,E,.JJ_J0J_81B7+27/1I;7/+1B+/;^^1817BGJ_+8J,/7+`2,e1E1G_+G%.G+7.8%+`.12+;BI720,7/+@D)+ "" +++1B+G%7+`27/7B87+,^+.J9_J1I7B7+5234+G,+01-7+.+G218_8J18+8_J1BI218.J+`2,I;8G+8,BG.1B1B0+.+KN= +++E7E?727I+21B0+./+.+E1eG;27+,^+G%277+P81/=81/3+81/=G2.B/3+G2.B/=G2.B/Q+,J7^1B+1/,E72/* KO=E7E?727I+8.G7B.B7 G2.B/Y81/3+XNYO

\++]%1/+8,-.J7BG+8.`G;27+/G2.G70_+E._+?7+;/7^;J+1B+/G.?1J1a1B0+91B7G18.JJ_+J.?1J7+=%7J18.J+.BI+ +++=/%77G+`7`G1I7+/78,BI.2_+/G2;8G;27/* \++]%7+27E.29.?J7+7^^1817B8_+,^+G%1/+@D)+1/+`2,`,/7I+G,+?7+I;7+G,+`27,20.B1a.G1,B+,^+G%7+ +++/;?/G2.G7* ),%23+4*5+67893+)*5+:.;-.073+<*=$*5+>2;??/3+@*+#*+AB07C*+D%7E*3+FBG*+HI*+HB0J*+.//03+K'3+ DJ.293+]*+b*5+>%.I1213+)*+@*+<*+AE*+D%7E*+:,8*+.//63+LLc3+LOK'R(LOK'V* LKMN(LKLM*

)*+),-.//.0%1

15 Myers The Oleﬁn Metathesis Reaction Chem 115 Cross Metathesis

Olefin categorization and rules for selectivity

Type I – Rapid homodimerization, homodimers reactive Reaction between two olefins of Type I...... Statistical CM Type II – Slow homodimerization, homodimers largely unreactive Reaction between two olefins of same type (non-Type I)...... Non-selective CM Type III – No homodimerization Reaction beween olefins of two different types...... Selective CM Type IV – Olefins inert to CM, but do not deactivate catalyst (spectator)

Selective Cross-Metathesis Reactions as a Function of Catalyst Structure:

MesN NMes i-Pr i-Pr P(c-Hex)3 N Cl CH Ph F3C 3 Cl Ph Ru O Mo Ru Cl H Ph F3C Cl H CH3 P(c-Hex)3 CH3 O P(c-Hex)3 H F3C 4-Ru 3-Ru CH3 1-Mo F3C Olefin type

terminal olefins, 1° allylic alcohols, esters, allyl boronate esters, allyl halides, styrenes (no large Type I terminal olefins, allyl silanes, 1° allylic alcohols, ortho substit.), allyl phosphonates, allyl silanes, terminal olefins, allyl silanes (fast homodimerization) ethers, esters, allyl boronate esters, allyl halides allyl phosphine oxides, allyl sulfides, protected allyl amines

styrenes (large ortho substit.), acrylates, Type II acrylamides, acrylic acid, acrolein, vinyl ketones, styrene, 2° allylic alcohols, vinyl dioxolanes, styrene, allyl stannanes (slow homodimerization) unprotected 3° allylic alcohols, vinyl epoxides, 2° vinyl boronate allylic alcohols, perfluoalkyl substituted olefins

1,1-disubstituted olefins, non-bulky trisub. olefins, Type III vinyl phosphonates, phenyl vinyl sulfone, 4° allylic vinyl siloxanes 3° allyl amines, acrylonitrile (no homodimerization) carbons (all alkyl substituents), 3° allylic alcohols (protected)

1,1-disubstituted olefins, disub a,b-unsaturated Type IV vinyl nitro olefins, trisubstituted allyl alcohols carbonyls, 4° allylic carbon-containing olefins, 1,1-disubstituted olefins (spectators to CM) (protected) perfluorinated alkane olefins, 3° allyl amines (protected)

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370. L. Blasdel

16 Myers The Oleﬁn Metathesis Reaction Chem 115 Non-selective Cross Metathesis: Two Type I Olefins Olefin 1 Olefin 2 producta,b Isolated Yield (%) E/Z Secondary allylic alcohols (Type II with Type I) 3 mol% catalyst OAc + CH3 AcO OAc CH3 OAc CH Cl , 40 °C, 12 h 3 82 10 : 1 2 2 BzO OAc 2 equiv. BzO 2 equiv. 3 80 % CH CH3 OAc 3 catalyst E/Z 3 50c (62)d 14 : 1 HO OAc HO 1 equiv. 3 3-Ru 3.2 : 1 CH CH3 OAc 3 4-Ru 7 : 1 3 53 6.7 : 1 TBDPSO OAc TBDPSO 2 equiv. 3 • 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 Quaternary allylic olefins (Type III with Type I) olefin to the more thermodynamically stable trans isomer. H3C CH3 H3C CH3 Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, OAc 93 >20 : 1 HO 3 HO OAc 125, 11360–11370. 2 equiv. 3

• Selectivity for the trans olefin can also be enhanced using sterically hindered substrates: O O O O 2 mol% 1-Mo OAc 91 >20 : 1 PhO + SiR3 PhO SiR3 3 H3C H C DME, 23 °C, 4 h 3 3 3 OAc 3 1 equiv. R Yield E/Z 1,1-Disubstituted olefins (Type III with Type I) CH3 72% 2.6 : 1

OAc Ph 77% 7.6 : 1 BzO 3 BzO OAc 3 80 4 : 1 CH3 2 equiv. CH3 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 O O homodimerization pathways. OTBS H N 7 H N OTBS 71 >20 : 1 2 1.2 equiv. 2 7 • The lower yield obtained with the unprotected alcohol is a result of homodimerization of CH3 CH3 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. O O CH3 8 23 4 : 1 HO HO CH3 OR 6 mol% 4-Ru OR 1.1 equiv. 8 + AcO CH3 CH3 AcO CH3 3 3 CH2Cl2, 40 °C, 12 h H C CH CH 3 3 3 O H C O 3 OAc 3 97 >20 : 1 R = H 58% yield H CH3 H 3 OAc R = TBS 97% yield CH3 1.0 equiv. CH3

Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360– a b 3–5 mol% 4-Ru, CH2Cl2, 40 °C. See last reference on left half of this page. 11370. c d With 2 equiv Olefin 2, the yield was 92%. Reaction was performed at 23 °C L. Blasdel

17 Myers The Oleﬁn Metathesis Reaction Chem 115

Olefin 1 Olefin 2 producta,b Isolated Yield (%) E/Z Selective Cross-Metathesis Reactions: OTr Type II and Type III O Type IV OTr O N O O O C(CH ) H 10 mol% 4-Ru 3 3 73 (H3C)3Si neat O N HO HO C(CH3)3 Type I + CH2Cl2, 40 °C, 4 h H

O 50% isolated yield O C(CH ) Si(CH3)3 3 3 73 1.5 : 1 E/Z neat 1.5 equiv t-BuO t-BuO C(CH3)3

CH3 O O CH3 OTr 83 2 : 1 O 3 CH3 Type III HO HO 3 CH3 OTr 4.0 equiv. Cl3C N O H 10 mol% 1-Mo Si(CH ) Cl C N 3 3 + CH2Cl2, 40 °C, 16 h 3 CH3 Type I H O O CH3 55 R = H 2 : 1 CH3 83 R = CH Si(CH ) 98% isolated yield EtO R 3 EtO CH 3 2 : 1 3 3 4.0 equiv. 3 3 >20 : 1 E/Z 1.5 equiv

F AcO OAc F Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446 98 >20 : 1 2.0 equiv. OAc (H3C)3Si 10 mol% 1-Mo F F H + Si(CH ) AcO OAc 3 3 H CH Cl , 40 °C, 8 h OAc 50 >20 : 1 CbzHN CO2CH3 2 2 CbzHN CO CH 2.0 equiv. 97% ee 2 3 F F 95% 92% ee O CO2CH3 92 >20 : 1 Brümmer, O; Rückert, A.; Blechert, S. Chem. Eur. J. 1997, 3, 441–446. OCH3 1.5–2.0 equiv. 5 mol% 1-Mo + R NC R NC O CO CH 2 3 CH2Cl2, 23 °C, 3 h OEt 87 >20 : 1 H C CH 3 3 1.5–2.0 equiv. H3C CH3 R yield (%) E/Z

CH2Si(CH3)3 76 1 : 3 CH3 O CH3 CO2CH3 (CH3)3OBn 60 1 : 7.6 OEt 5 >20 : 1 (CH ) CO Bn 44 1 : 5.6 1.5–2.0 equiv. 2 2 2 H3C CH3 H3C CH3

a 1–5 mol% 4-Ru, CH2Cl2, 40 °C. • The basis for the high cis-selectivity with acrylonitrile as substrate is not known. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360– Crowe, W. E.; Goldberg, D. R. J. Am. Chem. Soc. 1995, 117, 5162–5163. 11370. L. Blasdel and M. Movassaghi

18 Myers The Oleﬁn Metathesis Reaction Chem 115

Reagent preparation Examples in synthesis A Horner-Wadsworth-Emmons reagent: • En route to the ABS ring fragment of thyrsiferol:

O O CH O O 4 mol% 4-Ru 3 10 mol% 4-Ru + EtO P H C H3C O + OTBS EtO P OEt 3 O OEt CH Cl , 40 °C, 12 h EtO O CH2Cl2, 45 °C EtO 2 2 H3C OAc 87% Br >20 : 1 E/Z

Toste, F. D.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem. 2002, 74, 7–10. CH3 CH3 H C H3C O H C 3 O H3C 3 O O OTBS H3C OAc A Suzuki reagent: H3C OAc 2 O Br Br H C 3 CH H3C 3 CH3 starting material homodimer 44% E-isomer O CH 5 mol% 4-Ru O 64% after recycling the homodimer + 3 CH3 AcO B CH B 3 O 3 AcO O CH3 CH2Cl2, 40 °C, 12 h 3 CH McDonald, F. E.; Wei, X. Org. Lett. 2002, 4, 593–595. 3 CH3 58% 2.0 equiv >20 : 1 E/Z • CM can be difficult in the presence of strained olefins, as was found in the preparation of the AB ring fragment of ciguatoxin:

Morrill, C.; Funk, T. W.; Grubbs, R. H. Tetrahedron Lett. 2004, 45, 7733–7736. H O O OBn 5 mol% 3-Ru OBn One-pot CM and allylboration reactions: O OBn O OBn CH2Cl2, 23 °C, 30 min H OBn H OBn 95% compound A 40 mol% 3-Ru 1. 3 mol% 3-Ru CH Cl , 40 °C CH3 AcO 2 2 H3C OH CH2Cl2 40 °C, 24 h OAc O 33 h H3C + B Ph H3C O 2. PhCHO (2 equiv.), 23 °C Ph 2.0 equiv H H 88% O O OBn OBn 91 : 1 anti:syn + OBn O OBn AcO O AcO H H H OAc H OBn OAc OBn 19% 8% Yamamoto, Y.; Takahashi, M.; Miyaura, N. Synlett 2002, 128–130. via ring opening to compound A AB ring fragment of ciguatoxin

Oguri, H.; Sasaki, S.; Oishi, T.; Hirama, M. Tetrahedron Lett. 1999, 40, 5405–5408 L. Blasdel

19 Myers The Oleﬁn Metathesis Reaction Chem 115 Ring Opening Cross-Metathesis Metathesis of Enyne Substrates mol% Catalytic RCM of Dienynes: Construction of Fused Bicyclic Rings substrate product alkenea cat.b time yield E,E;E,Z n m n m n m n m CH OH C 3 2 CH2OCH3 [M]L A 6 96 94 2 : 1 [M]Ln n CO CH H3CO2C CO2CH3 H3CO2C 2 3 R R R R

• Fused [5.6.0], [5.7.0], [6.6.0], and [6.7.0] bicyclic rings have been successfully constructed by RCM of dienynes. Et Et B 2 14 85 2 : 1 H3C O O Et SiO O O O O OSiEt3 3 3 mol% 2-Ru OSiEt3 + 25 °C, 8 h Et Et 0.06 M CH3 c CH2Cl2 C 8 3 73 1.5 :1 CH3 NBoc NBoc dienyne diene O O RCM RCM 95% <3%

• The dienyne RCM is largely favored over the competing diene RCM. CH3OH2C CH2OCH3 A 2 89 15 NA

O O O O OSiEt3 O O OSiEt3 3-5 mol% 2-Ru

0.05-0.1 M a25 °C; 1.5 Equivalents of alkene used: A = trans-1,4-dimethoxybut-2-ene; C D 6 6 R B = trans-hex-3-ene; C = cis-hex-3-ene. Solvent: C6H6 (entries 1 and 2) or R b c CH2Cl2 (entries 3 and 4). Cat. = 2-Ru. Cat. = 3-Ru.

R yield (%) conditions • In these cases a preference for the E-olefin geometry is observed in ring opening H >98 23 °C, 15 min metathesis. CH3 95 23 °C, 8 h i-Pr 78 60 °C, 4 h • Higher yields were achieved by slow addition of the cyclic alkene to a solution of t-Bu NR the 1,2-disubstituted alkene. Ph 96 60 °C, 3 h CO2CH3 82 60 °C, 4h Si(CH3)3 NR • Faster and more efficient ring opening cross metathesis was observed using Sn(n-Bu)3 NR cis-hex-3-ene vs. trans-hex-3-ene. Cl, Br, I NR

Schneider, M. F.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 411–412. • Mo-, W- or Ti-based catalysts are not effective for the above transformations.

• Reaction rates decrease as the size of the acetylenic substituent increases. 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, • Substrates containing heteroatoms directly attached to the acetylene do not cyclize. 11603–11604. M. Movassaghi

20 Myers The Oleﬁn Metathesis Reaction Chem 115 yield mol% time conc. temp substrate product (%) 2-Ru (h) (M) (°C) Enyne Metathesis Reactions Catalyzed by PtCl2 OSiEt 3 OSiEt3 substrate product yield 88 6 8 0.06 65 PhO S SO Ph PhO S SO Ph 2 2 H C 2 2 CH3 3 96% OSiEt 3 OSiEt3 CH3 83 3 6 0.03 65 H CH O CH3 3 OCH3 O H OSiEt 70% 3 OSiEt3 O

78 15 1.5 0.01 100 O OCH3

CH H3C CH3 3 H H O OSiEt O 3 OSiEt3 54% 89 15 12 0.05 65 CH 3 CH3 CH CH3 3

CH3 O H3C O Ts H N H 88 3 6 0.05 65 80% TsN CH3 CH CH3 3 • Regiochemical control within unsymmetrical substrates is achieved by substitution of the a olefin required to undergo metathesis last. Reactions conducted in toluene at 80 °C using 4-10 mol% of PtCl2 • Unsymmetrical substrates containing equally reactive olefins produce a mixture of bicyclic products: OSiEt • In most cases commercial PtCl2 was used as received. OSiEt3 OSiEt3 3 RuLn RuLn • A pathway involving complexation of cationic Pt(II) with the alkyne has been proposed. RuLn • Remote alkenes are unaffected. RuLn CH CH3 CH3 3

OSiEt3 OSiEt3 OSiEt3 OSiEt3 RuL n Fürstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785–6786. LnRu CH3 CH3 CH3 86%, 1:1 CH3

Kim, S.-H.; Zuercher, W. J.; Bowden, N. B.; Grubbs, R. H. J. Org. Chem. 1996, 61, 1073–1081. M. Movassaghi, L. Blasdel

21 Myers The Oleﬁn Metathesis Reaction Chem 115

Enyne Metathesis in Synthesis Enyne Cross-Metathesis • 4-Ru outperforms 3-Ru in both rate and overall conversion in the cross-metathesis of ethylene CH3 CH3 and alkynes. TBSO TBSO TBSO substrate (+ethylene) product time (h) yield (%)

OCH 3 OR OR OTBS R = H 2.0 73 CH3 OTBS R = Ac 2.0 92 R = TBS 8.5 91 40 mol% 3-Ru 1. 50 mol% 3-Ru ethylene, toluene, 45 °C ethylene, CH2Cl2, 40 °C 2. TBAF, THF, 0 to 23 °C 31 % OAc OAc 42% (two steps) H3C 16 77 CH3 H3CO OTBS CH3 H H3C TBSO TBSO OCH3 AcO AcO CH3 OTBS 4.0 69 TBSO OAc OAc

H C H C NTs H C NTs 3 3 3 4.0 91 O O H CH3 (–)-Longithorone A O BnO 6.0 72 H OHC BnO O CH3 aReactions conducted in CH Cl at 23 °C using 5 mol% of 4-Ru at 60 psi of Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773–775. 2 2 ethylene pressure.

CO2CH3 H3CO2C • Reactions conducted at 1 atm of ethylene pressure typically gave low conversions even after 12 mol% 4-Ru extended reaction times. H3C CH3 The more reactive imidazolylidene 4-Ru can tolerate free hydroxyl groups and coordinating CH3 CH2Cl2, reflux, 3 h • CH3 H C functionality at the propargylic and homopropargylic positions. 3 H3C CH3 H3C CH3 CH3 • Chiral propargylic alcohols afford chiral diene products without loss of optical purity: O OHC OH AcO OH 4-Ru (5 mol%) OH

Ph ethylene (60 psi) Ph H3C H C CH 3 3 CH2Cl2, , 23 °C CH3 Guanacastepene A 99% ee 99% ee

Boyer, F.-D.; Hanna, I.; Ricard, L. Org. Lett. 2004, 6, 1817–1820. Smulik, J. A.; Diver, S. T. Org. Lett. 2000, 2, 2271–2274 L. Blasdel and M. Movassaghi

22 Myers The Oleﬁn Metathesis Reaction Chem 115 Kinetic Resolution via Asymmetric RCM Catalytic, Enantioselective RCM

H OSiEt3 H OSiEt3 R1 R1 H OSiEt3 CH3 5 mol% 12-Mo CH3 N + H3C CH3 i-Pr i-Pr t-Bu 22 ºC, 10 min Mo R CH3 CH3 N O 2 C6H6 Ph CH F3C O 3 O Mo H F3C CH3 t-Bu 19%, >99% ee 43%, 93% ee O CH3 H3C H H3C CH3 5 mol% 12-Mo CH3 H C CF3 H C 3 3 + CF3 CH 3 H 22 ºC, 2 min H H CH3 CH3 OSiEt3 C6H6 OSiEt3 OSiEt3 11-Mo 12-Mo: R1 = i-Pr R2 = Ph 13-Mo: R1 = CH3 R2 = Ph 50%, <5% ee 40%, <5% ee 14-Mo: R1 = Cl R2 = Ph 15-Mo: R1 = Cl R2 = CH3 • 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, 2 mol% 11-Mo 120, 4041–4042. + Et3SiO CH3 –20 ºC, 660 min Et3SiO CH3 Et3SiO Mo-alkylidene Catalyzed Kinetic Resolution and Enantioselective Desymmetrization CH3 toluene CH3 CH3 via RCM 38%, 48% ee 62% H C O 5 mol% 12-Mo O 3 + H C H H C H • The ﬁrst catalytic, asymmetric kinetic resolution via RCM was achieved, with low selectivity, using 3 C6H5CH3 3 R R R O the chiral alkylidene 11-Mo. H

Proposed Transition State Models for the Observed Selectivity recovered R temp. (ºC) time (h) conv. (%) SM ee (%) krel

Ar Ar n-C5H11 –25 6 63 92 10 H H OSiEt H N 3 N i-C4H9 –25 10 56 95 23 H C H C F3C 3 F3C 3 O Mo H O Mo OSiEt c-C H F3C F3C 3 6 11 –25 7 62 98 17 O O CH CH 3 3 c-C6H11 22 0.1 64 97 13 CF3 CF3 CF3 CF3 C6H5 –25 6 56 75 8

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

Ar = 2,6-(i-Pr)2C6H3 Mo or 13-Mo. O O

H H3C CH3 Fujimura, O.; Grubbs, R. H. J. Org. Chem. 1998, 63, 824–832. n-C5H11 C6H5 Fujimura, O.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 2499–2500. H3C M. Movassaghi

23 Myers The Oleﬁn Metathesis Reaction Chem 115 • The alkylidene catalysts 12-Mo and 13-Mo are very effective in catalytic, enantioselective • Desymmetrization metathesis reactions have been used to make a variety of heteroatom- desymmetrization processes, especially in the case of secondary allylic ethers. containing products:

H C O 3 H H3C CH3 H3C CH3 1-2 mol% 13-Mo Si H3C O 5 mol% 12-Mo O 22 °C, 5 min Ph O Si CH R R 3 Ph neat R CH CH Cl , 22 °C, 6 h H C 3 2 2 1. m-CPBA 3 CH R = H CH3 3 2. n-Bu4NF R = CH3 H3C 92% 93% ee • Remarkably, this catalytic, asymmetric RCM can be carried out in the absence of solvent, HO with <5% dimer formation. Ph OH CH3 • The catalytic, enantioselective desymmetrization of tertiary allylic ethers requires the use of H3C 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. 5 mol% 13-Mo O -–20 °C, 18 h O toluene 5 mol% 14-Mo CH 3 PhH, 22 °C, 12 h CH3 84%, 73% ee H3C 41%, >98% conv. O O O O 83% ee 5 mol% 13-Mo O -–20 °C, 18 h O toluene • Only 29% ee was observed using 12-Mo. 14-Mo is the catalyst of choice for synthesizing non-racemic acetals. 91%, 82% ee

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

• 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.

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. M. Movassaghi and L. Blasdel

24 Myers The Oleﬁn Metathesis Reaction Chem 115 • Ruthenium based catalysts can also be used for enantioselective desymmetrizing RCM for the preparation of allyl ethers: i-Pr i-Pr Ph Ph C6H2(i-Pr)3 N yield catalyst temp ee O i-Pr R substrate product (%) (mol%) (ºC) (%) CH3 N N Mo O Ph i-Pr R O CH X 3 Ru O O C H (i-Pr) Ph X 6 2 3 H C H3C CH3 3 64 17-Ru 40 90 PCy3 H (4) CH3 H C H3C CH3 3 16-Mo 17-Ru: R = H, X = I 18-Ru: R = i-Pr, X = Cl

H3C CH3 H3C CH3 • Catalyst 16-Mo was found to be effecive for the synthesis of cyclic enol ethers by an Si Si O O enantioselective desymmetrizing RCM: 77 18-Ru 40 92 H3C CH3 H3C (0.8) H CH3 H3C CH3 H3C yield 16-Mo time temp ee substrate product (%) (mol%) (h) (ºC) (%) Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 1840–1846.

• Synthesis of azaheterocycles CH3 O O CH3 70 10 6 22 90 • Arylamines are compatible with Mo catalysts: H3C CH3

CH3 O CH3 O catalyst 96 15 20 22 87 H C CH PhH, 22 °C 3 3 H3C N n H3C CH3 Ph H3C N n Ph Ph Ph

%mol n catalyst catalyst time yield ee O O 94 15 17 22 94 1 12-Mo 5 20 min 78% 98% H3C CH3 H3C CH3 CO2Me 2 12-Mo 2 7 h 90% 95% CO2CH3 3 15-Mo 5 20 min 93% >98%

*The absolute stereochemistry of the RCM products was not reported. *The absolute stereochemistry of the RCM products was not reported.

Lee, A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 5153–5157. Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.; Schrock, R. R. J Am. Chem. Soc. 2002, 124, 6991– 6997. David W. Lin, Fan Liu

25 Myers The Oleﬁn Metathesis Reaction Chem 115

• Mo catalysts can be used for the synthesis of cyclic amides and amines, although a high catalyst • Chiral MAP complexes are prepared from enantiomerically enriched monoprotected diols. They loading is often required. Free secondary amines are tolerated but only when the amine contains are sensitive to air and moisture and must be handled in the glovebox. a fully substituted !-carbon center. • These complexes are isolated as diastereomeric mixtures: H yield catalyst time temp ee N substrate product (%) (mol%) (h) (ºC) (%) H3C CH3 X i-Pr i-Pr O O N CH3 OTBS N N + 16-Mo N Mo Ph OH 91 48 22 >98 C6H6 (10) CH3 H3C N 22 °C, 1.0 h CH CH3 3 X CH3 enantiomerically i-Pr i-Pr CH3 CH3 enriched CH3 N 15-Mo N H3C CH3 CH3 95 24 22 71 (5) H3C Mo Ph N N O CH3 H Ph H Ph X X TBSO

CH For 19-Mo: >98% conv, dr = 5:1 CH3 3 "Monopyrrolide aryloxide For 20-Mo: 95% conv, dr = 7:1 (MAP) stereogenic-at-Mo" CH3 94 13-Mo 24 22 97 For 21-Mo: 60 ºC, 94% conv, dr = 3:1 complexes H (5) N CH3 N Cbz Cbz • Kinetic studies indicate that Curtin-Hammett kinetics are operating under the reaction conditions: these diastereomeric complexes rapidly equilibrate, and one diastereomer catalyzes RCM at a *The absolute stereochemistry of the RCM products was not reported. faster rate.

Sattely, E. S.; Cortez, G. A.; Moebius, D. C.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2005, 127, 8526–8533. catalyst yield ee catalyst yield ee substrate product (mol%) (%) (%) (mol%) (%) (%) • Monopyrrolide aryloxide (MAP) complexes 19–21 exhibit improved catalytic activity in enantioselective RCM desymmetrization reactions: N N 20-Mo 13-Mo CH >98 92 <75 30 H C 3 (1) (15) CH3 3 i-Pr i-Pr H3C CH3 N N H3C H3C Mo Ph O CH3 N X X N 19-Mo 13-Mo TBSO 86 81 ND 40 H C (3) (5) 19-Mo: X = Cl CH3 3 CH3 H3C 20-Mo: X = Br 21-Mo: X = I *The absolute stereochemistry of the RCM products was not reported. Monopyrrolide aryloxide (MAP) complexes Malcolmson, S. J.; Meek, S. J.; E. S. Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456, 933–937. David W. Lin, Fan Liu

26 Myers The Oleﬁn Metathesis Reaction Chem 115 Examples of Enantioselective Olefin Metathesis in Synthesis

• An enantioselective ring-opening-cross-metathesis (ROCM) reaction: N N catalyst Ph Ph N PhCH , 22 ºC N 3 H MesN N H >98% conv., 84% yield I 96% e.e. (e.r., 98:2) Ru catalyst yield ee O (mol%) (%) (%) Oi-Pr PtO (5.0 mol%) OPMB OPMB 2 19-Mo (1 mol%) 84 96 H (1.0 atm) CH H C CH 2 H3C 3 3 3 20-Mo (1 mol%) Ph (2.0 mol%) Na (NH3), t-BuOH 83 95 EtOH, 22 °C, 97% O 21-Mo (1 mol%) 93 93 Ph , no solvent Ph O Et2O, –78 ºC, 70% Other Mo catalysts <5 – –15 ºC, 62%, 88% ee N E:Z >98:2

N CH3 Et O H CH CH CH CH CH 3 3 3 3 3 (+)-quebrachamine O O Ph H3C O O OH O O PMBO OH Malcolmson, S. J.; Meek, S. J; Sattely, E. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456, 933– CH CH 3 3 937. Et Et single olefin regioisomer baconipyrone C Cl Cl

C6H2(i-Pr)3 N O Gillingham D. G., Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46, 3860–3864. CH3 O Mo CH3 O CH3 C6H2(i-Pr)3 H3C CH3 Si OH TBSO OTBS CH O 1. 18-Ru (0.75 mol%) OH CH3 3 CH H C 3 (3.0 mol%) CH3 H3C CH3 CH2Cl2, 40 ºC 3 2. KF, H O , KHCO CH H 2 2 3 H C 3 H3C CH3 THF, MeOH, 23 ºC 3 n-pentane, 22 ºC steps 64%, 92% ee 97%, 87% ee steps HO OH CH3 H3C OHC OH CH3 O CH3 CH3 CH3 CH3 H

5-epi-citreoviral H3C africanol

Weatherhead, G. S.; Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Proc. Natl. Acad. Sci., U.S.A. Funk, T. W. Org. Lett. 2009, 11, 4998–5001. 2004, 101, 5805–5809. Alpay Dermenci, David W. Lin, Fan Liu

27 Myers The Oleﬁn Metathesis Reaction Chem 115

Z-Selective Oleﬁn Metathesis yield 22-Mo time temp ee substrate Oleﬁn product (%) (mol%) (h) (ºC) (%) Z:E Soon-to-be-Published Review: Hoveyda, A. H.; Khan, R. K. M.; Torker, S.; Malcolmson, S. J. 2013 (We gratefully acknowledge Professor Hoveyda and co-workers for making this review available to us ahead of print). OCH3 OCH3 OTBS TBSO 80 1 0.5 22 94 95:5 H3C CH3 O CH3 CH3 N N N CH3 N CH3 H3C H C O Mo Ph 3 Mo Ph O CH3 O CH3 Br Br Br Br OTBS TBSO TBSO TBSO CH 54 2 1 22 99 88:12 O CH3 3 O 22-Mo 23-Mo

OBn OBn

Cl Cl Ph Ph 75 5 1 60 84 95:5 MesN N O N O N O W t-Bu O N Ru O OTBS OTBS i-Pr O i-Pr i-Pr i-Pr i-PrO Ph 83 2 1 22 94 96:4 O Ph i-Pr i-Pr O 24-W 25-Ru

• Because olefin metathesis is a reversible process, metathesis catalysts typically afford the Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844–3845. thermodynamically more stable trans olefin isomer. • Enol ethers can also be used: • In 2009, a Z-selective Ring Opening Cross Metathesis reaction was reported, the first example of Z-selective olefin metathesis: The bulky, freely rotating phenoxide ligand forces the alkene substituents to be cis in the metallocyclobutane intermediate: yield 22-Mo time temp ee substrate Oleﬁn product (%) (mol%) (h) (ºC) (%) Z:E

OTBS OTBS H3C On-Bu N N On-Bu 80 0.6 0.5 22 89 >98:2 R2 CH O OTBS M R1 3 OTBS 22-Mo (1 mol%) O Ph O Ph O Br Br O H3C Ph On-Bu C6H6, 22 ºC 79 3 0.5 22 89 >98:2 TBSO Ph CH On-Bu 85%, 97% ee 3 Z:E > 98:2

Yu, M.; Ibrahem, I.; Hasegawa, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 2788–2799. Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844–3845. David W. Lin, Fan Liu

28 Myers The Oleﬁn Metathesis Reaction Chem 115

• Z-Selective Cross Metathesis • Z-allyl- and Z-alkenylboron compounds • Mo-based catalysts have been developed for Z-selective cross metathesis of several substrate classes. 22-Mo (5 mol%) • Enol ethers (pin)B + (pin)B OPMB C6H6, 22 ºC OPMB (5.0 equiv) 92% yield, Z:E = 97:3 O 23-Mo (2.5 mol%) On-Bu O n-BuO

OPh C6H6, 22 ºC OPh (10 equiv) 73%, Z:E = 98:2 • Mo-based catalysts are sensitive to air and moisture and must be prepared in situ and handled in the glovebox:

OH Br Br • By decreasing the reaction pressure, the stoichiometry of the reaction can be improved: lowering TBSO H3C CH3 the pressure removes ethylene, which competitively reacts with the catalyst to form a highly CH3 N reactive metal alkylidene complex that can potentially catalyze unwanted Z- to E-isomerization. N CH3 H3C H3C CH3 Mo Ph CH3 N O CH3 N H3C Br Br Si(i-Pr)3 23-Mo (2.5 mol%) C16H33 Si(i-Pr)3 H3C Mo Ph C6H6, 22 °C, 1 h TBSO C16H33 + O O H3C CH3 1.0 torr, C6H6, 22 ºC; N (n-Bu) NF (2.0 equiv) (1.0 equiv) 4 CH3 23-Mo 85% yield, Z:E >98:2

Ibrahem, I.; Yu, M.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131, 3844–3845. Hock, A. S.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 16373–16375. Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011, 471, 461–466.

• Allylic amides and ethers • Tungsten-based catalysts are less reactive but more stable than Mo-based catalysts and can be handled in air. 24-W can be used for the synthesis of Z-allylboron compounds. Sensitive to isolation, Z-allylboron compounds were prepared in situ and used directly in subsequent reactions: 22-Mo (2.5 mol%) Br NPhth Br ( )6 NPhth ( ) OTBS + 6 7.0 torr, C6H6, 22 ºC; (3.0 equiv) 93% yield, Z:E = 96:4 OTBS C8H17 24-W (5 mol%) (pin)B + (pin)B C8H17

(5 equiv) 100 torr, C6H6, 22 ºC Meek, S. J.; O’Brien, R. V.; Llaveria, J.; Schrock, R. R.; Hoveyda, A. H. Nature 2011, 471, 461–466. 72% yield, dr = 96:4 PhCHO

OTBS OH C8H17 OH 22-Mo (3 mol%) C8H17 + Ph 7.0 torr, C6H6, 22 ºC; C8H17 (n-Bu)4NF F3C F3C (3 equiv) 64% yield, Z:E >98:2

Kiesewetter, E. T.; O’Brien, R. V.; Yu, E. C.; Meek, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Mann, T. J.; Speed, A. W. H.; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2013, 52, Chem. Soc. 2013, 135, 6026–6029. 8395–8400. David W. Lin, Fan Liu

29 Myers The Oleﬁn Metathesis Reaction Chem 115

• Ruthenium-based catalysts have also been developed for Z-selective cross-metathesis. • Z-selective Ring-Closing Metathesis (RCM) • Ru catalysts exhibit better functional group tolerance compared to Mo catalysts. In the example • Both Mo and W catalysts have been found to be effective for Z-selective ring-closing metathesis: below, free hydroxyl groups are tolerated:

MesN N n-Pr i-Pr i-Pr H O CH O N Ru 25-Ru (1 mol%) 3 CH3 O + N N N n-Pr ( ) OH CH3 N CH3 THF, 22 ºC 7 H3C H C i-PrO Mo Ph 3 Mo Ph HO 73% yield, 86:14 Z:E MesN NMes ( ) O CH3 O CH3 7 Br Br Br Br Cl 25-Ru (9.0 equiv) Ph TBSO Ru TBSO Cl H P(c-Hex)3 Herbert, M. B.; Marx, V. M.; Pederson, R. L.; and Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 4-Ru 22-Mo 26-W 310–314.

OAc ( ) H C OAc 25-Ru (0.5 mol%) 7 3 ( ) 7 THF, 35 ºC O O DFT calculations: H3C O catalyst O E isomer is favored by 1.2 kcal/mol, toluene 88:12 E/Z Keitz, B. K.; Endo, K.; Patel, P. R.; Herbert, M. B.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 134, 22 °C, 1 h thermodynamic 693–699. ratio expected

• This methodology was recently employed en route to a total synthesis of the chlorosulfolipid mytilipin A :

O O catalyst pressure yield C8H17 25-Ru (10 mol%) H C (mol%) (torr) (%) Z:E H15C7 + 15 7 DCE, 35 ºC C8H17 4-Ru (5.0) 760 61 21:79 (5.0 equiv) 83% yield, Z:E >95:5 22-Mo (3.0) 7 62 85:15 22-Mo (1.2) 7 56 92:8 26-W (5.0) 7 62 91:9 Cl O 30 mol % 25-Ru Cl H C O (added in 3 portions) 3 + Cl H3C Cl DCE, CH2Cl2, 35 °C, 32% Cl Kiesewetter, E. T.; O’Brien, R. V.; Yu, E. C.; Meek, S. J.; Schrock, R. R.; Hoveyda, A. H. J. Am. Z:E >95:5 Cl (3.0 equiv) Chem. Soc. 2013, 135, 6026–6029.

Chung, W.-j.; Carlson, J. S.; Bedke, D. K.; Vanderwal, C. D. Angew. Chem. Int. Ed. 2013, 52, 10052–10055. David W. Lin, Fan Liu

30 Myers The Oleﬁn Metathesis Reaction Chem 115

• Air-stable 24-W was found to be optimal for the ring-closing metathesis reaction in the synthesis of F epothilone C and nakadomarin A: F F F TBDPSO S F F CH H3C i-Pr i-Pr 3 CH3 CH CH3 N CH3 TBSO 3 1. 24-W (7.5 mol%) N N H C O CH3 H3C CH3 3 N CH Mo Ph H3C O mesitylene 2. HF•pyr H3C 3 W H3C 0.02 torr, 22 ºC THF, 81% CH3 F CH3 O O O O (1.05 g) 82%, Z:E = 94:6 F O Br Br TBS F TBSO TBDPSO S CH3 CH H C CH3 3 3 HO N H3C CH3 CH3 27-Mo 28-W O H3C O OH O • Tri-substituted alkenes can be prepared:

Epothilone C CH3 27-Mo (7.5 mol%) • In the example above, Mo catalysts led to lower selectivities. The authors propose that the less S CH3 reactive tungsten catalyst 24-W possesses the right level of activity to promote RCM without olefin CH benzene CH3 3 TBSO N 100 torr, 22 ºC isomerization. H3C CH3 O 73%, Z:E = 91:9 H C 3 CH O O O 3 H H TBS S 24-W (5 mol%) CH3 CH CH3 3 O O TBSO N N toluene, 760 torr, N H3C CH3 22 ºC, 52% O NBoc NBoc H3C O Z:E = 94:6 O O O O TBS OBoc OBoc Wang, C.; Haeffner, F; Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2013, 52, 1939–1943.

• 28-W can be handled in air under up to 80% humidity and can catalyze metathesis in the presence of free amines: H 24-W (5 mol%) H O O N toluene, 1.0 torr, N 22 ºC, 63% O N N O Z:E = 94:6 28-W (5.0 mol%) O NH O mesitylene NH n-Pr 0.6 torr, 22 °C n-Pr nakadomarin A 82% yield, E:Z = 91:9 epilachnene • In all cases above, a mixture of E/Z olefin isomers was obtained when traditional Ru catalysts were used.

Yu, M.; Wang, C.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Nature C. Wang, C.; M. Yu, M.; Kyle, A. F.; Jakubec, P.; Dixon, D. J.; Schrock, R. R.; Hoveyda, A. H. Chem. 2011, 479, 88–93. Eur. J. 2013, 19, 2726–2740. David W. Lin, Fan Liu

31 Myers The Oleﬁn Metathesis Reaction Chem 115

Metathesis of Alkynes and Diynes • Inspired by the activation of the triple bond of molecular nitrogen with molybdenum complexes of Review: the general type Mo[N(t-Bu)Ar]3 (see: Laplaza, C. E.; Cummins, C. C. Science, 1995, 268, 861), Fürstner, A.; Davies, P. W. Chem. Commun. 2005, 2307–2320. the reactivity of this class of molybdenum catalysts toward alkynes was explored. Fürstner, A. Angew. Chem. Int. Ed. 2013, 52, 2794–2819.

• The first well-defined pre-catalyst for alkyne metathesis was reported in 1981: X t-Bu t-Bu t-Bu t-Bu CH3 Mo N t-Bu Mo N t-Bu (t-BuO) W CH N N 3 3 Et Et N RX N CH3 CH3 CH3 Et n-Pr (0.04 mol%) CH3 CH3 CH3 CH3 CH3 CH3 n-Pr n-Pr pentane, 23 ºC CH3 CH3 CH3 CH3 equilibration in < 5 min 29-Mo 30-Mo, X = Cl 31-Mo, X = Br Wengrovius, J. H.; Sancho, J.; Schrock, R. R. J. Am. Chem. Soc. 1981, 103, 3932–3934.

• Mechanism: the mechanism of alkyne metathesis parallels that of alkene metathesis. • Oxidation of the Mo(III)-precatalyst 29-Mo occurs in situ upon addition of ~25 equivalents of additives

such as CH2Cl2, CH2Br2, CH2I2, and BnCl.

M R2 R2 • Alkyne metathesis may be achieved with equal efficiency either by in situ oxidation of precatalyst R2 M M 29-Mo or by use of pure Mo(IV)-catalysts 30-Mo and 31-Mo.

R1 R1 R1 R1 R1 R1

29-Mo (10 mol%) R CH3 R R CH2Cl2, Toluene

M R1 R = H 60% R = CN 58% R1 R2

Proposal: Katz, T. J.; McGinnis, J. J. Am. Chem. Soc. 1975, 97, 1592–1594. CH3 30-Mo (10 mol%) OR Experimental verification: Churchill, M. R.; Ziller, J. W.; Freudenberger, J. H.; Schrock, R. R. RO CH2Cl2, Toluene RO Organometallics 1984, 3, 1554–1562. R = CH3 59% • This tungsten catalyst was shown to be effective for alkyne ring-closing metathesis, but with R = THP 55% limited functional group compatibility (Lewis-basic functional groups such as basic nitrogens, polyethers, and many heterocycles are not tolerated): • Catalyst 30-Mo is sensitive to acidic protons such as those of secondary amides.

• Terminal alkynes are incompatible with the catalysts. CH3 O (t-BuO)3W CH3 O O O CH3 • Use of CH2Cl2 as the reaction solvent or the addition of ~25 equivalents of CH2Cl2 per mol of 29-Mo (6 mol%) O O O in toluene are equally effective. O C H Cl, 80 ºC, 73% 6 5 • Catalysts 30-Mo and 31-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. However, because they react with dinitrogen, they must be handled under an argon atomsphere. Fürstner, A.; Seidel, G. Angew. Chem. Int. Ed. 1998, 37, 1734–1736. . Fan Liu

32 Myers The Oleﬁn Metathesis Reaction Chem 115

Other Alkyne Metathesis Catalysts RCM of Diynes • Since the initial reports, newer alkyne metathesis pre-catalysts have been developed that show yield of product (%) using catalyst improved stability and functional group compatibilities: 30-Moa 33-Mob 34-Moc 35-Mod substrate product (10 mol%) (10 mol%) (2 mol%) (5 mol%) N • can be weighed in air but must be stored under an inert O O Ph3SiO OSiPh3 atomsphere. Mo O O • not compatible with epoxides, aldehydes, and acid chlorides Ph3SiO N O O O O 91 91 73 78

32-Mo CH3 CH3

N O CH3 O O Ph3SiO OSiPh3 Mo • can be stored indeﬁnitely on the benchtop. N O Ph3SiO 88 – – – N • The catalyst is activated by treatment with MnCl and O 2 N metathesis takes place at 80 ºC. N O CH3 O O

33-Mo

O O(CH2)10 CH 9 Ph 3 Ph Si Si 74 – – – Ph Ph Ph • air and moisture sensitive O(CH2)10 CH O 3 9 Ph3SiO OSiPh3 Mo • more reactive than other Mo catalysts; one of the most reactive Ph SiO OEt 3 2 metathesis catalysts known.

34-Mo O O 5 CH3 O O – 70 97 94 O O Ph CH 3 5 • can be weighed in air but must be stored under an inert O O Ph3SiO OSiPh3 Mo atomsphere. Ph3SiO N N • The catalyst is activated by treatment with MnCl2 and heating at 80 ºC. Subsequent RCM can take place at room aReactions conducted in toluene at 80 °C for 20-48 h; 30-Mo was generated in situ from 29-Mo temperature. and CH2Cl2 (~25 equiv). b • Excellent functional group compatibility: epoxides, acetals, MnCl2 (10 mol%), toluene, 80 ºC. 35-Mo c primary tosylates and heterocycles are all tolerated. toluene, 23 ºC, 5Å MS. d MnCl2 (5 mol%), toluene, 80 ºC; then addition of substrate, 5Å MS, 23 ºC • 5Å MS is often used in alkyne metathesis reactions to absorb 2-butyne and drive the reaction to completion. Fürstner, A.; Mathes, C.; Lehmann, C. W. J. Am. Chem. Soc. 1999, 121, 9453–9454 Bindl, M.; Stade, R.; Heilmann, E. K.; Picot, A.; Goddard, R.; Fürstner, A. J. Am. Chem. Soc. 2009, 131, Bindl, M.; Stade, R.; Heilmann, E. K.; Picot, A.; Goddard, R.; Fürstner, A. J. Am. Chem. Soc. 9468–9470. 2009, 131, 9468–9470. Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner. J. Am. Chem. Soc. 2010, 132, 11045–11057. Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner. J. Am. Chem. Soc. 2010, 132, 11045–11057. Fan Liu, M. Movassaghi

33 Myers The Oleﬁn Metathesis Reaction Chem 115

Alkyne Metathesis in Synthesis • Furan Synthesis: • Synthesis of Epothilone: O O O CH3 CH3 O CH3 CH3 (t-BuO)3W CH3 CH3O CH CH3O H C (10 mol%) 3 S 3 H3C OTBS CH3 DCC, DMAP O CH O H C H3C CH3 3 toluene, 85 ºC 3 CH N HO CH Cl , 23 ºC, 81% 3 78–81% CH3 2 2 CH3O CH3O OH O O O TBS TsOH, toluene 85 ºC, 85% CH3 O O CH3 O CH3 O HO CH3 S 9-I-9-BBN CH3O CH3 H C O 3 H3C OTBS N CH Cl , –10 ºC, 60% O H3C CH3 OH 2 2 O CH O CH 3 3 citreofuran O O O S TBS CH3 H C Fürstner, A.; Castanet, A. S.; Radkowski, K.; Lehmann, C. W. J. Org. Chem. 2003, 68, 1521–1528. 3 H3C OTBS 29-Mo (10 mol%) N H C CH 3 3 toluene, CH2Cl2 • Z,E-diene synthesis: O CH3 O O O 80 ºC, 80% H3C TBS CH3 CH3 CH3 1. Lindlar catalyst, O O H3C quinoline, H2 H3C 29-Mo (10 mol%) O CH2Cl2, 23 ºC, quant. O toluene, CH2Cl2 2. aq. HF,Et2O O MeCN, 79% O 80 ºC, 70% H OCH3 3. DMDO, CH Cl H OCH 2 2 3 TeocN –30 ºC, 70% TeocN S S O O O S CH3 1. Lindlar catalyst, CH3 H C quinoline, H 3 H3C OH O 2 N H C H3C CH3 3 CH2Cl2, 23 ºC, 82% O O 2. TBAF, THF CH 3 23 ºC, 62% O OH O O 3. aq. AcOH, H OH 60 ºC, 80% epothilone A HN S O Fürstner, A.; Mathes, C.; Lehmann, C. W. Chem. Eur. J. 2001, 7, 5299–5317. Fürstner, A.; Mathes, C. Grela, K. Chem. Commun. 2001, 1057–1059. latrunculin A Fürstner, A.; Laurent, T. Angew. Chem. Int. Ed. 2005, 44, 3462–2466. Fan Liu

34 Myers The Oleﬁn Metathesis Reaction Chem 115

• E,E-diene synthesis (In the example below, 5Å MS is used to absorb 2-butyne to drive the H3C CH3 reaction to completion): Ph R = p-CH3OC6H4 CH 3 K+ OSiR CH R3SiO Mo 3 3 CH3 CH3 R3SiO OSiR3 O O O CH3 O (5 mol%) O O OR RO O O H C 3 PhCH , 50 ºC CH CH HN HN 3 3 3 CH3 CH3 O O OR 5Å MS, 96% CH H CO 3 3 CH3 R = TBS OCH3 OMOM H3C OMOM H C conditions 3 H3C H3C H3C O O O O CH CH3 CH3 CH3 3 CH3 CH3 Si(OEt) 3 Cp*Ru(MeCN) PF conditions yield 3 6 (10 mol%), (EtO) SiH O O CH3 3 O O CH3 29-Mo (40–50 mol%) 79% CH2Cl2, 0 ºC OR RO OR RO toluene, CH2Cl2, 80 ºC H3C H3C 34-Mo (2 mol%) 79% + OR OR toluene, 5Å MS, 23 ºC, regioisomer R = TBS CH3 CH3 R = TBS

1. Cp*Ru(MeCN)3PF6 H3C (30 mol%), (EtO) SiH, 3 CH toluene, 23 ºC 1. AgF, MeOH, 3 O CH3 68%, E/Z > 4:1 H2O, THF O 2. AgF, MeOH, H O 2. TBAF, THF O 2 O O CH THF, 94% 23 ºC, 43–60% 3 CH CH HN 3 3 (3 steps) O 3. HClO4, 38–52% OH HO H CO H3C 3 OH H C OH 3 OH Tulearin C CH3 OH Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B.; Fürstner, A. Angew. Chem. Int. Ed. 2011, 50, 11373–11377. myxovirescin A1 • For comparison:

I CH3 I CH3

Fürstner, A.; Bonnekessel, M.; Blank, J. T.; Radkowski, K.; Seidel, G.; Lacombe, F.; Gabor, B.; 3-Ru (30 mol%) Mynott, R. Chem. Eur. J. 2007, 13, 8762–8783. O O CH3 CH Cl , 23 ºC O O CH3 Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner. J. Am. Chem. Soc. 2010, 132, 11045–11057. OR RO 2 2 H C >43% Fürstner, A.; Radkwoski, K. Chem. Commun. 2002, 2182–2183. 3 OR Lacombe, F.; Radkowski, K. Seidel, G.; Fürstner, A. Tetrahedron, 2004, 60, 7315–7324. E: Z = 1.9:1 H3C OPMB R = TBS OPMB For an alternative method of alkyne reduction to the E alkene, see: Sundararaju, B.; Fürstner, A. Angew. Chem. Int. Ed. 2013, DOI: 10.1002/anie.201307584. Mandel, A. L.; Bellosta, V.; Curran, D. P.; Cossy, J. Org. Lett. 2009, 11, 3282–3285. Fan Liu, Alpay Dermenci

35 Myers The Oleﬁn Metathesis Reaction Chem 115

• Synthesis of amphidinolide V: H N TBSO H N H O H O H N Mo H OTBS H H Ph SiO 29-Mo (20 mol%) 3 OSiPh3 H3C O O CH3 Ph SiO H H H3C OTBS 3 (50 mol%) toluene, CH Cl 2 2 O OTBS N 85 ºC, 66% toluene O 23 ! 130 ºC, 63% N

CH steps 3 H N Lindlar catalyst H O H H EtOAc, H2 H H 23 ºC, 88% OH

O N O

Amphidinolide V H3C haliclonacyclamine C Furstner, A.; Larionov, O.; Flugge, S. Angew. Chem. Int. Ed. 2007, 46, 5545–5548. Smith, B. J.; Sulikowski, G. A. Angew. Chem. Int. Ed. 2010, 49, 1599–1602. • Olefins are inert in macrocyclic alkyne metathesis:

CH CH3 3 CH Ph R = p-CH3OC6H4 O 3 (t-BuO)3W CH3 OAc CH K+ 3 O (10 mol%) R3SiO Mo OSiR3 toluene R SiO OSiR 100 ºC, 75% O O 3 3 H3C (5 mol%) CH3 O PhCH3, 5Å MS O 23 ºC, 88% O O

H3C H3C CH3 CH CH3 3 Lindlar catalyst H H quinoline, hexane Lindlar catalyst, EtOH, H2 O O O 23 ºC, 96% AcO O quinoline, H2 AcO O O O O EtOAc, 1-hexene 23 ºC, 84% H3C CH3 (S,S)-Dehydrohomoancepsenolidea (±)-Neurymenolide A Acetate (±)

Chaladaj, W.; Corbet, M.; Furstner, A. Angew. Chem. Int. Ed. 2012, 51, 6929–6933. Fürstner, A.; Dierkes, T. Org. Lett. 2000, 2, 2463–2465. Alpay Dermenci, Fan Liu

36 Myers The Oleﬁn Metathesis Reaction Chem 115

• Synthesis of leiodermatolide: • Diyne Metathesis

• Tungsten catalyst 36-W was found to be effective for diyne metathesis: CH3 TBSO Ph CH3 OH Ot-Bu Ot-Bu H C 3 t-BuO W Si Ot-Bu CH Si MOMO CH3 O 3 O O Ot-Bu t-BuO O + Ot-Bu CH3 CH3 CH3 Si 36-W t-BuO Ot-Bu (2 mol%) CH3 TBSO I EDC•HCl, DMAP CH 3 R CH3 R R I O CH3 CH2Cl2, 0 ºC, 89% H3C PhCH3, 5 Å MS, 23 ºC MOMO CH3 O CH3 OH Product Yield

TBSO 29-Mo (40 mol%) 97 CH3 CH3 toluene, CH2Cl2 MOMO I CH3 O 100 ºC, 72% H3C H C CH 95 CH3 O 3 3

5 steps

H3CO OCH3 97

O NH2 O Cl O O CH CH CH 3 3 HO 3 95 HO O CH3 CH3 O O Cl H3C O O CH3 O O OCH3 O leiodermatolide 96 O H3CO O

Willwacher, J.; Kausch-Busies, N.; Fürstner, A. Angew. Chem. Int. Ed. 2012, 51, 12041–12046. Me3Si SiMe3 80

Lysenko, S.; Volbeda, J.; Jones, P. G.; Tamm, M. Angew. Chem. Int. Ed. 2012, 51, 6757–6761. Alpay Dermenci, Fan Liu

37 Myers The Oleﬁn Metathesis Reaction Chem 115

• Diyne ring-closing metathesis:

O O

O O O O 36-W (4 mol%) O O PhCH3, 5 Å MS 23 ºC, 90%

90%

CH3 H3C

O O O O

36-W (4 mol%)

PhCH3, 5 Å MS 23 ºC, 80%

CH3 CH3

O O

Lysenko, S.; Volbeda, J.; Jones, P. G.; Tamm, M. Angew. Chem. Int. Ed. 2012, 51, 6757–6761.

Alpay Dermenci