32 the olefin metathesis reaction

Myers Chem 115 The Olefin Metathesis Reaction Cross Metathesis (CM): Reviews: 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) Nicolaou, K C.; Bulger, P G.; Sarlah, D Angew Chem., Int Ed Engl 2005, 44, 4490–4527 CM R2 R1 + R4 R3 R1 R3 + R4 R2 Grubbs, R H Tetrahedron 2004, 60, 7117–7140 • Self-dimerization reactions of the more valuable alkene may be minimized by the use of an excess of the more readily available alkene Chatterjee, A K.; Choi, T.-L.; Sanders, D P.; Grubbs, R H J Am Chem Soc 2003, 125, 11360–11370 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 Ring-Opening Metathesis Polymerization (ROMP): F3C ROMP F3C n O MesN i-Pr N Mo CH3 Ph CH3 CH3 O H F3C CH 1-Mo F3C Cl Cl P(c-Hex)3 Ru H P(c-Hex)3 2-Ru Ph Ph P(c-Hex)3 Cl Ph Ru H Cl P(c-Hex)3 3-Ru (Grubbs' 1st Generation Catalyst) NMes Cl Cl Ru Ph H P(c-Hex)3 4-Ru (Grubbs' 2nd Generation Catalyst) • ROMP is thermodynamically favored for strained ring systems, such as 3-, 4-, 8- and largermembered 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 • 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 • Block copolymers can be made by sequential addition of different monomers (a consequence of the "living" nature of the polymerization) • 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 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 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 • The electron-rich tricyclohexyl phosphine ligands of the d6 Ru(II) metal center in alkylidenes 2Ru 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 commercially available, but 1-Mo is significantly more expensive Scholl, M.; Ding, S.; Lee, C W.; Grubbs, R H Org Lett 1999, 1, 953–956 Schwab, P.; France, M B.; Ziller, J W.; Grubbs, R H Angew Chem., Int Ed Engl 1995, 34, 2039–2041 Nguyen, S.-B T.; Grubbs, R H J Am Chem Soc 1993, 115, 9858–9859 M Movassaghi, L Blasdel Myers Chem 115 The Olefin Metathesis Reaction Mechanism: Dissociative: P = P(c-Hex)3 EtO2C CO2Et • 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 P • 15 years later, Chauvin first proposed that olefin metathesis proceeds via metallacyclobutanes: Herisson, P J.-L.; Chauvin, Y Makromol Chem 1970, 141, 161–176 • It is now generally accepted that both cyclic and acyclic olefin metathesis reactions proceed via metallacyclobutane and metal-carbene intermediates: Grubbs, R H.; Burk, P L.; Carr, D D J Am Chem Soc 1975, 97, 3265–3266 = R Cl Ru P Cl H –P Cl Cl Ru H Ru H P P Cl H H H H R R R P Cl H Cl Cl Ru R R P Cl Cl P(c-Hex)3 H Ru H Cl P(c-Hex)3 Cl EtO2C CO2Et – C2H4 H P c-C5H6(CO2Et)2 mol% CD2Cl2, 25 ºC H Ru P EtO2C CO2Et Cl Ru P Cl H Cl Ru H P P Cl H P Cl H Cl Ru H Cl Ru Cl H +P • A kinetic study of the RCM of diethyl diallylmalonate using a Ru-methylidene describes two possible mechanisms for olefin metathesis: EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et P P 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 Cl P Ru • The "associative" mechanism assumes that an 18-electron olefin complex is formed which undergoes metathesis to form the cyclized product • Addition of equivalent of phosphine (with respect to catalyst) decreases the rate of the reaction by as much as 20 times, supporting the dissociative mechanism Cl P H Cl H R Cl Ru Cl H P Dias, E L.; Nguyen, S.-B T.; Grubbs, R H J Am Chem Soc 1997, 119, 3887–3897 Ru P Cl H Cl Ru H H R Cl H Cl H H EtO2C CO2Et Cl Ru P P R c-C5H6(CO2Et)2 P • It was concluded in this study that the "dissociative" pathway is the dominant reaction manifold (>95%) P R – C2H4 P Cl Ru H Cl H P Cl H P P EtO2C CO2Et Cl Ru EtO2C CO2Et M Movassaghi Myers Chem 115 The Olefin Metathesis Reaction Catalytic RCM of Dienes: Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM substrate product O N time (h) yield (%)a substratea O X X = CF3 N X = O t-Bu X 93 91 E E R R = CH3 yield with 3-Ru (%)b E E 93 100 98 100 NR 96 i-Pr t-Bu Ph O O Ph O Ph 25 97 Br NR NR CH2OH 98 decomp 97 100 96 100 E E Ph O R Ph 84 E E 86 CH3 O CH3 O Ph Ph E E 72 E E CH3 O O O CH3 Ph O Ph yield with 1-Mo (%)c product 87 E E – No RCMd No RCMd CH3 R a2-4 R = CO2H 87 CH2OH 88 CHO 82 R E E H3C E E CH3 mol% 2-Ru, C6H6, 20 ºC H3C • Five-, six-, and seven-membered oxygen and nitrogen heterocycles and cycloalkanes are formed efficiently H3C H N Cl– mol% 2-Ru CH2Ph N 20 ºC, 36 h CH2Cl2; NaOH 79% Fu, G C.; Nguyen, S.-B T.; Grubbs, R H J Am Chem Soc 1993, 115, 9856–9857 NR 61 96e 100e E E E E CH3 • 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 functionalities PhCH2 93 CH3 • Catalyst 2-Ru can be used in the air, in reagent-grade solvents (C6H6, CH2Cl2, THF, t-BuOH) • Free amines are not tolerated by the ruthenium catalyst; the corresponding hydrochloride salts undergo efficient RCM with catalyst 2-Ru NR E E H3C CH3 E E aE = CO2Et b0.01 M, CH2Cl2, mol% c0.1 M, C6H6, 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, 7310–7318 M Movassaghi Myers Chem 115 The Olefin Metathesis Reaction Recyclable Ru-Based Metathesis Catalysts Geminal Substitution MesN O R 95 7-Ru 7-Ru Boc N 23 ºC LnRu 95 CH3 • Although benzylidene 3-Ru is highly active in RCM of dienes in organic solvents, it has no catalytic acitivity in protic media solvent: CH2Cl2 CH3OH 80 7-Ru E E N Cl– H3C CH3 mol% 3-Ru 6-Ru E E E E H • 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 EtO2C CO2Et conversionc P Ru N(CH3)3+Cl– 6-Ru catalyst aE = CO Et b5 mol% catalyst (5- or 6-Ru), 0.37 M substrate, 45 °C cConversions were determined by 1H NMR dSubstrate conc = 0.1 M e30 h f2 h g10 mol% 6-Ru used • Alkylidene 7-Ru is a significantly more active catalyst than alkylidene 6-Ru in these cyclizations; this higher reactivity is attributed to the more electron-rich phosphines in 7-Ru • Cis-olefins are more reactive in RCM than the corresponding trans-olefins R Ph LnRu RuLn • Phenyl substitution within the starting material can also greatly increase the yield of RCM in organic solvents R LnRu R H N Ph • 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 H H H Cl– mol% 3-Ru R N Cl– CH2Cl2 R=H R = Ph 60% 100% Kirkland, T A.; Lynn, D M.; Grubbs, R H J Org Chem 1998, 63, 9904–9909 M Movassaghi Myers Chem 115 The Olefin Metathesis Reaction NHC Ruthenium Catalysts: RCM of functionalized dienes substratea N Mes Mes N Cl Ph Ru H Cl N Mes Mes N Cl Mes N Cl Ph Ru Ru CH3 CH3 Cl Ru H P(c-Hex)3 Cl 9-Ru 4-Ru substratea product 1-Mo O 8-Ru 4-Ru O O CH2 O O CH2 O 97 CH2 37 100 100 100 O t-Bu 24 93 40c 31 O CH3 O CH3 E E CH3 CH2 55 CH3 O 86 CH2 CH3 E E CH3 E E O 1.5 CH3 aE CH2 O 9-Ru E E H OH O O O t-Bu H3C 49 E E E E O CH2 10-Ru 3-Ru yield (%) CH2 O yield of product (%) using catalyst:b time (h) product N Mes Mes N P(c-Hex)3 P(c-Hex)3 8-Ru Ph H Cl H Cl P(c-Hex)3 N Mes 52 1.5 90 87 O CH2 93 H3C CH3 CH2 H OH 0.2 0 0.2 100 100 = CO2Et b5 mol% of catalyst, CD2Cl2, reflux c1.5 h aReactions conducted with mol% 10-Ru • 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, 2247–2250 For the first Ru-based metathesis catalyst employing the Arduengo carbene ligand, see: Weskamp, T.; Schattenmann, W C.; Spiegler, M.; Herrmann, W A Angew Chem., Int Ed Engl 1998, 37, 2490–2493 • !,"-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, 3783– 3784 M Movassaghi Myers Chem 115 The Olefin Metathesis Reaction RCM Applications in Synthesis: OH O Bn n-Bu2BOTf, Et3N CH2Cl2, ºC O N O Bn OH O N Cl O mol% 3-Ru CH2Cl2 82%, >99% de Bn HO HO O CH2=CHCHO –78 ! ºC O O O CH3 97% OH Cl O Pochonin C trans epoxide N O MOMO O O O Crimmins, M T.; King, B W J Org Chem 1996, 61, 4192–4193 MOMO CH3 O H MOMO mol% 4-Ru H toluene, 120 ºC 10 O BnO BnO H BnO CO2CH3 N BnO O mol% 2-Ru BnO 110 ºC, 48 h BnO H HO HO N HO O 70% H O H3C O TBSO O OPMB O H3C O CH3 H O MOMO O O O MOMO H mol% 4-Ru toluene, 120 ºC 10 O CH3 H O O MOMO H O 21% 71% • Pre-organization of the substrate can have a dramatic effect upon the reaction efficiency 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 macrocycle is formed in a much higher yield RuLn TBSO Cl H cis epoxide MOMO Hoye, T R.; Jeffrey, C S.; Tennakoon, M A.; Wang, J.; Zhao, H J Am Chem Soc 2004, 126, 10210–10211 10 mol% 5-Ru CH2Cl2, 40 ºC O H MOMO N • 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 OPMB O OH Overkleeft, H S.; Pandit, U K Tetrahedron Lett 1996, 37, 547–550 O CH3 87% Castanospermine TBSO O O OPMB O O Wang, X.; Bowman, E J.; Bowman, B J.; Porco, J A., Jr Angew Chem Int Ed 2004, 43, 3601– 3605 Barluenga, S.; Lopez, P.; Moulin, E.; Winssinger, N Angew Chem Int Ed 2004, 43, 2367–2370 L Blasdel and M Movassaghi Myers Chem 115 The Olefin Metathesis Reaction CH3 CH3 N H N H NHCOCF3 22 ºC, 10 h C6H6 91% OAc H H3C O H NHCOCF3 H O CH3 OAc O N OAc 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 N E O H N H O O O H3C OH N D H CH3 CH3 20 mol% 1-Mo OAc Manzamine A • The use of RCM in construction of both the D and the E rings of Manzamine A has been reported: Zhongmin, X.; Johannes, C W.; Houri, A F.; La, D S.; Cogan, D A.; Hofilena, G E.; Hoveyda, A H J Am Chem Soc 1997, 119, 10302–10316 Slight changes in substrate structure can control whether the E- or Z-olefin is formed: H H3C CH2OTDS H O N O 23 ºC, d C6D6 O 30% CH3 N O N O O CH3 CO2CH3 H O N H O 50 ºC, h C6D6 Ph CO2CH3 PO CH3O CH3 80% Z-olefin only 10 mol% 4-Ru CH2Cl2, 40% CH3 H3C O mol% 2-Ru CH3 O O OCH3 OP P = p-BrBz CH3 O N CH3 CH3 CH3 OP Borer, B C.; Deerenberg, S.; Bieraugel, H.; Pandit, U K Tetrahedron Lett 1994, 35, 3191–3194 Ph O H3C CH3 O 86% E-olefin only H H3C CH3 OCH3 O O 100 mol% 2-Ru N H3C CH2OTDS H3C CH3 O CH3 O O PO O CH3 OCH3 N O N O CH3 CH3 63% H3C O O Martin, S F.; Liao, Y.; Wong, Y.; Rein, T Tetrahedron Lett 1994, 35, 691–694 OHC H3C CH3 O O CH3 OH Coleophomone B OHC O CH3 CH3 OCH3 Coleophomone C Nicolaou, K C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C J N J Am Chem Soc 2005, M Movassaghi and L Blasdel 127, 8872–8888 Myers Chem 115 The Olefin Metathesis Reaction Solid-Phase Synthesis of Epothilone A: Synthesis of Epothilone C: • Small changes can drastically affect reaction outcome In the example below, TBS protective groups changes the E/Z selectivity O HO CH3 CH3 H3C CH3 R1O O R1 CH3 N O H3C S CH3 R1O H O Catalyst Conditions CH3 O O = Merrifield resin CH3 N H3C S N O H3C OR2 O R2 CH3 H3C CH3 S CH3 CH3 H3C CH3 H O OTBS H 3-Ru (0.75 equiv) 25 ºC, 48 h CH2Cl2 OR2 O Yield HO E/Z H H 1-Mo 50 mol%, PhH, 55 ºC 65% 2:1 H TBS 3-Ru 10 mol%, CH2Cl2, 25 ºC 85% : 1.2 TBS TBS 8-Ru mol%, CH2Cl2, 25 ºC 94% : 1.7 TBS TBS 4-Ru 50 mol%, PhH, 55 ºC 86% : 1.7 CH3 O H3C H3C H3C TBSO CH3 HO S CH3 O CH3 N H3C H3C H3C TBSO O O O O Nicolaou, K C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F.; Ninkovic, S.; Yang, Z.; Trujillo, J I J Am Chem Soc 1997, 119, 7960–7973 Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.; Kamenecka, T.; Sorensen, E J.; Danishefsky, S J J Am Chem Soc 1997, 119, 11073–11092 Schinzer, D.; Bauer, A.; Bohm, O M.; Limberg, A.; Cordes, M Chem Eur J 1999, 5, 2483– 2491 O OTBS 5.2% S CH3 N O H3C CH3 N 15.6% CH3 CH3 H3C CH3 S O 15.6% HO CH3 CH3 HO H CH3 H3C CH3 CH3 N O H3C O S H O OTBS 15.6% • The amount of alkylidene 3-Ru (75%) used was greater than the total yield of product (52%), perhaps reflecting the generation of a resin-bound Ru intermediate • Addition of n-octene or ethylene has been documented to provide a catalytic cycle; see: Maarseveen, J H.; Hartog, J A J.; Engelen, V.; Finner, E.; Visser, G.; Kruse, C G Tetrahedron Lett 1996, 37, 8249 Nicolaou, K C.; Winssinger, N.; Pastor, J.; Ninkovic, S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E Nature 1997, 387, 268–272 M Movassaghi and L Blasdel Myers Chem 115 The Olefin Metathesis Reaction Applications of Olefin Metathesis in Industry • BILN 2061 ZW was investigated as a potential medication for the treatment of hepatitis C: • A second-generation route was developed, which permitted higher reaction concentrations and lower catalyst loading: • First-generation route: MesN O O S O H N N O O O PNBO Br O N H CO2Me 5a-Ru (3 mol %) O H3C O toluene (0.01 M) 80 ºC, 83% Z:E >99:1 O O S O O O O CH3 NO2 (0.1 mol %) toluene (0.2 M), 110 ºC, 95%, Z:E >99:1 PNBO CO2CH3 OCH3 O H N O 5a-Ru H N N O O • During the reaction, nitrogen was bubbled through the reaction solution to remove ethylene O Boc N CO2CH3 N O O O N CH3 • 400 kg of the RCM product has been prepared using the first-generation route H N O N O H Br H N N Cl Cl Ru H3C O O 20.2-kg scale P(c-Hex)3 H Cl Cl Ru N H N O Boc N CO2CH3 NMe H3C S CO2H N H CH3 steps O N H BILN 2061 ZW • 5-Ru was not stable at 80 ºC for the duration of the reaction so the catalyst was added in several portions over 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 with HCl prior to use Farina, V.; Shu, C.; Zeng, X.; Wei, X.; Han, Z.; Yee, N K.; Senanayake, C H Org Process Res 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 Chem 115 The Olefin Metathesis Reaction • The alkylidene catalysts 12-Mo and 13-Mo are very effective in catalytic, enantioselective desymmetrization processes, especially in the case of secondary allylic ethers H3C O H3C CH3 R • Desymmetrization metathesis reactions have been used to make a variety of heteroatomcontaining products: R 1-2 mol% 13-Mo 22 °C, neat H3C CH3 Si O H H3C mol% 12-Mo O R H 3C R=H R = CH3 Ph O Si CH3 CH3 H3C CH2Cl2, 22 °C, h Ph 92% 93% ee m-CPBA n-Bu4NF CH3 CH3 HO Ph OH CH3 • Remarkably, this catalytic, asymmetric RCM can be carried out in the absence of solvent, with 20:1 de Kiely, A F.; Jernelius, J A.; Schrock, R R.; Hoveyda, A H J Am Chem Soc 2002, 124, 2868 mol% 13-Mo O -–20 °C, 18 h toluene O CH3 mol% 14-Mo PhH, 22 °C, 12 h O 41%, >98% conv 83% ee H3C 84%, 73% ee O CH3 O O mol% 13-Mo O -–20 °C, 18 h toluene O 91%, 82% ee • 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 • 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 Chem 115 The Olefin Metathesis Reaction • Ruthenium based catalysts can also be used for enantioselective desymmetrizing RCM for the preparation of allyl ethers: i-Pr i-Pr C6H2(i-Pr)3 N Ph O CH3 O Mo Ph O CH3 C6H2(i-Pr)3 N i-Pr X R Ph Ph N Ru i-Pr R substrate product H3C PCy3 temp (ºC) ee (%) 64 17-Ru (4) 40 90 77 18-Ru (0.8) 40 92 H3C CH3 H3C catalyst (mol%) O O X yield (%) H CH3 H3C CH3 17-Ru: R = H, X = I 18-Ru: R = i-Pr, X = Cl 16-Mo • Catalyst 16-Mo was found to be effecive for the synthesis of cyclic enol ethers by an enantioselective desymmetrizing RCM: H3C H3C CH3 Si O H3C CH3 Si O CH3 H3C H H3C substrate yield (%) product 16-Mo (mol%) time (h) temp (ºC) CH3 H3C CH3 ee (%) Funk, T W.; Berlin, J M.; Grubbs, R H J Am Chem Soc 2006, 128, 1840–1846 CH3 O O H3C 10 22 90 Ph • Arylamines are compatible with Mo catalysts: CH3 H3C CH3 CO2CH3 Ph CH3 96 15 20 22 CO2Me CH3 15 17 22 94 PhH, 22 °C N n Ph H3C 94 catalyst 87 O H3C CH3 CH3 O O H3C • Synthesis of azaheterocycles 70 CH3 O H3C CH3 N n Ph H3C n catalyst %mol catalyst time yield ee 12-Mo 20 78% 98% 12-Mo 7h 90% 95% 15-Mo 20 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 Chem 115 The Olefin Metathesis Reaction • Mo catalysts can be used for the synthesis of cyclic amides and amines, although a high catalyst loading is often required Free secondary amines are tolerated but only when the amine contains a fully substituted !-carbon center substrate yield (%) product O catalyst (mol%) time (h) temp (ºC) 16-Mo (10) 48 22 Mo N >98 N CH3 CH3 Ph CH3 OTBS OH + CH3 CH3 95 15-Mo (5) 24 22 i-Pr 71 H3C N H Ph H CH3 CH3 94 13-Mo (5) 24 22 97 N Cbz *The absolute stereochemistry of the RCM products was not reported For 19-Mo: >98% conv, dr = 5:1 For 20-Mo: 95% conv, dr = 7:1 For 21-Mo: 60 ºC, 94% conv, dr = 3:1 N N CH3 i-Pr Mo O X X TBSO CH3 CH3 N Cbz C6H6 22 °C, 1.0 h enantiomerically enriched CH3 N H Ph CH3 X CH3 CH3 H N X i-Pr N 91 H3C H3C i-Pr N CH3 • These complexes are isolated as diastereomeric mixtures: ee (%) O N • Chiral MAP complexes are prepared from enantiomerically enriched monoprotected diols They are sensitive to air and moisture and must be handled in the glovebox H3C Ph CH3 "Monopyrrolide aryloxide (MAP) stereogenic-at-Mo" complexes • 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 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 substrate product catalyst (mol%) yield (%) ee (%) catalyst (mol%) yield (%) ee (%) 20-Mo (1) >98 92 13-Mo (15) 98% conv., 84% yield 96% e.e (e.r., 98:2) I Ru H3C O Oi-Pr OPMB CH3 H3C Ph (2.0 mol%) O Ph Ph , no solvent OPMB CH3 Na (NH3), t-BuOH Et2O, –78 ºC, 70% O –15 ºC, 62%, 88% ee E:Z >98:2 Et O CH3 CH3 CH3 O CH3 O OH O ee (%) 19-Mo (1 mol%) 84 96 20-Mo (1 mol%) PtO2 (5.0 mol%) H2 (1.0 atm) 83 95 EtOH, 22 °C, 97% 21-Mo (1 mol%) 93 93 Other Mo catalysts 98:2 79 0.5 22 89 >98:2 OTBS OTBS H3C OTBS OTBS OTBS i-PrO O Ph Ph C6H6, 22 ºC Br TBSO O Br O 85%, 97% ee Z:E > 98:2 Ibrahem, I.; Yu, M.; Schrock, R R.; Hoveyda, A H J Am Chem Soc 2009, 131, 3844–3845 H3C Ph On-Bu Ph CH3 On-Bu Yu, M.; Ibrahem, I.; Hasegawa, M.; Schrock, R R.; Hoveyda, A H J Am Chem Soc 2012, 134, 2788–2799 David W Lin, Fan Liu 28 Myers Chem 115 The Olefin Metathesis Reaction • Z-allyl- and Z-alkenylboron compounds • Z-Selective Cross Metathesis • Mo-based catalysts have been developed for Z-selective cross metathesis of several substrate classes • Enol ethers (pin)B 23-Mo (2.5 mol%) O OPh (5.0 equiv) OPh C6H6, 22 ºC 73%, Z:E = 98:2 (10 equiv) OPMB O On-Bu n-BuO 22-Mo (5 mol%) + Br TBSO H3C C16H33 + O Si(i-Pr)3 C16H33 O 1.0 torr, C6H6, 22 ºC; (n-Bu)4NF 85% yield, Z:E >98:2 (1.0 equiv) (2.0 equiv) 23-Mo (2.5 mol%) OPMB • Mo-based catalysts are sensitive to air and moisture and must be prepared in situ and handled in the glovebox: • By decreasing the reaction pressure, the stoichiometry of the reaction can be improved: lowering the pressure removes ethylene, which competitively reacts with the catalyst to form a highly reactive metal alkylidene complex that can potentially catalyze unwanted Z- to E-isomerization Si(i-Pr)3 (pin)B C6H6, 22 ºC 92% yield, Z:E = 97:3 H3C H3C OH Br H3C H3C CH3 N N CH3 Mo H3C Ph CH3 N C6H6, 22 °C, h Br TBSO N N CH CH3 CH3 Ph CH3 Mo O CH3 Br 23-Mo 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 • 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: • Allylic amides and ethers NPhth OTBS + ( )6 Br (3.0 equiv) 22-Mo (2.5 mol%) 7.0 torr, C6H6, 22 ºC; 93% yield, Z:E = 96:4 Br ( )6 NPhth OTBS (pin)B + C8H17 (5 equiv) Meek, S J.; O’Brien, R V.; Llaveria, J.; Schrock, R R.; Hoveyda, A H Nature 2011, 471, 461–466 24-W (5 mol%) (pin)B C8H17 100 torr, C6H6, 22 ºC 72% yield, dr = 96:4 PhCHO OTBS OH + F3C C8H17 (3 equiv) C8H17 22-Mo (3 mol%) 7.0 torr, C6H6, 22 ºC; (n-Bu)4NF 64% yield, Z:E >98:2 F3C Mann, T J.; Speed, A W H.; Schrock, R R.; Hoveyda, A H Angew Chem Int Ed 2013, 52, 8395–8400 OH Ph C8H17 Kiesewetter, E T.; O’Brien, R V.; Yu, E C.; Meek, S J.; Schrock, R R.; Hoveyda, A H J Am Chem Soc 2013, 135, 6026–6029 David W Lin, Fan Liu 29 Myers Chem 115 The Olefin Metathesis Reaction • 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 below, free hydroxyl groups are tolerated: • Both Mo and W catalysts have been found to be effective for Z-selective ring-closing metathesis: N MesN O H O N O n-Pr Ru 25-Ru (1 mol%) + i-PrO HO () ( ) OH n-Pr THF, 22 ºC 73% yield, 86:14 Z:E MesN (9.0 equiv) Cl Herbert, M B.; Marx, V M.; Pederson, R L.; and Grubbs, R H Angew Chem Int Ed 2013, 52, 310–314 H3C () OAc O Br Cl Ru Br CH3 Ph CH3 TBSO H3C Br TBSO N N CH3 Mo O Br i-Pr CH3 Ph CH3 H P(c-Hex)3 22-Mo 4-Ru 26-W OAc () 25-Ru (0.5 mol%) Ph i-Pr CH3 Mo NMes 25-Ru N H3C N O THF, 35 ºC O O H3C catalyst DFT calculations: E isomer is favored by 1.2 kcal/mol, 88:12 E/Z thermodynamic ratio expected O toluene 22 °C, h Keitz, B K.; Endo, K.; Patel, P R.; Herbert, M B.; Grubbs, R H J Am Chem Soc 2011, 134, 693–699 • This methodology was recently employed en route to a total synthesis of the chlorosulfolipid mytilipin A : O H15C7 C8H17 25-Ru (10 mol%) + C8H17 DCE, 35 ºC 83% yield, Z:E >95:5 (5.0 equiv) 30 mol % 25-Ru (added in portions) O + H3C Cl Cl (3.0 equiv) 4-Ru (5.0) 22-Mo (3.0) 22-Mo (1.2) 26-W (5.0) Cl Cl catalyst (mol%) O H15C7 pressure (torr) yield (%) Z:E 760 61 21:79 7 62 56 62 85:15 92:8 91:9 O H3C Cl DCE, CH2Cl2, 35 °C, 32% Z:E >95:5 Chung, W.-j.; Carlson, J S.; Bedke, D K.; Vanderwal, C D Angew Chem Int Ed 2013, 52, 10052–10055 Cl Kiesewetter, E T.; O’Brien, R V.; Yu, E C.; Meek, S J.; Schrock, R R.; Hoveyda, A H J Am Chem Soc 2013, 135, 6026–6029 David W Lin, Fan Liu 30 Myers Chem 115 The Olefin Metathesis Reaction • Air-stable 24-W was found to be optimal for the ring-closing metathesis reaction in the synthesis of epothilone C and nakadomarin A: TBSO CH3 CH3 H3C CH3 O N O O TBS TBDPSO H3C S O H3C F (1.05 g) CH3 24-W (7.5 mol%) mesitylene 0.02 torr, 22 ºC 82%, Z:E = 94:6 CH3 F N CH3 i-Pr CH3 Ph CH3 N H3C CH3 i-Pr W O Br TBSO F N Br H3C 28-W CH3 27-Mo O H3C O F CH3 TBDPSO S N F O Mo H3C CH3 F CH3 O F H3C HF•pyr THF, 81% CH3 H3C CH3 HO F F OH O • Tri-substituted alkenes can be prepared: Epothilone C CH3 • In the example above, Mo catalysts led to lower selectivities The authors propose that the less reactive tungsten catalyst 24-W possesses the right level of activity to promote RCM without olefin isomerization TBSO CH3 CH3 H3C CH3 N O H3C O H O N NBoc O H 24-W (5 mol%) toluene, 760 torr, 22 ºC, 52% Z:E = 94:6 27-Mo (7.5 mol%) S CH3 benzene 100 torr, 22 ºC 73%, Z:E = 91:9 CH3 O O TBS TBSO O N OBoc O OBoc S N CH3 O H3C NBoc O CH3 CH3 H3C CH3 O O TBS 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 H 24-W (5 mol%) O N N toluene, 1.0 torr, 22 ºC, 63% Z:E = 94:6 O N N O O 28-W (5.0 mol%) NH n-Pr nakadomarin A • 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 2011, 479, 88–93 mesitylene 0.6 torr, 22 °C 82% yield, E:Z = 91:9 O O NH n-Pr epilachnene C Wang, C.; M Yu, M.; Kyle, A F.; Jakubec, P.; Dixon, D J.; Schrock, R R.; Hoveyda, A H Chem Eur J 2013, 19, 2726–2740 David W Lin, Fan Liu 31 Myers Chem 115 The Olefin Metathesis Reaction 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 Review: Fürstner, A.; Davies, P W Chem Commun 2005, 2307–2320 Fürstner, A Angew Chem Int Ed 2013, 52, 2794–2819 • The first well-defined pre-catalyst for alkyne metathesis was reported in 1981: (t-BuO)3W Et n-Pr t-Bu CH3 CH3 CH3 Et Et t-Bu N t-Bu N Mo N CH3 CH3 (0.04 mol%) n-Pr pentane, 23 ºC equilibration in < RX CH3 30-Mo, 31-Mo, Wengrovius, J H.; Sancho, J.; Schrock, R R J Am Chem Soc 1981, 103, 3932–3934 M R2 R1 M R1 R1 R2 R2 M R1 R1 t-Bu N t-Bu N Mo N CH3 CH3 CH3 CH3 29-Mo • Mechanism: the mechanism of alkyne metathesis parallels that of alkene metathesis X CH3 CH3 CH3 CH3 n-Pr t-Bu CH3 X = Cl X = Br • 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 • Alkyne metathesis may be achieved with equal efficiency either by in situ oxidation of precatalyst 29-Mo or by use of pure Mo(IV)-catalysts 30-Mo and 31-Mo R1 R M CH3 29-Mo (10 mol%) CH2Cl2, Toluene R R1 R1 R=H R = CN R2 Proposal: Katz, T J.; McGinnis, J J Am Chem Soc 1975, 97, 1592–1594 Experimental verification: Churchill, M R.; Ziller, J W.; Freudenberger, J H.; Schrock, R R Organometallics 1984, 3, 1554–1562 R CH3 RO 60% 58% 30-Mo (10 mol%) CH2Cl2, Toluene OR RO R = CH3 R = THP • This tungsten catalyst was shown to be effective for alkyne ring-closing metathesis, but with limited functional group compatibility (Lewis-basic functional groups such as basic nitrogens, polyethers, and many heterocycles are not tolerated): 59% 55% • Catalyst 30-Mo is sensitive to acidic protons such as those of secondary amides O (t-BuO)3W O O O (6 mol%) • Terminal alkynes are incompatible with the catalysts CH3 CH3 CH3 O O C6H5Cl, 80 ºC, 73% Fürstner, A.; Seidel, G Angew Chem Int Ed 1998, 37, 1734–1736 O O • Use of CH2Cl2 as the reaction solvent or the addition of ~25 equivalents of CH2Cl2 per mol of 29-Mo in toluene are equally effective • 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 Fan Liu 32 Myers Chem 115 The Olefin Metathesis Reaction Other Alkyne Metathesis Catalysts RCM of Diynes • Since the initial reports, newer alkyne metathesis pre-catalysts have been developed that show improved stability and functional group compatibilities: yield of product (%) using catalyst substrate N Ph3SiO Ph3SiO OSiPh3 Mo N • can be weighed in air but must be stored under an inert atomsphere O • not compatible with epoxides, aldehydes, and acid chlorides Ph3SiO O O O O O Mo OSiPh3 CH3 O • can be stored indefinitely on the benchtop O O N • The catalyst is activated by treatment with MnCl2 and metathesis takes place at 80 ºC N O 91 91 73 78 88 – – – 74 – – – – 70 97 94 CH3 CH3 N Ph3SiO product O 32-Mo 30-Moa 33-Mob 34-Moc 35-Mod (10 mol%) (10 mol%) (2 mol%) (5 mol%) N O O O N CH3 O O 33-Mo Ph Ph Ph3SiO Ph3SiO Mo OSiPh3 OEt2 • air and moisture sensitive Ph O(CH2)10 Si O(CH2)10 Mo N 35-Mo CH3 N O Si O O O O Ph Ph3SiO Ph O OSiPh3 Ph • more reactive than other Mo catalysts; one of the most reactive metathesis catalysts known 34-Mo Ph3SiO CH3 • can be weighed in air but must be stored under an inert atomsphere • The catalyst is activated by treatment with MnCl2 and heating at 80 ºC Subsequent RCM can take place at room temperature • Excellent functional group compatibility: epoxides, acetals, primary tosylates and heterocycles are all tolerated • 5Å MS is often used in alkyne metathesis reactions to absorb 2-butyne and drive the reaction to completion Bindl, M.; Stade, R.; Heilmann, E K.; Picot, A.; Goddard, R.; Fürstner, A J Am Chem Soc 2009, 131, 9468–9470 Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner J Am Chem Soc 2010, 132, 11045–11057 O CH3 O O CH3 O aReactions conducted in toluene at 80 °C for 20-48 h; 30-Mo was generated in situ from 29-Mo and CH2Cl2 (~25 equiv) bMnCl (10 mol%), toluene, 80 ºC ctoluene, 23 ºC, 5Å MS dMnCl (5 mol%), toluene, 80 ºC; then addition of substrate, 5Å MS, 23 ºC 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, 9468–9470 Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner J Am Chem Soc 2010, 132, 11045–11057 Fan Liu, M Movassaghi 33 Myers Chem 115 The Olefin Metathesis Reaction Alkyne Metathesis in Synthesis • Furan Synthesis: • Synthesis of Epothilone: O CH3 S H3C H3C CH3 H3C H3C CH3 HO N O CH3 (t-BuO)3W (10 mol%) CH3O OTBS DCC, DMAP CH3 CH3 O CH2Cl2, 23 ºC, 81% CH3 OH O CH3O O O HO H3C CH3 H3C H3C CH3 N O H3C H3C H3C CH3 N O OTBS CH3 O CH3O O O TBS 29-Mo (10 mol%) toluene, CH2Cl2 80 ºC, 80% Lindlar catalyst, quinoline, H2 CH2Cl2, 23 ºC, quant aq HF,Et2O MeCN, 79% DMDO, CH2Cl2 –30 ºC, 70% O CH3 9-I-9-BBN CH3O citreofuran O O TBS Fürstner, A.; Castanet, A S.; Radkowski, K.; Lehmann, C W J Org Chem 2003, 68, 1521–1528 • Z,E-diene synthesis: H3C CH3 CH3 CH3 O H3C 29-Mo (10 mol%) toluene, CH2Cl2 O O H O O H 80 ºC, 70% OCH3 TeocN S O O CH3 CH3 H3C H3C CH3 N O OH O H3C O CH3 O OH O epothilone A OCH3 TeocN O S O H3C S H3C CH3 O CH2Cl2, –10 ºC, 60% OH O CH3O O OTBS CH3 O CH3 O toluene, 85 ºC 78–81% TsOH, toluene 85 ºC, 85% CH3 S CH3 O CH3O O O TBS CH3 S O CH3 CH3 CH3 O H OH HN Lindlar catalyst, quinoline, H2 CH2Cl2, 23 ºC, 82% TBAF, THF 23 ºC, 62% aq AcOH, 60 ºC, 80% S 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 O latrunculin A Fürstner, A.; Laurent, T Angew Chem Int Ed 2005, 44, 3462–2466 Fan Liu 34 Myers • E,E-diene synthesis (In the example below, 5Å MS is used to absorb 2-butyne to drive the reaction to completion): CH3 H3C Ph CH3 CH3 CH3 O OMOM OCH3 conditions O O O CH3 CH3 conditions yield 29-Mo (40–50 mol%) toluene, CH2Cl2, 80 ºC 79% 34-Mo (2 mol%) toluene, 5Å MS, 23 ºC, 79% O CH3 O O CH3 CH3 HN H3CO CH3 OMOM O H3C H3C CH3 CH3 Si(OEt)3 O O CH3 OR RO H3C + regioisomer R = TBS OH Cp*Ru(MeCN)3PF6 (10 mol%), (EtO)3SiH CH2Cl2, ºC O CH3 O OR RO H3C OR CH3 CH3 OR R = TBS H3C CH3 AgF, MeOH, H2O, THF TBAF, THF 23 ºC, 43–60% (3 steps) O O H3C Tulearin C OH myxovirescin A1 PhCH3, 50 ºC 5Å MS, 96% OR R = TBS OH H3C R3SiO Mo OSiR3 OSiR3 R3SiO (5 mol%) H3C CH3 CH3 Cp*Ru(MeCN)3PF6 (30 mol%), (EtO)3SiH, toluene, 23 ºC 68%, E/Z > 4:1 AgF, MeOH, H2O THF, 94% HClO4, 38–52% CH3 OR RO H3C HN H3CO H3C O O O R = p-CH3OC6H4 K+ CH3 O HN CH3 CH3 O CH3 O O O CH3 H3C CH3 O O Chem 115 The Olefin Metathesis Reaction CH3 OH HO OH CH3 Lehr, K.; Mariz, R.; Leseurre, L.; Gabor, B.; Fürstner, A Angew Chem Int Ed 2011, 50, 11373–11377 • For comparison: I Fürstner, A.; Bonnekessel, M.; Blank, J T.; Radkowski, K.; Seidel, G.; Lacombe, F.; Gabor, B.; Mynott, R Chem Eur J 2007, 13, 8762–8783 Heppekausen, J.; Stade, R.; Goddard, R.; Fürstner J Am Chem Soc 2010, 132, 11045–11057 Fürstner, A.; Radkwoski, K Chem Commun 2002, 2182–2183 Lacombe, F.; Radkowski, K Seidel, G.; Fürstner, A Tetrahedron, 2004, 60, 7315–7324 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 O H3C CH3 O I CH3 O O 3-Ru (30 mol%) CH3 OR RO OPMB CH2Cl2, 23 ºC >43% E: Z = 1.9:1 R = TBS Mandel, A L.; Bellosta, V.; Curran, D P.; Cossy, J Org Lett 2009, 11, 3282–3285 H3C CH3 OR OPMB Fan Liu, Alpay Dermenci 35 Myers Chem 115 The Olefin Metathesis Reaction • Synthesis of amphidinolide V: TBSO H3C H H O O O H3C OTBS O H H H 29-Mo (20 mol%) N N H Mo Ph3SiO OSiPh3 Ph3SiO (50 mol%) CH3 OTBS toluene, CH2Cl2 85 ºC, 66% O OTBS N H H H toluene 23 ! 130 ºC, 63% O N H N CH3 steps H H O H H H OH O N Lindlar catalyst EtOAc, H2 23 ºC, 88% H 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: CH3 OAc O R = p-CH3OC6H4 Ph K+ CH3 (t-BuO)3W CH3 CH3 CH3 (10 mol%) toluene 100 ºC, 75% O R3SiO Mo OSiR3 OSiR3 R3SiO (5 mol%) O O H3C CH3 O O PhCH3, 5Å MS 23 ºC, 88% H3C CH3 CH3 O O H3C CH3 H H O AcO O (±)-Neurymenolide A Acetate Lindlar catalyst, quinoline, H2 EtOAc, 1-hexene 23 ºC, 84% O AcO O O O O O H3C Lindlar catalyst quinoline, hexane EtOH, H2 23 ºC, 96% CH3 (S,S)-Dehydrohomoancepsenolidea (±) 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 Chem 115 The Olefin Metathesis Reaction • Synthesis of leiodermatolide: • Diyne Metathesis • Tungsten catalyst 36-W was found to be effective for diyne metathesis: CH3 TBSO Ph CH3 Ot-Bu Ot-Bu t-BuO Si Si Ot-Bu W O O Ot-Bu t-BuO O Si Ot-Bu 36-W t-BuO Ot-Bu (2 mol%) OH H3C MOMO CH3 O CH3 + CH3 CH3 TBSO EDC•HCl, DMAP I CH3 CH2Cl2, ºC, 89% H3C MOMO CH3 CH3 CH3 I CH3 R CH3 O CH3 R O OH Product TBSO CH3 CH3 MOMO I CH3 O H3C Yield 97 29-Mo (40 mol%) toluene, CH2Cl2 100 ºC, 72% H3C O CH3 R PhCH3, Å MS, 23 ºC CH3 95 OCH3 97 steps H3CO O HO O NH2 O Cl CH3 CH3 HO CH3 95 CH3 O O H3C CH3 O CH3 O O Cl O O O O leiodermatolide OCH3 96 O H3CO Willwacher, J.; Kausch-Busies, N.; Fürstner, A Angew Chem Int Ed 2012, 51, 12041–12046 O 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 36-W (4 mol%) PhCH3, Å MS 23 ºC, 90% O O O O 90% CH3 H3C O O O O O O 36-W (4 mol%) PhCH3, Å MS 23 ºC, 80% CH3 CH3 Lysenko, S.; Volbeda, J.; Jones, P G.; Tamm, M Angew Chem Int Ed 2012, 51, 6757–6761 Alpay Dermenci 38 ... Chem 115 The Olefin Metathesis Reaction Enyne Cross -Metathesis Enyne Metathesis in Synthesis CH3 TBSO TBSO • 4-Ru outperforms 3-Ru in both rate and overall conversion in the cross -metathesis of... Liu 26 Myers Chem 115 The Olefin Metathesis Reaction Examples of Enantioselective Olefin Metathesis in Synthesis • An enantioselective ring-opening-cross -metathesis (ROCM) reaction: Ph N N catalyst... argon atomsphere Fan Liu 32 Myers Chem 115 The Olefin Metathesis Reaction Other Alkyne Metathesis Catalysts RCM of Diynes • Since the initial reports, newer alkyne metathesis pre-catalysts have