GRUBBS CATALYST C571. For Ring-closing Metathesis Of Sterically Challenging Substrates GRUBBS CATALYST C571. Cl 2.

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4 C57 C57 For Ring-closing Metathesis f Sterically Challenging Substrates C 7 H 0 Cl Ru Dichloro[,-bis(-methylphenyl)- -imidazolidinylidene] (-isopropoxyphenylmethylene) ruthenium(ii) CM RCM RMP RMP Ring pening Metathesis Polymerization This Hoveyda-Grubbs analog has ortho-tolyl substituents on the -heterocyclic carbene ligand (whereas the standard catalyst has mesityl groups). While C57 is active in cross metathesis, it s the most effective commercially available catalyst for forming sterically hindered olefins via RCM. The free ortho positions in the catalyst backbone provide more space around the ruthenium atom, which is thought to account for its increased activity toward sterically challenging substrates. CTACT IF C57 (0 mol%) PhMe, 50 o C H 85% more U.S. patents (including U.S. Patent os. 6,9,75, 7,7,55, 8,008,4), patents pending, and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; Synthesis of complex polycyclic scaffolds by metathesis rearrangement. 4 Schrodi, Y.; Pederson, R.L. Aldrichimica Acta 007, 40, 45. Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. rg. Lett. 008, 0, 44. Stewart, I. C.; Benitez, D.; Leary, D..; Tkatchouk, E.; Day, M. W.; Goddard, W. A. III; Grubbs, R. H. J. Am. Chem. Soc. 009,, 9. 4 Lam, J. K.; Schmidt, Y.; Vanderwal, C. D. rg. Lett. 0, 4, 5566.

5 C67 HVEYDA- D GEERATI The Go-to For Any Metathesis Reaction C H 8 Cl Ru Dichloro[,-bis(,4,6-trimethylphenyl)- -imidazolidinylidene] (isopropoxyphenylmethylene)ruthenium(ii) CM RCM RMP The Hoveyda-Grubbs Catalyst nd Generation catalyst is considered one of the best catalysts for cross metathesis (CM) and ring closing metathesis (RCM) because it works in most circumstances and is generally more reactive than the Grubbs Catalyst nd Generation at lower temperatures (5-0 C). It is also an efficient catalyst for the metathesis of electron-deficient substrates. RMP Ring pening Metathesis Polymerization CTACT IF more U.S. patents (including U.S. Patent os. 6,9,75, 7,7,55), patents pending, and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; H S C67 (0.5 mol%) PhMe 60-9 o C H Ring-closing metathesis to form the azapine core structure of SB , a cathepsin K inhibitor. S Schrodi, Y.; Pederson, R. L. Aldrichimica Acta 007, 40, 45. Zhao, S.; Sirasani, G.; Vaddypally, S.; Zdilla, M. J.; Andrade, R. B. Angew. Chem. Int. Ed. 0, 5, 809. Wang, H.; Goodman, S..; Dai, Q.; Stockdale, G. W.; Clark, W. M. rg. Proc. Res. Dev. 008,, 6. 90% 5.7 kg

6 C6 C6 For Z-Selective Reactions C H 4 4 Ru [-(-Methylethoxy-)phenylmethyl-C](nitrato-, ) {rel-(r,5r,7s)-tricyclo[...,7]decane-,-diyl [-(,4,6-trimethylphenyl)--imidazolidinyl--ylidene]} ruthenium CM RCM CTACT IF RMP RMP Ring pening Metathesis Polymerization more pending U.S. patents (including U.S. Patent Application o. /978,940) and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; The latest development in Grubbs Catalyst Technology, our Z-selective catalyst C6 bears a bulky adamantyl group on the HC ligand which chelates to ruthenium creating a highly sterically encumbered active catalyst. This bulk at the ruthenium center makes this catalyst highly sensitive to olefin geometry, giving Z-olefins with excellent selectivity in both ring-closing and cross metathesis reactions. Catalyst C6 has been demonstrated to perform in the presence of multiple polar functional groups in the synthesis of peptide macrocycles. It also reacts preferentially with Z-olefin substrates in alkenolysis and ring-opening reactions. + H C 0 H C6 (0.5 mol%) THF 70% 88: Z:E Z-Selective cross metathesis en route to an insect pheromone. 4 C 0 H Keitz, B. K.; Endo K.; Patel P. R.; Herbert M. B.; Grubbs R. H. J. Am. Chem. Soc. 0, 4, 69. Mangold, S. L.; 'Leary, D. J.; Grubbs, R. H. J. Am. Chem. Soc. 04, 6, 469. Keitz, B. K.; Fedorov, A.; Grubbs, R. H. J. Am. Chem. Soc. 0, 4, Herbert, M. B.; Marx, V. M.; Pederson, R. L.; Grubbs, R. H. Angew. Chem. Int. Ed. 0, 5, 0. H

7 C7 C7 For Cross Metathesis f Sterically Challenging Substrates C 7 H 50 Cl Ru Dichloro[,-bis(,6-diisopropylphenyl)- -imidazolidinylidene] (-isopropoxyphenylmethylene)ruthenium(ii) CM RCM RMP Despite its first report in the literature in 00, this catalyst has received relatively little attention. It has shown to be an efficient catalyst for alkenolysis and is the best reported catalyst for challenging cross metathesis reactions to prepare trisubstituted olefins. RMP Ring pening Metathesis Polymerization CTACT IF TBS + H C7 (0 mol%) CH Cl TBS H more U.S. patents (including U.S. Patent os. 6,6,80, 6,9,75, 7,7,55), patents pending, and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; 75% Cross metathesis of a complex intermediate with (+)--decen-4-ol en route to a total synthesis of (-)-Promysalin. Courchay, F. C.; Sworen, J. C.; Wagener, K. B. Macromolecules 00, 6, 8. Stewart, I. C.; Douglas, C. J.; Grubbs, R. H. rg. Lett. 008, 0, Steele, A. D.; Knouse, K. W.; Keohane, C. E.; Wuest, W. M. J. Am. Chem. Soc. 05, 7, 74.

8 C8 ST GEERATI The riginal. The Catalyst That Started It All. C 4 H 7 Cl P Ru Dichloro(benzylidene)bis (tricyclohexylphosphine)ruthenium(ii) CM RCM RMP Although not the first to be developed, this compound is generally known as the Grubbs Catalyst st Generation. It s great if you re trying an easy metathesis reaction (i.e. forming unhindered, unstrained products) for the first time because it tends to participate in fewer side reactions than the more active catalysts. Its long shelf-life and relatively low cost make it a common sight on the bench of organic chemists. RMP Ring pening Metathesis Polymerization CF CTACT IF F C CF H H Ph i. C8, CH Cl ii. Pb(Ac) 4 F C Ph more U.S. patents (including U.S. Patent os. 5,8,08), patents pending, and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; 97% Preparation of a densely substituted [4..0] bicycle, opened to a cyclooctene by oxidative cleavage en route to (-)-merrilactone. Vougioukalakis, G. C.; Grubbs, R. H. Chem Rev. 00, 0, 746. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc., 00, 5, Inoue, M.; Sato, T.; Hirama, M. Angew. Chem. Int. Ed. 006, 45, 484.

9 C848 D GEERATI The Most Published And Well-understood C 46 H 65 Cl PRu Dichloro[,-bis(,4,6-trimethylphenyl) -imidazolidinylidene](benzylidene) (tricyclohexylphosphine)ruthenium(ii) CM RCM RMP RMP Ring pening Metathesis Polymerization Commonly known as the Grubbs Catalyst nd Generation, this catalyst is one of the most widely-used homogenous metathesis catalysts. It provides a distinct increase in activity compared with st general systems in virtually all olefin metathesis reactions while maintaining functional group tolerance. As a consequence, it generally requires lower catalyst loadings than the st generation catalyst. Furthermore, it has been used in challenging cross metathesis (e.g.,-disubstituted olefins, tri-substituted olefins) or with deactivated olefins (e.g. vinyl phosphonates, α, β-unsaturated carbonyls). CTACT IF more U.S. patents (including U.S. Patent os. 7,9,758, 8,846,99), patents pending, and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; F C C848 (0% w/w) CH Cl 5 o C F C Preparation of a dihydroquinoline intermediate en route to a BACE- inhibitor. Trnka T. M., Grubbs R. H. Acc. Chem. Res. 00, 4, 8. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc., 00, 5, 60. Charrier,. et al Bioorg. Med. Chem. Lett. 009, 9, %

10 C949 C949 The First Metathesis Catalyst Used In Commercial API Production C 54 H 69 Cl PRu Dichloro[,-bis(,4,6-trimethylphenyl)- -imidazolidinylidene](-phenyl-h-inden- -ylidene)(tricyclohexylphosphine)ruthenium(ii) CM RCM RMP First described by olan and coworkers, this -phenylindenylidene substituted catalyst displays similar activity to that of Grubbs Catalyst nd Generation and has been used in multiple pharmaceutical chemistry applications. RMP Ring pening Metathesis Polymerization CTACT IF S Et C H H F F F F Cl Cl C949 Et 4 I CH Cl reflux S Et C ClF CC H 89% more U.S. patents (including U.S. Patent os. 7,9,758, 7,6,590, 8,846,99), patents pending, and associated foreign equivalents. Use of these catalysts may be subject to these and other patents and patents pending. Research quantities of these catalysts are available exclusively through Sigma-Aldrich ( ; Key macrocyclic ring closure toward protease inhibitor TMC 45. Clavier, H.; olan, S. P. Chem. Eur. J. 007,, 809. Horvath, A.; Wuyts, S.; Depre, D. P. M.; Couck, W. L. J.; Cuypers, J. L. J.; Harutyunyan, S.; Binot, G. F. S. (Janssen Pharmaceuticals, Inc., USA). Improved process for preparing an intermediate of the macrocyclic protease inhibitor TMC 45. PCT Int. Appl , May, 0.

Steric and Electronic Controllers in Ring-Closing Metathesis Reactions. Jennifer E. Farrugia October 29, 2003

Steric and Electronic Controllers in Ring-Closing Metathesis Reactions Jennifer E. Farrugia October 29, 2003 Steric and Electronic Controllers How do substrate sterics affect the reactivity/ selectivity