Synthetic Challenges in the Assembly of Macrocyclic HCV NS3/NS4A Protease Inhibitors: The Case of BILN 2061 and Its Analogs

Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 44)


The virally encoded serine protease NS3/NS4A is essential for the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The quest for the discovery of antiviral agents targeting the NS3/NS4A was initiated with a substrate-based hexapeptide as the lead structure. Evaluation of the conformational pre-organization of this ligand to the bioactive conformation led to the design of macrocyclic peptides, typified by the antiviral agents BILN 2061. Today, closely related analogs of BILN 2061 represent an important class of human therapeutics for the treatment of HCV infection. The critical steps in the synthesis of these compounds involves the cyclization of a tripeptide diene, containing a (1R,2S)-vinyl aminocyclopropylcarboxylate residue, via ring-closing metathesis (RCM). Conformational factors, ligand effects, and reaction conditions were evaluated, and a protocol was developed for the efficient production of these peptidomimetics in high yield and diastereomeric purity. The assembly of these challenging molecules and the key optimization studies are described.


Hepatitis C virus Macrocyclic peptides NS3/NS4A protease inhibitors 





1-Aminocyclopropanecarboxylic acid


Active pharmaceutical ingredient




Boehringer Ingelheim










Diethyl azodicarboxylate


Diisopropyl azodicarboxylate








Half maximal effective concentration






Food and Drug Administration




Hepatitis C virus


High-performance liquid chromatography


High-throughput screening




Half maximal inhibitory concentration


Pegylated interferon alpha


Potassium hexamethyldisilazide, potassium bis(trimethylsilyl)amide


Liquid chromatography–mass spectrometry


Lithium hexamethyldisilazide, lithium bis(trimethylsilyl)amide






Methyl tert-butyl ether




Nuclear magnetic resonance


Nonstructural protein 3






Parts per million


Ring-closing metathesis


Ribonucleic acid


Rotating-frame Overhauser effect spectroscopy


Room temperature


Structure–activity relationships


Substitution nucleophilic (bimolecular)


N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate




Trifluoromethanesulfonyl (triflyl)




Turnover number

Vinyl ACCA

1-Amino-2-vinylcyclopropanecarboxylic acid


  1. 1.
    Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362CrossRefGoogle Scholar
  2. 2.
    Tellinghuisen TL, Evans MJ, von Hahn T, You S, Rice CM (2007) Studying Hepatitis C virus: making the best of a bad virus. J Virol 81:8853–8867CrossRefGoogle Scholar
  3. 3.
    Hadziyannis SJ, Papatheodoridis GV (2003) Effects of host and virus related factors on interferon-α+ ribavirin and pegylated-interferon + ribavirin treatment outcomes in chronic hepatitis C patients. Expert Opin Pharmacother 4:541–551Google Scholar
  4. 4.
    Chander G, Sulkowski MS, Jenckes MW, Torbenson MS, Herlong F, Bass EB, Gebo KA (2002) Treatment of chronic hepatitis C: a systematic review. Hepatology 36:S135–S144CrossRefGoogle Scholar
  5. 5.
    Calcoen D, Elias L, Yu X (2015) What does it take to produce a breakthrough drug? Nat Rev Drug Discovery 14:161–162CrossRefGoogle Scholar
  6. 6.
    Belema M, Lopez OD, Bender JA, Romine JL, St. Laurent DR, Langley DR, Lemm JA, O’Boyle II DR, Sun J-H, Wang C, Fridell RA, Meanwell NA (2014) Discovery and development of hepatitis C virus NS5A replication complex inhibitors. J Med Chem 57:1643–1672Google Scholar
  7. 7.
    Chen KX, Njoroge FG, Vibulbham B, Prongay A, Pichardo J, Madison V, Buevich A, Chan T-M (2005) Proline-based macrocyclic inhibitors of the hepatitis C virus: stereoselective synthesis and biological activity. Angew Chem Int Ed 44:7024–7028CrossRefGoogle Scholar
  8. 8.
    Gale M Jr, Foy EM (2005) Evasion of intracellular host defence by hepatitis C virus. Nature 436:939–945CrossRefGoogle Scholar
  9. 9.
    Chen KX, Njoroge FG (2009) A review of HCV protease inhibitors. Curr Opin Invest Drugs 10:821–837Google Scholar
  10. 10.
    Llinàs-Brunet M, Bailey M, Fazal G, Ghiro E, Gorys V, Goulet S, Halmos T, Maurice R, Poirier M, Poupart M-A, Rancourt J, Thibeault D, Wernic D, Lamarre D (2000) Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors. Bioorg Med Chem Lett 10:2267–2270CrossRefGoogle Scholar
  11. 11.
    Ingallinella P, Altamura S, Bianchi E, Taliani M, Ingenito R, Cortese R, De Francesco R, Steinkühler C, Pessi A (1998) Potent peptide inhibitors of human hepatitis C virus NS3 protease are obtained by optimizing the cleavage products. Biochemistry 37:8906–8914CrossRefGoogle Scholar
  12. 12.
    Schechter I, Berger A (1967) On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 27:157–162CrossRefGoogle Scholar
  13. 13.
    LaPlante SR, Cameron DR, Aubry N, Lefebvre S, Kukolj G, Maurice R, Thibeault D, Lamarre D, Llinàs-Brunet M (1999) Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain. J Biol Chem 274:18618–18624CrossRefGoogle Scholar
  14. 14.
    Cicero DO, Barbato G, Koch U, Ingallinella P, Bianchi E, Nardi MC, Steinkühler C, Cortese R, Matassa V, De Francesco R, Pessi A, Bazzo R (1999) Structural characterization of optimized product inhibitors with the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein by NMR and modelling studies. J Mol Biol 289:385–396CrossRefGoogle Scholar
  15. 15.
    LaPlante SR, Aubry N, Bonneau PR, Kukolj G, Lamarre D, Lefebvre S, Li H, Llinàs-Brunet M, Plouffe C, Cameron DR (2000) NMR line-broadening and transferred NOESY as a medicinal chemistry tool for studying inhibitors of the hepatitis C virus NS3 protease domain. Bioorg Med Chem Lett 10:2271–2274CrossRefGoogle Scholar
  16. 16.
    Poupart M-A, Cameron DR, Chabot C, Ghiro E, Goudreau N, Goulet S, Poirier M, Tsantrizos YS (2001) Solid-phase synthesis of peptidomimetic inhibitors for the hepatitis C virus NS3 protease. J Org Chem 66:4743–4751CrossRefGoogle Scholar
  17. 17.
    Rancourt J, Cameron DR, Gorys V, Lamarre D, Poirier M, Thibeault D, Llinàs-Brunet M (2004) Peptide-based inhibitors of the hepatitis C virus NS3 protease : structure-activity relationship at the C-terminal position. J Med Chem 47:2511–2522CrossRefGoogle Scholar
  18. 18.
    Lohmann V, Körner F, Koch J-O, Herian U, Theilmann L, Bartenschlager R (1999) Replication of subgenomic hepatitis C virus RNAs in hepatoma cell lines. Science 285:110–113CrossRefGoogle Scholar
  19. 19.
    Tsantrizos YS, Bolger G, Bonneau P, Cameron DR, Goudreau N, Kukolj G, LaPlante SR, Llinàs-Brunet M, Nar H, Lamarre D (2003) Macrocyclic inhibitors of the NS3 protease as potential therapeutic agents of hepatitis C virus infections. Angew Chem Int Ed Engl 42:1356–1360CrossRefGoogle Scholar
  20. 20.
    Tsantrizos YS, Cameron DR, Faucher A-M, Ghiro E, Goudreau N, Halmos T, Llinàs-Brunet M (2000) Macrocyclic peptides active against the hepatitis C virus. Boehringer Ingelheim (Canada) Ltd. WO Pat Appl 0,059,929A1Google Scholar
  21. 21.
    Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, Bös M, Cameron D, Cartier M, Cordingley MG, Faucher A-M, Goudreau N, Kawai SH, Kukolj G, Lagacé L, LaPlante SR, Narjes H, Poupart M-A, Rancourt J, Sentjens RE, St George R, Simoneau B, Steinmann G, Thibeault D, Tsantrizos YS, Weldon SM, Yong C-L, Llinàs-Brunet M (2003) An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature 426:186–189CrossRefGoogle Scholar
  22. 22.
    Reiser M, Hinrichsen H, Benhamou Y, Reesink HW, Wedemeyer H, Avendano G, Riba N, Yong C-L, Nehmiz G, Steinmann GG (2005) Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C. Hepatology 41:832–835CrossRefGoogle Scholar
  23. 23.
    Jiménez JM, Rifé J, Ortuňo RM (1996) Enantioselective total syntheses of cyclopropane amino acids: natural products and protein methanologs. Tetrahedron Asymmetry 7:537–558CrossRefGoogle Scholar
  24. 24.
    Ooi T, Takeuchi M, Kameda M, Maruoka K (2000) Practical catalytic enantioselective synthesis of α, α-dialkyl-α-amino acids by chiral phase-transfer catalysis. J Am Chem Soc 122:5228–5229CrossRefGoogle Scholar
  25. 25.
    Belokon YN, Kochetkov KA, Churkina TD, Ikonnikov NS, Chesnokov AA, Larionov OV, Singh I, Parmar VS, Vyskocil S, Henri B, Kagan HB (2000) Asymmetric PTC C-alkylation catalyzed by chiral derivatives of tartaric acid and aminophenols. Synthesis of (R)- and (S)-α-methyl amino acids. J Org Chem 65:7041–7048CrossRefGoogle Scholar
  26. 26.
    Belokon YN, Bhave D, D’Addario D, Groaz E, Maleev V, North M, Pertrosyan A (2003) Catalytic, asymmetric synthesis of α, α-disubstituted amino acids. Tetrahedron Lett 44:2045–2048CrossRefGoogle Scholar
  27. 27.
    Beaulieu PL, Gillard J, Bailey MD, Boucher C, Duceppe J-S, Simoneau B, Wang X-J, Zhang L, Grozinger K, Houpis I, Farina V, Heimroth H, Krueger T, Schnaubelt J (2005) Synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (Vinyl-ACCA) derivatives: key intermediates for the preparation of inhibitors of the hepatitis C virus NS3 protease. J Org Chem 70:5869–5879CrossRefGoogle Scholar
  28. 28.
    O’Donnell MJ, Bennett WD, Bruder WA, Jacobsen WN, Knuth K, LeClef B, Polt RL, Bordwell FG, Mrozack SR, Cripe TA (1988) Acidities of glycine schiff bases and alkylation of their conjugate bases. J Am Chem Soc 110:8520–8525CrossRefGoogle Scholar
  29. 29.
    O’Donnell MJ, Polt RL (1982) A mild and efficient route to schiff base derivatives of amino acids. J Org Chem 47:2663–2666CrossRefGoogle Scholar
  30. 30.
    Charette AB, Côté B (1995) Stereoselective synthesis of all four isomers of coronamic acid: a general approach to 3-methanoamino acids. J Am Chem Soc 117:12721–12732CrossRefGoogle Scholar
  31. 31.
    Llinàs-Brunet M, Bailey MD, Bolger G, Brochu C, Faucher A-M, Ferland JM, Garneau M, Ghiro E, Gorys V, Grand-Maître C, Halmos T, Lapeyre-Paquette N, Liard F, Poirier M, Rhéaume M, Tsantrizos YS, Lamarre D (2004) Structure-activity study on a novel series of macrocyclic inhibitors of the hepatitis C virus NS3 protease leading to the discovery of BILN 2061. J Med Chem 47:1606–1608Google Scholar
  32. 32.
    Tsantrizos YS (2004) The design of a potent inhibitor of the hepatitis C virus NS3 protease: BILN2061-from the NMR tube to the clinic. Biopolymers 76:309–323CrossRefGoogle Scholar
  33. 33.
    Goudreau N, Brochu C, Cameron DR, Duceppe J-S, Faucher A-M, Ferland J-M, Grand-Maitre C, Poirier M, Simoneau B, Tsantrizos YS (2004) Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based β-strand mimics. J Org Chem 69:6185–6201CrossRefGoogle Scholar
  34. 34.
    Faucher A-M, Bailey M, Beaulieu P, Brochu C, Duceppe J-S, Ferland J-M, Ghiro E, Gorys V, Halmos T, Kawai SH, Poirier M, Simoneau B, Tsantrizos YS, Llinàs-Brunet M (2004) Synthesis of BILN 2061, an HCV NS3 protease inhibitor with proven antiviral effect in humans. Org Lett 6:2901–2904CrossRefGoogle Scholar
  35. 35.
    Poirier M, Aubry N, Boucher C, Ferland J-M, LaPlante S, Tsantrizos YS (2005) RCM of tripeptide dienes containing a chiral vinylcyclopropane moiety: impact of different Ru-based catalysts on the stereochemical integrity of macrocyclic products. J Org Chem 70:10765–10773CrossRefGoogle Scholar
  36. 36.
    Evans DA, Evrard DA, Rychnovsky SD, Früh T, Whittingham WG, DeVries KM (1992) A general approach to the asymmetric synthesis of vancomycin-related arylglycines by enolate azidation. Tetrahedron Lett 33:1189–1192CrossRefGoogle Scholar
  37. 37.
    Weck M, Mohr B, Sauvage J-P, Grubbs RH (1999) Synthesis of catenane structures via ring-closing metathesis. J Org Chem 64:5463–5471CrossRefGoogle Scholar
  38. 38.
    Mohr B, Weck M, Sauvage J-P, Grubbs RH (1997) High-yield synthesis of [2] catenanes by intramolecular ring-closing metathesis. Angew Chem Int Ed Engl 36:1308–1310CrossRefGoogle Scholar
  39. 39.
    Marsella MJ, Maynard HD, Grubbs RH (1997) Template-directed ring-closing metathesis: synthesis and polymerization of unsaturated crown ether analogs. Angew Chem Int Ed Engl 36:1101–1103CrossRefGoogle Scholar
  40. 40.
    Fürstner A, Dierkes T, Thiel OR, Blanda G (2001) Total synthesis of (−)-salicylihalamide. Chem Eur J 7:5286–5298CrossRefGoogle Scholar
  41. 41.
    Fürstner A, Thiel OR, Blanda G (2000) Asymmetric synthesis of the fully functional macrolide core of salicylihalamide: remote control of olefin geometry during RCM. Org Lett 2:3731–3734CrossRefGoogle Scholar
  42. 42.
    Meng D, Su D-S, Balog A, Bertinato P, Sorensen EJ, Danishefsky SJ, Zheng Y-H, Chou T-C, He L, Horwitz SB (1997) Remote effects in macrolide formation through ring-forming olefin metathesis: an application to the synthesis of fully active epothilone congeners. J Am Chem Soc 119:2733–2734CrossRefGoogle Scholar
  43. 43.
    Tsantrizos YS, Ferland J-M, McClory A, Poirier M, Farina V, Yee NK, Wang X, Haddad N, Wei X, Xu J, Zhang L (2006) Olefin ring-closing metathesis as a powerful tool in drug discovery and development-potent macrocyclic inhibitors of hepatitis C virus NS3 protease. J Organomet Chem 691:5163–5171CrossRefGoogle Scholar
  44. 44.
    Zeng X, Wei X, Farina V, Napolitano E, Xu Y, Zhang L, Haddad N, Yee NK, Grinberg N, Shen S, Senanayake CH (2006) Epimerization reaction of a substituted vinylcyclopropane catalyzed by ruthenium carbenes: mechanistic analysis. J Org Chem 71:8864–8875CrossRefGoogle Scholar
  45. 45.
    Yang Z-Q, Geng X, Solit D, Pratilas CA, Rosen N, Danishefsky SJ (2004) New efficient synthesis of resorcinylic macrolides via ynolides: establishment of cycloproparadicicol as synthetically feasible preclinical anticancer agent based on Hsp90 as the target. J Am Chem Soc 126:7881–7889CrossRefGoogle Scholar
  46. 46.
    Yamamoto K, Biswas K, Gaul C, Danishefsky SJ (2003) Effects of temperature and concentration in some ring closing metathesis reactions. Tetrahedron Lett 44:3297–3299CrossRefGoogle Scholar
  47. 47.
    Barrett AGM, Hamprecht D, James RA, Ohkubo M, Procopiou PA, Toledo MA, White AJP, Williams DJ (2001) Synthesis and characterization of coronanes: multicyclopropane-fused macrocyclic arrays. J Org Chem 66:2187–2196CrossRefGoogle Scholar
  48. 48.
    Itoh T, Mitsukura K, Ishida N, Uneyama K (2000) Synthesis of bis- and oligo-gem-difluorocyclopropanes using the olefin metathesis reaction. Org Lett 2:1431–1434CrossRefGoogle Scholar
  49. 49.
    Kingsbury JS, Harrity JPA, Bonitatebus PJ, Hoveyda AH (1999) A recyclable Ru-based metathesis catalyst. J Am Chem Soc 121:791–799CrossRefGoogle Scholar
  50. 50.
    Michrowska A, Bujok R, Harutyunyan S, Sashuk V, Dolgonos G, Grela K (2004) Nitro-substituted Hoveyda-Grubbs ruthenium carbines: enhancement of catalyst activity through electronic activation. J Am Chem Soc 126:9318–9325CrossRefGoogle Scholar
  51. 51.
    Scholl M, Trnka TM, Morgan JP, Grubbs RH (1999) Increased ring closing metathesis activity of ruthenium-based olefin metathesis catalysts coordinated with imidazolin-2-ylidene ligands. Tetrahedron Lett 40:2247–2250CrossRefGoogle Scholar
  52. 52.
    Weskamp T, Kohl FJ, Hieringer W, Gleich D, Herrmann WA (1999) Highly active ruthenium catalysts for olefin metathesis: the synergy of N-heterocyclic carbenes and coordinatively labile ligands. Angew Chem Int Ed Engl 38:2416–2419CrossRefGoogle Scholar
  53. 53.
    Huang J, Stevens ED, Nolan SP, Petersen JL (1999) Olefin metathesis-active ruthenium complexes bearing a nucleophilic carbene ligand. J Am Chem Soc 121:2674–2678CrossRefGoogle Scholar
  54. 54.
    Garber SB, Kingsbury JS, Gray BL, Hoveyda AH (2000) Efficient and recyclable monomeric and dendritic Ru-based metathesis catalysts. J Am Chem Soc 122:8168–8179CrossRefGoogle Scholar
  55. 55.
    Nicola T, Brenner M, Donsbach K, Kreye P (2005) First scale-up to production scale of a ring closing metathesis reaction forming a 15-member macrocycle as a precursor of an active pharmaceutical ingredient. Org Process Res Dev 9:513–515CrossRefGoogle Scholar
  56. 56.
    Yee NK, Farina V, Houpis I, Haddad N, Frutos RP, Gallou F, Wang X-J, Wei X, Simpson RD, Feng X, Fuchs V, Xu Y, Tan J, Zhang L, Xu J, Smith-Keenan LS, Vitous J, Ridges MD, Spinelli EM, Johnson M, Donsbach K, Nicola T, Brenner M, Winter E, Kreye P, Samstag W (2006) Efficient large-scale synthesis of BILN 2061, a potent HCV protease inhibitor, by a convergent approach based on ring-closing metathesis. J Org Chem 71:7133–7145CrossRefGoogle Scholar
  57. 57.
    Shu C, Zeng X, Hao M-H, Wei X, Yee NK, Busacca CA, Han Z, Farina V, Senanayake CH (2008) RCM macrocyclization made practical:An efficient synthesis of HCV protease inhibitor BILN 2061. Org Lett 10:1303–1306CrossRefGoogle Scholar
  58. 58.
    Fürstner A, Thiel OR, Ackermann L, Schanz H-J, Nolan SP (2000) Ruthenium carbene complexes with N,N′-bis(mesityl)imidazol-2-ylidene ligands: RCM catalysts of extended scope. J Org Chem 65:2204–2207CrossRefGoogle Scholar
  59. 59.
    Tallarico JA, Malnick LM, Snapper ML (1999) New reactivity from (PCy3)2Cl2Ru=CHPh: a Mild catalyst for Kharasch additions. J Org Chem 64:344–345CrossRefGoogle Scholar
  60. 60.
    Hu Y-J, Dominique R, Das SK, Roy R (2000) A facile new procedure for the deprotection of allyl ethers under mild conditions. Can J Chem 78:838–846CrossRefGoogle Scholar
  61. 61.
    Cadot C, Dalko PI, Cossy J (2002) Olefin isomerization by a ruthenium carbenoid complex. Cleavage of allyl and homoallyl groups. Tetrahedron Lett 43:1839–1841CrossRefGoogle Scholar
  62. 62.
    Hoye TR, Zhao H (1999) Some allylic substituent effects in ring-closing metathesis reactions: allylic alcohol activation. Org Lett 1:1123–1125CrossRefGoogle Scholar
  63. 63.
    Alcaide B, Almendros P, Alonso JM, Aly MF (2001) A novel use of Grubbs’ carbene. Application to the catalytic deprotection of tertiary allylamines. Org Lett 3:3781–3784CrossRefGoogle Scholar
  64. 64.
    Wipf P, Rector SR, Takahashi H (2002) Application in total synthesis of (-)-tuberostemonine. J Am Chem Soc 124:14848–14849CrossRefGoogle Scholar
  65. 65.
    Sutton AE, Seigal BA, Finnegan DF, Snapper ML (2002) New tandem catalysis: preparation of cyclic enol ethers through a ruthenium-catalyzed ring-closing metathesis–olefin isomerization sequence. J Am Chem Soc 124:13390–13391CrossRefGoogle Scholar
  66. 66.
    Arisawa M, Terada Y, Nakagawa M, Nishida A (2002) Selective isomerization of a terminal olefin catalyzed by a ruthenium complex: the synthesis of indoles through ring-closing metathesis. Angew Chem Int Ed 41:4732–4734CrossRefGoogle Scholar
  67. 67.
    Braddock DC, Matsuno A (2002) In situ tandem allylic acetate isomerisation-ring closing metathesis: 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ruthenium benzylidenes and palladium(0)–phosphine combinations. Tetrahedron Lett 43:3305–3308CrossRefGoogle Scholar
  68. 68.
    Braddock DC, Wildsmith AJ (2001) On the use of tandem allylic acetate isomerisation and ring-closing metathesis with palladium(0) phosphine complexes and ruthenium benzylidenes as orthogonal catalysts. Tetrahedron Lett 42:3239–3242CrossRefGoogle Scholar
  69. 69.
    Bielawski CW, Louie J, Grubbs RH (2000) Tandem catalysis: three mechanistically distinct reactions from a single ruthenium complex. J Am Chem Soc 122:12872–12873CrossRefGoogle Scholar
  70. 70.
    Watson MD, Wagener KB (2000) Tandem homogeneous metathesis/heterogeneous hydrogenation: preparing model ethylene/CO2 and ethylene/CO copolymers. Macromolecules 33:3196–3201CrossRefGoogle Scholar
  71. 71.
    Schmidt B (2004) Catalysis at the interface of ruthenium carbene and ruthenium hydride chemistry: organometallic aspects and applications to organic synthesis. Eur J Org Chem 2004:1865–1880CrossRefGoogle Scholar
  72. 72.
    Ulman M, Grubbs RH (1999) Ruthenium carbene-based olefin metathesis initiators: catalyst decomposition and longevity. J Org Chem 64:7202–7207CrossRefGoogle Scholar
  73. 73.
    Jordan RW, Khoury PR, Goddard JD, Tam W (2004) Ruthenium-catalyzed [2+2] cycloadditions between 7-substituted norbornadienes and alkynes: an experimental and theoretical study. J Org Chem 69:8467–8474CrossRefGoogle Scholar
  74. 74.
    Echavarren AM, Nevado C (2004) Non-stabilized transition metal carbenes as intermediates in intramolecular reactions of alkynes with alkenes. Chem Soc Rev 33:431–436CrossRefGoogle Scholar
  75. 75.
    Trost BM, Pinkerton AB, Toste FD, Sperrle M (2001) Synthesis of 1,1-disubstituted alkenes via a Ru-catalyzed addition. J Am Chem Soc 123:12504–12509CrossRefGoogle Scholar
  76. 76.
    Wender PA, Husfeld CO, Langkopf E, Love JA (1998) First studies of the transition metal-catalyzed [5+2] cycloadditions of alkenes and vinylcyclopropanes: scope and stereochemistry. J Am Chem Soc 120:1940–1941CrossRefGoogle Scholar
  77. 77.
    Wender PA, Takahashi H, Witulski B (1995) Transition metal catalyzed [5+2] cycloadditions of vinylcyclopropanes and alkynes: a homolog of the Diels–Alder reaction for the synthesis of seven-membered rings. J Am Chem Soc 117:4720–4721CrossRefGoogle Scholar
  78. 78.
    Dinnocenzo JP, Schmittel M (1987) Cyclopropane stereomutation catalyzed by one-electron oxidants. J Am Chem Soc 109:1561–1562CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Department of ChemistryMcGill UniversityMontrealCanada

Personalised recommendations