An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Marcus Baumann and
Ian R. Baxendale

Review
Published 30 Oct 2013

998 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
  
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3. Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
  
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4. Scheme 3: Synthesis of 3-picoline and nicotinic acid.
  
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5. Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
  
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6. Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
  
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7. Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
  
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8. Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
  
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9. Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
  
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10. Scheme 8: Synthesis of rosiglitazone.
  
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11. Scheme 9: Syntheses of 2-pyridones.
  
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12. Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
  
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13. Scheme 11: Polymer-assisted synthesis of rosiglitazone.
  
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14. Scheme 12: Synthesis of pioglitazone.
  
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15. Scheme 13: Meerwein arylation reaction towards pioglitazone.
  
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16. Scheme 14: Route towards pioglitazone utilising tyrosine.
  
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17. Scheme 15: Route towards pioglitazone via Darzens ester formation.
  
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18. Scheme 16: Syntheses of the thiazolidinedione moiety.
  
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19. Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
  
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20. Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
  
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21. Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
  
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22. Scheme 19: Synthesis of moxifloxacin.
  
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23. Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
  
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24. Scheme 21: Synthesis of levofloxacin.
  
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25. Scheme 22: Alternative approach to the levofloxacin core 1.125.
  
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26. Figure 3: Structures of nifedipine, amlodipine and clevidipine.
  
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27. Scheme 23: Mg₃N₂-mediated synthesis of nifedipine.
  
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28. Scheme 24: Synthesis of rac-amlodipine as besylate salt.
  
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29. Scheme 25: Aza Diels–Alder approach towards amlodipine.
  
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30. Scheme 26: Routes towards clevidipine.
  
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31. Figure 4: Examples of piperidine containing drugs.
  
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32. Figure 5: Discovery of tiagabine based on early leads.
  
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33. Scheme 27: Synthetic sequences to tiagabine.
  
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34. Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
  
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35. Scheme 28: Enantioselective synthesis of solifenacin.
  
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36. Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
  
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37. Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
  
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38. Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
  
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39. Scheme 30: Improved route to carmegliptin.
  
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40. Figure 9: Structures of lamivudine and zidovudine.
  
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41. Scheme 31: Typical routes accessing uracil, thymine and cytosine.
  
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42. Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
  
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43. Scheme 33: Synthesis of lamivudine.
  
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44. Scheme 34: Synthesis of raltegravir.
  
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45. Scheme 35: Mechanistic studies on the formation of 3.22.
  
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46. Figure 10: Structures of selected pyrimidine containing drugs.
  
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47. Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
  
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48. Scheme 37: Synthesis of imatinib.
  
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49. Scheme 38: Flow synthesis of imatinib.
  
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50. Scheme 39: Syntheses of erlotinib.
  
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51. Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
  
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52. Scheme 41: Synthesis of lapatinib.
  
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53. Scheme 42: Synthesis of rosuvastatin.
  
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54. Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
  
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55. Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
  
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56. Scheme 44: Syntheses of varenicline and its key building block 4.5.
  
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57. Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
  
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58. Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
  
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59. Scheme 46: Asymmetric synthesis of bortezomib.
  
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60. Figure 13: Structures of some prominent piperazine containing drugs.
  
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61. Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
  
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62. Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
  
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63. Scheme 48: Syntheses of azelastine (5.1).
  
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64. Figure 15: Structures of captopril, enalapril and cilazapril.
  
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65. Scheme 49: Synthesis of cilazapril.
  
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66. Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
  
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67. Scheme 50: Synthesis of lamotrigine.
  
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68. Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
  
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69. Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
  
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70. Scheme 52: Conventional synthesis of imiquimod (no yields reported).
  
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71. Scheme 53: Synthesis of imiquimod.
  
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72. Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
  
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73. Figure 18: Structures of various anti HIV-medications.
  
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74. Scheme 55: Synthesis of abacavir.
  
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75. Figure 19: Structures of diazepam compared to modern replacements.
  
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76. Scheme 56: Synthesis of ocinaplon.
  
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77. Scheme 57: Access to zaleplon and indiplon.
  
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78. Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
  
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79. Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
  
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80. Scheme 60: Early synthetic route to sildenafil.
  
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81. Scheme 61: Convergent preparations of sildenafil.
  
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82. Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
  
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83. Scheme 62: Short route to imidazotriazinones.
  
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84. Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
  
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85. Scheme 64: Bayer’s approach to the vardenafil core.
  
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86. Scheme 65: Large scale synthesis of vardenafil.
  
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87. Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
  
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88. Scheme 67: Different routes to temozolomide.
  
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89. Scheme 68: Safer route towards temozolomide.
  
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90. Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
  
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Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Full Text

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann,
Ian R. Baxendale,
Steven V. Ley and
Nikzad Nikbin

Review
Published 18 Apr 2011

622 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Structures of atorvastatin and other commercial statins.
  
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3. Figure 2: Structure of compactin.
  
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4. Scheme 1: Synthesis of pentasubstituted pyrroles.
  
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5. Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
  
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6. Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
  
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7. Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
  
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8. Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
  
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9. Scheme 6: Convergent synthesis towards atorvastatin.
  
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10. Figure 3: Binding pocket of sunitinib in the TRK KIT.
  
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11. Scheme 7: Synthesis of sunitinib.
  
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12. Scheme 8: Alternative synthesis of sunitinib.
  
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13. Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
  
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14. Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
  
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15. Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
  
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16. Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
  
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17. Scheme 13: Alternative introduction of the sulfonamide.
  
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18. Scheme 14: Negishi-type coupling to benzylic sulfonamides.
  
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19. Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
  
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20. Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
  
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21. Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
  
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22. Scheme 18: Improved synthesis of rizatriptan.
  
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23. Scheme 19: Larock-type synthesis of rizatriptan.
  
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24. Scheme 20: Synthesis of eletriptan.
  
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25. Scheme 21: Heck coupling for the indole system in eletriptan.
  
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26. Scheme 22: Attempted Fischer indole synthesis of elatriptan.
  
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27. Scheme 23: Successful Fischer indole synthesis for eletriptan.
  
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28. Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
  
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29. Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
  
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30. Scheme 26: Palladium-mediated synthesis of ondansetron.
  
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31. Scheme 27: Fischer indole synthesis of ondansetron.
  
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32. Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
  
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33. Figure 4: Structures of carvedilol 136 and propranolol 137.
  
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34. Scheme 29: Synthesis of the carbazole core of carvedilol.
  
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35. Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
  
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36. Scheme 31: Convergent synthesis of etodolac.
  
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37. Scheme 32: Alternative synthesis of etodolac.
  
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38. Figure 5: Structures of imidazole-containing drugs.
  
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39. Scheme 33: Synthesis of functionalised imidazoles towards losartan.
  
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40. Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
  
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41. Scheme 35: Synthesis of trisubstituted imidazoles.
  
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42. Scheme 36: Preparation of the imidazole ring in olmesartan.
  
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43. Scheme 37: Synthesis of ondansetron.
  
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44. Scheme 38: Alternative route to ondansetron and its analogues.
  
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45. Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
  
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46. Scheme 40: Synthesis of benzimidazole core pantoprazole.
  
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47. Figure 6: Structure of rabeprazole 194.
  
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48. Scheme 41: Synthesis of candesartan.
  
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49. Scheme 42: Alternative access to the candesartan key intermediate 216.
  
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50. Scheme 43: .Medicinal chemistry route to telmisartan.
  
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51. Scheme 44: Improved synthesis of telmisartan.
  
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52. Scheme 45: Synthesis of zolpidem.
  
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53. Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
  
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54. Figure 7: Structure of celecoxib.
  
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55. Scheme 47: Preparation of celecoxib.
  
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56. Scheme 48: Alternative synthesis of celecoxib.
  
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57. Scheme 49: Regioselective access to celecoxib.
  
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58. Scheme 50: Synthesis of pazopanib.
  
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59. Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
  
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60. Scheme 52: Regioselective synthesis of anastrozole.
  
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61. Scheme 53: Triazine-mediated triazole formation towards anastrozole.
  
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62. Scheme 54: Alternative routes to 1,2,4-triazoles.
  
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63. Scheme 55: Initial synthetic route to sitagliptin.
  
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64. Figure 8: Binding of sitagliptin within DPP-IV.
  
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65. Scheme 56: The process route to sitagliptin key intermediate 280.
  
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66. Scheme 57: Synthesis of maraviroc.
  
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67. Scheme 58: Synthesis of alprazolam.
  
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68. Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
  
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69. Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
  
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70. Scheme 60: Synthesis of itraconazole.
  
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71. Scheme 61: Synthesis of rufinamide.
  
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72. Scheme 62: Representative tetrazole formation in valsartan.
  
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73. Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
  
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74. Scheme 63: Early stage introduction of the tetrazole in losartan.
  
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75. Scheme 64: Synthesis of cilostazol.
  
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76. Figure 11: Structure of cefdinir.
  
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77. Scheme 65: Semi-synthesis of cefdinir.
  
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78. Scheme 66: Thiazole syntheses towards ritonavir.
  
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79. Scheme 67: Synthesis towards pramipexole.
  
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80. Scheme 68: Alternative route to pramipexole.
  
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81. Scheme 69: Synthesis of famotidine.
  
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82. Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
  
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83. Scheme 71: Synthesis of ziprasidone.
  
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84. Figure 12: Structure of mometasone.
  
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85. Scheme 72: Industrial access to 2-furoic acid present in mometasone.
  
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86. Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
  
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87. Scheme 74: Synthesis of nitrofurantoin.
  
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88. Scheme 75: Synthesis of benzofuran.
  
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89. Scheme 76: Synthesis of amiodarone.
  
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90. Scheme 77: Synthesis of raloxifene.
  
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91. Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
  
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92. Scheme 79: Gewald reaction in the synthesis of olanzapine.
  
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93. Scheme 80: Alternative synthesis of olanzapine.
  
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94. Figure 13: Access to simple thiophene-containing drugs.
  
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95. Scheme 81: Synthesis of clopidogrel.
  
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96. Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
  
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97. Scheme 83: Alternative synthesis of key intermediate 422.
  
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98. Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
  
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99. Scheme 84: Synthesis of timolol.
  
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100. Scheme 85: Synthesis of tizanidine 440.
  
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101. Scheme 86: Synthesis of leflunomide.
  
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102. Scheme 87: Synthesis of sulfamethoxazole.
  
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103. Scheme 88: Synthesis of risperidone.
  
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104. Figure 15: Relative abundance of selected transformations.
  
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105. Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
  
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Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

Full Text

A review of new developments in the Friedel–Crafts alkylation – From green chemistry to asymmetric catalysis

Magnus Rueping and
Boris J. Nachtsheim

Review
Published 20 Jan 2010

521 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: AlCl₃-mediated reaction between amyl chloride and benzene as developed by Friedel and Crafts.
  
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3. Figure 1: Most often used metal salts for catalytic FC alkylations and hydroarylations of arenes.
  
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4. Figure 2: 1,1-diarylalkanes with biological activity.
  
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5. Scheme 2: Alkylating reagents and side products produced.
  
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6. Scheme 3: Initially reported TeCl₄-mediated FC alkylation of 1-penylethanol with toluene.
  
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7. Scheme 4: Sc(OTf)₃-catalyzed FC benzylation of arenes.
  
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8. Scheme 5: Reductive FC alkylation of arenes with arenecarbaldehydes.
  
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9. Scheme 6: Iron(III)-catalyzed FC benzylation of arenes and heteroarenes.
  
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10. Scheme 7: A gold(III)-catalyzed route to beclobrate.
  
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11. Scheme 8: Catalytic FC-type alkylations of 1,3-dicarbonyl compounds.
  
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12. Scheme 9: Iron(III)-catalyzed synthesis of phenprocoumon.
  
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13. Scheme 10: Bi(OTf)₃-catalyzed FC alkylation of benzyl alcohols developed by Rueping et al.
  
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14. Scheme 11: (A) Bi(OTf)₃-catalyzed intramolecular FC alkylation as an efficient route to substituted fulvenes. ...
  
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15. Scheme 12: FC-type glycosylation of 1,2-dimethylindole and trimethoxybenzene.
  
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16. Scheme 13: FC alkylation with highly reactive ferrocenyl- and benzyl alcohols. The reaction proceeds even with...
  
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17. Scheme 14: Reductive FC alkylation of arenes with benzaldehyde and acetophenone catalyzed by the Ir-carbene co...
  
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18. Scheme 15: Formal synthesis of 1,1-diarylalkanes from benzyl alcohols and styrenes.
  
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19. Scheme 16: (A) Mo-catalyzed hydroarylation of styrenes and cyclohexenes. (B) Hydroalkylation–cyclization casca...
  
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20. Scheme 17: Bi(III)-catalyzed hydroarylation of styrenes with arenes and heteroarenes.
  
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21. Scheme 18: BiCl₃-catalyzed ene/FC alkylation reaction cascade – A fast access to highly arylated dihydroindene...
  
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22. Scheme 19: Au(I)/Ag(I)-catalyzed hydroarylation of indoles with styrenes, aliphatic and cyclic alkenes.
  
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23. Scheme 20: First transition-metal-catalyzed ortho-hydroarylation developed by Beller et al.
  
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24. Scheme 21: (A) Ti(IV)-mediated rearrangement of an N-benzylated aniline to the corresponding ortho-alkylated a...
  
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25. Scheme 22: Dibenzylation of aniline gives potentially useful amine-based ligands in a one-step procedure.
  
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26. Scheme 23: FC-type alkylations with allyl alcohols as alkylating reagents – linear vs. branched product format...
  
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27. Scheme 24: (A) First catalytic FC allylation and cinnamylation using allyl alcohols and its derivatives. (B) E...
  
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28. Scheme 25: FC allylation/cyclization reaction yielding substituted chromanes.
  
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29. Scheme 26: Synthesis of (all-rac)-α-tocopherol utilizing Lewis- and strong Brønsted-acids.
  
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30. Scheme 27: Au(III)-catalyzed cinnamylation of arenes.
  
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31. Scheme 28: “Exhaustive” allylation of benzene-1,3,5-triol.
  
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32. Scheme 29: Palladium-catalyzed allylation of indole.
  
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33. Scheme 30: Pd-catalyzed synthesis of pyrroloindoles from L-tryptophane.
  
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34. Scheme 31: Ru(IV)-catalyzed allylation of indole and pyrroles with unique regioselectivity.
  
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35. Scheme 32: Silver(I)-catalyzed intramolecular FC-type allylation of arenes and heteroarenes.
  
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36. Scheme 33: FC-type alkylations of arenes using propargyl alcohols.
  
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37. Scheme 34: (A) Propargylation of arenes with stoichiometric amounts of the Ru-allenylidene complex 86. (B) Fir...
  
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38. Scheme 35: Diruthenium-catalyzed formation of chromenes and 1H-naphtho[2,1-b]pyrans.
  
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39. Scheme 36: Rhenium(V)-catalyzed FC propargylations as a first step in the total synthesis of podophyllotoxin, ...
  
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40. Scheme 37: Scandium-catalyzed arylation of 3-sulfanyl- and 3-selanylpropargyl alcohols.
  
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41. Scheme 38: Synthesis of 1,3-diarylpropynes via direct coupling of propargyl trichloracetimidates and arenes.
  
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42. Scheme 39: Diastereoselective substitutions of benzyl alcohols.
  
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43. Scheme 40: (A) First diastereoselective FC alkylations developed by Bach et al. (B) anti-Selective FC alkylati...
  
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44. Scheme 41: Diastereoselective AuCl₃-catalyzed FC alkylation.
  
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45. Scheme 42: Bi(OTf)₃-catalyzed alkylation of α-chiral benzyl acetates with silyl enol ethers.
  
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46. Scheme 43: Bi(OTf)₃-catalyzed diastereoselective substitution of propargyl acetates.
  
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47. Scheme 44: Nucelophilic substitution of enantioenriched ferrocenyl alcohols.
  
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48. Scheme 45: First catalytic enantioselective propargylation of arenes.
  
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Beilstein J. Org. Chem. 2010, 6, No. 6, doi:10.3762/bjoc.6.6

Full Text

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

Marcus Baumann and
Ian R. Baxendale

Review
Published 17 Jul 2015

464 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Pharmaceutical structures targeted in early flow syntheses.
  
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3. Scheme 1: Flow synthesis of 6-hydroxybuspirone (9). Inserted photograph reprinted with permission from [45]. Copy...
  
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4. Figure 2: Configuration of a baffled reactor tube (left) and its schematic working principle (right).
  
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5. Scheme 2: McQuade’s flow synthesis of ibuprofen (16).
  
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6. Scheme 3: Jamison’s flow synthesis of ibuprofen sodium salt (17).
  
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7. Scheme 4: Flow synthesis of imatinib (23).
  
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8. Scheme 5: Flow synthesis of the potent 5HT1B antagonist 28.
  
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9. Scheme 6: Flow synthesis of a selective δ-opioid receptor agonist 33.
  
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10. Scheme 7: Flow synthesis of a casein kinase I inhibitor library (38).
  
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11. Scheme 8: Flow synthesis of fluoxetine (46).
  
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12. Scheme 9: Flow synthesis of artemisinin (55).
  
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13. Scheme 10: Telescoped flow synthesis of artemisinin (55) and derivatives (62–64).
  
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14. Scheme 11: Flow approach towards AZD6906 (65).
  
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15. Scheme 12: Pilot scale flow synthesis of key intermediate 73.
  
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16. Scheme 13: Semi-flow synthesis of vildagliptine (77).
  
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17. Scheme 14: Pilot scale asymmetric flow hydrogenation towards 83. Inserted photograph reprinted with permission...
  
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18. Figure 3: Schematic representation of the ‘tube-in-tube’ reactor.
  
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19. Scheme 15: Flow synthesis of fanetizole (87) via tube-in-tube system.
  
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20. Scheme 16: Flow synthesis of diphenhydramine^.HCl (92).
  
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21. Scheme 17: Flow synthesis of rufinamide (95).
  
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22. Scheme 18: Large scale flow synthesis of rufinamide precursor 102.
  
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23. Scheme 19: First stage in the flow synthesis of meclinertant (103).
  
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24. Scheme 20: Completion of the flow synthesis of meclinertant (103).
  
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25. Scheme 21: Flow synthesis of olanzapine (121) utilising inductive heating techniques.
  
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26. Scheme 22: Flow synthesis of amitriptyline·HCl (127).
  
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27. Scheme 23: Flow synthesis of E/Z-tamoxifen (132) using peristaltic pumping modules.
  
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28. Figure 4: Container sized portable mini factory (photograph credit: INVITE GmbH, Leverkusen Germany).
  
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29. Scheme 24: Flow synthesis of imidazo[1,2-a]pyridines 136 linked to frontal affinity chromatography (FAC).
  
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30. Figure 5: Structures of zolpidem (142) and alpidem (143).
  
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31. Scheme 25: Synthesis and screening loops in the discovery of new Abl kinase inhibitors.
  
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32. Figure 6: Schotten–Baumann approach towards LY573636^.Na (147).
  
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33. Scheme 26: Pilot scale flow synthesis of LY2886721 (146).
  
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34. Scheme 27: Continuous flow manufacture of alikiren hemifumarate 152.
  
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Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

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Cupreines and cupreidines: an established class of bifunctional cinchona organocatalysts

Laura A. Bryant,
Rossana Fanelli and
Alexander J. A. Cobb

Review
Published 07 Mar 2016

421 Accesses

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1. Graphical Abstract
2. Figure 1: The structural diversity of the cinchona alkaloids, along with cupreine, cupreidine, β-isoquinidine...
  
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3. Scheme 1: The original 6’-OH cinchona alkaloid organocatalytic MBH process, showing how the free 6’-OH is ess...
  
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4. Scheme 2: Use of β-ICPD in an aza-MBH reaction.
  
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5. Scheme 3: (a) The isatin motif is a common feature for MBH processes catalyzed by β-ICPD, as demonstrated by ...
  
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6. Scheme 4: (a) Chen’s asymmetric MBH reaction. Good selectivity was dependent upon the presence of (R)-BINOL (...
  
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7. Scheme 5: Lu and co-workers synthesis of a spiroxindole.
  
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8. Scheme 6: Kesavan and co-workers’ synthesis of spiroxindoles.
  
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9. Scheme 7: Frontier’s Nazarov cyclization catalyzed by β-ICPD.
  
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10. Scheme 8: The first asymmetric nitroaldol process catalyzed by a 6’-OH cinchona alkaloid.
  
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11. Scheme 9: A cupreidine derived catalyst induces a dynamic kinetic asymmetric transformation.
  
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12. Scheme 10: Cupreine derivative 38 has been used in an organocatalytic asymmetric Friedel–Crafts reaction.
  
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13. Scheme 11: Examples of 6’-OH cinchona alkaloid catalyzed processes include: (a) Deng’s addition of dimethyl ma...
  
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14. Scheme 12: A diastereodivergent sulfa-Michael addition developed by Melchiorre and co-workers.
  
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15. Scheme 13: Melchiorre’s vinylogous Michael addition.
  
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16. Scheme 14: Simpkins’s TKP conjugate addition reactions.
  
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17. Scheme 15: Hydrocupreine catalyst HCPN-59 can be used in an asymmetric cyclopropanation.
  
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18. Scheme 16: The hydrocupreine and hydrocupreidine-based catalysts HCPN-65 and HCPD-67 demonstrate the potential...
  
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19. Scheme 17: Jørgensen’s oxaziridination.
  
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20. Scheme 18: Zhou’s α-amination using β-ICPD.
  
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21. Scheme 19: Meng’s cupreidine catalyzed α-hydroxylation.
  
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22. Scheme 20: Shi’s biomimetic transamination process for the synthesis of α-amino acids.
  
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23. Scheme 21: β-Isocupreidine catalyzed [4 + 2] cycloadditions.
  
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24. Scheme 22: β-Isocupreidine catalyzed [2+2] cycloaddition.
  
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25. Scheme 23: A domino reaction catalyst by cupreidine catalyst CPD-30.
  
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26. Scheme 24: (a) Dixon’s 6’-OH cinchona alkaloid catalyzed oxidative coupling. (b) An asymmetric oxidative coupl...
  
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Beilstein J. Org. Chem. 2016, 12, 429–443, doi:10.3762/bjoc.12.46

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Recent advances on organic blue thermally activated delayed fluorescence (TADF) emitters for organic light-emitting diodes (OLEDs)

Thanh-Tuân Bui,
Fabrice Goubard,
Malika Ibrahim-Ouali,
Didier Gigmes and
Frédéric Dumur

Review
Published 30 Jan 2018

336 Accesses

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1. Graphical Abstract
2. Figure 1: Radiative deactivation pathways existing in fluorescent, phosphorescent and TADF materials.
  
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3. Figure 2: Boron-containing TADF emitters B1–B10.
  
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4. Figure 3: Diphenylsulfone-based TADF emitters D1–D7.
  
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5. Figure 4: Triazine-based TADF emitters T1–T3, T5–T7 and azasiline derivatives T3 and T4.
  
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6. Figure 5: Triazine-based TADF emitters T8, T9, T11–T14 and carbazole derivative T10.
  
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7. Figure 6: Triazine-based TADF emitters T15–T19.
  
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8. Figure 7: Triazine- and pyrimidine-based TADF emitters T20–T26.
  
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9. Figure 8: Pyrimidine-based TADF emitters T27–T30.
  
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10. Figure 9: Triazine-based TADF polymers T31–T32.
  
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11. Figure 10: Phenoxaphosphine oxide and phenoxathiin dioxide-based TADF emitters P1 and P2.
  
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12. Figure 11: CN-Substituted pyridine and pyrimidine derivatives CN-P1–CN-P8.
  
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13. Figure 12: CN-Substituted pyridine derivatives CN-P9 and CN-P10.
  
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14. Figure 13: Phosphine oxide-based TADF blue emitters PO-1–PO-3.
  
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15. Figure 14: Phosphine oxide-based TADF blue emitters PO-4–PO-9.
  
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16. Figure 15: Benzonitrile-based emitters BN-1–BN-5.
  
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17. Figure 16: Benzonitrile-based emitters BN-6–BN-11.
  
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18. Figure 17: Benzoylpyridine-carbazole hybrid emitters BP-1–BP-6.
  
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19. Figure 18: Benzoylpyridine-carbazole hybrid emitters BP-7–BP-10.
  
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20. Figure 19: Triazole-based emitters Trz-1 and Trz-2.
  
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21. Figure 20: Triarylamine-based emitters TPA-1–TPA-3.
  
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22. Figure 21: Distribution of the CIE coordinates of ca. 90 blue TADF emitters listed in this review.
  
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Beilstein J. Org. Chem. 2018, 14, 282–308, doi:10.3762/bjoc.14.18

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Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

Laura Carro

Review
Published 21 Nov 2018

329 Accesses

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1. Graphical Abstract
2. Figure 1: Illustration of a PPI modulator (stabilizer or inhibitor) vs a traditional drug target.
  
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3. Figure 2: Examples of protein–protein interaction modulators in clinical trials or in clinical use.
  
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4. Figure 3: Small-molecule inhibitors of PPIs in the β-sliding clamp.
  
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5. Figure 4: Crystal structure of the RU7 (9)-sliding clamp complex (PDB code 3D1G; adapted from Georgescu et al...
  
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6. Figure 5: Peptidic inhibitors of PPIs in the sliding clamp.
  
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7. Figure 6: SSB protein–protein interaction inhibitors identified by HTS.
  
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8. Figure 7: SSB protein–protein interaction inhibitors identified by FBDD.
  
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9. Figure 8: Examples of molecules that disrupt the ZipA/FtsZ interaction.
  
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10. Figure 9: Inhibitors of the NusB/NusE interaction.
  
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Beilstein J. Org. Chem. 2018, 14, 2881–2896, doi:10.3762/bjoc.14.267

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Copper(I)-catalyzed tandem reaction: synthesis of 1,4-disubstituted 1,2,3-triazoles from alkyl diacyl peroxides, azidotrimethylsilane, and alkynes

Muhammad Israr,
Changqing Ye,
Munira Taj Muhammad,
Yajun Li and
Hongli Bao

Full Research Paper
Published 23 Nov 2018

322 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: General methods for the synthesis of triazoles.
  
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3. Scheme 2: Substrate scope of the terminal alkynes. Conditions: 1 (0.5 mmol), 2a (0.75 mmol), TMSN₃ (0.75 mmol...
  
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4. Scheme 3: Substrate scope of the alkyl diacyl peroxides. Conditions: 1a (0.5 mmol), 2 (0.75 mmol), TMSN₃ (0.7...
  
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5. Scheme 4: Preliminary mechanistic studies.
  
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6. Scheme 5: Plausible reaction mechanism.
  
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Supp. Info

Beilstein J. Org. Chem. 2018, 14, 2916–2922, doi:10.3762/bjoc.14.270

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The chemistry of amine radical cations produced by visible light photoredox catalysis

Jie Hu,
Jiang Wang,
Theresa H. Nguyen and
Nan Zheng

Review
Published 01 Oct 2013

308 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: Amine radical cations’ mode of reactivity.
  
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3. Scheme 2: Reductive quenching of photoexcited Ru complexes by Et₃N.
  
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4. Scheme 3: Photoredox aza-Henry reaction.
  
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5. Scheme 4: Formation of iminium ions using BrCCl₃ as stoichiometric oxidant.
  
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6. Scheme 5: Oxidative functionalization of N-aryltetrahydroisoquinolines using Eosin Y.
  
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7. Scheme 6: Synthetic and mechanistic studies of Eosin Y-catalyzed aza-Henry reaction.
  
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8. Scheme 7: Oxidative functionalization of N-aryltetrahydroisoquinolines using RB and GO.
  
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9. Scheme 8: Merging Ru-based photoredox catalysis and Lewis base catalysis for the Mannich reaction.
  
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10. Scheme 9: Merging Au-based photoredox catalysis and Lewis base catalysis for the Mannich reaction.
  
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11. Scheme 10: Merging Ru-based photoredox catalysis and Cu-catalyzed alkynylation reaction.
  
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12. Scheme 11: Merging Ru-based photoredox catalysis and NHC catalysis.
  
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13. Scheme 12: 1,3-Dipolar cycloaddition of photogenically formed azomethine ylides.
  
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14. Scheme 13: Plausible mechanism for photoredox 1,3-dipolar cycloaddition.
  
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15. Scheme 14: Photoredox-catalyzed cascade reaction for the synthesis of fused isoxazolidines.
  
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16. Scheme 15: Plausible mechanism for the photoredox-catalyzed cascade reaction.
  
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17. Scheme 16: Photoredox-catalyzed α-arylation of glycine derivatives.
  
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18. Scheme 17: Photoredox-catalyzed α-arylation of amides.
  
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19. Scheme 18: Intramolecular interception of iminium ions by sulfonamides.
  
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20. Scheme 19: Intramolecular interception of iminium ions by alcohols and sulfonamides.
  
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21. Scheme 20: Intermolecular interception of iminium ions by phosphites.
  
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22. Scheme 21: Photoredox-catalyzed oxidative phosphonylation by Eosin Y.
  
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23. Scheme 22: Conjugated addition of α-amino radicals to Michael acceptors.
  
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24. Scheme 23: Conjugated addition of α-amino radicals to Michael acceptors assisted by a Brønsted acid.
  
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25. Scheme 24: Conjugated addition of α-amino radicals derived from anilines to Michael acceptors.
  
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26. Scheme 25: Oxygen switch between two pathways involving α-amino radicals.
  
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27. Scheme 26: Interception of α-amino radicals by azodicarboxylates.
  
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28. Scheme 27: α-Arylation of amines.
  
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29. Scheme 28: Plausible mechanism for α-arylation of amines.
  
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30. Scheme 29: Photoinduced C–C bond cleavage of tertiary amines.
  
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31. Scheme 30: Photoredox cleavage of C–C bonds of 1,2-diamines.
  
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32. Scheme 31: Proposed mechanism photoredox cleavage of C–C bonds.
  
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33. Scheme 32: Intermolecular [3 + 2] annulation of cyclopropylamines with olefins.
  
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34. Scheme 33: Proposed mechanism for intermolecular [3 + 2] annulation.
  
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35. Scheme 34: Photoinduced clevage of N–N bonds of aromatic hydrazines and hydrazides.
  
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Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

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Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

Daniel F. Sauer,
Johannes Schiffels,
Takashi Hayashi,
Ulrich Schwaneberg and
Jun Okuda

Review
Published 19 Nov 2018

304 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: Left: Mechanism of the olefin metathesis reaction postulated by Chauvin [2]. Right: Potential influenc...
  
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3. Scheme 2: (i) Ring-opening metathesis polymerization (ROMP), (ii) ring-closing metathesis (RCM) and (iii) cro...
  
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4. Figure 1: Common anchoring strategies for metal-complex or metal ion incorporation into protein scaffolds.
  
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5. Scheme 3: Biotinylated GH-type catalysts for conjugation to (strept)avidin and their catalyzed ring-closing m...
  
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6. Scheme 4: Whole-cell artificial metatheases designed by Ward et al. [47].
  
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7. Scheme 5: Coupling of GH-type catalysts Ru-4/5/6 to NB4 or NB11.
  
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8. Scheme 6: Anchoring and refolding of GH-type catalysts Ru-4/5/6 to FhuA.
  
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9. Figure 2: Top: NB4 (PDB 3WJB); bottom: NB4exp. Highlighted in blue are the additional two β-sheets. Highlight...
  
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Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

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