Combining the best of both worlds: radical-based divergent total synthesis

Kyriaki Gennaiou,
Antonios Kelesidis,
Maria Kourgiantaki and
Alexandros L. Zografos

Review
Published 02 Jan 2023

827 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: The power of radical retrosynthesis and the tactic of divergent total synthesis.
  
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3. Figure 1: Evolution of radical chemistry for organic synthesis.
  
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4. Scheme 2: Divergent total synthesis of α-pyrone-diterpenoids (Baran).
  
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5. Scheme 3: Divergent synthesis of pyrone diterpenoids by merged chemoenzymatic and radical synthesis (part I, ...
  
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6. Scheme 4: Divergent synthesis of pyrone diterpenoids by merged chemoenzymatic and radical synthesis (part II,...
  
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7. Scheme 5: Divergent synthesis of drimane-type hydroquinone meroterpenoids (Li).
  
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8. Scheme 6: Divergent synthesis of natural products isolated from Dysidea avara (Lu).
  
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9. Scheme 7: Divergent synthesis of kaurene-type terpenoids (Lei).
  
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10. Scheme 8: Divergent synthesis of 6-oxabicyclo[3.2.1]octane meroterpenoids (Lou).
  
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11. Scheme 9: Divergent synthesis of crinipellins by radical-mediated Dowd–Backwith rearrangement (Xie and Ding).
  
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12. Scheme 10: Divergent total synthesis of Galbulimima alkaloids (Shenvi).
  
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13. Scheme 11: Divergent synthesis of eburnane alkaloids (Qin).
  
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14. Scheme 12: Divergent synthesis of Aspidosperma alkaloids (Boger).
  
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15. Scheme 13: Photoredox based synthesis of (−)-FR901483 (160) and (+)-TAN1251C (162, Gaunt).
  
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16. Scheme 14: Divergent synthesis of bipolamines (Maimone).
  
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17. Scheme 15: Flow chemistry divergency between aporphine and morphinandione alkaloids (Felpin).
  
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18. Scheme 16: Divergent synthesis of pyrroloazocine natural products (Echavarren).
  
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19. Scheme 17: Using TEMPO to stabilize radicals for the divergent synthesis of pyrroloindoline natural products (...
  
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20. Scheme 18: Radical pathway for preparation of lignans (Zhu).
  
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21. Scheme 19: Divergent synthesis of DBCOD lignans (Lumb).
  
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Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

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Modern flow chemistry – prospect and advantage

Philipp Heretsch

Editorial
Published 06 Jan 2023

569 Accesses

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

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Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

Bilge Banu Yagci,
Selin Ezgi Donmez,
Onur Şahin and
Yunus Emre Türkmen

Full Research Paper
Published 17 Jan 2023

547 Accesses

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1. Graphical Abstract
2. Scheme 1: Examples of aza-Nazarov reactions.
  
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3. Scheme 2: Aza-Nazarov cyclization on gram scale.
  
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4. Scheme 3: Scope of the aza-Nazarov cyclization with acyclic imines. ^aThe syntheses of aza-Nazarov products 19b...
  
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5. Figure 1: X-ray crystal structure of compound 19l.
  
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6. Scheme 4: Proposed mechanism for the formation of diastereomers 19 and 22.
  
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7. Scheme 5: Preparation of acyl chloride 23.
  
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8. Scheme 6: Aza-Nazarov reaction tested using β-TMS-substituted acyl chloride 23.
  
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9. Scheme 7: Hydrolysis of N-acyliminium intermediates.
  
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10. Scheme 8: (a) Two possible pathways for the formation of 7 and (b) investigation of the reaction between imin...
  
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11. Scheme 9: (a) Preparation of acyl chlorides 6ba and 6bb in diastereomerically pure forms, (b) aza-Nazarov cyc...
  
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Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

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Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

Julian Spils,
Thomas Wirth and
Boris J. Nachtsheim

Letter
Published 03 Jan 2023

521 Accesses

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Album
1. Graphical Abstract
2. Scheme 1: Synthesis of acyclic (DIS) and cyclic (CDIS) diaryliodonium salts.
  
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3. Figure 1: Substrate scope using the optimized conditions of Table 3. Yield is based on collecting for 3 h 20 min (2....
  
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Beilstein J. Org. Chem. 2023, 19, 27–32, doi:10.3762/bjoc.19.2

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Improving the accuracy of ³¹P NMR chemical shift calculations by use of scaling methods

William H. Hersh and
Tsz-Yeung Chan

Full Research Paper
Published 10 Jan 2023

435 Accesses

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1. Graphical Abstract
2. Figure 1: Training set of tri- and tetracoordinate phosphorus compounds; chemical shifts are in ppm, referenc...
  
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3. Figure 2: (a) Plot of experimental vs calculated chemical shifts of tri- and tetracoordinate phosphorus compo...
  
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4. Figure 3: Plot of experimental vs calculated chemical shifts of training set compounds reported by Latypov et...
  
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5. Figure 4: “Large” compounds selected for ³¹P NMR calculation by Latypov [37].
  
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6. Figure 5: Stereoisomers and unusual phosphorus compounds used for chemical shift calculations.
  
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7. Figure 6: Phosphorus-catalyzed oxygen transfer reaction intermediates.
  
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8. Figure 7: Phosphirane reactions.
  
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9. Figure 8: (a) Plot of experimental vs scaled chemical shifts derived from the tri- and tetracoordinate phosph...
  
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Beilstein J. Org. Chem. 2023, 19, 36–56, doi:10.3762/bjoc.19.4

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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

425 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

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Navigating and expanding the roadmap of natural product genome mining tools

Friederike Biermann,
Sebastian L. Wenski and
Eric J. N. Helfrich

Perspective
Published 06 Dec 2022

393 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Examples of prominent natural products: N-butyrylhomoserine lactone (1), pyoverdin (2), malleicypro...
  
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3. Figure 2: Biosynthetic principles of (A) assembly line-like pathways and (B) discrete multi-enzymatic assembl...
  
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4. Figure 3: Universal (A, B, F) NP class and NP family-specific (C, D, F) signature sequences in NP BGCs and se...
  
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5. Figure 4: Concepts of algorithms in order of complexity and examples of genome mining tools that employ the r...
  
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6. Figure 5: Examples of peptide NPs, the corresponding BGCs of which were determined through retrobiosynthetic ...
  
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7. Figure 6: gcBGC prioritization process. The bar represents all identified gene clusters in one organism and i...
  
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8. Figure 7: Genome alignments of related organisms revealing the presence of syntenic (purple) as well as non-s...
  
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Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

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New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

Elenilson F. da Silva,
Krist Helen Antunes Fernandes,
Denise Diedrich,
Jessica Gotardi,
Marcia Silvana Freire Franco,
Carlos Henrique Tomich de Paula da Silva,
Ana Paula Duarte de Souza and
Simone Cristina Baggio Gnoatto

Full Research Paper
Published 09 Nov 2022

378 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Structures of RBV, betulinic acid (1), and ursolic acid (2).
  
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3. Scheme 1: Synthesis of 1-azido-3-nitrobenzene (c).
  
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4. Scheme 2: Synthesis of the triazole-substituted triterpene derivatives 7 and 8.
  
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5. Figure 2: (A) Activity of compound 8 in A549 cells infected with RSV. MTT assay 96 h after treatment. DMSO (0...
  
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6. Figure 3: Superposition of the top-ranked docking solution of compound 8 (carbon atoms in yellow, in stick re...
  
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Beilstein J. Org. Chem. 2022, 18, 1524–1531, doi:10.3762/bjoc.18.161

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NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

Dan Liu,
Yue Zhao and
Frederic W. Patureau

Letter
Published 16 Jan 2023

336 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Representative natural products and biologically active molecules containing an oxindole moiety [7-13].
  
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3. Scheme 1: Selected photocatalytic decarboxylative radical cascade reactions of N-arylamides.
  
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4. Scheme 2: Arylamide substrate scope with isolated yields of products.
  
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5. Scheme 3: Alkyl radical precursor scope with isolated yields of products.
  
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6. Scheme 4: Selected mechanistic experiments.
  
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Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

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Digyalipopeptide A, an antiparasitic cyclic peptide from the Ghanaian Bacillus sp. strain DE2B

Adwoa P. Nartey,
Aboagye K. Dofuor,
Kofi B. A. Owusu,
Anil S. Camas,
Hai Deng,
Marcel Jaspars and
Kwaku Kyeremeh

Full Research Paper
Published 28 Dec 2022

307 Accesses

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Album
1. Graphical Abstract
2. Figure 1: Primary structure of digyalipopeptide A (1).
  
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3. Figure 2: Key COSY and HMBC correlations for compound 1.
  
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4. Figure 3: Key TOCSY and NOESY correlations for compound 1.
  
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5. Figure 4: Liquid chromatography high resolution electrospray ionization mass spectrometry (LC–HRESIMS) sequen...
  
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6. Figure 5: The absolute stereochemistry of compound 1.
  
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7. Figure 6: Global natural products social molecular networking (GNPS).
  
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Beilstein J. Org. Chem. 2022, 18, 1763–1771, doi:10.3762/bjoc.18.185

Full Text

Combining the best of both worlds: radical-based divergent total synthesis

Modern flow chemistry – prospect and advantage

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

Two-step continuous-flow synthesis of 6-membered cyclic iodonium salts via anodic oxidation

Improving the accuracy of ³¹P NMR chemical shift calculations by use of scaling methods

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

Navigating and expanding the roadmap of natural product genome mining tools

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

Digyalipopeptide A, an antiparasitic cyclic peptide from the Ghanaian Bacillus sp. strain DE2B

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