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Some Aspects of the Chemistry of Small Ring Organic Molecules: 1-Azetines, 1-Azetidinones, 3-Oxo-β-sultams and Cyclopropenones

By P.A. O'Gorman


The -lactams and the related -sultams are attractive targets for synthesis because of their central importance in antibiotics such as the penicillins. These heterocycles are of further interest because of their potential as inhibitors of the serine protease class of enzymes113, believed to be responsible for diseases such as rheumatoid arthritis and cystic fibrosis.\ud This thesis will describe the synthesis of the 4-vinyl beta lactams (A)25, thiation of these compounds using Lawesson’s reagent to yield thio lactams (B) and subsequent conversion into the corresponding 1-azetine (C) using Meerwein’s reagent.\ud \ud Compound (C) provided a template for a series of cycloaddition reactions in order to produce a series of bicyclic heterocycles, represented by general structure (D). One reaction that was explored in this series was that between 1-azetines (C) and diphenylcyclopropenone (DPP) (E) which should have yielded the bicyclic adducts F). 93\ud \ud In the event the products isolated were not the anticipated cycloadducts (F) but rather the ring expanded compounds (G)114 obtained via sigmatropic rearrangement, the nucleus of which is an isomer of the azabicyclononane system, present in many important72 alkaloids such as anatoxin-a (H) and pinnamine (I).\ud \ud The project subsequently evolved to look at the possibility of synthesising other alkaloid nuclei such as the pyrrolizidines, indolizidines and pyrroloazepines through the reaction of the appropriate imines with cyclopropenones. These bicyclic systems are present in many natural products72 such as pyrrolam A (J) and indolizidine 223AB (K) and are of great interest for synthesis because of the wide range of biological activities they possess, such as the ability to block the nicotinic receptor channels.\ud \ud This thesis will therefore describe an effective synthesis of the heterocycles shown in Scheme A (where n = 1, 2 or 3).\ud \ud Further research into the reactions of 4-vinyl -lactams (A) has also been conducted with a view to synthesising analogues of the pyrrolobenzodiazepine, antitumour, antibiotic natural products, of which DC-81 (L) is an example.115 Thus, reaction of (A) with o-azidobenzoylchloride gave the N-substituted -lactam (M). Ring closure via an azide-alkene cycloaddition and loss of nitrogen gave either the aziridine compound (N) or the methyl imine (O).\ud \ud Overall the work described in this thesis pioneers initial research into the reactions of electron rich imines with cyclopropenones, positively demonstrating their use in the synthesis of analogues of alkaloid natural products

Topics: Q1, QD
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  1. (C=S). High Resolution Mass Spectroscopy: Electrospray (positive), calc.
  2. 1.83 (1H, ddd,
  3. 13C: c (100 MHz, CDCl3): 164.73 (C=O),
  4. 3.10 (1H, dd,
  5. 3.15 (1H, m, CH2 next to nitrogen), 2.38 (2H, q, J 7.6, CH2 on ring
  6. 3.8, CH2CSEt), 1.38 (1H, dddd, 13.1, 13.0, 4.2, 4.2, CH2CH2 CH2N), 1.14 (3H, t,
  7. 5.25 (1H, d, doi
  8. 7.10 (2H, m, 2ArH), 6.20 (1H, dd,
  9. 7.21 (2H, m, 2ArH), 6.09 (1H, ddd,
  10. 7.3, CCH2CH3), 1.78 (2H, m, CH2CH2CH2CH2N), 1.51 (2H, m, CH2CH2CSEt), 1.35 (1H, ddd,
  11. 7.59 (1H, d, J 8.1, ArH), 7.40 (1H, t,
  12. (1983). Acta doi
  13. Attempted synthesis of 1-(o-azidobenzoyl)-4-ethenyl-1-azetidin-2-one 1H: H (500 MHz, CDCl3): 7.66 (1H, d,
  14. CH2CSEt), 1.81 (1H, ddd,
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  19. Compound data for reaction with 7-ethyl-3,4,5,6-tetrahydro-2H-azepine IR: max (cm-1): 2907 (m),
  20. d,
  21. dd,
  22. ddd,
  23. dq,
  24. dq, 12.0, 7.5 S-CH2CH3), 1.66 (2H, m, CH2CH2CH2CH2N), 1.47 (1H, m, CH2CH2CSEt), 1.35 (1H, m, CH2CH2CSEt), 0.86 (3H, t,
  25. Experimental Compound data for reaction with 6-ethylthio-2,3,4,5-tetrahydropyridine IR: max (cm-1): 2989 (m), 2941 (m), 1689 (s), 1601 (s), 1522 (w), 1417 (m), 1375 (m), 1249 (m). NMR 1H: H (500 MHz, CDCl3): 7.39 (1H, d,
  26. High Resolution Mass Spectroscopy: Electrospray (positive), calc.
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  28. measured = 212.1108. 1H: H (500 MHz, CDCl3): 7.57 (1H, s, CH), 3.64 (1H, ddd,
  29. measured = 273.0725. 1H: H (400 MHz, CDCl3): 8.20 (1H, dd,
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  36. The use of fresh Meerwein’s reagent improved the yields of the 1-azetines.

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