LOGIN TO YOUR ACCOUNT

Username
Password
Remember Me
Or use your Academic/Social account:

CREATE AN ACCOUNT

Or use your Academic/Social account:

Congratulations!

You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.

Important!

Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message

CREATE AN ACCOUNT

Name:
Username:
Password:
Verify Password:
E-mail:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
O'Gorman, P.A.
Languages: English
Types: Doctoral thesis
Subjects: Q1, QD
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.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. (a) Shvekhgeimer, M.-G. A. Chemistry of Heterocyclic Compounds 2003, 39, 405-445; (b) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776-12777.
    • 2. Murai, T.; Sano, H.; Kawai, H.; Aso, H.; Shibahara, F. J. Org. Chem. 2005, 70, 8148-8153.
    • 3. Katritzky, A. R.; Zhu, L.; Lang, H.; Denisko, O.; Wang, Z. Tetrahedron 1995, 51, 13272-13276.
    • 4. (a) Saluste, C. G.; Whitby, R. J.; Furber, M. Tetrahedron Lett. 2001, 42, 6191-6194; (b) Kosugi, M.; Ogata, T.; Tamura, H.; Sano, H.; Migita, T. Chem. Lett. 1986, 1197-1200.
    • 5. Kuduk, S. D.; Ng, C.; Chang, R. K.; Bock M. G. Tetrahedron Lett. 2003, 44, 1437-1440.
    • 6. Oganisyan, A. S.; Grigoryan, G.O.; Noravyan, A.S. Khimiya Geterotsiklicheskikh Soedinenii 2001, 8, 1116-1119.
    • 7. Coustard, J-M. Tetrahedron 1996, 52, 9509-9520.
    • 8. Cousson, A.; Coustard, J-M. Tetrahedron 1998, 54, 6523-6528.
    • 9. Hamid, A.; Elomri, A.; Daïch, A. Tetrahedron Lett. 2006, 47, 1777- 1781.
    • 10. Agami, C.; Amiot, F.; Couty, F.; Dechoux, L. Tetrahedron Lett. 1998, 39, 5373-5374.
    • 11. Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197-1218.
    • 12. Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Am. Chem. Soc. 2006, 128, 8820-8828.
    • 13. (a) Restituyo, J. A.; Comstock, L. R.; Petersen, S. G.; Stringfellow, T.; Rajski, S. R. Org. Lett. 2003, 5, 4357- 4360; (b) Rose, M. W.; Xu, J.; Kale, T. A.; O'Doherty, G.; Barany, G.; Distefano, M. D. Peptide Sci. 2005, 80, 164-171.
    • 14. Pleynet, D. P. M.; Dutton, J. K.; Thornton-Pett, M.; Johnson A. P. Tetrahedron Lett. 1995, 36, 6321-6324.
    • 15. Ghosez, L.; Bayard, Ph.; Nshimyumukiza, P.; Gouverneur V.; Sainte, F.; Beaudegnies, R.; Rivera, M.; Frisque-Hesbain, A.-M.; Wynants, C. Tetrahedron 1995, 51, 11021-11042.
    • 16. Schaeffer, F. C.; Peters, G. A. J. Org. Chem. 1961, 26, 2778.
    • 17. Emde, H.; Domsch, D.; Feger, H.; Frick, U.; Götz, A.; Hergott, H. H.; Hoffman, K.; Kober, W.; Krägeloh, K.; Oesterle, T.; Steppan, W.; West, W.; Simchen, G. Synthesis 1982, 1.
    • 18. Ghosez, L.; Jnoff, E.; Bayard, Ph.; Sainte, F.; Beaudegnies, R. Tetrahedron 1999, 55, 3387-3400.
    • 19. Alvarez-Ibarra, C.; Csákÿ, A. G.; Martínez, M.; Luz Quiroga, M. Tetrahedron Lett. 1996, 36, 6573-6574.
    • 20. Ito, H.; Imai, N.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 1799-1800.
    • 21. Gerwick, W. H.; Proteau, P. J.; Nagle, D. G.; Hamel, E.; Blokhin, A.; Slate, D. L. J. Org. Chem. 1994, 59, 1243-1245.
    • 22. Graf, R. Justus Liebigs Ann. Chem. 1963, 661, 111.
    • 23. Meerwein, H. Org. Syn. 1966, 46, 120.
    • 24. Paquette, L. A.; Kakihana, T.; Hansen, J. F.; Phillips, J. C. J. Am. Chem. Soc. 1970, 93, 152-161.
    • 25. Durst, T.; O'Sullivan, M. J. J. Org. Chem. 1970, 35, 2043-2044.
    • 26. Hemming, K.; Morgan, D. T.; Smalley, R. K. J. Fluorine Chem. 2000, 106, 83-86.
    • 27. Hemming, K.; Redhouse, A. D.; Smalley, R. K.; Thompson, J. R.; Kennewell, P. D.; Westwood, R. Tetrahedron Lett. 1992, 33, 2231- 2234.
    • 28. Hemming, K.; Luheshi, A.-B. N.; Redhouse, A. D.; Smalley, R. K.; Thompson, J. R.; Kennewell, P. D.; Westwood, R. Tetrahedron 1993, 49, 4383-4408.
    • 29. Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim. Belg. 1978, 87, 229-238.
    • 30. Scrowston, R. M.; Miller, D. J.; Kennewell, P. D.; Westwood, R. Tetrahedron 1994, 50, 5159-5168.
    • 31. North, M. J. Chem. Soc., Perkin Trans. 1 1999, 2209-2229.
    • 32. Liu, J.-F.; Ye, P.; Sprague, K.; Sargent, K.; Yohannes, D.; Baldino, C. M.; Wilson, C. J.; Ng, S.-C. Org. Lett. 2005, 7, 3363-3366.
    • 33. Dufour, E.; Tam, W.; Nägler, D. K.; Storer, A. C.; Ménard, R. FEBS Letters, 1998, 433, 78-82.
    • 34. Dufour, E.; Storer, A.; Ménard, R. Biochemistry 1995, 34, 16382- 16388.
    • 57. Giovenzana, G. B.; Sisti, M.; Palmisano, G. Tetrahedron Asymm. 1997, 8, 515-518.
    • 58. Daly, J. W.; Garraffo, H. M.; Spande, T. F.; Decker, M. W.; Sullivan, J. P.; Williams, M.; Nat. Prod. Rep. 2000, 17, 131-135.
    • 59. Molander, G. A.; Hiersemann, M. Tetrahedron Lett. 1997, 38, 4347- 4350.
    • 60. Tong, S. T.; Barker, D. Tetrahedron Lett. 2006, 47, 5017-5020.
    • 61. Kumareswaran, R.; Gallucci, J.; RajanBabu, T. V. J. Org. Chem. 2004, 69, 9151-9158.
    • 62. Kim, N.; Choi, J.; Cha, J. K. J. Org. Chem. 1993, 58, 7096-7099.
    • 63. Patil, N. T.; Pahadi, N. K.; Yamamoto, Y. Tetrahedron Lett. 2005, 46, 2101-2103.
    • 64. Toyooka, N.; Dejun, Z.; Nemoto, H.; Garraffo, H. M.; Spande, T. F.; Daly, J. W. Tetrahedron Lett. 2006, 47, 577-580.
    • 65. Smith (III), A. B.; Kim, D. J. Org. Chem. 2006, 71, 2547-2557.
    • 66. Pearson, W. H.; Bergmeier, S. C.; Degan, S.; Lin, K.; Poon, Y.; Schkeryantz, J. M.; Williams, J. P. J. Org. Chem. 1990, 55, 5719- 5738.
    • 67. Williams, I.; Kariuki, B. M.; Reeves, K.; Cox, L. R. Org. Lett. 2006, 8, 4389-4392.
    • 68. Mann, J. Chemical Aspects of Biosynthesis, Oxford University Press 1994.
    • 69. Mattock, A. R. “Chemistry and Toxicology of Pyrrolizidine Alkaloids”, Academic Press, London, 1986.
    • 70. Duvall, J. R.; Fanghui, W.; Snider, B. B. J. Org. Chem. 2006, 71, 8579-8590.
    • 71. Pyne, S. G.; Davis, A. S.; Gates, N. J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Synlett 2004, 15, 2670-2680.
    • 72. Daly, J. W. Cell. Mol. Neurobiol. 2005, 25, 513-552.
    • 73. (a) Colombo, L.; Di Giacomo, M.; Scolastico, C.; Manzoni, L.; Belvisi, L.; Molteni, V. Tetrahedron Lett. 1995, 36, 625-628; (b) Robl, J. A. Tetrahedron Lett. 1994, 35, 393-396; (c) Genin, M. J.; Ojala, W. H.; Gleason, W. B.; Johnson, R. L.; J. Org. Chem. 1993, 58, 2234-2337.
    • 74. Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 1997, 119, 3409-3410.
    • 75. Malpass, J. R.; Hemmings, D. A.; Wallis, A. L. Tetrahedron Lett. 1996, 37, 3911-3914.
    • 76. For a review, see: Mansell, H. L. Tetrahedron 1996, 52, 6025-6061.
    • 77. (a) Parsons, P. J.; Camp, N. P.; Edwards, N.; Sumoreeah, L. R. Tetrahedron 2000, 56, 309-315; (b) Devlin, J. P.; Edwards, O. E.; Gorham, P. R.; Hunter, N. R.; Pike, R. K.; Stavric, B. Can. J. Chem. 1977, 55, 1367-1371; (c) Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6, 1329-1331.
    • 78. Carmichael, W. W.; Biggs, D. F.; Gorham, P. R. Science 1975, 187, 542.
    • 79. Spivak, C. E.; Witkop, B.; Alburquerque, E. X. Mol. Pharmacol. 1980, 18, 384.
    • 80. Spande, T. F.; Garraffo, H. M.; Edwards, M. W.; Yeh, H. J. C.; Pannell, L.; Daly, J. W. J. Am. Chem. Soc. 1992, 114, 3475.
    • 81. Hjelmgaard, T.; Søtofte, I.; Tanner, D. J. Org. Chem. 2005, 70, 5688-5697.
    • 82. Wilmouth, R. C.; Kassamally, S.; Westwood, N. J.; Sheppard, R. J.; Claridge, T. D. W.; Aplin, R. T.; Wright, P. A.; Pritchard, G. J.; Schofield, C. J. Biochemistry 1999, 38, 7989.
    • 83. Schaumann, E.; Rohr, A.; Adiwidjaja, G.; Tetrahedron Lett. 1980, 4277.
    • 84. Mihova, T. R.; Linden, A.; Heimgartner, H. Helv. Chim. Acta. 1996, 79, 2067.
    • 85. Pifferi, P.; Consonni, P.; Pelizza, G.; Testa, E.; J. Het. Chem. 1967, 4, 619-624.
    • 86. Zhang, H.; Chan, W, H.; Lee A, W, M.; Xia, P, F.; Wong, W, Y. Letters in Organic Chemistry, 2004, 1, 63-66.
    • 87. Macor, J. E.; Ordway, T.; Smith, R, L.; Verhoest, P. R.; Mack, R. A. J. Org. Chem. 1996, 61, 3228-3229.
    • 88. Staudinger, H.; Meyer, J. Helv. Chim. Acta. 1919, 2, 635.
    • 89. Freitag, D.; Schwab, P.; Metz, P, Tetrahedron Lett. 2004, 45, 3589- 3592.
    • 90. Singh, G, S. Tetrahedron 2003, 59, 7631-7649.
    • 91. The use of fresh Meerwein's reagent improved the yields of the 1- azetines.
    • 92. (a) Eicher, T.; Rohde, R. Synthesis 1985, 619-625; (b) Eicher, T.; Abdesaken, F.; Franke, G.; Weber, J. L. Tetrahedron Lett. 1975, 16, 3915-3918.
    • 93. Heimgartner, H.; Stierli, F.; Prewo, R.; Bieri, J. H. Helv. Chim. Acta 1983, 66, 1366-1375.
    • 94. Gomma, M. A. M. J. Chem. Soc. Perkin Trans 1 2002, 341-344.
    • 95. (a) Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1995, 36, 4787-4790; (b) Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M. Tetrahedron 1996, 52, 13605-13614.
    • 96. Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6, 1329-1331;
    • 97. (a) Takada, N.; Iwatsuki, M.; Suenaga, K.; Uemura, D. Tetrahedron Lett. 2000, 41, 6425-6428; (b) Kigoshi, H.; Hayashi, N.; Uemura, D. Tetrahedron Lett. 2001, 42, 7469-7471.
    • 98. Breslow, R.; Haynie. R.; Mirra, J. J. Am. Chem. Soc. 1959, 81, 247- 248.
    • 99. (a) Isaka, M.; Ejiri, S.; Nakamura, E. Tetrahedron 1992, 48, 2045- 2057; (b) Nakamura, M.; Isobe, H.; Nakamura, E. Chem. Rev 2003, 103, 1295-1326.
    • 100. Poloukhtine, A.; Popik, V, V. J. Org. Chem. 2003, 68, 7833-7840.
    • 101. Organic Synthesis, Coll. Vol. 6, p361 (1998); Vol. 57, p 41 (1977).
    • 102. (a) Hemming. K.; Patel. N. Tetrahedron Lett. 2004, 45, 7553-7556; (b) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433-465; (c) O'Neil, I. A.; Thompson, S.; Kalindjian, S. B.; Jenkins, T. C. Tetrahedron Lett. 2003, 44, 7809-7812.
    • 103. Gregson, S. J.; Howard, P. W.; Jenkins, T. C.; Kelland, L. R.; Thurston, D. E. Chem. Commun. 1999, 797-798.
    • 104. Artico, M.; Silvestri, R.; Pagnozzi, E.; Stefancich, G.; Massa, S.; Loi, A. G.; Putzolu, M.; Corrias, S.; Spiga, M. G.; La Colla, P. Bioorg. Med. Chem. 1996, 4, 837-850.
    • 105. (a) Giannotti, D.; Viti, G.; Sbraci, P.; Pestellini, V.; Volterra, G.; Borsini, F.; Lecci, A.; Meli, A.; Dapporto, P.; Paoli, P. J Med. Chem. 1991, 34, 1356-1362; (b) Krülle, T. M.; Wijkmans, J. C. H. M. Tetrahedron 2001, 57, 7021-7026.
    • 106. Hadjivassileva, T.; Thurston, D. E.; Taylor. P. W. Journal of Antimicrobial Chemotherapy 2005, 56, 513-518.
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article