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Bertram, Anna (2001)
Languages: English
Types: Unknown
This thesis describes investigations towards the self-assembly of heterocyclic amino acids to form cyclopeptides, including the natural products dendroamide A and nostacyclamide. The Introduction highlights a variety of different natural products including the lissoclinum cyclopeptides and other oxazole and thiazole based natural products. The conformation of the lissoc1inum cyclopeptides and the affect different substituents have on their conformation is explored. The ability of a variety of natural products to chelate metal ions and the evidence for metal ion chelation within the lissoclinum cyclopeptides is also discussed. The Introduction is concluded with a statement of the aims and objectives of our research. The Results and Discussion section of the thesis details the development of a novel cyc1ooligomerisation reaction of heterocyclic amino acids. This cyc1ooligomerisation is applied to the self-assembly of thiazole and oxazole amino acids to form analogues of naturally occurring cyc1opeptides. The protocol is then extended to the self-assembly of the natural products dendroamide A and nostacyclamide. Additionally the ability of metal ions to act as templates and promote the formation of particular products is illustrated throughout these studies. Detailed discussions are also presented within this section into the methods for thiazole and oxazole formation. The third part of the thesis is the Experimental section containing full details of the preparative work completed and listing spectroscopic and analytical data on all new compounds synthesised during this study.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • (I) a) V. Admi, U. Afek and S. Carmeli, J. Nas. Prod, 1996,59, 396; b) D. 1. Freeman and G. Pattenden, Tetrahedron Leu., 1998.39,3251.
    • (2) aj B. M. Degnan,C. 1. Hawkins,M. F. Lavin, E.l. McCaffery, D. L. Parry, A. L. van den Brenk and D. J. Waners, J. Med.
    • Chem., 1989,32, 1349; b) F. 1. Schmitz, M. B. Ksetbati, J. S.
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    • (3) a) Y. Hamamoto, M. Endo, M. Nagawaka, T. Nakanishi and K. Mizukawa, J. Chem: Soc., Chem. Commun., 1983,323; b) Y. Hamada, S. Kato and T. Shioiri, Tetrahedron Lett., 1985, 26,3223.
    • (4) For reviews on the isolation, structure and synthesis of the Lissoclinum cyclic peptides see a) P. Wipf, in Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletier.
    • Elsevier, Amsterdam,l998, vo112., p. 187; b) P. Wipf, Chem.
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    • (6) a) M. W. Bredenlcamp, C. W. Holzapfel and W. J. Zyl, Synth.
    • Commun., 1990, 20, 2235; b) E. Aguilar and A. I. Meyers, Tetrahedron Lett., 1994,35,2473; c) C. D. J. Boden, G.
    • Pattenden and T. Ye, Synlett. 1995,417.
    • (7) C. J. Moody and M. C. Bagley, J. Chem. Soc .• Perkin Trans.
    • (8) All new compounds gave satisfactory spectroscopic data together with high resolution mass spectrometric andlor microanalytical data.
    • (9) The following general cyclooligomerisation procedure is described: Diisopropylethylamine (3 eq.) and FDPP (1.5 eq.) were added to a suspension of 6 (2 mmo!) in anhydrous acetonitrile (42 mL) and the solution was stirred at ambient temperatuse for 18 h before evaporating to dryness in vacuo.
    • The residue was partitioned between ethyl acetate (SO mL) and aq, HO (2 M. SO mL) and the separated organic layer was washed with aq. HCl (2 M, SO mL). The combined aqueous solutions were back extracted with ethyl acetate (SO mL) and then the organic solutions were combined and washed successively with aq. NaOH (1 M, 2 x SO mL), H10 (SO mL) and brine (SO mL). The solution was dried (MgSO.) and the solvent was then removed under reduced pressure to leave a mixture of cyclic peptide products which were separated by column chromatography (silica gel) or by preparative HPLC (Dynamax Silica Gel Cartridge Column, 30 cm x 10 mm internal diameter).
    • (10) Spectroscopic data for 7: mp 258 - 26O·C (from EtlO); [a)19~ +126.8 (c = 0.53, CHCll); OH (360 MHz, CDCll) 8.45 (3H, d, J 9.3. 3 x NH), 8.1 (3H, 5, 3 x CH=C), 5.4 (3H, dd, J 9.3 and 5.8, 3 x NHCH), 2.3 (3H, m, 3 x CH(CHl)l)' 1.1 (9H, d, J 6.8, 3 x CHl). 1.0 (9H, d. J 6.8, 3 x CHl); lic (90 MHz, CDCIl) 168.6 (C=O), 159.7 (Cq), 149.1 (Cq), 123.4 (CH), 55.4 (CH), 35.3 (CH). 18.8 (CHl), 18.3 (CHl); mJz (ES) 569 (M- Na)·; Found C, 52.5; H. 5.6; N, 15.0 %. C,.HloN,OlS) requires C, 52.7; H, 5.5; N; 15.0 %.
    • Spectroscopic data for 8: mp 152 - 154·C (from EtlO); [a)19t +204.6 (c = 0.57, CHCl); OH (360 MHz, CDCI) 8.0 (4H, s, 4 x CH=C), 7.85 (4H,d,J9.1,4 x NH), 5.2 (4H,dd,J9.1 and 8.2,4 x NHCH), 2.6 (4H. m, 4 x CH(CH),), 1.2 (12H, d, J 6.7, 4 x CH), 1.0 (l2H, d, J 6.6. 4 x CH); Oc (90 MHz, CDCl) 169.3 (C=O), 160.3 (Cq), 148.9 (Cq), 124.2 (CH), 55.3 (CH).
    • 32.6 (CH), 19.6 (CH), 18.9 (CH); mJz (ES) 751 (M + Na)" 1479 (2M + Nay; Found C, 50.9; H, S.5; N, 14.6 %.
    • C)lH.oN.O.S •. 0.5 H10 requires C, 50.9; H, 5.7; N, 14.8 %.
    • (II) V. F. Bystrov, V. T. Ivanov, S. L. Ponnova, T. A. Balshova and Y. A. Ovchinnikov, Tetrahedron, 1973, Z9, 873.
    • (12) We thank Dr A. J. Blake of this Department for this information. Full details will be presented in a forthcoming full paper.
    • (13) P. WipfandC. P. Miller, l. Am. Chem. Soc., 1992,114.10975.
    • (14) K. D. Kepple, J. Pharm. Sci .. 1972.61. 1345.
    • (15) J. A. Dale. D. L. Dull and H. S. Mosher.J, Org. C~m., 1969, 34,2543.
    • (16) N. Sokolenko, G. Abbenante. M. J. Scanlon. A. Jones. L R.
    • (I) For reviews. see: a) Faulkner. D. J .• J. Nat. Prod. 2000. 17. I; b) Davidson. B. S .. Chern. Rev. 1993.93.1771.
    • (2) a) Degnan. B. M.; Hawkins. C. 1.; Lavin. M. F.; McCaffrey.
    • Chern. 1989.32.1349; b) Chang. J. S.; van der Helm. D.; Hossain. M. B.; Ksebati, M. B.; Schmitz. F. J.; Wang. J. L.. J.
    • Org. Chern. 1989.54.3463; c) Boden. C. D. J.; Pattenden, G .• J. Chern. Soc .. Perkin Trans. 12000.875.
    • (3) a) Admi, Y.; Afek, U.; Carmeli, S .• 1. Nat. Prod. 1996.59.
    • 396; b) Freeman. D. J.; Pattenden. G .. Tetrahedron Lett. 1998.
    • (4) a) Bowden. B. F.; Carroll. A. R.; Call, J. C.; Hockless, D. C.
    • R.; Skelton, B. W.; White. A. H., Aust. J. Chern. 1994.47,61; b) McKeever, B.; Pattenden, G., Tetrahedron Lett. 1999,40, 9317.
    • (5) Michael. J. P.; Pattenden, G., Angew. Chern. Int. Ed. Engl.
    • 1993,32, I.
    • (6) a) Bertram, A.; Hannam. J. S.; Jolliffe. K. A.; Gonzalez-Lopez de Turis6, F.; Pattenden, G .• Synlett 1999,1/. 1723. b) see also accompanying paper Blake, A. 1.; Hannam, J. S.; Jolliffe. K.
    • A.; Pattenden, G., Synlet! 2000. 1515.
    • (7) Moore, R. E.; Ogino, J.; Patterson, G. M.l.; Smith, C. D., J.
    • Nat. Prod. 1996, 59, 581.
    • (8) Satisfactory spectroscopic and mass spectrometry data were obtained for all new compounds. Spectroscopic data for synthetic 7: m.p. 146-148 °C (from CH~C1~); [1l)Dl~~+53.9 (c = 0.2. CHCll); AmiU(MeOH)/nm 224 (EidmJmol"cm-' 28,000); IR(cm-'): 3396, 1666, 1546; OH(360 MHz. CD1Cl~) 8.61 (IH. d. J = 7.4 Hz). 8.52 (l H. d. J = 7.5 Hz). 8.44 OH. d.
    • J = 7.4 Hz), 8.11 (1 H. s), 8.09 (1 H. s), 5.68 (1 H. dq, J = 8.1 and 6.8 Hz). 5.32 (l H, masked dd), 5.14 (I H. quintet. J = 6.6 Hz). 2.64 (3H. s), 2.27 0 H. m). 1.66 (3H. d. J = 6.7 Hz). 1.66 (3H. d, J = 6.7 Hz). 1.03 (3H. d. J = 6.8 Hz). 0.96 (3H, d. J 6.7 Hz); Oc (360 MHz. CDlCl1) 11.7 (q), 18.3 (q), 18.5 (q), 21.1 (q), 25.1 (q), 35.6 (d), 44.6 (d), 47.4 (d). 56.2 (d), 123.8 (d), 124.1 (d), 128.9 (s). 149.2 (5), 149.3 (s). 154.0 (5), 159.7 (s), 160.0(s}, 160.7 (s). 162.2 (s), 168.9 (s), 171.8 (s); HRMS (ES) mJz 511.1169; ca1cd for C21H2404N~SlNa ([M+Na)·): 511.1198.
    • (9) There is a possibility of II symmetrical and unsymmetrical thiazole/oxazole cyclopeptides being produced from 4. 8, and 9. i.e. the statistical yield of each cyclopeptide product would be 6.8% based on 75% yield.
    • d) Hawkins, C. 1.; Lavin, M. F.; Marshall, K. A.; Van den Brenk, A. L.; Watters, D. 1.,1. Med. Chern., 1990,33, 1634.
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