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Akademischer Austausch Dienst (DAAD) under the PhD fellowship program and Jacobs University for excellent facilities. [1] J. Klein, V. Saggiomo, L. Reck, U. Lüning, J. Sanders, Org. Biomol. Chem. 2012, 10, 60. [2] M. Kumar, R. Mahajan, V. Sharma (nee Bhallla), H. Singh, N. Sharma, I. Kaur, Tetrahedron Lett. 2001, 42, 5315. [3] M. Kumar, V. Sharma (nee Bhallla), J. Nagendra Babua, Tetrahedron 2003, 59, 3267. [4] J. Jiang, M. J. MacLachlan, Chem. Commun. 2009, 5695. [5] S. Akine, F. Utsuno, T. Nabeshima, Chem. Commun. 2010, 46, 1029. [6] S. Katsiaouni, S. Dechert, C. Brückner, F. Meyer, Chem. Commun. 2007, 951. [7] E. Katayev, N. Boev, V. Khrustalev, Y. Ustynyuk, I. Tananaev, J. Sessler, J. Org. Chem. 2007, 72, 2886. [8] S. Akine, D. Hashimoto, T. Saiki, T. Nabeshima, Tetrahedron Lett. 2004, 45, 4225. [9] V, Böhmer, Angew. Chem. Int. Ed. Engl. 1995, 34, 713. [10] A. Danil de Namor, R. Cleverley, M. Chem. Rev. 1998, 98, 2495. [11] For cyclodextrins see special edition of Chemical Review, edition 5, 1998. [12] J. Kim, I. Jung, S. Kim, E. Lee, J. Kang, S. Sakamoto, K. Yamaguchi, K. Kim, J. Am. Chem. Soc. 2000, 122, 540. [13] S. Kim, I. Jung, E. Lee, J. Kim, S. Sakamoto, K. Yamaguchi, K. Kim, Angew. Chem. Int. Ed. Engl. 2001, 40, 2119. [14] C. Pederson, J. Am. Chem. Soc. 1967, 89, 7017. [15] J. Gawroński, H. Kołbon, M. Kwit, A. Katrusiak, J. Org. Chem. 2000, 65, 5768. [16] N. Kuhnert, A. Lopez-Periago, Tetrahedron Lett. 2002, 43, 3329. [17] N. Kuhnert, A. Lopez-Periago, G. Rossignolo, Org. Biomol. Chem. 2005, 3, 524. [19] N. Kuhnert, C. Straßnig, A. Lopez-Periago, Tetrahedron: Asymm. 2002, 13, 123. [20] N. Kuhnert, C. Patel, F. Jami, Tetrahedron Lett. 2005, 46, 7575. [21] N. Kuhnert, B. Tang, Tetrahedron Lett. 2006, 47, 2985. [22] N. Kuhnert, D. Marsh, D. Nicolau, Tetrahedron: Asymm. 2007, 18, 1648. [23] H. Nour, M. Matei, B. Bassil, U. Kortz, N. Kuhnert, Org. Biomol. Chem. 2011, 9, 3258. [24] H. Nour, A. Lopez-Periago, N. Kuhnert, Rapid Comm. Mass Spectrom. 2012, accepted manuscript. [25] K. Tanaka, S. Hachiken, Tetrahedron Lett. 2008, 49, 2533. [26] C. Jakobsche, A. Choudhary, S. Miller, R. Raines, J. Am. Chem. Soc. 2010, 132, 6651. [27] M. Formica, V. Fusi, L. Giorgi, M. Micheloni, P. Palma, R. Pontellini, Eur. J. Org. Chem. 2002, 3, 402. [28] A. González-Álvarez, I. Alfonso, F. Lopez-Ortiz, A. Aguirre, S. Garcia-Granda, V. Gotor, Eur. J. Org. Chem. 2004, 5, 1117. [29] L. Wang, G.-T. Wang, X. Zhao, X.-K. Jiang, Z.-T. Li, J. Org. Chem. 2011, 76, 3531. [30] B.-Y. Lu, G.-J. Sun, J.-B. Lin, X.-K. Jiang , X. Zhao, Z.-T. Li, Tetrahedron Lett. 2010, 51, 3830. [31] C. Jakobsche, A. Choudhary, S. Miller, R. Raines, J. Am. Chem. Soc. 2010, 132, 6651. [32] H. Nour, N. Hourani, N. Kuhnert, Org. Biomol. Chem. 2012, submitted manuscript. [33] Molecular modelling was carried out using HyperChem software (Release 8.0). Hypercube, Inc., 1115 NW 4th Street, Gaineville, F1 32601 USA. Trial, version from http://www.hypercube.com [34] J. Stewart., J. Comput. Chem. 1989, 10, 221. [18] N. Kuhnert, G. Rossignolo, A. Lopez-Periago, Org. Biomol. Chem. 2003, 1, 1157. 7
Paper 5 Rapid Commu. Mass Spectrom., 2012, accepted manuscript Probing the dynamic reversibility and generation of dynamic combinatorial libraries in the presence of bacterial model oligopeptides as templating guests of tetra-carbohydrazide macrocycles using electrospray mass spectrometry Hany F. Nour, Tuhidul Islam, Marcelo Fernández-Lahore and Nikolai Kuhnert* Objectives of the work Functionalized tetra-carbohydrazide cyclophanes were successfully synthesized in excellent yields following the previously discussed approaches. The first objective of this work is to confirm the dynamic reversibility of the novel macrocycles. Two crossover experiments were conducted in order to prove the dynamic reversibility of tetra-carbohydrazide cyclophanes. In the first crossover experiment, three different pure macrocycles were mixed in a mixture of DMF/MeOH in presence of catalytic AcOH and the reaction was refluxed. In the second crossover experiment, the macrocyclic precursors were mixed in a mixture of DMF/MeOH in presence of catalytic AcOH and the reaction was refluxed. After eight days of reflux, the reaction reached the point of equilibrium, at which an almost identical statistical mixture of macrocycles was obtained. The second objective is to generate a DCL of tetracarbohydrazide cyclophanes in which the members possess more polar functionalities. Introducing such functionalities is expected to reinforce binding with biological guests. A DCL of eight highly functionalized cyclophane macrocycles was generated in solution by mixing two different dihydrazides with two different dialdehydes. The composition of the DCL was screened by ESI-TOF/MS and the molecular ion peaks for all expected members were observed and assigned based on their high resolution m/z values. Three members in the dynamic library showed recognition in the gas phase to a selection of oligopeptides which mimic bacterial cell wall structure. 80| P a g e
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The Development of Novel Antibiotic
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Declaration of Authorship I, Hany N
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Abstract Over the past few decades,
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Chapter 2 Trianglimine Chemistry
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Figure 2.4 Trianglimines 10-12 with
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Abbreviations ACN AcOH Ala Acetonit
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RMS ROESY SjGST TFA THF TLC TMS TOC
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Introduction complete remodel of th
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Introduction following protonation.
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Introduction Lehn and co-workers re
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Introduction Figure 1.8 Generation
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Introduction Figure 1.11 Synthetic
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Introduction Figure 1.13 Generation
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Introduction 1.3.11 Boronic ester e
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Introduction References 1. E. Mouli
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Introduction 51. B. Shi, M. F. Grea
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Introduction Figure 2.2 shows compu
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Introduction incorporate β-cyclode
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Introduction Trianglamine-Zn(R) 2 c
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Introduction 24. J. Gajewy, J. Gawr
Page 41 and 42: Scope of Work Scope of Work In this
Page 43 and 44: Scope of Work can be obtained from
Page 45 and 46: Scope of Work Figure 3.4 Structures
Page 47 and 48: Scope of Work References 1. G. Wrig
Page 49 and 50: Organic & Biomolecular Chemistry Ci
Page 51 and 52: Downloaded by Jacobs University Bre
Page 53 and 54: View Online Downloaded by Jacobs Un
Page 63 and 64: Paper 2 Rapid Commun. Mass Spectrom
Page 65 and 66: Trianglimine formation mechanism by
Page 75 and 76: Paper 3 Org. Biomol. Chem., 2012, 1
Page 81 and 82: View Online Table 2 Distances (Å)
Page 85 and 86: Paper 4 Chem. Eur. J., 2012, submit
Page 87 and 88: (4R,5R)- and (4S,5S)-dimethyl-2,2-d
Page 89 and 90: that two distinct conformational is
Page 91: the thimble was recharged with fres
Page 95 and 96: INTRODUCTION No single class of dru
Page 97 and 98: EXPERIMENTAL All the solvents and r
Page 99 and 100: (b) Refluxing macrocycles 5, 6 and
Page 101 and 102: Scheme 1. Graphical representation
Page 103 and 104: Figure 1. A plot of relative intens
Page 105 and 106: In contrast, formation of library m
Page 107 and 108: Figure 5. Generated dynamic library
Page 109 and 110: macrocycle 32 from the dynamic libr
Page 111 and 112: The polar carbamate group participa
Page 113 and 114: [2] WHO World health report 2003. h
Page 115 and 116: [32] B. Lienard, N. Selevsek, N. Ol
Page 117 and 118: FULL PAPER Synthesis and ESI-MS Com
Page 119 and 120: ability of the technique to provide
Page 121 and 122: aimed at assessing molecular recogn
Page 123 and 124: Paper 7 manuscript Synthesis, self-
Page 125 and 126: 2 Similar to the case of trianglimi
Page 127 and 128: 4 Receptor 7 showed enhanced recogn
Page 129 and 130: 6 The newly synthesized receptors s
Page 131 and 132: 8 27. Nour, H. F.; Hourani, N.; Kuh
Page 133 and 134: 120| P a g e Appendix
Page 135 and 136: Supplementary Information: Suppleme
Page 137 and 138: Supplementary Material (ESI) for Or
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Supplementary Material (ESI) for Or
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Page 151 and 152:
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Monitoring the [3+3]-cyclocondensat
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Monitoring the cyclocondensation re
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Product ions appeared as [M+H] + Fi
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Scheme 1. Assigned higher oligomers
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Supplementary Information: Synthesi
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Scheme 4. Proposed fragmentation me
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DMSO Figure 1. 1 H-NMR spectrum for
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Figure 6. 13 C-NMR spectrum for (4S
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Intens. 7 x10 1.5 200.7 1.0 0.5 0.0
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Intens. 7 x10 200.7 1.5 1.0 0.5 0.0
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Intens. 4 x10 577.2 2.0 1.5 1.0 451
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HN N O O R R NH O O N N HN R O O O
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Intens. 5 x10 727.2 2.0 1.5 1.0 O O
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Intens. 5 x10 697.1 1.5 1.0 728.2 0
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O O O O HN N O O NH N HN N O O NH N
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Figure 38. 1 H-NMR spectrum for mac
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Intens. 5000 276.8 4000 3000 2000 1
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Intens. 7 x10 599.1 1.5 1.0 0.5 0.0
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(a) HN N O O NH O O N (b) HN N O NH
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Scheme 11. Proposed fragmentation m
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Scheme 14. Proposed fragmentation m
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Intens. 4 x10 550.9 3 2 1 0 500 100
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Figure 68. 2D-ROESY spectrum for ma
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Supplementary Information: Novel sy
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Intens. 6 x10 0.8 0.6 0.4 240.9 459
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Figure 9. 1 H-NMR spectrum for macr
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Intens. 5 x10 1.5 968.1 1.0 0.5 813
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Intens. 5 x10 897.4 4 2 335.3 707.3
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Scheme 3. Suggested fragmentation m
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Molecular modelling data for the co
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Figure 1. 1 H NMR spectrum for dica
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Intens. 2000 1493.6091 Host-Guest 1
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Intens. [%] 100 775.3 80 388.1 60 4
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Intens. 600 N HN O O 467.1916 400 O
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Intens. 6000 5000 HN N O O O O NH N
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Table 1. High resolution ESI-TOF da
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i Figure 1. 1 H NMR spectrum for ma
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i Figure 5. 1 H NMR spectrum for ma
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i j Figure 9. 1 H NMR spectrum for
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i Figure 13. DEPT-135 spectrum for
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Scheme 1. General mechanism of frag
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Intens. [%] 100 80 60 40 20 0 O H N
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Intens. [%] 100 1131.3 80 60 40 20
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Intens. 1500 1528.6088 1000 500 150
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Intens. [%] 100 80 60 40 Free guest
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Intens. 4 x10 1085.3575 1.25 1.00 0
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Intens. [%] 100 80 Free guest 586.1
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Synthesis, self-assembly and ESI-MS
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O O HN NH HN O O NH HN O 11 O NH O
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O O HN NH HN O O NH HN O 9 O NH O O
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H 2 O DMSO DMSO Figure 6. 1 H-NMR a
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Intens. 5 x10 5 -MS 487.1588 4 3 2
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Intens. -MS 6 x10 0.8 0.6 0.4 0.2 1
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Intens. -MS 6 x10 O O 350.9 1.5 1.0
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Intens. [%] 100 -MS 486.9 Exact str
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Intens. [%] -MS 100 486.9 80 60 975
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Intens. [%] +MS 100 80 517.2 Exact
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Intens. [%] 100 80 60 +MS 388.1 775
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 80 +MS 1031.4939 7
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Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 -MS 2 586.1 80 60 4
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Intens. [%] 100 -MS 2 875.2 Exact s
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Table 1. High resolution ESI-TOF/MS
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4. H. Nour, A. López-Periago, N. K
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