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Downloaded by Jacobs University Bremen GGMBH on 09 July 2012 Published on 23 March 2011 on http://pubs.rsc.org | doi:10.1039/C0OB00944J View Online Fig. 3 C 3 -symmetrical (16–18) and the non-symmetrical (19–22) macrocyclisation products from the [3 + 3]-cyclocondensation reaction of (1R,2R)-1,2-diaminocyclohexane (15) with dialdehydes (11–14). isolated yield. It is worth noting that in previous work due to their water sensitivity trianglimines were always purified using crystallisation methods, whereas we give here for the first time in trianglimine chemistry an experimental procedure allowing purification by column chromatography. ESI mass spectrum for trianglimine (20) showed two peaks at m/z 1216 and 1238 corresponding to [M+H + ]and [M+Na + ], respectively (Fig. 4). Fig. 5a represents the 1 H-NMR spectrum for a crude mixture of trianglimines (17) and(20) before being purified by column chromatography (CC). The number of signals corresponding to This journal is © The Royal Society of Chemistry 2011 Org. Biomol. Chem., 2011, 9, 3258–3271 | 3261
View Online Downloaded by Jacobs University Bremen GGMBH on 09 July 2012 Published on 23 March 2011 on http://pubs.rsc.org | doi:10.1039/C0OB00944J Fig. 4 ESI-MS spectrum for trianglimine (20) (micrOTOF, CH 2 Cl 2 and MeOH). Fig. 5 Expanded 1 H-NMR spectra for (a) a crude mixture of trianglimines (17) and(20) before purification with CC, (b) the non-symmetrical trianglimine (20) after purification and (c) the C 3 -symmetrical trianglimine (17) after purification with CC (C 6 D 6 , 400 MHz). the azomethine protons for the C 3 -symmetrical trianglimine (17) should be two singlets and each signal should have an integration of three. For the non-symmetrical trianglimine (20), six different azomethine protons should be recognised. The presence of many signals in the region from d 8.8 to 9 ppm indicates that the crude mixture contains more than one isomer. Fig. 5b and 5c represent the 1 H-NMR spectra for both the non-symmetrical trianglimine (20) and its C 3 -symmetrical regioisomer (17), respectively. The 1 H-NMR spectrum for the non-symmetrical trianglimine (20) showed four singlets at d 8.94, 8.93, 8.89 and 8.18 ppm. Each signal had an integration of one. It also showed a broad signal at d 8.14 ppm with an integration of two corresponding to the six non-equivalent azomethine protons (Fig. 5b). On the other hand the 1 H-NMR spectrum for the C 3 -symmetrical trianglimine (17) showedtwosetofsingletsatd 8.90 and 8.19 ppm. Each signal had an integration of three corresponding to the six azometine protons (Fig. 5c). Furthermore, the IR spectra for regioisomers (17) and(20) showed an intense absorption band at n max 1637 cm -1 corresponding to the imine functional groups. In addition, all the protons and carbons could be unambiguously assigned by 1 H- 1 H-COSY, 1 H- 1 H-ROESY, HMBC and HMQC 2D-experiments. Monitoring the [3+3]-cyclocondensation reactions by direct infusion ESI-MS Here, we report the use of the high resolution ESI-mass spectrometry as an efficient technique for monitoring the progress of the [3+3]-macrocyclisation reactions. (1R,2R)-1,2- Diaminocyclohexane (15) reacted with dialdehyde (13) in dichloromethane at 0.1 M concentration. The mixture was stirred at room temperature for 43 h. Aliquots were taken at different time intervals, diluted and methanol added to the solution before being directly infused to the ESI-TOF-MS. Fascinatingly a total of 15 different reaction intermediates could be detected at different intensities and their appearance and disappearance monitored over the cause of the reaction. This represents to our knowledge the largest number of reaction intermediates ever observed in a single chemical reaction. All intermediates could be assigned on the basis of their high resolution m/z values. This method does not only allow monitoring of the progress of the reaction, previously not possible by TLC due to the acidic nature of silica plates, 25 but provides an intriguing insight into mechanistic aspects of this unusual reaction. Intermediates (23) and(24) were for example detected along with both the [2+2]-macrocyclisation product (25) and the starting material (13) after 3 h from the start of the experiment (Fig. 6). Most of these intermediates were completely consumed in the construction of trianglimine (22) after 43 h (Fig. 7). A peak at m/z 845, corresponding to the [2+2]-cyclocondensation intermediate (25) was still observed after that time. We assumed that intermediates (24), (25) and the final product (22) are non-symmetric, but in fact the peaks appearing at m/z 767, 845 and 1267 can also be related to their symmetrical counterparts. Although the [3+3]-macrocyclisation reaction of dialdehyde (13) with (1R,2R)-1,2-diaminocyclohexane (15) had resulted in the formation of the non-symmetrical trianglimine (22) along with its C 3 -symmetrical regioisomer, we could not succeed in separating the C 3 -symmetrical regioisomer because its R f value was very close to that of the non-symmetrical trianglimine (22). The chirality of the newly synthesised trianglimines was confirmed by circular dichromism (CD) spectra (Fig. 8). Trianglimines (18) and (21) have very similar UV absorption spectra with a slightly increased absorption for the non-symmetrical trianglimine (21). Large negative amplitudes were observed for the two regioisomers (18) and(21) atlª300 nm indicating negative Cotton effects. 3262 | Org. Biomol. Chem., 2011, 9, 3258–3271 This journal is © The Royal Society of Chemistry 2011
Page 1 and 2: The Development of Novel Antibiotic
Page 3 and 4: Declaration of Authorship I, Hany N
Page 5 and 6: Abstract Over the past few decades,
Page 7 and 8: Chapter 2 Trianglimine Chemistry
Page 9 and 10: Figure 2.4 Trianglimines 10-12 with
Page 11 and 12: Abbreviations ACN AcOH Ala Acetonit
Page 13 and 14: RMS ROESY SjGST TFA THF TLC TMS TOC
Page 15 and 16: Introduction complete remodel of th
Page 17 and 18: Introduction following protonation.
Page 19 and 20: Introduction Lehn and co-workers re
Page 21 and 22: Introduction Figure 1.8 Generation
Page 23 and 24: Introduction Figure 1.11 Synthetic
Page 25 and 26: Introduction Figure 1.13 Generation
Page 27 and 28: Introduction 1.3.11 Boronic ester e
Page 29 and 30: Introduction References 1. E. Mouli
Page 31 and 32: Introduction 51. B. Shi, M. F. Grea
Page 33 and 34: Introduction Figure 2.2 shows compu
Page 35 and 36: Introduction incorporate β-cyclode
Page 37 and 38: Introduction Trianglamine-Zn(R) 2 c
Page 39 and 40: 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: Downloaded by Jacobs University Bre
Page 55 and 56: 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 and 92: the thimble was recharged with fres
Page 93 and 94: Paper 5 Rapid Commu. Mass Spectrom.
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
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In contrast, formation of library m
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Figure 5. Generated dynamic library
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macrocycle 32 from the dynamic libr
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The polar carbamate group participa
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[2] WHO World health report 2003. h
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[32] B. Lienard, N. Selevsek, N. Ol
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FULL PAPER Synthesis and ESI-MS Com
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ability of the technique to provide
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aimed at assessing molecular recogn
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Paper 7 manuscript Synthesis, self-
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2 Similar to the case of trianglimi
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4 Receptor 7 showed enhanced recogn
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6 The newly synthesized receptors s
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8 27. Nour, H. F.; Hourani, N.; Kuh
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120| P a g e Appendix
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Supplementary Information: Suppleme
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Supplementary Material (ESI) for Or
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Page 141 and 142:
Page 143 and 144:
Page 145 and 146:
Page 147 and 148:
Page 149 and 150:
Page 151 and 152:
Page 153 and 154:
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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Page 195 and 196:
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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Page 209 and 210:
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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Page 217 and 218:
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
Page 275 and 276:
Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 80 +MS 1031.4939 7
Page 279 and 280:
Intens. [%] 100 +MS 517.2 Exact str
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Intens. [%] 100 -MS 2 586.1 80 60 4
Page 283 and 284:
Intens. [%] 100 -MS 2 875.2 Exact s
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Table 1. High resolution ESI-TOF/MS
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274 | P a g e
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276 | P a g e
Page 291:
4. H. Nour, A. López-Periago, N. K
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