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Paper 1 Org. Biomol. Chem., 2011, 9, 3258–3271 Synthesis of tri-substituted biaryl based trianglimines: formation of C 3 -symmetrical and non-symmetrical regioisomers Hany F. Nour, Marius F. Matei, Bassem S. Bassil, Ulrich Kortz and Nikolai Kuhnert* Reproduced by permission of The Royal Society of Chemistry http://pubs.rsc.org/en/content/articlelanding/2011/ob/c0ob00944j Objectives of the work The objective of this work is to synthesize highly functionalized trianglimine macrocycles, which can be used in the generation of DCLs. 4-Bromo-2-fluorobenzaldehyde reacted with secondary amines to form 2-functionalized aromatic monoaldehydes. The Suzuki-coupling reactions of 4-formylphenylboronic acid with the substituted monoaldehydes gave 2-functionalized-4,4ˋ-biphenyldialdehydes, which underwent successfully [3+3]˗cyclocondensation reactions with trans-(1R,2R)-1,2-diaminocyclohexane to give a mixture of regioisomeric trianglimine macrocycles. Separation of the regioisomers was a real challenge due to the ease of hydrolysis of the imine bonds. After several trials, the regioisomers were successfully separated on pretreated silica gel. ESI˗TOF/MS was used to monitor the progress of the macrocyclization reactions and to determine the time at which all intermediates were almost consumed in formation of the macrocycles. The new trianglimines were successfully reduced with NaBH 4 in a mixture of THF/MeOH to the corresponding trianglamines in almost quantitative yields. 35| P a g e
Organic & Biomolecular Chemistry Cite this: Org. Biomol. Chem., 2011, 9, 3258 www.rsc.org/obc Dynamic Article Links Synthesis of tri-substituted biaryl based trianglimines: formation of C 3 -symmetrical and non-symmetrical regioisomers† Hany F. Nour, Marius F. Matei, Bassem S. Bassil, Ulrich Kortz and Nikolai Kuhnert* View Online / Journal Homepage / Table of Contents for this issue PAPER Downloaded by Jacobs University Bremen GGMBH on 09 July 2012 Published on 23 March 2011 on http://pubs.rsc.org | doi:10.1039/C0OB00944J Received 27th October 2010, Accepted 6th January 2011 DOI: 10.1039/c0ob00944j 2-Functionalised aromatic monoaldehydes were synthesised in good to excellent yields by reacting 4-bromo-2-fluorobenzaldehyde with different secondary amines and phenol. The Suzuki-coupling reaction of the newly functionalised aromatic monoaldehydes with 4-formylphenylboronic acid afforded the corresponding 2-functionalised-4,4¢-biphenyldialdehydes in good yields (47–85%). The [3+3]-cyclocondensation reactions of the 2-functionalised-4,4¢-biphenyldialdehydes with (1R,2R)-1,2-diaminocyclohexane afforded a mixture of regioisomeric C 3 -symmetrical and non-symmetrical trianglimines. Reduction of the C 3 -symmetrical and the non-symmetrical trianglimines with NaBH 4 in a mixture of THF and MeOH afforded the corresponding trianglamines in high yields. Introduction Trianglimines form a class of chiral non-racemic macrocycles that are formed in a [3+3]-cyclocondensation reaction between a chiral non-racemic diamine and an aromatic dicarboxaldehyde, in which six new imine bonds are formed in a single reaction. The first member of this class of macrocycles has been introduced by Gawroński a decade ago; more recently the compounds were named trianglimines by our group due to their unique triangular geometry. 1–3 Hexa-amine macrocycles, which constitute reduced versions of their hexa-imine analogues are referred to as trianglamines. 4 Trianglimines combine a series of features and characteristics that make them promising compounds for molecular recognition applications including sensing, chiral recognition, etc., in many cases their potential is much superior if compared to their macrocyclic competitors such as calix- [n]-arenes, 5–8 cyclodextrins, 9 cucurbiturils 10,11 or crown ethers. 12 Trianglimines are chiral, and unlike in cyclodextrin chemistry both enantiomers of any derivative are readily available in a pure form and have been reported. 4 Trianglimines are obtained using a modular approach, in which two building blocks are reacted to form macrocyclic compounds with complete control over the size of the macrocycle, 13 electronic properties of the macrocycle and functional groups included. 14 These features make trianglimines in particular attractive for the molecular recognition of small and medium sized organic molecules with complementary School of Engineering and Science, Jacobs University Bremen, P.O. Box 750 561, 28725 Bremen, Germany. E-mail: n.kuhnert@jacobs-university.de; Fax: +49 421 200 3229; Tel: +49 421 200 3120 † Electronic supplementary information (ESI) available: 1 H, 13 CNMR and ESI-MS spectra. CCDC reference number 779417. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c0ob00944j functionalities and complementary size to be included in the macrocyclic host by well-designed building blocks. The [3+3]-cyclocondensation reaction is usually high yielding, with quantitative conversions not uncommon, at relatively high concentrations of the two building blocks. The formation of trianglimines is based on conformational bias rather than on a template effect or high dilution conditions, frequently used in other macrocyclic chemistry. 1 Despite these obviously attractive features of trianglimines, only few applications of trianglimines and their amine analogues in supramolecular chemistry have been reported. Gawroński and others have used trianglimines as organo-catalysts for asymmetric catalysis and they also reported the inclusion of solvent molecules into the trianglimine cavity. 1,15,16 Hodacova 17 reported on the binding of simple aromatic guests in the trianglimine cavity and finally we have reported on chiral recognition of trianglimines binding chiral carboxylic acids and amino acid derivatives. 18 In most of these cases, binding constants were reported with the best values in the region of 10 4 M -1 . A second currently existing obstacle in trianglimine and trianglamine chemistry is the poor water solubility. For any attractive application in supramolecular chemistry, host molecules should have satisfactory solubilities in aqueous solution. The imines themselves are of course sensitive to hydrolysis and water stable trianglamines obtained so far, possess water solubilities at neutral pH in low mM region only. In order to overcome these obstacles, in particular unsatisfactory binding constants and water solubilities, novel trianglamine derivatives are urgently required, in which these properties are improved. The strategy to achieve this must include the incorporation of further substituents in one of the trianglimine building blocks that due to their polar nature enhance water solubility and that at the same time offer suitable complementary binding motifs, including salt bridges, hydrogen bond donors and acceptors or further aromatic 3258 | 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: Scope of Work References 1. G. Wrig
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 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
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(b) Refluxing macrocycles 5, 6 and
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Scheme 1. Graphical representation
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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 149 and 150:
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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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274 | P a g e
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276 | P a g e
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4. H. Nour, A. López-Periago, N. K
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