New guanidinium compounds for the molecular recognition of carboxylates and contributions to the synthesis of bivalent NPY Y_1tn1-receptor antagonists [Elektronische Ressource] / vorgelegt von Thomas Suhs
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New guanidinium compounds for the molecular recognition of carboxylates and contributions to the synthesis of bivalent NPY Y_1tn1-receptor antagonists [Elektronische Ressource] / vorgelegt von Thomas Suhs

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New Guanidinium Compounds for the Molecular Recognition of Carboxylates and Contributions to the Synthesis of Bivalent NPY Y Receptor Antagonists 1 Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg vorgelegt von Thomas Suhs aus Regensburg 2006 Die vorliegende Arbeit entstand in der Zeit von Februar 2002 bis Dezember 2005 unter der Leitung von Herrn Prof. Dr. B. König am Institut für Organische Chemie der Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität Regensburg. Das Promotionsgesuch wurde eingereicht am: 02.03.2006 Das Kolloquium fand statt am: 24.03.2006 Prüfungsausschuß: Prof. Dr. W. Kunz (Vorsitzender) Prof. Dr. B. König (Erstgutachter) Prof. Dr. A. Buschauer (Zweitgutachter) Prof. Dr. H. Krienke (3. Prüfer) Meiner Familie Contents 1 A. Introduction 1. Introduction 1 2. Results and Discussion 2 3. Conclusion 25 4. References and notes 26 B. Main Part 33 1. Synthesis of Ethoxycarbonyl Amino Acids 33 1.1 Introduction 33 1.

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Published 01 January 2007
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New Guanidinium Compounds for the
Molecular Recognition of Carboxylates and
Contributions to the Synthesis of Bivalent NPY
Y Receptor Antagonists 1


Dissertation
zur Erlangung des Doktorgrades der Naturwissenschaften
(Dr. rer. nat.)
an der Fakultät für Chemie und Pharmazie
der Universität Regensburg





vorgelegt von
Thomas Suhs
aus Regensburg
2006 Die vorliegende Arbeit entstand in der Zeit von Februar 2002 bis Dezember 2005 unter
der Leitung von Herrn Prof. Dr. B. König am Institut für Organische Chemie der
Naturwissenschaftlichen Fakultät IV – Chemie und Pharmazie – der Universität
Regensburg.




















Das Promotionsgesuch wurde eingereicht am: 02.03.2006

Das Kolloquium fand statt am: 24.03.2006
Prüfungsausschuß: Prof. Dr. W. Kunz (Vorsitzender)
Prof. Dr. B. König (Erstgutachter)
Prof. Dr. A. Buschauer (Zweitgutachter)
Prof. Dr. H. Krienke (3. Prüfer)











Meiner Familie
















Contents


1 A. Introduction

1. Introduction 1
2. Results and Discussion 2
3. Conclusion 25
4. References and notes 26
B. Main Part 33

1. Synthesis of Ethoxycarbonyl Amino Acids 33
1.1 Introduction 33
1.2 Results and Discussion 34
1.3 Conclusion 41
1.4 Experimental Section 42
1.5 Appendix 56
1.6 References and notes 61

2. Synthesis of Fluorescent Guanidinium Amino Acids 63
2.1 Introduction 63
2.2 Synthesis of Fluorescent Guanidines 66
2.3 Spectroscopic Investigations of Fluorescent Guanidines 70
2.4 Synthesis of Dimers 76
2.5 Solid Phase Synthesis 83
2.6 Conclusion 85
2.7 Experimental Section 86
2.8 Appendix 107 2.9 References 110

3. Bivalent NPY Y Receptor Antagonists 112 1
3.1 Introduction 112
3.1.1 Neuropeptide (Y) 112
3.1.2 The Concept of Bivalent Ligands 116
3.2 Results and Discussion 118
3.3 Conclusion 141
3.4 Experimental Section 142
3.5 Appendix 161
3.6 References 164

C. Summary 169

D. Abbreviations 171

E. Appendix 173

F. Acknowledgments 174

G. Curriculum Vitae 176



A. Introduction

Synthesis of guanidines in solution

1. Introduction

Arginine, a naturally occuring amino acid with a guanidinium moiety, is found in
1numerous enzyme active sites and cell recognition motifs. Horseradish peroxidase,
2 3fumarate reductase and creatine kinase are just a few enzymes that have arginine-
containing active sites. The tripeptide sequence RGD (Arg-Gly-Asp) is a common cell-
4recognition motif responsible for the binding of the integrin receptors. This sequence
5has been used as a lead structure for the development of different integrin antagonists.
6Nonpeptide cyclic cyanoguanidines are used as HIV-1 protease inhibitors, while
7 carboxylic guanidino analogs are used as influenza neuroaminidase inhibitors.
8Guanidinium-based molecules are also extensively used as cardiovascular drugs,
9 10,11 12 antihistaminines, anti-inflammatory agents, antidiabetic drugs, antibacterial and
13 14 15antifungal drugs, antiprotozal and other antiparasitic drugs and antiviral drugs.
Guanidinium derivatives (Impromidine and related compounds) are also used as
16 17histamine H -receptor agonists and as NPY Y -receptor antagonists. 2 1
Guanidinium-containing compounds such as guanidinoacetic acid are used as artificial
18 19sweeteners, bicyclic guanidines catalyze the enantioselective Strecker synthesis and
20,21modified guanidines are also used as potential chiral superbases.
The guanidinium ion and its many derivatives have been widely studied in the context
22,23,24of anion binding.
The abundant involvement of arginine in the binding of anionic substrates to proteins
fostered the suspicion early on that interactions of a guanidinium ion with common
oxoanions must hold special virtues. Much later it was concluded from site-directed
mutagenesis experiments affecting the active sites of certain enzymes that in the protein
enviroment the energetic stabilization of a carboxylate by the guanidinium side chain of
arginine outmatches the analogous interaction with the primary ε-ammonium group of
25,26lysine by as much –21 kJ/mol. The reason for the strong interaction with oxoanions
lies in the peculiar binding pattern featuring two strong parallel hydrogen bonds in
27 addition to the electrostatic interaction (Scheme 1).
1

H H H H
N N
R C H R C H
N N N N
+ +
H H H H
--O O O O
PC R
O O
R
Scheme 1. Binding pattern of guanidinium groups with oxoanions found in many X-ray structures of the
corresponding salts.

28The guanidinium moiety is one of the most hydrophilic functional groups known.
Solvation by water is so efficient that despite the favorable binding pattern, ion pairing
-1 29with carboxylates and phosphates in aqueous solution is negligible (K < 5 M ). S
Bridging by water molecules may even allow the electrostatic repulsion to be overcome
30and lead to face-to-face dimerization of two guanidinium cations. The extreme
basicity of guanidine (13.5), which is conserved or even enhanced by prudent
31substitution, guarantees a fixed protonation state and opens the entire range of
accessible pH values for study.


2. Discussion

Guanidines from Thioureas

The thiourea moiety is converted into guanidinium functionalities in the presence of
different coupling reagents: N,N-dicyclohexylcarbodiimide (DCC), 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), mercury(II) chloride
(HgCl ), mercury(II) oxide (HgO), 2-chloro-1-methylpyridinium iodide (Mukaiyama`s 2
reagent)





2DCC Coupling

Iwanowicz and co-workers have reported the synthesis of novel guanidine-based
inhibitors of inosine monophosphate dehydrogenase through DCC coupling
32(Scheme 2).


H HHH MeNH , DCC MeMeO N N2MeMeO N N
RT
NS 92% MeNN
OO
1 2
H H H H
N Me N MeMeO N MeO NNH , DCC3
RT
S NH
73%N N 3
O O

Scheme 2. Synthesis of guanidines using DCC


EDC Coupling

Jefferson and co-workers have reported about a structure-activity relationship analysis
on a high-throughput small molecule screening lead for HCV-IRES translation
inhibition. The study led to the identification of a guanidine-based structure with low
33µM inhibitory activity. The thiourea, activated with 1-ethyl-3-(3´-
dimethylaminopropyl) carbodiimide (EDC), was treated with an arylamine to afford the
guanidine derivative (Scheme 3).

H H1) EDC, DIPEA, 0°C, DCM, 15 min N N N
2) Ph-(CH ) -NH , RT, 12 hH H fmoc2 2 2
N N N
fmoc N N
HO
N S
HO 4 5


Scheme 3. Synthesis of aryl-guanidines using EDC
3
34 Wollin and co-workers reported on the synthesis of cyanoguanidines (Scheme 4).

1) Thiocarbonyldiimidazole
DCM Ph
S2) NaNHCN, EtOH
H N Ph2 NC
N N
H H
6 7
O Ph
N
N NH28H
CN Ph
EDC, DMF, RT, 2 h O Ph N
N
69 % N N N
H H H
9

Scheme 4. Synthesis of cyanoguanidine β-amino acid derivative


Mukaiyama´s Reagent

Fan et al. have developed an efficient synthesis of N,N´-substituted guanidine
35derivatives via an aromatic sulfonyl-activated thiourea intermediate (Scheme 5). As
shown in Scheme 5, a primary amine 10 was first turned into the corresponding
pentafluorophenyl thiocarbamate. This allowed for the smooth synthesis of the
arylsulfonyl-activated thiourea 11, using PbfNHK (formed by treating PbfNH with 2
potassium tert-butoxide) as nucleophile. Compound 11 is an excellent guanidinylating
reagent. Treatment of 11 with an amine in the presence of Mukaiyama reagent (2-
chloro-1-methylpyridinium iodide) produced the subsequent guanidin derivatives 12a-d
in very good yields at room temperature in 12 – 18 h.

4BrBr Br 2 1R R
N
a, b H
c
NHNH *HCl NH2
110 R
N NHN S
PbfPbf 2R
1211
1 212a R = H, R = cyclohexyl, Yield: 88%
1 212b R = H, R = t-butyl, Yield: 84%
1 212c R = R = ethyl, Yield: 85%
1 212d R = R = isopropyl, Yield: 88%
a) pentafluorophenyl chloroformiate, DIPEA, CH Cl ; b) PbfNH , potassium t-butoxide,2 2 2
DMSO; c) Mukaiyama reagent, DIPEA, THF/DMF
Pbf:
O
S
O
O


Scheme 5. Arylsulfonylthiourea-assisted synthesis of N,N´-substituted guanidines

Nagashima and co-workers have reported on the synthesis of malonamide derivatives as
α β antagonists. The guanylation of compound 13 with N,N´-bis(tert-v 3
butoxycarbonyl)thiourea in the presence of 2-chloro-1-methylpyridine iodide
(Mukaiyama´s reagent) and NEt in dichloromethane afforded the tert-butoxycarbonyl 3
(Boc) protected guanidine derivative 14. Removal of the Boc groups with 4 M HCl –
36 dioxane afforded the desired guanidine compound 15. (Scheme 6).

5