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Short Note

Aza-27-crown-9 Amino Acid

Institute of Organic Chemistry, University of Regensburg, D-93040 Regensburg, Germany
*
Author to whom correspondence should be addressed.
Molbank 2010, 2010(1), M660; https://doi.org/10.3390/M660
Submission received: 24 February 2010 / Accepted: 3 March 2010 / Published: 4 March 2010

Abstract

:
A luminescent aza-27-crown-9 ether amino acid was prepared by a three-step reaction sequence. The compound signals ammonium ion binding by an increase in emission intensity.

Graphical Abstract

1. Introduction

Crown ethers of appropriate size are known to be suitable hosts for a variety of ions [1,2,3]. We have recently developed crown ether amino acids (CEAAs, 21-crown-7) with a luminescent moiety, which bind ammonium ions and indicate the recognition event by changes in their specific emission properties. The units can be covalently linked by peptide coupling to more extended receptors showing high specificity for N-terminal lysine in peptides [4,5] or with other recognition motifs binding for example histidine peptides [6,7]. The ability of benzo-27-crown-9 ethers to bind guanidinium ions is known [8,9], was applied in extraction experiments [10] and has been proven by crystal structures [11,12]. Examples of related chemosensors were employed for detecting naturally occurring toxins [13,14].

2. Synthesis

Tetraethyleneglycol ether chains are attached to 4,5-dihydroxyphthalic acid methyl ester (1) by reaction with an excess of tosylate 2 at elevated temperature in DMF under basic conditions. Subsequent tosylation and nucleophilic macrocyclisation with boc-ethylenediamine (5) gives the luminescent aza-27-crown-9 ether amino acid (6) in good overall yield of 45%.
Scheme 1. Synthesis of aza-27-crown-9 ether amino acid.
Scheme 1. Synthesis of aza-27-crown-9 ether amino acid.
Molbank 2010 m660 sch001
Conditions: (a) DMF, K2CO3, 90 °C, overnight; (b) THF, H2O, KOH, TsCl, 0 °C to RT, 3 h; (c) MeCN, H2O, K2CO3, KI, reflux, over night.

3. Experimental

Compound 1 [15,16,17], 2 [18] and 5 [19] were prepared following literature known procedures. The complete analytics for the intermediates 3 and 4 can be found in the supporting information.

Dimethyl 13-(2-(tert-butoxycarbonylamino)ethyl)-3,5,6,8,9,11,12,13,14,15,17,18,20,21,23,24-hexadecahydro-2H-benzo[k][1,4,7,10,13,16,19,22,25]octaoxaazacycloheptacosine-27,28-dicarboxylate (6)

(a) To a mixture of 0.68 g dimethyl-4,5-dihydroxyphthalate (1) (3 mmol) and 1.38 g K2CO3 (10 mmol) in DMF (5 mL), 3.5 g tetraethyleneglykole monotosylate (2) (10 mmol) in DMF (5 mL) were added and stirred under nitrogen at 60 °C overnight. After cooling to room temperature, the mixture was poured into 30 mL of ice-cold saturated NH4Cl solution. The resulting mixture was extracted four times with 10 mL of DCM. The combined organic phases were dried over MgSO4 and the solvent was evaporated. Traces of DMF were removed with the aid of a high-vacuum pump. The residue was purified by flash chromatography on silica gel (Et2O/EtOH 1:1, Rf = 0.16) to afford compound 3 as a yellow sticky oil (1.25 g, 2.16 mmol, 72% for step a).
(b) The product from the previous step (3) (1.16 g, 2.0 mmol) and 1.14 g of 4-toluenesulfonyl chloride (6.0 mmol) were dissolved in 20 mL of THF. A cold solution of potassium hydroxide (0.73 g, 13.0 mmol) in 3 mL of water was added dropwise at 0°C over a period of 1 h. The mixture was stirred for 2 h at room temperature and poured into 60 mL of a vigorously stirring mixture of water and diethylether (1:3; v/v). The aqueous phase was extracted three times with 30 mL of diethylether. The combined organic phases were washed once with 30 mL of saturated aqueous NH4Cl solution, then with 30 mL of water and dried over MgSO4. The solvent was evaporated to yield 4 as a pale yellow, sticky oil (1.62 g, 1.83 mmol, 91% for step b).
(c) Compound 4 (1.11 g, 1.25 mmol) was dissolved in acetonitrile (20 mL), containing 0.2 mL of water. The mono-boc-protected ethylene diamine 5 (205 mg, 1.25 mmol), KI (310 mg, 1.8 mmol) and K2CO3 (1.67 g, 12.5 mmol) were added successively. The mixture was refluxed overnight and filtered over celite after cooling. The filter cake was washed with acetonitrile and dichloromethane. After removal of the solvent under reduced pressure, the residue was purified by column chromatography (ethyl acetate / ethanol 3:1) to give the product 6 as a clear, yellow oil (Rf = 0.1) in an overall yield of 45% (610 mg, 0.85 mmol, 68% for step c).
MF: C34H57N2O14; FW: 717.84 g/mol; UV (MeOH): λ (ε) = 269 (8900), 225 (29600); IR (KBr): ν [cm-1] = 3360 (w), 2920 (m), 2946 (m), 2870 (m), 1714 (s), 1598 (m), 1516 (m), 1436 (m), 1351 (m), 1285 (s), 1251 (m), 1182 (s), 1122 (s), 1062 (m), 978 (m), 946 (m), 882 (w), 782 (m), 659 (w); MS (ESI-MS, CH2Cl2/MeOH + 10 mmol NH4OAc): e/z (%) = 703.4 (100, MH+); - HRMS (PI-LSIMS FAB, MeOH/Glycerine): calc. for C33H55N2O14+ [MH+]: 703.3653, found: 736.3659; EA (C34H57N2O14 * 2 H2O): calc. C 53.6, H 7.9, N 3.8, found. C 53.3, H 7.8, N 3.7.; 1H-NMR (300 MHz, CDCl3): δ [ppm] = 1.42 (s, 9 H), 2.74 (m, 2 H), 2.83 (m, 4 H), 3.20 (m, 2 H), 3.51–3.78 (m, 20 H), 3.80–3.96 (m, 4 H), 3.86 (s, 6 H), 4.20 (m, 4 H), 5.61 (bs, 1 H), 7.18 (s, 2 H); 13C-NMR (75 MHz, CDCl3): δ [ppm] = 28.5 (+, 3 C), 29.7 (-, 1 C), 38.9 (-, 1 C), 52.6 (+, 2 C), 54.3 (-, 2 C), 68.8 (-, 2 C), 69.2 (-, 2 C), 69.5 (-, 2 C), 70.5 (-, 2 C), 70.7 (-, 2 C), 70.7 (-, 2 C), 71.1 (-, 2 C), 78.9 (Cquat, 1 C), 113.7 (+, 2 C), 125.4 (Cquat, 2 C), 150.5 (Cquat, 2 C), 156.2 (Cquat, 1 C), 167.8 (Cquat, 2 C).
Figure 1. Absorption and emission spectra of compound 6 (c = 2.8 × 10-5 mol/L) in methanol solution.
Figure 1. Absorption and emission spectra of compound 6 (c = 2.8 × 10-5 mol/L) in methanol solution.
Molbank 2010 m660 g001

Supplementary materials

Supplementary File 1Supplementary File 2Supplementary File 3Supplementary File 4

Acknowledgements

We thank the Deutsche Forschungsgemeinschaft (GRK 760) and the University of Regensburg for support of this work.

References and Notes

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Späth, A.; König, B. Aza-27-crown-9 Amino Acid. Molbank 2010, 2010, M660. https://doi.org/10.3390/M660

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Späth A, König B. Aza-27-crown-9 Amino Acid. Molbank. 2010; 2010(1):M660. https://doi.org/10.3390/M660

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Späth, Andreas, and Burkhard König. 2010. "Aza-27-crown-9 Amino Acid" Molbank 2010, no. 1: M660. https://doi.org/10.3390/M660

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