Synthesis and amino acids complexation of tripodal hexasubstituted benzene chiral receptors

Accepted Manuscript Synthesis and Amino Acids Complexation of Tripodal Hexasubstituted Benzene Chiral Receptors Saowanaporn Choksakulporn, Auradee Punkvang, Yongsak Sritana-anant PII: DOI: Reference:

S0022-2860(14)01072-2 http://dx.doi.org/10.1016/j.molstruc.2014.10.059 MOLSTR 21055

To appear in:

Journal of Molecular Structure

Received Date: Revised Date: Accepted Date:

26 June 2014 18 September 2014 23 October 2014

Please cite this article as: S. Choksakulporn, A. Punkvang, Y. Sritana-anant, Synthesis and Amino Acids Complexation of Tripodal Hexasubstituted Benzene Chiral Receptors, Journal of Molecular Structure (2014), doi: http://dx.doi.org/10.1016/j.molstruc.2014.10.059

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Synthesis

and

Amino

Acids

Complexation

of

Tripodal

Hexasubstituted Benzene Chiral Receptors Saowanaporn Choksakulporna, Auradee Punkvangb, Yongsak Sritana-ananta* a

Department of Chemistry, Faculty of Science, Chulalongkorn University, Phayathai Rd, Pathumwan, Bangkok 10330, Thailand b

Division of Chemistry, Faculty of Sciences, Nakhon Phanom University, Nakhon Phanom 48000, Thailand E-mail: [email protected]; Tel. +662 2187632; Fax +662 2187598

Abstract The parent 1,3,5-triacetyl-2,4,6-trihydroxybenzene was prepared in up to 91% yield using a one-pot, one step reaction catalyzed by aluminum chloride. Its alkylations with 1,5-dibromopentane generated a symmetric tripodal hexasubstituted benzene precursor in the alternated conformer predicted by a theoretical calculation. Subsequent substitutions and reductions provided the corresponding tris-amine in 59% yield. Aminations of the tripodal precursor with (R)-(+)-1phenylethylamine obtained a chiral tris-amine ligand in 44% yield. 1H-NMR titrations of this ligand with each of three L-amino acid derivatives as guest molecules confirmed the presence of their complexes, in which the complex with alanine derivative displayed the strongest interactions with the ligand. Job plots suggested that all complexes composed of 1:2 ratios of the ligand and these guests. Theoretical calculations additionally revealed the structures and the associated binding parameters of the complexes. Keywords: Hexasubstituted benzene scaffold; tripodal ligand; amino acid receptor

Introduction Molecular scaffolds and their structural diversity building upon the scaffolds are at the heart of supramolecular chemistry with the goal to achieve effective bindings towards guest molecules by the aligned interactive arms on the respective scaffolds. The design of these hosts and their complementary guests would involve many related factors such as size, charge density, polarizability, position and shape.[1-3] When an equal number of interactive arms is present, multimacrocycles or three-dimensional cryptates are known to create very stable inclusion complexes with better selectivity and binding strength towards their guests than the non-cyclic or even monocyclic counterparts.[4,5] The rigidity imposed upon the cycles helps situate the binding arms and facilitate some degrees of preorganization. Nevertheless, the painstaking synthetic efforts

towards such rigidity and the usually required multidentate groups are the major hurdles and hinder the advance of the field. With relatively simple synthetic access and highly diverse varieties, tripodal ligands are among the most frequently investigated and successful host scaffolds.[6-11] One of the platforms that has particularly caught our interests is the hexasubstituted benzene scaffold.[12,13] Each pair of adjacent substituents minimizes their steric repulsion by adopting the thermodynamically favored conformation in which all subunits are arranged in fully up-down alternating configuration or the “ababab” geometry (Figure 1).[14-16] Such arrangement projected three groups perpendicularly on one face of benzene plane while the others turn toward the opposite direction. This facially segregated feature creates rigidity on this non-cyclic ligand, but allows some flexibility upon guest binding and avoids the difficulty of macrocyclic synthesis.

Figure 1 preorganized geometry of hexasubstituted benzene scaffold Most of the ligand designs based on hexasubstituted benzene focused on those derived from 1,3,5-trisubstituted-2,4,6-triethylbenzene precursor.[17-25] Some restrictions could be noticed from this scaffold. The synthetic strategies employed for incorporation of the binding arms onto the scaffold are relatively limited, and only three arms can be functionalized due to the unreactive ethyl groups. Such limitations can be sidestepped by employing 1,3,5-triacyl-2,4,6-trihydroxybenzene as the parent. The compound can be prepared simply in one step and further derivatized, similarly or differently, on both sides of the benzene plane. However, designs of ligands derived from this platform were relatively scarce and underutilized.[26-30] In this context, we wish to report our recent attempts to employ the scaffold towards molecular recognition especially those involves chiral biological related molecules such as amino acid derivatives.

Experimental section General information: 1H and

13

C NMR spectra were recorded on Varian Mercury 400 or Bruker

Avance 400 spectrometers, operated at 400 MHz for 1H and 100 MHz for

13

C nuclei. The FT-IR

spectra were recorded on a Perkin-Elmer spectrum RXI spectrometer. High resolution mass spectra were determined on Bruker Daltonik GmbH micrOTOF-Q II. All reagents and solvents were used as purchased or distilled prior to use.

Syntheses Synthesis of 1,3,5-triacetyl-2,4,6-trihydroxybenzene 1 Acetyl chloride (50 mL) was added to the mixture of phloroglucinol dihydrate (5.01 g, 30.9 mmol) and anhydrous AlCl3 (20.47 g, 154.5 mmol). The reaction was stirred under reflux for 1 h and quenched with 10% HCl (10 mL), water (150 mL) and filtered. The collected precipitate was recrystallized from ethanol to give colorless needle crystals of the product in 7.09 g, 91% yield, mp 155-156 °C (lit. mp 156 °C [31,32]); 1H NMR (CDCl3) δ: 17.16 (3H, s, -OH), 2.72 (9H, s, -C(O)CH3); 13C NMR (CDCl3) δ: 205.1, 175.9, 103.3, 33.0; IR (KBr, cm-1): 3427.0, 1620.2, 1579.8, 1296.7; HRMS (ESI/methanol) m/z: (M+Na)+ 275.0539 (Calcd for C12H12NaO6: 275.0532). Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-bromopentyloxy)benzene 2 Compound 1 (5.01 g, 19.9 mmol) was dissolved in acetonitrile (200 mL). 1,5Dibromopentane (32.7 mL, 238.8 mmol) and K2CO3 (41.15 g, 298.2 mmol) were added and the mixture was stirred under reflux for 48 h. The solvent was then removed and water (100 mL) was added. The solution was extracted with ethyl acetate. The organic layers were separated, combined, dried over anhydrous Na2SO4 and evaporated the solvent. The concentrated crude product was purified by column chromatography (90:10 hexane/ethyl acetate) to give colorless oil product in 10.7 g, 77% yield; 1H-NMR (CDCl3) δ: 3.82 (t, J = 6.4 Hz, 6H, -OCH2-), 3.40 (t, J = 6.7 Hz, 6H, -CH2Br), 2.52 (s, 9H, -C(O)CH3), 1.86 (m, 6H, -OCH2CH2-), 1.64 (m, 6H, -CH2CH2Br), 1.48 (m, 6H, -CH2CH2CH2-); 13

C-NMR (CDCl3) δ: 201.1, 153.9, 135.8, 129.1, 128.8, 128.8, 80.1, 32.8; IR (KBr, cm-1): 3031.9, 2920.0,

1698.9, 1572.4, 1197.8, 1081.1; HRMS (ESI/methanol) m/z: (M+H)+ 701.0323 (Calcd for C27H39Br3O6: 701.0334). Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-azidopentyloxy)benzene 3 Compound 2 (3.69 g, 5.3 mmol) was dissolved in acetone (24 mL). Sodium azide (1.37 g, 21.1 mmol) in water (6 mL) was added and the mixture was stirred under reflux for 8 h. The solvent was then removed and water (30 mL) was added. The mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and evaporated the solvent. The crude product was purified by column chromatography (CH2Cl2) to give the yellow oil product in 2.82 g, 85% yield; 1H NMR (CDCl3) δ: 3.82 (t, J = 6.4 Hz, 6H, -OCH2-), 3.27 (t, J = 6.8 Hz, 6H, -CH2N3), 2.52 (s, 9H, -C(O)CH3), 1.62 (m, 12H, -OCH2CH2- and -CH2CH2N3), 1.43 (dt, J = 12.6, 6.8 Hz, 6H, -CH2CH2CH2-); 13

C NMR (CDCl3) δ: 201.1, 154.2, 127.8, 77.6, 51.4, 32.8, 29.5, 28.6, 23.0; IR (neat, cm-1): 2943.4,

2867.9, 2084.1, 1700.8, 1570.2, 1349; HRMS (ESI/methanol) m/z: (M+H-N2)+ 558.3101 (Calcd for C27H39N7O6: 558.3040). Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-aminopentyloxy)benzene trihydrochloride 4 Compound 3 (0.3 g, 0.5 mmol) and ammonium chloride (0.23 g, 3.6 mmol) were dissolved in ethanol (3 mL) and water (10 mL) and then added zinc powder (0.14 g, 2.0 mmol). The mixture was

stirred vigorously at reflux temperature for 15 min. Ethyl acetate (15 mL) and 30% ammonia (5 mL) were added. The mixture was filtered, and the filtrate was washed with brine, dried over anhydrous Na2SO4 and removed the solvent. The concentrated crude product was converted into hydrochloride salt by adding methanol (5 mL) and 10% HCl (1 mL) and stirred for 3 h. The salt product 4 was purified by column chromatography using Sephadex LH-20 and methanol as the eluent. The product was obtained as yellow oil in 0.23 g, 90% yield. This compound was characterized as N-acetylated derivative using the following procedure. Compound 4 (0.18 g, 0.35 mmol) was treated with acetic anhydride (1 mL), DMAP (0.039 g, 0.35 mmol) and pyridine (2 mL). The reaction mixture was stirred at room temperature overnight. It was quenched with water (10 mL) and then extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4, concentrated and purified by column chromatography (80:20 ethyl acetate/methanol). The N-acetylated product was obtained as a white solid in 0.15 g, 69% yield; 1H NMR (Acetone-d6) δ: 7.06 (s, 3H, -NH-), 3.84 (t, J = 6.4 Hz, 6H, -OCH2-), 3.16 (q, J = 6.5 Hz, 6H, -CH2NH-), 2.51 (s, 9H, ArC(O)CH3), 1.84 (s, 9H, -NHC(O)CH3), 1.64 (m, 6H, -OCH2CH2-), 1.47 (dd, J = 14.7, 7.1 Hz, 6H, -CH2CH2NH-), 1.38 (dd, J = 14.9, 7.8 Hz, 6H, -CH2CH2CH2-); 13C NMR (Acetone-d6) δ: 201.0, 169.8, 154.8, 128.3, 77.9, 39.6, 32.9, 30.27, 30.1, 23.8, 22.9; IR (neat, cm-1): 3722.4, 3627.9, 2929.2, 2866.2, 1766.6, 1655.0, 1569.1, 1417.3, 1256.8, 1196.8, 1085.1; HRMS (ESI/methanol) m/z: (M+H)+ 634.3750 (Calcd for C33H51N3O9: 634.3704). Synthesis of 1,3,5-triacetyl-2,4,6-tris(5’-((R)-1-phenylethylamino)pentyloxy)benzene 5 Compound 2 (0.51 g, 0.7 mmol) was dissolved in in acetonitrile (25 mL). 1,5-(R)(+)Phenylethylamine (0.3 mL, 2.4 mmol) and K2CO3 (0.5 g, 3.5 mmol) were added and the mixture was stirred under reflux for 13 h. The solvent was then removed and water (20 mL) was added. The solution was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous Na2SO4 and evaporated the solvent. The concentrated crude product was purified by column chromatography using Sephadex LH-20 (80:20 methanol/water) to give the yellow oil product in 0.26 g, 44% yield; 1H NMR (400 MHz, CD3OD) δ 7.60 (d, J = 7.1 Hz, 1H, o-ArH), 7.54 – 7.41 (m, 14H, ArH), 4.58 (dd, J = 13.3, 6.5 Hz, 1H, -NH-C*HCH3), 4.39 (q, J = 6.5 Hz, 2H, -NHC*HCH3), 3.81 (t, J = 5.4 Hz, 6H, -OCH2-), 3.17-2.99 (m, 2H, -CH2NH-), 3.00-2.68 (ddd, J = 78.8, 16.5, 11.1 Hz, 4H, -CH2NH-), 2.48 (s, 9H, -C(O)-CH3), 1.69 (d, J = 6.7 Hz, 9H), 1.79 – 1.56 (m, 12H, -CH2-CH2- CH2-), 1.41 – 1.34 (m, 6H, -CH2CH2- CH2-); 13C NMR (100 MHz, CD3OD) δ 202.6, 155.4, 137.9, 130.7, 130.5, 130.4, 130.0, 128.7, 78.2, 59.7, 51.8, 46.9, 33.0, 30.7, 30.3, 26.9, 25.0, 24.0, 23.9, 19.8, 17.2; IR (neat, cm-1): 3401.7, 2943.4, 2867.9, 1700.8, 1569.1, 1417.2, 1256.8, 1196.8, 1085.1 (C-N st); HRMS (ESI/methanol) m/z: (M+H)+ 820.5286 (Calcd for C51H69N3O6: 820.5265). Binding studies

1

H NMR titrations and Job’s plots were used to determine the binding ratios between the

ligand and guests.[33] The selected guests are the enantiomeric pairs of alanine methylester hydrochloride (6), N-Boc-tryptophan (7) and N-Boc-valine (8). 1H NMR spectrum of the mixture was recorded after each addition of exact equivalent of guest solution until no change was observed in the spectrum. Complexes of ligand 5 with guests 6 and 8 were investigated in CDCl3 while those with guest 7 were studied in acetone-d6 due to its low solubility in CDCl3. The association constants (Kassoc) and predicted complex structures were computationally assessed using Autodock 3.05 program. Computational methods Structures of 2, ligand 5 and the selected guests including alanine methylester hydrochloride (6), N-Boc-tryptophan (7) and N-Boc-valine (8) were constructed using the standard tools available in GaussView 3.07 program. They were fully optimized by Hartree fock (HF) method with 6-31G* basis set (HF/6-31G*) implemented in the Gaussian 03 program. Two different conformers of 2, the abaabb and the fully alternated ababab conformers, were similarly constructed and fully optimized by HF/6-31G* method. The structures of 1:1 and 1:2 complexes of ligand 5 with guests 6, 7 and 8 were predicted by the molecular docking calculations using Autodock 3.05 program.[34] The optimized structure of each guest was first docked into the pocket of ligand 5 to generate the 1:1 complex. The obtained structure was then taken as the receptor, and another guest molecule was docked into its corresponding 1:1 complex to generate the 1:2 complex. With an exception of the number of genetic algorithm (GA) runs set to 50, all other parameters were set at default values. The structure with the lowest docked energy was selected as the best binding mode of each complex. The corresponding estimated free energy of binding (ΔG) and binding constants (Kassoc) of these complexes were then calculated and reported.

Results and Discussion Synthesis The parent 1,3,5-triacetyl-2,4,6-trihydroxybenzene 1 was successfully synthesized in onepot, one step process using the process modified from previous reports (Scheme 1).[31-32] The reaction was assumed to go through triple O-acylations of phloroglucinol followed by Fries rearrangements to the hexasubstituted product. Aluminum chloride was found to be the most efficient acid catalyst, yielding the product up to 91% (Table 1). Much lower yields were obtained with other acids in which incompletely rearranged intermediates and large amount of recovered substrate were observed in some cases. The optimum reaction time was approximately at 1 h.

Prolonged reflux may convert the highly steric crowded product back to the intermediate or other byproducts. The 1H-NMR signal of the phenolic protons of 1 appeared as a singlet at δ 17.16 ppm, indicating that the molecule is relatively flat with strong three intramolecular hydrogen bonds between the three hydroxy groups and the adjacent carbonyls.[35]

Scheme 1 Reagents and conditions: (i) AcCl, AlCl3; (ii) 1,5-dibromopentane, K2CO3, CH3CN; (iii) NaN3, acetone/H2O; (iv) Zn, NH4Cl; (v) 10% HCl, MeOH; (vi) (R)-(+)-1-phenylethylamine, K2CO3, CH3CN Table 1 The syntheses of 1,3,5-triacyl-2,4,6-trihydroxybenzene Entry

Catalyst

Time (h)

%Yield

1

AlCl3

1

91

2

TiCl4

1

40

3

FeCl3

1

32

4

BF3·OEt2

1

17

5

conc.H2SO4

4

14

6

AlCl3

4

70

The precursor 1 was alkylated at the hydroxyl groups to generate the symmetric tripodal scaffold. The synthesis of 2 was accomplished using 1,5-dibromopentane as the alkylating agents (Scheme 1). Based on our HF/6-31G* calculations, the energy of the optimized structure of 2 in its fully alternated ababab conformation was lower than that of the next most stable abaabb conformer by 6.3 kcal/mol (Figure 2). In this conformation, all bromopentoxy groups were oriented out of the same face of the central benzene plane, in the opposite direction to the methyl groups of

the three acetyl substituents. This result was later used as the guideline to computationally build the structure of the related ligand 5 as its fully alternated conformation in the following complexation study.

Figure 2 The most stable ababab (left) and the next most stable abaabb (right) conformers of 2 Nucleophilic substitutions of the scaffold 2 with sodium azide provided tris-azide 3 in 85% yield.[36] The subsequent reductions with Zn/NH4Cl turned the tris-azide intermediate to the corresponding tris-amine 4 in 90% yield.[37] The structure of the product 4 was confirmed as its trisN-acetyl derivatives from further excessive acylations. The overall yield of 4 calculated from the starting platform 1 was 59%. In another route, direct aminations of 2 with (R)-(+)-1phenylethylamine generated the chiral ligand 5 in 44% yield. Compound 5 was investigated for its ability to form complexes and discriminate enantiomers of three amino acid derivatives: alanine methylester hydrochloride 6, N-Boc-tryptophan 7 and NBoc-valine 8. The more abundant L-isomers of the amino acids were first selected for the investigation using 1H-NMR titration with increasing amount of guests. Ligand 5 showed significant downfield complexation-induced chemical shifts (CICS) in all cases especially around the stereogenic centers. On the other hand, the proton signals of guests immediately shifted upfield at the beginning of the titration, and gradually moved downfield upon further additions of guests. This wavering shift could arise from the initial hydrophobic environment surrounding the guest molecules upon complexation within the binding pocket of the ligand. As more guest molecules were added, interactions among themselves diminished the effect from the ligand and moved the NMR chemical shifts of the proton signals downfield. Because of the uncertain directions of the CICS of the NMR signals of the guests, the chemical shifts of the signals of two moieties of the ligand: the methine protons at the stereogenic centers and the adjacent methyl groups were chosen to be monitored. During the titration, the signals of the methine and the methyl protons of ligand 5 upon complexation with 6 displayed the strongest downfield shifts of 0.43 and 0.49 ppm, respectively (Figure 3). In comparison, the complexes with 7 and 8 gave the values of downfield shifts of these two signals to be 0.25, 0.20 and 0.38, 0.27 ppm, respectively. This indicated that the binding arms of

ligand 5 could interact with guest 6 stronger than the other two compounds. It could be assumed that the free amino and the ester groups on 6 could attract to the binding groups of the ligand better than the amide and the free carboxyl groups on 7 and 8.

Figure 3 Stack plots of 1H-NMR titration spectra of complex between ligand 5 and guest 6 Job plots of all complexes were obtained by the continuous variations method (Figure 4).[33] The aligned maxima of all plots at about 0.67 mole fraction of the guest suggested that the binding ratios between this ligand and these amino acid derivatives were 1:2. The tight hydrogen bonds between two guest molecules may prevail over the weaker interaction yet sufficient for complexation with the binding groups of ligand 5. This dimeric self-attraction of amino acid derivatives weakened the interactions with the host and reflected in the gradual downfield shifts of the proton signals of the guests observed in the NMR titrations. 0.160

ΔδHa(1-X)

0.120 0.080

6 7 8

0.040 0.000 0.000

0.200

0.400 0.600 0.800 mole fraction of guest

1.000

Figure 4 Job plots of CICS of the methine protons of ligand 5 from NMR titrations with guests 6, 7, 8

Computtatio onal stud s dies reeveaaled d the t reelatiivelyy m mod destt asso a ociation n cons c stan nts off th he com mplexees off liggand d 5 and d the th hreee gu uestts (TTable 2 2). The T ressultss paartlyy aggreeed with w h thee exxperimenttal datta that t t su uggeesteed bett b ter com mpllexaatio ons of ligaand 5 with the gueestss in n 1:2 ratio os exce e ept witth com mpo ound 8. In facct, the t difffereencee beetw ween n th he calcu c ulatted ΔG valuess off thee 1::1 and a 1:2 2 co omp plexees witth 7 and d 8 weere insig i gnifficant. Onlly th he com c mpleex with w h 6 clea c arly preeferred d thee 1::2 raatio o, prrobablyy du ue to thee prreseencee of th he free f e am min no grou g up. Part of o the t com mpllex staabilizatiion maay aris a se from m th he bilityy th hat thee tw wo gue g est molecu uless co ould d also bind to t each e h otther w within tthe pockeet of o th he posssib ligaand.. Th he pred p dicted stru uctu uress off the 1:2 com c mpleexess off liggand d 5 and d eaach of thee th hreee gu uestts are sho own n in Figu ure 5.

Tab ble 2 Associattion n co onstantts off the co omp plexxes of ligand 5 w with gueestss -ΔG(1:11)

Kasssoc (1:1)

-ΔG(1:2))

Kassocc (1:22)

kcal/m mol

(M M-1)

k /mol kcal

(M M-1)

6

1 7 1.47

11 1.97 7

1..61

15..17

7

2 4 2.34

52 2.03 3

2..37

54..74

8

1 8 1.38

10 0.28 8

1..31

9.1 14

Guest

a a)

b b)

c)) Figu ure 5 P Pred dicteed 1 1:2 com mplex stru s uctu uress of ligaand 5 with w h a) 6, b) b 7 and d c)) 8

The less abundant D-isomers of amino acid derivatives 6, 7 and 8 were next used as the guests to form complexes with ligand 5 in order to investigate the enantiomeric discrimination ability of the ligand. Surprisingly, the results from NMR titrations of the D- form of these guests also all preferred 1:2 complexes and were similar to those obtained from the previous experiments on the L-form. It could be deduced that the diastereomeric differentiations from ligand 5 were unfortunately too small to overcome the main attractive interactions that involved no chiral components. This lack of chiral distinction may be explained from the calculated structures of the complexes in Figure 5. The three arms of ligand 5 carrying the asymmetric moieties were extended away from the central core, where the dimeric pairs of the guest molecules preferentially situated and interacted with the host. The flexible long hydrocarbon chains that link the asymmetric groups to the core would be the reason for the failure to create an effective chiral binding pocket for the guests. It may be suggested that more rigidity on the linkers would be required to build a better ligand for chiral discrimination on this platform.

Conclusion The synthesis of hexasubstituted benzene derivatives based on the parent 1,3,5-triacetyl2,4,6-trihydroxybenzene 1 have been achieved. The synthetic procedure of the parent compound was optimized into one-pot, one step reflux using aluminum chloride catalyst. Alkylations of 1 with 1,5-dibromopentane produced the symmetric tripodal 2, which was theoretically predicted to be in fully alternated conformation. Substitutions of 2 with sodium azide provided tris-azide 3, which was reduced to the corresponding tris-amine 4. Direct aminations of 2 with (R)-(+)-1-phenylethylamine generated the desired chiral ligand 5. These relatively straightforward procedures provide a general access to functionalize the three hydroxyl groups directed toward one side of the hexasubstituted benzene plane. The other three alternated acetyl groups could then be modified to incorporate another set of functional moieties that pointed to the opposite side,[30] thereby creating a potentially ditopic bifunctional host on one platform. 1

H-NMR titrations of ligand 5 with each of three selected L-amino acid derivatives confirmed

the presence of their complexations, in which the complex with alanine derivative 6 displayed the strongest interactions with the ligand. Job plots of all complexes suggested that the preferred binding ratios between ligand 5 and these guests were 1:2, which partly agreed with the computational studies. Unfortunately, complexations of ligand 5 with the D-isomers of the guests gave similar results to those of their enantiomers, indicating that the ligand possessed no chiral discrimination ability among the amino acid derivatives being tested. The low rigidity of the aliphatic chain linking the binding moieties may be the reason for such ineffective enantiomeric

differentiation. One may envision that incorporating rigid groups such as aromatic rings or gemdimethyl groups as part of the linkers could improve the binding stability and chiral discriminating property. Such attempts would apparently add difficulties into the synthetic process and become a challenge for future design and synthesis of potential ligands from this platform. Acknowledgment The research funds from Thailand Research Fund (MRG4880176), and the National Research University project of CHE and the Ratchada phiseksomphot Endowment Fund (HR1155A), Chulalongkorn University, are highly appreciated. S. C. would like to thank the Development and Promotion of Science and Technology Talents Project (DPST) for the scholarship during the study. References [1] J. W. Steed, J. L. Atwood, Supramolecular Chemistry, 2nd ed., John Wiley & Sons, Chichester, 2009. [2] J.-M. Lehn, Supramolecular Chemistry: Concepts and Perspectives, Wiley-VCH, Weinheim, 1995. [3] R. D. Hancock, A. E. Martell, Ligand design for selective complexation of metal ions in aqueous solution, Chem. Rev. 89 (1989) 1875-1914. [4] M. Arthurs, V. McKee, J. Nelson, R. M. Town, Chemistry in cages: dinucleating azacryptand hosts and their cation and anion cryptates, J. Chem. Ed. 78 (2001) 1269-1271. [5] R. M. lzatt, K. Pawlak, J. S. Bradshaw, Thermodynamic and kinetic data for macrocycle interactions with cations and anions, Chem. Rev. 91 (1991) 1721-2085. [6] L. Siracusa, F. M. Hurley, S. Dresen, L. J. Lawles, M. N. Pérez-Páyan, A. P. Davis, Steroidal ureas as enantioselective receptors for an N-acetyl α-amino carboxylate, Org. Lett. 4 (2002) 46394642. [7] T. Opatz, R. M. J. Liskamp, Synthesis and screening of libraries of synthetic tripodal receptor molecules with three different amino acid or peptide arms: identification of iron binders, J. Comb. Chem. 4 (2002) 275-284. [8] P. Kocis, O. Issakova, N. F. Sepetov, M. Lebl, Kemp's triacid scaffolding for synthesis of combinatorial nonpeptide uncoded libraries, Tetrahedron Lett. 36 (1995) 6623-6626. [9] A. E. Lewis, H. H. Khodr, R. C. Hider, J. R. L. Smith, P. H. Walton, A manganese superoxide dismutase mimic based on cis,cis-1,3,5-triaminocyclohexane, Dalton Trans. (2004) 187-188. [10] C. Chamorro, R. M. J. Liskamp, Approaches to the solid phase of a cyclotriveratrylene scaffoldbased tripodal library as potential artificial receptors, J. Comb. Chem. 5 (2003) 794-801. [11] C. Kaewtong, S. Fuangswasdi, N. Muangsin, N. Chaichit, J. Vicens, B. Pulpoka, Novel C3vsymmetrical N7-hexahomotriazacalix[3]cryptand: a highly efficient receptor for halide anions, Org. Lett. 8 (2006) 1561-1564.

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Graphical abstract

Binding of alanine derivative as 1:2 complex by a new chiral tripodal ligand based on hexasubstituted benzene platform revealed by both experiment and theoretical calculation.

Highlights ·

New chiral and achiral ligands based on hexasubstituted benzene scaffold starting from phloroglucinol were prepared.

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The chiral ligand formed stable complexes with amino acid derivatives.

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The structures of the ligand and its complexes were confirmed both by experimental (NMR, IR) and computational studies.