Synthesis and spectroscopic studies of isosteviol-calix[4]arene and -calix[6]arene conjugates

Tetrahedron 61 (2005) 5457–5463

Synthesis and spectroscopic studies of isosteviol-calix[4]arene and -calix[6]arene conjugates Mayya Korochkina,a Marco Fontanella,b Alessandro Casnati,b,* Arturo Arduini,b Francesco Sansone,b Rocco Ungaro,b Shamil Latypov,a Vladimir Kataeva,* and Vladimir Alfonsova b

a A.E. Arbuzov Institute of Organic and Physical Chemistry, Arbuzov str. 8, Kazan 420088, Russian Federation Dipartimento di Chimica Organica ed Industriale dell’Universita`, Parco Area delle Scienze 17/A, I-43100 Parma, Italy

Received 28 January 2005; revised 14 March 2005; accepted 31 March 2005

Abstract—Novel calix[4]arene derivatives functionalized with two or four isosteviol units at the upper rim and a new calix[6]arene having six isosteviol moieties at the lower rim have been synthesized. The structures of these compounds have been confirmed by NMR and mass spectrometry data. All 1H and 13C NMR chemical shifts of isosteviol were fully assigned by extensive NMR spectroscopic methods, and used to clarify the structures and conformations of isosteviol-calixarene conjugates. q 2005 Elsevier Ltd. All rights reserved.

1. Introduction Calixarenes (1) have been widely used as scaffolds for the synthesis of receptors for cations, anions and neutral molecules.1 The main reason for the increasing importance of the use of calixarenes in supramolecular and bioorganic chemistry is the possibility of their easy functionalisation both at the lower and at the upper rim.2 Recently, the calix[4]arene scaffold was functionalized with amino acids at the upper rim and a novel series of biomimetic macrocyclic hybrid receptors possessing both polar groups and hydrophobic cavities as binding sites was elaborated. These compounds exhibit interesting complexation properties towards amino acids, small peptides3a–d and sugars.3e Calixarenes were also adorned at the upper3d,f,g or lower rim3h with glycoside units, thus obtaining receptors for anions and molecules able to efficiently and specifically interact with lectins thanks to the glycoside cluster effect. Calixarenes were also functionalized with steroidal derivatives and interesting receptors, able to act as artificial ion channels or enantioselective receptors for organic anions, obtained.3i–k

Keywords: Calixarenes; Isosteviol; NMR spectroscopy; Molecular modelling; Ab initio calculations. * Corresponding authors. Tel.: C39 0521 905458; fax: C39 0521 905472 (A.C.); tel./fax: C8 432 731872 (V.K.); e-mail addresses: [email protected]; [email protected] 0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2005.03.127

The isosteviol 2 (ent-16-oxobeyran-19-oic acid)4 is a diterpenoid which is obtained by acid-catalysed hydrolysis of stevioside,5a has anti-feeding action and inhibits the biosynthesis of gibberellins.6 Although the biotransformations of isosteviol are widely studied (see e.g., Ref. 7) only a few papers8 are devoted to its chemical transformations. Isosteviol 2 possesses a rigid tetracyclic framework with hydrophobic external and internal surfaces and polar groups at the ends of the molecule. It was found that tweezer-like structures based on isosteviol have hydrophobic internal cavities and form flaky-like structures having alternating hydrophobic and hydrophilic regions in the crystal.9 In solution these isosteviol derivatives behave as receptors and transport amino acids through liquid chloroform membranes.10 Moreover, isosteviol 2 itself appeared to bind small aromatic molecules forming crystal inclusion complexes whose supramolecular structure looks like a double chiral helix.11

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2. Results and discussion

Table 1. 13C and 1H NMR chemical shifts of isosteviol 2 (CDCl3, TMS as internal standard, 303 K, 150.86 and 600.13 MHz, respectively)

2.1. Full assignment of the isosteviol (2) NMR spectra

C

d (13C)

First of all we assigned carefully the NMR spectra of isosteviol 2 because there are still some uncertainties in the literature. The 1H NMR spectrum shows signals for three methyl groups at dZ1.26 (s, 3H, 18-H3), dZ0.99 (s, 3H, 17-H3) and dZ0.80 (s, 3H, 20-H3) as well as a number of multiplets in the range from 2.67 up to 0.93 ppm, where the only doublet of doublets at 2.65 (1H, dd, JZ18.7, 3.7 Hz) is unambiguously assigned to 15-Ha.5a,9b,12 Nevertheless, the full correlation of signals is necessary for analysis of the more complicated isosteviol-calixarene conjugates. The 13C NMR spectrum of isosteviol 2 shows 20 signals. Two of them correspond to the two carbonyl groups with characteristic chemical shifts dZ222.7 ppm (C-16) and dZ 183.6 ppm (C-19). The 13C NMR chemical shifts of all the hydrogenated carbons can be assigned unambiguously by HSQC experiments. The complete elucidation of the isosteviol 2 structure was achieved by the HMBC experiment. The HMBC correlations (Fig. 1a) between the proton signals at dZ0.99 (17-H3) and the carbon resonances at 222.7 ppm (C-16), 37.3 ppm (C-12) and 54.3 ppm (C-14); between the protons at 1.26 ppm (18-H3) and the carbon resonances at 183.6 ppm (C-19), 37.7 ppm (C-3) and 57.0 ppm (C-5); between the proton signals at 0.80 ppm (20-H3) and the carbon resonances at 39.8 ppm (C-1), 57.0 ppm (C-5) and 54.8 ppm (C-9) allowed us to carry out the full assignment of the proton and of the carbon spectra. The results are summarised in Table 1. The 13C NMR chemical shifts coincide with previously reported values.5a,7 It is worth noting that the assignment of all protons of diterpenoids is very rare in the chemistry of diterpenes, and for diterpenoid isosteviol 2 it has been accomplished for the first time. We know of only one paper concerning the analysis of the 1H NMR spectrum of isosteviol 25a where signals were assigned only to methyl groups and to the 12-H, 14-H, 15-H protons. However, the discrepancy in the

1

39.8

2 3

18.9 37.7

4 5 6

43.7 57.0 21.6

7

41.5

8 9 10 11 12 13 14 15 16 17 18 19 20

d (1H) 0.93 (1H, dd, JZ13.3, 3.9 Hz, 1-Hax) 1.85 (1H, d, 2-Hax) 1.04 (1H, dd, JZ13.7, 4.3 Hz, 3-Hax) 1.16 (1H, d, JZ12.1 Hz, 5-H) 1.77 (1H, d, 6-Hax) 1.50 (1H, dd, JZ13.4, 3.6 Hz, 7-Hax)

48.73 54.8 1.20 (1H, d, JZ14.2 Hz, 9-H) 38.2 20.3 1.24 (1H, d, 11-Hax) 37.3 1.38 (1H, dd, JZ12.4, 5.8 Hz, 12-Hax) 39.5 54.3 1.42 (1H, dd, JZ11.5, 3.4 Hz, 14-Hax) 48.75 2.65 (1H, dd, JZ18.7, 3.7 Hz, 15-Ha) 222.7 19.8 0.99 (3H, s, 17-H3) 29.0 1.26 (3H, s, 18-H3) 183.6 13.3 0.80 (3H, s, 20-H3)

1.75 (1H, d, 1-Heq) 1.46 (1H, d, 2-Heq) 2.18 (1H, d, JZ13.4 Hz, 3-Heq) 1.90 (1H, d, JZ13.8 Hz, 6-Heq) 1.68 (1H, d, JZ13.4 Hz, 7-Heq)

1.71 (1H, d, 11-Heq) 1.63 (1H, d, JZ13.1 Hz, 12-Heq) 1.56 (1H, dd, JZ11.7, 2.4 Hz, 14-Heq) 1.82 (1H, d, JZ18.5 Hz, 15-Hb)

assignment of the doublet at dZ2.18 appeared when comparing our results with previously published data5a which were based only on NOE experiment.5b This signal was previously assigned5a to 12-Hax, whereas we now attribute it to 3-Heq. According to our NOE (Fig. 1b) and particularly HMBC experiments (Fig. 1a) the assignments of 3-H and 12-H protons have to be exchanged (Table 1) in comparison with data from Ref. 5a. These conclusions are supported by DFT GIAO 6-31G(d)13 calculations of 1H and 13C chemical shifts of isosteviol 2 (with preliminary MM minimized geometry) performed with the help of GAUSSIAN 98.14 The calculated values both for 3-H and 12-H are very close to the experimental ones (Table 2), as well as a good correlation being observed between calculated and experimental values of 13C chemical shifts (Fig. 2). Interestingly, the assignment of 3-Heq to the signal at 2.18 ppm indicates that this proton is deshielded by C]O group and that the conformational preference of the carboxylic group in solution is quite close to that found in the crystal according to X-ray data15 (schematically represented in Fig. 1b). 2.2. Coupling of isosteviol to calixarenes As a starting material for introducing the isosteviol Table 2. Experimental and calculated values of some 1H chemical shifts of isosteviol 2

Figure 1. Diagnostic correlations for isosteviol 2: (a) HMBC, (b) NOESY.

3-Hax 3-Heq 12-Hax 12-Heq

dexp (ppm)

dcalc (ppm)

1.04 2.18 1.38 1.63

1.17 2.26 1.30 1.68

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Figure 2. Correlation between calculated and experimental chemical shifts of isosteviol 2.

13

C NMR

framework onto the calixarene system we used isostevioyl chloride 3, which was synthesized by the reaction of isosteviol 2 with an excess of thionyl chloride. We first, explored the possibility of introducing six isosteviol units at the lower rim of calix[6]arene. By reacting hexaaminocalix[6]arene 4 with isostevioyl chloride 3 and N,N-

Scheme 1.

Scheme 2.

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diisopropylethyl amine (DIPEA) in dry CH2Cl2 we isolated the lower rim isosteviol conjugate 5 in 48% yield (Scheme 1). The 1H NMR spectrum of 5 shows the equivalence of the six isosteviol units (three signals of methyl groups without splitting) and clear signals (doublet and triplet) in the aromatic part of the spectrum. The singlet at dZ3.90 for the ArCH2Ar protons indicates that the macrocycle is rapidly interconverting among different conformations. The mass spectrum, showing the presence of the peak corresponding to the molecular weight of compound 5, confirms that all six isosteviol units are linked to the calixarene scaffold. In order to introduce the isosteviol moieties on the calix[4]arene scaffold we used the upper rim diamino- (6) and tetraamino- (7) tetrapropoxycalix[4]arenes. Thus, by reacting diterpenoid 3 with (6) or (7) and DIPEA in dry CH2Cl2, we obtained the di- (8) or tetra- (9) functionalized compounds (Scheme 2) in 37 and 54% isolated yield, respectively. The electrospray mass spectra of both compounds 8 and 9 show peaks corresponding to the molecular ions plus sodium. Compound 9 shows the typical 1H NMR spectrum of a tetrafunctionalized calix[4]arene in the cone conformation in which equatorial and axial methylene protons resonate as two distinct doublets at dZ3.16 and 4.41 ppm, respectively. Calixarene

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aromatic protons give rise to two doublets at dZ6.75 and 6.86 ppm due to meta couplings with JZ2.4 Hz, as a consequence of the chirality of isosteviol. The 1H NMR spectrum of 8 shows that the two isosteviol moieties are equivalent as clearly indicated by the three singlets (0.89, 0.98, 1.35 ppm) of the methyl groups of the diterpenoid. In CDCl3 the relative position of the signals due to the aromatic protons of the substituted (doublets at dZ7.16 and 7.21 ppm) and unsubstituted (doublet and triplet at dZ6.17 and 6.25 ppm, respectively) aromatic nuclei, indicates3b that compound 8 adopts an open flattened cone conformation with the two unsubstituted aromatic rings pointing inwards and the other two aromatic rings bearing the isosteviol units pointing outwards from the aromatic cavity. The signals of equatorial and axial methylene protons resonate as doublets at dZ3.10 and 4.41 ppm, respectively, with the signal of the equatorial methylene bridge protons being splitted into two distinct doublets. This splitting, as well as that observed for the protons of substituted aromatic rings (two doublets at dZ7.16 and 7.21 ppm) are caused by the presence of the chiral isosteviol units. The 13C NMR spectrum of calix[4]arene 8 shows full set of signals both for the calixarene moiety and for the isosteviol fragment. The final elucidation of the structure was achieved by the use of 2D HMBC and 2D NOESY experiments. The diagnostic HMBC correlations (Fig. 3a) between the proton signals at dZ1.35 ppm (18-H3), dZ7.24 ppm (NH) and dZ1.26 ppm (3-Hax) with the carbon resonance at 174.7 ppm (C-19), as well as the HMBC correlation between proton signals at dZ7.24 ppm (NH) and the carbon resonance at 121.2 ppm (C-4 0 , C-6 0 ) gave additional proofs of the connection between the isosteviol moieties and the calixarene skeleton. NOE data (Fig. 3b) allowed us to fully assign all the signals of the calix[4]arene moiety and its propyloxy substituents at the lower rim (see Section 4 for 8). We failed to grow single crystals for X-ray study of compound 8 and modeled its conformation in vacuo using MM computations16 through Chem3D Ultra 6.0 program (CambridgeSoft Corp). The minimized open flattened cone

conformation17 obtained is shown in Figure 4. According to semiclassical model of anisotropy effect calculations18 performed for the open flattened cone conformer (MM optimized geometry), the protons H-10 0 , H-12 0 , H-11 0 of unsubstituted aromatic rings are indeed shielded if compared with benzene protons (0.74 and 0.66 ppm, respectively) by the substituted aromatic rings while the H-4 0 and H-6 0 protons are slightly deshielded (0.2 ppm). This is in a good agreement with the experimental data. The OCH2 fragments of the propoxy groups attached to the unsubstituted aromatic rings of 8 give rise to a clear and simple triplet (dZ3.64), while the analogous protons belonging to the other propoxy groups at dZ3.98 are slightly split and appear as a doublet of doublets with JZ8.1, 8.4 Hz, implying the non-equivalence of the geminal protons. Our computations are in good agreement with these experimental data. In fact, the minimized open flattened cone structure of calix[4]arene 8 (Fig. 4) shows that CAr–O–CH2– CH2–CH3 moieties have different preferred conformations, namely anti,anti for moieties attached to unsubstituted aromatic rings and gauche,anti for moieties attached to aromatic rings functionalized with isosteviol fragments.

3. Conclusions In conclusion, we have reported an efficient and easy synthetic procedure to introduce isosteviol moieties both at the lower and upper rims of calix[6]- or calix[4]arenes. Also thanks to the complete assignment of the 1H and 13C NMR

Figure 4. The open flattened cone conformation of functionalized calix[4]arene 8 in vacuo simulated by MM; hydrogen atoms are omitted.

Figure 3. Diagnostic HMBC (a) and 2D NOESY correlations (b) for difunctionalized calyx[4]arene. 8. Numbering of calixarene atoms according to Ref. 17, the apex prime notation being used to distinguish calixarene carbon atoms from isosteviol ones.

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spectra of isosteviol 2, which was obtained for the first time, it was also possible to assign all the 1H and 13C NMR signals in the spectra of the isosteviol-calixarene conjugates. A detailed conformational analysis of the disubstituted calix[4]arene 8 both in solution and in silico has been also carried out. We are currently investigating the potential of this class of neo-conjugates in the recognition of saccharides and organic anions of biological interest together with their capability to form artificial ion channels and act as transmembrane ionophores. 4. Experimental 4.1. Materials and methods Most of the solvents and all reagents were commercial and used without further purification. All dry solvents were prepared according to standard procedures and stored over molecular sieves. 1H NMR and 13C NMR spectra were recorded on Bruker AC 300, Bruker MSL 400 and Avance 600 spectrometers. NMR experiments on Avance 600 spectrometer were performed in dilute CDCl3 solutions at 303 K, the spectrometer being equipped with a 5 mm diameter broad band inverse probehead working at 600.13 MHz in 1H and 150.86 MHz in 13C experiments. Chemical shifts were referenced to the residual signal of CDCl3. Complete assignments of the 1H and 13C NMR spectra of the title compounds were accomplished by 2D COSY, HSQC, HMBC and NOESY experiments. In some cases 1D DPFGNOE method was used to measure NOE’s. Mass spectra by electrospray ionization (ESI) were recorded on a Micromass ZMD. Analytical TLC was performed using Merck prepared plates (silica gel 60 F-254 on aluminum). Merck silica gel (40–60 mm) was used for flash chromatography. 5,17-Diamino-25,26,27,28-tetra-n-propyloxycalix [4]arene (6) and 5,11,17,23-tetraamino-25,26,27,28-tetran-propyloxycalix[4]arene (7) were synthesized according to literature procedures.19,20 Calix[6]arene fuctionalized with six n-propyloxy moieties at lower rim was synthesized according to Ref. 21. Molecular mechanics (employing the MM2 force field16) were performed with CS Chem3D Ultra 6.0 (CambridgeSoft Corp.) on a AuthenticAMD Athlon (Im)computer. Ab initio electronic structure calculations were performed using GAUSSIAN 98.14 4.1.1. Isostevioyl chloride (3). A mixture of isosteviol 2 (0.5 g, 1.57 mmol) and freshly distilled thionyl chloride (0.5 ml, 2.5 mmol) was refluxed for 1 h. The unreacted excess of thionyl chloride was removed at reduced pressure. The residue was recrystallized from hexane to give 3 (yield 0.41 g, 77%). Mp 143–145 8C. IR-spectrum (mineral oil, n/cmK1): 1740 (C]O, ketone), 1800 (ClC]O). 1H NMR (400 MHz, CDCl3): d 0.81 (s, 3H, 20-H3), 0.97 (s, 3H, 17-H3), 1.35 (s, 3H, 18-H3), 0.90–1.90 (m, 18H, 1H2, 2H2, 3-Hax, 5-H, 6-H2, 7-H2, 9-H, 11-H2, 12-H2, 14-H2, 15-Hb), 2.35 (d, 1H, 3-Heq, JZ14.3 Hz), 2.63 (dd, 1H, 15-Ha, JZ 18.8, 3.9 Hz). Found (%): Cl, 9.93. Calcd for C20H29ClO2 (%): Cl, 10.52. 4.1.2. Synthesis of 37 0 ,38 0 ,39 0 ,40 0 ,41 0 ,42 0 -hexakis(isostevioylamido)-propyloxycalix[6]arene (5). A solution of calix[6]arene 4 (0.05 g, 0.07 mmol) in 1.5 ml of dry CH2Cl2

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and DIPEA (0.054 ml, 0.3 mmol) was added to the solution of isostevioyl chloride 3 (0.1 g, 0.3 mmol) in 5 ml of dry CH2Cl2. The reaction mixture was heated with stirring in a sealed tube at 80 8C for 48 h. The solvent was removed on rotary evaporator. The residue was purified by column chromatography (hexane/ethyl acetate 5:2). Yield 48%. Mp 208–210 8C. 1H NMR (300 MHz, [D6]DMSO, 363 K): d 0.73 (s, 18H, 20-H3), 0.91 (s, 18H, 17-H3), 1.11 (s, 18H, 18-H3), 0.92–1.90 (m, 120H, 1H2, 2H2, 3-Hax, 5-H, 6-H2, 7-H2, 9-H, 11-H2, 12-H2, 14-H2, 15-Hb, OCH2CH2CH2), 2.10 (d, 6H, 3-Heq, JZ14.1 Hz), 2.42 (d, 6H, 15-Ha, JZ 16.2 Hz), 3.42 (s, 12H, CH2NH), 3.79 (s, 12H, CH2O), 3.90 (s, 12H, ArCH2Ar ax), 6.74 (t, 6H, ArHpara, JZ7.8 Hz), 6.85 (d, 12H, JZ7.8 Hz, ArHmeta). 13C NMR (CDCl3): d 222.4 (C-16), 176.8 (C-19), 154.3 (Ar-ipso), 134.6 (Arortho), 128.9 (Ar-para), 124.1 (Ar-meta), 70.9 (OCH2CH2CH2–), 57.7 (C-5), 54.8 (C-9), 54.3 (C-14), 48.8 (C-8), 48.2 (C-15), 43.8 (C-4), 41.8 (C-7), 40.3 (C-1), 39.5 (C-13), 38.2 (C-10), 38.1 (C-3), 37.4 (C-12 and OCH2CH2CH2–), 30.4 (OCH2CH2CH2–), 30.3 (C-18), 29.7 (ArCH2Ar), 22.3 (C-6), 20.4 (C-11), 19.9 (C-17), 19.3 (C-2), 13.8 (C-20). MS (ESI, CH3OH) m/z: 2802 [MCNa]C. C180H246N6O18 (2781.98). 4.1.3. 5 0 ,17 0 -Bis(isostevioylamido)-25 0 ,26 0 ,27 0 ,28 0 -tetra-npropyloxycalix[4]arene (8). Isostevioyl chloride (3) (0.42 g, 1.2 mmol) and compound 6 (0.3 g, 0.48 mmol) were dissolved in dry CH2Cl2 (10 ml) and DIPEA (0.2 ml, 1.2 mmol) was added. The reaction mixture was heated with stirring in a sealed tube at 80 8C for 48 h. The solvent was evaporated and the residue purified by column chromatography (hexane/ethyl acetate 5:2) to give 0.21 g (37%) of 8. Mp 0210–220 8C. 1H NMR0 (600 MHz, CDCl3): d 0.86 (t, 6H, 0.89 C26 OCH2CH2CH3, C28 OCH2CH2CH3, JZ7.4 Hz), 0 (s, 6H, 20-H3),0 0.98 (s, 6H, 17-H3), 1.08 (t, 6H, C25 OCH2CH2CH3, C27 OCH2CH2CH (s, 6H, 3, JZ7.4 Hz), 1.35 0 0 18-H3), 1.86 (m, 4H, C25 OCH2CH2CH3, C27 OCH2CH2CH3), 0.90–1.90 (m, 34H, 1H2, 2H2, 3-Hax, 5-H, 6-Hax, , 14-H2, 15-Hb), 1.95 (m, 4H, 7-H02, 9-H, 11-H2, 12-H 0 2 C26 OCH2CH2CH3, C28 OCH2CH2CH3), 2.08 (d, 2H, 6-Heq, JZ13.0 Hz), 2.21 (d, 2H, 3-Heq, JZ14.0 Hz), 2.69 (dd, 2H, 4H, ArCH2Ar eq, JZ 15-Ha, JZ18.8, 3.6 Hz), 3.10 (2d, 0 27 0 , C OCH 13.3, 13.3 Hz), 3.64 (t, 4H, C25 OCH2CH2CH 3 20 CH20 CH3, JZ6.6 Hz), 3.98 (dd, 4H, C26 OCH2CH2CH3, C28 OCH2CH2CH3, JZ8.1, 8.4 Hz), 4.41 (d, 4H, ArCH2Ar ax, JZ13.3 Hz), 6.17 (d, 4H, ArH-10 0 ,12 0 , ArH-24 0 ,22 0 , JZ 7.8 Hz), 6.25 (t, 2H, ArH-11 0 , ArH-23 0 , JZ7.6 Hz), 7.16 (d, 2H, ArH-6 0 , ArH-16 0 , JZ2.6 Hz), 7.21 (d, 2H, ArH-4 0 , ArH-18 0 , JZ2.6 Hz), 7.24 (s, 2H, NH). 13C NMR (CDCl3): d 222.1 (C-16), 174.7 (C-19), 155.2 (Ar-ipso: C-25 0 , C-27 0 ), 154.9 (Ar-ipso: C-26 0 , C-28 0 ), 137.9 (Ar-ortho: C-3 0 , C-7 0 , C-15 0 , C-19 0 ), 132.9 (Ar-ortho: C-1 0 , C-9 0 , C-13 0 , C-21 0 ), 131.4 (Ar-para: C-5 0 , C-17 0 ), 127.4 (Ar-meta: C-10 0 , C-12 0 , 0 ), 121.2 (ArC-22 0 , C-24 0 ), 122.1 (Ar-para: C-11 0 , C-23 25 0 0 0 0 0 , C-6 , C-16 , C-18 ), 77.0 (C OCH CH3, meta: C-4 2CH 0 0 0 2 C27 OCH2CH2CH3), 76.5 (C26 OCH2CH2CH3, C28 OCH2CH2CH3), 57.9 (C-5), 54.9 (C-9), 54.3 (C-14), 48.7 (C-15), 48.4 (C-8), 44.6 (C-4), 41.8 (C-7), 40.2 (C-1), 39.6 (C-13), 38.4 (C-10), 38.2 0 (C-3), 37.3 (C-12), 31.1 (ArCH2Ar), 30.1 25 27 0 OCH CH CH , C OCH (C-18), 23.5 (C 2 2 3 2CH2CH3), 22.9 0 0 20.4 (C26 OCH2CH2CH3, C28 OCH2CH2CH3), 22.4 (C-6), 0 (C-11), 19.8 (C-17), 19.1 (C-2), 13.8 (C-20), 10.8 (C25 OCH20 0 CH2CH3, C27 OCH2CH2CH3), 9.7 (C26 OCH2CH2CH3,

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0

C28 OCH2CH2CH3). MS (ESI, CH3OH) m/z: 1246.1 [MC Na]C. C80H106N2O8 (1223.74). 4.1.4. 5 0 ,11 0 ,17 0 ,23 0 -Tetrakis(isostevioylamido)-25 0 ,26 0 , 27 0 ,28 0 -tetra-n-propyloxycalix[4]arene (9). Compound (9) was synthesized by the same procedure used for (5) from isostevioyl chloride (3) and calix[4]arene (7). The crude residue was purified by silica gel column chromatography eluting with a mixture of hexane and ethyl acetate with successive increases of ethyl acetate and affording the corresponding product 9 as white solid. Yield: 0.076 g (54%). Mp 140–145 8C. 1H NMR (600 MHz, CDCl3): d 0.76 (s, 12H, 20-H3), 0.96 (s, 12H, 17-H3), 1.00 (t, 12H, OCH2CH2CH3, JZ5.7 Hz), 1.23 (s, 12H, 18-H3), 1.67 (m, 8H, OCH2CH2CH3), 0.90–1.90 (m, 72H, 1H2, 2H2, 3-Hax, 5-H, 6-H2, 7-H2, 9-H, 11-H2, 12-H2, 14-H2, 15-Hb), 2.08 (d, 4H, 3-Heq, JZ16.2 Hz), 2.61 (dd, 4H, 15-Ha, JZ18.6, 3.3 Hz), 3.16 (d, 4H, ArCH2Ar eq, JZ12.9 Hz), 3.83 (t, 8H, OCH2CH2CH3, JZ7.6 Hz), 4.41 (d, 4H, ArCH2Ar ax, JZ 12.9 Hz), 6.75 (d, 4H, ArH, JZ2.4 Hz), 6.86 (d, 4H, ArH, JZ2.4 Hz), 7.21 (s, 4H, NH). 13C NMR (CDCl3): d 219.4 (C-16), 175.2 (C-19), 153.5 (Ar-ipso), 134.9 (Ar-ortho), 131.4 (Ar-para), 122.3 (Ar-meta), 77.0 (OCH2CH2CH3), 57.7 (C-5), 54.6 (C-9), 54.2 (C-14), 48.6 (C-15), 48.2 (C-8), 44.1 (C-4), 41.6 (C-7), 40.1 (C-1), 39.4 (C-13), 38.0 (C-10), 37.9 (C-3), 37.2 (C-12), 31.0 (ArCH2Ar), 30.0 (C-18), 23.0 (OCH2CH2CH3), 22.2 (C-6), 20.3 (C-11), 19.8 (C-17), 19.1 (C-2), 13.7 (C-20), 10.2 (OCH2CH2CH3). MS (ESI, CH 3OH) m/z: 1876.9 [MCNa] C. C120H 164 N4 O 12 (1854.65).

4. 5.

6.

7.

8.

Acknowledgements This work was supported by project no. 8 in the framework of the Agreement of cooperation between CNR (Italy) and Russian Academy of Science as well as by the grant of Russian Foundation for Basic Research no. 04-03-32133 and by FIRB (Project RBNE019H9K Manipolazione molecolare per macchine nanometriche). The CIM of the University of Parma is also acknowledged.

9.

References and notes 1. (a) Calixarenes in action; Mandolini, L., Ungaro, R., Eds.; Imperial College: London, 2000. (b) Calixarenes 2001; Asfari, Z., Bo˝hmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer Academic: Dordrecht, 2001. 2. (a) Casnati, A.; Ungaro, R., Calixarenes in spherical metal ion recognition. In Calixarenes in action; in Ref. 1a; pp 62–84. (b) Casnati, A.; Sansone, F.; Ungaro, R. In Calixarene receptors in ion recognition and sensing; Gokel, G. W., Ed.; Advances in supramolecular chemistry; Cerberus: Miami, 2003; Vol. 9, pp 165–218. 3. (a) Sansone, F.; Barboso, S.; Casnati, A.; Fabbi, F.; Pochini, A.; Ugozzoli, F.; Ungaro, R. Eur. J. Org. Chem. 1998, 897–905. (b) Lazzarotto, M.; Sansone, F.; Baldini, L.; Casnati, A.; Cozzini, P.; Ungaro, R. Eur. J. Org. Chem. 2001, 595–602. (c) Sansone, F.; Baldini, L.; Casnati, A.; Lazzarotto, M.; Ugozzoli, F.; Ungaro, R. Proc. Nat. Acad. Sci. U.S.A. 2002, 99,

10.

11.

12.

4847–4872. (d) Casnati, A.; Sansone, F.; Ungaro, R. Acc. Chem. Res. 2003, 4, 246–254. (e) Segura, M.; Sansone, S.; Bricoli, B.; Mun˜oz, E.; Vicent, C.; Casnati, A.; Ungaro, R. J. Org. Chem. 2003, 68, 6296–6303. (f) Sansone, F.; Chierici, E.; Casnati, A.; Ungaro, R. Org. Biomol. Chem. 2003, 1, 1802–1809. (g) Scha¨del, U.; Sansone, F.; Casnati, A.; Ungaro, R. Tetrahedron 2005, 61, 1149–1154. (h) Roy, M.; Kim, J. M. Angew. Chem., Int. Ed. 1999, 38, 369–372. (i) Yoshino, N.; Satake, A.; Kobuke, Y. Angew. Chem., Int. Ed. Engl. 2001, 40, 457–459. (j) Dukh, M.; Drasar, P.; Cerny, I.; Pouzar, V.; Shriver, J. A.; Kral, V.; Sessler, J. L. Supramol. Chem. 2002, 14, 237–244. (k) Maulucci, N.; De Riccardis, F.; Botta, C. B.; Casapullo, A.; Cressina, E.; Fregonese, M.; Tecilla, P.; Izzo, I. Chem. Commun. 2005, 1354–1356. Hanson, J. R. The tetracyclic diterpenes; Pergamon: Oxford, 1968; p 132. (a) Avent, A. G.; Hanson, J. R.; de Oliveira, B. H. Phytochemistry 1990, 29, 2712–2715.(b) It now appears clear that the NOE experiments performed in Ref. 5a are partly incorrect. In fact, when irradiating the methyl signal at dZ0.98 (17-H3), the 3-Hax (1.04 ppm) and 1-Hax (0.926 ppm) protons are also irradiated. This led to a NOE at 3-Heq (2.18) due to 3-Hax and not to 17-H3. (a) Nanayakkara, N. P. D.; Klocke, J. A.; Compadre, C. M.; Hussain, R. A.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 1987, 50, 434–441. (b) Costa, S.; Alvarez, M. Arq. Biol. Tecnol. 1994, 37, 1013–1017. (a) de Oliveira, B. H.; Strapasson, R. A. Phytochemistry 1996, 43, 393–395. (b) de Oliveira, B. H.; dos Santos, M. C.; Leal, P. C. Phytochemistry 1999, 51, 737–741. (a) Mosettig, E.; Nes, W. R. J. Org. Chem. 1955, 20, 884–899. (b) Mosettig, E.; Beglinger, U.; Dolder, F.; Lichti, H.; Quitt, P.; Waters, J. A. J. Am. Chem. Soc. 1963, 85, 2305–2309. (c) Coates, R. M.; Bertram, E. F. J. Org. Chem. 1971, 36, 2625–2631. (d) Hershenhorn, J.; Zohar, M.; Crammer, B.; Ziv, Z.; Weinstein, V.; Kleifeld, Y.; Lavan, Y.; Ikan, R. Plant Growth Reg. 1997, 23, 173–178. (a) Alfonsov, V. A.; Bakaleynik, G. A.; Gubaidullin, A. T.; Kataev, V. E.; Kovyljaeva, G. I.; Konovalov, A. I.; Litvinov, I. A.; Strobykina, I. Yu.; Andreeva, O. V.; Korochkina, M. G. Mendeleev Commun. 2000, 5, 177–178. (b) Alfonsov, V. A.; Andreeva, O. V.; Bakaleynik, G. A.; Beskrovny, D. V.; Kataev, V. E.; Kovyljaeva, G. I.; Litvinov, I. A.; Militsina, O. I.; Strobykina, I. Yu. Mendeleev Commun. 2003, 13, 234–235. (c) Alfonsov, V. A.; Andreeva, O. V.; Bakaleynik, G. A.; Beskrovny, D. V.; Gubaidullin, A. T.; Kataev, V. E.; Kovyljaeva, G. I.; Konovalov, A. I.; Korochkina, M. G.; Latypov, Sh. K.; Litvinov, I. A.; Musin, R. Z.; Strobykina, I. Yu. Zh. Obsch. Khim. 2003, 73, 1186–1197. (Russ). Militsina, O. I.; Strobykina, I. Yu.; Kataev, V. E.; Alfonsov, V. A.; Fedorova, O. V.; Ovchinnikova, I. G.; Rusinov, G. L. Mendeleev Commun. 2005, in press. (a) Alfonsof, V. A.; Bakaleynik, G. A.; Gubaidullin, A. T.; Kataev, V. E.; Kovyljaeva, G. I.; Konovalov, A. I.; Litvinov, I. A.; Strobykina, I. Ju.; Andreeva, O. V.; Korochkina, M. G. Mendeleev Commun. 1999, 6, 227–228. (b) Alfonsov, V. A.; Andreeva, O. V.; Bakaleynik, G. A.; Beskrovny, D. V.; Gubaidullin, A. T.; Kataev, V. E.; Kovyljaeva, G. I.; Konovalov, A. I.; Korochkina, M. G.; Litvinov, I. A.; Strobykina, I. Yu.; Musin, R. Z. Zh. Obsch. Khim. 2003, 73, 1323–1329. (Russ). Avent, A. G.; Hanson, J. R.; Hitchock, P. B.; de Oliveira, B. H. J. Chem. Soc., Perkin Trans. 1 1990, 2661–2665.

M. Korochkina et al. / Tetrahedron 61 (2005) 5457–5463

13. (a) de Dios, A. C. Progr. Nucl. Magn. Res. 1996, 29, 229–278. (b) Gomila, R. M.; Quinonero, D.; Rotger, C.; Garau, C.; Frontera, A.; Ballester, P.; Costa, A.; Deya, P. M. Org. Lett. 2002, 4, 399–401. (c) Kozlowski, P. M.; Wolinski, K.; Pulay, P.; Ye, B.-H.; Li, X.-Y. J. Phys. Chem. A 1999, 103, 420–425. 14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P.M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople J. A., Gaussian 98 (Revision A.3), Gaussian, Pittsburgh PA, 1998.

5463

15. (a) Alfonsov, V. A.; Bakaleynik, G. A.; Gubaidullin, A. T.; Kataev, V. E.; Kovyljaeva, G. I.; Konovalov, A. I.; Litvinov, I. A.; Strobykina, I. Ju. Zh. Obshch. Khim. 1998, 68, 1813–1821. Russ. J. Gen. Chem. 1998, 68, 1735–1743. (Engl. Transl.). 16. Burkert, U.; Allinger, N. Molecular mechanics In ACS Monograph 177; American Chemical Society: Washington, DC, 1982. 17. Gutsche, C. D. In Calixarenes revisited. Monographs in supramolecular chemistry; Stoddart, J. F., Ed.; RSC: London, 1998. 18. Haigh, C. W.; Mallion, R. B. In Progress in NMR spectroscopy, Vol. 13; Pergamon: New York, 1980; pp 303–344. 19. van Wagenigen, A. M. A.; Snip, E.; Verboom, W.; Reinhoudt, D. N.; Boerrigter, H. Liebigs Ann./Recueil 1997, 2235–2245. 20. Timmerman, P.; Boerrigter, H.; Verboom, W.; Reinhoudt, D. N. Recl. Trav. Chim. Pays-Bas 1995, 114, 103–111. 21. Casnati, A.; Della Ca’, N.; Fontanella, M.; Sansone, F.; Ugozzoli, F.; Ungaro, R.; Liger, K.; Dozol, J. -F Eur. J. Org. Chem. 2005, in press.