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INTRODUCTION
Methyl β-orcinolcarboxylate (1) and atranorin (2) (Fig. 1) are important natural products isolated from Bolivian Lichens. Atranorin has been characterized in Stereocaulon strictum1 Stereocaulon ramulosum2, Stereocaulon tomentosum3, Physcia sorediosa4; methyl β-orcinolcarboxylate is present in Stereocaulon ramulosum2. These compounds are reknown for manifesting a wide variety of biological activities, including antioxidant, antibacterial, anticancer, and antiangiogenic5),(6),(7),(8),(9),(10),(11),(12),(13),(14 among others. The growing interest in these compounds and their potential use in medical applications is evidenced by the increasing number of publications. Hence, correct structural determination and knowledge about the three-dimensional (3D) atomic structure are essential. NMR experimental data are employed in comparison with electronic and conformational properties of methyl β-orcinolcarboxylate and atranorin resulting from theoretical calculations. In the present comparative study of methyl β-orcinolcarboxylate and atranorin, precise quantum mechanical calculations were carried out, both in vacuo, with the aim of analyzing the conformational equilibria and finding the most stable corresponding equilibrium of the structures. This work is framed in a project that started with the computer-assisted study of 1H and 13C NMR spectra of 4-hydroxy-3-(3’-methyl-2’-butenyl)acetophenone isolated from Senecio graveolens and its microwave-assisted synthetic derivate, 4’-hydroxy-3’-(3-methyl-2-butenyl)chalcone15.
EXPERIMENTAL
NMR system and operating conditions
Spectra were run at 400 MHz and 125.77 MHz for 1H and 13C NMR, respectively, using CDCl3 as solvent. NMR assignments were done based on 1H, 13C 1D NMR and 1H-13C HSQC and HMBC 2D NMR experiments.
Compound (1), White crystals; m.p. 140 oC; 1H NMR (CDCl3), (400 MHz); δ 3.9 (3H, s, H-10), 2.4 (3H, s , H-8), 2.1 (3H, s, H-9), 6.2 (1H, s, H-5). 13C NMR (CDCl3), (125.77 MHz);δ 172.6, 162.6, 159.5, 139.8, 110.6, 108.9, 104.9, 51.5, 23.8, 7.5.
Compound (2), White crystals; m.p. 140 C; 1H NMR (CDCl3), (400 MHz); δ 6.44 (1H, s, H-5), 6.56 (1H, s, H-5’), 2.71 (3H, s, H-8), 10.39 (1H, s, H-9), 2.11 (3H, s, H-8’), 2.59 (3H, s, H-9’), 4.05 (3H, s, CH3O-7’), 12.53 (1H, s, OH), 12.59 (1H, s, OH). 13C NMR (CDCl3), (125.77 MHz);δ 103.8, 169.3, 108.8, 167.7, 113.1, 152.6, 169.9, 25.7, 194.0, 117.0, 163.1, 110.5, 152.2, 116.2, 140.1, 172.4, 24.2, 9.6, 52.5.
Computational details
The geometry of structures was optimized with the DFT methodology using 13C NMR chemical shifts of the compounds. In (1) each geometrically optimized conformer was calculated using the parameter B3LYP/631G* basis sets. The calculations for (2) were carried out in the same way as for (1). Molecular mechanics calculations were performed using the Spartan 18 modeling software. Solvent effects were not taken into account in any calculation. From X-ray crystallography data16),(17 the existence of compounds (1) and (2) in their solid state was known. In the present work we investigated all possible conformers of methyl δ-orcellinate and atranorin in order to establish a reliable starting point to further theoretically explore the complexing ability of these compounds.
RESULTS AND DISCUSSION
From X-ray crystallography data16),(17 a randomized conformational search of the methyl β-orcinolcarboxylate and atranorin was performed. The 8 more significant conformations of methyl β-orcinolcarboxylate and its 13C NMR chemical shifts were saved (Fig. 2). Figures 3 and 4 show that the two most significant conformers of methyl β-orcinolcarboxylate, have the intramolecular hydrogen bond between the 2-OH and 7-C=O. They also show the two conformer differences in the 4-OH positions. Conformer I (Fig. 2) exhibits the dihedral angle of 179.24 and in conformer II the angle is 0.26 (Fig. 3). Table 1 shows the calculated (δcalc) and experimental (δexp) 13C-NMR, 1H-NMR chemical shifts. Data comparison showed agreement between experimental and calculated NMR chemical shifts to an acceptable degree for conformer II. The comparison with image derived from X-ray analysis16 (Fig.5) ratifies the spectral and calculated data (C10H12O4, M r = 196.2, Monoclinic, P21/c, a = 7.043 (2) Å, b = 18.142 (7) Å, c = 7.238 (2) Å, β = 96.44 (2)°, V = 918.9 (4) ų, Z = 4) 16. The results presented in table 1 and 2 demonstrate an excellent predictive ability of this method for 1H and 13C NMR.
Fig. 4. Conformer II
Fig. 5. X-ray crystallography15
Table 1 Experimental and calculated 13C-NMR chemical shifts, CDCl3,δ from TMS, conformers I and II, compound 1
Atranorin (2) being a more complex molecule than compound 1, 128 conformers (at least) can be determined out of calculations using our current-use method. Thus, the fully optimized structure of atranorin was obtained at the B3LYP/6-31G* level. Two conformers were picked out and saved, 13C-NMR and 1H-NMR chemical shifts were scaled.
Table 2 The experimental and calculated 1H-NMR chemical shifts,CDCl3,δ from TMS, conformers I and II, compound 1
Tables 3 and 4 show the calculated (δcalc) and experimental (δexp) 13C-NMR and 1H-NMR chemical shifts of compound 2, respectively. The data comparison demonstrated a great agreement between experimental and calculated NMR chemical shifts for conformers A (Fig. 6) and B (Fig. 7). On the other hand, the comparison of X-ray crystallography structure of Fig. 8,17 (C19H18O8, M r = 374.33 Monoclinic, P21/n, a = 10.929 (3) Å, b = 10.976 (3) Å, c= 14.843 (3) Å, β = 109.745 (12) , V= 1675.7 (7) ų, Z=4)17 with both conformers shows a good matching with conformer B . These results (Tables 3 and 4) demonstrate an excellent predictive ability of the method for 1H and 13C NMR data.
The two aromatic rings form a dihedral angle of 60.38, differing from the previously reported Pbca polymorph, viz. 84 .5 In this work we calculated at the B3LYP/6-31G* two conformers A and B with the two aromatic rings forming a dihedral angle of 86.95 , different from the reported by X-ray crystallography. Nevertheless there is good agreement with the experimental values of NMR 1H and 13C.
Data statistical approach
Plotting the experimental 13C NMR (δexp) in CHCl3 vs. the δcalc for all species, a linear regression is obtained. This relationship is used to predict the chemical shifts (δcalc).
Table 3 The experimental and calculated 13C-NMR chemical shifts, CDCl3, δ from TMS, compound A and B
Table 4 The experimental and calculated 1H-NMR chemical shifts,CDCl3, δ from TMS, conformers A and B
The correlation between experimental chemical shifts and calculated isotropic screening constants for 13C, shows a homogeneous behavior for 13C independently on the calculated species with a correlation coefficient R2 0.9974 for methyl β-orcinolcarboxylate (Fig. 9) and 0.9966 for atranorin (Fig. 10).
Fig. 9 Experimental chemical shifts of methyl β-orcinolcarboxylate vs. isotropic magnetic from /B3LYP/6-31G* calculations for 13C
CONCLUSION
The experimental geometric parameters of the compound are comparable to the calculated values. The molecular structure was established by the evidence of short intra-molecular contact interactions. The 1H and 13C NMR chemical shifts calculations showed an excellent agreement with the experimental data. Overall, the agreement between theoretical and experimental values is agreeable for every structural and spectroscopic calculation. From X-ray bibliography we established the more stable conformers of 1 and 2, II and B, respectively.
