Detailed <sup>1</sup>H and <sup>13</sup>C NMR Spectral Data Assignment for Two Dihydrobenzofuran Neolignans

Medeiros, Talita C. T.; Dias, Herbert J.; Silva, Eliane O.; Fukui, Murilo J.; Soares, Ana Carolina F.; Kar, Tapas; Heleno, Vladimir C. G.; Donate, Paulo M.; Parreira, Renato L. T.; Crotti, Antônio E. M.

doi:10.5935/0103-5053.20150262

Abstract

In this work we present a complete proton (1H) and carbon 13 (¹³C) nuclear magnetic resonance (NMR) spectral analysis of two synthetic dihydrofuran neolignans (±)-trans-dehydrodicoumarate dimethyl ester and (±)-trans-dehydrodiferulate dimethyl ester. Unequivocal assignments were achieved by ¹H NMR, proton decoupled ¹³C (¹³C{¹H}) NMR spectra, gradient-selected correlation spectroscopy (gCOSY), J-resolved, gradient-selected heteronuclear multiple quantum coherence (gHMQC), gradient-selected heteronuclear multiple bond coherence (gHMBC) and nuclear Overhauser effect spectroscopy (NOESY) experiments. All hydrogen coupling constants were measured, clarifying all the hydrogen signals multiplicities. Computational methods were also used to simulate the ¹H and ¹³C chemical shifts and showed good agreement with the trans configuration of the substituents at C₇ and C₈.

Keywords:
neolignans; oxidative coupling; J-resolved; benzofurans

Introduction

Neolignans (NL) are a class of plant-derived natural products which are produced from shikimic acid pathway.¹1 Gottlieb, O. R.; Mem. Inst. Oswaldo Cruz1991, 86, 25. They differ from related lignans by the way the two C₆C₃ units are joined by other bonds. According to the International Union of Pure and Applied Chemistry (IUPAC) recommendations, the term lignan refers to structures where the two C₆C₃ units are β,β' (8-8') linked, whereas the term neolignan must be used for compounds that originate from coupling other than 8-8' coupling.²2 Moss, G. P.; Pure Appl. Chem.2000, 72, 1493.

Among NL, compounds exhibiting a dihydrobenzofuran moiety as structure feature have attracted special attention because their wide range of biological activities, such as antioxidant,³3 Huang, X. X.; Zhou, C. C.; Li, L. Z.; Peng, Y.; Lou, L. L.; Liu, S.; Li, D. M.; Ikejima, T.; Song, S. J.; Fitoterapia2013, 91, 217. antitumor,⁴4 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475. anti-inflammatory,⁵5 Cho, J. Y.; Baik, K. U.; Yoo, E. S.; Yoshikawa, K.; Park, M. H.; J. Nat. Prod.2000, 63, 1205. antileishmanial,⁶6 Cabral, M. M. O.; Barbosa-Filho, J. M.; Maia, G. L. A.; Chaves, M. C. O.; Braga, M. V.; de Souza, W.; Soares, R. O. A.; Exp. Parasitol.2010, 124, 319. trypanocidal,⁷7 Cabral, M. M. O.; Azambuja, P.; Gottlieb, O. R.; Garcia, E. S.; Parasitol. Res.1999, 85, 184.^,⁸8 Cabral, M. M. O.; Azambuja, P.; Gottlieb, O. R.; Kleffmann, T.; Garcia, E. S.; Schaub, G. A.; Parasitol. Res.2001, 87, 730. insecticidal⁹9 Chauret, D. C.; Bernard, C. B.; Arnason, J. T.; Durst, T.; Krishnamurty, H. G.; Sanchez-Vindas, P.; Moreno, N.; San Roman, L.; Poveda, L.; J. Agr. Food Chem.1996, 59, 152. and cytotoxic.³3 Huang, X. X.; Zhou, C. C.; Li, L. Z.; Peng, Y.; Lou, L. L.; Liu, S.; Li, D. M.; Ikejima, T.; Song, S. J.; Fitoterapia2013, 91, 217. Because of these biological activities, several synthetic methodologies have been proposed to build the basic skeleton of dihydrobenzofuran neolignans (DBNL).¹⁰10 Quideuau, S.; Ralph, J.; Holzforschung1994, 48, 12.

11 Li, Q.-B.; Hu, X.-C.; Chem. Lett.2012, 41, 1633.^-¹²12 Kao, C.-L.; Chern, J.-W.; J. Org. Chem.2002, 67, 6772. However, the oxidative coupling of phenylpropanoids is so far the most commonly reported synthetic route to obtain DBNL, such as compounds (±)-trans-dehydrodicoumarate dimethyl ester (2a) and (±)-trans-dehydrodiferulate dimethyl ester (2b; Figure 1). Compound 2b is reported to have antileishmanial,¹³13 Van Miert, S.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.; Lemière, G.; Pieters, L.; Bioorgan. Med. Chem.2005, 13, 661. antiplasmodial,¹³13 Van Miert, S.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.; Lemière, G.; Pieters, L.; Bioorgan. Med. Chem.2005, 13, 661. cytotoxic,¹³13 Van Miert, S.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.; Lemière, G.; Pieters, L.; Bioorgan. Med. Chem.2005, 13, 661. antiangiogenic,¹⁴14 Apers, S.; Paper, D.; Bürgermeister, J.; Barnikova, S.; Van Dyck, S.; Lemière, G.; Vlietinck, A.; Pieters, L.; J. Nat. Prod.2002, 65, 718. antitumor,¹⁵15 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475. and antioxidant¹⁶16 Rakotondramanana, D. L. A.; Delomenède, M.; Baltas, M.; Duran, H.; Bedos-Belval, F.; Rasoanaivo, P.; Negre-Salvayre, A.; Gornitzka, H.; Bioorg. Med. Chem.2007, 15, 6018. activities. Despite of these biological activities, nuclear magnetic resonance (NMR) data found in literature for both compounds are generally incomplete and, in some cases, inaccurate.¹⁴14 Apers, S.; Paper, D.; Bürgermeister, J.; Barnikova, S.; Van Dyck, S.; Lemière, G.; Vlietinck, A.; Pieters, L.; J. Nat. Prod.2002, 65, 718.^,¹⁵15 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.^,¹⁷17 Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775.^,¹⁸18 Kuo, Y. H.; Wu, C.-H.; J. Nat. Prod.1996, 59, 625; Snider, S. A.; Kontes, F.; J. Am. Chem. Soc.2009, 131, 1745.

Figure 1
Structures of dihydrobenzofuran neolignans 2a and 2b.

Owing to our interest in the detailed NMR study of natural¹⁹19 Heleno, V. C. G.; Crotti, A. E. M.; Constantino, M. G.; Lopes, N. P.; Lopes, J. L. C.; Magn. Reson. Chem.2004, 42, 364.

20 Heleno, V. C. G.; Oliveira, K. T.; Lopes, J. L. C.; Lopes, N. P.; Ferreira, A. G.; Magn. Reson. Chem.2008, 46, 576.^-²¹21 Soares, A. C. F.; Silva, A. N.; Matos, P. N.; Silva, E. H.; Lopes, N. P.; Lopes, J. L. C.; Sass, D. C.; Heleno, V. C. G.; Quim. Nova2012, 35, 2205. and synthetic²²22 Silva, R.; Heleno, V. C. G.; Albuquerque, S.; Bastos, J. K.; Silva, M. L. A.; Donate, P. M.; Silva, G. V. J.; Magn. Reson. Chem.2004, 42, 985.

23 Constantino, M. G.; Silva-Filho, L. C.; Cunha Neto, A.; Heleno, V. C. G.; Silva, G. V. J.; Lopes, J. L. C.; Spectrochim. Acta A2005, 61, 171.

24 Heleno, V. C. G.; Silva, R.; Pedersoli, S.; Albuquerque, S.; Bastos, J. K.; Silva, M. L. A.; Donate, P. M.; Silva, G. V. J.; Lopes, J. L. C.; Spectrochim. Acta A2006, 63, 234.^-²⁵25 Blau, L.; Menegon, R. F.; Ferreira, E. I.; Ferreira, A. G.; Boffo, E. F.; Tavares, L. A.; Heleno, V. C. G.; Chung, M. C.; Molecules2008, 13, 841. compounds, in this study we have performed a thorough assignment of all proton (¹H) and carbon 13 (¹³C) NMR data for the synthetic dihydrobenzofuran neolignans 2a and 2b using one- (1D) and two-dimensional (2D) NMR techniques.

Results and Discussion

The (±)-trans-dehydrodicoumaroate dimethyl ester (2a) and (±)-trans-dehydrodiferulate dimethyl ester (2b) were synthesized according to previous reported procedure,¹⁵15 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.^,¹⁷17 Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775.^,²⁶26 Maeda, S.; Masuda, H.; Tokoroyama, T.; Chem. Pharm. Bull.1995, 43, 935. which was outlined in Scheme 1. The ¹H and ¹³C NMR data for these compounds were previously published¹⁴14 Apers, S.; Paper, D.; Bürgermeister, J.; Barnikova, S.; Van Dyck, S.; Lemière, G.; Vlietinck, A.; Pieters, L.; J. Nat. Prod.2002, 65, 718.^,¹⁵15 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.^,¹⁷17 Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775.^,¹⁸18 Kuo, Y. H.; Wu, C.-H.; J. Nat. Prod.1996, 59, 625; Snider, S. A.; Kontes, F.; J. Am. Chem. Soc.2009, 131, 1745. but presented some imprecisions that should be corrected.

Scheme 1
(i) Ag₂O, (CH₃)₂CO:C₆H₆ 3:5, r.t., 20 h (2a: 36% yield; 2b: 43% yield).

The main ¹H and ¹³C NMR data for (±)-trans-dehydrodicoumaroate dimethyl ester (2a) and (±)-trans-dehydrodiferulate dimethyl ester (2b) are presented in Tables 1 and 3. Two-dimensional NMR data (gradient-selected correlation spectroscopy, gCOSY; gradient-selected heteronuclear multiple quantum coherence, gHMQC; gradient-selected heteronuclear multiple bond coherence, gHMBC; and nuclear Overhauser effect spectroscopy, NOESY) for the same compounds are given in Tables 2 and 4, respectively. Firstly, the ¹H NMR spectra were analyzed in detail, which made it possible to verify all chemical shifts. Further analysis of ¹H NMR spectra led to the measurement of most homonuclear hydrogen coupling constants. Some J values were measured only in J-resolved spectrum and all couplings were confirmed by gCOSY experiments. Then, most signals of the proton decoupled ¹³C (¹³C{¹H}) NMR spectra were assigned through gHMQC and distortionless enhancement by polarization transfer (DEPT) 135 experiments. The assignment of non-hydrogenated carbons was carried out by the use of gHMBC information and by comparison with calculated spectra.

Thumbnail

Table 1
¹H and ¹³C NMR data assignments for compound 2a (400 MHz, CDCl₃)

Thumbnail

Table 2
2D NMR data for compound 2a (400 MHz, CDCl₃)

Thumbnail

Table 3
¹H and ¹³C NMR data assignments for compound 2b (400 MHz, acetone-d₆)

Thumbnail

Table 4
2D NMR data for compound 2b (400 MHz, acetone-d₆)

¹H and ¹³C NMR data previously reported for compound2a and 2b were obtained in CDCl₃ or acetone-d₆. Most of the signals in the ¹H NMR spectrum were between δ_H 6.0 and δ_H 8.0, but the hydrogen signal multiplicities are ambiguous. In this work, we found that for compound2a in acetone-d₆, the signals at δ_H 7.6-7.7 are referred to four hydrogen atoms and their overlapping precluded their correct assignment (Figure 2). Therefore, CDCl₃ provided much clearer spectra for 2a, but not for 2b, due to the solvent influence on chemical shifts. For compound 2b, three hydrogen atoms resonate at δ_H 6.91 in the ¹H HMR spectrum in CDCl₃. On the other hand, the ¹H NMR signals of 2b were resolved by using acetone-d₆ as solvent, which allowed verification of the multiplicities, observation of the chemical shifts and measurement of the coupling constants.

Figure 2
Expansions of the ¹H NMR spectrum of compounds 2a and 2b obtained in CDCl₃ and acetone-d₆.

The ¹H NMR (400 MHz, CDCl₃) of compound 2a (Table 1) showed resonances for one trans disubstituted double bond at δ_H 6.32 (d, 1H, J 15.9 Hz) and δ_H 7.66 (ddd, 1H, J 0.6, 1.1, 15.9 Hz). The smaller coupling constant values of the signal at δ_H 7.66 could be measured only in the J-resolved spectrum. Analysis of the ¹H-¹H COSY spectrum data (Table 2) revealed some long-range couplings (⁴J): H₇/H₂, H₇/H₆, H_7'/H_2', H_7'/H_6'. From ¹H NMR and ¹H-¹H COSY spectra it was possible to establish the spin systems corresponding to the C_3'/C_2'/C_6'/C₈ and C₂/C₃/C₅/C₆/C₇ portions of 2a.

Assignments of the carbonyl C₉ and C_9' and methoxy groups C₁₀ and C_10' are directly performed and those groups can clearly be differentiated on the basis of the gHMBC spectrum (Table 2). The gHMBC correlations are observed between δ_C at 170.9 and the signals at δ_H 4.27 (H₈), 6.09 (H₇), and 3.83 (s, 3H); therefore, the δ_C at 170.9 is attributed to C₉, and δ_H at 3.83 is assigned to H₁₀. On the other hand, gHMBC correlations between δ_C at 167.9 and the signals at δ_H 7.66 (H_7'), 7.55 (H_7') and 3.81 (s, 3H) allowed to assign the δ_C167.9 to C_9', and the δ_H 3.81 to H_10'. In addition, the δ_c 51.7 and δ_c 52.9 were assigned to C_10' and C₁₀, respectively, on the basis of the correlations observed in the gHMQC spectrum with δ_H 3.81 (H_10') and δ_H 3.83 (H₁₀). Finally, the non-hydrogenated sp²-hybridized carbons C_1' (127.8), C_4'(161.2) and C_5' (125.1) were unambiguously assigned to C_1', C_4' and C_5' on the basis of their long-range C−H correlations in the gHMBC spectrum with δ_H 6.32 (H_8'), 7.43 (H_2') and 6.09 (H₇), respectively. Similarly, the assignment of C₁ and C₄ to δ_C 132.0 and 156.1 was established on the basis of the correlations with δ_H 7.27 (H₂=H₆) and 6.84 (H₃=H₅), respectively. Considering that C₄ is expected to be unshielded when compared to C₁ due to the inductive effect of the oxygen hydroxyl, this corroborates the assignment.

The ¹H NMR (400 MHz, acetone-d₆) data of compound2b are shown in Table 3 and their 2D NMR data are compilated in Table 4.

The structure of compound 2b is related to the natural dimer 3',4-di-O-methylcedrusin, which is one of the active compounds in dragon's blood. This blood-red latex, produced by some Croton species growing in the South America, is employed in traditional medicine for wound-healing and anticancer properties.²⁷27 Daquino, C.; Rescifina, A.; Spatafora, C.; Tringali, C.; Eur. J. Org. Chem2009, 36, 6289. Lemièreet al.¹⁷17 Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775. have previously reported the synthesis of 3',4-di-O-methylcedrusin and other related neolignans, including compound 2b, and assigned the ¹³C NMR data of these compounds on the basis of DEPT experiments and long-range of heteronuclear correlation (HETCOR) correlations. In this work, we found that the ¹³C NMR data assignment based on DEPT, gHMQC and gHMBC were similar to that reported by Lemière et al.¹⁷17 Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775. and therefore, will not be discussed in details here. On the other hand, the ¹H NMR data of compound 2b available in the literature seems inaccurate. Multiplicities of the signals of the ¹H NMR spectrum of 2b are often reported as singlet (H₁₀, H_10', H₁₁ and H_11'), doublet (H₂, H₅, H₇, H₈, H_7' and H_8'), doublet of doublets (H₆) or broad singlet (H_2' and H_6') and have not been previously explored. In this work, ¹H-¹H COSY and 2D J-resolved spectra were used to understand the multiplicity and to measure the coupling constants.

As reported for compound 2a, analysis of the ¹H-¹H COSY spectrum of 2b (Table 4) revealed a long-range coupling (⁴J) of H_7' (ddd, 1H, δ_H 7.63) with H_2' (δ_H 7.33) and H_6' (δ_H 7.29). The coupling constant values J_7',6' and J_7',2' were measured in the J-resolved spectrum to be 0.8 Hz and 0.4 Hz, respectively. Similarly, the signal at H_2' (dd, δ_H 7.33) correlates with δ_H 7.29 (H_6', J_2',6' 2.6 Hz) and δ_H7.63 (H_7'). A long-range coupling (⁴J) between H_6' and H₈ was also deduced from the correlations between δ_H 7.29 (ddd, H_6') and 4.47 (dd, H_8', J_7',8 1.4 Hz) in the ¹H-¹H COSY spectrum. It was possible to establish the spin systems corresponding to the C_2'/C_6'/C_7'/C₈ and C₂/C₃/C₅/C₆/C₇ portions of 2b. The long-range coupling (⁴4 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.J) of both H₂ and H₆ with H₇ has not been previously reported in the literature. In this work, we could measure the scalar coupling constants J_2,7 and J_6,7 in the J-resolved spectrum as being 0.8 and 0.6 Hz, respectively.

The relative stereochemistry of the substituents at C₇ and C₈ in (±)-2a and (±)-2b, only the trans-(7R,8R) stereoisomers, are reported in Figure 1 and Scheme 1 was determined on the basis of the J_7,8 value and some theoretical calculations, all corroborated by nuclear Overhauser effect (NOE) data (Figure 3).

Figure 3
Main nuclear Overhauser effect (NOE) correlations observed in the nuclear Overhauser effect spectroscopy (NOESY) spectra of compounds 2a and 2b.

Firstly, a comparison of J_7,8 values for 2a and 2b with J values reported for other dihydrobenzofuran neolignans,²⁸28 Li, S. L.; Iliefski, T.; Lundquist, K.; Wallis, A. F. A.; Phytochemistry1997, 46, 929. showed a clear agreement with the trans configuration. It is well-established in the literature that the coupling constant J_7,8 in the skeleton of neolignans is higher for cis isomers (8.2-8.4 Hz) than for the trans isomer (6.5-7.3 Hz).²⁸28 Li, S. L.; Iliefski, T.; Lundquist, K.; Wallis, A. F. A.; Phytochemistry1997, 46, 929. Nevertheless, it has also been reported that conclusions on the relative stereochemistry in five membered rings based on J values for vicinal hydrogens cannot be so reliable for some compounds, as these hydrogens are susceptible to a great variety of dihedral angles and that cis or trans H−H coupling constants can be exactly the same.²⁹29 Constantino, M. G.; Lacerda-Júnior, V.; Silva, G. V. J.; Magn. Reson. Chem.2003, 41, 641. On the other hand, Muñoz and Joseph-Nathan³⁰30 Muñoz, M. A.; Joseph-Nathan, P.; Magn. Reson. Chem.2009, 47, 578. suggested that different stereoisomers might show rather large differences in their ¹³C chemical shifts, and that these differences can be used for the structural identification, reassignment and confirmation. Thus, we decided to use theoretical calculations of ¹H and ¹³C chemical shifts as an extra effort to elucidate the relative stereochemistry of 2a and 2b. We hence calculated the ¹H and ¹³C chemical shifts for trans-(7R,8R and 7S,8S) and cis-(7S,8R and 7R,8S) stereoisomers of compounds 2a and 2b and plotted these results in a cross-comparison to experimental values obtained for these compounds. In our case, each group of experimental data was compared to the group of cis and trans calculated data. The database that shows better agreement with experimental data should indicate which isomer we are dealing with. As an evaluation of this comparison, two main values were considered: the root mean square (rms) error and the coefficient of determination (R²), as recently used to clarify conformation and configuration of several structures.³¹31 Lomas, J. S.; Magn. Reson. Chem.2014, 52, 745. This first one, the rms error, was obtained by the comparison of chemical shift values atom by atom, both hydrogen and carbon. In this case, rms value was always lower for trans compounds, regardless the comparison made: only ¹H chemical shifts (δ_H), only ¹³C chemical shifts (δ_C) or δ_H plus δ_C. Table 5 shows the rms values obtained, which clearly indicates trans configuration for both compounds 2a and 2b.

Thumbnail

Table 5
Root mean square (rms) values from the comparison of experimental ¹H and ¹³C chemical shifts of compounds 2a and 2b with those calculated for their cis-(7S,8R) and trans-(7R,8R) diastereoisomers

The coefficients of determination were obtained from graphics where ¹H and ¹³C experimental chemical shift values were plotted in one axis and the corresponding calculated values in the other one. Three different graphics were drawn for each structure: one with δ_H, one with δ_C and one with both δ_H and δ_C. Invariably, the values obtained for trans structures were closer to the experimental rather than the cis values. Figure 4 shows the example of R² obtained for compounds 2a and 2bversus¹H and ¹³C chemical shifts for the trans-(7R,8R) structure. The R² values for 2a and 2btrans-(7R,8R) were 0.9984 and 0.9974, respectively; while the R² value for the diasteroisomers cis-(7S,8R) were 0.9977 and 0.9963, respectively. These data also indicate that the obtained compounds have a trans configuration.

Figure 4
Graphics with ¹H plus ¹³C chemical shift (δ_H + δ_C, ppm) experimental values vs. calculated values for trans-(7R,8R) and cis-(7S,8R) diasteroisomers of neolignans 2a and 2b.

Moreover, H₇ exhibited significant NOE correlation with H₂ and H₆, in the NOESY spectrum (Table 4). However, NOE correlation of H₇ with H₈ is weak, indicating the relative trans configuration for compounds 2a and 2b. In addition, the trans stereochemistry is also consistent with the diastereoselectivity observed in previously reported syntheses of dihydrobenzofuran neolignans by oxidative coupling, in which the main product is normally a trans racemic mixture.³²32 Orlandi, M.; Rindone, B.; Molteni, G.; Rummakko, P.; Brunow, G.; Tetrahedron2001, 57, 371. In this work, the formation of a trans racemic mixture for both 2a and 2b was confirmed on the basis of their specific optical rotation values ([α]_D²⁵25 Blau, L.; Menegon, R. F.; Ferreira, E. I.; Ferreira, A. G.; Boffo, E. F.; Tavares, L. A.; Heleno, V. C. G.; Chung, M. C.; Molecules2008, 13, 841. = 0º).

Conclusions

The complete and unequivocal assignments of ¹H and ¹³C NMR data for two dihydrobenzofuran neolignans are achieved, leaving no ambiguities. This work included the measurement of all hydrogen homonuclear coupling constants values and all hydrogen signal multiplicities were clarified. Confirmation of the relative stereochemistry was also achieved by density functional theory (DFT) calculations and NOE experiments. This study provides an important ¹H and ¹³C NMR database for these two substances and eliminates all previous ambiguities. The stereochemistry was also confirmed by means of J values comparison. This is the first complete assignment reported for each one of these two compounds.

Experimental

Synthesis of compounds 2a and 2b

Dihydrobenzofuran neolignans 2a and 2b were synthesized as previously reported.¹⁵15 Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.^,¹⁷17 Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775.^,²⁶26 Maeda, S.; Masuda, H.; Tokoroyama, T.; Chem. Pharm. Bull.1995, 43, 935. Briefly, compounds 2a and 2b were obtained by oxidative coupling of methyl coumarate (1a) and methyl ferulate (1b) using Ag₂O as oxidant. The reactions were carried out employing a mixture of acetone and benzene (5:8, v/v) in a two-necked flask with aluminum foil, equipped with a magnetic stirrer and a gas tube of N₂ for 20 h at room temperature. The product was purified by column chromatography (2.2 × 100 cm, silica gel 60, 0.040-0.063 mm) with hexane and ethyl acetate (2:1, v/v) as eluent affording compounds 1 (36% yield) and 2 (43% yield) as mixture of trans-enantiomers. All structures were confirmed by NMR analysis.

NMR analyses

All ¹H and ¹³C NMR experiments were performed on a Bruker Avance DRX400 spectrometer (Karlsruhe, Germany, 400.13 MHz for ¹H and 100.61 MHz for ¹³C). A direct 5-mm probe head (BBO) was used for ¹³C{¹H} NMR experiments and an inverse 5-mm probe head (BBI) was used for other experiments. The ¹H NMR spectra were acquired with a solar water heating (SWH) of 8.28 kHz, a time domain (TD) of 64 K, and a number of scans (NS) of 16, which provided a digital resolution of ca. 0.126 Hz (¹H 30º pulse width = 8.5 μs). As for the ¹³C NMR spectra, an SWH of 23.98 kHz was employed, with TD of 32K and NS of 1024, giving a digital resolution of ca. 0.732 Hz (¹³C 30º pulse width = 14.25 μs). DEPT (512 scans), ¹H/¹H and ¹³C/¹H 2D chemical shift correlation experiments were carried out using standard pulse sequences supplied by the spectrometer manufacturer. Long-range ¹³C/¹H chemical shift correlations were obtained in experiments with delay values optimized for ²J(C,H) = 8 Hz. Experiments were performed at 300 K and the concentrations for all samples were in the range 10-15 mg mL⁻¹, in CDCl₃ or acetone-d₆, using tetramethylsilane (TMS) as internal reference.

Computational methods

Full geometry optimization and vibrational frequency calculations were carried out using the Gaussian09 program package,³³33 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian 09 Inc., USA, 2009. employing the B3LYP hybrid functional³⁴34 Becke, A. D.; J. Chem. Phys.1993, 98, 5648; Lee, C.; Yang, W.; Parr, R. G.; Phys. Rev. B1988, 37, 785. and 6-311+G(2d,p) basis set.³⁵35 Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A.; J. Chem. Phys.1980, 72, 650; Blaudeau, J.-P.; McGrath, M. P.; Curtiss, L. A.; Radom, L.; J. Chem. Phys.1997, 107, 5016; Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. V. R.; J. Comput. Chem.1983, 4, 294. The nature of the stationary point was determined by performing Hessian matrix analysis. ¹H and ¹³C NMR chemical shifts values are calculated within Gauge-Independent Atomic Orbital (GIAO) method,³⁶36 London, F.; J. Phys. Radium1937, 8, 397.

37 McWeeny, R.; Phys. Rev.1962, 126, 1028; Ditchfield, R.; Mol. Phys.1974, 27, 789.^-³⁸38 Wolinski, K.; Hinton, J. F.; Pulay, P.; J. Am. Chem. Soc.1990, 112, 8251. using the TMS as the reference molecule. The mixed option was included to consider the Fermi contact contribution and improve the accuracy of spin-spin coupling constants.³⁹39 Deng, W.; Cheeseman, J. R.; Frisch, M. J.; J. Chem. Theory Comput.2006, 2, 1028. All NMR calculations were performed at the mPW1PW91/6-311+G(2d,p) level of theory, following the recommendations from Tantillo and co-workers⁴⁰40 Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J.; Chem. Rev.2012, 112, 1839.

41 Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.; Rita, J.; Shaw, J. T.; Tantillo, D. J.; J. Am. Chem. Soc.2012, 134, 18550.^-⁴²42 Lodewyk, M. W.; Tantillo, D. J.; J. Nat. Prod.2011, 74, 1339. for ¹H and ¹³C computed chemical shifts. In addition, the solvent effect in the NMR calculations was taken into account via the self-consistent reaction field (SCRF) approach.⁴³43 Tomasi, J.; Mennucci, B.; Cammi, R.; Chem. Rev.2005, 105, 2999.

Supplementary Information

¹H NMR, ¹³C NMR and 2D NMR, IR and mass spectra of compounds are available free of charge at http://jbcs.sbq.org.br as a PDF file.

https://minio.scielo.br/documentstore/1678-4790/fLVKdwFGNjBYQDVvp5kVfBs/8dcdc4e0e53024ee3ddbd63cacb54403ae2b876c.pdf

FAPESP has sponsored the publication of this article.
#
These authors contributed equally to this work.

Acknowledgements

The authors thank the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; processes 2013/20094-0, 2009/12202-1 and 2011/07623-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; Science Without Borders Program, process 88881.068346/2014-01) for research fellowship and grants. We are very grateful to Vinicius Palaretti (FFCLRP-USP) for acquisition of the NMR spectra.

References

¹
Gottlieb, O. R.; Mem. Inst. Oswaldo Cruz1991, 86, 25.
²
Moss, G. P.; Pure Appl. Chem.2000, 72, 1493.
³
Huang, X. X.; Zhou, C. C.; Li, L. Z.; Peng, Y.; Lou, L. L.; Liu, S.; Li, D. M.; Ikejima, T.; Song, S. J.; Fitoterapia2013, 91, 217.
⁴
Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.
⁵
Cho, J. Y.; Baik, K. U.; Yoo, E. S.; Yoshikawa, K.; Park, M. H.; J. Nat. Prod.2000, 63, 1205.
⁶
Cabral, M. M. O.; Barbosa-Filho, J. M.; Maia, G. L. A.; Chaves, M. C. O.; Braga, M. V.; de Souza, W.; Soares, R. O. A.; Exp. Parasitol.2010, 124, 319.
⁷
Cabral, M. M. O.; Azambuja, P.; Gottlieb, O. R.; Garcia, E. S.; Parasitol. Res.1999, 85, 184.
⁸
Cabral, M. M. O.; Azambuja, P.; Gottlieb, O. R.; Kleffmann, T.; Garcia, E. S.; Schaub, G. A.; Parasitol. Res.2001, 87, 730.
⁹
Chauret, D. C.; Bernard, C. B.; Arnason, J. T.; Durst, T.; Krishnamurty, H. G.; Sanchez-Vindas, P.; Moreno, N.; San Roman, L.; Poveda, L.; J. Agr. Food Chem.1996, 59, 152.
¹⁰
Quideuau, S.; Ralph, J.; Holzforschung1994, 48, 12.
¹¹
Li, Q.-B.; Hu, X.-C.; Chem. Lett.2012, 41, 1633.
¹²
Kao, C.-L.; Chern, J.-W.; J. Org. Chem.2002, 67, 6772.
¹³
Van Miert, S.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.; Lemière, G.; Pieters, L.; Bioorgan. Med. Chem.2005, 13, 661.
¹⁴
Apers, S.; Paper, D.; Bürgermeister, J.; Barnikova, S.; Van Dyck, S.; Lemière, G.; Vlietinck, A.; Pieters, L.; J. Nat. Prod.2002, 65, 718.
¹⁵
Pieters, L.; Van Dyck, S.; Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G.; J. Med. Chem.1999, 42, 5475.
¹⁶
Rakotondramanana, D. L. A.; Delomenède, M.; Baltas, M.; Duran, H.; Bedos-Belval, F.; Rasoanaivo, P.; Negre-Salvayre, A.; Gornitzka, H.; Bioorg. Med. Chem.2007, 15, 6018.
¹⁷
Lemière, G.; Gao, M.; De Groot, A.; Dommisse, R.; Lepoivre, J.; Pieters, L.; Buss, V.; J. Chem. Soc. Perk. T. 11995, 13, 1775.
¹⁸
Kuo, Y. H.; Wu, C.-H.; J. Nat. Prod.1996, 59, 625; Snider, S. A.; Kontes, F.; J. Am. Chem. Soc.2009, 131, 1745.
¹⁹
Heleno, V. C. G.; Crotti, A. E. M.; Constantino, M. G.; Lopes, N. P.; Lopes, J. L. C.; Magn. Reson. Chem.2004, 42, 364.
²⁰
Heleno, V. C. G.; Oliveira, K. T.; Lopes, J. L. C.; Lopes, N. P.; Ferreira, A. G.; Magn. Reson. Chem.2008, 46, 576.
²¹
Soares, A. C. F.; Silva, A. N.; Matos, P. N.; Silva, E. H.; Lopes, N. P.; Lopes, J. L. C.; Sass, D. C.; Heleno, V. C. G.; Quim. Nova2012, 35, 2205.
²²
Silva, R.; Heleno, V. C. G.; Albuquerque, S.; Bastos, J. K.; Silva, M. L. A.; Donate, P. M.; Silva, G. V. J.; Magn. Reson. Chem.2004, 42, 985.
²³
Constantino, M. G.; Silva-Filho, L. C.; Cunha Neto, A.; Heleno, V. C. G.; Silva, G. V. J.; Lopes, J. L. C.; Spectrochim. Acta A2005, 61, 171.
²⁴
Heleno, V. C. G.; Silva, R.; Pedersoli, S.; Albuquerque, S.; Bastos, J. K.; Silva, M. L. A.; Donate, P. M.; Silva, G. V. J.; Lopes, J. L. C.; Spectrochim. Acta A2006, 63, 234.
²⁵
Blau, L.; Menegon, R. F.; Ferreira, E. I.; Ferreira, A. G.; Boffo, E. F.; Tavares, L. A.; Heleno, V. C. G.; Chung, M. C.; Molecules2008, 13, 841.
²⁶
Maeda, S.; Masuda, H.; Tokoroyama, T.; Chem. Pharm. Bull.1995, 43, 935.
²⁷
Daquino, C.; Rescifina, A.; Spatafora, C.; Tringali, C.; Eur. J. Org. Chem2009, 36, 6289.
²⁸
Li, S. L.; Iliefski, T.; Lundquist, K.; Wallis, A. F. A.; Phytochemistry1997, 46, 929.
²⁹
Constantino, M. G.; Lacerda-Júnior, V.; Silva, G. V. J.; Magn. Reson. Chem.2003, 41, 641.
³⁰
Muñoz, M. A.; Joseph-Nathan, P.; Magn. Reson. Chem.2009, 47, 578.
³¹
Lomas, J. S.; Magn. Reson. Chem.2014, 52, 745.
³²
Orlandi, M.; Rindone, B.; Molteni, G.; Rummakko, P.; Brunow, G.; Tetrahedron2001, 57, 371.
³³
Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian 09 Inc., USA, 2009
³⁴
Becke, A. D.; J. Chem. Phys.1993, 98, 5648; Lee, C.; Yang, W.; Parr, R. G.; Phys. Rev. B1988, 37, 785.
³⁵
Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A.; J. Chem. Phys.1980, 72, 650; Blaudeau, J.-P.; McGrath, M. P.; Curtiss, L. A.; Radom, L.; J. Chem. Phys.1997, 107, 5016; Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. V. R.; J. Comput. Chem.1983, 4, 294.
³⁶
London, F.; J. Phys. Radium1937, 8, 397.
³⁷
McWeeny, R.; Phys. Rev.1962, 126, 1028; Ditchfield, R.; Mol. Phys.1974, 27, 789.
³⁸
Wolinski, K.; Hinton, J. F.; Pulay, P.; J. Am. Chem. Soc.1990, 112, 8251.
³⁹
Deng, W.; Cheeseman, J. R.; Frisch, M. J.; J. Chem. Theory Comput.2006, 2, 1028.
⁴⁰
Lodewyk, M. W.; Siebert, M. R.; Tantillo, D. J.; Chem. Rev.2012, 112, 1839.
⁴¹
Lodewyk, M. W.; Soldi, C.; Jones, P. B.; Olmstead, M. M.; Rita, J.; Shaw, J. T.; Tantillo, D. J.; J. Am. Chem. Soc.2012, 134, 18550.
⁴²
Lodewyk, M. W.; Tantillo, D. J.; J. Nat. Prod.2011, 74, 1339.
⁴³
Tomasi, J.; Mennucci, B.; Cammi, R.; Chem. Rev.2005, 105, 2999.

Publication Dates

Publication in this collection
Jan 2016

History

Received
08 July 2015
Accepted
09 Oct 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[1] FAPESP has sponsored the publication of this article.

[2] #
These authors contributed equally to this work.

	δ_C^a a Multiplicities assigned on the basis of distortionless enhancement by polarization transfer (DEPT) 135 experiments;	δ_H (integral, multiplicity^b b multiplicities and coupling constant values measured within 1H NMR and J-resolved spectra with the help from 1H-1H correlation spectroscopy (COSY) results. ), J/ Hz
1	132.0 (C)	−
2=6	127.5 (CH)	7.27 (2H, ddd, J_2,5 = J_6,3 0.3, J_2,7 = J_6,7 0.6, J_2,3 = J_6,5 8.3)
3=5	115.7 (CH)	6.84 (2H, dd, J_3,6 = J_5,2 0.3, J_3,2 = J_5,6 8.3)
4	156.1 (C)	−
7	87.7 (CH)	6.09 (1H, dt, J_7,2 = J_7,6 0.6, J_7,8 7.2)
8	55.1 (CH)	4.27 (1H, dd, J_8,6' 1.4, J_8,7 7.2)
9	170.9 (C)	−
10	52.9 (CH₃)	3.83 (3H, s)
1'	127.8 (C)	−
2'	130.8 (CH)	7.43 (1H, ddd, J_2',7' 1.1, J_2',6' 2.0, J_2',3' 8.3)
3'	110.3 (CH)	6.89 (1H, dd, J_3',6' 0.4, J_3',2'8.3)
4'	161.2 (C)	−
5'	125.1 (C)	−
6'	124.9 (CH)	7.55 (1H, dddd, J_6',3' 0.4, J_6',7' 0.7, J_6',8 1.4, J_6',2'2.0)
7'	144.7 (CH)	7.66 (1H, ddd, J_7',6' 0.7, J_7',2' 1.1, J_7',8' 15.9)
8'	115.2 (CH)	6.32 (1H, d, J_8',7' 15.9)
9'	167.9 (C)	−
10'	51.7 (CH₃)	3.81 (3H, s)

C	H	gCOSY^a a Gradient-selected correlation spectroscopy;	gHMBC^b b gradient-selected heteronuclear multiple bond coherence;	gHMQC^c c gradient-selected heteronuclear multiple quantum coherence;	NOESY^d d nuclear Overhauser effect spectroscopy.
1	–	–	H₃ =H₅, H₇, H₈	–	–
2=6	2=6	H₃, H₅, H₇	H₃ =H₅, H₇	H₂=H₆	H₇, H₈
3=5	3=5	H₂, H₆	H₅	H₃=H₅	–
4	–	–	H₃ =H₅, H₂ =H₆	–	–
7	7	H₂=H₆, H₈	H₆, H₈	H₇	H₂=H₆^* * mean weak correlation.
8	8	H₇, H_6'	H₇, H_6'	H₈	H₂=H₆, H_6'^* * mean weak correlation.
9	–	–	H₇, H₈, H₁₀	–	–
10	10	–	−	H₁₀	–
1'	–	–	H_3', H_8'	–	–
2'	2'	H_3', H_6', H_7'	H_6', H_7'	H_2'	H_7', H_8'^* * mean weak correlation.
3'	3'	H_2', H_6'	−	H_3'	–
4'	–	–	H_2', H_3', H_6', H₇, H₈	–	–
5'	–	–	H₈, H_3'	–	–
6'	6'	H_2', H_3', H_7', H₈	H_2', H_7', H₈	H_6'	H_8', H_7', H₈^* * mean weak correlation.
7'	7'	H_2', H_8', H_6'	H_2', H_6', H_8'	H_7'	H_6'^* * mean weak correlation. , H_2'
8'	8'	_H7'	H_7'	H_8'	H_6'^* * mean weak correlation. , H_2'
9'	–	–	H_7', H_8', H_10'	–	–
10'	10'	–	–	H_10'	–

	δ_C^a a Multiplicities assigned on the basis of distortionless enhancement by polarization transfer (DEPT) 135 experiments;	δ_H (integral, multiplicity^b b multiplicities and coupling constant values measured within 1H-NMR and J-resolved spectra with the help from 1H-1H correlation spectroscopy (COSY) results. ); J/ Hz
1	132.5 (C)	–
2	111.2 (CH)	7.10 (1H, ddd, J_2,5 0.3, J_2,7 0.8, J_2,6 2.1)
3	149.1 (C)	–
4	148.5 (C)	–
5	116.3 (CH)	6.84 (1H, dd, J_5,2 0.3, J_5,6 8.3)
6	120.7 (CH)	6.92 (1H, ddd, J_6,7 0.6, J_6,2 2.1, J_6,5 8.3)
7	88.8 (CH)	6.04 (1H, ddd, J_7,6 0.6, J_7,2 0.8, J_7,8 7.3)
8	57.0 (CH)	4.47 (1H, dd, J_8,6' 1.4, J_8,7 7.3)
9	172.1 (C=O)	–
10	53.5 (CH₃)	3.81 (3H, s)
11	56.4 (CH₃)	3.84 (3H, s)
1'	129.9 (C)	–
2'	113.9 (CH)	7.33 (1H, dd, J_2',7' 0.4, J_2'6' 2.6)
3'	146.3 (C)	–
4'	151.5 (C)	–
5'	127.8 (C)	–
6'	119.5 (CH)	7.29 (1H, ddd, J_6',7' 0.8, J_6',8 1.4, J_6',2' 2.6)
7'	145.9 (CH)	7.63 (1H, ddd, J_7',2' 0.4, J_7',6' 0.8, J_7',8' 15.8)
8'	116.8 (CH)	6.44 (1H, d, J_8',7' 15.8)
9'	168.2 (C)	–
10'	52.1 (CH₃)	3.73 (3H, s)
11'	56.8 (CH₃)	3.92 (3H, s)

C	H	gCOSY^a a Gradient-selected correlation spectroscopy;	gHMBC^b b gradient-selected heteronuclear multiple bond coherence;	gHMQC^c c gradient-selected heteronuclear multiple quantum coherence;	NOESY^d d nuclear Overhauser effect spectroscopy.
1	–	–	H₂, H₆, H₇, H₈	–	–
2	2	H₅, H₆, H₇	H₅, H₆, H₇	H₂	H₇, H₈, H₁₁
3	–	–	H₂, H₅, H₁₁	H₃	–
4	–	–	H₂, H₅, H₆	–	–
5	5	H₂, H₆	H₆	H₅	–
6	6	H₂, H₅, H₇	H₂, H₅	H₆	H₇, H₈
7	7	H₂, H₆, H₈	H₂, H₆, H₈	H₇	H₆^* * mean weak correlation. , H₂
8	8	H_6', H₇	H₂, H_6'	H₈	H_6'^* * mean weak correlation. , H₂, H₆
9	–	–	H₇, H₈, H₁₀	H₉	–
10	10	–	−	H₁₀	–
11	11	–	−	H₁₁	H₂
1'	–	–	H_7', H_8'	H_1'	–
2'	2'	H_6', H_7'	H_6', H_7'	H_2'	H_7', H_8'^* * mean weak correlation. , H_11'
3'	–	–	H_11'	–	–
4'	–	–	H_2', H_6', H₇, H₈	–	–
5'	–	–	H₇, H_8'	–	–
6'	6'	H_7', H_2', H₈	H_2', H_7', H₈	H_6'	H_8', H_7', H₈^* * mean weak correlation.
7'	7'	H_2', H_6', H_8'	H_2', H_6', H_8'	H_7'	H_6', H_2',
8'	8'	H_7'	H_7'	H_8'	H_6', H_2'
9'	–	–	H_8', H_10'	–	–
10'	10'	–	–	H_10'	–
11'	11'	–	–	H_11'	H_2'

	Compound 2a^a a Calculated in CDCl3;		Compound 2b^b b calculated in acetone-d6.
	trans	cis	trans	cis
Only δ_H	0.46	0.49	0.39	0.42
Only δ_C	6.52	6.91	7.32	7.92
δ_H + δ_C	5.09	5.39	5.81	6.29

Brasil

Brasil

Detailed ¹H and ¹³C NMR Spectral Data Assignment for Two Dihydrobenzofuran Neolignans

Abstract

Introduction

Results and Discussion

Conclusions

Experimental

Synthesis of compounds 2a and 2b

NMR analyses

Computational methods

Supplementary Information

Acknowledgements

References

Publication Dates

History

Brasil

Brasil

Detailed 1H and 13C NMR Spectral Data Assignment for Two Dihydrobenzofuran Neolignans

Abstract

Introduction

Results and Discussion

Conclusions

Experimental

Synthesis of compounds 2a and 2b

NMR analyses

Computational methods

Supplementary Information

Acknowledgements

References

Publication Dates

History

Detailed ¹H and ¹³C NMR Spectral Data Assignment for Two Dihydrobenzofuran Neolignans