Atropoisomerism in Biflavones: The Absolute Configuration of

Article pubs.acs.org/jnp

Atropoisomerism in Biflavones: The Absolute Configuration of (−)-Agathisflavone via Chiroptical Spectroscopy Cody L. Covington,† Fernando M. S. Junior,†,‡ Jessica H. S. Silva,‡ Ricardo M. Kuster,‡ Mauro B. de Amorim,‡ and Prasad L. Polavarapu*,† †

Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States Instituto de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, 21941-902, Rio de Janeiro, RJ, Brazil

‡

S Supporting Information *

ABSTRACT: The first natural occurrence in optically active form of the dimeric flavonoid agathisflavone and definition of its axial chirality using chiroptical spectroscopic methods are described. The experimental electronic circular dichroism, electronic dissymmetry factor, optical rotatory dispersion, vibrational circular dichroism (VCD), and vibrational dissymmetry factor spectra of agathisflavone are presented and analyzed with their corresponding quantum chemical predictions to definitively assign the axial chirality of (−)-agathisflavone as (aS).

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rotatory dispersion (ORD). The other two methods, probing the chiral response from molecular vibrational transitions, are vibrational circular dichroism (VCD) and vibrational Raman optical activity (VROA). The simultaneous use of more than one of these methods is known to be necessary to provide reliable assignment of stereostructures.13,14 Since the interpretation of chiroptical spectra using empirical or semiempirical methods may give inaccurate results, the currently prevailing trend15 relies on the use of calculated spectra using reliable quantum chemical methods. Accordingly, the ACs of several chiral natural products and small molecules have been determined by chiroptical spectroscopic methods over the past several years.16−24 In this article the first natural occurrence of optically active agathisflavone (Figure 1), a biflavone-type dimeric flavonoid, with a C-6−C-8′′ interflavanyl bond, is reported. This compound was isolated from Schinus terebinthifolius Raddi (Anacardiaceae), known as Aroeira or the Brazilian pepper tree. This is a small tree with small globose fruits (red drupes), which are sources of a monoterpene-rich essential oil and of biflavonoids. The Brazilian pepper tree has been used in Brazilian folk medicine for a long time as an antipyretic, analgesic, and depurative and in the treatment of diseases of the urogenital system. Notably it has been reported to have antimicrobial, anti-inflammatory, and antiulcerogenic activities.25 Besides this source26,27 other plant families have also been used for the isolation of agathisflavone: Ochnaceae (Ouratea microdonta Engl., Ouratea polyantha Engl., and Ouratea sulcata Van Tiegh.),28−30 Anacardiaceae (Anacardium

tropisomerism in biflavones has been known since the 1960s.1,2 However, these compounds are still puzzling in the sense that, even after their first isolation in optically active form several decades ago, their configurational assignment remained to be established. The determination of the absolute configuration (AC), in terms of axial chirality, remains a challenging problem within this class of natural products.3 There has been growing evidence that the oxidative coupling catalytic processes that lead to biaryl compounds are atroposelective.4,5 The interest in atroposelective synthesis6 of this biologically active group of natural products is steadily increasing.7,8 Yet, there are only a few examples of AC determination for dimeric flavonoids containing a biaryl axis, and many of them are not even recognized as optically active.3 The first configurational analysis of a bicoumarin, a dimeric 2H-1-benzopyran-2-one analogous to biflavones (dimeric 2phenyl-4H-1-benzopyran-4-one derivatives), was made via electronic circular dichroism (ECD)9 using the exciton chirality (EC) method. However, this empirical method may not always be successful in establishing the correct AC.10,11 During the 1990s, Harada and co-workers showed how difficult the application of the EC-ECD method for biflavones can be. The first stereochemical analysis for biflavones was undertaken using experimental and calculated ECD spectra.12 X-ray diffraction, stereoselective synthesis, and NMR spectroscopy of diastereomeric complexes are among the traditional methods for AC determination. The former method suffers from the need to obtain good-quality crystals, while the latter two suffer from synthetic challenges. As practical alternatives, four different chiroptical spectroscopic methods are currently widely used for stereostructural assignments. Two of these methods, based on electronic transitions, are ECD and optical © 2016 American Chemical Society and American Society of Pharmacognosy

Received: May 3, 2016 Published: October 10, 2016 2530

DOI: 10.1021/acs.jnatprod.6b00395 J. Nat. Prod. 2016, 79, 2530−2537

Journal of Natural Products

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Figure 1. (Left) Structure of agathisflavone; (right) the flavone chromophores.

occidentale L. and Rhus pyroides Burch.),31,32 and Fabaceae (Cenostigma macrophyllum Tul. and Caesalpinia pyramidalis Tul).33,34 Agathisflavone might potentially be used in therapy because it has been shown to possess several biological properties, including inhibition of the growth of leukemia cells,32 affinity for the GABA A/benzodiazepine receptor,31 and enhancement of retinoic acid-induced neurogenesis.35 However, due to the dimeric nature of agathisflavone, which leads to overlapping of 13 C NMR signals, the complete and unambiguous assignment of its structure was achieved only in 2012.36 The possibility of atropoisomerism in agathisflavone has not been discussed, and its promising biological activities make it essential to determine its enantiomeric purity and absolute configuration. Only a few examples of dimeric flavonoids possessing an axis of chirality as the sole stereogenic element are known to be optically active, belonging to the cupressuflavone, the amentoflavone, and the agathisflavone groups.37−41 In the agathisflavone group, the only known optically active derivative is 7-O-methylagathisflavone, but its axial chirality has not been defined.41 Most of the other biflavones have not been checked for optical activity,37,42−44 and unambiguous assignment of the axial chirality was achieved for only a few.37−40 In this article, the combination of different chiroptical spectroscopic methods, namely, ECD, ORD, VCD, electronic dissymmetry factor (EDF), and vibrational dissymmetry factor (VDF), supported by corresponding quantum chemical predictions and the numerical measures of similarity between experimental and calculated spectra, permitted assignment of the (aS) absolute configuration of (−)-agathisflavone.

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RESULTS AND DISCUSSION The NMR chemical shifts for agathisflavone are in agreement with those described by Ba Njoc and co-workers.36 The 1H and 13 C NMR data are shown in Figures S5−S7 and the Structure Identification section of the Supporting Information. The enantiomeric purity was determined using chiral HPLC on AD-H, ID, and AS-H chiral columns. A single peak eluted on all these columns. The enantiomers of similar chiral flavonoids under the same conditions were resolved on these columns. The chiral HPLC analysis indicated that the compound is enantiomerically pure (Figures S14 and S15, Supporting Information, for chiral HPLC chromatograms). EA, ECD, and EDF Spectroscopic Analyses. The experimental electronic absorption (EA) spectrum of agathisflavone (Figure 2) in MeOH exhibits two intense bands, one around 330 nm (band I) and the other around 280 nm (band II). Band I is considered to be associated with a π−π*-type transition of the cinnamoyl type C6−C3 ring system, and band

Figure 2. Comparison of the calculated and experimental EA, ECD, and EDF spectra of (−)-(aS)-agathisflavone in MeOH. The Boltzmann-weighted spectra at the CAM-B3LYP/6-311++G(2d,2p)/ PCM level are simulated with Gaussian band shapes and a 20 nm bandwidth. Baseline tolerance of 1000 L mol−1 cm−1 was used for deriving the EDF spectra.

II is reminiscent of a π−π*-type transition of the A-ring benzoyl system (Figure 1).45 The restricted rotation of the flavone chromophores connected via a (6→8′′) bond gives rise to axial chirality. The potential energy barrier for rotation around this bond 2531



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calculated at the B3LYP/6-31G* level is sufficient (26.3 kcal/ mol) to prevent racemization. The experimentally observed electronic absorption band at 282 nm is associated with bisignate Cotton effects, with a positive Cotton effect at 266 nm and a negative one at 306 nm (see Figure 2). While this observation is consistent with exciton chirality interpretation of Cotton effects emanating from the chiral biaryl axis, the current emphasis is on reproducing the experimentally observed features in the ∼190−400 nm region using quantum chemical predicted spectra. The Boltzmannweighted EA and ECD spectra, derived from the 16 lowest energy conformations (Tables S1 and S2, Supporting Information) at the CAM-B3LYP/6-311++G(2d,2p)/PCM (polarizable continuum model) level for (aS)-agathisflavone, are shown and compared with the experimental spectra of (−)-agathisflavone in Figure 2. The dimensionless dissymmetry factor spectrum, i.e., the ratio of the ECD spectrum to the corresponding absorption spectrum, provides more insight for discriminating among diastereomers than its individual component spectra do.16,17 The experimental and calculated electronic EDF spectra are also shown in Figure 2. One of the major conformers of (aS)-agathisflavone is shown in Figure S2 of the Supporting Information. The experimental EA spectrum shows four resolved bands at 196, 227, 282, and 334 nm. In the calculated spectrum, the first two bands are clearly seen, while the latter two appeared as one coalesced band. The experimental ECD spectrum shows positive Cotton effects at 202 and 266 nm and negative Cotton effects at 217, 234, 306, and 316 nm. All of these experimentally observed features are seen to have counterparts in the calculations. Although there are significant differences in the observed and calculated band positions, the agreement between the experimental and calculated ECD spectra is considered to be satisfactory for the present purposes. Recently, a simplified time-dependent density functional theory (sTD-DFT)46,47 method was introduced to investigate the EA and ECD spectra of large molecules. Moreover, the solvent-mediated nonequilibrium structural effects were modeled by averaging over the spectra calculated for molecular dynamics (MD) snapshots that included the explicit solvent molecules.48 To investigate the effects of solvation on the EA, ECD, and EDF spectra of agathisflavone in MeOH, three separate calculations using MD snapshots of agathisflavone in MeOH were done: (a) sTD-DFT calculations on unoptimized MD snapshots at the CAM-B3LYP/6-311++G(2d,2p)/PCM level; (b) sTD-DFT calculations at the CAM-B3LYP/6-311++G(2d,2p)/PCM level on MD snapshots optimized at the B3LYP/6-31G*/PCM level; (c) full TD-DFT investigations using MD snapshots optimized at the B3LYP/6-31G*/PCM level. Owing to the size of the system, full TD-DFT investigations were limited to the CAM-B3LYP/6-31++G**/PCM level. These results are shown in Figure 3. The calculations using the unoptimized MD snapshots appear to reflect the experimental spectra better (vide infra). However, none of the calculations reproduce the breadth of the experimentally observed lowenergy ECD band down to 400 nm. The relative energies and intensities in the calculations are not perfectly matched with those observed in the experiment. As a result, the wide range of the electronic region being probed prevents one scale factor from providing a good match between calculated and experimentally observed transition wavelengths in the entire

Figure 3. Comparison of EA, ECD, and EDF spectra calculated for MD snapshots and simulated with Gaussian band shapes using a 20 nm bandwidth, with the experimental spectra for (−)-(aS)agathisflavone in MeOH. The MD snapshots included a solute molecule surrounded by MeOH molecules, and calculated spectra are shifted upward for clarity.

region. The similarity overlap plots, displaying the dependence of similarity overlap between experimental and predicted spectra as a function of wavelength scaling, for four different calculations are shown in Figure 4. The Boltzmann-weighted DFT spectra calculated at the optimized geometries (Figure 2) yield the following maximum similarity overlap values (top left panel of Figure 4): 0.28 for SimECD, 0.40 for SimEDF, and >0.7 for SimEA (see Similarity Analysis on p 43 of the Supporting Information). The corresponding values in full DFT calculations for MDoptimized geometries are (top right panel of Figure 4) 0.36, 0.46, and >0.7. These similarity overlap values suggest that there is a definite improvement in including explicit solvent influence through MD snapshots. The maximum SimECD, SimEDF, and SimEA values for sTD-DFT calculations for 2532



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Figure 4. Similarity overlap plots for the EA, ECD, and EDF spectra of (−)-(aS)-agathisflavone in MeOH.

unoptimized MD snapshots are (bottom left panel of Figure 4) 0.48, 0.69, and >0.8, while those for optimized geometries are (bottom right panel of Figure 4) 0.41, 0.58, and >0.8. Thus, the highest similarity overlap values are obtained in sTD-DFT calculations for unoptimized geometries. This observation is consistent with that of Grimme and co-workers,48 who found that sTD-DFT calculations for unoptimized MD geometries yielded better comparisons to the experimental spectra. The implications of this observation are not entirely clear, but it could be reflecting the importance of the dynamic representation of the solute in the solvent environment, as recently reported.48 The calculated and experimental spectra have higher similarity values for EDF than for ECD, in accordance with previous observations that a better perspective on agreement between experimental and calculated spectra can be gained from the comparison of EDF spectra.16,17,49 The visual agreement of experimentally observed ECD and EDF bands with those in the calculations (Figure 2) and similarity analysis (Figure 4) strongly supports the assignment of an (aS) configuration for (−)-agathisflavone. The current analysis shows how the properties of a large system (agathisflavone and 6−10 MeOH molecules) can be modeled by quantum chemical methods to yield informative results and could represent a future direction for improving the confidence in the assignment of ACs of natural products. ORD Analysis. The experimental discrete wavelength ORD curve is compared to that predicted for minimum energy structures as well as for MD snapshots (Figure 5). In the former case, wavelength-resolved specific rotations were obtained using linear response methods,50 as implemented in the Gaussian 09 program.51 In the latter case, rotational strengths obtained in the sTD-DFT method for electronic transitions in the 120−400 nm region are converted to wavelength-resolved specific rotations using the Kramers− Kronig (KK) transform.52 The experimental discrete wavelength ORD curve shows increasingly more negative specific rotations at shorter wavelengths (which may be in response to the broad negative Cotton effect in the 280−380 nm region). The Boltzmann-

Figure 5. Experimental and predicted ORD spectra for (−)-(aS)agathisflavone in MeOH. The predicted ORD is obtained for both minimum energy geometries (filled circles) and MD snapshots (dashed line).

weighted specific rotations predicted for minimum energy structures at the CAM-B3LYP/6-311++G(2d,2p)/PCM level also show the same trend. There is some disparity in the magnitudes of the specific rotation values seen in experiment and calculations, which can be reconciled with the corresponding disparities seen in experimental and calculated ECD spectra. The broad negative experimental Cotton effect extends from 280 to 400 nm, while the corresponding calculated negative Cotton effect (Figure 2) is somewhat narrower, extending from 300 to 350 nm. The general trend in the wavelength-dependent specific rotation values, however, is the same in both experimental and calculated data, i.e., starting out as small negative specific rotation at longer wavelength and becoming increasingly more negative at shorter wavelengths. The ORD curve obtained from KK-transformed rotational strengths in sTD-DFT calculations for both unoptimized and optimized MD geometries resembles that obtained in full DFT calculations as well as in the experiment. The influence of solvent-mediated nonequilibrium structures, as seen for ECD, is also seen for ORD. VA, VCD, and VDF Spectroscopic Analyses. Although the agreement between experimental and calculated ECD spectra and between experimental and calculated ORD curves 2533



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for (−)-agathisflavone is sufficient to suggest the AC assignment, it is important to additionally verify the AC assignments.13 For this reason the VCD spectra (Figures 6 and

Figure 7. VCD similarity analysis of (−)-(aS)-agathisflavone spectra obtained in methanol-d4 for three regions: (a) region I, 1900−1200 cm−1 (bottom); (b) region II, 1900−1500 cm−1 (middle); (c) region III, 1500−1200 cm−1 (top).

functional, although solvent perturbation may introduce deviations. In the present case, the hydrogen-bonding MeOH solvent can perturb the vibrations of groups that participate in hydrogen bonding and produce altered vibrational frequencies, VA, and VCD signals (in addition to a change in the Boltzmann population of the conformers). Without extensive calculations that include explicit solvent molecules, one cannot ascertain how the normal modes will be perturbed. One solution to the aforementioned problem is to carry out the similarity overlap comparison for different frequency regions separately. The MeOH solvent will hydrogen bond to the polar carbonyl groups and alter their vibrational frequencies in different ways than for the remainder of the molecule. By carrying out the similarity analysis for the separate regions, the agreement between experimental and simulated spectra is seen to improve considerably for the 1500−1200 cm−1 region (Figure 7), although the scale factor is still greater than 1, where SimVDF and SimVCD values are ∼0.6 and 0.5, respectively. The similarity overlap values for the 1900−1500

Figure 6. Comparison of experimental and B3LYP/6-311++G(2d,2p)/PCM-calculated VA, VCD, and VDF spectra for (−)-(aS)agathisflavone in methanol-d4.

7) were measured and analyzed as well. The VA, VCD, and VDF spectra were calculated for the 16 lowest energy conformers (Table S3, Supporting Information) at the B3LYP/6-311++G(2d,2p)/PCM level, and Boltzmannweighted spectra are compared to the experimental spectra in Figure 6. Although there are large VCD signals, a better match between experimental and simulated spectra can be seen when the calculated spectrum is shifted to the left with a scale factor of 1.02. The similarity overlap analysis for the 1900−1200 cm−1 region indicates a SimVDF value of ∼0.4. The vibrational x-axis scale factors are almost always less than 1.0 for the B3LYP 2534



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cm−1 region are not good, clearly reflecting the influence of hydrogen bonding in this region. To explore the effects of solvent on the VCD spectrum of (−)-agathisflavone, VCD calculations on MD-generated snapshots in MeOH solvent, with both open and closed internal carbonyl(CO-4/CO-4″)-phenolic (OH-5/OH-5″) hydrogen bonds, were also undertaken. The time-averaged MD spectra obtained at optimized geometries are shown in Figure S3, Supporting Information. To determine the convergence of the time-averaged MD spectra, the averaging was done with the first and second half of the snapshots. The closed H-bond MD spectra appear to be well converged, but the open H-bonding spectra may suffer from convergence issues (Figure S1, Supporting Information). Since the spectra predicted for open H-bonding do not seem to have any resemblance to the experimental spectra, which is in accordance with calculated and experimental evidence on strong internal CO-4/OH-5 Hbonding in flavonoids,53−55 further analysis of the open Hbonding structures was not performed. The calculations including the explicit MeOH solvent molecules improve the x-axis scaling factor required to align the experimental and calculated VCD spectra. This can be seen by comparing Figure S4, Supporting Information, with Figure 7. The maximum similarity obtained for MD-optimized predicted spectra (Figure S4, Supporting Information) is located at a scale factor of ∼1.006, but the corresponding scale factor for non-MDoptimized predicted spectra is ∼1.02. Nevertheless, the carbonyl stretching region is still not well matched between computed and experimental spectra. The similarity plots for the full region (1900−1200 cm−1) and for the 1900−1500 and 1500−1200 cm−1 regions are shown in Figure S4, Supporting Information. The similarity plots for the fingerprint (1500− 1200 cm−1) region have the maximum similarity ratings of 0.84, 0.60, and 0.61 for SimVA, SimVCD, and SimVDF, respectively. These values are significantly larger than the corresponding values in Figure 7. Thus, calculations including the explicit solvent molecules through MD simulations improved the similarity overlap and, hence, confidence in the assignment of the AC. In summary, an optically active form of agathisflavone has been isolated for the first time. The VCD, ECD, and ORD spectra have been measured, and the absolute configuration has been determined to be (−)-(aS) by comparison to the corresponding quantum chemical calculated spectra. Although the ECD spectrum of agathisflavone is quite complex, comparison with quantum chemical calculated spectra provided excellent reproduction of all ECD bands. Solvent-mediated nonequilibrium structural effects on ECD spectra were taken into account using MD snapshots. Solvent effects, clearly inferred from the VCD spectra, have complicated the VCD calculations. Nevertheless, extensive MD simulations and explicit solvent VCD calculations have considerably improved the confidence in the analysis of experimental spectra with quantum calculations. The VCD similarity was improved significantly when separate analyses were carried out for the carbonyl and fingerprint regions.

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measured for MeOH solution (1.38 mg/mL) using a Jasco J-720 spectrometer and a 0.1 mm quartz cell. The reported Δε values are in units of L mol−1 cm−1. VCD spectra in the 1800−1200 cm−1 region were measured for methanol-d4 (32 mg/mL), DMSO-d6, and pyridined5 solutions using a ChiralIR spectrometer and a 100 μm path length SL3 cell with BaF2 windows. Acetonitrile-d3 was not used due to poor sample solubility. The reported Δε values are in units of L mol−1 cm−1. 1 H NMR, APT, HSQC, and HMBC NMR spectra in methanol-d4 or DMSO-d6 using tetramethylsilane as internal standard were recorded on Bruker DRX 400 and 500 MHz spectrometers. Low-resolution ESIMS were obtained on a Macromass/Waters ZQ 4000 mass spectrometer, and high-resolution ESIMS on a TSQ Quantum Ultra AM, Finnigan, Triple Quadrupole operating at electrospray ionization mode. Cellulose acetate 20% (Sigma-Aldrich, St. Louis, MO), XAD-16 (Sigma-Aldrich), and Sephadex LH-20 (GE Healthcare Bio-Sciences AB, Björkgatan, Uppsala, Sweden) were used as stationary phases for column chromatography. An irregular C18 reversed-phase silica gel (GL-Sciences, Torrance, CA, USA) was used for analytical HPLC. Plant Material. Schinus terebinthifolius ripe fruits were provided by ́ farmers in the northern Espirito Santo State in Brazil. Morphological features identifying the plant material and the voucher specimen (No. 41895) were deposited in the Biology Museum Mello Leitão, Santa Teresa. Extraction and Isolation. The fresh fruits (500 g) were crushed in a blender with EtOH, and the mixture was transferred to an Erlenmeyer flask and allowed to stand for 15 days. After drying (54 g), the EtOH extract was suspended in a solution of MeOH/H2O (9:1) to be partitioned with n-hexane (3 × 300 mL). After removal of MeOH, the aqueous layer was partitioned between CH2Cl2 (3 × 300 mL) and EtOAc (3 × 300 mL), respectively. By this procedure, n-hexane (6.5 g), CH2Cl2 (8.7 g), EtOAc (11.9 g), and aqueous (20.8 g) extracts were obtained. The EtOAc fraction (2.0 g) was chromatographed on a Sephadex LH-20 open column with MeOH as the mobile phase. The obtained fractions (50) were developed on a silica gel TLC plate and sprayed with NP/PEG (a chromogenic reagent specific for flavonoids) to search for flavonoids, which were found to occur in fractions 23−30 (yellow spots). These fractions were pooled (440 mg) and subjected to a second Sephadex LH-20 separation, this time with MeOH/H2O (7:3) as the mobile phase. The flavonoid agathisflavone (20 mg) was obtained from fractions 38−46. Computational Details and Similarity Analysis. These details are provided on p 41, Supporting Information.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.6b00395. 1 H NMR, COSY, HSQC, HMBC, and APT spectra, chromatograms, Boltzmann populations, Cartesian coordinates of 16 lowest energy conformers, graphical view of the dominant conformer, computational methods, similarity analysis, and similarity plots (PDF)

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AUTHOR INFORMATION

Corresponding Author

*Phone: (615)322-2836. Fax: (615)322-4936. E-mail: Prasad.L. [email protected]. Notes

The authors declare no competing financial interest.

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EXPERIMENTAL SECTION

General Experimental Procedures. The optical rotation (OR) data at five different wavelengths, namely, 633, 589, 546, 436, and 405 nm, were determined in MeOH using an Autopol IV polarimeter. Three different concentrations, 0.03, 0.04, and 1.38 mg/mL, were used for these measurements. ECD spectra in the 190−450 nm region were

ACKNOWLEDGMENTS We wish to thank CNPq, CAPES, and an NSF grant (CHE1464874) for financial support and Dr. O. McConnell for assistance with chiral HPLC analysis. This work was conducted 2535



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in part using the resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University, Nashville, TN, USA.

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