Revision of the Absolute Configuration of Preussilides A–F

Note Cite This: J. Nat. Prod. 2017, 80, 2855-2859

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Revision of the Absolute Configuration of Preussilides A−F Established by the Exciton Chirality Method Gennaro Pescitelli* and Lorenzo Di Bari Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Moruzzi 13, 56124 Pisa, Italy S Supporting Information *

ABSTRACT: In a recent contribution to this Journal (J. Nat. Prod. 2017, 80, 1531−1540), Noumeur et al. reported the isolation and structure elucidation of six novel polyketides named preussilides A−F, endowed with remarkable antiproliferative activity. The absolute configuration of the new compounds was established mainly by analyzing excitoncoupled electronic circular dichroism (ECD) spectra. However, the application of the exciton chirality method (ECM) was incorrect, because the chirality defined by transition moments was assigned in a wrong way. A correct application of the ECM, substantiated by time-dependent density functional theory (TDDFT) calculations of ECD spectra, led us to revise the absolute configuration of Preussilides A−F. A brief discussion on the criteria required for a correct application of the ECM is also presented.

C

couplet, that is, two bands of opposite sign and similar intensity, with wavelengths centered on the two sides of the chromophore UV maximum. The positive or negative sign of the exciton couplet (defined as the sign of the long-wavelength branch) depends on the absolute arrangement between the two transition dipoles, which is in turn dictated by several factors including, most importantly, the absolute configuration. In the typical application of the ECM, one looks at the chirality defined by the two transition dipoles, that is, at their reciprocal angle of twist: clockwise for positive chirality and counterclockwise for negative chirality. Thereafter, a positive chirality is reflected in a positive exciton couplet, and a negative chirality in a negative exciton couplet. If the molecular conformation is known, one may immediately translate the established chirality into the desired piece of information, e.g., the absolute configuration. It is often said that the exciton chirality rule is nonempirical, because it is based on a wellestablished theoretical basis. In fact, one may quantitatively predict the sign and intensity of an exciton couplet using simple formulas that depend essentially on the geometry of transition dipole moments.10,12,15,16 On the other hand, when one applies the straightforward or visual method, the focus is exclusively put on a single geometrical parameter, namely, the torsion angle γ between the transition dipoles (Figure 1a). However, the geometrical dependence of the couplet sign on the geometry is more complex than just a simple function of γ. In fact, the couplet sign and amplitude depend on the so-called geometrical factor GFαβγ:12,15,16

hirality plays a fundamental role in the interaction between small molecules and living organisms,1 and for this reason, the assignment of absolute configuration is necessary for every novel chiral natural product discovered. In fact, more than 80% of all known natural products are chiral.2 A full stereochemical characterization is especially required for those natural compounds that show biological activity with the potential to be therapeutic agents or precursors thereof.3,4 Frequently, the assignment of relative and absolute configuration is the most difficult step in the structure elucidation process, and, not surprisingly, the revision of the configuration of one or more stereogenic elements is a common reason for structural revisions of natural products.5−7 Chiroptical techniques such as electronic circular dichroism (ECD) are commonly employed, in addition to total synthesis and X-ray diffractometry, to assign the absolute configuration of novel natural products, nowadays especially in combination with quantum-mechanical calculations.8,9 One of the advantages of ECD with respect to other chiroptical spectroscopies such as vibrational CD (VCD) and Raman optical activity (ROA)10 is that several approaches exist by which ECD data may lead to the absolute configuration in a straightforward way, e.g., without the need for calculations.11 The most efficient of these approaches is indisputably the exciton chirality method (ECM),12 which is still very popular in the context of natural products discovery.13,14 The ECM is applicable to molecules containing two or more chromophores endowed with electricdipole-allowed transitions, if the directions of the electric transition dipoles are known and suitably arranged with respect to each other (not parallel, coplanar, or collinear). The exciton coupling between the transition dipoles is responsible, among other things, for a typical ECD feature called an exciton © 2017 American Chemical Society and American Society of Pharmacognosy

Received: August 29, 2017 Published: October 17, 2017 2855

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applications is well exemplified by the case of preussilides A−F (1−6, Scheme 1) recently reported in this Journal.19 Scheme 1. Proposed19 (Left Column) and Revised (Right Column) Structures of Preussilides A−F (1−6)a

Figure 1. (a) Definition of geometrical parameters (angles α, β, and γ) necessary to estimate the geometry of exciton chirality. (b) Contour plot of GFαβγ calculated with eq 1 as a function of α and γ for β = 36° (corresponding to the situation found in 1). Yellow-red hues represent positive values of GF, and cyan-blue hues negative values. Notice the regions for which the sign of the torsion angle γ is at odds with the sign of GF. The markers show the collocation for (13S)-1 (green diamonds) and (13R)-epi-1 (red circles); the darker colors correspond to the most populated subset in each case. a

The proposed structure of 1 is indicated as (13R)-epi-1 in the text, and the revised structure as (13S)-1. The red bonds in the upper left structure highlight the atoms defining the dihedral angle ω14‑15‑16‑17, which deviates from planarity.

GFαβγ = sin α sin β sin γ(sin α sin β cos γ + 2 cos α cos β)

(1)

where α and β are the angles between each of the two transition dipoles and the line connecting the two point-dipoles (Figure 1a). The first factor in eq 1 arises from the rotational strength, while the second from the coupling potential.12,15,16 Both the rotational strength and the coupling potential determine the sign of the couplet, although the second factor is often neglected because the coupling potential isincorrectly assumed to be always positive.17,18 Apart from this issue, it is clear that the contribution of angles α and β cannot be overlooked. This fact can be appreciated from Figure 1b, showing the contour plot of GFαβγ as a function of α and γ for a fixed value of β = +36° (justified later). Clearly, there are regions of the plot for which the sign of the torsional angle γ does not coincide with the sign of the geometrical factor, which is the only quantity univocally related to the sign of the couplet. The simplest waystill not completely accurateto take angles α and β into account without sacrificing the immediacy of the visual approach is by choosing the correct viewpoint when looking at the transition dipole chirality. To do so, one must look along the line connecting the point-dipole centers, instead of using an off-line viewpoint in favor of a better appearance of the whole molecule. Second, one must consider the angle γ defined by the dipole directions chosen consistently, that is, in a way that α and β are both ≤90° (Figure 1a). The importance of choosing the correct viewpoint in exciton

The authors isolated six novel bicyclic polyketides from the endophytic fungus Preussia similis obtained from the medicinal plant Globularia alypum. Some of the compounds exhibited interesting biological activities, including antiproliferative effects against eukaryotes. The structures of preussilides A−F, including the relative configuration of the multiple chirality centers on the bicyclic ring, were elucidated by means of a combination of spectroscopic techniques. The absolute configuration at C-2 of preussilide A (1) was assigned as (2S) by the Mosher method.19 To assign the absolute configuration of the remaining chirality centers, the authors took advantage of the presence of two conjugated chromophores, namely, the endocyclic cis-diene (from C-4 to C-7) and the exocyclic trienoate (from C-14 to C-20) attached at C-13. The authors correctly speculated that the exciton coupling between these two chromophores would be dictated by the configuration at C-13. The ECD spectra of all compounds 1−6 in ethanol did in fact show a negative couplet between 240 and 340 nm with moderate intensity,20 indicating a negative chirality between transition dipole moments. The ECD spectrum of compound 1 is reproduced in Figure 2. For the quasi-planar cis-diene chromophore, the relevant π−π* transition is directed along the diene long axis and the point2856

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difficult to appreciate whether the dipole relative to the trienoate lies in the front or in the back with respect to the dipole relative to the diene. As we shall see below using more appropriate models, the correct chirality defined by the transition dipoles depicted in Figure 3 is positive and not negative as it may seem and as assumed by the authors. Then, we decided to reexamine the case of preussilides more accurately. In fact, if our hypothesis was correct, the absolute configuration of all chirality centers of preussilides A−F needed to be revised, with the only exception of C-2 for compound 1. We focused on compound 1, considering both the proposed configuration (2S,9R,11S,12S,13R)-1 [hence briefly indicated as (13R)-epi-1] and the revised configuration (2S,9S,11R,12R,13S)-1 [hence briefly indicated as (13S)-1], and ran a conformational analysis with molecular mechanics (MMFF force field) to find the most stable conformers. The set of NOEs described in the original paper (also shown in Figure 3)19 was employed as a postprocessor filter to eliminate conformers that did not satisfy the observed NOEs. The filtered conformational ensemble was then optimized with density functional theory (DFT) at the ωB97X-D/6-31G(d) level. In this way, we obtained several low-energy minima, namely, 52 conformers for (13R)-epi-1 and 44 for (13S)-1 with relative energies within 4 kcal/mol; the most stable conformers are shown in the Supporting Information. However, we noticed that the minima could be grouped into two subsets differing in the torsion around the C-15/C-16 bond. In fact, the dihedral angle ω14−15−16−17 (Scheme 1) may attain either a negative value around −45° (ω−) or a positive one around +45° (ω+). The preference is for ω+ for (13R)-epi-1 (64% overall population) and ω− for (13S)-1 (76% overall population). In each subset, the conformers varied mostly in the rotamerism of the C-1/C-3 chain, but, importantly, the relative arrangement between the two chromophores was almost unchanged within each subset (see structures in the Supporting Information). This allowed us to focus only on the two lowest energy conformers with ω+ and ω− in the following analysis, as representatives of the two subsets, after assigning them the overall population estimated for the respective subset. First, we again applied the exciton chirality method to the relevant conformations of (13R)-epi-1 and (13S)-1 adopting the correct viewpoint explained above. For (13R)-epi-1, both conformers with ω± define a positive chirality (Figure 4). Interestingly enough, the lowest energy DFT-optimized structure of (13R)-epi-1 is very similar to the PM3-optimized one reported in the original paper,19 demonstrating that the wrong absolute configuration assignment discussed here is not due to a conformational issue.21 Conversely, for (13S)-1, both conformers with ω± define a negative chirality (Figure 4). Because of the negative couplet found experimentally for 1 (Figure 2), the correct absolute configuration is then (13S)-1. A numerical estimation of the exciton chirality was also made by calculating the geometrical factor GFαβγ from eq 1. The relevant geometrical parameters were extracted from DFT geometries using the aforementioned position and direction of transition dipoles (depicted in Figure 4) and are listed in Table 1 along with the geometrical factor GFαβγ estimated thereof. For (13R)epi-1, the GF is positive and very similar for the representatives of the two ω± subsets; for (13S)-1, the GF is negative and again similar for both subsets (Table 1). The values corresponding to ω± subsets for each compound are represented with markers in Figure 1b. As explained above, the contour plot displays the dependence of GFαβγ as a function of angles α and γ, while

Figure 2. Experimental ECD spectrum of preussilides A adapted from ref 19, with permission, compared with spectra calculated with the TDDFT method for (13R)-epi-1 and (13S)-1 as described in the text. Calculated spectra were plotted as sums of Gaussians with a 0.45 eV exponential half-width; they were red-shifted by 5 nm and scaled using the same factor. The vertical scale is in arbitrary units.20

dipole may be placed halfway between the centers of the double bonds. For the trienoate system the situation is a little more complicated because the dihedral angle from C-14 to C-17 (highlighted in red in Scheme 1) is distorted from the ideal value of 180° due to the methyl groups (Me-24 and Me-25). Still, a reasonable choice would consider the relevant π−π* transition directed along the C-15/C-19 direction (or the equivalent C-14/C-20) and the point-dipole placed in the proximity of C-17. This seems in fact to have been the choice of the authors when drawing the transition dipoles in the molecular model of 1 they used to establish the exciton chirality.19 The model, here reproduced in Figure 3, has a

Figure 3. Model used by Noumeur et al. to establish the absolute configuration of compound 1.19 The model was obtained by PM3 geometry optimizations and agreed with observed NOEs (depicted by red curved double arrows). The black double arrows represent transition dipole moments which define a positive chirality and not a negative one as proposed (see the diagrams on the right). Reproduced from ref 19, with permission.

(2S,9R,11S,12S,13R) configuration and was obtained by PM3 geometry optimizations. Apparently, it was drawn from a viewpoint that offers a good perspective of the molecule, but it is far from the correct direction mentioned above, that is, the line connecting the point-dipole centers. Such a perspective may have misled the authors and made them assign a negative chirality between the transition dipoles. In fact, from the observer viewpoint for the model reported in Figure 3, it is 2857

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analysis we performed on compound 1 is also valid for preussilides B−F. It must be stressed that for none of the compounds structurally related to preussilides A−F recognized in the original paper, namely, antarones, 24 (dihydro)amigerone,25 and two unnamed polyketides,26 has the absolute configuration of the cyclic system been established to date. The source of the erroneous assignment lies in an incorrect application of the exciton chirality method, due to an improper viewpoint chosen to establish the chirality defined by transition moments. We would like to stress, however, that any visual application of the exciton chirality rule necessarily overlooks many of the structural parameters that ultimately decide the sign of the ECD couplet. Therefore, when new systems are encountered that fall outside well-known families such as bisbenzoates or other aromatic esters of 1,2-diols, 1,1′-binaphthyls, etc., and in general in all cases when the exciton chirality cannot be immediately established by molecular models, a quantitative confirmation is desirable. This does not necessarily amount to running quantum-mechanical calculations; quantitative exciton calculations are in fact quickly run either by applying exciton formulas as demonstrated above or alternatively by coupledoscillator calculations.27

Figure 4. Lowest energy DFT structures calculated at the ωB97X-D/ 6-31G(d) level for compounds (13R)-epi-1 (top) and (13S)-1 (bottom) representative of the two subsets with positive or negative dihedral angle ω14−15−16−17 (indicated as ω+ and ω−, respectively) and exciton chirality defined by the two relevant transition dipoles (blue double arrows).

Table 1. Structural Parameters and Exciton Chirality Geometrical Factors Estimated Thereof for the Conformational Representative of Compounds (13R)-epi-1 and (13S)-1 Corresponding to Subsets ω± Described in the Texta compound

conformational subset

α/degb

β/degb

γ/degb

GFαβγc

(13R)-epi-1

ω+ (major) ω− (minor) ω− (major) ω+ (minor)

+85 +85 +80 +88

+36 +36 +37 +36

+68 +62 −66 −56

+0.20 +0.21 −0.28 −0.19

(13S)-1

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COMPUTATIONAL SECTION

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ASSOCIATED CONTENT

Conformational searches were run with Spartan’16 (Wavenfunction, Irvine, CA, USA, 2016) using the Monte Carlo algorithm and Merck molecular force field (MMFF) with standard parameters and convergence criteria. DFT calculations were run with Spartan’16 with default grids and convergence criteria. TDDFT calculations were run with Gaussian’1628 with default grids and convergence criteria. The MMFF minima found for (13R)-epi-1 and (13S)-1 by conformational search were analyzed using as postprocessor filter the set of NOEs shown in Figure 3. The conformers satisfying the NOE filter were optimized with DFT at the ωB97X-D/6-31G(d) level in vacuo. As a result, 44 conformers were obtained for (13S)-1 and 52 conformers for (13R)-epi-1, within an energy window of 4 kcal/mol. The conformational set for each compound was divided into two subsets according to the positive or negative value assumed by the dihedral angle ω14−15−16−17 (ω+ or ω−), as discussed in the text. The lowest energy structure for each subset is shown in Figure 4, while all conformers with populations >3% at 298 K (estimated using internal energies) are shown in the Supporting Information. TDDFT calculations were run at the CAM-B3LYP/def2-SVP level of theory including 36 excited states (roots). Only the lowest energy structures of each ω+ or ω− subset were considered in TDDFT calculations; thereafter, the calculated ECD spectra were Boltzmann-averaged using the overall populations of the two subsets: for (13S)-1, 76% ω− and 24% ω+; for (13R)-epi-1, 36% ω− and 64% ω+. Calculated spectra were plotted as sums of Gaussians with a 0.45 eV exponential half-width using the program Specdis.29,30 The data shown in Table 1 were computed numerically, using eq 1 and the values of angles α, β, and γ extracted from DFT-optimized structures, as explained in the text. The contour plot shown in Figure 1 was obtained with the Mathematica 8 package, plotting eq 1 as a function of α and γ with β = 36°.

a Values of α, γ, and GF (for β = +36°) are also plotted in Figure 1b with markers. bSee definitions in Figure 1. Angle α refers to diene and β to trienoate. cFrom eq 1.

angle β was kept fixed at +36°, which is the value approximately found for all relevant structures considered (Table 1). Examining the plot and the values listed in Table 1, the chirality appraised from the correct visual inspection is substantiated by applying the exciton formula, which confirms for (13R)-epi-1 a positive chirality and for (13S)-1 a negative one (the latter is experimentally found). As an independent check, we performed quantum-mechanical ECD calculations22 on compounds (13R)-epi-1 and (13S)1 with the time-dependent DFT method (TDDFT) at the CAM-B3LYP/def2SVP level,8 using the DFT-optimized representative structures described above. The results are shown in Figure 2 and predict a positive exciton couplet for compound (13R)-epi-1 and a negative exciton couplet for the revised compound (13S)-1. Transition and orbital analysis on calculation outputs confirmed that the apparent couplet-like ECD features are in fact due to the exciton coupling between the π−π* transitions of the cis-diene and trienoate chromophores (Supporting Information). The vicinity in space and proper orientation between the chromophores make their nondegenerate exciton coupling strong enough to dominate the ECD spectrum.23 In conclusion, the reported absolute configurations of preussilides A−F (1−6)19 are incorrect and should be revised as shown on the right side of Scheme 1. In fact, all preussilides A−F (1−6) show consistent ECD spectra with a negative exciton couplet in the 240−340 nm region; therefore the

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.7b00740. DFT-optimized structures for the most stable conformers of (13R)-epi-1 and (13S)-1 and relevant data; transition and orbital analysis of (13S)-1 (PDF) 2858

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average sample concentration of 2.5 mM, 10 mdeg would correspond to 12 Δε units. (21) Pescitelli, G.; Di Bari, L.; Berova, N. Chem. Soc. Rev. 2011, 40, 4603−4625. (22) Srebro-Hooper, M.; Autschbach, J. Annu. Rev. Phys. Chem. 2017, 68, 399−420. (23) Pescitelli, G.; Di Bari, L. Chirality 2017, 29, 476−485. (24) Shiono, Y.; Seino, Y.; Koseki, T.; Murayama, T.; Kimura, K. Z. Naturforsch. 2008, 63b, 909. (25) Breinholt, J.; Kjær, A.; Olsen, C. E.; Rassing, B. R.; Rosendahl, C. N. Acta Chem. Scand. 1997, 51, 1241−1244. (26) Stierle, D. B.; Stierle, A. A.; Ganser, B. K. J. Nat. Prod. 1999, 62, 1147−1150. (27) Superchi, S.; Giorgio, E.; Rosini, C. Chirality 2004, 16, 422− 451. (28) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson, G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.; Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J. V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams; Ding, F.; Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson, T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.; Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov, V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 16, Revision A.03; Wallingford, CT, 2016. (29) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y.; Pescitelli, G. SpecDis version 1.71; Berlin, Germany, 2017, https://specdis-software. jimdo.com/. (30) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y.; Bringmann, G. Chirality 2013, 25, 243−249.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Gennaro Pescitelli: 0000-0002-0869-5076 Lorenzo Di Bari: 0000-0003-2347-2150 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Dr. Hu Kun (Kunming Institute of Botany) is kindly acknowledged for drawing our attention to the discussed case.

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REFERENCES

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