Schinortriterpenoids with Identical Configuration but Distinct ECD

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Schinortriterpenoids with Identical Configuration but Distinct ECD Spectra Generated by Nondegenerate Exciton Coupling Yi-Ming Shi,†,⊥ Kun Hu,†,‡,⊥ Gennaro Pescitelli,*,§ Miao Liu,† Xiao-Nian Li,† Xue Du,† Wei-Lie Xiao,† Han-Dong Sun,† and Pema-Tenzin Puno*,† †

State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, People’s Republic of China ‡ University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China § Dipartimento di Chimicae Chimica Industriale, Università di Pisa, Via Moruzzi 13, 56124, Pisa, Italy S Supporting Information *

ABSTRACT: Ten schinortriterpenoids with biogenetically related lancischiartane scaffolds, including the first 3-norlancischiartane (1) with unusual configuration inversions occurring at C-1 and C-10, were isolated from Schisandra lancifolia. Unusual ECD curve patterns observed in 6−8 were confirmed to be caused by nondegenerate exciton coupling, suggesting that ECD spectrum empirical comparison should be used with caution in configuration determination. Additionally, structure revision of 2, originally proposed as arisanlactone A, was completed using NMR computation and X-ray diffraction analysis.

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confirmed to share the same structure with arisanlactone A,7 which is revised and reclassified into lancischiartanes herein. In addition, it is worth mentioning that the diagnostic Cotton effects (CEs) for C-20 configurational determination in electronic circular dichroism (ECD) spectra, which are attributed to the α,β,γ,δ-unsaturated-γ-lactone chromophore in the side chain and occur around 275 nm (π → π* transition) as in 1−5, 9, and 10, were found to be rather ambiguous in compounds 6−8 (Table S1). The unusual phenomenon was caused by the newly emerged α,β-unsaturated-γ-lactone chromophore in ring B and its interaction with the chromophore in the side chain, which involves the nondegenerate exciton coupling (NDEC) mechanism.8 This paper elaborates on structural elucidation of 1, structural revision of 2, and a demonstration of the NDEC existing in 7. Schilancidilactone C (1) was obtained as colorless needle crystals. Its molecular formula was determined as C28H38O9 by HRESIMS (m/z 541.2423 [M + Na]+, calcd 541.2413), indicating ten degrees of unsaturation. Extensive analysis of the 1D NMR data (Table S3) pointed to an SNT with a hexacyclic structure for 1. Through careful analysis of the 1D and 2D NMR data (Figure S4), 1 was found to be highly similar to schilancitrilactone B9 in their rings D−G. Also, the 1 H−1H COSY correlations of H-5/H2-6/H2-7/H-8, along with the HMBC correlations between H2-19 and C-5, C-8, C-9, and C-10, constructed the typical seven-membered ring in 1 with oxygenated C-9 and C-10. Two methyl signals at δH 1.14 (s)

chinortriterpenoids (SNTs) are a class of highly oxygenated, rearranged terpenes exclusively discovered from plants of the Schisandraceae family.1 Since their debut in 2003,2 many phytochemical investigations have been conducted in the past decade, expanding the SNT repertoire to 19 biosynthetically related types with 213 members.3 The diversity of SNTs not only creates chemical space for the exploration of bioactive molecules4 but also provides interesting targets for synthetic chemists (Figure S1).1,5 From the structural point of view, the consecutive quaternary carbons, polycyclic fused ring systems in a sterically congested region, and flexible side chain with stereogenic centers characteristic of SNTs pose significant challenges for their structure elucidation, requiring the combination of theoretical calculations and chemical derivatizations with various NMR techniques.6 Schisandra lancifolia (Rehd. et Wils.) A. C. Smith, a woody climbing plant of the genus Schisandra, is mainly distributed in the southwest of China. Investigations on the chemical constituents of S. lancifolia collected from Nujiang prefecture was initiated in 2008, thus far leading to the discoveries of a range of new scaffolds (Figure S2). The HPLC profile of the SNTs fraction of S. lancifolia showed most of the peaks with a maximum UV absorption band around 275 nm, suggesting that lancischiartanes and their derivatives bearing an α,β,γ,δunsaturated-γ-lactone moiety in the side chains are the major components. In our present research, ten SNTs with a series of biogenetically related lancischiartane scaffolds were obtained (Figure 1). Among them, schilancidilactone C (1) represents the first 3-norlancischiartane with unusual configurational inversions occurring at C-1 and C-10. Compound 2 was © XXXX American Chemical Society

Received: January 18, 2018

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DOI: 10.1021/acs.orglett.8b00149 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Figure 2. ORTEP representation of crystal structures of 1 (left) and 2 (right).

diagnostic CEs around 275 nm in 6−8 (Figure 3) prevented us from determining the configuration of C-20 via previously

Figure 3. Experimental ECD spectra of 1 (green; typical curve) and 6−8 (orange, blue, red, respectively; atypical curves) in MeOH.

Figure 1. Chemical structures of SNTs isolated from S. lancifolia (1− 10) and S. propinqua (11). Originally proposed chemical structure of arisanlactone A.7

established empirical rules.9 Then, time-dependent densityfunctional theory (TDDFT)10 ECD theoretical calculations at the B3LYP-SCRF/6-31+G(d,p)//B3LYP/6-31G(d) level in MeOH with a polarizable continuum model (PCM) were employed to assign the absolute configurations of 6−8 (Figures S7, S8, and S10). The respective calculated ECD spectra of the two possible C-20 epimers of 6 (6a and 6b) and 7 (7a and 7b) were brought into comparisons with their experimental counterparts. The consistent calculated ECD curves provided by (6S,8R,9S,10S,12R,13R,14S,17R,20S,22E)-6 (6a), (8R,9S,10S,12R,13R,14S,17R,20S,22E)-7 (7a) allowed the establishment of the absolute configurations of 6 and 7. An X-ray diffraction analysis of 8 (Figure 4) with an imperfect Flack parameter of 0.4(6) and the subsequent TDDFT ECD calculation of two possible enantiomers at the same level of

and 1.31 (s) correlating with the oxygenated quaternary carbon δC 81.9 and 47.0 (C-5) were determined to be the characteristic 4,4-gem-dimethyl group. The last methyl at δH 1.38 (s), which exhibited correlations with C-10 and another ketal carbon atom at δC 105.3 (C-1), was assigned as C-2 and deduced to form biogenetically via degradation of C-3. Despite the inadequate evidence provided by the ROESY spectrum for configuration determination, a suitable crystal of 1 for X-ray diffraction analysis with Cu Kα radiation was obtained. The experiment validated the chemical structure of 1 with a sufficient Flack parameter of 0.3(3) and a Hooft parameter of 0.17(12), which unambiguously determined the absolute stereochemistry of 1 to be 1S, 5R, 8R, 9S, 10S, 12R, 13R, 14S, 17R, and 20S (Figure 2). Surprisingly, the C-1 and C-10 were found to have endured unusual configurational inversions compared to reported SNTs with C-1 hemiketal,1 such as schindilactones A−C.6a Structure elucidation of 2 manifested that it shared the same structure with the previously reported arisanlactone A,7 the configuration of C-13, C-17, and C-20 in whose structure was revised using NMR quantum chemical calculation and X-ray diffraction analysis (Figure S5, Table S2, and Figure 2). Accordingly, arisanlactone A is reclassified as a lancischiartane type instead of a wuweiziartane type. Then, the structures as well as the configurations of the close analogues of 2, schilancitrilactones D−F (3−5), were also safely established (see Supporting Information (SI) for details). The structures of other compounds, schilancitrilactones G− K (6−10), were mainly elucidated utilizing 1D and 2D NMR spectroscopy (see SI for details). However, the absence of the

Figure 4. ORTEP representation of crystal structure of 8. B

DOI: 10.1021/acs.orglett.8b00149 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters theory as stated above supported the absolute configuration of 8 to be assigned as 8R, 9S, 12R, 13R, 14S, 17S, 20S, and 22E. All reported compounds (1−10) possess biogenetically related lancischiartane scaffolds and uniform C-20S configurations. Inspecting the set of ECD spectra of compounds 1− 10 (Table S1), we can recognize a consistent pattern for 1−5, 9, and 10 which is in line with previously reported SNTs.9,11 In contrast, compounds 6−8 deviate substantially from the usual pattern. The structural difference between the two sets occurred mainly in ring B, which is mostly saturated and nonchromophoric in the former set (9 being exceptional and will be discussed below), while it all contains an α,βunsaturated lactone chromophore in the latter set. Therefore, an NDEC may exist between the α,β-unsaturated-γ-lactone in ring B and the α,β,γ,δ-unsaturated-γ-lactone in ring G,12 generating the atypical ECD pattern. To corroborate this hypothesis, we undertook a transition and molecular orbital (MO) analysis (Figure 5) using 7a-1, the

Figure 6. ECD spectra of 11 (orange) and 7 (green). Difference ECD spectrum between 7 and 11 (red, 7 minus 11), and that between 9 and 10 (blue, 9 minus 10).

Similar to the common degenerate exciton coupling, NDEC responds to the exciton chirality rule which states that the sign of the couplet is the same as the chirality defined by the coupled transition moments.8,12 The relevant chromophores in rings B and G were modeled with the two fragments shown in Figure S9. TDDFT calculations of the two fragments were undertaken at the CAM-B3LYP/def2TZVP//B3LYP/6311+G(d,p) level. The first π → π* transitions were characterized by the densities and the transition moment directions depicted (Figure S9). The moments were projected on conformer 7a-1 to assess their reciprocal arrangement and the chirality defined thereof (Figure 7). The negative dihedral

Figure 5. Key MOs involved in important transitions in the ECD spectrum of the conformer 7a-1 at the B3LYP-SCRF/6-31+G(d,p) level with PCM in MeOH.

lowest-energy conformer of 7a with 42.7% population, as an illustrative example. Three transitions concurred to the ECD in the long wavelength region (Table S32), where a negative CE was found experimentally: a π → π* transition in the α,β,γ,δunsaturated-γ-lactone (MO129 → MO130, positive rotational strength calculated at 286 nm); an n → π* transition on the same moiety (MO123 → MO130, negative rotational strength at 267 nm); and a charge-transfer transition from the α,βunsaturated-γ-lactone to the α,β,γ,δ-unsaturated-γ-lactone (MO128 → MO130, negative rotational strength at 268 nm). Moreover, the positive CE at 220 nm was allied with the π → π* transition of the α,β-unsaturated-γ-lactone (MO128 → MO131). Although the real occurrence of NDEC did not emerge clearly from the MO analysis, this latter demonstrated a high impact on the ECD spectrum exerted by the conjugated chromophore in ring B. To highlight the importance of NDEC from an experimental viewpoint, we compared the ECD spectra of 7 and schilancitrilactone L (11, Figure 1), a lancischiartane SNT isolated from S. propinqua sharing exactly the same ring system C−G as 3, but with a saturated B ring. This compound exhibits a positive CE at 275 nm with a g-value (Δε/ε) of 2 × 10−4, which is typical for lancischiartanes with an α,β,γ,δ-unsaturatedγ-lactone moiety (Figure S128). The difference ECD spectrum13 (7 minus 11) was plotted (Figure 6), which evidenced a seemingly negative exciton couplet between 200 and 300 nm possibly due to the NDEC between the two chromophores on rings B and G.

Figure 7. Negative exciton chirality between π → π* transitions for conformer 7a-1. A′A″ and B′B″ are transition dipoles, with A and B being their respective centers. The exciton chirality is defined by the dihedral angle A′−A−B−B′ (−44°; α, β < 90°).

angle A′−A−B−B′ (−44.0°) defined a negative exciton chirality, consistent with the negative exciton couplet seen in difference spectrum (7 minus 11) in Figure 6. It must be stressed that the NDEC mechanism is much weaker than its degenerate analog, and therefore it is easily overcome by other sources of ECD signals, if allowed by the molecular skeleton.14 This is certainly the case for the present compounds which feature multiple centers of chirality proximate to the chromophores, as demonstrated by the fact that the g-values for the difference spectrum shown in Figure 6 is around 5 × 10−4, a rather small value for an exciton coupling mechanism. This can be better appreciated by applying the spectrum difference method to compound 9. The difference ECD spectrum of 9 and its C-5/C-10 reduced analog 10 displayed no clear-cut exciton couplet (Figure 6). This observation suggests that, because of the Z geometry of the C-22/C-23 double bond in 9, the NDEC between the two chromophores becomes weaker. The impact of the C-22/C-23 geometry on ECD spectra emerges clearly by comparing C

DOI: 10.1021/acs.orglett.8b00149 Org. Lett. XXXX, XXX, XXX−XXX

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compounds 6−8 with an E configuration to 9 with a Z configuration (Figure 1). At this point, the atypical ECD curves of 6−8 have been explained. Still, it is quite interesting that the ECD spectra of compounds 6 and 7 are quite different (Figure 3), despite the strong structural similarity and consistent configuration of the corresponding chiral centers. A transition and orbital analysis was carried out on the lowest-energy conformers of 6a (Figure S130) and 7a (Figure 5), which revealed that the allylic α-OH in 6a-1 heavily affects the orbitals of the α,β-unsaturated lactone on ring B. For example, the bonding π orbital is HOMO−2 (MO131) in compound 6 and HOMO−1 (MO128) in 7. The energies are also pretty different (0.00382 hartree), which is responsible for the fact that in 7 this orbital is well localized, while in 6 it is overlapped with atomic orbitals up to ring F. The effects on the ECD curve of substituents in the allylic position to a conjugated system are well-known, for example for the diene chromophore.15 In conclusion, though an important technique for absolute configuration determination in natural products, ECD is also the source of many structural misassignments;16 for example, the recently corrected preussilides A−F were erroneously assigned due to an incorrect application of the exciton chirality method.17 Notably, the prevalent application of ECD spectrum empirical comparison also involves the risk of making mistakes in structure elucidation. While molecules with multiple chromophores are common in natural products, ECD empirical rules for configuration determination are often established for simple systems and their applicability can be further influenced by many factors, such as the NDEC and allylic substituents as discussed herein. For instance, the chemical structures of a number of 3,4:9,10-disecocycloartanes previously reported from the Schisandraceae plants,1 often possessing multiple chromophores, are being re-examined by our laboratory, because the empirical rules used for their C-22 configuration determination are generally inconsistent or even contradictory. Additionally, the potential interactions between chromophores were generally neglected. As a whole, this study underlines the importance of implementing various experimental techniques together with theoretical calculations when establishing the absolute configuration of complex natural products, rather than merely using empirical comparison.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Yi-Ming Shi: 0000-0001-6933-4971 Gennaro Pescitelli: 0000-0002-0869-5076 Pema-Tenzin Puno: 0000-0001-5212-3000 Author Contributions ⊥

Y-.M.S. and K.H. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grants 81373290, 21322204, and 81673329). The quantum chemical calculation sections were supported by the HPC Center of KIB, CAS. The authors thank the group of Prof. Hua-Liang Jiang in Shanghai Institute of Materia Medica, Chinese Academy of Sciences for completing conformational analysis in this paper.

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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.orglett.8b00149. Structure elucidation processes of 2−10; NMR data of 1−11; experimental section; 1D and 2D NMR, MS, ECD, UV, and IR spectra for 1−11; computational data of 2, 6−9; results of the biological activity evaluation (PDF) Accession Codes

CCDC 1579034 and 1579036−1579037 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/ cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. D

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DOI: 10.1021/acs.orglett.8b00149 Org. Lett. XXXX, XXX, XXX−XXX