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Published February 28, 2023 | Version v1
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Eudesmane type sesquiterpenes from the rhizomes of Atractylodes macrocephala and their bioactivities

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  • 1. ** & * & Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, China

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Zhang, Hai-Xin, Si, Jin-Guang, Li, Jing-Rong, Yu, Meng, Qin, Ling-Ling, Zhao, Chen-Xu, Zhang, Tao, Zou, Zhong-Mei (2023): Eudesmane type sesquiterpenes from the rhizomes of Atractylodes macrocephala and their bioactivities. Phytochemistry (113545) 206: 1-13, DOI: 10.1016/j.phytochem.2022.113545, URL: http://dx.doi.org/10.1016/j.phytochem.2022.113545

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urn:lsid:plazi.org:pub:64615067BE15C647A172FFA4221DFFAD

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Figure: 10.5281/zenodo.8230611 (DOI)
Figure: 10.5281/zenodo.8230613 (DOI)
Figure: 10.5281/zenodo.8230615 (DOI)
Figure: 10.5281/zenodo.8230617 (DOI)
Figure: 10.5281/zenodo.8230619 (DOI)

References

  • Compound 1 was isolated as yellow colored oil. The IR spectrum of 1 showed the presence of hydroxy and amide carbonyl (3073 and 1621 cm 1) functionalities. The molecular formula C21H23NO2 with 11 degrees of unsaturation was deduced from HRESIMS at m/z 322.1802 [M + H]+ and NMR spectroscopic data (Tables 1 and 3). The NMR spectroscopic data of 1 closely resembled those of cespilamide C (Wang et al., 2015), which was previously reported as a rare nitrogen-containing sesquiterpene with a phenylethyl group. Comparison of the NMR spectroscopic data between 1 and cespilamide C suggested that the phenylethyl unit at nitrogen atom in cespilamide C was replaced by 2'-hydroxyphenyl [δ H 6.96 (dd, J = 8.2, 1.3 Hz, H-3'), 7.25 (ddd, J = 8.2, 7.3, 1.6 Hz, H-4' ), 6.91 (td, J = 7.6, 1.3 Hz, H-5'), and 7.06 (dd, J = 7.6, 1.6 Hz, H-6'); δ C 122.8 (C-1' ), 155.3 (C-2'), 117.9, (C-3'), 130.8 (C-4' ), 120.8 (C-5'), and 131.2 (C-6' )] moiety in 1. The conclusion was confirmed by 2D NMR data analysis (Fig. 2) of 1, particularly by the 1H-1H COSY cross-peaks of H-3'/H-4'/H-5'/H-6' and the HMBC correlations from H-3' to C-1' and C-5', from H-4' to C-2' and C-6', from H-5' to C-1' and C-3' , and from H-6' to C-2' and C-4', together with the NOESY correlation (Fig. 3) of H-9/H-6'. Furthermore, the NOESY correlation of H3-14/H-6b suggested that the two six-membered rings should be trans -fused in 1. The experimental ECD spectrum was in well agreement with the calculated ECD spectrum (Fig. 5), assigning the absolute configuration of 1 as (5S, 10S)-1. Therefore, the structure of compound 1 was determined and designated as atramacronoid D.
  • Compound 3 was obtained as colorless needle crystals, with molecular formula of C15H26O2 deduced by HRESIMS and NMR spectroscopic data (Tables 1 and 3). Explanation of the 2D NMR spectroscopic data (Fig. 2) revealed that the planar structure of 3 was identical to that of eudesmanediol (Piet et al., 1995). The NOE cross-peak (Fig. 3) between H3-14 with H3-15 in the NOESY spectrum of 3 unraveled cofacial orientation of these protons on the same side of the ring system. Meanwhile, the NOE cross-peaks between H-1 with H-5 and between H3-14 with H-6b verified same orientation of these protons on another side of the ring system. Accordingly, 3 was determined to possess a relative stereochemical structure as illustrated in Fig. 3. Crystallization of 3 in acetonitrile yielded single crystals. Follow up X-ray diffraction analysis not only unambiguously corroborated the planar structure and relative configuration (Fig. 4), but also disclosed that 3 was a racemate with P -1 space group. Subsequent separation of 3 by chiral HPLC yielded 3a {[α] + 19 (c 0.1, CH3OH)} and 3b {[α] 17 (c 0.1, CH3OH)} in a ratio of approximately 1:1 ratio (Fig. S1). The absolute configurations of 3a and 3b were assigned as (1S, 4S, 5S, 10S)-3a and (1R, 4R, 5R, 10R)-3b by comparing the experimental ECD spectra with the ECD predicted from Time-Dependent Density Functional Theory (TDDFT) calculations, respectively (Fig. 5). Consequently, the structures of 3a and 3b were determined and trivially designated as (+ )- and ( )-atramacronoids F, respectively. In 1995, edudesmanediol obtained from biotransformation of germacrene B-1,10-epoxide was reported as 3b (Piet et al., 1995), but the optical rotation value and CD data of edudesmanediol were not provided. Compound 3a is an unreported compound.
  • Compound 6, yellow colored gum, had the molecular formula of C21H32O8 as indicated by (+ )-HRESIMS and NMR spectroscopic data (Tables 1 and 3). The NMR spectroscopic data of 6 were similar to those of 19, except resonances attributable to an additional 11-O -glucopyranosyl moiety. In addition, resonances of 3-methylene unit in 19 were replaced by those of hydroxymethine [δ H 4.24 (t, J = 2.7 Hz, H-3); δ C 73.3 (C-3)] in 6. These data demonstrated that 6 was 3-hydroxy-11-O - glucopyranoside derivative of 19. This was further confirmed by 2D NMR spectroscopic analysis (Fig. 2), particularly by the 1H-1H COSY cross-peaks of H2-1/H2-2/H-3 and H-1'/H-2'/H-3'/H-4'/H-5'/H2-6' and the key HMBC correlations from H-3 to C-1, C-5, and C-15, and from H-1' to C-11, in combination with their chemical shifts. Accordingly, the planar structure of 6 was unequivocally established as shown in Fig. 2. The β -anomeric configuration of the glucopyranosyl moiety was defined by the coupling constant [δ H 4.32 (d, J = 7.6 Hz, H-1' )] of the anomeric proton, and D-glucose was confirmed by gas chromatography (GC) analysis (retention time of 20.19 min) after acid hydrolysis of 6. In the NOESY spectrum (Fig. 3) of 6, the cross-peaks between H3-14 with H-3 and H-6b indicated that these protons oriented on the same side of the ring system, whereas H-5 was on the other side of the ring system. The ECD spectrum of 6 displayed a negative Cotton effect at 342 nm, corresponding to the n→π* transition of the conjugated carbonyl chromophore. Application of the octant rule for the cyclohexanone (Gawronski, 1982; Snatzke, 1965) predicted the absolute configuration as illustrated in Fig. S2. In addition, consistency between the calculated ECD and experimental ECD spectra (Fig. 5) supported the absolute stereochemical structure. Consequently, the structure of 6 was determined and designated as atramacronoid I.
  • Compound 7 had the molecular formula C20H30O4 as determined by (+ )-HRESIMS and NMR spectroscopic data (Tables 1 and 3). The NMR spectra of 7 in deuterated methanol (CD3OD) exhibited characteristic signals for 4'-oxo-4'-methoxybutyryl moiety [δ H 2.61-2.60 (m, H2-2'), 2.61-2.60 (m, H2-3') and 3.66 (s, H3-5'); δ C 174.6 (C-1'), 30.0 (C-2'), 30.0 (C-3'), 174.2 (C-4' ) and 52.2 (C-5')], in addition to the signals closely similar to those of atractylmacrol E previously reported and also currently obtained in this study from A. macrocephala (Wang et al., 2018). The above evidence suggested that 7 was a rare product derived from coupling between 4'-oxo-4'-methoxybutyryl moiety and atractylmacrol E, which was proved by its 2D NMR experimental data (Fig. 2). In particular, the HMBC correlation of H2-12/C-1' bore out an ester group formation between 4' -oxo-4' -methoxybutyryl moiety and atractylmacrol E unit. The NOE correlation (Fig. 3) between H3-14 with H-6b, together with the coupling pattern and coupling constants of H-6b (J6a,6b = J5,6b = 13.4 Hz) revealed that the anti -relationship between H-6b and H-5 and the trans fusion of the decalin system with the diaxial relationship of CH3-14 and H-5. The absolute configuration of 7 was supported by consistency of experimental ECD and calculated ECD spectra (Fig. 5). Accordingly, the structure of compound 7 was determined and designated as atramacronoid J.
  • Compound 8, yellow colored oil, had the molecular formula C17H20O4 as established by HRESIMS and NMR spectroscopic data (Tables 1 and 3). The NMR spectroscopic data of 8 closely resembled those of tubipolide A isolated from Tubipora musica (Duh et al., 2001). The only difference between them was that the double bond between C-1 and C-2 in tubipolide A shifted to between C-8 and C-9 in 8, which was supported by the HMBC correlations (Fig. 2) from H-9 to C-1, C-5, and C-7, and from H3-14 to C-1 and C-9, in combination with the 1H-H COSY cross-peaks of H2-1/H2-2/H-3. The NOESY correlation (Fig. 3) between H3-14 with H-6b verified that the relative configuration of C-5 and C-10 was trans. Comparing the experimental ECD and calculated ECD spectra (Fig. 5), the absolute configuration of 8 was assigned as (5R, 10S)-8. Therefore, the structure of 8 was ascertained and trivially designated as atramacronoid K.
  • Compound 12 was isolated as colorless needle crystals. Its molecular formula C15H24O2 with 4 degrees of unsaturation was deduced from HRESIMS at m/z 237.1857 [M + H]+ and NMR spectroscopic data (Tables 2 and 3). Its 1D NMR spectral data showed high resemblance to that of eudesma-4(14),11(13)-diene-7α,8a,12-triol (Wang et al., 2008). The two compounds mainly differed in replacement of the hydroxymethylene at C-11 in the known compound by methyl group in 12, which was supported by the HMBC correlations of H3-12/C-7, C-11, and C-13 (Fig. 2). In the NOESY spectrum of 12 (Fig. 3), the correlation between H3-14 with H2-6, along with the coupling pattern and coupling constants of H-5 (J5,6a = 12.8 and J5,6b = 2.4 Hz) revealed that trans fusion of the decalin system with the diaxial relationship of CH3-14 and H-5, and CH3-14 was arbitrarily assigned to be β -oriented. Meanwhile, the NOESY correlation between H-6a with H2-13, together with the coupling pattern and coupling constants of H-8 (J8,9a = 3.8 and J8,9b = 2.1 Hz) unraveled that both 7-OH and H-8 were α -oriented. The absolute configuration was assigned as (5S, 7S, 8R, 10R)-12 by comparing the experimental ECD spectrum with the predicted ECD spectrum (Fig. 5) from TDDFT calculations, which was further unequivocally confirmed by X-ray crystallographic data analysis (Fig. 4) with Flack parameter of 0.03(14). Accordingly, the structure of 12 was determined and trivially designated as atramacronoid O.
  • The known compounds were identified as eudesm-4(15)-ene-7β,11- diol (16) (Le et al., 2016), eudesm-4(15)-ene-7α,11-diol (17) (Wang et al., 2008), eudesm-4(15),7-diene-9α,11-diol (18) (Wang et al., 2008), eudesm-4(15),7-diene-11-ol-9-one (19) (Wang et al., 2008), 7β -hydroxy-7-epi- α -eudesmol (20) (Ding et al., 2016), 3-eudesmene-1β, 7,11-triol (21) (Okasaka et al., 2006), atractylmacrol E (22) (Wang et al., 2018), 4-oxoatractylenolide III (23) (Le et al., 2016), beishulenolide A (24) (Zhang et al., 1998), 6α -hydroxyeudesma-4(15),7(11),8 (9)-triene-12,8-olide (25) (Wang et al., 2014), 3β -acetoxyl-atractylenolide I (26) (Zhang et al., 2020), 3β -acetoxyl-atractylenolide II (27) (Zhang et al., 2017), 8β -methoxy-atractylenolide (28) (Cheng et al., 2009), and taenialactam A (29) (Cheng et al., 2009), by comparison of their MS and NMR spectroscopic data with the reported data.