Four new prenylated phloroglucinol derivatives from Hypericum scabrum

Tetrahedron Letters 57 (2016) 2244–2248

Contents lists available at ScienceDirect

Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Four new prenylated phloroglucinol derivatives from Hypericum scabrum Wan Gao a, Jia-Wen Hu a, Wei-Zhen Hou a, Fang Xu a, Jun Zhao b, Fang Xu b, Hua Sun a, Jian-Guo Xing b, Ying Peng a, Xiao-Liang Wang a, Teng-Fei Ji a,⇑, Li Li a,⇑, Zheng-Yi Gu b,⇑ a State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People’s Republic of China b Xinjiang Key Laboratory for Uighur Medicine, Institute of Materia Medica of Xinjiang, Urumqi 830004, People’s Republic of China

a r t i c l e

i n f o

Article history: Received 29 January 2016 Revised 6 April 2016 Accepted 8 April 2016 Available online 13 April 2016 Keywords: Hypericum PPAPs ECD Neuroprotection

a b s t r a c t Hyperibrins A D (1–4), polycyclic polyprenylated acylphloroglucinol derivatives, were identified from air-dried aerial parts of Hypericum scabrum. All structures were determined by NMR spectroscopic methods and experimental and calculated ECD spectra. Compounds 1, 3, and 4 showed significant neuroprotective effects on glutamate-induced toxicity in SK-N-SH cells. Additionally, compounds 3 and 4 showed moderate hepatoprotective activities against paracetamol-induced HepG2 cell damage. Ó 2016 Published by Elsevier Ltd.

Plants of the genus Hypericum (Guttiferae), which comprise about 400 species, have been used for centuries in traditional medicine for the treatment of burns, bruises, swelling, inflammation, anxiety, and bacterial and viral infections.1–3 A series of polycyclic polyprenylated acylphloroglucinols (PPAPs) have been isolated from plants of the Guttiferae family, possessing various biological activities.4–7 Thus, PPAPs have attracted attention from research in both chemistry and pharmacology. Through 2015, approximately 300 PPAPs have been identified, the majority being isolated from the genus Hypericum.8 In the course of our systematic phytochemical and biological search of plants that are employed as traditional herbs of China, four new PPAPs (1–4) were isolated from Hypericum scabrum. These diverse carbon skeletons were all derived from less complex monocyclic polyprenylated acylphloroglucinols (MPAPs) by different cycloadditions, such as aldol condensations and Diels–Alder additions.9–14 Their structures were determined by 1D and 2D NMR experiments and were subsequently confirmed by comparing with compounds that have been reported previously. Their absolute configurations were determined by the electronic circular dichroism (ECD) exciton chirality method. Additionally, parts of

⇑ Corresponding authors. Tel.: +86 10 60212117. E-mail addresses: [email protected] (T.-F. Ji), [email protected] (L. Li), [email protected] (Z.-Y. Gu). http://dx.doi.org/10.1016/j.tetlet.2016.04.026 0040-4039/Ó 2016 Published by Elsevier Ltd.

the compounds exhibited significant neuroprotective effects and hepatoprotective activities at 10 lM. The ethanol extract of air-dried aerial parts of H. scabrum was partitioned between H2O and petroleum ether. The petroleum ether layer was subjected to purification using a silica gel column

O

23

O

1

3

5

7

18

10

21

11 18 13

21

3

O 5

25

22 26

9

OH

31 3

9

10

11 13 16

17

20

10 16 O 32 2733

30

7

2

18 O 12 1

O 7

O 2 3

5

22

17

22 16 1

21

O 1

HO 23 6

9

17 14

25 HO 26

O

O 15 5

3

1

9

22

21 O

2733

30

4

Figure 1. Structures of 1–4.

13

10

O 7

31

32

14

2245

W. Gao et al. / Tetrahedron Letters 57 (2016) 2244–2248 Table 1 H NMR and

1

13

C NMR spectroscopic data for compounds 1–4a (d in ppm)

No.

1

2 dH (J in Hz)

dC 1 2 3 4

210.6 66.7 45.5 42.4

5

36.9

6

42.7

2.13 m 1.68 m 2.45 m

7 8 9 10

211.0 45.5 18.5 17.9

2.47 m 1.06 d (8.4) 1.08 d (8.4)

11 12

17.3 36.6

13

21.9

14 15 16 17

123.6 131.6 17.6 25.6

18

26.8

19 20 21 22

122.9 132.9 25.9 14.3

23 24 25 26 27

17.6

dH (J in Hz)

dC 208.9 61.3 45.7 36.6

3.85 s 1.84 m

4.67 s 2.09 m 1.44 m 2.00 m

42.2 75.5

1.00 s 1.50 m 1.25 m 2.07 m 1.49 m 4.98 t (5.6)

2.12 m 1.71 m 5.12 t (5.6)

dC

68.0 194.8 118.0 177.5

64.8

59.1

137.1 128.1

7.60 d (7.8)

119.6 135

22.0

2.04 m 1.82 m 4.98 t (7.2)

128.0

7.30 d (7.8)

26.3

1.68 s

132.4 128 128.1 26.2

7.45 7.30 7.60 2.88 3.00 4.20

18.1 192.6 137 129.2

1.68 s

7.70 d (7.2)

128.4

7.37 t (6.2)

133.2 128.4 129.2 29.0

7.53 7.37 7.70 3.10 1.85 4.34

1.60 s 1.72 s

26.4

23.8

2.08 (1H, m) 1.67 (1H, m) 5.09 (1H, t, 7.2) 1.58 (3H, s) 1.66 (3H, s) 1.30 (3H, s)

93.4 71.3 24.5 26.7 29.2 119.6 134.4 18.1 26.0 27.6

46.4 46.9 205.8 25.2

d (7.4) d (7.8) d (7.8) dd (14.8, 10.0) dd (14.8, 10,0) t (10.0)

1.16 s 1.19 s 2.46 dd (14.0, 7.2) 2.54 dd (14.0, 7.2) 5.02 t (6.4)

2.68 m 2.48 m 4.95 m

92.9 70.9 25.7 26.8 28.9

1.67 s 1.67 s 1.65 m 2.11 m 4.94 t (7.2)

1.30 s 1.19 s 2.45 m 2.16 m 4.95 m

124.9 132.9 25.9 18.2 22.2 27.1

1.54 s 1.67 s 1.43 s 1.20 s

t (6.2) t (6.2) d (7.2) dd (10.8, 9.2) dd (10.8, 3.6) dd (8.4, 3.6)

1.69 s 1.60 s 1.16 s 1.03 s

13

C NMR spectra measured at 125 Hz; obtained in CDCl3. Assignments supported by the 2D NMR spectra.

and preparative thin-layer chromatography coupled with RP-18 silica gel HPLC; a total of four new compounds resulted, based on two different structural types (Fig. 1). Hyperibrin A (1)15 was isolated as a colorless oil {[a]20 D 38.0 (c 0.05, CH3OH)}, and it showed a red spot on TLC plates when sprayed with an anisaldehyde-sulfuric acid reagent. The HRESIMS of 1 exhibited a protonated molecule at m/z 347.2935 ([M+H]+, D 1.1 mmu) consistent with a molecular formula of C23H38O2. The ultra violet (UV) spectrum of 1 showed maximum absorption at

(B)

203 nm (log e 3.80) and the IR spectrum showed absorption bands for carbonyl groups (1722 and 1696 cm 1). The 1H NMR spectrum of 1 indicated the presence of eight methyl groups [dH 1.00 (s), 1.01 (d, J = 5.2 Hz), 1.06 (d, J = 8.4 Hz), 1.08 (d, J = 8.4 Hz), 1.58 (s), 1.61 (s), 1.66 (s), 1.71 (s)], one methine proton [dH 3.85 (s)], and two olefinic protons [dH 4.98 (t, J = 5.6 Hz), 5.12 (t, J = 5.6 Hz)]. These data indicated the presence of one isopropyl group and two isoprenyl groups. The 13C NMR spectrum of 1 displayed signals for twentythree carbons. On the basis of these observations, compound 1 was a monocyclic polyprenylated acylphloroglucinol (MPAP) derivative. According to literature retrieval, the 1H and 13C NMR

O

1 5

2.83 d (14.8) 2.08 dd (12.0, 6.0) 1.48 m

0.99 s 1.48 m

122.3 133.5 17.9 25.9 15.8 24.8

23

39.2

16.4 37.5

28 29 30 31 32 33

O

1.43 m 1.97 dd (13.6, 4.0) 1.58 m

43.0 46.9 206.5 192.7

1.01 d (5.2)

(A)

dH (J in Hz)

dC

2.48 m 1.06 d (7.8) 1.05 d (7.8)

1.61 s 1.74 s

H NMR spectra measured at 400 MHz,

dH (J in Hz)

211.2 42.6 17.9 18.4

122.8 132.9 25.6 17.9

a 1

4

70.2 172.9 118.2 190.7

41.5

123.7 131.6 25.8 17.6

1.66 s 1.58 s

3

18

1 5

18 3

18

12

1

HMBC

O

HO

12 11

(B)

(A)

23 3

1

5

O

1

11

3

8 8

12

Figure 2. Selected key HMBC and ROESY correlations for 1.

2

3

5

11

ROESY

1 12

18

HMBC

2

11

ROESY

Figure 3. Selected key HMBC and ROESY correlations for 2.

2246

W. Gao et al. / Tetrahedron Letters 57 (2016) 2244–2248 (B)

(A) OH 17 18

O 22

O

12

3 5

1 9

O

3

10 22

O

5

9 7 27

7

27

1

32

HMBC

3

12

10

32

ROESY

3

Figure 4. Selected key HMBC and ROESY correlations for 3.

(A)

(B) 17

O 15

HO

O

3 5

22

O

23

1 9 10

22

3 1

5 9

O 7

4

10 33

7

2733

27

HMBC

4

ROESY

Figure 5. Selected key HMBC and ROESY correlations for 4.

spectroscopic data (Table 1) of 1 were similar to those of the known compound hyperscabrin B.10 Comparison of the 1H and 13C NMR data of 1 with those of hyperscabrin B suggested that 1 contained four fewer carbon atoms, including an olefinic moiety, suggesting that the C-6 isoprenyl group in hyperscabrin B might be replaced by a methyl group in 1. This deduction was confirmed by the key HMBC correlations from Me-23 (dH 1.01) to C-1 (dC 210.6), C-6 (dC 42.7), and C5 (dC 36.9), as shown in Figure 2. In the ROESY spectrum of 1, the proton signal at dH 3.85 (H-2) was correlated with those at dH 2.45 (H-6), 1.50 (H-12a), and 2.07 (H-13a), and the proton signal at dH 1.00 (H-11) was correlated with those at dH 2.47 (H-8) and 2.12 (H-18). Thus, methyls at C-3 and C-6, isobutyryl at C-2, and prenyl at C-4 were oriented on the same side, whereas the prenyl group at C-3 was on the opposite side. Hyperibrin B (2)16 was also obtained as a viscous colorless oil {[a]20 D 53.2 (c 0.08, CH3OH)}, possessing a molecular formula of C23H38O3 determined by the HRESIMS data (m/z 363.2884 [M +H]+, D +1.9 mmu) in accordance with its 13C NMR data. A difference of 16 atomic mass units between compound 2 and compound 1 was derived from the data above. The IR spectrum showed absorption bands for hydroxy (3450 cm 1) and carbonyl groups (1715 and 1710 cm 1). The 1H NMR spectrum of 2 indicated the presence of eight methyl groups [dH 0.99 (s), 1.05 (d, J = 1.6 Hz), 1.06 (d, J = 1.6 Hz), 1.30 (s), 1.58 (s), 1.60 (s), 1.66 (s), 1.72 (s)], one methine proton [dH 4.67 (s)], and two olefinic protons [dH 4.97 (t, J = 7.2 Hz), 5.09 (t, J = 7.2 Hz)], which were similar to those

Figure 6. Calculated and experimental ECD spectra of 1–4.

2247

W. Gao et al. / Tetrahedron Letters 57 (2016) 2244–2248

of 1 except for the presence of a hydroxy group in 2 and the position of one isoprenyl group. The structure of 2 was then deduced by direct comparison with 1 and was confirmed by analysis of its HSQC and HMBC spectra (Fig. 3). The relative configurations of all chiral centers of 2 were determined by interpretation of ROESY correlations. In the ROESY spectrum of 2, the proton signal at dH 4.67 (H-2) was correlated with those at dH 2.08 (H-18a) and 1.82 (H-13a), and the proton signal at dH 1.30 (H-23) was correlated with those at dH 1.06 (H-9) and 1.05 (H-10). In addition, the correlation between dH 0.99 (H-11), 2.00 (H-5), and 1.30 (H-23) could also be found in the ROESY spectrum. Thus, prenyl groups at C-3 and C-5 were oriented on the same side, whereas isobutyryl at C2 and methyls at C-3 and C-6 were on the opposite side. The molecular formula of hyperibrin C (3),17 {[a]20 D 92.5 (c 0.10, CH3OH)}, was determined to be C33H42O5 from its HRESIMS data (m/z 519.3090 [M+H]+, D 0.4 mmu). The strong IR absorptions implied the presence of hydroxy (3444 cm 1), carbonyl (1723 and 1700 cm 1), and benzoyl groups (1618 and 1581 cm 1). Its 1 H NMR spectrum contained signals of a monosubstituted benzene ring [dH 7.45 (1H, t, J = 7.4 Hz), 7.30 (2H, t, J = 7.8 Hz), and 7.60 (2H, d, J = 7.8 Hz)], two olefinic protons of isoprenyl groups (dH 4.94, 1H, t, J = 7.2 Hz; 5.02, 1H, t, J = 6.4 Hz), and eight methyls (dH 1.16, 1.19, 1.20, 1.43, 1.54, 1.67, 1.67, and 1.67). The 13C NMR spectrum of 3 showed three carbonyl carbons (dC 206.5, 192.7, and 190.7) and four olefinic carbons (dC 134.4, 133.5, 122.3, and 119.6). The analysis of 2D NMR spectra using HSQC and HMBC techniques enabled the assignment of 1H and 13C NMR signals. The foregoing data indicated that 3 was a benzoylphloroglucinol derivative that contained four isoprene units, which was similar to that of propolone C,18

HO

O

O

O R

with differences including the chemical shifts at C-2, -4, and -19. In the HMBC spectrum of 3, the correlations of the proton signals at dH 3.00 and 2.88 (H-17) with the carbon signal at dC 172.9 (C2), 118.2 (C-3), 190.7 (C-4), 93.4 (C-18), and 71.3 (C-19), indicated that 3 and propolone C have the same planar structure. Thus, 3 was deduced to be a diastereoisomer of propolone C and sampsonione N.19 In the ROESY spectrum of 3, the proton signal at dH 4.20 (H-18) was correlated with those at dH 2.46 and 2.54 (H-22), and the proton signal at dH 4.20 (H-18) was also correlated with those at dH 7.60 and 7.30 (H-12 and 13). Additionally, the correlations between H-17 (dH 2.88 and 3.00), H-27 (dH 2.11), and H-22 could also be found in the ROESY spectrum. On the basis of these correlations, the structure of compound 3 was assigned as shown in Figure 4. Hyperibrin D (4)20 had a molecular formula of C33H42O5 on the basis of HRESIMS data (m/z 519.3092 [M+H]+, D 0.2 mmu). The UV spectrum of 4 showed maximum absorption at 203 (log e 4.23) and 251 nm (log e 4.02), indicating the presence of a benzoyl group. The IR spectrum showed absorption bands for hydroxy (3420 cm 1) and carbonyl groups (1732 and 1677 cm 1). A comparison of the molecular formula, 1H and 13C NMR data of 4 with those of the known compound sampsonione P19 revealed that they had the same skeleton and differed only in configuration. And this deduction was confirmed by 2D NMR data. In the HMBC spectrum, the proton signal at dH 4.36 (H-23) was correlated with the carbon signals at dC 25.6 (C-25), 26.8 (C-26), 29.0 (C-22), 59.1 (C-5), 92.9 (C-23), and 177.4 (C-4). In the ROESY spectrum, the proton signal at dH 4.36 (H-23) was correlated with that at dH 3.10 (H-22a). The correlations between H-7 (dH 1.48 m), H-6b (dH 2.08), H-32

O

O

+

R

H 2O

O

O

+

R

O

O

+

O R

R

HY

-H DMAPP O

2 AOCS

O

O R

COOH O

O

O

GPP

R

PPO

DMAPP

O O

O O

O

O

OH

i

R

DMAPP

ii

HY

DMAPP

O

OH

O R

R

R1 OH

O

O

+

O

R

HO

OH

R1

O

HO

DMAPP

O

HO

R1

O

OH R

SCOA

R

HO

HO

R

O

O

R

O

SCOA

O

R

R O

O

O

O

O DMAPP

R1

HO

O R

OH R

R1 OH

O

OPP DMAPP

cyclization

O O

O

O

O

HO O

1

OH

R

O

R1

cyclization HO R

R1

O

O

R1

O

O R

O

HO R1

O

O

HO R

O

O

R1

OH R O

O OPP

4

3

R=i-Pr or Ph R1=prenyl

Scheme 1. Plausible biogenetic pathway for 1–4.

2248

W. Gao et al. / Tetrahedron Letters 57 (2016) 2244–2248

(dH 1.16), and H-10 (dH 2.68 and 2.48) also could be found in this spectrum. Therefore, the structure of 4 was assigned as shown in Figure 5. The absolute configurations of Hyperibrins A–D (1–4) were elucidated by calculated and experimental ECD spectra. Four pairs of enantiomers, (2R,3R,4S,6R)-1a, (2S,3S,4R,6S)-1b, (2R,3R, 5S,6S)-2a, (2S,3S,5R,6R)-2b, (1S,5R,7S,18R)-3a, (1R,5S,7R,18S)-3b, (1R,5S,7S,23R)-4a, and (1S,5R,7R,23S)-4b were calculated for ECD spectra based on the known relative configurations of 1–4. As a result, the overall pattern of the calculated ECD spectra of 1a, 2a, 3a, and 4b were in good agreement with the experimental data of 1–4, respectively (Fig. 6). Therefore, the absolute configurations of Hyperibrins A–D (1–4) were determined as depicted. Generally, most of the discovered PPAPs isolated from Hypericum formed a unique family of structurally related caged metabolites that were most likely biosynthesized from the biogenetically acceptable 2,4,6-trihydroxybenzophenon (i) via a series of C-alkylations with dimethylallyl diphosphate (DMAPP).21,22 Compounds 3 and 4 had a dihydrofuran ring that was mostly formed by cyclization of a 3-methylbut-2-enyl side chain with an enolic hydroxy group.23 However, the plausible biogenetic pathway of 1 and 2 was proposed to be generated from ii through a reduction reaction. The plausible biosynthetic pathway of 1–4 was proposed as shown in Scheme 1. Considering the fact that many PPAPs have been isolated previously and that these types of metabolites are associated with neurodegenerative diseases, such as Alzheimer’s disease,23 compounds 1–4 were evaluated for neuroprotective effects on the glutamate-induced toxicity in SK-N-SH cells. The result showed that compounds 1, 3, and 4 had significant neuroprotection at 10 lM (Table 2 in Supplementary material). Additionally, they were also bioassayed for hepatoprotective activity against paracetamolinduced HepG2 cell damage, and the hepatoprotective activity drug bicyclol was used as the positive control. As shown in Table 3, compounds 3 and 4 exhibited moderate hepatoprotective activity. Acknowledgments This work was supported financially by the Municipal Twelfth Five-year Major projects of China (201130105-4). Special thanks are given to Hua Sun and Ying Peng for technical support in bioassays and Mr. He for assistance with recording 2D NMR spectra. Supplementary data Supplementary data (the original ESIMS, UV, IR, 1D NMR, 2D NMR, and ECD spectra for all new compounds) associated with this

article can be found, in the online version, at http://dx.doi.org/10. 1016/j.tetlet.2016.04.026. References and notes 1. Hunt, E. J.; Lester, C. E.; Lester, E. A.; Tackett, R. L. Life Sci. 2001, 69, 181–190. 2. Konstantinos, A.; Prokopios, M.; Nikolas, F.; Alexios-Leandros, S.; Harris, P.; Dimitris, K. J. Nat. Prod. 2004, 67, 290–294. 3. Li, D. Y.; Zhu, H. C.; Qi, C. X.; Du, G.; Zhang, Y. H. Tetrahedron Lett. 2015, 56, 1953–1955. 4. Ciochina, R.; Grossman, R. B. Chem. Rev. 2006, 106, 3963–3986. 5. Naonobu, T.; Yuka, K.; Haruaki, I.; Takaaki, K.; Junichi, K. Tetrahedron Lett. 2009, 50, 4747–4750. 6. Singh, I. P.; Sidana, J.; Bharate, S. B.; Foley, W. J. Nat. Prod. Rep. 2010, 27, 393– 416. 7. de Oliveira, C. M. A.; Porto, A. M.; Bittrich, V.; Vencato, I.; Marsaioli, A. J. Tetrahedron Lett. 1996, 37, 6427–6430. 8. Yang, X. W.; Li, M. M.; Liu, X. J. Nat. Prod. 2015, 78, 885–895. 9. Liu, R. D.; Ma, J.; Yang, J. B.; Wang, Ai. G.; Su, Y. L. J. Asian Nat. Prod. Res. 2014, 7, 717–723. 10. Ma, J.; Ji, T. F.; Yang, J. B.; Ai, G.; Su, Y. L. J. Asian Nat. Prod. Res. 2012, 5, 508–514. 11. Michiko, M.; Yasuhiro, S.; Yoshihisa, T.; Gisho, H.; Michiho, I.; Yoshio, T.; Hirohumi, S.; Tomihiko, H.; Olimjon, K. J. Nat. Prod. 2002, 65, 290–294. 12. Naonobu, T.; Yoshihisa, T.; Yasuhiro, S.; Yuka, N.; Kenneth, B.; Lee, K. H.; Gisho, H.; Michiho, I.; Yoshio, T.; Olimjon, K.; Ozodbek, A. J. Nat. Prod. 2004, 67, 1870– 1875. 13. Kraus, G. A.; Nguyen, T. H.; Jeon, I. Tetrahedron Lett. 2003, 44, 659–661. 14. Mehta, G.; Bera, M. K. Tetrahedron Lett. 2004, 45, 1113–1116. 15. Hyperibrin A (1): colorless oil; [a]20 D 37.0 (c 0.05, MeOH); UV (MeOH) kmax (log e) 203 (3.80) nm; ECD (MeOH) kmax (De) 293 (3.72) nm; IR (KBr) mmax 2968, 2928, 1 1 1722, 1695, 1459, 1380 cm ; H and 13C NMR data, see Table 1; HRESIMS m/z 347.2935 [M+H]+ (calculated for C23H39O2, 347.2946). 16. Hyperibrin B (2): colorless oil; [a]20 D 53.2 (c 0.08, MeOH); UV (MeOH) kmax (log e) 202 (4.12) nm; ECD (MeOH) kmax (De) 300 (4.91) nm; IR (KBr) mmax 3450, 2964, 2930, 1718, 1710, 1456, 1380 cm 1; 1H and 13C NMR data, see Table 1; HRESIMS m/z 363.2884 [M+H]+ (calculated for C23H39O3, 363.2865). 17. Hyperibrin C (3): colorless oil; [a]20 D 92.5 (c 0.10, MeOH); UV (MeOH) kmax (log e) 203 (4.10), 249 (3.78) nm; ECD (MeOH) kmax (De) 250 (+15.83), 318 ( 5.94) nm; IR (KBr) mmax 3444, 2961, 2913, 1724, 1700, 1640, 1618, 1446, 1377 cm 1; 1 H and 13C NMR data, see Table 1; HRESIMS m/z 519.3090 [M+H]+ (calculated for C33H42O5, 519.3094). 18. Ingrid, M. H.; Mercedes, C. F.; Osmany, C. R.; Anna, L. P.; Luca, R. J. Nat. Prod. 2005, 68, 931–934. 19. Xiao, Z. Y.; Mu, Q.; Shiu, W. K.; Zeng, Y. H.; Simon, G. J. Nat. Prod. 2007, 70, 1779–1782. 20. Hyperibrin D (4): colorless oil; [a]20 182.2 (c 0.12, MeOH); UV (MeOH) kmax D (log e) 203 (4.23), 251 (4.02) nm; ECD (MeOH) kmax k (De) 264 (+18.23), 300 ( 9.87) nm; IR (KBr) mmax 3420, 2970, 2927, 1732, 1677, 1632, 1450, 1377 cm 1; 1H and 13C NMR data, see Table 1; HRESIMS m/z 519.3092 [M +H]+ (calculated for C33H42O5, 519.3094). 21. Tian, W. J.; Yu, Y.; Yao, X. J. Org. Lett. 2014, 16, 3448–3451. 22. Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 3621–3624. 23. Xu, W. J.; Zhu, M. D.; Wang, X. B.; Yang, M. H.; Luo, J.; Kong, L. Y. J. Nat. Prod. 2015, 78, 1093–1100.