Illisimonin A, a Caged Sesquiterpenoid with a Tricyclo[5.2.1.01,6

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Illisimonin A, a Caged Sesquiterpenoid with a Tricyclo[5.2.1.01,6]decane Skeleton from the Fruits of Illicium simonsii Shuang-Gang Ma,† Mi Li,† Ming-Bao Lin, Li Li, Yun-Bao Liu, Jing Qu,* Yong Li, Xiao-Jing Wang, Ru-Bing Wang, Song Xu, Qi Hou, and Shi-Shan Yu* 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, China S Supporting Information *

ABSTRACT: Illisimonin A, an unprecedented sesquiterpenoid with a tricyclo[5.2.1.01,6]decane skeleton, was isolated from the fruits of Illicium simonsii. The structure and absolute configuration of 1 were determined using extensive spectroscopic evidence and electronic circular dichroism (ECD) calculations. It was determined that 1 possesses a caged 2-oxatricyclo[3,3,0,14,7]nonane ring system fused to a five-membered carbocyclic ring and a five-membered lactone ring. A plausible biogenetic pathway for 1 was proposed, and 1 showed neuroprotective effects against oxygen-glucose deprivation (OGD)-induced cell injury in SHSY5Y cells with an EC50 value of 27.72 μM.

T

a bisabolane through a 5/6/6 tricarbocyclic precursor5d,9b by a Wagner−Meerwein rearrangement. We report the isolation, structure elucidation, plausible biogenetic formation, and biological evaluation of a novel caged sesquiterpenoid (Figure 1).

he genus Illicium, the only member of the family Illiciaceae, is a rich source of diverse sesquiterpenes. To date, eight types of sesquiterpenoids with different carbon skeletons have been reported, namely, seco-prezizaane, acorane, amorphane, allohimachalane, α-santalane, isocampherenane, allo-cedrane, and dunniane.1 Notably, more than 100 distinct biosynthetically relevant seco-prezizaane sesquiterpenoids isolated from the Illicium species can be categorized into seven subtypes according to their carbon skeletons: anisatin,2 majucin,1,3 pseudoanisatin,2a,d,4 cycloparvifloralone,4d,e,5 pseudomajucin,2g,4f,6 minwanensin,4f,h,i,7 and anislatctone.4d,8 Compounds in these families show diverse biological activities, including antimicrobial, neurotoxic, and neurotrophic effects,1,2g,5c which have attracted a substantial amount of attention from the synthetic organic and biological communities.9 Illicium simonsii Maxim., an evergreen shrub or tree of this genus, has historically been used as folk medicine to cure cystic hernia, gas pains in the chest, scabies and vomiting related to cold in the stomach. Previous investigations on this plant have proved that it is a rich source of sesquiterpenoids, and some highly oxygenated seco-prezizaane sesquiterpenes have been obtained from the stems, leaves, and fruits of I. simonsii.10 As a part of our search for structurally diverse sesquiterpenes from the genus Illicium, investigations on the chemical constituents of the fruits of I. simonsii were carried out. A unique sesquiterpene, illisimonin A (1), with a unique 5/5/5/5/5 pentacyclic scaffold featuring a caged 2-oxatricyclo[3,3,0,14,7]nonane ring system fused to a fivemembered carbocyclic ring and a five-membered lactone ring, was isolated from the fruits of I. simonsii. Notably, the structure of 1 is remarkable for its unprecedented skeleton with a novel C−C bond linkage (C6−C10), which has never been found in an Illicium sesquiterpenoid. Illisimonin A (1) represents the first example of a sesquiterpenoid with a 5/5/5 carbon-skeleton (tricyclo[5.2.1.01,6]decane), and it could be biosynthesized from © 2017 American Chemical Society

Figure 1. Structure of illisimonin A (1).

Illisimonin A (1)11 was obtained as a colorless oil. Its molecular formula, C15H20O6, was established from NMR data (Table 1) and a prominent pseudomolecular ion peak at m/z 319.1150 [M + Na]+ (calcd 319.1152) in HRESIMS and represents 6 degrees of unsaturation. The UV spectrum of 1 showed an absorption maximum at 203 nm and a shoulder peak at 215 nm. The IR spectrum displayed absorptions attributable to hydroxy (3389 cm−1) and γ-lactone (1774 cm−1) moieties. The 1 H NMR spectrum of 1 was taken in MeOD and displayed 17 nonlabile protons, all of which were in the high-field region (δH 0.90−3.80 ppm). Except for the three obvious methyl singlets at δH 1.27, 1.03, and 0.91, two isolated methylene groups [δH 1.97 (d, J = 14.5), 2.30 (d, J = 14.5)/δC 39.0 (C8) and δH 3.55 (d, J = 10.0), 3.79 (d, J = 10.0)/δC 69.7 (C14)] confirmed the presence of an AB spin system, and another proton spin system comprising C(2)H2−C(3)H2 (Figure 2) was easily identified by the 1H−1H COSY and HSQC correlations. Received: September 29, 2017 Published: October 27, 2017 6160

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The structure of 1 was unambiguously confirmed by detailed interpretation of the 2D NMR data (1H−1H COSY, HSQC, and HMBC) (Figures 1 and 2). Fragment C(2)H2−C(3)H2 and the HMBC correlations [see Figure 2 and Figures S8 and S13 in the Supporting Information (SI)] from H2-2 to C-1 and C-9, from H2-3 to C-4 and C-9, and from angular methyl H3-15 to C-1 and C-9 allowed the five-membered carbon ring (ring A, C1−C2− C3−C4−C9 in Figure 1) to be defined. HMBC correlations from isolated aliphatic methylene protons H2-8 to C-6, C-7, C-9, and C-10 constructed the five-membered B ring (C6−C7−C8− C9−C10). The third five-membered ring, the C ring (C4−C5− C6−C10−C9), was established by the HMBC correlations from H3-13 to C-4, C-5, and C-6. Consequently, a complex and sterically congested 5/5/5 tricarbocyclic skeleton (tricycle[5,2,1,01,6]decane) consisting of the three five-membered rings A−C was established, which was supported by the HMBC correlations from H3-12 to C-5, C-6, and C-7. Interestingly, the tricycle[5,2,1,01,6]decane-bridged system was also found in the molecular structure of nortriterpenoid schincalide A, which was isolated from Schisandra incarnate.12 The downfield chemical shift of C-7 (δC 111.5) and the key HMBC correlations from the oxygenated methylene protons H2-14 to C-4, C-5, and C-7 allowed us to determine the structure of the fourth fivemembered ring, the D ring (tetrahydrofuran ring, C5−C6−C7− O−C14), which contains a hemiketal moiety. Thus, the fused B/ C/D ring system gave a complex caged 2-oxatricyclo[3,3,0,14,7]nonane scaffold. Due to the presence of seven contiguous quaternary carbons (C-1, C-4, C-5, C-6, C-7, C-9, and C-10), it was difficult to confirm the remaining five-membered lactone (the E ring) by HMBC 2JCH and 3JCH correlations. Fortunately, a long-range HMBC experiment using a triple inverse TCI 500-S2 probehead and commonly used 8 Hz 1H−13C couplings showed the diagnostic 4JCH HMBC correlations from angular methyl H3-12 to C-11 and from the two methylene protons H2-8 and H2-3 to C-11, which confirmed the location of the lactone ring-E. Furthermore, the 1H NMR spectrum of 1 later obtained in aceton-d6 reaffirmed the above-mentioned three hydroxy groups, which were observed as sharp singlets (δH 3.56, 4.37, and 5.22) with obvious cross peaks in the 1H−13C HMBC experiment (see Figures 2 and S13 in SI). These correlations established that the three hydroxy groups were attached to C-1, C-7, and C-10, respectively. Thus, the planar structure of 1 was determined to be an unprecedented, highly oxygenated sesquiterpene lactone with a 5/5/5 tricarbocyclic skeleton (Figure 2). The rigidity of 1 facilitated the assignment of the relative configuration. The relative configuration of the chiral centers in rings A−E was unambiguously determined from a series of NOE experiments and the NOESY spectrum (see Figures S9−S10 in SI). In the NOE difference spectrum, diagnostic NOEs for Hα-8 and Hα-3 were observed after irradiation of Hα-14, and irradiation of H3-13 enhanced the signals for Hβ-14 and H3-12, which indicated that CH3-12 and CH3-13 were β-oriented as shown in Figure 3. In contrast, a strong NOEs for Hα-8, a weak NOE for Hβ-8, and obvious NOEs for Hα-2 were observed after irradiation of H3-15, revealing that CH3-15 was in the αorientation. Due to the steric restriction of the tricycle[5,2,1,01,6]decane-bridged system and the rigid connectivities of the five-membered lactone ring-E and the tetrahydrofuran ring-D, the relative configurations for C-4 and C-9 were assigned as R* and S*, respectively, and the relative configurations of 7OH and 10-OH were assigned as depicted in Figure 3.

Table 1. NMR Data for Illisimonin A (1) methanol-d4 no.

δC

1 2

76.7 46.5

3

23.1

4 5 6 7 8

104.9 52.8 63.9 111.5 39.0

9 10 11 12 13 14

71.0 88.4 177.6 6.0 16.7 69.7

15 1-OH 7-OH 10-OH

28.1

δH (J in Hz) Hα 2.25 (ddd, 14.0, 10.5, 3.5) Hβ 2.36 (ddd, 14.0, 8.5, 8.5) Hα 2.03 (ddd, 14.5, 10.5, 8.5) Hβ 1.91 (ddd, 14.5, 8.5, 3.5)

Hα 1.97 (d, 14.5) Hβ 2.30 (d, 14.5)

0.91 (s) 1.03 (s) Hα 3.79 (d, 10.0) Hβ 3.55 (d, 10.0) 1.27 (s)

acetone-d6 δC 76.1 46.7

23.0

103.1 52.3 63.3 111.2 38.9 70.0 88.1 175.1 5.9 16.8 69.2 28.5

δH (J in Hz) Hα 2.22 (ddd, 14.0, 10.5, 3.5) Hβ 2.37 (ddd, 14.0, 8.5, 8.5) Hα 2.02 (ddd, 14.4, 10.5, 8.5) Hβ 1.84 (ddd, 14.4, 8.5, 3.0)

Hα 1.96 (d, 13.8) Hβ 2.32 (d, 13.8)

0.90 (s) 1.02 (s) Hα 3.75 (d, 9.6) Hβ 3.48 (d, 9.6) 1.29 (s) 3.56 (s) 5.22 (s) 4.37 (s)

Figure 2. Key 1H−1H COSY and HMBC correlations of 1.

The 13C NMR and DEPT spectra of 1 in MeOD showed 15 carbon signals comprising one lactone carbonyl (δC 177.6), seven quaternary carbons (δC 111.5, 104.9, 88.4, 76.7, 71.0, 63.9, and 52.8), including at least one dioxygenated and three oxygenated carbons, four methylenes (one oxygenated carbon at δC 69.7 and three aliphatic carbons), and three methyls (Table 1). These results suggested that 1 was a highly oxygenated sesquiterpene lactone. Overall, 17 protons directly connected to carbons were accounted for based on the 1H NMR (acquired in methanol-d4) and DEPT spectra, and the analysis of the molecular formula indicated the existence of three hydroxy groups. Additionally, the presence of one carbonyl group accounted for one of the six degrees of unsaturation, which suggested that compound 1 possessed a pentacyclic ring system (rings A−E). 6161

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unprecedented tricycle[5,2,1,01,6]decane sesquiterpene skeleton, and we named this new skeleton “illisimonane”. The possible biosynthetic origin of the illisimonane skeleton is via a 5/6/6 tricarbocyclic allo-cedrane framework (2), which was also proposed to be the key biogenetic intermediate of sesquiterpenes with a seco-prezizaane skeleton (Scheme 1).5d,9b Since some Scheme 1. Proposed Biogenetic Pathway for 1

Figure 3. Key NOE correlations of 1.

To determine its absolute configuration, the CD spectrum of 1 was measured (in CH3OH), and the spectrum was dominated by a strong negative Cotton effect at λmax = 216 nm (see Figure S14 in SI) for the n → π* transition of the lactone ring moiety. However, analysis of the connectivity of the lactone group indicated the presence of a complex bridge-ring lactone, 6-oxadicyclo[2,2,1]nonane-2-one, which is a combination of γ-lactone and δ-lactone. It is difficult to determine the stereochemistry of the bridge-ring lactone based on Beecham’s rules13−15 since, so far, there are no clear relationships between the two possible configurations of this type of bridge-ring lactone derivative and their Cotton effects.16 Finally, the calculation of a theoretical electronic circular dichroism (ECD) spectrum using timedependent density functional theory (TDDFT), which has proven to be a powerful and reliable method in determining the absolute configurations of natural products,6 was utilized in combination with the experimental CD data. Conformational analysis of two possible enantiomers of 1 was performed using the MMFF94 molecular mechanics force field. The conformers were further optimized using Gaussian 03 at the B3LYP/6-31 G(d) level. The theoretical ECD spectra of 1 and its enantiomer in MeOH were then compared to the experimental ECD spectrum of 1 (Figure 4). This comparison revealed the highly oxygenated sesquiterpenes with allo-cedrane carbon skeleton have been reported from Illicium species,17 as an intermediate, allo-cedrane cation might undergo a series of selective oxidations, a condensation reaction, and a WagnerMeerwein rearrangement involving a 1,2-alkyl shift and a primary carbocation rearrangement to produce 3 with illisimonane skeleton. 3 could then be converted into 1 through a carbocation hydroxylation, a methyl oxidation, and a subsequent esterification. Because seco-prezizaane-type sesquiterpenoids possess neurotrophic properties,3h 1 was evaluated for neuroprotective effects against oxygen-glucose deprivation (OGD)-induced cell injury in SH-SY5Y cells.18 1 showed a neuroprotective effect with an EC50 value of 27.72 μM (95% confidence interval 23.68−32.44 μM) (see Table S1 in SI). Additionally, 1 did not show cytotoxic activities against the human tumor cell lines HCT-116, HepG2, BGC-823, A-549, or A2780 (IC50 > 10 μM). In conclusion, we have identified a novel class of sesquiterpenes with a tricycle[5,2,1,01,6]decane skeleton from Illicium simonsii, and we have proposed that the tricarbocyclic allo-cedrane is a direct biosynthetic precursor of sesquiterpene 1 with its caged 5/5/5/5/5 pentacyclic scaffold. Meanwhile, 1 showed neuroprotective effects against OGD-induced cell injury in SH-SY5Y cells. Altogether, the new illisimonane-type sesquiterpene increases the structural diversity of sesquiterpenes

Figure 4. Experimental and calculated ECD spectra of 1.

experimental spectrum best matched the curve calculated for the 1R,4R,5R,6R,7S,9S,10S isomer. Thus, the absolute configuration of 1 was determined to be 1R,4R,5R,6R,7S,9S,10S. Though a variety of sesquiterpenes have been reported from Illicium species, illisimonin A (1) is a structurally unique sesquiterpene possessing an unprecedented 5/5/5/5/5 pentacyclic scaffold including a caged 2-oxatricyclo[3,3,0,14,7]nonane ring system, one γ-lactone ring, and one tetrahydrofuran ring. To the best of our knowledge, compound 1 represents an 6162

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reported in the genus Illicium and provides a new skeleton for future explorations of potential neuroprotective agents.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03050. Detailed experimental procedures, MS, IR, UV, CD, and 1D and 2D NMR spectra for 1 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Yun-Bao Liu: 0000-0002-1338-0271 Shi-Shan Yu: 0000-0003-4608-1486 Author Contributions †

S.-G.M. and M.L. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful to the Department of Instrumental Analysis of our institute for the acquisition of UV, IR, NMR, and MS spectra. This work was supported by grants from CAMS Innovation Fund for Medical Sciences (No. 2016-I2M-1-010) and from the Natural Science Foundation of China (No. 21672261).

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REFERENCES

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DOI: 10.1021/acs.orglett.7b03050 Org. Lett. 2017, 19, 6160−6163