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Tetrahydropyran- and Tetrahydrofuran-Containing Diarylheptanoids from Hedychium coronarium Rhizomes Yi-Shan Lin,† Jung-Hsin Lin,†,‡,§ Chia-Chuan Chang,† and Shoei-Sheng Lee*,† †

School of Pharmacy, College of Medicine, National Taiwan University, 33 Linsen South Road, Taipei 100, Taiwan, Republic of China ‡ Research Center for Applied Sciences and §Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Sec. 2, Nankang, Taipei 115, Taiwan, Republic of China S Supporting Information *

ABSTRACT: Seven new diarylheptanoids (1−7) were isolated from the n-BuOH-soluble fraction of the rhizome of Hedychium coronarium. Hedycoropyrans A−C (1−3) contain a tetrahydropyran moiety, while hedycorofurans A−D (4−7) contain a tetrahydrofuran moiety, belonging to a rare structural class of diarylheptanoids. Their structures including stereochemistry were elucidated on the basis of 1D and 2D NMR and ECD spectroscopic analyses and HRESIMS data of the parent compounds and the isopropylidene derivatives of 4 and 7.

noside (9),4 adenosine (10),5 thymidine (11),6 and uridine (12),7 were isolated through various chromatographic methods. Compound 1 had a molecular formula of C20H24O7, as deduced from 13C NMR spectroscopic and HRESIMS data, implying nine indices of hydrogen deficiency. The 13C NMR spectrum of 1 showed resonances for 12 aromatic carbons composed of three oxygenated tertiary and two quaternary carbons, seven methines, five oxymethines, one methoxy, and two methylenes. The 1H NMR spectrum showed resonances for seven aromatic protons, constituting an AA′XX′ system (δ 6.69 and 7.06, JAX = 8.5 Hz) and an ABX system (δ 6.76, d, J = 8.2 Hz; δ 6.89, dd, J = 8.2, 1.8 Hz; δ 7.02, d, J = 1.8 Hz). These data suggested the presence of a 1,4-disubstituted and a 1,3,4trisubstituted phenyl group. The 1H NMR spectrum of 1 also showed resonances for one methoxy group (δ 3.86), five oxymethine protons, and four methylene protons (Table 1). Their coupling relationships and connectivity, H-2 (δ 4.48, d) ↔ H-3 (δ 3.38, dd) ↔ H-4 (δ 3.98, ddd) ↔ H2-5 (δ 1.85, ddd; 2.16, ddd) ↔ H-6 (δ 3.77, td) ↔ H-7 (δ 4.04, td) ↔ H2-8 (δ 2.60, dd; 2.82, dd), were verified by analysis of the COSY data (Figure S3, Supporting Information). The corresponding chemical shifts for the proton-attached carbons (Table 1) were assigned from analysis of an HSQC spectrum (Figure S4, Supporting Information). The HMBC spectrum (Figure S5, Supporting Information) showed key correlations of H-2 (δ 4.48)/C-1′ (δ 133.0, qC), C-2′ (δ 112.6,CH), C-6′ (δ 122.1, CH), and C-6 (δ 76.5, CH), of H2-8 (δ 2.60 and 2.82)/C-1″ (δ 130.9, qC) and C-2″/6″ (δ 131.5, CH), and of H-6 (δ 3.77)/C2 (δ 78.6, CH) (Table 1), revealing 1 to be a 1,7diarylheptanoid and C-2 to be linked to C-6 via an oxygen atom to form a tetrahydropyran skeleton. The coupling

Hedychium coronarium Koenig (Zingiberaceae) is a 1−3 m tall herb, widely growing at low elevations of India, Malaysia, Vietnam, southern China, and Taiwan.1 Several cytotoxic labdane-type diterpenoids have been identified from the rhizome of this plant, including coronarins A−D.2 The polar constituents, however, have rarely been reported and were the target of the present study. This report describes the isolation and characterization of the chemical constituents from the nBuOH-soluble fraction of the rhizome of H. coronarium.

■

RESULTS AND DISCUSSION The EtOH extract from the rhizome of H. coronarium was divided into fractions soluble in hexanes, MeCN, n-BuOH, and H2O by a liquid−liquid partitioning process. From the nBuOH-soluble fraction, 12 compounds, including seven new diarylheptanoids (Figure 1) and five known compounds (Table S1, Supporting Information), i.e., (4-hydroxy-2-methoxyphenyl)-β-D-glucopyranoside (8),3 4-hydroxyphenyl-β-D-glucopyra-

Received: May 31, 2014

Figure 1. Structures of compounds 1−7. © XXXX American Chemical Society and American Society of Pharmacognosy

A

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Table 1. 1H and 13C NMR Data of 1−3 and HMBC Data of 1 (Methanol-d4)a 1 position

δC

δH mult (J/Hz)

2

78.6, CH

4.48 d (9.2)

3 4 5

77.9, CH 70.7, CH 35.2, CH2

3.38 dd (9.2, 8.3) 3.98 ddd (10.9, 8.3, 5.1) 1.85 ddd (13.6, 10.9, 6.5)b 2.16 ddd (13.6, 5.1, 2.0)c 3.77 ddd (6.6, 6.5, 2.0)

6

76.5, CH

7 8

73.9, CH 40.6, CH2

1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″ 3″ 4″ 5″ 6″ MeO-3′ a1

133.0, 112.6, 148.7, 147.3, 115.7, 122.1, 130.9, 131.5, 116.0, 156.8, 116.0, 131.5, 56.4,

C CH C C CH CH C CH CH C CH CH CH3

2 δC

HMBC (C#)c 3 (w),d 4, 6 (vw),d 1′, 2′, 6′ 2, 4, 5, 1′ 3, 5 (vw) 3 (w), 4, 6, 7/3, 4

δH mult (J/Hz)

3 δC

δH mult (J/Hz)

77.1, CH

4.72 br s

79.3, CH

4.38 d (9.8)

72.3, CH 69.6, CH 30.2, CH2

3.55 br.d (3.4) 4.03 q-like (3.0) 1.41 dt (14.2, 1.9)c

73.71, CH 69.3, CH 35.5, CH2

2, 4, 5, 7 (w), 8 (vw)

74.2, CH

2.21 ddd (14.2, 12.4, 3.1)b 3.75 dt (12.4, 2.4)

73.75, CH

4.04 ddd (7.8, 6.6, 4.9) 2.60 dd (13.9, 7.8) 2.82 dd (13.9, 4.9) (pro-R)

5 (w), 6 (vw), 8, 1″ 6, 7, 1″, 2″/6″

76.3, CH 40.1, CH2

3.51 dd (9.8, 3.0) 4.14 q-like (2.9) 1.75 ddd (14.1, 3.3, 2.1)c 2.02 ddd (14.1, 11.8, 2.4)b 3.77 ddd (11.8, 3.2, 2.1) 3.59 ddd (7.4, 6.7, 3.2) 2.61 dd (13.4, 7.4) 2.77 dd (13.4, 6.7)

7.02 d (1.8)

2, 1′ (w), 3′, 4′, 6′

6.76 d (8.2) 6.89 dd (8.2, 1.8)

1′, 2′ (w), 3′, 4′, 6′ 2, 2′, 4′, 5′

7.06 d (8.5) 6.69 d (8.3)

8, 4″, 3″/5″ (w) 2″/6″, 4″

6.69 d (8.3) 7.06 d (8.5) 3.86 s

2″/6″, 4″ 8, 4″, 3″/5″ (w) 3′

133.1, 111.6, 148.7, 146.5, 115.7, 119.9, 131.0, 131.4, 116.1, 156.7, 116.1, 131.4, 56.4,

C CH C C CH CH C CH CH C CH CH CH3

3.60 ddd (7.3, 7.1, 2.5) 2.76 dd (13.4, 7.1) 2.93 dd (13.4, 7.3)

7.12 d (1.8)

6.78 d (8.1) 6.86 dd (8.3, 1.6) 7.01 d (8.5) 6.66 d (8.5) 6.66 d (8.5) 7.01 d (8.5) 3.88 s

75.9, CH 40.1, CH2

133.5, 112.7, 148.3, 147.2, 115.7, 122.0, 131.9, 117.7, 146.1, 144.6, 116.2, 121.8, 56.5,

C CH C C CH CH C CH C C CH CH CH3

7.08 d (1.8)

6.78 d (8.2) 6.92 dd (8.1, 1.9) 6.64 d (2.1)

6.65 d (8.1) 6.51 dd (8.1, 2.0) 3.89 s

H NMR and HMBC, 600 MHz; 13C NMR, 150 MHz. bAxially oriented. cEquatorially oriented. dw: weak, vw: very weak.

Figure 2. Key NOESY of 1 (A) and 4 (B) (methanol-d4, 600 MHz).

absolute configuration. The combined data established the structure of 1 as (2S,3R,4S,6R)-6-[(R)-1-hydroxy-2-(4hydroxyphenyl)ethyl]-2-(4-hydroxy-3-methoxyphenyl)tetrahydro-2H-pyran-3,4-diol (Figure 1). Compound 2 had the same molecular formula, C20H24O7, as 1, as deduced from 13C NMR spectroscopic and HRESIMS data. The 1H and 13C NMR spectra of 2 were similar to those of 1. The 2D NMR spectroscopic analysis of 2 (COSY, HSQC, NOESY, and HMBC; Figures S9−12, Supporting Information) led to complete 1H and 13C NMR assignments (Table 1). The 1 H NMR spectroscopic data of 2 indicated significant differences from those of 1 in the signals of H-1 through H4. Analysis of their coupling constants indicated H-4 (q-like, J = 3.0 Hz) and H-6 (dt, J = 12.4, 2.4 Hz) to be equatorially and axially oriented, respectively. The NOESY spectrum showed correlations of H-2 (δ 4.72, br s) to H-3 (δ 3.55) and H-6 (δ 3.75), consistent with H-2 and H-3 in axial and equatorial

constants (Table 1) revealed H-2, H-3, and H-4 to be axially oriented (J2,3 = 9.2 Hz, J3,4 = 8.3 Hz), with H-5 in an equatorial orientation. The ECD spectrum of 1 showed a positive Cotton effect (CE) at 230 nm, opposite that of adrenaline and nyasicoside,8 thus allowing the assignment of a (2S)configuration for 1. This assignment was supported by ECD calculation (vide inf ra). The NOESY spectrum (Figure S6, Supporting Information) showed mutual correlations of H-2, H-4, and H-7, confirming the axial orientation of H-2, H-4, and the C-6/C-7 bond and allowing the designation of a (3R,4S,6R) absolute configuration. This spectrum also showed an NOE correlation of MeO-3′/H-2′, locating the attached methoxy group, while the presence of Heq-5/H2-8 and absence of H2-8/ H-2 correlations (Figure 2) are consistent with the proposed conformation. From a molecular model and molecular dynamics analysis (Figure S7, Supporting Information), these NOE correlations are only feasible for a structure with a (7R) B

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Table 2. 1H and 13C NMR Data of 4−7 and HMBC Data of 4 (Methanol-d4)a 4 position 2 2a 3 4

δC mult 107.1, C 73.1, CH 72.8, CH 39.6, CH2

5

77.7, CH

6

38.7, CH2

7

32.5, CH2

1′ 2′ 3′ 4′ 5′ 6′ 1″ 2″

131.8, 104.7, 148.9, 134.6, 145.9, 110.0, 134.8, 113.1,

C CH C C C CH C CH

3″ 4″ 5″ 6″

148.8, 145.5, 116.0, 121.8,

C C CH CH

MeO-2 MeO-3′ MeO3″ a1

49.6, CH3 56.6, CH3 56.4, CH3

δ mult (J/Hz) 4.82 sb 4.23 dd (7.3, 5.8) 1.28 dt (12.4, 7.0), α 1.80 ddd (12.5, 6.7, 5.8), β 4.05 ddt (12.3, 7.0, 5.2) 1.50 m; 1.58 m 2.42 ddd (13.7, 9.4, 6.8) 2.56 ddd (13.7, 9.7, 5.4)

5 HMBC (C#)

δC mult

2, 3, 1′, 2′, 6′ 2a, 2, 4, 5

106.4, C 77.1, CH 71.8, CH

δC mult 107.1, C 73.1, CH 72.8, CH

40.6, CH2

4.56 s 4.27 dd (6.6, 3.3) 1.16 m, α

3, 7

77.4, CH

1.77 ddd (12.7, 5.7, 3.5), β 4.13 tt (7.9, 5.7)

77.7, CH

4 (w),c 5 (w), 7, 1″ (w) 5, 6, 1″, 2″, 6″

38.4, CH2

1.53 m, 1.67 m

38.7, CH2

32.8, CH2

2.45 ddd (13.8, 9.7, 6.5) 2.57 ddd (13.8, 9.8, 5.4)

32.1, CH2

2, 3, 5, 6

6.65 br s

2a, 1′, 3′, 4′, 6′

6.65 br s

2a, 1′, 2′, 4′, 5′

6.69 d (1.8)

7, 3″ (w), 4″, 6″

6.66 d (8.1) 6.56 dd (8.1, 1.8) 3.38 s 3.81 s 3.82 s

6 δ mult (J/Hz)

1″, 3″ 7, 2″, 4″ 2 3′ 3″

131.5, 104.9, 148.9, 134.6, 145.8, 110.1, 134.9, 113.1,

C CH C C C CH C CH

148.8, 145.4, 116.0, 121.7,

C C CH CH

56.6, CH3 56.4, CH3

6.65 d (1.8)

6.63 d (1.7) 6.71 d (1.9)

6.66 d (8.0) 6.57 dd (8.0, 1.9) 3.80 s 3.82 s

39.7, CH2

131.8, 104.7, 148.9, 134.6, 145.8, 109.9, 134.0, 130.3,

C CH C C C CH C CH

116.1, 156.4, 116.1, 130.3,

CH C CH CH

49.6, CH3 56.6, CH3

7 δ mult (J/Hz)

4.81 s 4.22 dd (7.3, 5.6) 1.25 dt (12.4, 7.1), α 1.78 ddd (12.4, 6.7, 5.7), β 4.04 ddt (12.4, 7.1, 5.3) 1.50 m, 1.58 m 2.42 ddd (13.8, 9.2, 6.8) 2.54 ddd (13.7, 9.6, 5.6) 6.64 br s

6.64 br s 6.95 d (8.5) 6.66 d (8.5) 6.66 d (8.5) 6.95 d (8.5) 3.38 s 3.80 s

δC mult 106.4, C 77.1, CH 71.8, CH

δ mult (J/Hz)

77.4, CH

4.55 s 4.26 dd (6.6, 3.2) 1.15 ddd (12.7, 8.7, 6.8), α 1.77 ddd (12.7, 5.7, 3.3), β 4.13 m

38.4, CH2

1.51 m, 1.65 m

32.3, CH2

2.44 ddd (13.9, 9.6, 6.5) 2.55 ddd (13.9, 9.6, 5.4)

40.6, CH2

131.5, 104.9, 148.8, 134.6, 145.8, 110.1, 134.1, 130.3,

C CH C C C CH C CH

116.0, 156.3, 116.0, 130.3,

CH C CH CH

56.6, CH3

6.64 d (1.6)

6.63 d (1.3) 6.96 d (8.3) 6.66 d (8.3) 6.66 d (8.3) 6.96 d (8.3)

3.79 s

H NMR and HMBC, 600 MHz; 13C NMR, 150 MHz. bChemical shift picked up from HSQC. cw: weak.

the replacement of the AA′XX′ system by an ABX system, reflecting 1,3,4-trisubstituted rings A and B, and significant differences for the signals of H-2 and H-3. Analysis of the coupling constants (J2,3 = 9.8 Hz; J6,5s = 11.8, 2.1 Hz) (Table 1) indicated axial orientations for H-2, H-3, and H-6 and equatorial for H-4, as also confirmed by NOE correlations of H-2 (δ 4.38)/H-6 (δ 3.77) and H-3 (δ 3.51)/Hax-5 (δ 2.02) in the NOESY spectrum. The HMBC spectrum showed correlations of H-2 (δ 4.38) and H2-8 (δ 2.61, 2.77) to the adjacent carbons as described above for 1 and 2, supporting 3 to be a 1,7-diarylheptanoid, and the correlations of MeO-3′ (δ 3.89) and H-5′ (δ 6.78)/C-3′ (δ 148.3) indicated C-3′ to be methoxylated. The ECD spectrum of 3 showed a negative CE at 233 nm, similar to that of 2, suggesting a (2R)-configuration. With this assignment, the (3S,4S,6R) absolute configurations were designated according to the orientations of the attached protons, elucidated by coupling constants and NOESY as described above. The coupling constant between H-6 and H-7 (3.2 Hz) and the NOE relationship of H-7/H2-5, but not of Hβ5/Hpro‑R-8, which might be observed from an energy-minimized conformation for the (7S)-isomer, obtained from MM2 calculation (Figure S20, Supporting Information), implied the same (7R)-configuration as in 1. These analyses established the structure of 3 as (2R,3S,4S,6R)-6-[(R)-1-hydroxy-2-(3,4-

orientations, respectively, as reflected by the small coupling constants (Table 1). Similar to that of 1, the HMBC spectrum showed key correlations of H-2 (δ 4.72)/C-1′ (δ 133.1), C-2′ (δ 111.6), C-6′ (δ 119.9), and C-6 (δ 74.2) and of H2-8 (δ 2.76 and 2.93)/C-1″ (δ 131.0) and C-2″/6″ (δ 131.4), supporting 2 as a 1,7-diarylheptanoid with C-2 linked to C-6 through an oxygen atom to form a tetrahydropyran skeleton. The ECD spectrum of 2 showed a negative CE at 230 nm, which is opposite that of 1, allowing the assignment of a (2R) absolute configuration. This suggestion was supported by ECD calculation (vide inf ra). With this assignment, the (3R,4S,6R) absolute configurations were designated by the orientations of the attached protons, elucidated by coupling constants and NOESY as described above. Thus, a (7R) absolute configuration could also be assigned to 2. On the basis of these analyses, the structure of 2 was established as (2R,3R,4S,6R)-6[(R)-1-hydroxy-2-(4-hydroxyphenyl)ethyl]-2-(4-hydroxy-3methoxyphenyl)tetrahydro-2H-pyran-3,4-diol (Figure 1). Compound 3 had a molecular formula of C20H24O8, as deduced from 13C NMR spectroscopic and HRESIMS data, containing one more oxygen than 1 and 2. The 2D NMR spectroscopic analysis of 3 (COSY, HSQC, NOESY, and HMBC; Figures S15−18, Supporting Information) led to complete 1H and 13C NMR assignments as shown in Table 1. The 1H NMR data of 3 were similar to those of 2, except for C

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dihydroxyphenyl)ethyl]-2-(4-hydroxy-3-methoxyphenyl)tetrahydro-2H-pyran-3,4-diol (Figure 1). Compound 4 had a molecular formula of C22H28O9, as deduced from 13C NMR spectroscopic and HRESIMS data. The 13C NMR spectrum of 4 showed resonances for 12 aromatic carbons composed of two quaternary, five oxygenated, and five methine carbons, in addition to 10 sp3 carbons, including a ketal carbon (δ 107.1), three oxymethines, three methoxys, and three methylenes. The 1H NMR spectrum showed resonances for five aromatic protons, i.e., an ABX system (δ 6.56, 6.66, and 6.69) and an A2 broad singlet (δ 6.65), reflecting the presence of a 1,3,4-trisubstituted and a 1,3,4,5-tetrasubstituted phenyl group. Among the signals from attached groups were three methoxy groups (δ 3.38, 3.81, 3.82), three oxymethine protons, including a singlet at δ 4.82, and six methylene protons (Table 2). The 2D NMR spectroscopic analysis of 4 (COSY, HSQC, NOESY, and HMBC; Figures S21−24, Supporting Information) led to complete 1H and 13C NMR assignments as shown in Table 2. The COSY spectrum (Figure S21, Supporting Information) showed the following 1H/1H correlations: H-3 (δ 4.23, dd) ↔ H2-4 (δ 1.28, dt; 1.80, ddd) ↔ H-5 (δ 4.05, ddt) ↔ H2-6 (δ 1.50, m; 1.58, m) ↔ H2-7 (δ 2.42, ddd; 2.56, ddd). Chemical shifts of those proton-bearing carbons were assigned from an HSQC spectrum (Table 2). A combination of these 2D NMR spectroscopic data and the correlations in the HMBC spectrum, H-2a (δ 4.82)/C-1′ (δ 131.8), C-2′ (δ 104.7), C-6′ (δ 110.0), C-2 (δ 107.1), and C-3 (δ 72.8), H2-7 (δ 2.42, 2.56)/C-1″ (δ 134.8), C-2″ (δ 113.1), and C-6″ (δ 121.8), and MeO-2 (δ 3.38)/C-2 (δ 107.1), revealed that 4 is a 2-methoxy-1,2,3,5tetraoxgenated-1,7-diarylheptanoid. The NOESY spectrum of 4 showed the following correlations: MeO-3′ (δ 3.81) ↔ H-2′ (δ 6.65) ↔ H-2a (δ 4.82)/H-3 (δ 4.23); MeO-2 (δ 3.38) ↔ H-5 (δ 4.05) ↔ H-4α (δ 1.80); and MeO-3″ (δ 3.82) ↔ H-2″ (δ 6.69) (Figure 2). For easier depiction of these correlations, the structure of 4 in Figure 2 is flipped horizontally through 180° compared to that in Figure 1. These correlations established the location of the three methoxy groups, and also suggested that MeO-2 was cis to H-5 and trans to H-3, and the presence of a tetrahydrofuran moiety in 4, formed by an ether linkage between C-2 and C-5. These analyses thus deduced the structure of 4 as 5-{[3-hydroxy-5-(4-hydroxy-3-methoxyphenethyl)-2-methoxytetrahydrofuran-2-yl]hydroxymethyl}-3-methoxybenzene-1,2-diol (Figure 1). The ECD spectrum of 4 showed a positive CE at 240 nm, which was opposite that of adrenaline and nyasicoside8 and reflected its (2aS)-configuration. Thus, 4 could have either a (2aS,2S,3S,5S)- or (2aS,2R,3R,5R)-configuration. Attempts to elucidate this issue by combination of NOESY data and a molecular modeling study, however, were inconclusive. Reaction of 4 with 2,2dimethoxypropane in the presence of p-TsOH yielded the isopropylidene derivative 4a. In the 1D NOESY study of 4a, H2a (δ 4.63, s) showed association with methyl-α (δ 1.33, s) and H-2′/H-6′ (δ 6.62, br s), while H-3 (δ 4.29, d) showed association with methyl-β (δ 1.45, s) (Figure 3). These data, when incorporated into a chemical model and assumption of a (2aS)-configuration, established MeO-2 and H-3 in 4 to be αand β-oriented, respectively. If MeO-2 and H-3 in 4 were βand α-oriented, respectively, both H-2a and H-3 in these two 1D NOESY spectra would show association with methyl-α. Hence a (2S,3S)-configuration for 4 was deduced. Accordingly, the (2aS,2S,3S,5S) absolute configuration for 4 was established.

Figure 3. 1D NOESY for 4a (A) and 7a (B) (methanol-d4, 600 MHz).

Compound 5 had a molecular formula of C21H26O9, as deduced from 13C NMR spectroscopic and HRESIMS data, a CH2 residue less than 4. The 1H and 13C NMR spectra of 5 were similar to those of 4 except for the lack of a methoxy signal (δH 3.38 and δC 49.6, MeO-2 in 4) (Table 2). The ECD spectrum of 5 was similar to that of 4. Thus, compound 5 was the C-2 hemiketal analogue of 4, i.e., 5-{(S)-[(2S,3S,5S)-2,3dihydroxy-5-(4-hydroxy-3-methoxyphenethyl)tetrahydrofuran2-yl]hydroxymethyl}-3-methoxybenzene-1,2-diol (Figure 1). Compound 6 had a molecular formula of C21H26O8, as deduced from 13C NMR spectroscopic and HRESIMS data, showing a CH2O residue less than 4. The 1H NMR spectrum of 6 was similar to that of 4 except for lacking an aromatic methoxy singlet and the presence of an AA′XX′ system (δ 6.66 and 6.95, J = 8.5 Hz) instead of an ABX system (Table 2). Thus, compound 6 was the 3″-demethoxy analogue of 4. The HMBC spectrum showed correlations of MeO-2 (δ 3.38)/C-2 (δ 107.1) and of MeO-3′ (δ 3.80) and H-6′ (δ 6.64)/C-3′ (δ 148.9), confirming the location of these two methoxy groups. The ECD spectrum of 6 was similar to that of 4. Therefore, the structure of compound 6 was established as 5-{(S)-[(2S,3S,5S)3-hydroxy-5-(4-hydroxyphenethyl)-2-methoxytetrahydrofuran2-yl]hydroxymethyl}-3-methoxybenzene-1,2-diol (Figure 1). Compound 7 had a molecular formula of C20H24O8, as deduced from 13C NMR spectroscopic and HRESIMS data, which had a CH2 residue less than 6. The 1H and 13C NMR spectra of 7 were similar to those of 6 except for the lack of a methoxy signal (δH 3.38 and δC 49.6, MeO-2 in 6). The ECD spectrum of 7 was similar to those of 4 and 6. Thus, compound 7 was the C-2 hemiketal analogue of 6, i.e., 5-{(S)-[(2S,3S,5S)2,3-dihydroxy-5-(4-hydroxyphenethyl)tetrahydrofuran-2-yl]hydroxymethyl}-3-methoxybenzene-1,2-diol (Figure 1). Reaction of 7 with 2,2-dimethoxypropane in the presence of pTsOH yielded the isopropylidene derivative 7a. In the 1D NOESY spectrum of 7a, H-2a (δ 4.61, s) and H-3 (δ 4.66, s) showed association with methyl-β (δ 1.41, s), H-2′ (δ 6.61, d), and H-6′ (δ 6.59, d), while H-5 (δ 4.17, m) showed association with methyl-α (δ 1.42, s) (Figure 3). These data established 7a as the 2,3-isopropylidene derivative of 7 and confirmed both 2OH and 3-OH in 7 to be α-oriented. The absolute configurations of 1, 2, and 4 were supported by quantum chemical calculations of the ECD spectra. The structure of (2S,3R,4S,6R,7R)-1 was optimized with the density functional theory (DFT) using the hybrid functional B3LY9 and the correlation-corrected basis set aug-cc-pVDZ.10 The ECD spectrum was calculated with the time-dependent density functional theory (TDDFT)12 using the same functional, B3LYP,9 the basis set aug-cc-pVDZ,10 and the C-PCM solvent model11 for acetonitrile. The quantum chemical calculations were carried out with Gaussian 09.13 The calculated ECD D

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(Bruker Daltonics) (HRESIMS). HPLC (Hitachi L-7100 system) separation was performed on an RP-18 column (Phenomenex Prodigy ODS-3, 250 × 10 mm, 5 μm; Phenomenex, Torrance, CA, USA). Centrifugal partition chromatography (CPC) was carried out on a Sanki CPC (model LLB-M, 230 mL). TLC analysis was carried out on silica gel plates (KG60-F254, Merck). Plant Material. The rhizomes of H. coronarium were collected in March 2011 in the Pin-Lin area, New Taipei City, Taiwan. The specimen obtained (NTU03012011) was authenticated by one of the authors (S.S.L.) and was deposited in the herbarium of the School of Pharmacy, National Taiwan University. Extraction and Isolation. The powdered dried rhizomes (14.5 kg) were extracted with 95% EtOH (3× 18 L, 40−50 °C). The EtOH extract (721.6 g), was suspended in H2O (2L) and partitioned against CHCl3 (3 × 2L) and n-BuOH (3× 2L) to give fractions soluble in CHCl3 (544.7 g) and n-BuOH (20.9 g). The n-BuOH-soluble fraction (20.0 g) was fractionated on a Sephadex LH-20 column (3.5 L, MeOH) to give 13 fractions. Separation of fraction 3 (708.4 mg) via a CPC, using the lower and upper layers of CHCl3−MeOH−H2O (2:2:1) as mobile and stationary phases, respectively, flow rate 1.5 mL/ min, rotation speed 800 rpm, gave five subfractions (Frs. 3-1−5); then it was switched to reverse mode to give five subfractions (Frs. 3r-1−5). Fraction 3-3 (58.2 mg) was purified on silica gel CC (0−20% MeOH− CHCl3) and a semipreparative RP-18 column (20% MeCN(aq), flow rate 2.4 mL/min) to give 4 (4.2 mg, tR 42 min) and 5 (1.5 mg, tR 17 min). Fractions 3-5 (63.1 mg) and 3r-5 (29.2 mg), showing similar TLC profiles, were combined and separated on silica gel CC (0−20% MeOH−CHCl3) to give five subfractions. Subfraction 2 (10.7 mg) yielded 6 (1.2 mg, tR 22 min) upon separation on a semipreparative RP-18 column (20% MeOH(aq), flow rate 2.4 mL/min), while subfraction 3 (2.7 mg) yielded 1 (0.8 mg, tR 10 min) under similar conditions except for elution with 18% MeOH(aq). Subfraction 4 (26.4 mg) was chromatographed on a Sephadex LH-20 (MeOH) and a semipreparative RP-18 column (16% MeCN(aq), flow rate 2.4 mL/ min) in sequence to give 1 (0.2 mg, tR 16 min), 2 (0.4 mg, tR 30 min), and thymidine (11) (0.3 mg, tR 7 min). Fraction 3r-4 (95.2 mg) yielded 3 (0.4 mg, tR 25 min) by sequential separation on silica gel CC (0−20% MeOH−CHCl3) and a semipreparative RP-18 column (25% MeOH(aq), flow rate 2.4 mL/min). Recrystallization of fraction 3r-2 (113.7 mg) from MeOH yielded (4-hydroxy-2-methoxyphenyl)-β-Dglucopyranoside (8) (6.2 mg). Silica gel CC of fraction 3r-1 (62.6 mg) (0−20% MeOH−CHCl3), followed by recrystallization from MeOH− CHCl3, gave 4-hydroxyphenyl-β-D-glucopyranoside (9) (2.0 mg). CPC fractionation on fraction 4 (520.1 mg), using the lower and upper layers of CHCl3−MeOH−H2O−n-PrOH (9:12:8:1) as the mobile and stationary phases, respectively, with a flow rate of 1.5 mL/ min and rotation speed of 800 rpm, gave eight subfractions (Frs.4-1− 8); then it was switched to reverse mode, which yielded three additional subfractions (Frs.4r-1−3). Fraction 4r-2 (48.0 mg) was uridine (12). Fractions 4-5 (94.2 mg) and 4-6 (95.3 mg) were separated in sequence on a Sephadex LH-20 column (75% MeOH(aq)) and a semipreparative RP-18 column (20% MeOH(aq), flow rate 2.4 mL/min) to give 5 (11.6 mg, tR 112 min) and 7 (20.7 mg, tR 92 min), respectively. Silica gel CC on fraction 5 (157.9 mg), eluted with 0−20% MeOH−CHCl3, gave 12 (7.8 mg). Recrystallization of fraction 7 (194.8 mg) from MeOH−H2O yielded adenosine (10) (40.0 mg). Hedycoropyran A (1): amorphous solid; [α]22D −86 (c 0.04, MeOH); UV (MeCN) λmax (log ε) 225 (3.93) and 279 (3.39) nm; ECD (MeCN, c 2.66 × 10−5 M) [θ]217 +4846, [θ]229 +8744, [θ]283 +1729; 1H and 13C NMR, see Table 1; NOESY (methanol-d4), see Figure 2; HMBC data (methanol-d4), see Table 1; ESIMS+ m/z [M + Na]+ 399; ESIMS− [M − H]− 375; HRESIMS− m/z 375.1445 [M − H]−, calcd for C20H23O7, 375.1449. Hedycoropyran B (2): amorphous solid; [α]22D −100 (c 0.02, MeOH); UV (MeCN) λmax (log ε) 222 (3.86) and 277 (3.37) nm; ECD (MeCN, c 2.66 × 10−5 M) [θ]231 −3226, [θ]285 +1556; 1H and 13 C NMR, see Table 1; NOESY data (methanol-d4) H-2/H-3, H-6, H2′ (w), H-6′; H-3/H-2, H-4, H-2′ (vw), H-6′ (w); H-4/H-3 (w), H25; Hax-5/H-4, Heq-5; Heq-5/H-4 (w), Hax-5, H-6 (w), H-7 (w); H-6/

spectrum of 1 was similar to the experimental one, both showing a positive Cotton effect around 230 nm (Figure 4),

Figure 4. Experimental and calculated ECD spectra of 1.

thus supporting the suggested absolute configurations of 1. This study also indicated that the C-2 phenyl group being linked to the stereogenic chiral center dominates the sign of the Cotton effect. On this basis and to reduce the computational cost, fragments of 1, 2, and 4 (Figure S63, Supporting Information), deleting C-8 and the C-8 phenyl group and assuming C-7 as methyl, were used for the TDDFT ECD calculations. The calculated ECD spectra of these fragments (Figure S63, Supporting Information) were also similar in shape to the experimental spectra of the parent compounds, supporting the suggested configurations. The calculated ECD spectrum of fragment 2 is almost the mirror image of fragment 1, ascribable to the opposite absolute configuration at C-2. This study led to the isolation of seven new diarylheptanoids, containing either a tetrahydropyran (1−3) or a tetrahydrofuran moiety (4−7). They were named hedycoropyrans A−C (1−3) and hedycorofurans A−D (4−7) after their plant origin and structural skeletons. Several diarylheptanoids containing a tetrahydropyran moiety, formed by an ether linkage between C-1 and C-5, had been isolated such as (−)-centrolobine from Brosimum potabile (Moraceae).14 The absolute configuration for this type of compounds had been established by a biomimetic synthesis approach.15,16 Hedycorofurans A−D (4−7) belong to a rare structural class of diarylheptanoids. Before this study, only two tetrahyrofuran-bearing diarylheptanoids, i.e., renealtins A and B,17 had been isolated, and their configurations had been solved by a synthetic approach.18 In the present study, compounds 1−7 were isolated as minor natural products, and each contains at least five hydroxy groups. The configurations in compounds 1−7 were determined mainly by ECD data, which were correlated with the calculated ECD, and NOESY spectroscopic analyses on the parent compounds and by selective 1D NOESY studies of the isopropylidene derivatives (4a and 7a). The C-6 configuration in 1−3 was tentatively assigned based on NOESY and chemical model analyses.

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EXPERIMENTAL SECTION

General Experimental Procedures. The optical rotations were measured on a JASCO DIP-370 polarimeter. UV spectra were measured in MeCN or MeOH on a U-2001 Hitachi double-beam spectrophotometer. The ECD spectra were recorded on a J-710 spectropolarimeter. 1H, 13C, and 2D NMR spectra were obtained on a Bruker Avance III 600 NMR spectrometer, equipped with a 5 mm cryoprobe (methanol-d4, δH 3.30 and δC 49.0 ppm), using standard pulse programs. Mass spectra were recorded on an Esquire 2000 (ESIMS) and a micrOTOF orthogonal ESI-TOF mass spectrometer E

DOI: 10.1021/np500441r J. Nat. Prod. XXXX, XXX, XXX−XXX

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Hedycorofuran D (7): amorphous solid; [α]26D −30 (c 0.1, MeOH); UV (MeOH) λmax (log ε) 225 (4.16) and 278.5 (3.57) nm; ECD (MeOH, c 2.55 × 10−5 M) [θ]238 +813, [θ]270 −798, [θ]309 +1046; 1H and 13C NMR, see Table 2; NOESY data (methanol-d4) H2a/H-3, H-2′, H-6′; H-3/H-2a (vw), H2-4, H-2′, H-6′; Hβ-4/H-3 (w), Hα-4, H2-6 (vw); Hα-4/H-3 (vw), Hβ-4, H-5, H-6a (vw); H-5/Hα-4, H-6a (w), H-6b (vw), H2-7 (vw); H-6a/Hβ-4 (vw), H-5 (w), H-6b, H7a (w), H-7b (vw); H-6b/Hβ-4 (vw), H-5 (vw), H-6a, H-7a (vw), H7b (w); H-7a/H-5 (vw), H-6a (w), H-6b (vw), H-7b, H-2″ (H-6″) (w); H-7b/H-5 (vw), H2-6, H-7a, H-2″ (H-6″) (w); H-2′/H-2a, H-3, MeO-3′; H-6′/H-2a, H-3; H-2″ (H-6″)/H2-7, H-3″ (H-5″); HMBC data (methanol-d4) H-2a/C-2, C-3, C-1′, C-2′, C-6′; H-3/C-2a, C-2 (w), C-4 (vw), C-5; Hβ-4/C-2, C-3, C-5, C-6; Hα-4/C-2, C-3, C-5 (vw), C-6 (w); H-5/C-3 (w), C-7; H2-6/C-4, C-5, C-7, C-1″; H2-7/C5, C-6, C-1″, C-2″ (C-6″); H-2′/C-2a, C-1′, C-3′, C-4′, C-6′; H-6′/C2a, C-2′, C-4′, C-5′; H-2″ (H-6″)/C-7, C-3″ (C-5″) (w), C-4″; H-3″ (H-5″)/C-1″, C-4″; MeO-3′/C-3′; ESIMS+ m/z 415 [M + Na]+; ESIMS− m/z 391 [M − H]−; HRESIMS− m/z 391.1380 [M − H]−, calcd for C20H23O8, 391.1398. Preparation of the 1,3-Isopropylidene Derivative of 4 (4a). Compound 4 (1.2 mg, 3.89 μmol) was reacted with 2,2dimethoxypropane (2.0 mL, 16.32 mmol) and p-TsOH (2 mg, 11.61 μmol) at 0 °C for 30 min and at room temperature for 30 min. The reaction mixture was diluted with CHCl3 (10 mL), washed with 5% KHCO3(aq) (10 mL) and H2O (10 mL), dried over MgSO4, and evaporated in vacuo to yield a residue, which was chromatographed on a semipreparative RP-18 column (35% MeCN(aq), flow rate 2.4 mL/ min) to give 4a (0.6 mg, tR 38 min): white, amorphous solid; 1H NMR (methanol-d4) δ 0.88 (1H, m, Hα-4), 1.33 (3H, s, CH3), 1.45 (3H, s, CH3), 1.83 (1H, m, H-6a), 2.00 (1H, m, H-6b), 2.33 (1H, m, Hβ-4), 2.64 (1H, m, H-7a), 2.72 (1H, m, H-7b), 3.63 (3H, s, MeO-2), 3.82 (3H, s, MeO-3′), 3.83 (3H, s, MeO-3″), 4.29 (1H, d, J = 5.8 Hz, H-3), 4.39 (1H, m, H-5), 4.63 (1H, s, H-2a), 6.62 (2H, br s, H-2′/6′), 6.65 (1H, dd, J = 8.1, 1.8 Hz, H-6″), 6.70 (1H, d, J = 7.9 Hz, H-5″), 6.80 (1H, d, J = 1.8 Hz, H-2″); 1D NOESY (methanol-d4), see Figure 3; HRESIMS− m/z 475.1881 [M − H]−, calcd for C25H31O9, 475.1974. Preparation of the 2,3-Isopropylidene Derivative of 7 (7a). Compound 7 (2.5 mg) was treated in a similar manner in which 4 was used for the preparation of 4a, except for elution with 26% MeCN(aq) for purification, to give 7a (0.6 mg, tR 55 min): white, amorphous solid; 1H NMR (methanol-d4) δ 0.85 (1H, ddd, J = 12.9, 11.0, 4.1 Hz, Hα-4), 1.41, (3H, s, CH3), 1.42, (3H, s, CH3), 1.54 (1H, m, H-6a), 1.67 (1H, m, H-6b), 1.81 (1H, dd, J = 13.0, 4.3 Hz, Hβ-4), 2.47 (1H, ddd, J = 13.8, 9.4, 7.0 Hz, H-7a), 2.57 (1H, ddd, J = 13.8, 9.2, 5.0 Hz, H-7b), 3.80, (3H, s, MeO-3′), 4.17 (1H, m, H-5), 4.61 (1H, s, H-2a), 4.66 (1H, d, J = 4.1 Hz, H-3), 6.59 (1H, d, J = 1.7 Hz, H-6′), 6.61 (1H, d, J = 1.9 Hz, H-2′), 6.66 (2H, d, J = 8.6 Hz, H-3″/5″), 6.97 (2H, d, J = 8.4 Hz, H-2″/6″); 1D NOESY (methanol-d4), see Figure 3; ESIMS+ m/z 455 [M + Na]+; ESIMS− m/z 413 [M − H]−; HRESIMS− m/z 431.1692 [M − H]−, calcd for C23H27O8, 431.1711.

H-2, Heq-5; H-7/Heq-5 (w), H-8a (w), H-2″ (H-6″) (vw); H-8a/H-7 (w), H-8b, H-2″ (H-6″) (w); H-8b/H-8a, H-2″ (H-6″); H-2′/H-2 (w), H-3 (w), MeO-3′; H-6′/H-2 (w), H-2 (vw); H-2″ (H-6″)/H-7 (w), H2-8, H-3″ (H-5″); HMBC data (methanol-d4) H-2/C-3, C-6, C1′, C-2′, C-6′; H-3/C-4 (w); Hax-5/C-6 (w); Heq-5/C-3, C-4; H-7/C8 (w); H2-8/C-6, C-7, C-1″, C-2″; H-2′/C-2, C-1′ (w), C-3′, C-4′, C6′; H-5′/C-1′, C-3′, C-4′; H-6′/C-2, C-2′, C-4′; H-2″ (H-6″)/C-8, C1″, C-3″ (C-5″) (w), C-4″; H-3″ (H-5″)/C-1″, C-4″; MeO-3′/C-3′; HRESIMS− m/z 375.1442 [M − H]−, calcd for C20H23O7, 375.1449. Hedycoropyran C (3): amorphous solid; [α]26D −150 (c 0.02, MeOH); UV (MeCN) λmax (log ε) 229 (4.14) and 277 (3.76) nm; ECD (MeCN, c 2.55 × 10−5 M) [θ]233 −6464, [θ]273 +433, [θ]287 −1095; 1H and 13C NMR, see Table 1; NOESY data (methanol-d4) H-2/H-6, H-2′, H-6′; H-3/H-4, Hax-5, H-2′, H-6′; H-4/H-3, H2-5; Hax-5/H-3 (w), H-4, Heq-5; Heq-5/H-4, Hax-5, H-6, H-7 (w); H-6/H-2, Heq-5, H-8b (w); H-7/H2-5 (w), H2-8; H-2′/H-2, H-3, MeO-3′; H-6′/ H-2, H-3 (w), H-5′; H-2″/H-7, H2-8; H-6″/H-7 (w), H2-8 (w), H-5″; HMBC data (methanol-d4) H-2/C-3, C-1′, C-2′, C-6′; H-3/C-2, C-1′ (w); H-4/C-3 (w), C-6 (w); Hax-5/C-3 (w), C-6 (w), C-7 (vw); Heq5/C-3 (vw), C-4 (vw), C-6 (vw); H2-8/C-6 (w), C-7, C-1″, C-2″, C6″; H-2′/C-2, C-1′ (w), C-3′, C-4′, C-6′; H-5′/C-1′, C-3′, C-4′; H-6′/ C-2, C-2′, C-4′, C-5′ (w); H-2″/C-8, C-4″, C-6″; H-5″/C-1″, C-3″, C4″ (w); H-6″/C-8, C-2″, C-4″, C-5″; MeO-3′/C-3′; ESIMS− m/z 391 [M − H]−; HRESIMS− m/z 391.1392 [M − H]−, calcd for C20H23O8, 391.1398. Hedycorofuran A (4): amorphous solid; [α]22D −70 (c 0.1, MeOH); UV (MeCN) λmax (log ε) 230 (4.09) and 280 (3.59) nm; ECD (MeCN, c 4.59 × 10−5 M) [θ]240 +1833, [θ]276 −2090; 1H and 13 C NMR, see Table 2; NOESY (methanol-d4), see Figure 2; HMBC data (methanol-d4), see Table 2; ESIMS+ m/z 459 [M + Na]+; ESIMS− m/z 435[M − H]−; HRESIMS− m/z 435.1655 [M − H]−, calcd for C22H27O9, 435.1661. Hedycorofuran B (5): amorphous solid; [α]22D −65 (c 0.2, MeOH); UV (MeCN) λmax (log ε) 230 (4.07) and 280 (3.53) nm; ECD (MeOH, c 2.47 × 10−5 M) [θ]239 +466, [θ]277 −1845, [θ]298 +2331; 1 H and 13C NMR, see Table 2; NOESY data (methanol-d4) H-2a/H-3, H-2′, H-6′; H-3/H-2a (w), H2-4, H-2′, H-6′; Hβ-4/H-3, Hα-4, H-5 (vw); Hα-4/H-3, Hβ-4, H-5; H-5/Hβ-4 (vw), Hα-4, H-6a (w), H-6b, H2-7 (vw); H-6a/Hβ-4 (vw), H-5 (vw), H-6b, H-7a, H-7b (w), H-2″ (H-6″) (vw); H-6b/Hβ-4 (vw), H-5 (vw), H-6a, H-7a (w), H-7b, H-2″ (H-6″) (vw); H-7a/H-5 (w), H2-6, H-7b, H-2″ (H-6″) (w); H-7b/H5 (vw), H2-6, H-7a, H-2″ (H-6″) (w); H-2′/H-2a, H-3, MeO-3′; H6′/H-2a, H-3; H-2″/H2-7, MeO-3″; H-6″/H-7a, H-7b, H-5″; HMBC data (methanol-d4) H-2a/C-2, C-3, C-1′, C-2′, C-6′; H-3/C-2, C-5 (w); H2-4/C-2, C-3, C-5, C-6; H-5/C-3 (vw), C-7; H2-6/C-4, C-5, C7, C-1″; H2-7/C-5, C-6, C-1″, C-2″, C-6″; H-2′/C-2a, C-4′, C-6′; H6′/C-2a, C-2′, C-4′, C-5′; H-2″/C-3″, C-4″, C-6″; H-5″/C-1″, C-3″, C-4″; H-6″/C-2″, C-4″; MeO-3′/C-3′; MeO-3″/C-3″; ESIMS+ m/z 445 [M + Na]+; ESIMS− m/z 421 [M − H]−; HREIMS− m/z 421.1500 [M − H]−, calcd for C21H25O9, 421.1504. Hedycorofuran C (6): amorphous solid; [α]22D −100 (c 0.1, MeOH); UV (MeCN) λmax (log ε) 226 (4.21) and 278.5 (3.50) nm; ECD (MeCN, c 2.46 × 10−5 M) [θ]242 +3878, [θ]288 −698; 1H and 13 C NMR, see Table 2; NOESY data (methanol-d4) H-2a/H-3, H-2′, H-6′, MeO-2; H-3/H-2a, H2-4, H-2′, H-6′; Hβ-4/H-3 (w), Hα-4, H2-6 (vw); Hα-4/H-3 (w), Hβ-4, H-5; H-5/Hβ-4 (vw), Hα-4, H-6a, H-6b (w), H2-7 (vw), MeO-2; H-6a/Hβ-4 (vw), H-5 (w), H-6b, H2-7, H-2″ (H-6″) (vvw); H-6b/Hβ-4 (vw), H-5 (vw), H-6a, H2-7, H-2″ (H-6″) (vvw); H-7a/H-5 (vvw), H2-6 (vw), H-7b, H-2″ (H-6″) (w); H-7b/H5 (vvw), H2-6, H-7a, H-2″ (H-6″) (w); H-2′/H-2a, H-3, MeO-3′; H2″ (H-6″)/H2-6 (vw), H2-7 (w), H-3″ (H-5″); MeO-2/H-2a, H-5, H2′ (H-6′) (w); HMBC data (methanol-d4) H-2a/C-2, C-3, C-1′, C-2′, C-6′; H-3/C-2a, C-2 (w), C-4 (w), C-5; H2-4/C-2, C-3, C-5, C-6; H5/C-3 (vw), C-7; H2-6/C-4 (w), C-5, C-7, C-1″; H2-7/C-5, C-6, C-1″, C-2″, C-6″; H-2′/C-2a, C-1′, C-3′, C-4′, C-6′; H-6′/C-2a, C-1′, C-2′, C-4′, C-5′; H-2″ (H-6″)/C-7, C-3″ (C-5″) (w), C-4″; H-3″ (H-5″)/ C-1″, C-4″; MeO-2/C-2; MeO-3′/C-3′; ESIMS+ m/z 429 [M + Na]+; ESIMS− 405 [M − H]−; HRESIMS− m/z 405.1547 [M − H]−, calcd for C21H25O8, 405.1555.

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ASSOCIATED CONTENT

S Supporting Information *

1D (1H and 13C) and 2D NMR (COSY, NOESY, HSQC, and HMBC), HRESIMS, and ECD spectra of 1−7 and 1D NOESY of 4a and 7a, favored conformations of 1 and 3, calculated ECD spectra of 1, fragments 1, 2, and 4, and 1H and 13C NMR data of known compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Tel/fax: +886 2 23916127. E-mail: [email protected]. Notes

The authors declare no competing financial interest. F

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ACKNOWLEDGMENTS This work was supported by the National Science Council, Taiwan, Republic of China, under the grant NSC 101-2325-B002-017. We are grateful to the National Center for HighPerformance Computing for computer time and facilities.

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REFERENCES

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DOI: 10.1021/np500441r J. Nat. Prod. XXXX, XXX, XXX−XXX