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Accepted Article Title: Guianolactones A and B, Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis. Authors: Keiichiro Higuchi, Yoshimi Tani, Takashi Kiuchi, Yasuko In, Takeshi Yamada, Osamu Muraoka, Naonobu Tanaka, and Reiko Tanaka This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Asian J. 10.1002/asia.201701298 Link to VoR: http://dx.doi.org/10.1002/asia.201701298
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Guianolactones A and B, Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis.
Abstract: Two novel rearranged limonoids, guianolactones A (1) and B (2), were isolated from Carapa guianensis Aubl. (Meliaceae) seeds. The structures of 1 and 2 with their absolute configurations were elucidated in detailed examinations using single crystal X-ray diffraction analyses and 2D NMR spectra. Guianolactone A (1) has a novel 5/6/6/6/6 pentacyclic core including two d-lactone and a tetrahydropyran ring, while guianolactone B (2) is a novel limonoid with a 6/6/5/6/6 pentacyclic core featuring a d-lactone and a tetrahydrofuran ring.
We previously described the isolation and structural determination of guianolides A and B, featured an unique policyclic skeleton from the seeds of C. guianensis.[18] As a continuation of this study, two novel structurally attractive limonoids, guianolactones A (1) and B (2) were isolated from the seeds of C. guianensis (Figure 1). We report herein the structure elucidation of 1 and 2 and the effects of the production of NO in LPS-activated mouse peritoneal macrophages.[19] 23
O
Limonoids are characteristic metabolites of Meliaceae and Rutaceae plants and have various structures and remarkable biological activities.[1] A large number of limonoids have recently been isolated by several researchers, such as phyllanthoids A and B,[2] aphanamixoid A,[3a,3b] walsucochins A and B,[4] chukrasones A and B,[5] tabulvelutin A,[6] cipacinoids A–D,[7] aphanamoide A,[8] thaixylomolins A–C,[9] trichiconins A–C,[10] and ciliatonoids A and B.[11] Carapa guianensis (Andiroba, Meliaceae) is a deciduous or semi-evergreen tropical tree with fragment flowers which occasionally grows to 50 meters in the rain forests of South America. Individuals residing in the Amazon use this tree to make many types of medicine. Its four-cornered woody nut has four cells, each of which contains two to four seeds with oily kernels. Seed oil from C. guianensis exhibits analgesic,[12] antibacterial,[13] anti-inflammatory,[14] anti-tumor,[15] anti-allergic,[16] and anti-arthritis and -rheumatism[17] activities.
[a]
Prof. R. Tanaka, K. Higuchi, Y. Tani, Dr. T. Kikuchi, Dr. Y. In, Dr. T. Yamada Osaka University of Pharmaceutical Sciences 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan E-mail: [email protected]
[b]
Dr. N. Tanaka, Graduate School of Pharmaceutical Sciences Tokushima University, E-mail: [email protected]
[c]
Prof. O. Muraoka Kinki University 3-4-1 Kowakae, Higashiosaka, E-mail: [email protected] Supporting information for this article is given via a link at the end of the document.
7
18
O
10
B 1
3
2
OH
E
22
O H
32 31
D2
30
O
16
O
OH
1
O
O 21
O
20 1'
O
D1
14
15
O 23
17
8
A
20
13
H C
9 5
29
O 21
H
19
6
28
E
22
18
O
17 13
O
O
7
19
H
B1 O
6 5
1
HO
A
28
2
O
B2 3
29
O
C
9
2'
14
H
2"
O
O
O
H H
32
15 8
30
H
31
H
D O
16
2a
O
OH
O HO
H
O H
O
O
O
2b
Figure 1. Strucutures of guianolactones A (1) and B (2a, 2b).
The seed oil of C. guianensis (2.03 kg) was chromatographed over silica gel to afford eight fractions (A–H). The limonoidcontaining fraction C (29.3 g) was rechromatographed over silica gel to give the residue C3 (57 mg). Residue C3 was further purified by HPLC (ODS, 70% MeOH) to afford 1 (4.72 mg) and 2 (6.33 mg). Guianolacone A (1)[20] was isolated as colorless crystals. Its molecular formula of C29H36O10 was determined by the HREIMS at m/z 544.2308 [M]+ (calcd 544.2308), which indicated 12 degrees of unsaturation. IR and UV absorptions at nmax; 1734, 1700, and 1695 cm–1 and lmax 244.5 nm implied the presence of carbonyl groups. The 13C NMR spectrum of 1 revealed that six out of 12 degrees of unsaturation came from three double bonds and three carbonyls; thus 1 was hexacyclic. The 13C NMR spectrum (Table 1), revealed 29 carbon resonances corresponding to six methyls (methyl ester), four methylenes, eight methines (3 x olefinic and 2 x oxygenated), and 11
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Keiichiro Higuchi,[a] Yoshimi Tani,[a] Takashi Kikuchi,[a] Yasuko In,[a] Takeshi Yamada,[a] Osamu Muraoka,[b] Naonobu Tanaka,[c] Reiko Tanaka*[a]
10.1002/asia.201701298
Chemistry - An Asian Journal
quaternary carbons (3 x olefinic, 2 x oxygenated, and 3 x ester carbonyls). The 1H and 13C NMR spectra (Table 1) showed the presence of four tertiary methyls [dH 1.00, 1.08, 1.16, and 1.20 (each 3H, s)], one methyl ester [dH 3.70; dC 51.8, 173.4], two dlactones, and a furan ring [dH 6.33, 7.31, and 7.41 (each 1H)]. Gross structure of guianolactone A (1) was established by analysis of the HMBC spectrum (Figure 2A): the correlations from H3-19 to C-1 (dC 80.5), C-5, C-9, and C-10; from H3-28 and H3-29 to C-3, C-4, and C-5, from H2-3 to C-1, C-2 (dC 176.1), C-4, C-5, and C-10; from 1-OH (dH 3.55) to C-1, C-2, and C-3 enabled the structure of A-ring to be cyclopentane. The HMBC correlations from H-5 to C-7 (dC 173.4), and from 7-OMe to C-7 showed the presence of a methylester at C-7. The B ring was a d-lactone based on the HMBC correlation from H-9 to C-1, C-5, C-8, and C10 by the transposition of C-30 to the D ring and insertion of oxygen atom. The C-ring was cyclohexane based on the HMBC correlations from H3-18 to C-12, C-13, C-14, and C-17.
to C-15, and C-31 revealed that the enolized keto group was attached at C-15. These results revealed that 1 was an unprecedented limonoid with a 5,6,6,6,6 ring system. The relative configuration of 1 was established by NOESY analysis (Figure 2B). The NOESY correlations from H-5 to H-17, and H3-28, from H-17 to H-22, and from H3-28 to C-30 showed that they were cofacial and b-oriented. Subsequently, the NOESY correlations from H-14 to H-9a, H3-18, and H3-32, from H3-18 to H-21, and from H-3a and H-6a to H3-19 indicated that they were a-oriented. A single crystal X-ray analysis of 1 was successfully performed with CuKa, which resulted in a Flack parameter of –0.01 (6) (CCDC 1529043).[22] Thus, the absolute configuration of 1 was established as 1S, 2R, 5S, 8R, 9R, 13R, 14S, 17S, and 30R (Figure 3). This is the first case in which C-30 was transposed to the D ring. 18
12 1H-1H
13
11
COSY
HMBC
6
7
1'
O
18
O
H
13
19
14
21 31 15
30 1
21
11
8
9
5
22
12
7
4
29
20
2
16
3
6
9
29
5
14
1
O
30
O 2
H
28 32
15
H
3
OH
17
8
10
4 28
O
17 10
23
32 20
19
1'
23
22
31
16
H O
O
O
OH
Figure 3. ORTEP drawing of 1.
A
B
Figure 2. HMBC, COSY (A) and NOESY (B) correlations of 1.
The most unique scaffold of the D1 and D2 rings were established by the HMBC spectrum, in which correlations from H-14 to C-8, C-12, C-15 (dC 93.9), C-16 (dC 169.8), C-17 (dC 76.2), C-30 (dC 94.5), and C-31 (dC 177.5); and from H-17 to C-20, C-21, C-22, and C-30 indicated the linkage of C-17 and C-30 via an oxygen atom to form a tetrahydropyran ring as D1, and the furan ring at C-17. The D2 ring was successively found to be a d-lactone based on the correlations from H-30 to C-8, C-9, C-14, and C-16 in the HMBC spectrum, therefore, 1 was found to be a 15-acyl limonoid, which was described in recent studies.[21a, 21b] HMBC correlations from 31-OH (dH 13.70) to C-15, C-31, and C-32, and from H3-32
Guianolactone B (2),[23] colorless crystals, possessed a molecular formula C31H38O11 based on HRFABMS (m/z 587.2493 [M + H]+, calcd 587.2492), indicating 13 degrees of unsaturation. The IR spectrum showed absorption at 3448, 1733 and 1718 cm1 , indicating hydroxy and carbonyl groups. The 1H and 13C NMR spectra (Table 1) of 2 gave dupilicated signals, which were attributed to the existence of an equilibrium mixture of keto-enol tautomers (2a and 2b). DEPT experiments confirmed the presence of seven methyls, three methylenes, nine methines (2 x oxygenated and 3 x olefinic), and 12 quaternary carbons (4 x carbonyls, 3 x olefinic) in 2a, and seven methyls, three methylenes, 10 methines (2 x oxygenated and 3 x olefinic), and 11 quaternary carbons (5 x carbonyls, 3 x olefinic) in 2b. Although guianolactones A (1) and B (2) were 15-acyl limonoids, 1 adopted an enol-form in solution, and 2 showed keto-enol tautomers (2a and 2b) in solution. The 1H-1H COSY spectrum revealed the presence of key spectral fragments as shown as bold lines (Figure 4A), based on the correlations of H-3 to H-30. In the HMBC spectrum of 2a and 2b (Figure 4A), correlations were observed between H-3/C-1 (dC 208.7 in 2a; dC 207.8 in 2b), C-2 (dC 99.5 in 2a; dC 100.0 in 2b), C-8, C-30; H-5/C-1, C-3, C-7; H-14/C-9, C-15 (dC 94.4 in 2a; dC 52.8 in 2b), C-17, C-30, C-31 (dC 173.8 in 2a; dC 203.0 in 2b); H-17 and H3-2”/C-2’; H-30/C-2, C-3, C-8, C-16 (dC 170.2 in 2a; dC 167.9 in 2b); H3-19/C-1, C-5, C-9, C10; 2-OH (dH 4.45 in 2a; dH 4.38 in 2b)/C-1, C-3, C-10, C-30; 31OH (dH 13.42)/C-15, C-31, C-32; and H3-32/C-15, C-31. Yang et al. reported tautomerism of nimbolinin-type limonoid, 12a/b-1-Otigloyl-1-O-deacetoxy-nimbolinin B.[24] Guianolactone B (2) showed to be a mixture of keto-enol
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13
Table 1. H and C NMR Data for guianolactone A (1) and tautomers of guianolactone B (2a and 2b) in CDCl3 #NAME?
1
2a (enol form)
dH (J in Hz)
position
dC
1 1-OH
dC
80.5
dH (J in Hz)
208.7
dC 207.8
3.55 s
2
176.1
99.5
2-OH 3
2b (keto form)
dH (J in Hz)
4.45 s 1.86 m
57.1
100.0 4.38 s
2.59 s
64.4
2.58 s
64.2
2.11d (14.3) 4
42.5
32.0
31.9
5
2.58 dd (10.6, 3.4)
50.9
2.83 dd (9.0, 4.2)
43.3
2.77 dd (9.0, 3.6)
43.2
6
2.31 dd (14.6, 3.4)
33.3
2.25 m (2H)
32.8
2.25 (2H, m)
32.8
2.41 d (14.6 ) 7
173.4
8 9
1.90 m
22.0
43.0
36.9
1.83 m
13
2.72 s
93.9
16
49.4
1.25 m
169.8
2.81 brs
50.4
94.4
3.57 d (1.2)
52.8
76.2
6.10 s
71.3
6.00 s
71.1
18
1.08 s (3H)
25.7
1.11 s (3H)
23.2
1.20 s (3H)
22.3
19
1.16 s (3H)
21.1
1.07 s (3H)
16.5
1.04 s (3H)
16.4
123.7 7.41dd (2.4, 1.5)
22 23
7.41 brs
140.7
7.74 brs
140.9
6.33 d (2.0)
110.7
6.36 dd (1.8, 1.2)d
110.1
6.35 dd (1.8, 1.2)d
109.9
7.31 t (1.8)
142.6
7.38 t (1.8)e
142.8
7.37 t (1.8)e
142.9
28
1.00 s (3H)
29.9
1.26 s (3H)
28.4
1.25 s (3H)
28.4
29
1.20 s (3H)
23.5
0.74 s (3H)
22.3b
0.73 s (3H)
22.4b
30
6.33 d (2.0)
94.5
5.23 s
81.4
5.21 s
82.3
31-OH 32 OMe
177.5 13.42 q (0.6)
2.03 s (3H) 3.70 s (3H)
19.5
3.72 s (3H)
51.8
1 3
52.2
OAc
2.34 s (3H) 3.72 s (3H)
21.3c
28.5
16
8
O 1
O
2
OH
3
O
H
O 2
OH O
chukrasone
15
H
H
O
OH
H H
O HO
OH
O
(II)
O
Acetalization
O
OH
O
OH
O
OH 30
32 31
O HO HO 16
O
O
H
Oxidation
OH
15 30
O
O
(I)
17
H
16 O
O
H
Hydrolysis, Insertion of C2 unit
30
O
O
OH
O
30
O H
O
O
OH
O
(III)
1
O
O
2.02 s (3H)f
21.6c
O
H O
8
O
1
52.2 170.3
170.3 2.04 s (3H)f
15
OH
O
O
2.08 brs (3H)
19.5
Lactonization
8
O
H
O
203.0
173.8
13.70 d (0.0.5)
H
O
17
O
H 30
O
O
O
17
122.5
122.7
141.3
31
O
O
167.9
4.86 s
21
O
40.2
48.4
170.2
O
O
36.8
17
20
a-f
19.6a
43.2
48.2
15
1.62 m
1.83 m
43.1 2.45 d (2.0)
60.9
1.89 m
1.25 m
2.02 ddd (13.8, 4.8, 2.0)
14
19.5a
1.62 m 1.94 m
1.58 td (13.5, 4.8)
78.8 1.86 m
49.4
1.97 m 12
61.4
52.5 1.95 m
173.8
79.8
53.4
10 11
173.8
78.0 1.87 dd (12.9, 4.4)
tautomers (2a and 2b) in solution, but existed in an enol-form (2a) in solid state. In order to, complete the structure, the X-ray diffraction (CuKa) analysis was performed for a single crystal of 2a and the absolute structure was determined as 2S, 3R, 8R, 14S, 17R, and 30R (Flack parameter of –0.1 (2) (CCDC 1529043)) (Figure 4B).[22] The X-ray diffraction pattern indicated the hemiketal moiety at C2, which combined with C-8 through the oxygen atom. Furthermore, C-2 was bound to C-3, and C-3 was bound to C-30. Bringmann et al., reported trangmolin D, which was the first example having C-3–C-30 connection in limonoids.[25] These results indicated that 2 was an unprecedented limonoid with a 6,6,5,6,6 ring system.
3
O O
H
O
H
O
8
[+OH]
1
O
30
2
2
O
HO
O O
30 H
O
H
O
Acetylation Acetalization
8 1
HO
OH
O
signals may be interchangeable
15
16
O
O H
3
3
(IV)
andirobin
30 H
2
H O
OH
O
O
(V)
O
O O
1H-1H
O
COSY
Hydrolysis, Insertion of C2 unit
HMBC
O
31
HO 16
O
Lactonization
O
O
H H O
15
OH O
HO
H
O
O H
O
OH
2
O 17
12 13
11
O
32
OH
(VI)
21 20
18
O
H
O H
O
22 1'
H O
HO
23
OH
H
Scheme 1. Plausible biogenetic pathways of 1 and 2.
2'
O
19
2"
7
32 9 10
6 5
O
2
HO
28
8
O
1
31
15
14
H
30
16
O
O
H
4
OH
3 29
A
H
23
22
21 20
1'
18
12 17
11 13
7 19
2'
2"
14
9
32 10
8
15
6 5
31
30 29 3
16 2
4 1 28
B Figure 4. HMBC, COSY (A) and ORTEP drawing (B) of 2a.
Although various limonoids have been reported from Meliaceae plant,1 guianolactones A (1) and B (2) are structurally unique compounds. The plausible biosynthetic pathways of 1 and 2 are proposed in Scheme 1. Chikurasone may be recognized as a precursor. The attack of 8-OH to 2-C=O, and cleavage between C-2 and C-30 in Chikurasone produce (I). Successively the hydrolysis between C-16 and 17-O in d-lactone, and the insertion of an acetyl group to C-15 would produce an intermediate (II). Its oxidation (II to III) and acetalization at C-30 may generate 1. A nucleophilic attack on the double bond at C-8 and C-30 could give an intermediate (IV) from andirobin. 26 Acetylation at 30-OH, and acetalization between C-8 and C-2 may afford an intermediate (V). Hydrolysis between C-16 and 17-O of D-ring, and insertion of an acetyl group to C-15 may produce an intermediate (VI), and then lactonization may produce 2 (Scheme 1).27 Guianolactone A (1) and B (2) and the positive control, LNMMA, were examined for their inhibitory effects on nitric oxide (NO) production induced by LPS in macrophages. Their cytotoxicities were also evaluated by the MTT assay. Compounds
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1 and 2 exhibited moderate inhibitory effects on NO production (IC50 1: 35.1 µM; 2: 75.2 µM) [L-NMMA (IC50 23.9 µM)] without cytotoxicity (IC50 >100 µM each). Li et al reported A- and B- rings in limonoids are mutable, while C- and D- rings are relatively conservative.[25] There have been many limonoids with cleavage between C-16 and C-17 in the Dring. However, there is no precedent in which C-30 transposes to the D-ring and C-30 constitutes D1 and D2 rings, similar to Guianolactone A (1).
Experimental Section
[8] [9] [10] [11] [12] [13] [14]
General Experimental Procedures. Optical rotations were measured using a JASCO DIP-1000 digital polarimeter. IR spectra were recorded on a Perkin-Elmer 1720X FTIR spectrophotometer. The 1H and 13C NMR spectra were ran using an Agilent-NMR-vnmrs 600 (1H: 600 MHz; 13C: 150 MHz) and an Agilent-NMR-vnmrs400 (1H: 400 MHz) in CDCl3 and C5D5N with tetramethylsilane as the internal standard. EIMS was recorded using a Hitachi 4000H double-focusing mass spectrometer (70 eV). Column chromatography (silica gel, 70–230 mesh; Merck) and medium-pressure liquid chromatography (MPLC; silica gel, 230–400 mesh; Merck) were conducted. HPLC was run on a JASCO PU-1586 instrument equipped with a differential refractometer (RI 1531). Material. The seed Oil of Carapa guianensis (2.03 kg) was collected in the Amazon, Brazil, in March, 2011. A voucher specimen (CG-01-1) was deposited in the Herbarium of the Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences. Extraction and Isolation. The seed Oil was chromatographed over silica gel to afford fractions A–H. Fraction A (Fr. No. 1-76, 900 g) was eluted with CHCl3, B (Fr. No. 77-110, 12.0 g) with CHCl3, C (Fr. No. 111-125, 21.0 g) with CHCl3:EtOAc = 5:1, D (Fr. No. 126-155, 10.9 g) with CHCl3:EtOAc = 5:1, E (Fr. No. 156-170, 1.4 g) with CHCl3:EtOAc = 2:1, F (Fr. No. 171-180, 2.4 g) with EtOAc, G (Fr. No. 181-195, 2.9 g) with EtOAc, and H (Fr. No. 196-208, 0.7 g) with EtOAc:MeOH = 5:1. Fraction C (29.3 g) was rechromatographed over silica gel to give the residue C3 (57 mg) which was separated by HPLC (ODS, 70% MeOH) to give 1 and 2.
[15] [16] [17] [18] [19] [20]
[21]
[22] [23]
[24]
Acknowledgements
[25]
We thank Mr. Akira Yoshino (NGO Green Heart) for the collection and plant material. We also thank Dr. Katsuhiko Minoura and Dr. Mihoyo Fujitake (Osaka University of Pharmaceutical Sciences) for NMR and MS mesurements.
[26] [27]
S-P. Yang, H-D. Chen, S-G. Liao, B-J. Xie, Z-H. Miao, J-M. Yue, Org. Lett., 2011, 13, 150–153. J. Li, M-Y. Li, T. Bruhn, F-Z. Katele, Q. Xiao, P. Pedpradab, J. Wu, G.Bringmann. Org. Lett., 2013, 15, 3682–3685. C-P. Liu, J-B. Xu, Y-S. Han, M-A. Wainberg, J-M. Yue, Org. Lett., 2014, 16, 5478–5481. C-P. Liu, G-C. Wang, L-S. Gan, C-H. Xu, Q-F. Liu, J. Dong, J-M. Yue, Org. Lett., 2016, 18, 2894–2897. C. Penido, K-A. Costa, R-J. Pennaforte, M-F. Costa, J-F. Pereira, A-C. Siani, M-G. Henriques, Inflammation res. 2005, 54, 295–303. V. P. Pereira, R-R. Oliveira, M-R. Figueiredo, Phytochem. Anal., 2009, 20, 77–81. C. Penido, F-P. Conte, M-S. Chagas, C-A. Rodrigues, J-F. Pereira, M-G. Henriques, Inflamm. Res. 2006, 55, 457–464. K. Nakanishi, Chem. Pharm. Bull. 1965, 13, 882–890. F-K. Ferraris, R. Rodrigues, V.P. da Silva, R. Figueiredo, C. Penido, M. G. M. O. Henriques, Int. Immunopharmacol. 2011, 11, 1–11. J. Miranda, N-C. Raimundo, M-F. Dolabela, M-N. da Silva, M-M. Povoa, J-G-S. Maia, J. Ethnopharmacol. 2012, 142, 679–683. T. Inoue, Y. Matsui, T. Kikuchi, Y. In, T. Yamada, O. Muraoka, S. Matsunaga. R. Tanaka, Org. Lett. 2013, 15, 3018–3021. Y. Matsui, T. Kikuchi, T. Inoue, O. Muraoka, T. Yamada, R. Tanaka, Molecules 2014, 19, 17130–17140. Guianolactone A (1); colorless crystals (in MeOH-CHCl3); mp 211– 25 212°C; [a]D –27.1° (c 0.100, EtOH); UV (EtOH) lmax (log e) nm 244.5 -1 + (3.34); IR nmax (KBr): 1734, 1700, 1695 cm ; HRMS (EI) m/z: [M] Calcd + for C29H36O10 544.2308; Found 544.2308; EIMS m/z 544 [M] (44), 484 + [M – HOAc] (48), 470 (7), 435 (11), 364 (17), 307 (30), 209 (24), 125 1 13 (100); H NMR and C NMR data, see Table 1. a) C-R. Zhang, C-Q. Fan, L. Zhang, S-P. Yang, Y. Wu, Y. Lu, J-M. Yue, Org. Lett., 2008, 10, 3183–3186.; b) J. Luo, J-S. Wang, X-B. Wang, XF. Huang, J-G. Luo, L-Y. Kong, Tetrahedron, 2009, 65, 3425–3431. H. D. Flack, Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39, 876– 881. 25 Guianolactone B (2); colorless crystals (in n-hexane-CH2Cl2); [a]D + 14.9° (c 0.100, EtOH); UV (EtOH) lmax (log e) nm 122.0 (3.71), 263.0 -1 (3.32); IR nmax (KBr) cm : 3448, 1733, 1718, 1227; HRMS (FAB) m/z [M + + H] Calcd for C31H39O11 587.2492; Found 587.2493; FABMS m/z 609 + + + [M + Na] (3), 587 [M + H] (6), 527 [587 – HOAc] (100), 498 (7), 483 1 13 (8), 433 (7), 147 (4), 121 (5), 95 (13); H NMR and C NMR data, see Table 1. S. Su, L. Shen, Y. Zhang, J. Liu, J. Cai, L. Hao, Y. Feng, S. Yang, Phytochem. Lett. 2013, 6, 418–423. W. Li, L. Shen, T. Bruhm, P. Pedpradab, J. Wu, G. Bringmann, Chem. Eur. J. 2016, 22, 11719–11727. W. D. Ollis, A. D. Ward, D. Arthur, H. Meirelles de Oliveira, R. Zelnik, Tetrahedron, 1970, 26, 1637-1645. J. Luo, J. S. Wang, X. B. Wang, X. F. Huang, J. G. Luo, L. Y. Kong, Tetrahedron, 2009, 65, 3425-3431.
Keywords: Guianolactone A• Guianolactone B• Carapa guianensis • limonoid• absolute configuration [1] [2] [3]
[4] [5] [6] [7]
Q-G. Tan, X-D. Luo, Chem. Rev., 2011, 111, 7437–7522. J-Q. Zhao, Y-M. Wang, H-P. He, S-H. Li, X-N. Li, C-R. Yang, D. Wang, H-T. Zhu, M. Xu, Y-J. Zhang. Org. Lett., 2013, 15 2414–2417. a) J-Y. Cai, Y. Zhang, S-H. Luo, D-Z. Chen, G-H. Tang, C-M. Yuan, Y-T. Di, S-H. Li, X-J. Hao, H-P. He, Org. Lett., 2012, 14, 2524–2527; b) J-Y. Cai, D-Z. Chen, S-H. Luo, N-C. Kong, Y. Zhang. Y-T. Di, Q. Zhang, J. Hua, S-X. Jing, S-L. Li, S-H. Li, X-J. Hao, H-P. He, J. Nat. Prod., 2014, 77, 472–482. M-L. Han, H. Zhang, S-P. Yang, J-M. Yue, Org. Lett., 2012, 14, 486–489. H-B. Liu, H. Zhang, P. Li, Z-B. Gao, J-M, Yue, Org. Lett., 2012, 14, 4438– 4441. J-L. Yin, Y-T. Di, X. Fang, E-D, Liu, H-Y. Liu, H-P. He, S-L. Li, S-F. Li, X-J. Hao, Tetrahedon Lett. 2011, 52, 3083–3085. J-H. Yu, Q-F. Liu, L. Sheng, G-C. Wang, J. Li, J-M. Yue, Org. Lett., 2016, 18, 444–447.
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Keiichiro Higuchi, Yoshimi Tani, Takashi Kikuchi, Yasuko In, Takeshi Yamada, Osamu Muraoka, Naonobu Tanaka, Reiko Tanaka* Page No. – Page No.
Two novel rearranged limonoids, guianolactones A (1) and B (2), were isolated from Carapa guianensis Aubl. (Meliaceae) seeds. The structures of 1 and 2 with the absolute configurations were determined by detailed examination of single crystal X-ray diffraction analyses and 2D NMRspectra.
Title: Guianolactones A and B, Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis
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Accepted Article Title: Guianolactones A and B, Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis. Authors: Keiichiro Higuchi, Yoshimi Tani, Takashi Kiuchi, Yasuko In, Takeshi Yamada, Osamu Muraoka, Naonobu Tanaka, and Reiko Tanaka This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). This work is currently citable by using the Digital Object Identifier (DOI) given below. The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. To be cited as: Chem. Asian J. 10.1002/asia.201701298 Link to VoR: http://dx.doi.org/10.1002/asia.201701298
A Journal of
A sister journal of Angewandte Chemie and Chemistry – A European Journal
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Guianolactones A and B, Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis.
Abstract: Two novel rearranged limonoids, guianolactones A (1) and B (2), were isolated from Carapa guianensis Aubl. (Meliaceae) seeds. The structures of 1 and 2 with their absolute configurations were elucidated in detailed examinations using single crystal X-ray diffraction analyses and 2D NMR spectra. Guianolactone A (1) has a novel 5/6/6/6/6 pentacyclic core including two d-lactone and a tetrahydropyran ring, while guianolactone B (2) is a novel limonoid with a 6/6/5/6/6 pentacyclic core featuring a d-lactone and a tetrahydrofuran ring.
We previously described the isolation and structural determination of guianolides A and B, featured an unique policyclic skeleton from the seeds of C. guianensis.[18] As a continuation of this study, two novel structurally attractive limonoids, guianolactones A (1) and B (2) were isolated from the seeds of C. guianensis (Figure 1). We report herein the structure elucidation of 1 and 2 and the effects of the production of NO in LPS-activated mouse peritoneal macrophages.[19] 23
O
Limonoids are characteristic metabolites of Meliaceae and Rutaceae plants and have various structures and remarkable biological activities.[1] A large number of limonoids have recently been isolated by several researchers, such as phyllanthoids A and B,[2] aphanamixoid A,[3a,3b] walsucochins A and B,[4] chukrasones A and B,[5] tabulvelutin A,[6] cipacinoids A–D,[7] aphanamoide A,[8] thaixylomolins A–C,[9] trichiconins A–C,[10] and ciliatonoids A and B.[11] Carapa guianensis (Andiroba, Meliaceae) is a deciduous or semi-evergreen tropical tree with fragment flowers which occasionally grows to 50 meters in the rain forests of South America. Individuals residing in the Amazon use this tree to make many types of medicine. Its four-cornered woody nut has four cells, each of which contains two to four seeds with oily kernels. Seed oil from C. guianensis exhibits analgesic,[12] antibacterial,[13] anti-inflammatory,[14] anti-tumor,[15] anti-allergic,[16] and anti-arthritis and -rheumatism[17] activities.
[a]
Prof. R. Tanaka, K. Higuchi, Y. Tani, Dr. T. Kikuchi, Dr. Y. In, Dr. T. Yamada Osaka University of Pharmaceutical Sciences 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan E-mail: [email protected]
[b]
Dr. N. Tanaka, Graduate School of Pharmaceutical Sciences Tokushima University, E-mail: [email protected]
[c]
Prof. O. Muraoka Kinki University 3-4-1 Kowakae, Higashiosaka, E-mail: [email protected] Supporting information for this article is given via a link at the end of the document.
7
18
O
10
B 1
3
2
OH
E
22
O H
32 31
D2
30
O
16
O
OH
1
O
O 21
O
20 1'
O
D1
14
15
O 23
17
8
A
20
13
H C
9 5
29
O 21
H
19
6
28
E
22
18
O
17 13
O
O
7
19
H
B1 O
6 5
1
HO
A
28
2
O
B2 3
29
O
C
9
2'
14
H
2"
O
O
O
H H
32
15 8
30
H
31
H
D O
16
2a
O
OH
O HO
H
O H
O
O
O
2b
Figure 1. Strucutures of guianolactones A (1) and B (2a, 2b).
The seed oil of C. guianensis (2.03 kg) was chromatographed over silica gel to afford eight fractions (A–H). The limonoidcontaining fraction C (29.3 g) was rechromatographed over silica gel to give the residue C3 (57 mg). Residue C3 was further purified by HPLC (ODS, 70% MeOH) to afford 1 (4.72 mg) and 2 (6.33 mg). Guianolacone A (1)[20] was isolated as colorless crystals. Its molecular formula of C29H36O10 was determined by the HREIMS at m/z 544.2308 [M]+ (calcd 544.2308), which indicated 12 degrees of unsaturation. IR and UV absorptions at nmax; 1734, 1700, and 1695 cm–1 and lmax 244.5 nm implied the presence of carbonyl groups. The 13C NMR spectrum of 1 revealed that six out of 12 degrees of unsaturation came from three double bonds and three carbonyls; thus 1 was hexacyclic. The 13C NMR spectrum (Table 1), revealed 29 carbon resonances corresponding to six methyls (methyl ester), four methylenes, eight methines (3 x olefinic and 2 x oxygenated), and 11
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Keiichiro Higuchi,[a] Yoshimi Tani,[a] Takashi Kikuchi,[a] Yasuko In,[a] Takeshi Yamada,[a] Osamu Muraoka,[b] Naonobu Tanaka,[c] Reiko Tanaka*[a]
10.1002/asia.201701298
Chemistry - An Asian Journal
quaternary carbons (3 x olefinic, 2 x oxygenated, and 3 x ester carbonyls). The 1H and 13C NMR spectra (Table 1) showed the presence of four tertiary methyls [dH 1.00, 1.08, 1.16, and 1.20 (each 3H, s)], one methyl ester [dH 3.70; dC 51.8, 173.4], two dlactones, and a furan ring [dH 6.33, 7.31, and 7.41 (each 1H)]. Gross structure of guianolactone A (1) was established by analysis of the HMBC spectrum (Figure 2A): the correlations from H3-19 to C-1 (dC 80.5), C-5, C-9, and C-10; from H3-28 and H3-29 to C-3, C-4, and C-5, from H2-3 to C-1, C-2 (dC 176.1), C-4, C-5, and C-10; from 1-OH (dH 3.55) to C-1, C-2, and C-3 enabled the structure of A-ring to be cyclopentane. The HMBC correlations from H-5 to C-7 (dC 173.4), and from 7-OMe to C-7 showed the presence of a methylester at C-7. The B ring was a d-lactone based on the HMBC correlation from H-9 to C-1, C-5, C-8, and C10 by the transposition of C-30 to the D ring and insertion of oxygen atom. The C-ring was cyclohexane based on the HMBC correlations from H3-18 to C-12, C-13, C-14, and C-17.
to C-15, and C-31 revealed that the enolized keto group was attached at C-15. These results revealed that 1 was an unprecedented limonoid with a 5,6,6,6,6 ring system. The relative configuration of 1 was established by NOESY analysis (Figure 2B). The NOESY correlations from H-5 to H-17, and H3-28, from H-17 to H-22, and from H3-28 to C-30 showed that they were cofacial and b-oriented. Subsequently, the NOESY correlations from H-14 to H-9a, H3-18, and H3-32, from H3-18 to H-21, and from H-3a and H-6a to H3-19 indicated that they were a-oriented. A single crystal X-ray analysis of 1 was successfully performed with CuKa, which resulted in a Flack parameter of –0.01 (6) (CCDC 1529043).[22] Thus, the absolute configuration of 1 was established as 1S, 2R, 5S, 8R, 9R, 13R, 14S, 17S, and 30R (Figure 3). This is the first case in which C-30 was transposed to the D ring. 18
12 1H-1H
13
11
COSY
HMBC
6
7
1'
O
18
O
H
13
19
14
21 31 15
30 1
21
11
8
9
5
22
12
7
4
29
20
2
16
3
6
9
29
5
14
1
O
30
O 2
H
28 32
15
H
3
OH
17
8
10
4 28
O
17 10
23
32 20
19
1'
23
22
31
16
H O
O
O
OH
Figure 3. ORTEP drawing of 1.
A
B
Figure 2. HMBC, COSY (A) and NOESY (B) correlations of 1.
The most unique scaffold of the D1 and D2 rings were established by the HMBC spectrum, in which correlations from H-14 to C-8, C-12, C-15 (dC 93.9), C-16 (dC 169.8), C-17 (dC 76.2), C-30 (dC 94.5), and C-31 (dC 177.5); and from H-17 to C-20, C-21, C-22, and C-30 indicated the linkage of C-17 and C-30 via an oxygen atom to form a tetrahydropyran ring as D1, and the furan ring at C-17. The D2 ring was successively found to be a d-lactone based on the correlations from H-30 to C-8, C-9, C-14, and C-16 in the HMBC spectrum, therefore, 1 was found to be a 15-acyl limonoid, which was described in recent studies.[21a, 21b] HMBC correlations from 31-OH (dH 13.70) to C-15, C-31, and C-32, and from H3-32
Guianolactone B (2),[23] colorless crystals, possessed a molecular formula C31H38O11 based on HRFABMS (m/z 587.2493 [M + H]+, calcd 587.2492), indicating 13 degrees of unsaturation. The IR spectrum showed absorption at 3448, 1733 and 1718 cm1 , indicating hydroxy and carbonyl groups. The 1H and 13C NMR spectra (Table 1) of 2 gave dupilicated signals, which were attributed to the existence of an equilibrium mixture of keto-enol tautomers (2a and 2b). DEPT experiments confirmed the presence of seven methyls, three methylenes, nine methines (2 x oxygenated and 3 x olefinic), and 12 quaternary carbons (4 x carbonyls, 3 x olefinic) in 2a, and seven methyls, three methylenes, 10 methines (2 x oxygenated and 3 x olefinic), and 11 quaternary carbons (5 x carbonyls, 3 x olefinic) in 2b. Although guianolactones A (1) and B (2) were 15-acyl limonoids, 1 adopted an enol-form in solution, and 2 showed keto-enol tautomers (2a and 2b) in solution. The 1H-1H COSY spectrum revealed the presence of key spectral fragments as shown as bold lines (Figure 4A), based on the correlations of H-3 to H-30. In the HMBC spectrum of 2a and 2b (Figure 4A), correlations were observed between H-3/C-1 (dC 208.7 in 2a; dC 207.8 in 2b), C-2 (dC 99.5 in 2a; dC 100.0 in 2b), C-8, C-30; H-5/C-1, C-3, C-7; H-14/C-9, C-15 (dC 94.4 in 2a; dC 52.8 in 2b), C-17, C-30, C-31 (dC 173.8 in 2a; dC 203.0 in 2b); H-17 and H3-2”/C-2’; H-30/C-2, C-3, C-8, C-16 (dC 170.2 in 2a; dC 167.9 in 2b); H3-19/C-1, C-5, C-9, C10; 2-OH (dH 4.45 in 2a; dH 4.38 in 2b)/C-1, C-3, C-10, C-30; 31OH (dH 13.42)/C-15, C-31, C-32; and H3-32/C-15, C-31. Yang et al. reported tautomerism of nimbolinin-type limonoid, 12a/b-1-Otigloyl-1-O-deacetoxy-nimbolinin B.[24] Guianolactone B (2) showed to be a mixture of keto-enol
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1
13
Table 1. H and C NMR Data for guianolactone A (1) and tautomers of guianolactone B (2a and 2b) in CDCl3 #NAME?
1
2a (enol form)
dH (J in Hz)
position
dC
1 1-OH
dC
80.5
dH (J in Hz)
208.7
dC 207.8
3.55 s
2
176.1
99.5
2-OH 3
2b (keto form)
dH (J in Hz)
4.45 s 1.86 m
57.1
100.0 4.38 s
2.59 s
64.4
2.58 s
64.2
2.11d (14.3) 4
42.5
32.0
31.9
5
2.58 dd (10.6, 3.4)
50.9
2.83 dd (9.0, 4.2)
43.3
2.77 dd (9.0, 3.6)
43.2
6
2.31 dd (14.6, 3.4)
33.3
2.25 m (2H)
32.8
2.25 (2H, m)
32.8
2.41 d (14.6 ) 7
173.4
8 9
1.90 m
22.0
43.0
36.9
1.83 m
13
2.72 s
93.9
16
49.4
1.25 m
169.8
2.81 brs
50.4
94.4
3.57 d (1.2)
52.8
76.2
6.10 s
71.3
6.00 s
71.1
18
1.08 s (3H)
25.7
1.11 s (3H)
23.2
1.20 s (3H)
22.3
19
1.16 s (3H)
21.1
1.07 s (3H)
16.5
1.04 s (3H)
16.4
123.7 7.41dd (2.4, 1.5)
22 23
7.41 brs
140.7
7.74 brs
140.9
6.33 d (2.0)
110.7
6.36 dd (1.8, 1.2)d
110.1
6.35 dd (1.8, 1.2)d
109.9
7.31 t (1.8)
142.6
7.38 t (1.8)e
142.8
7.37 t (1.8)e
142.9
28
1.00 s (3H)
29.9
1.26 s (3H)
28.4
1.25 s (3H)
28.4
29
1.20 s (3H)
23.5
0.74 s (3H)
22.3b
0.73 s (3H)
22.4b
30
6.33 d (2.0)
94.5
5.23 s
81.4
5.21 s
82.3
31-OH 32 OMe
177.5 13.42 q (0.6)
2.03 s (3H) 3.70 s (3H)
19.5
3.72 s (3H)
51.8
1 3
52.2
OAc
2.34 s (3H) 3.72 s (3H)
21.3c
28.5
16
8
O 1
O
2
OH
3
O
H
O 2
OH O
chukrasone
15
H
H
O
OH
H H
O HO
OH
O
(II)
O
Acetalization
O
OH
O
OH
O
OH 30
32 31
O HO HO 16
O
O
H
Oxidation
OH
15 30
O
O
(I)
17
H
16 O
O
H
Hydrolysis, Insertion of C2 unit
30
O
O
OH
O
30
O H
O
O
OH
O
(III)
1
O
O
2.02 s (3H)f
21.6c
O
H O
8
O
1
52.2 170.3
170.3 2.04 s (3H)f
15
OH
O
O
2.08 brs (3H)
19.5
Lactonization
8
O
H
O
203.0
173.8
13.70 d (0.0.5)
H
O
17
O
H 30
O
O
O
17
122.5
122.7
141.3
31
O
O
167.9
4.86 s
21
O
40.2
48.4
170.2
O
O
36.8
17
20
a-f
19.6a
43.2
48.2
15
1.62 m
1.83 m
43.1 2.45 d (2.0)
60.9
1.89 m
1.25 m
2.02 ddd (13.8, 4.8, 2.0)
14
19.5a
1.62 m 1.94 m
1.58 td (13.5, 4.8)
78.8 1.86 m
49.4
1.97 m 12
61.4
52.5 1.95 m
173.8
79.8
53.4
10 11
173.8
78.0 1.87 dd (12.9, 4.4)
tautomers (2a and 2b) in solution, but existed in an enol-form (2a) in solid state. In order to, complete the structure, the X-ray diffraction (CuKa) analysis was performed for a single crystal of 2a and the absolute structure was determined as 2S, 3R, 8R, 14S, 17R, and 30R (Flack parameter of –0.1 (2) (CCDC 1529043)) (Figure 4B).[22] The X-ray diffraction pattern indicated the hemiketal moiety at C2, which combined with C-8 through the oxygen atom. Furthermore, C-2 was bound to C-3, and C-3 was bound to C-30. Bringmann et al., reported trangmolin D, which was the first example having C-3–C-30 connection in limonoids.[25] These results indicated that 2 was an unprecedented limonoid with a 6,6,5,6,6 ring system.
3
O O
H
O
H
O
8
[+OH]
1
O
30
2
2
O
HO
O O
30 H
O
H
O
Acetylation Acetalization
8 1
HO
OH
O
signals may be interchangeable
15
16
O
O H
3
3
(IV)
andirobin
30 H
2
H O
OH
O
O
(V)
O
O O
1H-1H
O
COSY
Hydrolysis, Insertion of C2 unit
HMBC
O
31
HO 16
O
Lactonization
O
O
H H O
15
OH O
HO
H
O
O H
O
OH
2
O 17
12 13
11
O
32
OH
(VI)
21 20
18
O
H
O H
O
22 1'
H O
HO
23
OH
H
Scheme 1. Plausible biogenetic pathways of 1 and 2.
2'
O
19
2"
7
32 9 10
6 5
O
2
HO
28
8
O
1
31
15
14
H
30
16
O
O
H
4
OH
3 29
A
H
23
22
21 20
1'
18
12 17
11 13
7 19
2'
2"
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32 10
8
15
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31
30 29 3
16 2
4 1 28
B Figure 4. HMBC, COSY (A) and ORTEP drawing (B) of 2a.
Although various limonoids have been reported from Meliaceae plant,1 guianolactones A (1) and B (2) are structurally unique compounds. The plausible biosynthetic pathways of 1 and 2 are proposed in Scheme 1. Chikurasone may be recognized as a precursor. The attack of 8-OH to 2-C=O, and cleavage between C-2 and C-30 in Chikurasone produce (I). Successively the hydrolysis between C-16 and 17-O in d-lactone, and the insertion of an acetyl group to C-15 would produce an intermediate (II). Its oxidation (II to III) and acetalization at C-30 may generate 1. A nucleophilic attack on the double bond at C-8 and C-30 could give an intermediate (IV) from andirobin. 26 Acetylation at 30-OH, and acetalization between C-8 and C-2 may afford an intermediate (V). Hydrolysis between C-16 and 17-O of D-ring, and insertion of an acetyl group to C-15 may produce an intermediate (VI), and then lactonization may produce 2 (Scheme 1).27 Guianolactone A (1) and B (2) and the positive control, LNMMA, were examined for their inhibitory effects on nitric oxide (NO) production induced by LPS in macrophages. Their cytotoxicities were also evaluated by the MTT assay. Compounds
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1 and 2 exhibited moderate inhibitory effects on NO production (IC50 1: 35.1 µM; 2: 75.2 µM) [L-NMMA (IC50 23.9 µM)] without cytotoxicity (IC50 >100 µM each). Li et al reported A- and B- rings in limonoids are mutable, while C- and D- rings are relatively conservative.[25] There have been many limonoids with cleavage between C-16 and C-17 in the Dring. However, there is no precedent in which C-30 transposes to the D-ring and C-30 constitutes D1 and D2 rings, similar to Guianolactone A (1).
Experimental Section
[8] [9] [10] [11] [12] [13] [14]
General Experimental Procedures. Optical rotations were measured using a JASCO DIP-1000 digital polarimeter. IR spectra were recorded on a Perkin-Elmer 1720X FTIR spectrophotometer. The 1H and 13C NMR spectra were ran using an Agilent-NMR-vnmrs 600 (1H: 600 MHz; 13C: 150 MHz) and an Agilent-NMR-vnmrs400 (1H: 400 MHz) in CDCl3 and C5D5N with tetramethylsilane as the internal standard. EIMS was recorded using a Hitachi 4000H double-focusing mass spectrometer (70 eV). Column chromatography (silica gel, 70–230 mesh; Merck) and medium-pressure liquid chromatography (MPLC; silica gel, 230–400 mesh; Merck) were conducted. HPLC was run on a JASCO PU-1586 instrument equipped with a differential refractometer (RI 1531). Material. The seed Oil of Carapa guianensis (2.03 kg) was collected in the Amazon, Brazil, in March, 2011. A voucher specimen (CG-01-1) was deposited in the Herbarium of the Laboratory of Medicinal Chemistry, Osaka University of Pharmaceutical Sciences. Extraction and Isolation. The seed Oil was chromatographed over silica gel to afford fractions A–H. Fraction A (Fr. No. 1-76, 900 g) was eluted with CHCl3, B (Fr. No. 77-110, 12.0 g) with CHCl3, C (Fr. No. 111-125, 21.0 g) with CHCl3:EtOAc = 5:1, D (Fr. No. 126-155, 10.9 g) with CHCl3:EtOAc = 5:1, E (Fr. No. 156-170, 1.4 g) with CHCl3:EtOAc = 2:1, F (Fr. No. 171-180, 2.4 g) with EtOAc, G (Fr. No. 181-195, 2.9 g) with EtOAc, and H (Fr. No. 196-208, 0.7 g) with EtOAc:MeOH = 5:1. Fraction C (29.3 g) was rechromatographed over silica gel to give the residue C3 (57 mg) which was separated by HPLC (ODS, 70% MeOH) to give 1 and 2.
[15] [16] [17] [18] [19] [20]
[21]
[22] [23]
[24]
Acknowledgements
[25]
We thank Mr. Akira Yoshino (NGO Green Heart) for the collection and plant material. We also thank Dr. Katsuhiko Minoura and Dr. Mihoyo Fujitake (Osaka University of Pharmaceutical Sciences) for NMR and MS mesurements.
[26] [27]
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Keywords: Guianolactone A• Guianolactone B• Carapa guianensis • limonoid• absolute configuration [1] [2] [3]
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Keiichiro Higuchi, Yoshimi Tani, Takashi Kikuchi, Yasuko In, Takeshi Yamada, Osamu Muraoka, Naonobu Tanaka, Reiko Tanaka* Page No. – Page No.
Two novel rearranged limonoids, guianolactones A (1) and B (2), were isolated from Carapa guianensis Aubl. (Meliaceae) seeds. The structures of 1 and 2 with the absolute configurations were determined by detailed examination of single crystal X-ray diffraction analyses and 2D NMRspectra.
Title: Guianolactones A and B, Two Rearranged Pentacyclic Limonoids from the Seeds of Carapa guianensis
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