The first examples of seco-prezizaane-type norsesquiterpenoids with neurotrophic activity from Illicium jiadifengpi

Article abstract of DOI:10.1016/j.tetlet.2011.12.107

Two seco-prezizaane-type sesquiterpenoids (2R)-hydroxy-norneomajucin (1) and jiadifenone (2) that represent the first examples of nor-type were isolated from the methanol extract of the pericarps of Illicium jiadifengpi. Their structures and the absolute configuration of 1 were established by the analysis of spectroscopic data and chemical conversion of (2S)-hydroxyneomajucin to 1, respectively. In addition, compound 1 exhibited neurotrophic activity to significantly promote neurite outgrowth in the primary cultured rat cortical neurons at concentrations ranging from 1 to 10 μmol L^-1.

Full text of DOI:10.1016/j.tetlet.2011.12.107

Tetrahedron Letters 53 (2012) 1231–1235
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The first examples of seco-prezizaane-type norsesquiterpenoids
with neurotrophic activity from Illicium jiadifengpi
Miwa Kubo a, , Kana Kobayashi a, Jian-Mei Huang b, Kenichi Harada a, Yoshiyasu Fukuyama a,
⇑
⇑
a Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
b Faculty of Pharmaceutical Sciences, Beijing University of Chinese Medicine, Beijing 100029, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Two seco-prezizaane-type sesquiterpenoids (2R)-hydroxy-norneomajucin (1) and jiadifenone (2) that
represent the first examples of nor-type were isolated from the methanol extract of the pericarps of
Illicium jiadifengpi. Their structures and the absolute configuration of 1 were established by the analysis
of spectroscopic data and chemical conversion of (2S)-hydroxyneomajucin to 1, respectively. In addition,
compound 1 exhibited neurotrophic activity to significantly promote neurite outgrowth in the primary
Received 24 November 2011
Revised 22 December 2011
Accepted 26 December 2011
Available online 11 January 2012
cultured rat cortical neurons at concentrations ranging from 1 to 10 l .
mol LÀ1
Keywords:
(2R)-Hydroxy-norneomajucin
Jiadifenone
Ó 2012 Elsevier Ltd. All rights reserved.
seco-Prezizaane
Norsesquiterpenoid
Neurotrophic activity
The family Illiciaceae consists of a single genus, Illicium, which
contains 42 species. Over 70% of Illicium species are distributed
in southwestern and eastern Asia. The fruit of Illicium verum,
known as star-anise, is used for seasoning in Chinese and South-
east-Asian food.1 On the other hand, Japanese star-anise, Illicium
anisatum, is used to produce incense but its fruits contain a neuro-
toxic sesquiterpene, anisatin, which is a representative of seco-
prezizaane-type sesquiterpenoids.2 In the pursuit of non-peptide
neurotrophic compounds in plants, we have already found a few
interesting sesquiterpenoids with neurotrophic properties,3 for
example, merrilactone A,4 and jiadifenin5 and jiadifenolide,6 from
Illicium merrillianum and Illicium jiadifengpi, respectively. Thus,
the Illicium plants have made us fascinate the search for neurotro-
phin-mimic natural products. We have continued our study on the
chemical constituents of the pericarps of I. jiadifengpi collected in
the South-Western China, resulting in the first isolation of two no-
vel seco-prezizaane-type norsesquiterpenoids 1 and 2 named (2R)-
hydroxy-norneomajucin and jiadifenone, respectively. In this Let-
ter, we report the structures and the neurotrophic properties of 1
and 2 (Fig. 1).
pounds, such as (2S⁄)-hydroxyneomajucin (3),7 (2R⁄)-hydroxyneo-
majucin (4),9 neomajucin (5),8 majucin,8 1,2-epoxyneomajucin,9
2-oxo-3,4-dehydroxyneomajucin,7
2,3-dehydroxyneomajucin,10
(2S)-hydroxy-3,4-dehydroneomajucin,7 1,2-dehydroneomajucin,5
jiadifenoxolane B,6 and pseudomajucin.10
Compound 1 has the molecular formula C14H18O7, as deduced
from high resolution (HR) EI-MS at m/z 298.1055 [M]+. The IR spec-
trum displayed absorptions due to a hydroxy group at 3370 cmÀ1
and a c
-lactone moiety at 1771 cmÀ1. The 1H and 13C NMR data of
1 (Table 1) indicated the presence of a tertiary methyl group (dH
1.22), a secondary methyl group [dH 1.04 (d, J = 7.6 Hz)], an oxy-
methylene [dH 3.92 and 4.09 (each d, J = 10.0 Hz); dC 75.4 (C-13)],
two oxymethine [dH 4.66 (d, J = 5.6 Hz); dC 82.0 (C-7); dH 4.31 (dt,
J = 7.8, 4.9 Hz); dC 73.0 (C-2)], and two methylene [dH 2.28 (dd,
J = 12.2, 5.6 Hz), 2.75 (d, J = 12.2 Hz); dC 30.2 (C-8); dH 1.45 (dd,
The MeOH extract of the dried pericarps of I. jiadifengpi was frac-
tionated by silica gel and Sephadex LH-20 column chromatographies,
and finally purified by reverse-phase HPLC, leading to the isolation of
new compounds 1 and 2 along with the previously known com-
⇑
Corresponding authors. Tel.: +81 88 602 8435; fax: +81 88 655 3051.
E-mail addresses: miwa-k@ph.bunri-u.ac.jp (M. Kubo), fukuyama@ph.bunri-
Figure 1. Structures of 1–5.
u.ac.jp (Y. Fukuyama).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.107

1232
M. Kubo et al. / Tetrahedron Letters 53 (2012) 1231–1235
Table 1
1H (600 MHz) and 13C (150 MHz) NMR data for 1 and 2 in CD3OD
Position
1
2
dH
dC
dH
dC
1
2
2.60 (dq, 7.8, 7.6)
4.31 (dt, 7.8, 4.9)
2.44 (dd, 14.7, 7.8)
1.45 (dd, 14.7, 4.9)
38.8
73.0
43.7
138.6
210.2
36.5
3a
2.53 (dd, 18.9, 6.7)
2.03 (ddq, 18.9, 2.7, 0.6)
2.88 (dd, 6.7, 2.7)
3b
4
5
6
80.2
47.5
76.2
82.0
30.2
44.4
47.9
79.5
81.1
32.9
7
4.66 (d, 5.6)
2.75 (d, 12.2)
2.28 (dd, 12.2, 5.6)
4.15 (dd, 3.0, 3.0)
2.70 (ddq, 13.7, 3.0, 1.4)
2.74 (dd, 13.7, 3.0)
8a
8b
9
60.7
171.9
180.5
23.2
10
11
12
181.1
178.8
19.9
1.22 (3H, d, 0.8)
3.80 (d, 8.0)
a
1.22 (3H, s)
72.2
12b
4.10 (dq, 8.0, 0.8)
1.71 (3H, dd, 1.4, 0.6)
13
a
3.92 (d, 10.0)
4.09 (d, 10.0)
1.04 (3H, d, 7.6)
75.4
74.6
7.7
7.7
13b
14
Figure 3. NOESY correlations of 1.
which is the first example of seco-prezizaane-type norsesquiterpe-
noid, and thus 1 was named as (2R)-hydroxy-norneomajucin.
Next, we have decided to confirm the absolute structure of 1 by
synthesizing from (2R⁄)-hydroxyneomajucin (4). Previously, we
have demonstrated that jiadifenolide can be obtained from neo-
majucine by oxidizing the C-10 hydroxy group.6 Moreover, Dani-
shefsky’s group had succeeded in the total synthesis of ( )-
jiadifenin by applying our oxidative method in the final step.11 Fol-
lowing the previous protocol, the secondary hydroxy group at C-2
in 4 was first acetylated, but the reaction did not proceed presum-
ably because of a steric hindrance. Therefore, (2S⁄)-hydroxyneo-
majucin (3) was used for further elaboration. In the case of
compound 3, the secondary hydroxyl group at C-2 was readily
acetylated, and then the subsequent Jone’s oxidation gave rise to
6 as anticipated (Scheme 1). Hydrolysis of 6, followed by the oxida-
tion of the generated secondary alcohol at C-2 with IBX, gave rise
to ketone 7. Finally, the NaBH4 reduction of 7 solely led to the alco-
hol, all the spectroscopic data of which were identical with those of
compound 1. This chemical conversion confirmed that the absolute
configuration of 1 is the same as that of 3. Next, the Kusumi’s
method12 was applied to establish the absolute configuration of
J = 14.7, 4.9 Hz), 2.44 (dd, J = 14.7, 7.8 Hz); dC 43.7 (C-3)]. The afore-
mentioned spectroscopic data indicated that 1 belongs to majucin-
like seco-prezizaane-type sesquiterpenoids except for the absence
of a d-lactone ring, which is a characteristic of these sesquiterpe-
noids. Furthermore, the molecular formula indicated that the car-
bon number of 1 is one less than that of normal sesquiterpenoids,
implying that 1 is a norsesquiterpenoid. Therefore, the spectro-
scopic data of 1 failed to refer to those of the previously known
seco-prezizaane-type sesquiterpenoids. Extensive analyses of
1H–1H COSY, HMQC, and HMBC of 1 (Fig. 2) showed that 1 has
the same A–C ring system as (2R⁄)-hydroxyneomajucin (4). In addi-
tion, the ester carbon signal (dC 181.1) showed HMBC correlations
with each H-7, H-8, and H-1, thereby allowing us to form a c-lac-
tone ring D between C-7 and C-9. Since the NMR signal correspond-
ing to the C-11 position which commonly exists in all the majucin
derivatives was found to be missing, 1 was assumed to be a nor-
type of (2R⁄)-hydroxyneomajucin (4).
The relative stereochemistry of 1 was elucidated on the basis of
NOESY as shown in Figure 3. Namely, H-1/H-2, H-2/H-3
/H3-12 indicated that the methyl group at C-14 and the hydroxy
group at C-2 take b-configurations and the methyl group at C-12 is
in -configuration. In addition, both the methyl group at C-12 and
hydroxy group at C-6 were assigned as -configurations from the
NOE correlation of H3-14/H-8, and H-13b/H-3b and H-13 /H3-12.
a, and H-
3a
3, which has not yet been determined. The
Dd values as shown
a
in Figure 4, enabled us to unambiguously assign the C-2 configura-
tion in 3 and 4 as S and R, respectively. Accordingly, it was noted
that the absolute configuration of 1 is the same as that of (2S)-
hydroxyneomajucin (3).
a
a
On the basis of the aforementioned data, the structure of 1 was de-
duced to be represented as 11-nor-(2R)-hydroxyneomajucin,
Compound 2 has the molecular formula C13H16O5, as deduced in
the HR-EI-MS at m/z 252.1012 [M]+, indicating 6 degrees of unsat-
uration. Its IR spectrum revealed the presence of a hydroxy group
at 3417 cmÀ1, an
and a
a ,
,b-unsaturated carbonyl group at 1693 cmÀ1
c
-lactone moiety at 1770 cmÀ1. The 1H NMR data of 2 (Ta-
ble 1) showed a low-shifted signal at dH 1.71 (dd, J = 1.4, 0.6 Hz)
due to an olefinic methyl group, which long-range coupled to the
H-3b [dH 2.03 (ddq, J = 18.9, 2.7, 0.6 Hz)] and H-8a [dH 2.70 (ddq,
J = 13.7, 3.0, 1.4 Hz)]. The NMR spectrum of 2 was similar to that
of 2-oxo-3,4-dehydroxyneomajucin except for the absence of a d-
lactone ring.
Furthermore, the molecular formula of 2 indicated that the car-
bon number of 2 was two less than that of normal seco-prezizaane-
type sesquiterpenoids. Analyses of 1H–1H COSY, HMQC, and HMBC
experiments were carried out (Fig. 5). The HMBC correlations of H-
3 and H-4/C-2 and C-9, as well as H3-13/C-1 and C-2, revealed the
presence of 2-methylcyclopent-2-enone moiety A. The other HMBC
correlations showed that 2 has the same B–C ring system as 2-oxo-
3,4-dehydroxyneomajucin. The additional HMBC correlations, as
Figure 2. 13C NMR data and HMBC correlations of 1.

M. Kubo et al. / Tetrahedron Letters 53 (2012) 1231–1235
1233
Scheme 1. Chemical conversion of (2S)-hydroxyneomajucin (3) to 1.
Figure 4.
Dd values (ppm) for MTPA ester derivatives of 3.
Figure 6. The X-ray crystallographic molecular structure of 2.
degrees of unsaturation and the above spectroscopic data disclosed
that the plane structure of 2 is tricyclic in structure as depicted in
Figure 5. Fortunately, 2 gave single crystals suitable for X-ray crys-
tallographic analysis. The X-ray crystallographic structure of 213 as
shown in Figure 6 demonstrates that the d-lactone ring is not
formed, thereby resulting in a tricyclic structure. The CD spectrum
showed a negative Cotton effect (
the absolute configuration of 2. Thus, compound 2 named jiadife-
D
e
À4.3) at 249 nm,14 ensuring
none was determined to be
structure.
a unique dinorsesquiterpenoid
The plausible biosynthetic routes for 1 and 2 are postulated as
follows: the C-10 hydroxy group in 5 is oxidized to a highly
strained
a-keto-d-lactone A, which would be opened to an a-
keto-carboxylic acid, and then the acetal formation between C-7
and C-10 gives rise to a less strained five-membered acetal inter-
mediate B. The enzymatic decarboxylation of B would lead to C.
Oxidation at C-2 in C would provide 1, whereas the decarboxyl-
ation of C would lose both the C-10 carbon and the hydroxy group
at C-4 and then the C-2 position would be oxidized again, leading
to 2 (Scheme 2).
Figure 5. 13C NMR data HMBC correlations of 2.
shown in Figure 5, and the 13C NMR chemical shift values were
similar to those of majucin-type sesquiterpenoids, suggesting that
2 has the same structural core (B and C rings) as majucin-type ses-
quiterpenoids without the d-lactone ring. Taking account for six
Compound 1 has been found to exhibit a significant neurotro-
phic activity, such as greatly promoting neurite outgrowth in the

1234
M. Kubo et al. / Tetrahedron Letters 53 (2012) 1231–1235
Scheme 2. Plausible biosynthesis of 1 and 2.
exclusively occurring in the Illicium plants have great potential as
lead compounds to develop non-peptide neurotrophic agents use-
ful for the treatment of neurodegenerative diseases such as the
Alzheimer’s disease.3,6
Acknowledgments
We thank Dr. Masami Tanaka and Dr. Yasuko Okamoto (TBU)
for taking the 600 MHz NMR and mass spectra. This work was sup-
ported by a Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology of Japan
(23790035) and a Grant from MEXT-Senryaku.
Supplementary data
Supplementary data (experimental procedures and character-
ization data) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.12.107.
References and notes
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In conclusion, two novel seco-prezizaane-type sesquiterpenoids
1 and 2 were isolated from the pericarps of I. jiadifengpi. It should
be emphasized that 1 and 2 are the first examples of seco-preziza-
ane-type norsesquiterpenoids. Moreover, compound 1 has been
found to show neurite outgrowth-promoting activity in the pri-
mary cultured rat cortical neurons. The present study provides
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