New triterpenoids from the red sea sponge Siphonochalina siphonella

Article abstract of DOI:10.1021/np0003950

Clear differences were found when comparing the chemical content of the northern, Gulf of Eilat, to the southern-central, Dahlak archipelago, Red Sea sponge Siphonochalina siphonella. The Dahlak sponge was found to be richer in the more polar triterpenes. Nine new compounds (1-4, 7, 8, 15-17) were isolated and identified, among them two sipholane glycosides, sipholenoside A and B (7 and 8), and one compound, dahabinone A (17), possessing a new skeleton.

Full text of DOI:10.1021/np0003950

J . Nat. Prod. 2001, 64, 175-180
175
New Tr iter p en oid s fr om th e Red Sea Sp on ge Siph on och a lin a siph on ella
Yoel Kashman,* Tesfamariam Yosief, and Shmuel Carmeli
School of Chemistry, Tel-Aviv University, Ramat Aviv 69978, Israel
Received August 9, 2000
Clear differences were found when comparing the chemical content of the northern, Gulf of Eilat, to the
southern-central, Dahlak archipelago, Red Sea sponge Siphonochalina siphonella. The Dahlak sponge
was found to be richer in the more polar triterpenes. Nine new compounds (1-4, 7, 8, 15-17) were isolated
and identified, among them two sipholane glycosides, sipholenoside A and B (7 and 8), and one compound,
dahabinone A (17), possessing a new skeleton.
The Red Sea sponge Siphonochalina siphonella was
found to be a rich source of triterpenoids.1 So far, 10
compounds belonging to three different skeleta, namely,
system (the “left” and “right” halves of the molecules, as
-4
they will hereafter be addressed), linked together through
an ethylene bridge. Because of the latter bridge, the two
halves of the sipholanes can freely rotate against each
other; therefore, an X-ray diffraction analysis was required
the sipholanes,1 siphonellane, and neviotane, have been
reported. Examples of the various skeleta, shown below,
are sipholenol A (5), siphonellinol B (15), and neviotine B
,2
3
4
1
for determination of the entire relative configuration. The
(
16) (Scheme 1 and Chart 1).
In the frame of a comparison of northern to southern-
absolute configuration was later also determined by the
modified Mosher method. The proton and especially carbon
5
central Red Sea organisms, namely, Gulf of Eilat vs Dahlak
archipelago, Eritrea, an investigation of the pipe sponge
Siphonochalina siphonella (family Haliconidea, Levi 1965)
was undertaken. As a result, eight new triterpenoids were
isolated from the northern sponge, and an additional new
compound was isolated from the Dahlak specimen. The
comparison showed clear differences in the sponge-triter-
penoid compositions from the two regions. Samples col-
lected from the Dahlak region exhibited higher concentra-
tions of the more polar sipholanes; still sipholenol A (5)
was the major sipholane as in the north (2.5-2.8%, dry2
wt). The corresponding 4-keto analogue, sipholenone A (6),
however, was only found in the north sponge (1%, dry wt).
Changes were also observed for sipholenol F (3) (0.28% in
the southern-central against 0.05% in the north), siphole-
none D (2), and sipholenol H (4), which appeared in ca.
NMR spectrum are most valuable for identification and
comparison of the various parts of these molecules.
6
Sipholenols G, F, and H (1, 3, and 4) possess the same
left half as sipholenol A (5), and sipholenone D (2) the same
2
left half as sipholenone A (6). All four differ, however, from
the known compounds in the right part. All four were
chemically related to known sipholanes (see Schemes 1 and
2), thus unambiguously establishing their structures.
Sipholenol G (1) analyzed for C H O , possessing one
3
0
52
5
additional oxygen atom over sipholenol A (5). Comparison
of the 13C NMR spectra of 1 and 5 (Table 1) exhibited
identity of the left part of the molecules and replacement
of the 15(16)-double bond of the right half of 5 with an
epoxy group in 1 (δC 60.8 s (C-15) and 61.9 d (C-16); δH
2
2.94 (t, J ) 7.5 Hz, H-16)), as in sipholenol B. Clear proof
of the structure was obtained by m-chloroperbenzoic acid
epoxidation of sipholenol A (5) to afford sipholenol G (1)
1
0-fold amounts in the southern-central region. It is
possible that the chemical changes are connected with the
warmer seawater in Dahlak (31 versus 27 °C in Eilat, the
highest temperatures in summer).
(32%) and its 15,16-epoxy epimer 9 (22%) (δ 2.77 dd (J )
H
8.2, 4.8 Hz, H-16) against the triplet in 5) (Scheme 1). The
R-epoxy stereochemistry of 1 was determined according to
the signal of H-16, which is identical to this proton in
sipholenone B, for which the stereochemistry was inde-
Resu lts a n d Discu ssion
2
pendently established by chemical transformations.
Herewith are reported the structures of the nine new
triterpenoids from S. siphonella (Chart 1). Four compounds
The second compound, sipholenone D (2), analyzed for
30 50 4
C H O and, according to the NMR data (Table 1), was
(
1-4) are closely related to sipholenol A (5) and its 4-keto
2
2
determined to possess the left half of sipholenone A (6)
analogue, sipholenone A (6) (Scheme 1). Two additional
compounds, siphonellinol B (15) and neviotine B (16), are
closely related to the earlier reported siphonellinol A and
2
and the right part of sipholenol C. Indeed, J ones oxidation
3
(chromic acid in acetone) of the latter compound afforded
sipholenone D (2) (Scheme 1), confirming the suggested
structure.
4
neviotine A. From the northern sponge were also isolated
sipholenoside A (7), the first glycoside of these triterpe-
noids, namely, a 19-glycoside of sipholenone D (2), and
dahabinone A (17), a triterpene with a new skeleton, and
from the Dahlak sponge another glycoside (8) of sipholenol
A (5). The structure determination of the nine new com-
pounds, including chemical transformation, is described
below.
The first four isolated sipholanes (1 - 4), like all other
known sipholanes, are assembled from two bicyclic sys-
tems, a perhydrobenzoxepine and a [5,3,0]bicyclodecane
The third compound, sipholenol F (3), which analyzed
for C30
H
52
O
4
as compound 5, possesses, according to the
1
3
C NMR data (Table 1), the left half of sipholenol A (5)
and an isomeric (to 5) substituted right half. Acid treat-
ment of 3 (p-TsOH in CHCl ) (Scheme 2) afforded two
7
3
major compounds, the 15,19-diene 12 (10%) (δ 5.50 br dd
and 5.29 br s 1H each, 1.67 br s and 1.76 br s 3H each),
identical to the compound obtained from 5 under the same
2
acid conditions, and a 15,19-oxido derivative (11, 50%) (δ
1
.19 and 1.26 s, Me’s 15 and 19, respectively) (Scheme 2).
Obtaining the 15,19-ethereal bridge in 11 established
simultaneously the cis ring junction of the 5,7-bicyclic
*
To whom correspondence should be addressed. Tel: +972-3-6408419.
Fax: +972-3-6409293. E-mail: kashman@post.tau.ac.il.
1
0.1021/np0003950 CCC: $20.00
© 2001 American Chemical Society and American Society of Pharmacognosy
Published on Web 01/06/2001

1
76 J ournal of Natural Products, 2001, Vol. 64, No. 2
Kashman et al.
Ch a r t 1
Sch em e 1
system and the R-hydroxy stereochemistry of the 15-OH
s, and 143.0 s). As J ones oxidation of sipholenol H (4)
afforded the same 4,16-dioxo derivative (14) as that ob-
tained from oxidation of sipholenol E (13)2 (Scheme 2),
compound 4 has to be the 16R-epimer of sipholenol E (13).
The latter conclusion agrees with the NMR H-16 pattern
in 4 and 13.2
In addition to the above four compounds, two consider-
ably more polar ones, designated sipholenoside A (7) and
B (8), were obtained, one (7) from the northern sponge and
group, both essential for obtaining the ethereal linkage
between C-15 and C-19, which are separated by four bonds.
+
Sipholenol H (4), C30
H
52
O
5
(m/z 493, [MH ]), the fourth
isolated sipholane of the first group, possesses, according
to the 13C NMR data (Table 1), the perhydrobenzoxepine
left part of sipholenol A (5) and, as the right half, an
2
isomeric structure to sipholenol E’s right half. From the
1
3
C NMR data, it was clear that 4 contains, in its right
half, one secondary and one tertiary hydroxyl group as well
as a tetrasubstituted double bond (δ 83.0 d, 72.0 s, 125.8
the other (8) from the southern-central one. Sipholenoside
+
C
A analyzed for C36
H
60
O
8
from the MS (m/z 602, [M
-

New Triterpenoids from Siphonochalina
J ournal of Natural Products, 2001, Vol. 64, No. 2 177
Sch em e 2
Ta ble 1. 13C NMR Data of Sipholanes 1-8a,b
(+0.4 ppm) pointed to C-19 as the location of attachment
7d
8e
of the sugar unit. On the basis of the proton and carbon
position
1
2
3
4
5
atom NMR data, the sugar unit was determined to be
1
2
3
4
5
7
8
9
42.6
34.0
25.2
42.1
40.6
35.3
42.8
34.4
25.3
77.0
77.8
76.4
26.7
39.2
72.4
56.6
27.5
29.6
42.4
34.2
25.0
76.4
78.2
76.4
26.3
38.8
72.0
55.2
24.8
37.9
42.2
33.6
24.6
42.3
40.8
35.2
42.6
33.6
25.1
76.5
77.2
74.1
26.6
39.0
72.6
55.7
26.7
33.6
57.5
R-rhamnose.8
-12
Mild acidic hydrolysis of 7 afforded si-
pholenone D (2) and other elimination products that were
not identified as well as the sugar unit (Scheme 1). The
later monosaccharide was determined upon its NMR specta
76.6 217.4
75.9 216.3
77.9
76.6
26.6
39.0
71.8
55.8
27.6
82.6
81.3
26.6
40.8
72.4
58.0
33.5
78.0
76.2
26.2
38.6
71.9
55.7
26.4
82.4
81.3
26.4
41.4
72.8
58.1
32.8
13
and optical activity to be R-L-rhamnose.
Sipholenoside B (8) analyzed for C36
62 8
H O from the MS
+
m/z 622 [M ] peak. The NMR and MS data of 8 (Experi-
mental Section) pointed clearly to a second glycoside. Using
the same rationale described above for compound 7, the
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
3
33.1 132.7
56.0 140.7
33.4 134.1
57.3 139.7
aglycone of 8, according to the C NMR data, was
determined to be sipholenol A (5), and the sugar, L-
rhamnose, was attached to C-19.
42.0 125.8
72.9 143.0 142.7
39.7
30.5
47.1
60.8
61.9
30.4
46.9
81.3
37.0
24.0
52.9
37.1
12.8
21.2
28.9
30.0
30.4
25.3
28.1
33.4
33.8
32.1
21.3
50.1
73.1 135.6
37.2 121.7
24.0
50.9
33.3
12.5
20.6
26.3
28.8
26.6
23.6
22.3
30.0
33.8 143.3
31.7 121.1
83.0 120.9
Another compound that was isolated from the northern
sponge, with a polarity similar to siphalones 1-4, was
27.4
42.1
72.0
30.3
36.1
44.7
34.4
12.5
21.1
28.7
29.9
16.7
28.3
23.2
35.3
24.3
48.0
81.4
36.5
24.7
52.2
35.0
12.6
21.0
28.5
29.2
29.6
24.9
29.0
31.2
20.8
46.2
78.9
37.0
23.8
51.3
32.7
12.7
20.4
24.9
28.6
25.9
22.6
23.3
28.8
24.2
45.1
89.3
33.8
21.4
52.9
35.4
12.9
21.3
29.1
29.5
30.1
24.9
31.8
29.8
siphonellinol B (15) (Chart 1). This compound analyzed for
+
C
30
H
52
O
5
from its CIMS m/z 493 [M H] and NMR data.
36.2
47.6
34.7
13.3
21.3
28.9
30.3
28.4
21.8
24.6
35.5
The left ring system was found, from the NMR data
Experimental Section), to be identical to the left part of
(
sipholenol A (5) and to the corresponding left part of
3
siphonellinol A. The right substituted cyclohexane system
of 15 was identical to the corresponding part in siphonel-
linol A;3 however, the attached six-carbon chain was
different. Instead of the isopropylidene end of siphonellinol
3
A, compound 15 carries a -CH
2
CH(OH)C(CH
3
)dCH
2
end
group (δ 4.01 (br t, J ) 8.2, H-22), 4.85 (br s) and 4.93 (br
s) (2H-24), and 1.71 (s, Me-25)). The latter NMR data are
in good agreement with the data of a similar chain in the
Xenia metabolite xeniaphyllenol.14
a
CDCl3, Brucker AMX-360 or ARX-500 instruments, chemical
b
shifts refer to CDCl3 (δC ) 77 ppm). Multiplicities were deter-
mined by DEPT and HMQC experiments and are as required from
c
d
Neviotine B (16) was another triterpene isolated from
the northern sponge in minute amounts (0.005%, dry
the formulas. Interchangeable signals. δC-1′ to 6′ 93.7 d, 72.5 d,
e
7
7
2.2 d, 74.1 d, 67.8 d, 17.6 q ppm. δC-1′ to 6′ 94.2 d, 71.9 d, 70.5 d,
2.3 d, 67.6 d, 17.4 q ppm.
4
weight). Like neviotine A, 16 also contains seven methyl
groups (rather than eight in the sipholanes), and it pos-
+
H
2
O]) and 13C NMR data (Experimental Section). Charac-
teristic chemical shifts for sugar protons and especially for
sesses the same formula, C30
H
50
O
6
(m/z 507 [M H]).
Comparison of the NMR data of 16 with those of neviotine
4
the anomeric group (δ
d, in C
H
5.53 br d, J ) 1.3 Hz and δ
C
95.1
A established the same tricyclic half of the molecule.
+
5
D
5
N) as well as the m/z 456 [M - C
6
H
12
O
5
]
Changes, however, were observed in the second half of the
molecule. The MS and IR spectra of 16 are essentially
identical to those of neviotine A.4 Furthermore, CH-
correlations of 16 suggested the same hydrindane system
as in neviotine A. The almost identical carbon chemical
shifts of the five-membered ring of neviotine B and A
suggested for 16 a cis ring junction. Hence, the difference
between the neviotines, A and B, is most likely due to the
fragment, in the MS suggested a glycoside. Comparison of
the NMR data of 7 with the NMR data of the known
sipholanes established the aglycone as sipholenone D (2).
An excellent agreement was found for 25 out of the 36
carbon atom signals of 7 with the corresponding ones of
sipholenone D (2) (Table 1). Furthermore, the observed
changes in C-19 (+5.7 ppm), C-18 (-4.0 ppm), and C-22

1
78 J ournal of Natural Products, 2001, Vol. 64, No. 2
Kashman et al.
Sch em e 3. Biogenesis of the Various Triterpenoids
stereochemistry of C-15. Indeed, the largest changes in
chemical shifts were observed for Me-27 and C-15-17 and
C-23, surrounding C-15. Tentatively, 16 is suggested to be
the 15-epimer of neviotine A (Chart 1).
angle between H-18 and H-17 is possible. One of the methyl
groups adjacent to C-18, CH
3
-29, according to its chemical
shift (δ 1.23 s), has to be on C-19 (73.8 s) carrying an
H
oxygen. All the above data and taking into consideration
the isoprene rule suggested the oxa-6,7-bicyclic structure
of the right part of 17. The small amount of 17 available
and its instability prevented assignment of the right half
stereochemistry.
The last compound that was isolated in minute amounts
(0.003%, dry weight) from the northern sponge, collected
near Dahab, was designated dahabinone A (17). Compound
+
1
H
7 analyzed for C30
H
50
O
5
from the EIMS m/z 472 [M
-
1
3
All S. siphonella triterpenes are obtained, presumably,
by two separate cyclizations from di- or triepoxysqualenes.
In case of the sipholanes and neviotanes the cyclization
seems to be initiated by the biologically well-known acid-
catalyzed opening of the epoxy group, while in the case of
the siphonellinoles and dahaboine A cyclization of the right
part most likely starts from electrophilic protonation of a
double bond (Scheme 3). The suggested biogenesis of the
neviotanes seems to involve a more complex route including
functionalization of one methyl group, which is later
incorporated as a methylene in the hydrindane part.
Secondary reactions, mainly oxidations, are responsible for
the variety of the isolated triterpenoids.
2
O] and NMR data (Experimental Section). From the
C
NMR data, it was clear that 17 contains the same left part
2
as sipholenone A (6) and that the right half is without
precedent. Noticeable in the resonances of the left part was
the chemical shift of C-11 (δ 62.1 against 55.2 in siphole-
2
none A (6) ), a shift that could originate from a neighboring
2(13)-unsaturation in the ethylene bridge. The latter
1
functionality was established by a COSY experiment which
combined H-11 to H-13 (δ 1.81 (d, J ) 10, H-11); 5.84 (dd,
J ) 10, 15.6, H-12); 5.64 (d, J ) 15.6, H-13)). Of the six
degrees of unsaturation of dahabinone A, four were ac-
counted for by the perhydrobenzoxepine system and the
bridge double bond; compound 17’s right part therefore has
to be bicyclic. According to the NMR data (experimental),
the right half of 17 contains four methyls, three singlets,
and one doublet and an ethereal bridge between C-14 (δ
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. IR spectra were
recorded on a Nicolet 205 FT-IR spectrophotometer. LRMS and
9
2.3 s) and C-19 (δ 73.8 s). Furthermore, the low field of
1
HRMS were recorded on a Fisons, Autospec Q instrument. H
C-14 suggested a hemiketal carbon atom. Compound 17
changes rapidly under mildly acidic conditions (e.g., acidic
13
and C NMR spectra were recorded on Bruker AMX-360 and
ARX-500 spectrometers. All chemical shifts are reported with
CDCl
3
) to afford an Râ-unsaturated ketone, >C(11)HCHd
)C(16)H - (δ 1.92 (d, J ) 10.5, H-11), 6.87
dd, J ) 10.5, 15.6, H-12), 6.33 (d, J ) 15.6, H-13), 2.74
ddq, J ) 3.5, 9.4, 7.0, H-15), 1.13 (d, J ) 7.0, Me-28) and
.50 and 1.65 (m, 2H-16); δ 61.7 d, 142.4 d, 133.6 d, 202.9
respect to TMS (δ
H
) 0) and CDCl
3
C
(δ ) 77.0). J values are
CHCOCH(CH
(
(
3
2
given in Hz. Optical rotations were measured on a Perker-
Elmer Model 141 polarimeter using a 1 cm microcell.
An im a l Ma ter ia l. Siphonochalina siphonella (Levi, 1965)
2
1
C
1
was collected once near Na’ama in the Gulf of Eilat and a
4
second time near Sarad island, Dahlak archipelago, Eritrea,
in September 1995.
s, 45.4 d, 31.6 C-11-16)). The latter transformation
established the C-14 position of the hemiketal, adjacent to
the double bond. Characteristic for the suggested structure,
of 17, was also the proton signal of H-18 (δ 2.47 d, J )
Isola tion . Compounds 1-5, 7, and 15-17 were isolated
2
from the northern sponge as described previously. The various
2
compounds together with the earlier described compounds
5
.1), which correlated with three methyl groups (29-31).
were first separated on Sephadex LH-20 and then by repeated
chromatographies on Si gel, in amounts of 20-50 mg each (up
to 0.0001%, dry wt). The order of the different compounds
eminating from the Sephadex LH-20 column, eluted with
Being a doublet (coupled with H-17 alone) confirmed the
bridge head position of H-18 but could not determine the
stereochemistry of the ring junction, as in both the cis and
trans configurations, a conformation with a ca. 90° dihedral
CHCl -hexane (2:1), was 2, 5, 1, 4, 3, 7, 15, 16, and 17. The
3

New Triterpenoids from Siphonochalina
J ournal of Natural Products, 2001, Vol. 64, No. 2 179
Eritrean sponge (70 g, dry wt) was extracted three times with
Me-27), 1.77 (s, Me-28), 1.24 (s, Me-29), 1.04 (s, Me-30), 1.10
(s, Me-31), 4.95 (br s, H-1′), 3.70 (br d, J ) 3.4, H-2′), 3.84 (dd,
J ) 9.4, 3.4, H-3′), 3.40 (t, J ) 9.4, H-4′), 3.85 (dq, J ) 9.4,
EtOAc-MeOH (1:1) to afford, after evaporation, a brown gum
(4 g). The latter gum was partitioned between aqueous MeOH
1
3
and hexane, CCl
respectively, leaving 0.5 g in the aqueous phase. The hexane
fraction yielded mainly sipholenol A (5, 300 mg). The CCl
fraction afforded, upon Sephadex LH-20 chromatography
eluted with hexane-CHCl -MeOH (2:1:1) and further separa-
tions on VLC Si gel eluted with EtOAc-hexane, sipholenol A
5, 1 g), sipholenol F (3, 20 mg), sipholenol H (4, 8 mg), and
sipholenone D (2, 8 mg). The CHCl fraction afforded ad-
ditional amounts of sipholenol H (80 mg), sipholenone D (2,
4
, and CHCl
3
to give 1.0, 2.0, and 0.5 g,
6.3, H-5′), 1.26 (d, J ) 6.3, Me-6′); for C NMR see Table 1;
+ + +
EIMS m/z 622 [M ] (2), 604 [M - H
2
O] (10), 458 [M
O] (100).
Sip h on ellin ol B (15): glassy oil, IR (CHCl ) ν 3610, 3450,
-
+
4
C
6
H
12
O
5
] (58), 440 [M - C
6
H
12
O
5
- H
2
3
-1 1
3
2940, 1440, 1400, 1370, 1250, 1225, 1170, 1090 cm ; H NMR
δ 3.82 (d, J ) 6.7, H-4), 3.53 (dd, J ) 4.2, 11.7, H-7), 3.66 (dd,
J ) 3.7, 9.7, H-16), 4.01 (br t, J ) 8.2, H-22), 4.85 and 4.93 (br
s, 2H-24), 1.71 (br s, Me-25), 1.00 (s, Me-26), 1.13 (s, Me-27),
1.27 (s, Me-28), 1.24 (s, Me-29), 1.67 (s, Me-30), 1.06 (s, Me-
31); 13C NMR δ 41.9 (s, C-1), 33.5 (t, C-2), 24.3 (t, C-3), 75.7
(d, C-4), 77.0 (s, C-5), 75.5 (d, C-7), 25.7 (t, C-8), 38.3 (t, C-9),
71.2 (s, C-10), 54.9 (d, C-11), 25.6 (t, C-12), 29.6 (t, C-13), 134.6
(s, C-14), 127.7 (s, C-15), 70.4 (d, C-16), 25.7 (t, C-17), 31.3 (t,
C-18), 42.0 (s, C-19), 31.4 (t, C-20), 27.7 (t, C-21), 74.9 (d, C-22),
146.1 (s, C-23), 110.2 (t, C-24), 16.7 (q, Me-25), 12.1 (q, Me-
26), 28.0 (q, Me-27), 20.3 (q, Me-28), 29.8 (q, Me-29), 19.5 (q,
(
3
5
0 mg), and sipholenoside B (8, 55 mg).
Sip h olen ol G (1): amorphous powder, [R] -30° (c 0.05,
D
CHCl
3
); mp 173-175 °C; IR (CHCl ) ν 3590, 3450, 2920, 2860,
3
1
3
455, 1440, 1372, 1250 cm-1; 1H NMR δ 3.77 (d, J ) 6.6, H-4),
.52 (dd, J ) 11.9, 3.8, H-7), 2.94 (t, J ) 7.5, H-16), 1.01 (s,
Me-24), 1.24 (s, Me-25), 1.13 (s, Me-26), 1.22 (s, Me-27), 1.38
(
s, Me-28), 1.27 (s, Me-29), 1.04 (s, Me-30), 1.26 (s, Me-31); for
1
3
+
+
C NMR see Table 1; CIMS m/z (relative intensity) 493 [MH ]
Me-30), 20.6 (q, Me-31); CIMS m/z 493 [MH ] (7), 475 (18),
+
+
(
22), 475 [MH - H
Sip h olen ol D (2): glassy oil, [R]
CHCl ) ν 3450, 2990, 2970, 2870, 1725, 1460, 1390 cm ; H
2
O] (75), 457 [MH - H
2
O] (100).
457 (57), 439 (100), 421 (19); HREIMS 474.3715 (M - H
(calcd for C30 O) 474.3711).
Neviotin e B (16): glassy oil, [R]
(CHCl
2
O),
D
-35° (c 0.05, CHCl
3
-
); IR
H
50
O
4
(M - H
2
1 1
(
3
D
-53° (c 1.6, CHCl
3
); IR
NMR δ 3.17 (ddd, J ) 13.0, 11.0, 2.5, H-3), 2.09 (ddd, J ) 11.0,
6
5
Me-25), 1.25 (s, Me-26), 1.21 (s, Me-27), 1.12 (d, J ) 7.6, Me-
2
3
) ν 3590, 3390, 2925, 2915, 1750, 1460, 1450, 1378,
-1
1
.4, 1.8, H-3′), 2.98 (dd, J ) 11.4, 3.8, H-7), 2.27 (m, 2H-12),
.28 (t, J ) 7.0, H-13), 2.88 (m, H-15), 1.02 (s, Me-24), 1.31 (s,
1240, 1140, 1085, 1040, 965, 910 cm ; H NMR δ 4.14 (s, H-3),
5.08 (s, H-25), 4.97 (dd, J ) 3.0, 12.5, H-7), 2.26 (dt, J ) 5.0,
11.4, H-21), 1.32 (s, Me-24), 1.20 (s, Me-25), 0.68 (s, Me-26),
1.28 (s, Me-27), 0.91 (d, J ) 6.5, Me-29), 0.89 (d, J ) 6.5, Me-
1
3
8), 1.24 (s, Me-29), 0.88 (s, Me-30), 0.96 (s, Me-31); for
C
+
+
13
NMR see Table 1; EIMS m/z 456 [M - H
O] (24), 400 (50), 231 (70), 212 (100).
Sip h olen ol F (3): glassy oil; [R] -24° (c 0.5, CHCl
CHCl ) ν 3620, 3450, 2950, 1480, 1385, 1170, 1135, 1090, 915
2
O] (8), 438 [M
-
30), 1.25 (s, Me-31); C NMR δ 76.3 (s, C-1), 84.1 (d, C-2),
2
H
2
213.4 (s, C-4), 75.4 (d, C-5), 44.3 (s, C-6), 68.9 (d, C-7), 26.6 (t,
C-8), 36.6 (t, C-9), 43.5 (s, C-10), 55.0 (d, C-11), 23.4 (t, C-12),
23.6 (t, C-13), 61.1 (d, C-14), 75.4 (s, C-15), 31.4 (t, C-16), 26.6
(t, C-17), 54.1 (d, C-18), 88.1 (s, C-19), 36.3 (t, C-20), 35.9 (t,
C-21), 41.8 (s, C-22), 45.0 (t, C-23), 22.2 (q, Me-24), 26.8 (q,
Me-25), 14.6 (q, Me-26), 20.0 (q, Me-27), 33.9 (d, C-28), 17.3
(q, Me-29), 16.8 (q, Me-30), 33.0 (q, Me-31); CIMS m/z 507
D
3
); IR
(
3
1
-
1
cm ; H NMR δ 1.47 and 1.56 (m, 2H-2), 1.71 and 1.98 (m,
H-3), 3.81 (d, J ) 6.7, H-4), 3.52 (dd, J ) 4.4, 11.7, H-7), 1.39
and 1.79 (m, 2H-8), 1.51 and 1.63 (m, 2H-9), 0.94 (m, H-11),
.52 and 1.57 (m, 2H-12), 1.35 and 1.88 (m, 2H-13), 2.08 (m,
H-14), 1.06 and 1.75 (m, 2H-16), 1.31 and 1.72 (m, 2H-17), 2.46
m, H-18), 5.25 (brs, H-20), 1.70 and 1.82 (m, 2H-21), 1.90 (m,
2
1
+
[MH ] (19), 489 (66), 473 (12), 471 (58), 457 (47), 439 (21), 407
+
(
(29), 389 (100), 371 (77), 102 (72); HREIMS 488.3499 [M
O] (calcd for C30 , 488.3503).
Da h a bin on e A (17): amorphous powder, IR (CHCl
-
H-22), 1.00 (s, Me-24), 1.27 (s, Me-25), 1.13 (s, Me-26), 1.16 (s,
Me-27), 1.17 (s, Me-28), 1.73 (s, Me-29), 0.90 (s, Me-30), 1.09
H
2
48 5
H O
3
) ν 3400,
1
3
+
-1 1
(
s, Me-31); for C NMR see Table 1; EIMS m/z 476 [M ] (1),
2870, 1700, 1460, 1440, 1370, 1170, 1125, 1070 cm ; H NMR
δ 1.15 and 1.68 (m, 2H-2), 3.10 (ddd, J ) 13.4, 11.2, 2.2, H-3),
2.03 (m, H-3′), 2.98 (dd, J ) 8.7, 6.9, H-7), 1.81 (d, J ) 10.1,
H-11), 5.84 (dd, J ) 15.6, 10.1, H-12), 5.64 (d, J ) 15.6, H-13),
2.02 (m, H-15), 2.47 (d, J ) 5.1, H-18), 1.16 (s, Me-24), 1.32 (s,
Me-25), 1.25 (s, Me-26), 1.20 (s, Me-27), 0.79 (d, J ) 7.0, Me-
4
1
59 (1), 458 (5), 440 (6), 256 (12), 234 (52), 216 (20), 205 (6),
80 (15), 165 (15), 157 (33), 149 (19), 129 (26), 25 (100);
HREIMS m/z 476.3871 (calcd for C30
H
52
O
4
476.3868).
Sip h olen ol H (4): glassy oil; [R]
CHCl ) 3630, 3425, 2959, 1450, 1378, 1240 cm ; H NMR δ
.75 (d, J ) 6.7, H-4), 3.57 (dd, J ) 4.8, 12.0, H-7), 0.91 (br d,
D
-42° (c 0.1, CHCl ); IR ν
3
-
1 1
(
3
3
1
3
28), 1.23 (s, Me-29), 1.09 (s, Me-30), 1.06 (s, Me-31); C NMR
δ 41.4 (s, C-1), 40.4 (t, C-2), 35.5 (t, C-3), 217.5 (s, C-4), 82.6
(s, C-5), 81.0 (d, C-7), 27.1 (t, C-8), 38.7 (t, C-9), 71.2 (s, C-10),
62.1 (d, C-11), 125.9 (d, C-12), 133.5 (d, C-13), 92.3 (s, C-14),
40.5 (d, C-15), 35.2 (t, C-16), 28.3 (t, C-17), 46.3 (d, C-18), 73.8
(s, C-19), 41.9 (t, C-20), 24.1 (t, C-21), 32.2 (t, C-22), 33.0 (s,
C-23), 12.4 (q, Me-24), 20.6 (q, Me-25), 26.7 (q, Me-26), 28.8
H-11), 2.06 (dt, J ) 6, 12.0, H-13), 2.52 (dt, J ) 8.4, 12.0,
H-13′), 4.23 (br d, J ) 5.7, H-16), 1.79 (ddd, J ) 5.7, 13.5, 14.3,
H-17), 1.71 (ddd, J ) 4.2, 4.6, 14.3, H-18), 2.39 (br d, J ) 4.6,
H-22), 0.94 (s, Me-24), 1.25 (s, Me-25), 1.12 (s, Me-26), 1.20 (s,
Me-27), 1.86 (s, Me-28), 1.23 (s, Me-29), 0.74 (s, Me-30), 1.00
+
(
s, Me-31); CIMS m/z 493 [MH ] (100), 475 (43), 457 (96), 439
(
-
53), 249 (11), 235 (17); HREIMS 474.3716 (calcd for C30
O 474.3711).
Sip h olen osid e A (7): amorphous solid, [R]
CHCl ); IR (CHCl ) ν 3450, 2990, 2940, 2865, 1735, 1455, 1380
H
52
O
5
(q, Me-27), 19.2 (q, Me-28), 24.6 (q, Me-29), 25.0 (q, Me-30),
+
H
2
34.2 (q, Me-31); EIMS m/z 472 [M - H
2
O] (14), 454 (8), 447
] (4), 356 (2), 323
(6), 305 (60), 290 (100), 287 (18), 217 (15), 207 (29), 193 (27),
+
+
D
-18° (c 0.1,
[M - C
3
H
7
] (23), 370 [M - H
2
4 6 2
O - C H O
3
1
3
-1
+
cm ; H NMR δ 3.17 (ddd, J ) 13.3, 11.1, 2.2, H-3), 2.10 (ddd,
J ) 11.0, 6.3, 1.9, H-3′), 2.95 (dd, J ) 11.9, 4.0, H-7), 5.18 (t,
J ) 6.7, H-13), 2.81 (m, H-15), 1.03 (s, Me-24), 1.29 (s, Me-
2
1
178 (41), 161 (20), 149 (53); HREIMS 472.3551 [M - H
(calcd for C30 , 472.3554).
Ep oxid a tion of Sip h olen ol A (5) to Sip h olen ol G (2)
a n d 9. m-Chloroperbenzoic acid (36 mg) in CH Cl (3 mL) was
added to a suspension of sipholenol A (5, 55 mg) and Na HPO
(78 mg) in CH Cl (3 mL) at room temperature. After 4 h the
solution was washed with aqueous Na CO
(×2) and then
water. The organic phase was dried over MgSO and evapo-
rated to give a mixture of compounds 2 and 9 (57 mg), which
was separated on a Si gel column eluted with CH Cl -EtOAc
2
O]
48 4
H O
5), 1.23 (s, Me-26), 1.21 (s, Me-27), 1.11 (d, J ) 7.6, Me-28),
.21 (s, Me-29), 0.84 (s, Me-30), 0.97 (s, Me-31), 4.97 (br d, J
1.3, H-1′), 3.70 (br s, H-2′), 3.80 (dd, J ) 9.4, 3.1, H-3′), 3.47
2
2
2
4
)
2
2
(
t, J ) 9.4, H-4′), 3.87 (dq, J ) 9.4, 3.6, H-5′), 1.28 (d, J ) 6.3,
2
3
1
3
+
Me-6′); for C NMR see Table 1; EIMS m/z 602 [M - H
(
2
O]
O] (10).
-acetone);
); IR (KBr) ν 3450, 2960, 1255, 1050
4
+
+
4), 456 [M - C
6
H
12
O
6
] (3), 438 [M - C
6
H
12
O
6
- H
2
Sip h olen osid e B (8): powder, mp 237° (CHCl
3
2
2
[
R]
D
-
-22° (c 0.5, CHCl
3
(4:1) to give first sipholenol G (15 mg) and then compound 9
1
1
cm ; H NMR δ 1.45 and 1.60 (m, 2H-2), 1.75 and 1.85 (m,
(37 mg).
2
H-3), 3.85 (d, J ) 6.7, H-4), 3.55 (dd, J ) 11.9, 6.9, H-7), 1.30
and 1.73 (m, 2H-8), 1.50 and 1.62 (m, 2H-9), 0.86 (br s, H-11),
.22 and 1.50 (m, 2H-12), 1.79 and 1.95 (m, 2H-13), 5.49 (br
d, J ) 4.8, H-16), 2.01 and 1.75 (m, 2H-17), 1.82 (m, H-18),
.60 and 1.67 (m, 2H-20), 1.75 and 1.98 (m, 2H-21), 2.20 (m,
H-22), 0.98 (s, Me-24), 1.25 (s, Me-25), 1.14 (s, Me-26), 1.07 (s,
3
Com pou n d 9: amorphous powder, mp 174-176°; IR (CHCl )
-
1
1
ν 3575, 3455, 2920, 1445, 1435, 1370, 1250 cm ; H NMR δ
0.91 (s, 3H), 1.02 (s, 3H), 1.03 (s, 3H), 1.13 (s, 3H), 1.19 (s,
3H), 1.26 (s, 3H), 1.38 (s, 3H), 2.77 (dd, J ) 8.2, 4.8, 1H), 3.53
(dd, J ) 11.8, 4.2, 1H), 3.78 (d, J ) 6.6, 1H); 13C NMR δ 82.6
s, 77.8 s, 76.9 d, 76.5 d, 71.9 s, 60.6 d, 60.6 s, 56.3 d, 52.8 d,
1
1

1
80 J ournal of Natural Products, 2001, Vol. 64, No. 2
Kashman et al.
5
1.1 d, 48.6 d, 42.6 s, 38.9 t, 38.8 t, 34.2 t, 32.3 q, 31.4 q, 30.5
Hyd r olysis of Sip h olen osid e A (7) to Sip h olen on e D
(2). Sipholenoside A (7, 15 mg) in MeOH (5 mL) was refluxed
with 5% HCl (5 mL) for 6 h. The reaction mixture was then
t, 30.2 s, 29.1 q, 27.9 t, 26.7 t, 25.7 t, 25.5 q, 25.5 q, 25.3 t,
2
+
4.0 t, 21.6 t, 21.3 q, 12.9 q; CIMS m/z 493 [M H] (53), 475
+
+
[M H - H
2
O] (100), 457 [M H - 2H
2
O] (84).
neutralized with aqueous NaHCO
under vacuum. The residue was dissolved in CHCl
and then washed with H
3
and the solvent evaporated
Oxid a tion of Sip h olen ol C (10) to Sip h olen on e D (2).
3
(10 mL)
Sipholenol C (10, 10 mg) was oxidized with J ones reagent (2
drops) to give, after work up, siphoplenone D (2, 5 mg).
Acid ic Tr a n sfor m a tion of Sip h olen ol F (3) to Com -
2
O (2 × 5 mL) to afford sipholenol D
11
(2) in the organic phase and l-rhamnose (3 mg) in the aqueous
phase. The sugar was purified by chromatography on Sepha-
dex LH-20 eluted with MeOH.
p ou n d s 11 a n d 12. Sipholenol F (3, 10 mg) dissolved in CHCl
3
r-L-Rh a m n ose: white solid, [R]D -8.5 (c 0.05, H O); 1H
(3 mL) in the presence of pTsOH acid (1 mg) was kept at room
2
temperature for 2 weeks. The CHCl
3
was then removed under
NMR (pyridine-d ) δ 5.12, 3.92, 3.81, 3.45, 3.86 and 1.28 (3H)
5
(H-1-H-6); 13C NMR (pyridine-d ) 95.1 (d, C-1), 74.2 (d, C-2),
vacuum and the residue applied to a Si gel column using an
increasing percentage of EtOAc in hexane as eluent. The less
polar compound 12 was eluted with 20% EtOAc and the more
polar one, 11, with 30% EtOAc in hexane (4 mg each).
Compound 12 was identical in all respects to the compound
5
1
1
73.1 (d, C-3), 74.4 (d, C-4), 69.8 (d, C-5), 18.7 (q, CH -6).
3
Hyd r olysis of Sip h olen osid e B (8) to Sip h olen ol A (5).
Sipholenoside B (8, 15 mg) was hydrolyzed in the same manner
as described for 7 to afford sipholenol A (5) and R-L-rhamnose.
2
obtained from sipholenol A.
Com p ou n d 11: viscous gum; IR (CHCl ) ν 3450, 2940, 1460,
3
Refer en ces a n d Notes
1
1
1
)
4
380, 1170, 1080 cm-1; H NMR δ 0.80 (s, 3H), 0.97 (s, 6H),
(
1) Shmueli, U.; Carmely, S.; Groweiss, A.; Kashman, Y. Tetrahedron
Lett. 1981, 22, 709-712.
.12 (s, 3H), 1.16 (s, 3H), 1.19 (s, 3H), 1.26 (s, 6H), 3.52 (dd, J
+
11.9, 4.4, 1H), 3.80 (d, J ) 6.6, 1H); EIMS m/z 476 [M ] (1),
(
2) Carmely, S.; Kashman, Y. J . Org. Chem. 1983, 48, 3517-3525.
58 (14), 400 (3), 234 (39), 220 (12), 85 (100).
(3) Carmely, S.; Loya, Y.; Kashman, Y. Tetrahedron Lett. 1983, 24, 3673-
3
672.
Oxid a tion of Sip h olen ol H (4) a n d Sip h olen ol E (13)
(
(
4) Carmely, S.; Kashman, Y. J . Org. Chem. 1986, 51, 784-788.
5) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am. Chem.
Soc. 1991, 113, 4092-4096; J . Org. Chem. 1991, 56, 1296-1298.
to 4,6-Dion e 14. Sipholenol H (4, 5 mg) or sipholenol E (13,
mg) was dissolved in Me CO (5 mL), and one drop of J ones
5
2
reagent was added at 0 °C. After 15 min the excess oxidant
was destroyed by a drop of MeOH. The solvent was removed
(6) Carmely, S.; Kashman, Y. Magn. Reson. Chem. 1986, 24, 332-336.
(
7) Several typical MS fragmentations have been described for the
sipholanes.2 Thus C(11)-C(12) in sipholenal A (5) is cleaved to give
a peak at m/z 234 assigned to a substituted perhydroazulene, which
sequentially loses a four-carbon unit due to a cleavage of the five-
membered ring to give peaks at m/z 162, 163. In 3, on the other hand,
under vacuum and the residue dissolved in CHCl
solution was washed with water, aqueous NaHCO
water, and the solvent was removed under reduced pressure
to afford 14 (3 mg) as a amorphous material: IR (CHCl ) ν
600, 3480, 2930, 1710, 1650, 1460, 1378 cm ; H NMR δ 2.94
dd, J ) 4.1, 12.0, H-7), 2.20 (dt, J ) 6.5, 12.0, H-13), 2.70 (dt,
J ) 6.5, 12.0, H-13′), 2.34 (br dd, J ) 5.8, 18.5, H-17), 2.37
dd, J ) 12.0, 18.5, H-17′), 2.64 (br d, J ) 4.9, H-22), 1.17 (s,
Me-24), 1.32 (s, Me-25), 1.27 (s, Me-26), 1.18 (s, Me-27), 1.88
s, Me-28), 1.24 (s, Me-29), 0.74 (s, Me-30), 0.97 (s, Me-31);
3
(5 mL). This
3
, and more
peaks appear at 180 (15) and 181 (9) [162, 163 + H
2
O], suggesting a
3
1
5-hydroxy group, rather than 19-hydroxy.
-1 1
3
(
(
8) Yamaski, K.; Kohda, H.; Kobayashi, T.; Kasai, A.; Tanaka, O.
Tetrahedron Lett. 1976, 1005-1008.
9) Kassai, R.; Suzuo, M.; Asakawa, J . T.; Tanaka, O. Tetrahedron Lett.
(
1
977, 175-178.
(
(
10) Tori, K.; Seo, S.; Yoshimura, Y. Arita, H.; Tomita, Y. Tetrahedron
Lett. 1977, 179-182.
(11) Kasai, R.; Okihara, M.; Asakawa, J .; Mitzatani, K.; Tanaka, O.
(
+
+
+
Tetrahedron 1979, 35, 1427-1431.
CIMS m/z 489 [M H] (19), 471 [M H - H
2H O] (24).
Hyd r olysis of Sip h olen ol I (6) t o Sip h olen ol H (14).
2
O] (100), 453 [M H
(
(
12) Hung-Wen,; Nakanishi, K. Tetrahedron 1982, 38, 513-518.
13) Buckingham, J ., Ed. Dictionary of Natural Products; Chapman-
Hall: London, 1992; Vol. 5, p 4935.
-
2
Sipholenol I (6, 5 mg), in pyridine-dioxane (5 mL), was
refluxed for 18 h. The reaction mixture was then evaporated
under vacuum. The residue afforded, after removing the
solvent, sipholenol H (3 mg).
(14) Kashman, Y.; Growiss, A. J . Org. Chem. 1980, 45, 3814-3824.
(
15) The small available amounts of 17 precluded full characterization of
its acidic derivative.
NP0003950