Investigation of Pictet-Spengler type reactions of secologanin with histamine and its benzyl derivative

Article abstract of DOI:10.1021/np010415d

The reaction of secologanin (1) (mainly in its tetraacetylated form la) with histamine (2) and its benzyl derivative (2b) was investigated. With the benzylated amine (2b), the main product was the normal, tetraacetylated benzyl derivative of histeloside having the R configuration at the new center of chirality, C-1 (5b), with a small amount of an unidentified minor component (probably the 1S epimer 5a). In a slightly acidic medium, the reaction with histamine (2) gave two products in an approximately 6:4 ratio. The main compound proved to be the normal, tetraacetylated derivative of the lactam histelosamide with R configuration at C-1 (7b), and the minor product was the tetraacetylisohisteloside with S configuration at the same C-1 center (3a). When the reaction was carried out under acid-free conditions, in addition to the epimeric pair of the normal tetraacetylated lactam (7a, 7b) and the tetraacetylisohisteloside with 1S configuration (3a), tetraacetylneohistelosamide (8b) was also isolated, in which the cyclization took place at one of the cyclic nitrogens of the imidazole ring. Probably, this latter compound is an intermediate also in the formation of the normal isomers, but under slightly acidic conditions it rapidly isomerized into the normal alkaloid. The tendencies experienced previously in the tryptamine and dopamine series were observed also in the histamine series; that is, at C-1, the R configuration is favored over the S one, and lactamization is faster in the former than in the latter case. The structure of the products and their stereoschemistry were established by NMR spectroscopy.

Full text of DOI:10.1021/np010415d

J . Nat. Prod. 2002, 65, 649-655
649
In vestiga tion of P ictet-Sp en gler Typ e Rea ction s of Secologa n in w ith Hista m in e
a n d Its Ben zyl Der iva tive†,
Gyula Beke,‡ La´szlo´ F. Szabo´*,‡ and Benjamin Poda´nyi§
Institute of Organic Chemistry, Semmelweis University, Ho˜gyes u. 7, H-1092 Budapest, Hungary, and Chinoin Pharmaceutical
and Chemical Works, Ltd. (a Member of the Sanofi-Synthelabo Group), To´ u. 1-5, H-1045, Budapest, Hungary
Received August 24, 2001
The reaction of secologanin (1) (mainly in its tetraacetylated form 1a ) with histamine (2) and its benzyl
derivative (2b) was investigated. With the benzylated amine (2b), the main product was the normal,
tetraacetylated benzyl derivative of histeloside having the R configuration at the new center of chirality,
C-1 (5b), with a small amount of an unidentified minor component (probably the 1S epimer 5a ). In a
slightly acidic medium, the reaction with histamine (2) gave two products in an approximately 6:4 ratio.
The main compound proved to be the normal, tetraacetylated derivative of the lactam histelosamide with
R configuration at C-1 (7b), and the minor product was the tetraacetylisohisteloside with S configuration
at the same C-1 center (3a ). When the reaction was carried out under acid-free conditions, in addition to
the epimeric pair of the normal tetraacetylated lactam (7a , 7b) and the tetraacetylisohisteloside with 1S
configuration (3a ), tetraacetylneohistelosamide (8b) was also isolated, in which the cyclization took place
at one of the cyclic nitrogens of the imidazole ring. Probably, this latter compound is an intermediate
also in the formation of the normal isomers, but under slightly acidic conditions it rapidly isomerized
into the normal alkaloid. The tendencies experienced previously in the tryptamine and dopamine series
were observed also in the histamine series; that is, at C-1, the R configuration is favored over the S one,
and lactamization is faster in the former than in the latter case. The structure of the products and their
stereoschemistry were established by NMR spectroscopy.
It is well known, from the pioneering work of A. R.
Battersby and his group, that secologanin (1) reacts with
tryptamine and dopamine, giving strictosidine and vinco-
side, or deacetylisoipecoside and deacetylipecoside, respec-
tively, which are parent compounds of the large class of
terpenoid indole and ipecac alkaloids.1,2 Recently, we
investigated the regio- and stereoselectivity of these reac-
tions in detail.3-6 It now seems reasonable to presume that
a similar reaction occurs between secologanin and the
biogenic amine histamine.
a nitrogen atom of the imidazole ring as an alternative site
for ring closure. Therefore, it would be expected to form
both “normal” derivatives, such as those of tryptamine
derivatives, and regioisomer “neo” compounds, in which
N-3′ of the histamine unit is common in the two rings.
Moreover, among dopamine derivatives, the reversibility
of the reaction was observed, whereas in the tryptamine
series this could not be demonstrated under similar reac-
tion conditions. Such questions prompted us to investigate
the reaction of secologanin with histamine (2) and its
N-benzyl derivative (2b).
A large number of alkaloids containing the imidazole
ring have been isolated, which are, however, very different
both in structure and in origin from the usual terpenoid
indole and isoquinoline alkaloids.7-9 These compounds were
found both in plant families (Cactaceae, Euphorbiaceae,
Orchidaceae, etc.) and in bacteria (e.g., Aspergillus species),
fungi (e.g., Streptomyces and Penicillium species), and
animal sources (mainly marine sponges). Many of these
alkaloids could be derived formally or biogenetically from
histidine or histamine. Some can even be supposed to form
from histamine in a Pictet-Spengler reaction with an
appropriate oxo compound (e.g., glochidine and glochidi-
cine,10,11 spinacine,12,13 and spinaceamine14). However,
products formed from secologanin and its derivatives have
not been isolated. Of course, the question arises as to what
is the reason for the absence of this type of alkaloid? Does
histamine not react with secologanin, or is one of these
reaction partners not available in plants containing the
other partner, or is the enzyme catalyzing the reaction
absent? Histamine has one active position for electrophilic
substitution at a carbon atom, and, in addition, it also has
Resu lts a n d Discu ssion
At first, the reactions were carried out in acetonitrile as
a dipolar aprotic solvent, with the secologanin (1) used
mainly in the form of its tetraacetyl derivative (1a ), and
histamine (2) and its benzyl derivative (2b) as the dihy-
drochloride salt. The histaminium salt was (partially)
deprotonated by triethylamine.15 With the benzyl deriva-
tive of histamine (2b), one main product, the tetraacetyl
derivative of N-benzylhisteloside (5b), could be isolated
from the reaction mixture together with about 10% of an
impurity, which could be eliminated by chromatography,
but was not obtained in sufficient quantity to establish its
structure. This impurity was probably the benzylated 1S
epimer (5a ). To assign the configuration of the new center
of chirality in the main product (5b), it was hydrogenated
in the presence of palladium-charcoal with elimination of
the benzyl and saturation of the vinyl group. Unfortu-
nately, during this experiment, the acetyl groups were
partially hydrolyzed, and to obtain a pure compound for
analysis, the deacetylation was completed by treatment
with methanolic sodium methanolate solution. Finally, the
intermediate 14,15-dihydrohistelosamide (7c) obtained in
this manner was reacetylated with the inclusion of an
additional acetyl group at N-6 (7d ). In this latter com-
pound, the R configuration of C-1 was established un-
† Part 10 in the series Chemistry of Secologanin. For Part 9, see ref 6.
Dedicated to Professor Andra´s Messmer on the occasion of his 80th
birthday.
* To whom correspondence should be addressed. Tel: 36 12 17 12 95.
E-mail: szalasz@szerves.sote.hu.
‡ Semmelweis University.
§ Chinoin Pharmaceutical and Chemical Works, Ltd.
10.1021/np010415d CCC: $22.00
© 2002 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/10/2002

650 J ournal of Natural Products, 2002, Vol. 65, No. 5
Beke et al.
Ta ble 2. Product Distribution in the Reactions in Percent
Ta ble 1. Chemical Shifts of Aromatic Protons in the Products
of the Reactionsa
compound
% in B
% in C
H-7
H-6
H-8
H3a
H3b
H4a
H4b
H7a
H7b
H8a
H8b
H5a
H5b
H6a
H6b
38
<2
<2
<2
<2
62
<2
<2
10(?)
90
30
<2
<2
<2
8
33
<2
29
7.58
7.53
7.51
6.72
7.42
7.49
a
<2
<2
Figures in italics were obtained in an acid-free medium (see
text).
a
In ppm, % ) relative amount of isomers formed in the
reaction, s ) singlet, d ) doublet. Reaction conditions in B: 2‚2HCl
or 2b‚2HCl, 1a , triethylamine, acetonitrile. Reaction conditions
for C: 2, 1a , isopropanol.
Ta ble 3. Relative Orientation of H-1 and H-11 to H-10ProR
and H-10ProSa
equivocally by the coupling constants involving the H-10
atoms. As mild reaction conditions were applied during the
lactamization and the subsequent transformations, no
epimerization was expected at C-1 during these reactions;
therefore it might be assumed that the configuration of C-1
was R also in the starting ester (5b).
a
The reaction of secologanin with histamine gave two
main products, approximately in a 6:4 ratio. The lactam
tetraacetylhistelosamide (7b) and the ester tetraacetyliso-
histeloside (3a ) were separated by column chromatography.
However, the formation of neo compounds could not be
demonstrated. It was suspected that the proton associated
with either triethylamine or one of the basic nitrogen atoms
of the histamine was responsible for this phenomenon, as
it is reported in the literature16 that the initially formed
neo compounds could easily be isomerized into the normal
derivative in the presence of acid.
Therefore, the reaction was repeated with histamine
base in 2-propanol, where the only proton source was the
weak acidity of the solvent. From the reaction, which was
stopped before completion, four coupled products could be
isolated: in the normal series, the tetraacetylhistelos-
amide (7b) and its C-1 epimer (7a ), tetraacetylsohistelo-
side (3a ), and the neo compound tetraacetylneohistelosa-
mide (8b). The reaction mixtures were separated by
repeated column chromatography into pure individual
components. Although the epimeric lactams 7a and 7b
could not be separated, the former could be obtained by
lactamization of 3a , and the latter by the direct coupling
reaction in the presence of the triethylammonium ion (see
above).
We also tried to obtain the nonlactamized neo deriva-
tives. Therefore, the coupling reaction was carried out with
secologanin and histamine base in aqueous solution with-
out any catalyst. Unfortunately, even under these condi-
tions, only the lactam of the neo R series, i.e., neohiste-
losamide (8c) could be separated from the reaction mixture.
The relative amounts of the components of the crude
product mixtures were estimated by the intensity of the
low-field protons in the 1H NMR spectrum of the histamine
subunit (Table 1) and expressed as the percentage of the
total amount of the products. The normal derivatives gave
one singlet, while the neo compound gave two singlets in
this region. Lactamization was followed by a decrease of
the intensity of the singlet of the methoxycarbonyl group
at about 3.5 ppm. Likewise, the presence of the vinyl and
benzyl groups was established from the appropriate proton
signals. Determination of the configuration of C-1 required
stereochemical analysis (see later).
ap and sc indicate antiperiplanar and synclinal positions of
the appropriate protons, respectively.
The chromatograms of the crude reaction mixtures
combined with NMR data provided the product distribution
of the coupling reactions (Table 2). The data supported the
conclusions drawn from data of the analogous reactions in
the tryptamine and dopamine series. In the reaction, the
1R epimer was favored over the 1S epimer, and its amount
increased in the benzylated compound. Likewise, com-
pounds of the R series lactamized faster than those of the
S series. It seems that in the formation of the regioisomers
the presence or absence of the proton is important. In the
presence of acid, in the form of ammonium ion, the
formation of only the 1S epimer normal ester (3a ) and the
1R epimer normal lactam (7b) could be detected.
Thus, the reacting components determined the construc-
1
tion of the products, and the appropriate H and 13C NMR
parameters corresponded well to the expected values, so
the main task was to establish the stereochemistry of the
products. In this respect the situation was clear for the
histelosamides. In both the R and the S series, rotation
around carbon-carbon bonds attached to C-10 defined nine
staggered conformations, which may be characterized by
the synclinal or antiperiplanar position of H-1 and H-11
to H-10proR and H-10proS (Table 3). However, by analogy
with the examples analyzed previously by our group,4-6 in
each series only two conformations have the side-chain
nitrogen and methoxycarbonyl group in appropriate posi-
tions for lactamization (R12 and R33, as well as S13 and
S31, respectively). In 7b, the large coupling constants of
H-1 and H-11 to the same H-10 proton define both the
configuration of C-1 and the conformation around C-10 to
be R12. The only remaining major stereochemical problem
was the conformation of the tetrahydropyridine ring. The
necessarily â-axial orientation of the H-1 proton in the
usual representation involves the negative conformation
of the tetrahydropyridine ring. This was further supported
by the high chemical shift of one of the H-3 protons which
was produced by the anisotropic effect of the lactam
carbonyl group. This effect may operate only if the ap-
propriate C-H bond is coplanar to it. Conformational
analysis indicated that only H-3R may take up this

Pictet-Spengler Type Reactions
J ournal of Natural Products, 2002, Vol. 65, No. 5 651
orientation and only in a negative conformation of the
tetrahydropyridine ring. According to our previously ap-
plied stereochemical notation system,4-6 the stereostruc-
ture of 7b was characterized by R12NN.
tion indicates the â orientation of the benzyl group. This
orientation is favorable because it involves the antiperipla-
nar orientation of the two sterically “bulky” ligands at C-1
and N-2.
1
The configuration of C-1 in the ester compound 3a was
established likewise after lactamization. Since this reaction
required an acid catalyst and a long reaction time, this
suggested a 1S configuration at the new center of chirality.
This was proved by the appearance of the “anomalous”
chemical shift of one of the methyl singlets of the acetyl
group at 1.76 ppm in the 1H NMR spectrum recorded in
CDCl3. The relatively high value of the coupling constant
3J 15,16 (8.0 Hz) indicated the positive conformation of the
dihydropyran ring in accordance with other unsubstituted,
nonlactam derivatives of the S series (strictosidine,3 tet-
raacetyl-N-deacetylisoipecoside5). It was further supported
by a NOESY cross-peak between H-17 and one of the
protons of C-10. The similar positive conformation of the
tetrahydropyridine ring was derived by the same reasoning
that applied to 5b: in its NOESY spectrum, a cross-peak
was observed between H-1 and the axial proton of C-3. This
fact indicated that there is a short distance between these
functionalities which requires their cis diaxial relationship.
As the configuration of C-1 was proved to be S, this means
that H-1 is in R orientation, according to the usual
representation. However, an axial orientation of this proton
is possible only in the positive conformation of the tetra-
hydropyridine ring. The large coupling constants of H-1 and
H-11 to the two different protons of C-10 is characteristic
only for S11P P and S22P P conformations around C-11.
However, the distinction between them is not easy in this
case, as they are the two most “strain-free” ones in which
the least steric interactions are expected. Nevertheless,
according to the measurements on a computer-generated
model, one would expect between H-1 and H-17 a through-
space distance shorter than 2.8 Å in S22P P , or longer than
4.8 Å in S11P P . As no cross-peak was observed in the
NOESY spectrum of 3a between the two protons in
question, one may conclude that S11P P is the favored
conformer around C-10. This conclusion was further sup-
ported by the fact that most of the relevant 1H and 13C
NMR parameters of 3a are very close to those of stricto-
sidine, which has the same stereochemical notation. In
strictosidine, the S11 conformation was proved by mea-
surement of heteronuclear coupling constants.3
The values of the analogous parameters in the H NMR
spectrum of the lactams 7c and 7d as well as of the neo
lactams 8b and 8c were very close to those observed in
that of 7b. Consequently, their stereochemistry corresponds
likewise to R12NN.
In the 1H NMR spectrum of the lactam 7a , only H-11
had a large coupling constant to one of the H-10 protons,
which corresponds to the conformation 31 of the S series.
Thus, in principle, this single value should be sufficient to
establish the main features of the stereochemistry of 7a
(except for the conformation of the tetrahydropyridine ring;
see below). Fortunately, in the same spectrum, the methyl
singlet of one of the acetyl groups was also observed with
a relatively low chemical shift (1.76 ppm). This “anomalous”
chemical shift is well known from the literature and was
observed herein, too, in all lactam derivatives of tetra-
acetylsecologanin and biogenic amines having the S con-
figuration at the new center of chirality (in the tryptamine
derivatives at ca. 1.20 ppm and in the dopamine derivatives
at ca. 1.55 ppm). The phenomenon was analyzed in detail
in our previous papers,4,5 as well as work by Aimi et al.,17
and is produced by the anisotropic effect of the aromatic
ring when the C-2′ acetoxy group is in close proximity to
it. This steric arrangement is possible only if the compound
has S31 stereochemistry, along with negative conformation
in the dihydropyran and tetrahydropyridine rings, as well
as a double σ-conjugated effect around the glucosidic
O-bridge. In 7a , the negative conformation of the tetra-
hydropyridine ring was confirmed by the high chemical
shift of the H-3â atom.
Of the histeloside derivatives, the 2-benzyl compound 5b
of the R series and the parent compound 3a of the S series
could be isolated in sufficient amounts and with good
purity. In these compounds, the rotation around C-10 is
not blocked by lactamization, and all nine conformations
in both series had to be considered during the structure
determination.
In 5b the configuration of C-1 was derived after lactam-
ization as described above. The conformation of the dihy-
dropyran ring is negative, according to the small value of
3
the coupling constant J 16,17. The similar negative confor-
The results presented in this paper prove that, like
tryptamine and dopamine and their derivatives, histamine
and its derivatives can and do react with secologanin and
afford analogous products under controlled chemical condi-
tions. However, as mentioned in the Introduction, such
products have not been isolated from natural sources to
date. Although other types of alkaloids derived from
histamine have been isolated from plants, they are found
only in species that belong to other plant families than the
species containing either secologanin or its reaction prod-
ucts with tryptamine or dopamine. The cause of this
observation is still unknown, but is certainly not due to
the inability of secologanin to react with histamine.
mation of the tetrahydropyridine ring was derived from the
existence of a ROESY (rotating frame Overhauser effect
spectroscopy) cross-peak between the axial H-3 proton and
one of the C-10 protons. This fact requires a cis diaxial
relation of H-3 and C-10. Having C-1 with R configuration,
H-1 has to have â and C-10 R orientation in the usual
representation. The R-axial orientation of C-10 could be
taken up only in the positive conformation of the tetra-
hydropyridine ring. Measurements of through-space inter-
atomic distances on computer-generated molecular models
supported this orientation. Finally, large coupling con-
stants of H-1 and H-11 to the two different H-10 hydrogens
indicated (R)11 and (R)22 as possible conformers around
C-10. The distinction between the two possibilities was
easy. In the ROESY spectrum, a strong cross-peak was
observed between H-1 and H-16, indicating their proximity.
Measurements on computer-generated models showed in
the R11NP structure a 1.88 Å distance, and in the R22NP
structure, a 4.72 Å distance. Thus, the complete stereo-
chemistry of 5b is characterized as R11NP . As the H-3â
and H-4â protons gave cross-peaks with both hydrogens
of the methylene group of the benzyl subunit, this observa-
Exp er im en ta l Section
Gen er a l Exp er im en ta l P r oced u r es. NMR spectra were
recorded on a Bruker AM-200 spectrometer at 200 MHz (1H)
and 50 MHz (13C) or on a Bruker DRX-400 spectrometer at
400 MHz (1H) and 100 MHz (13C). The COSY, NOESY, and
ROESY spectra were measured with the standard Bruker
pulse programs of the XWINNMR software. For phase-
sensitive NOESY spectra a 600 ms mixing time was used. The
ROESY spectra were measured using a 300 ms CW pulse

652 J ournal of Natural Products, 2002, Vol. 65, No. 5
Beke et al.
Ch a r t 1
attenuated to a power level corresponding to a 100 µs 90°
pulse. The selective TOCSY spectra were measured with an
improved DPFG sequence.18
The organic solutions were dried with anhydrous sodium
sulfate. Thin-layer chromatography (TLC) was carried out on
Si gel plates.
Secologanin (1) was isolated from Lonicera xylosteum L.
(Caprifoliaceae) according to a method elaborated in our
Institute.19
Nr-Ben zylh ista m in e Dih yd r och lor id e (2b‚2HCl). His-
tamine (2, 0.450 g, 4 mmol) and benzaldehyde (0.4 mL, 4
mmol) were heated in benzene (0.30 mL) at 80 °C for 15 min.
After evaporation of the solvent in vacuo, the residue was
dissolved in MeOH (4 mL), NaBH4 (0.16 g, 4.23 mmol) was
added, and the reaction mixture was stirred for 2 h at room
temperature. After evaporation of the solvent, the residue was
dissolved in water (5 mL), stirred for 30 min at room temper-
ature, and extracted with CHCl3 (3 × 10 mL). The combined

Pictet-Spengler Type Reactions
J ournal of Natural Products, 2002, Vol. 65, No. 5 653
organic phases were washed with water and dried, and the
solvent was evaporated. The residue was taken up in cold
MeOH and saturated with HCl. After crystallization (EtOH,
Et2O), NR-benzylhistamine dihydrochloride (2b‚2HCl) was
obtained as a white crystalline product (0.45 g, 41%, mp 222-
224 °C (lit.20 225-227 °C); anal. C 52.28%, H 6.12%, N 15.19%,
calcd for C12H17N3Cl2, C 52.57%, H 6.25%, N 15.33%).
charcoal (0.04 g) at room temperature for 30 min. After
filtration of the catalyst, the solvent was removed in vacuo,
and the residue was dissolved in CHCl3 (1.2 mL) and MeOH
(0.8 mL), and 1 M methanolic NaOCH3 (0.01 mL, 0.01 mmol)
was added. The reaction mixture was stirred at room temper-
ature for 4 h. After evaporation of the solvent, 14,15-dihydro-
histelosamide (7c) was obtained as a beige amorphous material
[0.046 g, 83%, Rf 0.20 in MeCOOEt-i-PrOH-H2O (8:2:1)];
anal. C 56.00%, H 6.61%, N 9.19%, calcd for C21H29N3O8, C
55.87%, H 6.47%, N 9.31%; IR (KBr) νmax 3600-3100, 1657,
Rea ction of O,O,O,O-Tetr a a cetylsecologa n in (1a ) w ith
NR-Ben zylh istam in e Dih ydr och lor ide (2b‚2HCl). NR-Benz-
ylhistamine dihydrochloride (2b‚2HCl, 0.054 g, 0.2 mmol) was
refluxed for 5 min in a mixture of acetonitrile (1.0 mL) and
triethylamine (0.056 mL, 0.4 mmol) until partial dissolution
occurred, then O,O,O,O-tetraacetylsecologanin (1a , 0.11 g, 0.2
mmol) was added, and the mixture was refluxed for 90 min.
After evaporation of the solvent, the residue gave one spot by
TLC in EtOAc-EtOH-H2O (120:10:8) (Rf 0.55). The crude
total product, after chromatography on silica gel (15 g) with
EtOAc-EtOH-H2O (120:10:8), afforded a beige amorphous
solid, which proved to be O′,O′,O′,O′-tetraacetyl-2-benzylhiste-
loside [5b, 0.102 g, 69%, Rf 0.48 in EtOAc-EtOH-H2O (120:
10:8)]; anal. C 59.89%, H 6.21%, N 5.58%, calcd for C37H45N3O13,
C 60.07%, H 6.13%, N 5.68%. IR (KBr) νmax 1758, 1709, 1223,
1
1586, 1073 cm-1; H NMR (CD3OD, 200 MHz) δ 7.60 (1H, s,
4
3
H-7), 7.37 (1H, d, J 11,13 ) 2.4 Hz, H-13), 5.62 (1H, d, J 16,17
)
2
3
3
1.7 Hz, H-17), 5.03 (1H, dt, J 3R,3â ) 11.6, J 3R,4R ) 2.8, J 3R,4â
3
) 2.8 Hz, H-3R), 4.68 (1H, d, J 1′,2′ ) 7.9 Hz, H-1′), 4.67 (1H,
dd, 3J 1,10S ) 12.3, 3J 1,10R ) 3.6 Hz, H-1), 3.92 (1H, dd, 2J 6′a,6′b
)
)
3
2
11.7, J 5′,6′b ) 1.1, H-6′b), 3.69 (1H, dd, J 6′a,6′b ) 11.7, J 5′,6′a
4.3, H-6′a), 3.45-3.1 (5H, m, H-2′, H-3′, H-4′, H-5′, H-11), 3.0-
2
2.6 (3H, m, H-3â, H-4R, H-4â), 2.48 (1H, dt, J 10S,10R ) 12.7,
3J 1,10R ) 3.6, J 10R,11 ) 3.6 Hz, H-10proR), 1.87 (1H, m, H-16),
3
3
3
1.41 (1H, td, J 10S,10R ) 12.7, J 1,10S ) 12.3, J 10S,11 ) 12.7 Hz,
H-10proS), 1.37 (1H, m, H-15a), 1.10 (1H, m, H-15b), 0.97 (1H,
t, J 14,15 ) 7.1 Hz, H-14); 13NMR (CD3OD, 50 MHz) δ 166.5
3
1037 cm-1
.
(C-18), 148.9 (C-13), 136.2 (C-7), 134.3a (C-9), 126.4a (C-5),
109.6 (C-12), 99.6b (C-1′), 96.4b (C-17), 78.3c (C-3′), 77.9c (C-
5′), 74.8 (C-2′), 71.6 (C-4′), 62.7 (C-6′), 55.4 (C-1), 40.6 (C-3),
39.9 (C-16), 32.1 (C-10), 28.2 (C-11), 22.9 (C-4), 18.9 (C-15),
12.5 (C-14) (a-crevised assignments are possible).
O′,O′,O′,O′-Tetr aacetyl-2-ben zylh isteloside (5b). 1H NMR
(CDCl3, 400 MHz) chemical shifts and coupling constants of
overlapping signals were determined from a series of 1D
TOCSY spectra measured by the selective excitation of the H-1,
H-4R, H-10proS, and H-15 atoms. Double primes denote the
atoms of the phenyl ring of the benzyl group: δ 7.56 (1H, s,
H-7), 7.4-7.2 (5H, m, H-2′′, H-3′′, H-4′′, H-5′′, H-6′′), 7.30 (1H,
d, 4J 11,13 ) 1.1 Hz, H-13), 5.48 (1H, ddd, 3J 14Z,15 ) 17.1, 3J 14E,15
P r ep a r a tion of N6,O′,O′,O′,O′-P en ta a cetyl-14,15-d ih y-
dr oh istelosam ide (7d). 14,15-Dihydrohistelosamide (7c, 0.273
g, 0.605 mmol) was stirred in a mixture of Ac2O (2.0 mL) and
pyridine (2 drops) at room temperature for 8 h. Then, ice-cold
H2O (20 mL) was added, and the mixture was further stirred
for 30 min. The reaction mixture was extracted with CHCl3
(3 × 20 mL), and the combined organic phase was washed with
aqueous 5% NaHCO3 solution (20 mL) and H2O (20 mL) and
dried, and the solvent was evaporated. The beige amorphous
solid residue proved to be N6,O′,O′,O′,O′-pentaacetyl-14,15-
dihydrohiselosamide (7d ) [0.280 g, 70%, Rf 0.80 in MeCOOEt-
i-PrOH-H2O (8:2:1)]; anal. C 55.98%, H 5.95%, N 6.24%, calcd
for C31H39N3O13, C 56.27%, H 5.94%, N 6.35%; IR (KBr) νmax
3
3
) 10.2, J 15,16 ) 9.3 Hz, H-15), 5.25 (1H, t, J 2′,3′ ) 3J 3′,4′ ) 9.4
3
3
Hz, H-3′), 5.19 (1H, t, J 3′,4′ ) J 4′,5′ ) 9.4 Hz, H-4′), 5.13 (1H,
d, 3J 16,17 ) 4.4 Hz, H-17), 5.10 (1H, dd, 3J 2′,3′ ) 9.4, 3J 1′,2′ ) 8.0
3
2
Hz, H-2’), 5.09 (1H, dd, J 14E,15 ) 10.2, J 14E,14Z ) 1.7 Hz,
H-14E), 4.86 (1H, d, 3J 1′,2′ ) 8.1 Hz, H-1′), 4.84 (1H, dd, 3J 14Z,15
) 17.2, 2J 14E,14Z ) 1.7 Hz, H-14Z), 4.31 (1H, dd, 2J 6′a,6′b ) 12.4,
3J 5′,6′a ) 4.1 Hz, H-6′a), 4.23 (1H, dd, J 6′a,6′b ) 12.4, J 5′,6′b
)
2
3
2
2.4 Hz, H-6’b), 3.76 (1H, d, J NCHa,NCHb ) 12.9 Hz, Ha-benzyl-
3
3
3
CH2), 3.76 (1H, ddd, J 4′,5′ ) 9.4, J 5′,6′a ) 4.1, J 5’,6’b ) 2.4 Hz
H-5′), 3.62 (3H, s, OCH3), 3.55 (1H, d, J NCHa,NCHb ) 12.9 Hz,
1755, 1659, 1225, 1039 cm-1
;
1H NMR (CDCl3, 400 MHz) δ
2
Hb-benzyl-CH2), 3.51 (1H, dd, J 1,10S ) 9.1, J 1,10R ) 6.1 Hz,
7.95 (1H, s, H-7), 7.37 (1H, d, 4J 11,13 ) 2.4 Hz, H-13), 5.38 (1H,
3
3
2
3
3
3
3
3
H-1), 3.31 (1H, ddd, J 3R,3â ) 14.2, J 3R,4â ) 11.7, J 3R,4R ) 4.5
d, J 16,17 ) 1.9 Hz, H-17), 5.24 (1H, t, J 2′,3′ ) 9.6, J 3′,4′ ) 9.6
3 3
2
3
Hz, H-3R), 3.10 (1H, dd, J 3R,3â ) 14.2, J 3â,4â ) 5.5 Hz, H-3â),
Hz, H-3′), 5.12 (1H, m, H-3R), 5.10 (1H, t, J 3′,4′ ) 9.6, J 4′,5′ )
3 3
3
3
3
2.97 (1H, dt, J 10R,11 ) 9.6, J 10S,11 ) J 11,16 ) 5.4, H-11), 2.89
9.6 Hz, H-4′), 5.01 (1H, dd, J 1′,2′ ) 8.1, J 2′,3′ ) 9.6 Hz, H-2′),
3 3
2
3
3
(1H, ddd, J 4R,4â ) 16.2, J 3R,4â ) 11.7, J 3â,4â ) 5.5 Hz, H-4â),
2.43 (1H, dd, 2J 4R,4â ) 16.2, 3J 3R,4R, ) 4.5, H-4R), 2.15 (1H, ddd,
2J 10R10S ) 14.5, 3J 10R,11 ) 9.6 Hz, 3J 1,10R ) 6.1, H-10proR), 2.12,
2.05, 2.04, 1.96 (each 3H, each s, CH3CO), 2.06 (1H, ddd, 3J 15,16
4.91 (1H, d, J 1′,2′ ) 8.1 Hz, H-1′), 4.61 (1H, dd, J 1,10S ) 11.3,
3J 1,10R ) 3.5 Hz, H-1), 4.32 (1H, dd, 3J 5′,6′a ) 4.5, 2J 6′a,6′b ) 12.6
Hz, H-6′a), 4.15 (1H, dd, 3J 5′,6′b ) 2.3, 2J 6′a,6′b ) 12.6 Hz, H-6′b),
3.77 (1H, ddd, 3J 4′,5′ ) 9.6 Hz, 3J 5′,6′a ) 4.5 Hz, 3J 5′,6′b ) 2.3 Hz,
3
3
2
3
3
) 9.3, J 11,16 ) 5.4, J 16,17 ) 4.4 Hz, H-16), 1.55 (1H, ddd,
H-5′), 3.06 (1H, ddt, J 4R,4â ) 16.7, J 3â,4â ) 4.4, J 3R,4â ) 2.0
Hz, H-4â), 2.96 (1H, m, H-4R), 2.92 (1H, m, H-11), 2.83 (1H,
3
3
2J 10R10S ) 14.5, J 1,10S ) 9.1, J 10S,11 ) 5.4 Hz, H-10proS);
ROESY cross-peaks (s, strong; m, medium; w, weak) H-1:
H-10proR w, H-10proS m, H-11 w, H-14Z w, H-15 w, H-16 s;
H-3R: H-3â s, H-4R s, H-4â m, H-10proR w, H-11 w; H-3â:
H-3R s, H-4R m, H-4â s, Ha-benzyl-CH2 m, Hb-benzyl-CH2 w;
H-4R: H-3R s, H-3â m, H-4â s; H-4â: H-3R m, H-3â s, H-4R s,
Ha-benzyl-CH2 w, Hb-benzyl-CH2 w; H-10proR: H-1 w, H-3R
w, H-10proS s, H-11 w, H-17 w; H-10proS: H-1 w, H-10proR
s, H-11 w, H-15 w; H-11: H-1 w, H-3R w, H-10proR w,
H-10proS w, H-16 s, H-19 w; H-14Z: H-1 w, H-14E s, H-15 s,
H-16 s; H-15: H-1 w, H-10proS w, H-14E s, H-14Z s, H-16 w;
H-16: H-1 s, H-11 s, H-14Z m, H-15 w; 13C NMR (CDCl3, 50
MHz) δ 170.7, 170.2, 169.5, 169.1 (each CH3CO), 167.5 (C-18),
150.6 (C-13), 133.4 (C-7), 139.7 (C-1′′), 133.1 (C-15), 129.9 (C-
3′′), 129.9 (C-5′′), 128.4 (C-2′′), 128.4 (C-6′′), 127.0 (C-4′′), 119.8
(C-14), 111.9 (C-12), 96.5a (C-17), 95.6a (C-1′), 72.6b (C-3′), 72.1b
(C-5′), 70.8 (C-2′), 68.3 (C-4′), 61.6 (C-6′), 56.9 (CH2-benzyl),
51.8 (C-1), 51.2 (OCH3), 43.9 (C-3), 42.0 (C-16), 33.1 (C-10),
26.2 (C-11), 20.7, 20.6, 20.6, 20.2 (each CH3CO), 18.9 (C-4);
C-5 and C-9 did not appear (a, brevised assignment is also
possible).
2
3
3
ddd, J 3R,3â ) 13, J 3â,4R ) 11.5, J 3â,4â ) 4.4 Hz, H-3â), 2.61
(3H, s, CH3CN-6), 2.49 (1H, dt, 2J 10S,10R ) 13.2, 3J 1,10R ) 3J 10R,11
) 3.5 Hz, H-10proR), 2.10, 2.03, 2.0, 1.95 (each 3H, s, CH3-
2
3
CO), 1.91 (1H, m, H-16), 1.42 (1H, td, J 10S,10R ) 13.2, J 10S,11
) 13.2, 3J 1,10S ) 11.3 Hz, H-10proS), 1.38 (1H, m, H-15a), 1.08
3
(1H, m, H-15b), 0.95 (1H, t, J 14,15 ) 7.3, H-14); selected
NOESY cross-peaks supporting the N-6 position of one of the
acetyl groups (s, strong; m, medium; w, weak): CH3CON-6,
H-4 w, H-7s; 13C NMR (CDCl3, 50 MHz) δ 170.8, 169.7, 169.6,
169.6 (each CH3CO), 167.5 (CH3CON), 163.7 (C-18), 146.9 (C-
13), 139.8a (C-9), 136.8 (C-7), 125.2a (C-5), 109.0 (C-12), 96.2b
(C-1’), 95.5b (C-17), 72.6c (C-5’), 72.3c (C-3’), 70.7 (C-2’), 68.5
(C-4’), 62.0 (C-6’), 54.1 (C-1), 38.6 (C-3), 38.1 (C-16), 30.1 (C-
10), 27.4 (C-11), 23.9 (C-4), 23.7 (CH3CON), 20.9, 20.8, 20.8,
20.8 (each CH3CO), 17.8 (C-15), 12.1 (C-14) (a-crevised assign-
ments are possible).
Rea ction of O,O,O,O-Tetr a a cetylsecologa n in (1a ) w ith
Hista m in e Dih yd r och lor id e (2‚2HCl). Histamine dihydro-
chloride (2‚2HCl) (0.184 g, 0.1 mmol) was stirred in a mixture
of acetonitrile (5 mL) and triethylamine (0.28 mL, 2 mmol) at
70 °C until partial dissolution occurred, then O,O,O,O-tet-
raacetylsecologanin (1a , 0.557 g, 1 mmol) was added, and the
reaction mixture was further stirred for 5 h at 70 °C. After
evaporation of the solvent, the residue gave on TLC in EtOAc-
P r ep a r a tion of 14,15-Dih yd r oh istelosa m id e (7c). O′,O′,-
O′,O′-Tetraacetyl-2-benzylhisteloside (5b, 0.091 g, 0.123 mmol)
was dissolved in a mixture of MeOH (8 mL) and glacial acetic
acid (0.1 mL) and hydrogenated in the presence of 10% Pd on

654 J ournal of Natural Products, 2002, Vol. 65, No. 5
Beke et al.
i-PrOH-H2O (8:2:1) the following spots: 0.91 (unreacted 1a ),
0.45 (7b), 0.10 (3a ). The crude total product was chromato-
graphed on silica gel (0.04-0.063; 40 g), with EtOAc-i-PrOH-
H2O (8:2:1) (each fraction 7 mL). After removal of the solvent,
fractions 4-5 gave the starting material 1a (0.110 g), fractions
8-17 7b (0.246 g, 49.6% based on 1a consumed), and fractions
20-27 3a (0.160 g, 30.8%, based on 1a consumed).
0.90 (unreacted 1a ), 0.46 (7a and 7b), 0.38 (8b), 0.04 (3a ). The
crude total product was chromatographed on silica gel (0.04-
0.063; 85 g) with CHCl3-EtOH (10:1) and (after fraction 50)
CHCl3- i-PrOH-MeOH-H2O (9:3:4:1) (each fraction 8 mL).
After removal of the solvent, the combined fractions 6-16 gave
the starting material 1a (0.550 g), fractions 20-29 8b (0.185
g, 27.8% based on 1a consumed), and fractions 31-50 a
mixture of 7b and 7a in an approximately 4:1 ratio (0.264 g,
39.9% based on 1a consumed), which could not be separated.
Fractions 58-66 treated likewise gave 3a (0.205 g, 29.2%
based on 1a consumed).
O′,O′,O′,O′-Tetr aacetylisoh isteloside (3a): anal. C 55.20%,
H 6.15%, N 6.37%, calcd for C30H39N3O13, C 55.47%, H 6.05%,
N 6.47%; spectroscopic data, see above.
O′,O′,O′,O′-Tetr a a cetylh ystelosa m id e (7b) a n d O′,O′,-
O′,O′-tetr a a cetylisoh ystelosa m id e (7a ): beige amorphous
solid [Rf 0.25 in CHCl3-EtOH (10:1)]; IR (KBr) νmax 1757, 1662,
1606, 1226, 1064, 1035 cm-1; 1H NMR (C6D6, 200 MHz) δ major
(7b) 7.73 (1H, s, H-7), 7.31 (1H, d, 4J 11,13 ) 2.4 Hz, H-13), 5.50-
4.75 (9H, m, H-1′, H-2′, H-3′, H-4′, H-15, H-17, H-3R, H-14Z,
H-14E), 4.57 (1H, dd, 3J 1,10S ) 11.7, 3J 1,10R ) 4.4 Hz, H-1), 4.28
O′,O′,O′,O′-Tetr a a cetylisoh istelosid e (3a ): beige amor-
phous solid (Rf 0.66 in CHCl3-i-PrOH-MeOH-H2O (9:3:4:
1)); anal. C 55.34%, H 6.05%, N 6.47%, calcd for C30H39N3O13
,
C 55.47%, H 6.05%, N 6.47%; IR (KBr) νmax 1755, 1226, 1038
1
cm-1; H NMR (CD3OD, 400 MHz) δ 7.64 (1H, s, H-13), 7.58
3
(1H, s, H-7), 5.75 (1H, ddd J 14Z,15 ) 17.3, 3J 14E,15 ) 10.6, 3J 15,16
3
) 8.0 Hz, H-15), 5.54 (1H, d, J 16,17 ) 8.0 Hz, H-17), 5.33 (1H,
dd, 3J 14Z,15 ) 17.3, 2J 14E,14Z ) 1.4 Hz, H-14Z), 5.31 (1H, t, 3J 2′,3′
) 3J 3′,4′ ) 9.5 Hz, H-3′), 5.28 (1H, dd, 3J 14E,15 ) 10.6, 2J 14E,14Z
)
3
1.4 Hz, H-14E), 5.13 (1H, d, J 1′,2′ ) 8.1 Hz, H-1′), 5.05 (1H, t,
3J 3′,4′ ) 3J 4′,5′ ) 9.5 Hz, H-4′), 4.91 (1H, dd, 3J 2′,3′ ) 9.5, 3J 1′,2′
)
2
3
8.1 Hz, H-2′), 4.32 (1H, J 6′a,6′b ) 12.4, J 5′,6′a ) 4.5 Hz, H-6′a),
2
3
4.17 (1H, J 6′a,6′b ) 12.4, J 5′,6′b ) 2.5 Hz, H-6′b), 4.13 (1H, dd,
3J 1,10R ) 10, J 1,10S ) 3.2 Hz, H-1), 3.96 (1H, ddd, J 4′,5′ ) 9.5,
3
3
3J 5′,6′a ) 4.5, J 5′,6′b ) 2.5 Hz H-5′), 3.75 (3H, s, OCH3), 3.45
(1H, dd, J 6′a,6′b ) 12.4, J 5′,6′a ) 4.4 Hz, H-6′a), 4.06 (1H, dd,
3 3
3
2
3
2
3
(1H, dt, J 3R,3â ) 12.7, J 3â,4â
)
3J 3â,4R ) 5.4 Hz, H-3â), 3.17
2J 6′a,6′b ) 12.4, J 5′,6′b ) 2.4 Hz, H-6′b), 3.42 (ddd, J 4′,5′ ) 9.8,
3J 5′,6′a ) 4.4, 3J 5′,6′b ) 2.4 Hz, H-5′), 3.1-2.2 (6H, m, H-3â, H-4R,
H-4â, H-11, H-16, H-10proR), 1.97, 1.74, 1.74, 1.73 (each 3H,
s, CH3CO), 1.43 (1H, td, J 10S,10R ) 13.4, J 10S,11 ) 13.4, J 1,10S
) 11.7 Hz, H-10proS); minor (7a) 7.61 (1H, d, 4J 11,13 ) 2.4 Hz,
H-13), 7.36 (1H, s, H-7); selected signals from the 1H NMR
spectrum measured in CDCl3 (200 MHz) δ major (7b) 7.51 (1H,
2
3
3
(1H, ddd, J 3R,3â ) 12.7, J 3R,4â ) 8.2, J 3R,4R ) 5.4 Hz H-3R),
2.97 (1H, dt, J 10S,11 ) 10.8, J 10R,11 ) 3J 11,16 ) 4.8, H-11), 2.87
3
3
2
3
3
2
3
3
(1H, m, H-4â), 2.77 (1H, dt, J 4R,4â ) 15.6, J 3R,4R ) J 3â,4R
)
3
3
3
5.4 Hz, H-4R), 2.65 (1H, td, J 15,16 ) J 16,17 ) 8.0, J 11,16 ) 4.8
Hz, H-16), 2.14 (1H, ddd, 2J 10R,10S ) 14.3, 3J 10S,11 ) 10.8, J 1,10S
3
) 3.2 Hz, H-10proS) 2.03, 2.02, 2.00, 1.97 (each 3H, each s,
CH3COO), 1.96 (1H, overlap, H-10proR); NOESY cross-peaks
(in CD3OD; s, strong; m, medium; w, weak) H-1: H-3R w,
H-10proS m, H-11 w; H-3R: H-1 w, H-3â s, H-4R m; H-3â:
H-3R s, H-4â m, H-4R w; H-4R: H-3R m, H-3â w, H-4â s;
H-4â: H-3â m, H-4R s; H-10proR: H-10proS s, H-11 w, H-15
w; H-10proS: H-1 m, H-10proR s, H-17 s; H-11: H-1 w,
H-10proR w, H-16 s; H-13: OCH3 w; H-14Z: H-14E s, H-15
w, H-16 m; H-14E: H-14Z s, H-15 s; H-15: H-15proR w, H-14E
s, H-14Z w, H-16 w, H-17 w; H-16: H-11 s, H-14Z: m, H-15
w, H-17 m; H-17: H-10proS m, H-15 w, H-16m, H-1′ m; 13C
NMR (CD3OD, 50 MHz) δ 170.7, 170.2, 169.4, 169.4 (each
CH3CO), 168.4 (C-18), 152.9 (C-13), 133.7a (C-7), 133.2a (C-
15), 119.7 (C-14), 110.1 (C-12), 97.0b (C-17), 96.9b (C-1′), 72.5c
(C-5′), 72.1c (C-3′), 70.9 (C-2′), 68.1 (C-4′), 61.6 (C-6′), 51.7
(OCH3), 51.4 (C-1), 43.9 (C-16), 42.0 (C-3), 35.0 (C-10), 30.4
(C-11), 22.9 (C-4), 20.7, 20.6, 20.6, 20.6 (each CH3CO); C-5 and
C-9 did not appear (a-crevised assignments are possible).
O′,O′,O′,O′-Tetr a a cetylh istelosa m id e (7b): beige amor-
phous solid [Rf 0.51 in MeCOOEt-i-PrOH-H2O (8:2:1)]; anal.
C 56.12%, H 5.81%, N 6.65%, calcd for C29H35N3O12, C 56.39%,
4
s, H-7), 7.43 (1H, d, J 11,13 ) 2.2 Hz, H-13), 2.10, 2.04, 2.02,
1.97 (each 3H, s, CH3CO); minor (7a) 7.53 (1H, s, H-7), 7.35
4
(1H, d, J 11,13 ) 2.2 Hz, H-13), 2.09, 2.01, 1.93, 1.69 (each 3H,
s, CH3CO); 13C NMR (CDCl3, 50 MHz) δ major (7b), see above.
O′,O′,O′,O′-Tet r a a cet yln eoh ist elosa m id e (8b ): white
amorphous solid [Rf 0.40 in CHCl3-EtOH (10:1)]; anal. C
56.59%, H 5.91%, N 6.73%, calcd for C29H35N3O12, C 56.39%,
H 5.71%, N 6.80%; IR (KBr) νmax 1756, 1667, 1616, 1228, 1065,
1036 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 7.42 (1H, s, H-8),
4
7.38 (1H, d, J 11,13 ) 2.3, H-13), 6.72 (1H, s, H-6), 5.67 (1H,
dd, 3J 1,10S ) 10.2, 3J 1,10R ) 4.2 Hz, H-1), 5.50 (1H, dt, 3J 14Z,15
)
3
3
17.0, J 14E,15 ) 9.1, J 15,16 ) 9.1 Hz, H-15), 5.40-4.90 (6H, m,
H-1′, H-2′, H-3′, H-4′, H-14Z, H-14E), 5.33 (1H, d, 3J 16,17 ) 1.9
2
Hz, H-17), 4.84 (1H, m, H-3R), 4.32 (1H, dd, J 6′a,6′b ) 12.5,
3J 5′,6′b ) 2.2 Hz, H-6′b), 4.14 (1H, dd, J 6′a,6′b ) 12.5, J 5′,6a
)
2
3
3
3
4.5 Hz, H-6′a), 3.81 (1H, ddd, J 4’,5′ ) 9.8 Hz, J 5′,6′a ) 4.5 Hz,
3J 5′,6′b ) 2.2 Hz, H-5′), 3.07-2.69 (5H, m, H-3â, H-4R, H-4â,
H-11, H-16), 2.55 (1H, dt, 2J 10S,10R ) 12.8, 3J 1,10R ) 4.2, 3J 10R,11
) 4.2 Hz, H-10proR), 2.11, 2.04, 2.01, 1.95 (each 3H, s, CH3-
2
3
3
CO), 1.65 (1H, td, J 10S,10R ) J 10S,11 ) 12.8, J 1,10S ) 10.2 Hz,
H-10proS); 13C NMR (CDCl3, 50 MHz) δ 170.3, 169.7, 169.3,
169.2 (each CH3CO), 162.2 (C-18), 147.4 (C-13), 131.8 (C-15),
130.9 (C-8), 126.1 (C-5), 124.2 (C-6), 121.2 (C-14), 107.2 (C-
12), 96.9a (C-17), 95.8a (C-1′), 72.0 (C-5′, C-3′), 70.3 (C-2′), 67.9
(C-4′), 66.8 (C-1), 61.5 (C-6′), 42.3 (C-16), 37.9 (C-3), 32.0 (C-
10), 23.8 (C-11), 20.7 (C-4), 20.5, 20.3, 20.3, 20.3 (each CH3-
CO) (arevised assignment is also possible).
H 5.71%, N 6.80%; IR (KBr) νmax 1755, 1662, 1226, 1065 cm-1
1H NMR (CDCl3, 200 MHz) δ 7.51 (1H, s, H-7), 7.43 (1H, d,
;
3
3
4J 11,13 ) 2.4 Hz, H-13), 5.42 (1H, dt, J 14Z,15 ) 17.2, J 14E,15
)
9.6, 3J 15,16 ) 9.6 Hz, H-15), 5.27 (1H, d, 3J 16,17 ) 1.9 Hz, H-17),
5.3-4.9 (7H, m, H-1′, H-2′, H-3′, H-4′, H-3R, H-14Z, H-14E),
3
3
4.65 (1H, dd, J 1,10S ) 11.7, J 1,10R ) 3.8 Hz, H-1), 4.31 (1H,
dd, 2J 6′a,6′b ) 12.3, 3J 5′,6′a ) 4.4 Hz, H-6′a), 4.14 (1H, dd, 2J 6′a,6′b
3
3
3
) 12.3, J 5′,6′b ) 2.2 Hz, H-6′b), 3.76 (ddd, J 4′,5′ ) 9.8, J 5′,6′a
)
P r ep a r a t ion of O′,O′,O′,O′-Tet r a a cet ylisoh ist elosa -
m id e (7a ). O′,O′,O′,O′-Tetraacetylisohisteloside (3a , 0.074 g,
0.12 mmol) was dissolved in acetonitrile (4.0 mL). Triethy-
lamine (0.017 mL, 0.12 mmol) and triethylamine HCl (0.017
g, 0.12 mmol) were added and refluxed for 18 h. After
evaporation in vacuo, the residue was chromatographied on
silica gel (0.04-0.063, 10 g) with EtOAc-EtOH-H2O (120:
10:8) (each fraction 7 mL). The combined fractions 7-12 (each
5 mL) after removal of the solvent gave O′,O′,O′,O′-tetraacetyl-
isohistelosamide as a beige amorphous solid [7a , 0.050 g, 67%,
Rf 0.26 in MeCOOEt-EtOH-H2O (120:10:8)]; anal. C 56.64%,
H 5.86%, N 6.92%, calcd for C29H35N3O12, C 56.39%, H 5.71%,
N 6.80%; 1H NMR (C6D6, 70 °C, 400 MHz) (chemical shift and
coupling constants of H-10proS were determined from the 1D
TOCSY spectrum measured by the selective excitation of H-1)
4.4, 3J 5′,6′b ) 2.2 Hz, H-5′), 3.0-2.6 (3H, m, H-3â, H-4R, H-11),
2.69 (1H, ddd, 3J 15,16 ) 9.6, 3J 11,16 ) 5.9, 3J 16,17 ) 1.9 Hz, H-16),
2
3
2.60 (1H, m, H-4â), 2.45 (1H, dt, J 10S,10R ) 13.4, J 1,10R
)
3J 10R,11 ) 3.8 Hz, H-10proR), 2.10, 2.04, 2.01, 1.97 (each 3H, s,
2
3
3
CH3CO), 1.36 (1H, td, J 10S,10R ) 13.4, J 10S,11 ) 13.4, J 1,10S
)
11.7 Hz, H-10proS); 13C NMR (CDCl3, 50 MHz) δ 170.9, 170.3,
169.8, 169.7 (each CH3CO), 163.7 (C-18), 146.9 (C-13), 134.6
(C-7), 131.9 (C-15), 120.8 (C-14), 109.0 (C-12), 96.5a (C-17),
96.2a (C-1′), 72.6b (C-5′), 72.4b (C-3′), 70.7 (C-2′), 68.4 (C-4′),
61.9 (C-6′), 54.3 (C-1), 42.8 (C-16), 39.2 (C-3), 31.2 (C-10), 26.3
(C-11), 22.0 (C-4), 20.9, 20.9, 20.8, 20.8 (each CH3CO); C-5 and
C-9 did not appear (a,brevised assignments are possible).
Alter n a tive Rea ction of O,O,O,O-Tetr a a cetylsecolo-
ga n in (1a ) w ith Hista m in e (2). Histamine (2, 0.230 g, 2.07
mmol) and O,O,O,O-tetraacetylsecologanin (1a , 1.15 g, 2.07
mmol) were dissolved in 2-propanol (5 mL) and stirred at 70
°C for 4.5 h. After evaporation of the solvent, the residue gave
on TLC in EtOAc-i-PrOH-H2O (8:2:1) the following spots:
4
δ 7.62 (1H, d, J 11,13 ) 2.4 Hz, H-13), 7.11 (1H, s, H-7), 5.49
3
3
(1H, dt, J 14Z,15 ) 17.1, J 14E,15 ) 3J 15,16 ) 10.1 Hz, H-15), 5.31
3
3
3
(1H, t, J 2′,3′ ) J 3′,4′ ) 9.5 Hz, H-3′), 5.18 (1H, d, J 16,17 ) 2.0
Hz, H-17), 5.15 (1H, t, J 3′,4′ ) 3J 4′,5′ ) 9.5 Hz, H-4′), 5.06 (1H,
3

Pictet-Spengler Type Reactions
J ournal of Natural Products, 2002, Vol. 65, No. 5 655
3
3
2
dd, J 2′,3′ ) 9.5, J 1′,2′ ) 8.0 Hz, H-2′), 5.05 (1H, dd, J 3R,3â
)
(C-5), 124.3 (C-6), 121.1 (C-14), 108.4 (C-12), 99.9a (C-1′), 97.7a
(C-17), 78.4b (C-5′), 78.1b (C-3′), 74.9 (C-2′), 71,7 (C-4′), 68.7
(C-1), 62.8 (C-6′), 44.2 (C-16), 39.6 (C-3), 33.4 (C-10), 25.3
(C-11), 21.7 (C-4) (a,brevised assignments are possible).
3
3
12.7, J 3â,4â ) 5.8 Hz, H-3â), 4.99 (1H, dd, J 14E,15 ) 10.1,
J 14E,14Z ) 2.0 Hz, H-14E), 4.91 (1H, dd, 3J 14Z,15 ) 17.1, J 14E,14Z
2
2
3
) 2.0 Hz, H-14Z), 4,70 (1H, d, J 1′,2′ ) 8.0 Hz, H-1′), 4.43 (1H,
dd, 3J 1,10S ) 6.0, 3J 1,10R ) 2.4, Hz, H-1), 4.20 (1H, 2J 6’a,6′b ) 12.4,
3J 5′,6′a ) 4.5 Hz, H-6′a), 3.98 (1H, J 6′a,6′b ) 12.4, J 5′,6′b ) 2.4
2
3
Ack n ow led gm en t. Financial support of this work by the
National Scientific Research Foundation, Budapest, Hungary,
is gratefully acknowledged.
3
3
3
Hz, H-6′b), 3.20 (1H, ddd, J 4′,5′ ) 9.5, J 5′,6′a ) 4.5, J 5′,6′b
)
2.4 Hz H-5′), 2.83-2.68 (2H, m, H-4â, H-11), 2.58 (1H, ddd,
J 10R,10S ) 13.5, 3J 10R,11 ) 4.7, 3J 1,10R ) 2.4 Hz, H-10proR), 2.50
2
2
3
3
Refer en ces a n d Notes
(1H, ddd, J 3R,3â ) 12.7, J 3R,4â ) 11.7, J 3R,4R ) 4.7 Hz, H-3R),
2.32 (1H, ddd, 3J 15,16 ) 10.1, 3J 11,16 ) 6.2, J 16,17 ) 2.0 Hz, H-16),
(1) Battersby, A. R.; Burnett, A. R.; Parsons, P. G. J . J . Chem. Soc. 1969,
1193-1200.
(2) Battersby, A. R.; Burnett, A. R.; Parsons, P. G. J . J . Chem. Soc. 1969,
1187-1192.
(3) Patthy-Luka´ts, AÄ .; Ka´rolyha´zy, L.; Szabo´, L. F.; Poda´nyi, B. J . Nat.
Prod. 1997, 60, 69-75 (Part 2 in the series Chemistry of Secologanin).
(4) Patthy-Luka´ts, AÄ .; Kocsis, AÄ .; Szabo´, L. F.; Poda´nyi, B. J . Nat. Prod.
1999, 62, 1492-1499 (Part 6 in the series Chemistry of Secologanin).
(5) Beke, Gy.; Szabo´, L. F.; Poda´nyi, P. J . Nat. Prod. 2001, 64, 332-340
(Part 8 in the series Chemistry of Secologanin).
2
3
1.93 (1H, dd, J 4R,4â ) 15.4, J 3R,4R ) 4.7 Hz, H-4R), 1.82, 1.72,
1.71, 1.70 (each 3H, s, CH3CO), 1.73 (1H, td, 2J 10R,10S ) 3J 10S,11
3
) 13.5, J 1,10S ) 6.0 Hz, H-10proS); selected signals from the
1H NMR spectrum measured in CDCl3 (200 MHz) δ 7.58 (1H,
4
s, H-7), 7.34 (1H, d, J 11,13 ) 1.7 Hz, H-13) 2.09, 2.01, 1.96,
1.76 (each 3H, s, CH3CO); NOESY cross-peaks (in C6D6) H-1:
H-3R m, H-3â w, H-11 w, H-10proR m, H-10proS s; H-3R: H-1
m, H-3â s, H-3â: H-1 w, H-3â s; H-4R: H-4â m; H-10proR:
H-1 w, H-10proS m, H-11 w, H-16 w; 13C NMR (C6D6, 100
MHz) δ 170.7, 170.5, 169.8, 169.7 each s (CH3CO), 165.3 (C-
18), 147.0 (C-13), 134.6 (C-9), 133.6 (C-15), 120.7 (C-14), 111.3
(C-16), 96.8, 96.6 (C-17, C-1′), 73.6, 73.0 (C-3′, C-5′), 71.6 (C-
2′), 69.1 (C-4′), 62.1 (C-6′), 55.3 (C-1), 43.5 (C-3, C-16), 26.6
(C-10), 24.9 (C-11), 22.6 (C-4), 20.9, 20.8 (each CH3CO).
P r ep a r a tion of Neoh istelosa m id e (8c). Histamine (0.167
g, 1.5 mmol) and secologanin (0.583 g, 1.5 mmol) were
dissolved in water (3 mL), and the mixture was heated at 60
°C for 150 min. After evaporation of the solvent, the residue
gave on TLC in CHCl3-i-PrOH-MeOH-H2O (9:3:4:1) the
following spots: 0.80 (unreacted 1a ), 0.37 (8c). The crude total
product was flash chromatographed on silica gel (30 g, each
fraction 10 mL) with CHCl3-i-PrOH-MeOH-H2O (9:3:4:1).
After removal of the solvent, fractions 11 and 12 gave the
starting material 1a (0.04 g), and fractions 14-21 gave
neohistelosamide 8c [beige amorphous solid, 0.426 g, 68%
based on 1a consumed; Rf 0.36 in CHCl3-i-PrOH-MeOH-
H2O (9:3:4:1)]; anal. C 55.95%, H 6.17%, N 9.19%, calcd for
(6) Patthy-Luka´ts, AÄ .; Beke, Gy.; Szabo´, L. F.; Poda´nyi, B. J . Nat. Prod.
2001, 64, 1032-1039.
(7) Battersby, A. R.; Openshaw, H. T. In The Alkaloids; Manske, R. H.
F., Holmes, H. L., Eds.; Academic Press: New York, 1953; Vol. 3, pp
201-246.
(8) Maat, L.; Beyerman, H. C. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1983; Vol. 22, pp 281-333.
(9) Lewis, J . R. Nat Prod. Rep. 2001, 18, 95-128, and previous reviews
in this series.
(10) J ohns, S. R.; Lamberton, J . J . Chem. Soc., Chem. Commun. 1966,
312-313.
(11) J ohns, S. R.; Lamberton, J . Aust. J . Chem. 1967, 20, 555-560.
(12) Ackermann, D.; Mohr, M. Z. Biol. (Munich) 1937, 98, 37-42.
(13) Ackermann, D. Hoppe-Seyler’s Z. Physiol. Chem. 1962, 328, 275-
276.
(14) Erspamer, V.; Vitali, T.; Roseghini, M.; Cei, J . M. Experientia 1963,
19, 346-347.
(15) Histamine derivatives of secologanin are unknown from plant sources
and therefore may not be considered as natural products. However,
for the sake of simplicity, alkaloid-like names are used for the
compounds described in this paper, i.e., the parent name histeloside
for the tricyclic esters and the name histelosamide for the lactams.
In the formulas, a numbering system analogous to the ipecoside
derivatives5 was applied. In accordance with our previous papers,4
in the descriptions of the stereogenic elements, the letters R and S
are used for the configuration of the new chiral center C-1, the
numbers 11, 12, etc. for the rotation pattern around the methylene
bridge, the letters N and P for the negative and positive conformation
of the dihydropyran and tetrahydroyridine rings, and the letters A
and E for the axial and equatorial position of the eventual benzyl
group, respectively.
C
21H27N3O8, C 56.12%, H 6.06%, N 9.35%; IR (KBr) νmax 3700-
3100, 1659, 1074 cm-1; 1H NMR (CDCl3, 200 MHz) δ 7.76 (1H,
4
s, H-8), 7.47 (1H, d, J 11,13 ) 2.3 Hz, H-13), 6.76 (1H, s, H-6),
3
3
5.78 (1H, dd, J 1,10S ) 10.6, J 1,10R ) 4.2 Hz, H-1), 5.54 (1H, d,
3J 16,17 ) 1.8 Hz, H-17), 5.57 (1H, dt, J 14Z,15 ) 17.2, J 14E,15
)
3
3
(16) Lee, Y. S.; Kim, S. H.; J ung, S. H.; Lee, S. J .; Park, H. Heterocycles
1994, 37, 303-209.
3
3
9.8, J 15,16 ) 9.8 Hz, H-15), 5.54 (1H, d, J 16,17 ) 2 Hz, H-17),
2
3
5.35 (1H, dd, J 14Z,14R ) 2.2, J 14Z,15 ) 17.2 Hz, H-14Z), 5.27
(1H, dd, 2J 14Z,14E ) 2.2, 3J 14E,15 ) 9.8 Hz, H-14E), 4.72 (1H, ddd,
2J 3R,3â ) ∼12, 3J 3R,4R ) 4,7, 3J 3R,4â ) 3.3 Hz, H-3R), 4,69 (1H, d,
3J 1′,2′ ) 7.8, H-1′), 3.90 (1H, dd, 2J 6′a,6′b ) 11.9, 3J 5′,6′b ) 1.5 Hz,
(17) Takayama, H.; Ohmori, O.; Subhadhirasakul, S.; Kitajima, M.; Aimi,
N. Chem. Pharm. Bull. 1997, 45, 1231-1233.
(18) Ko¨ve´r, K. E.; Uhrin, D.; Hruby, V. J . J . Magn. Reson. 1998, 130, 162-
168.
(19) Dabi-Lengyel E.; Kocsis, AÄ .; Bo¨jthe-Horva´th, K.; Szabo´, L.; Ma´the´,
I.; Te´te´nyi, P.; Za´mbo´, I.; Varga-Bala´zs, M. Hung. Teljes HU 28, 415,
28 Dec 1983; Chem. Abstr. 1984, 100, 180105.
(20) Emmet, J . C.; Durant, G. J .; Ganellin, C. R.; Roe, A. M.; Turner, J .
L. J . Med. Chem. 1982, 25, 1168-1174.
2
3
H-6′b), 3.67 (1H, dd, J 6′a,6′b ) 11.9, J 5′,6a ) 5.4 Hz, H-6′a),
3.45-2.7 (10H, m, H-2′,-3′,-4′,-5′, H-3â, H-4R, H-4â, H-10R,
H-11, H-16), 1.65 (1H, ddd, J 10S,10R ) 13.5, J 10S,11 ) 12.6,
3J 1,10S ) 10.6 Hz, H-10proS); 13C NMR (CD3OD, 50 MHz) δ
165.5 (C-18), 149.9 (C-13), 133.9 (C-8), 133.4 (C-15), 128.2
2
3
NP010415D