Synthesis of active principles from the leaves of Moringa oleifera using S-pent-4-enyl thioglycosides

Article abstract of DOI:10.1016/S0008-6215(98)00223-7

α-l-Rhamnosides of 4-hydroxy-benzyl compounds with nitrile, carbamate, and thiocarbamate groups occurring in Moringa oleifera leaf extracts and the α-l-rhamnoside of anisaldehyde derivatives were synthesised. Electrophilic activation of S-pent-4-enyl thiorhamnosides was applied for the construction of glycosidic linkages. Copyright (C) 1997 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(98)00223-7

Carbohydrate Research 312 (1998) 33±44
Synthesis of active principles from the leaves of
Moringa oleifera using S-pent-4-enyl
thioglycosides
Michael Leuck, Horst Kunz *
Institut fur Organische Chemie, Johannes Gutenberg-Universitat Mainz, Johann-Joachim-Becher-Weg
È
È
18-20, D-55128 Mainz, Germany
Received 8 April 1998; accepted 27 July 1998
Abstract
ꢀ-l-Rhamnosides of 4-hydroxy-benzyl compounds with nitrile, carbamate, and thiocarbamate
groups occurring in Moringa oleifera leaf extracts and the ꢀ-l-rhamnoside of anisaldehyde deri-
vatives were synthesised. Electrophilic activation of S-pent-4-enyl thiorhamnosides was applied for
the construction of glycosidic linkages. # 1998 Elsevier Science Ltd. All rights reserved
Keywords: Aryl rhamnopyranosides; Moringa oleifera Lam.; S-Pent-4-enyl thioglycosides; O-Glycosides of 4-
hydroxy-benzyl carbamates,-thiocarbamates
1. Introduction
of 4-(ꢀ-l-rhamnopyranosyloxy)-benzyl compounds
containing isothiocyanate, nitrile, carbamate or
thiocarbamate groups and a benzaldehyde deriva-
tive [2,7±9] (Table 1).
Moreover, the l-rhamnose portions always ꢀ-
glycosidically linked to the aglycone, possesses
either free, 40-O-acetylated and per-O-acetylated
hydroxy groups. In addition, thiocarbamates occur
as E and Z isomers which show typical di€erences
in the chemical shifts of the NH protons in deut-
erated dimethyl sulfoxide [2,10] (Fig. 1).
Hypotensive e€ects of several compounds from
the ethanolic extract of leaves were studied
in vivo through intravenous administration to
anaesthetised rats. These studies identi®ed the
rhamnosylated 4-hydroxy-benzyl isothiocyanates,
carbamates and thiocarbamates as the pharmaco-
logically active principles of the extract. The e€ects
of all of these compounds were similar, reversible
Moringa oleifera Lam. belonging to the single-
genus family Moringaceae is a small fast-growing
ornamental tree widespread over the tropical
regions of Africa and Asia [1]. All parts of this tree
are applied in traditional medicine for the treat-
ment of human diseases, whereby the leaves enri-
ched in vitamins A and C are used as vegetables
[1±3]. Because of its coagulating and anti-
microbiotic properties, the powdered seeds are uti-
lised for water puri®cation [4,5].
The crude ethanolic extract of fresh uncrun-
ched leaves exhibits (in vivo and in vitro) strong
hypotensive and spasmolytic e€ects [6]. Phyto-
chemical studies on this extract led to the isolation
* Corresponding author. Fax: 49 6131 394786.
0008-6215/98/$Ðsee front matter # 1998 Elsevier Science Ltd. All rights reserved
PII S0008-6215(98)00223-7

34
M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
Table 1
Constituents of fresh ethanolic Moringa oleifera leaf extract [2,7±9]
X
R1
R2
R3
Comp.
Name
Ð
Ð
H
H
H
Ac
Ð
Ð
Ð
Ð
Ð
H
H
Ac
H
Ac
Ac
niazirin
niazirinin
Ð
1
H
Ac
Ð
Me
Me
Et
H
Ac
H
Ac
Ac
Ac
Ac
Ð
2
3
Ð
niazimin A+B
Ð
Et
Ac
Me
Me
Me
Et
H
H
Ac
H
H
Ac
Ac
H
4a
niazinin A
niazicin A
Ð
niazimicin
niaziminin A
5a
6a
Et
H
Ac
Me
Me
Me
Et
Et
Et
H
H
Ac
H
H
Ac
H
Ac
Ac
H
Ac
Ac
4b
niazinin B
niazicin B
Ð
Ð
niaziminin B
Ð
5b
6b
7b
and dose-dependent. Nitriles did not show any
hypotensive e€ect. Investigations on organs of
several animals indicated spasmolytic properties of
thiocarbamates in vitro along with the hypotensive
e€ects [9]. Nevertheless, these results showed so far
that no speci®c mechanism can be supposed for the
hypotensive and spasmolytic e€ects of these thio-
carbamates.
extract with nitrile, aldehyde, carbamate and thio-
carbamate functionalities according to the retro-
synthetic strategy shown in Scheme 1: Following
pathway A, the Moringa oleifera compounds are
synthesised via rhamnosylation of the phenolic
hydroxy group of the aglycone. This concept
should be successful if no side reactions on the
aglycone, e.g. on its thiocarbonyl group of thio-
carbamates, interfere with the glycosylation.
According to pathway B rhamnosylation of a
Here, we report on the synthesis of pharmacolo-
gically active constituents of Moringa oleifera leaf

M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
35
Fig. 1. Chemical shifts of the NH protons of thiocarbamate rotational isomers in Me2SO-d6 [2].
protected 4-hydroxy-benzylamine is carried out
2. Results and discussion
®rst. After deprotection of the rhamnosylated 4-
hydroxy-benzylamine building block, subsequent
conversion of the amine into the functional group
of the Moringa oleifera compound is carried out.
Side reactions on the functional group can be
avoided by this strategy. For the construction of
glycosidic linkages, S-pent-4-enyl thiorhamnoside
8 is used. Anomeric activation of this thiogly-
coside can be achieved by the reaction with soft
electrophiles.
S-Pent-4-enyl thiorhamnoside.ÐS-Pent-4-enyl
thioglycosides have proved to be ecient in the
construction of O-glycosyl amino acid and sac-
charide building blocks applied in the syntheses of
TN and T antigen glycopeptide sequences of
tumor-associated MUC-1 [11]. Attack of electro-
philes at the C±C double bond of S-pent-4-enyl
thioglycosides induces an intramolecular cyclisa-
tion generating the corresponding thiolane as the
anomeric leaving group. Alternatively, the reaction
of electrophiles with the anomeric sulfur also
leads to the activation of these thioglycosides.
As the soft activating electrophile, a mixture of
N-iodosuccinimide (NIS) and tri¯uoromethane-
sulfonic acid, has been applied advantageously for
this purpose. For the preparation of the S-pent-4-
enyl thiorhamnopyranoside 8, tetra-O-acetyl-l-
rhamnopyranose 9 [12] was reacted with 4-pentene-
1-thiol [11,13] in the presence of borontri¯uoride
(Scheme 2). The thiorhamnoside 8 was obtained as
a mixture of anomers (ꢀ=ꢁ ˆ 4:6 : 1).
Synthesis of Moringa compounds via rhamno-
sylation of the aglycone.ÐThe Moringa oleifera
derivatives with nitrile and aldehyde functionalities
were prepared according to the retrosynthetic
pathway A. To prevent side reactions of iodonium
ions with the reactive phenols, the mixture of
thiorhamnoside 8 and 4-hydroxy-benzonitrile 10 or
anisaldehyde 11, respectively, was treated with N-
iodosuccinimide/tri¯uoromethanesulfonic acid at
40 ꢀC to yield the nitrile derivative 1, occurring in
Moringa oleifera leaf extract and the benzaldehyde
compound 12 (Scheme 3). Removal of the O-acetyl
groups from 12 by Zemplen transesteri®cation led
Scheme 1.

36
M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
to 4-(ꢀ-l-rhamnopyranosyloxy)-benzaldehyde 13.
Alternative syntheses of the aldehydes 12 and 13
have already been reported [14]. For the synthesis
of thiocarbamate derivatives contained in Moringa
oleifera leaf extract, the thiocarbamate aglycone
had to be prepared ®rst (Scheme 4). As the starting
material 4-hydroxy-benzonitrile 14 was used. Its
phenolic hydroxy group was protected as the allyl
ether. In a two-step process, the nitrile function of
15 was reduced to give the amine which without
further puri®cation was thioacylated applying
Mukaiyama's conditions [15,16]. For this purpose,
the crude amine was reacted with O-ethyl-S-(1-
methyl-2-pyridinium)-dithiocarbonate generated in
situ from pyridinium derivative 16 and potassium
ethylxanthogenate in the presence of 1,8-di-
azabicylo[5.4.0]undec-7-ene (DBU) to yield the
thiocarbamate 17. Palladium(0)-catalyzed removal
of the allyl ether [17] furnished the aglycone 18.
To prevent side reactions at the thiocarbonyl
group during glycosylation using electrophilic acti-
vators, the rhamnosylation of aglycone 18 was
Scheme 2.
Scheme 3.
Scheme 4.

M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
37
carried out with rhamnosyl trichloroacetimidate 19
[18] in the presence of catalytic amounts of boron-
tri¯uoride (Scheme 5). However, even under these
conditions, rhamnosylation to give the thiocar-
bamate compound 7 was accompanied by the
formation of a number of by-products.
synthesised by reduction of the nitrile 15, subsequent
introduction of the benzyloxycarbonyl group and
®nal removal of the allyl ether (Scheme 6). Rham-
nosylation of 21 was achieved using N-iodosuccin-
imide/tri¯uoromethanesulfonic acid to yield the
protected rhamnosyloxy-benzylamine 22.
Synthesis of Moringa compounds via (thio)-
acylation of the 4-rhamnosyloxy-benzylamine.ÐAs
an alternative, the conversion of a rhamnosyloxy-
benzylamine building block precedingly prepared
by rhamnosylation of a protected 4-hydroxy-ben-
zylamine into the functional group of the active
principle should prevent such side reactions described
above. According to this strategy, N-benzyloxy-
carbonyl-protected 4-hydroxy-benzylamine 21 was
Acylation of the crude amine obtained by
hydrogenolytic removal of the benzyloxycarbonyl
group from 22 was carried out using methyl and
ethyl chloroformate in the presence of 1,8-diazabi-
cyclo[5.4.0]undec-7-ene to furnish O±methyl car-
bamate 2 or O-ethyl carbamate 3, respectively
(Scheme 7). Reaction of the crude amine with the
corresponding sodium salt of O-alkyl-S-carboxy-
methyl dithiocarbonate at elevated temperature
Scheme 5.
Scheme 6.
Scheme 7.

38
M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
[19] led to the O-methyl thiocarbamate 5 and the
O-ethyl thiocarbamate 7 in good yields. The
obtained active principles 5 and 7 were subjected to
Zemplen transesteri®cation in order to remove the
O-acetyl groups and gave the natural products
niazinin 4 and niazimicin 6.
sieves (2 g) in CH2Cl2 (60 mL) were stirred for 1 h
with exclusion of light. BF3 etherate (1.9 mL,
15.0 mmol) was added dropwise. After stirring for
20 h, TLC monitoring showed incomplete conver-
sion. Therefore, additional pentenethiol (1.60 g,
15.7 mmol) and BF3 etherate (1.9 mL, 15.0 mmol)
were added dropwise. After stirring for 24 h, the
mixture was neutralized by addition of satd
NaHCO3 and ®ltered through Celite. The organic
phase was washed with water, dried with MgSO4,
and concentrated in vacuo. Flash-chromatography
(5:1 petroleum ether±EtOAc) gave 8 (3.38 g, 90%)
as a yellow oil: Rf 0.35 (ꢀ anomer) and 0.24 (ꢁ
anomer), petroleum ether±EtOAc; ꢀ=ꢁ 4.6:1
(according to 1H NMR); 1H NMR (CDCl3,
200 MHz): ꢂ 5.74 (ddt, 1 H, Jtr 17.0, Jcis 10.2, Jvic
6.7 Hz, ±CH ˆ ), 5.47 (dd, 0.18 H, J1ꢁ,2ꢁ 0.9, J2ꢁ,3ꢁ
3.0 Hz, H-2ꢁ), 5.31 (dd, 0.82 H, J1ꢀ,2ꢀ 1.3, J2ꢀ,3ꢀ
3.3 Hz, H-2ꢀ), 5.21 (dd, 0.82 H, J3ꢀ,4ꢀ 10.1 Hz, H-
3ꢀ), 5.14 (d, 0.82 H, H-1ꢀ), 5.06 (t, 0.82 H, J
9.7 Hz, H-4ꢀ), 5.06±4.94 (m, 2.36 H, H-3ꢁ,4ꢁ,
=CH2), 4.69 (d, 0.18 H, H-1ꢁ), 4.20 (dq, 0.82 H,
J4ꢀ,5ꢀ 9.4, J5ꢀ,6ꢀ 6.2 Hz, H-5ꢀ), 3.59±3.45 (m, 0.18
H, H-5ꢁ), 2.72±2.44 (m, 2 H, SCH2), 2.22±2.07 (m,
2 H, CH2CH ˆ ), 2.16, 2.13, 2.03, 1.96, and 1.95 (5 s,
9 H, Ac), 1.76±1.61 (m, 2 H, SCH2CH2), 1.25 (d, 0.54
The structures of the synthesised compounds
which show correct analytical data were unequi-
vocally ascertained by FD mass spectrometry and
1
by high ®eld NMR spectroscopy. In the H NMR
spectrum of thiocarbamates 4±7 recorded in deut-
erated dimethyl sulfoxide, the NH signals appeared
at ꢂ 9.6. This indicates that in dimethyl sulfoxide
only the E isomer is present (Fig. 1). The NMR
data are in accordance with reported data of com-
pounds isolated from Moringa oleifera [2,7±9].
The described syntheses make the Moringa olei-
fera constituents accessible in preparative scale for
pharmacological investigations of their spasmolytic
and hypotensive properties. Not only O-alkyl but
also O-acetyl protected S-pentenyl thioglycosides
proved to be ecient glycosyl donors useful for a
stereoselective glycosylation of hydroxyamino acid
and saccharide derivatives [11] as well as that of
phenols, even such ones of reduced nucleophilicity,
e.g. 11. The applied strategies also are useful for
the search and the construction of more e€ective
and speci®c analogs of the natural drugs.
H, J5ꢁ,6ꢁ 6.2 Hz, H-6ꢁ), 1.20 (d, 2.46 H, H-6ꢀ); 13
C
NMR (CDCl3, 50.3 MHz): ꢂ 169.81 and 169.67
(CˆO), 137.23 (±CHˆ), 115.30 (ˆCH2), 82.22 (C-1),
74.75, 71.75, 70.65, and 70.22 (C-2ꢁ,3ꢁ,4ꢁ,5ꢁ),
71.34, 71.08, 69.29, and 66.81 (C-2ꢀ,3ꢀ,4ꢀ,5ꢀ),
32.37, 31.82, 30.62, 28.66, and 28.42 (CH2-Pent),
20.76, 20.62, and 20.49 (CH3-Ac), 17.53 (C-6ꢁ),
17.17 (C-6ꢀ).
3. Experimental
General methods.ÐMelting points were mea-
sured on a Buchi apparatus and are uncorrected.
1H NMR (200 or 400 MHz) and 13C NMR (50.3 or
100.6 MHz) spectra were recorded on a Bruker AC
200 or a Bruker AM 400 spectrometer. Chemical
shifts (ꢂ) are given relative to the signal of Me4Si.
Mass spectra were recorded on a Varian CH7A
(EI) or a Finnigan MAT-95 (FD) spectrometer.
Flash-chromatography was carried out using Silica
Gel 30±60 ꢃm (Baker). For column chromatography,
Silica Gel 0.063±0.200 mm (Baker) was used. TLC
was performed on aluminium foil coated with
Silica Gel 60 F254 (E. Merck, Darmstadt). Optical
rotation values were measured on a Perkin±Elmer
polarimeter 241. If not indicated otherwise, reac-
tions were carried out at room temperature.
4-(20,30,40-Tri-O-acetyl-ꢀ-l-rhamnopyranosyloxy)-
phenylacetonitrile (1).ÐA mixture of 8 (1460 mg,
3.9 mmol), 4-hydroxy-phenylacetonitrile 10 (346 mg,
2.6 mmol) and 4 A molecular sieves (0.5 g) in
CH2Cl2 (40 mLꢀ) was stirred for 30 min and then
ꢀ
cooled to 40 C. A cooled ( 40 C) solution of
NIS (877 mg, 3.9 mmol) and HOTf (0.09 mL,
1.0 mmol) in 3:1 CH2Cl2±MeCN (8 mL) was added.
ꢀ
After stirring for 2 h at 40 C, Et3N (2 mL) and
CH2Cl2 (50 mL) were added, and the mixture was
®ltered through Celite. The ®ltrate was washed with
aq 10% Na2S2O3 (50 mL) and brine (50 mL), dried
with MgSO4, and concentrated in vacuo. Puri®ca-
tion by ¯ash-chromatography (2.4:1 petroleum
ether±EtOAc) gave 1 (822 mg, 78%) as colourless
Pent-40-enyl 2,3,4-tri-O-acetyl-1-thio-l-rhamno-
pyranoside (8).ÐTetra-O-acetyl-l-rhamnopyranose
9 [12] (3.32 g, 10.0 mmol), 4-pentene-1-thiol
[11,13] (2.04 g, 20.0 mmol) and 4 A molecular
ꢀ
crystals: mp 103 C; Rf 0.20 (2:1 petroleum ether-
EtOAc). For analytical data, see Tables 2, 3, 5 and
7±9.

M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
39
Table 2
1H NMR chemical shifts (ꢂ in ppm) for compounds 1±7, 12, 13 and 22
a
Proton
1
CDCl3
2
CDCl3
3
CDCl3
4
5
6
7
12
Me2SO-d6 Me2SO-d6 Me2SO-d6 Me2SO-d6 CDCl3
13
Me2SO-d6
22
CDCl3
H-2,6
H-3,5
H-7
7.03, d
6.97, d
6.98, d
6.98, d (B) 7.07, d
6.97, d (A)
7.21, d (A) 7.23, d (A) 7.20, d (A) 7.23, d (A) 7.81, d
7.15, d (B) 7.18, d (B) 7.15, d (B) 7.18, d (B)
4.56, d (A) 4.57, d (A) 4.54, d (A) 4.56, d (A) 9.86, s
4.24, d (B) 4.25, d (B) 4.21, d (B) 4.23, d (B)
6.98, d (B) 7.08, d (B) 7.16, d
6.96, d (A) 7.07, d (A)
7.21, d
7.86, d
9.87, s
5.54, d
6.98, d
7.21, d
3.66, s
7.17, d
4.25, d
7.18, d
4.26, d
7.18, d
4.28, d
5.39, d
H-10
5.41, d
5.37, dd
5.45, dd
5.10, t
3.90, dq
1.15, d
Ð
Ð
Ð
Ð
5.38, d
5.36, dd
5.45, dd
5.09, t
3.91, dq
1.14, d
Ð
Ð
Ð
3.63, s
5.39, d
5.37, dd
5.45, dd
5.10, t
3.92, dq
1.15, d
Ð
Ð
Ð
Ð
5.33, d
5.64, d
5.30, dd
5.27, dd
4.95, t
3.90, dq
1.06, d
Ð
5.32, d
3.79, ddd
3.61, ddd
3.25, dt
3.44, dq
1.07, d
5.02, d
4.72, d
4.85, d
Ð
5.63, d
5.30, dd
5.27, dd
4.95, t
3.90, dq
1.06, d
Ð
Ð
Ð
Ð
5.53, d
5.39, dd
5.45, dd
5.12, t
3.88, dq
1.15, d
Ð
Ð
Ð
Ð
H-20
3.81, ddd
3.63, ddd
3.27, dt
3.45, dq
1.08, d
5.03, d
4.73, d
4.86, d
3.85, ddd 5.38, dd
3.65, ddd 5.46, dd
H-30
H-40
3.30, dt
3.39, dq
1.09, d
5.15, d
4.81, d
4.93, d
Ð
5.11, t
3.92, dq
1.16, d
Ð
Ð
Ð
H-50
H-60
HO-20
HO-30
HO-40
OCH3
Ð
Ð
3.88, s (B) 3.88, s (B)
3.87, s (A) 3.86, s (A)
Ð
OCH2CH3
OCH2CH3
Ð
Ð
Ð
Ð
4.09, q
1.20, t
Ð
Ð
4.38, q (A) 4.38, q (A)
4.37, q (B) 4.37, q (B)
1.23, t (A) 1.23, t (A)
1.19, t (B) 1.18, t (B)
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
CH2Ph
CH2Ph
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
Ð
5.08,s
7.32±7.25,
m
5.19, sb
NH
Ac
Ð
5.14, sb
5.04, sb
9.62, t (B) 9.63, t(B)
9.58, t (A) 9.60, t (A)
Ð
9.55, t
Ð
9.56, t
Ð
Ð
Ð
2.15, 2.01, 2.14, 2.01, 2.14, 2.01,
1.98, 3s 1.97, 3s 1.98, 3s
2.13, 2.04,
1.96, 3s
2.13, 2.04, 2.15, 2.01,
1.96, 3s
2.15, 2.02,
1.99, 3s
1.99, 3s
a
Recorded at 400 MHz.
Table 3
1H NMR coupling constants (J in Hz) for compounds 1±7, 12, 13 and 22
Coupling constant
1
2
3
4
5
6
7
12
13 22
J2,3=J5,6
J7,NH
8.5
Ð
8.5
5.9
8.5
5.6
8.5
8.5
8.5
8.5
8.8
Ð
8.5 8.4
5.6
5.9 (A)
6.2 (B)
1.8
3.2
9.1
9.1
6.2
4.4
5.6
5.9 (A)
6.2 (B)
1.8
3.5
10.0
9.7
6.2
Ð
Ð
Ð
5.9 (A)
6.2 (B)
1.8
3.4
9.4
9.4
6.2
4.1
5.6
5.9 (A)
6.2 (B)
1.5
3.5
10.3
9.7
6.2
Ð
Ð
Ð
0
0
0
0
0
0
J1 ,2
1.8
3.4
10.1
9.8
6.2
Ð
Ð
Ð
Ð
1.8
3.4
10.0
10.0
6.2
Ð
Ð
Ð
Ð
1.8
3.5
10.0
10.0
6.2
Ð
Ð
Ð
7.0
1.8
3.5
10.0
9.7
6.2
Ð
Ð
Ð
Ð
1.8 1.8
3.8 3.2
9.1 10.0
9.4 10.0
6.2 6.2
0
J2 ,3
0
J3 ,4
0
J4 ,5
0
J5 ,6
0
J2 ,OH
0
J3 ,OH
0
J4 OH
Jvic(OEt)
4.4
5.3
5.3
Ð
Ð
Ð
Ð
5.6
Ð
5.6
7.1
Ð
7.0
4-(20,30,40-Tri-O-acetyl-ꢀ-l-rhamnopyranosyloxy)-
benzaldehyde (12).ÐCompound 12 was obtained
from 8 (1460 mg, 3.9 mmol), 4-hydroxy-benzalde-
hyde 11 (318 mg, 2.6 mmol) and a mixture of NIS
(877 mg, 3.9 mmol) and HOTf (0.09 mL, 1.0 mmol)
under warming up to 20 ꢀC within 16 h, as
described for 1. Flash-chromatography (4:1 petro-
leum ether±EtOAc) yieldedꢀ 12 (635 mg, 62%) as
colourless crystals: mp 161 C; Rf 0.32 (2:1 petro-
leum ether±EtOAc). For analytical data, see
Tables 2, 3, 5 and 7±9.
4-(ꢀ-l-Rhamnopyranosyloxy)-benzaldehyde (13).Ð
A solution of 12 (1.00 g, 2.5 mmol) in MeOH
(20 mL) was stirred with 0.75 M NaOMe in MeOH
(0.8 mL) for 3 h and, subsequently, neutralised
with Amberlite IR-120. After ®ltration, the solvent
was evaporated in vacuo. Flash-chromatography
(1.5:1 petroleum ether±acetone) gave 13 (503 mg,

40
M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
Table 4
1H NMR chemical shifts (ꢂ in ppm) and coupling constants (J in Hz) in CDCl3 for compounds 15, 17, 18, 20, and 21
a
Proton
H-2,6
15
17
18
20
21
6.97±6.90, m
6.87, d
J2,3 8.6
7.23, d (A)
7.15, d (B)
J5,6 8.6
4.65, d (A)
J7,NH 5.4
4.36, d (B)
J7,NH 5.6
Ð
4.56, q (B)
4.49, q (A)
Jvic 7.1
6.97, d
J2,3 8.5
7.17, d (A)
7.05, d (B)
J5,6 8.4
4.63, d (A)
J7,NH 5.5
4.32, d (B)
J7NH 5.7
5.28, sb
4.55, q (B)
4.48, q (A)
Jvic 7.1
6.85, d
J2,3 8.5
7.18, d
J5,6 8.5
6.73, d
J2,3 8.5
7.09, d
J5,6 8.5
H-3,5
H-7
7.59±7.52, m
Ð
4.29, d
J7,NH 5.8
4.27, sb
HO-1
CH2CH3
Ð
Ð
Ð
Ð
5.12, sb
Ð
CH2CH3
Ð
1.36, t (B)
1.30, t (A)
4.53, dt
Jvic 5.3
Jall 1.4
1.35, t (B)
1.29, t (A)
Ð
Ð
Ð
Ð
CH2CH=CH2
4.56, dt
Jvic 5.3
Jall 1.4
4.50, dt
Jvic 5.3
Jall 1.4
CH2CH=CH2
CH2CH=CH2
6.01, ddt
Jtr 17.3
Jcis 10.5
5.39, dq
(CHtr)
6.04, ddt
Jtr 17.3
Jcis 10.5
5.40, dq
(CHtr)
Ð
Ð
6.03, ddt
Jtr 17.3
Jcis 10.5
5.38, dq
(CHtr)
Ð
Ð
5.31, dq
5.28, dq
5.27, dq
(CHcis)
5.11, s
7.33, s
5.00, sb
(CHcis
Ð
Ð
)
(CHcis
Ð
Ð
)
CH2Ph
CH2Ph
NH
Ð
Ð
5.12, s
7.33, s
5.12, sb
Ð
6.75, sb (B)
6.36, sb (A)
6.85, sb (B)
6.39, sb (A)
a
Spectra of compounds 15, 17, 20 and 21 were recorded at 200 MHz; the spectrum of compound 18 was recorded at 400 MHz.
ꢀ
75%) as colourless crystals: mp 105 C; Rf 0.23
(CHCl3±MeOH). For analytical data, see Tables 2,
3, 5 and 7.
[C3H5+]. For further analytical data, see Tables 4,
6 and 9.
N-Ethoxythiocarbonyl-4-allyloxy-benzylamine
(17).Ð(a) Reduction of the nitrile 15: A solution of
15 (2.55 g, 16 mmol) in Et2O (20 mL) was added to
a stirred mixture of LiAlH4 (0.91 g, 24 mmol) in
Et2O (70 mL). The mixture was heated under re¯ux
4-Allyloxy-benzonitrile (15).ÐTo a stirred mix-
ture of NaH (0.72 g, 24 mmol; 80% dispersion in
mineral oil) in DMF (20 mL) was added slowly a
solution of 4-hydroxy±benzonitrile 14 (2.38 g,
ꢀ
ꢀ
20 mmol) in DMF (5 mL) at 0 C. After the evolu-
for 24 h. After cooling to 0 C, water (20 mL) was
tion of H2 had deceased, allyl bromide (3.5 mL,
40 mmol) was added. The mixture was allowed to
warm up to room temperature and the stirring was
continued for 16 h. MeOH (20 mL) was added in
order to solvolyse the excess of NaH. The mixture
was subsequently poured into 1:1 Et2O±water
(300 mL). After separation, the water solution was
extracted twice with Et2O (150 mL). The combined
organic solutions were dried with MgSO4 and
concentrated in vacuo. Flash-chromatography (6:1
petroleum ether±EtOAc) gave 15 (3.15 g, quant)ꢀas
added dropwise under stirring. After dilution with
CH2Cl2 (200 mL), the mixture was ®ltered through
Celite. The ®ltrate was washed with brine
(200 mL), dried with MgSO4, and concentrated in
vacuo to yield the crude amine as a colourless
liquid. (b) Thioacylation of the amine: To a mix-
ture of 2-chloro-1-methyl±pyridinium iodide 16
(4.91 g, 19.2 mmol) in MeCN (60 mL) was added
potassium ethylxanthogenate (3.08 g, 19.2 mmol).
After stirring for 70 min, a solution of the amine in
MeCN (15 mL) and DBU (2.9 mL, 19.2 mmol) was
added, and the mixture was stirred for additional
12 h and, subsequently, poured into 1:1 Et2O±
water (400 mL). The organic layer was separated
ꢀ
colourless crystals: mp 43 C, lit. mp 43.6±44.4 C
[20]; Rf 0.46 (6:1 petroleum ether±EtOAc); EIMS:
m/z 159 (19) [M+.], 119 (5) [C7H5NO+.], 41 (100)

M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
41
Table 5
13C NMR data for compounds 1±7, 12, 13 and 22
a
Carbon
1
2
3
4
5
6
7
12
13
CDCl3 CDCl3 CDCl3 Me2SO-d6 CDCl3 Me2SO-d6 CDCl3 CDCl3 Me2SO-d6
22
CDCl3
C-1
C-2,6
155.51 155.15 155.18 155.20
116.98 116.50 116.55 116.36
116.27
129.18 128.77 128.79 128.65
128.52
156.43 155.14
116.69 116.28
116.63 116.22
129.26 128.64
129.03 128.61
131.31 131.50
130.89 131.32
155.39 160.43 160.84
116.60 116.50 116.49
155.17
116.53
b
C-3,5
C-4
129.24 131.78 131.57
129.03
131.29 131.55 130.44
130.95
ꢁ128
132.82
44.46
124.10 132.94 133.07 131.44
131.28
C-7
22.76
44.43
44.39
47.42
45.09
48.68
46.55
47.11
45.03
48.43
46.41
37.37
190.55
189.72
95.68
70.89
69.60
68.84
67.14
17.31
191.54 191.26
C-8
117.76 156.97 156.58 190.89
188.86
191.45 189.98
190.61 187.94
Ð
Ð
156.32
C-10
C-20±C-50
95.68
70.82
69.55
68.80
67.24
17.32
95.72
70.92
69.65
68.87
67.11
17.30
95.78
70.98
69.69
68.91
67.14
17.35
98.48
71.78
70.44
70.15
69.36
17.79
Ð
95.72
70.90
69.65
68.90
67.18
17.36
169.96
169.87
98.44
71.75
70.39
70.12
69.33
17.76
Ð
95.46
70.70
69.40
68.71
67.63
17.35
98.16
71.63
70.33
69.89
69.81
17.75
Ð
95.73
70.93
69.65
68.88
67.11
17.32
169.89
169.86
169.83
20.70
C-60
C ˆ O, Ac
169.89 169.90 169.92
169.86 169.86 169.87
169.79 169.83 169.84
169.92 169.87
169.89 169.77
169.82
Ch3, Ac
20.71
20.61
20.57
Ð
20.71
20.61
20.55
52.07
(OMe) 14.55
(OEt)
20.73
20.63
20.58
60.88
Ð
20.76
20.67
20.61
58.28
57.11
Ð
20.70
20.61
20.55
70.60
67.83
66.37
14.14
14.10
13.54
(OEt)
20.70
20.61
20.57
Ð
Ð
Ð
20.61
20.55
Other signals
57.17
56.42
(OMe)
66.02
65.22
136.48
128.79
128.40
128.01
66.75
(OMe) 14.14
13.93
(OEt)
(CH2Ph)
a
Recorded at 100.6 MHz; all signals with the exception of these of compound 13 were assigned by DEPT-135 spectra.
Signal lies below the signals of the CH2Ph group.
b
and the aqueous solution was extracted with Et2O
vent was evaporated in vacuo and the residue
diluted with 1:1 Et2O±water (200 mL). After
separation, the water solution was extracted twice
with Et2O (100 mL). The combined organic solu-
tions were washed with water (300 mL), dried with
MgSO4, and concentrated in vacuo. Puri®cation by
¯ash-chromatography (3:1 petroleum ether±
EtOAc) yieldedꢀ 18 (1.36 g, 88%) as colourless
crystals: mp 83 C; Rf 0.37 (3:1 petroleum ether±
EtOAc); ratio of rotamers A:B 1.4:1 (according
(200 mL). The combined organic layers were
washed with water (400 mL), dried with MgSO4,
and concentrated in vacuo. Flash-chromatography
(10:1 petroleum ether±EtOAc) gave 17 (2.65 g,
66%) as a yellow oil: Rf 0.40 (10:1 petroleum
ether±EtOAc); ratio of rotamers 1.7:1 (according
1
to H NMR); EIMS: m/z 251 (80) [M+.], 222 (82)
[C11H12NO2S+], 179 (42) [C10H11 OS+], 162 (32)
[C10H12NO+], 147 (41) [C10H11 O+], 121 (19)
[C8H9O+], 107 (29) [C7H7O+], 84 (19), 83 (31), 41
(100) [C3H5+]. For further analytical data, see
Tables 4, 6 and 9.
1
to H NMR); EIMS: m/z 211 (60) [M+.], 182 (44)
[C8H8NO2S+], 139 (29) [C7H7OS+], 122 (57)
[C7H8NO+], 107 (100) [C7H7O+], 95 (26)
[C6H7O+], 77 (36) [C6H5+]. For further analytical
data, see Tables 4, 6 and 9.
N-Ethoxythiocarbonyl-4-hydroxy-benzylamine
(18).ÐTo
a
stirred solution of 17 (1.83 g,
7.3 mmol), formic acid (0.42 mL, 11.0 mmol) and
triphenylphosphine (1.15 g, 4.4 mmol) in THF
(50 mL) palladium acetate (90 mg, 0.4 mmol) was
added under strict exclusion of O2. After the
mixture was heated under re¯ux for 20 h, the sol-
N-Ethoxythiocarbonyl-4-(20,30,40-tri-O-acetyl-ꢀ-l-
rhamnopyranosyloxy)-benzylamine (7).ÐA mixture
of tri-O-acetyl-ꢀ-l-rhamnopyranosyl trichloroacet-
imidate 19 [18] (1130 mg, 2.6 mmol), 18 (422 mg,
2.0 mmol) and 4 A molecular sieves (0.5 g) in CH2Cl2

42
M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
Table 6
13C NMR data in CDCl3 for compounds 15, 17, 18, 20 and 21
Table 8
Optical rotations for compounds 1±7, 12, 13, and 22
a
[ꢀ]2d3
Compound
[ꢀ]2d3
a
Carbon
15
17
18
20
21
Compound
C-1
C-2,6
C-3,5
161.61
115.24
133.69
158.13
114.86
129.25
129.04
128.79
155.16 158.01
115.52 114.88
155.54
115.54
ꢁ128 b
1
2
3
4
5
82.1 ꢀ
76.8 ꢀ
59.5 ꢀ
97.3 ꢀ
69.5 ꢀ
6
7
12
13
22
93.6 ꢀ
70.0 ꢀ
110.1 ꢀ
154.5 ꢀ
61.5 ꢀ
b
b
129.29 ꢁ128
129.11
128.53 130.74
128.10
C-4
103.75
118.95
Ð
129.64
a
c 1, CHCl3.
Lit. 37.8 ꢀ (c 0.1, CHCl3) [14].
C-7
48.55
46.49
48.45
46.47
44.56
44.58
b
C-8
190.28
189.41
133.09
117.65
68.74
190.12 156.30
189.03
156.73
ether±EtOAc); EIMS: m/z 297 (1) [M+.], 206 (100)
[C11H12NO3+], 91 (43) [C7H7+]. For further ana-
lytical data, see Tables 4, 6 and 9.
N-Benzyloxycarbonyl-4-hydroxybenzylamine
(21).ÐTo
9.9 mmol), formic acid (0.56 mL, 14.9 mmol) and
triphenylphosphine (1.55 g, 5.9 mmol) in THF
(60 mL) was added palladium acetate (112 mg,
0.5 mmol) under strict exclusion of O2. After the
mixture had been heated under re¯ux for 4.5 h,
followed by work-up as described for 18 and ¯ash-
chromatography (2:1 petroleum ether±EtOAc),
compound 21 (2.31 g, 91%) was obtained as col-
Other
131.87
68.10 136.55
66.51 128.77
14.07 128.41
(OEt) 127.99
68.80
136.12
128.87
128.48
128.15
67.02
signals 118.17
68.74
(OAll)
67.80
66.35
14.22
(OAll, OEt)
(CH2Ph) (CH2Ph)
133.23
117.48
66.69
(OAll)
a
stirred solution of 20 (2.93 g,
a
Spectra of compounds 15, 17, 18, and 21 were recorded at
50.3 MHz; the spectrum of compound 20 was recorded at
100.6 MHz.
b
Signal lies below the signals of the CH2Ph group.
ꢀ
ourless crystals: mp 90 C; Rf 0.21 (2:1 petroleum
ether±EtOAc); FDMS: m/z 257.1 [M+.]. For fur-
ther analytical data, see Tables 4, 6 and 9.
(15 mL) was stirred for 30 minꢀand then cooled to
ꢀ
20 C. Then, a cooled ( 20 C) solution of BF3
etherate (0.05 mL, 0.4 mmol) in CH2Cl2 (2 mL) was
N-Benzyloxycarbonyl-4-(20,30,40-tri-O-acetyl-ꢀ-l-
rhamnopyranosyloxy)-benzylamine (22).ÐA mix-
ture of 21 (515 mg, 2 mmol), NIS (675 mg, 3 mmol)
and 4 A molecular sieves (0.5 g) in CH2Cl2 (25 mL)
was stirred for 30min, then cooled to 40 C, and
HOTf (0.07 mL, 0.8 mmol) was added. Subse-
quently, a cooled ( 40 C) solution of 8 (1123 mg,
3 mmol) in CH2Cl2 (7 mL) was added. After stirring
for 2 h at 40 ꢀC, Et3N (2 mL) was added. Work-up
was carried out as described for 1 and ¯ash-chro-
matography (2.7:1 petroleum ether±EtOAc) yielded
22, 845 mg, 80%) as colourless crystals: mp 110 ꢀC;
Rf 0.22 (2:1 petroleum ether±EtOAc). For further
analytical data, see Tables 2, 3, 5, 8 and 9.
N-Methyloxycarbonyl-4-(20,30,40-tri-O-acetyl-ꢀ-l-
rhamnopyranosyloxy)-benzylamine (2).Ð(a) Removal
of the Z group from 22: A solution of 22 (1.06 g,
2.0 mmol) in MeOH (50 mL) was hydrogenated
under atmospheric pressure using Pd (black,
100 mg) for 6 h. Filtration through Celite, con-
centration of the ®ltrate in vacuo and drying in
high vacuum gave the crude amine as an amor-
phous solid. (b) Acylation of the amine: To a
solution of the amine in CH2Cl2 (20 mL) was
added methyl chloroformate (0.23 mL, 3.0 mmol)
ꢀ
added dropwise. After stirring for 2 h at 20 C,
Et3N (1 mL) and CH2Cl2 (50 mL) were added, and
the mixture was ®ltered through Celite. The ®ltrate
was washed with brine (50 mL), dried with MgSO4,
and concentrated in vacuo. Flash-chromatography
(2.5:1 petroleum ether±EtOAc) gave 7 (169 mg,
17%) as amorphous material. Analytical data are
in accordance with compound 7 obtained from
thioacylation (vide infra).
N-Benzyloxycarbonyl-4-allyloxy-benzylamine
(20).ÐReduction of 15 (2.39 g, 15.0 mmol) with
LiAlH4 (0.85 g, 22.5 mmol) was carried out as
described for 17. To the crude amine dissolved in
1:1 acetone-water (50 mL) were added Na2CO3
(0.79 g, 7.5 mmol) and N-(benzyloxycarbonyloxy)-
succinimide (3.74 g, 15.0 mmol). After stirring for
2.5 h, the mixture was poured into 1:1 Et2O±water
(200 mL). The separated aqueous solution was
washed twice with Et2O (100 mL). The combined
organic solutions were washed with water, dried
with MgSO4, and concentrated in vacuo. Puri®ca-
tion by ¯ash-chromatography (5:1 petroleum
ether±EtOAc) yieldedꢀ20 (3.38 g, 76%) as colour-
less crystals: mp 71 C; Rf 0.20 (5:1 petroleum
ꢀ
ꢀ

M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
43
Table 9
Elemental analyses for compounds 1±8, 12, 13, 17, 18, 20±22
Comp.
Formula
Calcd:
Found:
%C
%H
%N
%S
%C
%H
%N
%S
1
2
3
4
5
6
7
8
12
13
17
18
20
21
22
C20H23NO8
C21H27NO10
C22H29NO10
C15H21NO6S
C21H27NO9S
C16H23NO6S
C22H29NO9S
C17H26O7S
C19H22O9
59.26
55.63
56.53
52.47
53.72
53.77
54.65
54.53
57.87
58.20
62.12
56.85
72.71
70.02
61.24
5.72
6.00
6.25
6.16
5.80
6.49
6.05
7.00
5.62
6.01
6.82
6.20
6.44
5.88
5.90
3.46
3.09
3.00
4.08
2.98
3.92
2.90
Ð
Ð
Ð
Ð
9.34
6.83
8.97
6.63
8.56
Ð
59.31
55.60
56.61
52.56
53.53
53.78
54.61
54.37
57.79
58.06
62.04
56.88
72.73
69.94
61.19
5.76
6.09
6.33
6.16
5.82
6.58
6.06
7.00
5.66
6.07
6.95
6.25
6.34
5.92
6.03
3.41
2.97
2.83
4.08
2.81
3.81
2.74
Ð
Ð
Ð
Ð
9.32
6.91
8.97
6.63
8.51
Ð
Ð
Ð
Ð
Ð
C13H16O6
Ð
Ð
C13H17NO2S
C10H13NO2S
C18H19NO3
C15H15NO3
C27H31NO10
5.57
6.63
4.71
5.44
2.65
12.76
15.18
Ð
Ð
Ð
5.62
6.57
4.70
5.30
2.45
12.69
15.21
Ð
Ð
Ð
and DBU (0.45 mL, 3.0 mmol). After stirring for
2 h, the mixture was diluted with CH2Cl2 (100 mL),
extracted twice with brine (100 mL), dried with
MgSO4, and concentrated in vacuo. Flash-chro-
matography (2:1 petroleum ether±EtOAc) yielded
2 (559 mg, 62%) as amorphous material: Rf 0.14
(2:1 petroleum ether±EtOAc). For further analy-
tical data, see Tables 2, 3, 5 and 7±9.
petroleum ether±EtOAc) yielded 5 (1.04 g, 62%) as
amorphous material: Rf 0.17 (2.5:1 petroleum
ether±EtOAc); ratio of rotamers A:B 3.8:1
(according to H NMR). For further analytical
data, see Tables 2, 3, 5 and 7±9.
1
N-Methoxythiocarbonyl-4-(ꢀ-l-rhamnopyrano-
syloxy)-benzylamine (niazinin) (4).ÐA solution of
5 (939 mg, 2.0 mmol) in MeOH (20 mL) was treated
with 0.75 M NaOMe in MeOH (0.6 mL). The mix-
ture was stirred for 45 min and, subsequently, neu-
tralised with Amberlite IR-120. After ®ltration, the
solvent was evaporated in vacuo. Flash-chromatog-
raphy (1.5:1 petroleum ether±acetone) gave 4
(640 mg, 93%) as amorphous material: Rf 0.16
(10:1 CHCl3±MeOH); ratio of rotamers A:B 3.5:1
N-Ethoxycarbonyl-4-(20,30,40-tri-O-acetyl-ꢀ-l-
rhamnopyranosyloxy)-benzylamine (3).ÐRemoval
of the Z group from 22 (1.06 g, 2.0 mmol) and
subsequent acylation of the crude amine with ethyl
chloroformate (0.29 mL, 3.0 mmol) were carried
out as described for 2 and gave after ¯ash-chro-
matography (2.5:1 petroleum ether±EtOAc) 3
(623 mg, 67%) as amorphous material: Rf 0.10
(2.5:1 petroleum ether±EtOAc). For further analy-
tical data, see Tables 2, 3, and 7±9.
1
(according to H NMR). For further analytical
data, see Tables 2, 3, 5 and 7±9.
N-Ethoxythiocarbonyl-4-(20,30,40-tri-O-acetyl-ꢀ-
l-rhamnopyranosyloxy)-benzylamine (7).ÐCom-
pound 7 was obtained by removal of the Z group
from 22 (3.44 g, 6.5 mmol) in MeOH (150 mL) with
Pd (black, 300 mg) and subsequent thioacylation of
the crude amine with sodium S-carboxymethyl-O-
ethyl dithiocarbonate (1.98 g, 9.8 mmol), prepared
by neutralisation of S-carboxymethyl-O-ethyl-
dithiocarbonate [21] with 2 M NaOH in acetone
followed by recrystallisation from acetone-water.
The reaction was conducted in DMF (70 mL)
within 2.5 h according to the procedure described
for 5 and gave after ¯ash-chromatography (3.3:1
petroleum ether±EtOAc) 7 (2.05 g, 65%) as amor-
phous material: Rf 0.35 (2:1 petroleum ether±
EtOAc); ratio of rotamers A:B 3.5:1 (according to
N-Methoxythiocarbonyl-4-(20,30,40-tri-O-acetyl-
ꢀ-l-rhamnopyranosyloxy)-benzylamine
(5).Ð
Removal of the Z group from 22 (1.91 g,
3.6 mmol) in MeOH (100 mL) with Pd (black,
180 mg) was carried out as described for 2. A stir-
red solution of the crude amine in DMF (60 mL)
was treated with sodium S-carboxymethyl-O-
methyldithiocarbonate (1.36 g, 7.2 mmol) prepared
by neutralisation of S-carboxymethyl-O-methyl-
dithiocarbonate [21] with 2 M NaOH in acetone
followed by recrystallisation from acetone±water.
ꢀ
After heating this mixture at 80 C for 2 h, it was
poured into CH2Cl2 (300 mL), washed twice with
brine (200 mL), dried with MgSO4, and con-
centrated in vacuo. Flash-chromatography (2.4:1

44
M. Leuck, H. Kunz/Carbohydrate Research 312 (1998) 33±44
1H NMR); 13C NMR (CDCl3, 50.3 MHz; gated-
[6] S. Siddiqui and M.I. Khan, Pak. J. Sci. Ind. Res.,
11 (1968) 268±272.
decoupled): ꢂ 95.40 (d, JC,H 173.2 Hz, C-10). For
1
[7] S. Faizi, B.S. Siddiqui, R. Saleem, S. Siddiqui,
K. Aftab, and A.H. Gilani, J. Chem. Soc., Perkin
Trans. 1, 1994, 3035±3040.
[8] S. Faizi, B.S. Siddiqui, R. Saleem, S. Siddiqui,
K. Aftab, and A.H. Gilani, J. Nat. Prod., 57 (1994)
1256±1261.
[9] S. Faizi, B.S. Siddiqui, R. Saleem, S. Siddiqui,
K. Aftab, and A.H. Gilani, Phytochemistry, 38
(1995) 957±963.
[10] R.A. Baumann, J. Org. Chem., 32 (1967) 4129-
4132.
further analytical data, see Tables 2, 3, 5 and 7±9.
N-Ethoxythiocarbonyl-4-(ꢀ-l-rhamnopyranosyl-
oxy)-benzylamine (niazimicin) (6).ÐRemoval of
the O-acetyl groups from 7 (1.32 g, 2.7 mmol) in
MeOH (25 mL) was carried out as described for 4.
Puri®cation by ¯ash-chromatography (1:1 petro-
leum ether±acetone) gave 6 (920 mg, 95%) as
amorphous material: Rf 0.21 (10:1 CHCl3±MeOH);
ratio of rotamers A:B 3.3:1 (according to 1H
NMR). For further analytical data, see Tables 2, 3,
5 and 7±9.
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Acknowledgements
This work was supported by the Deutsche For-
schungsgemeinschaft and by the Fonds der Che-
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