Synthesis of rhamnosylated diosgenyl glucosides as mimetics of cytostatic steroidal saponins from Ornithogalum saundersiae and Galtonia candicans

Article abstract of DOI:10.1039/b309066c

The synthesis of mimetic 3 of the steroid saponins 1 and 2 was investigated. As a substitute for the complex 22-homo-23-nor-steroid moieties A and B in 1 and 2 diosgenin C was introduced. The silyl protected thioorthoester 20 was successfully employed for glucosylation. After selective 2-O-deacetylation, the glucosylated diosgenyl acceptor 23 was rhamnosylated. The 4-O-p-methoxybenzoylated donor 12 gave only minor yields. By using the tri-O-benzoyl protected donor 15 the α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl-(1→3β) -diosgenin derivative 25 was obtained.

Full text of DOI:10.1039/b309066c

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Synthesis of rhamnosylated diosgenyl glucosides as mimetics
of cytostatic steroidal saponins from Ornithogalum saundersiae
and Galtonia candicans
René Suhr, Pascal Pfefferkorn, Saskia Weingarten and Joachim Thiem*
Institute of Organic Chemistry, University of Hamburg, Martin-Luther-King-Platz 6,
D-20146 Hamburg, Germany. E-mail: thiem@chemie.uni-hamburg.de;
Fax: ϩ49 40 42838 4325; Tel: ϩ49 40 42838 4241
Received 5th August 2003, Accepted 23rd October 2003
First published as an Advance Article on the web 11th November 2003
The synthesis of mimetic 3 of the steroid saponins 1 and 2 was investigated. As a substitute for the complex
22-homo-23-nor-steroid moieties A and B in 1 and 2 diosgenin C was introduced. The silyl protected thioorthoester
20 was successfully employed for glucosylation. After selective 2-O-deacetylation, the glucosylated diosgenyl acceptor
23 was rhamnosylated. The 4-O-p-methoxybenzoylated donor 12 gave only minor yields. By using the tri-O-benzoyl
protected donor 15 the α--rhamnopyranosyl-(1 2)-β--glucopyranosyl-(1 3β)-diosgenin derivative 25 was
obtained.
Introduction
Due to the coevolution of plants with different kinds of
damaging organisms plant extracts and natural products
obtained thereof show a broad spectrum of biological activities
with a high potential for medicinal applications. A diverse class
of compounds, concerning their effect and structure are the
saponins, complex glycosides with a steroid, a steroid alkaloid
or triterpene aglycon, which presumably support the plant in
their defence against fungi. The main building blocks of these
compounds consist of a relatively small number of common
monosaccharides and the various sapogenins.
Several groups are involved in systematic research into the
constitution and biological effects of this interesting class
of compounds. Sashida and Mimaki et al. discovered the
p-hydroxybenzoylated α--rhamnopyranosyl-(1 2)-β--gluco-
pyranosyl-(1 3β)-22-homo-23-nor-cholestane derivative (1)
from Ornithogalum saundersiae1 and the non-acylated ketal 2
from Galtonia candicans.2 They also showed these compounds
to have high cytostatic potential concurrent with a low effect on
non-transformed cells. As a part of our research on saponin
chemistry,3–5 our synthetic interest focussed on the sugar
parts of these molecules. Therefore, the complex 22-homo-23-
norcholestane steroid moiety was substituted by the easily
accessible diosgenin 4 to give the structural mimetics 3 and 3a
as synthetic targets (Scheme 1).
Scheme 1 The rearranged Rha–Glc-cholestane glycoside (1, Ornitho-
galum Saundersiae, Liliaceae) shows potential cytostatic activity (IC50
=
21 nM for the Leukaemia HL-60 cell line and 18 nM for the Leukaemia
MOLT-4 cell line), whereas only a small activity is found for the
deacylated derivative 1a. For the rearranged Rha–Glc-cholestane
glycoside Candicanosid A (2, Galtonia candicans, Liliaceae), IC50 = 32
nM for the Leukaemia HL-60 cell line. Compounds 3 and 3a are
structural mimetics and are synthetic targets.
Results and Discussion
Synthesis of rhamnopyranosyl donors
-Rhamnose is one of the few naturally occurring -sugars.
Because of the axially configured 2-position determination of
donor with a suitable benzoate function, and the latter after
glycosylation substitution with different benzoates leads to
a library of saponins. Because of the anomeric effect, -rhamno-
pyranose donors generally preferentially give α-glycosides. To
enhance the tendency for α-glycoside formation, 2-O-acyl
donors, in this case the benzoates 15/169 were synthesized from
14, which shows 1,2-trans selectivity in the glycosylations.
3
the α- and β-glycosides by the J1,2 coupling constants (0 to <
1
ca. 3 Hz in H NMR) is difficult. However, the anomeric con-
figuration can be determined by 1H coupled 13C NMR with the
1JCH coupling constants in the range of 160 (α) to 170 Hz (β).6–8
Scheme 2 shows the synthesis of the differentially protected
methyl (6/7)8 and ethyl thiorhamnopyranosides (14) from
the 2,3,4-tri-O-acetylated compounds8,9 by treatment of the
-rhamnopyranose tetraacetate (5)10,11 with TMSSMe–
TMSOTf and ethanethiol–BF3ؒOEt2, respectively. The iso-
propylidene group was introduced onto 6 and 7 resulting in an
unprotected 4-position, which was protected with a p-methoxy-
benzoyl or TBDMS group, respectively. The former results in a
Synthesis of glucopyranosyl donors
In order to obtain selective protection of the 3, 4 and 6
positions of glucose, the orthoester methodology was chosen.
To obtain a glucosyl donor which can be easily activated the
thio derivative 3,4,6-tri-O-acetyl-1,2-O-(ethylthioethylidene)-
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
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Scheme 2 Reagents and conditions: a: 1) TMSSMe, TMSOTf, CH2Cl2, Ar, 0 ЊC – > rt; 2) NaOMe–MeOH; b: 1) EtSH, BF3ؒOEt2, CH2Cl2, Ar, 0 ЊC –
> rt; 2) NaOMe–MeOH; c: benzoyl chloride, pyridine, DMAP (cat.) over night, 0 ЊC – > rt; d: dimethoxypropane, CH2Cl2, TosOH (cat.); e: pMBzCl,
pyridine, CH2Cl2, 0 ЊC – > rt; f: TBDMSCl, DMF, imidazole.
Scheme 3 Reagents and conditions: a: EtSH, sym-collidine, NBu4Br, anhydr. acetonitrile; b: NaOMe–MeOH; c: 1) TBDPSCl, 12 h; 2) TIPDSCl2
(0.95 eq.), 6 h, 0 ЊC – > rt, argon, imidazole, DMF; d: EtSH, abs. CH2Cl2, Ar, TMSOTf (cat.), MS 4 Å, rt, 5 min; e: anhydr. Et2O–CH2Cl2 1 : 1, argon,
MS 4 Å; 1) NIS, 2 h; 2) TfOH (cat.), 2 h; f: DMTST, CH2Cl2, MS 4 Å, 24 h; g: K2CO3–MeOH; h: NIS, anhydr. Et2O–CH2Cl2 1 : 1, argon, MS 4 Å; i:
DMTST, Et2O, MS 4 Å.
α--glucopyranose (18)12 was synthesized in 62% yield (Scheme
Glycosylations
3). After deacetylation, a two step silyl protection of the 6
position, with tert-butyldiphenylsilyl (TBDPS), and the 3,4-
trans-diequatorial position, with the 1,2-trans-diol selective
1,1,3,3-tetraisopropyl-1,3-disiloxan-1,3-diyl (TIPDS) protect-
ing group, was successful in yielding the thioorthoester donor
20, which can be activated directly or rearranged to the thio-
glycoside 21.
The activation of thioglycosides by NIS–TfOH was first
described by van Boom et al.13 and was later modified by the
same group for the activation of sugar thioorthoesters.14 The
donor 20 was activated by this procedure and 21 was activated
by the DMTST (dimethyl(methylthio)sulfonium triflate)
method for the glycosylation of diosgenin 4. A mixture of
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
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donor 20 and acceptor 4 was stirred in diethyl ether–dichloro-
methane 1 : 1, and N-iodosuccinimide (NIS) was added to acti-
vate the thio function to yield an intermediate diosgenin sugar
orthoester within 2 h. This underwent rearrangement by addi-
tion of a catalytic amount of trifluoromethanesulfonic acid to
give after another 2 h the 2-O-acetylated diosgenyl glucoside 22.
The 2-O-acetate has to be cleaved in the next step without
provoking a migration of the silyl group; to achieve this
K2CO3–MeOH was used under mild conditions. Thus, the
acceptor 23 was obtained in 42% yield in two steps.
A remarkably difficult step was the subsequent 2-O-rhamno-
sylation; donor 12 and acceptor 23 were reacted under NIS
activation to give the target molecule 24 in poor yield. Some
β-rhamnosylation occurred because of the missing acyl
neighbouring group in position 2 and perhaps conformational
influence caused by the isopropylidene group.
(12 mL). After cooling in an ice bath p-methoxybenzoyl chlor-
ide (1 mL) was added slowly and the mixture was stirred for 6 d.
Dichloromethane was added and the mixture was washed twice
with saturated NaHCO3 solution and once with water, dried
over MgSO4, filtered, evaporated and distilled with toluene.
After flash chromatography compound 9 was obtained (1.955 g,
5.3 mmol, 96%). Colourless solid; C18H24O6S (MW 368.446 g
molϪ1); mp: 89 ЊC; [α]546 = Ϫ24 (c = 0.57, CHCl3); TLC (petrol-
eum ether (PE)–ethyl acetate (EA) 1 : 1): Rf = 0.78 (UV, H2SO4).
1H NMR (400 MHz, CDCl3): δ = 8.00, 7.05 (2 × d, 2 × 2H,
3
CH3OC6H4COO), 5.46 (s, 1H, H-1), 5.16 (dd, 1H, H-4, J3,4
=
7.6, 3J4,5 = 10.2 Hz), 4.31 (dd, 1H, H-3, 3J2,3 = 5.6, 3J3,4 = 7.6 Hz),
4.24 (d, 1H, H-2, 3J2,3 = 5.6 Hz), 4.17 (dq, 1H, H-5, 3J4,5 = 10.2,
3J5,6 = 6.1 Hz), 3.85 (s, 3H, CH3OC6H4COO), 2.16 (s, 3H,
SCH3), 1.62, 1.34 (2 × s, 2 × 3H, C(CH3)2), 1.22 (d, 3H, CH3-6,
3J5,6 = 6.1 Hz) ppm.
Acceptor 23 was rhamnosylated using the tri-O-benzoyl
donor 159 with activation by DMTST to yield the disaccharide
saponin 25 in satisfactory yield. Further studies towards the
target molecules are under investigation.
Methyl 4-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-1-
thio-ꢀ-L-rhamnopyranoside (10)
In a 100 mL round flask compound 88 (0.306 g, 1.00 mmol) was
dissolved in anhydr. DMF (10 mL) and cooled in an ice bath.
Imidazole (115 mg, 1.7 mmol) and tert-butyldimethylchloro-
silane (257 mg, 1.7 mmol) were added and stirred for 5 d at rt.
The reaction was monitored by TLC. After complete con-
version of the starting material the reaction was stopped by
addition of a ten-fold excess of toluene and the resulting
mixture was washed three times with saturated NaHCO3 solu-
tion and once with water, dried over sodium sulfate, filtered
and evaporated. After flash chromatography (PE–EA 20 : 1)
compound 10 (323 mg, 0.93 mmol, 93%) was obtained. Colour-
less syrup; C16H32O4SSi (MW 348.574 g molϪ1); [α]546 = Ϫ33
Experimental
General Procedures
Thin layer chromatography was performed on precoated plates
of silica gel 60 (F254, Merck) with detection by UV absorption
or by spraying the plates with 20% ethanolic sulfuric acid and
subsequent heating. Column chromatography was performed
on silica gel 60 (230–400 mesh, 40–63 µm; Merck, Machery-
Nagel or ICN) using the flash technique and the given solvents.
NMR spectra were recorded with the Bruker spectrometers
AMX-400 (400 MHz 1H, 100.67 MHz 13C) and DRX-500
(500 MHz 1H, 125.77 MHz 13C). Tetramethylsilane (0.00 ppm)
was added as internal standard, or especially for silylated
compounds, the solvent residual peak was used.15 Signal
multiplicity dd∼t; ddd∼dt: double doublet appearing as a
pseudotriplet. Mass spectra were recorded with a Bruker
Biflex III MALDI-TOF-Mass spectrometer (positive reflector
mode, Matrix: DHB = dihydroxybenzoic acid).16 Melting points
were determined using an Olympus BH polarising microscope
with a Mettler FP82 hot plate or an Apotec melting point
apparatus and are not corrected. Optical rotations were deter-
mined with a Perkin-Elmer 241 PE polarimeter (NaD = 589 nm);
[α] values are measured in 10Ϫ1 deg cm2 gϪ1. Elemental analyses
were performed in the microanalytical laboratory of the
Institute of Organic Chemistry of the University of Hamburg.
Solvents for the reactions were distilled or dried before use.
Dichloromethane (CaH2) and diethyl ether (sodium wire/
benzophenone) for glycosylation reactions were dried freshly
under argon before use or stored over MS 4 Å. Methanol was
dried by refluxing over magnesium and subsequent distillation
and then stored over MS 3 Å. Commercially available anhydr.
acetonitrile, anhydr. pyridine and anhydr. DMF (Fluka) were
used. Reagents were used with the available purity offered by
the producer. DMTST was synthesized by a modified method
according to the literature17 and stored under argon with strict
exclusion of moisture at ca. Ϫ15 ЊC. It was warmed to room
temperature before use. Reactions in inert gas atmosphere were
performed under a slight excess pressure of argon or nitrogen
by the Schlenck or balloon technique in glassware which was
heated under vacuum before use.18 Molecular sieves were
activated under high vacuum at ca. 130–250 ЊC for several
hours (usually over night), cooled under a slight excess pressure
of argon or nitrogen and used freshly activated.
1
(c = 0.7, CHCl3); TLC (PE–EA 20 : 1): Rf = 0.44 (H2SO4). H
NMR (400 MHz, CDCl3): δ = 5.36 (s, 1H, H-1), 4.14 (d, 1H,
H-2, 3J2,3 = 5.6 Hz), 3.97 (dd, 1H, H-3, 3J2,3 = 5.6, 3J3,4 = 7.1 Hz),
3.87 (dq, 1H, H-5, 3J4,5 = 9.7, 3J5,6 = 6.1 Hz), 3.38 (dd, 1H, H-4,
3J3,4 = 7.1, 3J4,5 = 9.7 Hz), 2.11 (s, 3H, SCH3), 1.52, 1.33 (2 × s,
3
2 × 3H, C(CH3)2), 1.24 (d, 3H, CH3-6, J5,6 = 6.1 Hz), 0.84 (s,
9H, C(CH3)3), 0.14, 0.09 (2 × s, 2 × 3H, Si(CH3)2) ppm. 13C
NMR (100.67 MHz, CDCl3): δ = 109.0 (C(CH3)2), 81.3 (C-1),
78.9 (C-3), 76.8 (C-2), 76.4 (C-4), 66.6 (C-5), 28.2, 26.5
(C(CH3)2), 25.9 (C(CH3)3), 17.9 (C-6), 13.3 (SCH3), Ϫ3.9,
Ϫ4.9 (Si(CH3)2) ppm.
Methyl 2,3-O-isopropylidene-1-thio-ꢁ-L-rhamnopyranoside (11)
Compound 78 (100 mg, 0.51 mmol), 2,2-dimethoxypropane
(1 mL) and p-toluenesulfonic acid monohydrate (5 mg, 0.03
mmol) were stirred at rt. The reaction was monitored by TLC
and stopped after 15 min by neutralisation with triethylamine
(1.5 mL). The mixture was evaporated to dryness and after flash
chromatography with (PE–EA 1 : 1) compound 11 (103 mg,
0.44 mmol, 86%) was obtained. Colourless solid; C10H18O4S
(MW 234.314 g molϪ1); mp: 75 ЊC; [α]546 = ϩ107 (c = 1.24,
CHCl3); TLC (PE–EA 1 : 3): Rf = 0.51 (H2SO4). 1H NMR (400
3
MHz, CDCl3): δ = 4.73 (d, 1H, H-1, J1,2 = 2.0 Hz), 4.29 (dd,
1H, H-2, 3J1,2 = 2.0, 3J2,3 = 5.6 Hz), 3.98 (dd, 1H, H-3, 3J2,3 = 5.6,
3J3,4 = 7.1 Hz), 3.48 (ddd, 1H, H-4, 3J4,OH = 3.6, 3J3,4 = 7.1, 3J4,5
=
3
3
10.2 Hz), 3.27 (dq, 1H, H-5, J4,5 = 9.7, J5,6 = 6.1 Hz), 2.30 (s,
3H, SCH3), 2.17 (d, 1H, OH, 3J4,OH = 4.1 Hz), 1.58, 1.55 (2 × s,
3
2 × 3H, C(CH3)2), 1.36 (d, 3H, CH3-6, J5,6 = 6.1 Hz) ppm.
13C NMR (100.67 MHz, CDCl3): δ = 110.5 (2 × C(CH3)2), 82.1
(C-1), 80.2 (C-3), 76.3 (C-2), 75.1 (C-4), 74.8 (C-5), 28.2, 26.4
(2 × C(CH3)2), 17.5 (C-6), 14.8 (SCH3) ppm.
Methyl 2,3-O-isopropylidene-4-O-p-methoxybenzoyl-1-thio-ꢁ-L-
Methyl 2,3-O-isopropylidene-4-O-p-methoxybenzoyl-1-thio-
ꢀ-L-rhamnopyranoside (9)
In a 50 mL round flask compound 88 (1.7 g, 5.5 mmol) was
rhamnopyranoside (12)
Compound 78 (592 mg, 3.0 mmol), 2,2-dimethoxypropane
(6 mL) and p-toluenesulfonic acid monohydrate (31 mg,
0.03 mmol) were stirred at rt. The reaction was monitored by
dissolved in pyridine (2 mL) and anhydr. dichloromethane
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
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TLC and stopped after 30 min by neutralisation with triethyl-
amine (8 mL). The mixture was evaporated to dryness and
dissolved in anhydr. dichloromethane (1 mL) and pyridine
(1.0 mL, 4 eq, 12 mmol). Then a solution of p-methoxybenzoyl
chloride (614 mg, 3.6 mmol) in anhydr. dichloromethane (1 mL)
was added dropwise at 0 ЊC. The reaction was stirred for 18 h
while the temperature slowly increased to rt. Dichloromethane
was added and the mixture was washed twice with saturated
NaHCO3 solution and once with water, dried over MgSO4,
filtered, evaporated and distilled with toluene. After flash
chromatography (PE–EA 3 : 1) compound 12 (831 mg, 2.3
mmol, 75%) was obtained. Colourless solid; C18H24O6S (MW
368.446 g molϪ1); mp: 121 ЊC; [α]546 = ϩ79 (c = 0.75, CHCl3);
The solvent was removed under reduced pressure. The resulting
mixture was distilled with toluene four times and dissolved in
methanol (150 mL); 1 M methanolic sodium methanolate was
added until a pH of 9.5 was reached and the mixture was stirred
over night. The solution was then neutralized with acetic acid,
evaporated to dryness and dissolved in methanol. A suitable
amount of silica gel was added and the methanol was removed
under reduced pressure. The obtained powdery mixture was
placed on a prepacked column (PE–EA 1 : 1) and chromato-
graphed with PE–EA 1 : 1
1 : 2
0 : 1
EA–MeOH 10 : 1.
Compound 14 (8.05 g, 38.7 mmol 79%) was obtained and dis-
solved in pyridine (25 mL). The solution was cooled in an ice
bath and benzoyl chloride (14.81 mL, 127.5 mmol) and DMAP
(cat.) were added and the resulting solution was stirred over
1
TLC (PE–EA 1 : 1): Rf = 0.70 (UV, H2SO4). H NMR (400
MHz, CDCl3): δ = 7.99, 6.92 (2 × d, 2 × 2H, CH3OC6H4COO,
night at 0 ЊC
rt. The crude product was dissolved in
3
3
3J = 9.2, 9.2 Hz), 5.16 (dd, 1H, H-4, J3,4 = 7.1, J4,5 = 9.1 Hz),
4.78 (d, 1H, H-1, 3J1,2 = 2.0 Hz), 4.37 (dd, 1H, H-2, 3J1,2 = 2.0,
3J2,3 = 5.6 Hz), 3.87 (s, 3H, CH3OC6H4COO), 4.30 (dd, 1H, H-3,
dichloromethane and a suitable amount of silica gel was added.
The dichloromethane was removed cautiously under reduced
pressure and the obtained powdery mixture was placed on a
prepacked column and chromatographed with PE–EA 9 : 1.
The pure α-anomer 15 (13.21 g, 25.4 mmol, 66%) and the
anomeric mixture 15–16 (4.43 g, 8.51 mmol, 22%, α : β ≈ 1 : 4 by
1H NMR) were obtained. 15: colourless syrup; C29H28O7S (MW
520.594 g molϪ1); [α]D = ϩ91.9 (c = 0.9, CHCl3); lit.:9 no data
given; TLC (PE–EA 2 : 1): Rf = 0.55 (PE–EA 9 : 1), Rf = 0.16
(UV, H2SO4). 1H NMR (400 MHz, CDCl3): δ = 8.17, 8.00, 7.84
(3 × m, 3 × 2H, C6H5COO), 7.65–7.13 (m, 9H, C6H5COO),
5.82–5.69 (m, 3H, H-2, H-3, H-4), 5.50 (s, 1H, H-1), 5.57 (m,
1H, H-5), 2.83–2.67 (m, 2H, SCH2CH3), 1.39 (t, 3H, SCH2CH3,
3J = 7.3 Hz) ppm. 13C NMR (100.67 MHz, CDCl3): δ = 165.72,
3
3
3
3J2,3 = 5.6, J3,4 = 7.1 Hz), 3.56 (dq, 1H, H-5, J4,5 = 8.6, J5,6
=
6.1 Hz), 2.32 (s, 3H, SCH3), 1.65, 1.38 (2 × s, 2 × 3H, C(CH3)2),
3
1.30 (d, 3H, CH3-6, J5,6 = 6.1 Hz) ppm. 13C NMR (100.67
MHz, CDCl3): δ = 165.3 (CH3OC6H4COO), 163.6, 122.1, 113.7
(CH3OC6H4COO), 110.9 (C(CH3)2), 82.3 (C-1), 77.2 (C-3), 76.2
(C-2), 74.3 (C-4), 74.2 (C-5), 55.5 (OCH3), 26.3, 27.6 (C(CH3)2),
17.9 (SCH3), 14.8 (C-6) ppm.
Methyl 4-O-tert-butyldimethylsilyl-2,3-O-isopropylidene-1-
thio-ꢁ-L-rhamnopyranoside (13)
Compound 78 (0.333 g, 1.71 mmol), 2,2-dimethoxypropane
(4 mL) and p-toluenesulfonic acid monohydrate (16 mg,
0.03 mmol) were stirred at rt. The reaction was monitored
by TLC and stopped after 20 min by neutralisation with
triethylamine (5 mL). The mixture was evaporated to dryness,
dissolved in anhydr. DMF (10 mL) and cooled in an ice bath.
Imidazole (136 mg, 2 mmol) and tert-butyldimethylchlorosilane
(301 mg, 2 mmol) were added and the mixture was stirred for
2 d at rt. The reaction was monitored by TLC. After complete
conversion of the starting material the reaction was stopped by
addition of a ten-fold excess of toluene and the resulting
mixture was washed three times with saturated NaHCO3
solution and once with water, dried over sodium sulfate, filtered
and evaporated. After flash chromatography (PE–EA 20 : 1)
compound 13 (417 mg, 1.20 mmol, 70%) was obtained. Colour-
less syrup; C16H32O4SSi (MW 348.574 g molϪ1); [α]D = ϩ54
(c = 1.4, CHCl3); TLC (PE–EA 2 : 1): Rf = 0.76 (UV, H2SO4). 1H
NMR (400 MHz, CDCl3): δ = 4.56 (d, 1H, H-1, 3J1,2 = 1.0 Hz),
4.12 (dd, 1H, H-2, 3J1,2 = 1.0, 3J2,3 = 5.6 Hz), 3.80 (dd, 1H, H-3,
3J2,3 = 6.6, 3J3,4 = 6.6 Hz), 3.30 (dd, 1H, H-4, 3J3,4 = 7.1, 3J4,5 = 8.7
165.50, 165.36 (3 × C6H5COO), 133.47, 133.34, 133.13, 129.92–
1
129.50, 129.30–128.30 (3 × C6H5COO), 82.35 (C-1, JH,C
=
169.4 Hz), 72.82, 72.22 (C-2, C-3), 70.59 (C-4), 67.54 (C-5),
25.98 (SCH2CH3), 17.90 (C-6), 15.24 (SCH2CH3) ppm. 16:
syrup; C29H28O7S (MW 520.594 g molϪ1); TLC (PE–EA 2 : 1):
Rf = 0.30, (PE–EA 9 : 1): Rf = 0.06 (UV, H2SO4). 1H NMR (400
MHz, CDCl3): δ = 8.09, 7.96, 7.77 (3 × m, 3 × 2H, C6H5COO),
3
7.63–7.20 (m, 9H, C6H5COO), 5.98 (dd, 1H, H-2, J1,2 = 1.0,
3J2,3 = 3.1 Hz), 5.66–5.56 (m, 2H, H-3, H-4), 5.50 (d, 1H, H-1,
3J1,2 = 0.8 Hz), 3.89 (m, 1H, H-5), 2.84–2.76 (m, 2H, SCH2CH3),
3
1.45 (d, 3H, CH3-6, J5,6 = 6.4 Hz), 1.32 (t, 3H, SCH2CH3,
3J = 7.5 Hz) ppm. 13C NMR (100.67 MHz, CDCl3): δ =
165.71–165.63 (3 × C6H5COO), 133.36, 133.18, 130.19–129.69,
129.30–128.96, 128.55–128.25 (3 × C6H5COO), 82.53 (C-1),
75.30 (C-5), 72.70, 71.41 (C-3, C-4), 71.68 (C-2), 25.78
(SCH2CH3), 18.05 (C-6), 14.91 (SCH2CH3) ppm.
3,4,6-Tri-O-acetyl-1,2-O-(1-ethylthioethylidene)-ꢀ-D-
glucopyranose (18)
3
3
Hz), 3.09 (dq, 1H, H-5, J4,5 = 8.7, J5,6 = 6.6 Hz), 2.14 (s, 3H,
SCH3), 1.41, 1.22 (2 × s, 2 × 3H, C(CH3)2), 1.15 (d, 3H, CH3-6,
3J5,6 = 6.6 Hz), 0.75 (s, 9H, C(CH3)3), 0.14, 0.08 (2 × s, 2 × 3H,
Si(CH3)2) ppm. 13C NMR (100.67 MHz, CDCl3): δ = 110.0
(C(CH3)2), 82.3 (C-1), 80.5 (C-3), 76.3 (C-2), 76.1 (C-5), 75.6
(C-4), 28.1, 26.4 (C(CH3)2), 25.9 (C(CH3)3), 18.2 (C-6), 14.8
(SCH3), Ϫ4.0, Ϫ4.9 (Si(CH3)2) ppm.
In a 250 mL round flask 2,3,4,6-tetra-O-acetyl-α--gluco-
pyranosyl bromide (17, 20.75 g, 50.46 mmol)19 was dissolved in
anhydr. acetonitrile (55 mL) under an argon atmosphere and
sym-collidine (8.63 mL, 65.1 mmol) and tetrabutylammonium
bromide (1.65 g, 5 mmol) were added. The flask was sealed with
a septum and an argon filled balloon was attached. Ethanethiol
(5 mL, 67.7 mmol) was added by a syringe and the mixture was
stirred overnight. The reaction was monitored by TLC until
conversion was complete. The solvent was removed under
reduced pressure. The resulting mixture was distilled with
toluene four times, dissolved in peroxide-free diethyl ether and
washed seven times with water to remove the collidinium
hydrobromide; the residue was filtered and evaporated to
dryness. The crude product was purified by flash chromato-
graphy (PE–EA–NEt3 3 : 2 : 0.1) to obtain 18 (12.23 g, 31.17
mmol, 62%). Colourless syrup; C16H24O9S (MW 392.422 g
molϪ1); [α]D = ϩ28.3 (c = 1, CHCl3); lit.:12 syrup, [α]D = ϩ32.1
(c = 1, CHCl3); TLC (PE–EA–NEt3 3 : 2 : 0.1): Rf = 0.46
(H2SO4). 1H NMR (400 MHz, CDCl3): δexo = 5.70 (d, 1H, H-1,
Ethyl 2,3,4-tri-O-benzoyl-1-thio-ꢀ-L-rhamnopyranoside (15) and
ethyl 2,3,4-tri-O-benzoyl-1-thio-ꢁ-L-rhamnopyranoside (16)
In a 250 mL round flask -rhamnopyranose tetraacetate10,11 (5,
16.20 g, 48.75 mmol) was dissolved under an argon atmosphere
in anhydr. dichloromethane (60 mL). The flask was sealed with
a septum and an argon filled balloon was attached. Ethanethiol
(5.78 mL, 78.00 mmol) was added by a syringe and the mixture
was cooled in an ice bath. Then boron trifluoride–etherate
(15.44 mL, 121.9 mmol) was added by a syringe. The reaction
was monitored by TLC with PE–EA 2 : 1 (Rf (5) = 0.82, Rf (14)
= 0.55) until conversion was complete after 90 min. The
reaction was stopped by cooling in an ice bath, injecting
triethylamine (20 mL) to the mixture and stirring for 10 min.
3
3
3J1,2 = 5.1 Hz), 5.20 (dd∼t, 1H, H-3, J2,3 = 2.0, J3,4 = 2.5 Hz),
4.90 (dd, 1H, H-4, 3J3,4 = 2.5, 3J4,5 = 9.7 Hz), 4.47 (dd, 1H, H-2,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
4376

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3J1,2 = 5.1, 3J2,3 = 2.0 Hz), 4.19 (d, 2H, H-6a,b, 3J5,6 = 4.1 Hz), 3.97
(ddd∼dt, 1H, H-5, 3J4,5 = 9.7, 3J5,6a = 3J5,6b = 4.1 Hz), 2.61 (q, 2H,
SCH2CH3), 2.13 (s, 3H, CH3COO), 2.09 (2 × s, 2 × 3H,
2 × CH3COO), 1.96 (s, 3H, endo-CH3C[OR]2SEt,exo), 1.25 (t,
71.6 (C-4), 63.1 (C-6), 29.1 (endo-CH3C[OR]2SEt,exo), 24.8
(SCH2CH3), 19.3 (C(CH3)3), 17.5–17.1 (tBu-, CH(CH3)2), 15.2
(SCH2CH3), 13.0–12.2 (CH(CH3)2) ppm.
3
3H, SCH2CH3, J = 7.6 Hz) ppm. 13C NMR (100.67 MHz,
Ethyl 2-O-acetyl-6-O-(tert-butyldiphenylsilyl)-3,4-O-(1,1,3,3-
tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-D-glucopyranoside
(21)
CDCl3):δexo=170.7,169.7,169.2(CH3COO),116.3(CH3C[OR]2SEt),
97.3 (C-1), 73.1, 69.8, 68.4, 66.8 (C-2, C-3, C-4, C-5), 63.1
(C-6), 27.4 (endo-CH3C[OR]2SEt,exo), 24.9 (SCH2CH3), 20.8
(CH3COO), 15.1 (SCH2CH3) ppm.
In a 100 mL round flask compound 20 (935 mg, 1.25 mmol) was
distilled with toluene three times. Then freshly activated MS
4 Å were added. The round flask was sealed with a septum,
flushed with argon via a syringe, and an argon filled balloon was
attached. Fresh anhydr. dichloromethane (20 mL) was added,
and the mixture was stirred for 30 min at rt. Then ethanethiol
(28 µL, 0.125 mmol) was added and stirring was continued for a
further 30 min. In another round flask under strict anhydrous
conditions and argon atmosphere a mixture of TMSOTf
(0.23 mL) and anhydr. dichloromethane (0.77 mL) was freshly
1,2-O-(1-Ethylthioethylidene)-ꢀ-D-glucopyranose (19)
Compound 1812 (5.40 g, 13.76 mmol) was dissolved in anhydr.
methanol (40 mL) under an argon atmosphere and a 1 M
methanolic sodium methanolate solution (1.1 mL) was added.
The reaction mixture was stirred for 1.5 h at rt and was moni-
tored by TLC until conversion was complete (PE–EA–NEt3
3 : 2 : 0.1: Rf(18) = 0.46, Rf(19) = 0). The crude product was
purified by flash chromatography (EA–EtOH–NEt3 10 : 1 : 0.1)
to obtain 19 (3.06 g, 11.49 mmol, 84%), as well as 603 mg 19
together with some sym-collidine. Colourless oil; C10H18O6S
(MW 266.312 g molϪ1); [α]D = ϩ6.5 (c = 1, CHCl3); TLC
(EA–EtOH–NEt3 10 : 1 : 0.1): Rf = 0.26 (H2SO4). 1H NMR (400
prepared. The orthoester rearrangement was started by the
᎐
addition of a 0.1 mL of this mixture (᎐ 23 µL, 0.125 mmol
᎐
TMSOTf ) to the reaction mixture and stopped after stirring for
5 min by addition of triethylamine (0.2 mL). The molecular
sieves were filtered over Celite and washed with dichloro-
methane. The filtrate was evaporated and the resulting syrup
was distilled twice with toluene. After flash chromatography
with PE–Et2O 30 : 1 compound 21 (419 mg, 0.56 mmol, 45%,
3
MHz, CDCl3): δexo = 5.79 (d, 1H, H-1, J1,2 = 5.1 Hz), 4.42
(dd∼t, 1H, H-2, 3J1,2 = 5.1, 3J2,3 = 4.6 Hz), 4.00 (dd∼t, 1H, H-3,
3J2,3 = 4.1, 3J3,4 = 4.1 Hz), 3.90–3.82 (m, 2H, H-6a,b), 3.78 (dd,
3
3
3
1
1H, H-4, J3,4 = 4.1, J4,5 = 8.7), 3.66 (dd, 1H, H-5, J4,5 = 9.2
α : β ≈ 1 : 4 by H NMR) was obtained. Colourless solid;
3
Hz), 2.62 (q, 2H, SCH2CH3, J = 7.6, 7.1 Hz), 1.93 (s, 3H,
C38H62O7SSi3 (MW 747.217 g molϪ1); calc.: C 61.08, H 8.36;
found: C 61.37, H 8.40%; TLC (PE–Et2O–NEt3 30 : 1 : 0.1): Rf
= 0.36 (UV, H2SO4). 1H NMR (400 MHz, CDCl3): δ = 7.74–7.65
(m, 2 × 4H, 2 × tBuPh2Si), 7.44–7.31 (m, 2 × 6H, 2 × tBuPh2Si),
5.59 (d, 1H, H-1a, 3J1,2 = 5.6 Hz), 4.99–4.92 (m, 2 × 1H, H-2a,
H-2β), 4.44 (d, 1H, H-1β, 3J1,2 = 10.2 Hz), 4.10 (ddd, 1H, H-5a,
3J4,5 = 8.1, 3J5,6a = 2.0, 3J5,6b = 6.2 Hz), 3.97 (dd, 1H, H-6aβ, 3J5,6a
3
endo-CH3C[OR]2SEt,exo), 1.25 (t, 3H, SCH2CH3, J = 7.6, 7.1
Hz) ppm. 13C NMR (100.67 MHz, CDCl3): δexo = 116.0
(CH3C[OR]2SEt), 98.3 (C-1), 75.9, 73.2, 72.3, 69.1 (C-2, C-3,
C-4, C-5), 62.2 (C-6), 28.0 (endo-CH3C[OR]2SEt,exo), 24.9
(SCH2CH3), 14.2 (SCH2CH3) ppm.
2
= 2.0, J6a,6b = 11.2 Hz), 3.97–3.90 (m, 2H, H-3a, H-6aa), 3.83
6-O-tert-Butyldiphenylsilyl-3,4-O-(1,1,3,3-tetraisopropyl-1,3-
disiloxane-1,3-diyl)-1,2-O-(1-ethylthioethylidene)-ꢀ-D-gluco-
pyranose (20)
3
2
(dd, 1H, H-6bβ, J5,6b = 5.6, J6a,6b = 11.2 Hz), 3.80 (dd, 1H,
3
2
H-6ba, J5,6b = 6.1, J6a,6b = 11.2 Hz), 3.76–3.67 (m, 2H, H-3β,
H-4β), 3.61 (dd, 1H, H-4a, 3J3,4 = 9.7, 3J4,5 = 8.1 Hz), 3.57 (ddd,
3
3
In a 10 mL round flask compound 19 (1.26 g, 4.74 mmol)
was dissolved in anhydrous DMF (3 mL) under argon and
imidazole (645 mg, 9.48 mmol) was added. The mixture was
cooled in an ice bath while tert-butyldiphenylchlorosilane (1.21
mL, 4.74 mmol) was added, and stirred for 12 h at rt. The
reaction was monitored by TLC (PE–EA–NEt3 10 : 1 : 0.1:
Rf(19) = 0, Rf (intermediate) = 0.28). After complete conversion
of the starting material to the intermediate the mixture was
cooled again in an ice bath and another portion of imidazole
(1.25 g, 18.4 mmol) and TIPDS-dichloride (1.42 mL, 4.45
mmol, 0.95 eq.) were added. The reaction was stirred in an ice
bath for 6 h and observed by TLC (PE–EA–NEt3 10 : 1 : 0.1).
After completion a 10-fold excess of toluene was added, the
solution was washed three times with saturated NaHCO3
solution and once with water, dried over sodium sulfate and
evaporated. The product was purified by flash chromatography
(PE–Et2O–NEt3 30 : 1 : 0.015) to obtain compound 20 (2.095 g,
2.8 mmol, 63% based on TIPDS-dichloride, 59% based on 19).
1H, H-5β, J4,5 = 8.1, J5,6 = 2.0, 6.1 Hz), 2.81–2.65 (m, 2H,
SCH2CH3), 2.64–2.48 (m, 2H, SCH2CH3), 2.08 (2 ×s, 2 × 3H,
2 × CH3COO), 1.28 (m, 3H, SCH2CH3), 1.24 (m, 3H, SCH2-
CH3), 1.11–0.84 (m, 2 × tBuPh2Si, 2 × ROSiiPr2OSiiPr2OR)
ppm. 13C NMR (100.67 MHz, CDCl3): δ = 169.40 (CH3COO),
135.81–135.32, 133.69, 133.42, 129.54–127.56 (2 × tBuPh2Si),
82.83 (C-1β), 81.13 (C-5β), 80.70 (C-1a), 79.04, 73.00 (C-3β,
C-4β), 83.17 (C-3a), 73.53 (C-4a), 72.89 (C-2a), 72.73 (C-5a),
72.06 (C-2β), 63.43 (C-6a, C-6β), 26.81 (2 × (CH3)3CPh2Si),
23.69 (SCH2CH3β), 20.86 (CH3COOβ), 19.25 ((CH3)3CPh2Si),
17.40–17.15 ((CH3)2CH), 14.86 (SCH2CH3β), 12.86, 12.74,
12.29, 12.14 (4 × (CH3)2CHβ) ppm.
Diosgen-3ꢁ-yl 2-O-acetyl-6-O-tert-butyldiphenylsilyl-3,4-O-
(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-ꢁ-D-glucopyrano-
side (22)
Method e (cf. Scheme 3). Diosgenin (4, 122 mg, 0.29 mmol),
20 (200 mg, 0.27 mmol), anhydr. diethyl ether (2.2 mL) and
anhydr. dichloromethane (2.2 mL) were placed under an argon
atmosphere in a dry two neck flask together with powdery and
dry MS 4 Å (ca. 500 mg) and were stirred for 1 h. Then
N-iodosuccinimide (61 mg, 0.27 mmol) was added. After
another 2 h of stirring a solution (0.2 mL) of triflic acid (0.1
mL) in Et2O–CH2Cl2 1 : 1 (9.9 mL) was added via a syringe. The
reaction was monitored by TLC (PE–EA 15 : 1). A five-fold
excess of dichloromethane was added and molecular sieves
were removed by filtration over Celite. The Celite was washed
with dichloromethane. The red filtrate was decolorised with
10% aqueous sodium disulfite solution, washed once with
saturated NaHCO3, and dried over sodium sulfate. The solvent
was removed and the crude product was purified twice by flash
Colourless solid; C38H62O7SSi3 (MW 747.217 g molϪ1); [α]D
=
ϩ64.5 (c = 1, CHCl3); TLC (PE–EA–NEt3 10 : 1 : 0.1): Rf =
1
0.69; (PE–Et2O–NEt3 30 : 1 : 0.1): Rf = 0.50 (UV, H2SO4). H
NMR (400 MHz, CDCl3): δexo = 7.71–7.66 (m, 4H, o-Ph), 7.44–
3
7.33 (m, 6H, Ph), 5.87 (d, 1H, H-1, J1,2 = 5.1 Hz), 4.15 (dd∼t,
3
3
1H, H-2, J1,2 = 5.1, J2,3 = 5.1 Hz), 3.98 (dd, 1H, H-6a,
3J5,6a = 2.1, J6a,6b = 11.2 Hz), 3.89 (dd, 1H, H-6b, J5,6b = 4.3,
2J6a,6a = 11.2 Hz), 3.79 (dd∼t, 1H, H-3, 3J2,3 = 5.1, 3J3,4 = 4.6 Hz),
3.74 (m, 1H, H-4), 3.69 (m, 1H, H-5), 2.61 (q, 2H, SCH2CH3,
3J = 7.6 Hz), 1.93 (s, 3H, endo-CH3C[OR]2SEt,exo), 1.25 (t,
2
3
3
3H, SCH2CH3, J = 7.6 Hz), 1.04 (s, 9H, tBu), 1.10–0.91 (m,
28H, 4 × iPr) ppm. 13C NMR (100.67 MHz, CDCl3): δexo
=
133.8, 133.4, 135.9, 135.7, 129.6, 129.5, 127.5 (Ar), 114.7
(CH3C[OR]2SEt), 98.9 (C-1), 79.5 (C-3), 78.9 (C-2), 74.6 (C-5),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
4377

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chromatography (PE–EA 15 : 1) to give compound 22 (153 mg,
0.139 mmol, 52%).
(ddd∼q, 1H, H-16, 3J = 7.6, 7.1 Hz), 3.98 (dd, 1H, H-6Јa, 3J5Ј,6Јa
= 1.5, 2J6Јa,6Јb = 10.7 Hz), 3.78 (dd, 1H, H-6Јb, 3J5Ј,6Јb = 6.6, 2J6Јa,6Јb
= 10.7 Hz), 3.70–3.59 (m, 2H, H-3, H-3Ј), 3.54 (dd∼t, 1H, H-4Ј,
3J = 9.2, 8.6 Hz), 3.47 (dd, 1H, H-26eq), 3.44–3.34 (m, 3H, H-2Ј,
H-5Ј, H-26ax), 2.43 (m, 1H), 2.32 (m, 2H), 2.09–0.76 (m, 68H,
steroid H, iPr, tBu) ppm. 13C NMR (100.67 MHz, CDCl3):
δ = 140.8 (C-5), 135.7, 135.6, 133.6, 129.5, 127.6 (Ar), 121.2
(C-6), 109.3 (C-22), 100.7 (C-1Ј), 81.0 (C-16), 80.1, 79.0 (C-3,
C-3Ј), 77.8, 74.2 (C-2Ј, C-5Ј), 73.2 (C-4Ј), 67.1 (C-26), 63.9
(C-6Ј), 62.1, 56.5, 41.6, 40.0, 38.9, 37.2, 32.2, 31.4, 30.7, 30.3,
30.0, 29.4, 28.3 (steroid C), 26.8 (C(CH3)3), 19.4, 19.3, 17.3–
17.2, 16.3, 14.5 (C-18, Ϫ19, Ϫ21, Ϫ27, CH(CH3)2, C(CH3)3),
12.8–12.2 (CH(CH3)2) ppm.
Method f (cf. Scheme 3). Diosgenin (4, 232 mg, 0.56 mmol),
21 (380 mg, 0.51 mmol) and MS 4 Å (ca. 500 mg) were stirred
under argon in dichloromethane (40 mL) for 1 h. Then DMTST
(394 mg, 1.53 mmol) was added. The reaction mixture was
stirred for 24 h at rt. After completion triethylamine (0.5 mL)
was added and the mixture was stirred for another 10 min. The
molecular sieves were removed by filtration over Celite, and the
filtrate was evaporated in the presence of a suitable amount
of silica gel. The obtained powdery mixture was placed
on a prepacked column of silica gel and chromatographed
with PE–EA 30 : 1 to give compound 22 (151 mg, 0.142 mmol,
28%).
Diosgen-3ꢁ-yl 6-O-tert-butyldiphenylsilyl-2-O-(2,3-O-isopropyl-
idene-4-O-p-methoxybenzoyl-L-rhamnopyranosyl)-3,4-O-
(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-ꢁ-D-glucopyrano-
side (24)
Colourless solid; C63H98O10Si3 (MW 1099.703 g molϪ1); mp:
85.3 ЊC; [α]D = Ϫ36.8 (c = 1, CHCl3); TLC (PE–EA 15 : 1): Rf =
1
0.24 (UV, H2SO4). H NMR (400 MHz, CDCl3): δ = 7.68 (d,
3
4H, Ar), 7.45–7.35 (m, 6H, Ar), 5.34 (br d, 1H, H-6, J = 4.1
In a dried two neck flask the donor 12 (52 mg, 0.14 mmol) and
acceptor 23 (112 mg, 0.106 mmol) were dissolved in anhydr.
diethyl ether (1.1 mL) and anhydr. dichloromethane (1.1 mL)
under an argon atmosphere. Powdery and activated molecular
sieves 4 Å (ca. 1 g) were added and stirred for 1 h. Then NIS (32
mg, 0.14 mmol) was added and the reaction was monitored
by TLC (PE–EA 10 : 1, Rf(23) = 0.20, Rf(12) = 0.04). A five-fold
excess of dichloromethane was added and molecular sieves
were removed by filtration over Celite. The Celite was washed
with dichloromethane. The red filtrate was decolorised with
10% aqueous sodium disulfite solution, washed once with
saturated NaHCO3, and dried over sodium sulfate. The solvent
was removed and the crude product was purified twice by flash
chromatography (PE–EA 10 : 1) to give compound 24 (21 mg,
0.015 mmol, 14%, α : β = 2.9 : 1 by 1H NMR). Colourless solid;
C78H116O15Si3 (MW 1378.003 g molϪ1); TLC (PE–EA 10 : 1): Rf
= 0.13 (UV, H2SO4). 1H NMR (400 MHz, CDCl3): δ = 8.01–7.95
(m, 2H, CH3OC6H4COO), 7.70–7.65 (m, 4H, Ar), 7.43–7.31 (m,
6H, Ar), 6.87 (d, 2H, CH3OC6H4COO, 3J = 8.8 Hz), 5.54 (s, 1H,
H-1Љ), 5.40 (d, 1H, H-6, 3J = 5.0 Hz), 5.31 (d, 1H, H-6β, 3J = 5.0
3
3
Hz), 4.88 (dd∼t, 1H, H-2Ј, J1Ј,2Ј, J2Ј,3Ј = 8.7 Hz), 4.51 (d, 1H,
H-1Ј, 3J1Ј,2Ј = 8.1 Hz), 4.41 (q, 1H, H-16, 3J = 7.1, 7.6 Hz), 3.98
3
2
(dd, 1H, H-6Јa, J5Ј,6Јa ≈ 0, J6Јa,6Јb = 10.7 Hz), 3.80 (dd, 1H,
3
2
H-6Јb, J5Ј,6Јb = 6.6, J6Јa,6Јb = 10.7 Hz), 3.71 (dd∼t, 1H, H-3Ј,
3
3
3J2Ј,3Ј = 8.6, J3Ј,4Ј = 9.2 Hz), 3.60 (dd∼t, 1H, H-4Ј, J3Ј,4Ј = 9.2,
3J4Ј,5Ј = 8.6 Hz), 3.56–3.44 (m, 2H, H-3, H-26eq), 3.41–3.34 (m,
2H, H-5Ј, H-26ax), 2.33–2.18 (m, 2H), 2.05 (s, 3H, CH3COO),
1.90–1.40, 1.29–0.76 (m, steroid H) ppm. 13C NMR (100.67
MHz, CDCl3): δ = 169.2 (CH3COO), 140.8 (C-5), 135.7, 135.5,
133.7, 133.6, 129.5, 127.5 (Ar), 121.4 (C-6), 109.3 (C-22), 99.7
(C-1Ј), 80.8 (C-16), 79.4 (C-3), 77.7 (C-3Ј), 76.9 (C-5Ј), 73.4
(C-2Ј), 66.7 (C-26), 63.8 (C-6Ј), 62.1, 56.5, 50.1, 41.6, 31.6, 30.3
(CH), 40.3, 36.9 (C-10, C-13), 39.7, 38.6, 37.4, 32.1, 32.0, 29.5,
28.8 (CH2), 26.8 (C(CH3)3), 20.9 (CH3COO), 17.3–17.1 (steroid
C, CH(CH3)2), 19.4, 19.3, 16.4, 14.5 (C-18, Ϫ19, Ϫ21, Ϫ27),
12.7–12.1 (CH(CH3)2) ppm.
Diosgen-3ꢁ-yl 6-O-tert-butyldiphenylsilyl-3,4-O-(1,1,3,3-tetra-
isopropyl-1,3-disiloxane-1,3-diyl)-ꢁ-D-glucopyranoside (23)
3
Hz), 5.11 (d, 1H, H-1Љβ, J1Љ,2Љ = 1.3 Hz), 5.08 (dd, 1H, H-4Љ,
Diosgenin (4, 352 mg, 0.85 mmol), 20 (600 mg, 0.8 mmol),
anhydr. diethyl ether (5 mL) and anhydr. dichloromethane
(5 mL) were placed under argon atmosphere in a dry two neck
flask together with powdery and dry MS 4 Å ( (1 g) and were
stirred for 1 h. Then N-iodosuccinimide (181 mg, 0.8 mmol)
was added. After another 2 h of stirring a solution (0.2 mL) of
triflic acid (0.1 mL) in Et2O–CH2Cl2 1 : 1 (9.9 mL) was added
via a syringe. The reaction was monitored by TLC (PE–EA
15 : 1, Rf(22) = 0.24). A five-fold excess of dichloromethane was
added and molecular sieves were removed by filtration over
Celite. The Celite was washed with dichloromethane. The red
filtrate was decolorised with 10% aqueous sodium disulfite
solution, washed once with saturated NaHCO3, and dried over
sodium sulfate. The solvent was removed and the crude product
was purified twice by flash chromatography (PE–EA 15 : 1) to
give compound 22, which was converted as follows. Under
argon the purified compound was placed in anhydr. methanol
(10 mL) and small portions of dichloromethane were added
until the solid was completely dissolved. A solution (5 mL) of
potassium carbonate (5.6 g) in methanol (70 mL) was added
and the reaction mixture was stirred for 3 d at rt. The reaction
was monitored by TLC (PE–EA 15 : 1, Rf(22) = 0.24). The pH
was lowered to 4 by stirring with Amberlite IR 120 (Hϩ). The
resin was removed by filtration and the solvent was evaporated.
The crude product was purified by flash chromatography
(PE–EA 15 : 1) to give compound 23 (355 mg, 0.336 mmol,
42%). Colourless solid; C61H96O9Si3 (MW 1057.666 g molϪ1);
mp: 92.8–93.3 ЊC; [α]D = Ϫ46.5 (c = 1, CHCl3); TLC (PE–EA
3
3
3J3Љ,4Љ = 7.6, J4Љ,5Љ = 10.6 Hz), 5.02 (dd, 1H, H-4Љβ, J3Љ,4Љ = 6.0,
3J4Љ,5Љ = 8.2 Hz), 4.58 (d, 1H, H-1Јβ, 3J1Ј,2Ј = 8.2 Hz), 4.49 (d, 1H,
H-1Ј, 3J1Ј,2Ј = 7.9 Hz), 4.47–4.38 (m, 2H, H-16, H-5Љ), 4.37–4.34
3
3
(m, 2H, H-2Љβ, H-3Љβ), 4.29 (dd, 1H, H-3Љ, J2Љ,3Љ = 5.4, J3Љ,4Љ
=
3
7.3 Hz), 4.22 (d, 1H, H-2Љ, J2Љ,3Љ = 5.4 Hz), 4.01–3.97 (m, 2H,
H-6Јa, H-6Јaβ), 3.85 (s, 3H, OMe), 3.83–3.72 (m, 4H, H-3Ј,
H-3Јβ, H-6Јb, H-6Јbβ), 3.71–3.62 (m, 2H, H-3, H-2Ј), 3.61–3.54
(m, 2H, H-3β, H-2Јβ), 3.54–3.44 (m, 4H, H-4Ј, H-4Јβ, H-26a,
H-26aβ), 3.43–3.32 (m, 4H, H-5Ј, H-5Јβ, H-26b, H-26bβ),
2.47–0.75 (m, steroid H, iPr, tBu) ppm. 13C NMR (100.67 MHz,
CDCl3): δ = 165.4 (CH3OC6H4COO), 135.6–127.6 (Ar), 121.6
(C-6), 113.5 (γ-CH3OC6H4COO), 109.3 (C-22), 99.9 (C-1Ј),
97.4 (C-1Љ), 80.9 (C-3Ј), 80.8 (C-16), 79.0 (C-3), 77.5 (C-5Ј), 77.3
(C-2Ј), 75.9, 75.8 (C-2Љ, C-3Љ), 75.6 (C-4Љ), 73.0 (C-4Ј), 66.4
(C-26), 64.0 (C-6Ј, C-5Љ), 55.4 (CH3OC6H4COO), 41.6–12.2
(steroid C, iPr, tBu) ppm.
Diosgen-3ꢁ-yl 2-O-(2,3,4-tri-O-benzoyl-ꢀ-L-rhamnopyranosyl)-
6-O-tert-butyldiphenylsilyl-3,4-O-(1,1,3,3-tetraisopropyldisi-
loxane-1,3-diyl)-ꢁ-D-glucopyranoside (25)
In a 100 mL round flask acceptor 23 (96 mg, 0.09 mmol) and
donor 159 (84 mg, 0.16 mmol, 1.8 eq) were dissolved under an
argon atmosphere in fresh anhydr. diethyl ether (80 mL). MS
4 Å (ca. 2 g) was added, the flask was sealed with a septum, an
argon filled balloon was attached and the mixture was stirred
for 2 h at rt. The reaction was started by addition of DMTST
(120 mg, 0.46 mmol, 5 eq.), and the mixture was stirred for 12 h
at rt. To stop the reaction triethylamine (0.2 mL) was added and
the mixture was stirred for 10 min. The molecular sieves were
filtered over Celite. Silica gel (ca. 10 mL) was added to the
1
15 : 1): Rf = 0.15 (UV, H2SO4). H NMR (400 MHz, CDCl3):
δ = 7.70–7.65 (m, 4H, Ar), 7.43–7.30 (m, 6H, Ar), 5.35 (d, 1H,
3
3
H-6, J = 5.1 Hz), 4.47 (d, 1H, H-1Ј, J1Ј,2Ј = 8.1 Hz), 4.41
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
4378

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filtrate and the solvent was removed. The obtained powdery
mixture was placed on a prepacked column of silica gel
(PE–EA 30 : 1) and chromatographed with PE–EA 30 : 1
PE–EA 10 : 1 to give compound 25 (74 mg, 0.05 mmol, 53%).
Colourless plates; C88H118O16Si3 (MW 1516.125 g molϪ1); calc.:
Acknowledgements
Support of this study by the Fonds der Chemischen Industrie is
gratefully acknowledged.
C 69.71, H 7.84; found: C 69.01, H 7.88%; mp: 117.6 ЊC; [α]D
=
References
ϩ27.7 (c = 1, CHCl3); TLC (PE–EA 5 : 1): Rf = 0.36 (UV,
H2SO4). MALDI TOF MS (DHB, positive mode): 1515.94 [M
ϩ H]ϩ (calc.: 1515.78), 1537.98 [M ϩ Na]ϩ (calc.: 1537.76),
1553.94 [M ϩ K]ϩ (calc.: 1553.74). 1H NMR (400 MHz,
CDCl3): δ = 8.04, 7.93, 7.80 (3 × dd, 3 × 2H, o-Bz, Jo,m = 7.1, Jo,p
= 1.0, 1.5 Hz), 7.69 (dd, 4H, o-SiPh2tBu, Jo,m = 6.6, Jo,p = 1.5 Hz),
7.60 (dt, 1H, p-Bz, Jm,p = 7.6, Jo,p = 1.0, 1.5 Hz), 7.52–7.45 (m,
2H, m/p-Bz), 7.45–7.21 (m, 11H, m/p-Bz, m/p-SiPh2tBu),
5.83–5.77 (m, 2H, H-2Љ, H-3Љ), 5.63 (dd∼t, 1H, H-4Љ, 3J3Љ,4Љ = 9.7,
3J4Љ,5Љ = 10.2 Hz), 5.53 (br s, 1H, H-1Љ, J1Љ,2Љ ≈ 0 Hz), 5.45 (br d,
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3
3
1H, H-6, J = 4.6 Hz), 4.94 (dq, 1H, H-5Љ, J4Љ,5Љ = 10.2, J5Љ,6Љ
=
3
6.2 Hz), 4.64 (d, 1H, H-1Ј, J1Ј,2Ј = 8.1 Hz), 4.44 (ddd∼q, 1H,
3
3
H-16, J = 7.6, 14.8 Hz), 4.01 (dd, 1H, H-6Јa, J5Ј,6Јa = 1.0,
2J6Јa,6Јb = 9.2 Hz), 3.91 (dd∼t, 1H, H-3Ј, 3J = 9.2, 8.2 Hz),
3.81–3.70 (m, 3H, H-3, H-2Ј, H-6Јb), 3.54–3.42 (m, 3H, H-4Ј,
H-5Ј, H-26a), 3.39 (dd∼t, 1H, H-26b, J = 11.2, 10.7 Hz), 2.63
2
3
(m∼dd, 1H, H-4eq, J4eq,4ax = 13.2, J3,4eq = 2.5 Hz), 2.46 (m∼t,
2
3
1H, H-4ax, J4eq,4ax = 13.2, J3,4ax = 11.2 Hz), 2.16 (m∼d, 1H,
CH, J = 11.7 Hz), 2.07–1.97 (m, 2H, CH), 1.93–0.77 (m, steroid
H, Si–iPr), 1.37 (d, 3H, H-6Љ), 1.07 (bs, 9H, Si–tBu). 13C NMR
(100.62 MHz, CDCl3): δ = 165.8, 165.7, 165.3 (3 × C6H5COO),
140.5 (C-5), 135.8–135.7 (SiPh2tBu), 133.8–133.1 (m-Bz),
130.0–129.6 (o-Bz), 128.6–127.7 (Ar), 122.1 (C-6), 109.4 (C-22),
100.0 (C-1Ј), 98.2 (C-1Љ), 81.2 (C-3Ј), 81.0 (C-16), 79.5 (C-3),
76.8 (C-5Ј), 76.6 (C-2Ј), 73.6 (C-4Ј), 72.2 (C-4Љ), 70.5, 70.3
(C-2Љ, C-3Љ), 67.0 (C-26), 66.5 (C-5Љ), 64.2 (C-6Ј), 39.9 (C-4),
37.4, 37.0 (C-10, C-13), 62.3, 56.6, 50.2, 41.8, 31.7, 30.4 (C-8,
C-9, C-14, C-17, C-20, C-25), 40.4, 39.2, 32.3, 32.1, 31.6,
30.2, 29.0, 20.9 (C-1, C-2, C-7, C-11, C-12, C-15, C-23, C-24),
26.9 (SiC(CH3)3), 19.4, 17.4, 16.4, 14.7 (C-18, C-19, C-21,
C-27), 17.5–17.3 (SiCH(CH3)2, C-6Љ), 13.1, 12.7, 12.3, 12.1
(SiCH(CH3)2).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 3 7 3 – 4 3 7 9
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