A novel strategy towards the synthesis of orthogonally functionalised 4-aminoglycosides.

Article abstract of DOI:10.1039/b309823k

A tethered nucleophilic substitution strategy for the stereoselective introduction of axially oriented amino functions on suitably protected gluco- and mannopyranosides is presented. The obtained oxazine is a versatile building block, which after some manipulation, could be used in the construction of highly functionalised oligosaccharides.

Full text of DOI:10.1039/b309823k

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A novel strategy towards the synthesis of orthogonally
functionalised 4-aminoglycosides
Leendert J. van den Bos, Jeroen D.C. Codée, Jacques H. van Boom, Herman S. Overkleeft and
Gijsbert A. van der Marel*
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, PO Box 9502,
2300 RA Leiden, The Netherlands. E-mail: marel_g@chem.leidenuniv.nl;
Fax: ϩ31 71 5274307; Tel: ϩ31 71 5274280
Received 18th August 2003, Accepted 26th September 2003
First published as an Advance Article on the web 21st October 2003
A tethered nucleophilic substitution strategy for the stereoselective introduction of axially oriented amino functions
on suitably protected gluco- and mannopyranosides is presented. The obtained oxazine is a versatile building block,
which after some manipulation, could be used in the construction of highly functionalised oligosaccharides.
Introduction
The broad variety of naturally occurring carbohydrate struc-
tures originates, apart from the large number of possible inter-
glycosidic linkages, from the wide diversity encountered in their
monosaccharide constituents. Aminosugars,1 hexapyranoses
bearing diversely functionalised amino groups at different posi-
tions, represent an important category of carbohydrate units,
found in numerous oligosaccharides and glycoconjugates. For
instance, aminosugars are not only important as essential com-
ponents of bacterial capsular polysaccharides,2 but also as
structural elements of aminoglycoside antibiotics.3 The bio-
logical importance of natural products containing aminosugars
demands the development of efficient synthetic routes to these
monosaccharides. Our focus in this field is directed towards the
stereoselective introduction of C-4 amino functions cis relative
Scheme 1 Reagents and conditions: i, Cl3CCN, DBU, DCM, 0 ЊC, 89%.
ii, Tf2O, pyr, DCM, 0 ЊC. iii, DiPEA, 80%. iv, 80% AcOH in H2O, then
Ac2O, pyr, 89%.
to the neighbouring C-5 hydroxymethyl group of hexapyrano-
sides.4
A convenient route to the regio- and stereoselective introduc-
tion of nitrogen substituents entails the use of tethered nitrogen
nucleophiles.5 In this respect, allylic trichloroacetimidates have
been employed in an Overman rearrangement to provide the
corresponding allylic trichloroacetamides.6 Alternatively, IBX7
or NIS-mediated8 cyclisation of allylic trichloroacetimidates
gives the corresponding trans-disposed iodo-oxazolines. In line
with these studies, we here report a novel, straightforward
synthesis of orthogonally protected 4-amino glycosides. A key
element of our strategy is the selective introduction of a trichlo-
roacetimidate moiety at OH-6 of partially protected gluco- and
mannopyranosides. The hydroxyl at C-4 is transformed into a
suitable leaving group amenable to base-induced substitution
by the tethered imidate moiety to provide the corresponding
oxazine. We further demonstrate that, after hydrolysis and
suitable protection, the thus obtained aminoglycosides can be
readily applied as building blocks in oligosaccharide synthesis.
scopic analysis. Transformation of 1 via a three-step one pot
procedure afforded oxazine 4 in slightly improved yield (89%
over 3 steps). Acidic hydrolysis of 4 and acetylation of the
intermediate aminoalcohol gave methyl 4-acetamido-6-O-
acetyl-2,3-di-O-benzyl-4-deoxy-α--galactopyranoside 5.
Next, diversely functionalised manno- and glucopyranosides
were employed in the tethered nucleophilic substitution
sequence (Table 1). Subjection of methyl 2,3-di-O-benzyl-α--
mannopyranoside 610 to the three-step one pot procedure
afforded oxazine 7, albeit in a moderate yield (entry 1). Closer
inspection of the sequence of reactions revealed that the first
two steps, which entailed installation of the 6-O-imidate and
4-O-triflate functions, proceeded with equal efficiency as
observed for the synthesis of its glucopyranose congener 3
(Scheme 1). Arguably, the axial oriented 2-O-benzyl group in
mannopyranoside 6 may cause 1,3-diaxial strain in the transi-
tion state hampering the formation of oxazine 7. Hydrolysis
and acetylation of 7 gave fully protected 4-deoxy-4-amino-
taloside 8.
At this stage, we were interested in finding out whether
our approach could be applied to protected thioglycosides,
representing useful building blocks in the assembly of oligo-
saccharides (entries 2–4).11 To our satisfaction, ethyl 2,3-O-
isopropylidene-1-thio-α--mannopyranoside 912 was readily
transformed into oxazine 10 (entry 2). Unmasking of the
oxazine ring in 10 proceeded with concomitant partial hydroly-
sis of the isopropylidene protecting group, leading, after acetyl-
ation, to the mixture of 4-deoxy-4-aminotalosides 11 and 12 in
Results and discussion
As a first example, the transformation of methyl 2,3-di-O-
benzyl-α--glucopyranoside 19 into methyl 4-acetamido-6-O-
acetyl-2,3-di-O-benzyl-4-deoxy-α--galactopyranoside 5 was
undertaken (Scheme 1). Treatment of
1 with trichloro-
acetonitrile (Cl3CCN) in the presence of a catalytic amount of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) led to the selective
formation of 6-O-acetimidate 2 in 89% yield. Installation of the
4-O-triflate (Tf2O, pyridine) followed by base-mediated cyclis-
ation of resulting 3 gave oxazine 4 (80% yield, 2 steps), the
structural integrity of which was fully established by spectro-
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 6 0 – 4 1 6 5
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
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Table 1 Different examples of tethered nucleophilic inversion
was shown to be a more potent thiophilic promoter system than
the analogous benzenesulfinyl piperidine (BSP)–Tf2O21 com-
bination recently developed by the Crich laboratory. Addition
of methyl glucoside 25,22 to the activated donor, smoothly
afforded disaccharide 26 as an anomeric mixture in excellent
yield (Scheme 2).23
Entry Substrate
1
Oxazinea (yield)c
Productb (yield)c
Conclusion
2
3
4
In summary, a new, straightforward synthetic procedure for
the construction of 4-amino-4-deoxyglycosides, and their
application as donors and acceptors in condensation reactions
towards disaccharides, is presented. Future research will be
devoted to implementation of this strategy in the synthesis of
complex oligosaccharides containing aminoglycoside moieties.
a Cl3CCN, DBU, DCM, 0 ЊC, then Tf2O, pyr, DCM, 0 ЊC, then DiPEA.
b 80% AcOH in H2O, then Ac2O, pyr. c Isolated yields.
good overall yield. An unexpected difference in efficiency in the
outcome of the three-step oxazine synthesis was observed in
the case of ethyl thioglucosides 1313 and 1414 (entry 3). In both
cases, selective installation of the primary trichloroacetimidate
proceeded uneventfully. However, treatment of the intermediate
6-O-acetimidate in 13 with triflic anhydride and pyridine fol-
lowed by DiPEA mediated cyclisation afforded oxazine 15 in a
rather poor yield. The latter may be ascribed to the high nucleo-
philic nature of the anomeric thioacetal. A decrease in nucleo-
philicity15 of the thioacetal by installation of an electron
withdrawing 2-O-benzoyl, as in 14, led after the triflation–
substitution sequence to formation of oxazine 16 in satisfactory
yield. Analogously, application of the sequence of reactions to
phenyl 2-azido-3-O-benzyl-2-deoxy-1-thio-α--glycoside 18,16
bearing an electron withdrawing azide at C-2, provided the 2,4-
diamino derivative 19 in a good yield (entry 4). Both oxazines
16 and 19 were readily hydrolysed and acetylated leading to the
4- acetamidogalactosides 17 and 20 in 61% and 94% yield,
respectively.
Orthogonally protected oxazine 19 was selected as a
model compound to be used both as donor and acceptor in
ensuing glycosylation reactions. Diaminogalactosides possess-
ing differently functionalised amino functions are frequently
encountered in natural products, for instance as 2-acetamido-4-
amino-2,4,6-trideoxy-galactopyranosides present in the capsu-
lar polysaccharides of Bacteroides fragilis.2 Furthermore, we
recently demonstrated17 that partially protected thioglycosides
can be effectively employed as acceptor glycosides in the
dehydrative condensation procedure developed by Gin et al.18
Aglycon 21 was readily obtained after acidic hydrolysis of
oxazine 19 and subsequent selective reaction of the amine with
N-(benzyloxycarbonyloxy)succinimide (ZOSu). Dehydrative
condensation was accomplished by activating 2,3,4,6-tetra-O-
benzyl-α/β--galactopyranose 2319 under the influence of di-
phenylsulfide bis(triflate) prepared in situ, followed by addition
of acceptor 21 to afford the α-linked thiodisaccharide 24 in 65%
yield. Next, the fully orthogonally protected thiodonor 22 was
prepared by acetylation of compound 21. Activation of this
highly “disarmed”15 donor was accomplished by treatment
with diphenylsulfoxide (DPS)–triflic anhydride (Tf2O)20 which
Scheme 2 Reagents and conditions: i, 80% AcOH in H2O, then ZOSu,
pyr, rt, 95%. ii, Ac2O, pyr, quant. iii, 23, DPS, Tf2O, TTBP, DCM,
Ϫ60 ЊC, then 21, 65%. iv, 22, DPS, Tf2O, DCM, Ϫ60 ЊC, then 25, 95%.
Experimental
General
1H and 13C NMR spectra were recorded on a Jeol JNM-FX-200
(200/50.1 MHz) and a Bruker AV-400 (400/100 MHz) spectro-
meter. Chemical shifts are given in ppm (δ) relative to tetra-
methylsilane as internal standard. Coupling constants are given
in Hz. All given 13C spectra are proton decoupled. Mass spectra
were recorded with PE/SCIEX API 165 with electronspray
interface and Q-Star Applied Biosystems Q-TOF (TOF-
section). Optical rotations were measured on a Propol auto-
matic polarimeter. Traces of water in the donor and acceptor
glycosides, diphenylsulfoxide and TTBP were removed by co-
evaporation with toluene. TTBP was synthesised as described
by Crich et al.24 Dichloromethane (DCM, Baker) was boiled
under reflux over P2O5 for 2 h and was distilled immediately
prior to use. Solvents used for flash chromatography and TLC
were of technical grade and distilled before use. Flash chrom-
atography was performed on Baker silica gel (0.063–0.200 mm).
TLC-analysis was conducted on DC-fertigfolien (Schleicher &
Schuell, F1500, LS254) with detection by UV-absorption
(254 nm) were applicable and by spraying with 20% sulfuric
acid in ethanol followed by charring at ∼150 ЊC or by spraying
with a solution of (NH4)6Mo7O24ؒH2O (25 g lϪ1) in 10% sulfuric
acid followed by charring at ∼150 ЊC. Free amine functions were
detected by spraying with a ninhydrin solution in EtOH
followed by charring at ∼150 ЊC.
Oxazine 4
A solution of methyl 2,3-di-O-benzyl-α--glucopyranoside 1
(0.5 g; 1 mmol) in 5 ml DCM was cooled to 0 ЊC under an Ar
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 6 0 – 4 1 6 5
4161

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atmosphere. Subsequently trichloroacetonitrile (0.10 mL; 1.05
mmol; 1.05 eq.) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3 µL;
0.01 mmol; 0.01 eq.) were added to the solution. According to
TLC analysis, all starting material was consumed after 5 min.
Subsequent treatment of the reaction mixture with pyridine
H-6), 4.60 (d, 1H, J = 3.4 Hz, H-1), 4.61 (dd, 1H, J = 11.9 Hz,
J = 5.0 Hz, H-6), 4.64 (d, 1H, J = 11.9 Hz, CHHPh), 4.76 (d,
2H, J = 11.6 Hz, 2 × CHHPh), 4.97 (d, 1H, J = 11.3 Hz,
CHHPh), 7.29–7.37 (m, 10H, CH(Ar)), 8.23 (br s, 1H, NH);
13C NMR (100.8 MHz, CHCl3): δ = 55.1 (CH3(OMe)), 68.5
(C-6), 69.6 (C-5), 70.0 (C-4), 73.2 (CH2(Bn)), 75.6 (CH2(Bn)),
79.6 (C-2), 81.0 (C-3), 98.1 (C-1), 127.8–128.5 (Ar), 137.9
(Cq(Bn)), 138.6 (Cq(Bn)); MS (m/z, ESI): 518.1 (M ϩ Hϩ), 540.0
(M ϩ Naϩ).
(0.4 mL;
5 mmol; 5 eq.) and trifluoromethanesulfonic
anhydride (0.24 mL; 1.5 mmol; 1.5 eq.) afforded the triflated
product in 5 min at 0 ЊC. Base induced cyclisation was accom-
plished by addition of diisopropylethylamine (1.0 mL; 5 mmol;
5 eq.) and stirring was continued for 3½ h. The reaction mixture
was purified by flash chromatography (20% EtOAc–PE).
Oxazine 7
Removal of the eluent gave 0.40 g (0.80 mmol; 80%) of the title
Oxazine 7 was obtained from methyl 2,3-di-O-benzyl-α--
mannopyranoside 6 via the same procedure as described for the
conversion of compound 1 to 4. The reaction mixture was puri-
fied by flash chromatography (15% EtOAc–PE). Removal of
the eluent gave 75 mg (0.15 mmol, 41%) of the title compound
22
compound 4 as a yellow oil. TLC: 35% EtOAc in PE. [α]D
:
ϩ63.4 (c = 1, CHCl3). IR (cmϪ1): 1718, 1679, 1510, 1496, 1454,
1352, 1220, 1195, 1089, 1043, 1028, 1001 1H NMR (400 MHz,
CHCl3): δ = 3.37 (s, 3H, CH3(OMe)), 3.62 (dd, 1H, J = 3.5 Hz,
J = 10.1 Hz, H-2), 3.94 (m, 1H, H-4), 4.04 (br d, 1H, J = 2.0 Hz,
H-5), 4.13 (dd, 1H, J = 10.1 Hz, J = 4.4 Hz, H-3), 4.29 (d, 1H,
J = 11.8 Hz, H-6), 4.42 (dd, 1H, J = 11.8, J = 1.3 Hz, H-6), 4.60
(d, 1H, J = 3.5 Hz, H-1), 4.65 (d, 1H, J = 11.8 Hz, CHHPh);
4.77–4.88 (m, 3H, CHHPh, CH2Ph), 7.25–7.47 (m, 10H,
H(Ar)); 13C NMR (100.8 MHz, CHCl3): δ = 54.1 (C-4), 55.7
(Me), 60.4 (C-5), 69.2 (C-6), 71.8 (CH2(Bn)), 73.8 (CH2(Bn)),
75.2 (C-3), 75.6 (C-2), 99.5 (C-1), 127.4–128.3 (CH(Ar)), 138.3
1
7 as a yellow oil. H NMR (400 MHz, CHCl3): δ = 3.38 (s,
3H, CH3(OMe)), 3.66 (t, 1H, J = 2.6 Hz, H-2), 4.01 (m, 2H,
J = 2.6 Hz, J = 4.7 Hz, H-4, H-5), 4.06 (dd, 1H, J = 4.6 Hz,
J = 2.6 Hz, H-3), 4.28 (d, 1H, J = 11.2 Hz, H-6), 4.54 (dd, 1H,
J = 11.5 Hz, J = 2.6 Hz, H-6), 4.66 (d, 2H, J = 12.3 Hz,
2 × CHHPh), 4.78 (d, 1H, J = 12.0 Hz, CHHPh), 4.85 (d, 1H,
J = 2.7 Hz, H-1), 4.86 (d, 1H, J = 12.5 Hz, CHHPh), 7.31 (m,
10H, H(Ar)); 13C NMR (100.8 MHz, CHCl3): δ = 52.4 (C-4),
55.4 (CH3(OMe)), 61.4 (C-5), 68.7 (C-6), 70.9 (CH2(Bn)), 72.7
(CH2(Bn)), 74.1 (C-2, C-3), 101.0 (C-1), 127.6–128.4 (Ar), 138.3
(C (Bn)), 138.9 (C (Bn)), 153.0 (C᎐NH); MS (m/z, ESI): 500
᎐
q
q
(M ϩ Hϩ).
(C (Bn)), 138.9 (C (Bn)), 151.8 (C᎐N); MS (m/z, ESI): 500.0 (M
᎐
q
q
ϩ Hϩ), 522.1 (M ϩ Naϩ).
Methyl 4-acetamido-6-O-acetyl-2,3-di-O-benzyl-4-deoxy-ꢀ-D-
galactopyranose 5
Methyl 4-acetamido-6-O-acetyl-2,3-di-O-benzyl-4-deoxy-ꢀ-D-
talopyranoside 8
A solution of oxazine 4 (0.44 g; 0.89 mmol) in 5 mL 80%
AcOH–H2O was stirred for 30 min at ambient temperature.
After removal of the solvent under reduced pressure, the resi-
due was co-evaporated several times with toluene. The crude
product was subsequently dissolved in 4 mL pyridine and
treated with 1 mL Ac2O. Stirring was continued for 8 h before
the solvent was removed in vacuo. After co-evaporation with
toluene the crude mixture was purified by flash chromatography
(30% EtOAc–PE). Removal of the eluent gave 0.49 g (0.79
mmol, 89%) of the title compound 5 as a yellow oil. TLC: 35%
EtOAc–PE. [α]D22: ϩ 2.8 (c = 1, CHCl3). IR: 1739, 1651, 1369,
Compound 8 was prepared from oxazine 7 via the same pro-
cedure as described for the conversion of compound 4 into 5.
The reaction mixture was purified by flash chromatography
(20% EtOAc–PE). Removal of the eluent gave 43 mg (0.096
mmol, 64%) of the title compound 4 as a yellow oil. TLC: 40%
EtOAc–PE. [α]D22: ϩ36.8 (c = 0.66, CHCl3). IR (cmϪ1): 1739,
1670, 1515, 1454, 1369, 1230, 1114, 1041. 1H NMR (400 MHz,
CHCl3): δ = 1.81 (s, 3H, NHAc), 2.06 (s, 3H, CH3(Ac)), 3.34 (s,
3H, CH3(OMe)), 3.76 (m, 1H, J = 1.6 Hz, H-2), 3.81 (dd, 1H,
J = 4.2 Hz, J = 3.1 Hz, H-3), 3.97 (m, 1H, H-5), 4.12 (dd,
1H, J = 8.0 Hz, J = 3.6 Hz, H-6), 4.24 (dd, 1H, J = 11.7 Hz,
J = 4.2 Hz, H-6), 4.43 (d, 1H, J = 11.6 Hz, CHHPh), 4.66 (m,
1H, H-4), 4.68 (d, 2H, J = 11.2 Hz, 2 × CHHPh), 4.76 (d, 1H,
J = 11.0 Hz, CHHPh), 4.81 (d, 1H, J = 1.2 Hz, H-1), 6.95 (d,
1H, J = 9.3 Hz, NH), 7.30 (m, 10H, H(Ar)); 13C NMR (100.8
MHz, CHCl3): δ = 20.8 (CH3(Ac)), 23.2 (CH3(Ac)), 46.5 (C-4),
54.8 (CH3(OMe)), 64.0 (C-6), 68.2 (C-5), 69.9 (CH2(Bn)), 72.1
(C-3), 74.1 (CH2(Bn)), 76.2 (C-2), 99.9 (C-1), 127.5–128.4 (Ar),
1
1232, 1195, 1155, 1099, 1028; H NMR (400 MHz, CHCl3):
δ = 2.04 (s, 3H, CH3(Ac)), 2.06 (s, 3H, CH3(Ac)), 3.38 (s, 3H,
CH3(OMe)), 3.45–3.49 (dd, 1H, J = 4.0 Hz, J = 10.1 Hz, H-2),
3.96–4.00 (dd, 1H, J = 10.7 Hz, J = 4.7 Hz, H-3), 4.08–4.15 (m,
3H, H-5, H-6, H-6), 4.52 (d, 1H, J = 11.1 Hz, CHHPh), 4.64 (d,
1H, J = 4.0 Hz, H-1), 4.65 (d, 1H, J = 12.2 Hz, CHHPh), 4.77 (t,
1H, J = 4.4 Hz, H-4), 4.78 (d, 1H, J = 11.1 Hz, CHHPh), 4.86
(d, 1H, J = 12.2 Hz, CHHPh), 5.60 (d, 1H, J = 10.1 Hz, NH),
7.26–7.39 (m, 10H, H(Ar)); 13C NMR (100.8 MHz, CHCl3):
δ = 20.8 CH3(Ac)), 23.5 (CH3(Ac)), 47.6 (C-4), 55.4 (CH3-
(OMe)), 63.2 (C-6), 66.7 (C-5), 71.7 (CH2(Bn)), 73.6 (CH2(Bn)),
75.3 (C-2), 76.0 (C-3), 98.6 (C-1), 127.7–128.4 (Ar), 137.9
137.6 (C (Bn)), 137.8 (C (Bn)), 170.7 (C᎐O); HRMS: (M ϩ H)
᎐
q
q
calcd for C15H33NO7 458.2101, found 458.2174.
(C (Bn)), 138.2 (C (Bn)), 170.5 (C᎐O) HRMS: (M ϩ H) calcd
Oxazine 10
᎐
q
q
for C15H33NO7 458.2101, found 458.2097.
Oxazine 10 was obtained from ethyl 2,3-O-isopropylidene-
1-thio-α--mannopyranoside 9 via the same procedure as
described for the conversion of compound 1 into 4. The reac-
tion mixture was purified by flash chromatography (10%
EtOAc–PE). Removal of the eluent gave 216 mg (0.55 mmol,
Methyl 2,3-di-O-benzyl-6-trichloroacetimidate-ꢀ-D-
glucopyranoside 2
To a stirred solution of methyl 2,3-di-O-benzyl-α--gluco-
pyranoside 1 (1.79 g; 5 mmol) in 25 ml DCM at 0 ЊC was added
trichloroacetonitrile (0.5 mL; 5 mmol, 1 eq.) and 1,8-diaza-
bicyclo[5.4.0]undec-7-ene (5 µL; 0.05 mmol; 0.05 eq.). Stirring
was allowed for 45 min after which the reaction mixture was
concentrated (waterbath ∼ 30 ЊC). Flash chromatography (20%
EtOAc–PE) and removal of the eluent gave 2.23 g. (4.31 mmol,
89%) of the title compound 2 as a colourless oil. TLC: 50%
EtOAc–PE. 1H NMR (400 MHz, CHCl3): δ = 3.39 (s, 3H,
CH3(OMe)), 3.46 (dd, 1H, J = 9.0 Hz, H-4), 3.50 (dd, 1H,
J = 9.6 Hz, J = 3.6 Hz, H-2), 3.82 (t, 1H, J = 9.2 Hz, H-3), 3.87
(m, 1H, J = 10.1 Hz, J = 5.0 Hz, H-5), 4.48 (d, 1H, J = 11.8 Hz,
1
54%) of the title compound 10 as a yellow oil. H NMR (400
MHz, CHCl3): δ = 1.23 (t, 3H, J = 7.4 Hz, CH3(SEt)), 1.27 (s,
3H, CH3(isoprop.)), 1.47 (s, 3H, CH3(isoprop.)), 2.62 (m, 2H,
CH2(SEt), 4.19 (d, 1H, J = 7.2 Hz, H-2), 4.23 (m, 1H, H-4), 4.27
(s, 1H, H-5), 4.28 (m, 1H, H-6), 4.35 (m, 1H, H-6), 4.67
(dd, 1H, J = 7.2 Hz, J = 3.7 Hz, H-3), 5.07 (s, 1H, H-1); 13C
NMR (100.8 MHz, CHCl3): δ = 14.7 (CH3(SEt)), 24.9 (CH3-
(isoprop.)), 25.4 (CH2(SEt)), 26.1 (CH3(isoprop.)), 49.5 (C-4),
61.1 (C-5), 67.2 (C-6), 72.0 (C-2), 76.0 (C-3), 81.4 (C-1), 110.4
(C (isoprop.), 154.1 (C᎐N); MS (m/z, ESI): 390 (M ϩ Hϩ), 412
᎐
q
(M ϩ Naϩ).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 6 0 – 4 1 6 5
4162

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Ethyl 4-acetamido-6-O-acetyl-2,3-O-isopropylidene-1-thio-ꢀ-D-
talopyranoside 11
J = 4.2 Hz, H-3), 3.96 (d, 1H, J = 2.1 Hz, H-5), 4.06 (br s, 1H,
H-4), 4.37 (d, 1H, J = 11.7 Hz, H-6), 4.52 (d, 1H, J1,2 = 9.5 Hz,
H-1), 4.62 (dd, 1H, J = 11.7 Hz, J = 1.6 Hz, H-6), 4.70–4.80 (dd,
2H, J = 12.8 Hz, CH2Ph), 5.40 (t, 1H, J = 9.5 Hz, J = 9.4 Hz,
H-3), 7.18–8.03 (m, 10H, H(Ar)); 13C NMR (100.8 MHz,
CHCl3): δ = 14.7 (CH3(SEt)), 22.1 (CH2(SEt)), 53.1 (C-4), 67.8
(C-5), 68.7 (C-2), 69.3 (C-6), 70.9 (CH2(Bn)), 77.3 (C-3), 82.5
(C-1), 127.6–133.0 (Ar), 129.9 (Cq(Bz)), 137.7 (Cq(Bn)), 165.0
Compound 11 was prepared from oxazine 10 via the same pro-
cedure as described for the conversion of compound 4 into 5.
The reaction mixture was purified by column chromatography
(EtOAc). Removal of the eluent gave 77 mg (0.22 mmol, 40%)
of the title compound 11 as a yellow oil, together with 50 mg
(0.13 mmol, 21%) ethyl 4-acetamido-2,3,6-tri-O-acetyl-1-thio-
α--talopyranoside 12. TLC: 40% EtOAc–PE. [α]D22: ϩ142.0
(c = 1, CHCl3). IR (cmϪ1): 1739, 1666, 1519, 1373, 1235, 1211,
1083, 1037, 1002; 1H NMR (400 MHz, CHCl3): δ = 1.32 (t, 3H,
J = 7.4 Hz, CH3(SEt), 1.34 (s, 3H, CH3(isoprop.)), 1.50 (s, 3H,
CH3(isoprop.)), 2.04 (s, 3H, CH3(Ac)), 2.06 (s, 3H, CH3(Ac)),
2.57 (m, 1H, CHH(SEt)), 2.74 (m, 1H, CHH(SEt)), 4.05 (dd,
1H, J = 5.9 Hz, J = 1.0 Hz, H-2), 4.10 (dd, 1H, J = 11.8 Hz,
J = 4.1 Hz, H-6), 4.23 (d, 1H, J = 11.8 Hz, H-6), 4.34 (t, 1H,
J = 5.9 Hz, H-3), 4.38 (m, 1H, H-5), 4.47 (m, 1H, H-4), 5.52 (s,
1H, H-1), 5.86 (d, 1H, J = 9.9 Hz, NH) 13C NMR (100.8 MHz,
CHCl3): δ = 15.1 (CH3(SEt)), 21.6 (CH3(Ac)), 24.3 (CH3(Ac)),
24.8 (CH2(SEt)), 26.2 (CH3(isoprop.)), 27.1 (CH3(isoprop.)),
46.5 (C-4), 64.1 (C-6), 67.5 (C-5), 72.2 (C-3), 74.6 (C-2), 80.1
(C᎐N); MS (m/z, ESI): 544.1 (M ϩ Hϩ), 568.3 (M ϩ Naϩ).
᎐
Ethyl 4-acetamido-6-O-acetyl-2-O-benzoyl-3-O-benzyl-4-deoxy-
1-thio-ꢁ-D-galactopyranoside 17
Compound 17 was prepared from oxazine 16 via the same pro-
cedure as described for the conversion of compound 4 into 5.
The reaction mixture was purified by flash chromatography
(45% EtOAc–PE). Removal of the eluent gave 33 mg (0.066
mmol, 61%) of the title compound 17 as a yellow oil. TLC: 35%
EtOAc–PE. [α]D22: ϩ14.0 (c = 0.42, CHCl3). IR (cmϪ1): 1720,
1
1647, 1550, 1454, 1369, 1242; H NMR (400 MHz, CHCl3):
δ = 1.24 (t, 3H, J = 7.4 Hz, CH3(SEt)), 2.07 (s, 3H, CH3(Ac)),
2.08 (s, 3H, CH3(Ac)), 2.65–2.71 (m, 2H, J = 7.4 Hz, CH2(SEt)),
3.74 (dd, 1H, J = 9.7 Hz, J = 4.6 Hz, H-3), 3.86 (dd, 1H,
J = 6.3 Hz, J = 1.2 Hz, H-5), 4.21 (d, 2H, J = 6.3 Hz, H-6), 4.46
(d, 1H, J = 12.6 Hz, CHHPh), 4.56 (d, 1H, J = 10.1 Hz, H-1),
4.70 (d, 1H, J = 12.6 Hz, CHHPh), 4.89–4.92 (m, 1H, H-4), 5.22
(t, 1H., J = 9.9 Hz, H-2), 5.96 (d, 1H, J = 10.1 Hz, NH), 7.09–
8.01 (m, 10H, H(Ar)); 13C NMR (100.8 MHz, CHCl3): δ = 14.9
(CH3(SEt)), 20.8 (CH3(Ac)), 23.3 (CH3(Ac)), 25.2 (CH2(SEt)),
46.6 (C-4), 63.0 (C-6), 69.9 (C-2), 70.4 (CH2(Bn)), 76.0 (C-5),
76.6 (C-3), 84.8 (C-1), 127.6–133.2 (Ar), 129.5 (Cq(Bz)), 137.2
(C-1), 110.0 (C (isoprop.), 170.5 (C᎐O), 171.3 (C᎐O); HRMS:
᎐
᎐
q
(M ϩ H) calcd for C15H26NO6S 348.1403, found 348.1434.
Ethyl 4-acetamido-2,3,6-tri-O-acetyl-1-thio-ꢀ-D-tallopyranoside
12
TLC: 40% EtOAc–PE. 1H NMR (400 MHz, CHCl3): δ = 1.30 (t,
3H, J = 7.4 Hz, CH3(SEt)), 2.00 (s, 3H, CH3(Ac)), 2.04 (s, 3H,
CH3(Ac)), 2.07 (s, 3H, CH3(Ac)), 2.20 (s, 3H, CH3(Ac)), 2.66
(m, 2H, CH2(SEt)), 4.12 (dd, 1H, J = 11.8 Hz, J = 4.6 Hz, H-6),
4.22 (dd, 1H, J = 11.7 Hz, J = 7.7 Hz, H-6), 4.59 (dd, 1H,
J = 10.3 Hz, J = 3.6 Hz, H-4), 4.65, (m, 1H, H-5), 5.17 (t, 1H,
J = 3.6 Hz, H-3), 5.21 (m, 1H, J = 3.5 Hz, H-2), 5.31 (s, 1H,
H-1), 6.19 (d, 1H, J = 10.1 Hz, NH); 13C NMR (100.8 MHz,
CHCl3): δ = 14.5 (CH3(SEt)), 20.5 (CH3(Ac)), 20.6 (CH3(Ac)),
21.0 (CH3(Ac)), 23.2 (CH3(Ac)), 24.9 (CH2(SEt)), 46.9 (C-4),
62.8 (C-6), 65.7 (C-2), 68.2 (C-5), 70.6 (C-3), 82.5 (C-1), 168.7
(C (Bn)), 170.4 (C᎐O), 170.7 (C᎐O) HRMS: (M ϩ H) calcd for
᎐
᎐
q
C26H32NO7S 502.1821, found 502.1828.
Oxazine 19
Oxazine 19 was obtained from phenyl 2-azido-3-O-benzyl-2,4-
dideoxy-1-thio-β--glucopyranoside 18 via the same procedure
as described for the conversion of compound 1 into 4. The
reaction mixture was purified by flash chromatography (30%
EtOAc–PE). Removal of the eluent gave 4.16 g (8.2 mmol, 74%)
of the title compound 19 as a yellow oil. TLC: 40% EtOAc–PE.
[α]D22: ϩ46.2 (c = 1, CHCl3). IR (cmϪ1): 2110, 1678, 1226,
1172; 1H NMR (400 MHz, CHCl3): δ = 3.37 (t, 1H, J = 9.8 Hz,
H-2), 3.62 (dd, 1H, J = 9.6 Hz, J = 4.4 Hz, H-3), 3.83 (dd,
1H, J = 3.7 Hz, J = 1.5 Hz, H-5), 3.88 (d, 1H, J = 4.1 Hz,
H-4), 4.35 (m, 2H, J = 10.0 Hz, H-1, H-6), 4.62 (dd, 1H,
J = 12.16 Hz, H-6), 4.72 (d, 1H, J = 12.1 Hz, CHHPh), 4.80 (d,
1H, J = 12.1 Hz, CHHPh), 7.26–7.55 (m, 10H, H(Ar)); 13C
NMR (100.8 MHz, CHCl3): δ = 51.8 (C-4), 60.0 (C-5), 68.0
(C-2), 69.4 (C-6), 71.2 (CH2(Bn)), 79.1 (C-3), 85.4 (C-1), 127.9–
(C᎐O), 169.3 (C᎐O), 169.9 (C᎐O), 170.3 (C᎐O); MS (m/z, ESI):
᎐
᎐
᎐
᎐
414 (M ϩ Naϩ).
Oxazine 15
Oxazine 15 was obtained from ethyl 2,3-di-O-benzyl-1-thio-β-
-glucopyranoside 13 via the same procedure as described for
the conversion of compound 1 into 4. The reaction mixture was
purified by flash chromatography (20% EtOAc–PE). Removal
of the eluent gave 63 mg (0.12 mmol, 21%) of the title com-
pound 15 as a yellow oil. 1H NMR (400 MHz, CHCl3): δ = 1.23
(t, 3H, J = 7.6 Hz, CH3(SEt)), 2.60–2.70 (m, 2H, J = 7.5 Hz,
CH2(SEt)), 3.55 (t, 1H, J = 9.2 Hz, H-2), 3.75 (dd, 1H, J = 8.9
Hz, J = 4.3 Hz, H-3), 3.83 (br s, 1H, H-5), 3.93 (br s, 1H, H-4),
4.32 (d, 1H, J = 11.7 Hz, H-6), 4.39 (d, 1H, J = 9.4 Hz, H-1),
4.55 (d, 1H, J = 10.2 Hz, H-6), 4.78–4.89 (m, 4H, 2 × CH2Ph),
7.25–7.44 (m, 10H, CH(Ar)); 13C NMR (100.8 MHz, CHCl3):
δ = 15.0 (CH3(SEt)), 22.9 (CH2(SEt)), 53.3 (C-4), 67.4 (C-5),
67.4 (C-6), 69.4 (CH2(Bn)), 71.6 (CH2(Bn)), 76.6 (C-2), 80.3
(C-3), 83.9 (C-1), 127.6–133.0 (Ar), 138.1 (Cq(Bn)), 138.2
(C (Bn)), 154.4 (C᎐N); MS (m/z, ESI): 532.1 (M ϩ Hϩ), 554.1
134.2 (Ar), 129.5 (C (SPh)), 137.4 (C (Bn)), 153.7 (C᎐N); MS
᎐
q
q
(m/z, ESI): 513.4 (M ϩ Hϩ), 535.0 (M ϩ Naϩ).
Phenyl 4-acetamido-6-O-acetyl-2-azido-3-O-benzyl-2,4-dide-
oxy-1-thio-ꢁ-D-galactopyranoside 20
Compound 20 was prepared from oxazine 19 via the same pro-
cedure as described for the conversion of compound 4 into 5.
The reaction mixture was purified by flash chromatography
(45% EtOAc–PE). Removal of the eluent gave 1.06 g (2.27
mmol, 94%) of the title compound 20 as a yellow oil. TLC:
40% EtOAc–PE. [α]D22: Ϫ22.2 (c = 0.24, CHCl3). IR (cmϪ1):
2110, 1739, 1654, 1535, 1438, 1365, 1230, 1103, 1037; 1H NMR
(400 MHz, CHCl3): δ = 1.96 (s, 3H, CH3(Ac)), 2.06 (s, 3H,
CH3(Ac)), 3.27 (1H, t, J = 10.0 Hz, H-2), 3.53 (dd, 1H, J = 9.7
Hz, J = 4.2 Hz, H-3), 3.74 (dd, 1H, J = 7.0 Hz, J = 5.0 Hz, H-5),
4.09–4.23 (m, 2H, H-6), 4.38 (d, 1H, J = 10.3 Hz, H-1), 4.50 (d,
1H, J = 10.8 Hz, CHHPh), 4.75 (d, 1H, J = 6.9 Hz, H-4), 4.78
(d, 1H, J = 10.8 Hz, CHHPh), 5.43 (d, 1H, J = 10.1 Hz, NH),
7.30–7.59 (m, 10H, H(Ar)); 13C NMR (100.8 MHz, CHCl3):
᎐
q
(M ϩ Naϩ).
Oxazine 16
Oxazine 16 was obtained from ethyl 2-O-benzoyl-3-O-benzyl-1-
thio-β--glucopyranoside 14 via the same procedure as des-
cribed for the conversion of compound 1 into 4. The reaction
mixture was purified by flash chromatography (20% EtOAc–
PE). Removal of the eluent gave 63 mg (0.12 mmol, 64%) of
1
the title compound 16 as a yellow oil. H NMR (400 MHz,
CHCl3): δ = 1.19 (t, 3H, J = 7.5 Hz, CH3(SEt)), 2.67–2.75
(m, 2H, J = 7.5 Hz, CH2(SEt)), 3.90–3.93 (dd, 1H, J = 9.4 Hz,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 6 0 – 4 1 6 5
4163

View Online
δ = 20.7 (CH3(Ac)), 23.3 (CH3(Ac)), 45.7 (C-4), 61.2 (C-2), 62.8
(C-6), 71.4 (CH2(Bn)), 75.7 (C-5), 79.4 (C-3), 86.1 (C-1), 128.1–
1 eq.) in 1 ml DCM. Stirring was continued and the reaction
mixture was allowed to warm to 0 ЊC. Subsequently the reaction
was quenched by addition of triethylamine (0.16 mL; 2 mmol,
20 eq.). Flash chromatography (20% EtOAc–PE) and removal
of the eluent afforded 66 mg of the title compound 24 (65 µmol,
65%) as a yellow oil. TLC: 50% EtOAc–PE. [α]D22: ϩ13.2 (c = 1,
CHCl3). IR (cmϪ1): 2110, 1716, 1496, 1454, 1215, 1096, 1030 1H
NMR (400 MHz, CHCl3): δ = 3.18 (t, 1H, J = 10.0 Hz, H-2Ј),
3.45 (m, 2H, J = 6.7 Hz, J = 9.7 Hz, H-3, H-6), 3.53 (dd, 1H,
J = 9.3 Hz, J = 6.4 Hz, H-6), 3.59 (q, 1H, J = 5.9 Hz, H-6Ј), 3.75
(m, 2H, H-5Ј, H-6Ј), 3.83 (dd, 1H, J = 10.0 Hz, J = 2.7 Hz, H-3),
3.89 (s, 1H, H-4), 3.95 (t, 1H, J = 6.3 Hz, H-5), 4.02 (dd, 1H,
J = 10.1 Hz, J = 3.6 Hz, H-2), 4.32 (d, 1H, J = 10.0 Hz, H-1Ј),
4.38 (s, 1H, H-4Ј), 4.40 (m 2H, CH2Ph)), 4.56 (d, 1H, J = 11.4
Hz, CHHPh), 4.69 (t, 2H, J = 13.0 Hz, CH2Ph), 4.80 (m, 3H,
CHHPh, CH2Ph), 4.81 (d, 1H, J = 3.2 Hz, H-1Ј), 4.92 (d, 1H,
J = 11.4 Hz, CHHPh), 5.06 (dd, 2H, J = 12.2 Hz, CH2(Z)),
7.20–7.37 (m, 35H, H(Ar)); 13C NMR (100.8 MHz, CHCl3):
δ = 48.5 (C-4Ј), 61.2 (C-3Ј), 67.0 (CH2(Z)), 67.6 (C-6Ј), 69.1
(C-6), 69.4 (C-5Ј), 71.3 (CH2(Bn)), 73.1 (CH2(Bn)), 73.4 (CH2-
(Bn)), 73.5 (CH2(Bn)), 74.7 (CH2(Bn)), 74.9 (C-4), 76.5 (C-2),
76.7 (C-5), 78.9 (C-3), 79.8 (C-2Ј), 86.2 (C-1Ј), 98.2 (C-1),
124.7–133.2 (Ar), 131.5 (Cq(SPh)), 136.1–138.7 (Cq(Bn)), 156.3
133.8 (Ar), 130.9 (C (SPh)), 136.6 (C (Bn)), 170.3 (C᎐O);
᎐
q
q
HRMS: (M ϩ H) calcd for C23H27N4O5S 471.1624, found
471.1745.
Phenyl 4-(N-benzyloxycarbonyl)-amino-2-azido-3-O-benzyl-2,4-
dideoxy-1-thio-ꢁ-D-galactopyranoside 21
Oxazine 19 (0.81 g, 1.58 mmol) was stirred in 5 mL 80% AcOH
in H2O at ambient temperature. After 15 min, the clear solution
was diluted with toluene, concentrated and co-evaporated sev-
eral times with toluene. The crude oil was dissolved in 5 mL
DCM followed by addition of NEt3 (0.26 mL; 2.0 mmol, 1.25
eq.) and ZOSu (0.40 g; 1.6 mmol, 1.01 eq.). The reaction mix-
ture was stirred for 8 h at room temperature before EtOAc was
added. The mixture was washed with 50 mL 1M HCl. The
water-layer was extracted twice with 50 mL EtOAc. The com-
bined organic layers were dried (MgSO4), filtered and concen-
trated in vacuo. Flash chromatography (50% EtOAc–PE) and
removal of the eluent afforded 844 mg (1.50 mmol, 95%) of the
title compound 21 as a colourless oil. TLC: 50% EtOAc–PE.
[α]D22: Ϫ6.2 (c = 1, CHCl3). IR (cmϪ1): 2110, 1705, 1512, 1257,
1
1215, 1056. H NMR (200 MHz, CHCl3): δ = 3.01 (br s, 1H,
(C᎐O); HRMS: (M ϩ H) calcd for C H N O S 1043.4259,
᎐
61 63
4
10
OH), 3.24 (t, 1H, J = 9.9 Hz, H-2), 3.57 (m, 3H, H-3, H-6), 3.72
(m, 1H, H-5), 4.36 (m, 2H, J = 10.2 Hz, H-1, H-4), 4.50 (d, 1H
J = 10.9 Hz, CHHPh), 4.68 (d, 1H, J = 11.3 Hz, CHHPh), 4.83
(d, 1H, J = 7.8 Hz, NH), 5.12 (s, 2H, CH2(Z)); 13C NMR (50.4
MHz, CHCl3): δ = 47.5 (C-4), 60.5 (C-6), 61.1 (C-2), 67.0
(CH2(Z)), 70.8 (CH2(Bn)), 77.9 (C-5), 78.8 (C-3), 86.1 (C-1),
127.6–132.6 (Ar), 131.3 (Cq(SPh)), 135.8 (Cq(Z)), 136.6
found 1043, 4280.
Methyl 2,3,4-tri-O-benzoyl-6-O-(6-O-acetyl-4-(N-benzyloxy-
carbonyl)-amino-2-azido-3-O-benzyl-2,4-dideoxy-ꢀ/ꢁ-D-
galactopyranosyl)-ꢀ-D-glucopyranoside 26
A solution of phenyl 6-O-acetyl-4-(N-benzyloxycarbonyl)-
amino-2-azido-3-O-benzyl-2,4-dideoxy-1-thio-β--galacto-
pyranoside 22 (53 mg; 0.1 mmol) and diphenylsulfoxide (25 mg;
0.12 mmol, 1.2 eq.) in 3 ml DCM was stirred over 100 mg
activated 4 Å molecular sieves for 30 min. The mixture was
cooled to Ϫ78 ЊC before triflic acid anhydride (22 µL; 0.13
mmol, 1.3 eq.) was added. The mixture was stirred for 5 min
followed by addition of methyl 2,3,4-tri-O-benzoyl-α--gluco-
pyranoside 25 (75 mg; 0.1 mmol, 1 eq.) in 1 ml DCM. The
mixture was allowed to warm to 0 ЊC. Subsequently the reaction
was quenched by addition of triethylamine (0.16 mL; 2 mmol,
20 eq.). Flash chromatography (30% EtOAc–PE) and removal
of the eluent afforded 92 mg of the title compound 26 (95 µmol,
95%) as a colourless oil. TLC: 50% EtOAc–PE. IR (cmϪ1):
2110, 1724, 1519, 1450, 1245, 1091, 1026; 1H NMR (400 MHz,
CHCl3): δ = 4.27 (d, 0.5H, J = 8.0 Hz, H-1Ј(β-anomer)), 4.90 (d,
0.5H, J = 3.4 Hz, H-1Ј(α-anomer)), 4.27 (d, 1H, J = 3.5 Hz,
H-1); 13C NMR (100,8 MHz, CHCl3): δ = 96.8 (C-1), 97.9
(C-1Ј(α-anomer)), 102.5 (C-1Ј(β-anomer)); HRMS: (M ϩ H)
calcd for C51H51N4O15 959.3345, found 959.3394.
(C (Bn)), 157.3 (C᎐O); HRMS: (M ϩ H) calcd for C H -
᎐
q
27 29
N4O5S 521.1780, found 521.1829.
Phenyl 6-O-acetyl-4-(N-benzyloxycarbonyl)-amino-2-azido-3-O-
benzyl-2,4-dideoxy-1-thio-ꢁ-D-galactopyranoside 22
Compound 21 (593 mg, 1.14 mmol) was dissolved in 5 mL
pyridine followed by the addition of 2.5 mL Ac2O. The reaction
mixture was stirred for 2 h at room temperature. The mixture
was concentrated and co-evaporated several times with toluene.
After flash chromatography (30% EtOAc–PE) and removal of
the eluent, 606 mg of the title compound 22 (1.14 mmol,
quant.) was obtained as a colourless oil. TLC: 50% EtOAc–PE.
[α]D22: Ϫ13.4 (c = 1, CHCl3). IR (cmϪ1): 2110, 1716, 1510, 1454,
1365, 1226, 1103, 1037; 1H NMR (200 MHz, CHCl3): δ = 2.04
(s, 3H, CH3(Ac)), 3.27 (t, 1H, J = 10.2 Hz, J = 9.7 Hz, H-2), 3.51
(dd, 1H, J = 9.9 Hz, J = 4.3 Hz, H-3), 3.71 (t, 1H, J = 5.8 Hz,
H-5), 4.20 (m, 2H, J = 5.1 Hz, H-6), 4.34 (d, 1H, J = 10.2 Hz,
CHHPh), 4.42 (m, 1H, H-4), 4.52 (d, 1H, J = 11.0 Hz,
CHHPh), 4.83 (d, 2H, J = 10.6 Hz, H-1, NH), 5.08 (s, 2H,
CH2(Z)), 7.25–7.54 (m, 10H, H(Ar)); 13C NMR (50.4 MHz,
CHCl3): δ = 20.7 (Ac), 48.0 (C-4), 61.2 (C-2), 62.9 *C-6), 67.2
(CH2(Z)), 71.4 (CH2(Bn)), 75.6 (C-5), 79.6 (C-3), 86.3 (C-1),
127.9–133.4 (Ar), 131.1 (Cq(SPh)), 136.0 (Cq(Z)), 136.7
Acknowledgements
The authors would like to acknowledge the Council for
Chemical Sciences of the Netherlands Organisation for
Scientific Research (CW-NWO) for financial support.
(C (Bn)), 156.2 (C᎐O(Z)), 170.5 (C᎐O(Ac)); MS (m/z, ESI):
᎐
᎐
q
563.3 (M ϩ Hϩ), 585 (M ϩ Naϩ).
References
Phenyl 4-(N-benzyloxycarbonyl)-amino-2-azido-3-O-benzyl-6-
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ꢁ-D-galactopyranoside 24
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 4 1 6 0 – 4 1 6 5
4164

View Online
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