Conformationally Restricted Oxazolidin-2-one Fused Bicyclic Iminosugars as Potential Glycosidase Inhibitors

Article abstract of DOI:10.1002/ejoc.202001053

The synthesis of fused bicyclic oxazolidin-2-one (OZO) iminosugars was achieved through a tandem Staudinger reduction/retro-Michael/intramolecular Michael addition from the corresponding OZO azidosugars. Those precursors, based on both aldopentofuranoses and ketofuranohexoses backbones, were obtained following alkylation and oxidation of the related oxazolidine-2-thione (OZT) azidosugars. Eight OZO based iminosugars were isolated in good yields and evaluated for their potency as glycosidases inhibitors, thus extending the family of known 1-Deoxynojirimycin (DNJ) bicyclic analogues.

Full text of DOI:10.1002/ejoc.202001053

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Bicyclic Iminosugars
Conformationally Restricted Oxazolidin-2-one Fused Bicyclic
Iminosugars as Potential Glycosidase Inhibitors
Maria Domingues,[a,b] Justyna Jaszczyk,[a] Maria Isabel Ismael,[b]
José Albertino Figueiredo,[b] Richard Daniellou,[a] Pierre Lafite,[a] Marie Schuler,*[a] and
Arnaud Tatibouët*[a]
Abstract: The synthesis of fused bicyclic oxazolidin-2-one bones, were obtained following alkylation and oxidation of the
(OZO) iminosugars was achieved through a tandem Staudinger related oxazolidine-2-thione (OZT) azidosugars. Eight OZO
reduction/retro-Michael/intramolecular Michael addition from based iminosugars were isolated in good yields and evaluated
the corresponding OZO azidosugars. Those precursors, based for their potency as glycosidases inhibitors, thus extending the
on both aldopentofuranoses and ketofuranohexoses back- family of known 1-Deoxynojirimycin (DNJ) bicyclic analogues.
Introduction
and potent inhibitors for potential therapeutical applications,
as well as tools for chemical biology and extremely useful
Glycoside hydrolases or glycosidases (GHs)[1a] are carbohydrate probes for a better understanding of the mode of action of
processing enzymes responsible for the hydrolysis of the glyco- these enzymes.[1b–1g] Most GHs inhibitors are carbohydrate mi-
sidic bond, which is a widespread biological process. Thus, metics[2] and among them, iminosugars (sugars with an endo-
glycosidases can be used as therapeutic targets for the treat- cyclic nitrogen atom) have attracted considerable attention
ment of several diseases such as diabetes, viral infection, lysoso- since the discovery of nojirimycin A.[3] At physiological pH, the
mal storage disorder or cancers. This is why great efforts have nitrogen atom of the iminosugar is protonated and these
been made over recent years to design and synthesize selective charged species mimic the cationic transition state of the natu-
Figure 1. Examples of iminosugars used as therapeutics, synthetic analogues and proposed work.
ral substrate, which allows the carbohydrate analogue to com-
pete and inhibit the hydrolysis process. Thus, iminosugars
display a high therapeutical potential, which is illustrated by
[a] Dr. M. Domingues, Dr. J. Jaszczyk, Prof. R. Daniellou, Dr. P. Lafite, Dr. M.
Schuler, Prof. A. Tatibouët
Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans,
CNRS-UMR 7311, BP 6759, 45067 Orléans cedex 02, France
E-mail: marie.schuler@univ-orleans.fr
arnaud.tatibouet@univ-orleans.fr
https://www.icoa.fr/en/tatibouet
N-butyl-1-deoxynojirimycin
B
(Miglustat, ZavescaTM
)
and
Miglitol C (GlysetTM), both clinically used for the control of
Gaucher′s disease related to disturbed lysosomal storage and
type II diabetes, respectively (Figure 1).[4] As a result, much ef-
fort has been made around the structural variation of 1-deoxy-
nojirimycin D (DNJ)-like compounds. However, despite their
therapeutic potential, most iminosugars suffer from a low spe-
cificity probably due to their flexible conformation. Conse-
[b] Dr. M. Domingues, Dr. M. I. Ismael, Dr. J. A. Figueiredo
Departamento de Química, Unidade I&D FibEnTech da Universidade da
Beira Interior,
Av. Marquês d'Ávila e Bolama, 6201-001 Covilhã, Portugal
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202001053.
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quently, bicyclic iminosugars such as pyrrolidizines, indoli- thionocarbonyl source such as thiophosgene or carbon disulf-
zidines and nortropanes have attracted attention due to their ide, or directly on reducing sugars by reacting with thiocyanic
rigid structures, which induce higher and more specific GH acid.[9,10] This last approach was the one favored in this work
inhibitory activity.[5] The synthesis of conformationally locked since it gives a rapid access to the OZT using safe, non-toxic
iminosugars such as imidazopiperidine derivatives, triazole and reagents in mild conditions, usually in good yields. It also has
tetrazole fused iminosugars, has also been explored. Indeed the the advantage of rapidly giving the parent OZO derivatives
modification of the sp3 nitrogen atom into a sp2 function such through oxidation. Four different pentoses series have been
as pseudoamide type (urea, thiourea, carbamate) led to innova- explored, while for the ketohexoses, we chose to work from 1-
tive glycomimetics with increased selectivities and retaining O-benzyl-D-fructopyranose and 1-O-protected-
good inhibitory activities.[6] For example, compounds E & F are (methyl, benzyl and allyl).
potent and selective inhibitors of yeast α-glucosidase (Ki =
L-sorbopyranose
2.2 μ
M and 40 μM
respectively with complete α specificity).[7]
Synthesis of OZO(T) Azidosugars
The OZT fused sugars were obtained from native
Our group has also reported the synthesis of castanospermine
G analogues bearing oxazole-2-(3)-thione moieties H.[8]
In this work, we explored the synthesis of modified oxazol-
idinethiones (OZT) and oxazolidinones (OZO) iminosugars (I)
(Scheme 1). We were concerned with the development of
efficient synthetic pathways towards common precursors
amenable to both OZT and OZO fused iminosugars. Both aldo-
pentoses and ketohexoses templates were targeted, in order to
thoroughly investigate the structure-activity relationship of
these novel glycomimetics as potential glycosidase inhibitors.
Our synthetic approach relies on an innovative tandem Staud-
inger reduction-aminocyclisation of OZT azidosugars (III) or
OZO azidosugars (II) accessible from native sugars via the corre-
sponding OZT sugars (IV).[9]
D
-ribose,
D
-xylose, - and -arabinose, following previously reported pro-
D
L
cedure.[9a] The primary alcohol position was then activated
through Garegg's iodination[11] and the OZT 5-iodosugars 2a–
2d were obtained in good yields ranging from 74 % to 90 %
(Scheme 2).
Scheme 2. Synthesis of fused OZT 5-iodopentoses- 2a–2d.
The following step was the introduction of the azido moiety
through nucleophilic displacement of the iodo group. When
first working on the -ribose based OZT 2a, classical conditions
D
using sodium azide in DMF led to the desired compound 4a
but in a poor 11 % yield, mainly due to the degradation of the
starting material (Scheme 3). Prior protection of the free
hydroxyl at the C-3 position with a tert-butyldimethylsilyl group
(TBDMS) did not allow the formation of the desired azide. Based
on the isolated products, we assume that the unstable 5-azido
product undergoes ring opening at the hemiaminal C-1 posi-
tion followed by tautomeric equilibrium to lead to the oxazole-
2-thione 5a in 54 % yield. This product was observed by NMR
spectroscopy as a mixture of two isomers 5a and 5a′ resulting
from the migration of the TBDMS group on both hydroxyl
groups. Similar results were obtained when performing the re-
Scheme 1. Retrosynthetic pathway to bicyclic OZT(O) fused iminosugars
(ketohexoses and pentoses).
Results and Discussion
actions in
D-arabino series (data not shown).
Two main approaches are used to introduce the OZT function
To avoid these parasite reactions, we decided to focus on
in the sugar precursors, either from a ꢀ-amino alcohol with a the preparation of the corresponding OZO (Scheme 4). Thus,
Scheme 3. Synthesis of OZT 5-azido-
D-ribose derivative 4a.
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OZT 5-iodo- -ribofuranose 2a was alkylated using benzyl brom-
D
ide in the presence of triethylamine in dichloromethane and
the S-benzylated product was obtained in a good 73 % yield.
S-Alkylation could be assessed by 13C NMR spectroscopy, from
the chemical shift of C=S which moved from 189 ppm down to
173 ppm after alkylation. Subsequent nucleophilic substitution
of the iodogroup with sodium azide was successful and gave
the desired 5-azido compound 8a in an excellent 92 % yield.
From there, the OZO function could be obtained through an
oxidative desulfurisation with m-chloroperbenzoic acid
(m-CPBA) and sodium bicarbonate.[9b,9f] However, the OZO 5-
azido- -ribose 10a was only isolated in a low 21 % yield. The
D
protection of 3-OH with a TBDMS increased the yield of the
oxidation up to 80 % (11a). The desilylation step was unfortu-
nately quite low yielding (28 %), making the overall synthetic
pathway less interesting than the direct one.
Scheme 4. Synthesis of OZO 5-azido-D-ribose 10a.
With this synthetic sequence in hands, similar conditions
were applied to the OZT 5-iodo-
D-arabino, L-arabino and D-xylo
derivatives 2b–2d (Scheme 5). The three OZTs 8b–8d could be
obtained in good yields (58–78 %) over 2 steps and the corre- The azido group could be installed using the usual three steps
sponding final OZO 5-iodosugars derivatives 10b–10d were ob- sequence involving Garegg's iodination, S-benzylation and nu-
tained with yields close to 60 %.
cleophilic displacement of the iodine with sodium azide to give
Scheme 5. Exemplification with pentoses.
16e with a 40 % overall yield. Finally, oxidation with mCPBA
afforded the desired OZO 17e in a good 70 % yield.
In the
tions as for aldopentoses (Scheme 6). 1-O-benzyl-2:3,4:5-
di-O-isopropylidene- -fructose 12e was first prepared from
-fructose in two steps.[9b,9d] Acid hydrolysis of both acetals af- order to simultaneously introduce both alkyl groups at a later
forded the 1-O-benzyl- -fructopyranose which could be directly stage in the sequence and then perform the transformation
condensed with potassium thiocyanate to give the desired OZT of the OZT into OZO before introducing the azido group. The
1-O-benzyl- -fructofuranose 13e in 72 % yield over two steps. synthetic pathway is shorter than the one described for the
D-fructose series, we decided to apply similar condi-
D
In the L-sorbose series, we slightly modified our strategy in
D
D
D
Scheme 6. Synthesis of OZO 6-azido-1-O-benzyl-
D-fructose 17e.
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D
-fructo series and allows the introduction of diverse protecting Synthesis of Iminosugars. One-Pot Staudinger Reduction/
groups on the C-1 position later in the sequence. To this end, retro-Michael/Michael Addition
the OZT group was introduced on native -sorbose to give the
L
Cyclisation of the aldopentoses derivatives was first studied.
The OZT 5-azido- -ribose was first submitted to Staudinger re-
OZT furanose, which conformation was locked by the introduc-
tion of the 4,6-O-isopropylidene group (Scheme 7). From this
OZT furano intermediate 18, bisalkylation could be achieved
using either benzyl bromide, allyl bromide or methyl iodide as
the electrophile in N,N-dimethylformamide, in the presence of
sodium hydride. The bisalkylated products 19–21f were thus
isolated in good yields ranging from 67 to 85 %.
D
duction[12] using 5 equivalents of triphenylphosphine in a 5:1
THF/water mixture at room temperature overnight (Table 1, en-
try 1). Unfortunately, only the aminosugar 34a could be iso-
lated, in a very low 7 % yield, rather than the desired imino-
sugar. As a control experiment, the reduction conditions were
also applied to the S and 3-O-protected compounds 9a and the
corresponding aminosugar 35a was isolated in a much better
86 % yield (entry 2). When moving to OZO derivatives, the
3-O-TBDMS protected D-ribose derivative gave the iminosugar
37a/a′ in 51 % yield (entry 3). These iminosugars were formed
as a mixture of 2 isomers (separable by column chromatogra-
phy) resulting from the migration of the silylated protecting
group from the 3- to the 4-OH position. When changing the
conditions to Pd/C in ethanol and ammonium formate, the
iminosugar 37a/a′ was isolated in a lower 44 % yield and the
migration of the silyl group was also observed (entry 4). In both
cases, the aminosugar 36a was also observed up to 30 % but
could not be isolated as a pure product. For the unprotected
Scheme 7. L-Sorbose approach: synthesis of bisalkylated intermediates.
Bisalkylated products 19f and 21f were then submitted to
m-CPBA oxidation to form the corresponding OZO, followed by
acid hydrolysis of the isopropylidene acetal (Scheme 8). Benzyl-
and methyl OZO 19f and 21f were obtained in reasonable
yields of 55 and 52 % respectively. Introduction of the azide was
achieved in the usual conditions, by nucleophilic substitution
of the 6-iodo derivatives 28f and 30f with sodium azide. Finally,
azide 10a, the OZO
D
-ribo-iminosugar 38a was observed by
NMR analysis of the crude mixture but could not be isolated
due to purification difficulties and separation of the polar
iminosugar from the triphenylphosphine oxide by-product (en-
try 5). Reverse phase silica gel column chromatography was
also attempted with no success. To overcome this problem, sup-
ported PS-PPh3 was used but, once again, the iminosugar 38a
was detected but not isolated pure. However, the structure of
38a could be confirmed by comparison with a pure sample
obtained from desilylation of iminosugars 37a and 37a′. More
the
L-sorbo OZO precursors 31f and 33f were obtained over 6
steps in 15 and 11 % yields from
L-sorbose. For the allyl deriva-
tive, due to the presence of the reactive double bond and the
possible side reactions, the formation of the OZO could be
achieved using a basic hydrolysis with sodium hydroxide in
ethanol. Once the acetal hydrolyzed, the desired OZO 1-O-allyl-
sugar 26f was obtained in 50 % yield over 2 steps. The synthesis
of the 6-iodo derivative under Garegg's conditions also turned
out to be problematic with a very low 17 % yield, so the azido
group was installed via the tosylate 29f with an overall yield of
39 % over two steps for compound 32f.
interestingly, the
the corresponding iminosugar 38d in a moderate 41 % yield
(entry 8) while - and -arabino azides led to iminosugars 38b
D
-xylo precursor 10d allowed the formation of
D
L
and 38c in good 67 % and 66 % yields respectively (entries 6
and 7).
Finally, we managed to access OZT 5-azidoD-ribose 4a, OZO
The optimized conditions for the aldopentose azides were
5-azidoaldopentoses 10a–10d and OZT 6-azidoketohexoses then applied to the ketohexoses derivatives (Table 2). We first
17e and 31–33f, which were then engaged in the cyclisation studied the cyclisation of one OZT derivative we already had in
towards the corresponding iminosugars.
hands. However, the OZT azido L-sorbo derivative 44f gave
Scheme 8.
L-Sorbose approach: synthesis of OZO 1-O-protected-6-azido sugars.
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Table 1. Staudinger reduction of pentoses-derived OZO(T) sugars.
nor the sugar series influenced the good outcome of the reac-
tion (entries 5 to 7).
Table 2. Staudinger reduction applied to ketohexoses OZT 44f and OZO 17e,
31–33f.
[a] 44f was prepared from iodation/azidation of OZT 1-O-Bn-L
-sorbose[9b] (see
SI for experimental details). [b] Iminosugar not detected. [c] ni = could not
be isolated. [d] Amino sugar not detected.
While optimizing the cyclisation of the benzylated L-sorbo
[a] Iminosugar not detected. [b] Global yield: the 3-OTBDMS 37a (15 %) and
4-OTBDMS 37a′ (36 %) iminosugars were isolated; aminosugar 36a was also
detected. [c] Using HCO2NH4, Pd/C, EtOH, 12 h, 45 °C; global yield: 3-OTBDMS
(14 %) and 4-OTBDMS (30 %); aminosugar 36a was also detected but couldn't
be purified. [d] Both PPh3 and PPh3-PS. [e] 4 % of SM 10d also recovered. [f]
5 % of aminosugar 36d also isolated.
derivative 31f, the reaction was completed after 4 h at 50 °C
(entry 4). However, after silica gel column chromatography, the
iminosugar 40f was obtained as a mixture of two compounds,
shown to be isomers by mass spectrometry analysis. Careful
comparison with previous results (entry 3) revealed these two
compounds as the aminosugar 39f and the iminosugar 40f. The
solely the aminosugar 45f in 50 % yield. When we heated the equilibrium between both forms is favored in polar, protic me-
reaction at 50 °C, the aminosugar 45f was isolated with a lower dia. NMR monitoring of a solution of a 45:55 mixture amino/
22 % yield whereas the corresponding iminosugar was not de- iminosugar (obtained from column chromatography), in deuter-
tected (entries 1 and 2). At room temperature the OZO deriva- ated methanol showed that the ratio evolves over time: after 8
tive 31f gave the aminosugar 39f, which was identified by NMR days, an equilibrium is reached at a 25:75 ratio of amino/imino
but could not be isolated as a pure product (entry 3). Heating forms (see supporting information, Figure S2). Finally, the whole
the reaction at 50 °C overnight gave the desired iminosugar procedure was optimised to isolate the pure iminosugar and
40f in a good 67 % yield (entry 4). All the other OZO azidoketo- avoid the formation of the amino form. To this end we discov-
hexoses 17e, 32f–33f gave also the desired iminosugars 40e ered that all the work-up, purification and analyses should be
and 40f–42f in moderate to good yields from 55 to 70 %. Nei- carried out in non-protic solvents as much as possible (entries
ther the nature of the protecting group (benzyl, allyl or methyl) 4–7).
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Scheme 9. Postulated mechanism: one-pot retro-Michael/Michael addition (example of L-sorbo series).
Finally, we proposed the following mechanism for this cycli- the pentoses (C-1) and 75 ppm for the ketohexoses (C-2), with
sation (Scheme 9 - example of -sorbo derivative): following Δ ppm of around 20 ppm) confirmed the aminoketalic bicyclic
L
Staudinger reduction of the azido group into the amine A, the structure. For the pentoses iminosugars, the vicinal proton-
cyclisation can occur through a retro-Michael reaction leading proton coupling constants around the six-membered ring are
to the imine intermediate C followed by a Michael addition of indicative of a 4C1 chair conformation for the
D
-xylo iminosugar
the amine onto the C-2 position (C-1 for the pentoses). This 38d and the
L-arabino 38c (Figure 3), with the α-pseudo-
retro-Michael reaction can be catalysed by traces of base or
nucleophile, such as triphenylphosphine or another amine resi-
due. However, for the OZT, the softer sulfur atom is a better
stabilizing group for the negative charge than the oxygen atom
B, which probably disfavors the formation of the imine
intermediate and terminates the reaction at the amino-OZT
product.
anomeric substituent being axial, thus fitting the anomeric ef-
fect (see supporting information for detailed J values, Table S2.
1
On the contrary, the
D
-arabino derivative adopts a C4 confor-
mation, the ꢀ-pseudoanomeric substituent thus being also ax-
ial. For the D-ribo derivative, coupling constants were not clearly
discriminant but we assumed a 1C4 chair, due to similar J1,2
value and J4,5 values in favor of H4 being equatorial. Overall,
To summarise, the preparation and the cyclisation of the OZT some coupling constants values were slightly lower to what was
azidosugars turned out more problematic than the OZO ana- expected, especially close to the junction with the OZO (notably
logues. Indeed, no OZT iminosugar could be isolated, only the
corresponding aminosugars that were quite unstable (degrada-
tion when heating). However, eight OZO-fused bicyclic imino-
sugars were synthetized: compounds 40–42f and 40e based on
ketohexoses scaffolds and 38a-d based on aldopentoses (Fig-
ure 2).
J
2-3 ca. 6.5–6.8Hz for 38b–d), so it is likely that the chair confor-
mation is somehow twisted. In the ketohexoses family, the
L
-sorbo derivatives display large J4,5 and medium J3,4 coupling
constant values, in agreement with a 2C5 conformation (only
OBn derivative 40f shown). In addition, a large J5,6 coupling
constant, could be measured for 40f which reinforces the hy-
All the structures were confirmed by NMR spectroscopy (1H, pothesis that H5 is axial. Similarly, the
D
-fructo derivative is likely
2
13C and 2D correlations). The high field shift of the pseudoano- to adopt a C5 conformation due to J3,4 and J5,6 values similar
meric carbon resonance (signals observed around 66 ppm for to the L-sorbo derivatives (Figure 3 and SI).
Figure 2. Summary of prepared OZO fused iminosugars.
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Figure 3. Conformational analysis of bicyclic iminosugars (400 MHz NMR; aldopentoses spectra were recorded in CD3OD, for ketohexoses different solvents
had to be used, see SI for experimental details).
Conformational Analysis – Molecular Modelling
solvent (see experimental part and SI for more details). Confor-
mational search followed by minimization of each conformer
Conformational analysis of each series of iminosugars was per- was achieved. The results for the pentose series are in agree-
formed on a DFT-6-31G++ level using Spartan software in polar ment with the conclusions of the NMR analysis in favour of a
Figure 4. Geometrically DFT-optimised conformations of iminosugars 38a, 38b and 38d of the pentose series together with the
-fructo compounds.[a]
L-sorbo 40f and the 1-O–Me
D
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4C1 conformation for the
D
-xylo derivative 38d and a 1C4 Experimental Section
conformation for the
D
-arabino 38b and -ribo derivatives 38a
D
General methods. Flash silica column chromatography was per-
formed on silica gel 60N (spherical, neutral, 40–63 μm) or using a
Reveleris® flash chromatography system. The reactions were moni-
tored by thin layer chromatography (TLC) on silica gel 60F254 pre-
coated aluminium plates. Compounds were visualized under UV
light and by charring with a 10 % H2SO4 ethanolic solution spray
or a solution of potassium permanganate. Solvents were dried by
standard methods: THF was purified with a dry station GT S100
immediately prior use, dichloromethane was distilled from P2O5;
methanol and N,N-dimethylformamide were dried with molecular
sieves; pyridine and triethylamine were dried with potassium
hydroxide. Molecular sieves were activated prior use by heating for
4 h at 500 °C. All other commercial solvents and reagents were used
without further purification. All reactions were carried out under
dry argon atmosphere. Melting points were determined in open
capillary tubes using a Büchi 510 apparatus and are uncorrected.
The infrared spectra of compounds were recorded on a Perkin–
Elmer PARAGON 1000 PC instrument, and values are reported in
cm–1. Optical rotation were recorded on a Jasco P2000 polarimeter
at 20 °C, values are given in deg dm–1 g–1 mL with concentrations
reported in g/100mL. 1H NMR and 13C NMR were recorded with
Bruker Avance II 250 MHz or an Avance III HD Nanobay 400 MHz
(Figure 4). Similarly, to the NMR data analysis, the determination
of the -ribo conformer 38a proved to be more difficult as two
D
closely related conformers were in balance: a 1C4 conformer
showing 5 possible energy minimum conformers representing
a Boltzmann weight of 0.263 while the boat structures (4 con-
formers) represent a heavier Boltzmann weight of 0.486. The
possible 4C1 conformer proved far less important (0.046 BW).
Relying on the NMR data, the most probable conformer in solu-
tion might be the 1C4 with a much higher flexibility. On the
contrary, only the 4C1 conformer of the
observed. For the ketohexose series, the conformational search
D
-xylopyranose 38d was
was performed on 1-O-methyl derivatives such as -sorbo 42f.
L
In both series, the optimised conformers turned out to be a 2C5
structure.
Glycosidase Inhibitory Activity
The inhibitory potency of the synthesized compounds was
assessed against a range of GHs: α/ꢀ-
D
-glucosidase, α/ꢀ-D-ga-
1
spectrometer. Assignments of both H and 13C signals were based
lactosidase, α/ꢀ- -mannosidase, and ꢀ-
D
D-glucuronidase (see SI,
on DEPT 135 sequence, homo- and heteronuclear 2D correlations.
Chemical shifts are reported in parts per million (ppm) using tetra-
methylsilane as the internal standard. Coupling constants (J) are
reported and expressed in Hertz (Hz), splitting patterns are desig-
nated as b (broad), s (singlet), d (doublet), dd (doublet of doublet),
q (quartet), dt (doublet of triplet), ddd (doublet of doublet of dou-
blet), m (multiplet). High-resolution mass spectra (HRMS) were per-
formed on a Maxis Bruker 4G by the “Federation de Recherche”
ICOA/CBM (FR2708) platform in the electrospray ionisation (ESI)
mode. The following solvents have been abbreviated: ethyl acetate
(EA), petroleum ether (PE), tetrahydrofuran (THF), and DMF (N,N-
dimethylformamide), DMSO (dimethyl sulfoxide).
Figures S1, S2 and Table S1). Unfortunately, most of the com-
pounds showed little or no inhibition when assayed at 1 mM.
Still, only OZO
38c were able to inhibit around 40 % of ꢀ-
-galactosidase activities respectively. Both compounds turned
out to be competitive inhibitors of each enzyme with respective
Ki values of 68.3 2.2 μ (ꢀ-Glu) and 445 90 μ (α-Gal), hence
D
-arabino and
L-arabino iminosugars 38b and
D
-glucosidase and α-
D
M
M
exhibiting similar inhibition constants as previously reported
sp2-iminosugars, in the sub-millilolar range.[7b] Iminosugar 38b
derived from ꢀ-
turally related to ꢀ-
chemistry are conserved. More interestingly, the OZO imino-
sugar 38c based on ꢀ- -arabinopyranose, is more closely related
to the structure of α- -galactopyranose. Thus, there is still a
D
-arabinopyranose, could eventually be struc-
D
-glucopyranose, as C-1 and C-4 stereo-
Glucosidase inhibition assay.
L
α-
D
-glucosidase (from S. cerevisiae), ꢀ-
-galactosidase (from green coffee beans), ꢀ-
-mannosidase (from jack beans), ꢀ-
(from bovine liver) were purchased from Sigma (St Louis, USA). ꢀ-
D
-glucosidase (from almonds),
-galactosidase
-glucuronidase
D
α-
D
D
(from E. coli), α-
D
D
reasonable scope for variations in the structure of these mixed
OZO iminosugar structures to further improve their inhibitory
potency and understand their selectivity and mechanisms of
interaction with glycosidases.
D
-mannosidase (from D. thermophilum) was cloned, and expressed
as described previously.[13] 4-nitrophenylglycosides substrates were
purchased from Carbosynth (UK).
GHs activities were assayed for 30 minutes at 37 °C in 200 μL reac-
tion mixture containing 4-nitrophenylglycoside substrate, inhibitor
Conclusion
(1 m
M) in Tris buffer (50 mM, pH 7.0) or 2-(N-morpholino)ethane-
sulfonic (MES) buffer (50 m
origin and concentration of enzymes, substrate concentration, ···
are reported in supporting information, table S1). After incubation,
M
, pH 5.0) (individual conditions, e.g.
We have developed a novel and efficient synthetic pathway to-
wards 1,2-fused oxazolidinone iminosugars a new class of
glycosidase inhibitors. Our strategy relies on an innovative
Staudinger reduction/retro-Michael/aza-Michael sequence and
allowed for the preparation of both aldopentoses and ketohex-
oses based bicyclic OZO iminosugars. Eight novel compounds
were synthesized and evaluated as potential GHs inhibitors,
thus extending the family of conformationally restricted bicyclic
100 μL of 1
released para-nitrophenol was quantified by absorbance measure-
ment at 405 nm (ε405 = 19500
–1 cm–1). Product formation rates
M sodium carbonate was added, and the amount of
M
were extracted and uncatalytic activities were determined using
DMSO instead of inhibitor as control. Means and standard devia-
tions were calculated from 3 independent data.
DNJ analogues. Both
showed moderate inhibition properties with remarkable selecti-
vity on ꢀ- -glucosidase and α- -galactosidase respectively, thus
encouraging the synthesis of novel GHs inhibitors built with
this unusual scaffold.
D- and L-arabino based iminosugars
Enzyme inhibition mechanism and Ki calculation were done by de-
termining enzymatic activities in presence of a range of substrate
and inhibitor concentrations for the corresponding enzyme. Model
fitting and constants determination from 3 independent experi-
ments were done using Prism 4 (GraphPad).
D
D
Eur. J. Org. Chem. 0000, 0–0
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© 2000 Wiley-VCH GmbH

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EurJOC
European Journal of Organic Chemistry
3
DFT calculations.
3J4-5b = 7.2 Hz, H-4), 4.24–4.27 (m, 1H, H-3), 5.11 (dd, 1H, J2-3
=
3
3
1.1 Hz, J2-1 = 5.6 Hz, H-2), 5.88 (d, 1H, J1-2 = 5.6 Hz, H-1), 5.95 (d,
Quantum chemical calculations using the density functional theory
(DFT) method were performed. The initial geometries for these
compounds have been generated using molecular modeling Spar-
tan Student (wavefunction.in). Automated complete geometry opti-
mizations were performed using the DFT method by employing
B3LYP/6-31 G** basic set function on Spartan Student software. SCF
model: A restricted hybrid HF-DFT SCF calculation was performed
using Pulay DIIS + Geometric Direct Minimization Polarizable Con-
tinuum solvation model was applied. Solvation: C-PCM dielectric =
37.22. Cartesian coordinates are detailed in the supporting informa-
tion.
1H, JOH-3 = 4.4 Hz, OH-3), 10.99 (s, 1H, NH); 13C NMR (100 MHz,
3
[D6]DMSO): δ (ppm) = 6.2 (CH2-5), 76.4 (CH-3), 85.4 (CH-4), 89.5 (CH-
1), 91.2 (CH-2), 188.1 (C=S); IR (neat) (ν, cm–1) = 3296 (NH + OH),
˜
1151 (C=S), 1035 (CN), 607 (C-I); HRMS (ESI+): m/z = calculated for
C6H9INO3S ([M + H]+): 301.9342, found 301.9341.
5-Deoxy-5-iodo-1-N,2-O-thiocarbonyl-ꢀ-L-arabinofuranosyl-
amine (2c). General procedure 1 was followed using OZT 1c (1.70 g,
8.89 mmol) and gave after purification (PE/EA: 60:40) the desired
OZT iodo compound 2c as a white solid (1.97 g, 74 %). Rf = 0.52
(PE/EA: 40:60); m.p. 172–176 °C; [α]2D0 = +52 (c 1, MeOH); 1H NMR
3
(250 MHz, [D6]DMSO): δ (ppm) = 3.14 (dd, 1H, J5b-4 = 7.3 Hz,
Synthesis of OZO(T) azidosugars.
3J5b-5a = 10.5 Hz, H-5b), 3.19 (dd, 1H, 3J5a-4 = 7.1 Hz, 3J5a-5b = 10.5 Hz,
H-5a), 4.04 (td, 1H, 3J4-3 = 2.3 Hz, J4-5a = 3J4-5b = 7.2 Hz, H-4), 4.24–
D-ribo, arabino and xylo furanosylamines 1a,1b and 1d were pre-
pared following literature procedures 9[a,b] OZT 6-Azido-1-O-benzyl-
L-sorbose 44f was prepared from 1-O-benzyl-2-N,3-O-thiocarbonyl-
3
3
3
4.26 (m, 1H, H-3), 5.12 (dd, 1H, J2-3 = 0.6Hz, J2-1 = 5.7 Hz, H-2),
3
3
5.89 (d, 1H, J1-2 = 5.7 Hz, H-1), 5.96 (d, 1H, JOH-3 = 4.4 Hz, OH),
10.99 (s, 1H, NH); 13C NMR (100 MHz, [D6]DMSO): δ (ppm) = 6.2
(CH2-5), 76.4 (CH-3), 85.5 (CH-4), 89.6 (CH-1), 91.3 (CH-2), 188.1
α-L-sorbofuranosylamine 9[b]
.
1-N,2-O-Thiocarbonyl-ꢀ-L-arabinofuranosylamine (1c). L-Arabi-
nose (3 g, 19.6 mmol, 1 equiv.) was suspended in water (0.5 M) then
KSCN (4.5 g, 46.3 mmol, 2.4 equiv.) and HCl 37 % (10 mL, 6.1 equiv.)
were added. The pink solution obtained was stirred at 55 °C for
24–48h. Water was removed by co-evaporation with toluene under
reduced pressure and the crude product was purified by silica gel
column chromatography using pure EA, to yield the desired prod-
uct 1c as a brown solid (3.1 g, 83 %). Rf = 0.66 (EA/MeOH, 90:10);
m.p. 130–134 °C; [α]2D0 = +54 (c 1, MeOH); 1H NMR (250 MHz,
[D6]DMSO): δ (ppm) = 3.17–3.37 (m, 2H, H-5), 3.85–3.92 (m, 1H,
(C=S); IR (neat) (ν, cm–1) = 3311 (OH + NH), 1488 (C-N), 1036 (C=S),
˜
607 (C-I); HRMS (ESI+): m/z = calculated for C6H9INO3S ([M + H]+):
301.9342, found 301.9341.
5-Deoxy-5-iodo-1-N,2-O-thiocarbonyl-α-D-xylofuranosylamine
(2d). General procedure 1 was followed using OZT 1d (1.7 g,
8.90 mmol) and gave after purification (PE/EA, 50:50) the desired
OZT iodo compound 2d as a white solid (2.01 g, 75 %). Rf = 0.3 (PE/
EA: 50:50); m.p. 168–170 °C; [α]2D0 = +24 (c 0.33, MeOH); 1H NMR
3
3
(250 MHz, CDCl3): δ (ppm) = 3.22 (dd, 1H, J5b-4 = 7.2 Hz, J5b-5a
=
3
H-4), 3.23–3.26 (m, 1H, H-3), 4.95 (t, 1H, J = 5.4 Hz, OH-5), 5.05 (d,
3
9.8 Hz, H-5b), 3.28–3.36 (m, 1H, H-5a), 3.90 (td, 1H, J4-3 = 2.6 Hz,
3
3
1H, J1-2 = 5.7 Hz, H-2), 5.70 (d, 1H, JOH-3 = 4.3 Hz, OH-3), 5.80 (d,
3J4-5a
=
3J4-5b = 6.9 Hz, H-4), 4.23 (dd, 1H, J3-4 = 2.7 Hz, J3-OH
=
=
3
3
3
1H, J1-2 = 5.7Hz, H-1), 10.82 (s, 1H, NH); 13C NMR (62.5 MHz,
3
3
5.3 Hz, H-3), 5.12 (d, 1H, J2-1 = 5.4 Hz, H-2), 5.81 (d, 1H, JOH-2
[D6]DMSO): δ (ppm) = 60.9 (CH2-5), 74.3 (CH-3), 87.1 (CH-4),
89.3 (CH-1), 91.5 (CH-2), 188.2 (C=S); IR (neat) (ν, cm–1) = 3304
(OH + NH), 1482 (C-N), 1034 (C=S); HRMS (ESI+): m/z = calculated
for C6H10NO4S ([M + H]+): 192.0325, found 192.0329.
3
5.3 Hz, OH), 5.88 (d, 1H, J1-2 = 5.4 Hz, H-1), 10.8 (s, 1H, NH);
13C NMR (62.5 MHz, CDCl3): δ (ppm) = 0.0 (CH2-5), 72.6 (CH-3), 80.4
(CH-4), 88.7 (CH-1), 90.0 (CH-2), 188.4 (C=S); IR (cm– 1
)
(neat) (ν, cm–1) = 3314 (NH +OH), 1155 (C=S), 628 (C-I); HRMS (ESI+):
˜
m/z = calculated for C6H9INO3S ([M + H]+): 301.9342, found
General procedure 1: iodation of OZT sugar. OZT sugar (1 equiv.)
was dissolved in THF (0.3 M) and cooled to 0 °C, then Ph3P
(2 equiv.), imidazole (2 equiv.) and iodine (2.5 equiv.) were added
and the suspension was stirred for 2h at r.t. The resulting mixture
was concentrated under reduced pressure then purified by silica
gel column chromatography using PE/EA, yielding 2a–2d, 14e.
301.9339.
1-O-Benzyl-6-deoxy-6-iodo-2-N,3-O-thiocarbonyl-ꢀ-D-fructo-
furanosylamine (14e). General procedure 1 was followed using
OZT 13e[9b] (3.70 g, 8.7 mmol), triphenylphosphine (2.0 equiv.), im-
idazole (2.5 equiv.) and iodine (2.0 equiv.) for 5 hours. The desired
OZT iodo compound 14e was obtained after purification (PE/EA =
70:30) as a white sticky foam (2.40 g, 66 %). Rf = 0.49 (PE/EA: 70:30);
[α]2D0 = –21 (c 1.02, MeOH); 1H NMR (400 MHz, CDCl3): δ (ppm) =
5-Deoxy-5-iodo-1-N,2-O-thiocarbonyl-α-D-ribofuranosylamine
(2a). General procedure 1 was followed using OZT 1a (710 mg,
3.72 mmol) and gave after purification (PE/AE: 30:70) the desired
OZT iodo compound 2a as a yellow solid (1.01 g, 90 %). Rf = 0.71
(EA/PE: 90:10); m.p. 171–174 °C; [α]2D0 = +24 (c 0.33, MeOH); 1H NMR
2
3
3.11–3.18 (m, 2H, H-6b, OH), 3.22 (dd, 1H, J6a-6b = 10.5 Hz, J6a-5
=
2
6.7 Hz, H-6a), 3.68 (d, 1H, J1b-1a = 9.9 Hz, H-1b), 3.76 (d, 1H,
2J1a-1b = 9.9 Hz, H-1a), 4.42–4.49 (m, 1H, H-5), 4.54 (d, 1H, J4-OH
=
3
(250 MHz, [D6]DMSO): δ (ppm) = 3.26–3.33 (m, 2H, H-5b and H-4),
9.3 Hz, H-4), 4.61 (d, 1H, 2J = 11.8 Hz, CH2 Bn), 4.67 (d, 1H, 2J =
11.8 Hz, CH2 Bn), 5.01 (s, 1H, H-3), 7.29–7.49 (m, 5H, CH Ar);
13C NMR (100 MHz, CDCl3): δ (ppm) = 3.8 (CH2-6), 69.8 (CH2-1), 74.4
(CH2 Bn), 76.5 (CH-4), 89.3 (CH-5), 93.1 (CH-3), 100.1 (C-2), 128.3 (CH
Ar), 128.8 (CH Ar), 129.0 (CH Ar), 136.1 (Cq Ar), 188.4 (C=S); IR (neat)
3
3.53–3.57 (m, 1H, H-5a), 3.72–3.77 (m, 1H, H-3), 5.16 (t, 1H, J2-3
=
3J2-1 = 5.3 Hz, H-2), 5.73 (d, 1H, J1-2 = 5.5Hz, H-1), 5.88 (d, 1H,
3JOH-3 = 6.2 Hz, OH), 10.79 (s, 1H, NH); 13C NMR (62.5 MHz,
[D6]DMSO): δ (ppm) = 6.5 (CH2-5), 74.9 (CH-3), 77.0 (CH-4), 84.8 (CH-
3
2), 87.5 (CH-1), 189.5 (C=S); IR (neat) (ν, cm–1) = 3279 (OH + NH),
˜
(ν, cm–1) = 3233 (NH+OH), 3028 (Csp2-H), 1310 (C-O), 1091 (C=S),
1518 (C-N), 1073 (C=S), 601 (C-I); HRMS (ESI+): m/z = calculated for
˜
1027 (C-N), 510 (C-I); HRMS (ESI+): m/z = calculated for C14H17INO4S
C6H9INO3S ([M + H]+): 301.9342, found 301.9341.
([M + H]+): 421.9917, found 421.9917.
5-Deoxy-5-iodo-1-N,2-O-thiocarbonyl-ꢀ-D-arabinofuranosyl-
amine (2b). General procedure 1 was followed using OZT 1b
(697 mg, 3.65 mmol) and gave after purification (PE/EA, 70:30) the
desired OZT iodo compound 2b as a white solid (934 mg, 85 %).
1-O-Benzyl-6-deoxy-6-iodo-2-N,3-O-thiocarbonyl-α-L-sorbo-
furanosylamine (43f). General procedure 1 was followed using
1-O-benzyl-2-N,3-O-thiocarbonyl-α-L-sorbofuranosylamine 9[b]
Rf = 0.45 (PE/EA: 50:50); m.p. 169–173 °C; [α]2D0 = –24 (c 0.407, (860 mg, 2.8 mmol) and gave after silica gel column chromatogra-
MeOH); 1H NMR (400 MHz, [D6]DMSO): δ (ppm) = 3.14 (dd,
phy (PE/EA: 70:30) the desired product as a brown oil (680 mg,
3
3
3
1H, J5b-4 = 7.3 Hz, J5b-5a = 10.5 Hz, H-5b), 3.19 (dd, 1H, J5a-4
=
=
59 %). Rf = 0.71 (PE/EA: 50:50); 1H NMR (400 MHz, CDCl3): δ (ppm) =
3
3
3
3
7.1 Hz, J5a-5b = 10.5 Hz, H-5a), 4.04 (td, 1H, J4-3 = 2.2 Hz, J4-5a
2.98 (d, 1H, JOH-4= 10.5 Hz, OH), 3.23–3.31 (m, 2H, CH2-6), 3.67 (d,
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2
2
1H, J1b-1a = 9.9 Hz, H-1b), 3.76 (d, 1H, J1a-1b = 9.9 Hz, H-1a), 4.28–
(C=N), 607 (C-I); HRMS (ESI+): m/z = calculated for C13H15INO3S ([M
4.32 (m, 1H, H-5), 4.47 (dd, 1H, 3J4-OH = 10.5 Hz, J5-4 = 2.4 Hz, H-4),
+ H]+): 391.9812, found 391.9810.
3
2
2
4.60 (d, 1H, J = 11.8 Hz, CH2Bn), 4.67 (d, 1H, J = 11.8 Hz, CH2Bn),
5.01 (s, 1H, H-3), 7.26–7.41 (m, 5H, CH Ar); 13C NMR (100 MHz,
CDCl3): δ (ppm) = –3.0 (CH2-6), 69.3 (CH2-1), 73.7 (CH-4), 74.3 (CH2
Bn), 82.3 (CH-5), 91.8 (CH-3), 99.0 (C-2), 128.2 (CH Ar), 128.9 (CH Ar),
129.0 (CH Ar), 136.0 (Cq Ar), 189.0 (C=S); MS (ESI+): m/z = 422.0 ([M
+ H]+), 439.0 ([M + Na]+).
2-Benzylsulfanyl-4,5-dihydro-(5-deoxy-5-iodo-α-D-xylofurano-
so) [2,1-d]-1,3-oxazole (6d). General procedure 2 was followed
using OZT 2d (926 mg, 3.08 mmol) and gave after purification (PE/
EA: 80:20) the desired OZT iodo compound 6d as a white solid
(856 mg, 71 %). Rf = 0.67 (PE/EA: 50:50); m.p. 144–146 °C [α]D20
=
+46 (c 0.48, CHCl3); 1H NMR (250 MHz, CDCl3): δ (ppm) = 2.66 (d,
3
General procedure 2: benzylation of OZT sugars.
1H, JOH-3 = 5.6 Hz, OH), 3.23–3.35 (m, 2H, CH2-5), 3.86 (ddd, 1H,
3
3
2
3J4-3 = 2.6 Hz, J4-5a = 5.9 Hz, J4-5b = 8.8 Hz, H-4), 4.26 (d, 1H, J =
OZT iodosugar (1 equiv.) was dissolved in THF (0.1
M) and cooled
13.2 Hz, CH2 Bn), 4.32 (d, 1H, 2J = 13.2 Hz, CH2 Bn), 4.40–4.43 (m,
to –5 °C, then the Et3N (4 equiv.) and BnBr (2 equiv.) were added
and the solution was stirred for 2 h at r.t. The resulting mixture was
concentrated under reduced pressure and then purified by silica
gel column chromatography using PE/EA, yielding 6a-d.
3
2
1H, H-3), 4.88 (d, 1H, J2-1 = 5.4 Hz, H-2), 6.19 (d, 1H, J1-2= 5.4 Hz,
H-1), 7.28–7.40 (m, 5H, CH Ar); 13C NMR (62.5 MHz, CDCl3): δ
(ppm) = –2.1 (CH2-5), 36.6 (CH2 Bn), 74.5 (CH-3), 79.4 (CH-4), 88.2
(CH-2), 100.4 (CH-1), 128.0 (CH Ar), 128.9 (CH Ar), 129.1 (CH Ar),
136.1 (Cq Ar), 170.4 (N=CS); IR (neat) (ν, cm–1) = 3473 (OH), 1589
2-Benzylsulfanyl-4,5-dihydro-(5-deoxy-5-iodo-α-D-ribofurano-
so) [2,1-d]-1,3-oxazole (6a). General procedure 2 was followed
using OZT 2a (1.13 g, 3.74 mmol) and gave after purification (PE/
EA: 90:10) the desired OZT iodo compound 6a as an orange solid
(1.07 g, 73 %). Rf = 0.85 (PE/EA: 50:50); m.p. 86–88 °C; [α]2D0 = +35
(c 0.39, CHCl3); 1H NMR (250 MHz, CD3OD): δ (ppm) = 3.17 (ddd,
˜
(C=N), 616 (C-I); HRMS (ESI+): m/z = calculated for C13H15INO3S ([M
+ H]+): 391.9812, found 391.9810.
2-Benzylsulfanyl-4,5-dihydro-(1-O-benzyl-6-deoxy-6-iodo-ꢀ-D-
fructofuranoso) [2,1-d]-1,3-oxazole (15e). General procedure 2
was followed using OZT 14e (500 mg, 1.19 mmol) during 24h and
gave after purification (PE/EA: 70:30) the desired product 15e as a
yellow oil (465 mg, 76 %). Rf = 0.64 (PE/EA: 70:30); [α]2D0 = –28 (c
3
3
3
1H, J4-5a = 2.8 Hz, J4-5b = 6.0 Hz, J4-3 = 8.9 Hz, H-4), 3.31–3.38 (m,
3
3
1H, H-5b), 3.59 (dd, 1H, J5a-4 = 2.8 Hz, J5a-5b = 11.1 Hz, H-5a), 3.91
3
3
2
(dd, 1H, J3-2 = 5.5 Hz, J3-4 = 8.9 Hz, H-3), 4.32 (d, 1H, J = 13.3 Hz,
1.04, MeOH); 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.87 (t, 1H,
CH2 Bn), 4.39 (d, 1H, 2J = 13.3 Hz, CH2 Bn), 4.99 (t, 1H, J2-3
=
3
2
2J6b-6a
=
3J6b-5 = 10.0 Hz, H-6b), 3.04 (dd, 1H, J6a-6b = 10.2 Hz,
3J2-1 = 5.4 Hz, H-2), 5.96 (d, 1H, J1-2 = 5.3 Hz, H-1), 7.29–7.39 (m,
3H, CH Ar), 7.42–7.46 (m, 2H, CH Ar); 13C NMR (62.5 MHz, CD3OD):
δ (ppm) = 4.9 (CH2-5), 36.8 (CH2 Bn), 77.0 (CH-3), 78.0 (CH-4), 84.9
(CH-2), 99.7 (CH-1), 128.7 (CH Ar), 129.7 (CH Ar), 130.0 (CH Ar), 137.9
3
3J6a-5 = 6.0 Hz, H-6a), 3.54 (d, 1H, J1b-1a = 10.0 Hz, H-1b), 3.40–3.65
2
2
2
(bs, 1H, O-H), 3.96 (d, 1H, J1a-1b = 10.0 Hz, H-1a), 4.22 (d, 1H, J =
13.3 Hz, CH2 SBn), 4.26 (d, 1H, 2J = 13.3 Hz, CH2 SBn), 4.38 (dd,
3J5-6a = 6.0 Hz, J5-6b = 9.9 Hz, H-5), 4.41 (bs, 1H, H-4), 4.57 (d, 1H,
3
(Cq Ar), 173.2 (N=CS); IR (neat) (ν, cm–1) = 3184 (OH), 1566 (C=N),
˜
2J = 11.7 Hz, CH2 OBn), 4.68 (d, 1H, J = 11.7 Hz, CH2 OBn), 4.76 (s,
2
606 (C-I); HRMS (ESI+): m/z = calculated for C13H15INO3S ([M + H]+):
1H, H-3), 7.24–7.41 (m, 10H, CH Ar); 13C NMR (100 MHz, CDCl3):
δ (ppm) = 4.4 (CH2-6), 36.6 (CH2 SBn), 72.0 (CH2-1), 74.2 (CH2 OBn),
76.7 (CH-4), 88.5 (CH-5), 90.9 (CH-3), 110.7 (C-2), 128.0 (CH Ar), 128.1
(CH Ar), 128.4 (CH Ar), 128.8 (CH Ar), 129.1 (CH Ar), 136.2 (Cq Ar),
391.9812, found 391.9810.
2-Benzylsulfanyl-4,5-dihydro-(5-deoxy-5-iodo-α-D-arabino-
furanoso) [2,1-d]-1,3-oxazole (6b). General procedure 2 was fol-
lowed using OZT 2b (500 mg, 1.66 mmol) and gave after purifica-
tion (PE/EA: 70:30) the desired OZT iodo compound 6b as a brown
oil (578 mg, 89 %). Rf = 0.53 (PE/EA: 50:50); [α]2D0 = –44 (c 0.9, CHCl3);
136.8 (Cq Ar), 170.4 (C-S); IR (neat) (ν, cm–1) = 3399 (NH + OH), 3062
˜
(Csp2-H), 2863, 1581 (N=C), 1109 (C-O), 1027 (C-N), 695 (C-S), 513
(C-I); HRMS (ESI+): m/z = calculated for C21H23INO4S ([M + H]+):
512.0387, found 512.0388.
1H NMR (400 MHz, CDCl3): δ (ppm) = 2.88 (dd, 1H, J5b-4 = 9.5 Hz,
3
3J5b-5a = 10.3 Hz, H-5b), 3.04–3.09 (m, 1H, OH), 3.09 (dd, 1H, 3J5a-4
=
=
General procedure 3: silylation of OZT sugars.
5.3 Hz, 3J5a-5b = 10.3 Hz, H-5a), 4.18 (ddd, 1H, J4-3 = 2.5 Hz, J4-5a
3
3
3
2
5.3 Hz, J4-5b = 9.5 Hz, H-4), 4.25 (d, 1H, J = 13.4 Hz,CH2 Bn), 4.29
OZT iodosugar (1 equiv.) was dissolved in anhydrous DMF (0.1 M)
then imidazole (2.5 equiv.) and TBDMSCl (1.2 equiv.) were added
and the solution was stirred overnight at r.t. Ethyl acetate was
added, and the resulting solution was washed with water 4 times
and dried with MgSO4. The resulting mixture was filtered, concen-
trated under reduced pressure and then purified by silica gel col-
umn chromatography using PE/EA, yielding 3a and 7a.
(d, 1H, 2J = 13.4 Hz,CH2 Bn), 4.42–4.43 (m, 1H, H-3), 4.91 (dd, 1H,
3J2-3 = 1.2 Hz, J2-1 = 5.9 Hz, H-2), 6.14 (d, 1H, J1-2 = 5.9 Hz, H-1),
7.25–7.39 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) = 5.1
(CH2-5), 36.5 (CH2 Bn), 78.6 (CH-3), 85.9 (CH-4), 90.2 (CH-2), 101.1
(CH-1), 128.0 (CH Ar), 128.8 (CH Ar), 129.2 (CH Ar), 136.2 (Cq Ar),
3
3
170.3 (C=N); IR (neat) (ν, cm–1) = 3241 (OH), 1579 (C=N), 606 (C-I);
˜
HRMS (ESI+): m/z = calculated for C13H15INO3S ([M + H]+): 391.9812,
3-tert-Butyldimethysilyl-5-deoxy-5-iodo-1-N,2-O-thiocarbonyl-
α-D-ribofuranosylamine (3a). General procedure 3 was followed
found 391.9811.
2-Benzylsulfanyl-4,5-dihydro-(5-deoxy-5-iodo-ꢀ-L-arabino- using OZT 2a (2.78 g, 9.23 mmol) and gave after purification (PE/
furanoso) [2,1-d]-1,3-oxazole (6c). General procedure 2 was fol-
lowed using OZT 2c (1.43 g, 4.75 mmol) and gave after purification
(PE/EA: 70:30) the desired OZT iodo compound 6c as a colorless oil
EA, 95:5) the desired silylated compound 3a as a white solid (2.26 g,
59 %). Rf = 0.79 (EA/PE: 50:50); m.p. 138–140 °C; [α]2D0 = +63
(c 0.49, CHCl3); 1H NMR (250 MHz, CD3OD): δ (ppm) = 0.24, 0.25 (s ×
(1.49 g, 80 %). Rf = 0.53 (PE/EA: 50:50); [α]2D0 = +39 (c 1, MeOH); 2, 6H, Si(CH3)2)), 1.00 (s, 9H, SiC(CH3)3), 3.34–3.40 (m, 2H, H-5b,
3
3
3
1H NMR (400 MHz, CDCl3): δ (ppm) = 2.90 (t, 1H, J5b-5a
=
3J5b-4
=
H-4), 3.56–3.63 (m, H-5a), 4.07 (dd, 1H, J3-2 = 5.2 Hz, J3-4 = 8.4 Hz,
H-3), 5.20 (t, 1H, 3J2-1 = 3J2-3 = 5.3 Hz, H-2), 5.79 (d, 1H,3J1-2 = 5.3 Hz,
H-1); 13C NMR (62.5 MHz, CD3OD): δ (ppm) = –4.4 (Si(CH3)2), –4.6
(Si(CH3)2), 5.2 (CH2-5), 18.9 (SiC(CH3)3), 26.2 (SiC(CH3)3), 77.9 (CH-3),
9.7 Hz, H-5b), 3.09 (dd, 1H, 3J5a-4 = 5.4 Hz, J5a-4 = 10.4 Hz, H-5a),
3
3.76 (bs, 1H, OH), 4.16–4.20 (m, 1H, H-4), 4.26 (s, 2H,CH2 Bn), 4.41–
4.42 (m, 1H, H-3), 4.93 (d, 1H, 3J2-3 = 5.8 Hz, H-2), 6.13 (d, 1H, 3J1-2
=
5.8 Hz, H-1), 7.24–7.41 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3): 78.1 (CH-4), 85.9 (CH-2), 89.4 (CH-1), 192.1 (C=S); IR (neat) (ν,
˜
δ (ppm) = 5.2 (CH2-5), 36.4 (CH2 Bn), 78.4 (CH-3), 85.7 (CH-4), 90.3
(CH-2), 100.8 (CH-1), 128.0 (CH Ar), 128.8 (CH Ar), 129.1 (CH Ar), HRMS (ESI+): m/z = calculated for C12H23INO3SSi ([M + H]+):
136.0 (Cq Ar), 170.5 (N=CS); IR (neat) (ν, cm–1) = 3233 (OH), 1580
416.0207, found 416.0205.
cm–1) = 3180 (NH), 1484 (C-N), 1247 (C-O), 1146 (C=S), 632 (CI);
˜
Eur. J. Org. Chem. 0000, 0–0
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© 2000 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202001053
EurJOC
European Journal of Organic Chemistry
2-Benzylsulfanyl-4,5-dihydro-(3-tert-butyldimethylsilyl-5-de- 2-Benzylsulfanyl-4,5-dihydro-(5-azido-5-deoxy-α-D-ribofurano-
oxy-5-iodo-α-D-ribofuranoso) [2,1-d]-1,3-oxazole (7a). General
procedure 3 was followed using OZT 6a (613 mg, 1.48 mmol) and
gave after purification (PE/EA: 80:20) the desired product 7a as an
orange oil (650 mg, 87 %). Rf = 0.95 (PE/EA: 50:50); [α]2D0 = +67
(c 0.49, CHCl3); 1H NMR (250 MHz, CD3OD): δ (ppm) = 0.22 (s, 6H,
so) [2,1-d]-1,3-oxazole (8a). General procedure 4 was followed
using OZT 6a (1.89 g, 4.85 mmol) and gave after purification
(PE/EA: 90:10) the desired product 8a as a brown oil (1.37 g, 92 %).
Rf = 0.81 (PE/EA: 80:20); [α]2D0 = +23 (c 0.22, MeOH); 1H NMR
(400 MHz, CDCl3): δ (ppm) = 3.06 (bs, 1H, OH), 3.37 (dd, 1H, 3J5b-4
=
3
3
3
Si(CH3)2 ), 0.97 (s, 9H, SiC(CH3)3), 3.07 (ddd, 1H, J4-5a = 3.1 Hz,
4.6 Hz, J5b-5a = 13.3 Hz, CH2-5), 3.37 (dd, 1H, J4-5a = 2.8 Hz,
3
3
3
3
3J4-5b = 4.8 Hz, J4-3 = 8.2 Hz, H-4), 3.33 (dd, 1H, J5b-4 = 4.8 Hz,
3J4-5b = 4.6 Hz, J4-3 = 9.1 Hz, H-4), 3.66 (dd, 1H, J5a-4 = 2.8 Hz,
3J5b-5a = 11.3 Hz, H-5b), 3.56 (dd, 1H, 3J5a-4 = 3.1 Hz, 3J5a-5b = 11.3 Hz,
H-5a), 4.02 (dd, 1H, J3-2 = 5.4 Hz, J3-4 = 8.4 Hz, H-3), 4.32 (s, 2H,
CH2 Bn), 4.94 (t, 1H, J2-3 = J2-1 = 5.4 Hz, H-2), 5.98 (d, 1H, J1-2
3J5a-5b = 13.3 Hz, H-5a ), 4.05 (dd, 1H, J3-2 = 5.7 Hz, J3-4 = 9.1 Hz,
3
3
3
3
H-3), 4.27 (d, 1H, 2J = 13.3 Hz, CH2 Bn ), 4.32 (d, 1H, 2J = 13.3 Hz,
3
3
3
3
3
3
=
CH2 Bn), 4.85 (t, 1H, J2-3 = J2-1 = 5.5 Hz, H-2), 5.99 (d, 1H, J1-2 =
5.4 Hz, CH-1), 5.3 Hz, H-1), 7.31–7.38 (m, 3H, CH Ar), 7.42–7.46 (m,
5.2 Hz, CH-1), 7.24–7.39 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3):
2H, CH Ar); 13C NMR (62.5 MHz, CD3OD): δ (ppm) = –4.5 (Si(CH3)2), δ (ppm) = 36.5 (CH2 Ar), 50.2 (CH2-5), 72.5 (CH-3), 76.8 (CH-4), 82.4
–4.2 (Si(CH3)2), 5.6 (CH2-5), 18.8 (SiC(CH3)3), 26.2 (SiC(CH3)3), 36.7 (CH-2), 98.9 (CH-1), 127.8 (CH Ar ), 128.7 (CH Ar ), 128.9 (CH Ar ),
(CH2 Ar), 77.6 (CH-4), 78.0 (CH-3), 84.1 (CH-2), 100.0 (CH-1), 128.7
136.1 (Cq Ar), 170.8 (C=N); IR (neat) (ν, cm–1) = 3241 (OH), 2096 (N3),
˜
(CH Ar), 129.7 (CH Ar), 129.9 (CH Ar), 137.9 (Cq Ar), 172.9 (N=CS); IR 1581 (C=N); HRMS (ESI+): m/z = calculated for C13H15N4O3S ([M +
(cm–1) (neat) (ν, cm–1) = 1591 (N=C), 1251 (C-O), 672 (C-I); HRMS
H]+): 307.0859, found 307.0861.
˜
(ESI+): m/z = calculated for C19H29INO3SSi ([M + H]+): 506.0677,
2-Benzylsulfanyl-4,5-dihydro-(5-azido-3-tert-butyldimethylsilyl-
5-deoxy-α-D-ribofuranoso) [2,1-d]-1,3-oxazole (9a). General pro-
cedure 4 was followed using OZT 7a (373 mg, 0.739 mmol) and
gave after purification (PE/EA, 80:20) the desired product 9a as a
yellow oil (230 mg, 74 %). Rf = 0.84 (PE/EA: 20:80); [α]2D0 = +77
(c 0.22, CHCl3); 1H NMR (250 MHz, CD3OD): δ (ppm) = 0.19, 0.21 (s ×
found 506.0675.
General procedure 4: synthesis of OZT azidosugars.
Iodosugar derivative (1 equiv.) was dissolved in anhydrous DMF
(0.05 M) then NaN3 (5 equiv.) was added and the solution was
heated at 80 °C for 3h. Ethyl acetate was added and the resulting
solution was washed with water 4 times and dried with MgSO4. The
resulting mixture was filtered, concentrated under reduced pressure
and then purified by silica gel column chromatography using
PE/EA.
3
2, 6H, Si(CH3)2), 0.97 (s, 9H, SiC(CH3)3), 3.34 (dd, 1H, J5b-4 = 4.6 Hz,
3J5b-5a = 13.4 Hz, H-5b), 3.49 (ddd, 1H, 3J4-5a = 2.6 Hz, 3J4-5b = 4.6 Hz,
3
3
3J4-3 = 8.8 Hz, H-4), 3.64 (dd, 1H, J5a-4 = 2.6 Hz, J5a-5b = 13.4 Hz,
3
3
H-5a), 4.21 (dd, 1H, J3-2 = 5.4 Hz, J3-4 = 8.8 Hz, H-3), 4.33 (s, 2H,
3
3
CH2 Bn), 4.93 (t, 1H, J2-3
= =
3J2-1 = 5.4Hz, H-2), 6.00 (d, 1H, J1-2
5.4 Hz, H-1), 7.29–7.38 (m, 3H, CH Ar), 7.42–7.46 (m, 2H, CH Ar);
13C NMR (62.5 MHz, CD3OD): δ (ppm) = –4.9 (Si(CH3)2), –4.5
(Si(CH3)2), 18.9 (SiC(CH3)3), 26.2 (SiC(CH3)3), 36.7 (CH2 Ar), 51.2
(CH2-5), 74.3 (CH-3), 78.7 (CH-4), 83.9 (CH-2), 100.4 (CH-1), 128.7
(CH Ar), 129.7(CH Ar), 130.0 (CH Ar), 137.9 (Cq Ar), 173.1 (N=CS); IR
5-Azido-5-deoxy-1-N,2-O-thiocarbonyl-α-D-ribofuranosylamine
(4a). General procedure 4 was followed using OZT 3a (1.12 g,
3.71 mmol) and gave after purification (PE/AE: 80:20) the desired
OZT azido compound 4a as a brown solid (88 mg, 11 %). Rf = 0.68
(EA/PE: 50:50); m.p. 138–140 °C; [α]2D0 = +54 (c 1, MeOH); 1H NMR
(cm–1) (neat) (ν, cm–1) = 2097 (N3), 1592 (N=C), 1251 (C-O); HRMS
3
3
˜
(250 MHz, CD3OD): δ (ppm) = 3.42 (dd, 1H, J5b-4 = 5.3 Hz, J5b-5a
=
(ESI+): m/z = calculated for C19H29N4O3SSi ([M + H]+): 421.1724,
3
3
13.6 Hz, H-5b), 3.70 (dd, 1H, J5a-4 = 2.5 Hz, J5a-5b = 13.6 Hz, H-5a),
found 421.1729.
3
3
3
3.79 (ddd, 1H, J4-5a = 2.5 Hz, J4-5b = 5.3 Hz, J4-3 = 9.3 Hz, H-4),
3
3
3
4.12 (dd, 1H, J3-2 = 5.3 Hz, J3-4 = 9.3 Hz, H-3), 5.19 (t, 1H, J2-3
=
2-Benzylsulfanyl-4,5-dihydro-(5-azido-5-deoxy-ꢀ-D-arabino-
furanoso) [2,1-d]-1,3-oxazole (8b). General procedure 4 was fol-
lowed using OZT 6b (371 mg, 0.95 mmol) and gave after purifica-
tion (PE/EA, 95:5) the desired OZT 8b as a white solid (221 mg,
76 %). Rf = 0.67 (PE/EA: 60:40); m.p. 95–98 °C; [α]2D0 = +2 (c 0.6,
CHCl3); 1H NMR (400 MHz, CDCl3): δ (ppm) = 2.85 (bs, 1H, OH), 3.14
3J2-1 = 5.3 Hz, H-2), 5.82 (d, 1H, J1-2 = 5.3 Hz, H-1); 13C NMR
3
(62.5 MHz, CD3OD): δ (ppm) = 51.6 (CH2-5), 73.5 (CH-3), 79.0 (CH-
4), 86.2 (CH-2), 89.5 (CH-1), 192.1 (C=S); IR (neat) (ν, cm–1) = 3274
˜
(OH + NH), 2101 (N3), 1517 (C-N), 1111 (C=S); HRMS (ESI+): m/z =
calculated for C6H9N4O3S ([M + H]+): 217.0390, found 217.0391.
3
3
(dd, 1H, J5b-4 = 6.1 Hz, J5b-5a = 12.9 Hz, H-5b), 3.25 (dd, 1H,
5-((1R,2R)-3-Azido-1-O-tert-butyldimethylsilyloxy-2-hydroxy-
propyl)-2-(3H)-oxazolethione & 5-((1R,2R)-3-Azido-2-O-tert-
butyldimethylsilyloxy-1-hydroxypropyl)-2-(3H)-oxazolethione
(5a/5a'). Obtained following general procedure 4 from OZT 3a
(1.00 g, 2.47 mmol) after purification (PE/EA: 94:6) as a 2:1 mixture
of isomers 5a/5a′ as an orange oil (441 mg, 54 %). Rf = 0.5 (PE/EA:
50:50); 1H NMR (400 MHz, CDCl3): δ (ppm) = 0.00 (s, 3H, Si(CH3)2),
0.02 (s, 1.5H, Si(CH3)2′), 0.10 (s, 3H, Si(CH3)2), 0.12 (s, 1.5H,
3J5a-4 = 6.5 Hz, J5a-5b = 12.9 Hz, H-5a), 4.04 (ddd, 1H, J4-3 = 3.5 Hz,
3
3
3J4-5a
=
3J4-5b = 6.3 Hz, H-4), 4.26 (dd, 1H, J3-2 = 1.6 Hz, J3-4
=
=
3
3
3
3
3.6 Hz, H-3), 4.28 (s, 2H, CH2 Bn), 4.88 (dd, 1H, J2-3 = 1.6 Hz, J2-1
3
5.9 Hz, H-2), 6.07 (d, 1H, J1-2 = 5.9 Hz, H-1), 7.27–7.39 (m, 5H, CH
Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) = 36.5 (CH2 Bn), 51.9 (CH2-
5), 77.6 (CH-3), 83.6 (CH-4), 90.2 (CH-2), 100.7 (CH-1), 128.0 (CH Ar),
128.8 (CH Ar), 129.2 (CH Ar), 136.2 (Cq Ar), 170.3 (C=N); IR (neat)
(ν, cm–1) = 3172 (OH), 2101 (N3), 1584 (C=N); HRMS (ESI+): m/z =
˜
3
Si(CH3)2′), 0.85, 0.87 (s × 2, 15H, SiC(CH3)3), 3.45 (d, 1H, J = 4.2 Hz,
calculated for C13H15N4O3S ([M + H]+): 307.0859, found 307.0858.
CH2N′), 3.46–3.55 (m, 2H, CH2N), 4.02–4.14 (m, 1.5H, H-2, H-2′), 4.58
(d, 1H, 3J = 6.6 Hz, H-1), 4.65 (d, 0.5H, 3J = 6.3 Hz, H-1′), 6.84 (bs,
2-Benzylsulfanyl-4,5-dihydro-(5-azido-5-deoxy-ꢀ-L-arabino-
1.5H, H-4 oxazole), 11.49 (bs, 1.2H, NH); 13C NMR (100 MHz, CDCl3): furanoso) [2,1-d]-1,3-oxazole (8c). General procedure 4 was fol-
δ (ppm) = –5.0 (Si(CH3)2), –4.6 (Si(CH3)2), –4.4 (Si(CH3)2), 18.0
(SiC(CH3)3′), 18.1 (SiC(CH3)3), 25.7 (SiC(CH3)3), 25.8 (SiC(CH3)3), 52.9
(CH2N), 53.3 (CH2N′), 67.4 (CH-1′), 67.9 (CH-1), 72.3 (CH-2), 72.5 (CH-
2′), 113.8 (CH-4 oxazole′), 114.1 (CH-4 oxazole), 149.0 (C-2 oxazole′),
lowed using OZT 6c (650 mg, 1.66 mmol) and gave the desired OZT
8c as a white solid (500 mg, 98 %); it was used in the next step
without any further purification. Rf = 0.53 (PE/EA: 40:60); 1H NMR
3
2
(400 MHz, CDCl3): δ (ppm) = 3.14 (dd, 1H, J5b-4 = 5.9 Hz, J5b-5a
=
3
2
149.3 (C-2 oxazole), 178.89 (C=S′); 178.94 (=CS); IR (neat) (ν, cm–1) = 12.9 Hz, H-5b), 3.22 (dd, 1H, J5a-4 = 6.6 Hz, J5a-5b = 12.9 Hz, H-5a),
˜
3126 (OH + NH), 2101 (N3), 1651 (C=C), 1471 (C=N), 1252 (C-O), 3.53 (bs, 1H, OH), 4.04 (td, 1H, J4-3 = 3.4 Hz, 3J4-5a = 3J4-5b = 6.3 Hz,
3
1077 (C=S); HRMS (ESI+): m/z = calculated for C12H23N4O3SSi ([M +
H-4),4.24–4.25 (m, 1H, H-3), 4.27 (s, 2H, CH2 Bn), 4.89 (dd, 1H,
H]+): 331.1255, found 331.1254.
3J2-3 = 1.6 Hz, J2-1 = 6.0 Hz, H-2), 6.05 (d, 1H, J1-2 = 5.9 Hz, H-1),
3
3
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© 2000 Wiley-VCH GmbH

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European Journal of Organic Chemistry
3
3
7.26–7.38 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) = 36.4
(CH2 Bn), 51.9 (CH2-5), 77.3 (CH-3), 83.6 (CH-4), 90.3 (CH-2), 100.6
(CH-1), 128.0 (CH Ar), 128.8 (CH Ar), 129.2 (CH Ar), 136.0 (Cq Ar),
3J4-5b = 4.5 Hz, J4-3 = 8.9 Hz, H-4), 4.20 (dd, 1H, J3-2 = 5.3 Hz,
3J3-4 = 8.9 Hz, H-3), 4.96 (t, 1H, J2-1 = J2-3 = 5.3 Hz, H-2), 5.71 (d,
1H, 3J1-2 = 5.3 Hz, H-1); 13C NMR (62.5 MHz, CD3OD): δ (ppm) = –5.0
(Si(CH3)2), –4.6 (Si(CH3)2), 18.9 (SiC(CH3)3), 26.1 (SiC(CH3)3), 51.2
(CH2-5), 73.7 (CH-3), 78.8 (CH-4), 80.3 (CH-2), 86.9 (CH-1), 160.9
3
3
170.5 (C=N); IR (neat) (ν, cm–1) = 3176 (OH), 2102 (N3), 1584 (C=N);
˜
HRMS (ESI+): m/z = calculated for C13H15N4O3S ([M + H]+): 307.0859,
found 307.0861.
(C=O); IR (neat) (ν, cm–1) = 3325 (NH), 2104 (N3), 1753 (C=O), 1251
˜
(C-O); HRMS (ESI+): m/z = calculated for C12H23N4O4Si ([M + H]+):
2-Benzylsulfanyl-4,5-dihydro-(5-azido-5-deoxy-α-D-xylofurano-
so) [2,1-d]-1,3-oxazole (8d).General procedure 4 was followed
using OZT 6d (250 mg, 0.64 mmol) and gave after purification
(PE/EA: 90:10) the desired OZT azido compound 8d as a white solid
315.1483, found 315.1483.
5-Azido-1-N,2-O-carbonyl-5-deoxy-α-D-ribofuranosylamine
(10a). Method A: general procedure 5 was followed using OZT 8a
(1.300 g, 4.25 mmol) and gave after purification (PE/EA, 50:50) the
desired product 10a as a white solid (180 mg, 21 %). Method B:
5-azido-5-deoxy-3-O-tert-butyldimethysilyl-1-N,2-O-carbonyl-α-D-
ribofuranosylamine 11a (0.5 g, 1.6 mmol, 1 equiv.) was suspended
in dry THF (12 mL, 0.12 M) at 0 °C, then TBAF (1M in THF) (3.8 mL,
3.8 mmol, 2.4 equiv.) was added. The solution was stirred at room
temperature overnight then diluted with ethyl acetate. The organic
phase was washed twice with brine, dried with MgSO4, filtered and
the solvent evaporated under reduced pressure. The crude product
was purified by silica gel column chromatography using PE/AE
(50:50) to give the desired product 10a as a white solid (90 mg,
28 %). Rf = 0.40 (PE/EA: 20:80); m.p. 116–121 °C; [α]2D0 = +36 (c 1.3,
MeOH); M.S (IS+): m/z = 201.0 [M + H]+; 1H NMR (400 MHz, CD3OD):
δ (ppm) = 3.38 (dd, 1H, 3J5b-4 = 5.4 Hz, 2J5b-5a = 13.6 Hz, H-5b), 3.65
(161 mg, 82 %). Rf = 0.74 (PE/EA: 70:30); m.p. 117–120 °C; [α]D20
=
+18 (c 0.48, CHCl3); M.S (IS+): m/z = 307.0 [M + H]+, 329.0 [M + Na]+;
1H NMR (400 MHz, CDCl3): δ (ppm) = 3.11 (bs, 1H, OH), 3.58–3.66
3
3
(m, 2H, CH2-5), 3.70 (td, 1H, J4-3 = 2.8 Hz, J4-5a
=
3J4-5b = 5.9 Hz,
2
H-4), 4.24–4.32 (m, 2H, CH2 Bn and H-3), 4.30 (d, 1H, J = 13.2 Hz,
3
3
CH2 Bn), 4.83 (d, 1H, J2-1 = 5.4 Hz, H-2), 6.15 (d, 1H, J1-2 = 5.4 Hz,
H-1), 7.28–7.38 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) =
36.5 (CH2 Bn), 48.9 (CH2-5), 74.7 (CH-3), 77.0 (CH-4), 88.4 (CH-2), 99.7
(CH-1), 128.0 (CH Ar), 128.8 (CH Ar), 129.1 (CH Ar), 136.1 (Cq Ar),
170.5 (C=N); IR (cm–1) (neat) (ν, cm–1) = 3139 (OH), 2088 (N3), 1584
˜
(C=N).
2-Benzylsulfanyl-4,5-dihydro-(6-azido-1-O-benzyl-6-deoxy-ꢀ-D-
fructofuranoso)[2,1-d]-1,3-oxazole (16e). General procedure 4
was followed using OZT 15e (393 mg, 0.77 mmol) in anhydrous
DMF (0.08 M) with sodium azide (250 mg, 3.84 mmol, 5.0 equiv.).
The reaction mixture was heated at 80 °C for 3h. After usual workup,
silica gel column chromatography (PE/EA: 80:20) gave the desired
product 16e as a colourless oil (264 mg, 80 %). Rf = 0.28 (PE/EA:
80:20); [α]2D0 = +13 (c 1.04, MeOH); 1H NMR (250 MHz, CDCl3):
δ (ppm) = 3.02 (dd, 1H, 2J6b-6a = 12.8 Hz, 3J6b-5 = 6.1 Hz, H-6b), 3.17
3
2
(dd, 1H, J5a-4 = 2.6 Hz, J5a-5b = 13.6 Hz, H-5a), 3.82–3.86 (m, 1H,
3
3
H-4), 4.02 (dd, 1H, J3-2 = 5.4 Hz, J3-4 = 9.3 Hz, H-3), 4.95 (t, 1H,
3J2-3 = J2-1 = 5.3 Hz, H-2), 5.68 (d, 1H, J1-2 = 5.3 Hz, H-1); 13C NMR
3
3
(100 MHz, CD3OD): δ (ppm) = 51.7 (CH2-5), 73.0 (CH-3), 78.3 (CH-4),
80.6 (CH-2), 86.5 (CH-1), 160.6 (C=O); IR (neat) (ν, cm–1) = 3300 (NH),
˜
2099 (N3), 1716 (C=O).
2
3
3
5-Azido-1-N,2-O-carbonyl-5-deoxy-ꢀ-D-arabinofuranosylamine
(10b). General procedure 5 was followed using OZT 8b (1.35 g,
4.39 mmol) and gave after purification (PE/EA: 50:50) the desired
OZO 10b as a white solid (509 mg, 58 %). Rf = 0.24 (PE/EA: 50:50);
(dd, 1H, J6a-6b = 12.8 Hz, J6a-5 = 7.8 Hz, H-6a), 3.47 (d, 1H, JOH-4
=
2
11.0 Hz, OH), 3.59 (d, 1H, J1b-1a = 10.0 Hz, H-1b), 4.00 (d, 1H,
2J1a-1b = 10.0 Hz, H-1a), 4.15–4.34 (m, 4H, H-4, H-5, CH2 SBn), 4.58
2
2
(d, 1H, J = 11.7 Hz, CH2 OBn), 4.71 (d, 1H, J = 11.7 Hz, CH2 OBn),
4.76 (s, 1H, H-3), 7.22–7.44 (m, 10H, CH Ar); 13C NMR (62.5 MHz,
CDCl3): δ (ppm) = 36.4 (CH2 SBn), 52.0 (CH2-6), 72.2 (CH2-1), 74.2
(CH2 OBn), 76.1 (CH-4), 86.9 (CH-5), 90.8 (CH-3), 110.4 (C-2), 128.0
(CH Ar), 128.2 (CH Ar), 128.5 (CH Ar), 128.8 (CH Ar), 128.9 (CH Ar),
m.p. 133–137 °C; [α]2D0 = +32 (c 0.34, MeOH); 1H NMR (400 MHz,
3
CD3OD): δ (ppm) = 3.33–3.41 (m, 2H, CH2-5), 4.03 (ddd, 1H, J4-3
=
=
3
3
3
3.5 Hz, J4-5a = 4.5 Hz, J4-5b = 6.7Hz, H-4), 4.21 (dd, 1H, J3-2
1.4 Hz, 3J3-4 = 3.6 Hz, H-3), 4.86 (dd, 1H, 3J2-3 = 1.4 Hz, 3J2-1 = 5.6 Hz,
3
H-2), 5.72 (d, 1H, J1-2 = 5.6 Hz, H-1); 13C NMR (100 MHz, CD3OD): δ
129.2 (CH Ar), 136.1 (Cq Ar), 136.9 (Cq Ar), 170.2 (C-S); IR (neat) (ν,
˜
cm–1) = 3408 (NH + OH), 3062 (Csp2-H), 2919 (C-H), 2098 (N3), 1581
(N=C), 1099 (C-O), 1027 (C-N), 636 (C-S); HRMS (ESI+): m/z = calcu-
lated for C21H23N4O4S ([M + H]+): 427.1434, found 427.1429.
(ppm) = 53.4 (CH2-5), 77.4 (CH-3), 85.6 (CH-4), 88.1 (CH-2 or CH-1),
88.2 (CH-1 or CH-2), 159.8 (C=O); IR (neat) (ν, cm–1) = 3296 (NH +
˜
OH), 2100 (N3), 1731 (C=O), 1093 (CN); HRMS (ESI+): m/z = calculated
for C6H9N4O4 ([M + H]+): 201.0618, found 201.0618, 223.0 [M + Na]+.
General procedure 5: oxidation of OZT into OZO.
5-Azido-1-N,2-O-carbonyl-5-deoxy-ꢀ-L-arabinofuranosylamine
(10c). General procedure 5 was followed using OZT 8c (500 mg,
1.63 mmol) and gave after purification (PE/EA: 60:40 to 40:60) the
desired OZO 10c as a white solid (180 mg, 55 %). Rf = 0.45 (PE/EA:
Azidosugar derivative (1 equiv.) 8a-d, 9a was dissolved in anhy-
drous DCM (0.1 M) then NaHCO3 (3 equiv.) was added and the
reaction mixture was cooled to 0 °C. The m-CPBA (3 equiv.) was
added and the solution was stirred for 20 min at 0 °C. The reaction
mixture was warmed up to r.t and allowed to react for 12h at r.t.
The solution was neutralized by addition of Na2S2O5 and then con-
centrated under reduced pressure. The resulting residue was dis-
solved in methanol and filtered. The resulting filtrate was concen-
trated under reduced pressure and then purified by silica gel col-
umn chromatography using PE/EA, yielding 10a-d, 11a and 17e.
20:80); m.p. 128–132 °C; [α]2D0 = –51 (c 1, MeOH); 1H NMR (400 MHz,
3
CD3OD): δ (ppm) = 3.33–3.41 (m, 2H, CH2-5), 4.03 (ddd, 1H, J4-3
=
=
3
3
3
3.6 Hz, J4-5a = 4.9 Hz, J4-5b = 6.8 Hz, H-4), 4.22 (dd, 1H, J3-2
1.4 Hz, 3J3-4 = 3.7 Hz, H-3), 4.86 (dd, 1H, 3J2-3 = 1.4 Hz, 3J2-1 = 5.7 Hz,
H-2), 5.72 (d, 1H, J1-2 = 5.7 Hz, H-1); 13C NMR (100 MHz, CD3OD):
3
δ (ppm) = 53.4 (CH2-5), 77.4 (CH-3), 85.6 (CH-4), 88.1 (CH-2 or CH-
1), 88.2 (CH-1 or CH-2), 159.9 (C=O); IR (neat) (ν, cm–1) = 3302 (OH
˜
+ NH), 2102 (N3), 1728 (C=O), 1034 (C-N); HRMS (ESI+): m/z = calcu-
5-Azido-3-O-tert-butyldimethysilyl-1-N,2-O-carbonyl-5-deoxy-
α-D-ribofuranosylamine (11a). General procedure 5 was followed
using OZT 9a (215 mg, 0.512 mmol) and gave after purification (PE/
EA, 85:15) the desired product 11a as a white solid (129 mg, 80 %).
lated for C6H9N4O4 ([M + H]+): 201.0618, found 201.0622.
5-Azido-1-N,2-O-carbonyl-5-deoxy-α-D-xylofuranosylamine
(10d). General procedure 5 was followed using OZT 8d (1.26 g,
Rf = 0.26 (PE/EA: 80:20); m.p. 86–89 °C; [α]2D0 = +80 (c 0.43, CHCl3); 4.12 mmol) and gave after purification (PE/EA: 50:50) the desired
1H NMR (250 MHz, CD3OD): δ = 0.19, 0.21 (s × 2, 6H, Si(CH3)2)), 0.97
OZO 10d as a brown oil (495 mg, 60 %). Rf = 0.43 (PE/EA: 20:80);
3
1
(s, 9H, SiC(CH3)3), 3.32–3.39 (m, 1H, H-5b), 3.69 (dd, 1H, J5a-4
=
[α]2D0 = –18 (c 0.96, MeOH); H NMR (400 MHz, CD3OD): δ (ppm) =
2.6 Hz, J5a-5b = 13.7 Hz, H-5a), 3.85 (ddd, 1H, J4-5a = 2.6 Hz, 3.48–3.58 (m, 2H, CH2-5), 4.05 (ddd, 1H, 3J4-3 = 2.9 Hz, 3J4-5a = 5.3 Hz,
3
3
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3
3J4-5b = 7.1 Hz, H-4), 4.24 (d, 1H, J3-2 = 2.8 Hz, H-3), 4.87 (d, 1H, sorbofuranosylamine 18 (3.0 g, 11.5 mmol) and gave after purifica-
3
3J2-1 = 5.4 Hz, H-2), 5.79 (d, 1H, J1-2 = 5.4 Hz, H-1); 13C NMR tion (PE/EA, 80:20 to 70:30) the desired bisprotected OZT 20f as a
(100 MHz, CD3OD): δ (ppm) = 50.4 (CH2-5), 74.8 (CH-3), 79.4 (CH-4),
colourless oil (3.04 g, 78 %). Rf = 0.56 (PE/EA: 70:30); [α]2D0 = –73 (c
1.01, MeOH); 1H NMR (250 MHz, CDCl3): δ (ppm) = 1.38 (s, 3H, CH3),
86.7 (CH-2), 87.4 (CH-1), 160.1 (C=O); IR (cm–1) (neat) (ν, cm–1) =
˜
3241 (NH + OH), 2088 (N3), 1694 (C=O), 1082 (CN); HRMS (ESI+): 1.44 (s, 3H, CH3), 3.64 (bs, 1H, H-5), 3.68 (dm, 2H, 2J = 10.0 Hz, CH2O
m/z = calculated for C6H9N4O4S ([M + H]+): 201.0618, found allyl), 3.78 (d, 1H, J1b-1a = 10.5 Hz, H-1b), 3.86 (d, 1H, J1a-1b
=
2
2
201.0619.
10.5 Hz, H-1a), 4.02–4.17 (m, 4H, CH2S allyl, CH2-6), 4.35 (bs, 1H, H-
4), 4.75 (s, 1H, H-3), 5.11–5.33 (m, 4H, =CH2 O- and S-allyl), 5.82–
6.00 (m, 2H, HC= O- and S-allyl); 13C NMR (100 MHz, CDCl3):
δ (ppm) = 18.9 (CH3), 29.0 (CH3), 35.0 (CH2 O-allyl), 59.7 (CH2-6 or
CH2 S-allyl), 71.0 (CH-5), 71.5 (CH2-1), 72.8 (CH2 S-allyl or CH2-6), 73.3
(CH-4), 88.2 (CH-3), 97.9 (C-2 or iPr), 109.4 (iPr or C-2), 117.0 (=CH2
O- or S-allyl), 118.9 (=CH2 O- or S-allyl), 132.4 (=CH O-allyl), 134.8
6-Azido-1-O-benzyl-2-N,3-O-carbonyl-6-deoxy-ꢀ-D-fructo-
furanosylamine (17e). General procedure 5 was followed using
OZT 16e (1.14 g, 2.7 mmol) and gave after silica gel column chro-
matography (PE/EA: 60:40) the desired product 17e as a yellow oil
(600 mg, 70 %). Rf = 0.32 (PE/EA: 60:40); [α]2D0 = +22 (c 1.04, MeOH);
2
1H NMR (400 MHz, CD3OD): δ (ppm) = 3.35–3.43 (dd, 1H, J6b-6a
=
(=CH S-allyl), 168.8 (C-S); IR (neat) (ν, cm–1) = 2995 (C-H), 1598 (C=
˜
3
2
13.3 Hz, J6b-5 = 6.6 Hz, H-6b), 3.48 (dd, 1H, J6a-6b = 13.3 Hz,
N), 1113 (C-O), 1075, 919 (Csp2-H), 849 (C-S); HRMS (ESI+): m/z =
3J6a-5 = 4.4 Hz, H-6a), 3.72 (d, 1H, J1b-1a = 10.3 Hz, H-1b), 3.77 (d,
2
calculated for C16H24NO5S ([M + H]+): 342.1367, found 342.1372.
2
3
3
1H, J1a-1b = 10.3 Hz, H-1a), 4.16 (dt, 1H, J5-6b = 6.6 Hz, J5-4
=
3J5-6a = 4.4 Hz, H-5), 4.30 (dd, 1H, J4-5 = 4.4 Hz, J4-3 = 2.1 Hz, H-4),
4.66 (d, 1H, 2J = 11.9 Hz, CH2 Bn), 4.69 (d, 1H, 2J = 11.9 Hz), 4.84 (d,
1H, 3J3-4 = 2.1 Hz, H-3), 7.32–7.45 (m, 5H, CH Ar); 13C NMR (100 MHz,
CD3OD): δ (ppm) = 53.1 (CH2-6), 71.3 (CH2-1), 74.5 (CH2-Bn), 78.1
(CH-4), 85.5 (CH-5), 88.8 (CH-3), 97.6 (C-2), 128.7 (CH Ar), 128.8 (CH
3
3
2-Methylsulfanyl-4,5-dihydro-(4,6-O-isopropylidene-1-O-
methyl-α-L-sorbofuranoso) [2,1-d]-1,3-oxazole (21f). General
procedure 6 was followed using 4,6-O-isopropylidene-2-N,3-O-thio-
carbonyl-α-L-sorbofuranosylamine 18 (5.04 g, 19.3 mmol) and gave
after purification (PE/EA, 50:50) the desired bisprotected OZT 21f
Ar), 129.4 (CH Ar), 139.0 (Cq Ar), 159.2 (C=O); IR (neat) (ν, cm–1) =
˜
as a colourless oil (3.74 g, 67 %). Rf = 0.49 (PE/EA: 50:50); [α]D20
=
3217 (NH + OH), 2081 (N3), 2372, 2405, 1728 (C=O); HRMS (ESI+):
m/z = calculated for C14H17N4O5 ([M + H]+): 321.1193, found
321.1192.
–84 (c 1.02, MeOH); 1H NMR (400 MHz, CDCl3): δ (ppm) = 1.40 (s,
3H, CH3 iPr), 1.45 (s, 3H, CH3 iPr), 2.51 (s, 3H, SCH3), 3.46 (s, 3H,
2
OCH3), 3.64–3.67 (m, 1H, H-5), 3.69 (d, 1H, J1b-1a = 10.3 Hz, H-1b),
2
3.83 (d, 1H, J1a-1b = 10.3 Hz, H-1a), 4.03–4.13 (m, 2H, CH2-6), 4.37
General procedure 6: O- and S-protection of OZT ketoses.
3
(d, 1H, J4-5 = 2.3 Hz, H-4), 4.73 (s, 1H, H-3); 13C NMR (100 MHz,
OZT iodosugar (1 equiv.) 18 was dissolved in anhydrous DMF (0.3
M) and cooled to –5 °C, then sodium hydride 60 % (2.5 equiv.) was
added portionwise, and after ten minutes, BnBr or allyl bromide or
methyl iodide (2.5 equiv.) was added dropwise. The reaction mix-
ture was stirred at –5 °C, 30 min and then overnight at r.t. The
reaction mixture was quenched by addition of cold water and di-
luted with EA. The organic phase was washed 3 times with cold
water, twice with a saturated aqueous NaCl solution, dried with
MgSO4 and filtered. The solvent was evaporated under reduced
pressure. The residue was purified by silica gel flash column chro-
matography using PE/EA to give the desired bisalkylated com-
pounds 19–21f.
CDCl3): δ (ppm) = 14.8 (CH3 iPr), 18.8 (S-CH3), 29.1 (CH3 iPr), 59.7
(CH2-6), 60.0 (O-CH3), 70.9 (CH-5), 73.2 (CH-4), 74.1 (CH2-1), 88.4 (CH-
3), 97.9 (C-2 or Cq iPr), 109.2 (Cq iPr or C-2), 170.3 (C-S); IR (neat) (ν,
˜
cm–1) = 2933 (C-H), 1598 (C=N), 1194 (C-O), 1114 (C-N), 1072, 849
(C-S); HRMS (ESI+): m/z = calculated for C12H20NO5S ([M + H]+):
290.105670, found 290.105873.
General procedure 7: oxidation of OZT ketoses into OZO
The bisprotected OZT (1.0 equiv.) 19–21f was dissolved in DCM (0.1
M). Sodium bicarbonate (5.0 equiv.) was added at 0 °C. After 10
minutes m-CPBA (3.5 equiv.) was added. The reaction was stirred at
r.t. for the next 15 hours, then was stopped by adding cooled water
and sodium metabisulfite (1.85 equiv.) and diluted with DCM. The
2-Benzylsulfanyl-4,5-dihydro-(1-O-benzyl-4,6-O-isopropyl-
idene-α-L-sorbofuranoso) [2,1-d]-1,3-oxazole (19f). General pro-
cedure 6 was followed using 4,6-O-isopropylidene-2-N,3-O-thio-
carbonyl-α-L-sorbofuranosylamine 18 (2.5 g, 9.6 mmol) and gave
after purification (PE/EA: 80:20) the desired bisprotected OZT 19f
organic phase was washed three times with 1
M NaOH solution and
twice with a saturated aqueous NaCl solution, dried with MgSO4
and filtered. The solvent was evaporated under reduced pressure.
The residue was purified by silica gel flash column chromatography
using PE/EA to give the desired 1-O-protected OZO 22–24f.
as a colourless oil (3.59 g, 85 %). Rf = 0.24 (PE/EA: 80:20); [α]D20
=
–65 (c 0.91, CHCl3); 1H NMR (250 MHz, CDCl3): δ (ppm) = 1.33 (s,
1-O-Benzyl-2-N,3-O-carbonyl-4,6-O-isopropylidene-α-L-sorbo-
furanosylamine (22f). General procedure 7 was followed using 1-
O,S-dibenzyl-4,6-O-isopropylidene-2-N,3-O-thiocarbonyl-α-L-sorbo-
furanosylamine 19f (1.3 g, 2.9 mmol) and gave after purification
(PE/EA, 50:50) the desired OZO 22f as a white foam (567 mg, 58 %).
Rf = 0.41 (PE/EA: 50:50); [α]2D0 = –45 (c 1.11, CHCl3); 1H NMR
(250 MHz, CDCl3): δ (ppm) = 1.33 (s, 3H, CH3), 1.44 (s, 3H, CH3), 3.67
3
3H, CH3), 1.43 (s, 3H, CH3), 3.58 (q, 1H, J5-6
=
3J5-4 = 2.0 Hz, H-5),
2
3.82 (d, 1H, J1b-1a = 10.5 Hz, H-1b), 3.91 (d, 1H, J1a-1b = 10.5 Hz,
H-1a), 4.06 (d, 2H, J6-5 = 2.0Hz, CH2-6), 4.25 (d, 1H, 2J = 13.2 Hz,
3
3
2
CH2 SBn), 4.32 (d, 1H, J4-5 = 2.4 Hz, H-4), 4.37 (d, 1H, J = 13.2 Hz,
CH2SBn), 4.64 (s, 2H, CH2 OBn), 4.78 (s, 1H, H-3), 7.25–7.40 (m, 10H,
CH Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) = 18.8 (CH3), 29.0 (CH3),
35.7 (CH2 S-Bn), 59.7 (CH2-6), 71.0 (CH-5), 71.5 (CH2-1), 73.2 (CH-4),
73.7 (CH2 O-Bn), 88.3 (CH-3), 97.9 (C-2 or Cq iPr), 109.4 (Cq iPr or C-
2), 127.6 (CH Ar), 127.7 (CH Ar), 127.8 (CH Ar), 128.4 (CH Ar), 128.8
(CH Ar), 129.2 (CH Ar), 136.4 (Cq Ar), 138.4 (Cq Ar), 169.0 (C-S); IR
2
2
(d, 1H, J1b-1a = 10.2 Hz, H-1b), 3.77 (d, 1H, J1a-1b = 10.2 Hz, H-1a),
3
3.94 (q, 1H, J5-6a
= =
3J5-6a 3J5-4 = 2.2 Hz, H-5), 4.01 (bd, 1H,
2J6a-6b = 13.7 Hz, H-6b), 4.09 (dd, J6a-5 = 2.2 Hz, J6a-6b = 13.6 Hz,
3
2
3
2
1H, H-6a), 4.40 (d, 1H, J4-5 = 2.2 Hz, H-4), 4.60 (d, 1H, J = 12.1 Hz,
CH2 Bn), 4.66 (d, 1H, 2J = 12.1 Hz, CH2 Bn), 4.67 (s, 1H, H-3), 6.19
(bs, 1H, NH), 7.27–7.39 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3):
δ (ppm) = 18.7 (CH3), 29.0 (CH3), 59.7 (CH2-6), 70.3 (CH2-1), 71.5 (CH-
5), 72.7 (CH-4), 73.7 (CH2 Bn), 85.7 (CH-3), 96.0 (C-2 or Cq iPr), 98.0
(Cq iPr or C-2), 128.0 (CH Ar), 128.1 (CH Ar), 128.6 (CH Ar), 137.3 (Cq
(neat) (ν, cm–1) = 3059 (Csp2-H), 1596 (C=N), 1114 (C-O), 1072, 696
˜
(C-S); HRMS (ESI+): m/z = calculated for C24H28NO5S ([M + H]+):
442.1682, found 442.1687.
2-Allylsulfanyl-4,5-dihydro-(1-O-allyl-4,6-O-isopropylidene-α-L-
sorbo furanoso) [2,1-d]-1,3-oxazole (20f). General procedure 6
was followed using 4,6-O-isopropylidene-2-N,3-O-thiocarbonyl-α-L-
Ar), 156.9 (C=O); IR (neat) (ν, cm–1) = 3312 (NH), 3043 (Csp2-H), 1762
˜
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(C=O), 1377 (C-O), 1058 (C-N); HRMS (ESI+): m/z = calculated for
1746 (C=O), 1366 (C-O), 1097 (C-O), 1038 (C-N); HRMS (ESI+): m/z =
C17H22NO6 ([M + H]+): 336.1440, found 336.1441.
calculated for C14H18NO6 ([M + H]+): 296.1128, found 296.1129.
1-O-Allyl-2-N,3-O-carbonyl-α-L-sorbofuranosylamine (26f).
General procedure 8 was followed using 4,6-O-isopropylidene OZO
23f (800 mg, 2.8 mmol) and gave after silica gel column chromatog-
raphy (PE/EA: 50:50 to pure EA) the desired product 26f as a brown
oil (352 mg, 51 %). Rf = 0.46 (EA); [α]2D0 = –9 (c 1.02, MeOH); 1H NMR
1-O-Allyl-2-N,3-O-carbonyl-4,6-O-isopropylidene-α-L-sorbo-
furanosylamine (23f). The OZT 4,6-O-bisallylated 20f (690 mg,
2.0 mmol, 1.0 equiv.) was dissolved in 16.0 mL of EtOH and 4.0 mL
of 3 M NaOH solution. The mixture was heated at 80 °C for 5 h. The
mixture was then cooled down at r.t. and diluted with EA. The or-
ganic layer was washed four times with a saturated aqueous NaCl
solution, dried with MgSO4 and then filtered. The solvent was evap-
orated under reduced pressure. The desired product 23f was ob-
tained as a colourless oil and was used without any further purifica-
tion (0.42 g, 72 %). Rf = 0.50 (PE/EA: 50:50); [α]2D0 = –49 (c 0.69,
2
(250 MHz, CD3OD): δ (ppm) = 3.62 (d, 1H, J1b-1a = 10.3 Hz, H-1b),
2
3
3.71 (d, 1H, J1a-1b = 10.3 Hz, H-1a), 3.77 (dd, 1H, J6b-6a = 11.6 Hz,
3J6b-5 = 6.4 Hz, H-6b), 3.86 (dd, 1H, J6a-6b = 11.6 Hz, 3J6a-5 = 4.9 Hz,
3
3
3
3
H-6a), 4.03 (ddd, 1H, J5-4 = 2.8 Hz, J5-6a = 4.9 Hz, J5-6b = 6.4 Hz,
H-5), 4.08 (dt, 2H, 3J = 5.6 Hz, 4J = 1.45 Hz, CH2 allyl), 4.24 (d, 1H,
3J4-5 = 2.8 Hz, H-4), 4.67 (s, 1H, H-3), 5.20 (dm, 1H, Jcis= 10.4 Hz, =
3
1
MeOH); H NMR (250 MHz, CDCl3): δ (ppm) = 1.38 (s, 3H, CH3), 1.46
CH2), 5.31 (dq, 1H, 3Jtrans = 17.3 Hz, 3Jcis= 4J = 2Jgem = 1.7 Hz, =CH2),
2
(s, 3H, CH3), 3.67 (d, 1H, J1b-1a = 10.3 Hz, H-1b), 3.78 (d, 1H,
5.93 (ddt, 1H, Jtrans = 17.3 Hz, Jcis = 10.4 Hz, 3J = 5.6 Hz, HC=);
13C NMR (100 MHz, CD3OD): δ (ppm) = 60.6 (CH2-6), 71.2 (CH2-1),
73.5 (CH2 allyl), 75.1 (CH-4), 82.1 (CH-5), 87.8 (CH-3), 97.3 (C-2), 117.7
3
3
2J1a-1b = 10.3 Hz, H-1a), 3.95–3.99 (m, 1H, H-5), 4.04–4.17 (m, 4H,
3
CH2-6, CH2 allyl), 4.42 (d, 1H, J4-5 = 2.2 Hz, H-4), 4.68 (s, 1H, H-3),
3
3
5.19–5.33 (m, 2H, =CH2), 5.89 (ddt, Jtrans = 17.3 Hz, Jcis = 10.3 Hz,
2Jgem = 5.7 Hz, 1H, HC=allyl), 6.15 (bs, 1H, NH); 13C NMR (100 MHz,
CDCl3): δ (ppm) = 18.8 (CH3), 29.1 (CH3), 59.8 (CH2-6 or CH2 allyl),
70.6 (CH2-1), 71.5 (CH-5), 72.7 (CH-4), 72.8 (CH2 allyl or CH2-6), 85.7
(CH-3), 95.9 (C-2 or Cq iPr), 98.0 (Cq iPr or C-2), 118.1 (=CH2), 134.0
(=CH2 allyl), 135.6 (HC= allyl), 159.9 (C=O); IR (neat) (ν, cm–1) = 3339
˜
(NH + OH), 1743 (C=O), 1374 (C-O), 1042 (C-N), 972 (Csp2-H); HRMS
(ESI+): m/z = calculated for C10H16NO6 ([M + H]+): 246.0972, found
264.0971.
(HC=), 156.9 (C=O); IR (neat) (ν, cm–1) = 3291 (N-H), 1766 (C=O),
˜
2-N,3-O-Carbonyl-1-O-methyl-α-L-sorbofuranosylamine (27f).
General procedure 8 was followed using OZO 4,6-O-isopropylidene
24f (1.16 g, 4.5 mmol) and gave the desired product 27f as a white
solid (930 mg, 95 %). Rf = 0.30 (EA); 1H NMR (250 MHz, CD3OD):
1378 (C-O), 1061 (C-N), 848 (Csp2-H); HRMS (ESI+): m/z = calculated
for C13H20NO6 ([M + H]+): 286.1285, found 286.1286.
2-N,3-O-Carbonyl-1-O-methyl-4,6-O-isopropylidene-α-L-sorbo-
furanosylamine (24f). General procedure 7 was followed using 1-
O,S-dimethyl-4,6-O-isopropylidene-2-N,3-O-thiocarbonyl-α-L-sorbo-
furanosylamine 21f (2.5 g, 8.7 mmol) and gave after purification
(PE/EA, 50:50) the desired OZO 24f as a colourless oil (1.23 g, 55 %).
Rf = 0.27 (PE/EA: 50:50); [α]2D0 = –54 (c 1.08, MeOH); 1H NMR
(250 MHz, CDCl3): δ (ppm) = 1.39 (s, 3H, CH3), 1.46 (s, 3H, CH3), 3.46
2
δ (ppm) = 3.43 (s, 3H, OCH3), 3.56 (d, 1H, J1b-1a = 10.2 Hz, H-1b),
2
3
3.64 (d, 1H, J1a-1b = 10.2 Hz, H-1a), 3.77 (dd, 1H, J6b-6a = 11.6 Hz,
3J6b-5 = 6.4 Hz, H-6b), 3.86 (dd, 1H, J6a-6b = 11.6 Hz, 3J6a-5 = 4.9 Hz,
3
3
3
3
H-6a), 3.77(ddd, 1H, J5-4 = 2.8 Hz, J5-6a = 4.9 Hz, J5-6b = 6.4 Hz,
H-5), 4.23 (d, 1H, J4-5 = 2.8 Hz, H-4), 4.64 (s, 1H, H-3); 13C NMR
3
(100 MHz, CD3OD): δ (ppm) = 59.7 (CH3), 60.6 (CH2-6), 73.7 (CH2-1),
82.0 (CH-4), 87.8 (CH-5), 97.1 (CH-3), 159.9 (C=O); IR (neat) (ν,
2
˜
(s, 3H, OCH3), 3.62 (d, 1H, J1b-1a = 10.1 Hz, H-1b), 3.73 (d, 1H,
cm–1) = 3380 (NH + OH), 2995 (C-H), 1743 (C=O), 1370 (C-O), 1022
(C-N); HRMS (ESI+): m/z = calculated for C8H14NO6 ([M + H]+):
220.0815, found 220.0814.
2J1a-1b = 10.1 Hz, H-1a), 3.95–4.00 (m, 1H, H-5), 4.04 (dm, 1H,
3J6b-6a = 13.6 Hz, H-6b), 4.14 (dd, 1H, 3J6a-5 = 2.3 Hz, 3J6a-6b = 13.6 Hz,
H-6a), 4. 43 (d, 1H, 3J4-5 = 2.3 Hz, H-4), 4.68 (s, 1H, H-3), 5.92 (bs, 1H,
NH); 13C NMR (100 MHz, CD3OD): δ (ppm) = 19.0 (CH3), 29.4 (CH3),
59.8 (O-CH3), 60.7 (CH2-6), 72.6 (CH-5), 73.5 (CH2-1), 74.1 (CH-4), 86.7
(CH-3), 97.4 (C-2 or Cq iPr), 99.1 (Cq iPr or C-2), 159.7 (C=O); IR (neat)
General Procedure 9: iodation of OZO 1-O-protected ketoses.
OZO 4,6-unprotected 25–27f (1.0 equiv.) were dissolved in THF
(0.2M) under argon atmosphere. Then triphenylphosphine
(2.0 equiv.) and imidazole (2.0 equiv.) were added. After 10 minutes
iodine (1.5 equiv.) was added. The mixture was heated at 60 °C for
the next 3 h. The solvent was evaporated under reduced pressure.
The residue was dissolved in EA and water. Once the layers were
separated, the aqueous phase was extracted 2 times with EA. The
combined organic phases were washed three times with water and
twice with a saturated aqueous NaCl solution, dried with MgSO4
and then filtered. The solvent was evaporated under reduced pres-
sure. The residue was purified by silica gel flash column chromatog-
raphy using PE/EA (70:30) to give the desired compounds 28–30f.
(ν, cm–1) = 3288 (NH + OH), 2939 (C-H), 1765 (C=O), 1198 (C-N),
˜
1114 (C-O), 1056; HRMS (ESI+): m/z = calculated for C11H18NO6 ([M
+ H]+): 260.1128, found 260.1126.
General procedure 8: deprotection of 4,6-O-isopropylidene.
The OZO 4,6-O-isopropylidene monoprotected (1.0 equiv.) was dis-
solved in a mixture acetic acid/water, 4:1 (0.05–0.1 M) and the reac-
tion mixture was stirred at 55 °C for 4 h. The solvent was evaporated
under reduced pressure and the residue co-evaporated several
times with toluene. The desired product was used in most cases
without any further purification in the next step.
1-O-Benzyl-2-N,3-O-carbonyl-6-deoxy-6-iodo-α-L-sorbofurano-
sylamine (28f). General procedure 9 was followed using OZO 25f
(1.19 g, 4 mmol) and gave after silica gel column chromatography
(PE/EA: 70:30) the desired product 28f as a pale yellow solid (1.37 g,
83 %). Rf = 0.39 (PE/EA: 60:40); m.p. 124–125 °C; [α]2D0 = –14 (c 1.05,
MeOH); 1H NMR (400 MHz, CDCl3): δ (ppm) = 3.14 (bs, 1H, OH),
1-O-Benzyl-2-N,3-O-carbonyl-α-L-sorbofuranosylamine (25f).
General procedure 8 was followed using OZO 4,6-O-isopropylidene
22f (500 mg, 1.5 mmol) and gave the desired product 25f as a
colourless oil (450 mg, 97 %). Rf = 0.36 (PE/EA: 60:40); 1H NMR
2
(250 MHz, CDCl3): δ (ppm) = 3.70 (d, 1H, J1b-1a = 10.0 Hz, H-1b),
3.73–3.84 (m, 2H, H-1a, OH-4), 3.93–4.09 (m, 2H, CH2-6), 4.11–4.18 3.20–3.35 (m, 2H, CH2-6), 3.64 (d, 1H, 2J1b-1a = 9.8 Hz, H-1b), 3.76 (d,
2
2
(m, 1H, H-5), 4.30–4.38 (m, 1H, H-4), 4.60 (d, 1H, J = 11.9 Hz, CH2 1H, J1a-1b = 9.8 Hz, H-1a), 4.29–4.40 (m, 2H, H-4, H-5), 4.60 (d, 1H,
Bn), 4.66 (d, 1H, 2J = 11.9 Hz, CH2 Bn), 4.70 (s, 1H, H-3), 6.01 (bs, 1H,
NH), 7.28–7.44 (m, 5H, CH Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) =
2J = 11.8 Hz, CH2 Bn), 4.67 (d, 1H, J = 11.8 Hz, CH2 Bn), 4.78 (s, 1H,
2
H-3), 5.90 (bs, 1H, NH), 7.27–7.46 (m, 5H, CH Ar); 13C NMR (100 MHz,
61.1 (CH2-6), 70.7 (CH2-1), 74.2 (CH2 Bn), 75.2 (CH-4), 80.3 (CH-5), CDCl3): δ (ppm) = –2.2 (CH2-6), 70.2 (CH2-1), 73.8 (CH-4 or CH-5),
86.8 (CH-3), 95.3 (C-2), 128.2 (CH Ar), 128.7 (CH Ar), 128.9 (CH Ar),
74.2 (CH2 Bn), 82.0 (CH-5 or CH-4), 86.5 (CH-3), 95.7 (C-2), 128.2 (CH
Ar), 128.8 (CH Ar), 129.0 (CH Ar), 136.2 (Cq Ar), 156.6 (C=O); IR (neat)
136.5 (Cq Ar), 156.7 (C=O); IR (neat) (ν, cm–1) = 3298 (NH + OH),
˜
Eur. J. Org. Chem. 0000, 0–0
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© 2000 Wiley-VCH GmbH

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EurJOC
European Journal of Organic Chemistry
(ν, cm–1) = 3257 (NH + OH), 1740 (C=O), 1416 (C=C), 1366 (C-O),
6-Azido-1-O-benzyl-6-deoxy-2-N,3-O-carbonyl-α-L-sorbofura-
˜
1028 (C-O), 1045(C-N); HRMS (ESI+): m/z = calculated for C14H17INO5 nosylamine (31f). General procedure 10 was followed using OZO
([M + H]+): 406.0145, found 406.0146.
28f (1.20 g, 3.0 mmol) and gave after silica gel column chromatog-
raphy (PE/EA: 55:45) the desired product 31f as a yellow solid
(0.95 g, 92 %). Rf = 0.27 (PE/EA: 60:40); m.p. 107–110 °C; [α]2D0 = +3
1-O-Allyl-2-N,3-O-carbonyl-6-O-p-toluenesulfonyl-α-L-sorbo-
furanosylamine (29f). The 4,6-unprotected OZO 26f (100 mg,
0.41 mmol, 1.0 equiv.) was dissolved in 5.0 mL of anhydrous DCM
under argon atmosphere. Then triethylamine (0.18 mL, 1.22 mmol,
3.0 equiv.) and DMAP (0.005 g, 0.04 mmol, 0.1 equiv.) were added.
After 10 min, 4-toluenesulfonyl chloride (0.094 g, 0.49 mmol,
1.2 equiv.) was added at 0 °C. The reaction was stirred for the next
15 h at r.t. The reaction mixture was diluted with DCM and water.
The organic layer was washed once with ammonium chloride, once
with a saturated aqueous sodium bicarbonate solution and twice
with a saturated aqueous NaCl solution, dried with MgSO4 and fil-
tered. The solvent was evaporated under reduced pressure. The resi-
due was purified by silica gel flash column chromatography using
PE/EA (50:50 to 30:70). The desired product was obtained as a yel-
low oil (91 mg, 56 %). Rf = 0.67 (PE/EA: 30:70); [α]2D0 = –2 (c 1.05,
1
(c 0.97, MeOH); H NMR (400 MHz, CDCl3): δ (ppm) = 3.20 (bs, 1H,
2
OH), 3.50–3.62 (m, 2H, CH2-6), 3.68 (d, 1H, J1b-1a = 9.8 Hz, H-1b),
2
3.80 (d, 1H, J1a-1b = 9.8 Hz, H-1a), 4.16–4.28 (m, 2H, H-4, H-5), 4.62
(d, 1H, 2J = 11.8 Hz, CH2 Bn), 4.68 (d, 1H, 2J = 11.8 Hz, CH2 Bn), 4.75
(s, 1H, H-3), 5.67 (bs, 1H, NH), 7.28–7.44 (m, 5H, CH Ar); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 49.5 (CH2-6), 70.2 (CH2-1), 74.0 (CH-4
or CH-5), 74.3 (CH2 Bn), 80.0 (CH-5 or CH-4), 86.4 (CH-3), 95.3 (C-2),
128.2 (CH Ar), 128.8 (CH Ar), 129.0 (CH Ar), 136.2 (Cq Ar), 156.3
(C=O); IR (neat) (ν, cm–1) = 3238 (NH + OH), 3030 (Csp2-H), 2104
˜
(N3), 1741 (C=O), 1661 (C=C) 1073 (C-O); HRMS (ESI+): m/z = calcu-
lated for C14H17N4O5 ([M + H]+): 321.1193, found 321.1191.
1-O-Allyl-6-azido-2-N,3-O-carbonyl-6-deoxy-α-L-sorbofurano-
sylamine (32f). General procedure 10 was followed using OZO 29f
(99 mg, 0.25 mmol) and gave after silica gel column chromatogra-
phy (PE/EA: 55:45) the desired product 32f as a yellow solid (0.47 g,
70 %). Rf = 0.35 (PE/EA: 60:40); m.p. 73–74 °C; [α]2D0 = +10 (c 1.01,
1
MeOH); H NMR (250 MHz, CDCl3): δ (ppm) = 2.46 (s, 3H, CH3), 3.41
3
2
(d, 1H, JOH-4 = 10.3 Hz, OH), 3.65 (d, 1H, J1b-1a = 10.1 Hz, H-1b),
2
3
3.73 (d, 1H, J1a-1b = 10.1 Hz, H-1a), 4.06 (dm, 2H, J = 5.8 Hz, CH2
allyl), 4.13–4.41 (m, 4H, H-4, H-5, CH2-6), 4.72 (s, 1H, H-3), 5.20–5.25
(m, 1H, =CH2 allyl), 5.28 (dq, 1H, 3Jcis = 10.3 Hz, 2Jgem = 4J = 1.5 Hz, =
CH2 allyl), 5.83 (ddt, 1H, 3Jtrans = 17.2 Hz, 3Jcis = 10.3 Hz, 3J = 5.8 Hz,
1
3
MeOH); H NMR (250 MHz, CDCl3): δ (ppm) = 3.34 (d, 1H, JOH-4
=
2
10.6 Hz, OH), 3.54–3.63 (m, 2H, CH2-6), 3.68 (d, 1H, J1b-1a = 9.9 Hz,
H-1b), 3.78 (d, 1H, J1a-1b = 9.9 Hz, H-1a), 4.12 (dm, 2H, J = 5.8 Hz,
3
3
3
HC= allyl), 6.43 (bs, 1H, NH), 7.37 (dm, 2H, J = 8.6 Hz, CH Ar), 7.81
CH2 allyl), 4.18–4.31 (m, 2H, H-4, H-5), 4.78 (s, 1H, H-3), 5.26–5.37
(dm, 2H, J = 8.6 Hz, CH Ar); 13C NMR (100 MHz, CDCl3): δ (ppm) =
3
3
3
(m, 2H, =CH2), 5.93 (ddt, 1H, Jtrans = 17.2 Hz, Jcis = 10.3 Hz, 3J =
5.8 Hz, HC= allyl), 6.26 (bs, 1H, NH); 13C NMR (100 MHz, CDCl3):
δ (ppm) = 49.5 (CH2-6), 70.3 (CH2-1), 73.1 (CH2 allyl), 73.9 (CH-4 or
CH-5), 80.1 (CH-5 or CH-4), 86.4 (CH-3), 95.4 (C-2), 119.5 (=CH2 allyl),
21.5 (CH3), 67.1 (CH2-6), 69.8 (CH2-1), 72.6 (CH2 allyl), 73.2 (CH-4 or
CH-5), 78.5 (CH-5 or CH-4), 85.8 (CH-3), 95.5 (C-2), 118.9 (=CH2 allyl),
127.9 (CH Ar), 129.9 (CH Ar), 132.2 (Cq Ar), 132.7 (CH= allyl), 145.1
(Cq Ar), 156.5 (C=O); IR (neat) (ν, cm–1) = 3360 (NH + OH), 1755 (C=
˜
132.9 (=CH allyl), 156.5 (C=O); IR (neat) (ν, cm–1) = 3254 (NH + OH),
˜
O), 1598 (C=C), 1369 (S=O), 1173 (S=O), 1074 (C-O); HRMS (ESI+):
m/z = calculated for C17H22NO8S ([M + H]+): 400.1060, found
400.1058.
2104 (N3), 1737 (C=O), 1288 (C-O), 1042 (C-N), 666 (Csp2-H); HRMS
(ESI+): m/z = calculated for C10H15N4O5 ([M + H]+): 271.1036, found
271.1035.
2-N,3-O-Carbonyl-6-deoxy-6-iodo-1-O-methyl-α-L-sorbofurano-
sylamine (30f). General procedure 9 was followed using OZO 27f
(2.16 g, 9.9 mmol) and gave after silica gel column chromatography
(PE/EA: 70:30) the desired product 30f as a white foam (2.77 g,
85 %). Rf = 0.30 (PE/EA: 50:50); m.p. 162–163 °C; [α]2D0 = –11 (c 1.02,
MeOH); 1H NMR (400 MHz, CD3OD): δ (ppm) = 3.27 (dd, 1H,
6-Azido-2-N,3-O-carbonyl-6-deoxy-1-O-methyl-α-L-sorbofura-
nosylamin>e (33f). General procedure 10 was followed using OZO
30f (714 mg, 2.17 mmol) and gave after silica gel column chroma-
tography (PE/EA: 40:60) the desired product 33f as a colourless oil
(406 mg, 77 %). Rf = 0.36 (PE/EA: 40:60); [α]2D0 = +9 (c 1.04, MeOH);
3
1H NMR (400 MHz, CDCl3): δ (ppm) = 3.32 (d, 1H, JOH-4 = 10.3 Hz,
3
2
2J6b-6a = 9.7 Hz, J6b-5 = 6.4 Hz, H-6b), 3.37 (dd, 1H, J6a-6b = 9.7 Hz,
OH), 3.49 (s, 3H, CH3), 3.61–3.57 (m, 2H, CH2-6), 3.65 (d, 1H, 2J =
3J6a-5 = 7.7 Hz, H-6a), 3.42 (s, 3H, OCH3), 3.55 (d, 1H, 2J1b-1a = 10.2 Hz,
2
3
9.9 Hz, H-1a), 3.74 (d, 1H, J = 9.9 Hz, H-1b), 4.21 (ddd, 1H, J5-4
=
2
3
2.5 Hz, 3J = 5.6 Hz, 3J = 6.4 Hz, H-5), 4.24 (dd, 1H, 3J4-5 = 2.5 Hz,
3J4-OH = 10.1 Hz, H-4), 4.76 (s, 1H, H-3), 6.29 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3): δ (ppm) = 49.4 (CH2-6), 59.9 (CH3), 73.0 (CH2-1),
73.8 (CH-4), 79.9 (CH-5), 86.3 (CH-3), 95.4 (C-2), 156.9 (C=O); IR (neat)
H-1b), 3.61 (d, 1H, J1a-1b = 10.2 Hz, H-1a), 4.21 (ddd, 1H, J5-4
=
2.7 Hz, 3J5-6b = 6.4 Hz, 3J5-6a = 7.7 Hz, H-5), 4.29 (d, 1H, 3J4-5 = 2.7 Hz,
H-4), 4.70 (s, 1H, H-3); 13C NMR (100 MHz, CD3OD): δ (ppm) = –1.8
(CH2-6), 59.7 (OCH3), 73.6 (CH2-1), 74.7 (CH-4) 82.5 (CH-), 87.7
(CH-3), 97.6 (C-2), 159.73 (C=O); IR (neat) (ν, cm–1) = 3170 (NH +
(ν, cm–1) = 3318 (NH + OH), 2936 (C-H), 2100 (N3), 1746 (C=O),
˜
˜
1259 (C-O), 1110 (C-O), 1038 (C-N); HRMS (ESI+): m/z = calculated
OH), 1739 (C=O), 1376 (C-O), 1060 (C-O), 1030 (C-N), 509 (C-I); HRMS
(ESI+): m/z = calculated for C8H13INO5 ([M + H]+): 329.9832, found
329.9831.
for C8H13N4O5 ([M + H]+): 245.088, found 245.0877.
6-Azido-1-O-benzyl-6-deoxy-2-N,3-O-thiocarbonyl-α-L-sorbo-
furanosylamine (44f). General procedure 10 was followed using
OZT 43f (1.20 g, 3.0 mmol) and gave after silica gel column chroma-
General Procedure 10: azidation of 1-O-protected ketoses
OZOs.
The 6-iodo/6-OTs derivative 28–30f (1.0 equiv.) was dissolved in tography (PE/EA: 70:30) the desired product 44f (0.14 g, 40 %). Rf =
anhydrous DMF (0.15M) under argon atmosphere. After 10 minutes,
sodium azide (4.0 equiv.) was added. The mixture was heated at 1H, JOH,4 = 10.2 Hz, OH), 3.59 (d, 2H, J6-5 = 6.1Hz, CH2-6), 3.71 (d,
0.63 (PE/EA: 50:50); 1H NMR (400 MHz, CDCl3): δ (ppm) = 3.15 (d,
3
2
2
70 °C for the next 15 hours. The reaction mixture was quenched by
addition of cold water and diluted with EA. The aqueous phase was
extracted 2 more times with EA. The combined organic phases were
washed 3 times with cold water, twice with a saturated aqueous
1H, J1b-1a = 10.0 Hz, H-1b), 3.80 (d, 1H, J1a-1b = 9.9 Hz, H-1a), 4.17
(td, 1H, 3J5-6 = 6.1 Hz, 3J5-4 = 2.6 Hz, H-5), 4.34 (dd, 1H, 3J4-5 = 2.5 Hz,
3J4-OH = 10.2 Hz, H-4), 4.61 (d, 1H, 2J = 11.8 Hz, CH2 Bn), 4.68 (d, 1H,
2J = 11.8 Hz, CH2 Bn), 4.97 (s, 1H, H-3); 7.26–7.41 (m, 5H, CH Ar),
NaCl solution, dried with MgSO4 and filtered. The solvent was evap- 7.52 (s, 1H, NH); 13C NMR (100 MHz, CDCl3): δ (ppm) = 49.2 (CH2-6),
orated under reduced pressure. The residue was purified by silica
69.3 (CH2-1), 73.8 (CH-4), 74.3 (CH2 Bn), 80.3 (CH-5), 91.7 (CH-3), 98.7
gel flash column chromatography (PE/EA: 55:45) to give the desired (C-2), 128.2 (CH Ar), 128.8 (CH Ar), 129.0 (CH Ar), 136.1 (Cq Ar), 189.0
6-iodoOZOs 31–33f.
(C=S); MS (ESI+): m/z = 337.5 ([M + H] +); 359.5 ([M + Na] +).
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Synthesis of iminosugars.
Method A: general procedure 11a was followed using azidoOZO 11a
(300 mg, 0.96 mmol) and purification was achieved through silica
gel column chromatography (PE/EA, 50:50).
General procedure 11: Staudinger reduction/cyclisation.
a) For pentoses derivatives: OZT/OZO sugar derivative (1 equiv.) was
dissolved in H2O/THF (1:5, 0.1 M) then Ph3P (5 equiv.) was added
and the solution was stirred for overnight at r.t. The resulting mix-
ture was concentrated under reduced pressure and then purified
by silica gel column chromatography using EA/MeOH.
Method B: azidoOZO 11a (270 mg, 0.860 mmol, 1 equiv.) was dis-
solved in 10 mL of EtOH at room temperature. Pd/C (183 g,
1.720 mmol, 2 equiv.) and HCO2NH4 (163 mg, 2.580 mmol, 3 equiv.)
were added and the reaction mixture was allowed to react for 12
hours at 44 °C. It was then filtered through celite and the solvent
evaporated under reduced pressure. The crude residue was purified
by silica gel column chromatography using EA as eluent.
b) For ketoses derivatives: OZO/OZT sugar derivative (1 equiv.) was
dissolved in H2O/THF (1:4, 0.05 M) then Ph3P (1 equiv.) was added
and the solution was heated at 50 °C for 3–15h. The resulting
mixture was concentrated under reduced pressure, co-evaporated
three times with toluene and then purified by silica gel column
chromatography using EA/acetone.
4-O-tert-Butyldimethylsilyl-2-N,3-O-carbonyl-1,5-dideoxy-1,5-
imino-α-D-ribopyranosylamine (37a).
Method A: 15 % yield, white solid; Method B: 14 % yield. Rf = 0.31
(EA/MeOH: 85:15); m.p. 134–137; [α]2D0 = +33 (c 0.36, MeOH); 1H
NMR (250 MHz, CDCl3): δ (ppm) = 0.066, 0.096 (s × 2, 6H, Si(CH3)2),
0.89 (s, 9H, SiC(CH3)3), 2.83 (dd, 1H, 3J4-5b = 5.0 Hz, 3J5b-5a = 13.7 Hz,
5-Amino-5-deoxy-1-N,2-O-thiocarbonyl-α-D-ribofuranosyl-
amine (34a). Aminosugar 34a was isolated as a colorless oil (9 mg,
7 %) from OZT 4a (150 mg, 0.69 mmol) in conditions of general
procedure 11a, after purification (PE/EA: 50:50). Rf = (PE/EA: 80:20);
[α]2D0 = +30 (c 0.13, MeOH); M.S (IS+): m/z = 191.0 [M + H]+, 213.0
[M + Na]+; 1H NMR (250 MHz, CD3OD): δ (ppm) = 2.83 (dd, 1H,
3J5b-4 = 6.7 Hz, 3J5b-5a = 13.6 Hz, H-5b ), 3.07 (dd, 1H, 3J5a-4 = 3.2 Hz,
3J5a-5b = 13.6 Hz, H-5a ), 3.66 (ddd, 1H, 3J4-5a = 3.2 Hz, 3J4-5b = 6.7 Hz,
3
3
H-5b), 3.07 (dd, 1H, J5a-4 = 5.5 Hz, J5a-5b = 13.7 Hz, H-5a), 3.77–
3
3.86 (m, 1H, H-3), 3.91 (q, 1H, J4-3
=
3J4-5a
=
3J4-5b = 4.9 Hz, H-4),
3
3
3
4.59 (dd, 1H, J2-3 = 4.3 Hz, J2-1 = 6.3 Hz, H-2), 4.79 (d, 1H, J1-2
=
6.5 Hz, H-1), 6.53 (bs, 1H, NH or OH); 13C NMR (62.5 MHz, CDCl3): δ
(ppm) = –4.7 (Si(CH3)2), –4.5 (Si(CH3)2), 18.3 (SiC(CH3)3), 25.8
(SiC(CH3)3), 25.9 (SiC(CH3)3), 44.2 (CH2-5), 66.0 (CH-1), 66.6 (CH-4),
68.9 (CH-3), 76.4 (CH-2), 159.3 (C=O); IR (neat) (ν, cm–1) = 3290 (NH
3
3
3J4-3 = 9.6 Hz H-4), 3.96 (dd, 1H, J3-2 = 5.3 Hz, J3-4 = 9.5 Hz, H-3),
5.15 (t, 1H, J2-1
˜
+ OH), 1723 (C=O), 1248 (SiCH3); HRMS (ESI+): m/z = calculated for
=
3J2-3 = 5.3 Hz, H-2), 5.76 (d, 1H, J1-2 = 5.3 Hz,
3
3
C12H25N2O4Si ([M + H]+): 289.1578, found 289.1580.
H-1); 13C NMR (62.5 MHz, CD3OD): δ (ppm) = 42.9 (CH2-5), 74.3
(CH-3), 79.6 (CH-4), 86.5 (CH-2), 89.5 (CH-1), 192.1(C=S); IR (neat) (ν,
3-O-tert-Butyldimethylsilyl-2-N,3-O-carbonyl-1,5-dideoxy-1,5-
imino-α-D-ribopyranosylamine (37a′). Method A: 36 % yield,
white solid; Method B: 30 % yield. Rf = 0.17 (EA/MeOH: 85:15); m.p.
98–102 °C; [α]2D0 = +30 (c 0.36, MeOH); 1H NMR (250 MHz, CDCl3):
δ (ppm) = 0.13, 0.15 (s × 2, 6H, Si(CH3)2), 0.93 (s, 9H, SiC(CH3)3), 2.83
˜
cm–1) = 3371 (NH + OH), 1118 (C=S).
2-Benzylsulfanyl-4,5-dihydro-(3-O-tertbutyldimethylsilyl-5-
amino-5-deoxy-α-D-ribofuranoso) [2,1-d]-1,3-oxazole (35a).
Amino sugar 35a was isolated as an orange oil (488 mg, 86 %),
following reaction of OZT 9a (604 mg, 1.44 mmol) in conditions of
general procedure 11a, after purification (PE/EA: 50:50). Rf = 0.27
(PE/EA: 90:10); [α]2D0 = +61 (c 0.75, CHCl3); 1H NMR (250 MHz,
CD3OD): δ (ppm) = 0.15, 0.17 (s × 2, 6H, Si(CH3)2), 0.93 (s, 9H,
SiC(CH3)3), 2.72 (dd, 1H, 3J5b-4 = 7.1 Hz, 3J5b-5a = 13.4 Hz, H-5b), 2.96
3
3
(dd, 1H, J5b-4 = 4.3 Hz, J5b-5a = 14.0 Hz, H-5b), 3.07 (dd, 1H,
3
3
3J5a-4 = 4.8 Hz, J5a-5b = 14.0 Hz, H-5a), 3.83 (q, 1H, J4-3
= =
3J4-5a
3J4-5b = 3.9 Hz, H-4), 3.91 (t, 1H, J3-2
=
3J3-4 = 4.2 Hz, H-3), 4.44–
3
3
4.48 (m, 1H, H-2), 4.71 (d, 1H, J1-2 = 5.9 Hz, H-1), 6.53 (bs, 1H, NH
or OH); 13C NMR (62.5 MHz, CDCl3): δ (ppm) = –4.7 (Si(CH3)2), –4.5
(Si(CH3)2), 18.3 (SiC(CH3)3), 25.8 (SiC(CH3)3), 25.9 (SiC(CH3)3), 44.2
(CH2-5), 66.0 (CH-1), 66.6 (CH-4), 68.9 (CH-3), 76.4 (CH-2), 159.3
3
3
(dd, 1H, J5a-4 = 3.0 Hz, J5a-5b = 13.4 Hz, H-5a), 3.38 (ddd, 1H,
3J4-5a = 3.0 Hz, J4-5b = 7.1 Hz, J4-3 = 8.9Hz, H-4), 3.99 (dd, 1H,
3
3
(C=O); IR (neat) (ν, cm–1) = 3272 (NH + OH), 1749 (C=O), 1244
˜
3J3-2 = 5.4 Hz, J3-4 = 8.9 Hz, H-3), 4.29 (s, 2H, CH2 Bn), 4.88 (t, 1H,
3
(C-O); HRMS (ESI+): m/z = calculated for C12H25N2O4Si ([M + H]+):
3J2-1 = 3J2-3 = 5.4 Hz, H-2), 5.94 (d, 1H, 3J1-2 = 5.4 Hz, H-1), 7.26–7.35
(m, 3H, CH Bn), 7.38–7.42 (m, 2H, CH Bn); 13C NMR (62.5 MHz,
CD3OD): δ (ppm) = –4.9 (Si(CH3)2), –4.4 (Si(CH3)2), 18.9 (SiC(CH3)3),
26.2 (SiC(CH3)3), 36.7 (CH2 Ar), 43.3 (CH2-5), 75.4 (CH-3), 80.2 (CH-4),
84.3 (CH-2), 100.3 (CH-1), 128.8 (CH Ar), 129.7(CH Ar), 130.0 (CH Ar),
289.1578, found 289.1580.
2-N,3-O-Carbonyl-1,5-dideoxy-1,5-imino-α-D-ribopyranosyl-
amine (38a). To a solution of 3- and 4-O-silylated iminosugars 37a
and 37a′ (0.135 g, 0.469 mmol) in THF/H2O (6:1 (28 mL) at 0 °C, was
added TFA (12 mL). The reaction mixture was then allowed to react
4 hours at room temperature. After evaporation under reduced
pressure, the crude residue was purified using silica gel column
chromatography (EA/MeOH: 80:20) to give the deprotected imino-
sugar 38a as a white solid (13 mg, 16 %). Rf = 0.23 (EA/MeOH:
80:20); m.p 90–93 °C; [α]D20 = +23 (c 1.29, MeOH); 1H NMR (400 MHz,
137.9 (Cq Ar), 172.7 (N=CS); IR (neat) (ν, cm–1) = 3386 (NH2), 1591
˜
(N=C),, 1250 (C-O); HRMS (ESI+): m/z = calculated for C19H31N2O3SSi
([M + H]+): 395.1819, found 395.1817.
5-Amino-1-N,2-O-carbonyl-5-deoxy-α-D-xylofuranosylamine
(36d). Amino sugar 36d was isolated as a colorless oil (17 mg, 5 %)
following reaction of OZT 10d (406 mg, 2.03 mmol) in conditions
of general procedure 11a, after purification (EA/MeOH: 95:5). Rf =
0.28 (EA/MeOH: 80:20); M.S (IS+): m/z = 175.0 [M + H]+; 1H NMR
(400 MHz, CD3OD): δ (ppm) = 3.27–3.33 (m, 1H, H-5b), 3.52 (dd, 1H,
3
3
CD3OD): δ (ppm) = 2.85 (dd, 1H, J5b-4 = 5.0 Hz, J5b-5a = 13.6 Hz,
3
3
H-5b), 2.95 (dd, 1H, J5a-4 = 6.1 Hz, J5a-5b = 13.6 Hz, H-5a), 3.81–
3
3
3
3
3.84 (bq, J4-3 = J4-5a = J4-5b = 4.8 Hz, 1H, H-4), 3.91 (t, 1H, J3-4
=
3
3
3J3-2 = 4.2 Hz, H-3), 4.57 (dd, 1H, J2-3 = 4.2 Hz, J2-1 = 6.4 Hz, H-2),
3
3
3J5a-4 = 6.9 Hz, J5a-5b = 14.2 Hz, H-5a), 3.93 (td, 1H, J4-3 = 2.6 Hz,
4.78 (d, 1H, J1-2 = 6.4 Hz, H-1); 13C NMR (100 MHz, CD3OD):
3
3J4-5a = 3J4-5b = 6.6 Hz, H-4), 4.18 (d, 1H, J3-4 = 2.6 Hz, H-3), 4.87 (d,
3
δ (ppm) = 44.4 (CH2-5), 66.8 (CH-1), 67.2 (CH-4), 68.6 (CH-3), 77.8
1H, J2-1 = 5.4 Hz, H-2), 5.74 (d, 1H, J1-2 = 5.4 Hz, H-1); 13C NMR
3
3
(CH-2), 161.6 (C=O); IR (neat) (ν, cm–1) = 3242 (NH + OH), 1716
˜
(C=O), 1082 (CN); HRMS (ESI+): m/z = calculated for C6H11N2O4 ([M
(100 MHz, CD3OD): δ (ppm) = 39.0 (CH2-5), 74.6 (CH-3), 79.9 (CH-4),
86.5 (CH-2), 87.3 (CH-1), 160.3 (C=O); IR (neat) (ν, cm–1) = 3241 (NH
+ H]+): 175.0713, found 175.0714.
˜
+ OH), 1703 (C=O), 1082 (CN).
2-N,3-O-Carbonyl-1,5-dideoxy-1,5-imino-ꢀ-D-arabinopyranosyl-
amine (38b). General procedure 11a was followed using OZO 10b
(247 mg, 1.24 mmol). Purification using silica gel column chroma-
4/3-O-tert-Butyldimethylsilyl-5-amino-1-N,2-O-carbonyl-5-de-
oxy-α-D-ribopyranosylamine (37a/37a′).
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EurJOC
European Journal of Organic Chemistry
tography (pure EA) gave the desired product 38b as an orange oil
chromatography (pure EA then EA/Acetone, 50:50) gave the desired
(76 mg, 67 %). Rf = 0.31 (EA/MeOH: 90:10); [α]2D0 = –155 (c 1, MeOH); product 40f as a white sticky solid (62 mg, 67 %). Rf = 0.42 (EA/
3
1H NMR (400 MHz, CD3OD): δ (ppm) = 2.82 (dd, 1H, J5b-4 = 4.3 Hz,
3J5b-5a = 13.9 Hz, H-5b), 2.96 (dd, 1H, 3J5a-4 = 2.6 Hz, 3J5a-5b = 13.9 Hz,
MeOH: 90:10); [α]2D0 = –71 (c 0.81, EA); 1H NMR (400 MHz, D2O):
2
3
δ (ppm) = 2.73 (dd, 1H, J6b-6a = 12.8 Hz, J6b-5 = 10.2 Hz, H-6b),
3
3
2
3
H-5a), 3.78 (dd, 1H, J3-4 = 3.0 Hz, J3-2 = 6.6 Hz, H-3), 3.83 (dt, 1H,
3.01 (dd, 1H, J6a-6b = 12.8 Hz, J6a-5 = 4.6 Hz, H-6a), 3.50–3.56 (m,
1H, H-5), 3.58 (d, 1H, J1b-1a = 10.2 Hz, H-1b), 3.63 (d, 1H, J1a-1b =
3J4-5a = 3J4-3 = 2.9 Hz, 3J4-5b = 4.3 Hz, H-4), 4.42 (t, 1H, 3J2-3 = 3J2-1
=
2
2
6.7 Hz, H-2), 5.00 (d, 1H, J1-2 = 6.8 Hz, H-1); 13C NMR (100 MHz, 10.2 Hz, H-1a), 3.69 (dd, 1H, J4-5 = 9.3 Hz, J4-3 = 6.7 Hz, H-4), 4.32
3
3
3
3
CD3OD): δ (ppm) = 44.5 (CH2-5), 67.6 (CH-1), 68.6 (CH-4), 72.3 (CH-
(d, 1H, J3-4 = 6.7 Hz, H-3), 4.64–6.70 (m, 2H, CH2 Bn), 7.37–7.65 (m,
3), 80.2 (CH-2), 161.1 (C=O); IR (neat) (ν, cm–1) = 3276 (NH + OH),
5H, CH Ar); 13C NMR (62.5 MHz, [D6]DMSO): δ (ppm) = 44.1 (CH2-6),
˜
1718 (C=O), 1076 (C-N); HRMS (ESI+): m/z = calculated for C6H11N2O4 69.7 (CH-5), 72.5 (CH2 Bn), 74.1 (CH2-1), 74.5 (C-2), 77.2 (CH-4), 81.1
([M + H]+): 175.0713, found 175.0716.
(CH-3), 127.4 (CH Ar), 127.5 (CH Ar), 128.3 (CH Ar), 138.0 (Cq Ar),
157.5 (C=O); IR (neat) (ν, cm–1) = 3307 (NH + OH), 1743 (C=O); HRMS
˜
2-N,3-O-Carbonyl-1,5-dideoxy-1,5-imino-ꢀ-L-arabinopyranosyl-
amine (38c). General procedure 11a was followed using OZO 10c
(250 mg, 1.25 mmol). Purification using silica gel column chroma-
tography (EA/MeOH: 90:10) gave the desired product 38c as a white
solid (145 mg, 66 %). Rf = 0.36 (EA/MeOH: 70:30); m.p. 117–120 °C;
[α]2D0 = +153 (c 0.44, MeOH); 1H NMR (400 MHz, CD3OD): δ (ppm) =
(ESI+): m/z = calculated for C14H19N2O5 ([M + H]+): 295.1288, found
295.1288.
1-O-Allyl-2-N,3-O-carbonyl-2,6-dideoxy-2,6-imino-α-L-sorbo-
pyranosylamine (41f). General procedure 11b was followed using
OZO 32f (100 mg, 0.37 mmol). Purification using silica gel column
chromatography (pure EA then EA/Acetone, 50:50) gave the desired
product 41f as a yellow foam (63 mg, 70 %). Rf = 0.32 (EA/MeOH:
90:10); [α]2D0 = –72 (c 0.81, EA); 1H NMR (400 MHz, (CD3)2CO): δ
3
3
2.82 (dd, 1H, J5b-4 = 4.3 Hz, J5b-5a = 13.8 Hz, H-5b), 2.95 (dd, 1H,
3J5a-4 = 2.7 Hz, J5a-5b = 13.9 Hz, H-5a), 3.77 (dd, 1H, J3-4 = 3.0 Hz,
3
3
3J3-2 = 6.5 Hz, H-3), 3.82 (dt, 1H, J4-3
= =
3J4-5a = 2.9 Hz, J4-5b
3
3
3
=
3J2-1 = 6.7 Hz, H-2), 4.98 (d, 1H,
2
4.3 Hz, H-4), 4.41 (t, 1H, J2-3
(ppm) = 2.62–2.71 (m, 1H, H-6b), 2.93 (dd, 1H, J6a-6b = 12.6 Hz,
3J1-2 = 6.8 Hz, H-1); 13C NMR (100 MHz, CD3OD): δ (ppm) = 44.6
2
3J6a-5 = 4.5 Hz, H-6a), 3.33–3.41 (m, 1H, H-5), 3.42 (d, 1H, J1b-1a
=
2
(CH2-5), 67.6 (CH-1), 68.6 (CH-4), 72.3 (CH-3), 80.2 (CH-2), 161.2
9.2 Hz, H-1b), 3.46 (d, 1H, J1a-1b = 9.2 Hz, H-1a), 3.51 (ddd, 1H,
(C=O); IR (neat) (ν, cm–1) = 3328 (OH + NH), 1723(C=O), 1024 (C-N);
3
3
˜
3J4-5 = 9.0 Hz, J4-3 = 6.7 Hz, J4-OH = 4.6 Hz, H-4), 4.01 (d, 1H,
HRMS (ESI+): m/z = calculated for C6H11N2O4 ([M + H]+): 175.0713,
3JOH-5 = 4.3 Hz, OH-5), 4.03–4.11 (m, 3H, H-3, CH2-allyl), 4.54 (d, 1H,
3JOH-4 = 4.6 Hz, OH-4), 5.15 (dq, 1H, Jcis = 10.6 Hz, Jgem
=
=
4J =
4J =
3
2
found 175.0715.
3
2
1.5 Hz, =CH2 allyl), 5.29 (dq, 1H, Jtrans = 17.3 Hz, Jgem
2-N,3-O-Carbonyl-1,5-dideoxy-1,5-imino-α-D-xylopyranosyl-
amine (38d). General procedure 11a was followed using OZO 10d
(406 mg, 2.03 mmol). Purification using silica gel column chroma-
tography (EA/MeOH: 80:20) gave the desired product 38d as a
white solid (146 mg, 41 %). Rf = 0.21 (EA/MeOH: 80:20); m.p. 153–
156 °C; [α]2D0 = +44 (c 0.27, MeOH); 1H NMR (400 MHz, CD3OD):
δ (ppm) = 2.68 (dd, 1H, 3J4-5b = 9.7 Hz, 3J5b-5a = 12.7 Hz, H-5b), 2.88
1.8 Hz, =CH2 allyl), 5.90 (ddt, 1H, 3Jtrans= 17.3 Hz, 3Jcis= 10.6 Hz, 3J =
5.4 Hz, HC= allyl), 6.46 (bs, 1H, NH); 13C NMR (100 MHz, (CD3)2CO):
δ (ppm) = 45.0 (CH2-6), 71.2 (CH-5), 72.8 (CH2-allyl), 75.0 (CH2-1),
75.6 (C-2), 78.6 (CH-4), 81.9 (CH-3), 117.2 (=CH2), 135.5 (HC= allyl),
157.9 (C=O); IR (neat) (ν, cm–1) = 3296 (NH + OH), 1749 (C=O); HRMS
˜
(ESI+): m/z = calculated for C10H17N2O5 ([M + H]+): 245.1131, found
3
3
245.1130.
(dd, 1H, J5a-4 = 4.6 Hz, J5a-5b = 12.7 Hz, H-5a), 3.40 (ddd, 1H,
3J4-5a = 4.6 Hz, J4-3 = 8.7 Hz, J4-5b = 9.7Hz, H-4), 3.55 (dd, 1H,
3
3
6-Amino-2-N,3-O-carbonyl-6-deoxy-1-O-methyl-α-L-sorbo-
pyranosylamine (42f). General procedure 11b was followed using
OZO 33f (145 mg, 0.59 mmol). Purification using silica gel column
chromatography (pure EA then EA/Acetone, 50:50) gave the desired
product 42f as a pale yellow sticky solid (80 mg, 62 %). Rf = 0.27
(EA/MeOH: 90:10); [α]D20 = –89 (c 0.60, EA); 1H NMR (400 MHz,
[D6]DMSO): δ (ppm) = 2.37–2.44 (m, 1H, CH2-6a), 2.63 (bs, 1H, NH),
2.72 (td, 1H, J6b-5 = 3.4 Hz, J6b-6a = 12.5 Hz, CH2-6b), 3.09–3.16 (m,
1H, H-5), 3.19–3.26 (m, 3H, 2H of CH2-1 and 1H, H-4), 3.29 (s, 1H,
CH3), 3.88 (d, 1H, J3-4 = 6.4 Hz, H-3), 4.85 (d, 1H, JOH-5 = 4.6 Hz, OH-
5), 5.35 (d, 1H, JOH-4 = 5.1 Hz, OH-4), 7.51 (s, 1H, NH); 13C NMR
(100 MHz, (CD3)2SO): δ (ppm) = 44.0 (CH2-6), 58.9 (CH3), 69.6 (CH-
5), 74.3 (CH2-1), 76.5 (CH-4), 77.1 (CH-3), 80.9 (C-2), 157.4 (C=O); IR
3J3-2 = 6.5 Hz, J3-4 = 8.8 Hz, H-3), 4.24 (t, 1H, J2-1 = J2-3 = 6.8 Hz,
3
3
3
H-2), 5.02 (d, 1H, J1-2 = 7.0 Hz, H-1); 13C NMR (100 MHz, CD3OD): δ
3
(ppm) = 44.3 (CH2-5), 68.5 (CH-1), 70.8 (CH-4), 77.3 (CH-3), 81.3 (CH-
2), 161.2 (C=O); IR (neat) (ν, cm–1) = 3241 (NH + OH), 1696 (C=O),
˜
1082 (CN); HRMS (ESI+): m/z = calculated for C6H11N2O4 ([M + H]+):
175.0713, found 175.0718.
1-O-Benzyl-2-N,3-O-carbonyl-2,6-dideoxy-2,6-imino-ꢀ-D-fructo-
pyranosylamine (40e). General procedure 11b was followed using
OZO 17e (100 mg, 0.31 mmol). Purification using silica gel column
chromatography (pure EA then EA/Acetone, 50:50) gave the desired
product 40e as a pale yellow sticky solid (54 mg, 55 %). Rf = 0.34
(EA/MeOH: 90:10); [α]D20 = –69 (c 0.88, EA); 1H NMR (400 MHz,
(CD3CN): δ (ppm) = 2.14 (bs, 1H, NH), 2.80 (dd, 1H, 2J6b-6a = 14.0 Hz,
(neat) (ν, cm–1) = 3359 (NH + OH), 1739 (C=O); HRMS (ESI+): m/z =
˜
calculated for C8H15N2O5 ([M + H]+): 219.0975, found 219.0976.
2
3
3J6b-5 = 4.0 Hz, H-6b), 2.89 (dd, 1H, J6a-6b = 14.0 Hz, J6a-5 = 2.1 Hz,
H-6a), 3.03 (bs, 1H, OH), 3.36–3.47 (bs, 1H, OH), 3.42 (d, 1H, 2J1b-1a
=
6-Amino-1-O-benzyl-6-deoxy-2-N,3-O-thiocarbonyl-α-L-sorbo-
pyranosylamine (45f). General procedure 11a was followed using
OZT 44f (170 mg, 0.51 mmol). Purification using silica gel column
chromatography (EA/MeOH: 90:10) gave the aminosugar 45f as a
white solid (78 mg, 50 %). Rf = 0.15 (EA/MeOH: 80:20); m.p 87–91 °C;
9.3 Hz, H-1b), 3.49 (d, 1H, 2J1a-1b = 9.3 Hz, H-1a), 3.65 (dd, 1H,
3J4-3 = 6.5 Hz, J4-5 = 3.1 Hz, H-4), 3.68–3.73 (m, 1H, H-5), 4.18 (d,
3
1H, 3J3-4 = 6.5 Hz, H-3), 4.52–4.61 (m, 2H, CH2 Bn), 5.74 (bs, 1H, NH),
7.28–7.41 (m, 5H, CH Ar); 13C NMR (100 MHz, CD3CN): δ (ppm) =
44.2 (CH2-6), 68.0 (CH-5), 73.5 (CH-4), 74.0 (CH2 Bn), 74.6 (CH2-1),
75.2 (C-2), 80.5 (CH-3), 128.7 (CH Ar), 129.4 (CH Ar), 139.1 (Cq Ar),
1
[α]2D0 = –10.4 (c 0.193, MeOH); M.S (IS+): m/z = 311.4 ([M + H]+); H
3
3
NMR (400 MHz, CD3OD): δ (ppm) = 2.98 (dd, 2H, J = 1.5 Hz, J6-5
=
158.2 (C=O); IR (neat) (ν, cm–1) = 3307 (NH + OH), 1732 (C=O); HRMS
5.8 Hz, CH2-6), 3.69 (d, 1H, 2J = 10.4 Hz, CH2-1a), 3.77 (d, 1H, 2J =
10.4 Hz, CH2-1b), 3.93 (td, 1H, J5-6 = 5.7 Hz, J5-4 = 2.9 Hz, CH-5),
˜
(ESI+): m/z = calculated for C14H19N2O5 ([M + H]+): 295.1288, found
3
3
295.1287.
3
4.30 (d, 1H, J4-5 = 2.9 Hz, CH-4), 4.62 (d, 2H, ABq, CH2 Bn), 4.89 (s,
1-O-Benzyl-2-N,3-O-carbonyl-2,6-dideoxy-2,6-imino-α-L-sorbo-
pyranosylamine (40f). General procedure 11b was followed using
1H, CH-3), 7.26–7.36 (m, 5H, CH Ar). 13C NMR (100 MHz, CD3OD): δ
(ppm) = 40.6 (CH2-6), 70.6 (CH2-1), 74.7 (CH2 Bn), 75.4 (CH-4), 82.3
OZO 31f (100 mg, 0.31 mmol). Purification using silica gel column (CH-5), 92.6 (CH-3), 100.8 (C-2), 128.9 (CH Ar), 129.0 (CH Ar), 129.5
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Full Paper
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EurJOC
European Journal of Organic Chemistry
(CH Ar), 139.0 (Cq Ar), 190.8 (C=S); IR (neat) (ν, cm–1)= 3160 (NH +
OH), 1093 (C=S), 997 (CN).
885–903; f) D. S. Alonzi, K. A. Scott, R. A. Dwek, N. Zitzmann, Biochem.
Soc. Trans. 2017, 45, 571–582; g) P. Greimel, J. Spreitz, A. E. Stutz, T. M.
Wrodnigg, Curr. Top. Med. Chem. 2003, 3, 513–523.
˜
1
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Acknowledgments
This work has been partly supported by the Université d'Or-
léans, the Centre National de la Recherche Scientifique (CNRS),
the FEDER and LABEX SynOrg (ANR-11-LABX-0029). JAJ and MD
thank the Erasmus and Leonardo program for their fellowships.
We thank Irene Tejedor for the preparation of precursor 44f.
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Keywords: Iminosugar · Oxazolidinone ·
Oxazolidinethione · Glycosidase inhibitor
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Received: July 31, 2020
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© 2000 Wiley-VCH GmbH

Full Paper
doi.org/10.1002/ejoc.202001053
EurJOC
European Journal of Organic Chemistry
Bicyclic Iminosugars
M. Domingues, J. Jaszczyk,
M. I. Ismael, J. A. Figueiredo,
R. Daniellou, P. Lafite, M. Schuler,*
A. Tatibouët* ..................................... 1–19
Conformationally Restricted Oxazo-
lidin-2-one Fused Bicyclic Imino-
sugars as Potential Glycosidase
Inhibitors
The synthesis of unprecedented bi- OZO azidosugars, themselves obtained
cyclic oxazolidin-2-one (OZO) fused through oxidation of oxazolidin-2-thi-
iminosugars is described. The key step one (OZT) precursors. The iminosugars
involves a tandem Staudinger/retro were subsequently evaluated as glyco-
Michael/aza Michael sequence from sidase inhibitors.
doi.org/10.1002/ejoc.202001053
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
19
© 2000 Wiley-VCH GmbH