N-Thiocarbonyl iminosugars: Synthesis and evaluation of castanospermine analogues bearing oxazole-2(3H)-thione moieties

Article abstract of DOI:10.1002/ejoc.201300720

A straightforward and efficient synthetic route to a new class of glycosidase inhibitors containing an oxazole-2(3H)-thione moiety has been devised. The approach involves the formation of α-hydroxy ketones, which, after condensation with thiocyanic acid, leads to the formation of the heterocycle. By exploiting the ability of the nitrogen atom of oxazoline-2-thione precursors to act as nucleophiles in intramolecular addition, castanospermine analogues could be readily prepared in good overall yields. Glycosidase inhibitory activity compared to oxazolidinethione analogues showed a strong influence of the double bond, for example with pseudoiminosugar 19, by suppressing α-glucosidase inhibition and introducing, to a moderate level, β-glucosidase inhibitory activity. Reactivities showed the propensity of oxazole-2(3H)-thiones - especially when fused on carbohydrate frames - to convert into 1,3-oxazolidine-2-thione aminals through nucleophilic addition to the double bond, leading to unexpected tricyclic structure 21. Oxazole-2(3H)-thione moieties have been anchored onto carbohydrates in a five-step sequence that allows access to castanospermine analogues. Copyright

Full text of DOI:10.1002/ejoc.201300720

FULL PAPER
DOI: 10.1002/ejoc.201300720
N-Thiocarbonyl Iminosugars: Synthesis and Evaluation of Castanospermine
Analogues Bearing Oxazole-2(3H)-thione Moieties
Sandrina Silva,*[a,b] Elena M. Sánchez-Fernández,[c] Carmen Ortiz Mellet,[c]
Arnaud Tatibouët,*[a] Amélia Pilar Rauter,[b] and Patrick Rollin[a]
Keywords: Drug discovery / Carbohydrates / Iminosugars / Inhibitors / Nucleoside mimics
A straightforward and efficient synthetic route to a new class
of glycosidase inhibitors containing an oxazole-2(3H)-thione
pared to oxazolidinethione analogues showed a strong influ-
ence of the double bond, for example with pseudoiminosugar
moiety has been devised. The approach involves the forma- 19, by suppressing α-glucosidase inhibition and introducing,
tion of α-hydroxy ketones, which, after condensation with
thiocyanic acid, leads to the formation of the heterocycle. By
exploiting the ability of the nitrogen atom of oxazoline-2-
thione precursors to act as nucleophiles in intramolecular ad-
dition, castanospermine analogues could be readily prepared
in good overall yields. Glycosidase inhibitory activity com-
to a moderate level, β-glucosidase inhibitory activity. Reac-
tivities showed the propensity of oxazole-2(3H)-thiones – es-
pecially when fused on carbohydrate frames – to convert into
1,3-oxazolidine-2-thione aminals through nucleophilic ad-
dition to the double bond, leading to unexpected tricyclic
structure 21.
sugar (+)-castanospermine C displays higher enzyme speci-
ficity when compared with related compounds A or B, and
this has been ascribed to the conformational restriction im-
posed by the rigidity of the system, particularly at the bond
equivalent to C(5)–C(6) in hexopyranosides. Nevertheless,
the anomeric specificity remains poor, which is not surpris-
ing when considering the absence of a pseudoanomeric sub-
stituent with a precise configuration at the glycosidic site.
Introduction
Over the years, the chemistry and biomedical potential
of iminosugars and their analogues have received a great
deal of attention from the scientific community.[1] These mi-
metics of native sugars, in which the ring oxygen is replaced
by a nitrogen atom, frequently exhibit powerful inhibitory
activity towards carbohydrate-processing enzymes, includ-
ing glycosidases and glycosyltransferases. Because these en-
zymes are involved in a plethora of key biochemical pro-
cesses, compounds that allow their actions to be controlled
have great potential for the treatment of a variety of dis-
eases including viral infections,[2] bacterial infections,[3] ly-
sosomal storage disorders,[4] cancer,[5] and diabetes.[6] How-
ever, most iminosugars are not selective and inhibit en-
zymes acting on anomeric substrates and some isoenzymes.
Selectivity is, of course, a key issue and this behaviour has
hampered their clinical application.[7] As an example (Fig-
ure 1), the piperidine-type iminosugars nojirimycin A and
its 1-deoxy analogue B, which have the same hydroxylation
pattern as d-glucose, are potent inhibitors of α- and β-glu-
cosidases.[8] The related bicyclic indolizidine-type imino-
[a] ICOA UMR 7311, Université d’Orléans, CNRS,
BP6759, 45067 Orléans Cedex 2, France
http://www.univ-orleans.fr/icoa/synthese/tatibouet/
[b] Centro de Química e Bioquímica/Departamento de Química e
Bioquímica, Faculdade de Ciências da Universidade de Lisboa,
Campo Grande, Edifício C8,
Figure 1. Structure of representative iminosugars.
In principle, installation of an oxygen substituent with a
clearly defined orientation at the pseudoanomeric position
in glycomimetic structures should increase the anomeric
selectivity towards glycosidases by matching the stereo-
complementarity of the scissile aglyconic oxygen atom in
5 Piso, 1749-016 Lisboa, Portugal
[c] Departamento de Quimica Orgânica, Facultad de Química,
Universidad de Sevilla,
41012 Sevilla, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300720.
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the natural substrate with the crucial bilateral carboxylic gous to C-3 in monosaccharides corresponding to C-7 in
groups in the active site of the enzyme.[9–11] The instability the indolizidine (trivial name for octahydroindolizine) nota-
of the hemiaminal functional group prevents implementa- tion, and the inhibitory activity towards a panel of com-
tion of this strategy in classical iminosugars. Replacing the mercial glycosidases in comparison with oxazolidine-2-
sp3 nitrogen atom with a pseudoamide-type nitrogen (with thione partners are reported.
substantial sp2 character) has been shown to dramatically
enhance the stability at N–C–O segments by virtue of the
generalized anomeric effect, simultaneously promoting the
axial orientation of pseudoanomeric groups even in the case
of reducing hemiaminal-type derivatives.[12] For instance,
the bicyclic carbamate and thiocarbamate nojirimycin de-
rivatives D and E were found exclusively in the α-configura-
tion in water solution.[13] Interestingly, they behaved as very
selective inhibitors of α-glucosidases. Structure-activity
studies indicated that the endocyclic oxygen of the thio-
carbamate ring was critical for inhibitory activity.[14] Modi-
fications at the hydroxyl groups equivalent to OH-2 and
OH-4 in d-glucopyranose also abolished enzyme bind-
ing.[14] The α-glucosidase inhibition activity was signifi-
cantly decreased after modification at OH-3, e.g., epimeri-
zation to the d-allo-configured bicyclic (thio)carbamates F
and G, but a higher enzyme selectivity was also observed.
Figure 2. Retrosynthetic analysis for the target OXT-piperidine bi-
cyclic glycomimetics.
Results and Discussion
Synthesis of OXT Castanospermine Analogues
Taking advantage of our experience in the synthesis and
Further results have shown that modifications at the sp2- behaviour of the oxazole-2(3H)-thione (OXT) motif,[21] we
iminosugar framework[15] and the incorporation of substit- have performed the synthesis of a new class of castanosper-
uents at selected positions[16] offers unprecedented opportu- mine analogues in which the five-membered ring is replaced
nities to control the affinity and selectivity towards glycos- by an OXT. A retrosynthetic analysis based on previous
idases, leading to the identification of compounds with work by Ortiz Mellet[13] presupposes that the bicyclic
great potential for anticancer[17] and pharmacological chap- framework of iminosugars of type I can be built up through
erone therapies.[18]
intramolecular nucleophilic addition of the nitrogen atom
Structural studies on sp2-iminosugar:glycosidase com- of five-membered ring (thio)carbamates with pseudo-C-nu-
plexes have shown that the piperidine ring of the bicyclic cleoside structure III, to the masked carbonyl in aldose pre-
core is significantly distorted from its initial chair confor- cursors (Figure 2).
mation after binding at the active site.[19] Flexibility at this
The initial synthetic objective of this work was to de-
region seems to be an important aspect.[20] We conceived velop the simplest preparation of appropriate structures of
that the incorporation of a carbon–carbon double bond at type III, which, after hydrolysis, would deliver OXT-piper-
the five-membered thiocarbamate ring would alter the idine bicyclic derivatives I. The latter is closely related to
ground state conformation of the glycomimetic, which castanospermine, with a hydroxylation pattern of the six-
should translate into differences on the glycosidase inhibi- membered ring similar to that of d-glucose.
tion profile. To test this hypothesis we have now synthesised
Starting from commercially available 1,2:5,6-di-O-iso-
oxazoline-2-thione-piperidine bicyclic glycomimetics with propylidene-α-d-glucofuranose (DAG, 1), and following
general structure I (Figure 2). The synthetic strategy for the standard procedures,[22,23] benzylation of the 3-hydroxyl
preparation of compounds modified at the position analo- group and regioselective 5,6-O-isopropylidene cleavage in
Scheme 1. Reagents and conditions: (a) BnBr, NaH, DMF, room temp., 8 h, quantitative; (b) AcOH/H2O (7:3), room temp., 8 h, 83%; (c)
Bu2SnO, NBS, CHCl3, toluene, 85%; (d) KSCN, acid, solvent, reflux, 24 h (89–94%).
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N-Thiocarbonyl Iminosugars
acidic medium led to the formation of diol 2 in 83% overall
The overall yields (41–67%) for the multi-step processes
yield. Subsequent regioselective oxidation of the 5-hydroxyl leading to the target d-ribo configured pseudo-C-nucleoside
group was performed according to Grindley,[24] by using N- 10 were satisfactory and the synthesis proved efficient also
bromosuccinimide (NBS) to efficiently oxidize a dibutyl- for the d-xylo configured derivative. Although the second
stannylene acetal, providing the 5-keto sugar 3 in 85% yield process (Method B) is longer and more costly, this allowed
with a very high kinetic rate, as evidenced by the rapid de- ketone formation in higher yield and good reproducibility –
colouration of the reaction medium. Finally, our standard parameters to be taken into consideration when scaling up
conditions (KSCN, EtOH, HCl) for OXT formation[21] the reaction.
were applied to reach the target compound 4 in 89% yield.
To generate OXTs as a feeler of the furanose ring, able
Performing the reaction with TsOH·H2O in an aprotic sol- to furnish oxaindolizine-type derivatives structurally-related
vent increased the yield of pseudo-C-nucleoside 4 to 94% to castanospermine, the synthesis of d-xylo- and d-ribo-
(Scheme 1), with 63% overall yield from DAG 1.
type derivatives devoid of ether protection of the 3-OH was
To gain insight into the selectivity of these indolizidine required. These d-ribo and d-xylo precursors were prepared
analogues against glycosidases, the preparation of the C-3 by starting from DAG (1) or its d-allo epimer 5. Selective
epimer of 4, with d-ribo configuration, was then envisaged. hydrolysis of the 5,6-O-isopropylidene was performed with
To this end, DAG (1) was first subjected to a standard epi- 70% aqueous AcOH[31,32] to deliver triols 11 and 12 in
merization sequence involving pyridinium dichromate quantitative yield. Subsequent regioselective oxidation of
(PDC) mediated oxidation[25–27] and stereoselective NaBH4 the 5-OH group required optimisation of the reaction con-
mediated reduction,[28] providing 1,2:5,6-di-O-isopropylid- ditions. By making use of the Bu2SnO/NBS system, α-hy-
ene-α-d-allofuranose (5) in good yield (Scheme 2). After droxy ketones 13 and 14 were isolated in 73 and 62% yield,
benzylation of the 3-OH,[29] the corresponding diacetonide respectively. Replacing NBS by Br2 as oxidant[33,34] resulted
was selectively hydrolysed[26] to afford diol 6 in 75% overall in a yield increase to 89 and 79%, respectively. It could be
yield. Regioselective oxidation of the 5-hydroxyl group was observed, once again, that the oxidative conversion of a d-
then carried out by using the Bu2SnO/NBS system[24] to gluco species 11 is more efficient than that of its d-allo epi-
provide 5-keto sugar 7 in 60% yield (Method A). The low mer 12, due to easier dimer formation in the second case.
yields obtained for this d-ribo keto sugar in comparison to
However, in our hands, and contrary to the literature,[35]
those obtained for the d-xylo configured derivative 3 may bromine proved more effective than NBS for the oxidation
be due to partial dimerisation of the α-hydroxy ketone, of carbohydrate-based dialkylstannylene acetals. The α-hy-
which depends on the configuration at C-3, as suggested in droxy keto sugars 13 and 14 were then condensed with thio-
the literature.[24] Hence, dimerisation occurs to a larger ex- cyanic acid under standard conditions (EtOH, HCl,
tent for 7 than for 3, in which the orientation of the C- KSCN),[21] affording oxazole-2(3H)-thiones 15 and 16 in
3 substituent exerts a higher steric impedance against the good yield (Scheme 3). Performing the reaction with
formation of dimers. To prevent dimerisation, an alternative TsOH·H2O in a 1:1 tetrahydrofuran (THF)/N,N-dimethyl-
synthesis of 7 was planned following a two-step strategy formamide (DMF) solution allowed the yields to be in-
(Method B). The primary hydroxyl group of 6 was first re- creased to 86 and 89%, respectively, thus raising the overall
gioselectively O-silylated,[30] affording derivative 8, which yield for the preparation of 15 and 16 to 77 and 70%,
was subsequently oxidized to furnish 5-keto sugar 9 in 97% respectively.
overall yield from 6. When submitted to thiocyanic acid
Pseudo-C-nucleosides 4, 10, 15 and 16 can be prepared
condensation, ketone 7, directly, and ketone 9, after con- in reproducibly high overall yields. Curiously, the conver-
comitant desilylation, led to the formation of OXT 10 in an sion of 13–14 into OXTs 15–16 was highly regioselective
excellent 92% yield (Scheme 2).
and no traces of isomeric six-membered ring thiocarbamate
Scheme 2. Reagents and conditions: (a) PDC/Ac2O, CH2Cl2, quantitative; (b) NaBH4, EtOH/H2O (56:44), room temp., 3 h, 84%; (c)
BnBr, NaH, DMF, room temp., 8 h, quantitative; (d) AcOH/H2O (7:3), room temp., 8 h, 89%; (e) Bu2SnO, NBS, CHCl3, toluene, 60%;
(f) TBDMSCl, imidazole, DMF, room temp., 5 h, 97%; (g) PDC/Ac2O, CH2Cl2, quantitative; (h) KSCN, TsOH·H2O, THF, reflux, 92%.
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Scheme 4. Reagents and conditions: TFA/H2O (2:1), CH2Cl2.
Scheme 3. Reagents and conditions: (a) AcOH/ H2O (7:3), room
temp., 8 h; (b) Bu2SnO, NBS (or Br2); (c) KSCN, solvent, acid.
Switching to 6 m HCl as acidic medium led to very sim-
ilar results. The reluctance of compound 4 to undergo intra-
molecular cyclisation might be ascribed to the high steric
hindrance caused by the benzyl group in the 3-position. The
spatial rearrangement of the latter hampers N-nucleophilic
attack on the masked aldehyde, thus impeding the forma-
tion of the corresponding pseudo-iminosugar. A hydrated
form of the OXT, displaying a hemiaminal-type function, is
obtained instead.[36]
Compounds 18–20 existed in water solution as equilib-
rium mixtures of the corresponding R and S epimers at the
hemiaminal-type pseudoanomeric stereocentre (Table 1).
This situation is strikingly different from that encountered
in the case of the reference (thio)carbamate glycomimetics
D–G, for which a single diastereomer, matching the stereo-
chemistry of α-glucopyranosides, was isolated. The vicinal
J5,6 proton–proton coupling constant values indicated that
in both epimeric forms the pseudoanomeric hydroxyl group
adopted the axial orientation. Probably, the presence of the
C(8a)=C(1) double bond, which forces planarity at the
C(8)–C(8a)–N segment, gives a half-chair conformation
that endows the molecule with a less pronounced anomeric
effect. A similar scenario has been previously reported for
related bicyclic sp2 iminosugar glycomimetics incorporating
a C(7)=C(8) double bond.[15f]
(which would result from competitive participation of the
3-OH in the condensation) could be detected. The structure
1
of OXTs was first confirmed by 13C and H NMR spec-
troscopy. The characteristic chemical shift for a C=S bond
in OXT structures was detected at δ = 179.0 ppm for 4 and
10, δ = 180.9 ppm for 15 and δ = 181.9 ppm for 16. The H-
5 resonance appeared at ca δ = 7.20 ppm for 4 and 10, δ =
7.55 ppm for 15, and δ = 7.64 ppm for 16.
OXT 15 could be crystallised and its structure was con-
firmed by crystallographic analysis, showing only one
stereoisomer in the unit (Figure 3).
Figure 3. ORTEP diagram for compound 15 (CCDC-950949).
Table 1. α/β Ratios and 13C NMR shifts for C-5 in anomeric mix-
tures 18, 19 and 20.
The feasibility of the intramolecular nucleophilic ad-
dition of the nitrogen atom in pseudo-C-nucleoside thio-
carbamates was then investigated with the previously syn-
thesised oxazole-2(3H)-thiones. Acid-catalysed hydrolysis of
the anomeric acetal protecting group led to contrasting re-
sults. The 3-O-benzyl d-xylo derivative 4 was converted in
83% yield into trihydroxylated OZT 17 as a mixture of
stereoisomers. Quite differently, when submitted to the
α/β ratio [%]
13C NMR δ [ppm]
α
β
18
19
20
84:16
57:43
77:23
80.7
79.5
82.8
78.1
83.9
80.7
Overall, by exploiting the nucleophilic potency of the
same hydrolysis conditions, the 3-O-benzyl d-ribo epimer NH of oxazoline-2-thiones in intramolecular addition to
10, as well as the pseudo-C-nucleosides 15 and 16 afforded the masked aldehyde of hexose precursors, the castanosper-
the bicyclic structures 18, 19 and 20 in 89, 87 and 88% mine analogue 19 and 7-epi-castanospermine analogues 18
yield, respectively (Scheme 4).
and 20 were readily prepared.
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N-Thiocarbonyl Iminosugars
Scheme 5. Reagents and conditions: (a) Ph3P=CHCOOMe, benzoic acid, THF, reflux, 8 h, 87%.
The design and synthesis of iminosugar derivatives em- NOE was observed between NH and H-3 and H-4. The
bodying a C–C bond linked to their pseudo-anomeric posi- formation of 21 from the transient open-chain Wittig inter-
tion (iminosugar C-glycosides[37–39]) has attracted attention mediate results from a competition between two cyclisation
since α-homonojirimycin was first synthesized by Liu[40] processes involving electrophilic sites C-3 and C-7. It ap-
and thereafter isolated from a natural source.[41] It has pears that the Michael induced ring-closure based on the
proven to be a potent and, more significantly, selective in- NH is disfavoured, when compared to OH-4 attack on the
hibitor of α-glycosidases from the mouse gut and human electrophilic C=N bond under basic conditions (Scheme 5).
intestine. Having in mind the synthesis of new α-homonojir-
This interesting result brings again to question the
imycin analogues, we planned the ring-opening of the imi- pseudo-aromaticity of an oxazole-2(3H)-thione ring, which
nosugar by a stabilised Wittig reagent.[42–44] Subsequent was discussed in our previous papers.[21,36] The propensity
base-catalysed recyclisation of the activated olefin would af- of oxazole-2(3H)-thiones – especially when fused on carbo-
ford a compound with a skeleton type H (Scheme 5). With hydrate frames – to convert into OZT aminals through nu-
this aim, compound 18 was treated with (methoxycarb- cleophilic addition to the double bond is exemplified above
onylmethylene)triphenylphosphorane in THF heated to re- by the formation of compound 17.
flux in the presence of a catalytic amount of benzoic acid,
to increase the E-selectivity.[45] Compound 21 was formed
and could be isolated in 87% yield.
Glycosidase Inhibitory Activity Evaluation
The structure of 21, and particularly the configuration of
the newly formed stereocentres, was ascertained by NMR
The new glycomimetics 18–20 were screened as glycosi-
analysis using bidimensional NOESY, in which a strong dase inhibitors against β-galactosidase (from bovine liver),
Table 2. Comparison of inhibitory activities (Ki, μm) for compounds E, 18–20 and 24.[a]
[a] ni means no inhibitory activity was observed at [I] 2 mm against β-glucosidase (almonds), α-galactosidase (green coffee), β-galactosidase
(E. coli), α-mannosidase (Jack beans), β-mannosidase (Helix pomatia) and amyloglucosidase (Aspergillus niger).
Eur. J. Org. Chem. 2013, 7941–7951
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S. Silva, A. Tatibouët et al.
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β-galactosidase (from Escherichia coli), β-glucosidase (from overall yields, showing that the strategy used for the forma-
almonds), α-glucosidase (from yeast), α-galactosidase (from tion of these bicyclic structures is quite efficient. In contrast
green coffee), isomaltase, trehalase (from pork kidney), α- to what has been reported for D–G (for which the α-anomer
1
mannosidase (from jack bean), β-mannosidase (from Helix was exclusively observed in solution), the H NMR spectra
pomatia) and amyloglucosidase (from Aspergillus níger) and recorded for the newly formed pseudo-iminosugars revealed
the Ki values obtained are collected in Table 2. The corre- the presence of both α and β-diastereomers at the hemiami-
sponding Ki values for the previously reported[14] d-gluco- nal centre. This result could be explained by comparison of
thiocarbamate E is included for comparative purposes. Ad- oxazole-2(3H)-thione (OXT) and OZT structures. Whereas
ditionally, the 7-O-benzyl derivative of E (24) was prepared in iminosugar glycomimetics D–G, the imino nitrogen has
in 70% overall yield by thiocarbonylation of 5-amino-5- substantial sp2 character, the presence in 18–20 of the
deoxy-1,2-O-isopropylidene-3-O-benzyl-α-d-glucofuranose C(8a)=C(1) double bond, forces planarity at the C(8)–
(22)[46] and subsequent removal of the anomeric ketal by C(8a)–N segment, which results in a half-chair conforma-
acid hydrolysis and it was also evaluated as a glycosidase tion that endows the molecule with a higher flexibility, thus
inhibitor (Scheme 6).
allowing the anomeric effect to be fulfilled for both ano-
mers. When applying stabilised Wittig conditions to hemia-
minal 18, a psicofurano-configured spiranic OZT was
formed in excellent yield and, surprisingly, with total
stereocontrol. This transformation is particularly interest-
ing because an enantiomerically pure spiro-OZT is easily
formed, which would not be feasible by condensing a ketose
with thiocyanic acid.[47] Furthermore, compound 21 dis-
plays a rich chemical potential, notably with the Michael
acceptor segment introduced.
Regarding the Wittig mechanism, the preferred internal
cyclisation through 4-OH is made possible due to the low
aromaticity character of the ring. This assumption was fur-
ther confirmed by theoretical calculations related to the
electronic density in the oxazole-2(3H)-thione ring (Fig-
ure 4).
Scheme 6. Reagents and conditions: (a) CS2, DCC, CH2Cl2, –10 °C
to r.t, 2 h, 90%; (b) TFA/H2O (9:1), 79%.
Surprisingly, introduction of the double bond in 19 sig-
nificantly reduced the inhibition of yeast α-glucosidase
(maltase), when compared to the reference (compound E).
However inhibition of isomaltase was only slightly affected
(Table 2), whereas trehalase, an α-glucosidase towards
which the reference E was not active, was significantly in-
hibited by 19 (Ki = 87 μm). Weak inhibition of β-gluco-
sidase was also noticed (Ki = 274 μm). The C-7 epimer 20
was a more potent and selective inhibitor of isomaltase (Ki
= 52 μm); although it also exhibited some affinity towards
maltase and trehalase, the corresponding inhibition con-
Figure 4. Electronic density in oxazole-2(3H)-thione ring calculated
stants were about one order of magnitude higher (Ki = 319 by GAMESS, using force-field type B3LYP/3-21G.
and 416 μm, respectively). This behaviour is drastically dif-
ferent from that observed for the oxazolidine analogue G,
sharing d-allo configuration, which did not inhibit any of
the assayed α-glucosidases. Benzylation of 20 at O-7 (Ǟ18)
After minimisation with GAMESS, LUMO, using force-
field type B3LYP/3-21G, it appeared that the C(4)–C(5) seg-
ment in oxazole-2(3H)-thione is relatively poor in electrons
cancelled the isomaltase inhibition activity and affected to
and in a more pronounced form on the C-4 carbon atom,
a much lesser extent the affinity towards maltase and trehal-
which could explain the nucleophilic attack on C-5.
ase (Ki = 688 and 505 μm, respectively).
The glycosidase inhibition evaluation of the new imi-
nosugar glycomimetics highlights the effect of structural
modifications on the biological activity and supports the
need for developing efficient synthetic methodologies tar-
geting further improvement in glycosidase inhibitor proper-
Conclusions
ties.
We have developed a straightforward and efficient syn-
thetic route to a new class of glycosidase inhibitors, con-
taining an oxazole-2(3H)-thione moiety. The approach in-
volves the formation of α-hydroxy ketones which, after con-
densation with thiocyanic acid, lead to the formation of
pseudo-C-nucleoside precursors. By exploiting the ability of
the nitrogen atom of oxazoline-2-thione precursors to act
as a nucleophile in intramolecular addition to the masked
aldehyde group of hexose precursors, castanospermine ana-
Experimental Section
General: Anhydrous reactions were performed under an argon at-
mosphere in predried flasks, using anhydrous solvents (distilled
when necessary according to ref.[49]). TLC on precoated aluminum-
back plates (Merck Kieselgel 60F254) were visualised by UV light
logues 18, 19 and 20 could be readily prepared in good (254 nm) and by charring after exposure to a 10% H2SO4 solution
7946 Eur. J. Org. Chem. 2013, 7941–7951
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N-Thiocarbonyl Iminosugars
in methanol or to a 5% solution of phosphomolybdic acid in eth-
anol. Flash column chromatography was carried out using Kiesel-
gel Si60, 40–63 μm (E. Merck). Melting points [°C] were obtained
with a Büchi 510 capillary apparatus and are uncorrected. Optical
rotations were measured at 20 °C with a Perkin–Elmer 341 polari-
= 11.7 Hz, 2 H, OCH2Ph), 5.74 (d, J1–2 = 3.8 Hz, 1 H, H-1), 7.28–
7.40 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.7,
–4.8 (Me2Si), 18.5 (CIV-tBu), 26.0 (tBu), 26.7, 26.9 (Me2C), 63.9
(C-6), 72.1 (C-5), 72.3 (OCH2Ph), 77.9 (C-2), 78.0 (C-3), 78.1 (C-
4), 104.2 (C-1), 113.1 (Me2C), 128.1, 128.2, 128.6 (CH-Ph), 137.7
(CIV-Ph) ppm. HRMS: calcd. for C22H36O6SiNa [M + Na]+
447.2179; found 447.2183.
1
meter with a path length of 1 dm. H and 13C NMR spectra were
recorded with a 250 MHz Bruker Avance DPX250 spectrometer
or a 400 MHz Bruker Avance2 spectrometer. Chemical shifts are
expressed in parts per million (ppm) downfield from TMS internal
standard and coupling constants are given in Hz. IR absorption
frequencies (Thermo-Nicolet AVATAR 320 spectrometer) are given
in cm–1. Mass spectra were recorded with a Perkin–Elmer Sciex
API 300 spectrometer for negative (ISN) and positive (ISP) electro-
spray ionisation. High-resolution mass spectra (HRMS) were re-
corded with a MicrOTOF-QII spectrometer in the electrospray ion-
isation (ESI) mode or in chemical ionisation (CI) mode.
3-O-Benzyl-6-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-
ribo-hexofuranos-5-ulose (9): Compound 8 (150.0 mg, 0.35 mmol)
was dissolved in anhydrous CH2Cl2 (10 mL). PDC (79.0 mg,
0.21 mmol) and Ac2O (0.13 mL, 1.38 mmol) were added and the
reaction was heated to reflux and stirred for 2 h. After concentra-
tion of the mixture in vacuo, the residue was applied to a short
silica gel column (EtOAc) and the filtrate was co-evaporated with
toluene (3ϫ). Compound 9 was obtained quantitatively as a yellow
oil. [α]D = +16 (c = 1.0, CHCl , 25 °C). IR (NaCl): ν = 1727 (C=O),
˜
3
Materials:
3-O-Benzyl-1,2-O-isopropylidene-α-d-xylo-hexofur-
1461 (Ph), 1215 (Si(CH3)2) cm–1. 1H NMR (400 MHz, CDCl3): δ
= 0.08 (s, 6 H, Me2Si), 0.91 (s, 9 H, tBuSi), 1.36 and 1.60 (2ϫ s, 6
H, Me2C), 3.87 (dd, J2–3 = 4.0 Hz, J3–4 = 9.1 Hz, 1 H, H-3), 4.49
(s, 2 H, H-6a, H-6b), 4.54 (t, J2–3 = 4.5 Hz, 1 H, H-2), 4.60 (d, 1
H, H-4), 4.63 and 4.75 (2ϫ d, AB system, Jgem = 11.9 Hz, 2 H,
OCH2Ph), 5.81 (d, J1–2 = 4.5 Hz, 1 H, H-1), 7.31–7.39 (m, 5 H,
Ph) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.7, –4.8 (Me2Si),
18.6 (CIV-tBu), 25.9 (tBu), 26.6, 27.0 (Me2C), 68.0 (C-6), 72.5
(OCH2Ph), 77.9 (C-2), 79.6 (C-3), 80.0 (C-4), 104.7 (C-1), 113.7
(Me2C), 128.2, 128.6, 129.1 (CH-Ph), 137.1 (CIV-Ph), 205.0
(C=O) ppm. MS (IS): m/z = 423.5 [M + H]+. HRMS: calcd. for
C22H35O6Si [M + H]+ 423.2203; found 423.2211.
anos-5-ulose (3) was obtained in three steps from DAG (1), as pre-
viously reported.[24] 3-O-Benzyl-1,2-O-isopropylidene-α-d-ribo-
hexofuranos-5-ulose (7) was prepared in five steps from DAG (1),
as previously reported.[48] (5R,6R,7R,8R,8aR)5,6,7,8-Tetrahydroxy-
3-(thio)xo-2-oxaindolizidines were prepared by following reported
procedures.[14]
4-[(4R)-3-O-Benzyl-1,2-O-isopropylidene-α-D-threofuranos-4-C-yl]-
1,3-oxazoline-2-thione (4): The ulose 3 (83.3 mg, 0.27 mmol) and
KSCN (39.8 mg, 0.41 mmol) were dissolved in THF (10 mL). After
cooling at –5 °C, TsOH·H2O (102.7 mg, 0.54 mmol) was carefully
added and the mixture was heated to reflux with stirring for 24 h,
then cooled by adding crushed ice. After extraction with EtOAc
(3ϫ 25 mL), the combined organic phase was washed with satu-
rated aqueous NaHCO3, water, and brine, and finally dried with
MgSO4. After filtration and concentration under vacuum, the resi-
due was purified by column chromatography (PE/EtOAc, 8:2) to
afford 4 (88.7 mg, 94%) as a yellow oil. [α]D = –16 (c = 1.0, MeOH,
4-[(4R)-3-O-Benzyl-1,2-O-isopropylidene-α-D-erythrofuranos-4-C-
yl]-1,3-oxazoline-2-thione (10); Method A (from 9): The ulose 9
(114.1 mg, 0.27 mmol) and KSCN (39.8 mg, 0.41 mmol) were dis-
solved in THF (15 mL). After cooling at –5 °C, TsOH·H2O
(102.7 mg, 0.54 mmol) was carefully added and the mixture was
heated to reflux and stirred for 24 h, then cooled by adding crushed
ice. After extraction with EtOAc (3ϫ 25 mL), the combined or-
ganic phase was washed with saturated aqueous NaHCO3, water,
and brine, and finally dried with MgSO4. After filtration and con-
centration under vacuum, the residue was purified by column
chromatography (cyclohexane/EtOAc, 6:4) to afford 10 (86.7 mg,
92%) as a white solid. Method B (from 7): The ulose 7 (100.0 mg,
0.32 mmol) and KSCN (46.6 mg, 0.48 mmol) were dissolved in
THF (15 mL). After cooling at –5 °C, TsOH·H2O (121.7 mg,
0.64 mmol) was carefully added and the mixture was heated to re-
flux and stirred for 24 h, then cooled by adding crushed ice. After
extraction with EtOAc (3ϫ 25 mL), the combined organic phase
was washed with saturated aqueous NaHCO3, water, and brine,
and finally dried with MgSO4. After filtration and concentration
under vacuum, the residue was purified by column chromatography
(cyclohexane/EtOAc, 6:4) to afford 10 (102.8 mg, 92%) as a white
solid; m.p. 174–175 °C. [α]D = –50 (c = 1.0, MeOH, 25 °C). IR
25 °C). IR (NaCl): ν
= 3230 (NH), 2986, 2909, 1636 (C=C),
˜
max
1492, 1130 (N–CS–O), 1469, 1464 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 1.32 and 1.50 (2ϫ s, 6 H, Me2C), 4.02 (d, J3Ј–4Ј
3.1 Hz, 1 H, H-3Ј), 4.45 and 4.65 (2 ϫ d, AB system, Jgem
=
=
11.7 Hz, 2 H, OCH2Ph), 4.69 (d, J1Ј–2Ј = 3.3 Hz, H-2Ј), 5.04 (d,
J3Ј–4Ј = 3.1 Hz, 1 H, H-4Ј), 5.99 (d, 1 H, H-1Ј), 7.20–7.27 (m, 3 H,
H-5, Ph), 7.29–7.38 (m, 3 H, Ph), 11.00 (br. s, 1 H, NH) ppm. 13C
NMR (100 MHz, CDCl3): δ = 26.0, 26.7 (Me2C), 72.1 (C-4Ј), 72.4
(OCH2Ph), 82.0 (C-2Ј), 82.4 (C-3Ј), 104.8 (C-1Ј), 112.4 (Me2C),
125.9 (C-4), 128.1, 128.4, 128.7 (CH-Ph), 134.8 (C-5), 136.2 (CIV-
Ph), 179.0 (C=S) ppm. HRMS: calcd. for C17H20NO5S [M + H]+
350.1062; found 350.1054.
3-O-Benzyl-6-tert-butyldimethylsilyl-1,2-O-isopropylidene-α-D-
allofuranose (8): To diol 6 (117.9 mg, 0.38 mmol) dissolved in anhy-
drous DMF (10 mL) at 0 °C were added imidazole (51.7 mg,
0.76 mmol) and TBDMSCl (85.8 mg, 0.57 mmol). The reaction
was stirred for 5 h at room temperature, then treated with crushed
ice. After extraction with EtOAc (3ϫ 20 mL), the combined or-
ganic phase was washed with water and brine, and finally dried
with MgSO4. After filtration and concentration under vacuum, the
residue was purified by column chromatography (PE/EtOAc, 7:3)
(NaCl): ν = 3223 (NH), 2987, 2910, 1650 (C=C), 1497, 1112 (N–
˜
CS–O), 1465, 1454 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.37
and 1.61 (2 ϫ s, 6 H, Me2C), 3.89 (dd, J2Ј–3Ј = 4.0 Hz, J3Ј–4Ј
9.0 Hz, 1 H, H-3Ј), 4.52 and 4.75 (2 ϫ d, AB system, Jgem
=
=
11.8 Hz, 2 H, OCH2Ph), 4.68 (br. t, 1 H, H-2Ј), 4.87 (d, 1 H, H-
to afford 8 (156.5 mg, 97 %) as a white solid; m.p. 115–116 °C. 4Ј), 5.83 (d, J1Ј–2Ј = 3.4 Hz, 1 H, H-1Ј), 7.20 (s, 1 H, H-5), 7.25–
1
[α]D = +43 (c = 0.5, CHCl3, 25 °C). H NMR (400 MHz, CDCl3): 7.36 (m, 5 H, Ph), 11.78 (br. s, 1 H, NH) ppm. 13C NMR
δ = 0.06 (s, 6 H, Me2Si), 0.89 (s, 9 H, tBuSi), 1.58 and 1.59 (2ϫ s,
6 H, Me2C), 2.53 (d, J5–OH = 3.1 Hz, 1 H, OH), 3.62–3.72 (m, 2
H, H-6a, H-6b), 3.88–3.93 (m, 1 H, H-5), 3.96 (dd, J2–3 = 4.5 Hz,
J3–4 = 8.7 Hz, 1 H, H-3), 4.06 (dd, J4–5 = 4.2 Hz, 1 H, H-4), 4.55
(t, J2–3 = 4.5 Hz, 1 H, H-2), 4.60 and 4.76 (2ϫ d, AB system, Jgem
(100 MHz, CDCl3): δ = 26.4, 26.8 (Me2C), 70.5 (C-4Ј), 72.6
(OCH2Ph), 77.0 (C-2Ј), 80.7 (C-3Ј), 104.3 (C-1Ј), 113.8 (Me2C),
128.3 (C-4), 128.3, 128.5, 128.6 (CH-Ph), 134.8 (C-5), 136.6 (CIV-
Ph), 179.1 (C=S) ppm. HRMS: calcd. for C17H20NO5S [M + H]+
350.1062; found 350.1056.
Eur. J. Org. Chem. 2013, 7941–7951
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7947

S. Silva, A. Tatibouët et al.
FULL PAPER
1,2-O-Isopropylidene-α-
D
-xylo-hexofuranos-5-ulose (13): Triol 11 After cooling at –5 °C, TsOH·H2O (262.5 mg, 1.38 mmol) was care-
(178.4 mg, 0.81 mmol) was dissolved in anhydrous MeOH (10 mL)
and dibutyltin oxide (403.3 mg, 1.62 mmol) was added. After heat-
ing to reflux and stirring for 2 h, the solvent was evaporated and
the residue was dried under vacuum for 30 min. The residue was
then taken up in anhydrous CH2Cl2 (10 mL) and Br2 (42 μL,
0.82 mmol) was added. The resulting solution was stirred for
20 min, then the solvent was evaporated and the residue was puri-
fied by column chromatography (PE/EtOAc, 1:1) to afford 13
(157.3 mg, 89%) as a colourless oil. [α]D = –50 (c = 1.1, CHCl3,
fully added and the mixture was heated to reflux and stirred for
24 h, then cooled by adding crushed ice. After extraction with
EtOAc (3ϫ 25 mL), the combined organic phase was washed, with
saturated aqueous NaHCO3, water, and brine, and finally dried
with MgSO4. After filtration and concentration under vacuum, the
residue was purified by column chromatography (PE/EtOAc, 4:6)
to afford 16 (159.2 mg, 89%) as a white solid; m.p. 145–146 °C.
[α]D = –57 (c = 1.5, CHCl , 25 °C). IR (NaCl): ν = 3479 (OH),
˜
3
3200 (NH), 2986, 2940, 1655 (C=C), 1474, 1374, 1140 (N–CS–
1
25 °C). IR (NaCl): ν = 1727 (C=O) cm–1. 1H NMR (400 MHz,
O) cm–1. H NMR (400 MHz, [d6]acetone): δ = 1.31 and 1.49 (2ϫ
˜
CDCl3): δ = 1.33 and 1.48 (2ϫ s, 6 H, Me2C), 3.83 (br. s, 1 H, s, 6 H, Me2C), 4.18–4.19 (m, 1 H, H-3Ј), 4.45 (br. s, 1 H, OH), 4.69
OH), 4.12 (br. s, 1 H, OH), 4.46 (d, J6–OH = 3.5 Hz, 2 H, H-6a, H-
6b), 4.55 (d, J1–2 = 3.5 Hz, 1 H, H-2), 4.56 (d, J3–4 = 3.3 Hz, 1 H,
H-3), 4.75 (d, J3–4 = 3.3 Hz, 1 H, H-4), 6.06 (d, 1 H, H-1) ppm.
(br. t, J2Ј–3Ј = 4.2 Hz, 1 H, H-2Ј), 4.73 (d, J3Ј–4Ј = 9.0 Hz, 1 H, H-
4Ј), 5.82 (d, J1Ј–2Ј = 3.6 Hz, 1 H, H-1Ј), 7.63 (s, 1 H, H-5), 11.90
(br. s, 1 H, NH) ppm. 13C NMR (100 MHz, [d6]acetone): δ = 27.6,
13C NMR (100 MHz, CDCl3): δ = 26.3, 26.9 (Me2C), 68.0 (C-6), 27.9 (Me2C), 73.6 (C-4Ј), 76.4 (C-3Ј), 80.8 (C-2Ј), 105.8 (C-1Ј),
76.3 (C-3), 84.6 (C-2), 85.3 (C-4), 105.8 (C-1), 112.5 (Me2C), 209.1
(C=O) ppm. HRMS: calcd. for C9H14O6Na [M + Na]+ 241.0688;
found 241.0686.
114.3 (Me2C), 130.2 (C-4), 136.7 (C-5), 181.9 (C=S) ppm. HRMS:
calcd. for C10H14NO5S [M + H]+ 260.0593; found 260.0586.
4-Hydroxy-4-[(4ЈS)-3-O-benzyl-α-D-threofuranos-4Ј-C-yl]-1,3-oxaz-
4-[(4R)-1,2-O-Isopropylidene-α-
D
-threofuranos-4-C-yl]-1,3-oxaz-
olidine-2-thione (17): A solution of oxazole-2(3H)-thione 4
oline-2-thione (15): The ulose 13 (151.0 mg, 0.69 mmol) and KSCN
(101.0 mg, 0.29 mmol) in CH2Cl2/TFA/H2O (2:2:1, 10 mL) was
(100.6 mg, 1.04 mmol) were dissolved in THF/DMF (1:1, 15 mL). stirred at room temperature for 3 h. The solvent was removed under
After cooling at –5 °C, TsOH·H2O (262.5 mg, 1.38 mmol) was care-
fully added and the mixture was heated to reflux and stirred for
24 h, then cooled by adding crushed ice. After extraction with
EtOAc (3ϫ 25 mL), the combined organic phase was washed with
saturated aqueous NaHCO3, water, and brine, and finally dried
with MgSO4. After filtration and concentration under vacuum, the
residue was purified by column chromatography (cyclohexane/
reduced pressure and the residue was co-evaporated several times
with water and, after concentration under vacuum, purified by col-
umn chromatography (PE/EtOAc, 7:3) to afford the stereoisomeric
mixture 17 (78.8 mg, 83 %; α/β: 3:7) as a yellow oil. 1H NMR
(250 MHz, CDCl3): δ = 4.02 (d, J3Јα–4Јα = 3.2 Hz, 4Ј-Hα), 4.16 (br.
s, 3Ј-Hβ), 4.35–4.37 (m, 2Ј-Hβ), 4.63–4.70 (m, 2Ј-Hα, 4Ј-Hβ, OCH2-
Phα, OCH2Phβ, H-5aα, H-5aβ, H-5bα, H-5bβ), 4.99 (d, J3Јα–4Јα
=
EtOAc, 1:2) to afford 15 (153.9 mg, 86%) as a yellow solid; m.p. 3.2 Hz, 3Ј-Hα), 5.68 (br. s, 1Ј-Hβ), 5.99 (d, J1Јα–2Јα = 3.8 Hz, 1Ј-
148–149 °C. [α]D = –58 (c = 0.6, CHCl , 25 °C). IR (NaCl): ν =
Hα), 7.28–7.35 (m, Ph), 9.80 (br. s, NH) ppm. 13C NMR
3480 (OH), 3240 (NH), 2974, 2954, 1655 (C=C), 1503, 1375, 1108 (62.89 MHz, CDCl3): δ = 73.4, 73.6 (OCH2Ph), 74.9, 75.0 (C-4Јα,
(N–CS–O) cm–1 1H NMR (400 MHz, CDCl3): δ = 1.28 and C-4Јβ), 77.4, 77.5 (C-5), 78.1, 79.8 (C-2Јα, C-2Јβ), 83.6, 83.8 (C-
1.44 (2ϫ s, 6 H, Me2C), 3.41 (br. s, 1 H, OH), 4.32 (d, J3Ј–4Ј
2.8 Hz, 1 H, H-3Ј), 4.63 (d, J1Ј–2Ј = 3.5 Hz, 1 H, H-2Ј), 5.12 (d, 1
˜
3
.
=
3Јα, C-3Јβ), 97.0 (C-1Јα), 105.0 (C-1Јβ), 112.6, 112.7 (C-4), 127.5,
128.1, 128.7, 128.9, 129.0, 129.4 (CH-Ph), 135.4, 135.6 (CIV-Ph),
H, H-4Ј), 5.98 (d, 1 H, H-1Ј), 7.56 (s, 1 H, H-5), 11.59 (br. s, 1 H, 187.6, 188.3 (C=S) ppm. HRMS: calcd. for C14H18NO6S
NH) ppm. 13C NMR (100 MHz, [d6]acetone): δ = 27.6, 28.0
(Me2C), 75.1 (C-4Ј), 77.4 (C-3Ј), 86.8 (C-2Ј), 106.4 (C-1Ј), 113.3
(Me2C), 128.4 (C-4), 136.4 (C-5), 180.9 (C=S) ppm. HRMS: calcd.
for C10H14NO5S [M + H]+ 260.0593; found 260.0600.
[M + H]+ 328.0855; found 328.0845.
(6R,7R,8R)-7-Benzyloxy-5,6,8-trihydroxy-2,3,5,6,7,8-hexahydro-
3-thioxo-2-oxaindolizine (18): A solution of OXT 10 (101.0 mg,
0.29 mmol) in CH2Cl2/TFA/H2O (2:2:1, 10 mL) was stirred at room
temperature for 3 h. The solvent was removed under reduced pres-
sure and the residue was co-evaporated several times with water
and, after concentration under vacuum, purified by column
chromatography (PE/EtOAc, 1:1) to afford the anomeric mixture
18 (79.8 mg, 89%; α/β: 8:2) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 3.67 (br. s, OH), 3.82 (dd, J6β–7β = 4.0, J7β–8β = 1.5 Hz,
7-Hβ), 3.98 (dd, J6α–7α = 3.9, J7α–8α = 1.6 Hz, 7-Hα), 4.06 (br. s,
OH), 4.18–4.23 (m, 6-Hα 6-Hβ), 4.73 and 4.80 (2ϫ d, AB system,
Jgem = 11.3 Hz, 2 H, OCH2Ph), 4.84 (br. s, H-8α, H-8β), 5.47 (br.
1,2-O-Isopropylidene-α-D-ribo-hexofuranos-5-ulose (14): Triol 12
(178.4 mg, 0.81 mmol) was dissolved in anhydrous MeOH (10 mL)
and dibutyltin oxide (403.3 mg, 1.62 mmol) was added. After heat-
ing to reflux and stirring for 2 h, the solvent was evaporated and
the residue was dried under vacuum for 30 min. The residue was
taken up in anhydrous CH2Cl2 (10 mL) and Br2 (42 μL, 0.82 mmol)
was added. The resulting solution was stirred for 20 min, then the
solvent was evaporated and the residue was purified by column
chromatography (PE/EtOAc, 2:8) to afford 14 (139.6 mg, 79%) as
a colourless oil. [α]D = +63 (c = 1.2, CHCl , 25 °C). IR (NaCl): ν s, OH), 5.54 (br. t, J5β–6β = 4.3 Hz, H-5β), 5.69 (d, J1α–8aα = 3.5 Hz,
˜
3
= 1730 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.36 and
H-5α), 5.99 (d, J5β–OH = 4.5 Hz, OH), 7.30–7.36 (m, Ph, H-1α, H-
1.58 (2ϫ s, 6 H, Me2C), 4.09–4.15 (m, 3 H, H-3, H-6a, H-6b), 4.39 1β) ppm. 13C NMR (100 MHz, CDCl3): δ = 61.6 (C-8α), 61.9 (C-
(d, J3–4 = 9.2 Hz, 1 H, H-4), 4.50 (br. s, 2 H, OH), 4.65 (br. t, J2–
8β), 68.9 (C-6β), 71.8 (C-6α), 72.9 (OCH2Ph-α), 73.5 (OCH2Ph-β),
74.0 (C-7α), 75.5 (C-7β), 78.1 (C-5β), 80.7 (C-5α), 128.3, 128.4,
= 4.1 Hz, 1 H, H-2), 5.89 (d, J1–2 = 3.8 Hz, 1 H, H-1) ppm. 13C
3
NMR (100 MHz, CDCl3): δ = 26.4, 26.5 (Me2C), 66.1 (C-6), 73.8 128.6, 128.7, 128.9, 129.0, 129.6 (CH-Ph), 134.4 (CIV-Ph, C-1α),
(C-3), 78.8 (C-2), 81.8 (C-4), 104.2 (C-1), 113.4 (Me2C), 207.8
(C=O) ppm. HRMS: calcd. for C9H14O6Na [M + Na]+ 241.0688;
found 241.0676.
134.6 (C-1β), 136.6 (C-8aβ), 136.9 (C-8aα), 178.1, 178.2
(C=S) ppm. HRMS: calcd. for C14H15NO5SNa [M + Na]+
332.0569; found 332.0586.
4-[(4R)-1,2-O-Isopropylidene-α-
oline-2-thione (16): The ulose 14 (151.0 mg, 0.69 mmol) and KSCN
D
-erythrofuranos-4-C-yl]-1,3-oxaz-
(6R,7S,8R)-5,6,7,8-Tetrahydroxy-2,3,5,6,7,8-hexahydro-3-thioxo-
2-oxaindolizine (19): A solution of the oxazole-2(3H)-thione 15
(100.6 mg, 1.04 mmol) were dissolved in THF/DMF (1:1, 15 mL). (101.0 mg, 0.39 mmol) in CH2Cl2/TFA/H2O (2:2:1, 10 mL) was
7948
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 7941–7951

N-Thiocarbonyl Iminosugars
stirred at room temperature for 3 h. The solvent was removed under
reduced pressure and the residue was co-evaporated several times
with water and, after concentration under vacuum, purified by col-
umn chromatography (EtOAc) to afford the anomeric mixture 19
(74.4 mg, 87%; α/β: 57:43) as a colourless oil. 1H NMR (400 MHz,
benzyl-α-d-glucofuranose (22;[46] 408 mg, 1.32 mmol, 1.0 equiv.) in
anhydrous CH2Cl2 (12 mL) at –10 °C. The reaction mixture was
allowed to reach room temperature and stirred for 2 h (TLC moni-
toring). After solvent removal under reduced pressure, the residue
was purified by column chromatography (1:5Ǟ1:2.5 EtOAc/PE) to
[d6]acetone): δ = 3.64–3.74 (m, 6-Hα, 7-Hβ), 3.88–3.93 (m, 7-Hα, afford the OZT 23 (417 mg, 90%) as a white foam. [α]D = –88 (c
6-Hβ), 4.28 (d, J6α–OH = 6.8 Hz, OH), 4.43–4.47 (m, 8-Hα, OH),
= 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.35 and 1.52 (2ϫ
4.58–4.62 (m, 8-Hβ), 4.87 (d, J7β–OH = 4.7 Hz, OH), 4.92–5.00 (m, s, 6 H, Me2C), 4.03 (d, J3,4 = 3.5 Hz, 1 H, H-3Ј), 4.23–4.30 (m, 2
OH), 5.41 (t, J5β–6β = 4.8 Hz, 5-Hβ), 5.67 (t, J5α–6α = 3.8 Hz, 5-
Hα), 5.86 (d, J5β–OH = 4.8 Hz, OH), 6.04 (d, J5α–OH = 3.8 Hz, OH),
H, H-4Ј, H-4), 4.49 and 4.76 (2ϫ d, AB system, Jgem = 12.0 Hz, 2
H, OCH2Ph), 4.69 (d, 1 H, H-2Ј), 4.69–4.72 (m, 2 H, H-5), 5.95
7.39 (d, J1α–8aα = 1.8 Hz, 1-Hα), 7.43 (d, J1β–8aβ = 1.7 Hz, 1- (d, J1,2 = 3.5 Hz, 1 H, H-1Ј), 7.30–7.50 (m, 5 H, Ph) ppm. 13C
Hβ) ppm. 13C NMR (100 MHz, [d6]acetone): δ = 66.6 (C-8β), 67.8
(C-8α), 71.2 (C-7α), 71.8 (C-7β), 74.5, 75.3 (C-6), 79.5 (C-5α), 83.9
(C-5β), 131.7, 131.8 (C-8a), 133.6 (C-1β), 133.7 (C-1α), 179.6
(C=S) ppm. HRMS: calcd. for C7H10NO5S [M + H]+ 220.0280;
found 220.0271.
NMR (125.7 MHz, CDCl3): δ = 26.3, 26.8 (Me2C), 55.2 (C-4), 71.7
(OCH2Ph), 72.7 (C-5), 80.1 (C-4Ј), 81.3 (C-3Ј), 81.7 (C-2Ј), 105.3
(C-1Ј), 112.3 (Me2C), 128.1, 128.4, 128.7 (CH-Ph), 137.0 (CIV-Ph),
189.6 (C=S) ppm. MS (ESI): m/z = 374.0 [M + Na]+. C17H21NO5S
(351.42): calcd. C 58.10, H 6.02, N 3.99, S 9.12; found C 58.15, H
5.93, N 3.81, S 8.94.
(6R, 7R, 8R)-5,6,7,8-Tetrahydroxy-2,3,5,6,7,8-hexahydro-3-thioxo-
2-oxaindolizine (20): A solution of OXT 16 (101.0 mg, 0.39 mmol)
in CH2Cl2/TFA/H2O (2:2:1, 10 mL) was stirred at room tempera-
ture for 3 h. The solvent was removed under reduced pressure and
the residue was co-evaporated several times with water and, after
concentration under vacuum, purified by column chromatography
(EtOAc) to afford the anomeric mixture 20 (75.2 mg, 88%; α/β:
77:23) as a colourless oil. 1H NMR (400 MHz, [d6]acetone): δ =
2.86 (br. s, OH), 3.90–3.91 (m, 6-Hβ), 3.98–3.99 (m, 6-Hα), 4.05–
4.06 (m, 7-Hα), 4.17 (br. s, 7-Hβ), 4.70–4.71 (m, 8-Hβ), 4.77 (br. s,
8-Hα), 5.50 (d, J5α–6α = 3.9 Hz, 5-Hα), 5.53 (d, J5β–6β = 4.9 Hz, 5-
Hβ), 7.41 (s, 1-Hβ), 7.47 (s, 1-Hα) ppm. 13C NMR (100 MHz,
[d6]acetone): δ = 64.9 (C-8α), 65.9 (C-8β), 68.9 (C-6β), 70.6 (C-7α),
74.3 (C-7β), 75.0 (C-6α), 80.7 (C-5β), 82.8 (C-5α), 132.9 (C-8a),
135.6 (C-1), 180.2 (C=S) ppm. HRMS: calcd. for C7H10NO5S [M
+ H]+ 220.0280; found 220.0271.
Conversion of 23 into the Hemi-Aminal 24: A solution of the OZT
23 (200 mg, 0.57 mmol) in 90% TFA/H2O (6 mL) was stirred at
room temperature for 1 h. After solvent removal under reduced
pressure, the residue was coevaporated several times with water,
treated with NaOH 0.1 n until pH 8, then concentrated under re-
duced pressure. The resulting residue was purified by column
chromatography (1:1Ǟ2:1 EtOAc/PE) to give 24 (140 mg, 79%) as
a white foam. [α]D = +20 (c = 1.0, MeOH). H NMR (500 MHz,
MeOD): δ = 3.45 (t, J8,8a = 9.5 Hz, 1 H, 8-H), 3.55 (dd, 1 H, 6-H),
3.72 (t, J6,7 = J7,8 = 9.5 Hz, 1 H, 7-H), 4.07–4.15 (m, 1 H, 8-Ha),
1
4.46 (dd, J1b,8a = 6.0 Hz, 1 H, 1-Hb), 4.70 (t, J1a,1b = J1a,8a
9.0 Hz, 1 H, 1-Ha), 4.88 and 4.93 (2 ϫ d, AB system, Jgem
=
=
11.0 Hz, 2 H, OCH2Ph), 5.81 (d, J5,6 = 3.5 Hz, 1 H, H-5), 7.25–
7.50 (m, 5 H, Ph) ppm. 13C NMR (125.7 MHz, MeOD): δ = 57.0
(C-8a), 71.1 (C-1), 71.3 (C-6), 73.5 (C-8), 75.1 (OCH2Ph), 78.8 (C-
5), 81.4 (C-7), 127.2–127.8 (CH-Ph), 138.9 (CIV-Ph), 186.6
(CS) ppm. MS (ESI): m/z = 334.0 [M + Na]+. C14H17NO5S
(311.35): calcd. C 54.01, H 5.50, N 4.50, S 10.30; found C 53.87,
H 5.29, N 4.27, S 10.08.
(2S,3S,4S,5S,1ЈE)-2-(2Ј-Methoxycarbonyl)vinyl-3-benzyloxy-4-
hydroxy-6-aza-1,8-dioxaspiro[4.4]nonane-7-thione (21): The imino-
sugar 18 (92.8 mg, 0.30 mmol) was dissolved in anhydrous THF
(10 mL). (Methoxycarbonylmethylene)triphenylphosphorane
(0.42 g,1.26 mmol) and benzoic acid (2.6 mg, 0.021 mmol) were
added and the reaction was heated to reflux and stirred for 8 h.
The solvent was removed under reduced pressure and the residue
was purified by column chromatography (PE/EtOAc, 6:4) to afford
21 (95.4 mg, 87%) as a yellow oil. [α]D = +33 (c = 0.6, CHCl3,
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra.
25 °C). IR (NaCl): ν = 3480 (OH), 3250 (NH), 3032, 2922, 2852,
˜
Acknowledgments
1715 (C=O), 1648 (C=C), 1484, 1170 (N–CS–O) cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.04 (d, J4–OH = 4.8 Hz, 1 H, OH), 3.75
(s, 3 H, OMe), 3.95 (t, J3–4 = J2–3 = 4.6 Hz, 1 H, 3-H), 4.13 (br. t,
J3–4 = 4.6 Hz, 1 H, 4-H), 4.54 (d, Jgem = 11.0 Hz, 1 H, 9-Hb), 4.58
(dt, J2–2Ј = 1.7, J2–3 = J2–1Ј = 4.6 Hz, 1 H, 2-H), 4.63 and 4.69 (2ϫ
d, AB system, Jgem = 11.5 Hz, 2 H, OCH2Ph), 4.95 (d, 1 H, H-9a),
6.10 (dd, J1Ј–2Ј = 15.6 Hz, 1 H, H-2Ј), 6.84 (dd, 1 H, H-1Ј), 7.31–
7.39 (m, 5 H, Ph), 8.58 (br. s, 1 H, NH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 52.1 (OMe), 72.8 (C-4), 73.6 (OCH2Ph), 76.9 (C-9),
79.7 (C-2), 81.1 (C-3), 98.9 (C-5), 122.4 (C-2Ј), 128.3, 128.9, 129.1
(CH-Ph), 136.3 (CIV-Ph), 143.8 (C-1Ј), 166.6 (C=O), 189.9
(C=S) ppm. HRMS: calcd. for C17H20NO6S [M + H]+ 366.1011;
found 366.1000.
The authors thank the Partenariat Hubert Curien (PHC) Franco-
Portugais (programme PESSOA), the Université d’Orléans, the
Universidade de Lisboa, the Spanish Ministerio de Economía y
Competitividad (MINECO) [contract numbers SAF2010-15670,
co-financed by the Fondos Europeos para el Desarrollo Regional
(FEDER)] and the Fundación Ramón Areces for financial sup-
port. S. S. thanks Portuguese Fundação do Ministério de Ciência
e Tecnologia (FCT) for the fellowship (SFRH/BD/16937/2004).
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Received: May 16, 2013
Published Online: October 9, 2013
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7951