2′-modified neamine analogues from thiomannosides through glycosidation-stereoinversion

Article abstract of DOI:10.1002/ejoc.201200084

Conveniently protected neamine analogues were synthesized with a free 2′-OH group for further functionalization. An approach was investigated involving a stereoselective α-glycosidation reaction of 3,4-O-dimethoxybutanediyl-2-O-silyl protected thiomannosides with a 2-deoxystreptamine derivative. Subsequent 2-O-deprotection followed by anoxidation-reduction sequence led to α-glucosides withstereoinversion at C-2′. The scope of the procedure for the syntheses of α-glucosides was explored with three distinct model acceptors. Thiomannoside coupling, 2-O-deprotection, and oxidation were straightforward, whereas the outcome of the reduction step was clearly acceptor-dependent. Copyright

Full text of DOI:10.1002/ejoc.201200084

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FULL PAPER
DOI: 10.1002/ejoc.201200084
2Ј-Modified Neamine Analogues from Thiomannosides through Glycosidation–
Stereoinversion
Daniel Gironés,[a] Marcel Hanckmann,[a] Floris P. J. T. Rutjes,[a] and Floris L. van Delft*[a]
Keywords: Carbohydrates / Oxygen heterocycles / Glycosidation / Oxidation / Reduction
Conveniently protected neamine analogues were synthe-
sized with a free 2Ј-OH group for further functionalization.
An approach was investigated involving a stereoselective α-
oxidation–reduction sequence led to α-glucosides with
stereoinversion at C-2Ј. The scope of the procedure for the
syntheses of α-glucosides was explored with three distinct
glycosidation reaction of 3,4-O-dimethoxybutanediyl-2-O- model acceptors. Thiomannoside coupling, 2-O-deprotec-
silyl protected thiomannosides with a 2-deoxystreptamine
derivative. Subsequent 2-O-deprotection followed by an
tion, and oxidation were straightforward, whereas the out-
come of the reduction step was clearly acceptor-dependent.
Introduction
Aminoglycosides form a class of compounds with strong
bactericidal activity, because of the ability to interfere with
the fidelity of mRNA translation to the appropriate pro-
tein.[1–6] Unfortunately, the clinical usefulness of aminogly-
cosides is diminished by emerging resistance of bacteria, in
particular because of aminoglycoside-modifying enzymes.[7]
In recent years, there has been a search for synthetic amino-
glycoside analogues to circumvent this resistance and other
undesired effects such as nephro- and ototoxicity.[8] How-
ever, the synthesis and functionalization of aminoglycoside
structures are synthetically challenging. The regioselective
protection of the heteroatoms followed by chemical modifi-
cation is laborious, thus thwarting the rapid preparation of
structural libraries as is usual in a medicinal chemistry set-
ting.
The structure of pseudodisaccharide neamine (1, Fig-
ure 1) is the central scaffold of most relevant aminoglycos-
ides. It consists of a 2,6-diaminoglucose ring (I) and a 2-
deoxystreptamine ring (II), linked by an α-configured
glycosidic bond. Interestingly, the aminocyclitol 2-deoxy-
streptamine (2-DOS) is universally conserved in aminogly-
coside antibiotics, thus suggesting an essential role for the
binding of aminoglycosides to ribosomal RNA. Neamine is
easily obtained from natural sources. However, the plethora
of amino and hydroxy groups impedes a facile differentia-
tion, leading to lengthy protective group manipulation stra-
tegies.
Figure 1. Structure of neamine (1).
We are particularly interested in the selective manipula-
tion of the neamine 2Ј-position. Most of the reported li-
braries of neamine analogues focus on the functionalization
of other positions in neamine,[9] mainly because of the diffi-
culty of solely exposing the 2Ј-position. Additionally, NMR
and crystallographic studies of the neomycin and paromo-
mycin families have shown the presence of an internal hy-
drogen bond that involves the 2Ј-position in the bioactive
conformation.[2,3] We reasoned that the availability of a nea-
mine intermediate with an uniquely exposed heteroatom at
the 2Ј-position would be valuable for further investigations.
We intend to construct protected neamine analogues,
ready for selective 2Ј-functionalization, by employing a con-
vergent strategy commencing with individual building
blocks. An essential element of the present study towards
such neamine analogues involves the α-stereodirected
glycosidation reaction between a thioglycoside derivative (2)
and the suitably protected 2-DOS (3, Scheme 1).
In this direction, there is no broadly applicable solution
for the stereoselective installation of a 1,2-cis-glycosidic
bond,[10,11] often leading to α/β mixtures with ratios de-
pending on the coupling conditions and carbohydrate ac-
ceptor. There are coupling methods that aim to circumvent
this problem, such as intramolecular aglycon delivery.[12,13]
Several authors have obtained good results with different
techniques. Demchenko et al. reported a promising modi-
[a] Institute for Molecules and Materials,
Radboud University Nijmegen,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
Fax: +31-24-36-53393
E-mail: f.vandelft@science.ru.nl
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200084.
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FULL PAPER
chloroformate, and the differentiation of the two vicinal di-
ols was performed by selectively introducing a cyclohexyl-
idene group at O-5 and O-6. Next, the residual sugar diol
was oxidatively cleaved to give a dialdehyde, followed by β-
elimination. In addition to carbamates, an alternative mode
of amine masking was also performed by introducing azide
as reported by Arenz et al.[33] A diazo-transfer reaction on
neamine (1) with triflyl azides generated tetraazido com-
pound 6 in good yield.[34–36] The differentiation of the two
vicinal diols was performed, as before, by introducing a cy-
clohexylidene group.[37] The oxidative cleavage of the sugar
diol, followed by β-elimination, afforded diazido 2-DOS
precursor 9 (Scheme 2). Both 8 and 9 served as useful build-
ing blocks for the generation of neamine analogues.[38]
Scheme 1. Synthesis of neamine analogues; R1 = silyl ethers, R2 =
NHCbz (Cbz = carbobenzyloxy) or N3.
fied thiocyanide method[14] and more recently used S-
benzoxazolyl glycosides,[15] both are promoters of 1,2-cis
glycosylation. Lemieux’s halide-catalyzed glycosidation
conditions,[16] with preference for α-linked dissacharide for-
mation, have been extensively applied to the syntheses of
α-glucosides.[10,11] Another promising strategy was recently
introduced by Boons et al. to control the stereoselectivity
of glycosidation reactions,[17,18] but its straightforward ap-
plication was hampered by the prerequisite of the enantio-
pure formation of a 2Ј-O-thioether. A method for the for-
mation of 1,2-cis-manno-configured carbohydrates involves
stereoinversion at C-2Ј. Such β-mannosides can be obtained
from the oxidation of 2-hydroxy-β-glucosides to 2-ketogly-
cosides intermediates followed by a stereoselective re-
duction.[19–25] Additionally, the stereoselective reduction of
α-2-ulosides to 1,2-cis-α-glycosides has been reported for
several deoxysugars.[26–29]
We utilized thiomannosides in the glycosidation step, as
the α-glycosidation reaction of mannoses is particularly fac-
ile and stereoselective. Next, we investigated the conditions
for inversion at C-2Ј, leading to the syntheses of α-config-
ured glucosides with high stereoselectivity. This paper re-
ports the successful syntheses of 2Ј-modified neamine and
other α-glucosides, preceded by the coupling of thiomanno-
sides and the inversion of the configuration at C-2Ј.
Scheme 2. Reagents and conditions: (a) 1,1-dimethoxycyclohexane,
TsOH (p-toluenesulfonic acid), DMF (dimethylformamide) or
MeCN; (b) (1) NaIO4, MeOH or THF/H2O, (2) Et3N or N-but-
ylamine, MeOH.
Thioglycoside Coupling and O-2Ј Deprotection
Crich et al.[39] reported the use of a Ley’s bis(acetal)-type
protecting group[40–43] on thiomannoside donors. The 3,4-
O-dimethoxybutanediyl (DMB) protection was found to
have excellent features for the promotion of α-stereoselec-
tive couplings.[44] In addition, it allowed the straightforward
differentiation between the 2- and 6-OH positions.[45] Thus,
thiomannoside 10 was readily obtained from phenyl-1-thio-
α-d-mannopyranoside by the preferential protection with a
DMB moiety on the trans-vicinal alcohols[44] and the con-
version of the 6-OH into an azido group.[45]
The protection of the 2-OH was required for glycosid-
ation. We opted for using a silyl group with the advantage
that it can be readily and selectively removed by treatment
with a fluoride source. Thus, the treatment of 10 with tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and
Results and Discussion
2-Deoxystreptamine as a Building Block
2-Deoxystreptamine plays a central role in the bioactivity 2,6-lutidine in dichloromethane afforded compound 11 in
of most aminoglycoside antibiotics.[30] The asymmetrical 93% yield (Scheme 3). Glycosidation was performed with
functionalization of 2-DOS can be obtained by the selective 2-DOS derivative 8 as the acceptor. The activation of the
hydrolysis of neomycin to afford neamine[31] (1), followed thioglycoside was generated by using the system of 1-(phen-
by the sequential protection and hydrolysis of the glycosidic ylsulfinyl)piperidine/triflic anhydride (PSP/Tf2O),[46–49]
bond. The procedure reported by Vourloumis et al. was ap- which formed a potent metal-free thiophile. The reaction
plied to generate the conveniently protected 2-DOS deriva- was quenched with triethyl phosphite,[50,51] improving the
tive 8 (Scheme 2).[32] First, the amino groups of neamine (1) yield and facilitating purification. The glycosidation gave 13
were protected by Cbz groups upon treatment with benzyl in good yield and complete α-stereoselectivity (Scheme 3).
2
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2Ј-Modified Neamine Analogues from Thiomannosides
49:1 gluco/manno ratio. Purification by silica gel column
chromatography afforded the desired α-d-glucoside 20 in
81% yield.[52,53]
Scheme 3. Reagents and conditions: (a) TBSOTf, 2,6-lutidine,
CH2Cl2, r.t.; (b) HMDS (hexamethyldisilazane), cat. TMSCl (tri-
methylsilyl chloride) CH3CN; (c) 8, PSP, Tf2O, TTBP (2,4,6-tri-
tert-butylpyrimidine), 4 Å MS (molecular sieves), CH2Cl2, –60 °C;
(d) 9, PSP, Tf2O, TTBP, 4 Å MS, CH2Cl2, –60 °C; (e) TBAF (tetra-
n-butylammonium fluoride), THF (tetrahydrofuran), r.t.
Scheme 4. Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, r.t.; (b) reduction for 18: l-selectride, THF, r.t.; reduction
for 19: NaBH4, MeOH, r.t.
The next step was the removal of the silyl group with the
When l-selectride was applied to 19, bearing azides in-
aim to expose the 2Ј-OH functionality uniquely. However, stead of benzyloxy carbamates on the 2-DOS moiety, the
the TBS protection proved to be invulnerable under the in- crude gluco/manno ratio dropped to 8:5. In search for an
fluence of TBAF. An alternative treatment with HF/pyr- improvement in the stereoselectivity, lithium tri-tert-butoxy-
idine led to slow degradation of 13. The unexpected sta- aluminiumhydride and sodium borohydride were also
bility of the TBS group prompted us to attempt the cou- tested, giving crude gluco/manno ratios of 10:6 and 13:5,
pling and deprotection sequence with a more labile silyl respectively. Sodium borohydride gave the best result with
ether. Thus, thiomannoside 10 was treated with hexamethyl- preference for the desired stereoisomer, and α-d-glucoside
disilazane and a catalytic amount of trimethylsilyl chloride 21 was isolated in 61% yield, along with recovery of 19 in
in acetonitrile to give, after filtration and evaporation, tri- 20% yield.[52,53]
methylsilyl (TMS) protected 12 in excellent yield and purity.
Under the influence of PSP/Tf2O activation, 12 and 8
Deprotection of 15 and 20
were coupled without affecting the TMS group. The reac-
tion afforded only α-isomer 14. Moreover, TMS deprotec-
tion with TBAF proceeded rapidly and smoothly to obtain
the pseudodisaccharide 16 with a free 2Ј-OH group in 91%
yield. Finally, TMS-protected thiomannoside 12 was glyco-
sidated with the diazido 2-DOS derivative 9, and 15 was
obtained after purification in 71% yield, along with a small
inseparable fraction (2% yield) of the α/β mixture (ratio
4:5). As expected in this case, treatment of 15 with TBAF
in THF removed the TMS group uneventfully to afford 17
in quantitative yield (Scheme 3).
We considered it important to prove that the removal of
the protecting groups employed in the synthesis was pos-
sible, therefore compounds 15 and 20 were subjected to de-
protection conditions. Additionally, 15 would generate an
interesting new neamine analogue, displaying a manno-con-
figuration on the sugar ring. Compound 15 was subjected
to a 9:1 mixture of TFA (trifluoroacetic acid)/H2O for
4 min, leading to the hydrolysis of the DMB, cyclohexylid-
ene acetal, and TMS groups in a single step to afford 22 in
good yield.[54] The reaction time was found to be critical,
as longer exposure led to hydrolysis of the glycosidic bond.
The azide reduction of 22 was successfully performed by a
Staudinger reaction with trimethylphosphane. Chromatog-
raphy on silica gel followed by ion-exchange chromato-
Inversion of Configuration at C-2Ј
After the successful syntheses of free 2Ј-OH α-mannos- graphic purification gave the new neamine analogue 23 con-
ides 16 and 17, we envisaged their application as intermedi- taining a 6-deoxy-6-aminomannose ring. After treatment
ates towards free 2Ј-OH α-glucosides. An epimerization at with acetic acid, the product was isolated as a triammonium
C-2Ј was conducted by an oxidation–reduction sequence. acetate salt (Scheme 5).
Compound 16 was exposed to Dess–Martin periodinane
The removal of the protecting groups of 20 was per-
leading to the rapid and complete oxidation at C-2Ј. The formed in three steps without intermediate purification.
resulting crude 2-ulose 18, isolated in acceptable purity Under acidic conditions as aforementioned, the hydrolysis
(Ͼ90%) as indicated by NMR analysis, was subjected to of the acetals was followed by the reduction of the 6Ј-azido
reduction without purification as a consequence of its in- group in the crude intermediate under Staudinger condi-
herent instability. Reduction under the action of l-selectride tions. The remaining benzyloxycarbonyl groups were hydro-
proceeded with excellent stereoselectivity (Scheme 4), and genolyzed, and again, performing chromatography on silica
1
the analysis of the crude product by H NMR revealed a gel followed by ion-exchange purification afforded 2Ј-de-
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Table 1. Results for coupling reaction of 11 and 12 and 2Ј-O-depro-
tection.
Scheme 5. Reagents and conditions: (a) TFA/H2O (9:1, v/v), r.t.;
(b) (1) P(CH3)3, THF/H2O/1 m NaOH (10:1:0.1, v/v/v), (2) AcOH.
amino-2Ј-hydroxyneamine 24 (Scheme 6). Although synthe-
sized in a different manner, the same neamine analogue had
been reported earlier by Wong et al.[55]
1
[a] Based on crude H NMR spectroscopy. [b] Isolated yield.
duced only the basic hydrolysis of the benzyl ester, instead
of the removal of the silyl ether. The addition of acetic acid
to reduce the basicity of TBAF avoided the undesired carb-
amate hydrolysis, but the silyl ether remained unaffected.
To circumvent this problematic, TMS-protected thioman-
noside 12 was employed. N-Cbz-l-serine benzyl ester was
coupled to 12, and removal of the TMS group from 28 oc-
curred smoothly with TBAF in THF to afford 31 in near
quantitative yield (Table 1, Entry 4).
Scheme 6. Reagents and conditions: (a) (1) TFA/H2O (9:1, v/v), r.t.,
(2) P(CH3)3, THF/H2O/1 m NaOH (10:1:0.1, v/v/v), (3) cat. Pd/C,
H2 (1 atm), MeOH/AcOH (1:1, v/v).
Scope of the Coupling–Epimerization Methodology
Finally, the oxidation–reduction protocol was applied to
the manno-configured glycosides 29–31. In all cases, Dess–
Martin periodinane oxidation worked uneventfully, and the
crude 2-ulose intermediates 32–34 were subjected to re-
duction without purification. The reduction conditions
were explored by using 1–2 equiv. of reducing agent (see
Scheme 8 and Table 2). The stereoselectivity results were
The previous positive results led us to investigate the va-
lidity of the coupling–epimerization sequence with other
substrates. Three model acceptors were selected and cou-
pled to either 11 or 12 under PSP/Tf2O conditions (see
Scheme 7 and Table 1).
1
based on H NMR analyses of the stereogenic C-2 center
in the crude products.[52,53]
Scheme 7. (a) RЈOH (see Table 1), PSP, Tf2O, TTBP, 4 Å MS,
CH2Cl2, –60 °C; (b) TBAF, THF, r.t.
Diisopropylidene-d-glucose was glycosylated with
thiomannoside 11 to afford 25 in 93% yield and complete
α stereoselectivity. Here, the TBS protecting group was
cleanly removed upon treatment with 1.1 equiv. of TBAF,
leading to 29 in high yield (Table 1, Entry 1).
Scheme 8. Reagents and conditions: (a) Dess–Martin periodinane,
CH2Cl2, r.t.; (b) reduction (see Table 2).
The reduction of intermediate 32 under the action of
bulky l-selectride proceeded with complete stereoselectivity.
Glycosylation of diisopropylidene-d-galactopyranose No trace of mannoside could be detected, and α-d-glucos-
with 11 afforded 85% of disaccharide 26 as a 41:1 ratio of ide 35 was isolated in 84% yield (Table 2, Entry 1). For 33,
the α/β mixture. By employing silica chromatography, com- the application of the bulky reducing agent lithium tri-tert-
pound 26 was partially separated from its β isomer in 69% butoxyaluminiumhydride gave better stereoselective results
yield. Treatment with TBAF liberated the 2Ј-OH group to than those obtained by using l-selectride (Table 2, Entry 6).
afford 30 (Table 1, Entry 2).
Finally, the treatment of the crude l-serine α-d-arabino-
Glycosylation of N-Cbz-l-serine benzyl ester with 11 hexosidulose 34 with hydride sources led to degradation of
gave solely the α-coupled product 27 in good yield (Table 1, the substrate. The milder borane–dimethyl sulfide complex
Entry 3). However, subsequent treatment with TBAF in- induced a completely stereoselective reduction, but instead
4
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2Ј-Modified Neamine Analogues from Thiomannosides
Table 2. Reaction conditions and results for reduction of 32–34.[a]
1
[a] All reactions were performed at room temperature. [b] Crude H NMR analysis. [c] Isolated yield for the best ratio.
of affording the desired gluco-configured alcohol 37, the
manno-configured 31 was isolated as the sole product
(Table 2, Entry 10).
Experimental Section
General Methods and Materials: The solvents were distilled from
the appropriate drying agents prior to use and stored under nitro-
gen. The reactions were carried out under an inert atmosphere of
dry nitrogen or argon. Standard syringe techniques were applied
for the transfer of dry solvents and air- or moisture-sensitive rea-
gents. The Rf values were obtained by using thin layer chromatog-
raphy (TLC) on silica gel-coated plates (Merck 60 F254) with the
Conclusions
The enantiopure and asymmetrically protected 2-DOS
derivatives were obtained in a few straightforward steps indicated solvent mixture. The compounds were detected by UV
light, ammonium molybdate solution, potassium permanganate,
ninhydrin, or anisaldehyde/H2SO4. The melting points were mea-
sured with a Büchi melting point B-545. The IR spectra were re-
corded with an ATI Mattson Genesis Series FTIR or a Bruker
Tensor 27 FTIR spectrometer. The NMR spectroscopic data were
recorded with Bruker DMX 300 (300 MHz) and Varian 400
(400 MHz) spectrometers, using CDCl3 or D2O solutions (unless
otherwise reported). The chemical shifts are given in ppm with re-
spect to tetramethylsilane (TMS) or HDO (δ = 4.79 ppm)[56] as the
internal standard. The coupling constants are reported as J values
from readily available neamine (1). The resulting 2-DOS
precursors served as versatile scaffolds for new neamine-
type aminoglycosides.
Acetal-protected thiomannoside donors proved to be ef-
ficient in promoting the α-glycosidation reaction. The in-
stallation of a TMS protecting group at the 2-O-position
gave access to free 2Ј-OH neamine analogues 16 and 17 by
straightforward deprotection. The epimerization at C-2Ј
was performed by an oxidation–reduction method. A Dess–
Martin oxidation followed by reduction with a hydride in Hz. The peak assignments in the 13C NMR spectra were made
on the basis of 2D gHSQC (gradient heteronuclear single quantum
correlation) and gHMBC (gradient heteronuclear multiple-bond
correlation) spectra. Column or flash chromatography was carried
out using ACROS silica gel (0.035–0.070 mm, and ca. 6 nm pore
diameter). Ion-exchange column chromatography was carried out
source successfully yielded α-glucosides 20 and 21. These
compounds may find suitable application in the syntheses
of new 2Ј-modified neamine analogues by further function-
alization at the free 2Ј-OH group.
The scope of the coupling–stereoinversion sequence was
studied with three model acceptors, leading to glycosidation
with excellent stereoselectivity in all cases. However, the re-
duction step required optimization for each individual sub-
strate. Nevertheless, with one exception, all of the α-manno-
+
using Amberlite CG-50 resin in the NH4 form. The optical rota-
tions were determined with a Perkin–Elmer 241 polarimeter. The
high resolution mass spectra were recorded with a JEOL AccuTOF
(ESI) or a MAT900 (EI, CI, and ESI). The elemental analyses were
carried out with a Carlo Erba Instruments CHNS-O EA 1108 ele-
sides were efficiently converted into the corresponding α- ment analyser.
glucosides in 49–84% yield.
General Procedure for Glycosidation of Thiomannosides: The thio-
The presented methodology may find suitable applica-
tion in the target-oriented synthesis of α-glucosides, specifi-
cally when the presence of a free 2Ј-OH group is desired.
For example, it would be of interest to generate 2Ј-O-alkyl-
ated or 2Ј-O-functionalised neamine-type derivatives in
search for enhanced antibacterial activity.
mannoside donor of choice and PSP (1.2 equiv.) were added to a
flask, and the mixture was coevaporated with dry toluene (3ϫ).
The mixed reagents were redissolved in dry CH2Cl2 under an argon
atmosphere. TTBP (2.0–2.5 equiv.), which was previously dried in
a desiccator, and activated powdered MS (4 Å) were added. The
reaction mixture was cooled to –60 °C, and Tf2O (1.2 equiv.) was
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added slowly. After 15 min, a solution of the glycosyl acceptor of
choice (1.2–1.3 equiv.) in dry CH2Cl2 was slowly added. The reac-
tion mixture was stirred for 20 min at –60 °C, then slowly warmed
to –20 °C, and quenched with P(OEt)3 (1.1–1.2 equiv.). The mix-
ture was warmed to room temperature and filtered. The filtrate was
washed with saturated NaHCO3 and then brine, dried with MgSO4,
and concentrated under reduced pressure. Purification was per-
formed by silica gel chromatography to afford the desired product.
20 min, the reaction was slowly warmed to –20 °C and quenched
with P(OEt)3 (118.3 μL, 0.690 mmol, 1.2 equiv.). Purification was
performed by silica gel chromatography using a mixture of EtOAc/
heptane with Et3N (1%) to afford 13 (426 mg, 0.460 mmol, 80%)
as a white powder, m.p. 140–142 °C. Rf = 0.26 (EtOAc/heptane,
1
2:5). [α]2D0 = +84.0 (c = 1, CH2Cl2). H NMR (400 MHz, CDCl3):
δ = 7.38–7.29 (m, 10 H), 5.21 (d, J = 11.9 Hz, 1 H), 5.13–5.05 (m,
4 H), 4.85 (br. s, 1 H), 4.79 (d, J = 8.0 Hz, 1 H), 3.98–3.90 (m, 3
H), 3.83–3.74 (m, 4 H), 3.54–3.51 (m, 2 H), 3.39–3.27 (m, 5 H),
3.18 (s, 3 H), 2.55–2.52 (m, 1 H), 1.69–1.43 (m, 9), 1.33–1.30 (m, 2
H), 1.24 (s, 3 H), 1.18 (s, 3 H), 0.90 (s, 9 H), 0.11 (3 H), 0.07 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.44, 155.30, 136.17,
135.99, 128.31, 128.22, 128.18, 127.95, 127.85, 112.75, 100.31,
99.46, 99.34, 80.54, 78.35, 77.20, 70.94, 70.37, 67.56, 67.09, 66.93,
63.76, 51.11, 50.98, 49.62, 47.89, 47.61, 36.64, 36.32, 35.99, 25.83,
25.04, 23.83, 23.66, 18.40, 17.96, 17.87, –4.57, –4.87 ppm. IR
Phenyl
6-Azido-2-O-(tert-butyldimethylsilyl)-6-deoxy-3,4-O-
-mannopyranoside
[(2S,3S)-2,3-dimethoxybutane-2,3-diyl]-1-thio-α-
D
(11): To a solution of thiomannoside 10 (50 mg, 0.122 mmol) and
2,6-lutidine (39 μL, 0.336 mmol, 3.0 equiv.) in dry CH2Cl2 (5 mL)
was added tert-butyldimethylsilyl triflate (TBSOTf, 42 μL,
0.183 mmol, 1.5 equiv.). After 2 h, the TLC showed that starting
material remained, and extra 2,6-lutidine (3.0 equiv.) and TBSOTf
(1.5 equiv.) were added. After 10 h, the reaction was quenched with
MeOH, and the solvents were evaporated under reduced pressure.
Purification by silica gel chromatography afforded 11 (60 mg,
0.114 mmol, 93%) as a thick oil that solidified slowly to give an
amorphous solid. Rf = 0.5 (EtOAc/heptane, 1:9). [α]2D0 = +177.7 (c
(neat): ν = 3300, 2096, 1691, 1126, 1038 cm–1. HRMS (ESI): calcd.
˜
for C46H67N5O13SiNa [M + Na]+ 948.4402; found 948.4429.
4-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-2-O-(trimethylsilyl)-α-D-mannopyranosyl}-1,3-bis[N-(benzyl-
1
oxycarbonyl)]-5,6-O-cyclohexylidene-2-deoxystreptamine (14): The
general procedure for glycosidation was applied to thiomannoside
12 (600 mg, 1.241 mmol) and PSP (311.7 mg, 1.489 mmol,
1.2 equiv.) in dry CH2Cl2 (25 mL). TTBP (771 mg, 3.102 mmol,
2.5 equiv.) and activated powdered MS (4 Å, 350 mg) were added
at room temperature, followed by Tf2O (250.5 μL, 1.489 mmol,
1.2 equiv.) at –60 °C. Then, 2-DOS 8[57] (823.7 mg, 1.613 mmol,
1.3 equiv.) in dry CH2Cl2 (20 mL) was added. After 20 min, the
reaction was slowly warmed to –20 °C and quenched with P(OEt)
3 (255.3 μL, 1.489 mmol, 1.2 equiv.). Purification was performed by
silica gel chromatography using a mixture of EtOAc/heptane with
Et3N (1%) to afford 14 (826 mg, 0.934 mmol, 75%) as a white pow-
der, m.p. 89–90 °C. Rf = 0.24 (EtOAc/heptane, 1:3). [α]2D0 = +79.3
= 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.49–7.46 (m, 2
H), 7.34–7.24 (m, 3 H), 5.33 (d, J = 0.98 Hz, 1 H), 4.34–4.29 (m,
1 H), 4.15–4.10 (m, 2 H), 3.87 (dd, J = 9.9 Hz, J = 2.6 Hz, 1 H),
3.53 (dd, J = 13.2 Hz, J = 2.3 Hz, 1 H), 3.37 (dd, J = 13.2 Hz, J
= 5.9 Hz, 1 H), 3.29 (s, 3 H), 3.21 (s, 3 H), 1.28 (s, 3 H), 1.27 (s, 3
H), 0.91 (s, 9 H), 0.13 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 133.98, 131.24, 128.87, 127.19, 99.77, 99.45,
89.73, 71.92, 71.37, 68.56, 63.91, 50.65, 48.00, 47.70, 25.82, 18.38,
17.92, 17.77, –4.49, –4.65 ppm. IR (neat): ν = 2828, 2094, 1143,
˜
1052 cm–1. HRMS (ESI): calcd. for C24H39N3O6SSiNa [M + Na]+
548.2227; found 548.2276.
Phenyl 6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-2-O-(trimethylsilyl)-1-thio-α-D-mannopyranoside (12): To a
solution of thiomannoside 10 (1.8 g, 4.374 mmol) in acetonitrile
(90 mL) were added MS (4 Å, 1 g), HMDS (4.53 mL, 21.87 mmol,
1
(c = 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.36–7.29 (m,
10 H), 5.21 (d, J = 11.9 Hz, 1 H), 5.14–5.04 (m, 4 H), 4.94 (br. s,
1 H), 4.88 (d, J = 8.4 Hz, 1 H), 3.97–3.70 (m, 7 H), 3.55–3.47 (m,
2 H), 3.41–3.36 (m, 2 H), 3.30 (s, 3 H), 3.18 (s, 3 H), 2.54–2.52 (m,
1 H), 1.68–1.50 (m, 8 H), 1.48–1.44 (m, 1 H), 1.38–1.27 (m, 2 H),
1.26 (s, 3 H), 1.19 (s, 3 H), 0.15 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.63, 155.46, 136.35, 136.14, 128.44, 128.35, 128.23,
128.09, 127.94, 112.85, 100.65, 99.66, 99.52, 80.68, 78.47, 77.40,
71.03, 70.45, 67.64, 67.20, 67.07, 64.17, 51.21, 51.16, 49.71, 48.01,
47.83, 36.76, 36.46, 36.18, 25.18, 24.10, 23.89, 18.12, 18.03,
5.0 equiv.), and
a
catalytic amount of TMSCl (55.5 μL,
0.437 mmol, 0.1 equiv.). After 24 h, the reaction mixture was fil-
tered through diatomaceous earth, and the solvent was evaporated
under reduced pressure to afford analytically pure 12 (2.10 g,
4.350 mmol, 99%) as a white powder, m.p. 103–104 °C. Rf = 0.36
(EtOAc/heptane, 1:12). [α]2D0 = +191.6 (c = 0.5, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.51–7.49 (m, 2 H), 7.34–7.24 (m, 3 H),
5.39 (s, 1 H), 4.36–4.31 (m, 1 H), 4.17–4.15 (m, 1 H), 4.00 (t, J =
10.0 Hz, 1 H), 3.86 (dd, J = 10.0 Hz, J = 2.7 Hz, 1 H), 3.52–3.43
(m, 2 H), 3.29 (s, 3 H), 3.22 (s, 3 H), 1.30 (s, 3 H), 1.28 (s, 3 H),
0.16 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 134.39, 131.42,
129.22, 127.51, 100.23, 99.85, 90.25, 72.45, 71.72, 69.01, 64.62,
0.63 ppm. IR (neat): ν = 3309, 2099, 1694, 1127, 1039 cm–1. HRMS
˜
(FAB): calcd. for C43H62N5O13Si [M + H]+ 884.4113; found
884.4122.
4-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-2-O-(trimethylsilyl)-α-D-mannopyranosyl}-1,3-diazido-1,3-dide-
51.10, 48.39, 48.14, 18.31, 18.18, 1.06 ppm. IR (neat): ν = 2828,
˜
amino-5,6-O-cyclohexylidene-2-deoxystreptamine (15): The general
procedure for glycosidation was applied to thiomannoside 12
(82 mg, 0.170 mmol) and PSP (42.7 mg, 0.204 mmol, 1.2 equiv.) in
dry CH2Cl2 (3 mL). TTBP (106 mg, 0.425 mmol, 2.5 equiv.) and
activated powdered MS (4 Å, 70 mg) were added at room tempera-
ture, followed by Tf2O (34.3 μL, 0.204 mmol, 1.2 equiv.) at –60 °C.
Then, 2-DOS 9[58] (60 mg, 0.204 mmol, 1.2 equiv.) in dry CH2Cl2
(2 mL) was added. After 20 min, the reaction was slowly warmed to
–20 °C and quenched with P(OEt)3 (35 μL, 0.204 mmol, 1.2 equiv.).
Purification was performed by silica gel chromatography using a
mixture of EtOAc/heptane with Et3N (1 %) to afford α-coupled
product 15 (80 mg, 0.120 mmol, 71%) as a white solid and an in-
separable fraction of the α/β mixture in a 4:5 ratio (2 mg,
2098, 1138, 1124, 864, 845 cm–1. HRMS (ESI): calcd. for
C21H33N3O6SSiNa [M
+
Na]+ 506.1757; found 506.1780.
C21H33N3O6SSi (483.65): calcd. C 52.15, H 6.88, N 8.69; found C
52.17, H 6.87, N 8.49.
4-O-{6-Azido-2-O-(tert-butyldimethylsilyl)-6-deoxy-3,4-O-
[(2S,3S)-2,3-dimethoxybutane-2,3-diyl]-α-D-mannopyranosyl}-1,3-
bis[N-(benzyloxycarbonyl)]-5,6-O-cyclohexylidene-2-deoxystrept-
amine (13): The general procedure for glycosidation was applied to
thiomannoside 11 (302 mg, 0.575 mmol) and PSP (144.4 mg,
0.690 mmol, 1.2 equiv.) in dry CH2Cl2 (15 mL). TTBP (286 mg,
1.150 mmol, 2.0 equiv.) and activated powdered MS (4 Å, 150 mg)
were added at room temperature, followed by Tf2O (116.6 μL,
0.690 mmol, 1.2 equiv.) at –60 °C. Then, 2-DOS 8[57] (382 mg, 0.003 mmol, 2%). Analytical data are given for α-coupled product
0.748 mmol, 1.3 equiv.) in dry CH2Cl2 (9 mL) was added. After
15. M.p. 144–146 °C; Rf = 0.24 (EtOAc/heptane, 1:12). [α]2D0
=
6
www.eurjoc.org
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20084
/KAP1
Date: 16-07-12 10:07:36
Pages: 12
2Ј-Modified Neamine Analogues from Thiomannosides
1
+119.2 (c = 1, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 5.19 (s,
CH2Cl2 (2ϫ), and the combined organic layers were washed with
brine, dried with anhydrous Na2SO4, and filtered. The solvent was
evaporated. To the crude intermediate dissolved in THF (25 mL)
1 H), 4.10–4.05 (m, 1 H), 3.97–3.91 (m, 2 H), 3.88–3.79 (m, 2 H),
3.64–3.58 (m, 1 H), 3.50–3.36 (m, 5 H), 3.21 (s, 3 H), 3.20 (s, 3 H),
2.32 (dt, J = 13.7 Hz, J = 5.0 Hz, 1 H), 1.68–1.46 (m, 11 H), 1.26 was added L-selectride (1 m in THF, 1.478 mL, 2.0 equiv.). After
(s, 3 H), 1.25 (s, 3 H), 0.15 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 113.65, 100.81, 99.82, 99.65, 79.85, 79.36, 76.84, 71.52,
70.49, 67.62, 63.92, 60.75, 57.55, 50.78, 47.93, 47.77, 36.40, 36.19,
10 h, H2O (20 mL) was added, and the reaction was neutralized
with AcOH (127 μL, 2.217 mmol, 3.0 equiv.). The THF was evapo-
rated, and the H2O layer was extracted with CH2Cl2. The combined
organic extracts were washed with brine, dried with MgSO4, and
filtered. The solvent was evaporated. The crude product was puri-
fied by silica gel chromatography to afford a small quantity of
manno-configured 16 (10 mg, 0.012 mmol, 1.6%) and 20 (488 mg,
0.601 mmol, 81%) as a white powder, m.p. 109–110 °C. Rf = 0.39
(EtOAc/heptane, 3:2). [α]2D0 = +108.2 (c = 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.33–7.28 (m, 10 H), 5.21 (br. s, 1 H), 5.18–
5.06 (m, 6 H), 3.96–3.92 (m, 1 H), 3.87–3.89 (m, 5 H), 3.59–3.40
(m, 4 H), 3.31 (s, 3 H), 3.28–3.25 (m, 1 H), 3.23 (s, 3 H), 2.51 (br.
s, 2 H), 1.68–1.53 (m, 9 H), 1.48–1.36 (m, 2 H), 1.32 (s, 3 H), 1.24
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.51, 155.47,
136.07, 128.41, 128.21, 128.09, 128.07, 113.26, 99.70, 99.62, 99.16,
80.12, 79.53, 78.20, 70.00, 69.94, 69.76, 67.20, 67.05, 66.60, 51.83,
50.54, 49.59, 48.18, 48.09, 36.58, 36.27, 25.12, 24.00, 23.90, 18.11,
33.92, 24.98, 23.92, 23.71, 17.90, 17.80, 0.40 ppm. IR (neat): ν =
˜
2100, 1127, 1036 cm–1. HRMS (ESI): calcd. for C27H45N9O9SiNa
[M + Na]+ 690.3007; found 690.3002.
4-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-mannopyranosyl}-1,3-bis[N-(benzyloxycarbonyl)]-5,6-O-cy-
clohexylidene-2-deoxystreptamine (16): TBAF (1 m in THF, 333 μL,
1.1 equiv.) was added to a stirred solution of 14 (268 mg,
0.303 mmol) in THF (10 mL). The reaction mixture was stirred for
1 h, and the solvent was evaporated under reduced pressure. Purifi-
cation was performed by silica gel chromatography using a mixture
of EtOAc/heptane with Et3N (1 %) to afford 16 (225 mg,
0.277 mmol, 91%) as a white powder, m.p. 110–111 °C. Rf = 0.24
(EtOAc/heptane, 2:3). [α]2D0 = +90.5 (c = 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.36–7.30 (m, 10 H), 5.30 (s, 1 H), 5.21 (d,
J = 9.9 Hz, 1 H), 5.12–5.05 (m, 3 H), 4.96 (br. s, 1 H), 4.86 (d, J
= 8.6 Hz, 1 H), 4.00–3.90 (m, 4 H), 3.79–3.75 (m, 3 H), 3.54–3.48
(m, 2 H), 3.40–3.35 (m, 2 H), 3.31 (s, 3 H), 3.21 (s, 3 H), 2.55–2.52
(m, 1 H), 2.45 (br. s, 1 H), 1.63–1.56 (m, 8 H), 1.37–1.33 (m, 3 H),
1.30 (s, 3 H), 1.21 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
155.53, 155.48, 136.29, 136.14, 128.46, 128.39, 128.24, 128.11,
128.02, 112.95, 100.25, 99.97, 98.78, 80.56, 78.38, 77.27, 70.47,
69.77, 67.90, 67.22, 67.08, 64.14, 51.24, 51.11, 49.63, 48.23, 48.09,
17.96 ppm. IR (neat): ν = 3314, 2832, 2100, 1696, 1137, 1027 cm–1.
˜
HRMS (FAB): calcd. for C40H53N5O13Na [M + Na]+ 834.3538;
found 834.3591.
4-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-glucopyranosyl}-1,3-diazido-1,3-dideamino-5,6-O-cyclo-
hexylidene-2-deoxystreptamine (21): Dess–Martin periodinane
(37 mg, 0.088 mmol, 2.0 equiv.) was added to a stirred solution of
compound 17 (26 mg, 0.044 mmol) in CH2Cl2 (3 mL). After 10 h,
the reaction was diluted with CH2Cl2 (3 mL), and the resulting
solution was quenched with NaOH (1 m solution, 4 mL). The mix-
ture was stirred for 20 min, after which the organic layer was sepa-
rated. The water layer was extracted with CH2Cl2 (2ϫ), and the
combined organic layers were dried with MgSO4, and filtered. The
solvent was evaporated. The crude intermediate was dissolved in
MeOH (2 mL), and NaBH4 (3.3 mg, 0.088 mmol, 2.0 equiv.) was
added. After 1 h, the solvent was evaporated, and the residue was
dissolved in CH2Cl2. The resulting solution was washed with satu-
rated NH4Cl, dried with MgSO4, and filtered. The solvent was
evaporated again. The crude product was purified by silica gel
chromatography to afford some quantity of manno-configured 17
(5.3 mg, 0.009 mmol, 20%) and 21 (16 mg, 0.027 mmol, 61%) as a
colorless gum. Rf = 0.26 (EtOAc/heptane, 1:2). [α]2D0 = +168.2 (c =
36.59, 36.40, 25.25, 24.07, 23.98, 18.11, 18.09 ppm. IR (neat): ν =
˜
3413, 3313, 2098, 1697, 1134, 1115 cm–1. HRMS (FAB): calcd. for
C40H54N5O13 [M + H]+ 812.3718; found 812.3712.
4-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-mannopyranosyl}-1,3-diazido-1,3-dideamino-5,6-O-cyclo-
hexylidene-2-deoxystreptamine (17): TBAF (1 m in THF, 268 μL,
1.1 equiv.) was added to a stirred solution of 15 (163 mg,
0.244 mmol) in THF (20 mL). The reaction mixture was stirred for
2 h, and the solvent was evaporated under reduced pressure. Purifi-
cation was performed by silica gel chromatography using a mixture
of EtOAc/heptane with Et3N (1 %) to afford 17 (144 mg,
0.242 mmol, 99%) as a colorless gum. Rf = 0.24 (EtOAc/heptane,
1:3). [α]2D0 = +111.7 (c = 1, CH2Cl2). 1H NMR (400 MHz, CDCl3):
δ = 5.38 (s, 1 H), 4.10–4.06 (m, 1 H), 40.3–3.99 (m, 2 H), 3.96 (br.
s, 1 H), 3.86–3.81 (m, 1 H), 3.66–3.57 (m, 1 H), 3.53–3.37 (m, 5
H), 3.23 (s, 3 H), 3.22 (s, 3 H), 2.54 (br. s, 1 H), 2.30 (dt, J =
13.5 Hz, J = 5.0 Hz, 1 H), 1.65–1.58 (m, 8 H), 1.48 (q, J = 13.5 Hz,
1 H), 1.38–1.37 (m, 2 H), 1.30 (s, 3 H), 1.27 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 113.73, 100.35, 100.08, 98.74, 79.66,
79.42, 76.49, 70.95, 69.73, 67.82, 63.85, 60.89, 57.38, 50.71, 48.12,
48.04, 36.34, 36.20, 33.91, 25.00, 23.89, 23.75, 17.84, 17.80 ppm.
1
1, CH2Cl2). H NMR (400 MHz, CDCl3): δ = 5.36 (d, J = 3.9 Hz,
1 H), 4.13–4.08 (m, 1 H), 3.92 (t, J = 9.9 Hz, 1 H), 3.81–3.76 (m,
2 H), 3.67–3.56 (m, 3 H), 3.51–3.38 (m, 4 H), 3.27 (s, 3 H), 3.26 (s,
3 H), 2.35 (dt, J = 13.0 Hz, J = 5.0 Hz, 1 H), 1.68–1.59 (m, 8 H),
1.50 (q, J = 13.0 Hz, 1 H), 1.39–1.36 (m, 2 H), 1.33 (s, 3 H), 1.29
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 114.10, 99.89,
99.83, 98.88, 79.41, 79.24, 78.75, 70.11, 70.05, 69.86, 66.52, 61.18,
57.38, 50.45, 48.21, 48.11, 36.29, 36.27, 34.08, 24.95, 23.86, 23.79,
17.92, 17.78 ppm. IR (neat): ν = 3464, 2832, 2100, 1136, 1030 cm–1.
˜
IR (neat): ν = 3464, 2098, 1135, 1035 cm–1. HRMS (ESI): calcd.
˜
HRMS (ESI): calcd. for C24H37N9O9Na [M + Na]+ 618.2612;
found 618.2560.
for C24H37N9O9Na [M + Na]+ 618.2612; found 618.2593.
4-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
4-O-(6-Azido-6-deoxy-α-D-mannopyranosyl)-1,3-diazido-1,3-dide-
diyl]-α-
D
-glucopyranosyl}-1,3-bis[N-(benzyloxycarbonyl)]-5,6-O-
amino-2-deoxystreptamine (22): Compound 15 (100 mg,
0.150 mmol) was dissolved in TFA/H2O (9:1, v/v, 3 mL), and after
stirring for 4 min, the solvent was rapidly evaporated under reduced
pressure. Purification was performed by silica gel chromatography
using 3% of MeOH in EtOAc as the eluent. After evaporation of
the solvent, the product was coevaporated (3ϫ) with MeOH[54] to
afford 22 (53 mg, 0.132 mmol, 88%) as a colorless gum. Rf = 0.27
(MeOH/EtOAc, 3%). [α]2D0 = +71.1 (c = 0.35, MeOH). 1H NMR
cyclohexylidene-2-deoxystreptamine (20): Dess–Martin periodinane
(627 mg, 1.478 mmol, 2.0 equiv.) was added to a stirred solution of
compound 16 (600 mg, 0.739 mmol) in CH2Cl2 (20 mL). After
10 h, the reaction was diluted with CH2Cl2 (20 mL), and the re-
sulting solution was quenched with NaOH (1 m solution, 30 mL).
The mixture was vigorously stirred for 10 min, after which the or-
ganic layer was separated. The water layer was extracted with
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20084
/KAP1
Date: 16-07-12 10:07:36
Pages: 12
D. Gironés, M. Hanckmann, F. P. J. T. Rutjes, F. L. van Delft
FULL PAPER
(400 MHz, CD3OD): δ = 5.39 (d, J = 1.6 Hz, 1 H), 4.12–4.07 (m,
1 H), 3.96 (dd, J = 3.1 Hz, J = 1.8 Hz, 1 H), 3.72 (dd, J = 9.57 Hz,
J = 3.1 Hz, 1 H), 3.64 (t, J = 9.57 Hz, 1 H), 3.51–3.34 (m, 6 H),
ture, followed by Tf2O (19.2 μL, 0.104 mmol, 1.2 equiv.) at –60 °C.
Then, diisopropylidene-d-glucose[59] (32 mg, 0.123 mmol,
1.3 equiv.) in dry CH2Cl2 (1.5 mL) was added. After 20 min, the
3.27–3.23 (m, 1 H), 2.22 (dt, J = 12.5 Hz, J = 4.1 Hz, 1 H), 1.39 reaction was slowly warmed to –20 °C and quenched with
(q, J = 12.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CD3OD): δ =
P(OEt)3 (17.9 μL, 0.104 mmol, 1.1 equiv.). Purification was per-
formed by silica gel chromatography to afford 25 (60 mg,
102.47, 80.96, 77.90, 77.79, 74.17, 72.23, 72.01, 69.21, 61.89, 61.00,
52.95, 33.30 ppm. IR (neat): ν = 3361, 2102, 1039 cm–1. HRMS 0.089 mmol, 93%) as a colorless thick oil. Rf = 0.35 (EtOAc/hep-
˜
(ESI): calcd. for C12H19N9O7Na [M + Na]+ 424.1305; found
424.1299.
tane, 1:4). [α]2D0 = +103.0 (c = 1, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 5.82 (d, J = 3.7 Hz, 1 H), 4.90 (d, J = 1.6 Hz, 1 H),
4.63 (d, J = 3.5 Hz, 1 H), 4.26 (d, J = 2.7 Hz, 1 H), 4.17–4.00 (m,
5 H), 3.91–3.87 (m, 2 H), 3.79 (dd, J = 10.0 Hz, J = 2.7 Hz, 1 H),
3.60 (dd, J = 13.1 Hz, J = 2.1 Hz, 1 H), 3.52 (dd, J = 13.1 Hz, J
= 6.1 Hz, 1 H), 3.25 (s, 3 H), 3.20 (s, 3 H), 1.49 (s, 3 H), 1.40 (s, 3
H), 1.30 (s, 6 H), 1.27 (s, 3 H), 1.26 (s, 3 H), 0.90 (s, 9 H), 0.11 (s,
3 H), 0.06 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 112.21,
109.57, 105.51, 102.95, 100.08, 99.82, 84.20, 81.73, 81.16, 72.91,
71.82, 70.40, 68.17, 67.99, 64.05, 51.05, 48.51, 48.08, 27.43, 27.31,
26.60, 26.19, 25.87, 18.74, 18.31, 18.18, –4.20, –4.39 ppm. IR
4-O-(6-Amino-6-deoxy-α-D-mannopyranosyl)-2-deoxystreptamine
(23): Compound 22 (18 mg, 0.045 mmol) was dissolved in THF/
H2O/1 m NaOH (10:1:0.1, v/v/v, 2.5 mL) and P(CH3)3 (1 m in THF,
202 μL, 0.202 mmol, 4.5 equiv.) was added. The reaction was
stirred for 12 h, and the solvent was evaporated. The residue was
purified by silica gel column chromatography (Rf = 0.16, 25%
NH4OH/CH2Cl2/nBuOH/EtOH, 6:2:4:5). The remaining silica and
organic solvents were removed by using ion-exchange column
+
(neat): ν = 2832, 2098, 1129, 1039, 840 cm–1. HRMS (FAB): calcd.
chromatography (0.5ϫ5 cm) with Amberlite CG-50 in its NH4
˜
for C30H54N3O12Si [M + H]+ 676.3477; found 676.3445.
form (1 m NH4OH as the eluent). The eluent was evaporated under
reduced pressure. The product was dissolved in water (5 mL), and
2 drops of glacial acetic acid were added. After lyophilization, com-
pound 23 (16 mg, 0.032 mmol, 71%) was obtained as a sticky pow-
6-O-{6-Azido-2-O-(tert-butyldimethylsilyl)-6-deoxy-3,4-O-
[(2S,3S)-2,3-dimethoxybutane-2,3-diyl]-α-
D-mannopyranosyl}-
1,2:3,4-di-O-isopropylidene-α- -galactopyranose (26): The general
D
der. [α]2D0 = +52.6 (c = 0.35, H2O). H NMR (400 MHz, D2O): δ =
1
procedure for glycosidation was applied to thiomannoside 11
(193 mg, 0.367 mmol) and PSP (92 mg, 0.440 mmol, 1.2 equiv.) in
dry CH2Cl2 (6 mL). TTBP (228 mg, 0.917 mmol, 2.5 equiv.) and
activated powdered MS (4 Å, 100 mg) were added at room tem-
perature, followed by Tf2O (74 μL, 0.440 mmol, 1.2 equiv.) at
–60 °C. Then, diisopropylidene-d-galactose[60] (115 mg,
0.440 mmol, 1.2 equiv.) in dry CH2Cl2 (5 mL) was added. After
20 min, the reaction was slowly warmed to –20 °C and quenched
with P(OEt)3 (76 μL, 0.440 mmol, 1.2 equiv.). Purification was per-
formed by silica gel chromatography to afford α-coupled product
26 (170 mg, 0.252 mmol, 69%) as a colorless gum and an insepa-
rable fraction of the α/β mixture in an 8:1 ratio (40 mg,
0.059 mmol, 16 %). Analytical data are given for the α-coupled
product 26. Rf = 0.33 (EtOAc/heptane, 1:5). [α]2D0 = +82.2 (c = 1,
5.43 (d, J = 1.8 Hz, 1 H), 4.14 (dd, J = 3.1 Hz, J = 2.1 Hz, 1 H),
3.97–3.92 (m, 1 H), 3.89 (dd, J = 9.6 Hz, J = 3.1 Hz, 1 H), 3.80
(dd, J = 10.2 Hz, J = 9.0 Hz, 1 H), 3.66 (t, J = 9.6 Hz, 1 H), 3.59
(t, J = 9.0 Hz, 1 H), 3.52 (t, J = 10.2 Hz, 1 H), 3.49–3.41 (m, 2 H),
3.33–3.27 (m, 1 H), 3.23 (dd, J = 13.5 Hz, J = 7.8 Hz, 1 H), 2.47
(dt, J = 12.5 Hz, J = 4.2 Hz, 1 H), 1.95 (s, 9 H), 1.85 (q, J =
12.5 Hz, 1 H) ppm. 13C NMR (75 MHz, D2O): δ = 179.77, 100.41,
78.45, 74.60, 72.14, 69.50, 69.17, 68.99, 67.15, 49.23, 47.99, 39.88,
˜
27.76, 22.08 ppm. IR (neat): GnϾ = 3170, 2912, 1538, 1402, 1044,
1009, 652 cm–1. HRMS (ESI): calcd. for C12H25N3O7Na [M +
Na]+ 346.1590; found 346.1580.
4-O-(6-Amino-6-deoxy-α-D-glucopyranosyl)-2-deoxystreptamine
(24): Compound 20 (60 mg, 0.074 mmol) was dissolved in TFA/
H2O (9:1, v/v, 2.5 mL), and after stirring for 4 min, the solvent
was rapidly evaporated under reduced pressure. The residue was
dissolved in THF/H2O/1 m NaOH (10:1:0.1, v/v/v, 4 mL), and
P(CH3)3 (1 m in THF, 222 μL, 0.222 mmol, 3.0 equiv.) was added.
The reaction was stirred for 12 h, and the solvent was evaporated.
The crude intermediate was dissolved in MeOH/AcOH (10:1, v/v,
5.5 mL), and Pd on carbon (60 mg) was added. The reaction was
stirred under H2 (1 atm) for 20 h. The mixture was filtered through
Celite, washing with H2O, and the solvents were evaporated. The
residue was purified by silica gel chromatography (25% NH4OH/
CH2Cl2/nBuOH/EtOH, 6:2:4:5). The remaining silica and organic
solvents were removed by using ion-exchange column chromatog-
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 5.52 (d, J = 4.9 Hz, 1
H), 4.77 (d, J = 1.2 Hz, 1 H), 4.61 (dd, J = 7.8 Hz, J = 2.3 Hz, 1
H), 4.31 (dd, J = 5.0 Hz, J = 2.4 Hz, 1 H), 4.20 (dd, J = 7.9 Hz, J
= 1.8 Hz, 1 H), 4.06–3.99 (m, 2 H), 3.91–3.84 (m, 3 H), 3.81–3.71
(m, 2 H), 3.48 (dd, J = 13.1 Hz, J = 2.1 Hz, 1 H), 3.32 (dd, J =
13.1 Hz, J = 5.9 Hz, 1 H), 3.22 (s, 3 H), 3.19 (s, 3 H), 1.51 (s, 3 H),
1.44 (s, 3 H), 1.32 (s, 3 H), 1.31 (s, 3 H), 1.25 (s, 3 H), 1.24 (s, 3
H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 109.43, 108.61, 100.18, 99.77, 99.51, 96.44,
71.34, 71.19, 70.92, 70.73, 70.48, 67.98, 65.16, 64.92, 63.82, 50.71,
48.14, 47.79, 26.42, 26.29, 26.02, 25.25, 24.86, 18.56, 18.08, 17.98,
–4.35, –4.64 ppm. IR (neat): ν = 2832, 2097, 1126, 1070 cm–1
.
˜
HRMS (FAB): calcd. for C30H54N3O12Si [M + H]+ 676.3477;
found 676.3434.
+
raphy (0.5ϫ5 cm) with Amberlite CG-50 in its NH4 form (1 m
NH4OH as the eluent). The eluent was evaporated under reduced
pressure. The product was dissolved in water (5 mL), and 2 drops
of glacial acetic acid were added. After lyophilization, compound
24 (23 mg, 0.046 mmol, 62%) was obtained as a sticky powder.
Analytical data were identical to those reported by Wong et al.[55]
3-O-{6-Azido-2-O-(tert-butyldimethylsilyl)-6-deoxy-3,4-O-
[(2S,3S)-2,3-dimethoxybutane-2,3-diyl]-α-
D-mannopyranosyl}-N-
(benzyloxycarbonyl)- -serine Benzyl Ester (27): The general pro-
L
cedure for glycosidation was applied to thiomannoside 11 (114 mg,
0.217 mmol) and PSP (54.4 mg, 0.260 mmol, 1.2 equiv.) in dry
CH2Cl2 (5.5 mL). TTBP (135 mg, 0.543 mmol, 2.5 equiv.) and acti-
3-O-{6-Azido-2-O-(tert-butyldimethylsilyl)-6-deoxy-3,4-O-
[(2S,3S)-2,3-dimethoxybutane-2,3-diyl]-α-
D-mannopyranosyl}- vated powdered MS (4 Å, 75 mg) were added at room temperature,
1,2:5,6-di-O-isopropylidene-α- -glucofuranose (25): The general
procedure for glycosidation was applied to thiomannoside 11
(50 mg, 0.095 mmol) and PSP (23.9 mg, 0.114 mmol, 1.2 equiv.) in
D
followed by Tf2O (44 μL, 0.260 mmol, 1.2 equiv.) at –60 °C. Then
N-Cbz-l-serine benzyl ester (86 mg, 0.260 mmol, 1.2 equiv.) in dry
CH2Cl2 (4.5 mL) was added. After 20 min, the reaction was slowly
dry CH2Cl2 (2.5 mL). TTBP (69 mg, 0.280 mmol, 2.0 equiv.) and warmed to –20 °C and quenched with P(OEt)3 (44.6 μL,
activated powdered MS (4 Å, 30 mg) were added at room tempera- 0.260 mmol, 1.2 equiv.). Purification was performed by silica gel
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20084
/KAP1
Date: 16-07-12 10:07:36
Pages: 12
2Ј-Modified Neamine Analogues from Thiomannosides
chromatography to afford 27 (135 mg, 0.181 mmol, 83%) as a col-
orless oil. Rf = 0.31 (EtOAc/heptane, 1:4). [α]2D0 = +108.3 (c = 1,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.38 (m, 10 H), 5.68
(d, J = 8.6 Hz, 1 H), 5.19 (s, 2 H), 5.14 (s, 2 H), 4.60–4.58 (m, 2
Purification by silica gel chromatography gave 29 (36 mg,
0.064 mmol, 86%) as a colorless oil. Rf = 0.42 (EtOAc/heptane,
1
1:1). [α]2D0 = +94.6 (c = 1, CH2Cl2). H NMR (400 MHz, CDCl3):
δ = 5.85 (d, J = 3.3 Hz, 1 H), 5.11 (s, 1 H), 4.70 (d, J = 3.3 Hz, 1
H), 4.05–3.93 (m, 3 H), 3.80–3.72 (m, 3 H), 3.46 (dd, J = 13.1 Hz, H), 4.28 (br. s, 1 H), 4.16–4.06 (m, 3 H), 4.02–3.89 (m, 5 H), 3.56
J = 2.0 Hz, 1 H), 3.27 (dd, J = 13.1 Hz, J = 6.0 Hz, 1 H), 3.21 (s, (d, J = 13.0 Hz, 1 H), 3.43 (dd, J = 13.0 Hz, J = 7.0 Hz, 1 H), 3.26
3 H), 3.19 (m, 3 H), 1.26 (s, 3 H), 1.25 (s, 3 H), 0.89 (s, 9 H), 0.11
(s, 3 H), 3.23 (s, 3 H), 2.54 (br. s, 1 H), 1.48 (s, 3 H), 1.39 (3 H),
(s, 3 H), 0.03 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
1.31 (br. s, 9 H), 1.28 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
169.66, 155.75, 136.06, 135.04, 128.58, 128.46, 128.14, 128.06, = 111.89, 109.14, 105.15, 101.24, 100.30, 99.94, 83.51, 81.63, 81.15,
102.27, 99.80, 99.54, 71.50, 70.31, 68.79, 67.91, 67.57, 67.35, 63.49, 72.47, 70.82, 69.38, 67.92, 67.73, 63.95, 50.80, 48.33, 48.08, 26.96,
54.67, 50.57, 48.18, 47.82, 25.97, 18.51, 18.07, 17.97, –4.32, 26.92, 26.21, 25.47, 17.93, 17.87 ppm. IR (neat): ν = 3481, 2840,
˜
–4.64 ppm. IR (neat): ν = 3333, 2830, 2099, 1725, 1130, 1038 cm–1.
2103, 1139, 1079, 1031 cm– 1 . HRMS (FAB): calcd. for
C24H40N3O12 [M + H+ 562.2612; found 562.2620.
˜
HRMS (FAB): calcd. for C36H52N4O11SiNa [M + Na]+ 767.3300;
found 767.3312.
6-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
3-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-mannopyranosyl}-1,2:3,4-di-O-isopropylidene-α-D-galac-
diyl]-2-O-(trimethylsilyl)-α-
D-mannopyranosyl}-N-(benzyloxy-
topyranose (30): TBAF (1 m in THF, 193 μL, 1.1 equiv.) was added
to a stirred solution of 26 (118 mg, 0.175 mmol) in THF (8 mL).
After 3.5 h, TLC showed only a half conversion. Additional TBAF
(1 m in THF, 87 μL, 0.5 equiv.) was added. The reaction mixture
was stirred for 10 h, and the solvent was evaporated. The crude
product was purified by silica gel chromatography to afford 30
(94 mg, 0.167 mmol, 95%) as a colorless gum. Rf = 0.26 (EtOAc/
heptane, 2:3). [α]2D0 = +93.2 (c = 0.5, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 5.51 (d, J = 5.1 Hz, 1 H), 4.90 (s, 1 H), 4.60 (dd, J =
7.9 Hz, J = 2.4 Hz, 1 H), 4.30 (dd, J = 5.0 Hz, J = 2.4 Hz, 1 H),
4.21 (dd, J = 7.9 Hz, J = 1.9 Hz, 1 H), 4.02–3.89 (m, 5 H), 3.81
(dd, J = 10.7 Hz, J = 6.9 Hz, 1 H), 3.73 (dd, J = 10.7 Hz, J =
6.6 Hz, 1 H), 3.48 (dd, J = 13.1 Hz, J = 2.5 Hz, 1 H), 3.42 (dd, J
= 13.1 Hz, J = 5.7 Hz, 1 H), 3.25 (s, 3 H), 3.22 (s, 3 H), 2.52 (br.
s, 1 H), 1.53 (s, 3 H), 1.43 (s, 3 H), 1.32 (br. s, 6 H), 1.30 (s, 3 H),
1.26 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 109.43, 108.64,
100.35, 99.97, 99.56, 96.36, 71.09, 70.81, 70.77, 70.50, 69.71, 68.15,
66.01, 65.46, 64.05, 50.76, 48.37, 48.16, 26.40, 26.27, 25.24, 24.87,
carbonyl)- -serine Benzyl Ester (28) and the β Isomer: The general
L
procedure for glycosidation was applied to thiomannoside 12
(180 mg, 0.372 mmol) and PSP (93 mg, 0.446 mmol, 1.2 equiv.) in
dry CH2Cl2 (6 mL). TTBP (231 mg, 0.930 mmol, 2.5 equiv.) and
activated powdered MS (4 Å, 90 mg) were added at room tempera-
ture, followed by Tf2O (75 μL, 0.446 mmol, 1.2 equiv.) at –60 °C.
Then N-Cbz-l-serine benzyl ester (147 mg, 0.446 mmol, 1.2 equiv.)
in dry CH2Cl2 (5 mL) was added. After 20 min, the reaction was
slowly warmed to –20 °C and quenched with P(OEt)3 (76 μL,
0.446 mmol, 1.2 equiv.). Purification was performed by silica gel
chromatography to afford 28 (195 mg, 0.277 mmol, 75%) and its β
isomer (7 mg, 0.010 mmol, 3%), both as colorless oils (α/β, 28:1).
Analytical data are given for both isomers. Data for 28: Rf = 0.28
(EtOAc/heptane, 1:4). [α]2D0 = +101.1 (c = 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.32 (m, 10 H), 5.69 (d, J = 8.6 Hz,
1 H), 5.24 (d, J = 12.3 Hz, 1 H), 5.18–5.14 (m, 3 H), 4.61–4.58 (m,
2 H), 3.98–3.88 (m, 3 H), 3.81–3.71 (m, 3 H), 3.44 (dd, J = 13.0 Hz,
J = 2.2 Hz, 1 H), 3.37 (dd, J = 13.0 Hz, J = 6.5 Hz, 1 H), 3.21 (s,
3 H), 3.19 (s, 3 H), 1.28 (s, 3 H), 1.25 (s, 3 H), 0.14 (s, 9 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 169.64, 155.75, 136.06, 135.11,
128.55, 128.44, 128.10, 128.04, 102.45, 99.86, 99.55, 71.31, 70.45,
68.84, 68.00, 67.51, 67.34, 63.83, 54.62, 50.68, 48.18, 47.84, 18.07,
18.07, 18.02 ppm. IR (neat): ν = 3487, 2830, 2098, 1132, 1114,
˜
1069, 1042 cm–1. HRMS (FAB): calcd. for C24H39N3O12Na [M +
Na]+ 584.2431; found 584.2444.
3-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-mannopyranosyl}-N-(benzyloxycarbonyl)-L-serine Benzyl
17.98, 0.83 ppm. IR (neat): ν = 3327, 2831, 2099, 1725, 1129,
˜
1038 cm–1. HRMS (FAB): calcd. for C33H47N4O11Si [M + H]+
703.3011; found 703.3007. Data for β Isomer: Rf = 0.14 (EtOAc/
heptane, 1:4). [α]2D0 = +66.4 (c = 0.5, CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.37–7.31 (m, 10 H), 5.62 (d, J = 8.0 Hz, 1 H), 5.30–
5.12 (m, 4 H), 4.59–4.57 (m, 1 H), 4.43 (s, 1 H), 4.36 (dd, J =
10.1 Hz, J = 3.6 Hz, 1 H), 3.95–3.83 (m, 3 H), 3.56–3.49 (m, 2 H),
3.38–3.36 (m, 2 H), 3.24 (s, 3 H), 3.18 (m, 3 H), 1.27 (m, 3 H), 1.24
(s, 3 H), 0.12 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
169.45, 155.73, 136.18, 135.27, 128.49, 128.46, 128.15, 128.11,
128.07, 100.78, 99.86, 99.61, 77.36, 74.92, 70.23, 69.12, 67.49,
67.24, 64.18, 54.56, 50.70, 48.19, 47.95, 18.05, 17.89, 0.76 ppm. IR
Ester (31): TBAF (1 m in THF, 219 μL, 1.1 equiv.) was added to a
stirred solution of 28 (140 mg, 0.199 mmol) in THF (25 mL). After
1.5 h, TLC showed a half conversion. Additional TBAF (1 m in
THF, 100 μL, 0.5 equiv.) and 2 drops of AcOH were added.[61] Af-
ter 4 h, the solvent was evaporated under reduce pressure. Purifica-
tion was performed by silica gel chromatography to afford 31
(120 mg, 0.191 mmol, 96%) as a colorless gum. Rf = 0.40 (EtOAc/
heptane, 1:1). [α]2D0 = +102.9 (c = 1.15, CH2Cl2). 1H NMR
(400 MHz, CDCl3): δ = 7.38–7.32 (m, 10 H), 5.67 (d, J = 8.4 Hz,
1 H), 5.27 (d, J = 12.1 Hz, 1 H), 5.14–5.11 (m, 3 H), 4.66 (s, 1 H),
4.61–4.59 (m, 1 H), 3.99–3.94 (m, 3 H), 3.83–3.77 (m, 2 H), 3.67–
3.66 (m, 1 H), 3.44 (dd, J = 13.1 Hz, J = 2.3 Hz, 1 H), 3.36 (dd, J
= 13.1 Hz, J = 6.0 Hz, 1 H), 3.23 (s, 3 H), 3.22 (s, 3 H), 2.41 (br.
s, 1 H), 1.30 (s, 3 H), 1.27 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 169.50, 155.72, 136.01, 135.08, 128.59, 128.50, 128.45,
128.27, 128.14, 128.13, 100.90, 100.35, 99.99, 70.69, 69.37, 69.13,
67.98, 67.56, 67.37, 63.73, 54.60, 50.58, 48.43, 48.18, 18.03,
(neat): ν = 3438, 3335, 2832, 2097, 1725, 1128, 1050 cm–1. HRMS
˜
(ESI): calcd. for C33H46N4O11SiNa [M + Na]+ 725.2830; found
725.2841.
3-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-mannopyranosyl}-1,2:5,6-di-O-isopropylidene-α-D-gluco-
furanose (29): TBAF (1 m in THF, 81.4 μL, 1.1 equiv.) was added
to a stirred solution of 25 (50 mg, 0.074 mmol) in THF (3 mL).
The reaction mixture was stirred for 10 h, and the solvent was evap-
orated. The residue was dissolved in EtOAc, and the resulting solu-
tion was washed with H2O. The H2O layer was extracted with ad-
ditional EtOAc, and the combined organic layers were washed with
brine, dried with MgSO4, and evaporated under reduced pressure.
18.00 ppm. IR (neat): ν = 3434, 3339, 2833, 2098, 1720, 1133, 1114,
˜
1036 cm–1. HRMS (FAB): calcd. for C30H39N4O11 [M + H]+
631.2615; found 631.2623.
3-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-
D-glucopyranosyl}-1,2:5,6-di-O-isopropylidene-α-D-gluco-
furanose (35): Dess–Martin periodinane (147 mg, 0.346 mmol,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

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/KAP1
Date: 16-07-12 10:07:36
Pages: 12
D. Gironés, M. Hanckmann, F. P. J. T. Rutjes, F. L. van Delft
FULL PAPER
1.5 equiv.) was added to a stirred solution of compound 29
(130 mg, 0.231 mmol) in CH2Cl2 (6 mL). After 10 h, the reaction
was diluted with CH2Cl2 (6 mL), and the resulting solution was
quenched with NaOH (1 m solution, 10 mL). The mixture was
stirred for 30 min, after which the organic layer was separated. The
water layer was extracted with CH2Cl2 (2ϫ), and the combined
organic layers were dried with MgSO4 and filtered. The solvent
was evaporated. The crude intermediate 32 was dissolved in THF
(6 mL), and l-selectride (1 m in THF, 346 μL, 1.5 equiv.) was
added. After 2 h, the reaction was quenched with MeOH, and the
solvent was evaporated. The residue was dissolved in CH2Cl2, and
the resulting solution was washed with saturated NH4Cl, dried with
MgSO4, and filtered. The solvent was evaporated again. The crude
product was purified by silica gel chromatography to give solely
compound 35 (109 mg, 0.194 mmol, 84%) as a colorless oil. Rf =
0.24 (EtOAc/heptane, 1:2). [α]2D0 = +112.3 (c = 1, CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 5.92 (d, J = 3.5 Hz, 1 H), 5.07 (d,
J = 3.7 Hz, 1 H), 4.83 (d, J = 3.5 Hz, 1 H), 4.29–4.22 (m, 2 H),
4.19–4.14 (m, 2 H), 4.02–3.95 (m, 2 H), 3.80 (t, J = 10.0 Hz, 1 H),
3.69 (td, J = 10.0 Hz, J = 3.7 Hz, 1 H), 3.57–3.53 (m, 2 H), 3.38–
3.32 (m, 2 H), 3.29 (s, 3 H), 3.24 (s, 3 H), 1.49 (s, 3 H), 1.41 (s, 3
H), 1.33 (s, 3 H), 1.32 (s, 6 H), 1.29 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 112.50, 109.82, 105.98, 101.64, 100.00,
99.99, 85.40, 83.25, 81.86, 73.63, 70.75, 70.51, 70.31, 68.54, 67.22,
51.13, 48.48, 48.21, 27.42, 27.15, 26.63, 25.45, 18.27, 18.15 ppm.
Acknowledgments
The work described here was financially supported by the Council
for Chemical Sciences of The Netherlands Organization for Scien-
tific Research (NWO).
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IR (neat): ν = 3450, 2833, 2099, 1138, 1027 cm–1. HRMS (FAB):
˜
calcd. for C24H40N3O12 [M + H]+ 562.2612; found 562.2600.
6-O-{6-Azido-6-deoxy-3,4-O-[(2S,3S)-2,3-dimethoxybutane-2,3-
diyl]-α-D-glucopyranosyl}-1,2:3,4-di-O-isopropylidene-α-D-galacto-
pyranose (36): Dess–Martin periodinane (80 mg, 0.188 mmol,
2.0 equiv.) was added to a stirred solution of compound 30 (53 mg,
0.094 mmol) in CH2Cl2 (4 mL). After 10 h, the reaction was diluted
with CH2Cl2 (4 mL), and the resulting solution was quenched with
NaOH (1 m solution, 5 mL). The mixture was stirred for 30 min,
after which the organic layer was separated. The water layer was
extracted with CH2Cl2 (2ϫ), and the combined organic layers were
dried with MgSO4 and filtered. The solvent was evaporated. The
crude intermediate 33 was dissolved in THF (4 mL), and LiAl-
(OtBu)3H (1.1 m in THF, 128 μL, 1.5 equiv.) was added. After 2 h,
the reaction was quenched with MeOH, and the solvent was evapo-
rated. The residue was dissolved in CH2Cl2, and the resulting solu-
tion was washed with saturated NH4Cl, dried with MgSO4, and
filtered. The solvent was evaporated again. The crude product was
purified by silica gel chromatography to afford manno-configured
product 30 (9 mg, 0.016 mmol, 17%) and 36 (26 mg, 0.046 mmol,
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49%) as a colorless gum. Rf = 0.27 (EtOAc/heptane, 1:1). [α]2D0
=
+129.8 (c = 1, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 5.51 (d,
J = 5.1 Hz, 1 H), 4.93 (d, J = 3.9 Hz, 1 H), 4.62 (dd, J = 7.9 Hz,
J = 2.4 Hz, 1 H), 4.33 (dd, J = 5.0 Hz, J = 2.4 Hz, 1 H), 4.25 (dd,
J = 7.8 Hz, J = 2.0 Hz, 1 H), 4.02–3.92 (m, 3 H), 3.85 (t, J =
9.9 Hz, 1 H), 3.74–3.70 (m, 2 H), 3.62 (t, J = 9.9 Hz, 1 H), 3.53
(dd, J = 13.3 Hz, J = 2.3 Hz, 1 H), 3.36 (dd, J = 13.1 Hz, J =
5.3 Hz, 1 H), 3.29 (s, 3 H), 3.25 (s, 3 H), 2.58 (br. s, 1 H), 1.54 (s,
3 H), 1.44 (s, 3 H), 1.33 (s, 9 H), 1.28 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 109.59, 108.81, 99.75, 99.74, 99.37, 96.26,
71.22, 70.81, 70.65, 70.40, 69.92, 69.68, 67.78, 66.68, 65.87, 50.53,
48.29, 48.18, 26.38, 26.25, 25.23, 24.81, 18.12, 17.98 ppm. IR
(neat): ν = 3469, 2829, 2100, 1135, 1070, 1032 cm–1. HRMS (ESI):
˜
calcd. for C24H39N3O12Na [M + Na]+ 584.2432; found 584.2437.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the 1H NMR and 13C NMR spectra for all new
compounds.
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20084
/KAP1
Date: 16-07-12 10:07:36
Pages: 12
2Ј-Modified Neamine Analogues from Thiomannosides
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[51] Triethyl phosphite traps the remaining active sulfur species.
[52] The inversion of configuration at C-2Ј was confirmed by 1H
NMR spectroscopy, examining the changes in the anomeric
proton coupling constant. The α-glucosides showed a typical
anomeric coupling constant of 3.7–3.9 Hz and were generally
distinct from the mannosides by a longer retention time (lower
Rf value) on silica gel.
Triflyl azide is unstable and must be freshly generated from
triflic anhydride and sodium azide. It can be explosive when
dried and should be handled in solution, before the addition
of the amine.
[35]
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[57] Compound 8 = 1,3-di-N-benzyloxycarbonyl-5,6-O-cyclohex-
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[58] Compound 9 = 1,3-diazido-1,3-dideamino-5,6-O-cyclohexylid-
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[59] Diisopropylidene-d-glucose = 1,2:5,6-di-O-isopropylidene-α-d-
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Received: January 24, 2012
Published Online: ᭿
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Job/Unit: O20084
/KAP1
Date: 16-07-12 10:07:36
Pages: 12
D. Gironés, M. Hanckmann, F. P. J. T. Rutjes, F. L. van Delft
FULL PAPER
Neamine Analogues
D. Gironés, M. Hanckmann,
F. P. J. T. Rutjes, F. L. van Delft* .... 1–12
2Ј-Modified Neamine Analogues from
Thiomannosides through Glycosidation–
Stereoinversion
Neamine analogues with a free 2Ј-OH
group were synthesized through a stereo-
selective α-glycosidation reaction of 3,4-O-
dimethoxybutanediyl-2-O-silyl-protected
thiomannosides, followed by a 2-O-depro-
tection and an oxidation–reduction se-
quence, leading to stereoinversion at C-2Ј.
The scope of such a procedure for the syn-
theses of α-glucosides was explored with
three distinct model acceptors.
Keywords: Carbohydrates / Oxygen hetero-
cycles / Glycosidation / Oxidation / Re-
duction
12
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