Stereoselective synthesis of protected 3-amino-3,6-dideoxyaminosugars

Article abstract of DOI:10.1039/c2ob25793a

New syntheses of densely functionalized protected derivatives of 3-amino-3,6-dideoxyaminosugars have been accomplished in an efficient and straightforward manner. The key step of such approaches involves a highly stereoselective titanium-mediated aldol addition of a chiral α-bromo ketone, easily available from lactate esters, to crotonaldehyde. Further functional group transformations, including a new regioselective Staudinger-aza-Wittig reaction of an azidodiacetate, afford in a few steps and high yield the desired carbohydrates as advanced intermediates capable of participating in subsequent glycosylation reactions. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob25793a

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PAPER
Stereoselective synthesis of protected 3-amino-3,6-dideoxyaminosugars†
Joaquim Nebot, Pedro Romea* and Fèlix Urpí*
Received 25th April 2012, Accepted 6th June 2012
DOI: 10.1039/c2ob25793a
New syntheses of densely functionalized protected derivatives of 3-amino-3,6-dideoxyaminosugars have
been accomplished in an efficient and straightforward manner. The key step of such approaches involves a
highly stereoselective titanium-mediated aldol addition of a chiral α-bromo ketone, easily available from
lactate esters, to crotonaldehyde. Further functional group transformations, including a new regioselective
Staudinger–aza-Wittig reaction of an azidodiacetate, afford in a few steps and high yield the desired
carbohydrates as advanced intermediates capable of participating in subsequent glycosylation reactions.
Introduction
The biological activity of a significant class of complex secon-
dary metabolites synthesized by plants, fungi, and bacteria
depends, in a large extent, on deoxyaminosugars moieties
embedded in their structures.1 This applies to well-known
14-membered-ring macrolides, such as erythromycin A, whose
antibiotic properties are due to D-desosamine-ribosome hydro-
gen-bond interactions blocking the tunnel that channels the
nascent peptides away from the peptidyl transferase center,2 or to
the vancomycin analogs containing modified deoxyaminosugars,
which are specially effective against resistant bacteria because
they interact directly with bacterial proteins involved in the trans-
glycosylation step of the cell wall biosynthesis.3 The specific
character of these interactions is emphasized by the occasional
presence of both enantiomers of some deoxyaminosugars in
such metabolites, as occurs in the case mycosamine. Thereby,
D-mycosamine is attached to the macrolactone ring of polyene
macrolide antibiotics amphotericin B, nystatin, and pimaricin,4
whereas L-mycosamine has been located in a family of antifungal
macrolactams5 (Fig. 1).
Despite the dramatic influence of the deoxyaminosugar
moiety on the biological activity of these secondary meta-
bolites,1,6 the construction of the aglycon part and the develop-
ment of increasingly efficient glycosylation methodologies have
received more attention than the synthesis of the carbohydrate
itself.7 Thus, most of the synthetic approaches to suitably pro-
tected deoxyaminosugars rely on appropriate manipulations of
readily available precursors like glucose.8 These chiron
approaches9 have the advantage of being amenable to large scale
preparations, but they often involve too many non-strategic steps
Fig. 1 Natural products containing D- and L-mycosamine
and their efficiency becomes low. Instead, synthetic approaches
rooted on stereoselective grounds usually improve ideality but
often require more elaborate reagents and experimental con-
ditions.10 The synthesis of mycosamine can illustrate the pros
and cons of both approaches. Indeed, Nicolaou reported the
preparation of a protected mycosamine derivative from an easily
available benzylideneglucopyranoside in fourteen steps and 29%
overall yield,11,12 whereas Franck–Neumann obtained a fully
protected mycosamine aldehyde starting from an optically pure
tricarbonyliron α-amino ketone and a chiral lactaldehyde in five
steps and 54% yield.13 Therefore, it would be highly desirable to
design new synthetic sequences to gain access to such densely
functionalized targets in a few steps using simple reagents and
experimental procedures.14,15
Departament de Química Orgànica, Universitat de Barcelona, Martí i
Franqués 1–11, 08028 Barcelona, Catalonia, Spain.
E-mail: pedro.romea@ub.edu, felix.urpi@ub.edu
†Electronic supplementary information (ESI) available: structural
studies and NMR spectra. See DOI: 10.1039/c2ob25793a
In this context, we envisaged that stereoselective methodo-
logies developed by our group might furnish protected
L-3-amino-3,6-dideoxyaldohexoses 1 and 2 (Scheme 1) from
structurally simple starting materials in a straightforward,
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Scheme 1
flexible, and efficient manner.16 Our retrosynthetic analysis relies
on a substrate-controlled reaction from chiral α-bromo ketone 3,
easily available in optically pure form from (S) lactate esters.16b
As outlined in Scheme 1, we anticipated that highly diastereo-
selective titanium-mediated aldol addition of 3 to crotonaldehyde
followed by displacement of bromine by a nitrogenated nucleo-
phile and stereoselective reduction of the carbonyl group of aldol
4 would give an advanced intermediate 5 containing all the
stereocenters. Then, functional group transformations and sub-
sequent removal of silicon protecting group should render pro-
tected derivatives of L-mycosamine 1 in a straightforward
manner. Moreover, this synthetic approach could also be used
to prepare 3-amino-3,6-dideoxyglucopyranose 2, a precursor of
L-mycaminose,17 provided that a suitable protecting group facili-
tated the epimerization of the C2 stereocenter. Herein, we
describe our studies towards the stereoselective synthesis of pro-
tected L-3-amino-3,6-dideoxypyranose derivatives capable to be
employed in the synthesis of metabolites possessing these
deoxyaminosugars.
silyloxy ketone 3 and crotonaldehyde, which would be followed
by the displacement of the bromine by an azido group and the
anti-reduction of the carbonyl group (Scheme 2). As expected,
the titanium-mediated aldol addition of 3 to crotonaldehyde pro-
ceeded with a complete stereocontrol, providing syn-aldol 4 as a
single diastereomer in 78% yield. This reaction proved to be
highly reliable and afforded the desired syn-aldol 4 in near
80% yield at 10 mmol scale under very mild conditions. Having
prepared the carbon backbone, we next assessed the introduction
of an azide through displacement of the bromine atom in 4.
To our surprise, this apparently simple reaction was more com-
plicated than expected because long reaction times or slight
excesses of NaN3 produced the epimerization of Cα in variable
extents. Finally, it was found that stoichiometric amounts of
NaN3 in DMSO at room temperature furnished a mixture that
could be submitted to the Evans–Chapman–Carreira conditions
to afford azidopolyol 5 as a single diastereomer in 72% yield
over two steps.18 Thus, advanced intermediate 5 possessing all
the stereocenters had been prepared in a straightforward manner
from lactate-derived ketone 3 in three steps and 56% overall
yield.
Results and discussion
With azidopolyol 5 in hand, the conversion of the carbon–
carbon double bond into the required aldehyde and the selective
reduction of the azido group appeared as the most important
hurdles to achieve the synthesis of the desired deoxyamino-
sugars. Thus, we envisioned different synthetic approaches
depending on the way these reactions were orchestrated.
Initial steps
Keeping in mind such an analysis, we first focused our attention
on the synthesis of intermediate 5. The key step of our approach
was the substrate-controlled aldol reaction of α-bromo α′-
Scheme 2 Reagents and conditions: (a) (i) TiCl2(i-PrO)2, i-Pr2NEt, CH2Cl2, −20 °C; (ii) Crotonaldehyde, −78 to −20 °C, 78%; (b) NaN3, DMSO,
rt; (c) Me4NHB(OAc)3, 1 : 1 CH3CN–AcOH, −35 to −20 °C, 72% over two steps.
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First approach to the synthesis of L-mycosamine
particularly appealing because an acetate protecting group and
the amino group could be masked in a single and stable hetero-
cycle, which could deliver both functional groups at any stage of
the synthetic sequence. Surprisingly, this sort of transformation
is well documented for aldehydes and ketones but there are few
reports involving less electrophilic esters.20,21 We were also
aware that the presence of two acetate groups flanking the azide
introduced a serious problem of regioselectivity, since both
esters were rather similar and the intramolecular aza-Wittig reac-
tion could produce two oxazoline heterocycles 9a and 9b
(Scheme 4). There were no precedents on such regioselective
issues, so the lack of reactivity of the ester groups was com-
pounded by the potential formation of two products. Neverthe-
less, we expected that any mixture of oxazoline isomers 9a and
9b could be carried ahead and furnish the desired carbohydrate.
We began exploring the conversion of azidopolyol 5 into the cor-
responding aldehyde (Scheme 3). Initially, both hydroxyl groups
in 5 were protected with acetic anhydride affording diester 6 in
excellent yield. Then, the oxidation of the alkene was carried out
quantitatively following the osmate-periodate procedure and the
resultant sensitive aldehyde 7 was immediately treated with HF
to remove the silicon protecting group, which delivered pure
2,4-di-O-acetyl-3-azido-3,6-dideoxy-α-L-mannopyranose
8 in
67% over two steps.19
Scheme 3 Reagents and conditions: (a) Ac2O, Et3N, DMAP cat,
CH2Cl2, rt, 97%; (b) K2OsO4·2H2O (4 mol%), NaIO4, 2,6-lutidine, 3 : 1
1,4-dioxane–H2O, rt; (c) HF, CH3CN, rt, 67% over two steps.
Thus, we had accomplished the stereoselective synthesis of
the azido derivative of L-mycosamine 8 from α-bromo α′-silyl-
oxy ketone 3 in six steps and 36% overall yield under very mild
conditions. The success of this sequence led us to explore in
depth the whole strategy and to assess other approaches in which
the azide was reduced and protected before oxidizing the
carbon–carbon double bond, as described below.
Scheme 4
To our delight, simple treatment of 6 with PMe3 under water-
free conditions at room temperature provided oxazoline 9a with
an outstanding regioselectivity in excellent yield (Scheme 5).
1
Indeed, H NMR analysis of the reacting mixture uncovered the
formation of 9a : 9b in a ratio greater than 20 : 1 and a further
chromatographic purification afforded pure oxazolines 9a and
9b in 90% and 4% yield respectively. Thus, this transformation
entailed the reduction of the azide and the selective addition of
the putative iminophosphorane to the syn-acetate group at C3,
likely as a result of the lower steric hindrance of eclipsed tran-
sition state I leading to 9a (Scheme 5). This remarkable result
not only proves that a Staudinger–aza-Wittig tandem reaction
Second approach to the synthesis of L-mycosamine
Taking advantage of azidodiester 6, we envisioned that the phos-
phine-mediated reduction of the azide followed by the attack of
the resultant iminophosphorane to a neighboring acetate might
produce an oxazoline (Scheme 4). This one-step transformation
involving
a Staudinger and an aza-Wittig reaction was
Scheme 5 Reagents and conditions: (a) PMe3, THF, rt, 9a in 90%, 9b in 4%.
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may be carried out on acyclic azidodiacetates under very mild
conditions to afford the corresponding oxazolines in excellent
yield but also in high regioselectivity favoring the syn neighbor-
ing acetate group.
of the alkene and removal of the silicon protecting group furn-
ished fully protected L-mycosamine 14 under mild conditions.
Unfortunately, ester protecting groups were not completely stable
under these conditions, so both steps were not easily reproduci-
ble and the resulting deoxyaminosugar was contaminated by tiny
amounts of unknown impurities.
This drawback led us to look for a more reliable protecting
group strategy. Hence, isopropylidene acetal was chosen as the
new protecting group for 1,3-diol 5 because it could be removed
simultaneously to the TBS group avoiding undesired side reac-
tions. Furthermore, such a cyclic protecting group might facili-
tate the epimerization of the C2 stereocenter and to provide the
diastereomeric L-mycaminose-like deoxyaminosugar.
In accordance to this new design, azidopolyol 5 was readily
converted into the isopropylidene acetal 15 (Scheme 8), which
was used to confirm the relative configuration of the stereo-
centers embedded in the 1,3-dioxane ring by 1D and 2D NMR
analyses.18 Treatment of this azido derivative 15 with PMe3 and
hydrolysis of the resultant iminophosphorane in wet THF gave
the desired primary amine, which was in situ protected as the
corresponding Cbz carbamate 16 in 96% yield. Clean oxidation
of 16 afforded aldehyde 17, which was used in the next step
without further purification. Finally, concurrent removal of the
silicon and the isopropylidene protecting groups by HF provided
a 65 : 35 α,β-mixture of N-benzyloxycarbonyl L-mycosamine 18
in 74% yield.19
With a reliable access to advanced intermediate 9a on hand,
we were ready to assess the conversion of the olefin into the
aldehyde and the removal of the silicon protecting group
(Scheme 6). Oxidation of the alkene using previously optimized
conditions gave quantitatively aldehyde 10, which was judged
1
pure enough by H NMR to be used in the next steps without
further purification. Regrettably, all our attempts to remove the
TBS group failed and we always obtained complex mixtures
instead of the hemiacetal form of protected L-mycosamine. A
change in the order of the later steps was also unsuccessful.
Indeed, deprotection of silyl ether in oxazoline 9a gave alcohol
11 in 94% yield, but further oxidation of the remaining alkene
under a wide set of conditions only produced complex reaction
mixtures.
Scheme 6 Reagents and conditions: (a) K2OsO4·2H2O (4 mol%),
NaIO4, 2,6-lutidine, 3 : 1 1,4-dioxane–H2O, rt, 95%; (b) TBAF, THF, rt,
94%.
Considering that the heterocyclic moiety might be responsible
for these failures, oxazoline 9a was opened with BnOCOCl to
provide carbamate 12 in excellent yield (Scheme 7).22 As
expected, this substrate proved to be more suitable and oxidation
Scheme 8 Reagents and conditions: (a) Me2C(OMe)2, PPTS cat.,
CH2Cl2, rt, 89%; (b) (i) PMe3, H2O, THF, rt. (ii) BnOCOCl, NaHCO3,
MeOH, rt, 96%; (c) K2OsO4·2H2O (4 mol%), NaIO4, 2,6-lutidine, 3 : 1
1,4-dioxane–H2O; (d) HF, CH3CN, rt, 74% over two steps.
Thus, the synthetic sequence outlined in Scheme 8 represents
a highly stereoselective and efficient approach to the synthesis of
an N-protected L-mycosamine derivative from lactate-derived
ketone 3 in seven steps and 36% yield. Furthermore, aldehyde
17 was a key intermediate to prepare a C2 epimer, that is a pre-
cursor of L-mycaminose.
Scheme 7 Reagents and conditions: (a) BnOCOCl, Na2CO3, 1 : 1
CH2Cl2–H2O, rt, 96%; (b) K2OsO4·2H2O (4 mol%), NaIO4, 2,6-luti-
dine, 3 : 1 1,4-dioxane–H2O, rt; (c) HF, CH3CN, rt.
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Synthesis of L-3-amino-3,6-dideoxyglucopyranose
by these highly reliable transformations and the appropriate
orchestration of subsequent functional group modifications,
including a new regioselective Staudinger–aza-Wittig reaction of
an azidodiacetate, provide the aforementioned protected deoxy-
aminosugars in a fews steps and high overall yield. Hence, the
synthesis of these carbohydrates, capable to be engaged in glyso-
sylation reactions, has been accomplished in a highly stereo-
selective, efficient, and straightforward manner.
The formyl group at 1,3-dioxane 17 adopting a twist-boat con-
formation was pivotal to promote the epimerization of C2 stereo-
center by a mild base. Indeed, oxidation of fully protected
aminopolyol 16 and simple stirring of 17 in the presence of
sodium carbonate gave the more stable chairlike aldehyde 19 in
74% yield (Scheme 9). Then, simultaneous deprotection of the
silyl ether and the isopropylidene acetal under the experimental
conditions previously optimized afforded in 78% yield a 40 : 60
α,β-mixture of N-benzyloxycarbonyl L-3-amino-3,6-dideoxyglu-
copyranose 20, a protected precursor of L-mycaminose.17,19
Thus, the synthesis of deoxyaminosugar 20 has been completed
in eight steps and a remarkable 28% overall yield from chiral
ketone 3. These figures together with those achieved in former
cases prove that the strategy outlined in Scheme 1 is a powerful
tool to synthesize 3-amino-3,6-dideoxyaminosugars in a highly
stereoselective, efficient, and straightforward manner.
Experimental section
General methods
Specific rotations were determined at 20 °C on a Perkin-Elmer
241 MC polarimeter. IR spectra were recorded on either a
Nicolet 6700 FT spectrometer and only the more representative
frequencies (cm−1) are reported. 1H NMR (300 MHz) and
13C NMR (75.4 MHz) spectra were recorded on a Unity-Plus
300 spectrometer. 1H NMR (400 MHz) and 13C NMR
(100.6 MHz) spectra were recorded on a Varian-Mercury 400
1
spectrometer. H NMR chemical shifts (δ) are quoted in ppm
and referenced to internal TMS (δ 0) for CDCl3, or referenced to
solvent residual peak for CD3OD (δ 3.31) and C6D6 (δ 7.16).
Coupling constants (J) are quoted in Hz; data are reported as
follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet;
m, multiplet; br, broad. 13C NMR chemical shifts (δ) are quoted
in ppm and referenced to CDCl3 (δ 77.0) and CD3OD (δ 49.0).
Where appropriate, 2D techniques were also used to assist in
structure elucidation. High resolution mass spectra (HRMS)
were obtained with a Agilent 1100 spectrometer by the Unitat
d’Espectrometria de Masses, Centres Científics i Tecnològics,
Universitat de Barcelona. Flash column chromatography was
performed on SDS silica gel 60 (35–70 μm). Analytical thin-
layer chromatography was carried out on Merck Kieselgel
60 F254 plates. All reactions were conducted in oven-dried glass-
ware with anhydrous solvents. The solvents and reagents were
purified and dried according to standard procedures.
Scheme 9 Reagents and conditions: (a) K2OsO4·2H2O (4 mol%),
NaIO4, 2,6-lutidine, 3 : 1 1,4-dioxane–H2O; (b) Na2CO3, MeOH, rt,
74% over two steps; (c) HF, CH3CN, rt, 78%.
Finally, treatment of 20 with acetic anhydride afforded poly-
acetylated deoxyaminosugar 21 as a 40 : 60 mixture of diastereo-
1
mers (Scheme 10), whose H and 13C NMR peaks for the major
(2S,4R,5S,6E)-4-Bromo-2-tert-butyldimethylsilyloxy-5-hydroxy-
6-octen-3-one (4). Recently distilled Ti(i-PrO)4 (1.66 mL,
5.6 mmol) was added to a solution of TiCl4 (615 μL, 5.6 mmol)
in CH2Cl2 (10 mL) at 0 °C under N2. The resultant mixture was
stirred for 10 min at 0 °C, diluted with CH2Cl2 (10 mL) and
further stirred for 10 min at room temperature, which afforded an
almost colorless solution. This TiCl2(i-PrO)2 solution in CH2Cl2
(11.2 mmol) was carefully added via cannula (+1 mL CH2Cl2)
to a solution of 3 (2.87 g, 10.2 mmol) in CH2Cl2 (30 mL) at
−78 °C under N2, which developed a yellow-orange color.
It was stirred for 3–4 min at −78 °C and i-Pr2NEt (1.95 mL,
11.2 mmol) was added dropwise. The resultant mixture was
stirred for 15 min at −78 °C and 1.5 h at −20 °C. Eventually, the
color of the reaction mixture became dark orange. Then, it was
cooled at −78 °C and recently distilled crotonaldehyde
(1.26 mL, 15.3 mmol) was added dropwise. The mixture was
stirred for 2 h at −78 °C and 1 h at −20 °C. The reaction
was quenched by addition of sat NH4Cl (50 mL). The mixture
was diluted with Et2O, washed with H2O, sat NaHCO3, and
brine, and the aqueous layers were extracted with Et2O.
The organic extracts were dried and concentrated. Spectroscopic
anomer matched to the data reported in the literature for the
β-1,2,4-tri-O-acetyl-3-amino-N-benzyloxycarbonyl-3,6-dideoxygluco-
pyranose.23
Scheme 10 Reagents and conditions: (a) Ac2O, pyr, rt, 95%.
Conclusions
Several protected L-3-amino-3,6-dideoxyaminosugars have been
prepared from an easily available lactate-derived ketone 3. The
kernel of our strategy lies on the titanium-mediated aldol reaction
of such chiral ketone followed by the SN2 substitution of the
bromine and the substrate-controlled reduction of the carbonyl
group. The introduction of the most important structural features
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analysis (1H NMR) of the residue showed a single diastereomer
of the expected aldol, which was purified by column chromato-
graphy (from hexanes–EtOAc 99 : 1 to 90 : 10) to afford 2.79 g
(7.9 mmol, 78%) of 4 as a colorless oil. Rf = 0.25 (hexanes–
EtOAc 90 : 10); [α]D +63.2 (c 1.00, CHCl3); IR (film): νmax
diluted with Et2O, washed with 1 M HCl, sat NaHCO3, and
brine. The organic layer was dried and concentrated and the
resulting residue was purified by column chromatography
(hexanes–EtOAc 90 : 10), affording 760 mg (1.90 mmol, 97%)
of 6 as a colorless oil. Rf = 0.35 (hexanes–EtOAc 90 : 10);
[α]D +18.2 (c 1.00, CHCl3); IR (film): νmax 2932, 2858, 2103,
3471, 2956, 2933, 2887, 2857, 1721, 1671, 1254, 1115 cm−1
;
1H NMR (400 MHz, CDCl3) δ 5.84 (1H, dqd, J 15.3, J 6.6,
J 1.1, CHvCHCH3), 5.44 (1H, ddq, J 15.3, J 6.5, J 1.7,
CHvCHCH3), 4.82 (1H, d, J 6.1, CHBr), 4.49–4.44 (1H, m,
CHOH), 4.31 (1H, q, J 6.9, CHOTBS), 1.71 (3H, ddd, J 6.6,
J 1.7, J 0.9, CHvCHCH3), 1.46 (3H, d, J 6.9, CH3CHOTBS),
0.93 (9H, s, SiC(CH3)3), 0.11 (3H, s, SiCH3), 0.09 (3H, s,
SiCH3); 13C NMR (100.6 MHz, CDCl3) δ 206.9, 130.8, 128.2,
73.8, 71.3, 50.3, 25.7, 22.4, 18.0, 17.8, −4.6, −5.0; HRMS
(ESI): m/z calcd for C14H2779BrNaO3Si [M + Na]+ 373.0805,
found 373.0798; calcd for C14H2781BrNaO3Si [M + Na]+
375.0780, found 375.0779.
1753, 1372, 1232 cm−1; H NMR (300 MHz, CDCl3) δ 5.95
1
(1H, dqd, J 15.3, J 6.6, J 0.7, CHvCHCH3), 5.50 (1H, ddq,
J 15.3, J 8.3, J 1.7, CHvCHCH3), 5.30–5.23 (1H, m,
AcOCHCHvCH), 4.95 (1H, dd, J 8.1, J 2.4, TBSOCH-
CHOAc), 4.01 (1H, dq, J 8.1, J 6.2, CHOTBS), 3.71 (1H, dd,
J 7.7, J 2.4, CHN3), 2.07 (3H, s, CH3CO2), 2.05 (3H, s,
CH3CO2), 1.75 (1H, dd, J 6.6, J 1.7, CHvCHCH3), 1.13 (3H,
d, J 6.2, CH3CHOTBS), 0.90 (9H, s, SiC(CH3)3), 0.10 (6H, s,
Si(CH3)2); 13C NMR (75.4 MHz, CDCl3) δ 169.8, 169.7, 133.7,
125.8, 74.4, 72.9, 66.9, 61.9, 25.8, 21.1, 20.7, 20.0, 18.0,
17.9, −4.1, −5.0; HRMS (ESI): m/z calcd for C18H34N3O5Si
[M + H]+ 400.2262, found 400.2261.
(2S,3R,4S,5S,6E)-4-Azido-2-tert-butyldimethylsilyloxy-6-octene-
3,5-diol (5). A mixture of 4 (1.846 g, 5.25 mmol) and NaN3
(358 mg, 5.5 mmol) in DMSO (20 mL) was stirred for 2 h at
room temperature under N2. It was diluted with Et2O and
washed with H2O and brine. The aqueous layers were extracted
with Et2O and the combined organic extracts were dried and
concentrated. Filtration of the residue through a short pad of
silica (hexanes–EtOAc 90 : 10) afforded a yellow oil, which was
used in the next step without further purification.
2,4-Di-O-acetyl-3-azido-3,6-dideoxy-α-L-mannopyranose (8). A
mixture of 6 (133 mg, 0.33 mmol), K2OsO4·2H2O (5 mg, 4 mol
%), NaIO4 (285 mg, 1.33 mmol), and 2,6-lutidine (80 μL,
0.69 mmol) in 3 : 1 1,4-dioxane–H2O (4 mL) was stirred at room
temperature for 4 h, when a TLC analysis showed that the start-
ing material had been consumed. It was diluted with Et2O and
washed with H2O. The aqueous layer was extracted with Et2O
and the organic extracts were dried and concentrated.
A solution of this oil in CH3CN (20 + 2 mL) was carefully
added to a mixture of Me4NHB(OAc)3 (11.16 g, 42.4 mmol) in
1 : 1 CH3CN–AcOH (50 mL) at −35 °C under N2 [the Me4NHB
(OAc)3 solution had been previously stirred for 1 h at room
temperature]. The stirring continued for 5 h and the reacting
mixture was kept in the fridge (−20 °C) overnight. Then, it was
stirred at 0 °C for 20 min, quenched by addition of 0.5 M solu-
tion of Rochelle salt (75 mL), and stirred for 1 h. It was diluted
with CH2Cl2, washed with sat NaHCO3, dried, and concentrated.
The resultant residue was purified by column chromatography
(from hexanes–EtOAc 98 : 2 to 80 : 20) affording 1.190 g
The residue containing aldehyde 7 was treated with 0.5 M HF
in CH3CN (2.8 mL, 1.4 mmol) and the resulting brown solution
was stirred for 4 h at room temperature. The reacting mixture
was diluted with Et2O, washed with sat NaHCO3, and the
aqueous layer was extracted with Et2O twice. The organic
extracts were dried and concentrated. The resulting brown oil
was purified by column chromatography (from hexanes–EtOAc
95 : 5 to 50 : 50) to obtain 61 mg (0.22 mmol, 67% yield over
two steps) of 8 as a colorless oil. Rf = 0.20 (hexanes–EtOAc
70 : 30); [α]D −13.3 (c 0.60, CHCl3); IR (film): νmax 3434,
2929, 2110, 1755, 1374, 1223, 1049 cm−1; 1H NMR (300 MHz,
CDCl3) δ 5.20–5.15 (2H, m, HOCHCHOAc), 5.09 (1H, pseudo
t, J ≈ 10.1, CH3CHCHOAc), 4.07 (1H, dq, J 9.8, J 6.2,
CH3CHO), 3.86 (1H, dd, J 10.4, J 3.2, CHN3), 3.00 (1H, br s,
OH), 2.16 (3H, s, CH3CO2), 2.15 (3H, s, CH3CO2), 1.22 (3H, d,
J 6.2, CH3CHO); 1H NMR (400 MHz, C6D6) δ 5.41 (1H,
pseudo t, J ≈ 10.0, CH3CHCHOAc), 5.21 (1H, dd, J 3.3, J 2.0,
HOCHCHOAc), 4.86 (1H, br s, CHOH), 3.88 (1H, dq, J 9.8,
J 6.3, CH3CHO), 3.72 (1H, dd, J 10.4, J 3.3, CHN3), 2.03 (1H,
br s, OH), 1.67 (3H, s, CH3CO2), 1.61 (3H, s, CH3CO2), 1.17
(3H, d, J 6.3, CH3CHO); 13C NMR (75.4 MHz, CDCl3)
δ 170.1, 169.6, 91.4, 71.6, 71.4, 66.4, 58.3, 20.9, 20.8, 17.4;
HRMS (ESI): m/z calcd for C10H15N3NaO6 [M + Na]+
296.0853, found 296.0852; calcd for C10H14N3O5 [M – OH]+
256.0927, found 256.0928.
1
(3.77 mmol, 72%) of 5 as a single diastereomer by H NMR.
Colorless oil. Rf = 0.25 (hexanes–EtOAc 80 : 20); [α]D +41.6
(c 1.10, CHCl3); IR (film): νmax 3402, 2958, 2933, 2889, 2860,
2107, 1675, 1465, 1258, 1092 cm−1 1H NMR (400 MHz,
;
CDCl3) δ 5.86 (1H, dqd, J 15.3, J 6.5, J 1.1, CHvCHCH3),
5.59 (1H, ddq, J 15.3, J 7.0, J 1.7, CHvCHCH3), 4.41–4.37
(1H, m, CHOHCHvCH), 3.83 (1H, dq, J 7.0, J 6.1, CHOTBS),
3.67–3.62 (1H, m, TBSOCHCHOH), 3.58 (1H, dd, J 5.1, J 2.5,
CHN3), 2.53 (1H, br s, OH), 2.32 (1H, br s, OH), 1.76 (1H, br
d, J 6.5, CHvCHCH3), 1.23 (3H, d, J 6.1, CH3CHOTBS), 0.89
(9H, s, SiC(CH3)3), 0.10 (3H, s, SiCH3), 0.09 (3H, s, SiCH3);
13C NMR (75.4 MHz, CDCl3) δ 130.2, 129.9, 74.8, 73.7, 68.6,
64.6, 25.8, 19.7, 17.9 (×2), −4.1, −5.0; HRMS (ESI): m/z calcd
for C14H30N3O3Si [M + H]+ 316.2051, found 316.2048; calcd
for C14H29N3NaO3Si [M + Na]+ 338.1870, found 338.1869.
(4S,5R)-4-((1S,2E)-1-Acetoxy-2-buten-1-yl)-5-((S)-1-tert-butyl-
dimethylsilyloxyethyl)-2-methyl-2-oxazoline (9a). A 1 M solu-
tion of PMe3 in THF (0.88 mL, 0.88 mmol) was added dropwise
to a solution of 6 (321 mg, 0.80 mmol) in toluene (3 mL) at
room temperature under N2. A few minutes later, a gas began to
evolve slowly and the stirring was kept for 45 min at room
(2S,3R,4S,5S,6E)-3,5-Di-O-acetyl-4-azido-2-O-tert-butyldimethyl-
silyl-6-octene-2,3,5-triol (6). A mixture of
5
(620 mg,
1.96 mmol), Ac2O (0.75 mL, 8.0 mmol), Et3N (2.2 mL,
15.8 mmol), and DMAP (25 mg, 0.2 mmol) in CH2Cl2 (30 mL)
was stirred at room temperature for 45 min under N2. It was
6400 | Org. Biomol. Chem., 2012, 10, 6395–6403
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temperature. The resulting mixture was diluted with CH2Cl2 and
washed with brine. The aqueous layer was extracted with
CH2Cl2 and the organic extracts were dried and concentrated.
The resulting oil was purified by column chromatography (from
hexanes–EtOAc 90 : 10 to 50 : 50) affording 257 mg
(0.72 mmol, 90%) of 9a and 11 mg (31 μmol, 4%) of a minor
oxazoline isomer, 9b.
(75.4 MHz, CDCl3) δ 169.9, 169.5, 155.8, 136.4, 132.1, 128.5,
128.2, 125.8, 74.8, 73.6, 67.4, 66.9, 52.0, 25.7, 21.1, 20.9, 19.6,
17.9, 17.8, −4.3, −5.1; HRMS (ESI): m/z calcd for
C26H42NO7Si [M + H]+ 508.2725, found 508.2726; calcd for
C26H41NNaO7Si [M + Na]+ 530.2544, found 530.2542.
2,4-Di-O-acetyl-N-benzyloxycarbonyl-L-mycosamine (14). The
same experimental procedure described for 8 was followed for
this material, obtaining 14 slightly contaminated by an unknown
9a: Colorless oil. Rf = 0.40 (hexanes–EtOAc 50 : 50); [α]D
−60.7 (c 0.95, CHCl3); IR (film): νmax 2931, 2858, 1748, 1679,
impurity. Rf
=
0.50 (hexanes–EtOAc 35 : 65); 1H NMR
1
1374, 1235, 1021 cm−1; H NMR (400 MHz, CDCl3) δ 5.80
(400 MHz, CDCl3) δ 7.40–7.29 (5H, m, ArH), 5.20 (1H, d,
J 1.7, OCHOH), 5.14 (1H, d, J 12.3, OCHaHbPh), 5.03 (1H, d,
J 12.3, OCHaHbPh), 5.00 (1H, dd, J 3.3, J 1.7, OCHOH-
CHOAc), 4.95 (1H, d, J 9.6, NH), 4.80 (1H, dd, J 10.6, J 9.9,
CH3CHCHOAc), 4.47–4.38 (1H, m, CHNH), 4.16 (1H, dq,
J 9.7, J 6.2, CH3CHO), 3.16 (1H, br s, OH), 2.14 (3H, s,
CH3CO2), 1.94 (3H, s, CH3CO2), 1.18 (3H, d, J 6.2, CH3CHO);
1H NMR (75.4 MHz, CDCl3) δ 171.1, 170.2, 155.7, 136.3,
128.5, 128.2, 91.0, 72.7, 72.2, 67.0, 66.2, 49.8, 21.0, 20.6, 17.5.
(1H, dqd, J 15.3, J 6.6, J 0.8, CHvCHCH3), 5.43 (1H, ddq,
J 15.3, J 7.2, J 1.6, CHvCHCH3), 5.22–5.18 (1H, m, AcOCH),
4.15 (1H, ddd, J 6.0, J 4.8, J 1.2, CHN), 4.06 (1H, dd, J 6.0,
J 3.7, TBSOCHCHO), 3.92 (1H, qd, J 6.4, J 3.7, CHOTBS),
2.06 (3H, s, CH3CO2), 1.98 (3H, d, J 1.2, NvCCH3), 1.72 (1H,
ddd, J 6.6, J 1.6, J 0.4, CHvCHCH3), 1.10 (3H, d, J 6.4,
CH3CHOTBS), 0.86 (9H, s, SiC(CH3)3), 0.06 (3H, s, SiCH3),
0.04 (3H, s, SiCH3); 13C NMR (75.4 MHz, CDCl3) δ 170.0,
165.7, 131.4, 125.9, 84.9, 75.9, 69.4, 68.5, 25.6, 21.2, 19.1,
17.9, 17.9, 13.9, −4.5, −4.9; HRMS (ESI): m/z calcd for
C18H34NO4Si [M + H]+ 356.2252, found 356.2260; calcd for
C18H33NNaO4Si [M + Na]+ 378.2071, found 378.2070.
(2S,3R,4S,5S,6E)-4-Azido-2-O-tert-butyldimethylsilyl-3,5-O-
isopropylidene-6-octene-2,3,5-triol (15). A solution of
5
(260 mg, 0.82 mmol) and a crystal of PPTS in 1 : 1 Me2C-
(OMe)2–CH2Cl2 (20 mL) was stirred at room temperature over-
night under N2. The mixture was concentrated and the resulting
white solid was purified by column chromatography (CH2Cl2)
affording 260 mg (0.73 mmol, 89%) of 15. Colorless oil. Rf =
0.60 (CH2Cl2); [α]D +66.5 (c 1.00, CHCl3); IR (film):
9b: Colorless oil. Rf = 0.45 (hexanes–EtOAc 50 : 50);
[α]D +64.3 (c 0.35, CHCl3); IR (film): νmax 2930, 2857, 1748,
1675, 1378, 1233, 1105 cm−1 1H NMR (300 MHz, CDCl3)
;
δ 5.77 (1H, dqd, J 15.2, J 6.6, J 1.0, CHvCHCH3), 5.41 (1H,
ddq, J 15.2, J 7.9, J 1.7, CHvCHCH3), 4.93–4.86 (1H, m,
OCHCHvCH), 4.82 (1H, dd, J 7.9, J 2.8, CHOAc), 4.43–4.36
(1H, m, CHN), 4.06 (1H, dq, J 7.9, J 6.3, CHOTBS), 2.06 (3H,
s, CH3CO2), 1.98 (3H, d, J 1.2, NvCCH3), 1.72 (1H, ddd,
J 6.6, J 1.6, J 0.7, CHvCHCH3), 1.08 (3H, d, J 6.3,
CH3CHOTBS), 0.88 (9H, s, SiC(CH3)3), 0.10 (3H, s, SiCH3),
0.08 (3H, s, SiCH3); 13C NMR (75.4 MHz, CDCl3) δ 170.2,
164.9, 130.9, 125.6, 82.1, 74.7, 67.8, 67.7, 25.8, 21.4, 19.9,
17.9, 17.9, 14.1, −4.3, −4.7; MS (CI): m/z (%) 356 [M + H]+
(100).
1
νmax 2931, 2860, 2099, 1472, 1258, 1225, 1113 cm−1; H NMR
(400 MHz, CDCl3) δ 5.87 (1H, dqd, J 15.3, J 6.5, J 1.0,
CHvCHCH3), 5.61 (1H, ddq,
J 15.3, J 7.1, J 1.7,
CHvCHCH3), 4.28–4.23 (1H, m, OCHCHvCHCH3), 3.98
(1H, dq, J 8.8, J 6.0, CHOTBS), 3.58 (1H, dd, J 8.8, J 3.5,
TBSOCHCHO), 3.48 (1H, dd, J 6.2, J 3.5, CHN3), 1.76
(3H, ddd, J 6.5, J 1.7, J 0.8, CHvCHCH3), 1.41 (3H, s,
(CH3)C(CH3)), 1.35 (3H, s, (CH3)C(CH3)), 1.20 (3H, d, J 6.0,
CH3CHOTBS), 0.89 (9H, s, SiC(CH3)3), 0.11 (6H, s, Si(CH3)2);
13C NMR (100.6 MHz, CDCl3) δ 130.1, 129.4, 101.2, 74.2,
73.8, 66.7, 62.9, 25.9, 24.5, 24.3, 20.9, 18.0, 17.9, −3.8, −5.0;
HRMS (ESI): m/z calcd for C17H33N3NaO3Si [M + Na]+
378.2183, found 378.2183.
(2S,3R,4S,5S,6E)-3,5-Di-O-acetyl-4-amino-N-benzyloxycarbonyl-
2-O-(tert-butyldimethylsilyl)-6-octene-2,3,5-triol (12). A 5%
Na2CO3 aq solution (5.2 mL, 2.5 mmol) was added to a solution
of 9 (180 mg, 0.5 mmol) and BnOCOCl (120 μL, 0.8 mmol) in
CH2Cl2 (5 mL) and the resulting mixture was stirred at room
temperature overnight under N2. It was diluted with Et2O,
washed with brine, and the aqueous layer was extracted with
Et2O. The organic extracts were dried and concentrated. The
residue was purified by column chromatography (from hexanes–
EtOAc 95 : 5 to 75 : 25), which furnished 248 mg (0.49 mmol,
96%) of 12 as a colorless oil. Rf = 0.35 (hexanes–EtOAc
90 : 10); [α]D −3.4 (c 1.1, CHCl3); IR (film): νmax 3357, 2955,
(2S,3R,4S,5S,6E)-4-Amino-N-benzyloxycarbonyl-2-O-tert-butyl-
dimethylsilyl-3,5-O-isopropylidene-6-octene-2,3,5-triol (16). A
1 M solution of PMe3 in THF (0.26 mL, 0.26 mmol) was added
dropwise to a solution of 15 (84 mg, 0.24 mmol) and H2O
(17 μL, 0.95 mmol) in THF (2 mL) at room temperature under
N2. The resulting mixture was stirred at room temperature
for 36 h and the volatiles were removed in vacuo using toluene
(3 × 4 mL).
Then, BnOCOCl (52 μL, 0.35 mmol) was slowly added to a
mixture of the residue and NaHCO3 (30 mg, 0.35 mmol) in
MeOH (2.75 mL) at 0 °C under N2. The resulting mixture was
stirred at this temperature for 5 min and at room temperature for
1.5 h. It was partitioned with CH2Cl2 and brine and the aqueous
layer was extracted with CH2Cl2. The organic extracts were dried
and concentrated. The resulting oil was purified by column
chromatography (from hexanes–EtOAc 98 : 2 to 90 : 10), to
obtain 105 mg (0.23 mmol, 96%) of 16. Colorless oil. Rf = 0.20
(hexanes–EtOAc 90 : 10); [α]D −9.5 (c 0.60, CHCl3); IR (film):
2931, 2857, 1736, 1508, 1373, 1234, 1055 cm−1
;
1H NMR
(400 MHz, CDCl3) δ 7.38–7.31 (5H, m, ArH), 5.78 (1H, dq,
J 15.3, J 6.6, CHvCHCH3), 5.48–5.40 (1H, m, CHvCHCH3),
5.14 (1H, d,
J 12.3, OCHaHbPh), 5.12–5.02 (2H, m,
AcOCHCHvCH and NH), 5.05 (1H, d, J 12.3, OCHaHbPh),
4.97 (1H, dd, J 6.4, J 1.8, TBSOCHCHOAc), 4.29–4.22 (1H, m,
CHNH), 3.91 (1H, quint, J 6.3, CHOTBS), 2.04 (3H, s,
CH3CO2), 2.01 (3H, s, CH3CO2), 1.66 (1H, dd, J 6.6, J 1.2,
CHvCHCH3), 1.12 (3H, d, J 6.3, CH3CHOTBS), 0.88 (9H, s,
SiC(CH3)3), 0.04 (3H, s, SiCH3), 0.03 (3H, s, SiCH3); 13C NMR
This journal is © The Royal Society of Chemistry 2012
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νmax 3393, 3033, 2955, 2930, 2856, 1729, 1505, 1380, 1253,
resulting brown oil was used in the next step without further
purification.
1
1223 cm−1; H NMR (400 MHz, CDCl3) δ 7.36–7.30 (5H, m,
ArH), 5.92 (1H, d, J 8.4, NH), 5.77 (1H, dq, J 15.2, J 6.2,
CHvCHCH3), 5.72–5.63 (1H, m, CHvCHCH3), 5.12 (1H, d,
J 12.4, PhCHaHbO), 5.05 (1H, d, J 12.4, PhCHaHbO), 4.16–4.11
(1H, m, OCHCHvCHCH3), 3.95–3.88 (2H, m, CHNH and
CHOTBS), 3.71 (1H, dd, J 6.0, J 3.6, TBSOCHCHO),
1.72 (3H, d, J 6.2, CHvCHCH3), 1.37 (3H, s, (CH3)C(CH3)),
1.36 (3H, s, (CH3)C(CH3)), 1.14 (3H, d, J 6.0, CH3CHOTBS),
0.88 (9H, s, SiC(CH3)3), 0.04 (3H, s, SiCH3), 0.03 (3H, s,
SiCH3); 13C NMR (75.4 MHz, CDCl3) δ 156.0, 136.7, 129.7,
128.4, 128.0, 127.9, 100.3, 76.1, 71.1, 68.2, 66.5, 51.8, 26.4,
25.8, 24.9, 20.0, 18.0, 17.9, −4.6, −5.1; HRMS (ESI): m/z calcd
for C25H41NNaO5Si [M + Na]+ 486.2646, found 486.2632.
A mixture of this residue and Na2CO3 (530 mg, 5.0 mmol) in
MeOH (15 mL) was stirred at room temperature under N2 for
36 h. The reaction mixture was partitioned with CH2Cl2 and
brine and the aqueous layer was extracted twice with CH2Cl2.
The organic extracts were dried and concentrated. The resultant
oil was purified by column chromatography (from hexanes–
EtOAc 95 : 5 to 70 : 30) affording 165 mg (0.36 mmol, 74%
yield over two steps) of 19. Colorless oil. Rf = 0.25 (hexanes–
EtOAc 70 : 30); [α]D +68.1 (c 0.65, CHCl3); IR (film): νmax
3366, 2955, 2930, 2896, 2856, 1741, 1724, 1506, 1471, 1259,
1
1207, 1122, 1097 cm−1; H NMR (300 MHz, CDCl3) δ 9.59
(1H, s, CHO), 7.40–7.30 (5H, m, ArH), 5.39 (1H, d, J 9.3, NH),
5.07 (1H, d, J 12.2, PhCHaHbO), 5.00 (1H, d, J 12.2,
PhCHaHbO), 4.45 (1H, d, J 1.7, CHCHO), 4.37 (1H, dt, J 9.3,
J 1.7, CHNH), 3.79 (1H, dq, J 7.6, J 6.1, CHOTBS), 3.66 (1H,
dd, J 7.6, J 1.7, TBSOCHCHO), 1.51 (3H, s, (CH3)C(CH3)),
1.46 (3H, s, (CH3)C(CH3)), 1.17 (3H, d, J 6.1, CH3CHOTBS),
0.88 (9H, s, SiC(CH3)3), 0.03 (3H, s, SiCH3), 0.00 (3H, s,
SiCH3); 13C NMR (75.4 MHz, CDCl3) δ 196.2, 155.8, 136.1,
128.5, 128.3, 128.2, 100.2, 79.0, 75.9, 67.1, 66.6, 45.3, 29.3,
25.9, 20.2, 18.9, 17.9, −4.2, −5.1; HRMS (ESI): m/z calcd for
C23H38NO6Si [M + H]+ 452.2463, found 452.2470.
N-Benzyloxycarbonyl-L-mycosamine (18). A mixture of 16
(38 mg, 82 μmol), K2OsO4·2H2O (1.5 mg, 4 mol%), NaIO4
(70 mg, 0.33 mmol), and 2,6-lutidine (19 μL, 0.17 mmol) in
3 : 1 1,4-dioxane–H2O (1 mL) was stirred at room temperature
for 2 h, when a TLC analysis showed that the starting material
had been consumed. It was diluted with Et2O and washed with
H2O. The aqueous layer was extracted with Et2O and the organic
extracts were dried and concentrated. The resulting brown oil
was used in the next step without further purification.
This residue was treated with 0.5 M HF in CH3CN (1.2 mL,
0.6 mmol) and the resulting brown solution was stirred for 2.5 h
at room temperature. The reacting mixture was diluted with
Et2O, washed with sat NaHCO3, and the aqueous layer was
extracted with EtOAc. The organic extracts were dried and con-
centrated. The resulting brown oil was purified by column
chromatography (from CH2Cl2 to CH2Cl2–MeOH 90 : 10) to
obtain 18 mg (60 μmol, 74% yield over two steps) of 18 as a
3-Amino-N-benzyloxycarbonyl-3,6-dideoxy-L-glucopyranose (20).
A 0.5 M solution of HF in CH3CN (1.1 mL, 0.55 mmol) was
added to 19 (35 mg, 77 μmol) and the resulting mixture was
stirred for 6 h at room temperature under N2. It was diluted with
a 70 : 30 mixture of sat brine–NaHCO3 (25 mL) and extracted
with EtOAc (6 × 25 mL). The organic layers were dried and con-
centrated and the resultant oil was purified by column chromato-
graphy (from CH2Cl2 to CH2Cl2–MeOH 90 : 10), which allowed
to isolate 18 mg (60 μmol, 78%) of 20 as a 40 : 60 mixture of
α- and β-anomers according to its 1H NMR. Rf = 0.20 (CH2Cl2–
MeOH 90 : 10); IR (KBr): νmax 3348, 2931, 1690, 1558, 1313,
1
65 : 35 mixture of α- and β-anomers according to its H NMR.
Rf = 0.20 (CH2Cl2–MeOH 90 : 10); IR (KBr): νmax 3440, 3320,
2966, 2912, 1689, 1544, 1264, 1076, 1048 cm−1 1H NMR
;
(400 MHz, CD3OD) δ for α-18 7.40–7.26 (5H, m, ArH),
5.09 (2H, s, OCH2Ph), 4.96 (1H, d, J 1.2, OCHOH), 3.93–3.88
(1H, m, CH3CHO), 3.93 (1H, dd, J 10.4, J 3.2, CHN),
3.78–3.75 (1H, m, OCHOHCHOH), 3.36–3.24 (2H, m,
1
1285, 1252, 1063 cm−1; H NMR (400 MHz, CD3OD) δ for
α-20 7.40–7.25 (5H, m, ArH), 5.10 (2H, s, OCH2Ph), 5.04 (1H,
d, J 3.7, OCHOH), 3.91 (1H, dq, J 9.5, J 6.3, CH3CHO),
3.80–3.72 (1H, m, CHNHCbz), 3.49–3.41 (1H, m, OCHOH-
CHOH), 3.05–2.98 (1H, m, OCH(CH3)CHOH), 1.21 (3H, d,
J 6.3, CH3); 1H NMR (400 MHz, CD3OD) δ for β-20 7.40–7.25
(5H, m, ArH), 5.10 (2H, s, OCH2Ph), 4.50 (1H, d, J 7.6,
OCHOH), 3.49–3.41 (1H, m, CHN), 3.39 (1H, dq, J 9.3, J 6.2,
CH3CHO), 3.19 (1H, dd, J 10.2, J 7.6, OCHOHCHOH),
3.09–3.02 (1H, m, OCH(CH3)CHOH), 1.27 (3H, d, J 6.2, CH3);
13C NMR (100.6 MHz, CD3OD) δ for α-20 93.5, 75.8, 72.4,
68.8, 57.5; 13C NMR (100.6 MHz, CD3OD) δ for β-20 159.7,
159.6, 138.4, 129.4, 128.9, 98.7, 75.5, 74.7, 74.5, 67.5, 61.0,
18.3; HRMS (ESI): m/z calcd for C14H19NNaO6 [M + Na]+
320.1104, found 320.1104.
1
CH3CHCHOH), 1.25 (3H, d, J 6.4, CH3); H NMR (400 MHz,
CD3OD) δ for β-18 7.40–7.26 (5H, m, ArH), 5.09 (2H, s,
OCH2Ph), 4.76 (1H, s, OCHOH), 3.78–3.75 (1H, m, OCHOH-
CHOH), 3.60 (1H, dd, J 10.0, J 3.2, CHN), 3.36–3.24 (2H, m,
CH3CHCHOH), 1.29 (3H, d, J 6.0, CH3); 13C NMR (75.4 MHz,
CD3OD) δ for α-18 158.8, 138.3, 129.4, 128.9, 95.4, 72.4, 72.0,
69.7, 67.5, 55.0, 18.3; 13C NMR (75.4 MHz, CD3OD) δ for
β-18 95.6, 74.7, 71.8, 58.3, 54.8; HRMS (ESI): m/z calcd
for C14H20NO6 [M + H]+ 298.1285, found 298.1299; calcd for
C14H19NNaO6 [M + Na]+ 320.1104, found 320.1104.
(2S,3R,4R,5S)-3-Amino-N-benzyloxycarbonyl-5-O-tert-butyldi-
methylsilyl-2,4-dihydroxy-2,4-O-isopropylidenehexanal (19). A
mixture of 16 (230 mg, 0.5 mmol), K2OsO4·2H2O (8.3 mg,
4 mol%), NaIO4 (430 mg, 2.0 mmol), and 2,6-lutidine (120 μL,
1.0 mmol) in 3 : 1 1,4-dioxane–H2O (6 mL) was stirred at room
temperature for 2 h, when a TLC analysis showed that the start-
ing material had been consumed. It was diluted with Et2O and
washed with H2O. The aqueous layer was extracted with Et2O
and the organic extracts were dried and concentrated. The
Acylation of 20. A solution of 20 (8.0 mg, 27 μmol) and
Ac2O (105 μL, 1.1 mmol) in pyridine (18 μL, 0.22 mmol) in a
small vial under N2 was stirred at room temperature for one day.
The reacting mixture was diluted with water (20 mL) and
extracted with EtOAc (3 × 20 mL). The organic extracts were
washed with brine, dried, and concentrated. The resultant oil was
purified by column chromatography (from hexanes–EtOAc
6402 | Org. Biomol. Chem., 2012, 10, 6395–6403
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View Article Online
6 For the role of mycosamine on the biological activity of amphotericin B,
see: (a) N. Matsumori, Y. Sawada and M. Murata, J. Am. Chem. Soc.,
2005, 127, 10667; (b) V. Paquet, A. A. Volmer and E. M. Carreira,
Chem.–Eur. J., 2008, 14, 2465; (c) D. S. Palacios, I. Dailey,
D. M. Siebert, B. C. Wilcock and M. D. Burke, Proc. Natl. Acad.
Sci. U. S. A., 2011, 108, 6733; (d) M. P. Croatt and E. M. Carreira, Org.
Lett., 2011, 13, 1390.
7 For a recent example, see: Y.-S. Lee, J.-W. Jung, S.-H. Kim, J.-K. Jung,
S.-M. Paek, N.-J. Kim, D.-J. Chang, J. Lee and Y.-G. Suh, Org. Lett.,
2010, 12, 2040, and references therein.
8 R. Rai, I. McAlexander and C.-W. T. Chang, Org. Prep. Proced. Int.,
2005, 37, 337.
9 S. Hanessian, S. Giroux and B. L. Merner, Design and Strategy in
Organic Synthesis: from the Chiron Approach to Catalysis, Wiley-VCH,
Weinheim, 2012.
95 : 5 to 65 : 35) affording 11.0 mg (26 μmol, 95%) of 1,2,4-tri-
O-acetyl-3-amino-N-benzyloxycarbonyl-3,6-dideoxy-L-gluco-
pyranose (21) as a 40 : 60 mixture of α- and β-anomers accord-
ing to its 1H NMR. White solid. Rf = 0.25 (hexanes–EtOAc
65 : 35); IR (KBr): νmax 3351, 3035, 2984, 2940, 1747, 1705,
1537, 1376, 1224, 1048 cm−1 1H NMR (400 MHz, CDCl3)
;
δ for α-21 7.39–7.25 (5H, m, ArH), 6.19 (1H, d, J 3.5,
OCHOAc), 5.20–5.00 (2H, m, OCH2Ph), 4.94 (1H, dd, J 11.1,
J 3.5, OCHOAcCHOAc), 4.80–4.75 (1H, m, NH), 4.65 (1H, t,
J 10.2, OCH(CH3)CHOAc), 4.28 (1H, pseudo q, J 10.6, CHN),
4.06–3.95 (1H, m, CH3CHO), 2.16 (3H, s, CH3CO2), 1.93 (3H,
s, CH3CO2), 1.92 (3H, s, CH3CO2), 1.17 (3H, d, J 6.3,
1
10 For an insightful analysis of ideality in synthesis, see: T. Gaich and
P. S. Baran, J. Org. Chem., 2010, 75, 4657.
CH3CHO); H NMR (400 MHz, CDCl3) δ for β-21 7.39–7.25
(5H, m, ArH), 5.70 (1H, d, J 8.4, OCHOAc), 5.20–5.00 (2H, m,
OCH2Ph), 4.90–4.82 (1H, m, NH), 4.89 (1H, dd, J 10.6, J 8.4,
OCHOAcCHOAc), 4.63 (1H, t, J 10.0, OCH(CH3)CHOAc),
4.06–3.95 (1H, m, CHN), 3.73 (1H, dq, J 9.5, J 6.3, CH3CHO),
2.09 (3H, s, CH3CO2), 1.93 (6H, s, CH3CO2), 1.22 (3H, d,
J 6.3, CH3CHO); 13C NMR (100.6 MHz, CDCl3) δ for α-21
89.0, 69.6, 68.4, 52.2, 17.4; 13C NMR (100.6 MHz, CDCl3)
δ for β-21 170.4, 170.1, 169.1, 169.0, 156.3, 156.1, 136.4,
136.4, 128.5, 128.1, 128.1, 128.0, 92.0, 73.5, 73.2, 72.0, 70.7,
66.8, 55.8, 20.9, 20.8, 20.5, 20.4, 17.3; HRMS (ESI): m/z calcd
for C20H25NNaO9 [M + Na]+ 446.1422, found 446.1412; calcd
for C20H29N2O9 [M + NH4]+ 441.1867, found 441.1863.
11 (a) K. C. Nicolaou, R. A. Daines, T. K. Chakraborty and Y. Ogawa,
J. Am. Chem. Soc., 1987, 109, 2821; (b) K. C. Nicolaou, R. A. Daines,
Y. Ogawa and T. K. Chakraborty, J. Am. Chem. Soc., 1988, 110, 4696.
12 For a more recent synthesis, see: J. M. Manthorpe, A. M. Szpilman and
E. M. Carreira, Synthesis, 2005, 3380.
13 M. Franck-Neumann, L. Miesch-Gross and C. Gateau, Eur. J. Org.
Chem., 2000, 3693.
14 For an enlightening example of the difficulties associated to the synthesis
of aminosugars and the attachment to the aglycone, see: (a) Z. Xu,
C. W. Johannes, D. S. La, G. E. Hofilena and A. H. Hoveyda, Tetrahe-
dron, 1997, 53, 16377; (b) Z. Xu, C. W. Johannes, A. F. Houri, D. S. La,
D. A. Cogan, G. E. Hofilena and A. H. Hoveyda, J. Am. Chem. Soc.,
1997, 119, 10302.
15 For other stereoselective approaches to the synthesis of aminosugars, see:
(a) J. A. Bodkin, G. B. Bacskay and M. D. McLeod, Org. Biomol.
Chem., 2008, 6, 2544; (b) F. Pfrengle and H.-U. Reissig, Chem. Soc.
Rev., 2010, 39, 549.
16 (a) J. Nebot, S. Figueras, P. Romea, F. Urpí and Y. Ji, Tetrahedron, 2006,
62, 11090; (b) J. Nebot, P. Romea and F. Urpí, J. Org. Chem., 2009, 74,
7518; (c) J. Esteve, C. Jiménez, J. Nebot, J. Velasco, P. Romea and
F. Urpí, Tetrahedron, 2011, 67, 6045.
17 Mycaminose is the common name for 3-dimethylamino-3,6-dideoxy-
glucopyranose, the aminosugar component of the 16-membered macro-
lide tylosin.
18 The relative configuration of 5 was secured by NMR analyses of isopro-
pylidene acetal 15 described in Scheme 8, see: (a) S. D. Rychnovsky
and D. J. Skalitzky, Tetrahedron Lett., 1990, 31, 945; (b) D. A. Evans,
D. L. Rieger and J. R. Gage, Tetrahedron Lett., 1990, 31, 7099;
(c) S. D. Rychnovsky, B. Rogers and G. Yang, J. Org. Chem., 1993, 58,
3511.
Acknowledgements
Financial support from the Spanish Ministerio de Ciencia e
Innovación (MICINN) and Fondos EU FEDER (Grant
CTQ2009-09692), and the Generalitat de Catalunya
(2009SGR825) as well as a doctorate studentship (Universitat de
Barcelona) to J. N. are gratefully acknowledged.
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