Synthesis of 2-nitroglycals from glycals using the tetrabutylammonium nitrate-trifluoroacetic anhydride-triethylamine reagent system and base-catalyzed ferrier rearrangement of acetylated 2-nitroglycals

Article abstract of DOI:10.1021/jo401165y

A reagent system comprising tetrabutylammonium nitrate-trifluoroacetic anhydride-triethylamine has been developed for the synthesis of 2-nitroglycals from various protected glycals. The base-catalyzed Ferrier rearrangement on tri-O-acetylated 2-nitroglycals has been reported for the first time. Reactivity of these nitroacetates and associated selectivity has been examined, and some of the products have been converted into 2,3-diamino-2,3-dideoxyglycosides and methyl N-acetyl-d-lividosaminide.

Full text of DOI:10.1021/jo401165y

Article
pubs.acs.org/joc
Synthesis of 2‑Nitroglycals from Glycals Using the
Tetrabutylammonium Nitrate−Trifluoroacetic Anhydride−
Triethylamine Reagent System and Base-Catalyzed Ferrier
Rearrangement of Acetylated 2‑Nitroglycals
Suresh Dharuman, Preeti Gupta, Pavan K. Kancharla, and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
S
* Supporting Information
ABSTRACT: A reagent system comprising tetrabutylammo-
nium nitrate−trifluoroacetic anhydride−triethylamine has
been developed for the synthesis of 2-nitroglycals from various
protected glycals. The base-catalyzed Ferrier rearrangement on
tri-O-acetylated 2-nitroglycals has been reported for the first
time. Reactivity of these nitroacetates and associated selectivity
has been examined, and some of the products have been
converted into 2,3-diamino-2,3-dideoxyglycosides and methyl
N-acetyl-D-lividosaminide.
is only soluble in acetonitrile. Therefore, we decided to use
tetrabutylammonium nitrate (TBAN), as a precursor for
nitronium ion, which is soluble in many organic solvents. In
this paper, we report our results on the development of a
reagent system TBAN−trifluoroacetic anhydride (TFAA)−
Et3N, which gives exclusively 2-nitroglycals from glycals
(Scheme 1), thus avoiding the formation of nitroacetamides.12
INTRODUCTION
■
The 2-nitroglycals have been recognized as important synthons
in carbohydrate chemistry in the recent past.1 This is because of
the presence of a conjugated nitroolefin and an enol ether
moiety that offer many possibilities of synthetic manipulations.
For example, such a combination makes these substrates useful
for the Michael addition, Diels−Alder reactions, (2 + 3)
cycloadditions etc.1,2 In addition, the nitro group can be
converted into many other useful functionalities such as a
carbonyl and an amino group, apart from it being reductively
removed.2 As a result, the 2-nitroglycals have been utilized as
excellent glycosyl donors1,3 in the synthesis of glycoproteins,4
glycosyl amino acids,5 and aminosugars.6 They are also used in
the synthesis of bicyclic hybrid molecules,5b,7 fused hetero-
cycles,8 C-glycosides,9 2C-branched sugars,10 etc. While a
number of methods have been reported2 for the preparation of
conjugated nitroalkenes, the synthesis of 2-nitroglycals is not
well-reported in the literature. Most of the reported
reactions3a,11 either employ harsh conditions or the reagents
are expensive, and hence, there is a need for developing better
alternatives given the synthetic potential of 2-nitroglycals.
Scheme 1. Methods for Conversion of Glycals to 2-
Nitroglycals
RESULTS AND DISCUSSION
■
It is assumed that in the present reagent system, nitronium
trifluoroacetate species D is generated in situ which reacts with
an olefin to form nitro trifluoroacetate F via a carbocation E as
shown in Scheme 2. Thus, treatment of an olefin with TBAN−
TFAA13 only and monitoring the progress of the reaction by
thin-layer chromatography indicated formation of more than
We have recently reported a reagent system comprising of
acetyl chloride−silver nitrate−acetonitrile12 which allows
conversion of glycals into the corresponding 2-nitroglycals as
well as 2-nitro-1-acetamides depending on the experimental
conditions. As we are mainly interested in the synthesis of 2-
nitroglycals and thus avoid the formation of nitroacetamide
byproducts occurring via acetonitrile attack at the carbocation,
we considered using other organic solvents. The change of
nitronium ion source thus became necessary since silver nitrate
Received: May 28, 2013
Published: August 9, 2013
© 2013 American Chemical Society
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Scheme 2. Tentative Mechanism for the Formation of
Nitroolefins
Table 1. Reactions of Various Glycals Using the Reagent
System TBAN−TFAA−Et3N
two products, and we assumed these to be a mixture of nitro
trifluoroacetates. Attempts to isolate these products led to
substantial decomposition. Hence, once the starting material
was completely consumed, based on TLC monitoring, 1.0
equiv of Et3N was added into the same pot to cause elimination
of the trifluoroacetate moieties to form nitroolefin G as a single
product.
The standardized experimental conditions require the use of
1.1 equiv of TBAN, 1.1 equiv of TFAA, followed by addition of
1.0 equiv of Et3N per 1.0 equiv of the olefin. Several glycals
were successfully converted to the corresponding 2-nitroglycals
in moderate to fairly good yields. Our results are summarized in
Table 1. 3,4,6-Tri-O-benzyl and 3,4,6-tri-O-acetyl glycals viz. 1a,
1b, 1c, and 1d were converted to the corresponding 2-
nitroglycals 2a, 2b, 2c, and 2d, and their spectral data were in
agreement with the reported data.5a,11b
In addition, we also performed the reaction of 3,4,6-tri-O-
methyl-D-glucal 1e, 4,6-O-benzylidene-D-glucal 1f, and 3,4-di-O-
benzyl-D-arabinal 1g to obtain the 2-nitroglycals 2e, 2f, and 2g,
respectively. The structures of these products were confirmed
1
from their spectral data. Thus, typically, in their H NMR
spectra the presence of a singlet for the C-1 olefin proton at δ
8.12−8.17 was observed. The IR spectra showed a strong peak
at 1501−1509 cm−1, which is characteristic of an unsaturated
nitro group. Likewise, the −OTBDPS-protected galactal 1h was
subjected to these reaction conditions to obtain the
corresponding 2-nitroglycal 2h in fairly good yield. These
examples clearly show that the acid-sensitive groups were not
affected in these reactions, and thus, this reagent system is more
mild and efficient as compared to previously reported methods.
This reagent system was also used to examine the reactivity
of some non-carbohydrate olefins. Thus, cyclohexene 3a, 2,3-
dihydropyran 3b, styrene 3c, and trans-stilbene 3d were
successfully converted to the corresponding conjugated nitro-
olefins 4a, 4b, 4c, and 4d in moderate to fairly good yields
whose spectral data matched with the literature reported
data14a−c,9b (Table 2). Interestingly, when trans-stilbene was
treated with this reagent system, the product obtained was cis-
a
Triethylamine was not used.
the hitherto unknown Ferrier rearrangement on tri-O-
acetylated 2-nitroglycals and examine the reactivity of these
nitro acetates and study the associated selectivity.
First, we treated 3,4,6-tri-O-acetyl-2-nitrogalactal with cyclo-
hexanol in the presence of a Lewis acid catalyst such as
TMSOTf or BF3·OEt2, but the desired rearranged product was
not formed. Next, we attempted the reaction using t-BuOK as a
base expecting that cyclohexanol might add to the nitroolefin in
a Michael addition fashion followed by the loss of the acetate
group to give the Ferrier type rearranged product. Unfortu-
nately, however, the reaction was very slow and did not
improve even after stirring for 24 h. It is known in the literature
that alcohols readily add to 3,4,6-tri-O-benzylated 2-nitro-
galactal in presence of DMAP3b as a catalyst to give the
corresponding Michael adducts. Following this protocol,
addition of 0.1 equiv of DMAP to the reaction mixture gave
the desired Ferrier product 6d in 78% yield, whose structure
1
α-nitrostilbene 4d. This was confirmed from its H NMR
spectrum and literature comparison, where olefinic proton
appears at δ 8.2 ppm for the cis-α-nitrostilbene but in the case
of trans-α-nitrostilbene it appears at δ 6.8 ppm.14d,e
Although the chemistry of benzyl-protected 2-nitroglycals
has been extensively studied by others as well as by
us,1,3−5,6b,7−10 the chemistry of acetylated nitroglycals is
surprisingly not very well known in the literature. In
continuation of our interest in exploring the chemistry of 2-
nitroglycals, and with the present results in hand, we wanted to
study the nucleophilic additions on acetylated 2-nitroglycals. As
the Ferrier rearrangement15 is an important method to obtain
O-glycosides from glycals, it was of interest to us to investigate
1
was confirmed from H NMR and IR spectral analysis. Thus,
typically a peak at δ 7.23 corresponding to C-3 olefin proton
was found to appear as a doublet in its H NMR spectrum. It
1
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Under the same reaction conditions, the same alcohols (5a−
e) were found to add on to tri-O-acetyl-2-nitro-D-glucal 2d also,
and again the products (7a−e) were obtained in moderate to
fairly good yields (Scheme 5).
Table 2. Reactions of Non-carbohydrate Olefins Using
TBAN−TFAA−Et3N Reagent System
Scheme 5. Addition of Various Alcohols to Tri-O-acetyl-2-
nitroglucal 2d
The stereochemistry of the newly generated stereocenter at
the anomeric carbon in galactal series was proved by the single-
crystal X-ray studies of the reference compound 6d.16 On the
other hand, in the glucal series the stereochemistry was
established by the spectral analysis, including NOE studies, of
compounds 17 and 18 (Scheme 9) obtained from 7a. The α
selectivity observed in the alcohol addition to both glucal as
well as galactal derivatives is interesting and can be explained by
using a transition-state model as shown in Scheme 6.
also showed a strong peak at 1537 cm−1 in the IR spectrum
corresponding to the stretching frequency of an unsaturated
nitro group. In order to confirm the role of DMAP, we
performed the reaction only in the presence of DMAP without
adding an extra base, and this also led to the rearranged product
in good yields. Finally, after exploring various conditions for the
addition of different alcohols to acetylated 2-nitroglycals, it was
found that DMAP alone was a suitable catalyst for the Ferrier
rearrangement. To the best of our knowledge, this is the first
base-catalyzed Ferrier rearrangement reported. Optimization
studies were carried out to conclude that 10 mol % of DMAP
and 1.1 equiv of an alcohol were sufficient to carry out this
transformation (Scheme 3).
Next, we studied the reactivity of nitrogen and sulfur
nucleophiles onto 2c and 2d. For this purpose, TMSN3 and
thiophenol were used as nucleophiles. To our surprise, the
azide and the thiophenol moieties were found to add at C-3,
instead of forming the expected Ferrier products by
nucleophilic attack at C-1. The structures of the products
1
were confirmed from spectral studies. Thus, in the H NMR
spectrum of 9a, the peak of C-1 olefinic proton appeared at δ
8.30, characteristic of an unsaturated nitroolefin. Further, in the
IR spectrum of 9a, a peak appeared at 2112 cm−1
corresponding to the azide group, along with a strong peak at
1508 cm−1, again characteristic of an unsaturated nitro group.
The products of azide and thiophenol addition were obtained
in fairly good yields, as summarized in Table 3. However,
addition of PhSH to 2d gave a mixture of products, as was
evident from the crude 1H NMR spectrum, which could not be
purified as they were unstable during column chromatographic
purification. The azide and SPh groups were equatorially
oriented at C-3 position which was confirmed at later stages by
analyzing the spectral details of some of the advanced
intermediates as shown in Schemes 7 and 8.
Proposed Mechanism. The selectivity in this Ferrier
rearrangement is believed to be entirely based on the role of
DMAP, which directs the attack of nucleophiles such as
alcohols, azide, and thiophenol moieties. Accordingly, the
addition of DMAP should occur preferably from the β-side in a
pseudo axial manner to replace the allylic acetate via SN2′
mechanism resulting in the transition state H (Scheme 6). The
oxygen nucleophiles then attack at C-1 in an SN2 fashion to
release DMAP to give axially oriented compounds K and L.
However, in the case of TMSN3 or PhSH, the attack takes place
at the C-3 position through SN2′ mechanism to give
equatorially oriented compounds I and J. The difference in
the regioselectivity can be explained on the basis of HSAB
concept,17 where oxygen nucleophiles being hard bases add on
to the hard acid center C-1. On the other hand, azide and
Scheme 3. Reaction of Acetylated 2-Nitroglycals with
Various Alcohols in the Presence of DMAP
Having the reaction conditions optimized, we then examined
the addition of different alcohols viz. 5a, 5b, 5c, and 5e to tri-O-
acetyl-2-nitro-D-galactal 2c which successfully gave the
corresponding rearranged products 6a, 6b, 6c, and 6e,
respectively, in moderate to fairly good yields (Scheme 4).
Scheme 4. Addition of Various Alcohols to Tri-O-acetyl-2-
nitrogalactal 2c
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Scheme 6. Proposed Mechanism for the Formation of C-1,C-3-Substituted Products
Scheme 7. Synthesis of Differentially Protected 2,3-Diamino-2,3-dideoxy Galactosides
NOE analysis (H-3/H-5, H-3/H-4, H-1/H-2) as shown in
Figure 1. Reduction of the NO2 group with Raney Ni followed
Table 3. Addition of TMSN3, PhSH to 3,4,6-tri-O-acetyl-2-
nitroglycals 2c and 2d
Figure 1. NOE analysis of compounds 11 and 14.
by protection of the crude amine as Cbz and Boc amines using
appropriate reagents as shown in Scheme 7 led to the formation
of differentially protected 2,3-diamino derivatives 12 and 13.
Likewise, compound 9c was treated with MeOH/t-BuOK to
give a single compound 14 in 91% yield. The stereochemistry
of the newly formed centers was established with the help of 1H
NMR (J1,2 = 3.9 Hz and J2,3 = 12.5 Hz) and 2D NMR
experiments, including NOE analysis (H-3/H-2, H-3/H-4, H-
1/H-2) as shown in Figure 1. The final compound 15 was
obtained by reducing the nitro group to amine with Zn/HCl/
AcOH, followed by acetylation using Ac2O and Et3N (Scheme
8). The use of Raney Ni to reduce the nitro group was avoided
as it was anticipated that the −SPh group at C-3 might undergo
reductive desulfurization.
thiophenol moieties are soft bases and thus prefer to add on
soft acid center C-3 (Scheme 6).
Synthesis of Differentially Protected 2,3-Diamines.
2,3-Diamino-2,3-dideoxy sugars are integral parts of lip-
opolysachharides which are found in Gram-negative bacteria.18
In the present study, it was envisaged that compound 9a (cf.
Table 3) could be a good precursor to obtain 2,3-diamino
sugars. With this view in consideration, addition of tert-butyl
alcohol to nitroolefin 9a was carried out in the presence of a
catalytic amount of t-BuOK. It is expected that the resulting O-
glycoside could serve as a glycosyl donor, after selective
deprotection19 of the −OtBu group to a free −OH at the
anomeric center, followed by its activation. The desired
Michael adduct 10 was obtained in 71% yield, the azido
group was selectively reduced using PPh3/H2O, and the
resulting amine was protected with acetyl chloride and Et3N
to form the N-acetyl derivative 11. The stereochemistry of the
Synthesis of Methyl N-Acetyl-4,6-di-O-acetyl-α-D-liv-
idosaminide (18). Lividosamine is a 2-amino-2,3-dideoxyglu-
coside that is present in the core structure of aminoglycoside
antibiotics lividomycin A and 3′-deoxykanamycin C.20 Hence,
Scheme 8. Synthesis of 2-Amino-3-phenylthio-2,3-dideoxy-
O-methyl Galactoside
1
newly formed stereocenters in 11 was confirmed from the H
NMR spectral analysis (J1,2 = 4.0 Hz and J2,3 = 11.6 Hz), and
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Scheme 9. Synthesis of Methyl N-Acetyl-α-D-lividosaminide
using freshly distilled and dry solvents. The visualization of spots on
TLC plates was effected by exposure to iodine or spraying with 10%
H2SO4 and charring. Column chromatography was performed over
silica gel (100−200 mesh) using hexane and ethyl acetate as eluents.
Mass spectra were obtained from high-resolution ESI mass
spectrometer using a Q-TOF analyzer.
the synthesis of methyl N-acetyl-α-D-lividosaminide has
assumed importance in recent years.6b,21 Application of the
above-described Ferrier rearrangement has been demonstrated
by utilizing the product 7a (cf. Scheme 5) for the synthesis of
methyl N-acetyl-α-D-lividosaminide as shown in Scheme 9.
Reduction of the double bond and the NO2 group in one pot is
a challenging task as the substrate 7a contains acetate groups.
Our initial attempts for one-pot reduction of nitroolefin with
reagents such as NaBH4, BH3·SMe2,22 and Raney Ni/H2 failed
to give the corresponding desired amine. However, reduction of
the double bond using Pd/C−H2, followed by the reduction of
the nitro group with the freshly prepared platinized Raney Ni
(T4),6b gave the desired amine. The crude amine, obtained
upon filtration of the catalyst, was acetylated using Ac2O and
Et3N. The diastereomeric mixture so obtained was separated
using a chromatotron (sold by Harrison Research, USA) to give
compounds 17 and 18 in a ratio of 1:2.1. The spectral data of
the major isomer viz. methyl N-acetyl-α-D-lividosaminide 18
was identical with the literature data reported for it.21a The
General Procedure (A) for Synthesis of Nitroolefins. To a
stirred solution of olefins (0.240 mmol) and tetrabutylammonium
nitrate (TBAN) (0.264 mmol) in dry CH2Cl2 (2 mL) at 0 °C under
N2 atmosphere was added dropwise trifluoroacetic anhydride (TFAA)
(0.264 mmol). After the addition was completed, the reaction was
brought to room temperature slowly and stirred for 1 h. On
consumption of starting material (TLC monitoring) the reaction
vessel was again cooled to 0 °C, Et3N (0.240 mmol) was slowly added
and the reaction mixture stirred for 15 min. After completion of the
reaction (single spot in TLC), the reaction mixture was quenched with
10 mL of ice−water. Extraction was done with CH2Cl2 (3 × 10 mL),
and the combined organic extracts were washed with water (1 × 10
mL) and brine (1 × 10 mL) and then dried over Na2SO4.
Concentration in vacuo gave a crude residue which was purified by
column chromatography to obtain pure nitroolefins.
(2R,4aR,8S,8aS)-7-Nitro-2-phenyl-4,4a,8,8a-tetrahydropyrano-
[3,2-d][1,3]dioxin-8-yl Acetate (2f). Using general procedure A,
compound 2f was isolated as a white solid: mp 171−175 °C; yield
52%; Rf 0.30 (hexane/ethyl acetate, 4:1); [α]2D8 = +170.0 (c 0.20,
CH2Cl2); IR (neat) νmax 2921, 2851, 1753, 1636, 1509, 1374, 1350,
1264, 1226, 1092 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H),
7.47−7.36 (m, 5H), 6.38 (d, J = 7.6 Hz, 1H), 5.55 (s, 1H), 4.51 (dd, J
= 5.2, 10.7 Hz, 1H), 4.12 (dd, J = 5.2, 10.4 Hz, 1H), 4.05−4.02 (m,
1H), 3.92 (t, J = 10.4, 1H), 2.10 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 169.5, 156.0, 136.0, 129.5, 128.4, 126.1, 101.7, 71.0, 67.3,
64.5, 20.8; HRMS calcd for C15H15NNaO7 [M + Na]+ 344.0746,
found 344.0746.
(3S,4S)-3,4-Bis(benzyloxy)-5-nitro-3,4-dihydro-2H-pyran (2g).
Using general procedure A, compound 2g was isolated as a colorless
oil: yield 72%; Rf 0.45 (hexane/ethyl acetate, 4:1); [α]2D8 = +200.0 (c
0.95, CH2Cl2); IR (neat) νmax 2924, 2870, 1635, 1501, 1455, 1343,
1279, 1225, 1090 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.12 (s, 1H),
7.39−7.27 (m, 10H), 5.00−4.99 (m, 1H), 4.93 (d, J = 10.6 Hz, 1H),
4.82 (d, J = 10.6 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 12.0
Hz, 1H), 4.23−4.15 (m, 2H), 3.81−3.77 (m, 1H); 13C NMR (125
MHz, CDCl3) δ 156.6, 138.0, 137.1, 131.9−127.7 (Ar-C), 74.6, 72.3,
71.8, 67.2, 64.3; HRMS calcd for C19H19NNaO5 [M + Na]+ 364.1161,
found 364.1167.
General Procedure (B) for Base-Catalyzed Ferrier Rearrange-
ment. To a stirred solution of an acetylated 2-nitroglycal (0.315
mmol) and an alcohol (0.347 mmol) in dry CH2Cl2 (2 mL) at room
temperature under N2 atmosphere was added DMAP (0.031 mmol),
and the reaction mixture was stirred for 2 h. After consumption of
starting material (TLC monitoring), evaporation of solvents in vacuo
gave a crude residue which was purified by column chromatography to
obtain pure product.
1
structure of the minor isomer 17 was confirmed by H NMR
studies where the signal at δ 5.88 as a doublet corresponds to
N−H proton. The stereochemistry of newly generated
stereocenter was confirmed from NOE experiments.16 The
optical rotation value of compound 17 matches with the
reported data.21c
Thus, methyl N-acetyl-α-D-lividosaminide was synthesized
from 3,4,6-tri-O-acetyl-2-nitroglucal via base-catalyzed Ferrier
rearrangement using methanol followed by simple synthetic
manipulations in only four steps. To the best of our knowledge,
this is the shortest and the most efficient method for the
synthesis of 18 so far.
CONCLUSIONS
■
A reagent system comprising tetrabutylammonium nitrate−
trifluoroacetic anhydride−triethylamine (TBAN−TFAA−
Et3N) has been developed for efficient synthesis of 2-
nitroglycals from glycals using mild reaction conditions. The
first example of base-catalyzed Ferrier rearrangement in glycals
with different alcohols has been reported using DMAP as a
catalyst. Under the same reaction conditions, azide and
thiophenol were added at C-3 position. Using this strategy,
products obtained were successfully converted to differentially
protected 2,3-diamino-2,3-dideoxy glycosides. Finally, a short
synthesis of methyl N-acetyl-D-lividosaminide has been carried
out in four steps.
EXPERIMENTAL SECTION
■
Methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-threo-hex-2-eno-
pyranoside (6a). Using general procedure B, compound 6a was
isolated as a colorless oil: yield 75%; Rf 0.60 (hexane/ethyl acetate,
4:1); [α]2D8 = −70.0 (c 0.30, CH2Cl2); IR (neat) νmax 2925, 2853, 1746,
1643, 1537, 1371, 1218, 1110, 1069 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.23 (d, J = 5.5 Hz, 1H), 5.54 (s, 1H), 5.38 (dd, J = 3.0, 5.8
Hz, 1H), 4.38−4.36 (m, 1H), 4.27−4.25 (m, 2H), 3.52 (s, 3H), 2.10
(s, 3H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5, 169.8,
General Experimental Methods. IR spectra were recorded with
FT-IR as a thin film or using KBr pellets and are expressed in cm−1. 1H
(500 MHz) and 13C (125 MHz) NMR spectra were recorded using
CDCl3 as a solvent. Chemical shifts are reported in ppm downfield to
tetramethylsilane. Coupling constants are reported and expressed in
hertz; splitting patterns are designated as br (broad), s (singlet), d
(doublet), dd (double doublet), m (multiplet). Optical rotations were
measured using a polarimeter at 28 °C. All reactions were carried out
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150.4, 127.8, 92.9, 66.2, 62.4, 61.8, 56.6, 20.8, 20.5; HRMS calcd for
C11H16NO8 [M + H]+ 290.0876, found 290.0878.
(4′-Methoxyphenyl)methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-
α-D-erythro-hex-2-enopyranoside (7c). Using general procedure B,
compound 7c was isolated as a colorless oil: yield 74%; Rf 0.30
(hexane/ethyl acetate, 4:1); [α]2D8 = +165.0 (c 0.80, CH2Cl2); IR
(neat) νmax 2939, 2838, 1746, 1536, 1371, 1354, 1227, 1113, 1070
cm−1; 1H NMR (500 MHz, CDCl3) δ 7.28−7.25 (m, 2H), 7.17 (d, J =
2.0 Hz, 1H), 6.89−6.87 (m, 2H), 5.66 (s, 1H), 5.57 (d, J = 10.6 Hz,
1H), 4.76 (d, J = 10.9 Hz, 1H), 4.66 (d, J = 10.9 Hz, 1H), 4.29−4.18
(m, 3H), 3.79 (s, 3H), 2.11 (s, 6H); 13C NMR (125 MHz, CDCl3) δ
170.6, 169.8, 159.7, 148.2, 132.8, 130.1, 128.4, 114.0, 91.6, 71.5, 66.5,
64.5, 62.0, 55.3, 20.8, 20.7. HRMS calcd for C18H21NNaO9 [M + Na]+
418.1114, found 418.1110.
Cyclohexyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-erythro-hex-
2-enopyranoside (7d). Using general procedure B, compound 7d
was isolated as a colorless oil: yield 62%; Rf 0.50 (hexane/ethyl acetate,
4:1); [α]2D8 = −62.5 (c 0.25, CH2Cl2); IR (neat) νmax 2936, 2859, 1747,
1682, 1536, 1369, 1350, 1222, 1109, 1059 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.14 (d, J = 2.3 Hz, 1H, H-3), 5.69 (s, 1H, H-1), 5.53 (dd, J
= 2.3, 9.6 Hz, 1H, H-4), 4.30−4.27 (m, 2H, H-6, H-6′), 4.23−4.22 (m,
1H, H-5), 3.76−3.74 (m, 1H, cyclohex-H), 2.13 (s, 3H, COCH3), 2.08
(s, 3H, COCH3), 1.93−1.87 (m, 2H, cyclohex-H), 1.73−1.70 (m, 2H,
cyclohex-H), 1.52−1.26 (m, 6H, cyclohex-H); 13C NMR (125 MHz,
CDCl3) δ 170.6, 169.9, 148.7, 132.2, 91.1, 78.6, 66.3, 64.6, 62.2, 33.4,
31.6, 25.5, 24.0 23.7, 20.8, 20.7; HRMS calcd for C16H23NNaO8 [M +
Na]+ 380.1321, found 380.1324.
Allyl 4,6-Di-O-acetyl-2,3-dideoxy2-nitro-α-D-erythro-hex-2-eno-
pyranoside (7e). Using general procedure B, compound 7e was
isolated as a colorless oil: yield 63%; Rf 0.50 (hexane/ethyl acetate,
4:1); [α]2D8 = +210.0 (c 0.50, CH2Cl2); IR (neat) νmax 2936, 2874,
1746, 1649, 1537, 1428, 1371, 1352, 1109, 1058 cm−1; 1H NMR (500
MHz, CDCl3) δ 7.18 (d, J = 2.1 Hz, 1H), 5.97−5.91 (m, 1H), 5.62 (s,
1H), 5.56 (dd, J = 2.1, 6.7 Hz, 1H), 5.33 (dd, J = 0.9, 17.4 Hz, 1H),
5.25 (dd, J = 0.9, 10.3 Hz, 1H), 4.32−4.20 (m, 5H), 2.13 (s, 3H), 2.10
(s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.6, 169.8, 148.2, 133.1,
132.8, 118.7, 91.4, 70.6, 66.4, 64.4, 62.0, 20.7; HRMS calcd for
C13H17NaNO8 [M + Na]+ 338.0852, found 338.0855.
General Procedure (C) for the Synthesis of 9a, 9b, and 9c.
To a stirred solution of an acetylated 2-nitroglycal (0.630 mmol) and
TMSN3 (0.694 mmol) or PhSH (0.694 mmol) in dry CH2Cl2 (2 mL)
was added DMAP (3.8 mg, 0.063 mmol) under N2 atmosphere at
room temperature, and the reaction mixture was stirred for 10−15
min. After the consumption of starting material (TLC monitoring),
concentration in vacuo gave a crude residue which was purified by
short column chromatography to obtain pure product (compounds
were not very stable in column).
Benzyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-threo-hex-2-eno-
pyranoside (6b). Using general procedure B, compound 6b was
isolated as a colorless oil: yield: 68%; Rf 0.40 (hexane/ethyl acetate,
4:1); [α]2D8 = −90.0 (c 0.40, CH2Cl2); IR (neat) νmax 2927, 1748, 1537,
1
1371, 1353, 1222, 1061, 1026 cm−1; H NMR (500 MHz, CDCl3) δ
7.38−7.31(m, 5H, Ar−H), 7.28 (d, J = 5.7 Hz, 1H, H-3), 5.77 (s, 1H,
H-1), 5.38 (dd, J = 2.8, 5.7 Hz, 1H, H-4), 4.83 (d, J = 11.2 Hz, 1H,
OCHPh), 4.72 (d, J = 11.2 Hz, 1H, OCHPh), 4.48−4.45 (m, 1H, H-
5), 4.29−4.20 (m, 2H, H-6, H-6′), 2.12 (s, 3H, COCH3), 2.09 (s, 3H,
COCH3); 13C NMR (125 MHz, CDCl3) δ 170.4, 169.7, 150.3, 136.1,
128.5−127.9 (Ar-C), 91.2, 71.3, 66.3, 62.4, 61.7, 20.7, 20.5; HRMS
calcd for C17H19NNaO8 [M + Na]+ 388.1008, found 388.1007.
(4′-Methoxyphenyl)methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-
α-D-threo-hex-2-enopyranoside (6c). Using general procedure B,
compound 6c was isolated as a colorless oil: yield 84%; Rf 0.35
(hexane/ethyl acetate, 4:1); [α]2D8 = −64.0 (c 0.50, CH2Cl2); IR (neat)
νmax 2937, 1748, 1612, 1536, 1515, 1370, 1354, 1248, 1223, 1060,
1029 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.28−7.25 (m, 3H), 6.90−
6.88 (m, 2H), 5.74 (s, 1H), 5.37 (dd, J = 2.7, 5.4 Hz, 1H), 4.76 (d, J =
10.9 Hz, 1H), 4.64 (d, J = 10.9 Hz, 1H), 4.47−4.44 (m, 1H), 4.28−
4.24 (m, 2H), 3.79 (s, 3H), 2.10 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 170.2, 169.8, 159.8, 150.5, 130.2, 128.2, 127.9, 114.0, 90.9,
71.0, 66.4, 62.5, 61.8, 55.3, 20.8, 20.5; HRMS calcd for C18H21NNaO9
[M + Na]+ 418.1114, found 418.1111.
Cyclohexyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-threo-hex-2-
enopyranoside (6d). Using general procedure B, compound 6d was
isolated as a colorless crystalline solid: mp 101− 104 °C yield 78%; Rf
0.50 (hexane/ethyl acetate, 4:1); [α]2D8 = −49.3 (c 0.75, CH2Cl2); IR
(neat) νmax 2936, 2859, 1747, 1537, 1370, 1224, 1063, 1031 cm−1; 1H
NMR (500 MHz, CDCl3) δ 7.23 (d, J = 5.7 Hz, 1H), 5.77 (s, 1H),
5.38 (dd, J = 2.9, 5.7 Hz, 1H), 4.49−4.46 (m, 1H), 4.28−4.21 (m,
2H), 3.78−3.74 (m, 1H), 2.10 (s, 3H), 2.06 (s, 3H), 1.93−1.91 (m,
2H), 1.73−1.70 (m, 2H), 1.53−1.19 (m, 6H); 13C NMR (125 MHz,
CDCl3) δ 170.5, 169.8, 151.0, 127.4, 90.7, 78.2, 66.2, 62.7, 61.9, 33.4,
31.5, 25.5, 24.0, 23.8, 20.7, 20.6; HRMS calcd for C16H23NNaO8 [M +
Na]+ 380.1321, found 380.1321.
Allyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-threo-hex-2-enopyr-
anoside (6e). Using general procedure B, compound 6e was isolated
as a colorless oil: yield 67%; Rf 0.40 (hexane/ethyl acetate, 4:1); [α]D28
= −54.0 (c 1.00, CH2Cl2); IR (neat) νmax 2937, 1748, 1645, 1537,
1371, 1352, 1221, 1106, 1063, 1028 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.27 (d, J = 5.5 Hz, 1H), 5.97−5.89 (m, 1H), 5.71 (s, 1H),
5.39 (dd, J = 2.7, 5.5 Hz, 1H), 5.31 (dd, J = 1.2, 17.1 Hz, 1H), 5.25
(dd, J = 1.2, 10.4 Hz, 1H), 4.44−4.41 (m, 1H), 4.30−4.18 (m, 4H),
2.10 (s, 3H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.5,
169.8, 150.4, 133.1, 127.9, 118.8, 90.9, 70.1, 66.3, 62.5, 61.8, 20.8, 20.6;
HRMS calcd for C13H18NO8 [M + H]+ 316.1032, found 316.1030.
Methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-erythro-hex-2-
enopyranoside (7a). Using general procedure B, compound 7a was
isolated as a colorless oil: yield 69%; Rf 0.50 (hexane/ethyl acetate,
4:1); [α]2D8 = +117.0 (c 0.35, CH2Cl2); IR (neat) νmax 2938, 1745,
1612, 1534, 1370, 1231, 1109, 1029 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.17 (d, J = 2.1 Hz, 1H), 5.57−5.55 (m, 1H), 5.46 (s, 1H),
4.28−4.18 (m, 3H), 3.54 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.6, 169.8, 148.1, 132.7, 128.1, 93.4, 66.3,
64.4, 62.03, 57.08, 20.79; HRMS calcd for C11H16NO8 [M + H]+
290.0876, found 290.0876
Benzyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-erythro-hex-2-
enopyranoside (7b). Using general procedure B, compound 7b was
isolated as a colorless oil: yield 56%; Rf 0.45 (hexane/ethyl acetate,
4:1); [α]2D8 = +128.0 (c 0.45, CH2Cl2); IR (neat) νmax 2936, 1745,
1535, 1370, 1350, 1221, 1082, 1025 cm−1; 1H NMR (500 MHz,
CDCl3) δ 7.36−7.33 (m, 5H), 7.19 (d, J = 2.1 Hz, 1H), 5.70 (s, 1H),
5.58 (d, J = 9.4 Hz, 1H), 4.83 (d, J = 11.3 Hz, 1H), 4.75 (d, J = 11.3
Hz, 1H), 4.28−4.16 (m, 3H), 2.12 (s, 3H), 2.10 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 170.6, 169.8, 148.1, 136.4, 132.9−128.4 (Ar−C),
91.9, 71.9, 66.5, 64.4, 61.9, 20.8, 20.7; HRMS calcd for C17H19NaNO8
[M + Na]+ 388.1008, found 388.1008.
((2R,3R,4R)-3-Acetoxy-4-azido-5-nitro-3,4-dihydro-2H-pyran-2-
yl)methyl Acetate (9a). Using general procedure C, compound 9a was
isolated as a colorless oil: yield 78%; Rf 0.60 (hexane/ethyl acetate,
4:1); [α]2D8 = +180.0 (c 0.35, CH2Cl2); IR (neat) νmax 2924, 2853,
2112, 1750, 1640, 1508, 1372, 1349, 1212, 1126, 1052 cm−1; 1H NMR
(500 MHz, CDCl3) δ 8.30 (s, 1H), 5.10 (d, J = 1.7 Hz, 1H), 4.78 (d, J
= 2.8 Hz, 1H), 4.34−4.28 (m, 3H), 2.11 (s, 6H) 13C NMR (125 MHz,
CDCl3) δ 170.3, 169.3, 155.5, 129.2, 72.9, 65.2, 61.0, 52.9, 20.7, 20.6.
HRMS calcd for C10H12NaN4O7 [M + Na]+ 323.0604, found
323.0604.
((2R,3S,4R)-3-Acetoxy-4-azido-5-nitro-3,4-dihydro-2H-pyran-2-
yl)methyl Acetate (9b). Using general procedure C, compound 9b
was isolated as a colorless oil: yield 65%; Rf 0.60 (hexane/ethyl acetate,
4:1); [α]2D8 = +215.0 (c 0.40, CH2Cl2); IR (neat) νmax 2923, 2111,
1748, 1641, 1509, 1369, 1349, 1211, 1158, 1050 cm−1; 1H NMR (500
MHz, CDCl3) δ 8.17 (s, 1H), 5.18 (d, J = 4.2 Hz, 1H), 5.10 (dd, J =
4.2, 10.5 Hz, 1H), 4.46−4.4.37 (m, 3H), 2.19 (s, 3H), 2.11 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 170.3, 169.3, 155.5, 129.2, 72.8, 65.3,
60.4, 53.4, 20.6, 20.4. HRMS calcd for C10H16N5O7 [M + NH4]+
318.1050, found 318.1051.
((2R,3S,4R)-3-Acetoxy-5-nitro-4-(phenylthio)-3,4-dihydro-2H-
pyran-2-yl)methyl Acetate (9c). Using general procedure C,
compound 9c was isolated as a colorless oil: yield 86%; Rf 0.55
(hexane/ethyl acetate, 4:1); [α]2D8 = +95.0 (c 0.20, CH2Cl2); IR (neat)
1
νmax 2964, 2850, 1749, 1638, 1508, 1371, 1344, 1211, 1026 cm−1; H
8447
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NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.60−7.57 (m, 2H), 7.38−
7.31 (m, 3H), 5.23 (d, J = 1.2 Hz, 1H), 4.77−4.74 (m, 1H), 4.39 (br s,
1H), 4.34−4.27 (m, 2H), 2.11 (s, 3H), 2.01 (s, 3H); 13CNMR (125
MHz, CDCl3) δ 170.4, 169.5, 154.4, 133.0−129.0 (Ar-C), 72.9, 66.9,
61.9, 43.2, 20.7; HRMS calcd for C16H18NO7S [M + H]+ 368.0804,
found 368.0803.
tert-Butyl 3-Acetamido-4,6-di-O-acetyl-2-(benzyloxycarbonyla-
mino)-2,3-dideoxy-α-D-galactopyranoside (12). Using general pro-
cedure D, compound 12 was isolated in 92% yield (over two steps) as
a colorless oil: Rf 0.60 (hexane/ethyl acetate, 1:2); [α]2D8 = +33.3 (c
0.15, CH2Cl2); IR (neat) νmax 3314, 2955, 2925, 2854, 1747, 1707,
1
1659, 1457, 1227, 1057 cm−1; H NMR (500 MHz, CDCl3) δ 7.36−
7.29 (m, 5H), 5.91 (d, J = 7.5 Hz, 1H), 5.31 (d, J = 2.5 Hz, 1H), 5.16
(d, J = 12.0 Hz, 1H), 5.14 (br s, 1H), 4.99 (d, J = 12.0 Hz, 1H), 4.91
(d, J = 9.7 Hz, 1H), 4.37−4.30 (m, 2H), 4.05−3.97 (m, 3H), 2.14 (s,
3H), 2.00 (s, 3H), 1.74 (s, 3H), 1.24 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 170.7, 170.5, 170.2, 157.3, 136.2, 128.6−128.1 (Ar−C),
92.0, 76.2, 68.9, 67.2, 66.9, 62.4, 49.8, 49.5, 37.1, 32.0, 29.7, 28.5, 23.0,
22.7, 20.8; HRMS calcd for C24H34N2NaO9 [M + Na]+ 517.2162,
found 517.2162.
tert-Butyl 4,6-Di-O-acetyl-3-azido-2,3-dideoxy-2-nitro-α-D-galac-
topyranoside (10). To a stirred solution of compound 9a (100 mg,
0.333 mmol) dissolved in t-BuOH (3 mL) was added t-BuOK (0.33
mg, 0.033 mmol), and the reaction mixture was stirred for 7 h. After
the consumption of starting material (TLC monitoring), t-BuOH was
evaporated to give a crude product which was dissolved in EtOAC (20
mL), washed with water (2 × 20 mL) and brine (2 × 10 mL), and
then dried over Na2SO4. Concentration in vacuo gave a crude residue
which was purified by column chromatography to obtain pure
compound 10: yield 102 mg (71%), colorless oil: Rf 0.70 (hexane/
ethyl acetate, 4:1); [α]2D8 = +80.0 (c 0.30, CH2Cl2); IR (neat) νmax
2980, 2920, 2850, 2117, 1750, 1640, 1561, 1372, 1226, 1122, 1016
cm−1; 1H NMR (500 MHz, CDCl3) δ 5.62 (d, J = 3.6 Hz, 1H), 5.51−
5.50 (m, 1H), 4.61 (dd, J = 4.0, 11.0 Hz, 1H), 4.56 (dd, J = 3.3, 11.0
Hz, 1H), 4.39−4.37 (m, 1H), 4.09−4.01 (m, 2H), 2.13 (s, 3H), 2.04
(s, 3H), 1.19 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 170.4, 169.8,
91.0, 82.8, 67.6, 66.7, 61.8, 56.9, 28.5, 27.9, 20.7, 20.6; HRMS calcd for
C14H26N5O8 [M + NH4]+ 392.1781, found 392.1781.
tert-Butyl 3-Acetamido-4,6-di-O-acetyl-2,3-dideoxy-2-nitro-α-D-
galactopyranoside (11). To a stirred solution of azido compound
10 (50 mg, 0.133 mmol) dissolved in THF (1 mL) were added PPh3
(52 mg, 0.200 mmol) and H2O (4 μL, 0.200 mmol) at room
temperature, and the reaction mixture was stirred for 8 h. After
consumption of the starting material (TLC monitoring), the reaction
mixture was quenched with 2 mL of H2O, extracted with EtOAc (2 ×
10 mL), washed with water (1 × 10 mL) and brine (1 × 10 mL), and
then dried over Na2SO4. Concentration under vacuum gave a crude
residue which was passed through a short silica gel column using 1%
Et3N in hexane/ethyl acetate (4:1) as eluent. Solvent was evaporated,
and the residue was dissolved in dry CH2Cl2 and cooled to 0 °C. To
this were added dry Et3N (0.022 mL) and acetyl chloride (0.011 mL)
followed by DMAP (1.6 mg) and the mixture stirred for 15 min. After
completion of reaction (TLC monitoring), the reaction mixture was
quenched with H2O (10 mL), extracted with CH2Cl2 (2 × 10 mL),
washed with brine (1 × 10 mL), and then dried over Na2SO4.
Concentration in vacuo gave a crude residue which was purified by
column chromatography to obtain pure compound 11 as a semisolid:
yield 30 mg (58% over two steps); Rf = 0.30 (hexane/ethyl acetate,
2:3), [α]2D8 = +117.0 (c 0.40, CH2Cl2); IR (neat) νmax 3379, 2976,
2923, 1748, 1656, 1557, 1371, 1226, 1060, 1015 cm−1; 1H NMR (500
MHz, CDCl3) δ 5.77 (d, J = 8.6 Hz, N−H), 5.63 (d, J = 4.0 Hz, 1H,
H-1), 5.39 (d, J = 3.5 Hz, 1H, H-4), 5.18−5.14 (m, 1H, H-3), 4.77
(dd, J = 4.0, 11.7 Hz, 1H, H-2), 4.46−4.43 (m, 1H, H-5), 4.03−4.01
(m, 2H, H-6, H-6′), 2.14 (s, 3H, COCH3), 2.03 (s, 3H, COCH3), 1.92
(s, 3H, NCOCH3), 1.19 (s, 9H, t-Bu−H); 13C NMR (125 MHz,
CDCl3) δ 170.5, 169.9, 169.7, 90.9, 82.7, 69.0, 67.0, 61.9, 45.6, 28.0,
23.1, 20.7; HRMS calcd for C16H26N2NaO9 [M + Na]+ 413.1536,
found 413.1536.
tert-Butyl 3-Acetamido-4,6-di-O-acetyl-2-(tert-butoxycarbonyla-
mino)-2,3-dideoxy-α-D-galactopyranoside (13). Using general pro-
cedure D, compound 13 was isolated in 87% yield (over two steps) as
a colorless oil: Rf 0.75 (hexane/ethyl acetate, 1:2), [α]2D8 = +128.0 (c
0.25, CH2Cl2); IR (neat) νmax 3346, 2977, 1748, 1695, 1454, 1392,
1
1299, 1171, 1051 cm−1; H NMR (500 MHz, CDCl3) δ 6.12 (br s,
1H), 5.32 (br s, 1H), 5.12 (br s, 1H), 4.64 (br s, 1H), 4.39−4.31 (m,
2H), 3.99−3.98 (m, 3H), 2.13 (s, 3H), 2.06 (s, 3H), 1.94 (s, 3H), 1.25
(s, 9H), 1.19 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 170.7, 170.5,
170.2, 157.0, 92.1, 80.4, 78.2, 78.0, 76.0, 68.9, 66.9, 62.5, 50.3, 48.7,
28.6, 28.3, 23.1, 20.8; HRMS calcd for C21H36N2NaO9 [M + Na]+
483.2319, Found 483.2311.
Methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-3-phenythio-α-D-gal-
actopyranoside (14). To a stirred solution of compound 9c (100 mg,
0.272 mmol), dissolved in MeOH (3 mL), was added t-BuOK (3.1
mg, 0.027 mmol), and the reaction mixture was stirred for 24 h. The
solvent MeOH was evaporated to give a crude product which was
dissolved in EtOAc (1 × 20 mL), washed with water (2 × 10 mL) and
brine (1 × 10 mL), and then dried over Na2SO4. Concentration in
vacuo gave a crude residue which was purified by column
chromatography to obtain 102 mg (91%) of pure compound 14 as
a colorless oil: Rf 0.55 (hexane/ethyl acetate, 4:1), [α]2D8 = +192.0 (c
0.55, CH2Cl2); IR (neat) νmax 2924, 2851, 1748, 1561, 1373, 1220,
1065 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.60−7.57 (m, 2H, Ar-H),
7.38−7.33 (m, 3H, Ar-H), 5.42 (d, J = 3.1 Hz, 1H, H-4), 5.20 (d, J =
3.9 Hz, 1H, H-1), 4.79 (dd, J = 3.9, 12.5 Hz, 1H, H-2), 4.12−4.08 (m,
2H, H-6, H-6′), 4.02−3.99 (m, 1H, H-5), 3.88 (dd, J = 3.3, 12.5 Hz,
1H, H-3), 3.36 (s, 3H, OCH3), 2.21 (s, 3H, COCH3), 2.06 (s, 3H,
COCH3); 13C NMR (125 MHz, CDCl3) δ 170.5, 169.9, 134.5−129.1
(Ar-C), 96.6, 83.4, 68.1, 67.7, 62.5, 55.7, 48.8, 20.8; HRMS calcd for
C17H21NaNO8S [M + Na]+ 422.0886, found 422.0882.
Methyl 2-Acetamido-4,6-di-O-acetyl-2,3-dideoxy-3-phenythio-α-
D-galactopyranoside (15). Compound 14 (60 mg, 0.150 mmol) was
dissolved in a mixture of THF (7 mL), concentrated HCl (0.3 mL),
acetic acid (1.6 mL), and H2O (3.0 mL) and cooled to 0 °C. Zn dust
(195 mg, 3.00 mmol) was added to it portionwise. After 1 h of stirring
at 0 °C, the residue was filtered, and the reaction mixture was diluted
with CH2Cl2 (20 mL), washed with water (1 × 10 mL), saturated
aqueous NaHCO3 (1 × 10 mL), and brine (1 × 10 mL), and dried
over anhydrous Na2SO4. After evaporation of the solvents, the crude
amine was dissolved in dry CH2Cl2 at 0 °C, treated with Et3N (0.025
mL, 0.180 mmol) and acetic anhydride (0.017 mL, 0.180 mmol)
followed by DMAP (2.0 mg, 0.014 mmol), and stirred for 15 min.
After completion of reaction (TLC monitoring), the reaction mixture
was quenched with H2O (5 mL), extracted with CH2Cl2 (3 × 10 mL),
washed with brine (1 × 10 mL), and then dried over Na2SO4.
Concentration in vacuo gave a crude residue which was purified by
column chromatography to obtain 34 mg (56% over 2 steps) of
compound 15 as a colorless oil: Rf 0.3 (hexane/ethyl acetate, 1:2),
[α]2D8 = +40.0 (c 0.40, CH2Cl2); IR (neat) νmax 3285, 2924, 2854, 1746,
General Procedure (D) for Raney Ni Hydrogenation. The
nitroacetamide 11 (50 mg, 0.128 mmol) was added to a stirred
solution of freshly prepared Raney nickel catalyst (100 mg) in EtOH,
and the reaction mixture was stirred under H2 atmosphere for 14 h at
room temperature. After completion of reaction (TLC monitoring),
the reaction mixture was filtered and the solvent was evaporated under
vacuum to give the crude amine. To this amine, dissolved in CH2Cl2
(1 mL), was added Et3N (0.021 mL, 0.153 mmol) and 50% CbzCl
(0.044 mL, 0.153 mmol) added to obtain product 12 or Boc2O (0.036
mL, 0.153 mmol) to obtain product 13. After 4 h of stirring at room
temperature, the reaction mixture was quenched with H2O (10 mL),
extracted with CH2Cl2 (3 × 10 mL), washed with brine (1 × 10 mL),
and then dried over Na2SO4. The solvent was evaporated and the
crude product was purified by column chromatography to obtain pure
products.
1
1660, 1440, 1226, 1127, 1054 cm−1; H NMR (500 MHz, CDCl3) δ
7.43−7.41 (m, 2H), 7.31−7.27 (m, 3H), 5.54 (d, J = 9.4 Hz, 1H), 5.32
(br s, 1H), 4.73 (d, J = 3.4 Hz, 1H), 4.55−4.50 (m, 1H), 4.11 (dd, J =
4.6, 11.2, 1H), 4.05−4.02 (m, 1H), 3.95 (dd, J = 7.4, 11.1 Hz, 1H),
3.44−3.36 (m, 1H), 3.35 (s, 3H), 2.17 (s, 3H), 2.03 (s, 3H), 1.96 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 170.6, 170.4, 170.0, 134.1−
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Article
128.0 (Ar-C), 98.3, 68.6, 67.9, 63.1, 55.2, 51.5, 48.2, 23.4, 20.8; HRMS
calcd for C19H25NaNO7S [M + Na]+ 434.1249, found 434.1250.
Methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-arabino-hexa-
pyronoside and Methyl 4,6-Di-O-acetyl-2,3-dideoxy-2-nitro-α-D-
ribo-hexapyronoside (16). To a solution of compound 7a (300 mg,
1.0 mmol) in EtOAc (5 mL) was added 10% Pd/C (30 mg). The
suspension was stirred under an atmosphere of H2 for 0.5 h at room
temperature. After consumption of the starting material (TLC
monitoring), the insoluble material was filtered off. The filtrate was
concentrated under reduced pressure to give a residue, which was
purified by silica gel column chromatography to afford compound 197
mg of 16 (65%) as a colorless oil: Rf 0.45 (hexane/ethyl acetate, 4:1);
ACKNOWLEDGMENTS
■
We thank the Department of Science and Technology, New
Delhi, for financial help in form of a J. C. Bose fellowship (JCB/
SR/S2/JCB-26/2010). S.D. thanks the CSIR, New Delhi, for a
senior research fellowship. P.G. and P.K.K. thank the University
Grants Commission for senior research fellowships.
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1
IR (neat) νmax 2924, 2851, 1744, 1556, 1372, 1236, 1047 cm−1; H
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NMR (500 MHz, CDCl3, 2.1:1 mixture of isomers) δ 5.25−5.24 (m,
1H, both isomer), 4.83−4.77 (m, 1H, both isomer), 4.59−4.55 (m,
1H, both isomer), 4.27−4.13 (m, 2H, both isomer), 3.96−3.92 (m,
1H, both isomer), 3.46 (s, 3H, minor isomer), 3.42 (s, 3H, major
isomer), 2.83−2.75 (m, 1H, minor isomer), 2.63−2.59 (m, 1H, major
isomer), 2.40−2.33 (m, 1H, major isomer), 2.10−2.07 (m, 1H, minor
isomer), 2.07−2.03 (s, 6H, both isomer); 13C NMR (125 MHz,
CDCl3) δ 170.7, 169.7, 97.0, 96.2, 82.0, 79.6, 75.1, 68.5, 68.0, 65.6,
63.4, 62.7, 62.1, 62.0, 55.8, 55.6, 27.0, 26.8, 20.9, 20.8; HRMS calcd for
C11H17NaNO8 [M + Na]+ 314.0852, found 314.0853
Procedure for Synthesis of Methyl N-Acetyl-α-D-lividosami-
nide (18) and Its Isomer (17). To a solution of compound 16 (200
mg, 0.686 mmol) in 2 mL of EtOAc was added freshly prepared
platinised Raney Ni (T4) (400 mg) in ethanol, and the reaction
mixture was stirred for 12 h under H2 atmosphere at room
temperature. After completion of the reaction, the mixture was filtered
through a Celite pad and washed with MeOH, and the filtrate was
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(0.11 mL) and acetic anhydride (0.076 mL) followed by DMAP (8
mg), and the mixture was stirred for 0.5 h. The reaction mixture was
quenched with H2O (15 mL), extracted with CH2Cl2 (2 × 20 mL),
washed with brine (1 × 20 mL), and then dried over Na2SO4.
Concentration in vacuo gave a crude mixture of diastereomers which
were separated by using chromatotron to obtain 17 and 18 in 24% and
50% yields, respectively.
Methyl 2-acetamido-4,6-di-O-acetyl-2,3-dideoxy-α-D-arabino-
hexapyronoside (17): yield 24%; Rf = 0.1 (hexane/ethyl acetate,
1:4); [α]2D5 = +68.0 (c 0.25, CH2Cl2) [lit.21c [α]2D5= +67.3 (c 1.0,
CHCl3)]; 1H NMR (500 MHz, CDCl3) δ 5.88 (d, J = 8.0 Hz, N−H),
4.83 (dt, J = 5.1, 10.8 Hz, H-4), 4.52 (br s, 1H, H-1), 4.26−4.24 (m,
1H, H-6′), 4.22−4.20 (m, 1H, H-2), 4.10 (dd, J = 2.3, 12.0 Hz, H-6),
3.94 (ddd, J = 2.3, 5.7, 8.0 Hz, H-5), 3.38 (s, 3H, OCH3), 2.12−1.96
(m, 2H, H-3, H-3′), 2.09 (s, 3H, COCH3), 2.04 (s, 3H, COCH3), 2.01
(s, 3H, NCOCH3); 13C NMR (125 MHz, CDCl3) δ 170.8, 170.1,
169.6, 99.2, 68.2, 64.4, 63.0, 55.1, 47.8, 29.7, 23.5, 21.0; HRMS calcd
for C13H22NO7 [M + H]+ 304.1396, found 304.1390.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Details on general experimental methods, structural character-
ization of compounds 2f−17, copies of 1H NMR and 13C NMR
spectra of all the new compounds, COSY and NOE spectra of
the compounds 11, 14, and 17, and crystallographic details for
compound 6d (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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N. R.; Flewelling, S. A.; MacDonald, J. P.; Downey, C. R.; Cohen, E.
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AUTHOR INFORMATION
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Corresponding Author
*Fax: 0091-512-259 0007. E-mail: vankar@iitk.ac.in.
J.; Zubkov, O. A. Org. React. 2003, 62, 569−736. (d) Vorbruggen, H.;
̈
Notes
Ruh-Pohlenz, C. Org. React. 2000, 55, 1−630.
(16) See the Supporting Information.
The authors declare no competing financial interest.
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