Ceric ammonium nitrate-catalyzed azidation of 1,2-anhydro sugars: Application in the synthesis of structurally diverse sugar-derived morpholine 1,2,3-triazoles and 1,4-oxazin-2-ones

Article abstract of DOI:10.1021/jo200260w

Azidation of 1,2-anhydro sugars with NaN₃ in CH₃CN by using a catalytic amount of ceric ammonium nitrate has been accomplished in a regio- and stereoselective manner. Various 1,2-anhydro sugars produced 2-hydroxy-1-azido sugars in good yields which, in turn, were converted to structurally diverse sugar-derived morpholine triazoles and sugar oxazin-2-ones. These sugar derivatives were tested against various commercially available glycosidases, and two of them were found to be active in the micromolar range.

Full text of DOI:10.1021/jo200260w

ARTICLE
pubs.acs.org/joc
Ceric Ammonium Nitrate-Catalyzed Azidation of 1,2-Anhydro Sugars:
Application in the Synthesis of Structurally Diverse Sugar-Derived
Morpholine 1,2,3-Triazoles and 1,4-Oxazin-2-ones
Y. Suman Reddy, A. P. John Pal, Preeti Gupta, Alafia A. Ansari, and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur ꢀ208 016, India
S Supporting Information
b
ABSTRACT: Azidation of 1,2-anhydro sugars with NaN3 in CH3CN
by using a catalytic amount of ceric ammonium nitrate has been
accomplished in a regio- and stereoselective manner. Various 1,2-
anhydro sugars produced 2-hydroxy-1-azido sugars in good yields
which, in turn, were converted to structurally diverse sugar-derived
morpholine triazoles and sugar oxazin-2-ones. These sugar deriva-
tives were tested against various commercially available glycosidases,
and two of them were found to be active in the micromolar range.
’ INTRODUCTION
Further, the Ferrier type of rearrangement, using Me3SiN3 along
with a Lewis acid-like Yb(OTf)3,19a Sc(OTf)3,19b and InBr3
19c
The importance of 1,2,3-triazole derivatives as biologically
important molecules having activities such as antibacterial,1 anti-
HIV,2 herbicidal,3 antitumor,4 tuberculosis inhibition,5 tyrosinase
inhibition,6 antiallergic,7 and glycosidase inhibition8 has been
well documented in the literature in recent years. As a result,
several reports have appeared9 dealing with the synthesis of a
variety of triazole derivatives including carbohydrate-fused
triazoles.10 Likewise, the morpholine moiety has been found to
be an excellent pharmacophore in medicinal chemistry11 and it
has been a part of a number of important drugs currently on the
market.11a,gꢀj Therefore, many new approaches toward the synth-
esis of morpholine derivatives have been reported in the literature.12
The preparation of 1,2,3-triazoles is conveniently performed by
using the well-known13 “click chemistry” whereby an acetylene
and an azide moiety are readily fused under a modified protocol.14 It
would thus be interesting to synthesize molecules possessing these
moieties fused with carbohydrates and evaluate their biological
properties.
For this purpose, D-glycosyl azides could act as useful entities
which are also known to be powerful building blocks in organic as
well as in medicinal chemistry.15 Nitrogen atom attached to the
anomeric carbon in the form of an azide group can be used for the
synthesis of N-glycopeptides,16a,b and amino sugars.16c Further,
the nitrogen atom attached to the anomeric carbon could play a
predominant role in the synthesis of monocyclic17aꢀc and bicyclic
iminosugars17d,e as useful glycosidase inhibitors. D-Glycopyrano-
syl azides can be obtained from direct nucleophilic displacement
by an azide group using Me3SiN3 or metal azides (lithium, sodium,
or silver) as nucleophilic azide sources18 and leaving groups such as
an acetate or a halide moiety (chloride or bromide) at the
anomeric center of a carbohydrate molecule. We have recently
developed a novel reagent system comprising Me3SiN3 and
Me3SiONO2 to convert glycals to 1-azido-2-deoxy sugars.16a
has been reported to obtain enopyranosyl azides. Azidation of
1,2-anhydro sugars using lithium azide and THF in the presence
of DIBAL as a Lewis acid catalyst has been reported by Chung
et al.20a Ceric ammonium nitrate (CAN) is a versatile reagent and
is used for a variety of functional group transformations.20b
Among them, regioselective azidolysis of noncarbohydrate ep-
oxides by using NaN3 in t-BuOH and CAN as a catalyst under
refluxing conditions, as reported by Iranpoor and Kazemi,20c
caught our attention for the present study. Although the reagent
system works well with a variety of epoxides, the solvent as
t-BuOH and the refluxing conditions did not seem to be compatible
for use on 1,2-anhydro sugars in the present study. Hence, we have
used a modified solvent system, viz., acetonitrile and water, that
works well with a number of 1,2-anyhdro sugars.
In conjunction with our continued interest toward the func-
tionalization of glycals16a,c,21 for possible application toward the
synthesis of N-glycopetides,16a and other useful synthons,16c and
the synthesis of glycosidase inhibitors17a,b,e,22 we hereby report
an extremely simple and mild method using ceric ammonium
nitrate (CAN)-catalyzed opening of 1,2-anyhdro sugars to form
vicinal trans-azido alcohols. Further, we also report the utility of
these azido alcohols in the synthesis of carbohydrate-fused
morpholine triazoles and carbohydrate-fused 1,4-oxazin-2-ones
and report their glycosidase inhibition activity.
’ RESULTS AND DISCUSSION
Preparation of 1,2-anhydro sugars was carried out from the
corresponding glycals by reaction with the in situ-generated
dimethyl dioxirane (DMDO) by following a procedure developed
Received: February 7, 2011
Published: June 16, 2011
r
2011 American Chemical Society
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Scheme 1. Reaction of 1,2-Anhydroglucopyranose 1a with
NaN3 in the Presence of CAN
Table 1. Conversion of 1,2-Anhydro Sugars to 1,2-Azido
Alcohols
by Dondoni et al.23 (Scheme 1). In initially attempted experi-
ments, treatment of l,2-anhydro-3,4,6-tri-O- benzyl-D-glucopyr-
anose 1a with the reagent system comprising 10 mol % of CAN
and 3 equiv of sodium azide in acetonitrile for a long time led to
no reaction. However, addition of a drop of water allowed the
reaction to be completed within 5 min, and 3,4,6-tri-O-benzyl-β-
D-glucopyranosyl azide 2a24 was obtained in 80% yield as the
only product.
The spectral data of this compound was an absolute match
with the literature data.24 The stereochemistry of the product was
found to be trans with the anomeric proton appearing as a doublet at
δ 4.51 with J = 8.8 Hz, which indicated that this reaction proceeded
through a regio- and stereoselective oxirane ring-opening via an SN2
mechanism. The reaction was compatible with other protecting
groups such as p-methoxy benzyl ethers and acetates. Thus,
examination of the other glycal-derived 1,2-anhydro sugars
(Table 1) such as 1,2-anhydro-3,4-di-O-benzyl-6-deoxy-D-gluco-
pyranose 1b,25 1,2-anhydro-3,4,6-tri-O-(p-methoxy)benzyl-D-
glucopyranose 1c,26 1,2-anhydro-3,4,6-tri-O-acetyl-D-glucopyra-
nose 1d,23 and 1,2-anhydro-3,4-di-O-benzyl-D-xylopyranose 1e27
led to the formation of the corresponding glycopyranosyl azido
alcohols in moderate to good yields (Table 1) with β-selectivity.25
Consequently, the azido alcohols were also converted into
morpholine triazoles (vide infra) whose structural elucidation
also confirmed that these are trans-azido alcohols. The reaction
was then extended to other 1,2-anhydropyranoses, such as 1,2-
anhydro-3,4-di-O-benzyl-L-arabinopyranose28 1f which afforded
compound 2f in good yield (83%), however, as a mixture of
diastereomers in a 8:2 ratio with R-anomer 2f-r having formed as
the minor product. The stereochemistry of the major product
was found to be trans with the anomeric proton appearing as a
doublet at δ 4.44 with J = 8.3 Hz, whereas for the minor product
(R-isomer) the anomeric proton appeared as a doublet at δ 5.41
with J = 3.6 Hz. We then studied the reaction of the galacto
derivative 1g23 under similar conditions, which afforded a mixture of
diastereomers 2g again in 8:2 ratio but in excellent yield.
a Yields of chromatographically pure compounds. b Combined yields of
both anomers after column chromatography.
Further, 1,2-anhydro-3,5-di-O-benzyl-D-lyxofuranose 1h and
1,2-anhydro-3,5,6-tri-O-benzyl-D-glucofuranose 1i were also
synthesized by using a known literature procedure29 and were
converted into the corresponding azido alcohols 2h and 2i,
respectively, in moderate yields (Table 1).25 The coupling
constant of the anomeric proton (H-2) at δ 4.53 being 2.4 Hz
indicated15b the trans relationship between H-2 and H-3 in
compound 2h which ascertains that the reaction proceeded
through a regio- and stereoselective oxirane ring-opening mostly
via an SN2 mechanism. Besides, the stereochemical outcome was
also confirmed from the Hꢀ H COSY and NOE (Figure 1)
spectral data. In an NOE experiment, irradiation of the signal for
H-6 and H-60 led to the enhancement of the signal for H-2, and
there was no enhancement of the signals for H-3 and H-4.
Likewise, irradiation of the signal for H-3 led to the enhancement
of the signal for H-5 and there was no enhancement of the signal
for H-6 and H-60. This indicated that the carbon side chain,
benzyloxy group at C-4, and hydroxyl group at C-3 are in cis
Figure 1. 1H NOE correlations of compound 2h.
relationship with each other. Thus, it was concluded that the
azide group at the anomeric carbon is R-oriented and conse-
quently the absolute stereochemistry at the anomeric center (i.e.,
C-2) and at C-3 being 2S and 3S, respectively.
A tentative mechanism for this transformation is shown in
Scheme 2. The reaction is presumably initiated by the electron
transfer from oxirane ring to the CAN, and regio- and stereo-
selective concomitant opening by sodium azide, through an SN2
mechanism, could lead to the product formation. It was observed
that glucal derivatives gave better selectivity than the galactal
1
1
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derivatives which in turn gave a mixture of the R and β glycosyl
azides (Table 1). This is not surprising, as the lack of stereo-
selectivity in ring-opening of galacto-1,2-anhydropyranosugars
has been previously observed by Danishefsky and co-workers.30
After the development of an improved protocol for Huisgen
1,3-dipolar cycloaddition between azides and alkynes by
Sharpless,13,14 the reaction has witnessed a renewed interest to
procure a variety of biologically important 1,2,3-triazoles. Be-
cause we were able to prepare stereoselectively the 1,2-azido
alcohols from 1,2-anhydro sugars easily, we have explored the
conversion of D-glycopyranosyl azido alcohols into tricyclic
[1,2,3]triazolo[1,5-d][1,4]oxazines upon sequential alkylation
with propargyl bromide followed by intramolecular thermal
cycloaddition reaction (Scheme 3). These molecules were pre-
pared with a view to assess their glycosidase inhibition activities,
as 1,2,3-triazole derivatives have been reported8 to be glycosidase
inhibitors.
the structure assigned to it. A few more azido alcohols, viz., 2b,
2e, 2f (β-isomer), 2g (β-isomer), 2h, and 2i, were also subjected
to the sequential alkynylation and cyclization. In the case of
galacto-configured azides 2f, 2g, 2h, and 2i, the reaction mixture
required heating to effect cycloaddition to form the triazole-fused
tricyclic compounds 7 (88%), 8 (90%), 9 (90%), and 10 (92%)
respectively.
In order to increase structural diversity, compound 4 was
subjected to global deprotection with 20% Pd(OH)2/C in
methanol at 5 atm H2 for 30 h, which resulted in the removal
of all the benzyl protecting groups to form product 11 in 93%
yield. The tricyclic compound 11 represents a combination of
D-glucose, morpholine, and triazole whose structure and stereo-
1
chemical outcome was deduced from 1Hꢀ H COSY and
1
1Hꢀ H NOESY experiments along with mass spectral data of
its peracetylated derivative 18. Compound 11 was acetylated
using the standard conditions (Ac2O/Py) to get the triacetate 18
1
Thus, compound 2a upon treatment with propargyl bromide
in the presence of NaH in DMF gave the propargylated azido
compound 3 which was not isolated, and the crude reaction
mixture was further quenched with water and stirred at room
temperature for a further 15 min to afford the triazole-fused
in 88% yield. Two-dimensional H NMR spectral studies of
compound 18 showed cross-peaks (Figure 2) between H-9a,
1
1
H-6, and H-8 in the Hꢀ H NOESY spectrum, and no cross-
peaks were observed between H-7 and H-9a. This indicated that
H-9a, H-6, and H-8 are in cis relationship.
1
tricyclic molecule 4 in 96% yield. The H NMR spectrum of 4
An interaction between H-5a and H-7 proton signals was also
observed. No interaction signals were observed between H-5a
and H-8, indicating that H-5a, H-7, and the hydroxylmethyl
moiety are in cis relationship. Therefore it was concluded that the
orientation of the nitrogen at the anomeric center (i.e., C-9a) and
showed a sharp singlet at δ 7.52 near the aromatic region, typical
for the 1,2,3-triazole hydrogen. In addition, the absence of the
azide peak in the IR spectrum and HRMS [M + H]+ peak at
514.2344 (calculated 514.2342) in the mass spectrum confirmed
1
oxygen at C-5a are β and R, respectively. These 1Hꢀ H NOESY
Scheme 2. Tentative Mechanism for CAN-Catalyzed
Opening of Epoxide
data confirm the absolute stereochemistry at the anomeric center
(i.e., C-9a) and at C-5a of the carbohydrate moiety to be 9aR
and 5aR, respectively (Figure 2). Likewise, rhamno 12, xylo 13,
arabino 14, galacto 15, lyxo 16, and furanogluco 17 derived
tricyclic compounds were made and their structures and stere-
1
1
1
1
ochemical outcome deduced from Hꢀ H COSY and Hꢀ H
NOESY experiments along with mass spectrometry (Table 2).25
1
Figure 2. 1Hꢀ H NOESY contacts recorded for compounds 18.
Scheme 3. Synthesis of Sugar-Derived Morpholine Triazoles from Azido Alcohols
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Table 2. Conversion of 1,2-Azido Alcohols to 1,2,3-Triazole Derivatives
Interestingly, in case of compound 8, the deprotection of the
benzyl groups afforded the sugar-fused morpholine triazole
derivative 15 as a crystalline compound, and thus its stereo-
chemistry was confirmed by X-ray crystallographic analysis.25
We have further exploited the azido alcohols in synthesizing
the sugar-fused oxazin-2-ones. Thus, D-glycopyranosyl azides,
when subjected to sequential alkylation with ethyl bromoace-
tate, azide reduction followed by cyclization, and deprotection
of the benzyl groups led to the sugar-fused oxazin-2-ones
(Scheme 4).
The reaction of azido alcohol 2a with ethyl bromoacetate and
sodium hydride in DMF gave the azido ester 24 in good yield.
Treatment of the azido ester 24 with 20% Pd(OH)2/C in ethanol
under 5 atm of hydrogen for 35 h resulted in the reduction of
azide followed by cyclization and deprotection of the benzyl
groups in one pot to provide compound 31 in 93% yield. The
structure and stereochemical outcome of the sugar oxazin-2-one
1
1
31 was deduced from 1Hꢀ H COSY and 1Hꢀ H NOESY exper-
iments along with mass spectrometry of its triacetate derivative
36 obtained in 68% yield from 31 using the standard conditions
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Scheme 4. Synthesis of Sugar-Derived Oxazin-2-ones from
Azido Alcohols
Interestingly, the oxazin-2-one derivatives 33 and 35 were
obtained as crystalline compounds whose X-ray crystallographic
analysis25 unequivocally established their structures as shown.
Enzyme Inhibition Studies. Enzyme inhibition activity of
these tricyclic molecules has been studied with five commercially
available glycosidases. These results revealed that one of
the tricyclic compounds, viz., 11 exhibited selectivity toward
R-glucosidase (yeast) and the IC50 value was found to be
34.9 μM, but it showed no inhibition of β-glucosidase (almonds),
β-galactosidase (bovine liver), R-galactosidase (coffee beans),
and R-mannosidase (jack beans). The tricyclic compound 12
showed no inhibition of β-glucosidase, R-mannosidase, and
β-galactosidase, but it inhibited R-galactosidase and R-glucosidase
at 37.6 μM and 72.2 μM concentrations, respectively. On the
other hand, tricyclic molecules derived from xylose, arabinose,
and galactose, viz., 13, 14, 15, 16, and 17 did not show any
activity against all tested enzymes. Clearly, there is a change in
terms of specificity as well as the inhibition constant values as a
result of the combination of the structural features. This further
suggests that structural variations of these hybrid molecules could
promote better and specific glycosidase inhibition. The sugar
oxazin-2-ones also were tested against the same glycosidases, as
discussed above, however, the inhibitions were rather poor.
’ CONCLUSIONS
In summary, we have reported that NaN3/CAN/H2O is a
useful reagent system to prepare sugar-derived vicinal azido
alcohols from 1,2-anhydro sugars. These sugar-derived vicinal
azido alcohols are converted into structurally diverse sugar-
derived morpholine triazoles and sugar oxazin-2-ones and some
of which have been found to be moderate to good inhibitors
against some glycosidases. It is especially worth mentioning that
compound 11 is a selective R-glucosidase inhibitor and showed
fairly good activity in the micromolar range. Further work to
extend the scope of the present study is in progress.
1
Figure 3. 1Hꢀ H NOESY contacts recorded for compound 36.
(Ac2O/Py, 2 h). The appearance of a peak in 1H NMR spectrum
at δ 6.74 corresponding to the NH proton and the absence of the
peak at δ 2.5 corresponding to NAc suggested compound 36 to
be a tri-O-acetyl-oxazin-2-one. However, acetylation for a longer
reaction time (15 h) led to the formation of the tetraacetate 37 in
64% yield. Two-dimensional 1H NMR spectral studies of com-
pound 36 (Figure 3) showed cross-peaks between H-4a, H-6,
1
1
and H-8 in the Hꢀ H NOESY spectrum and no cross-peaks
were observed between H-7 and H-4a, indicating that H-4a, H-6,
and H-8 are in cis relationship. An interaction between H-8a and
H-7 proton signals was also observed; however, no interaction
signals were observed between H-8a and H-6 which suggested
that H-8a and the hydroxyl methyl are in cis relationship.
Thus, it was concluded that the orientation of the nitrogen at
the anomeric center (i.e., C-4a) and oxygen at the C-8a are β and
R, respectively, and the absolute stereochemistry at the anomeric
center (C-4a) and C-8a of the carbohydrate moiety to be 4aR and
8aR, respectively (Figure 3). Likewise, rhamno 32, xylo 33,
arabino 34, and galacto 35 derived oxazin-2-ones were made
from azido alcohols 2b, 2e, 2f, and 2g, and their structures and
’ EXPERIMENTAL SECTION
General Experimental Methods. IR spectra were recorded with
FTIR as a thin film or using KBr pellets and are expressed in cmꢀ1. 1H
(400 or 500 MHz) and 13C (100 or 125 MHz) NMR spectra were
recorded using CDCl3, D2O, or CD3OD as solvents. The absolute
configurations of the new compounds are assigned with the help of
1
NOE and 1Hꢀ H NOESY experiments. 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), q (quartet), m (multiplet).
Optical rotations were measured using polarimeter at 28 °C. All reactions
were carried out using freshly distilled and dried solvents. The visualiza-
tion 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 (100ꢀ200 mesh) using hexane and ethyl acetate as eluents.
Mass spectra were obtained from high resolution ESI mass spectrometer.
General Procedure for Inhibition Assay. The enzymes and all
the corresponding substrate were purchased from Sigma Aldrich
Chemical Co. Inhibition studies of the tricyclic and bicyclic molecules
11, 12, 13, 14, 15, 16, 17, 31, 32, 33, 34, and 35 were determined by
measuring the residual hydrolytic activities of the glycosidases. The
substrate concentration (3 mM) was prepared in 0.025 M citrate buffer
with pH 4.0, and test compounds were preincubated with the enzymes
for 1 h at 37 °C. The enzyme reaction was initiated by the addition of
100 μL substrate, and the controls were run simultaneously in the
1
1
stereochemical outcome were established from Hꢀ H COSY
1
and 1Hꢀ H NOESY experiments along with mass spectrometry
of their peracetylated derivatives (Table 3).25 Interestingly,
irrespective of the geometry of the anomeric azide, the geometry
of the final coupled product was β at the anomeric center. Thus,
the minor R-isomeric azido alcohols 2f-r and 2g-r were con-
verted into corresponding azido esters 40 and 41 (Scheme 5),
and their reductions and deprotections were carried out by using
hydrogenolysis to form 34 and 35, respectively. In continuation,
the azido alcohols 2h and 2i were also converted into their
corresponding azido esters 29 and 30, respectively, but subse-
quent reduction under hydrogenation conditions led to a com-
plex mixture of products in both the cases.
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Table 3. Conversion of 1,2-Azido Alcohols to Sugar-Fused Oxazin-2-ones
Scheme 5. Conversion of the r-Azido Alcohols into Their Corresponding r-Azido Esters
absence of the test compound. The reaction was terminated at the end of
the 10 min by the addition of 0.05 M borate buffer (pH 9.8), and the
absorbance of the liberated p-nitrophenol was measured at 405 nm using
Schimadzu spectrophotometer UV-160A. One unit of glycosidase
activity is defined as the amount of enzyme that hydrolyzed 1 μM of
p-nitrophenyl pyranoside per min at 25 °C.31
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General Procedure A for the Synthesis of Azido Alcohols.
To a stirred solution of requisite 1,2-anhydro sugar (100 mg, 0.23 mmol)
in dry acetonitrile (6 mL) were added sodium azide (45 mg, 0.69 mmol)
and CAN (12 mg, 0.02 mmol). Then water (100 μL) was introduced
into the reaction mixture. After completion of the reaction (TLC
monitoring, approximately 5 min), the reaction was quenched with aq
saturated sodium bicarbonate (4 mL) and extracted with ethyl acetate
(3 ꢁ 4 mL). The combined organic extracts were washed with brine
(10 mL). The organic layer was dried over Na2SO4 and filtered and
the solvent removed in vacuo. Purification of the azido alcohols was
accomplished by column chromatography.
General Procedure B for the Synthesis of Fused Tricyclic of
Sugar Morpholine Triazoles. To a solution of azido alcohol (80 mg,
0.17 mmol) in DMF (3 mL) at 0 °C were added sodium hydride (5 mg,
0.20 mmol) and propargyl bromide (19 mg, 0.16 mmol), and the
mixture was stirred until the complete consumption of azido alcohol
(TLC monitoring, approximately 5 min). The reaction mixture was
quenched with water (1 mL) and stirring continued at rt to 70 °C for the
required amount of time. DMF was evaporated under vacuum, and the
resultant slurry was extracted with ethyl acetate (3 ꢁ 3 mL). The
combined organic extracts were washed with brine (10 mL) and filtered
through anhydrous Na2SO4. Evaporation of the solvent gave a crude
product which was purified by column chromatography on silica gel
(hexane/ethyl acetate as eluents) to obtain the triazole-fused compounds.
General Procedure C: Deprotection of Benzyl Groups. The
cyclized product (100 mg, 0.19 mmol) was dissolved in 4 mL of MeOH,
20% Pd(OH)2/C (100 mg) was added, and the mixture was stirred
under 5 atm of H2 for 30ꢀ34 h at room temperature. The catalyst was
filtered through Celite and concentrated in vacuo to obtain the tricyclic
molecules, which were purified by column chromatography.
General Procedure D for the O-Alkylation of Azido Alco-
hols. To a stirred solution of an alcohol (100 mg, 0.21 mmol) in DMF
(4 mL) at 0 °C was added a 60% suspension of NaH in paraffin oil (8 mg,
0.33 mmol). After 30 min, ethyl bromoacetate (42 mg, 0.25 mmol) was
added dropwise at 0 °C and the reaction mixture stirred for 30 min at
room temperature. Excess NaH was quenched by pouring the reaction
mixture into ice, and then the mixture was extracted with diethyl ether
(3 ꢁ 10 mL) followed by washing with water (3 ꢁ 10 mL). The organic
layer was dried with MgSO4 and concentrated in vacuo and the crude
product purified by column chromatography to get the azido ester.
General Procedure E: Reduction of Azide, Cyclization, and
Deprotection of Benzyl Groups. The azido ester (100 mg, 0.19
mmol) was dissolved in 4 mL of EtOH and treated with 20% Pd(OH)2/
C (100 mg), and the resultant mixture was stirred under 5 atm H2 for
30ꢀ34 h at room temperature. The catalyst was filtered through Celite,
and the filtrate was concentrated in vacuo to obtain a bicyclic molecule
which was subjected to column chromatography to obtain pure bicyclic
sugar oxazin-2-one.
afford the 1,2-anhydropyranoses (94 mg, yield: 99%) as a white syrup.
The crude product could not be purified because of decomposition of
the 1,2-anhydro sugar. This crude 1,2 anhydro sugar 1b (75 mg, 0.23
mmol) was subjected to azidolysis by using general procedure A to give
2b (63 mg, Yield 74%) as a white solid. Mp: 139ꢀ141 °C. Rf = 0.55
(hexane/EtOAc, 1:1). [R]28 = ꢀ5.0 (c 0.6, CH2Cl2). IR (CH2Cl2)
D
νmax: 3444, 3031, 2921, 2852, 2113, 1731, 1597, 1495, 1454, 1360, 1316,
1247, 1117, 1071, 916, 736, 698 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ
7.44ꢀ7.25 (m, 10H, Ar-H), 4.90ꢀ4.83 (m, 3H, 3 ꢁ OCHPh), 4.66 (d, J =
10.9 Hz, 1H, OCHPh), 4.49 (d, J = 8.6 Hz, 1H), 3.53ꢀ3.48 (m, 2H),
3.42 (t, J = 8.8 Hz, 1H), 3.20 (t, J = 9.15 Hz, 1H), 2.30 (s, 1H), 1.34 (d, J
= 5.7 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 138.3, 137.8,
128.7ꢀ128.0 (m, Ar-C), 90.1, 84.4, 82.9, 75.5, 75.4, 74.3, 73.8, 17.9.
HRMS calcd for C20H23N3O4Na [M + Na]+ 392.1586, Found:
392.1585.
(2R,3R,4R,5R,6R)-2-Azido-4,5-bis(4-methoxybenzyloxy)-6-((4-methoxy-
benzyloxy)methyl)tetrahydro-2H-pyran-3-ol (2c). 1,2-Anhydropyra-
nose 1c26 was subjected to azidolysis using general procedure A to
give 2c (yield: 83%) as a yellow liquid. Rf = 0.5 (hexane/EtOAc, 1:1).
[R]28D = +6.0 (c 1.0, CH2Cl2). IR (neat) νmax: 3432, 2922, 2852, 2113,
1611, 1586, 1513, 1462, 1420, 1361, 1301, 1248, 1174, 1114, 1033, 819,
681, 518 cmꢀ1. 1H NMR (400 MHz, CDCl3):δ7.30ꢀ7.24 (m, 4H, Ar-H),
7.07 (m, 2H, Ar-H), 6.90ꢀ6.81 (m, 6H, Ar-H), 4.82 (d, J = 10.9 Hz, 1H,
OCHPh), 4.72 (dd, J = 11.0 Hz, 10.5 Hz, 2H, 2 ꢁ OCHPh), 4.61 (br s,
2H, 2 ꢁ OCHPh), 4.56 (d, J = 11.9 Hz, 1H, OCHPh), 4.48 (dd, J = 8.5
Hz, 7.5 Hz, 2H), 3.79 (br s, 9H, OMe), 3.69ꢀ3.67 (m, 1H), 3.58 (t, J =
9.2 Hz, 1H), 3.51ꢀ3.46 (m, 2H), 3.39 (t, J = 8.8 Hz, 1H), 2.30 (br s,
1H). 13C NMR (125 MHz, CDCl3): δ 159.5, 159.4, 159.3, 133.1,
130.5ꢀ128.7 (m, Ar-C), 114.1ꢀ113.9 (m, Ar-C), 90.2, 84.2, 76.0, 75.0,
74.7, 73.9, 73.2, 67.9, 65.1, 55.3. HRMS calcd for C30H35N3O8Na [M +
Na]+ 588.2322, Found: 588.2321.
(2R,3R,4R,5R)-2-Azido-4,5-bis(benzyloxy)tetrahydro-2H-pyran-3-ol (2e).
1,2-Anhydropyranose 1e27 was subjected to azidolysis using general proce-
dure A to give 2e (yield: 77%) as a yellow oil. Rf = 0.65 (hexane/EtOAc,
1:1).[R]28D = ꢀ28.8 (c 1.25, CH2Cl2). IR (neat) νmax: 3328, 3064, 3030,
2984, 2927, 2873, 2115, 1603, 1494, 1372, 1312, 1240, 1091, 1061, 1025,
1
1002, 897, 736, 696, 646, 604 cmꢀ1. H NMR (400 MHz, CDCl3): δ
7.37ꢀ7.24 (m, 10H, Ar-H), 4.84 (d, J = 11.4 Hz, 1H, OCHPh), 4.76 (d, J =
11.4 Hz, 1H, OCHPh), 4.68ꢀ4.63 (m, 3H), 4.06 (dd, J = 11.7 Hz, 11.6 Hz,
1H), 3.58 (dd, J = 8.0 Hz, 8.0 Hz, 1H), 3.53ꢀ3.51 (m, 1H), 3.45ꢀ3.39
(m, 2H), 2.81 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 138.0, 137.5,
128.5ꢀ127.8 (m, Ar-C), 90.5, 80.8, 76.3, 74.4, 72.8, 71.1, 64.2. HRMS calcd
for C19H21N3O4Na [M + Na]+ 378.1430, Found: 378.1430.
(3R,4R,5S)-2-Azido-4,5-bis(benzyloxy)tetrahydro-2H-pyran-3-ol (2f).
1,2-Anhydropyranose 1f28 was subjected to azidolysis by using general
procedure A to give chromatographically separable diastereomeric mixture
of 2f and 2f-r in 8:2 ratio, respectively (combined yield: 83%).
Major Diastereomer: (2R,3R,4R,5S)-2-Azido-4,5-bis(benzyloxy)tetrahydro-
2H-pyran-3-ol (2f). (β-Anomer, yield: 67%): colorless thick liquid. Rf =
0.55 (hexane/EtOAc, 1:1). [R]28D = +110.0 (c 1.0, CH2Cl2). IR (neat)
νmax: 3328, 3032, 2863, 2120, 1453, 1365, 1313, 1243, 1125, 1072, 1022,
General Procedure F: Acetylation of Alcohols. Bicyclic and
tricyclic molecules were subjected to acetylation with excess of pyridine
and Ac2O (1:1, 2 mL) at room temperature for 2ꢀ15 h. Removal of the
solvent under reduced pressure gave a residue that was purified by
column chromatography to obtain an acetylated product.
(2R,3R,4R,5R,6R)-2-Azido-4,5-bis(benzyloxy)-6-methyltetrahydro-2H-
pyran-3-ol (2b). The corresponding glycal (100 mg, 0.32 mmol) was
dissolved in an ice-cooled biphasic solution of CH2Cl2 (0.85 mL),
acetone (0.09 mL), and saturated aqueous NaHCO3 (1.4 mL). The
mixture was vigorously stirred, and a solution of Oxone (102 mg,
0.65 mmol) in H2O (0.8 mL) was added dropwise. The crude reaction
was vigorously stirred at 0 °C for 30 min and was then allowed to
warm to room temperature until TLC indicated complete consumption
of the glycal (∼2 h). The organic phase was separated and the
aqueous phase extracted with CH2Cl2 (2 ꢁ 4 mL). The combined
organic phases were dried over MgSO4, filtered, and concentrated to
932, 768, 734, 696, 595 cmꢀ1 1H NMR (400 MHz, CDCl3): δ
.
7.38ꢀ7.25 (m, 10H, Ar-H), 4.73 (d, J = 12.2 Hz, 1H, OCHPh), 4.61
(t, J = 11.9 Hz, 2H, 2 ꢁ OCHPh), 4.50 (d, J = 11.9 Hz, 1H, OCHPh),
4.44 (d, J = 8.3 Hz, 1H), 4.14 (dd, J = 13.1 Hz, 12.9 Hz, 1H), 3.90 (t, J =
8.9 Hz, 1H), 3.74 (br s, 1H), 3.41ꢀ3.37 (m, 2H), 2.59 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 137.7, 137.5, 128.5ꢀ127.7 (m, Ar-C), 90.8, 80.3,
71.6, 71.4, 71.3, 70.2, 65.4. HRMS calcd for C19H21N3O4Na [M + Na]+
378.1430, Found: 378.1433.
Minor Diastereomer: (2S,3R,4R,5S)-2-Azido-4,5-bis(benzyloxy)tetrahydro-
2H-pyran-3-ol (2f-r). (R-Anomer, yield: 16%): colorless thick liquid.
Rf = 0.55 (hexane/EtOAc, 1:1). [R]28 = +24.0 (c 1.25, CH2Cl2). IR
D
(neat) νmax: 3334, 3090, 3065, 3031, 2902, 2867, 2120, 1639, 1494,
1454, 1406, 1349, 1333, 1312, 1242, 1122, 1081, 1047, 1017, 988, 920,
5978
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ARTICLE
1
883, 834, 766, 739, 698, 667, 592, 565 cmꢀ1. H NMR (400 MHz,
CDCl3): δ 7.34ꢀ7.25 (m, 10H, Ar-H), 5.41 (d, J = 3.6 Hz, 1H),
4.63 (dd, J = 12.4 Hz, 12.7 Hz, 3H, 3 ꢁ OCHPh), 4.53 (d, J = 11.7 Hz,
1H, OCHPh), 4.18 (br d, J = 8.3 Hz, 1H), 3.90ꢀ3.87 (m, 1H), 3.78
96.3, 79.3, 78.3, 78.0, 73.9, 73.4, 73.4, 73.3, 69.7. HRMS calcd for
C27H30N3O5 [M + H]+ 476.2185, Found: 476.2184.
(5aR,6S,7R,8R,9aR)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-4,5a,6,-
7,8,9a-hexahydropyrano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (4).
Azido alcohol 2a (80 mg, 0.16 mmol) was converted into tricyclic
molecule by using general procedure B to give 4 (83 mg, yield 96%) as a
light yellow thick liquid. Rf = 0.3 (hexane/EtOAc, 6:4). [R]28D = ꢀ36.66
(c 1.20, CH2Cl2). IR (neat) νmax: 3062, 3030, 2921, 2868, 1716, 1595,
1553, 1495, 1453, 1352, 1317, 1249, 1208, 1096, 1027, 984, 913, 822,
(d, J = 12.2 Hz, 2H), 3.65 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 2.33 (s, 1H). 13
NMR (100 MHz, CDCl3): δ 137.8, 137.7, 128.5ꢀ127.7 (m, Ar-C), 89.5,
72.3, 71.9, 71.7, 68.1, 68.0, 62.44. HRMS calcd for C19H21N3O4Na
[M + Na]+ 378.1430, Found: 378.1432.
(3R,4R,5S,6R)-2-Azido-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-3-ol (2g). 1,2-Anhydropyranose 1g23 was sub-
jected to azidolysis using general procedure A to give chromatographically
separable diastereomeric mixture of 2g and 2g-r in 8:2 ratio, respectively
(combined yield 89%).
C
1
738, 698, 643 cmꢀ1. H NMR (400 MHz, CDCl3): δ 7.52(s, 1H),
7.39ꢀ7.14 (m, 15H, Ar-H), 5.27 (d, J = 8.5 Hz, 1H), 5.11 (d, J = 14.9 Hz,
1H), 4.99 (d, J = 11.2 Hz, 1H, OCHPh), 4.90ꢀ4.80 (m, 3H), 4.64 (d, J =
11.9 Hz, 1H, OCHPh), 4.52 (t, J = 11.9 Hz, 2H, 2 ꢁ OCHPh),
3.99ꢀ3.83 (m, 5H), 3.61 (t, J = 8.8 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δ 138.0, 137.7, 131.8, 128.4ꢀ127.7 (m, Ar-C), 83.1, 81.7, 79.8,
78.6, 76.7, 75.4, 75.0, 73.6, 67.6, 62.8. HRMS calcd for C30H32N3O5
[M + H]+ 514.2342, Found: 514.2344.
Major Diastereomer: (2R,3R,4R,5S,6R)-2-Azido-4,5-bis(benzyloxy)-
6-(benzyloxymethyl)tetrahydro-2H-pyran-3-ol (2g). (β-Anomer, yield:
71%): colorless thick liquid. Rf = 0.5 (hexane/EtOAc, 9:1). [R]28
=
D
ꢀ9.1 (c 1.1, CH2Cl2). IR (neat) νmax: 3439, 3063, 3031, 2919, 2871, 2116,
1605, 1496, 1453, 1334, 1249, 1209, 1094, 1027, 930, 736, 698, 606, 464. 1H
NMR (400 MHz, CDCl3): δ 7.37ꢀ7.23 (m, 15H, Ar-H), 4.85 (d, J = 11.4
Hz, 1H, OCHPh), 4.71 (d, J = 11.7 Hz, 1H, OCHPh), 4.58 (d, J = 11.7 Hz,
2H, 2 ꢁ OCHPh), 4.51ꢀ4.42 (m, 3H), 3.95 (d, J = 2.2 Hz, 1H), 3.87 (t, J =
8.9 Hz, 1H), 3.68ꢀ3.59 (m, 3H), 3.40 (dd, J = 9.5 Hz, 9.7 Hz, 1H), 2.48 (br
s, 1H). 13C NMR (100 MHz, CDCl3):δ138.2, 137.6, 128.5ꢀ127.6 (m, Ar-
C), 90.4, 82.0, 75.7, 74.5, 73.5, 72.4, 72.3, 70.5, 68.2. HRMS calcd for
C27H29N3O5Na [M + Na]+ 498.2005, Found: 498.2006.
Minor Diastereomer: (2S,3R,4R,5S,6R)-2-Azido-4,5-bis(benzyloxy)-
6-benzyloxymethyl)tetrahydro-2H-pyran-3-ol (2g-r). (R-Anomer, yield:
18%): yellow liquid. Rf = 0.6 (hexane/EtOAc, 1:1). [R]28D = +5.33 (c 1.5,
CH2Cl2). IR (neat) νmax: 3438, 3063, 3030, 2921, 2855, 2116, 1592, 1495,
1453, 1336, 1248, 1210, 1094, 1026, 928, 736, 698, 604 cmꢀ1. 1H NMR
(400 MHz, CDCl3):δ7.34ꢀ7.24 (m, 15H, Ar-H), 5.46 (d, J= 4.4 Hz, 1H),
4.84 (d, J = 11.2 Hz, 1H, OCHPh), 4.71 (d, J = 11.4 Hz, 1H, OCHPh), 4.58
(d, J = 11.4 Hz, 1H, OCHPh), 4.53 (t, J = 11.1 Hz, 2H, 2 ꢁ OCHPh), 4.43
(d, J= 11.7 Hz, 1H, OCHPh), 4.25 (dd, J= 10.0 Hz, 9.7 Hz, 1H), 4.08ꢀ4.04
(m, 1H), 4.00 (br s, 1H), 3.63ꢀ3.56 (m, 3H), 2.24 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 138.2, 137.6, 128.5ꢀ127.7 (m, Ar-C), 89.8, 79.1, 74.6,
73.5, 73.3, 72.2, 71.8, 68.3, 68.1. HRMS calcd for C27H29N3O5Na
[M + Na]+ 498.2005, Found: 498.2002.
(5aR,6S,7R,8R,9aR)-6,7-Bis(benzyloxy)-8-methyl-4,5a,6,7,8,9a-
hexahydropyrano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (5). Azido
alcohol 2b was converted into tricyclic molecule by using general
procedure B to give 5 (yield 92%) as a colorless thick liquid. Rf = 0.35
(hexane/EtOAc, 6:4). [R]28D = ꢀ68.66 (c 1.5, CH2Cl2). IR (neat) νmax
:
3062, 3031, 2979, 2897, 1602, 1496, 1453, 1353, 1316, 1250, 1209, 1155,
1
1097, 1009, 986, 904, 827, 740, 698, 636, 559 cmꢀ1. H NMR (400
MHz, CDCl3): δ 7.53 (s, 1H), 7.39ꢀ7.25 (m, 10H, Ar-H), 5.27 (d, J =
8.5 Hz, 1H), 5.12 (d, J = 14.8 Hz, 1H), 4.99 (d, J = 11.2 Hz, 1H,
OCHPh), 4.95 (d, J = 10.7 Hz, 1H, OCHPh), 4.90 (d, J = 14.8 Hz, 1H),
4.82 (d, J = 11.2 Hz, 1H, OCHPh), 4.68 (d, J = 11.0 Hz, 1H, OCHPh),
3.89ꢀ3.82 (m, 2H), 3.62ꢀ3.57 (m, 1H), 3.36 (t, J = 8.8 Hz, 1H), 1.48
(d, J = 6.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 138.0, 137.7,
131.7ꢀ127.9 (m, Ar-C), 83.0, 82.9, 81.6, 80.2, 75.7, 75.4, 75.1, 62.8,
18.0. HRMS calcd for C23H26N3O4 [M + H]+ 408.1923, Found:
408.1922.
(5aR,6S,7R,9aR)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-4,5a,6,7,8,9a-
hexahydropyrano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (6). Azido
alcohol 2e was converted into tricyclic molecule by using general
procedure B to give 6 (yield: 95%) as a thick liquid. Rf = 0.40 (hexane/
EtOAc, 6:4). [R]28 = ꢀ54.0 (c 1.5, CH2Cl2). IR (neat) νmax: 3030,
D
(2S,3S,4R,5R)-2-Azido-4-(benzyloxy)-5-(benzyloxymethyl)tetrahydrofuran-
3-ol (2h). 1,2-Anhydropyranose 1h29 was subjected to azidolysis using
general procedure A to give 2h (yield: 64%) as a colorless thick liquid.
Rf = 0.6 (hexane/EtOAc, 1:1). [R]28D = +16.0 (c 0.5, CH2Cl2). IR (neat)
νmax: 3378, 3064, 3031, 2919, 2869, 2109, 1496, 1453, 1361, 1241, 1146,
2867, 1642, 1496, 1453, 1370, 1247, 1204, 1098, 1010, 985, 826, 740,
698, 643 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.51(s, 1H), 7.40ꢀ7.25
(m, 10H, Ar-H), 5.19 (d, J = 8.8 Hz, 1H), 5.11 (d, J = 15.1 Hz, 1H), 4.95
(d, J = 11.4 Hz, 1HꢀOCHPh), 4.90ꢀ4.78 (m, 3H), 4.66 (d, J = 11.4 Hz,
1H, OCHPh), 4.25 (dd, J = 12.6 Hz, 11.4 Hz, 1H), 3.82ꢀ3.73 (m, 2H),
3.63ꢀ3.50 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 138.0, 137.5,
131.7, 128.5ꢀ127.8 (m, Ar-C), 83.7, 80.8, 79.5, 75.0, 73.9, 67.5, 62.8.
HRMS calcd for C22H24N3O4 [M + H]+ 394.1767, Found: 394.1767.
(5aR,6S,7S,9aR)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-4,5a,6,7,-
8,9a-hexahydropyrano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (7).
Azido alcohol 2f was converted into tricyclic molecule by using general
procedure B to give 7 (yield: 88%) as a yellow liquid. Rf = 0.45 (hexane/
1068, 1027, 909, 737, 698. cmꢀ1. H NMR (400 MHz, CDCl3): δ
1
7.33ꢀ7.26 (m, 10H, Ar-H), 5.35 (s, 1H, ꢀOH), 4.67 (d, J = 11.2 Hz, 1H,
OCHPh), 4.60 (d, J = 11.7 Hz, 1H, OCHPh), 4.53 (d, J = 2.4 Hz, 1H,
H-2), 4.51 (s, 1H), 4.44 (d, J = 11.2 Hz, 1H, OCHPh), 4.42ꢀ4.38 (m,
1H, H-5), 4.36ꢀ4.32 (m, 1H, H-4), 3.93 (dd, J = 4.8, 10.4 Hz, 1H, H-3),
3.66ꢀ3.57 (m, 2H, H-6, H-60). 13C NMR (100 MHz, CDCl3): δ 137.3,
136.9, 128.4ꢀ127.8 (m, Ar-C), 96.0, 78.6, 76.8, 73.9, 72.6, 72.4,
67.4. HRMS calcd for C19H21N3O4Na [M + Na]+ 378.1430, Found:
378.1437.
EtOAc, 6:4). [R]28 = ꢀ18.6 (c 1.5, CH2Cl2). IR (neat) νmax: 3031,
D
2865, 1657, 1496, 1453, 1376, 1350, 1292, 1243, 1214, 1179, 1094, 1060,
1
1026, 987, 940, 826, 738, 699, 652, 596 cmꢀ1. H NMR (400 MHz,
(2S,3S,4R,5R)-2-Azido-4-(benzyloxy)-5-((R)-1,2-bis(benzyloxy)ethyl)-
tetrahydrofuran-3-ol (2i). 1,2-Anhydropyranose 1i29 was subjected to
azidolysis using general procedure A to give 2i (yield: 61%) as a colorless
CDCl3): δ 7.51(s, 1H), 7.39ꢀ7.26 (m, 10H, Ar-H), 5.15ꢀ5.09 (m, 2H),
4.96 (d, J = 15.1 Hz, 1H), 4.81ꢀ4.68 (m, 4H), 4.34 (br d, J = 13.2 Hz,
1H), 4.17ꢀ4.13 (m, 1H), 3.86 (br s, 1H), 3.75ꢀ3.67 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 137.7, 137.5, 131.9, 128.4ꢀ127.5 (m, Ar-C),
84.6, 77.1, 73.3, 72.5, 72.4, 72.0, 67.3, 62.8. HRMS calcd for C22H24-
N3O4 [M + H]+ 394.1767, Found: 394.1764.
thick liquid. Rf = 0.65 (hexane/EtOAc, 1:1). [R]28 = +60.00 (c 1.1,
D
CH2Cl2). IR (neat) νmax: 3437, 3062, 3030, 2925, 2863, 2110, 1602,
1495, 1453, 1360, 1317, 1243, 1065, 1028, 902, 737, 697 cmꢀ1. 1H NMR
(500 MHz, CDCl3): δ 7.37ꢀ7.24 (m, 15H, Ar-H), 5.30 (d, J = 15.3 Hz,
1H, ꢀOH), 4.83 (d, J = 11.3 Hz, 1H, OCHPh), 4.61 (dd, J = 11.3 Hz,
11.3 Hz, 2H, 2 ꢁ OCHPh), 4.54ꢀ4.46 (m, 3H), 4.44ꢀ4.42 (m, 1H),
4.34ꢀ4.32 (m, 1H), 4.04ꢀ4.00 (m, 2H), 3.95ꢀ3.92 (m, 1H), 3.81 (dd,
J = 10.4 Hz, 10.7 Hz, 1H), 3.73 (dd, J = 10.7 Hz, 10.7 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 138.1, 137.8, 137.3, 128.6ꢀ127.2 (m, Ar-C),
(5aR,6S,7S,8R,9aR)-6,7-Bis(benzyloxy)-8-(benzyloxymethyl)-4,5a,-
6,7,8,9a-hexahydropyrano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (8).
Azido alcohol 2g was converted into tricyclic molecule by using general
procedure B to give 8 (yield 90%) as a colorless thick liquid. Rf = 0.3
(hexane/EtOAc, 6:4). [R]28D = ꢀ38.00 (c 1.0, CH2Cl2). IR (neat) νmax
:
5979
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The Journal of Organic Chemistry
ARTICLE
3030, 2869, 1725, 1601, 1495, 1452, 1355, 1271, 1210, 1101, 987, 825,
738, 698 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.49(s, 1H), 7.38ꢀ7.29
(m, 15H, Ar-H), 5.21 (d, J = 8.5 Hz, 1H), 5.09 (d, J = 15.1 Hz, 1H),
4.97 (d, J = 11.2 Hz, 1H, OCHPh), 4.93 (d, J = 14.8 Hz, 1H), 4.86 (d,
J = 12.2 Hz, 1H, OCHPh), 4.75 (d, J = 12.2 Hz, 1H, OCHPh), 4.62 (d, J =
11.2 Hz, 1H, OCHPh), 4.51ꢀ4.48 (m, 3H), 4.12 (dd, J = 10.0 Hz, 10.0 Hz,
2H), 3.98ꢀ3.95 (m, 1H), 3.79ꢀ3.75 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 138.0, 137.8, 137.4, 131.9, 128.4ꢀ127.4 (m, Ar-C), 84.2, 78.6,
77.2, 76.8, 75.4, 74.4, 73.6, 72.9, 67.2, 62.8. HRMS calcd for C30H32N3O5
[M + H]+ 514.2342, Found: 514.2347.
(c 0.75, MeOH). 1H NMR (400 MHz, D2O): δ 7.52 (s, 1H), 5.29 (d, J =
8.5 Hz, 1H), 5.07 (d, J = 15.3 Hz, 1H), 4.83 (d, J = 15.4 Hz, 1H), 4.14 (d,
J = 11.7 Hz, 1H), 3.68 (d, J = 7.5 Hz, 1H), 3.57ꢀ3.52 (m, 2H),
3.41ꢀ3.37 (m, 1H). 13C NMR (100 MHz, D2O): δ 134.2, 129.8, 84.1,
78.5, 73.6, 70.4, 69.1, 63.4. HRMS calcd for C8H12N3O4 [M + H]+
214.0828, Found: 214.0827.
(5aR,6S,7S,9aR)-4,5a,6,7,8,9a-Hexahydropyrano[3,2-b][1,2,3]triazolo-
[1,5-d][1,4]oxazine-6,7-diol (14). Compound 7 was subjected to global
deprotection by using general procedure C to give 14 (yield: 88%) as a
liquid. Rf = 0.45 (MeOH/EtOAc, 1:9). [R]28D = ꢀ5.0 (c 0.6, MeOH).
1H NMR (400 MHz, D2O): δ 7.53 (s, 1H), 5.26 (d, J = 8.3 Hz, 1H), 5.07
(d, J = 15.6 Hz, 1H), 4.86 (d, J = 15.4 Hz, 1H), 4.10 (d, J = 13.1 Hz, 1H),
4.00 (br s, 1H), 3.96ꢀ3.92 (m, 2H), 3.74ꢀ3.69 (m, 1H). 13C NMR (100
MHz, D2O): δ 134.2, 129.9, 84.6, 76.5, 70.9, 70.2, 69.4, 63.4. HRMS
calcd for C8H12N3O4 [M + H]+ 214.0828, Found: 214.0829.
(5aS,6S,7R,8aS)-6-Benzyloxy)-7-(benzyloxymethyl)-5a,6,7,8a-tetra-
hydro-4H-furo[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (9). Azido alco-
hol 2h was converted into tricyclic molecule by using general procedure
B to give 9 (yield 90%) as a light yellow thick liquid. Rf = 0.45 (hexane/
EtOAc, 1:1). [R]28 = +11.6 (c 2.0, CH2Cl2). IR (neat) νmax: 3062,
D
3030, 2919, 2863, 1721, 1636, 1496, 1453, 1384, 1357, 1251, 1203, 1139,
(5aR,6S,7R,8R,9aR)-8-(Hydroxymethyl)-4,5a,6,7,8,9a-hexahydropy-
rano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine-6,7-diol (15). Compound
8 was subjected to global deprotection by using general procedure C to
give 15 (yield: 88%) as a white crystalline compound. Mp: 273ꢀ275 °C.
Rf = 0.45 (MeOH/EtOAc, 1:9). [R]28D = ꢀ6.0 (c 1.0, MeOH). 1H NMR
(400 MHz, D2O): δ 7.55 (s, 1H, H-2b), 5.35 (d, J = 8.4 Hz, 1H, H-9a),
5.09 (d, J = 15.3 Hz, 1H, H-4), 4.87 (d, J = 15.6 Hz, 1H, H-40), 4.01ꢀ3.93
(m, 3H, H-7, H-10, H-100), 3.81ꢀ3.67 (m, 3H, H-5a, H-8, H-6). 13C
NMR (125 MHz, D2O): δ 133.5, 129.3, 83.4, 79.1, 75.8, 69.8, 68.9, 62.8,
61.0. HRMS calcd for C9H14N3O5 [M + H]+ 244.0933, Found: 244.0936.
(5aS,6S,7R,8aS)-7-(Hydroxymethyl)-5a,6,7,8a-tetrahydro-4H-furo-
[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazin-6-ol (16). Compound 9 was
subjected to global deprotection by using general procedure C to give
1
1078, 1046, 1026, 1005, 790, 737, 698 cmꢀ1. H NMR (500 MHz,
CDCl3): δ 7.53(s, 1H), 7.33ꢀ7.24 (m, 10H, Ar-H), 5.79 (d, J = 8.6 Hz,
1H), 5.23 (d, J = 14.9 Hz, 1H), 5.04 (d, J = 15.75 Hz, 1H), 4.90 (d, J =
11.7 Hz, 1H, OCHPh), 4.73ꢀ4.69 (m, 2H), 4.67 (d, J = 11.7 Hz, 1H,
OCHPh), 4.58 (dd, J = 11.7 Hz, 11.7 Hz, 2H, 2 ꢁ OCHPh), 3.94ꢀ3.90
(m, 1H), 3.85ꢀ3.79 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 137.9,
137.5, 131.1, 128.5ꢀ127.6 (m, Ar-C), 83.3, 82.8, 82.4, 73.7, 73.7, 73.2,
67.8, 64.7. HRMS calcd for C22H24N3O4 [M + H]+ 394.1767, Found:
394.1765.
(5aS,6S,7R,8aS)-6-(Benzyloxy)-7-((R)-1,2-bis(benzyloxy)ethyl)-5a,-
6,7,8a-tetrahydro-4H-furo[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine (10).
Azido alcohol 2i was converted into tricyclic molecule by using general
procedure B to give 10 (yield 92%) as a light yellow thick liquid. Rf = 0.4
16 (yield: 86%) as a colorless oil. Rf = 0.45 (MeOH/EtOAc, 2:8).
1
[R]28 = +56.0 (c 0.25, MeOH). H NMR (500 MHz, CD3OD): δ
(hexane/EtOAc, 1:1). [R]28D = ꢀ13.20 (c 2.0, CH2Cl2). IR (neat) νmax
:
D
7.60(s, 1H), 5.70 (d, J = 8.6 Hz, 1H), 5.24 (d, J = 15.1 Hz, 1H), 5.08
(d, J = 15.2 Hz, 1H), 4.60ꢀ4.54 (m, 2H), 3.92ꢀ3.86 (m, 3H). 13C NMR
(125 MHz, CD3OD): δ 134.0, 129.7, 86.8, 84.7, 82.7, 68.6, 65.2, 61.7.
HRMS calcd for C8H11N3O4Na [M + Na]+ 236.0647, Found: 236.0640.
(R)-1-((5aS,6S,7R,8aS)-6-Hydroxy-5a,6,7,8a-tetrahydro-4H-furo-
[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazin-7-yl)ethane-1,2-diol (17). Com-
pound 10 was subjectedtoglobaldeprotectionbyusing general procedure
3030, 2923, 2855, 1646, 1496, 1453, 1357, 1304, 1249, 1208, 1124, 1092,
1049, 1027, 984, 737, 697 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.55(s,
1H), 7.36ꢀ7.23 (m, 15H, Ar-H), 5.86 (d, J = 8.6 Hz, 1H), 5.23 (d, J = 15.1
Hz, 1H), 5.04 (d, J = 15.1 Hz, 1H), 4.97 (d, J = 10.8 Hz, 1H, OCHPh), 4.77
(d, J = 11.4 Hz, 1H, OCHPh), 4.66ꢀ4.63 (m, 2H), 4.61ꢀ4.58 (m, 2H),
4.55ꢀ4.52 (m, 1H), 4.48 (d, J = 11.2 Hz, 1H, OCHPh), 4.15ꢀ4.12 (m,
1H), 3.97ꢀ3.91 (m, 2H), 3.78 (dd, J = 4.9 Hz, 10.9 Hz, 1H). 13C NMR
(125 MHz, CDCl3): δ 138.6, 138.4, 137.6, 131.1, 128.8ꢀ127.6 (m, Ar-C),
83.8, 82.7, 81.9, 75.5, 74.1, 73.5, 73.4, 72.5, 69.6, 64.7. HRMS calcd for
C30H32N3O5 [M + H]+ 514.2342, Found: 514.2343.
C to give 17 (yield: 88%) as a colorless oil. Rf = 0.45 (MeOH/EtOAc,
1
2:8). [R]28 = +55.7 (c 0.70, MeOH). H NMR (500 MHz, D2O): δ
D
7.54(s, 1H), 5.64 (d, J = 8.5 Hz, 1H), 5.15 (d, J = 15.4 Hz, 1H), 5.02 (d, J =
15.4 Hz, 1H), 4.63 (t, J = 3.7 Hz, 1H), 4.38 (dd, J = 9.1 Hz, 3.4 Hz, 1H),
3.98ꢀ3.94 (m, 2H), 3.76 (dd, J = 12.3 Hz, 12.0 Hz, 1H), 3.63 (dd, J = 5.4
Hz, 5.4 Hz, 1H). 13C NMR (125 MHz, D2O): δ 132.8, 129.3, 83.6, 83.3,
80.1, 68.6, 67.0, 64.2, 62.7. HRMS calcd for C9H13N3O5Na [M + Na]+
266.0753, Found: 266.0760.
(5aR,6S,7R,8R,9aR)-8-(Hydroxymethyl)-4,5a,6,7,8,9a-hexahydropy-
rano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine-6,7-diol (11). Compound
4 (52 mg, 0.1 mmol) was subjected to global deprotection by using
general procedure C to give 11 (23 mg, Yield: 93%) as a white solid. Mp:
286ꢀ288 °C. Rf = 0.45 (MeOH/EtOAc, 1:9). [R]28D = ꢀ17.00 (c 1.0,
MeOH). 1H NMR (400 MHz, D2O): δ 7.53 (s, 1H), 5.39 (d, J = 8.5 Hz,
1H), 5.07 (d, J = 15.4 Hz, 1H), 4.84 (d, J = 15.6 Hz, 1H), 3.88 (d, J = 10.4
Hz, 1H), 3.78ꢀ3.67 (m, 3H), 3.49ꢀ3.40 (m, 2H). 13C NMR (100 MHz,
D2O): δ 134.2, 129.8, 83.3, 80.3, 78.5, 73.5, 70.7, 63.4, 61.3. HRMS calcd
for C9H13N3O5Na [M + Na]+ 266.0753, Found: 266.0754.
(5aR,6S,7R,8R,9aR)-8-(Acetoxymethyl)-4,5a,6,7,8,9a-hexahydropy-
rano[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazine-6,7-diyl Diacetate (18).
Compound 11 (15 mg, 0.06 mmol) was acetylated by using general
procedure F to give 18 (20 mg, Yield: 88%) as a white amorphous solid.
Rf = 0.5 (hexane/EtOAc, 1:1). [R]28 = ꢀ16.42 (c 0.7, CH2Cl2). IR
D
(neat) νmax: 2919, 1737, 1434, 1377, 1226, 1175, 1142, 1115, 1075,
1044, 1014, 983, 965, 924, 822, 757, 636, 602, 564, 480, 436 cmꢀ1. 1H
NMR (400 MHz, CDCl3): δ 7.57 (s, 1H, H-2b), 5.44 (t, J = 8.3 Hz, 2H,
H-9a, H-6), 5.26 (t, J = 9.6 Hz, 1H, H-7), 5.13 (d, J = 15.1 Hz, 1H, H-4),
4.90 (d, J = 15.1 Hz, 1H, H-40), 4.42 (d, J = 12.6 Hz, 1H, H-10), 4.41 (d,
J = 12.6 Hz, 1H, H-100), 4.14ꢀ4.11 (m, 1H, H-8), 3.68 (t, J = 9.2 Hz, 1H,
H-5a), 2.12 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.08 (s, 3H, OAc). 13C
NMR (100 MHz, CDCl3): δ 170.5, 169.4, 131.7, 128.5, 83.0, 75.5, 71.4,
68.0, 63.0, 61.3, 21.0ꢀ20.5 (OAc). HRMS calcd for C15H19N3O8Na
[M + Na]+ 392.1070, Found: 392.1063.
(5aR,6S,7R,8R,9aR)-8-Methyl-4,5a,6,7,8,9a-hexahydropyrano[3,2-b]-
[1,2,3]triazolo[1,5-d][1,4]oxazine-6,7-diol (12). Compound 5 was sub-
jected to global deprotection by using general procedure C to give 12
(yield: 87%) as a thick liquid. Rf = 0.5 (MeOH/EtOAc, 1:9). [R]28
=
D
ꢀ29.00 (c 1.0, MeOH). 1H NMR (400 MHz, D2O): δ 7.58 (s, 1H), 5.41
(d, J = 8.5 Hz, 1H), 5.12 (d, J = 15.4 Hz, 1H), 4.89 (d, J = 15.6 Hz, 1H),
3.82ꢀ3.72 (m, 2H), 3.49ꢀ3.45 (m, 1H), 3.26 (t, J = 9.0 Hz, 1H), 1.34
(d, J = 6.1 Hz, 3H). 13C NMR (100 MHz, D2O): δ 135.9, 131.6, 85.0,
80.5, 78.5, 78.0, 75.0, 65.1, 19.3. HRMS calcd for C9H14N3O4 [M + H]+
228.0984, Found: 228.0980.
(5aR,6S,7R,9aR)-4,5a,6,7,8,9a-Hexahydropyrano[3,2-b][1,2,3]triazolo-
[1,5-d][1,4]oxazine-6,7-diol (13). Compound 6 was subjected to global
deprotection by using general procedure C to give 13 (yield: 83%) as a
(5aR,6S,7R,8R,9aR)-8-Methyl-4,5a,6,7,8,9a-hexahydropyrano[3,2-
b][1,2,3]triazolo[1,5-d][1,4]oxazine-6,7-diyl Diacetate (19). Com-
pound 12 was acetylated by using general procedure F for 2 h to give
colorless liquid. Rf = 0.55 (MeOH/EtOAc, 1:9). [R]28 = ꢀ10.66
19 (yield: 83%) as a colorless oil. Rf = 0.5 (hexane/EtOAc, 1:1). [R]28
=
D
D
5980
dx.doi.org/10.1021/jo200260w |J. Org. Chem. 2011, 76, 5972–5984

The Journal of Organic Chemistry
ARTICLE
ꢀ32.00 (c 0.5, CH2Cl2). IR (neat) νmax: 2922, 1748, 1591, 1452, 1376,
1238, 1156, 1097, 1045, 986, 925 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ
7.53 (s, 1H, H-2b), 5.37ꢀ5.33 (m, 2H, H-9a, H-6), 5.09 (d, J = 15.1 Hz,
1H, H-40), 4.94 (t, J = 9.2 Hz, 1H, H-7), 4.86 (d, J = 15.1 Hz, 1H, H-40),
3.99ꢀ3.96 (m, 1H, H-8), 3.63ꢀ3.59 (m, 1H, H-5a), 2.10 (s, 3H, OAc),
2.09 (s, 3H, OAc), 1.39 (d, J = 6.3 Hz, 3H, H-10). 13C NMR (125 MHz,
CDCl3): δ 170.1, 169.7, 131.6, 128.5, 83.0, 74.1, 73.3, 71.4, 63.0, 20.7,
20.6, 17.4. HRMS calcd for C13H18N3O6 [M + H]+ 312.1196, Found:
312.1198.
give 24 (83 mg, yield: 88%). Rf: 0.34 (hexane:ethyl acetate, 4:2). [R]28
D
= ꢀ20.0 (c 1.5, CH2Cl2). IR (neat) νmax: 3008, 3063, 3031, 2981, 2916,
2868, 2115, 1754, 1603, 1496, 1453, 1363, 1251, 1209, 1099, 1028, 736,
698 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.33ꢀ7.13 (m, 15H, Ar-H),
4.94 (d, J = 11.0 Hz, 1H, OCHPh), 4.81 (t, J = 10.3 Hz, 2H, 2 ꢁ
OCHPh), 4.67 (d, J = 8.5 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H, OCHPh),
4.52 (d, J = 11.0 Hz, 1H, OCHPh), 4.43 (d, J = 15.6 Hz, 1H), 4.28 (d, J =
15.6 Hz, 1H), 4.21ꢀ4.16 (m, 3H), 3.74ꢀ3.64 (m, 3H), 3.60 (d, J = 9.0
Hz, 1H), 3.52ꢀ3.50 (m, 1H), 3.22 (t, J = 8.8 Hz, 1H), 1.25 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 169.5, 138.3, 137.92,
128.3ꢀ127.6 (m, Ar-C), 89.7, 89.6, 84.4, 83.0, 77.3, 75.6, 75.0, 73.5,
70.0, 68.3, 60.8, 14.1. HRMS calcd for C31H35N3O7Na [M + Na]+
584.2373, Found: 584.2372.
(5aR,6S,7R,9aR)-4,5a,6,7,8,9a-Hexahydropyrano[3,2-b][1,2,3]triazolo-
[1,5-d][1,4]oxazine-6,7-diyl Diacetate (20). Compound 13 was acety-
lated using general procedure F for 2 h to give 20 (yield: 77%) as a
colorless oil. Rf = 0.5 (hexane/EtOAc, 1:1). [R]28 = ꢀ88.0 (c 0.5,
D
CH2Cl2). IR (neat) νmax: 2919, 1634, 1360, 1222, 1049, 829, 750, 683,
639, 598, 472 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 7.54 (s, 1H, H-2b),
5.42 (t, J = 9.6 Hz, 1H, H-6), 5.33 (d, J = 8.5 Hz, 1H, H-9a), 5.18ꢀ5.10
(m, 2H, H-7, H-4), 4.89 (d, J = 15.1 Hz, 1H, H-40), 4.44 (dd, J = 11.7 Hz,
11.7 Hz, 1H, H-8), 3.74ꢀ3.68 (m, 1H, H-80), 3.63ꢀ3.58 (m, 1H, H-5a),
2.14 (s, 3H, OAc), 2.08 (s, 3H, OAc). 13C NMR (100 MHz, CDCl3): δ
169.9, 169.7, 131.6, 128.4, 83.7, 76.8, 70.9, 68.7, 66.1, 63.0, 20.7, 20.6.
HRMS calcd for C12H16N3O6 [M + H]+ 298.1039, Found: 298.1039.
(5aR,6S,7S,9aR)-4,5a,6,7,8,9a-Hexahydropyrano[3,2-b]-
Ethyl 2-((2R,3R,4S,5R,6R)-2-Azido-4,5-bis(benzyloxy)-6-methylte-
trahydro-2H-pyran-3-yloxy)acetate (25). Azido alcohol 2b was sub-
jected to esterification by using general procedure D to give 25 (yield:
82%) as a liquid. Rf: 0.34 (hexane:ethyl acetate, 4:2). [R]28D = ꢀ13.0 (c
1.5, CH2Cl2). IR (neat) νmax: 3068, 3031, 2980, 2914, 2870, 2113, 1748,
1598, 1496, 1444, 1386, 1359, 1256, 1211, 1149, 1114, 1090, 1052, 1031,
1
1006, 941, 910, 859, 834, 753, 699, 641 cmꢀ1. H NMR (400 MHz,
CDCl3): δ 7.33ꢀ7.25 (m, 10H, Ar-H), 4.94 (d, J = 11.0 Hz, 1H,
OCHPh), 4.84 (dd, J = 10.9 Hz, 11.0 Hz, 2H, 2 ꢁ OCHPh), 4.66ꢀ4.61
(m, 2H), 4.43 (dd, J = 15.6 Hz, 11.0 Hz, 1H), 4.28 (d, J = 15.8 Hz, 1H),
4.24ꢀ4.16 (m, 2H), 3.66 (t, J = 9.0 Hz, 1H), 3.50ꢀ3.43 (m, 1H),
[1,2,3]triazolo[1,5-d][1,4]oxazine-6,7-diyl Diacetate (21). Compound
14 was acetylated by using general procedure F for 2 h to give 21 (yield:
83%) as a colorless oil. Rf = 0.5 (hexane/EtOAc, 1:1). [R]28D = ꢀ13.0
(c 0.75, CH2Cl2). IR (neat) νmax: 2923, 1745, 1635, 1453, 1374, 1238,
1124, 1091, 1039, 961, 926, 530 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ
7.53 (s, 1H, H-2b), 5.42 (br s, 1H, H-7), 5.31ꢀ5.29 (m, 2H, H-9a, H-6).
5.09 (d, J = 15.3 Hz, 1H, H-4), 4.92 (d, J = 14.9 Hz, 1H, H-40), 4.30 (br d,
J = 13.7 Hz, 1H, H-8), 4.05 (br d, J = 13.7 Hz, 1H, H-80), 3.97 (dd, J = 8.4
Hz, 8.8 Hz, 1H, H-5a), 2.13 (s, 3H, OAc), 2.09 (s, 3H, OAc). 13C NMR
(125 MHz, CDCl3): δ 169.9, 169.8, 131.6, 128.4, 84.4, 74.1, 69.2, 68.1,
68.0, 62.9, 20.7, 20.6. HRMS calcd for C12H16N3O6 [M + H]+ 298.1039,
Found: 298.1039.
3.21ꢀ3.14 (m, 2H), 1.31 (d, J = 6.1 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13
C
NMR (100 MHz, CDCl3): δ 169.5, 138.3, 137.8, 128.4ꢀ127.0 (m, Ar-
C), 89.5, 84.2, 83.3, 82.7, 75.6, 75.3, 73.4, 70.0, 60.9, 17.7, 14.1. HRMS
calcd for C24H30N3O6 [M + H]+ 456.2135, Found: 456.2136.
Ethyl 2-((2R,3R,4S,5R)-2-Azido-4,5-bis(benzyloxy)tetrahydro-2H-
pyran-3-yloxy)acetate (26). Azido alcohol 2e was subjected to ester-
ification by using general procedure D to give 26 (yield: 84%) as a liquid.
Rf: 0.34 (hexane:ethyl acetate, 4:2). [R]28D = ꢀ13.0 (c 1.0, CH2Cl2). IR
(neat) νmax: 3064, 3032, 2982, 2923, 2117, 1753, 1624, 1496, 1455,
1369, 1242, 1207, 1100, 1028, 738, 699, 463 cmꢀ1. 1H NMR (500 MHz,
CDCl3): δ 7.34ꢀ7.25 (m, 10H, Ar-H), 4.87 (s, 2H), 4.70 (d, J = 11.7 Hz,
1H, OCHPh), 4.60 (dd, J = 8.3 Hz, 11.7 Hz, 2H), 4.33 (dd, J = 16.0 Hz,
15.7 Hz, 2H), 4.20ꢀ4.14 (m, 2H), 3.87 (dd, J = 11.7 Hz, 11.7 Hz, 1H),
3.66ꢀ3.52 (m, 2H), 3.26 (dd, J = 10.3 Hz, 10.0 Hz, 1H), 3.13 (t, J = 8.5
Hz, 1H), 1.24 (t, J = 7.15 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
169.6, 138.3, 137.8, 128.4ꢀ127.8 (m, Ar-C), 90.3, 83.4, 82.5, 77.2, 75.5,
73.4, 70.0, 65.7, 60.9, 14.1. HRMS calcd for C23H28N3O6 [M + H]+
442.1978, Found: 442.1982.
((5aS,6S,7R,8aS)-6-Acetoxy-5a,6,7,8a-tetrahydro-4H-furo[3,2-b]-
[1,2,3]triazolo[1,5-d][1,4]oxazin-7-yl)methyl Acetate (22). Compound
16 was acetylated by using general procedure F to give 22 (yield: 80%) as
a light yellow oil. Rf = 0.5 (hexane/EtOAc, 1:4). [R]28D = +37.14 (c 0.35,
CH2Cl2). IR (neat) νmax: 2922, 2851, 1746, 1594, 1372, 1224, 1079,
1027 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 7.56 (s, 1H, H-2b), 5.84
(t, J = 4.0 Hz, 1H, H-6), 5.71 (d, J = 8.5 Hz, 1H, H-8a), 5.20 (d, J = 14.9
Hz, 1H, H-4), 5.07 (d, J = 15.2 Hz, 1H, H-40), 4.91ꢀ4.88 (m, 1H, H-7),
4.38ꢀ4.34 (m, 2H, H-9, H-90), 3.92 (dd, J = 4.0 Hz, 8.5 Hz, 1H, H-5a),
2.16 (s, 3H, OAc), 2.08 (s, 3H, OAc). 13C NMR (125 MHz, CDCl3): δ
170.5, 169.3, 130.9, 128.8, 83.1, 80.8, 79.7, 67.9, 64.6, 61.3, 20.7, 20.5.
HRMS calcd for C12H15N3O6Na [M + Na]+ 320.0859, Found: 320.0857.
(R)-1-((5aS,6S,7R,8aS)-6-Acetoxy-5a,6,7,8a-tetrahydro-4H-furo-
[3,2-b][1,2,3]triazolo[1,5-d][1,4]oxazin-7-yl)ethane-1,2-diyl Diacetate
(23). Compound 17 was acetylated by using general procedure F to give
Ethyl 2-((2R,3R,4S,5S)-2-Azido-4,5-bis(benzyloxy)tetrahydro-2H-
pyran-3-yloxy)acetate (27). Azido alcohol 2f was subjected to ester-
ification by using general procedure D to give 27 (yield: 78%) as a
colorless oil. Rf: 0.34 (hexane:ethyl acetate, 4:2). [R]28D = +10.0 (c 0.6,
CH2Cl2). IR (neat) νmax: 2918, 2113, 1752, 1587, 1452, 1366, 1253,
1207, 1143, 1094, 1055, 1025, 930, 737, 698 cmꢀ1. 1H NMR (400 MHz,
CDCl3): δ 7.36ꢀ7.25 (m, 10H, Ar-H), 4.72 (d, J = 12.6 Hz, 1H,
OCHPh), 4.64ꢀ4.61 (m, 4H), 4.38 (dd, J = 16.1 Hz, 15.8 Hz, 2H),
4.20ꢀ4.07 (m, 3H), 3.70 (br s, 1H), 3.64ꢀ3.56 (m, 2H), 3.35 (br d, J =
12.9 Hz, 1H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
169.8, 137.9, 137.8, 128.4ꢀ127.5 (m, Ar-C), 90.0, 79.8, 79.4, 72.1, 71.8,
71.3, 70.1, 64.7, 60.8, 14.1. HRMS calcd for C23H27N3O6Na [M + Na]+
464.1798, Found: 464.1797.
23 (yield: 93%) as a yellow oil. Rf = 0.5 (hexane/EtOAc, 1:4). [R]28
=
D
+36.0 (c 0.5, CH2Cl2). IR (neat) νmax: 2924, 2853, 1747, 1641, 1446,
1
1374, 1227, 1143, 1124, 1074, 1049, 1020, 954, 692 cmꢀ1. H NMR
(500 MHz, CDCl3): δ 7.56 (s, 1H, H-2b), 5.87 (t, J = 4.0 Hz, 1H, H-6),
5.74 (d, J = 8.6 Hz, 1H, H-8a), 5.40ꢀ5.37 (m, 1H, H-1), 5.20 (d, J = 15.1
Hz, 1H, H-4), 5.07 (d, J = 15.2 Hz, 1H, H-40), 4.84 (dd, J = 10.0 Hz, 10.0
Hz, 1H, H-7), 4.72 (dd, J = 12.3 Hz, 12.6 Hz, 1H, H-2), 4.24 (dd, J = 12.3
Hz, 12.6 Hz, 1H, H-20), 3.95 (dd, J = 8.3 Hz, 4.0 Hz, 1H, H-5a), 2.11
(s, 3H, OAc), 2.06 (s, 3H, OAc), 2.00 (s, 3H, OAc). 13C NMR (125
MHz, CDCl3): δ 170.4, 169.4, 169.3, 131.0, 128.9, 83.7, 79.6, 77.2, 67.3,
67.3, 64.6, 62.2, 20.7ꢀ20.5 (OAc). HRMS calcd for C15H20N3O8 [M +
H]+ 370.1250, Found: 370.1255.
Ethyl 2-((2R,3R,4S,5S,6R)-2-Azido-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-3-yloxy)acetate (28). Azido alcohol 1g was sub-
jected to esterification by using general procedure D to give 28 (yield:
83%). Rf: 0.34 (hexane:ethyl acetate, 4:2). [R]28 = +4.0 (c 0.5,
D
CH2Cl2). IR (neat) νmax: 3063, 3030, 2918, 2869, 2115, 1755, 1605,
1
1496, 1453, 1365, 1254, 1208, 1147, 1111, 1027, 737, 698 cmꢀ1. H
Ethyl 2-((2R,3R,4S,5R,6R)-2-Azido-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-3-yloxy)acetate (24). Azido alcohol 2a (80 mg,
0.16 mmol) was subjected to alkylation by using general procedure D to
NMR (500 MHz, CDCl3): δ 7.34ꢀ7.23 (m, 15H, Ar-H), 4.88 (d, J =
11.0 Hz, 1H, OCHPh), 4.71 (s, 2H), 4.66 (d, J = 7.7 Hz, 1H), 4.56 (d, J =
11.0 Hz, 1H, OCHPh), 4.46ꢀ4.33 (m, 4H), 4.19ꢀ4.09 (m, 2H), 3.91
5981
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ARTICLE
(br s, 1H), 3.63ꢀ3.53 (m, 5H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 169.9, 138.3, 138.1, 137.7, 128.3ꢀ127.5 (m, Ar-C),
90.0, 82.0, 80.1, 75.5, 74.7, 73.7, 73.0, 72.8, 70.5, 68.4, 60.9, 14.2. HRMS
calcd for C31H35N3O7Na [M + Na]+ 584.2373, Found: 584.2371.
Ethyl 2-((2S,3S,4S,5R)-2-Azido-4-(benzyloxy)-5-(benzyloxymethyl)-
tetrahydrofuran-3-yloxy)acetate (29). Azido alcohol 2h was subjected
to alkylation by using general procedure D to give 29 (yield: 70%). Rf:
Hz, 17.1 Hz, 2H), 3.85ꢀ3.80 (m, 2H), 3.72 (dd, J = 10.0 Hz, 10.3 Hz,
1H), 3.60 (br d, J = 13.1 Hz, 1H), 3.39 (dd, J = 8.5 Hz, 8.5 Hz, 1H). 13
C
NMR (125 MHz, D2O): δ 171.7, 80.9, 74.9, 69.5, 68.9, 68.8, 67.3.
HRMS calcd for C7H12NO5 [M + H]+ 190.0715, Found: 190.0717.
(4aR,6R,7R,8S,8aR)-7,8-Dihydroxy-6-(hydroxymethyl)hexahydropyrano-
[3,2-b][1,4]oxazin-3(2H)-one (35). Compounds 28 and 41 were sub-
jected to global deprotection by using general procedure E to give 35
0.6 (hexane:ethyl acetate, 4:1). [R]28 = +73.75 (c 0.8, CH2Cl2). IR
(yield: 85%) as a white solid. Mp: 238ꢀ240 °C. Rf = 0.45 (MeOH/
D
1
EtOAc, 1:9). [R]28 = ꢀ10.0 (c 0.4, MeOH). H NMR (500 MHz,
(neat) νmax: 2928, 2109, 1750, 1600, 1453, 1372, 1302, 1238, 1209,
1152, 1048, 863, 782, 737, 698 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ
7.35ꢀ7.26 (m, 10H, Ar-H), 5.50 (d, J = 3.1 Hz, 1H), 4.80 (d, J = 11.7 Hz,
1H, OCHPh), 4.60 (d, J = 12.0 Hz, 2H, 2 ꢁ OCHPh), 4.48 (d, J = 12.0
Hz, 1H, OCHPh), 4.42 (dd, J = 11.4 Hz, 11.7 Hz, 1H), 4.23ꢀ4.17 (m,
5H), 3.84 (t, J = 3.4 Hz, 1H), 3.73ꢀ3.72 (m, 2H), 1.28 (t, J = 7.1 Hz,
3H). 13C NMR (125 MHz, CDCl3): δ 169.9, 138.1, 137.8, 128.5ꢀ127.7
(m, Ar-C), 93.4, 84.0, 79.5, 77.2, 73.5, 73.5, 69.2, 67.9, 61.2, 14.2. HRMS
calcd for C23H27N3O6Na [M + Na]+ 464.1798, Found: 464.1795.
Ethyl 2-((2S,3S,4S,5R)-2-Azido-4-(benzyloxy)-5-((R)-1,2-bis(benzyloxy)-
ethyl)tetrahydrofuran-3-yloxy)acetate (30). Azido alcohol 2i was sub-
jected to alkylation by using general procedure D to give 30 (yield: 72%).
Rf: 0.34 (hexane:ethyl acetate, 4:2). [R]28D = +46.66 (c 1.35, CH2Cl2).
IR (neat) νmax: 3030, 2982, 2929, 2109, 1752, 1599, 1496, 1453, 1423,
D
D2O): δ 4.54 (d, J = 8.4 Hz, 1H, H-4a). 4.20 (dd, J = 17.2 Hz, 16.8 Hz,
2H, H-2, H-20), 3.90 (s, 1H, H-7), 3.76 (dd, J = 10.3 Hz, 10.3 Hz, 1H,
H-8), 3.71ꢀ3.62 (m, 3H, H-6, H-9, H-90), 3.45 (dd, J = 8.4 Hz, 8.4 Hz,
1H, H-8a). 13C NMR (125 MHz, D2O): δ 171.8, 80.6, 78.0, 75.2, 70.0,
69.2, 67.4, 61.0. HRMS calcd for C8H14NO6 [M + H]+ 220.0821,
Found: 220.0825.
(4aR,6R,7R,8S,8aR)-6-(Acetoxymethyl)-3-oxooctahydropyrano-
[3,2-b][1,4]oxazine-7,8-diyl Diacetate (36). Compound 31 was acety-
lated by using general procedure F for 2 h to give 36 (yield: 68%) as a
colorless oil. Rf = 0.5 (hexane/EtOAc, 1:1). [R]28 = ꢀ5.0 (c 0.4,
D
CH2Cl2). IR (neat) νmax: 3457, 2920, 2851, 1745, 1681, 1431, 1370,
1229, 1086, 1048 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 6.74 (br s, 1H,
H-4), 5.28 (t, 1H, J = 9.4 Hz, H-8), 5.11 (t, 1H, J = 9.6 Hz, H-7), 4.68 (d,
1H, J = 8.0 Hz, H-4a), 4.34ꢀ4.14 (m, 4H, H-9, H-90, H-2, H-20),
3.84ꢀ3.82 (m, 1H, H-6), 3.42 (t, 1H, J = 9.0 Hz, H-8a), 2.10 (s, 3H,
OAc), 2.08 (s, 3H, OAc), 2.05 (s, 3H, OAc). 13C NMR (125 MHz,
CDCl3): δ 170.5, 170.1, 169.4, 168.0, 80.9, 75.7, 74.3, 71.6, 68.4, 68.0,
61.6, 20.7ꢀ20.5. HRMS calcd for C14H19NO9Na [M + Na]+ 368.0958,
Found: 368.0959.
1
1380, 1302, 1208, 1152, 1114, 1094, 1056, 1028, 737, 698 cmꢀ1. H
NMR (400 MHz, CDCl3): δ 7.33ꢀ7.25 (m, 15H, Ar-H), 5.43 (d, J = 5.4
Hz, 1H), 4.94 (d, J = 10.9 Hz, 1H, OCHPh), 4.74 (d, J = 11.2 Hz, 1H,
OCHPh), 4.57ꢀ4.43 (m, 4H), 4.30ꢀ4.04 (m, 7H), 3.89ꢀ3.83 (m, 2H),
3.64 (dd, J = 5.1 Hz, 4.6 Hz, 1H), 1.28 (t, J = 7.0 Hz, 3H). 13C NMR (125
MHz, CDCl3): δ 169.8, 138.6, 138.5, 138.4, 128.4ꢀ127.5 (m, Ar-C),
93.8, 86.3, 79.3, 77.5, 75.8, 73.9, 73.5, 72.2, 69.7, 68.1, 61.2, 14.2. HRMS
calcd for C31H35N3O7Na [M + Na]+ 584.2373, Found: 584.2377.
(4aR,6R,7S,8S,8aR)-7,8-Dihydroxy-6-(hydroxymethyl)hexahydropyrano-
[3,2-b][1,4]oxazin-3(2H)-one (31). Compound 24 (80 mg, 0.14 mmol)
was subjected to global deprotection by using general procedure E to
(4aR,6R,7R,8S,8aR)-6-(Acetoxymethyl)-4-acetyl-3-oxooctahydropy-
rano[3,2-b][1,4]oxazine-7,8-diyl Diacetate (37). Compound 31 was
acetylated by using general procedure F for 15 h to give 37 (yield: 70%)
as a colorless oil. Rf = 0.5 (hexane/EtOAc, 1:1). [R]28D = ꢀ35.83 (c 1.2,
CH2Cl2). IR (neat) νmax: 2924, 1748, 1643, 1419, 1370, 1305, 1234,
1093, 1049, 614 cmꢀ1. 1H NMR (500 MHz, CDCl3): δ 5.32 (t, J = 9.3
Hz, 1H, H-8). 5.12 (m, 2H, H-4a, H-7), 4.42 (d, J = 17.1 Hz, 1H, H-2),
4.29 (dd, J = 12.6 Hz, 12.6 Hz, 1H, H-9), 4.22 (d, J = 17.1 Hz, 1H, H-20),
4.05 (dd, J = 12.6 Hz, 12.6 Hz, 1H, H-90), 3.89ꢀ3.86 (m, 1H, H-6), 3.56
(t, J = 9.7 Hz, 1H, H-8a), 2.54 (s, 3H, NꢀAc), 2.07 (s, 6H, OAc), 2.03 (s,
3H, OAc), 1.21 (d, J = 5.1 Hz, 3H, H-9). 13C NMR (125 MHz, CDCl3):
δ 171.5, 170.6, 170.1, 169.6, 168.3, 81.3, 75.6, 74.7, 72.4, 70.0, 68.5, 61.5,
28.0, 20.8, 20.6. HRMS calcd for C16H21NO10Na [M + Na]+ 410.1063,
Found: 410.1067.
give 31 (29 mg, Yield: 94%) as a colorless liquid. Rf = 0.45 (MeOH/
1
EtOAc, 1:9). [R]28 = ꢀ5.71 (c 0.35, MeOH). H NMR (500 MHz,
D
D2O): δ 4.56 (d, J = 8.0 Hz, 1H) 4.18 (d, J = 17.2 Hz, 1H), 4.10 (d, J =
17.2 Hz, 1H), 3.75 (d, J = 12.6 Hz, 1H), 3.58 (dd, J = 13.0 Hz, 10.3 Hz,
2H), 3.44ꢀ3.41 (m, 1H), 3.32 (t, J = 9.1 Hz, 1H), 3.14 (dd, J = 8.0 Hz,
9.2 Hz, 1H). 13C NMR (125 MHz, D2O): δ 171.7, 79.8, 78.5, 76.8, 72.9,
70.2, 67.0, 60.5. HRMS calcd for C8H14NO6 [M + H]+ 220.0821,
Found: 220.0825.
(4aR,6R,7S,8S,8aR)-7,8-Dihydroxy-6-methylhexahydropyrano[3,2-
b][1,4]oxazin-3(2H)-one (32). Compound 25 was subjected to global
deprotection by using general procedure E to give 32 (yield: 86%) as a
liquid. Rf = 0.45 (MeOH/EtOAc, 1:9). [R]28D = ꢀ14.00 (c 1.0, MeOH).
1H NMR (400 MHz, D2O): δ 4.54 (d, J = 8.2 Hz, 1H), 4.13 (dd, J = 17.0
Hz, 16.8 Hz, 2H), 3.54ꢀ3.42 (m, 2H), 3.16ꢀ3.07 (m, 2H), 1.16 (d, J =
6.3 Hz, 3H). 13C NMR (100 MHz, D2O): δ 172.4, 80.4, 77.8, 76.4, 75.3,
73.3, 67.6, 17.4. HRMS calcd for C8H14NO5 [M + H]+ 204.0872,
Found: 204.0874.
(4aR,6R,7R,8S,8aR)-4-Acetyl-6-methyl-3-oxooctahydropyrano[3,2-
b][1,4]oxazine-7,8-diyl Diacetate (38). Compound 32 was acetylated
by using general procedure F for 10 h to give 38 (yield: 74%) as a
colorless oil. Rf = 0.5 (hexane/EtOAc, 1:1). [R]28 = ꢀ30.0 (c 0.6,
D
CH2Cl2). IR (neat) νmax: 2986, 2943, 1750, 1721, 1584, 1418, 1371,
1332, 1305, 1237, 1214, 1177, 1128, 1111, 1087, 1059, 618, 577,
1
539 cmꢀ1. H NMR (500 MHz, CDCl3): δ 5.26 (t, J = 9.1 Hz, 1H,
H-8), 5.12 (d, J = 9.1 Hz, 1H, H-4a), 4.82 (t, J = 8.8 Hz, 1H, H-7), 4.41
(d, J = 16.6 Hz, 1H, H-2), 4.21 (d, J = 16.6 Hz, 1H, H-20), 3.74 (br s, 1H,
H-6), 3.51 (t, J = 9.15 Hz, 1H, H-8a), 2.54 (s, 3H, NꢀAc), 2.06 (s, 3H,
OAc), 2.05 (s, 3H, OAc), 1.21 (d, J = 5.1 Hz, 3H, H-9). 13C NMR (125
MHz, CDCl3): δ 171.7, 170.1, 169.8, 168.4, 81.0, 75.9, 73.9, 72.9, 72.7,
69.9, 28.0, 20.7, 20.6, 17.5. HRMS calcd for C14H20NO8 [M + H]+
330.1189, Found: 330.1189.
(4aR,7R,8S,8aR)-7,8-Dihydroxyhexahydropyrano[3,2-b][1,4]oxazin-
3(2H)-one (33). Compound 26 was subjected to global deprotection by
using general procedure E to give 33 (yield: 89%) as a white crystalline
compound. Mp: 207ꢀ209 °C. Rf = 0.45 (MeOH/EtOAc, 1:9). [R]28
=
D
ꢀ12.00 (c 1.0, MeOH). 1H NMR (500 MHz, D2O): δ 4.47 (d, J = 8.4 Hz,
1H), 4.12 (dd, J = 16.8 Hz, 17.2 Hz, 2H), 3.88 (dd, J = 11.4 Hz, 11.8 Hz,
1H), 3.57ꢀ3.48 (m, 2H), 3.28ꢀ3.23 (m, 1H), 3.12 (t, J = 8.7 Hz, 1H).
13C NMR (125 MHz, D2O): δ 171.7, 80.6, 76.8, 72.9, 69.8, 67.4, 66.9.
HRMS calcd for C7H11NO5Na [M + Na]+ 212.0535, Found: 212.0536.
(4aR,7S,8S,8aR)-7,8-Dihydroxyhexahydropyrano[3,2-b][1,4]oxazin-
3(2H)-one (34). Compounds 27 and 40 were subjected to global
deprotection by using general procedure E to give 34 (yield: 87%) as
a liquid. Rf = 0.45 (MeOH/EtOAc, 1:9). [R]28D = +4.00 (c 0.5, MeOH).
1H NMR (400 MHz, D2O): δ 4.39 (d, J = 8.2 Hz, 1H), 4.13 (dd, J = 17.1
(4aR,7S,8S,8aR)-4-Acetyl-3-oxooctahydropyrano[3,2-b][1,4]oxazine-
7,8-diyl Diacetate (39). Compound 34 was acetylated by using general
procedure F for 10 h to give 39 (yield: 76%) as a colorless oil. Rf = 0.5
(hexane/EtOAc, 1:1). [R]28D = ꢀ11.66 (c 0.6, CH2Cl2). IR (neat) νmax
1H NMR (500 MHz, CDCl3): δ 5.36 (br s, 1H, H-7), 5.17 (dd, J = 10.3
Hz, 3.8 Hz, 1H, H-8), 5.04 (d, J = 9.1 Hz, 1H, H-4a), 4.43 (d, J = 17.2 Hz,
1H, H-2), 4.28 (d, J = 17.5 Hz, 1H, H-20), 4.00 (d, J = 13.8 Hz, 1H, H-6),
:
.
2922, 2853, 1745, 1648, 1370, 1311, 1237, 1125, 1100, 1060, 605 cmꢀ1
5982
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ARTICLE
3.87ꢀ3.83 (m, 2H, H-8a, H-60), 2.55 (s, 3H, NꢀAc), 2.14 (s, 3H, OAc),
2.06 (s, 3H, OAc). 13C NMR (125 MHz, CDCl3): δ 171.9, 169.9, 169.8,
168.5, 82.5, 73.2, 70.0, 70.0, 68.4, 67.4, 28.0, 20.8, 20.6. HRMS calcd for
C13H17NO8Na [M +Na]+ 338.0852, Found: 338.0856.
(2) (a) Da Silva, F. C.; De Souza, M. C. B V.; Frugulhetti, I. I. P.;
Castro, H. C.; Souza, S. L. O.; de Souza, T. M. L.; Rodrigues, D. Q.;
Souza, A. M. T.; Abreu, P. A.; Passamani, F.; Rodrigues, C. R.; Ferreira,
V. F. Eur. J. Med. Chem. 2009, 44, 373. (b) Alvarez, R.; Velazquez, S.;
San-Felix, A.; Aquaro, S.; De Clercq, E.; Perno, C. F.; Karlsson, A.;
Balzarini, J.; Camarasa, M. J. J. Med. Chem. 1994, 37, 4185.
(3) Wamhoff, H. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 5, p 669.
(4) Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.; Tew,
D.; Meek, T. D.; Hofmann, G. A.; Schulz-Pritchard, C. K.; Smith, W. W.;
Janson, C. A.; Ryan, M. D.; Zhang, G. F.; Johanson, K. O.; Kirkpatrick,
R. B.; Ho, T. F.; Fisher, P. W.; Mattern, M. R.; Johnson, R. K.; Hansbury,
M. J.; Winkler, J. D.; Ward, K. W.; Veber, D. F.; Thompson, S. K. J. Med.
Chem. 2005, 48, 5644.
Ethyl 2-((2S,3R,4S,5S)-2-Azido-4,5-bis(benzyloxy)tetrahydro-2H-
pyran-3-yloxy)acetate (40). Azido alcohol 1fr was subjected to ester-
ification by using general procedure D to give 40 (yield: 80%). Rf: 0.34
(hexane:ethyl acetate, 4:2). [R]28D = +103.57 (c 0.7, CH2Cl2). IR (neat)
νmax: 3031, 2925, 2115, 1746, 1632, 1495, 1454, 1379, 1261, 1211, 1103,
1052, 878, 739, 697, 463 cmꢀ1 1H NMR (400 MHz, CDCl3): δ
.
7.33ꢀ7.25 (m, 10H, Ar-H), 5.63 (d, J = 5.8 Hz, 1H), 4.69ꢀ4.60 (m,
4H), 4.37 (s, 2H), 4.18 (dd, J = 14.4 Hz, 14.4 Hz, 2H), 3.92 (dd, J = 3.8
Hz, 3.9 Hz, 1H), 3.84ꢀ3.73 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 170.7, 138.0, 137.8, 128.4ꢀ127.5 (m, Ar-C),
88.9, 77.5, 76.5, 72.8, 72.2, 71.5, 69.7, 62.0, 60.9, 14.1. HRMS calcd for
C23H28N3O6 [M + H]+ 442.1978, Found: 442.1974.
(5) Costa, M. S.; Boechat, N.; Rangel, E. A.; Da Silva, F. C.;
De Souza, A. M. T.; Rodrigues, C. R.; Castro, H. C.; Junior, I. N.;
Lourenco, M. C. S.; Wardell, S. M. S. V.; Ferreira, V. F. Bioorg. Med.
)
Ethyl 2-((2S,3R,4S,5S,6R)-2-Azido-4,5-bis(benzyloxy)-6-(benzyloxymethyl)-
tetrahydro-2H-pyran-3-yloxy)acetate (41). Azido alcohol 1g-r was
subjected to esterification by using general procedure D to give 41
(yield: 85%) as a light yellow oil. Rf: 0.34 (hexane:ethyl acetate, 4:2).
Chem. 2006, 14, 8644.
(6) Bock, V. D.; Speijer, D.; Hiemstra, H.; van Maarseveen, J. H. Org.
Biomol. Chem. 2007, 5, 971.
(7) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med.
Chem. 1986, 29, 2262.
[R]28 = +31.42 (c 0.7, CH2Cl2). IR (neat) νmax: 3063, 3030, 2981,
D
(8) (a) Heightman, T. D.; Vasella, A.; Tsitsanou, K. E.; Zographos,
S. E.; Skamnaki, V. T.; Oikonomakos, N. G. Helv. Chim. Acta 1998,
81, 853. (b) Krulle, T. M.; Fuente, C. D.; Pickering, L; Aplin, R. T.;
Tsitsanou, K. E.; Zographos, S. E.; Oikonomakos, N. G.; Nash, R. J.;
Griffiths, R. C.; Fleet, G. W. Tetrahedron: Asymmetry 1997, 8, 3807.
(c) Heightman, T. D.; Locatelli, M.; Vasella, A. Helv. Chim. Acta 1996,
79, 2190.
(9) (a) Ramachary, D. B.; Reddy, G. B.; Mondal, R. Tetrahedron Lett.
2007, 48, 7618. (b) Chuprakov, S.; Chernyak, N.; Dudnik, A. S.;
Gevorgyan, V. Org. Lett. 2007, 9, 2333. (c) Gil, M. V.; Arevalo, M. J.;
Lopez, O. Synthesis 2007, 1589. (d) Krivopalov, V. P.; Shkurko, O. P.
Russ. Chem. Rev. 2005, 74, 339. (e) Godovikova, T. I.; Ignateva, E. L.;
Khmelnitskii, L. I. Chem. Heterocycl. Compd. 1989, 25, 113. (f) Wu,
Y. M.; Deng, J.; Chen, Q. Y. Synlett 2006, 645.
2922, 2871, 2116, 1747, 1731, 1604, 1496, 1453, 1372, 1344, 1306, 1276,
1
1210, 1181, 1145, 1108, 1057, 1028, 737, 698 cmꢀ1. H NMR (500
MHz, CDCl3): δ 7.36ꢀ7.25 (m, 15H, Ar-H), 5.74 (d, J = 4.2 Hz, 1H)
4.87 (d, J = 11.4 Hz, 1H, OCHPh), 4.69 (s, 2H), 4.51 (dd, J = 11.4 Hz,
11.8 Hz, 2H, 2 ꢁ OCHPh), 4.42ꢀ4.31 (m, 3H), 4.18ꢀ4.14 (m, 2H),
4.03 (t, J = 6.5 Hz, 1H), 3.97 (d, J = 9.9 Hz, 2H), 3.78 (d, J = 9.9 Hz, 1H),
3.54 (d, J = 6.1 Hz, 2H), 1.25 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.8, 138.3, 138.2, 137.8, 128.6ꢀ127.5 (m, Ar-C), 89.1,
79.3, 77.6, 74.9, 74.1, 73.6, 72.2, 71.5, 70.0, 68.4, 61.1, 14.2. HRMS calcd
for C31H36N3O7 [M + H]+ 562.2553, Found: 562.2555.
’ ASSOCIATED CONTENT
S
(10) (a) Sudhir, V. S.; Kumar, N. Y. P.; Baig, R. B. N.; Chandrasekaran,
S. J. Org. Chem. 2009, 74, 7588. (b) Yanai, H.; Obara, S.; Taguchi, T. Org.
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Supporting Information. General experimental proce-
b
dures and characterization data for all new compounds, copies of
1H NMR, 13C NMR, Hꢀ H COSY, and Hꢀ H NOESY
spectra, and single X-ray crystallographic data for compounds
15, 33, 35. This material is available free of charge via the Internet
at http://pubs.acs.org.
1
1
1
1
(11) For a review see: (a) Wijtmans, R.; Vink, M. K. S.; Schoemaker,
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’ AUTHOR INFORMATION
Corresponding Author
*Fax: 0091-0512-259 7492. E-mail: vankar@iitk.ac.in.
’ ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research,
New Delhi, for financial support [Grant No. 01(2298)/09/
EMR-II] and the Department of Science and Technology,
New Delhi, for J. C. Bose National Fellowship (JCB/SR/S2/
JCB-26/2010) to Y.D.V. Y.S.R. and A.A.A. thank the Council of
Scientific Industrial Research, New Delhi, for Senior Research
Fellowships, and A.P.J.P. and P.G. thank the University Grant
Commission, New Delhi, for Senior Research Fellowships.
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