Chemistry of 2-nitroglycals: A one-pot three-component stereoselective approach toward 2-C-branched O-galactosides

Article abstract of DOI:10.1021/jo101735u

A convenient one-pot three-component approach for the synthesis of 2-C-branched O-glycosides has been developed from 2-nitroglycals. These 2-C-branched sugars have been shown to be precursors for a variety of biologically and synthetically relevant molecu

Full text of DOI:10.1021/jo101735u

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Chemistry of 2-Nitroglycals: A One-Pot Three-Component
Stereoselective Approach toward 2-C-Branched O-Galactosides
Pavan K. Kancharla and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
vankar@iitk.ac.in
Received September 5, 2010
A convenient one-pot three-component approach for the synthesis of 2-C-branched O-glycosides has
been developed from 2-nitroglycals. These 2-C-branched sugars have been shown to be precursors for
a variety of biologically and synthetically relevant molecules.
Introduction
of enormous importance in organic synthesis, particularly as
it can readily be converted into an amino or a hydroxyl-
amino7 group. Also, the nitro groups allow the generation of
a reactive radical in the presence of n-Bu3SnH-AIBN8 that
could be exploited further. As a result, 2-nitroglycals serve as
useful intermediates in the synthesis of 2-deoxy-2-amino
glycosides, which are constituents of several nucleoside and
aminoglycosidic antibiotics.9 The base-catalyzed 2-nitrogly-
cal concatenation is extensively studied and has also been
applied in the synthesis of mucins,10a a family of highly
O-glycosylated glycoproteins that play an important role in
various biological processes.10b,c
2-Nitroglycals are versatile intermediates for the stereo-
selective synthesis of various glycosides.1 Besides being good
Michael acceptors, they also permit (2 þ 3) and (2 þ 4)
cycloadditions, thus permitting the preparation of a number
of other useful carbohydrate derived synthons. Optimized
conditions have been developed for the stereoselective addi-
tion of a variety of nucleophiles to the 2-nitroglycals, result-
ing in the synthesis of several O-glycosides,2 thioglycosides,3
glycophosphonates,4 C-glycosides,5 and N-glycosides (for the
synthesis of nucleosides).6 Further, the nitro functionality is
(1) (a) Schmidt, R. R.; Vankar, Y. D. Acc. Chem. Res. 2008, 41, 1059.
(b) Xue, W.; Sun, J.; Yu, B. J. Org. Chem. 2009, 74, 5079. (c) Zhang, Q.; Sun,
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Angew. Chem., Int. Ed. 2005, 44, 2001. (c) Zhang, T; Yu, C.-Y.; Huang, Z.-T.;
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New York, 2001; p 307.
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McKenzie, I. F. C. Bioessays 1992, 14, 619. (c) Varki, A. Glycobiology
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DOI: 10.1021/jo101735u
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Kancharla and Vankar
JOCArticle
Although C-glycosides can be readily prepared11 from glycals,
their derivatives, and other monosaccharides, C-functionaliza-
tion at centers other than the anomeric carbon is still a
challenge for chemists. Since C-branched sugars are abun-
dant in nature and many antibiotics12 and natural products13
contain these branched sugars as structural subunits, several
approaches toward them have been reported in the litera-
ture.14 Further, some methods of introducing a carbon chain
at C-2 require multisteps,15 while others involve the use
of toxic reagents such as mercury and tin16 or moisture-
sensitive organolithium and Grignard reagents.17 However,
notable contribution has been made by Linker and co-
workers18 in the synthesis of 2-C-branched sugars through
ceric ammonium nitrate mediated addition of active methyl-
enes to glycals that were extended to the synthesis of glyco-
aminoacids,19 glycoacetic acids,20 and glycosamines.21 The
other effective ways of entering into 2-C-branched sugars
include the usage of 1,2-cyclopropanated sugars and related
systems22 and many others.23
2-nitroglycals as synthons for the synthesis of 2-C-branched
sugars. Since R,β-unsaturated nitro compounds are known
to undergo intramolecular Michael-Michael26 and Michael-
Henry aldol27 cascade in a two-component reaction, we
anticipated the utility of 2-nitroglycals in a one-pot three-
component approach to attain the 2-C-branched glycosides.
One-pot reactions,28 being practically single-step reactions,
are easier to handle than stepwise synthesis. Our approach
toward the synthesis of 2-C-branched O-glycosides also
allows further functionalization due to the presence of the
nitro group.
Results and Discussion
Schmidt et al. have reported that O-nucleophiles, for
stereoelectronic reasons, selectively add1a from the R-side
to 2-nitrogalactals in the presence of a strong base, generat-
ing a nitronate ion intermediate.1,2b This nitronate ion after
protonation from the β-side provides the 2-deoxy-2-nitro-
R-galactosides. Our aim was to trap the nitronate ion inter-
mediate with a suitable carbon electrophile to generate the
2-C-branched glycosides. For this purpose, in our initial
attempt we have added 1 equiv of acrylonitrile to a stirring
reaction mixture of 2-nitrogalactal 1 (Table 1) and benzyl
alcohol in the presence of a catalytic amount of KOtBu in
THF for 2 h. To our delight, we observed the formation of a
clean new product as gauged by thin layer chromatographic
analysis; however, the reaction could not proceed further
to completion even after several hours. Optimization of the
reaction conditions led us to use 2.5 equiv of acrylonitrile
at 25 °C under the same conditions, which led to a clean
reaction. Further, out of the four possible isomers that can
result as a result of the generation of two new stereocenters,
the one-pot Michael-Michael reaction on 2-nitrogalactal
led to the exclusive formation of a single diastereomer 3 of
2-nitro-2-C-branched glycoside in 75% yield. The scope of
the reaction was explored by using different alcohols as
Michael donors and methyl acrylate as well as acrylonitrile
as the second Michael acceptors, and our results are sum-
marized in Table 1.
The stereochemical outcome of the Michael-Michael
addition was proved unambiguously by the X-ray crystal
structure29 obtained for compound 4 (see Supporting
Information) wherein the two new groups added at C-2,
i.e., the propargyl group and the -CH2CH2COOMe, were
found to be placed in a 1,2-diaxial fashion. Further, the
stereochemistry was also assigned through COSY and NOE
analysis of the acetamido derivative 31, vide infra, derived
from the nitro compound 5 (see Supporting Information).
The generation of the stereocenter at the anomeric position
is in consonance with the results reported by Schmidt et al.,
Our group has been actively involved in the chemistry of
nitro sugars in general24 and 2-nitroglycals in particular en
route to the development of novel glycosidase inhibitors5,25
and in the synthesis of 2-deoxy-2-amino C-glycosides.5a In
view of the above-mentioned developments in the synthe-
sis of 2-C-branched sugars and our interest in developing
the chemistry of nitrosugars, we were prompted to use
(11) (a) Postema, M. H. D.; Piper, J. L.; Betts, R. L.; Valeriote, F. A.;
Pietraszkewicz, H. J. Org. Chem. 2005, 70, 829. (b) Postema, M. H. D.
C-Glycoside Synthesis, 1st ed.; CRC Press: Boca Raton, 1995.
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G. W. J. Tetrahedron: Asymmetry 2009, 20, 2357. (c) Booth, K. V.;
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Weymouth-Wilson, A. C.; Fleet, G. W. J. Tetrahedron Lett. 2009, 50, 5088.
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Chem. 2009, 74, 5093. (e) Otero, J. M.; Estevez, A. M.; Soengas, R. G.;
Estevez, J. C.; Nash, R. J.; Fleet, G. W. J.; Estevez, R. J. Tetrahedron:
Asymmetry 2008, 19, 2443.
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forsch. B 1994, 50, 294.
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23, 69. (c) Giese, B.; Groninger, K. Tetrahedron lett. 1984, 25, 2743.
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(b) akoto, C. O.; Rainier, J. D. Angew Chem, Int. Ed. 2008, 47, 8055.
(c) Doddi, V. R.; Kancharla, P. K.; Reddy, Y. S.; Kumar, A.; Vankar,
Y. D. Carbohydr. Res. 2009, 344, 606.
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Tetrahedron 2008, 64, 11925. Yin, J.; Sommermann, T.; Linker, T.
Chem. Eur. J. 2007, 13, 10152 and references therein.
;
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Chem. Commun. 2004, 2624.
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Hungate, R. W.; Julian, L. D.; Kaizerman, J. A.; McMinn, D. L.; Rew, Y.;
Sun, D.; Yan, S.; Powers, J. P. J. Org. Chem. 2007, 72, 7455. (b) Zu, L.; Li, H.;
Xie, H.; Wang, J.; Jiang, W.; Tang, Y.; Wang, W. Angew. Chem., Int. Ed.
2007, 46, 3732.
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Chen, H.; Xu, Z.-Y. Adv. Synth. Catal. 2008, 350, 2610. (b) Tan, B.; Chua, J.;
Li, Y.; Zhonf, G. Org. Lett. 2008, 10, 2437.
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(29) CCDC number for the crystal data of the compound 4: 789893. We
thank Mr. Ashutosh Kumar Mishra for solving the crystal structure of the
compound.
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TABLE 1. One-Pot Michael-Michael Reaction with 2-Nitrogalactal
i.e., the nucleophilic attack occurs at the anomeric center
from the R-side, whereas the second stereocenter generated
at the C-2 carbon results according to the transition state
depicted in Figure 1.
The nitronate ion generated at the C-2 center, during the
electrophile trapping, orients itself in the conformation 11
rather than 12 due to the possible unfavorable 1,3-diaxial
interaction between the C-4-O-benzyl group and the nitro
group, thus allowing the electrophilic attack from β-side.
We also subjected the 2-nitrogalactal to one-pot Michael-
Henry aldol reaction (Table 2) with paraformaldehyde as an
electrophile with the same set of alcohols as initial Michael
donors. Although the yields of the products 13-17 were
moderate in comparison to the Michael-Michael reaction,
FIGURE 1. Transition states to depict the stereochemical outcome
of the products.
we again observed the exclusive formation of the diaxially
substituted Michael-Henry aldol adducts in all of the cases
as confirmed on the basis of COSY and NOE studies. Thus,
for example, during NOE spectral studies of compound 16
(Figure 2), irradiation of the signal for H-2 at δ 5.06 showed
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TABLE 2. One-Pot Michael-Henry Addition with 2-Nitrogalactal
FIGURE 2. Diagnostic NOE correlations observed for the com-
pounds 16, 19, and 20.
3.53, respectively, suggesting the axial and equatorial orien-
tation of the propargyl group, respectively. Besides, irra-
diation of H-5 proton at δ 4.74 and at 4.54 in either cases,
i.e., compounds 19 and 20, respectively, did not result
in the enhancement of protons of the side chain at C-2
indicating the equatorial orientation of the -CH2CH2CN
group (Figure 2).
Synthesis of 2-C-Branched Amino Sugar, Amino Acid, and
Spirolactam. 2-Amino-2-deoxy-O-glycosides are constitu-
ents of several nucleoside and aminoglycosidic anitibiotics,31
and the abundance of 2-N-acetamidosugars,32 N-acetylglu-
cosamine and N-acetylgalactosamine in glycoproteins, pro-
teoglycans, and glycolipids makes them attractive targets for
metabolic engineering. The recent study of metabolic cell
surface engineering with the artificial C-2-carbon isosters33
shows the need of more number of such analogues. In the
present study, the above-described Michael-Michael and
Michael-Henry aldol adducts have been shown to be the
precursors for the synthesis of some novel 2-C-branched-
2-amino O-glycosides by successfully reducing the nitro group
of the compound 5 to amino group by using Zn/HCl/AcOH
and subsequently protecting as N-acetate 31 (Scheme 1).
Compound 4 was also subjected to these conditions
followed by treatment with triethylamine, which resulted in
an interesting sugar-derived C2-spiro-γ-lactam 32 (Scheme 2).
However, by subjecting the crude amino product to an excess
of acetic anhydride in the presence of triethylamine led to the
γ-amino butyric acid (GABA) derivative 33, thus providing
an elegant entry into biologically important sugar amino
acids34 (SAA). Absence of the methyl singlet at δ 3.52 in the
1H NMR spectrum and appearance of a strong absorption at
1670 cm-1 in FT-IR spectrum for the compound 32, as well
aOverall yield for 2 steps.
no enhancement in the signals for H-4 and H-6 that appeared
at δ 4.78 and 4.12, respectively, suggesting the axial orienta-
tion of the allyloxy group, but showed enhancement in the
signal for one of the methylenic protons of the -CH2OH
group. Besides, irradiation of those methylenic protons did
not result in any enhancement of the signal for H-4, indicat-
ing the axial orientation of the -CH2OH group.
The above-described method has also been applied on
2-nitroglucal 18 for the generation of the corresponding
gluco derivatives of 2-C-branched-2-nitro-O-glycosides.
The reactions were performed using acrylonitrile, methyl
acrylate, and paraformaldehyde as the electrophiles. The
yields and the diastereoselectivity were found to be poor, as
expected, due to the poor stereoselectivity of the first Michael
addition.30 Unlike 2-nitrogalactal, addition of the electro-
phile in this case took place from the equatorial side and the
nitro group was axially oriented, suggesting the absence of
or reduced 1,3-diaxial repulsions in the intermediate, thus
forming thermodynamically stable products rather than
kinetically controlled products. However, trace amounts of
the other two diastereomers were also observed in all of the
cases (21, 24, 30) (Table 3) whose structures could not be
established due to the difficulty in procuring them in pure
forms. The stereochemical outcome of both diastereomers
was confirmed through NOE analysis (Figure 2) of com-
pounds. Thus, for example, irradiation of the signal for H-2
of the major diastereomer 19 at δ 5.14 did not result in the
enhancement of the signals for either H-4 or H-6 protons
appearing at δ 3.85-3.89. On the other hand, in the other
diastereomer 20, irradiation of the signal for H-2 at δ 4.80 led
to the enhancement of H-4 and H-6 protons at δ 3.67 and
1
as appearance of a methyl singlet at δ 1.7 in the H NMR
spectrum and absorption at 1695 cm-1 in FT-IR spectrum of
compound 33 along with other spectroscopical evidence,
confirmed the formation of the spirolactam 32 and the sugar
amino acid derivative 33 ,respectively.
Radical Cyclization of 2-C-Branched 2-Nitrosugars. The
nitro functionality was further exploited to show the utility
of these adducts by treating them with n-Bu3SnH in the
presence of AIBN. Tertiary nitro containing molecules being
excellent substrates for radical reactions helped us to develop
a simple route for the generation of two C-C bonds at the
C-2 position of the sugar molecules starting from 2-nitrogly-
cals, which otherwise may require many steps. Although
bicyclic sugars are reported in the literature through radical
(31) Glycochemistry Principles, Synthesis, and Applications; Wang, P. G.,
Bertozzi, C. R., Eds.; Marcel Dekker, Inc.: New York, 2001.
(32) Zheng, Z.; Cummings, R. D.; Pummill, P. E.; Kincade, P. W. J. Clin.
Invest. 1997, 100, 1217.
(33) Hang, H. C.; Bertozzi, C. R. J. Am. Chem. Soc. 2001, 123, 1242.
(34) Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev.
2002, 102, 491.
(30) Khodair, A. I.; Pachamuthu, K.; Schmidt, R. R. Synthesis 2004,
1, 53.
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TABLE 3. One-Pot Michael-Michael and Michael-Henry Addition with 2-Nitroglucal
aOverall yield for 2 steps.
SCHEME 1. Synthesis of 2-C-Branched N-Acetyl
Galactosamine Derivative
trapped the triple bond of the tethered propargyl group
intramolecularly, to yield a bicyclic sugar 38 (Scheme 3).
Interestingly, when the same reaction was performed on
compound 15, the cyclization process did not stop at the
bicyclic stage and a further 6-endo cyclization was observed
in tandem after the radical transfer from vinyl to a more
stable O-benzylic postion in the proximity, resulting in a
complex tricyclic molecule 40 (Scheme 3). It is likely that the
radical 36 picks up a hydrogen atom R to the ester moiety
from -CH2COOMe via a six-membered transition state in an
intramolecular fashion resulting in a stabilized electrophilic
radical that is then reduced by n-Bu3SnH leading to 38. In
contrast, radical 37 prefers to form a more stabilized radical 39
resulting in the tricycle 40, rather than forming a radical Rto the
-OAc group. Cyclization to form 40 had occurred stereospe-
cifically resulting in a single diastereomer, although two new
stereocenters were generated. The structure of this intriguing
skeleton was unambiguously assigned using all the spectral data
including COSY, DEPT-135, and NOE analysis (Figure 3).
The appearance of two protons below δ 2.0 and another
proton at δ 2.81 in the 1H NMR spectrum of compound 40
indicated the saturation of the exocyclic double bond formed
after the initial cyclization. Extensive and careful analysis of
the COSY and DEPT-135 spectra revealed that the inter-
mediate compound 37 with an exocyclic double bond under-
went a further cyclization to form a tricycle (Scheme 3).
SCHEME 2. Synthesis of C2-Spiro-γ-lactam and Synthesis
of C-Glycosylated GABA Derivative
cyclizations,35 the present study appears to be the first one to
show the radical chemistry of 2-nitrosugars and also to
synthesize bicyclic sugars with a quaternary center at the
C-2 position.
When compound 4 was treated with 1.1 equiv of n-Bu3SnH
and 2 mol % of AIBN, the tertiary radical generated at C-2
(35) (a) Yanada, R.; Koh, Y.; Nishimori, N.; Matsumura, A.; Obika, S.;
Mitsuya, H.; Fujii, N.; Takemoto, Y. J. Org. Chem. 2004, 69, 2417.
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2000, 65, 5440.
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SCHEME 3. Radical Chemistry of 2-C-Branched 2-Nitrosugars
Further, irradiation of the signal for proton H-8 at δ 2.81
resulted in the enhancement of the signal for the protons
H-1, H-7, and H-9 at δ 5.36, 4.15, and 1.90, respectively.
Further, irradiation of the signal for proton H-3 at δ 3.98
showed enhancement in the signals for the protons correspond-
ing to H-5 as well as H-10 at δ 4.25 and 4.81, respectively,
indicating a cis-1,3-diaxial relation between the protons H-3 and
H-10. This data confirmed the absolute stereochemistry at the
two new stereocenters generated (Figure 3).
be the subunit of natural products striatin C,36 which is
highly active against a variety of Gram-positive bacteria and
has been isolated from the basidiomycete Cyathus striatus,
and also erinacine J,37 which was isolated from Hericium
erinaceum.
SCHEME 4. Synthetic Evidence for the Formation of the
Tricyclic Molecule
Conclusion
FIGURE 3. Diagnostic NOE correlations observed for the tricyclic
compound 40.
In summary, we have developed a simple one-pot three-
component approach toward the synthesis of 2-C-branched
2-nitro-O-glycosides. The utility of the method has been
shown by exploring the functionalities of the Michael-
Michael and Michael-Henry aldol products toward synthesizing
biologically relevant 2-C-branched galactosamine, a sugar
amino acid derivative, and a sugar-based spirolactam. The
adducts were also utilized in radical cyclizations to generate
bicyclic sugar as well as generating a stereochemically intriguing
tricyclic molecule.
Further, despite the possibility of both 5-exo and 6-endo
cyclizations, the steric constraints of the double bond per-
haps allows the cyclization to take place in the 6-endo mode.
As a further synthetic proof for the formation of tricyclic
molecule, compound 40 was subjected to hydrogenolysis to
get a bicyclic sugar, and the crude free hydroxyl derivative
was acetylated using excess acetic anhydride in the presence
1
of triethylamine to obtain a tetraacetate 42. Its H NMR
spectrum showed the presence of phenyl protons above δ 7.0
along with the four methyl peaks δ 2.0 corresponding to four
acetate groups, indicating the transfer of the benzyl group
from C-3 position to C-9 during the hydrogenolysi,s which is
possible only if the precursor was a tricycle (Scheme 4). Thus,
we obtained a stereochemically complex tricyclic structure in
two steps from 2-nitrogalactal with four new stereocenters
generated in a stereoselective fashion. Interestingly, the tri-
cyclic core structure of the compound 40 has been found to
Experimental Section
General Procedure for the One-Pot Michael-Michael Addi-
tion Reactions. To a stirred solution of 2-nitroglycal (100 mg,
0.21 mmol) and an alcohol (0.22 mmol) in THF (1 mL) was
(36) Hecht, H.-J. J. Chem. Soc., Chem. Commun. 1978, 665.
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2006, 62, 8463.
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added dropwise a solution of potassium tert-butoxide (1 mL,
10 mg/mL) in THF at 0 °C. The reaction mixture was brought
to room temperature and stirred for 1 h, after which methyl
acrylate/acrylonitrile (0.52 mmol) was added. After stirring the
reaction mixture for an additional 1 h, it was then neutralized
with Amberlite IRA resin (Hþ form). The resin was filtered off,
and the solvent was evaporated to get the crude product. Puri-
fication of the residue by column chromatography yielded the
Michael-Michael adducts.
General Procedure for the One-Pot Michael-Henry aldol Addi-
tion Reactions. To a stirred solution of 2-nitroglycal (100 mg,
0.21 mmol) and an alcohol (0.22 mmol) in THF (1 mL) was
slowly added a solution of potassium tert-butoxide (1 mL,
10 mg/mL) in THF at 0 °C. After complete addition, the
reaction mixture was brought to room temperature. After the
reaction mixture stirred for 1 h, paraformaldehyde (0.22 mmol)
was added. After completion of the reaction, the mixture was
neutralized with Amberlite IRA resin (Hþ form). The resin was
filtered off, and the solvent was evaporated to get the crude
product. Purification of the residue by column chromatography
yielded the Michael-Henry aldol adducts.
3-((2S,3R,4R,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
3-nitro-2-(prop-2-ynyloxy)tetrahydro-2H-pyran-3-yl)propanenitrile
=
(5). Yield: 81%; Rf: 0.40 (hexane/ethyl acetate, 4:1), [R]28
D
þ64.2 (c 0.95, CH2Cl2). IR (neat) νmax: 3064, 3032, 2923, 2856,
2251, 2122, 1602, 1554, 1496, 1453, 1354, 740, 700 cm-1. 1H NMR
(400 MHz, CDCl3): δ 7.37-7.16 (m, 15H, Ar-H), 5.05 (s, 1H,
H-2), 4.80 (d, J = 10.2 Hz, 1H), 4.71-4.67 (m, 3H, 2 -OCHPh,
H-4), 4.54-4.47 (m, 3H, 3 -OCHPh), 4.19 (d, J = 2.4 Hz, 2H,
-OCH2CtCH), 4.10-4.05 (m, 2H, H-5, H-6), 3.64 (t, J =9.0Hz,
1H, H-7) 3.57 (dd, J =5.8 Hz, J = 9.2 Hz, 1H, H-70), 3.12(m, 1H),
2.81 (m, 1H), 2.64 (t, J= 6.3 Hz, 1H), 2.44 (t, J= 2.4 Hz, 1H), 2.20
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 137.5, 137.0,
128.5-127.6 (m, Ar-C), 118.7, 99.5, 90.9, 76.0, 73.7, 73.6, 69.9,
67.8, 55.6, 30.8, 13.7. HRMS calcd for C33H35N2O7 [M þ H]þ
571.2444, found 571.2448.
Methyl-3-((2S,3R,4R,5R,6R)-2-(allyloxy)-4,5-bis(benzyloxy)-
6-(benzyloxymethyl)-3-nitrotetrahydro-2H-pyran-3-yl)propanoate
(6). Yield: 77%; Rf: 0.60 (hexane/ethyl acetate, 4:1), [R]28
=
D
þ41.4 (c 0.84, CH2Cl2). IR (neat) νmax: 3030, 2923, 2869, 1736,
1548, 1452, 1095, 1057, 737, 697 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.34-7.16 (m, 15H, Ar-H), 5.77 (m, 1H, -OCH2-
CHdCH2), 5.24-5.17 (m, 2H, -OCH2CHdCH2), 4.95 (s, 1H,
H-2), 4.85 (d, J = 10.7 Hz, 1H), 4.78 (d, J = 10.9 Hz, 1H), 4.74 (d,
J = 10.7 Hz, 1H), 4.68 (d, J = 2.9 Hz, 1H, H-4), 4.53-4.43 (m,
3H), 4.14-4.05 (m, 3H, -OCHH0CHdCH2, H-5, H-6), 3.96 (d,
J = 6.3 Hz, J = 12.9 Hz, 1H, OCHH0CHdCH2), 3.66-3.55 (m,
2H, H-7, H-70), 3.51 (s, 3H), 3.07 (m, 1H) 2.92 (m, 1H), 2.60 (m,
1H), 2.22 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 173.0, 137.9,
137.7, 137.5, 132.5, 129.3-127.5 (m, Ar-C), 118.3, 100.4, 91.8,
75.6, 75.5, 73.8, 73.5, 73.3, 69.4, 69.4, 69.0, 68.4, 51.3, 29.9, 29.9.
HRMS calcd for C34H40NO9 [M þ H]þ 606.2703, found 606.2706.
((2S,3R,4R,5R,6R)-2-(Allyloxy)-4,5-bis(benzyloxy)-6-(benzyl-
oxymethyl)-3-nitrotetrahydro-2H-pyran-3-yl)methanol (16). Yield:
67%; Rf: 0.52 (hexane/ethyl acetate, 4:1), [R]28D = þ22.6 (c 3.5,
CH2Cl2). IR (neat) νmax: 3502, 3029, 2919, 1640, 1548, 1494, 1339,
General Procedure for Acetylation Reactions. The compound
(50 mg) was taken up in a mixture of acetic anhydride and
triethylamine (1:1, 1 mL) and stirred for 1 h. Volatiles were evapo-
rated in rotary evaporator and the residue was purified through
column chromatography to yield the acetylated products.
Methyl-3-((2S,3R,4R,5R,6R)-2,4,5-tris(benzyloxy)-6-(benzyl-
oxymethyl)-3-nitrotetrahydro-2H-pyran-3-yl)propanoate (2). Yield
82%; Rf: 0.35 (hexane/ethyl acetate, 9:1), [R]28D = þ50.0 (c 0.3,
CH2Cl2). IR (neat) νmax: 3064, 3031, 2921, 2854, 1736, 1591, 1548,
1453, 1261, 1094, 1045, 737, 697 cm-1 1H NMR (400 MHz,
.
CDCl3): δ 7.36-7.15 (m, 20H, Ar-H), 4.98 (s, 1H), 4.84 (d, J =
10.7 Hz, 1H), 4.80 (d, J = 9.5 Hz, 1H), 4.75-4.64 (m, 2H),
4.54-4.42 (m, 4H), 4.07 (m, 2H), 3.63 (m, 1H), 3.54 (m, 1H), 3.50
(s, 3H), 3.50 (s, 1H), 3.07 (m, 1H), 2.90 (m, 1H), 2.87 (m, 1H), 2.21
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 173.0, 140.8, 137.9,
137.7, 137.5, 135.9, 128.4-126.9 (m, Ar-C), 100.6, 91.8, 75.5, 73.8,
73.5, 73.3, 70.2, 69.6, 68.4, 65.3, 51.3, 29.9, 29.6. HRMS calcd for
C38H42NO9 [M þ H]þ 656.2860, found 656.2866.
1081, 1040, 734, 694 cm-1 1H NMR (500 MHz, CDCl3):
.
δ 7.37-7.18 (m, 15H, Ar-H), 5.80 (m, 2H), 5.06 (s, 1H, H-5),
4.87 (d, J = 10.3 Hz, 1H), 4.81 (d, J = 2.3 Hz, 1H, H-5), 4.78 (d,
J = 4.9 Hz, 1H, H-4), 4.75 (d, J = 10.3 Hz, 1H), 4.72 (dd, J = 2.7
Hz, J=12.2 Hz, 1H, -CHOH), 4.70 (m, 1H), 4.53 (d, J = 11.8 Hz,
1H), 4.50 (d, J = 11.1 Hz, 1H), 4.44 (d, J = 11.8 Hz, 1H), 4.31 (t,
J = 12.2 Hz, 1H), 4.13 - 4.07 (m, 2H, H-6, allylic -CH), 3.97 (dd,
J = 6.1 Hz, J = 12.6 Hz, 1H, allylic -CH0), 3.65 (dd, J = 7.6 Hz,
J = 9.1 Hz, 1H, H-7), 3.57 (dd, J = 6.1 Hz, J = 9.1 Hz, 1H, H-70),
3.30 (dd, J = 2.7 Hz, J = 11.1 Hz, 1H, -OH); 13C NMR (75
MHz, CDCl3): δ 137.7, 136.9, 132.5, 128.7-127.7 (m, Ar-C),
127.0, 118.6, 97.4, 92.1, 75.9, 73.9, 73.8, 73.7, 69.2, 68.9, 68.2,
65.4, 65.4. HRMS calcd for C31H36NO8 [M þ H]þ 550.2441,
found 550.2443.
3-((2S,3R,4R,5R,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-
3-nitrotetrahydro-2H-pyran-3-yl)propanenitrile (3). Yield: 75%;
Rf : 0.32 (hexane/ethyl acetate, 9:1), [R]28D = þ73.3 (c 0.3, CH2Cl2).
IR (neat) νmax: 3030, 2922, 2852, 2248, 1607, 1549, 1495, 1456,
1352, 734, 696 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.31-7.07
(m, 20H, Ar-H), 4.83 (s, 1H), 4.72 (d, J=10.2 Hz, 1H), 4.65-
4.61 (m, 2H), 4.61 (d, J = 12.6 Hz, 1H), 4.50-4.37 (m, 4H),
4.01-4.00 (d, J = 4.4 Hz, 2H), 3.62-3.60 (t, J =6.3 Hz, 1H), 3.57
(dd, J = 7.3 Hz, J = 4.4 Hz, 1H) 3.47 (dd, J=5.8 Hz, J = 9.2 Hz,
1H), 3.03 (m, 1H), 2.75 (m, 1H), 2.55 (t, J = 6.3 Hz, 1H), 2.12
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 140.9, 137.6, 137.5,
137.1, 135.7, 128.7-127.0 (m, Ar-C), 119.0, 100.2, 91.2, 76.0, 73.8,
73.7, 73.6, 70.5, 69.7, 30.9, 13.8. HRMS calcd for C37H39N2O7
[M þ H]þ 623.2757, found 623.2752.
Preparation of Compounds 19 and 20. 2-Nitroglucal was
subjected to the general procedure with propargyl alcohol as
the Michael donor and acrylonitrile as the Michael acceptor to
obtain the crude product, which was purified by column chro-
matography to give compounds 19 and 20.
Methyl-3-((2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-(benzyloxy-
methyl)-3-nitro-2-(prop-2-ynyloxy)tetrahydro-2H-pyran-3-yl)pro-
panoate (4). Yield: 81%; Rf: 0.32 (hexane/ethyl acetate, 9:1),
[R]28D = þ55.0 (c 0.8, CH2Cl2). IR (neat) νmax; 3060, 3032, 2924,
2853, 2120, 1733, 1548, 1450, 1373, 743, 699 cm-1. 1H NMR (400
MHz, CDCl3): δ 7.34-7.16 (m, 15H, Ar-H), 5.11 (s, 1H), 4.85 (d,
J = 10.7 Hz, 1H), 4.78 (d, J = 10.7 Hz, 1H), 4.74 (d, J = 10.5 Hz,
1H), 4.65 (d, J = 3.2 Hz, 1H), 4.51-4.43 (m, 3H), 4.19 (d, J = 2.4
Hz, 2H), 4.08-4.05 (m, 2H), 3.63 (t, J = 9.5 Hz, 1H) 3.57 (dd, J =
6.8 Hz, J = 9.4 Hz, 1H), 3.52 (s, 3H), 3.07 (m, 1H), 2.92 (m, 1H),
2.65 (m, 1H), 2.41 (m, 1H), 2.20 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 172.9, 137.9, 137.8, 137.7, 128.4-127.6 (m, Ar-C),
100.2, 91.6, 75.6, 73.8, 73.6, 73.4, 69.9, 68.1, 55.5, 51.3, 30.0, 29.9.
HRMS calcd for C34H38NO9 [M þ H]þ 604.2547, found 604.2545.
3-((2S,3R,4R,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
3-nitro-2-(prop-2-ynyloxy)tetrahydro-2H-pyran-3-yl)propanenitrile
(19).Yield: 36%; Rf: 0.55 (hexane/ethyl acetate, 4:1), [R]28D =-44.0
(c 0.35, CH2Cl2). IR (neat) νmax: 3063, 3031, 2924, 2868, 2249, 2121,
1553, 1496, 1362, 1108, 1058, 1026, 738, 698 cm-1. 1H NMR (400
MHz, CDCl3):δ7.36-7.14 (m, 15H, Ar-H), 5.12 (s, 1H, H-2), 4.99
(d, J = 10.2 Hz, 1H), 4.91 (d, J = 10.2 Hz, 1H), 4.81 (d, J=10.7 Hz,
1H), 4.74 (t, J = 4.6 Hz, 1H, H-5), 4.66 (d, J = 12.2 Hz, 1H), 4.51
(m, 2H), 4.21 (d, J = 2.4 Hz, 1H), 3.88 (m, 2H, H-4, H-6), 3.77 (dd,
J = 1.7 Hz, J = 12.9 Hz, 1H, H-7), 3.65 (br, d, J = 10.7 Hz, 1H,
H-70), 2.94 (m, 1H), 2.64-2.48 (m, 2H), 2.47 (d, J = 2.4 Hz, 1H),
2.25 (m, 1H). 13C NMR (125 MHz, CDCl3): δ 137.6, 137.5, 137.3,
128.5-127.6 (m, Ar-C), 118.6, 99.1, 91.4, 79.4, 76.4, 76.0, 75.3,
J. Org. Chem. Vol. 75, No. 24, 2010 8463

Kancharla and Vankar
JOCArticle
73.6, 72.0, 67.4, 60.3, 55.5, 29.6. 13.5. HRMS calcd for C33H35N2O7
[M þ H]þ 571.2444, found 571.2449.
(100 MHz, CDCl3): δ 169.5, 137.9, 137.7, 137.5, 128.5-127.5
(m, Ar-C), 120.9, 97.9, 78.9,78.1, 75.7, 75.0, 74.2, 73.6, 73.4,
69.6, 68.5, 63.2, 54.4, 27.9, 12.7. HRMS calcd for C35H38KN2O6
[M þ K]þ 621.2367, found 621.2367.
3-((2R,3S,4R,5S,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
3-nitro-2-(prop-2-ynyloxy)tetrahydro-2H-pyran-3-yl)propaneni-
trile (20). Yield: 28%; Rf: 0.31 (hexane/ethyl acetate, 4:1),
[R]28D = -17.7 (c 0.45, CH2Cl2). IR (neat) νmax: 3061, 3028,
2920, 2851, 2249, 2120, 1553, 1453, 1363, 1116, 1082, 1021, 739,
698 cm-1. 1H NMR (400 MHz, CDCl3): δ 7.38-7.16 (m, 15H,
Ar-H), 4.98 (d, J = 11.4 Hz, 1H), 4.80 (s, 1H, H-2), 4.74-4.57
(m, 5H), 4.54 (d, J = 4.4, 1H, H-5), 4.38 (m, 2H), 3.86-3.79 (m,
2H, H-7, H-70), 3.67 (d, J = 8.5 Hz, 1H, H-4), 3.53 (d, J = 9.7,
2.2 Hz, 1H, H-6), 2.65-2.54 (m, 2H), 2.52 (m, 1H), 2.48 (m, 1H),
2.09 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 137.7, 137.4,
136.7, 128.8-127.9 (m, Ar-C), 119.1, 96.8, 91.6, 81.4, 76.5,
75.8, 75.5, 74.8, 73.7, 68.3, 55.7, 29.6, 13.0. HRMS calcd for
C33H35N2O7 [M þ H]þ 571.2444, found 571.2447.
Methyl-3-((3aR,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-(benzyloxy-
methyl)-3-methylenehexahydro-2H-furo[2,3-b]pyran-3a-yl)pro-
panoate (38). To a solution of compound 4 (110 mg) in benzene
were added n-Bu3SnH (0.47 mL, 1.77 mmol) and AIBN (19 mg),
and the mixture was refluxed for 5 h. After monitoring the
disappearance of the starting material by TLC analysis, the
volatiles were removed, and the residue was purified by column
chromatography to obtain the bicyclic sugar 38 (65 mg) in 64%
yield. Rf: 0.35 (hexane/ethyl acetate, 4:1), [R]28D = þ40.0 (c 0.1,
CH2Cl2). IR (neat) νmax: 3087, 3063, 2954, 2854, 1739, 1454,
1369, 1235, 1028, 736, 698 cm-1. 1H NMR (400 MHz, CDCl3): δ
7.34-7.26 (m, 15H, Ar-H), 5.14 (s, 1H, H-7a), 5.00 (m, 2H,
H-8, H-80), 4.81 (d, J = 11.4 Hz, OCHPh), 4.79 (d, J = 11.2 Hz,
OCHPh), 4.58 (m, 5H, 4(OCHPh), H-2), 4.33 (m, 1H, H-20),
4.23 (m, 1H, H-5), 3.96 (t, J= 2.6 Hz, 1H, H-4), 3.71(m, 2H, H-6,
H-60), 3.60 (s, 3H, COOCH3), 3.53 (d, J=2.6 Hz, 1H, H-3),
2.35 (m, 2H, H-10, H-100), 2.26 (m, 2H, H-9, H-90). 13C NMR
(100 MHz, CDCl3): δ 174.0, 148.5, 138.0, 137.9, 128.3-127.4
(m, Ar-C), 106.8, 102.9, 79.1, 73.7, 73.4, 72.3, 71.8, 68.8, 68.3,
50.4, 29.0, 28.9, 22.8. HRMS calcd for C34H39O7 [M þ H]þ
559.2696, found 559.2699.
N-((2S,3R,4R,5R,6R)-4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
3-(2-cyanoethyl)-2-(prop-2-ynyl-oxy)tetrahydro-2H-pyran-3-yl)-
acetamide (31). Compound 5 (60 mg) 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 (135 mg, 20 equiv)
was added to it portion-wise. After 1 h of stirring at 0 °C, the
residue was filtered, and the reaction mixture was diluted with
CH2Cl2 (30 mL), washed with water, saturated aqueous NaH-
CO3, and water, and dried over anhydrous Na2SO4. After evap-
oration of the solvents the crude amine was dissolved in 0.5 mL
of acetic anhydride and 0.5 mL of triethylamine and was stirred
for 0.5 h. Removal of volatiles under reduced pressure followed
by purification on silica gel afforded the corresponding N-acetyl
galactosamine (53 mg) in 88% yield. Rf: 0.65 (hexane/ethyl
Acknowledgment. We thank the Council of Scientific and
Industrial Research, New Delhi for financial support [Grant
No. 01(2298)/09/EMR-II]. P.K.K. thanks the University
Grants Commission for a senior research fellowship.
acetate, 7:3), [R]28 = -29.8 (c 0.5, CH2Cl2). IR (neat) νmax
:
3407, 3288, 3029, 2920, 2852, 2248, 2120, 1674, 1452, 1365, 1097,
D
1
1043, 738, 698 cm-1. H NMR (400 MHz, CDCl3): δ 7.92 (s,
Supporting Information Available: Details on general ex-
perimental methods; copies of 1H NMR and 13C NMR spectra
of all the new compounds, COSY and NOE spectra of com-
pounds 5, 6, 16, 19, 20, 31, and 40; DEPT-135 spectrum of
compound 40; and the crystallographic details of compound 4 in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
1H, NH), 7.37-7.22 (m, 15H, Ar-H), 4.84 (s, 1H, H-2), 4.79
(d, J = 11.2 Hz, 1H), 4.60-4.43 (m, 5H), 4.21 (m, 2H), 3.94 (m,
1H, H-5), 3.90 (t, J = 7.0 Hz, 1H, H-6), 3.68 (d, J = 3.1 Hz, 1H,
H-4), 3.63 (dd, J=9.2, 7.3 Hz, 1H, H-7), 3.56 (dd, J=9.0, 5.8
Hz, 1H, H-70), 2.94-2.83 (m, 2H), 2.73 (m, 1H), 2.39 (t, J = 2.2
Hz, 1H, acetylinic), 2.10 (m, 1H) 2.00 (s, 3H, NHAc). 13C NMR
8464 J. Org. Chem. Vol. 75, No. 24, 2010