In situ 1,3-dipolar azide cycloaddition reaction: Synthesis of functionalized D-glucose based chiral piperidine and oxazepine analogues

Article abstract of DOI:10.1016/j.tet.2004.04.036

Functionalized furanose-fused piperidines 4-6 and oxazepines 15-17, useful precursors for structurally unique bioactive nucleosides as well as for potential glycosidase inhibitors, have been synthesized by the application of 1,3-dipolar azide cycloaddition (DAC) reaction on D-glucose based substrates. The strategy works well even with the nucleoside analogue 8, affording the bicyclic nucleoside analogues 11 and 12.

Full text of DOI:10.1016/j.tet.2004.04.036

Tetrahedron 60 (2004) 4959–4965
In situ 1,3-dipolar azide cycloaddition reaction: synthesis of
functionalized D-glucose based chiral piperidine and
oxazepine analogues
*
Subhankar Tripathi, Kaushik Singha, Basudeb Achari and Sukhendu B. Mandal
Division of Medicinal Chemistry, Indian Institute of Chemical Biology, Jadavpur, 4, Raja S.C. Mullick Road, Kolkata 700 032, India
Received 25 February 2004; revised 19 March 2004; accepted 14 April 2004
Abstract—Functionalized furanose-fused piperidines 4-6 and oxazepines 15-17, useful precursors for structurally unique bioactive
nucleosides as well as for potential glycosidase inhibitors, have been synthesized by the application of 1,3-dipolar azide cycloaddition (DAC)
reaction on D-glucose based substrates. The strategy works well even with the nucleoside analogue 8, affording the bicyclic nucleoside
analogues 11 and 12.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussions
The 1,3-dipolar azide cycloaddition (DAC) reaction con-
stitutes a simple method, which has been widely used in the
synthesis of alkaloids1 and many other heterocycles of
diverse structures.2 In recent years, effort has been made to
explore cycloaddition on carbohydrate derived alkenes/
alkynes. This has led to elegant methodologies for the
synthesis of chiral triazoles,3 azole-piperidinoses,4 tetra-
zoles,5 glucotriazole carboxylate,6 and various iminosugars7
en route to nucleoside analogues8 and inhibitors of
glycosidases,9 glycogen phosphorylases6 and glycosyl
transferases.10 For our project directed towards the synthesis
of new carbohydrate based piperidine and oxazepine
analogues, we decided to use this reaction on suitably
crafted precursors. The allyl group is easy to introduce into
the carbohydrate core and is particularly amenable for such
cycloadditions. The precursors 1-3, already used in our
laboratory for other synthetic schemes, appeared as
convenient starting materials.11 The expected products
could allow introduction of various nucleobases directly
onto the anomeric center of a furanose ring or via easy
opening of the ring. In this paper, we report the work
undertaken to investigate the scope of this reaction for
developing functionalized chiral piperidine and oxazepine
analogues.
The carbohydrate-derived precursors 1-3 on tosylation and
subsequent treatment with sodium azide furnished, after
column chromatography, TLC pure (in different solvent
systems) products. However, these exhibited two sets of 1H
and 13C NMR peaks for many of the protons and carbons.
The formation of a mixture of enamine and imine A and B
(presumably through the generation of an aziridine ring
followed by its opening) was suggested by the fact that the
signals at d 1.78 (s), 2.01 (s), 1.98 (d), and 2.33 (d) in the 1H
NMR disappeared on D2O exchange. In support, the 13C
NMR showed signals at d 143.8 and 164.3, close to the
expected shieldings for the enamine and imine carbons,
respectively. In addition, the presence of three signals for
methylene carbons at d 35.5, 40.0 and 48.0 indicated
formation of the mixture. Acetylation of the mixture,
without further purification, furnished single N-acetylated
products 4-6 in fairly good yields (Scheme 1). In the 13C
NMR spectrum of 5 for example, the presence of carbon
signals at d 169.4, 142.6, 108.5 and 23.7 suggested the
presence of amide carbonyl, olefinic quaternary as well as
methine carbons. Additionally, the methyl proton signal at d
2.17 (d, J¼0.9 Hz, allylic coupling) testified to the location
of a vinylic methyl group.
When the reaction was performed on a substrate with a pre-
installed nucleoside base in the furanose ring, it took an
unexpectedly different course. For this study, the tosylate 7
of 1 (Scheme 2) was first treated with acid to remove the
isopropylidene protecting group and then subjected to
acetylation to furnish 8 as a mixture of anomers.
Treatment of this mixture with bis-O-trimethylsilyl)uracil
Keywords: DAC reaction; Synthesis; Chiral piperidines and oxazepines;
D-Glucose.
*
Corresponding author. Tel.: þ91-33-473-3491; fax: þ91-33-473-5197;
e-mail address: sbmandal@iicb.res.in
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.036

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S. Tripathi et al. / Tetrahedron 60 (2004) 4959–4965
Scheme 1. 1,3-DAC reaction on 3-C-allyl glucose precursors.
Scheme 2. Preparation of nucleoside derivative 9.
and TMS-OTf in dichloroethane, under the conditions
reported by Vorbru¨ggen,12 furnished the nucleoside deriva-
tive 9. The neighbouring acetoxy group, as is known from
earlier studies,13 guides the orientation of the nucleoside
base in the product 9.
On treatment with sodium azide, 9 underwent 1,3-DAC
reaction to afford a difficult to purify product, which was
therefore directly acetylated. Column chromatographic
purification furnished the nucleoside analogues 10 and 11
in 3:1 ratio (Scheme 3).
The peak at nmax,2106 cm21 in the IR spectra of the
products clearly indicated the presence of azide function-
ality. The FABMS of both the nucleosides showed pseudo
molecular ion peaks at m/z 451 (MþHþ) and 473 (MþNaþ).
Among the three methylene carbon signals in the 13C NMR
spectrum, the one at d,45.0 may be assigned to the carbon
1
carrying the azide group. In the H NMR spectrum, the
coupling constants J2,3 are found to be somewhat different
for 10 (6.1 Hz) and 11 (8.5 Hz). This may be due to
difference in dihedral angle of the H–C2–C3–H unit (408 in
10 and 188 in 11 in the energy-minimized structures
Scheme 3. 1,3-DAC reaction on nucleoside derivative 9.

S. Tripathi et al. / Tetrahedron 60 (2004) 4959–4965
4961
obtained using Chem. Office 6.0. For this, a presentation of
the structure was created in Chem Draw and transferred to
Chem 3D, taking care to ensure that the stereochemistry at
different centers of the conformer were correct. After initial
energy minimization using MM2 programme, molecular
dynamics was run. The generated conformer was tested by
MM2 to reach the energy minimized conformer. The
piperidine ring in 11 exists in chair conformation
(J4a,5a¼13.0 Hz and J4a,e¼14.7 Hz), whereas the same
ring in 10 is in the twist-boat form (J4a,5a¼12.3 Hz and
J4a,e¼14.0 Hz), since the chair conformation is destabilized
due to 1,3-diaxial interaction between acetoxy group at C-3a
and azidomethyl group at C-5.
The formation of the above products may be rationalized by
assuming that the 1,3-DAC reaction proceeds through the
generation of a triazoline intermediate, which after nitrogen
elimination leads to an aziridine intermediate. This quickly
isomerizes in case of 1-3 to afford imine/enamine mixture
(Fig. 1), or is opened by azide attack (in case of 9).
Figure 3. cis-Aziridine with N lone pair and ring juncture H b-oriented.
than C-allyl group at C-3 of the carbohydrate derived
precursor. The substrates 12-14 were chosen, prepared and
characterized according to our established protocols.14 Both
cis and trans substituted substrates 13 and 14 could be tested
besides one (12) carrying a bulky group (TBDMS) in one of
the substituents.
When 12 was subjected to mesylation followed by reaction
with sodium azide, it afforded the oxazepine analogue 15.
However, the aziridino-oxazepine derivative 16 was
obtained in low yield by DAC reaction upon 13, while 14
afforded 17 with triazolo-oxazepine moiety (Scheme 4).
The absence of allyl functionality in 15-17 was shown by
the disappearance of signals for the vinyl proton(s) in the
region between d 4.84–6.34. Retention of the 1,2-O-
isopropylidene groups in all the products and the tertiary
butyl dimethyl silyl functionality in 15 was evident from
Figure 1. Proposed mechanism for the formation of imine/enamine
mixture.
1
their characteristic signals in the H NMR spectra. The IR
To understand the nature of the aziridine intermediate, we
carried out molecular modeling studies. This revealed that
the minimium energy conformations of the two trans-
aziridine isomers (161.3 or 173.9 kcal/mol) are far greater in
steric energy than the corresponding cis-aziridine isomers
(146.6 or 147.1 kcal/mol), which are close to each other in
steric energy. The formation of the isomeric mixture of
nucleoside derivatives is thus possible through the inter-
mediacy of non-isolable cis-aziridines (Figs. 2 and 3).
spectrum of 15, but not those of 16 and 17, showed a strong
band at 2105 cm21 for the azide group. The presence of the
CH2N3 moiety in 15 was confirmed by the appearance of
one double doublet at d 3.16 (J¼7.5, 12.0 Hz) and a doublet
1
1
at d 3.28 (J¼12.0 Hz) in its H NMR spectrum. In the H
NMR spectrum of 16, the appearance of two upfield
doublets at d 1.49 and 2.18 clearly indicated the formation
of an aziridine moiety. However, the stereochemistry at the
aziridine ring juncture could not be ascertained. Mass
spectrum as well as 13C NMR spectrum confirmed the
structures indicated.
In another variation of the reaction, the cycloaddition
reaction was attempted on substrates carrying O-allyl rather
The results of the cycloaddition reactions with O-allyl
substituted substrates suggest that the course of the reaction
remains similar to that observed with the C-allyl substituted
substrates, that is, initial triazoline formation followed by
nitrogen elimination to the aziridine, which could be
isolated, albeit in low yield, in case of 13. In case of 12
the aziridine moiety did not survive under the reaction
condition and decomposed in nucleophilic attack by azide
ion. The formation of a triazole product 17 from 14 may be
explained by assuming that the initial triazoline possibly
had a trans ring fusion and was therefore prone to oxidation,
brought about in this case perhaps by atmospheric oxygen.
In conclusion, we have applied the 1,3-DAC reaction on
D-glucose derived unactivated olefin precursors to construct
Figure 2. cis-Aziridine with N lone pair and ring juncture H a-oriented.

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S. Tripathi et al. / Tetrahedron 60 (2004) 4959–4965
Scheme 4. 1,3-DAC reaction on glucose derived substrates 12–14.
chiral piperidine and oxazepine rings, fused to ribose
moiety, which may be elaborated to iminosugars, oxo-
iminosugars and nucleoside analogues. The scope and
limitation of the method to synthesize other such systems
with different heterocycles of varied ring sizes is under
study.
and imine A and B (350 mg). An aliquot of the mixture
(50 mg) was then acetylated with Ac2O/Py. The crude
acetylated product was purified by chromatography on silica
gel column using Pet. ether–EtOAc (13:7) to yield 4
(35 mg, 61%) as a foamy solid; [Found: C, 57.83; H, 6.73;
N, 4.33. C15H21NO6 requires C, 57.87; H, 6.80; N, 4.50%];
(a(2D0¼2356 (c 0.3, CHCl3); IR (KBr): nmax 1733, 1670,
1401, 1380, 1237, 1210, 1067, 1030 cm21 1H NMR
;
(CDCl3, 300 MHz): d 1.33 (s, 3H), 1.53 (s, 3H), 2.07 (s,
3H), 2.17 (d, 3H, J¼0.9 Hz), 2.19 (s, 3H), 3.23 (d, 1H,
J¼13.5 Hz), 4.12 (dd, 1H, J¼2.7, 13.5 Hz), 4.32 (brs, 1H),
4.86 (d, 1H, J¼3.6 Hz), 5.47 (s, 1H), 5.70 (d, 1H,
J¼3.6 Hz); 13C NMR (CDCl3, 75 MHz): d 21.2(q),
22.3(q), 23.7(q), 26.9(q), 27.1(q), 45.6(t), 76.6(d), 78.6(s),
81.6(d), 105.2(d), 108.5(d), 113.1(s), 142.6(s), 169.4(s),
171.3(s); FABMS: m/z at 312 (MHþ).
3. Experimental
Melting points were taken in open capillaries and are
uncorrected. IR spectra were measured on a JASCO 700
spectrophotometer. 1H and 13C NMR spectra were
measured either on a JEOL FX-100 or a Bruker AM 300
L spectrometer using TMS as internal standard. Mass
spectra were obtained using a JEOL AX-500 spectrometer
operating at 70 eV. Optical rotations were measured in a
JASCO DIP 360 polarimeter. HPLC was performed on m
Bondapake C18 column (7.38£300 mm). Flash chromato-
graphy was carried out on LiChroprepw RP-18 (Merck).
3.1.2. (3aR,3bR,7aR,8aR)-1-(3b-Benzyloxy-2,2,5-tri-
methyl-3a,7,7a,8a-tetrahydro-3bH-1,3,8-trioxa-6-aza-
cyclopenta[a]inden-6-yl) ethanone (5). Compound 5.
Yield 60%; sticky mass; [Found: C, 66.62; H, 7.12; N,
3.69. C20H25NO5 requires C, 66.83; H, 7.01; N, 3.90%];
(a(2D0¼2132 (c 0.84, CHCl3); IR (neat): nmax 1673, 1391,
1217, 1135, 1099, 1069, 1026, 1030 cm21 1H NMR
;
3.1. (3aR,3bR,7aR,8aR)-Acetic acid 6-acetyl-2,2,5-
trimethyl-3a,7,7a,8a-tetrahydro-6H-1,3,8-trioxa-6-aza-
cyclopenta[a]inden-3b-yl ester (4)
(CDCl3, 300 MHz): d 1.37 (s, 3H), 1.61 (s, 3H), 2.18 (s,
3H), 2.22 (s, 3H), 3.22 (d, 1H, J¼13.5 Hz), 4.01 (dd, 1H,
J¼3.0, 13.5 Hz), 4.36 (brs, 1H), 4.45 (d, 1H, J¼3.3 Hz),
4.65 (d, 1H, J¼11.0 Hz), 4.69 (d, 1H, J¼11.0 Hz), 5.16 (s,
1H), 5.68 (d, 1H, J¼3.3 Hz), 7.32 (m, 5H); 13C NMR
(CDCl3, 75 MHz): d 22.9 (q), 24.1 (q), 27.9 (q), 30.1 (q),
46.6 (t), 66.9 (t), 78.0 (d), 78.5 (s), 82.5 (d), 105.7 (d), 109.9
(d), 114.1 (s), 128.1 (d), 128.2 (d, 2C), 128.7 (d, 2C), 138.9
(s), 142.7 (s), 172.0 (s); FABMS: m/z at 360 (MHþ).
3.1.1. Typical procedure for 4. To a stirred solution of 1
(500 mg, 2.17 mmol) in CH2Cl2 (30 ml) containing Et3N
(1 ml) was added TsCl (415 mg, 2.18 mmol) and the stirring
was continued for 8 h at rt. The mixture was washed with
brine (3£10 ml), dried (Na2SO4), and concentrated. The
crude product was purified by column chromatography
using CHCl3 as eluent to furnish 7 (768 mg, 93%). 7
(500 mg, 1.30 mmol) in dry DMF (5 ml) was reacted with
NaN3 (393 mg, 4.7 equiv.) at 90 8C for 5 h under N2. The
solvent was evaporated and the crude mass was extracted
with CHCl3 (30 ml). The extract was washed with brine,
dried (Na2SO4), and concentrated. The residue was
subjected to reverse phase flash column chromatography
using CH3CN–H2O (1:4) to furnish a mixture of enamine
3.1.3. (3aR,3bR,7aR,8aR)-Acetic acid 6-acetyl-2,2-cyclo-
hexylidenyl-5-methyl-3a,7,7a,8a-tetrahydro-6H-1,3,8-
trioxa-6-aza-cyclopenta[a]inden-3b-yl
Compound 6. Yield 62%; thick liquid; [Found: C, 61.52;
ester
(6).
H, 7.00; N, 3.83. C18H25NO6 requires C, 61.52; H, 7.17; N,

S. Tripathi et al. / Tetrahedron 60 (2004) 4959–4965
4963
3.99%]; (a(2D0¼2247 (c 0.5, CHCl3); IR (KBr): nmax 1743,
midin-1-yl)-octahydro-furo[2,3-c]pyridin-3-yl ester (10)
(2R,3R,3aR,5S,7aR)-acetic acid 3a-acetoxy-6-acetyl-5-
azidomethyl-2-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-
yl)-octahydro-furo[2,3-c]pyridin-3-yl ester (11). NaN3
(50 mg) was added to the uridine derivative 9 (300 mg,
0.57 mmol) in DMF (8 ml) and the mixture was heated at
110 8C for 4 h under N2. Usual work up followed by
purification through reverse phase column chromatography
(CH3CN–H2O 1:4) afforded a crude residue (175 mg). A
part of the residue (60 mg) was acetylated with Ac2O/Py
and the mixture was purified by HPLC (solvent: CH3CN–
H2O 3:7) to furnish 10 (35 mg, 40%) and 11 (11 mg, 13%).
1671, 1399, 1371, 1242, 1128, 1046 cm21 1H NMR
;
(CDCl3, 300 MHz): d 1.37 (m, 2H), 1.64 (m, 6H), 1.74
(m, 2H), 2.07 (s, 3H), 2.17 (s, 3H), 2.19 (s, 3H), 3.22 (d, 1H,
J¼13.7 Hz), 4.11 (dd, 1H, J¼3.0, 13.7 Hz), 4.31 (s, 1H),
4.83 (d, 1H, J¼3.3 Hz), 5.48 (s, 1H), 5.71 (d, 1H,
J¼3.3 Hz); 13C NMR (CDCl3, 75 MHz): d 21.2(q),
22.3(q), 23.6 (t), 23.7(q), 24.0(t), 24.9(t), 36.4(t), 36.9(t),
45.7(t), 76.7(d), 78.8(s), 81.1(d), 104.9(d), 108.8(d),
113.8(s), 142.6(s), 169.4(s), 171.3(s); FABMS: m/z at
352(MHþ).
3.1.4. Toluene-4-sulfonic acid 6-allyl-6-hydroxy-2,2-
dimethyl-tetrahydrofuro[2,3-d][1,3]dioxol-5-ylmethyl
ester (7). Compound 7. Yield 93%; sticky mass; [Found: C,
56.18; H, 6.00. C18H24O7S requires C, 56.23; H, 6.29%];
(a(2D0¼þ40 (c 0.3, CHCl3); IR (neat): nmax 3397 (br), 1599,
1361, 1175, 816, 754 cm21; 1H NMR (CDCl3, 300 MHz): d
1.32 (s, 3H), 1.52 (s, 3H), 2.40 (s, 3H), 2.45 (dd, 1H, J¼7.0,
15.5 Hz), 2.52 (dd, 1H, J¼8.0, 15.5 Hz), 4.17–4.24 (m,
3H), 4.36 (d, 1H, J¼3.6 Hz), 5.11s, 1H), 5.20 (m, 2H), 5.68
(d, 1H, J¼3.6 Hz), 5.86 (m, 1H), 7.28 (d, 2H, J¼8.1 Hz),
7.76 (d, 2H, J¼8.1 Hz); 13C NMR (CDCl3, 75 MHz): d 22.0
(q), 27.0(q), 27.2(q), 35.7 (t), 67.6(t), 79.5 (d), 82.5(d),
84.1(s), 104.5(d), 113.4(s), 119.4(t), 127.9(d, 2C), 130.2(d,
2C), 132.4(d), 133.6(s), 145.0(s); FABMS: m/z at 385
(MHþ).
Compound 10. Foamy solid; [Found: C, 47.78; H, 4.88; N,
18.38. C18H22N6O8 requires C, 48.00; H, 4.92; N, 18.66%];
(a(2D0¼þ8 (c 0.5, CHCl3); IR (KBr): nmax 3453 (br), 2106,
1751, 1691, 1428, 1375, 1230, 1074 cm21 1H NMR
;
(CDCl3, 300 MHz): d 2.11 (s, 3H), 2.13 (s, 3H), 2.15 (s,
3H), 2.37 (dd, H, J¼6.3, 14.0 Hz), 2.57 (t-like, 1H, J¼12.3,
14.0 Hz), 3.31 (dd, 1H, J¼2.5, 12.5 Hz), 3.85 (m, 3H), 4.56
(s, 1H), 4.71 (m, 1H), 5.03 (d, 1H, J¼8.5 Hz), 5.83 (d, 1H,
J¼8.2 Hz), 6.26 (d, 1H, J¼8.5 Hz), 6.97 (d, 1H, J¼8.2 Hz),
8.49 (brs, 1H); 13C NMR (CDCl3, 75 MHz): d 20.4 (q),
21.7(q), 21.9 (q), 28.0 (t), 45.7 (t), 47.5 (d), 53.1(t), 71.9 (d),
80.0 (d), 80.9 (s), 82.6 (d), 104.8 (d), 137.8 (d), 150.4 (s),
161.8 (s) 169.8 (s), 169.9 (s), 171.7 (s); FABMS: m/z at 451
(MHþ), 473 (MNaþ).
3.1.5. (2R,3R,4R,5R)-Acetic acid 4-acetoxy-3-allyl-5-(2,4-
dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2-(toluene-4-sul-
fonyloxymethyl)-tetrahydrofuran-3-yl ester (9). Uracil
(600 mg, 5.36 mmol) was dissolved in hexamethyl
disilazane (10 ml). TMSCl (2 drops) was added to it and
the mixture was heated at reflux under N2 for 12 h. The
solvent was evaporated in vacuo, the residue dissolved in
DCE (5 ml) and added to a stirred solution of the triacetate
mixture 8 (715 mg, 1.52 mmol) in DCE (5 ml). After adding
TMS–OTf (0.8 ml) the solution was stirred for 4 h at rt
when tlc showed complete disappearance of the starting
material. The mixture was neutralized with solid NaHCO3,
treated with water (2–3 drops), and the solvent was
evaporated in rotary evaporator. The residue was extracted
with CHCl3–MeOH mixture (49:1, 20 ml), washed with
brine, dried, and concentrated. The crude product was
purified by silica gel column chromatography eluting with
methanolic CHCl3 (2%) to afford 9 (400 mg, 50%) as a
foam; [Found: C, 52.58; H, 5.15; N, 5.21. C23H26N2O10S
requires C, 52.87; H, 5.02; N, 5.36%]; (a(2D0¼215.9 (c 0.49,
CHCl3); IR (KBr): nmax 1746, 1696, 1371, 1222,
Compound 11. Foamy solid; [Found: C, 48.12; H, 4.90; N,
18.60. C18H22N6O8 requires C, 48.00; H, 4.92; N, 18.66%];
(a(2D0¼þ15 (c 0.54, CHCl3); IR (KBr): nmax 3474 (br),
2106, 1743, 1697, 1634, 1427, 1377, 1236, 1069 cm21; 1H
NMR (CDCl3, 300 MHz): d 2.09 (s, 6H), 2.15 (s, 3H), 2.36
(t-like, 1H, J¼13.0, 14.7 Hz), 2.70 (dd, 1H, J¼4.8,
14.8 Hz), 3.34 (dd, 1H, J¼2, 12.3 Hz), 3.45 (dd, 1H,
J¼10.8, 14.0 Hz), 3.91 (m, 2H), 4.27 (m, 1H), 4.43 (dd, 1H,
J¼6.4, 10.2 Hz), 5.53 (d, 1H, J¼6.1 Hz), 5.78 (d, 1H,
J¼8.1 Hz), 5.86 (d, 1H, J¼6.1 Hz), 7.20 (d, 1H, J¼8.1 Hz),
9.23 (brs, 1H); 13C NMR (CDCl3, 75 MHz): d 20.7 (q), 21.6
(q), 22.5 (q), 33.3 (t), 45.1(t), 48.2 (d), 52.9 (t), 76.3 (d), 78.8
(d), 81.9 (s), 92.4 (d), 103.7 (d), 142.1 (d), 150.4 (s), 163.0
(s), 169.8 (s), 170.5 (s), 170.9 (s); FABMS: m/z at 451
(MHþ), 473 (MNaþ).
3.1.7. (3aR,3bR,6R,8R,8aS,9aR)-6-Azidomethyl-8-(tert-
butyldimethyl-silanyloxymethyl-2,2-dimethyl-octa-
hydro-1,3,4,9-tetraoxa-7-aza-cyclopent[a]azulene (15).
To a stirred solution of 12 (418 mg, 1.12 mmol) in
CH2Cl2 (30 ml) containing Et3N (0.5 ml) was added MsCl
(1 equiv.) and the mixture was stirred for 2 h under N2. The
solution was thoroughly washed with brine (3£10 ml), dried
(Na2SO4), and concentrated to furnish a mesyl derivative.
Without further purification this was dissolved in DMF
(10 ml) and treated with NaN3 (300 mg). The reaction
mixture was heated at 130 8C under N2 for 10 h. Usual work
up followed by column chromatography using CHCl3–
MeOH (99:1) afforded 15 (250 mg, 56%) as a thick liquid;
[Found: C, 52.00; H, 8.20; N, 13.21. C18H34N4O5Si requires
C, 52.15; H, 8.27; N, 13.51%]; (a(2D0¼29.4 (c 0.54, CHCl3);
IR (neat): nmax 2100, 1470, 1373, 1255, 1098, 1037,
1
1179 cm21; H NMR (CDCl3, 300 MHz): d 2.06 (s, 3H),
2.13 (s, 3H), 2.47 (s, 3H, merged with one proton signal),
3.14 (dd, 1H, J¼7.2, 14.5 Hz), 4.27 (dd, 1H, J¼2.1,
11.4 Hz), 4.36 (dd, 1H, J¼2.8, 11.4 Hz), 4.76 (brs, 1H),
5.04 (m, 2H), 5.26 (d, 1H, J¼8.1 Hz), 5.55 (m, 1H), 5.69 (d,
1H, J¼8.1 Hz), 6.16 (d, 1H, J¼8.1 Hz), 7.40 (d, 2H,
J¼8.1 Hz), 7.52 (d, 1H, J¼8.1 Hz), 7.82 (d, 2H, J¼8.1 Hz),
7.98 (brs, 1H); 13C NMR (CDCl3, 75 MHz): d 20.6, 21.7
(2C), 35.6, 67.1, 76.0, 81.0, 84.0, 85.1, 103.5, 119.5, 127.9
(2C), 129.9, 130.3 (2C), 136.0, 139.1, 146.0, 150.6, 162.3,
169.7, 170.2; FABMS: m/z at 523 (MHþ).
1
838 cm21; H NMR (CDCl3, 300 MHz): d 0.063 (s, 3H),
3.1.6. (2R,3R,3aR,5R,7aR)-Acetic acid 3a-acetoxy-6-
acetyl-5-azidomethyl-2-(2,4-dioxo-3,4-dihydro-2H-pyri-
0.076 (s, 3H), 0.91 (s, 9H), 1.35 (s, 3H), 1.60 (s, 3H), 2.99
(m, 1H), 3.16 (dd, 1H, J¼7.5, 12.0 Hz), 3.27 (d, 1H,

4964
S. Tripathi et al. / Tetrahedron 60 (2004) 4959–4965
Bergmeier, S. C.; Degan, S.; Lin, K. C.; Poon, Y. F.;
Schkeryantz, J. M.; William, J. P. J. Org. Chem. 1990, 55,
5719. (c) Pearson, W. H.; Lin, K. C. Tetrahedron Lett. 1990,
31, 7571.
J¼12.0 Hz), 3.31(dd, 1H, J¼4.5, 11.5 Hz), 3.42 (m, 1H),
3.75 (d, 2H, J¼4.8 Hz), 4.00 (dd, 1H, J¼1.5, 11.7 Hz), 4.21
(dd, 1H, J¼4.5, 9.3 Hz), 4.41 (t-like, 1H, J¼8.1 Hz), 4.58
(t-like, 1H, J¼3.9 Hz), 5.72 (d, 1H, J¼3.3 Hz); 13C NMR
(CDCl3, 75 MHz): d 25.50 (q), 25.54 (q), 18.1(s), 25.8 (q),
26.1 (q, 3C), 26.7 (q), 53.2 (t), 56.2 (d), 57.9 (d), 62.0 (t),
75.3 (t), 78.4 (d), 79.6 (d), 79.7(d), 103.0 (d), 113.0 (d);
FABMS: m/z at 415 (MHþ).
3. (a) Blass, B. E.; Coburn, K. R.; Faulkner, A. L.; Seibel, W. L.;
Srivastava, A. Tetrahedron Lett. 2003, 44, 2153. (b) Moore,
´
M.; Norris, P. Tetrahedron Lett. 1998, 39, 7027. (c) Kovacs, J.;
´
´
´
Pinter, I.; Peredy, M. K.; Argay, G.; Kalman, A.; Descotes, G.;
Praly, J.-P. Carbohydr. Res. 1999, 316, 112. (d) Freeze, S.;
Norris, P. Heterocycle 1999, 51, 1807. (e) Flessner, T.; Wong,
C.-H. Tetrahedron Lett. 2000, 41, 7805.
3.1.8. (3aR,3bR,7aR,8aR)-2,2-Dimethyl-3a,5,6,7,7a,8a-
hexahydro-3bH,5aH-1,3,4,8-tetraoxa-6a-aza-cyclopro-
pan[f]cyclopent[a]azulene (16). MsCl (0.35 ml) and Et3N
(0.5 ml) were added to a solution of 13 (750 mg, 3.26 mmol)
in CH2Cl2 (30 ml) and the mixture was stirred at rt for 2 h.
The solvent was evaporated and the crude mesyl derivative
was dissolved in DMF (10 ml). NaN3 (800 mg) was added
to it and the mixture was heated at 90 8C for 5 h. Usual work
up and purification afforded 16 (185 mg, 25%) as a gum;
[Found: C, 57.86; H, 7.34; N, 5.88. C11H17NO4 requires C,
58.14; H, 7.54; N, 6.17%]; (a(2D0¼28.8 (c 1.17, CHCl3). IR
´ ´
4. Contelles, J. M.; Jimenez, C. A. Carbohydr. Polym. 2001, 45,
129.
5. (a) Ernet, P.; Vasella, A. Helv. Chim. Acta 1991, 74, 2043.
(b) Ernet, P.; Vasella, A.; Weber, M.; Rupitz, K.; Withers, S. G.
Carbohydr. Res. 1993, 250, 113. (c) Brandstetter, T. W.;
Davis, B.; Hyett, D.; Smith, C.; Hackett, L.; Winchester, B. G.;
Fleet, G. W. J. Tetrahedron Lett. 1995, 36, 7511. (d) Davis,
B. G.; Nash, R. J.; Watson, A. A.; Colin, S.; Fleet, G. W. J.
Tetrahedron 1999, 55, 4501.
1
(neat): nmax 1455, 1377, 1216, 1164, 1023, 873 cm21. H
6. Kru¨lle, T. M.; de la Fuente, C.; Pickering, L.; Alpin, R. T.;
Tsitsanou, K. E.; Zographos, S. E.; Oikonomakos, N. G.;
Nash, R. J.; Griffiths, R. C.; Fleet, G. W. J. Tetrahedron:
Asymmetry 1997, 8, 3807.
NMR (CDCl3, 300 MHz): d 1.35 (s, 3H), 1.49 (d, 1H,
J¼3.3 Hz), 1.64 (s, 3H), 2.18 (d, 1H, J¼5.1 Hz), 2.34 (t, 1H,
J¼10.8 Hz), 2.44 (m, 1H), 3.21 (dd, 1H, J¼4.2, 9.0 Hz),
3.27 (dd, 1H, J¼11.1, 13.2 Hz), 3.83 (d, 1H, J¼11.1 Hz),
4.23 (t-like, 1H, J¼9.0 Hz), 4.50 (dd, 1H, J¼4.5, 13.5 Hz),
4.67 (t-like, 1H, J¼3.9 Hz), 5.75 (d, 1H, J¼3.6 Hz). 13C
NMR (CDCl3, 75 MHz): d 26.2 (q), 26.3 (q), 35.4 (d), 35.5
(t), 56.7(t), 72.1(t), 75.3 (d), 78.4 (d), 88.6 (d), 104.0 (d),
113.5 (s); FABMS: m/z at 228 (MHþ).
7. (a) Norris, P.; Horton, D.; Giridhar, D. E. Tetrahedron Lett.
1996, 37, 3925. (b) Gothelf, K. V.; Jorgensen, K. A. Chem.
Rev. 1998, 98, 863. (c) Takebayashi, M.; Hiranuma, S.; Kanie,
Y.; Kajimoto, T.; Kanie, O. J. Org. Chem. 1999, 64, 5280.
(d) Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc.
1999, 121, 3046.
8. Schramm, V. L.; Tyler, P. C. Current Topics in Medicinal
Chemistry; Reitz, A. B., Ed.; Bentham Science, 2003; Vol. 3,
pp 525–540.
3.1.9. (3aR,3bS,9aR,10aR)-2,2-Dimethyl-3a,9,9a,10a-
tetrahydro-3bH,5H-1,3,4,10-tetraoxa-7,8,8a-triaza-
cyclopent[f]cyclopent[a]azulene (17). Compound 17 was
prepared from 14 using procedure as adopted in the
preparation of 16.
9. Iminosugars as Glycosidase Inhibitors; Stu¨tz, A. E., Ed.;
Wiley: Weinheim, 1999.
10. Hayashi, T.; Murray, B.; Wang, R.; Wong, C. H. Bioorg. Med.
Chem. 1997, 5, 497.
11. Commercially available diacetone glucose was converted15 to
the diol 1 through oxidation of C-3 OH group followed by
Grignard reaction with allyl magnesium bromide, selective
deprotection of 5,6-ketal, vicinal diol cleavage and sodium
borohydride reduction of the aldehyde. Compound 2 was,
however, prepared15 by benzylation of the above Grignard
product and thereafter following a sequence of reactions
similar to that in case of 1. 1,2:5,6-Di-O-cyclohexylidene-3-C-
allyl-a-D-allofura-nose was obtained from D-glucose via
conventional steps and converted to 3 following a sequence
of reactions similar to that in case of 1. Characteristic data
for 1,2:5,6-di-O-cyclohexylidene-3-C-allyl-a-D allofuranose:
mp 106–108 8C; [a]D20¼þ44.8 (c 0.85, CHCl3); 1H NMR
(CDCl3, 300 MHz): d 1.41–1.68 (m, 20H), 2.18 (dd, 1H,
J¼6.0, 14.4 Hz), 2.65 (dd, 1H, J¼5.4, 14.4 Hz), 2.78 (s, 1H),
3.79 (d, 1H, J¼7.8 Hz), 3.90 (m, 1H), 4.13 (m, 2H), 4.33
(d,1H, J¼3.6 Hz), 5.15 (d,1H, J¼17.3 Hz), 5.19 (d, 1H,
J¼10.2 Hz), 5.77 (d, 1H, J¼3.6 Hz), 5.99 (m, 1H); 13C NMR
(CDCl3, 75 MHz): d 23.9, 24.26, 24.30, 24.5, 25.3, 25.5, 35.2,
36.4, 36.66, 36.70, 37.3, 68.2, 73.3, 79.1, 81.3, 82.8, 103.7,
110.6, 113.6, 119.1, 133.2. For 3: mp 155–156 8C;
[a]2D0¼þ56.68 (c 0.54, CHCl3); 1H NMR (CDCl3,
300 MHz): d 1.41 (t, 2H, J¼5.0 Hz), 1.56 (m, 4H), 1.69 (m,
2H), 1.79 (t, 1H, J¼5.4 Hz), 1.95 (brs, 1H), 2.14 (dd, 1H,
J¼8.2, 14.6 Hz), 2.42 (dd, 1H, J¼5.9, 14.6 Hz), 2.77 (d, 1H,
J¼1.1 Hz), 3.81 (m, 2H), 3.93 (dd, 1H, J¼3.8, 7.2 Hz), 4.29
Yield 62%; gum; [Found: C, 52.08; H, 5.88; N, 16.32.
C11H15N3O4 requires C, 52.17; H, 5.97; N, 16.59%];
(a(2D0¼þ9.7 (c 0.2, CHCl3); IR (neat): nmax 1644, 1574,
1379, 1218, 1082, 1021, 754 cm21 1H NMR (CDCl3,
;
300 MHz): d 1.29 (s, 3H), 1.47 (s, 3H), 3.78 (d, 1H,
J¼2.6 Hz), 4.51 (dd, 1H, J¼9.5, 13.0 Hz), 4.54 (d, 1H,
J¼3.7 Hz), 4.64 (m, 1H), 4.77 (dd, 1H, J¼4.7, 13.0 Hz),
4.84 (d, 1H, J¼6.8 Hz), 5.54 (d, 1H, J¼6.8 Hz), 5.97 (d, 1H,
J¼3.6 Hz), 7.31(s, 1H); 13C NMR (CDCl3, 75 MHz): d
26.2, 26.7, 44.4, 79.2, 84.1, 86.8, 88.6, 105.4, 112.6, 121.3,
149.8; FABMS: m/z at 254 (MHþ).
Acknowledgements
The work has been supported by a grant from DST (Govt. of
India) given to S. B. M. One of the authors (S. T.) thanks
C.S.I.R. for awarding him a Junior Research Fellowship.
References and notes
1. Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607.
2. (a) Adamo, I.; Benedetti, F.; Berti, F.; Nardin, G.; Norbedo, S.
Tetrahedron Lett. 2003, 44, 9095. (b) Pearson, W. H.;

S. Tripathi et al. / Tetrahedron 60 (2004) 4959–4965
4965
(d, 1H, J¼3.9 Hz), 5.15 (m, 2H), 5.75 (d, 1H, J¼3.9 Hz), 5.91
(m, 1H).
1.58 (s, 3H), 2.52 (d, 1H, J¼2.7 Hz), 3.66 (dd, 1H, J¼7.5,
10.3 Hz), 3.72 (dd, 1H, J¼3.8, 10.3 Hz), 3.94 (m, 2H), 4.02
(dd, 1H, J¼3.8, 8.7 Hz), 4.09 (tdd, 1H, J¼1.2, 5.9, 12.6 Hz),
4.22 (tdd, 1H, J¼1.2, 5.9, 12.6 Hz), 4.62 (t, 1H, J¼3.9 Hz),
5.29 (m, 2H), 5.75 (d, 1H, J¼3.6 Hz), 5.97 (m, 1H). 13C NMR
(CDCl3, 75 MHz): d 25.4 (2C), 18.4, 25.9 (3C), 26.6, 26.8,
63.8, 71.5, 72.0, 77.8, 77.9, 104.0, 112.9, 117.9, 118.0, 134.5.
13: 1H NMR (CDCl3þD2O, 300 MHz): d 1.32 (s, 3H), 1.47 (s,
3H), 3.75 (dd, 1H, J¼3.6, 6.0 Hz), 3.82 (dd, 1H, J¼2.7,
6.0 Hz), 3.87 (m, 1H), 4.03 (dd, 1H, J¼3.6, 7.5 Hz), 4.08–
4.15 (m, 2H), 4.55 (d, 1H, J¼3.6 Hz), 5.19–5.35 (m, 2H),
5.85–5.98 (m, 2H). 14: 1H NMR (CDCl3þD2O, 300 MHz): d
1.36 (s, 3H), 1.58 (s, 3H), 3.73 (dd, 1H, J¼3.5, 5.8 Hz), 3.75
(dd, 1H, J¼2.8, 5.8 Hz), 3.92 (dd, 1H, J¼4.0, 6.0 Hz), 4.01–
4.24 (m, 2H), 4.63 (t-like, 1H, J¼3.9 Hz), 5.24–5.36 (m, 2H),
5.78 (d, 1H, J¼3.6 Hz), 5.85–6.01 (m, 1H).
12. Vorbru¨ggen, H.; Krolikiewicz, K.; Bennua, B. Chem. Ber.
1981, 114, 1234.
13. Bar, N. C.; Patra, R.; Achari, B.; Mandal, S. B. Tetrahedron
1997, 53, 4727.
14. The 3-O-allylated substrates 12-14 were prepared from
diacetone D-glucose. The compound 12 was obtained through
the oxidation of the hydroxyl group, reduction of the carbonyl
group to 3-epi alcohol, allylation of the generated hydroxyl
group, removal of 5,6-O- isopropylidene group, and finally,
selective protection of primary hydroxyl group at C-6 with
tert. butyl dimethylsilyl group. The precursors 13 and 14 were
generated through allylation of the corresponding hydroxyl
groups of diacetone D-glucose/D-allose followed by selective
cleavage of 5,6-ketal, vicinal diol cleavage and reduction of
the formed aldehyde. 12: 1H NMR (CDCl3, 300 MHz): d
0.079 (s, 3H), 0.088 (s, 3H), 0.90, 0.91(2£s, 9H), 1.36 (s, 3H),
15. Bar, N. C.; Roy, A.; Achari, B.; Mandal, S. B. J. Org. Chem.
1997, 62, 8948.