1,3-Dipolar cycloaddition reaction of a d-galactose derived nitrone with allyl alcohol: synthesis of polyhydroxylated perhydroazaazulene alkaloids

Article abstract of DOI:10.1016/j.tetasy.2007.05.012

Diastereofacial intermolecular 1,3-dipolar cycloaddition of d-galactose derived nitrone with allyl alcohol followed by tosylation afforded, in a 1:1 ratio endo- and exo-isooxazolidines 4a and 4b with complete diastereoselectivity at the nitrone carbon. Th

Full text of DOI:10.1016/j.tetasy.2007.05.012

Tetrahedron: Asymmetry 18 (2007) 1176–1182
1,3-Dipolar cycloaddition reaction of a D-galactose derived
nitrone with allyl alcohol: synthesis of polyhydroxylated
perhydroazaazulene alkaloids
Omprakash P. Bande,a Vrushali H. Jadhav,a Vedavati G. Puranikb and Dilip D. Dhavalea,*
aDepartment of Chemistry, Garware Research Centre, University of Pune, Pune 411 007, India
bCentre for Material Characterization, National Chemical Laboratory, Pune 411 008, India
Received 26 March 2007; accepted 7 May 2007
Abstract—Diastereofacial intermolecular 1,3-dipolar cycloaddition of D-galactose derived nitrone with allyl alcohol followed by tosyl-
ation afforded, in a 1:1 ratio endo- and exo-isooxazolidines 4a and 4b with complete diastereoselectivity at the nitrone carbon. The
N–O bond reductive cleavage and SN2 displacement afforded the pyrrolidine ring with a galactose appendage that on acetonide cleavage
and reductive amino-cyclization afforded pentahydroxylated perhydroazaazulenes 1a and 1b.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
structure activity relationship study of hydroxylated perhy-
droazaazulenes 1, which are synthesized and evaluated for
glycosidase inhibitory activities. In addition, it has been
thought that the presence of the polyhydroxylated seven
membered ring in 1, could also exhibit a change in the con-
formation of the bicyclic system, due to the hydrogen
bonding of the hydroxyl groups with the ring nitrogen,
causing them to act as DNA minor groove binding ligands
as in the case of hydroxylated azepanes.6 In this respect,
Lindsay and Pyne first reported trihydroxy perhydroaza-
azulenes,7a while Gomez-Guillen et al. have reported the
syntheses of a hexahydroxy- and pentahydroxy-perhydro-
azaazulenes.7b Another report from Geyer et al. described
the synthesis of a tetrahydroxy-octahydro-5-oxo-thiazolo-
(3,2-a)azepine from D-c-glucuronolactone and converted
it into hexapeptide mimetic, and studied the polyproline
II helix conformation.8 A report from our laboratory de-
scribes the synthesis of tetrahydroxy-perhydroazaazulenes
using a Johnson–Claisen rearrangement of the D-glucose
derived allylic alcohols.9 As part of our interest in this
area,10 we recently reported the 1,3-dipolar cycloaddition
(DC) reaction of 1,4-furanosyl nitrone (obtained from D-
glucose) with allyl alcohol in the synthesis of 2-hydroxy-
1-deoxycastanospermine analogues.10c During this study
we noticed that the DC of a nitrone to allyl alcohol occurs
with perfect regioselectivity, wherein the oxygen of the 1,3-
dipole attacks the more highly substituted carbon of the
double bond, while the p-facial stereoselectivity at the
Amongst substituted perhydroazaazulenes, a group of
hydroxyl-substituted perhydroazaazulenes 1 (Fig. 1) is an
emerging class of compounds. These compounds are also
considered as higher-ring homologues of polyhydroxylated
indolizidine alkaloids. The diverse bioactivities of indolizi-
dine iminosugars,1 for example, naturally occurring cast-
anospermine2
2
and its analogues, as promising
glycosidase inhibitors in the treatment of various diseases
such as diabetes,3 cancer4 and viral infections, including
AIDS5 are known in the literature. This has prompted a
R1
R2
3
2
3
2
4
1
1
4
N
5
6
N
OH
9a
5
H
8a
H
9
8
8
HO
OH
6
OH
HO
7
OH
7
HO
OH
1a, R1 = OH, R2 = H
1b, R2 = OH, R1 = H
2
Figure 1. Iminosugars and analogues.
*
Corresponding author. Tel.: +91 2025601225; fax: +91 2025691758;
e-mail: ddd@chem.unipune.ernet.in
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.012

O. P. Bande et al. / Tetrahedron: Asymmetry 18 (2007) 1176–1182
1177
R1
R2
9
R1
R2
O
Bn
H
O
d
N
R
Bn
b
N
a
N
N
8
8
H
R2
R1
R
7
R
Sugar
7
6
6
Sugar
Sugar
R
R
3
1a, R = R1 = OH, R2 = H
1b, R = R2 = OH, R1 = H
8a, R = R1 = OAc, R2 = H
8b, R = R2 = OAc, R1= H
5a, R1= OH, R2= H, R = Bn
5b, R1= H, R2= OH, R = Bn
7a, R1= OH, R2= H, R = Cbz
7b, R1= H, R2= OH, R = Cbz
4a, R1=CH2OTs, R2= H
4b, R1=H, R2= CH2OTs
e
c
Sugar =
O
5
O
O
4
1
O
2
3
O
Scheme 1. Reagents and conditions: (a) (i) allyl alcohol, 100 ꢁC, 2.5 h, (ii) TsCl, pyridine, 0 ꢁC to 25 ꢁC, 6 h; (b) Zn, Cu(OAc)2, AcOH, 70 ꢁC, 1 h; (c) (i)
HCOONH4, Pd/C, MeOH, 80 ꢁC, 1 h, (ii) CbzCl, NaHCO3, MeOH, 0 ꢁC to 25 ꢁC, 2.5 h; (d) (i) TFA–H2O (4:1), 25 ꢁC, 2 h, (ii) HCOONH4, Pd/C,
MeOH, 80 ꢁC, 1.5 h; (e) Ac2O, pyridine, DMAP, 0 ꢁC to 25 ꢁC, 12 h.
nitrone and allyl carbon was found to be low, affording all
four possible diastereomers. It has been reported by Pedro
Merino et al. that the furanosyl nitrones give low p-facial
diastereoselectivity, while the pyranosyl nitrones afford
high p-facial diastereoselectivity at the prochiral nitrone
carbon.11 With this view in mind, we decided to exploit
1,3-DC reaction12 of a D-galactose derived nitrone 3 with
allyl alcohol which would be regio- and p-facial diastereo-
selective at the nitrone carbon, while the endo- and exo-
selectivity at the allyl carbon would lead to the formation
of anti- and syn-isoxazolidines. The isoxazolidines thus
obtained on tosylation followed by N–O bond reductive
cleavage and in situ nucleophilic tosyl substitution would
afford pyrrolidines with a D-galactose appendage that on
N-Cbz protection, cleavage of the acetonide functionalities
and reductive amino-cyclization (C6 amino functionality of
pyrrolidine with C1-hemiacetal) would lead to the forma-
tion of the seven membered ring of the azaazulene skeleton
required for the target molecule. Although a few reports
are currently available with regard to the use of DC of
the nitrones to allyl alcohol,13 the application of this strat-
egy to nitrone 3 towards the synthesis of perhydroazaazu-
lene analogues, to the best of our knowledge, is still not
known. Our efforts in the successful implementation of this
methodology for the synthesis of polyhydroxy perhydro
azaazulenes 1a and 1b are reported herein.
In the next step, the mixture of isoxazolidines 4a and 4b
was subjected to N–O bond reductive cleavage using Zn-
acetic acid, which on chromatographic separation afforded
the corresponding pyrrolidines 5a and 5b in a 1:1 ratio in
84% yield. This one pot two-step reaction of 4 most likely
involves the in situ generation of a b-amino alcohol that
concomitantly undergoes nucleophilic displacement of the
–O-tosyl group leading to the formation of 8-hydroxy-pyr-
rolidine-ring skeleton 5. Fortunately pyrrolidine 5b, which
has a lower Rf compared to 5a, was isolated as a crystalline
solid. Single crystal X-ray analysis (Fig. 2) established the
absolute configurations at the newly generated C6 and
C8 stereocentres as (R) and (S), respectively. Having
known the structure of 5b, the stereochemical assignment
in 5a was derived from the correlation study. For this, we
considered oxidizing the C8-hydroxyl groups in 5a and
5b to the corresponding C8-keto products that will enable
us to determine whether 5a and 5b are C6-epimeric are not,
and from the X-ray data correlation of 5b, assign the abso-
lute stereochemistry at C8 in 5a.
Thus, pyrrolidines 5a and 5b were individually subjected to
the Swern oxidation (Scheme 2) that afforded the same
ketone 6 (confirmed on the basis of the spectral, analytical
data and the super imposable IR spectra). As the absolute
configuration at C6 in 5b was established as (R), the same
absolute configuration (6R) was assigned to 5a, while the
absolute configuration at C8 in 5b was determined to be
(S) and as 5a was found to be the C8 epimeric alcohol,
the C8 configuration in 5a was therefore assigned as (R).
2. Results and discussion
The required nitrone 3 was prepared from D-galactose as
reported earlier.14 The 1,3-DC of 3 to allyl alcohol at
100 ꢁC for 2.5 h afforded an inseparable mixture of isoxaz-
olidines in 90% yield (after chromatographic purification),
which upon further treatment with p-toluenesulfonylchlo-
ride in pyridine afforded an inseparable diastereomeric
mixture of tosyloxylated isoxazolidines 4a and 4b in the
ratio 1:1 as evident from the 1H NMR spectrum of column
purified material (Scheme 1).
Pyrrolidines 5a and 5b were derived from isoxazolidines 4a
and 4b, respectively. Therefore it is evident that DC of nit-
rone 3 to allyl alcohol (and subsequent tosylation) is highly
diastereoselective wherein the addition of the allyl alcohol
takes place exclusively from the Re face of nitrone 3 leading
to the formation of endo- and exo-isoxazolidines in a 1:1
ratio. This observation was found to be analogous to that
reported by Merino et al.11 and Gomez-Guillen et al.7b in
which the DC of nitrone 3 with methyl acrylate afforded
the Re-endo cycloadduct as the only isolable product due
to the favoured secondary orbital overlap of –COOMe
group;12c the same effect is absent in the DC of nitrone 3
with allyl alcohol, resulting in the formation of endo- and
While our work was in progress, Gomez-Guillen et al. have published a
report on the DC of a D-galactose derived nitrone with methyl acrylate
towards the synthesis of 1a.

1178
O. P. Bande et al. / Tetrahedron: Asymmetry 18 (2007) 1176–1182
O
O
O
O
H
O
H
O
O
O
Re face
OH
Si face
OH
O
O
H
H
N
N
O
O
Bn
Bn
TS II
TS I
Figure 3. The Felkin-Anh models.
tion with benzyl chloroformate afforded N-Cbz protected
pyrrolidines 7a in 80% yield. Finally, 7a was treated with
TFA:H2O (4:1) and the hemiacetal thus obtained was sub-
jected to hydrogenation (ammonium formate, 10% Pd/C,
in methanol reflux) to afford pentahydroxy-perhydroaza-
azulene 1a as a viscous liquid. The spectral and analytical
data of 1a were found to be in accordance with that repor-
25
25
ted.7b {½aꢀD ¼ þ7:0 (c 0.5, MeOH) [lit.7b ½aꢀD ¼ þ6:1 (c 0.5,
MeOH)]}. Compound 1a was treated with acetic anhydride
in pyridine to afford per-acetylated derivative 8a. The same
sequence of reactions with 5b afforded N-Cbz protected
pyrrolidine 7b, which on acetonide cleavage and reductive
amino-cyclization afforded pentahydroxy-perhydroazaazul-
ene 1b which was characterized as its peracetyl derivative
8b. The spectral and analytical data of 7b, 1b and 8b were
found to be in agreement with the given structures.
Figure 2. ORTEP diagram of compound 5b.
Bn
O
DMSO, (COCl)2,
5a and 5b
N
(Et)3N, -78 °C to
25 °C, 3h.
Sugar
6
3. Conclusions
Scheme 2.
In conclusion, the DC of D-galactose derived nitrone 3 with
allyl alcohol is highly regio- and Re facial stereoselective.
However, the endo- and exo-addition affords anti- and
syn-isoxazolidines in nearly equal amounts. The tosylation
of cycloadducts followed by N–O bond reductive cleavage
afforded pyrrolidines 5a and 5b in high yields, which were
converted to the corresponding pentahydroxylated per-
hydroazaazulenes 1a and 1b.
exo- products in a 1:1 ratio. The above results were com-
pared with our earlier report10c on the 1,3-DC of furanosyl
nitrone with allyl alcohol and it was noted that pyranosyl
nitrone 3 offered high p-facial selectivity when compared
to furanosyl nitrone as reported by others.11
2.1. Explanation for the observed stereoselectivity in the
DC reaction
4. Experimental
The observed p-facial diastereoselectivity could be rational-
ized on the basis of Felkin-Anh like transition states (TS).
Out of the four TS, we considered the TS I in which the
bulky C-4 substituent is kept perpendicular to C@N and
the other TS II, wherein the electronegative pyranose ring
oxygen is perpendicular to C@N (Fig. 3). We believe that,
in TS I, the approach of the allyl alcohol from the Re face
of the C@N is favoured over the Si face approach in TS II
due to the interactions of the bulky C4-substituent, leading
to the formation of isoxazolidines with exclusively (R)-
absolute configuration at the nitrone carbon (C6). The
approach of the allyl alcohol in endo/exo orientation, how-
ever, affords 4a and 4b in equal amounts.
4.1. General methods
Melting points were recorded with Thomas Hoover melting
point apparatus and are uncorrected. IR spectra were re-
corded with FTIR as a thin film or in Nujol mull or using
KBr pellets and are expressed in cmꢁ1. H (300 MHz) and
1
13C (75 MHz) NMR spectra were recorded using CDCl3 or
D2O as a solvent. Chemical shifts were reported in d unit
(ppm) with reference to TMS as the internal standard
and J values are given in Hz. Decoupling and DEPT exper-
iments confirmed the assignments of the signals. Elemental
analyses were carried out with C, H-analyzer. Optical rota-
tions were measured using polarimeter at 25 ꢁC. Thin layer
chromatography was performed on pre-coated plates
(0.25 mm, silica gel 60 F254). Column chromatography
was carried out with silica gel (100–200 mesh). The reac-
In the subsequent step, treatment of 5a with ammonium
formate and 10% Pd/C followed by selective amine protec-

O. P. Bande et al. / Tetrahedron: Asymmetry 18 (2007) 1176–1182
1179
25
tions were carried out in oven-dried glassware under dry
N2. Methanol, pyridine, acetone, benzene, toluene, acetoni-
trile and dichloromethane were purified and dried before
use. 10% Pd–C was purchased from Aldrich and/or Fluka.
After decomposition of the reaction with water, the work-
up involves washing of the combined organic layers with
water, brine, drying over anhydrous sodium sulfate and
evaporation of solvent at reduced pressure.
Rf = 0.60 (n-hexane/ethyl acetate = 4/6); ½aꢀD ¼ þ36:0 (c
0.05, CHCl3); IR (Nujol) 3550–3200, 1612, 1454 cmꢁ1; H
1
NMR (300 MHz, CDCl3 + D2O) d 1.22 (s, 3H, CH3),
1.23 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.56 (s, 3H, CH3),
1.97 (ddd, J = 13.5, 8.4, 6.0 Hz, 1H, H-7a), 2.23 (dt,
J = 13.5, 6.0 Hz, 1H, H-7b), 2.39 (dd, J = 10.0, 5.4 Hz,
1H, H-9a), 3.07 (dd, J = 10.0, 5.4 Hz, 1H, H-9b), 3.27
(apparent q, J = 6.0 Hz, 1H, H-6), 3.62 (d, J = 13.5 Hz,
1H, NCH2Ph), 3.64 (dd, J = 6.0, 1.5 Hz, 1H, H-5), 4.22
(d, J = 13.5 Hz, 1H, NCH2Ph), 4.29 (dd, J = 5.1, 2.1 Hz,
1H, H-2), 4.34 (t, 5.4 Hz, 1H, H-8), 4.42 (dd, J = 8.0,
1.8 Hz, 1H, H-4), 4.60 (dd, J = 8.0, 2.1 Hz, 1H, H-3),
5.56 (d, J = 5.1 Hz, 1H, H-1), 7.18–7.21 (m, 5H, Ar-H);
13C NMR (75 MHz, CDCl3) d 24.1, 25.0, 25.8, 26.2
(CH3), 37.5 (C-7), 60.1, 60.9, 61.8 (C-6, C-9, CH2Ph),
69.5, 70.6, 70.7, 71.1, 77.4 (C-2, C-3, C-4, C-5, C-8), 96.4
(C-1), 108.1, 108.6 (O–C–O), 126.6, 128.0, 128.5, 139.4
(Ar-C). Anal. Calcd for C22H31NO6: C, 65.17; H, 7.71.
Found: C, 65.22; H, 7.65.
4.2. 6,7,9-Trideoxy-6,9-(N-benzylimino)-1,2:3,4-di-O-iso-
propylidene-8(R)-hydroxy-b-L-threo-D-galacto-non-1,5-
pyranose 5a and 6,7,9-trideoxy-6,9-(N-benzylimino)-1,2:3,4-
di-O-isopropylidene-8(S)-hydroxy-a-D-erythreo-D-galacto-
non-1,5-pyranose 5b
Nitrone 3 (2.0 g, 5.5 mmol) and allyl alcohol (3.1 g,
55 mmol) were heated at 100 ꢁC for 2 h. The reaction mix-
ture was concentrated under reduced pressure and purified
by column chromatography (n-hexane/ethyl acetate = 75/
25) to afford a mixture of cycloadducts as a thick liquid
(2.1 g, 90%). To a mixture of cycloadducts (2.1 g,
4.9 mmol) in dry pyridine (5 mL), cooled at 0 ꢁC, was
added p-toluenesulfonylchloride (1.12 g, 5.8 mmol), and
stirred at room temperature for 4 h. The reaction mixture
was quenched with cold water and extracted with ethyl ace-
tate to give a thick oil that on purification by column chro-
matography (n-hexane/ethyl acetate = 90/10) afforded an
inseparable mixture of isoxazolidines as a thick liquid
(2.5 g, 87%). Zinc dust (0.56 g, 8.6 mmol) was added to a
solution of copper(II) acetate (0.025 g, 0.16 mmol) in gla-
cial acetic acid (1 mL) under a nitrogen atmosphere and
the mixture was stirred at room temperature for 10 min un-
til the colour disappeared. The above mixture of isoxazol-
idines (1.0 g, 1.7 mmol) in glacial acetic acid (1.5 mL) and
water (0.5 mL) was added successively and the reaction
mixture was heated at 70 ꢁC for 2 h. On cooling to room
temperature, the sodium salt of EDTA (0.1 g) was added
and the mixture was stirred for 10 min and then made alka-
line to pH 10 by addition of 3 M NaOH. Extraction with
chloroform, work-up and separation by flash column chro-
matography by eluting first with n-hexane/ethyl ace-
4.3. Crystal data
Single crystals of compound 5b were grown by slow evap-
oration of the solution in chloroform. Colourless crystal of
approximate size 0.43 · 0.11 · 0.09 mm was used for data
collection on Bruker SMART APEX CCD diffractometer
using MoKa radiation with fine focus tube with 50 kV
and 30 mA. Crystal to detector distance 6.05 cm,
512 · 512 pixels/frame, multiscan data acquisition. Total
scans = 5, total frames = 2798, oscillation/frame ꢁ0.3ꢁ,
exposure/frame = 25.0 s/frame, maximum detector swing
angle = ꢁ30.0ꢁ, beam centre = (260.2,252.5), in plane spot
width = 1.24, SAINT integration, h range = 2.07–25.00ꢁ,
completeness to h of 25.0ꢁ is 99.9%. SADABS correction
applied, C22H31NO6, M = 405.48. Crystals belong to
monoclinic, space group P21, a = 11.5010(6), b =
˚
8.8460(5),
c = 11.8760(7) A,
b = 114.757(1)ꢁ
V =
1097.19(11) A , Z = 2, Dc = 1.227 mg mꢁ3, l(MoKa) =
0.089 mmꢁ1, T = 293(2) K, 12,262 reflections measured,
3857 unique [I > 2r(I)], R value 0.0456, wR2 = 0.0978. All
the data were corrected for Lorentzian, polarization and
absorption effects. SHELX-97 (ShelxTL)ref was used for
structure solution and full matrix least squares refinement
on F2. Hydrogen atoms were included in the refinement
as per the riding model.
3
˚
tate = 80/20 gave 5a (0.307 g, 42%) as a thick oil;
25
Rf = 0.59 (hexane/ethyl acetate = 4/6); ½aꢀD ¼ ꢁ24 (c
1
0.41, CHCl3); IR (Neat) 3540–3200, 1632, 1458 cmꢁ1; H
NMR (300 MHz, CDCl3 + D2O) d 1.21 (s, 3H, CH3),
1.22 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.55 (s, 3H, CH3),
2.1 (ddd, J = 15.3, 10.2, 5.1 Hz, 1H, H-7a), 2.20–2.38 (m,
2H, H-7b, H-9a), 2.87 (dd, J = 9.6, 1.5 Hz, 1H, H-9b),
3.0 (dt, J = 7.2, 3.0 Hz, 1H, H-6), 3.45 (d, J = 13.2 Hz,
1H, NCH2Ph), 3.9 (br s, 1H, H-5), 4.11 (d, J = 2.1 Hz,
1H, H-4), 4.15 (d, J = 13.2 Hz, 1H, NCH2Ph), 4.24–4.40
(m, 2H, H-2 and H-8), 4.61 (dd, J = 7.8, 2.1 Hz, 1H, H-
3), 5.63 (d, J = 4.8 Hz, 1H, H-1), 7.19–7.38 (m, 5H, Ar-
H). 13C NMR (75 MHz, CDCl3) d 24.0, 24.8, 25.6, 25.9
(CH3), 35.5 (C-7), 58.5 (NCH2Ph), 61.0, 62.2 (C-9, C-6),
68.1, 70.4, 70.6, 70.7, 71.6 (C-2, C-3, C-4, C-5, C-8), 96.3
(C-1), 108.2, 108.6 (O–C–O), 126.5, 127.8, 128.3, 138.9
(Ar), Anal. Calcd for C22H31NO6: C, 65.17; H, 7.71.
Found: C, 65.20; H, 7.53.
4.4. 6,7,9-Trideoxy-6,9-(N-benzoxycarbonylimino)-1,2:3,4-
di-O-isopropylidene-8(S)-hydroxy-b-L-threo-D-galacto-non-
1,5-pyranose 7a
A solution of compound 5a (0.20 g, 0.49 mmol), 10% Pd/C
(0.075 g) and ammonium formate (0.18 g, 2.9 mmol) in
methanol (4 mL) was refluxed for 1 h. The reaction mixture
was filtered through Celite and the filtrate was evaporated
to give a thick oil. To a solution of amino alcohol (0.15 g,
0.45 mmol) in methanol–water (10 mL, 9:1), cooled to
0 ꢁC, were added benzylchloroformate (0.091 g,
0.60 mmol), sodium bicarbonate (0.114 g, 1.3 mmol) and
the solution was stirred for 2.5 h. Methanol was evapo-
rated under reduced pressure. After the usual work-up
and further purification by column chromatography
(n-hexane/ethyl acetate = 90/10), 7a (0.176 g, 80%) was
Further elution with n-hexane/ethyl acetate = 78/22 affor-
ded 5b (0.30 g, 42%) as a white solid; mp = 120 ꢁC;

1180
O. P. Bande et al. / Tetrahedron: Asymmetry 18 (2007) 1176–1182
obtained as
a
thick liquid; Rf = 0.33 (hexane/ethyl
column chromatography (n-hexane/ethyl acetate = 90/10)
25
acetate = 7/3); ½aꢀD ¼ 8:0 (c 0.05, CHCl3); IR (Neat)
afforded 7a (0.07 g, 70%) as a thick liquid; Rf = 0.70 (n-
25
3600–3250, 1697, 1400 cmꢁ1 1H NMR (300 MHz,
;
hexane/ethyl acetate = 5/5); ½aꢀD ¼ ꢁ26:6 (c 0.30, CHCl3);
CDCl3 + D2O) d 1.30 (s, 3H, CH3), 1.39 (s, 3H, CH3),
1.40 (s, 3H, CH3), 1.41 (s, 3H, CH3), 2.21 (ddd, J = 15.0,
10.0, 4.8 Hz, 1H, H-7a), 2.53 (br d, J = 15.0 Hz, 1H, H,
H-7b), 3.45 (dd, J = 11.1, 4.8 Hz, 1H, H-9a), 3.55 (br d,
J = 11.1 Hz, 1H, H-9b), 4.17 (d, J = 10.0 Hz, 1H, H-6),
4.18–4.28 (m, 1H, H-8), 4.3 (dd, J = 4.8, 2.1 Hz, 1H, H-
2), 4.36 (br d, J = 8.1 Hz, 1H, H-4), 4.42 (br s, 1H, H-5),
4.60 (dd, J = 8.1, 2.1 Hz, 1H, H-3), 5.1 (ABq, J =
12.3 Hz, 2H, NCOCH2Ph), 7.20–7.5 (m, 5H, Ar-H); 13C
NMR (75 MHz, CDCl3) d 23.8, 24.7, 25.4, 25.5 (CH3),
34.0 (C-7), 55.8 (C-9), 58.7 (C-6), 66.2, 66.4 (C-5, CH2Ph),
69.7, 70.3, 70.6, 71.9 (C-2, C-3, C-4, C-8), 96.0 (C-1), 108.9
(O–C–O), 127.3, 127.48, 127.9, 136.3 (Ar-C), 154.8 (C@O);
Anal. Calcd for C23H31NO8: C, 61.46; H, 6.95. Found: C,
61.50; H, 6.99.
IR (Neat) 1749, 1654 cmꢁ1; 1H NMR (300 MHz, CDCl3) d
1.38 (s, 3H, CH3), 1.39 (s, 3H, CH3), 1.42 (s, 3H, CH3),
1.49 (s, 3H, CH3), 2.57 (dd, J = 19.2, 7.5 Hz, 1H, H-7a),
2.70–2.90 (m, 2H, H-9a, H-7b), 3.26 (d, J = 17.7 Hz, 1H,
H-9b), 3.36 (ddd, J = 9.9 Hz, 1H, H-6), 3.49 (d,
J = 12.9 Hz, 1H, CH2Ph), 4.14 (br s, 1H, H-5), 4.21 (d,
J = 12.9 Hz, 1H, CH2Ph), 4.28 (dd, J = 7.8, 2.1 Hz, 1H,
H-4), 4.33 (dd, J = 7.8, 2.1 Hz, 1H, H-2), 4.63 (dd,
J = 7.8, 2.1 Hz, 1H, H-3), 5.60 (d, J = 4.8 Hz, 1H, H-1),
7.18–7.40 (m, 5H, Ar-H); 13C NMR (75 MHz, CDCl3); d
24.3, 24.8, 25.9, 26.3 (CH3), 39.5 (C-7), 58.4, 60.5, 61.6
(C-6, CH2Ph, C-9), 65.6 (C-5), 70.5, 71.0, 72.3 (C-2, C-3,
C-4), 96.6 (C-1), 108.3, 109.2 (O–C–O), 127.2, 128.3,
128.6, 137.0 (Ar-C); Anal. Calcd for C22H29NO6:
C, 65.49; H, 7.24. Found: C, 65.30; H, 7.39.
4.5. 6,7,9-Trideoxy-6,9-(N-benzoxycarbonylimino)-1,2:3,4-
di-O-isopropylidene-8(S)-hydroxy-a-D-erythreo-D-galacto-
non-1,5-pyranose 7b
4.7. (2R,6S,7R,8S,9R,9aR)-2,6,7,8,9-Pentahydroxy-perhy-
droazaazulene 1a
A solution of 7a (0.20 g, 0.45 mmol) in TFA–H2O (6 mL,
4:1) was stirred at 25 ꢁC for 4 h. Trifluoroacetic acid was
co-evaporated with benzene to furnish a thick liquid. A
solution of the above product (0.160 g, 0.43 mmol), 10%
Pd/C (0.100 g) and ammonium formate (0.16 g, 2.6 mmol)
in methanol (4 mL) was refluxed for 1.5 h. The reaction
mixture was filtered through Celite and the filtrate was
evaporated. Purification by column chromatography (chlo-
Compound 5b (0.15 g, 0.36 mmol) was treated with 10%
Pd/C (0.05 g) and ammonium formate (0.13 g, 2.17 mmol),
in methanol (3 mL), followed by benzylchloroformate
(0.068 g, 0.45 mmol) and sodium bicarbonate (0.083 g,
0.97 mmol), as described in the synthesis of 7a. Further
purification by column chromatography (n-hexane/ethyl
acetate = 85/15) afforded 7b (0.12 g, 77%) as a white
solid; Mp = 117 ꢁC; Rf = 0.625 (hexane/ethyl acetate = 5/
roform/methanol = 85/15) afforded 1a (0.085 g, 87%) as a
25
25
5); ½aꢀD ¼ þ400 (c 0.03, CHCl3); IR (Nujol) 3600–3200,
thick liquid; Rf = 0.30 (methanol); ½aꢀD ¼ þ7:0 (c 0.5,
1685,
1415,
1346 cmꢁ1
;
1H
NMR
(300 MHz,
MeOH); IR (Neat) 3676–3250 cmꢁ1
;
1H NMR
CDCl3 + D2O) d 1.22 (s, 3H, CH3), 1.25 (s, 3H, CH3),
1.30 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.96 (ddd, J = 11.7,
8.4, 3.0 Hz, 1H), 2.52 (dt, J = 11.7, 6.3 Hz, 1H, H-7b),
3.38–3.68 (m, 2H, H-9a, H-9b), 4.13–4.34 (m, 3H, H-6,
H-8, H-2), 4.34–4.46 (br s, 2H, H-3, H-4), 4.56 (br d,
J = 7.2 Hz, 1H, H-3), 5.08 (ABq, J = 12 Hz, 2H, CH2Ph),
5.47 (d, J = 4.8 Hz, 1H, H-1), 7.18–7.40 (m, 5H, Ar-H); 13C
NMR (75 MHz, CDCl3) d 24.5, 25.5, 26.1, 26.3 (CH3), 35.1
(C-7), 54.9 (C-9), 58.4 (C-6), 66.6, 66.9 (CH2Ph), 70.9(s),
71.4, 72.5 (C-2, C-3, C-4, C-5), 96.76 (C-1), 109.4 (O–C–
O), 128.0, 128.6, 136.9 (Ar-C), 155.5 (C@O).
(300 MHz, D2O) d 1.8 (dd, J = 14.0, 5.1 Hz, 1H, H-1a),
2.66 (ddd, J = 14.0, 9.3, 5.1 Hz, 1H, H-1b), 2.71–2.86 (m,
1H, H-5a), 2.92–3.23 (m, 2H, H9a, H3a), 3.25 (d,
J = 11.7, 1H, H-3b), 3.61 (dd, J = 13.5, 6.6 Hz, 1H, H-
5b), 3.80 (dd, J = 9.3, 6.6 Hz, 1H, H-9), 3.94 (d,
J = 6.6 Hz, 1H, H-8), 4.20 (d, J = 6.6 Hz, 1H, H-7), 4.22
(apparent q, J = 6.6 Hz, 1H, H-6), 4.42–4.52 (m, 1H, H-
2); 13C NMR (75 MHz, D2O) d 41.5 (C-1), 60.1 (C-5),
67.3 (C-3), 69.8, 69.9, 71.3 (C-9, C-6, C-2), 75.8(s), 77.0
(C-7, C-8, C-9); Anal. Calcd for C9H17NO5: C, 49.51; H,
7.82. Found: C, 49.79; H, 7.77.
Due to the presence of the N-Cbz functionality, the
1H NMR of the compound shows broad signals and
13C NMR shows doubling of signals. Anal. Calcd
for C23H31NO8: C, 61.46; H, 6.95. Found: C, 61.66; H,
6.92.
4.8. (2S,6S,7R,8S,9R,9aR)-2,6,7,8,9-Pentahydroxy-perhy-
droazaazulene 1b
A solution of 7b (0.20 g, 0.45 mmol) in TFA–H2O (6 mL,
4:1) followed by treatment with 10% Pd/C (0.100 g) and
ammonium formate (0.16 g, 2.6 mmol) as described in the
synthesis of 1a, and purification by column chromatogra-
4.6. 6,7,9-Trideoxy-6,9-(N-benzylimino)-1,2:3,4-di-O-iso-
propylidene-a-D-galacto-non-1,5-pyranose 6
phy (chloroform/methanol = 80/20) afforded 1b (0.056 g,
25
82%) as a thick liquid; Rf = 0.4 (methanol); ½aꢀD ¼ þ90:9
To a solution of oxalyl chloride (0.033 g, 0.26 mmol) in
CH2Cl2 (2 mL) at ꢁ78 ꢁC was added DMSO (0.04 g,
0.51 mmol) and the mixture was stirred for 15 min. A solu-
tion of alcohol 5a/5b (0.1 g, 0.23 mmol) in CH2Cl2 (3 mL)
was added, and the mixture was stirred at ꢁ78 ꢁC for an
additional 1 h. Triethylamine (0.12 g, 1.1 mmol) was
added, and the mixture was allowed to warm to room
temperature. Usual work-up followed by purification by
(c 0.11, MeOH); IR (Neat) 3429–3230 cmꢁ1
;
1H
NMR (300 MHz, D2O) d 1.95 (dt, J = 13.5, 6.9 Hz, 1H,
H-1a), 2.14 (ddd, J = 13.5, 7.2, 3.9 Hz, 1H, H-1b), 2.46–
2.62 (m, 2H, H-3a, H-5a), 2.81 (apparent q, J = 8.4 Hz,
1H, H-9a), 3.31 (dd, J = 12.9, 6.6 Hz, 1H, H-5b), 3.38
(dd, J = 11.4, 5.4 Hz, 1H, H-3b), 3.54 (dd, J = 9.0,
6.0 Hz, 1H, H-9), 3.82–3.92 (m, 2H, H-7, H-8), 4.0 (appar-
ent q, J = 6.8 Hz, 1H, H-6), 4.26–4.42 (m, 1H, H-2). The

O. P. Bande et al. / Tetrahedron: Asymmetry 18 (2007) 1176–1182
1181
assignments of the signals were confirmed by decoupling
experiments. 13C NMR (75 MHz, D2O); d 40.5 (C-1),
59.9 (C-3), 63.9 (C-5), 67.6 (C-9a), 68.7, 68.9 (C-2, C-6),
74.8, 75.4, 75.7 (C-7, C-8, C-9). Anal. Calcd for
C9H17NO5: C, 49.31; H, 7.82. Found: C, 49.51; H, 8.01.
21/2005) and UGC, New Delhi, for the grant to purchase
the high-field (300 MHz) NMR facility.
References
4.9. (2R,6S,7R,8S,9R,9aR)-2,6,7,8,9-Penta-acetoxy-perhy-
droazaazulene 8a
1. (a) Elbein, A. D.; Molyneux, R. J. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley-Inter-
science: New York, 1987; Vol. 5; (b) Howard, A. S.; Michael,
J. P. In The Alkaloids; Brossi, A., Ed.; Academic Press: New
York, 1986; Vol. 28, Chapter 3; (c) Michael, J. P. Nat. Prod.
Rep. 1990, 9, 485–523.
To an ice-cooled solution of 1a (0.04 g, 0.18 mmol) in dry
pyridine (0.649 g, 8.2 mmol) were added acetic anhydride
(1.65 g, 16 mmol), DMAP (0.0021 g, 0.018 mmol) and the
mixture was stirred for 12 h at room temperature. The
reaction was decomposed with cold water (2 mL), followed
by the usual work-up and further purification by column
chromatography (n-hexane/ethyl acetate = 90/10) afforded
2. (a) Zho, H.; Hans, S.; Cheng, X.; Mootoo, D. R. J. Org.
Chem. 2001, 66, 1761–1767; (b) Svansson, L.; Johnston, B.
D.; Gu, J.-H.; Patrik, B.; Pinto, B. M. J. Am. Chem. Soc.
2000, 122, 10769–10775; (c) Izquiedro, I.; Plaza, M. T.;
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A.; Henderson, I.; Pan, Y. T.; Elbein, A. D. J. Org. Chem.
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Schmidt, D. D.; Wingender, W. Angew. Chem. 1981, 20, 744–
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Tyler, P. C.; Hartley, O.; Winchester, B. G. Tetrahedron 1997,
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penta-acetate 8a (0.06 g, 77%) as a thick liquid; Rf = 0.25
25
(n-hexane/ethyl acetate = 6/4); ½aꢀD ¼ þ208 (c 1.05,
CHCl3); IR (Nujol) 1732 cmꢁ1 1H NMR (300 MHz,
;
CDCl3) d 1.92–2.16 (m, 16H, CH3), 2.44–2.51 (m, 2H, H-
1b, H-5a), 2.53–2.63 (m, 2H, H-3a, H-9a), 3.40 (d,
J = 10.8 Hz, 1H, H-3b), 3.60 (dd, J = 13.2, 6.3 Hz, 1H,
H-5b), 5.0 (dd, J = 9.0, 6.0 Hz, 1H, H-9), 5.20 (t,
J = 4.5 Hz, 1H, H2), 5.39–5.78 (m, 3H, H-6, H-7, H-8);
13C NMR (75 MHz, CDCl3); d 20.8(s), 20.8, 21.8 (CH3),
31.8 (C-1), 55.1, 61.4, 65.0 (C-3, C-5, C-9a), 69.6, 72.1,
72.6, 73.1, 75.0 (C-2, C-6, C-7, C-8, C-9), 169.2, 169.3(s),
169.5, 170.6 (C@O); Anal. Calcd for C19H27NO10: C,
53.14; H, 6.34. Found: C, 53.40; H, 6.60.
4. Humphries, M. J.; Matsumoto, K.; White, S. L.; Olden, K.
Cancer Res. 1986, 46, 5215–5222.
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acher, T. W. Proc. Nat. Acad. Sci. 1988, 85, 9229–9233; (b)
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Krieger, M.; Rosen, C.; Rohrschneider, L.; Haseltine, W. A.;
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4.10. (2S,6S,7R,8S,9R,9aR)-2,6,7,8,9-Penta-acetoxy-perhy-
droazaazulene 8b
Compound 1b (0.028 g, 0.126 mmol) was treated with dry
pyridine (0.45 g, 5.74 mmol), acetic anhydride (1.15 g,
11.2 mmol), and DMAP (0.0015 g, 0.012 mmol) as
described in the synthesis of 8a. Further purification by
column chromatography (n-hexane/ethyl acetate = 85/15)
afforded 8b (0.045 g, 83%) as a thick liquid; Rf = 0.29 (n-
25
hexane/ethyl acetate = 6/4); ½aꢀD ¼ þ324:3 (c 0.0185,
CHCl3); IR (Neat) 1738 cmꢁ1
;
1H NMR (300 MHz,
CDCl3) d 1.88–2.10 (m, 1H, H-1a), 2.04 (s, 3H, CH3),
2.05 (br s, 6H, CH3), 2.07 (s, 3H, CH3), 2.08 (s, 3H,
CH3), 2.10–2.18 (m, 1H, H-1b), 2.54–2.74 (m, 2H, H-3a,
H-5a), 2.88 (apparent q, J = 8.4 Hz, 1H, H-9a), 3.30 (dd,
J = 13.2, 6.3 Hz, 1H, H-5b), 3.59 (dd, J = 10.8, 5.4 Hz,
1H, H-3), 4.86 (dd, J = 8.7, 6.3 Hz, 1H, H-9), 5.02–5.18
(m, 2H, H-6), 5.26 (dd, J = 6.3, 2.0 Hz, 1H, H-8), 5.32
(dd, J = 6.6, 2.0 Hz, 1H, H-8); 13C NMR (75 MHz,
CDCl3) d 20.7, 20.7, 20.8, 20.8, 21.0 (CH3), 38.3 (C-1),
56.4, 61.9, 65.3 (C-3, C-5, C-9a) 69.9, 72.3(s), 72.6, 74.4
(C-6, C-7, C-8, C-9, C-2), 169.1, 169.3, 169.3, 169.4,
170.1 (C@O). Anal. Calcd for C19H27NO10: C, 53.14; H,
6.34. Found: C, 53.28; H, 6.58.
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Acknowledgements
We are grateful to Professor M. S. Wadia for helpful dis-
cussions. O.P.B. is thankful to CSIR, New Dehli, for the
Junior Research Fellowship. We gratefully acknowledge
DST (New Delhi), for the financial support (SR/S1/OC-

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