Synthesis of hybrids of d-glucose and d-galactose with 1-deoxynojirimycin analogues using ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2008.01.005

Four hybrids of azasugars with d-glucose and d-galactose have been synthesized from 3-nitro-2,3-unsaturated-O-glycosides. All the hybrid molecules showed moderate activity against β-galactosidase, the one derived from d-glucose and 1,4-dideoxygulonojirimy

Full text of DOI:10.1016/j.tet.2008.01.005

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 2379e2390
www.elsevier.com/locate/tet
Synthesis of hybrids of D-glucose and D-galactose with 1-deoxynojirimycin
analogues using ring-closing metathesis
*
Amit Kumar, Girish K. Rawal, Yashwant D. Vankar
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 21 September 2007; received in revised form 7 December 2007; accepted 3 January 2008
Available online 5 January 2008
Abstract
Four hybrids of azasugars with D-glucose and D-galactose have been synthesized from 3-nitro-2,3-unsaturated-O-glycosides. All the hybrid
molecules showed moderate activity against b-galactosidase, the one derived from D-glucose and 1,4-dideoxygulonojirimycin 18, and 26, which
is a hybrid of D-glucose and 1,4-dideoxymannohomonojrimycin, showed selectivity toward a-glucosidase and b-galactosidase, respectively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: RCM; Diastereoselective hydroxylation; Stereoselective nucleophilic addition
1. Introduction
improved properties.10 In view of this, we have recently re-
ported11 the synthesis of new hybrid molecules made up of
1-deoxynojirimycin analogues and D-glucose and D-galactose
and reported their glycosidase inhibitory properties. In these
hybrid molecules, the anomeric carbon was a part of the bicy-
clic system and thus was not free. In designing glycosidase in-
hibitors the mimicking of charge and geometry of the
transition states involved in the mechanism of glycosidase in-
hibition have been addressed seriously.3 It could thus be of in-
terest to study the glycosidase inhibitory properties of hybrid
molecules made up of 1-deoxynojirmycin analogues and D-
glucose and D-galactose with an alkoxy group being present
at the anomeric carbon. Recently, Jenkins and co-workers12 re-
ported the syntheses of aza-heteroannulated sugars, which are
hybrids of D-glucose and azepanes akin to 1-deoxyhomonojir-
imycin analogues,12a and hybrids of D-glucose and pyrrolidine
derivatives bearing a methoxy group at the anomeric car-
bons.12b In view of the importance of 1-deoxynojirmycin9
and our own interest in the chemistry of aliphatic nitro com-
pounds especially that of carbohydrate based,11,13 we hereby
report the synthesis and biological evaluation of four new
hybrid molecules made up of D-glucose and D-galactose, and
1-deoxynojirmycin analogues.
Carbohydrate processing enzymes viz. glycosidases and
glycosyl transferases are involved in the biosynthesis of glyco-
conjugates, which play important roles1 in many cellular
functions such as cellecell adhesion, cell differentiation, rec-
ognition of microorganisms, etc. via carbohydrateecarbohy-
drate and carbohydrateeprotein interactions. These cellular
functions and related diseases could be controlled2 by inhibit-
ing the carbohydrate processing enzymes. As a result,
development of glycosidase inhibitors has become3 an active
area of research and a number of useful inhibitors have been
developed and marketed against diseases such as type II
diabetes,4 influenza,5 and Gaucher’s disease.6 In addition, ef-
forts in developing glycosidase inhibitors against cancer,7
HIV,8 and other diseases have also been reported. Among
many glycosidase inhibitors, azasugars such as nojirimycin,
1-deoxynojirimycin, and their analogues have received a large
attention.9
Further, hybrid molecules, which are generally made up of
either natural products or a combination of a natural product
and synthetic compounds are known to have altered or
A general retrosynthetic analysis for the synthesis of these
new hybrid molecules is presented in Scheme 1, which
* Corresponding author. Fax: þ91 512 259 0007.
E-mail address: vankar@iitk.ac.in (Y.D. Vankar).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.005

2380
A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
indicates the importance of 3-nitro-2,3-unsaturated glycosides
and ring-closing metathesis in our synthetic endeavors. The
synthesis begins with the elaboration of methyl 4,6-O-benzyl-
idine-2,3-dideoxy-3-nitro-a and b-D-erythro-hex-2-enopyra-
nosides 1.14
from the same side of the methoxy group, most likely because
of the formation of the five membered transition state (Fig. 1).
This result is opposite to that of the literature report,16
where attack of the Gilman reagent on 3-nitro-2,3-unsaturated
glycosides occurs from the side opposite to the anomeric
eOCH3 group mainly on the basis of steric factors. On the
other hand, in the present case it appears that the polarized
species CH2]CHMgBr coordinates with the eOCH3 group
as shown in Figure 2 leading to the observed product. Reduc-
tion of 2 with LiAlH4 followed by protection of the free amine
as NHBoc group gave a 1:1 mixture of two isomers 3a and 3b
in 80% yield, which could be readily separated by column
chromatography. Clearly, epimerization of 2 had occurred
even under mild conditions (ꢀ10 ꢁC to room temperature).
The structures of 3a and 3b were confirmed by 1H NMR spec-
troscopic analysis, COSY, and NOE interaction experiments.
Thus, NOE interactions were observed between H-3 and
H-1 in 3b with J3,4¼9.76 Hz indicating that H-3 and H-4 are
diaxially oriented, which was not the case with 3a. Both the
isomers 3a and 3b underwent smooth allylation with allyl
bromide in the presence of NaH to give dienes 4a and 4b in
87% and 94% yields, respectively.
O
OCH3
H
O
OCH3
H
O
OCH3
H
OH
O
O
HO
HO
Ph
O
Ph
O
OAc
OAc
H
H
H
BocN
BocN
HN
OH
n
n
n
O
OCH3
H
O
OCH3
O
O
Ph
O
n
H
Ph
O
N
NO2
1
Boc
Scheme 1.
2. Results and discussions
Ring-closing metathesis of diene 4b by using the second
generation Grubbs catalyst B17 gave the expected bicyclic
compound 5 in 85% yield. However, compound 4a failed to
undergo metathesis reaction under varying conditions, most
probably because of the trans diaxial orientation of the two di-
ene moieties. We, therefore, proceeded further with compound
5 whose dihydroxylation with OsO4/N-methylmorpholine
N-oxide (NMO) gave diol 6 in 85% yield and its acetylation
gave the diacetate 7 in 86% yield. The cis dihydroxy groups
were found to have a-geometry as revealed by 1H NMR
and NOE spectroscopic analyses15 of the corresponding
Treatment of 3-nitrosugar derivative 114 (Scheme 2) with
vinyl magnesium bromide gave 2 as a single product in 73%
yield as confirmed from its 1H NMR and COSY spectral
data15 and the stereochemistry of 2 was confirmed by NOE in-
teraction experiments. Thus, irradiation of H-1 enhances the
peaks corresponding to H-2, H-3, and H-5 while no NOE cor-
relation was observed between H-2 and H-4. Further, the
values of J1,2¼1.96 Hz and J2,3¼5.36 Hz revealed that a cis
(axialeequatorial) relationship exists between these hydro-
gens. It is clear that attack of the nucleophile takes place
O
3
OCH3
O
OCH3
CH2=CHMgBr, THF,
5
1
O
OCH3
O
O
O
1. LiAlH4, THF, 0 °C-RT
2. Boc2O, Et3N, CH2Cl2
Ph
O
Ph
O
Ph
O
0 °C - RT, 20 min
73%
R2
NO2
2
R1
NO2
1
3a R1 =H, R2 = NHBoc (39%)
3b R1= NHBoc, R2 = H (41%)
9 O 1 OCH
O
OCH3
B (6 mol%), CH2Cl2
3 1. OsO4, NMO, acetone /
,
O
O
H2O/ tBuOH (1:1: 0.5)
allylbromide, NaH,
DMF, 0 °C- RT, 1h
reflux
7
3
Ph
O
Ph
O
2. Ac2O, Et3N,CH2Cl2,
RT, 4 h
85%
5 h, 85%
R2
R1
BocN
4a R1 = H, R2 = NBocAllyl (87%)
4b R1 = NBocAllyl, R2 = H (94%)
5
9
1
O
7
OCH3
OH
O
N
OCH3
O
OCH3
HO
HO
1. 80% AcOH aq,
reflux, 4 h
AcO
AcO
O
Ac2O, py, 4 h
80%
OAc
OAc
3
OAc
OAc
Ph
O
2. NaOMe, MeOH,
RT, 20 min
N
OH
BocN
H
5
Ac
3. amberlite (H+) resin
9
7
8
OH
OH
N
H
OH
10
Scheme 2.

A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
2381
_
bromide to 1 as observed earlier (vide supra). It is likely
that the relatively bulkier allyl group allows the nucleophile
to attack from the side opposite to the OCH3 group. Reduction
of 20 with LiAlH4 followed by protection of the free amine as
NHBoc gave a 1:1 mixture of two isomers 21a and 21b in 78%
yield that could be readily separated by column chromatogra-
phy. The structures of compounds 21a and 21b were con-
δ
+
δ
MgBr
O
OCH3
O
O
Ph
O
N
+
_
O
Figure 1. Chelation controlled nucleophilic attack on 3-nitro 2,3-unsaturated
glucoside 1.
1
firmed by H NMR spectroscopic analysis, COSY, and NOE
interaction experiments.15
The NHBoc group in 21a is axially oriented and attempted
N-allylation failed under a variety of conditions possibly be-
cause of the steric hindrance. However, compound 21b under-
went smooth allylation with allyl bromide in the presence of
NaH at 0 ꢁC to room temperature over 1 h to give compound
22 in 95% yield. Ring-closing metathesis of diene 22 by using
the first generation Grubbs’ catalyst A17 produced the ex-
pected bicyclic compound 23 in 91% yield. Dihydroxylation
of 23 was carried out with OsO4/N-methylmorpholine N-oxide
(NMO) to form diol 24 in 89% yield, which was converted
into the diacetate 25 by acetylation using Ac2O/Et3N. The
cis dihydroxy groups in 24 were found to have a-geometry
pentaacetate 9, obtained later. Compound 9 showed NOE cor-
relation between H-1, H-2, H-7, and H-9; and H-3, H-4, H-5b,
and H-8.15 Removal of benzylidene and N-Boc protecting
group of diacetate 7 by heating it in 80% aq AcOH for 2 h18
followed by deacetylation under Zamplen condition gave the
desired tetrahydroxy compound 8, which represents a hybrid
of D-glucose and 1,4-dideoxymannonojirimycin 10 and was
characterized as the corresponding acetyl derivative 9.
Similarly, the isomeric 3-nitroglucal derivative14 11
(Scheme 3), having the anomeric eOCH3 group in a orienta-
tion, was also transformed into a bicyclic compound 18, a
hybrid of D-glucose and 1,4-dideoxygulonojirimycin 19.
Interestingly, the direction of the addition of vinyl magnesium
bromide was again dependent on the geometry of the eOCH3
group at the anomeric carbon. Thus, adduct 12 was obtained as
a single product in 75% yield whose structure was confirmed
1
as revealed by H NMR and NOESY spectroscopic analyses
of the corresponding pentaacetate 26a. For compound 26a,
in its NOESY spectrum, strong crosspeaks were observed be-
tween H1eH3a, H3beH2, H2eH4, and H4eH5, which con-
firmed the structure assigned to it as shown in Figure 2.
Compound 26 represents a hybrid of D-glucose and 1,4-di-
deoxymannohomonojirimycin (26b).
Similarly, 3-nitrogalactal derivative14 27 (Scheme 5) was
also transformed into a bicyclic compound 34, which is a hy-
brid of D-galactose and 1,4-dideoxygulohomonojirimycin 35a
by following the same reaction sequence as shown in Scheme
4. Spectroscopic details of all the compounds are given in Sup-
plementary data.
The hybrid azasugars 8, 18, 26, and 34 were evaluated for
inhibition activity toward a few commercially available glyco-
sidases20 at millimolar concentration (Table 1). All the hybrid
molecules 8, 18, 26, and 34 showed reasonable inhibition
against b-galactosidase (entry 4). However, compound 18
showed specific inhibition of a-glucosidase (entry 1) whereas
26 inhibited b-galactosidase (entry 4).
1
by H NMR spectral data and NOE experiments.
Thus, NOE interactions between H-4 and H-2 in 12, and the
values of J1,2¼3.16 Hz and J2,3¼10.52 Hz revealed a (equator-
ialeaxial) relationship between H-1 and H-2 and trans diaxial
relationship between H-2 and H-3. Reduction of 12 followed
by protection of free amine as eNHBoc gave two isomers
13a and 13b in 1:1.3 ratio. The isomer 13b underwent smooth
allylation with allyl bromide in the presence of NaH to give
diene 14 in 87% yield whereas the isomer 13a failed to un-
dergo allylation. Diene 14 was then converted to the desired
hybrid bicyclic molecule 18, which was characterized as its
pentaacetate 18a, by following the same reaction sequence
as described in Scheme 1. Details of the experiments leading
to 18 are given in Supplementary data.
A hybrid molecule containing higher homologue of the 1-
deoxynojirimycin was prepared from 3-nitroglucal 1 (Scheme
4) as well as from the corresponding 3-nitrogalactal derivative
27 (Scheme 5). Treatment of 1 (Scheme 4) with allyl magne-
sium chloride gave a single product 20 in 69% yield. Surpris-
ingly, addition of the Grignard reagent takes place from the
direction opposite to the anomeric methoxy group,19 in con-
trast to the direction of the addition of vinyl magnesium
3. Conclusion
We have synthesized four novel hybrids of D-glucose as
well as D-galactose and 1-deoxynojirimycin analogues starting
from 3-nitro-2,3-unsaturated glycosides, which act as moder-
ate glycosidase inhibitors. It is likely that structural variations
of these hybrid molecules could lead to better/altered glycosi-
dase inhibitions.
H
H3CO
O
H
H
1
H
H
OAc
OAc
4. Experimental
3
5
H
9
7
N
11
4.1. General
Ac
H
OAc
OAc
26a
Figure 2. NOEs observed in compound 26a.
1
The H NMR, NOE, and 13C NMR spectra were recorded
on JEOL-JNM 400 MHz and 100 MHz spectrometers,

2382
A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
O
OCH3
O
OCH3
CH2=CHMgBr, THF,
O
OCH3
O
O
O
1. LiAlH4, THF, 0 °C-RT
Ph
O
Ph
O
2. Boc2O, Et3N, CH2Cl2
83%
Ph
O
0 °C - RT, 20 min
75%
R2
R1
NO2
12
NO2
13a R1 = H, R2 = NHBoc (35%)
13b R1= NHBoc, R2 = H (48%)
11
OCH3
O
O
O
N
OCH3 1. OsO4, NMO, acetone /
O
allylbromide, NaH,
B (2mol%), CH2Cl2,
H2O/ tBuOH (1:1: 0.5)
13b
DMF, 0 °C- RT, 1h
87%
Ph
O
Ph
O
2. Ac2O, Et3N,CH2Cl2,
RT, 4 h
83%
reflux
92%
NH
Boc
Boc
15
14
O
N
OCH3
1. 80% AcOH aq,
reflux, 4 h
O
OCH3
O
N
OCH3
OAc
HO
HO
AcO
O
Ac2O, py, 4h
78%
OH
OH
OAc
OAc
2. NaOMe, MeOH,
RT, 20 min
AcO
Ph
O
N
OAc
3. amberlite (H+) resin
70%
H
Ac
Boc
17
18a
18
OH
H
OH
N
H
H
OH
19
Scheme 3.
respectively. The chemical shift values are reported in parts
per million using CDCl3 as internal reference. All reactions
were carried out using freshly distilled and dry solvents. Col-
umn chromatography was performed over silica gel (100e200
mesh) using hexane and ethyl acetate as eluent. The separation
of isomers was performed on Chromatotron using plates
coated with silica gel PF254 (E-Merck, Germany). Rotation
values were recorded on Autopol II automatic polarimeter at
the wavelength of sodium D-line (589 nm) at 25 ꢁC. Elemental
analyses were carried out on a Thermoquest CE-instruments
EA-1110 C, H, N, S analyzer. Melting points were determined
using a FischereJohn melting point apparatus. The mass
O
OCH3
O
OCH3
O
O
1. LiAlH4, THF, 0 °C-RT
2. Boc2O, Et3N, CH2Cl2
CH2=CHCH2MgCl, THF,
1
0 °C - RT, 30 min
69%
Ph
O
Ph
O
R2
R1
NO2
21a R1 = H, R2 = NHBoc (35%)
21b R1 = NHBoc, R2 = H (38%)
20
O
N
OCH3
O
OCH3
1
O
11
O
O
allyl bromide, NaH,
A (5 mol%), CH2Cl2,
21b
9
Ph
O
DMF, 0 °C- RT, 1h
95%
Ph
reflux
91%
3
7
N
5
Boc
Boc
23
22
OCH3
O
OCH3
O
HO
HO
1. OsO4, NMO, acetone /
H2O/ tBuOH (1:1: 0.5)
1. 80% AcOH aq,
O
reflux, 4 h
Ph
O
2. NaOMe, MeOH,
RT, 20 min
2. Ac2O, Et3N,CH2Cl2,
N
N
OH
OH
OAc
RT, 4 h
90%
H
Boc
3. amberlite (H+) resin
OAc
3
24: R3 = H
25: R = Ac
26
O
N
OCH3
OH
OH
AcO
AcO
H
H
Ac2O, py, 4h
81%
N
H
OAc
OAc
Ac
OH
26b
Scheme 4.
26a

A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
2383
O
OCH3
CH2=CHCH2MgCl,
O
OCH3
1. LiAlH4, THF, 0 °C-RT
O
OCH3
O
O
O
Ph
O
Ph
O
Ph
O
2. Boc2O, Et3N, CH2Cl2
THF, -60 °C - RT, 3 h
73%
R2
NO2
NO2
R1
29
82%
27
28
29a R1 = NHBoc, R2 = H
29b R1 = H, R2 = NHBoc
O
N
OCH3
O
OCH3
O
O
A (6 mol%), CH2Cl2,
reflux 92%
allyl bromide, NaH,
DMF, 0 °C- RT, 1h
94%
29a
Ph
O
Ph
O
O
NH
Boc
Boc
31
30
O
OCH3
O
N
OCH3
HO
HO
1. 80% AcOH aq,
reflux, 4 h
1. OsO4, NMO, acetone /
H2O/ tBuOH (1:1: 0.5)
Ph
O
2. NaOMe, MeOH,
RT, 20 min
2. Ac2O, Et3N,CH2Cl2,
N
OH
OH
OAc
H
RT, 2 h
Boc
3. amberlite (H+) resin
83%
OAc
76%
33
34
O
OCH3
OH
OH
H
AcO
AcO
Ac2O, py, 2h
78%
N
H
N
H
OAc
OAc
OH
Ac
35a
35
Scheme 5.
spectra were recorded on a Micromass Quattro II Triple Quad-
rupole Mass Spectrometer.
(1 mmol) in THF (5 mL). The reaction mixture was slowly
brought to room temperature and stirred for 0.5e1.5 h. The
reaction mixture was cooled to 0 ꢁC, treated with EtOAc
(2 mL) and water (3 mL), and neutralized with 1 N NaOH
and stirred for 1 h. The resulting white precipitate was re-
moved by filtration through a Celite pad and the filtrate was
extracted with ethyl acetate (3ꢂ20 mL). The organic layer
was washed with brine and dried over anhydrous Na2SO4. Re-
moval of the solvent gave a crude amine, which was dissolved
in dichloromethane (5 mL) and treated with Et3N (0.18 mL,
1.3 mmol) and (Boc)2O (216 mg, 1.2 mmol) at room temper-
ature and then the mixture was stirred for 3 h. The reaction
mixture was extracted with dichloromethane (3ꢂ20 mL) and
organic layer was washed with water and brine. Usual
work up gave a crude product, which was purified by column
chromatography gave the two separable isomers in equal
ratio.
4.1.1. General procedure (A): vinylation and allylation of
3-nitro-2,3-glycals
To a stirred solution of a 3-nitro-glycal derivative 1 or 11
(1 mmol) in THF (4 mL) at ꢀ10 ꢁC was added dropwise vinyl
magnesium bromide (1.5 mmol) or allyl magnesium chloride
(2 mmol). The reaction was slowly brought to room tempera-
ture for 1 h and after completion of reaction (TLC monitor-
ing), the reaction mixture was quenched with saturated aq
NH4Cl and extracted with ethyl acetate (2ꢂ50 mL). The or-
ganic layer was washed with brine, dried over anhydrous
Na2SO4, and concentrated to obtain a crude product, which
was purified by column chromatography.
4.1.2. General procedure (B): reduction of the nitro group
using lithium aluminum hydride
To a suspension of LiAlH4 (76 mg, 2 mmol) in THF at
0 ꢁC was added dropwise a solution of a nitro compound
4.1.3. General procedure (C): N-allylation of Boc protected
amine
To a stirred solution of Boc protected amine (1 mmol) in
dry DMF at 0 ꢁC were added allyl bromide (144 mg,
1.22 mmol) and NaH (72 mg, 3.06 mmol). The reaction mix-
ture was stirred for 1 h at 0 ꢁC and after completion of reac-
tion (TLC monitoring) it was quenched with saturated aq
NH4Cl and extracted with diethyl ether (3ꢂ20 mL). The ex-
tract was washed with water and brine, and dried over anhy-
drous Na2SO4. Evaporation of the solvent gave a crude
product, which was purified by column chromatography to
give diene.
Table 1
IC50 (mM) values for compounds 8, 18, 26 and 34a
Entry
Enzyme
8
18
26
34
1
2
3
4
a
a-Glucosidase (rice)
NI
NI
3.3
NI
NI
8.5
NI
NI
NI
NI
NI
8.5
b-Glucosidase (almonds)
a-Galactosidase (coffee beans)
b-Galactosidase (bovine liver)
NI
4.68
NI
4.68
Inhibition studies were carried out at millimolar concentration, optimal pH
of the enzymes, and 37 ꢁC. NIe no inhibition at 5 mM concentration of the
inhibitor.

2384
A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
4.1.4. General procedure (D): for ring-closing metathesis of
diene
d 7.44e7.35 (m, 5H, AreH), 5.89 (ddd, 1H, J¼17.0, 10.2,
3.1 Hz, eCH]CH2), 5.56 (s, 1H, PheCH), 5.33e5.15 (br
dd, 2H, J¼17.0, 10.2 Hz, eCH]CH2), 4.82 (dd, 1H,
J¼10.5, 5.3 Hz, H-3), 4.65 (d, 1H, J¼2.0 Hz, H-1), 4.44 (dd,
1H, J¼10.5, 4.6 Hz, H-6e), 4.34 (t, 1H, J¼10.7 Hz, H-4),
3.95 (t, 1H, J¼10.2 Hz, H-6a), 3.54 (s, 3H, OMe), 3.52e3.49
(m, 1H, H-5), 3.32e3.29 (m, 1H, H-2). 13C NMR (100 MHz,
CDCl3): d 136.4, 129.2, 128.2, 127.8, 125.9, 122.6, 102.5,
101.7, 86.0, 74.1, 68.6, 67.3, 57.5, 49.9. ESMS: m/z 344
[MþNa]þ. Anal. Calcd for C16H19NO6 (321.12): C, 59.81;
H, 5.96; N, 4.36. Found: C, 60.10; H, 5.98; N, 4.39.
To a stirred solution of a diene (0.928 mmol) in dry CH2Cl2
(15 mL) at room temperature was added Grubbs’ catalyst A or
B (42 mg, 0.055 mmol). The reaction mixture was stirred at
same temperature for 4e6 h and after completion of reaction
(TLC monitoring), the solvent was evaporated and the crude
product was purified by column chromatography to give cy-
clized product.
4.1.5. General procedure (E): dihydroxylation using OsO4/
NMO
To a stirred solution of an olefin (0.54 mmol) in acetone/
water/tert-butanol (1:1:0.4) at room temperature were added
NMO$H2O (0.67 mmol) and OsO4 (0.002 equiv). The reaction
mixture was stirred for 12e14 h (monitored by TLC) and it
was treated with Na2S2O5 (228 mg, 0.67 mmol). The reaction
mixture was further stirred for 1 h and extracted with EtOAc
(2ꢂ30 mL). The organic layer was washed with 1 N HCl, wa-
ter, and finally with brine. Usual work up gave a crude prod-
uct, which was purified by column chromatography.
4.1.8.2. tert-Butyl(2R,4aR,6R,7S,8S,8aS)-6-methoxy-2-phenyl-
7-vinylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (3a).
Nitro olefins 2 were reduced to amino olefins 3a and 3b
using the general procedure (B) and purified over silica gel
column chromatography. Yield: 39% (colorless solid, mp
212e214 ꢁC). [a]D28 ꢀ31.7 (c 0.85, CH2Cl2). IR (CH2Cl2)
nmax: 1527, 1680 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
d
7.48e7.34 (m, 5H, AreH), 6.10e6.01 (m, 1H,
eCH]CH2), 5.58 (s, 1H, PheCH), 5.34 (dd, 1H, J¼18.5,
10.0 Hz, eCH]CH2), 5.32e5.21 (m, 1H, eCH]CH2),
4.89 (br s, 1H, NH), 4.77 (d, 1H, J¼2.2 Hz, H-1), 4.39 (dd,
1H, J¼10.0, 4.36 Hz, H-6e), 3.98 (br s, 1H, H-3), 3.89 (dd,
1H, J¼4.1, 9.5 Hz, H-4), 3.78 (t, 1H, J¼10.0 Hz, H-6a),
3.71 (dd, 1H, J¼9.5, 4.1 Hz, H-5), 3.51 (s, 3H, OMe),
3.32e3.24 (m, 1H, H-2), 1.41 (s, 9H, tert-butyl). 13C NMR
(100 MHz, CDCl3): d 155.9, 134.1, 132.8, 129.8, 128.3,
126.1, 119.3, 101.9, 101.1, 74.7, 69.4, 65.3, 57.2, 52.1, 48.0,
29.7, 28.3. MSES: m/z 414 [MþNa]þ. Anal. Calcd for
C21H29NO6 (391.20): C, 64.43; H, 7.47; N, 3.58. Found: C,
64.34; H, 7.50; N, 3.62.
4.1.6. General procedure (F): acetylation of diol
A stirred solution of a diol (l mmol) in dry CH2Cl2 (5 mL)
was treated with Et3N (0.34 mg, 2.5 mmol), acetic anhydride
(275 mg, 2.7 mmol), and catalytic amount of DMAP. The re-
action mixture was stirred for 3 h and after completion of re-
action (TLC monitoring) it was extracted with ethyl acetate
(2ꢂ10 mL). The organic phase was washed with 1 N HCl, wa-
ter, and finally with brine. Usual work up gave a crude prod-
uct, which was purified by column chromatography to give
diacetate.
4.1.7. General procedure (G): for benzylidene, N-Boc, and
acetyl group deprotection
4.1.8.3. tert-Butyl(2R,4aR,6R,7S,8R,8aS)-6-methoxy-2-phenyl-7-
vinylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (3b).
The procedure followed was identical with that described
for the preparation of 3a to give compound 3b. Yield: 41%
(colorless solid, mp 205e207 ꢁC). [a]D28 ꢀ53.3 (c 0.15,
A solution of a diacetate (1 mmol) in 80% aq AcOH
(10 mL) was kept for 4 h at 80e90 ꢁC. After cooling, the mix-
ture was evaporated and the evaporation was repeated azeo-
tropically with ethanol, toluene, and ethanol. Deacetylation
of this crude compound was done under Zamplen condition
(NaOMe in MeOH) at room temperature, which was filtered
through Amberlite (Hþ) ion exchange resin for the enzyme in-
hibition studies.
CH2Cl2). IR (CH2Cl2) nmax: 1530, 1685 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) (mixture of rotamers): d 7.48e7.34 (m,
10H, AreH both rotamer), 5.84e5.98 (m, 2H, eCH]CH2,
both rotamer), 5.52 (s, 1H, PheCH, for minor), 5.48 (s, 1H,
PheCH, for major), 5.42e5.21 (m, 4H, eCH]CH2, both ro-
tamer), 4.65 (d, 1H, J¼1.96 Hz, H-1 major), 4.60 (d, 1H,
J¼2.2 Hz, H-1 minor), 4.32 (dd, 1H, J¼10.4 Hz, H-6e),
4.13e4.05 (m, 1H, H-2 minor), 3.88e3.69 (t, 2H,
J¼10.5 Hz, H-4, H-6a), 3.57e3.54 (m, 2H, H-5, H-3), 3.54
(s, 3H, OMe), 3.51 (s, 3H, OMe minor), 3.39 (t, 1H,
J¼9.7 Hz, H-3, minor), 3.10e3.07 (m, 1H, H-2), 1.43 (s,
9H, tert-butyl, major), 1.42 (s, 9H, tert-butyl, minor). 13C
NMR (100 MHz, CDCl3): d 155.2, 137.0, 136.3, 134.4,
130.8, 130.5, 130.1, 129e128 (m, aromatic), 126.0, 122.1,
121.8, 121.5, 103.5, 103.3, 102.9, 102.7, 83.7, 80.7, 79.5,
77.5, 77.3, 75.9, 69.8, 68.5, 65.1, 62.6, 61.0, 57.0, 54.1,
52.0, 49.5, 47.6, 28.2, 27.6, 27.6. MSES: m/z 414 [MþNa]þ.
Anal. Calcd for C21H29NO6 (391.20): C, 64.43; H, 7.47; N,
3.58. Found: C, 64.36; H, 7.50; N, 3.60.
4.1.8. General procedure (H): for acetylation
Acetylation of the tetrahydroxy compound was done using
pyridine and acetic anhydride (1:1, 2 mL) at room temperature
for 10 h. Usual work up followed by column chromatography
gave the pure pentaacetate.
4.1.8.1. (2R,4aR,6R,7S,8R,8aS)-6-Methoxy-8-nitro-2-phenyl-
7-vinylhexahydropyrano[3,2-d][1,3]dioxine (2). Methyl 4,6-
O-benzylidene-2,3-dideoxy-3-nitro-b-glucopyranoside
was
vinylated using the general procedure (A) and purified over silica
gel column chromatography. Yield: 73% (colorless solid, mp
197e198 ꢁC). [a]D28 ꢀ98.7 (c 2.3, CH2Cl2). IR (CH2Cl2)
nmax: 1557, 1642 cmꢀ1
.
1H NMR (400 MHz, CDCl3):

A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
2385
4.1.8.4. tert-Butylallyl((2R,4aR,6R,7S,8S,8aS)-6-methoxy-2-
phenyl-7-vinylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)carba-
mate (4a). Amino olefin 3a was N-allylated using the general
procedure (C) to give 4a (87%) as a colorless oil. Yield: 85%
(colorless oil). [a]D28 ꢀ58.4 (c 0.65, CH2Cl2). IR (CH2Cl2)
both rotamer), 1.46 (s, 9H, tert-butyl, rotamer-1), 1.37 (s,
9H, tert-butyl, rotamer-2). 13C NMR (100 MHz, CDCl3):
d 155.2, 137.2, 128.1e125.3 (m, aromatic), 122.1, 121.6,
102.7, 102.6, 101.7, 101.1, 80.0, 74.1, 68.7, 68.2, 67.9, 57.2,
51.8, 50.3, 41.1, 40.6, 40.4, 40.3, 28.2. MSES: m/z 426
[MþNa]þ. Anal. Calcd for C22H29NO6 (403.20): C, 65.49;
H, 7.24; N, 3.47. Found: C, 65.50; H, 7.50; N, 3.50.
nmax: 1695, 1560 cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
7.53e7.32 (m, 5H, AreH), 5.96e5.81 (m, 2H, eCH]CH2),
5.53 (s, 1H, PheCH), 5.15e4.86 (m, 4H, 2ꢂeCH]CH2),
4.59 (br s, 1H), 4.35 (br s, 1H), 3.84e3.79 (m, 2H), 3.66
(s, 1H), 3.49 (s, 3H, OMe), 3.08e3.06 (m, 2H, allylic),
1.40 (s, 9H, tert-butyl). 13C NMR (100 MHz, CDCl3):
d 155.9, 137.9e125.9 (m, aromatic), 119.0, 117.2, 102.8,
101.6, 101.2, 81.8, 80.1, 74.8, 70.6, 64.3, 56.5, 56.2, 41.9,
28.2, 28.1, 22.5. MSES: m/z 454 [MþNa]þ. Anal. Calcd for
C24H33NO6 (431.23): C, 66.80; H, 7.71; N, 3.24. Found: C,
66.98; H, 7.50; N, 3.20.
4.1.8.7. (7R,8S,8aR)-Diacetoxy-9-methoxy-3-phenyl-octahydro-
2,4,10-trioxa-5-aza-phenanthrene-5-carboxylic acid tert-butyl
ester (7). Diol was acetylated using the general procedure
(F) to give 7 (85%) as colorless solid, mp 220e222 ꢁC.
[a]2D8 ꢀ6.7 (c 0.15, CH2Cl2). IR (CH2Cl2) nmax: 1685 cmꢀ1
.
1H NMR (400 MHz, CDCl3) (mixture of rotamers): d 7.31e
7.45 (m, 10H, AreH, both rotamer), 5.60 (dd, 2H, J¼11.7,
3.4 Hz, H-3, both rotamer), 5.49 (s, 1H, PheCH, major),
5.44 (s, 1H, PheCH, minor), 5.21 (br s, 1H, H-4, minor),
5.09 (br s, 1H, H-4, major), 4.87 (dd, 1H, J¼10.7, 5.1 Hz,
H-10e, minor), 4.83 (s, 2H, H-1, both rotamer), 4.59 (dd,
1H, J¼10.8, 5.3 Hz, H-10e, major), 4.31e4.37 (m, 3H, H-8,
both rotamer and H-7), 4.23 (dd, 1H, J¼15.4, 1.9 Hz, H-50,
major), 3.88e3.78 (m, 4H, H-9 and H-10, both rotamer),
3.53 (m. 2H, H-2, both rotamer), 3.44 (s, 3H, OMe, minor),
3.41(s, 3H, OMe, major), 3.19 (br d, 1H, J¼15.1 Hz, H-2, ma-
jor), 3.08 (br d, 1H, J¼14.8 Hz, H-2, minor), 2.11e1.99 (4ꢂs,
12H, OCOCH3, both rotamer), 1.43 (s, 9H, tert-butyl, major),
1.36 (s, 9H, tert-butyl, minor). 13C NMR (100 MHz, CDCl3):
d 170.0, 169.9, 169.8, 155.1, 154.9, 136.9, 129.0e128.9 (m,
aromatic), 126.1, 126.0, 104.2, 104.1, 101.9, 101.5, 80.6,
80.5, 72.7, 72.6, 69.1, 68.9, 68.7, 68.6, 67.5, 65.3, 65.2,
57.6, 57.5, 53.9, 52.4, 41.8, 40.8, 39.9, 39.7, 31.1, 29.6,
28.2, 28.0, 20.9, 14.1. MSES: m/z 544 [MþNa]þ. Anal. Calcd
for C26H35NO10 (521.23): C, 59.87; H, 6.76; N, 2.69. Found:
C, 60.00; H, 6.80; N, 2.70.
4.1.8.5. tert-Butylallyl((2R,4aR,6R,7S,8R,8aS)-6-methoxy-2-
phenyl-7-vinylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)carba-
mate (4b). Amino olefin 3b was N-allylated using the general
procedure (C) to give 4b (94%) as colorless oil. Yield: 90%.
[a]2D8 ꢀ100.0 (c 0.15, CH2Cl2). IR (CH2Cl2) nmax: 1695,
1560 cmꢀ1 1H NMR (400 MHz, CDCl3) (mixture of ro-
.
tamers): d 7.49e7.34 (m, 10H, AreH both rotamer), 6.00e
5.96 (m, 2H, eCH]CH2), 5.74e5.71 (m, 1H, eCH]CH2,
minor rotamer), 5.49 (s, 1H, PheCH), 5.29e5.13 (dd, 4H,
J¼17.0, 10.2 Hz, 2ꢂeCH]CH2), 5.04e4.88 (dd, 4H,
J¼17.8, 9.0 Hz, 2ꢂeCH]CH2, minor rotamer), 4.66 (br s,
1H), 4.55 (s, 1H, minor rotamer), 4.35e4.28 (m, 3H), 3.87
(m, 4H, both rotamer), 3.68 (br s, 1H, minor rotamer), 3.52
(m, 1H and OMe, both rotamer), 3.11e3.09 (m, 2H, allylic),
1.44e1.42 (s, 9H, tert-butyl, both rotamer). 13C NMR
(100 MHz, CDCl3): d 155.9, 137.9e125.9 (m, Aromatic,
both rotamer), 117.9, 116.9, 115.3, 104.9, 104.5, 100.8, 80.1,
79.8, 68.8, 68.0, 57.0, 56.7, 55.6, 44.4, 43.1, 31.1, 30.8,
28.2. MSES: m/z 454 [MþNa]þ. Anal. Calcd for C24H33NO6
(431.23): C, 66.80; H, 7.71; N, 3.24. Found: C, 66.90; H,
7.50; N, 3.25.
4.1.8.8. (3R,4S,4aR,5R,7R,8S,8aR)-7-(Acetoxymethyl)-1-acetyl-
5-methoxyoctahydro-1H-pyrano[4,3-b]pyridine-3,4,8-triyl tri-
acetate (9). Diacetate was converted to pentaacetate using
the general procedure (G) followed by general procedure (H)
to give 9 (80%) as colorless solid, mp 186e188 ꢁC. [a]D28
4.1.8.6. 9-Methoxy-3-phenyl-1,4a,4b,8a,9,10a-hexahydro-6H-
2,4,10-trioxa-5-aza-phenanthrene-5-carboxylic acid tert-butyl
ester (5). Diene 4b was subjected to ring-closing metathesis
following the general procedure (D) and purified over silica
gel column chromatography. Yield: 85% (colorless oil). [a]D28
ꢀ7.3 (c 0.85, CH2Cl2). IR (CH2Cl2) nmax: 1743, 1653 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 5.56 (dd, 1H, J¼11.7, 3.2 Hz,
H-3), 5.30 (br s, 1H, H-4), 5.16e5.12 (m, 2H, H-8, and H-7),
4.58 (s, 1H, H-1), 4.24 (d, 2H, J¼3.4 Hz, H-10a and H-10e),
3.83 (dd, 1H, J¼15.6, 2.7 Hz, H-50), 3.76 (br s, 1H, H-9), 3.45
(s, 3H, OMe, minor), 3.44 (3H, OMe, major), 2.65 (br d, 1H,
J¼11.7 Hz, H-2), 2.11e1.99 (m, 16H, eOCOCH3, eNCOCH3,
and H-5). 13C NMR (100 MHz, CDCl3): d 170.7e169.6(m),
103.5, 73.3, 67.7, 67.6, 65.0, 64.9, 62.9, 62.4, 57.6, 51.5, 44.4,
39.2, 21.5, 20.9, 20.8. MSES: m/z 482 [MþNa]þ. Anal. Calcd
for C20H29NO11 (459.44): C, 52.28; H, 6.36; N, 3.05. Found:
C, 52.35; H, 6.40; N, 3.10.
ꢀ52.3 (c 0.65, CH2Cl2). IR (CH2Cl2) nmax
:
1685,
1654 cmꢀ1 1H NMR (400 MHz, CDCl3) (mixture of ro-
.
tamers): d 7.46e7.30 (m, 10H, AreH, both rotamer), 6.05
(br t, 2H, J¼9.76 Hz, H-3 both rotamer), 5.86 (br dd, 1H,
J¼8.0, 10.7 Hz, H-4, rotamer-1), 5.79 (br dd, 1H, J¼8.0,
10.7 Hz, H-4, rotamer-2), 5.49e5.47 (2ꢂs, 2H, PheCH, ro-
tamer-1 and -2), 4.74 (dd, 1H, J¼4.8, 9.7 Hz, H-10e, ro-
tamer-1), 4.60 (d, 2H, J¼2.6 Hz, H-1, both rotamer), 4.47
(dd, 1H, J¼10.0, 5.4 Hz, H-10e, rotamer-2), 4.33e4.29 (m,
3H, H-8, both rotamer and H-10a), 4.21 (dd, 2H, H-50, both
rotamer), 3.75e3.66 (m, 3H, H-9, both rotamer and H-7),
3.55 (s, 3H, OMe, rotamer-1), 3.50 (s, 3H, OMe, rotamer-2),
3.45 (dd, 1H, J¼11.2, 5.1 Hz, H-5), 2.95 (br m, 1H, H-5,
4.1.8.9. (2R,4aR,6S,7R,8R,8aS)-6-Methoxy-8-nitro-2-phenyl-7-
vinylhexahydropyrano[3,2-d][1,3]dioxine (12). This com-
pound was prepared in 75% yield from 11 by using the
same procedure as described for 2. Yield: 75% (colorless solid,

2386
A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
mp 176e178 ꢁC). [a]D28 þ63.2 (c 0.15, CH2Cl2). IR (CH2Cl2)
(400 MHz, CDCl3) (mixture of rotamers): d 7.49e7.34 (m,
10H, AreH, both rotamer), 5.81e5.67 (m, 3H, eCH]H2,
both rotamers), 5.41 (s, 1H, PheCH, both rotamers), 5.21e
4.93 (m, 6H, 2ꢂeCH]CH2, both rotamers), 4.68 (br t,
1H, J¼8.1 Hz, minor rotamers), 4.62e60 (m, 2H), 4.27e4.22
(m, 2H), 3.91e3.68 (m, 6H, both rotamers), 3.55e3.47 (m,
1H), 3.48(s, OMe both rotamers), 2.63e2.51 (m, 2H, allylic),
1.44e1.42 (s, 9H, tert-butyl, both rotamer). 13C NMR
(100 MHz, CDCl3): d 156.1, 137.9e125.9 (m, aromatic, both
rotamers), 118.9, 116.9, 114.3, 101.6, 101.1, 80.1, 79.8,
68.8, 68.0, 57.0, 56.7, 55.6, 49.6, 47.4, 44.1, 28.7, 28.2.
MSES: m/z 454 [MþNa]þ. Anal. Calcd for C24H33NO6
(431.23): C, 66.80; H, 7.71; N, 3.24. Found: C, 66.92; H,
7.50; N, 3.21.
1
nmax: 1557, 1642 cmꢀ1. H NMR (400 MHz, CDCl3): d 7.42
(d, 2H, J¼3.4 Hz, AreH), 7.35 (d, 3H, J¼3.1 Hz, AreH),
5.67e5.76 (ddd, 1H, J¼17.1, 7.3, 2.4 Hz, eCH]CH2), 5.57
(s, 1H, PheCH), 5.25 (dd, 2H, J¼9.2, 2.6 Hz, eCH]CH2),
4.98 (t, 1H, J¼10.5 Hz, H-3), 4.7 (d, 1H, J¼3.1 Hz, H-1),
4.3 (dd, 1H, J¼4.3, 10.0 Hz, H-6e), 4.19 (t, 1H, J¼9.7 Hz,
H-4), 3.96 (ddd, 1H, J¼10.0, 9.6, 4.6 Hz, H-5), 3.86 (t, 1H,
J¼10.2 Hz, H-6a), 3.39 (s, 3H, OMe), 3.01 (ddd, 1H,
J¼11.9, 3.2, 3.1 Hz, H-2). 13C NMR (100 MHz, CDCl3):
d 136.4, 130.9, 129.2, 128.2, 126.0, 121.3, 101.3, 100.2,
86.6, 78.3, 68.9, 62.9, 62.2, 55.4, 50.4. MSES: m/z 344
[MþNa]þ. Anal. Calcd for C16H19NO6 (321.12): C, 59.81;
H, 5.96; N, 4.36. Found: C, 60.20; H, 5.97; N, 4.20.
4.1.8.10. tert-Butyl(2R,4aR,6S,7R,8S,8aS)-6-methoxy-2-phenyl-
7-vinylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (13a).
This compound was obtained in 35% yield by following the
general procedure (B): colorless solid, mp 198e200 ꢁC.
[a]2D8 þ17.6 (c 0.15, CH2Cl2). IR (CH2Cl2) nmax: 1530,
4.1.8.13.
9-Methoxy-3-phenyl-1,4a,4b,8a,9,10a-hexahydro-
6H-2,4,10-trioxa-5-aza-phenanthrene-5-carboxylic acid tert-
butyl ester (15). Diene underwent RCM using the general
procedure (D) and purified over silica gel column chromato-
graphy. Yield: 92%. [a]2D8 þ36.0 (c 0.25, CH2Cl2). IR
1685 cmꢀ1. H NMR (400 MHz, CDCl3): d 7.49e7.35 (m,
(CH2Cl2) nmax: 1685, 1654 cmꢀ1 1H NMR (400 MHz,
.
1
5H, AreH), 5.81 (ddd, 1H, J¼16.8, 10.0, 3.2 Hz, eCH]
CH2), 5.53 (s, 1H, PheCH), 5.17 (dd, 2H, J¼10.0, 8.2 Hz,
eCH]CH2), 4.60 (d, 1H, J¼3.4 Hz, H-1), 4.27 (dd, 1H,
J¼4.8, 10.2 Hz, H-6e), 3.92e3.87 (m, 2H, H-4 and H-5),
3.7 (t, 2H, J¼10.4 Hz, H-3 and H-6a), 3.37 (s, 3H, OMe),
1.45e1.43 (m, 1H, H-2), 1.39 (s, 9H, tert-butyl). 13C NMR
(100 MHz, CDCl3): d 155.5, 137.4, 134.8, 128.9, 128.1,
126.1, 118.8, 101.7, 101.4, 79.7, 76.6, 69.1, 63.9, 55.0, 51.2,
29.6, 28.2. MSES: m/z 414 [MþNa]þ. Anal. Calcd for
C21H29NO6 (391.20): C, 64.40; H, 7.47; N, 3.58. Found: C,
64.30; H, 7.50; N, 3.62.
CDCl3): d 7.51e7.34 (m, 5H, AreH), 5.79 (tt, 1H, J¼5.6,
2.6 Hz, H-3), 5.7 (s, 1H, PheCH), 5.6 (br d, 1H, J¼10.0 Hz,
H-4), 4.83 (br s, 1H, H-50), 4.76 (d, 1H, J¼3.9 Hz, H-1),
4.43 (br d, 1H, J¼16.6 Hz, H-5), 4.30 (dd, 1H, J¼16.0,
10.7 Hz, H-10e), 3.85e3.78 (m, 2H, H-8 and H-9), 3.63 (br
d, 1H, J¼4.1, 7.0 Hz, H-10a), 3.57 (br s, 1H, H-7), 3.38 (s,
3H, OMe), 2.87e2.80 (m, 1H, H-2), 1.47 (s, 9H, tert-butyl).
13C NMR (100 MHz, CDCl3): d 154.7, 137.5, 128.8, 128.2,
126.8, 126.0, 124.7, 101.3, 100.2, 80.1, 78.2, 69.1, 65.1,
56.4, 55.1, 47.1, 41.1, 28.5. MSES: m/z 426 [MþNa]þ.
Anal. Calcd for C22H29NO6 (403.20): C, 65.49; H, 7.24; N,
3.47. Found: C, 65.50; H, 7.50; N, 3.50.
4.1.8.11. tert-Butyl(2R,4aR,6S,7R,8R,8aS)-6-methoxy-2-phenyl-
7-vinylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (13b).
Yield: 48% (colorless solid, mp 186e188 ꢁC). [a]D28 þ5.80
4.1.8.14. (7S,8R,8aS)-Diacetoxy-9-methoxy-3-phenyl-octahydro-
2,4,10-trioxa-5-aza-phenanthrene-5-carboxylic acid tert-butyl
ester (17). Diol was acetylated using the general procedure
(F) to give 17 (83%) as colorless solid, mp 208e210 ꢁC.
1
(c 1.55, CH2Cl2). IR (CH2Cl2) nmax: 1530, 1685 cmꢀ1. H
NMR (400 MHz, CDCl3) (mixture of rotamers): d 7.49e7.34
(m, 10H, AreH, both rotamer), 5.79e5.76 (m, 1H, eCH]
CH2, minor rotamers), 5.74e5.67 (m, 1H, eCH]CH2), 5.49
(s, 1H, PheCH), 5.39e5.13 (m, 4H, eCH]CH2, both
rotamer), 4.69e4.67 (m, 2H, minor rotamers), 4.66e4.62 (m,
1H), 4.50e4.47 (m, 2H, both rotamers), 4.35e4.28 (m, 2H,
both rotamer), 3.87e3.70 (m, 4H, both rotamer), 3.52 (s, 6H,
OMe, both rotamers), 3.09e3.06 (m, 1H, allylic, minor
rotamer), 2.63e2.60 (m, 2H, allylic), 1.44e1.42 (s, 9H, tert-
butyl, both rotamers). 13C NMR (100 MHz, CDCl3): d
137.9e125.9 (m, aromatic, both rotamers), 118.9, 101.7,
101.4, 68.8, 63.9, 55.0, 51.0, 30.8, 28.2. MSES: m/z 414
[MþNa]þ. Anal. Calcd for C21H29NO6 (391.20): C, 64.43;
H, 7.47; N, 3.58. Found: C, 64.32; H, 7.50; N, 3.56.
[a]2D8 þ36.42 (c 0.85, CH2Cl2). IR (CH2Cl2) nmax: 1685 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d 7.48e7.34 (m, 5H, AreH),
5.66 (s, 1H, PheCH), 5.20 (br s, 1H, H-4), 5.15 (dd, 1H,
J¼11.8, 3.2 Hz, H-3), 4.98e4.94 (m, 1H, H-8), 4.67 (d, 1H,
J¼3.8 Hz, H-1), 4.47 (br d, 1H, J¼12.1 Hz, H-50), 4.31 (dd,
1H, J¼11.0, 5.3 Hz, H-10e), 3.80 (d, 2H, J¼6.8 Hz, H-8 and
H-10a), 3.39 (t, 1H, J¼10.7 Hz, H-7), 3.31 (s, 3H, OMe),
2.90 (br d, 1H, J¼15.6 Hz, H-5), 2.57 (ddd, 1H, J¼11.3,
3.9, 3.6 Hz, H-2), 2.09 (s, 3H, OCOCH3), 2.01 (s, 3H,
OCOCH3), 1.47 (s, 9H, tert-butyl). 13C NMR (100 MHz,
CDCl3): d 170.0, 169.6, 154.4, 137.3, 128.7, 128.1, 125.9,
101.2, 97.4, 80.0, 71.2, 69.0, 67.9, 63.9, 57.4, 55.1, 48.4,
41.3, 28.3, 20.9, 20.6. MSES: m/z 544 [MþNa]þ. Anal. Calcd
for C26H35NO10 (521.23): C, 59.87; H, 6.76; N, 2.69. Found: C,
60.03; H, 6.80; N, 2.75.
4.1.8.12. tert-Butylallyl((2R,4aR,6S,7R,8R,8aS)-6-methoxy-2-
phenyl-7-vinylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)carba-
mate (14). Amino olefin 13a was N-allylated using the general
procedure (C) to give 14b (87%) as a colorless oil. [a]2D8 þ12.1
(c 1.4, CH2Cl2). IR (CH2Cl2) nmax: 1695, 1562 cmꢀ1. 1H NMR
4.1.8.15. (3S,4R,4aS,5S,7R,8S,8aR)-7-(Acetoxymethyl)-1-acetyl-
5-methoxyoctahydro-1H-pyrano[4,3-b]pyridine-3,4,8-triyl tri-
acetate (18a). Diacetate was converted to pentaacetate using

A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
2387
the general procedure (G) followed by the general procedure
(H) to give 18a (78%) as colorless solid, mp 174e176 ꢁC.
[a]2D8 þ40.0 (c 0.06, CH2Cl2). IR (CH2Cl2) nmax: 1742,
4.1.8.18. tert-Butyl(2R,4aR,6R,7R,8R,8aS)-7-allyl-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (21b).
Yield: 43% (colorless solid, mp 121e123 ꢁC). [a]D28 ꢀ23.6
1654 cmꢀ1
.
1H NMR (400 MHz, CDCl3) (mixture of ro-
(c 0.90, CH2Cl2). IR (CH2Cl2) nmax: 3338, 1680, 1527 cmꢀ1
.
tamers): 5.33 (br d, 1H, J¼2.2 Hz, rotamer-1), 5.21 (br d,
1H, J¼2.2 Hz, rotamer-2), 5.00 (br dd, 1H, J¼11.4, 2.9 Hz,
rotamer-1), 4.88 (br dd, 1H, J¼11.4, 2.9 Hz, rotamer-2),
4.88 (t, 1H, J¼10.0 Hz), 4.71 (dd, 1H, J¼3.6, 12.7 Hz), 4.33
(dd, 1H, J¼4.8, 12.4 Hz), 4.18e4.16 (m, 2H), 4.09 (dd, 1H,
J¼12.2, 2.2 Hz), 3.95e3.91 (m, 2H, both rotamer), 3.85 (dd,
1H, J¼3.6.9 Hz), 3.33 (s, 3H, OMe, minor), 3.31 (s, 3H,
OMe, major), 3.07 (dd, 1H, J¼12.7, 2.7 Hz,), 2.98 (t, 1H,
J¼10 Hz), 2.81 (dd, 1H, J¼14.6 Hz), 2.63 (ddd, 1H, J¼14.1,
3.6, 3.2 Hz), 2.18e1.99 (m, 30H, both rotamer). 13C NMR
(100 MHz, CDCl3): d 172.2, 170.8, 169.9, 169.7, 169.5,
97.1, 96.6, 70.4, 69.2, 68.4, 68.0, 67.5, 67.3, 63.2, 62.6,
55.9, 55.4, 55.1, 47.6, 43.3, 40.4, 29.7, 29.3, 20.9, 20.8,
20.7, 20.5. MSES: m/z 482 [MþNa]þ. Anal. Calcd for
C20H29NO11 (459.44): C, 52.28; H, 6.36; N, 3.05. Found: C,
52.35; H, 6.40; N, 3.10.
1H NMR (400 MHz, CDCl3): d 7.54e7.34 (m, 5H, AreH),
5.94e5.80 (ddd, 1H, J¼17.3, 15.8, 7.3 Hz, eCH]CH2),
5.55 (s, 1H, PheCH), 5.20 (dd, 2H, J¼17.0, 15.8 Hz,
eCH]CH2), 4.36 (d, 1H, J¼9.0 Hz, H-1), 4.33 (dd, 1H,
J¼10.5, 4.8 Hz, H-6e), 3.85 (t, 1H, J¼10.2 Hz, H-6a), 3.75
(t, 1H, J¼9.5 Hz, H-4), 3.54 (s, 3H, OMe), 3.39 (ddd, 1H,
J¼14.4, 9.5, 4.8 Hz, H-5), 3.09 (t, 1H, J¼10.0 Hz, H-3),
2.26e2.47 (m, 2H, allylic), 2.04e1.98 (m, 1H, H-2), 1.46 (s,
9H, tert-butyl). 13C NMR (100 MHz, CDCl3): d 153.8, 137.1,
134.4, 129.0e127.5 (m, aromatic), 126.0, 125.7, 118.4,
104.5, 101.4, 83.6, 73.2, 68.9, 67.3, 61.2, 57.0, 43.8, 42.2,
30.3, 27.6. MSES: m/z 428 [MþNa]þ. Anal. Calcd for
C22H31NO6 (405.22): C, 65.17; H, 7.71; N, 3.45. Found: C,
65.33; H, 7.74; N, 3.51.
4.1.8.19. tert-Butylallyl((2R,4aR,6R,7R,8R,8aS)-7-allyl-6-me-
thoxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)carba-
mate (22). Amino olefin was N-allylated using the general
procedure (C) and purified over silica column chromatog-
raphy. Yield: 95% (colorless oil). [a]2D6 ꢀ42.2 (c 0.90,
4.1.8.16. (2R,4aR,6R,7R,8R,8aS)-7-Allyl-6-methoxy-8-nitro-2-
phenylhexahydropyrano[3,2-d][1,3]dioxine (20). Methyl 4,6-
O-benzylidene-2,3-dideoxy-3-nitro-b-glucopyranoside was
allylated using the general procedure (A) and purified over silica
gel column chromatography. Yield: 73% (colorless solid, mp
CH2Cl2). IR (CH2Cl2) nmax
:
1696 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) (mixture of rotamers): d 7.49e7.34 (m,
10H, AreH, both rotamers), 5.96e5.81 (m, 2H, eCH]
CH2), 5.38 (s, 1H, PheCH), 5.20e5.05 (m, 4H, 2ꢂeCH]
CH2), 4.57 (br s, 1H, minor rotamer), 4.35e4.28 (m, 2H),
4.06 (br dd, 1H, J¼16.1, 10.2 Hz, minor rotamer), 3.85 (br
d, 1H, J¼10.9 Hz, minor rotamer), 3.76 (t, 1H, J¼10.3 Hz),
3.60e3.35 (m, 5H and OMe), 2.32e2.21 (m, 2H, allylic),
1.91e1.86 (m, 1H), 1.44, 1.42 (2ꢂs, 9H, tert-butyl, both
rotamers). 13C NMR (100 MHz, CDCl3): d 155.9, 137.9e
125.9 (m, aromatic, both rotamer), 117.9, 116.9, 115.3,
104.9, 104.5, 100.8, 80.1, 79.8, 68.8, 68.0, 57.0, 56.7, 55.6,
44.4, 43.1, 31.1, 30.8, 28.2. MSES: m/z 468 [MþNa]þ.
Anal. Calcd for C25H35NO6 (445.25): C, 67.39; H, 7.92; N,
3.14. Found: C, 67.40; H, 7.95; N, 3.50.
65e67 ꢁC). [a]D28 ꢀ38.7 (c 4.75, CH2Cl2). IR (CH2Cl2) nmax
:
1556, 1642 cmꢀ1. H NMR (400 MHz, CDCl3): d 7.43e7.34
(m, 5H, AreH), 5.84 (ddd, 1H, J¼7.3, 11.6, 16.8 Hz, eCH]
CH2), 5.57 (s, 1H, PheCH), 5.20 (dd, 2H, J¼11.2, 5.1 Hz,
eCH]CH2), 4.73 (t, 1H, J¼10.0 Hz, H-3), 4.34 (m, 2H, H-1
and H-6e), 4.13 (t, 1H, J¼9.5 Hz, H-4), 3.85 (t, 1H,
J¼10.4 Hz, H-6a), 3.54 (s, 3H, OMe), 3.42 (m, 1H, H-5), 2.36
(m, 2H, allylic), 2.09 (m, 1H, H-2). 13C NMR (100 MHz,
CDCl3): d 131.4, 129.2, 128.1, 126.0, 120.1, 116.5, 102.7,
101.5, 86.9, 85.0, 68.7, 66.4, 57.3, 44.4, 30.9. MSES: m/z 358
[MþNa]þ. Anal. Calcd for C17H21NO6 (335.14): C, 60.89; H,
6.31; N, 4.18. Found: C, 60.95; H, 6.50; N, 4.30.
1
4.1.8.17. tert-Butyl(2R,4aR,6R,7R,8S,8aS)-7-allyl-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (21a).
Nitro olefins 20 were reduced to amino olefins 21a and 21b
using the general procedure (B) and purified over silica gel
column chromatography. Yield: 35% (colorless solid, mp
125e127 ꢁC). [a]D28 ꢀ26.6 (c 0.15, CH2Cl2). IR (CH2Cl2)
4.1.8.20. 6-Methoxy-2-phenyl-4,4a,6,6a,7,10,11a,11b-octahy-
dro-1,3,5-trioxa-11-aza-cyclohepta[a]naphthalene-11-carboxy-
lic acid tert-butyl ester (23). Diene underwent RCM using
the general procedure (D) and purified over silica gel column
chromatography. Yield: 91%. [a]2D6 ꢀ26.6 (c 1.5, CH2Cl2). IR
nmax: 1527, 1680 cmꢀ1
.
1H NMR (400 MHz, CDCl3):
(CH2Cl2) nmax: 1691, 1654 cmꢀ1 1H NMR (400 MHz,
.
d 7.43e7.34 (m, 5H, AreH), 5.90e5.85 (m, 1H, eCH]
CH2), 5.49 (s, 1H, PheCH), 5.12 (br s, 2H, eCH]CH2),
4.35e4.28 (m, 3H, H-1, H-6e, and NH), 3.81 (br s, 1H, H-
4), 3.71 (t, 1H, J¼10.0 Hz, H-6a), 3.45 (s, 3H, OMe), 3.38
(m, 2H, H-5, H-3), 2.40 (m, 2H, allylic), 1.71e1.68 (m, 1H,
H-2), 1.42 (s, 9H, tert-butyl). 13C NMR (100 MHz, CDCl3):
d 155.6, 137.3, 134.5, 128.7, 128.0, 126.0, 117.5, 104.5,
101.2, 80.8, 79.5, 68.7, 67.6, 57.0, 52.2, 46.3, 30.9, 28.2.
MSES: m/z 428 [MþNa]þ. Anal. Calcd for C22H31NO6
(405.22): C, 65.17, H, 7.71; N, 3.45. Found: C, 65.27; H,
7.70; N, 3.50.
CDCl3) (mixture of rotamers): d 7.49e7.34 (m, 10H, AreH,
both rotamers), 5.70 (m, 4H, H-5, H-4, both rotamer), 5.50
(2ꢂs, 2H, PheCH, both rotamer), 4.55 (br t, 1H,
J¼14.8 Hz, H-60, rotamer-1), 4.37e4.31 (m, 5H, H-11e, H-
1, both rotamers, and H-6), 4.18 (m, 2H, both rotamers),
3.84 (t, 2H, J¼10.2 Hz, H-11a), 3.56 (2ꢂs, 6H, OMe),
3.45e3.34 (m, 4H, H-10 and H-8, both rotamers), 2.54 (m,
2H, H-6, both rotamers), 2.17e2.03 (m, 2H, H-3, H-30),
1.60e1.58 (m, 2H, H-2, both rotamers), 1.42 (s, 9H, tert-butyl,
minor-1), 1.33 (s, 9H, tert-butyl, major). 13C NMR (100 MHz,
CDCl3): d 155.6, 137.4, 130.1e126.2 (m, aromatic), 104.9,

2388
A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
104.8, 101.7, 101.2, 80.0, 79.8, 78.3, 69.1, 69.0, 68.9, 68.8,
60.0, 58.6, 57.2, 57.1, 46.2, 40.3, 39.5, 28.3, 28.2, 28.1,
27.8. MSES: m/z 418 [MþH]þ. Anal. Calcd for C23H31NO6
(417.22): C, 66.10; H, 7.58; N, 3.35. Found: C, 66.50; H,
7.48; N, 3.34.
4.1.8.23. (2R,4aR,6R,7R,8R,8aR)-7-Allyl-6-methoxy-8-nitro-2-
phenylhexahydropyrano[3,2-d][1,3]dioxine (28). Methyl 4,6-
O-benzylidene-2,3-dideoxy-3-nitro-b-galactopyranoside was
allylated using the general procedure (A) and purified over
silica gel column chromatography. Yield: 73% (colorless solid,
mp 71e72 ꢁC). [a]D23 þ40.0 (c 0.60, CH2Cl2). IR (CH2Cl2)
1
4.1.8.21.
(8R,9S)-Diacetoxy-6-methoxy-2-phenyldecahydro-
nmax: 1556, 1642 cmꢀ1. H NMR (400 MHz, CDCl3): d 7.43
1,3,5-trioxa-11-aza-cyclohepta[a]naphthalene-11-carboxylic
acid tert-butyl ester (25). Diol was acetylated using the gen-
eral procedure (F) to give 25 (90%) as colorless solid, mp
(d, 2H, J¼3.6 Hz, AreH), 7.33 (d, 3H, J¼4.2 Hz, AreH),
5.72e5.78 (ddd, J¼17.5, 9.3 Hz, 1H, eCH]CH2), 5.55 (s,
1H, PheCH), 5.10 (dd, 2H, J¼17.5, 10.0 Hz, eCH]CH2),
4.62 (dd, 1H, J¼12.2, 3.6 Hz), 4.54 (br d, 1H, J¼3.6 Hz, H-
4), 4.39 (d, 1H, J¼12.4 Hz, H6e), 4.26 (d, 1H, J¼8.7 Hz, H-
1), 4.14 (d, 1H, J¼12.4 Hz, H6a), 3.54 (s, 3H, OMe), 3.47
(br s, 1H, H-5), 2.86e2.84 (m, 1H, H-2), 2.55e2.51 (m,
1H, allylic), 2.25e2.30 (m, 1H, allylic). 13C NMR
(100 MHz, CDCl3): d 136.8, 132.5, 128.9, 128.0, 126.0,
119.5, 102.4, 100.5, 85.1, 72.6, 69.0, 66.6, 56.8, 37.0, 30.8.
MSES: m/z 358 [MþNa]þ. Anal. Calcd for C17H21NO6
(335.14): C, 60.89; H, 6.31; N, 4.18. Found: C, 60.95; H, 6.50;
N, 4.30.
95e97 ꢁC. [a]2D6 ꢀ60.0 (c 0.60, CH2Cl2). IR (CH2Cl2) nmax
:
1
1745, 698 cmꢀ1. H NMR (400 MHz, CDCl3) (mixture of ro-
tamers): d 7.49e7.34 (m, 10H, AreH, both rotamers), 5.49 (s,
1H, PheCH, rotamer-1), 5.45 (s, 1H, PheCH, rotamer-2),
5.42e5.40 (m, 1H, H-4, rotamer-1), 5.33 (br s, 1H, H-4, ro-
tamer-2), 4.84 (tt, 1H, J¼7.3, 3.4 Hz, H-5, rotamer-1), 4.75
(tt, 1H, J¼7.3, 3.4 Hz, H-5, rotamer-2), 4.34e4.29 (m, 5H,
H-11e, H-1, both rotamers and H-60, rotamer-1), 4.05 (t, 1H,
J¼10.2 Hz, H-11a, rotamer-1), 3.86e3.81 (m, 3H, H-11a,
both rotamer, H-8), 3.68 (br d, 1H, J¼12.6 Hz, H-6), 3.56e
3.52 (m, 2H, H-9), 3.47 (2ꢂs, 3H, OMe), 3.40e3.34 (m,
1H, H-10), 3.25e3.19 (m, 2H, H-6, both rotamers), 2.27 (m,
4H, H-3 and H-30, both rotamers), 2.14, 2.01 (2ꢂs, 6H,
OCOCH3, rotamer-1), 2.10, 1.99 (2ꢂs, 6H, NHCOCH3, ro-
tamer-2), 1.48 (s, 9H, tert-butyl, rotamer-1), 1.27 (s, 9H,
tert-butyl, rotamer-2). 13C NMR (100 MHz, CDCl3):
d 170.0, 169.4, 169.1, 155.3, 137.1, 129.0e127.9 (m, aro-
matic), 126.4, 125.9, 104.6, 104.5, 101.9, 100.7, 80.7, 80.6,
79.2, 79.0, 72.0, 71.7, 68.8, 68.6, 67.3, 66.9, 58.6, 57.4,
57.1, 57.0, 41.1, 40.2, 39.6, 39.4, 28.0, 27.8, 26.9, 21.0,
20.7. MSES: m/z 536 [MþH]þ. Anal. Calcd for C27H37NO10
(535.24): C, 60.55; H, 6.96; N, 2.62. Found: C, 60.50; H,
7.00; N, 2.65.
4.1.8.24. tert-Butyl(2R,4aR,6R,7R,8R,8aR)-7-allyl-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (29a).
Compound 29a was prepared in 52% yield from compound
28 following the procedure used for the preparation of 3a
(colorless solid, mp 83e85 ꢁC). [a]D23 þ73.3 (c 0.30,
CH2Cl2). IR (CH2Cl2) nmax: 1530, 1685 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d 7.49 (d, 2H, J¼3.6 Hz, AreH), 7.34
(s, 3H, AreH), 5.83e5.92 (ddd, J¼15.8, 7.56 Hz, 1H,
eCH]CH2), 5.52 (s, 1H, PheCH), 5.07 (s, 1H, NH), 4.98
(dd, 2H, J¼30.0, 10.7 Hz, eCH]CH2), 4.29 (br d, 1H,
J¼12.4 Hz, H6e), 4.20 (d, 1H, J¼8.56 Hz, H-1), 4.03 (br d,
1H, J¼12.2 Hz, H6a), 3.94 (br s, 1H, H-4), 3.86 (br t, 1H,
J¼10.0 Hz, H-3), 3.52 (s, 3H, OMe), 3.38 (br s, 1H, H-5),
2.23e2.33 (m, 2H, allylic), 1.95e1.91 (m, 1H, H-2), 1.41 (s,
9H, tert-butyl). 13C NMR (100 MHz, CDCl3): d 155.4, 137.9,
134.8, 129.2, 128.2, 126.5, 117.2, 104.3, 101.3, 79.7, 74.1,
69.5, 67.1, 56.8, 51.1, 40.8, 40.5, 28.4. MSES: m/z 428
[MþNa]þ. Anal. Calcd for C22H31NO6 (405.22): C, 65.17;
H, 7.71; N, 3.45. Found: C, 65.37; H, 7.75; N, 3.50.
4.1.8.22. (3R,4S,5aR,6R,8R,9S,9aR)-8-(Acetoxymethyl)-1-ace-
tyl-6-methoxydecahydropyrano-[4,3-b]azepine-3,4,9-triyl tri-
acetate (26a). Diacetate was converted to pentaacetate using
the general procedure (G) followed by the general procedure
(H) to give 26a (81%) as colorless solid, mp 78e80 ꢁC.
[a]2D6 ꢀ10.5 (c 0.85, CH2Cl2). IR (CH2Cl2) nmax: 1743,
1653 cmꢀ1 1H NMR (400 MHz, CDCl3) (mixture of ro-
.
tamers): d 5.39 (t, 1H, J¼4.4 Hz, H-4, minor), 5.34 (t, 1H,
H-4, J¼4.4 Hz, major), 4.94 (t, 1H, J¼9.8 Hz, H-9, minor),
4.80 (t, 1H, J¼9.8 Hz, H-9, major), 4.73e4.70 (m, 1H, H-5,
major), 4.63 (t, 1H, J¼10.2 Hz, H-8), 4.37 (dd, 1H, J¼12.2,
5.1 Hz, H-11e), 4.29 (d, 1H, J¼8.2 Hz, H-1), 4.17e4.11 (m,
2H, H-11a, major and minor), 4.00e3.95 (m, 1H, H-60, mi-
nor), 3.90 (ddd, 1H, J¼6.8, 4.6, 1.9 Hz, H-10), 3.75e3.73
(m, 1H, H-10, minor), 3.52e3.50 (m, 1H, H-60), 3.49 (s, 3H,
OMe), 3.37 (dd, 1H, J¼15.3, 2.6 Hz, H-6), 3.10 (dd, 1H,
J¼15.3, 2.6 Hz, H-6, minor), 2.23e1.96 (m, 31H, OCOCH3,
NCOCH3 and H-3), 1.48e1.43 (m, 1H, H-30). 13C NMR
(100 MHz, CDCl3): d 172.2e170.0 (m), 104.0, 73.1, 72.1,
68.7, 67.0, 62.7, 57.0, 56.3, 42.8, 38.7, 26.0, 21.7, 21.0,
20.8, 20.6. MSES: m/z 474 [MþH]þ. Anal. Calcd for
C21H31NO11 (473.19): C, 53.27; H, 6.60; N, 2.96. Found: C,
53.20; H, 6.50; N, 3.00.
4.1.8.25. tert-Butyl(2R,4aR,6R,7R,8S,8aR)-7-allyl-6-methoxy-2-
phenylhexahydropyrano[3,2-d][1,3]dioxin-8-ylcarbamate (29b).
Yield: 30%, colorless oil. [a]2D3 þ13.3 (c 0.15, CH2Cl2). IR
(CH2Cl2) nmax: 1530, 1685 cmꢀ1
.
1H NMR (400 MHz,
CDCl3) (mixture of rotamers): d 7.49e7.34 (m, 10H, AreH,
both rotamer), 5.85e5.76 (m, 1H, eCH]CH2), 5.55 (s, 1H,
PheCH), 5.09e5.00 (m, 2H, eCH]CH2), 4.67 (br s, 1H, mi-
nor rotamer), 4.42e4.07 (m, 6H), 3.75e3.31 (m, 5H and OMe,
both rotamer), 2.29e2.28 (m, 1H, allylic, minor rotamer),
1.89e1.78 (m, 2H, allylic), 1.44e1.42 (s, 9H, tert-butyl, both
rotamer). 13C NMR (100 MHz, CDCl3): d 153.8, 137.1,
134.4, 129.2, 128.4, 128.2, 127.5, 126.0, 125.7, 118.4, 118.0,
104.5, 101.4, 83.6, 68.3, 67.3, 61.2, 57.0, 43.8, 42.2, 30.3,
27.6, 27.3. MSES: m/z 428 [MþNa]þ. Anal. Calcd for
C22H31NO6 (405.22): C, 65.17; H, 7.71; N, 3.45. Found: C,
65.29; H, 7.70; N, 3.52.

A. Kumar et al. / Tetrahedron 64 (2008) 2379e2390
2389
4.1.8.26. tert-Butylallyl((2R,4aR,6R,7R,8R,8aR)-7-allyl-6-meth-
oxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-8-yl)carbamate
(30). Amino olefin was N-allylated using the general proce-
dure (C) and purified over silica gel column chromatography.
Yield: 94% (colorless oil). [a]2D3 þ64.0 (c 1.5, CH2Cl2). IR
H-30), 2.09, 2.00 (2s, 6H, OCOCH3, major), 2.08, 1.98 (2s,
6H, OCOCH3, minor), 1.49 (s, 9H, tert-butyl, minor), 1.48 (s,
9H, tert-butyl, major), 1.28e1.23 (m, 1H, H-5). 13C NMR
(100 MHz, CDCl3): d 170.3, 169.3, 155.4, 138.0, 128.7,
128.0, 126.1, 104.6, 100.58, 100.50, 81.2, 74.2,72.2, 67.6,
67.3, 67.2, 59.2, 56.4, 43.1, 33.1, 28.2, 27.1, 21.1, 20.8.
MSES: 536 [MþH]þ. Anal. Calcd for C27H37NO10 (535.24):
C, 60.55; H, 6.96; N, 2.62. Found: C, 60.50; H, 7.00;
N, 2.65.
(CH2Cl2) nmax: 1696 cmꢀ1 1H NMR (400 MHz, CDCl3):
.
d 7.40e7.34 (m, 5H, AreH), 5.70e5.64 (m, 2H, eCH]
CH2), 5.45 (s, 1H, PheCH), 4.98e4.82 (m, 4H, 2ꢂeCH]
CH2), 4.29e4.19 (m, 3H), 3.93 (br s, 2H), 3.73e3.67 (m,
2H, H-3 and H-4), 3.45 (s, 3H, OMe), 3.31 (s, 1H, H-5),
2.24e2.22 (m, 2H, allylic), 2.06e2.00 (m, 1H, H-2), 1.37 (s,
9H, tert-butyl). 13C NMR (100 MHz, CDCl3): d 165.9,
137.9e125.9 (m, aromatic), 117.3, 115.1, 104.8, 100.8, 80.2,
79.8, 69.6, 67.0, 56.7, 55.3, 47.4, 37.9, 30.8, 28.3. MSES:
m/z 468 [MþNa]þ. Anal. Calcd for C25H35NO6 (445.25): C,
67.39; H, 7.92; N, 3.14. Found: C, 67.41; H, 7.92; N, 3.52.
4.1.8.29. (3R,4S,5aR,6R,8R,9R,9aR)-8-(Acetoxymethyl)-1-ace-
tyl-6-methoxydecahydropyrano[4,3-b]azepine-3,4,9-triyl triace-
tate (35). Diacetate was converted to pentaacetate using
the general procedure (G) followed by the general procedure
(H) to give 35 (78%) as colorless solid, mp 88e90 ꢁC.
[a]2D6 þ10.5 (c 0.85, CH2Cl2). IR (CH2Cl2) nmax: 1743,
1
1653 cmꢀ1. H NMR (400 MHz, CDCl3): d 5.32 (br s, 1H,
4.1.8.27. 6-Methoxy-2-phenyl-4,4a,6,6a,7,10,11a,11b-octahy-
dro-1,3,5-trioxa-11-aza-cyclohepta[a]naphthalene-11-carboxy-
lic acid tert-butyl ester (31). Diene underwent RCM using the
general procedure (D) and purified over silica gel column
chromatography. Yield: 92%. [a]2D3 þ76.0 (c 1.25, CH2Cl2). IR
H-8), 5.27 (br s, 1H, H-4), 4.59 (br d, 1H, J¼10.5 Hz, H-5),
4.19 (dd, 1H, J¼13.6, 2.4 Hz, H-8), 4.14 (d, 1H, J¼8.3 Hz,
H-1), 4.08 (qt, 1H, J¼9.5, 4.9 Hz, H-110), 3.88 (t, 1H,
J¼6.6 Hz, H-11), 3.47e3.40 (m, 2H, H-10 and H-6), 3.46
(s, 3H, OMe), 3.32 (br d, 1H, J¼13.9 Hz, H-60), 2.43e2.35
(m, 1H, H-2), 2.27 (dd, 1H, J¼14.8, 5.6 Hz, H-3), 1.97e
2.14 (m, 15H, 4ꢂOCOCH3, NCOCH3), 1.22e1.20 (m, 1H,
H-30). 13C NMR (100 MHz, CDCl3): d 171.9e169.6 (m),
104.4, 73.1, 71.9, 67.3, 67.1, 61.8, 57.4, 57.0, 43.7, 33.6,
29.6, 27.5, 21.9e20.7 (m). MSES: m/z 474 [MþH]þ. Anal.
Calcd for C21H31NO11 (473.19): C, 53.27; H, 6.60; N, 2.96.
Found: C, 53.30; H, 6.40; N, 2.90.
1
(CH2Cl2) nmax: 1685, 1654 cmꢀ1. H NMR (400 MHz, CDCl3)
(mixture of rotamers): d 7.47 (d, 2H, J¼5.12 Hz, AreH), 7.33
(d, 3H, J¼6.0 Hz, AreH, major and minor), 5.63 (br d, 2H,
J¼5.1 Hz, H-5, H-4), 5.54 (s, 1H, PheCH, major), 5.52 (s,
1H, PheCH, minor), 4.31 (br d, 2H, J¼12.2 Hz, H-8 and
H-60), 4.22 (d, 1H, J¼8.2 Hz, H-1), 4.31 (br s, 1H, H-9),
4.09e4.00 (m, 2H, H-11, H-110), 3.82 (br d, 2H, J¼16.3 Hz,
H-6, major and minor), 3.50 (s, 3H, OMe, major), 3.47
(s, 3H, OMe, minor), 3.40 (br s, 1H, H-10), 2.63e2.55 (m,
2H, H-3, H-30, major and minor), 1.95e1.92 (m, 1H, H-2),
1.46 (s, 9H, tert-butyl, minor), 1.42 (s, 9H, tert-butyl, major).
13C NMR (100 MHz, CDCl3): d 155.9, 154.8, 138.1, 137.8,
129.2e128.5 (m, aromatic), 126.1, 126.0, 104.9, 104.8,
100.7, 100.6, 79.9, 75.5, 75.2, 69.6, 68.7, 60.7, 59.4, 56.5,
56.4, 42.9, 42.3, 39.2, 39.0, 29.0e28.3 (m). MSES: m/z 440
[MþNa]þ. Anal. Calcd for C23H31NO6 (417.22): C, 66.10;
H, 7.58; N, 3.35. Found: C, 66.40; H, 7.48; N, 3.34.
Acknowledgements
We thank the Department of Science and Technology, New
Delhi, for financial support to Y.D.V. in the form of Ramanna
Fellowship (Grant No. SR/S1/RFOC-04/2006). A.K. and
G.K.R. thank Council of Scientific and Industrial Research
for senior research fellowships.
Supplementary data
4.1.8.28. (8R,9S)-Diacetoxy-6-methoxy-2-phenyldecahydro-1,3,5-
trioxa-11-aza-cyclohepta[a]naphthalene-11-carboxylic acid tert-
butyl ester (33). Diol was acetylated using the general
procedure (F) to give 33 (83%) as colorless solid, mp 121e
1H and 13C NMR spectra of compounds reported in this ar-
ticle can be found in the online version. Supplementary data
associated with this article can be found in the online version,
at doi:10.1016/j.tet.2008.01.005.
123 ꢁC. [a]2D3 þ71.0 (c 1.25, CH2Cl2). IR (CH2Cl2) nmax
:
1685 cmꢀ1 1H NMR (400 MHz, CDCl3) (mixture of ro-
.
References and notes
tamers): d 7.52e7.33 (m, 5H, AreH, major and minor), 5.56
(s, 1H, PheCH, major), 5.54 (s, 1H, PheCH, minor), 5.53
(br s, 1H, H-4), 4.76 (dt, 1H, J¼10.5, 7.1 Hz, H-5, major),
4.72 (dt, 1H, J¼10.5, 7.1 Hz, H-5, minor), 4.35 (d, 1H,
J¼8.2 Hz, H-1, minor), 4.32 (dd, 1H, J¼12.2, 1.2 Hz, H-
110), 4.20 (d, 1H, J¼8.3 Hz, H-1, major), 4.17 (br d, 1H,
J¼1.7 Hz, H-9), 4.11 (d, 1H, J¼6.3 Hz, H-11, minor), 4.06
(dd, 1H, J¼12.4, 1.9 Hz, H-11, major), 3.87 (dd, 1H,
J¼12.7, 2.7 Hz, H-8), 3.58e3.50 (m, 2H, H-6, H-60), 3.50e
3.48 (m, 1H, H-10, major and minor), 3.48 (s, 3H, OMe),
2.72e2.68 (m, 1H, H-2), 2.33 (dd, 1H, J¼14.6, 5.8 Hz,
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20. All the enzymes (a-galactosidase, b-galactosidase, a-glucosidase, and b-
glucosidase) and the corresponding substrate were purchased from Sigma
Chemicals Co. The inhibition potencies of the sugareazasugar hybrids 8,
18, 26, and 34 were evaluated using a-glycosidases. The IC50 values ob-
tained are summarized in Table 1.