A phosphine-mediated synthesis of 1,4-oxazepine- and 1,5-oxazocine-based sugar hybrids from deoxysugar azides

Article abstract of DOI:10.1055/s-0030-1260218

An efficient and convenient method was developed for the synthesis of novel 1,4-oxazepine- and 1,5-oxazocine-based sugar hybrids from readily available deoxysugar azides by means of tributylphosphine-mediated tandem reactions. The resulting glycoconjugate

Full text of DOI:10.1055/s-0030-1260218

PAPER
3523
A Phosphine-Mediated Synthesis of 1,4-Oxazepine- and 1,5-Oxazocine-Based
Sugar Hybrids from Deoxysugar Azides1
Novel Sugar
H
u
ybrids Base
r
e
O
xazepine
s
and1,5-O
h
xazocine Framewo
E
rks . Kurhade,a,b Videsh T. Salunkhe,a V. Siddaiah,b Debnath Bhuniya,a D. Srinivasa Reddy*a,c
a
Discovery Chemistry, Advinus Therapeutics Ltd., Quantum Towers, Plot No. 9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi,
Pune 411057, India
b
c
Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India
National Chemical Laboratory (CSIR, India), Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India
Fax +91(20)66539620; E-mail: ds.reddy@ncl.res.in
Received 20 June 2011
ever, replacement of an aromatic R1 group with a cy-
cloalkyl group did not produce the desired compounds
(results not shown), suggesting that aromatic groups may
be necessary.
Abstract: An efficient and convenient method was developed for
the synthesis of novel 1,4-oxazepine- and 1,5-oxazocine-based sug-
ar hybrids from readily available deoxysugar azides by means of
tributylphosphine-mediated tandem reactions. The resulting glyco-
conjugates might be useful in increasing the diversity of sugar back-
bones, and could find applications as potential glycomimetics and
in drug discovery.
Having obtained encouraging results with various ynones,
we next treated 1-(4-chlorophenyl)-3-phenylprop-2-yn-1-
one with various sugar azides2k,m,9 (Scheme 2). The 6-azi-
do-3,6-dideoxysugar azides 12 and 13, which have differ-
ent stereochemistries at the C-4-position, reacted
smoothly to give the corresponding 1,4-oxazepines 14 and
15, respectively. To examine the reactivity of secondary
azides in the present method, we treated the secondary
sugar azide 16 with the ynone to form the desired product
17 in good yield.
Key words: tandem reactions, heterocycles, carbohydrates,
alkynes, oxazepines, oxazocines, azides
Synthesis of carbohydrate-based hybrids with biological-
ly interesting scaffolds is an attractive area of research be-
cause of the wide range of applications of these
compounds, especially in the area of drug discovery.2
Apart from showing very different pharmacodynamic ef-
fects to those of their individual congeners, these hybrid
molecules often exhibit unusual pharmacokinetic proper-
ties such as tissue permeability and improved aqueous sol-
ubility.3 These considerations led us to initiate a research
project into the design and synthesis of sugar hybrids
based on well-documented biologically active oxazepine
and oxazocine scaffolds.4,5 While we were exploring var-
ious methods6 for constructing oxazepine heterocycles,
our attention was drawn to the recent serendipitous dis-
covery of a simple and straightforward method for the
preparation of 1,4-oxazepines from azido alcohols by
François-Endelmond and co-workers.5c We applied this
method to the synthesis of novel 1,4-oxazepine-based
deoxysugar hybrids starting from readily available de-
oxysugar azides. Subsequently, we broadened the scope
of this method to 1,5-oxazocine-based sugar hybrids.
To broaden the scope of our method, we attempted the
corresponding reactions of 1,3-azido alcohol-containing
sugar azides to form 1,5-oxazocine-based sugar hybrids,
essentially under the same the conditions as described
above. The reaction between deoxysugar azide 18 and
ynones gave the corresponding 1,5-oxazocine-fused sugar
hybrids 19 (Scheme 2). We prepared 6-deoxymannose
azide derivative 20 from commercially available methyl
a-D-mannopyranoside and we examined its reaction with
various ynones. In all the cases, the corresponding 1,5-ox-
azocine-based mannose hybrids 21–25 were obtained in
good yields (Table 2). It is noteworthy that we prepared
1,5-oxazocines from 1,3-azido alcohols for the first time
from the literature5c
R3
R3
Initially, we choose the readily accessible deoxysugar
azide 1 (Table 1),7 which we treated with a variety of
ynones8 in the presence of tributylphosphine under similar
conditions to those previously described.5c To our delight,
most of the ynones reacted with 1 and to give the desired
1,4-oxazepine-based sugar hybrids 2–11 in good yields
(Table 1). Changing the nature of the substituents on the
phenyl ring or replacing the phenyl in the ynone with a 2-
thienyl group had little or no effect on the reaction. How-
HO
N3
Bu3P
O
+
N
toluene, r.t.
R1
O
R1
R2
R2
this work
R2
O
N
Bu3P
O
HO
N3
R2
sugar
sugar
+
R1
R1
SYNTHESIS 2011, No. 21, pp 3523–3529
x
x.
x
x
.
2
0
1
1
Advanced online publication: 15.09.2011
DOI: 10.1055/s-0030-1260218; Art ID: T74011SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Strategy for preparing oxazepine- and oxazocine-based
sugar hybrids

3524
S. E. Kurhade et al.
PAPER
Table 1 Synthesis of 1,4-Oxazepine-Based D-Glucofuranoside De-
Table 2 Synthesis of 1,5-Oxazocine-Based Mannose Hybrids
rivatives
O
OMe
N3
N3
O
O
O
HO
O
HO
H
O
BnO
1
20
Bu3P, toluene, r.t.
R1
N
N
R1
6
O
OMe
1
O
5
1
Bu3P, toluene, r.t.
O
3
O
6
O
O
5
8
R2
8
R2
2
2
4
11
O
3
11
O
R1
R1
H
O
OBn
R2
R2
O
2–11
21–25
Product
R1
Ph
R2
Ph
Ph
Ph
Ph
Yield (%)
Product
21
R1
R2
Ph
Ph
Yield (%)
2
3
61
77
72
68
60
58
59
57
70
42
4-ClC6H4
2-thienyl
2-thienyl
Ph
66
54
49
43
51
4-ClC6H4
2-thienyl
3-FC6H4
2-thienyl
Ph
22
4
23
4-MeOC6H4
5
24
Ph
Ph
6
3-MeC6H4
4-t-BuC6H4
4-t-BuC6H4
4-MeOC6H4
4-MeOC6H4
Ph
25
3-FC6H4
7
jected to further manipulations to increase the diversity of
available sugar frameworks. We have also broadened the
range of methods available for the synthesis of the 1,5-ox-
azocine framework, starting from readily available azido
deoxysugars with 1,3-azido alcohol functionalities.
8
4-EtC6H4
Ph
9
10
11
2-thienyl
4-F3CC6H4
All reagents, starting materials, and solvents (including dry sol-
vents) were obtained from commercial suppliers and used without
further purification. Reactions were carried out in oven-dried glass-
ware under a positive pressure of argon, unless otherwise men-
tioned. Column chromatography was performed on silica gel
(Rankem, 100–200 mesh). Deuterated solvents (Cambridge Isotope
Laboratories) for NMR spectroscopic analyses were used as re-
ceived. All NMR spectra were recorded on Varian 400-MHz spec-
trometer. All chemical shifts are quoted in ppm, relative to TMS,
using the residual solvent peak as a reference standard. Optical ro-
tation was recorded on a Rudolph Autopol-V Polarimeter at 589 nm
(sodium D-line). Mass spectra were measured on an Agilent MSD/
VL with ESI ionization. HRMS data were determined on a JEOL
MS Route 600 H instrument or by MALDI-TOF using 2,5-dihy-
droxybenzoic acid as the solid matrix. IR spectra were recorded on
a Perkin-Elmer 100 FT-IR spectrometer. Ynones were prepared
from alkynes and acyl chlorides according to a previously described
protocol.8
Bu3P
toluene, r.t.
R1
N
N3
O
O
O
O
O
HO
R
O
O
R
R2
12 R = α-H
13 R = β-H
14 R = α-H (68%)
15 R = β-H (56%)
R2
O
HO
O
O
O
O
O
N3
H
O
N
H
BnO
BnO
R1
R1
16
17 (63%)
N
O
O
N3
O
HO
R2
19 (50%)
1 = 4-ClC6H4
R2 = Ph
18
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-5,7-diphenyl-2,3-dihydro-1,4-
oxazepine (2); Typical Procedure
R
Bu3P (66 mL, 0.32 mmol) was added to a soln of 6-azido-3-O-ben-
zyl-6-deoxy-1,2-O-isopropylidine-a-D-glucofuranose7 (75 mg,
0.22 mmol) and BzC≡CPh (50 mg, 0.32 mmol) in anhyd toluene un-
der argon. The mixture was stirred overnight at r.t. and then concen-
trated under reduced pressure to give a crude product that was
purified by column chromatography (silica gel, EtOAc–hexanes,
Scheme 2
by a tributylphosphine-mediated tandem aza-Wittig reac-
tion and intramolecular cyclization.
To summarize, we have developed a simple method for 4:1); yield: 61%; [a]D24.9 –119.8 (c 0.25, MeOH).
preparing novel sugar hybrids based on 1,4-oxazepine and
1,5-oxazocine frameworks, starting from readily available
deoxysugar azides by a tributylphosphine-mediated tan-
dem reaction sequence. These compounds may be useful
for screening in various biological targets or may be sub-
IR (thin film): 697, 763, 801, 1026, 1076, 1163, 1216, 1260, 1374,
1450, 1566, 1623 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.76 (dd, J = 15.2, 6.0 Hz, 1 H, C=NCH2),
4.18 (d, J = 3.2 Hz, 1 H, glucofuranose H-3), 4.36 (dd, J = 8.8, 3.2
Synthesis 2011, No. 21, 3523–3529 © Thieme Stuttgart · New York

PAPER
Novel Sugar Hybrids Based on 1,4-Oxazepine and 1,5-Oxazocine Frameworks
3525
Hz, 1 H, glucofuranose H-4), 4.54 (d, J = 11.6 Hz, 1 H, OCH2Ph),
4.61 (dd, J = 8.8, 5.2 Hz, 1 H, OCH oxazepine), 4.68–4.72 (m, 2 H,
OCH2Ph and glucofuranose H-2), 4.94 (d, J = 14.4 Hz, 1 H,
C=NCH2), 5.98 (d, J = 3.6 Hz, 1 H, glucofuranose H-1), 6.26 (s, 1
H, oxazepine H-9), 7.18–7.25 (m, 5 H), 7.33–7.42 (m, 6 H), 7.55–
7.58 (m, 2 H), 7.78–7.80 (m, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 166.1 (oxazepine C-10), 161.0
(oxazepine N=C-8), 141.6, 137.2, 136.0, 129.9, 129.4, 128.4 (4 C),
128.2 (2 C), 127.9, 127.7 (2 C), 127.3 (2 C), 126.4 (2 C), 111.9
[acetonide C(Me2)], 105.3 (oxazepine C-9), 97.1 (glucofuranose
C-1), 82.2 (glucofuranose C-2), 81.3 (glucofuranose C-4), 80.2
(glucofuranose C-3), 79.0 (OCH2Ph), 72.1 (oxazepine OCH), 57.2
(=NCH2), 26.8 [C(CH3)2], 26.3 [C(CH3)2].
(glucofuranose C-2), 81.2 (glucofuranose C-4), 80.2 (glucofuranose
C-3), 79.1 (OCH2Ph), 72.0 (oxazepine OCH), 57.0 (oxazepine
=NCH2), 26.8 [C(CH3)2], 26.2 [C(CH3)2].
HPLC-MS: m/z = 504.2 [M + 1]; purity (%) = 97.4; tR = 12.89 min.
HRMS (ESI): m/z [M + H]+ calcd for C29H30SNO5: 504.1844;
found: 504.1844.
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-5-(3-fluorophenyl)-7-phenyl-
2,3-dihydro-1,4-oxazepine (5)
Yield: 68%; [a]D24.3 –158.0 (c 0.5, MeOH).
IR (thin film): 696, 756, 788, 885, 1024, 1076, 1114, 1164, 1216,
1383, 1451, 1569, 1623, 1724 cm–1.
HPLC-MS: m/z = 498.3 [M + 1]; tR = 14.05 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C31H32NO5:
498.2280; found: 498.2279.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.75 (dd, J = 15.2, 6.0 Hz, 1 H, C=NCH2),
4.18 (d, J = 2.4 Hz, 1 H, glucofuranose H-3), 4.36 (dd, J = 8.8, 2.8
Hz, 1 H, glucofuranose H-4), 4.52 (d, J = 12 Hz, 1 H, OCH2Ph),
4.59 (dd, J = 8.4, 5.6 Hz, 1 H, oxazepine OCH), 4.68–4.72 (m, 2 H,
OCH2Ph and glucofuranose H-2), 4.94 (d, J = 14.8 Hz, 1 H,
C=NCH2), 5.98 (d, J = 4.0 Hz, 1 H, glucofuranose H-1), 6.20 (s, 1
H, oxazepine H-9), 7.09 (ddd, J = 10.8, 8.4, 2.8 Hz, 1 H), 7.18–7.24
(m, 5 H), 7.32–7.42 (m, 4 H), 7.50–7.58 (m, 4 H).
13C NMR (100.6 MHz, CDCl3): d = 164.7 (oxazepine C-10), 162.8
(d, J = 246 Hz), 161.3 (oxazepine N=C-8), 144.0 (d, J = 7.0 Hz),
137.2, 135.9, 130.0, 129.7 (d, J = 7.7 Hz), 128.5 (4 C), 128.0, 127.7
(2 C), 126.4 (2 C), 122.9, 116.2 (d, J = 21.7 Hz), 114.3 (d, J = 22.6
Hz), 111.9 [acetonide C(Me2)], 105.3 (oxazepine C-9), 96.6 gluco-
furanose C-1), 82.2 (glucofuranose C-2), 81.3 (glucofuranose C-4),
80.2 (glucofuranose C-3), 79.0 (OCH2Ph), 72.1 (oxazepine OCH),
57.4 (=NCH2), 26.8 [C(CH3)2], 26.3 [C(CH3)2].
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-5-(4-chlorophenyl)-7-phenyl-
2,3-dihydro-1,4-oxazepine (3)
Yield: 77%; [a]D24.2 –139.6 (c 0.5, MeOH).
IR (thin film): 667, 696, 755, 886, 1014, 1076, 1164, 1217, 1374,
1404, 1450, 1573, 1623, 1726 cm–1.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.75 (dd, J = 14.8, 5.6 Hz, 1 H, C=NCH2),
4.18 (d, J = 2.0 Hz, 1 H, glucofuranose H-3), 4.35 (dd, J = 8.8, 3.2
Hz, 1 H, glucofuranose H-4), 4.54 (d, J = 11.6 Hz, 1 H, OCH2Ph),
4.58 (dd, J = 8.4 Hz, 1 H, OCH oxazepine), 4.68–4.72 (m, 2 H,
OCH2Ph and glucofuranose H-2), 4.92 (d, J = 15.2 Hz, 1 H,
C=NCH2), 5.98 (d, J = 3.2 Hz, 1 H, glucofuranose H-1), 6.18 (s, 1
H, oxazepine H-9), 7.19–7.24 (m, 5 H), 7.33–7.42 (m, 5 H), 7.55 (d,
J = 8.0 Hz, 2 H), 7.73 (d, J = 8.0 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 164.8 (oxazepine C-10), 161.3
(oxazepine N=C-8), 140.1, 137.2, 136.0, 135.4, 130.0, 128.7 (2 C),
128.5 (4 C), 128.4 (2 C), 128.0, 127.7 (2 C), 126.4 (2 C), 112.0
[acetonide C(Me2)], 105.3 (oxazepine C-9), 96.6 (glucofuranose
C-1), 82.2 (glucofuranose C-2), 81.3 (glucofuranose C-4), 80.3
(glucofuranose C-3), 79.0 (OCH2Ph), 72.1 (oxazepine OCH), 57.3
(=NCH2), 26.9 [C(CH3)2], 26.3 [C(CH3)2].
HPLC-MS: m/z = 516.2 [M + 1]; purity (%) = 95.5; tR = 12.94 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C31H31FNO5:
516.2186; found: 516.2197.
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-(3-methylphenyl)-5-(2-thien-
yl)-2,3-dihydro-1,4-oxazepine (6)
Yield: 60%; [a]D22.6 –139.0 (c 0.5, MeOH).
IR (thin film): 699, 753, 787, 844, 886, 1076, 1025, 1164, 1216,
1243, 1382, 1433, 1571, 1601, 1618 cm–1.
HPLC-MS: m/z = 532.2 [M + 1]; purity (%) = 95.3; tR = 13.99 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C31H31ClNO5:
532.1890; found: 532.1926.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 2.36 (s, 3 H, C6H4CH3), 3.74 (dd, J = 15.2,
6.0 Hz, 1 H, C=NCH2), 4.17 (d, J = 3.2 Hz, 1 H, glucofuranose H-
3), 4.35 (dd, J = 8.8, 2.8 Hz, 1 H, glucofuranose H-4), 4.53 (d, J =
12.4 Hz, 1 H, OCH2Ph), 4.58 (dd, actual merged in doublet J = 8.8,
6.0 Hz, 1 H, OCH oxazepine) 4.67–4.71 (m, 2 H, OCH2Ph and glu-
cofuranose H-2 are merged), 4.86 (d, J = 15.2 Hz, 1 H, C=NCH2),
5.97 (d, J = 3.2 Hz, 1 H, glucofuranose H-1), 6.34 (s, 1 H, oxazepine
H-9), 7.05 (app. t, J = 3.6 Hz, 1 H), 7.17–7.27 (m, 7 H), 7.33–7.39
(m, 3 H), 7.42 (d, J = 3.6 Hz, 1 H).
13C NMR (100.6 MHz, CDCl3): d = 160.9 (oxazepine C-10), 159.8
(oxazepine N=C-8), 147.5, 138.1, 137.2, 136.0, 130.8, 128.5 (2 C),
128.4 (2 C), 127.9 (2 C), 127.6, 127.3, 127.1, 126.2, 123.7, 111.9
[acetonide C(Me2)], 105.3 (oxazepine C-9), 95.2 (glucofuranose C-
1), 82.2 (glucofuranose C-2), 81.3 (glucofuranose C-4), 80.2 (glu-
cofuranose C-3), 79.1 (OCH2Ph), 72.1 (oxazepine OCH), 57.1
(=NCH2), 26.8 [C(CH3)2], 26.3 [C(CH3)2], 21.5 (m-CH3-Ph).
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-phenyl-5-(2-thienyl)-2,3-dihy-
dro-1,4-oxazepine (4)
Yield: 72%; [a]D22.9 –150.9 (c 0.5, MeOH).
IR (thin film): 696, 765, 850, 886, 1076, 1114, 1163, 1215, 1277,
1571, 1618 cm–1.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.75 (dd, J = 14.8, 5.6 Hz, 1 H, C=NCH2),
4.17 (d, J = 2.8 Hz, 1 H, glucofuranose H-3), 4.35 (dd, J = 8.8, 3.2
Hz, 1 H, glucofuranose H-4), 4.52 (d, J = 12.0 Hz, 1 H, OCH2Ph),
4.60 (dd, J = 8.4, 6.0 Hz, 1 H, oxazepine OCH), 4.68–4.71 (m, 2 H,
OCH2Ph and glucofuranose H-2), 4.87 (d, J = 15.2 Hz, 1 H,
C=NCH2), 5.98 (d, J = 3.6 Hz, 1 H, glucofuranose H-1), 6.35 (s, 1
H, oxazepine H-9), 7.05 (app. t, J = 8.8, 4.0 Hz, 1 H), 7.17–7.25 (m,
5 H), 7.34–7.48 (m, 5 H), 7.57 (d, J = 7.6 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 160.8 (oxazepine C-10), 159.8
(oxazepine N=C-8), 147.3, 137.2, 136.0, 130.0, 128.6, 128.4 (4 C),
127.9, 127.7 (2 C), 127.3, 126.5 (2 C), 126.4, 111.9 [acetonide
C(CH3)2], 105.3 (oxazepine C-9), 95.3 (glucofuranose C-1), 82.1
HPLC-MS: m/z = 518.3 [M + 1]; purity (%) = 98.6; tR = 13.62 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C30H32NO5S:
518.2001; found: 518.2041.
Synthesis 2011, No. 21, 3523–3529 © Thieme Stuttgart · New York

3526
S. E. Kurhade et al.
PAPER
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-(4-tert-butylphenyl)-5-phenyl-
2,3-dihydro-1,4-oxazepine (7)
1H NMR (400 MHz, CDCl3): d =1.35 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.67 (dd, J = 14.4, 4.4 Hz, 1 H, C=NCH2),
3.86 (s, 3 H, C6H4OCH3), 4.20 (d, J = 2.8 Hz, 1 H, glucofuranose
H-3), 4.43 (dd, J = 7.6, 2.4 Hz, 1 H, glucofuranose H-4), 4.53 (d,
J = 12.0 Hz, 1 H, OCH2Ph), 4.64 (app. t, J = 6.0 Hz, 1 H, OCH ox-
azepine), 4.70–4.76 (m, 2 H, glucofuranose H-2 and OCH2Ph), 4.95
(d, J = 15.2 Hz, 1 H, C=NCH2), 6.00 (d, J = 2.8 Hz, 1 H, glucofura-
nose H-1), 6.21 (s, 1 H, oxazepine H-9), 6.88 (d, J = 8.8 Hz, 2 H),
7.19–7.26 (m, 5 H), 7.44–7.55 (m, 5 H), 7.80 (d, J = 7.2 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 168.4 (oxazepine C-10), 166.9
(oxazepine N=C-8), 166.1, 162.3, 138.5, 137.1, 131.2, 128.9 (2 C),
128.7 (2 C), 128.6 (2 C), 128.1 (2 C), 127.9 (2 C), 127.1, 114.1 (2
C), 112.1 [acetonide C(Me2)], 105.4 (oxazepine C-9), 94.8 (gluco-
furanose C-1), 82.0 (glucofuranose C-2), 81.1 (glucofuranose C-4),
80.8 (glucofuranose C-3), 78.7 (OCH2Ph), 72.0 (oxazepine OCH),
55.6 (4-C6H4OCH3), 54.4 (=NCH2), 26.9 [C(CH3)2], 26.3
[C(CH3)2].
Yield: 58%; [a]D24.5 –138.5 (c 1, MeOH).
IR (thin film): 698, 754, 824, 1024, 1076, 1113, 1163, 1216, 1279,
1374, 1570, 1582, 1623 cm–1.
1H NMR (400 MHz, CDCl3): d =1.35 [s, 12 H, acetonide CH3, and
C(CH3)3], 1.51 (s, 3 H, acetonide CH3), 3.75 (dd, J = 14.8, 5.6 Hz,
1 H, C=NCH2), 4.20 (d, J = 2.8 Hz, 1 H, glucofuranose H-3), 4.36
(dd, J = 8.8, 3.2 Hz, 1 H, glucofuranose H-4), 4.58 (d, J = 11.6 Hz,
1 H, OCH2Ph), 4.63 (dd actually merged in doublet, J = 9.5, 5.6 Hz,
1 H, oxazepine OCH), 4.69 (d, J = 3.6 Hz, 1 H, glucofuranose H-2),
4.72 (d, J = 12 Hz, 1 H, OCH2Ph), 4.94 (d, J = 14.8 Hz, 1 H,
C=NCH2), 5.99 (d, J = 3.6 Hz, 1 H, glucofuranose H-1), 6.26 (s, 1
H, oxazepine H-9), 7.19–7.26 (m, 5 H), 7.37–7.44 (m, 5 H), 7.53 (d,
J = 8.4 Hz, 2 H), 7.79–7.81 (m, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 166.2 (oxazepine C-10), 161.0
(oxazepine N=C-8), 153.4, 141.8, 137.3, 133.3, 129.3, 128.5 (2 C),
128.3 (2 C), 127.9, 127.8 (2 C), 127.3 (2 C), 126.3 (2 C), 125.4 (2
C), 111.9 [acetonide C(Me2)], 105.3 (oxazepine C-9), 96.7 (gluco-
furanose C-1), 82.2 (glucofuranose C-2), 81.4 (glucofuranose C-4),
80.2, (glucofuranose C-3), 79.0 (OCH2Ph), 72.2 (oxazepine OCH),
57.3 (=NCH2), 34.8 [C(CH3)3], 31.3 [(3 C, C(CH3)3], 26.8
[C(CH3)2], 26.3 [C(CH3)2].
HPLC-MS: m/z = 528.3 [M + 1]; purity (%) = 98.9; tR = 13.38 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C32H34NO6:
528.2386; found: 528.2421.
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-(4-methoxyphenyl)-5-(2-thi-
enyl)-2,3-dihydro-1,4-oxazepine (10)
Yield: 70%; [a]D23.0 –171.7 (c 0.25, MeOH).
HPLC-MS: m/z = 554.4 [M + 1]; purity (%) = 98.4; tR = 15.71 min.
IR (thin film): 755, 838, 1027, 1075, 1116, 1178, 1255, 1278, 1385,
1435, 1510, 1567, 1608 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C35H40NO5: 554.2906; found:
554.2888.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.72 (dd, J = 15.2, 5.6 Hz, 1 H, C=NCH2),
3.84 (s, 3 H, p-OCH3), 4.16 (d, J = 3.2 Hz, 1 H, glucofuranose H-
3), 4.35 (dd, J = 8.4, 2.8 Hz, 1 H, glucofuranose H-4), 4.52 (d, J =
12 Hz, 1 H, OCH2Ph) 4.58 (dd, J = 8.4, 5.6 Hz, 1 H, OCH ox-
azepine), 4.68–4.71 (m, 2 H, OCH2Ph and glucofuranose H-2), 4.85
(d, J = 15.2 Hz, 1 H, C=NCH2), 5.97 (d, J = 3.6 Hz, 1 H, glucofura-
nose H-1), 6.29 (s, 1 H, oxazepine H-9), 6.87 (d, J = 8.8 Hz, 2 H),
7.05 (app. t, J = 4.4 Hz, 1 H), 7.17–7.26 (m, 5 H), 7.34 (d, J = 5.2
Hz, 1 H), 7.46 (br s, 1 H), 7.51 (d, J = 8.8 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 161.2 (oxazepine C-10), 159.8
(oxazepine N=C-8), 137.2, 128.6, 128.5 (3 C), 128.3, 128.0 (2 C),
127.9 (2 C), 127.7 (3 C), 127.4, 113.8 (2 C), 111.9 [acetonide
C(Me2)], 105.3 (oxazepine C-9), 93.9 (glucofuranose C-1), 82.2
(glucofuranose C-2), 81.3 (glucofuranose C-4), 80.2 (glucofura-
nose C-3), 79.1 (OCH2Ph), 72.1 (oxazepine OCH), 56.9 (4-
C6H4CH3), 55.4 (=NCH2), 26.8 [C(CH3)2], 26.3 [C(CH3)2].
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-(4-tert-butylphenyl)-5-(4-eth-
ylphenyl)-2,3-dihydro-1,4-oxazepine (8)
Yield: 59%; [a]D24.2 –190.0 (c 0.5, MeOH).
IR (thin film): 697, 754, 825, 1024, 1074, 1113, 1163, 1216, 1279,
1575, 1607 cm–1.
1H NMR (400 MHz, CDCl3): d =1.26 (t, J = 7.6 Hz, 3 H, CH2CH3),
1.34 [s, 12 H, acetonide CH3, and C(CH3)3], 1.50 (s, 3 H, acetonide
CH3,), 2.70 (q, J = 7.6 Hz, 2 H, CH2CH3), 3.67 (dd, J = 15.2, 5.2
Hz, 1 H, C=NCH2), 4.20 (d, J = 2.0 Hz, 1 H, glucofuranose H-3),
4.40 (dd, J = 8.0, 2.4 Hz, 1 H, glucofuranose H-4), 4.56 (d, J = 12.4
Hz, 1 H, OCH2Ph), 4.64–4.76 (m, 3 H, oxazepine OCH, glucofura-
nose H-2 and OCH2Ph), 4.95 (d, J = 14.8 Hz, 1 H, C=NCH2), 5.99
(d, J = 2.8 Hz, 1 H, glucofuranose H-1), 6.29 (s, 1 H, oxazepine H-
9), 7.19–7.25 (m, 5 H), 7.29 (d, J = 7.6 Hz, 2 H), 7.40 (d, J = 8.4
Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 7.6 Hz, 2 H).
HPLC-MS: m/z = 534.3 [M + 1]; purity (%) = 96.7; tR = 12.94 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C30H32NO6S:
534.1950; found: 534.1988.
13C NMR (100.6 MHz, CDCl3): d = 168.4 (oxazepine C-10), 166.1
(oxazepine N=C-8), 155.1, 148.2, 137.1, 135.3, 132.1, 128.5 (2 C),
128.3 (2 C), 128.2 (2 C), 128.0, 127.9 (2 C), 126.9 (2 C), 125.7 (2
C), 112.1 [acetonide C(Me2)], 105.4 (oxazepine C-9), 95.6 (gluco-
furanose C-1), 82.9 (glucofuranose C-2), 81.1 (glucofuranose C-4),
80.9 (glucofuranose C-3), 78.7 (OCH2Ph), 72.0 (oxazepine OCH),
54.2 (=NCH2), 35.0 [C(CH3)3], 31.2 [3 C, C(CH3)2], 28.8
(CH2CH3), 26.9 [C(CH3)2], 26.3 [C(CH3)2], 15.3 (CH2CH3).
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-phenyl-5-[4-(trifluorometh-
yl)phenyl]-2,3-dihydro-1,4-oxazepine (11)
Yield: 42%; [a]D24.9 –152.4 (c 0.25, MeOH).
HPLC-MS: m/z = 582.4 [M + 1]; purity (%) = 99.9; tR = 17.53 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C37H44NO5:
IR (thin film): 766, 851, 887, 1068, 1109, 1123, 1216, 1325, 1385,
1494, 1566, 1622 cm–1.
582.3219; found: 582.3259.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.51
(s, 3 H, acetonide CH3), 3.77 (dd, J = 14.8, 5.2 Hz, 1 H, C=NCH2),
4.19 (d, J = 2.4 Hz, 1 H, glucofuranose H-3), 4.37 (d, J = 8.8 Hz, 1
H, glucofuranose H-4), 4.53–4.64 (m, 2 H, OCH2Ph and OCH ox-
azepine), 4.69–4.74 (m, 2 H, glucofuranose H-2 and OCH2Ph), 4.96
(d, J = 14.4 Hz, 1 H, C=NCH2), 5.99 (d, J = 3.2 Hz, 1 H, glucofura-
nose H-1), 6.20 (s, 1 H, oxazepine H-9), 7.19–7.24 (m, 5 H), 7.31–
7.45 (m, 3 H), 7.56 (d, J = 7.2 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H),
7.90 (d, J = 8.4 Hz, 2 H).
(2R)-2-[(3aR,5S,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-(4-methoxyphenyl)-5-phenyl-
2,3-dihydro-1,4-oxazepine (9)
Yield: 57%; [a]D24.4 –184.5 (c 1, MeOH).
IR (thin film): 699, 750, 846, 1026, 1074, 1178, 1256, 1484, 1509,
1539, 1604 cm–1.
Synthesis 2011, No. 21, 3523–3529 © Thieme Stuttgart · New York

PAPER
Novel Sugar Hybrids Based on 1,4-Oxazepine and 1,5-Oxazocine Frameworks
3527
13C NMR (100.6 MHz, CDCl3): d = 164.9 (oxazepine C-10), 161.6
(oxazepine N=C-8), 145.0, 137.2, 135.8, 130.2 (2 C), 128.6 (2 C),
128.5 (2 C), 128.0 (2 C), 127.7 (2 C), 127.7 (2 C), 126.5 (2 C),
125.3, 125.2, 112.0 [C(Me2)], 105.3 (oxazepine C-9), 96.5 (gluco-
furanose C-1), 82.2 (glucofuranose C-2), 81.3 (glucofuranose C-4),
80.2 (glucofuranose C-3), 78.9 (OCH2Ph), 72.2 (oxazepine OCH),
57.6 (=NCH2), 26.9 [C(CH3)2], 26.3 [C(CH3)2].
IR (thin film): 767, 815, 1012, 1074, 1163, 1215, 1373, 1454, 1490,
1571, 1618 cm–1.
1H NMR (400 MHz, CDCl3): d =1.36 (s, 3 H, acetonide CH3), 1.53
(s, 3 H, acetonide CH3), 3.96 (dd, J = 11.6, 5.2 Hz, 1 H, OCH2 ox-
azepine), 4.08 (app. t, J = 10.4, 5.6 Hz, 1 H, C=NCH), 4.29 (d, J =
2.8 Hz, 1 H, glucofuranose H-3), 4.44 (d, J = 12.4 Hz, 1 H,
OCH2Ph), 4.62 (d, J = 11.6 Hz, 1 H, OCH2Ph), 4.67 (d, J = 3.6 Hz,
1 H, glucofuranose H-2), 4.88 (dd, J = 6.0, 2.9 Hz, 1 H, glucofura-
nose H-4), 5.01 (d, J = 11.6 Hz, 1 H, OCH2 oxazepine), 6.07 (d,
J = 3.6 Hz, 1 H, glucofuranose H-1), 6.20 (s, 1 H, oxazepine H-9),
7.10–7.24 (m, 5 H), 7.34–7.40 (m, 5 H), 7.68 (d, J = 7.6 Hz, 2 H),
7.74 (d, J = 8.4 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 163.5 (oxazepine C-10), 162.5
(oxazepine N=C-8), 140.0, 137.3, 136.2, 135.3, 130.0, 128.8 (2 C),
128.4 (2 C), 128.4 (2 C), 128.3 (2 C), 127.8, 127.7 (2 C), 126.6 (2
C), 111.7 [acetonide C(Me2)], 105.3 (oxazepine C-9), 96.0, (gluco-
furanose C-1), 82.4 (glucofuranose C-2), 82.0 (glucofuranose C-4),
81.8 (glucofuranose C-3), 74.7 (OCH2Ph), 71.8 (oxazepine OCH),
65.0 (=NCH2), 26.9 [C(CH3)2], 26.4 [C(CH3)2].
HPLC-MS: m/z = 566.2 [M + 1]; purity (%) = 91.7.0; tR = 14.72
min.
(2R)-5-(4-Chlorophenyl)-2-[(3aR,5R,6aR)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-phenyl-2,3-dihydro-1,4-ox-
azepine (14)
Yield: 68%; [a]D23.5 –146.0 (c 1, MeOH).
IR (thin film): 755, 817, 890, 1014, 1059, 1092, 1162, 1216, 1373,
1449, 1572, 1593, 1622 cm–1.
1H NMR (400 MHz, CDCl3): d =1.34 (s, 3 H, acetonide CH3), 1.55
(s, 3 H, acetonide CH3), 1.86–1.93 (m, 1 H, glucofuranose CH2, H-
3), 2.30 (dd, J = 4.4, 3.6 Hz, 1 H, glucofuranose CH2, H-3), 3.61 (dd,
J = 14.8, 5.2 Hz, 1 H, C=NCH2), 4.21 (t, J = 4.8 Hz, 1 H, glucofura-
nose H-4), 4.51 (dd, J = 10.4, 5.2 Hz, 1 H, C=NCH2), 4.68 (d, J =
15.2 Hz, 1 H, OCH oxazepine), 4.80 (app. s, 1 H, glucofuranose H-
2), 5.89 (d, J = 2.8 Hz, 1 H, glucofuranose H-1), 6.15 (s, 1 H, ox-
azepine H-9), 7.32–7.44 (m, 5 H), 7.66–7.70 (m, 4 H).
13C NMR (100.6 MHz, CDCl3): d = 165.0 (oxazepine C-10), 161.9
(oxazepine N=C-8), 139.8, 135.9, 135.5, 130.2, 128.7 (2 C), 128.5
(2 C), 128.4 (2 C), 126.7 (2 C), 111.5 [acetonide C(Me2)], 105.7
(oxazepine C-9), 96.4 (glucofuranose C-1), 84.0, (glucofuranose C-
2), 80.4 (glucofuranose C-4), 77.9, (oxazepine OCH), 56.9
(=NCH2), 35.1 (glucofuranose C-3), 26.8 [C(CH3)2], 26.2
[C(CH3)2].
HPLC-MS: m/z = 532.3 [M + 1]; purity (%) = 97.3; tR = 14.28 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C31H31ClNO5:
532.1890; found: 532.1840.
(6aS,10aS)-4-(4-Chlorophenyl)-2-phenyl-6,6a,8,9,10,10a-
hexahydropyrano[3,2-b][1,5]oxazocine (19)
Yield: 50%; [a]D24.7 –328.3 (c 1, MeOH).
IR (thin film): 764, 799, 986, 1089, 1125, 1273, 1350, 1448, 1487,
1575, 1593, 1618 cm–1.
1H NMR (400 MHz, CDCl3): d =1.64–75 (m, 2 H, deoxysugar CH2,
H-3), 1.79 (d, J = 8 Hz, 1 H, deoxysugar CH2, H-2), 2.25 (d, J = 10.4
Hz, 1 H, deoxysugar CH2, H-2), 3.42 (dd, J = 23.6, 9.2 Hz, 2 H,
deoxysugar CH2, H-2), 3.98 (app. t, J = 13.2 Hz, 2 H, C=NCH2),
4.15–4.21 (m, 1 H, deoxysugar CH2, H-2), 4.34 (d, J = 11.2 Hz, 1
H, deoxysugar H-5), 5.60 (s, 1 H, oxazepine H-9), 7.33 (d, J = 8.4
Hz, 2 H), 7.36–7.42 (m, 3 H), 7.67 (d, J = 7.6 Hz, 2 H), 7.85 (d, J =
8.4 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 166.4 (oxazocine C-10), 160.6
(oxazocine N=C-8), 138.5, 136.3, 135.9, 129.9, 129.4 (2 C), 128.4
(2 C), 128.2 (2 C), 126.7 (2 C), 93.9 (oxazocine C-9), 75.6 (deoxy-
glucose C-5), 72.9 (deoxyglucose C-4), 68.2 (deoxyglucose C-1),
55.2 (oxazocine NCH2), 30.0 (deoxyglucose C-3), 25.2 (deoxyglu-
cose C-2).
HPLC-MS: m/z = 426.2 [M + 1]; purity (%) = 97.3; tR = 11.70 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C24H25ClNO4:
426.1472; found: 426.1466.
(2R)-5-(4-Chlorophenyl)-2-[(3aR,5R,6aR)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-7-phenyl-2,3-dihydro-1,4-ox-
azepine (15)
Yield: 56%; [a]D25.0 –147.5 (c 1, MeOH).
IR (thin film): 755, 817, 850, 1030, 1091, 1163, 1214, 1381, 1406,
1149, 1575, 1593, 1619 cm–1.
1H NMR (400 MHz, CDCl3): d =1.32 (s, 3 H,, acetonide CH3), 1.47
(s, 3 H, acetonide CH3), 2.30–2.33 (m, 2 H, glucofuranose CH2, H-
3), 3.88 (dd, J = 15.2, 5.2 Hz, 1 H, C=NCH2), 4.32 (app.q, J = 6.8
Hz, 1 H, glucofuranose H-4), 4.41 (d, J = 14.8 Hz, 1 H, C=NCH2),
4.52 (dd, J = 7.2, 5.6 Hz, 1 H, OCH oxazepine), 4.77 (dd, J = 7.2,
3.6, 1 H, glucofuranose H-2), 5.83 (d, J = 7. 3.6 Hz, 1 H, glucofura-
nose H-1), 6.15 (s, 1 H, oxazepine H-9), 7.33–7.46 (m, 5 H), 7.67
(d, J = 8.4 Hz, 2 H), 7.77 (d, J = 8.4 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 165.3 (oxazepine C-10), 162.4
(oxazepine N=C-8), 140.0, 136.2, 135.5, 130.2, 128.7 (2 C), 128.4
(4 C), 127.1 (2 C), 113.2 [C(Me2)], 106.5 (oxazepine C-9), 96.5
(glucofuranose C-1), 83.9 (glucofuranose C-2), 80.6 (glucofuranose
C-4), 79.0 (oxazepine OCH), 57.3 (=NCH2), 33.7 (glucofuranose
C-3), 27.4 [C(CH3)2], 26.5 [C(CH3)2].
HPLC-MS: m/z = 354.2 [M + 1]; purity (%) = 97.60; tR = 10.76 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C21H21ClNO2:
354.1260; found: 354.1249.
(3aS,4S,5aR,11aR,11bS)-8-(4-Chlorophenyl)-4-methoxy-2,2-
dimethyl-10-phenyl-3a,4,5a,6,11a,11b-hexahydro[1,3]dioxo-
lo[4,5]pyrano[3,2-b][1,5]oxazocine (21)
Yield: 66%; [a]D24.3 –252.3 (c 1, MeOH).
IR (thin film): 695, 762, 825, 988, 1088, 1136, 1244, 1382, 1488,
1593, 1622 cm–1.
1H NMR (400 MHz, CDCl3): d =1.32 (s, 3 H, acetonide CH3), 1.33
(s, 3 H, acetonide CH3), 3.44 (s, 3 H, mannose OCH3), 3.90 (app. t,
J = 10.8 Hz, 2 H, C=NCH2), 4.17 (d, J = 5.6 Hz, 1 H, mannose H-
2), 4.25 (app. t, J = 9.2 Hz, 1 H, mannose H-4), 4.39–4.47 (m, 2 H,
mannose H-3 and H-5), 4.99 (s, 1 H, mannose H-1), 5.62 (s, 1 H,
oxazocine H-9), 7.33 (d, J = 8.4 Hz, 2 H), 7.35–7.42 (m, 3 H), 7.72
(d, J = 7.2 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 2 H).
HPLC-MS: m/z = 426.2 [M + 1]; purity (%) = 95.2; tR = 10.71 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C24H25ClNO4:
426.1472; found: 426.1466.
(3R)-3-[(3aR,5R,6S,6aR)-6-(Benzyloxy)-2,2-dimethyltetrahy-
drofuro[2,3-d][1,3]dioxol-5-yl]-5-(4-chlorophenyl)-7-phenyl-
2,3-dihydro-1,4-oxazepine (17)
13C NMR (100.6 MHz, CDCl3): d = 166.7 (oxazocine C-10), 161.1
(oxazocine N=C-8), 138.8, 136.0, 135.8, 130.1, 129.3 (2 C), 128.4
(2 C), 128.3 (2 C), 126.8 (2 C), 109.6 [acetonide C(Me2)], 98.7 (ox-
azocine C-9), 94.3 (mannose C-1), 76.3 (mannose C-3), 76.1 (man-
Yield: 63%; [a]D24.6 +66.4 (c 1, MeOH).
Synthesis 2011, No. 21, 3523–3529 © Thieme Stuttgart · New York

3528
S. E. Kurhade et al.
PAPER
nose C-5), 76.0 (mannose C-4), 62.2 (mannose C-2), 55.2 (mannose
OCH3), 53.5 (oxazocine NCH2), 28.1 [C(CH3)2], 26.3 [C(CH3)2].
4.99 (s, 1 H, mannose H-1), 5.68 (s, 1 H, oxazocine H-9), 7.35–7.42
(m, 6 H), 7.73 (d, J = 6.8 Hz, 2 H), 7.86 (d, J = 7.2 Hz, 2 H).
HPLC-MS: m/z = 456.3 [M + 1]; purity (%) = 94.9; tR = 12.32 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C25H27ClNO5:
456.1577; found: 456.1606.
13C NMR (100.6 MHz, CDCl3): d = 168.0 (oxazocine C-10), 160.8
(oxazocine N=C-8), 140.4, 136.0, 130.0 (2 C), 128.4 (2 C), 128.2 (2
C), 128.0 (2 C), 126.9 (2 C), 109.7 [acetonide C(Me2)], 98.8 (oxazo-
cine C-9), 95.0 (mannose C-1), 76.3 (mannose C-3), 76.3 (mannose
C-5), 76.1 (mannose C-4), 62.3 (mannose C-2), 55.2 (mannose
OCH3), 53.4 (oxazocine NCH2), 28.1 [C(CH3)2], 26.4 [C(CH3)2].
(3aS,4S,5aR,11aR,11bS)-4-Methoxy-2,2-dimethyl-10-phenyl-8-
(2-thienyl)-3a,4,5a,6,11a,11b-hexahydro[1,3]dioxolo[4,5]pyra-
no[3,2-b][1,5]oxazocine (22)
HPLC-MS: m/z = 422.3 [M + 1]; purity (%) = 92.0; tR = 11.65 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C25H28NO5:
Yield: 54%; [a]D24.8 –145.9 (c 1, MeOH).
IR (thin film): 762, 855, 988, 1089, 1136, 1169, 1221, 1279, 1382,
1448, 1493, 1578, 1618 cm–1.
422.1967; found: 422.1962.
(3aS,4S,5aR,11aR,11bS)-8-(3-Fluorophenyl)-4-methoxy-2,2-
dimethyl-10-phenyl-3a,4,5a,6,11a,11b-hexahydro[1,3]dioxo-
lo[4,5]pyrano[3,2-b][1,5]oxazocine (25)
1H NMR (400 MHz, CDCl3): d =1.32 (s, 3 H, acetonide CH3), 1.33
(s, 3 H, acetonide CH3), 3.44 (s, 3 H, mannose OCH3), 3.88 (app. t,
J = 10.4 Hz, 2 H, C=NCH2), 4.17 (d, J = 5.6 Hz, 1 H, mannose, H-
2), 4.27–4.33 (m, 2 H, mannose, H-3, H-4), 4.44 (app. t, J = 5.6 Hz,
1 H, mannose H-5), 5.01 (s, 1 H, mannose H-1), 5.83 (s, 1 H, oxazo-
cine H-9), 7.02 (app. t, J = 4.8 Hz, 1 H), 7.36–7.46 (m, 5 H), 7.73
(d, J = 6.8 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): d = 161.8 (oxazocine C-10), 160.5
(oxazocine N=C-8), 146.4, 136.0, 130.1, 128.8, 128.5 (2 C), 127.8,
127.2, 126.9 (2 C), 109.7 [acetonide C(Me2)], 98.7 (oxazocine C-9),
93.3 (mannose C-1), 76.4 (mannose C-3), 76.3 (mannose C-5), 76.1
(mannose C-4), 62.5 (mannose C-2), 55.3 (mannose OCH3), 53.0
(oxazocine NCH2), 28.1 [C(CH3)2], 26.4 [C(CH3)2].
Yield: 51%; [a]D24.9 –267.8 (c 0.5, MeOH).
IR (thin film): 698, 762, 866, 988, 1054, 1090, 1136, 1177, 1221,
1269, 1383, 1448, 1483, 1572, 1625 cm–1.
1H NMR (400 MHz, CDCl3): d =1.34 [s, 6 H, acetonide C(CH3)2],
3.45 (s, 3 H, mannose OCH3), 3.91 (t, J = 10.Hz, 2 H, C=NCH2),
4.18 (d, J = 5.2 Hz, 1 H, mannose, H-2), 4.26 (t, J = 8.4 Hz, 1 H,
mannose H-4), 4.41–4.78 (m, 2 H, mannose H-3, H-5), 5.00 (s, 1 H,
mannose H-1), 5.64 (s, 1 H, oxazocine H-9), 7.10 (app. t, J = 8.4
Hz, 1 H), 7.30–7.44 (m, 4 H), 7.58–7.63 (m, 2 H), 7.72 (d, J = 6.8
Hz, 2 H).
HPLC-MS: m/z = 428.2 [M + 1]; purity (%) = 96.5; tR = 11.25 min.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C23H26NO5S:
428.1531; found: 428.1554.
13C NMR (100.6 MHz, CDCl3): d = 166.7 (oxazocine C-10), 162.8
(d, J = 244.1 Hz), 161.2 (oxazocine N=C-8), 135.8, 130.1, 129.7,
129.6, 128.5 (2 C), 126.9 (2 C), 123.7, 117.0 (d, J = 21.3 Hz), 114.9
(d, J = 22.5 Hz), 109.7 [acetonide C(Me2)], 98.8 (oxazocine C-9),
94.4 (mannose C-1), 76.4 (mannose C-3), 76.2 (mannose C-5), 76.1
(mannose C-4), 62.2 (mannose C-2), 55.2 (mannose OCH3), 53.5
(oxazocine NCH2), 28.1 [C(CH3)2], 26.3 [C(CH3)2].
(3aS,4S,5aR,11aR,11bS)-4-Methoxy-10-(4-methoxyphenyl)-2,2-
dimethyl-8-(2-thienyl)-3a,4,5a,6,11a,11b-hexahydro[1,3]dioxo-
lo[4,5]pyrano[3,2-b][1,5]oxazocine (23)
Yield: 49%; [a]D24.9 –221.2 (c 0.25, MeOH).
HPLC-MS: m/z = 440.3 [M + 1]; purity (%) = 91.7; tR = 12.03 min.
IR (thin film): 752, 854, 979, 1027, 1055, 1075, 1177, 1255, 1382,
1430, 1510, 1611 cm–1.
HRMS (MALDI-TOF): m/z [M + H]+ calcd for C25H27FNO5:
440.1873; found: 440.1836.
1H NMR (400 MHz, CDCl3): d =1.32 (s, 3 H, acetonide CH3), 1.33
(s, 3 H, acetonide CH3), 3.43 (s, 3 H, mannose OCH3), 3.84 (s, 3 H,
4-C6H4OCH3), 3.84–3.90 (m, actual triplet merged in singlet, 2 H,
C=NCH2), 4.17 (d, J = 5.6 Hz, 1 H, mannose H-2), 4.25–4.33 (m, 2
H, mannose, H-3, H-4), 4.43 (app. t, J = 6.0 Hz, 1 H, mannose H-
5), 5.00 (s, 1 H, mannose H-1), 5.75 (s, 1 H, oxazocine H-9), 6.91
(d, J = 8.8 Hz, 2 H), 7.01 (app. t, J = 4.4 Hz, 1 H), 7.35 (d, J = 5.2
Hz, 1 H), 7.41 (d, J = 2 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 2 H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H and 13C NMR spectra of all final products and in-
termediates, together with experimental procedures for preparing
the new deoxysugar azides.
13C NMR (100.6 MHz, CDCl3): d = 161.9 (oxazocine C-10), 161.2
(oxazocine N=C-8), 160.5 (4-C6H4OCH3), 146.7, 128.6, 128.5 (2
C), 127.7, 127.2 (2 C), 113.8 (2 C), 109.7 [acetonide C(Me2)], 98.7
(oxazocine C-9), 92.0 (mannose C-1), 76.4 (mannose C-3), 76.3
(mannose C-5), 76.1 (mannose C-4), 62.6 (mannose C-2), 55.5 (4-
C6H4OCH3), 55.2 (mannose OCH3), 52.9 (oxazocine NCH2), 28.1
[C(CH3)2], 26.4 [C(CH3)2].
Acknowledgment
We are grateful to Dr Rashmi Barbhaiya, Dr Kasim Mookhtiar, and
Dr Venkata Palle for their support and encouragement. Help from
the analytical department in recording spectral data is appreciated.
The authors thank Venkat Panchangula and Ajeet Singh of NCL,
Pune, for the MALDI spectra. Suggestions from the reviewers hel-
ped us in refining the manuscript, and we appreciate their help.
HPLC-MS: m/z = 458.3 [M + 1]; purity (%) = 95.1; tR = 11.85 min.
References
(3aS,4S,5aR,11aR,11bS)-4-Methoxy-2,2-dimethyl-8,10-diphe-
nyl-3a,4,5a,6,11a,11b-hexahydro[1,3]dioxolo[4,5]pyrano[3,2-
b][1,5]oxazocine (24)
(1) Advinus Publication No. ADV-A-013.
(2) For selected reviews and publications on sugar hybrids, see:
(a) Meutermans, W.; Le, G. T.; Becker, B. ChemMedChem
2006, 1, 1164. (b) Varki, A. Glycobiology 1993, 3, 97.
(c) Reddy, B. G.; Vankar, Y. D. Angew. Chem. Int. Ed. 2005,
44, 2001. (d) Chakraborty, T. K.; Srinivasu, P.; Tapadar, S.;
Mohan, B. K. Glycoconjugate J. 2005, 22, 83. (e) Dedola,
S.; Nepogodiev, S. A.; Field, R. A. Org. Biomol. Chem.
2007, 5, 1006. (f) Nandurdikar, R. S.; Subrahmanyam, A.
Yield: 43%; [a]D24.9 –237 (c 0.5, MeOH).
IR (thin film): 696, 762, 868, 987, 1016, 1090, 1054, 1136, 1221,
1382, 1447, 1497, 1574, 1624 cm–1.
1H NMR (400 MHz, CDCl3): d =1.33 [s, 6 H, acetonide C(CH3)2],
3.44 (s, 3 H, mannose OCH3), 3.92 (dd, J = 16, 9.6 Hz, 2 H,
C=NCH2), 4.17 (d, J = 5.6 Hz, 1 H, mannose H-2), 4.29 (t, J = 8.0
Hz, 1 H, mannose H-4), 4.42–4.48 (m, 2 H, mannose H-3, H-5),
Synthesis 2011, No. 21, 3523–3529 © Thieme Stuttgart · New York

PAPER
Novel Sugar Hybrids Based on 1,4-Oxazepine and 1,5-Oxazocine Frameworks
3529
V.; Kaliappan, K. P. Eur. J. Org. Chem. 2010, 2788.
Bottcher, H.; Seyfried, C. A.; Sundell, S. J. Med. Chem.
1999, 42, 2235. (e) Robl, J. A.; Sun, C.-Q.; Stevenson, J.;
Ryono, D. E.; Simpkins, L. M.; Cimarusti, M. P.; Dejneka,
T.; Slusarchyk, W. A.; Chao, S.; Stratton, L.; Misra, R. N.;
Bednarz, M. S.; Asaad, M. M.; Cheung, H. S.; Abboa-Offei,
B. E.; Smith, P. L.; Mathers, P. D.; Fox, M.; Schaeffer, T. R.;
Seymour, A. A.; Trippodo, N. C. J. Med. Chem. 1997, 40,
1570.
(g) Stark, M.; Thiem, J. Carbohydr. Res. 2006, 341, 1543.
(h) Sylvain, I.; Zerrouki, R.; Granet, R.; Huang, Y. M.;
Lagorce, J. F.; Guilloton, M.; Blais, J. C.; Krausz, P. Bioorg.
Med. Chem. 2002, 10, 57. (i) Kashyap, S.; Hotha, S.
Tetrahedron Lett. 2006, 47, 3307. (j) Idutsu, Y.; Sasaki, A.;
Matsumura, S.; Toshima, K. Bioorg. Med. Chem. Lett. 2005,
15, 4332. (k) Abrous, L.; Jokiel, P. A.; Friedrich, S. R.;
Hynes, J. Jr.; Smith, A. B. III; Hirschmann, R. J. Org. Chem.
2004, 69, 280. (l) Toshima, K.; Ozawa, T.; Kimura, T.;
Matsumura, S. Bioorg. Med. Chem. Lett. 2004, 14, 2777.
(m) Kurhade, S. E.; Mengawade, T.; Bhuniya, D.; Palle, V.
P.; Reddy, D. S. Org. Biomol. Chem. 2011, 9, 744; and
references cited therein.
(5) To our knowledge, only three instances of related oxazepine-
based sugar hybrids are documented in the literature, see:
(a) Abrous, L.; Hynes, J. Jr.; Friedrich, S. R.; Smith, A. B.
III; Hirschmann, R. Org. Lett. 2001, 3, 1089. (b) Tripathi,
S.; Singha, K.; Achari, B.; Mandal, S. B. Tetrahedron 2004,
60, 4959. (c) François-Endelmond, C.; Carlin, T.; Thuery,
P.; Loreau, O.; Taran, F. Org. Lett. 2010, 12, 40.
(6) (a) McEvoy, F. J.; Greenblatt, E. N.; Osterberg, A. C.; Allen,
G. R. Jr. J. Med. Chem. 1970, 13, 295. (b) Yale, H. L.;
Sowinski, F. J. Med. Chem. 1964, 7, 609. (c) Yale, H. L.;
Beer, B.; Pluscec, J.; Spitzmiller, E. R. J. Med. Chem. 1970,
13, 713. (d) Yale, H. L.; Sowinski, F. J. Med. Chem. 1967,
10, 1022. (e) Allen, R. C.; Reitano, P. A.; Urbach, H. J. Med.
Chem. 1978, 21, 838. (f) Mishra, J. K.; Panda, G. J. Comb.
Chem. 2007, 9, 32. (g) Sridharan, V.; Maiti, S.; Menendez,
J. S. J. Org. Chem. 2009, 74, 9365.
(3) (a) Monsigny, M.; Roche, A.-C.; Midoux, P.; Mayer, R. Adv.
Drug Delivery Rev. 1994, 14, 1. (b) Poduslo, J. F.; Curran,
G. L. Mol. Brain Res. 1994, 23, 157. (c) Polt, R.; Porreca,
F.; Szabo, L. Z.; Bilsky, E. J.; Davis, P.; Abbruscato, T. J.;
Davis, T. P.; Harvath, R.; Yamamura, H. I.; Hruby, V. J.
Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 7114. (d) Wadhwa,
M. S.; Rice, K. G. J. Drug Targeting 1995, 3, 111.
(e) Lerchen, H.-G.; Baumgarten, J.; Piel, N.; Kolb-
Bachofen, V. Angew. Chem. Int. Ed. 1999, 38, 3680.
(f) Egleton, R. D.; Mitchell, S. A.; Huber, J. D.; Janders, J.;
Stropova, D.; Polt, R.; Yamamura, H. I.; Hruby, V. J.; Davis,
T. P. Brain Res. 2000, 881, 37. (g) Davis, B. G.; Robinson,
M. A. Curr. Opin. Drug Discovery Devel. 2002, 5, 279.
(h) Jakas, A.; Horvat, S. Bioorg. Chem. 2004, 32, 516.
(i) Sampathkumar, S.-G.; Campbell, C. T.; Weier, C.;
Yarema, K. J. Drugs Future 2006, 31, 1099.
(7) Wang, J.; Li, J.; Tuttle, D.; Takemoto, J. Y.; Chang, C.-W.
T. Org. Lett. 2002, 4, 3997.
(8) Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.; Charmant,
J.; Kantacha, A. Chem. Commun. 2005, 1037.
(9) Procedures for the synthesis of new deoxysugar azides are
described in the Supporting Information; see also:
(4) (a) Serrano-Wu, M. H.; St. Laurent, D. R.; Chen, Y.; Huang,
S.; Lam, K.-R.; Matson, J. A.; Mazzucco, C. E.; Stickle, T.
M.; Tully, T. P.; Wong, H. S.; Vyas, D. M.;
(a) Nicolaou, K. C.; Hwang, C. K.; Marron, B. E.; DeFrees,
S.; Couladouro, E. A.; Abe, Y.; Carrol, P. J.; Snyder, J. P.
J. Am. Chem. Soc. 1990, 112, 3040. (b) Delgado, M.;
Martin, J. D. J. Org. Chem. 1999, 64, 4798. (c) Yadav, J.
S.; Prathap, I.; Tadi, B. P. Tetrahedron Lett. 2006, 47, 3773.
(d) Kucera, D.; Haley, G. J.; Rueden, E. J.; Wang, T. WO
140549, 2008; Chem. Abstr., 2008, 149, 576804. (e) Wu,
X.; Tang, X.; Xian, M.; Braunschweiger, P. G.; Wang, P. G.
Bioorg. Med. Chem. 2002, 10, 2303. (f) Fan, Q.-H.; Ni, N.-
T.; Li, Q.; Zhang, L.-H.; Ye, X.-S. Org. Lett. 2006, 8, 1007.
Balasubramanian, B. N. Bioorg. Med. Chem. Lett. 2002, 12,
2757. (b) Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. Bioorg.
Med. Chem. 2005, 13, 5717. (c) Seto, S.; Tanioka, A.;
Ikeda, M.; Izawa, S. Bioorg. Med. Chem. Lett. 2005, 15,
1485. (d) Liao, Y.; Venhuis, B. J.; Rodenhuis, N.;
Timmerman, W.; Wikstrom, H.; Meire, E.; Bartoszyk, G. D.;
Synthesis 2011, No. 21, 3523–3529 © Thieme Stuttgart · New York