Regioselective epoxide opening of epoxyamides derived from d-glucose. Cyclization approaches to azepanes

Article abstract of DOI:10.1016/j.tetasy.2012.12.005

Epoxyamides obtained from d-glucose have been evaluated as tools to obtain polyhydroxyazepanes. The stereoselectivity in formation of the epoxyamides was proven to be dependent of the protecting group. The conversion of epoxyamides into epoxyalcohols was

Full text of DOI:10.1016/j.tetasy.2012.12.005

Tetrahedron: Asymmetry 24 (2013) 156–163
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Tetrahedron: Asymmetry
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Regioselective epoxide opening of epoxyamides derived from D-glucose.
Cyclization approaches to azepanes
⇑
Noe Oña, Antonio Romero-Carrasco, M. Soledad Pino-González
Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 December 2012
Accepted 14 December 2012
Epoxyamides obtained from D-glucose have been evaluated as tools to obtain polyhydroxyazepanes. The
stereoselectivity in formation of the epoxyamides was proven to be dependent of the protecting group.
The conversion of epoxyamides into epoxyalcohols was necessary to obtain polyhydroxyazepanes,
because the direct cyclization of 2-N-amides to azepanecarboxamides was unsuccessful from derivatives
obtained from D-glucose. Epoxyamides and epoxyalcohols were regioselectively (alpha) opened by nitro-
gen nucleophiles. Reduction of diethyl epoxyamide by catalytic transfer hydrogenation gave the alpha
deoxy product.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
isomer of epoxides 2a, 2b and 2c, respectively (Scheme 2). The best
result was obtained for R = Me.
Iminosugars, carbohydrate mimics with a basic nitrogen instead
of an oxygen in the ring, have attracted considerable attention
from synthetic and medicinal chemists, biologists and clinical
researchers due to their potent inhibition of glycoprotein and gly-
colipid processing enzymes such as glycosidases and glycosyl-
transferases.1 Most of the work on the design and synthesis of
these inhibitors has focused on five- and six-membered iminocycl-
itols. On the other hand, the seven-membered analogues (poly-
hydroxyazepanes)2 have received less attention, although several
multistep syntheses have been reported.3 With an interest in
developing strategies for synthesizing new iminosugar and aze-
pane derivatives, we designed a methodology based on the use of
epoxyamides4 obtained from monosaccharide derivatives.5 We re-
ported the synthesis of diverse functionalized azepanes from diac-
etone mannose;6 herein we extend this methodology starting from
the inexpensive diacetone glucose (Scheme 1). Not only is our aim
to synthesize hydroxyazepanes, but also to study the influence of
the benzyl protecting group on the stereoselective epoxide forma-
tion. Additionally, the best conditions to open the epoxides regio-
selectively were established.
The absolute configuration of epoxides 2 was first tentatively
assigned on the basis of the expected configuration, by comparison
with structures previously obtained.8 These epoxides 2a, 2b and 2c
O
O
OP
PO
PO
OP
R2NOC
[N]
HO
O
O
O
O
OP
OP
[N]
OP
PO
OP
H
H
2. Results and discussion
Y
N
N
HO
HO
The known D
-gluco-diol 17 obtained from diacetone glucose was
OH
OH
HO
cleaved by periodic oxidation and the crude aldehyde was reacted
with sulfur ylides Me2SCHCONR2 (R: Et, Bn, Me) to give only the
HO
HO
polyols
OH
OH
amides: Y = CONR2
amines: Y = CH2NR2
⇑
Corresponding author. Tel.: +34 952134260; fax: +34 952131941.
E-mail address: pino@uma.es (M.S. Pino-González).
Scheme 1. Azepane synthesis via epoxyamides.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.12.005

N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
157
O
O
HO
HO
O
R2N
C
R2N
OH
R2N
OAc
C
C
O
O
OBn
a) NaIO4.SiO2, CH2Cl2
O
OBn
AcCl, py
CH2Cl2
NaN3
O
O
OBn
OBn
b) Me2S+CH2CONR2,Cl-
40% aq. NaOH
CH2Cl2
N3
N3
DMF, AcOH cat.
O
O
O
O
O
O
2a R = Et
2b R = Bn
2c R = Me
3a R = Et
3b R = Bn
3c R = Me
O
O
4b
R = Bn
R = Me
only 1 isomer
1
4c
BnNH2
EtOH
H2, Pd/C
aq. NH3
O
C
O
R2N
OH
R2N
OH
C
O
OBn
O
OBn
BnHN
H2N
O
O
O
O
5b
5c
R = Bn
R = Me
6b
R = Bn
R = Me
6c
Scheme 2. Regioselective opening of epoxyamides.
HO
HO
O
OH
O
O
7
a) NaIO4.SiO2, CH2Cl2
b) Me S+CH2CONEt2,Cl-
2
40% aq. NaOH, CH2Cl2
Et2NOC
O
Et2NOC
O
O
O
OH
OH
+
O
O
2:1
O
O
2 isomers
9
8
a) BnBr, NaH
b) NaN3, DMF, cat. AcOH
Figure 1. Preferred conformation10 for aldehydes A and B obtained by oxidation
from 7 and 1 and favoured re face attack in B.
OH
Et2NOC
N3
OH
Et2NOC
N3
O
O
OBn
OBn
and 6c could be obtained by catalytic hydrogenation of azido deriv-
atives 3b and 3c.
+
O
O
With the aim of determining the influence of the bulky benzyl
ether in the stereoselective formation of expoxides 2, we chose
the C-3 deprotected compound 7 instead of diol 1 (Scheme 3).
The results showed the benzyl protecting group essential for
achieving complete selectivity, since a 2:1 mixture of epoxyamides
8 and 9 was obtained from starting triol 7. The protection of the hy-
droxyl group at C-3 in the intermediate aldehyde (Fig. 1B)10 in-
creases steric hindrance towards the si face attack by the ylide.
Thus, the favoured re face attack leads to the formation of only
one epoxyamide. A clear dependence on the benzyl group in the
other stereoselective additions to the carbonyl group has been pre-
viously observed.11
The formation of two epoxyamides was of interest in order to
obtain 2-nitrogen amide derivatives with different configurations,
as possible precursors for a stereodivergent synthesis of hydrox-
yazepanes. Epoxyamides 8 and 9 were irresoluble by chromatogra-
phy. Therefore, we attempted to protect the free hydroxyl group,
by acetylation or benzylation of the mixture. In both cases, we
were unsuccessful in separating the protected epoxyamides. Next,
we treated the benzylated mixture with NaN3, under the same con-
ditions as for epoxyamides 2, and obtained a mixture of azido
O
O
3a
10
Scheme 3. Formation of the two trans-epoxyamides from the debenzylated
compound 7.
were opened regioselectively by NaN3 with catalytic AcOH to give
azido derivatives 3a, 3b and 3c.
Acetylation of 3b and 3c with acetyl chloride gave acetyl deriv-
atives 4b and 4c, which allowed us to better determine the struc-
ture from the NMR data. X-ray crystallographic analysis of
compound 3a9 determined the correct structure for the azido
derivatives and corroborated the proposed configuration for epox-
ides 2.
In order to obtain other nitrogen derivatives, epoxyamides 2b
and 2c were treated with BnNH2, giving compounds 5b and 5c,
respectively. Analogously, treatment with aq NH3 in a sealed tube
gave amino amides 6b and 6c. All of these reactions showed a com-
plete regioselectivity with nucleophile attack and epoxide opening
at the alpha position of the amide. Additionally, amino amides 6b

158
N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
2a
10
3a
HCO2NH4
3 hours
3 days
8
a) HCO2NH4, Pd/C
Pd/C, MeOH
MeOH, Δ
8+11
Δ
b) CbzCl,
NaHCO3
O
O
O
R2NOC
Et2NOC
OH
OH
Et2N
OH
O
Et2N
C
C
O
O
OH
O
OH
OH
NHCbz
NHCbz
+
OH
O
O
O
O
O
O
14a = Et
15
O
O
a) H2, Pd/C
11
8
MeOH, Δ
14c = Me
5c
b) CbzCl
NaHCO3
Me2C(OMe)2
Amberlyst
a) TFA/H2O
b) H2,Pd/C or
Pd(OH)2/C
MeOH,HCl
O
O
EtO
Et2N
C
C
CONEt2
O
O
CONR2
O
OH
OH
O
O
O
OH
OH
O
O
H2N
H2N
O
O
HO
HO
O
O
OH
OH
1311
12
17
16a = Et
16c = Me
Scheme 4. Regioselective reduction by catalytic transfer hydrogenation.
O
O
H
N
H
Et2N
R2NOC
N
HO
OH
OH
HO
OH
HO
HO
OH
19
18
Scheme 5. Attempts to cyclize carbamates 14a, 14c and 15 to azepanes.
of H-1 and H-5 and of the two H-6 with H-3 and H-4; this spatial
disposition is only possible for isomer 12 (Fig. 2).12 These results
confirmed the absolute (R)-configuration at C-5 in 12 and the C-6
regioselective epoxide opening in the reduction process.
With azidocompounds 3a and 10 in hand, we continued with
the azepane synthesis (Scheme 5). Catalytic transfer hydrogenation
and subsequent protection with benzyloxycarbonyl chloride gave
carbamate compounds 14a and 15, respectively. The dimethyl
amide 14c could be obtained via the benzyl amino derivative 5c
by catalytic hydrogenation and further treatment with benzyloxy-
carbonyl chloride and sodium bicarbonate. Hydrolysis of carba-
mates 14a, 14c or 15, separately, with aq trifluoroacetic acid and
further hydrogenation in the presence of 10% Pd/C, hydrochloric
acid and methanol might lead to the carboxamide azepanes 18
and 19. However, a complex mixture of compounds was achieved.
The NMR spectra showed predominantly the formation of stable
pyranoses 16 and 17. Increasing the hydrogenation times caused
secondary products to form and azepanes 18 and 19 could not be
characterized. Catalytic transfer hydrogenation gave similar re-
sults. An alternative was hydrolysis of the amino derivatives 6 fol-
lowed by catalytic hydrogenation, but this gave an analogous
mixture of products. Difficulties in the cyclization to azepanes of
Figure 2. NOE experiments for 12.
amides 3a and 10, which could be separated. The major isomer had
the same NMR data to that of azide 3a obtained from diol 1.
Epoxyamide 8 was also obtained by debenzylation of 2a
(Scheme 4). Thus, epoxyamide 2a was subjected to catalytic trans-
fer hydrogenation with ammonium formate and 10% Pd/C in meth-
anol for 3 h, giving the debenzylated compound 8. When the
reduction was continued for 3 d under the same conditions, a chro-
matographically irresoluble mixture was obtained. 1H NMR
showed it was a mixture of epoxide 8 and diol 11 (2:3, 8/11), a re-
sult of regioselective epoxide reduction. Increasing the reaction
time gave a more complex mixture. Treatment of the mixture
8/11 with 2,2-dimethoxypropane and AmberlystÒ 15 led to the
acetalization of diol 11 to give di-O-isopropylidene derivative 12.
This tricyclic compound 12 could be isolated and compared with
the ester analogue 13, obtained by asymmetric reduction.10 We
were able to observe NOE effects that showed the spatial proximity
other D
-glucose derivatives have been described13 and the only
product obtained was aminohexopyranose.
In order to obtain pentahydroxyazepanes, epoxyamides 2a and
2b were treated separately with Red-AlÒ in THF, followed by
NaBH4 in MeOH (Scheme 6); this combined reduction14 gave

N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
159
HO
spectrometers at room temperature. Chemical shifts (ppm) are re-
ported relative to the residual solvent peak. Multiplicities are des-
ignated as: singlet (s), doublet (d), triplet (t), multiplet (m) and b
(broad). Coupling constants J are expressed in Hertz units. NMR
assignments were undertaken based on two-dimensional COSY
and gHMQC experiments. IR spectra of the azido compounds
showed the N3 typical band at 2324–2352 cmꢀ1. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter. High resolu-
tion mass spectra (HRMS) were recorded with a Micromass Auto-
SpecQ instrument of the University of Granada.
O
a) RedAl
THF, 0 ºC
O
OBn
2a
2b
or
b) NaBH4
O
MeOH, 0 ºC
O
20
NaN3, Me3B
DMF, Δ
H
4.2. Typical procedure for the synthesis of epoxyamides from
diol 1
OH
HO
HO
N
O
22
from
OR
X
OH
HO
ref. 16
The crude aldehyde obtained from 2.27 g (7.32 mmol) of diol 1
by periodic oxidation3 was dissolved in dichloromethane (32 mL)
after which the sulfonium salt R2S+CH2CONR2ꢁClꢀ (R: Et, Bn or
Me, 1.2 equiv) and 40% aq NaOH (7.8 mL) were added. The reaction
mixture was stirred at room temperature and monitored by TLC.
After completion of the reaction (over 1 h), water was added and
the organic phase separated. The aqueous phase was extracted
with dichloromethane (twice) and the organic layers were washed
with water, dried over NaSO4 and evaporated in vacuo to obtain
epoxides 2a, 2b and 2c, which were purified by flash column chro-
matography to give the pure epoxyamides as colourless syrups.
O
OH
HO
O
23
21
X = N3, R = Bn
a) HCO2NH4
Pd/C, MeOH, Δ
b) CbzCl, Et3N
22
X = NHCbz, R = H
Scheme 6. Synthesis of polyhydroxylated azepane 23.
epoxyalcohol 20 in 68% yield (two steps). The 1H NMR data of com-
pound 20 matched with that described for this stereoisomer, pre-
viously obtained by
4.2.1. N,N-Diethyl-5,6-anhydro-3-O-benzyl-1,2-O-
isopropylidene-L-glycero-a-D-gluco-heptofuranuronamide 2a
a
stereodivergent method.15 Finally, we
Sixty percent yield, two steps. Rf: 0.3 (1:1 hexanes/ethyl ace-
tate). ½a 2D0
ꢂ
ꢀ 22 (c 1.2, AcOEt). 1H NMR (CDCl3, 400 MHz, d ppm):
obtained azidoalcohol 21 with complete regioselectivity, which
was hydrogenated to the aminoalcohol and protected as its carba-
mate 22. This compound can be transformed into azepane 23 fol-
7.30–7.20 (m, 5H, Ph), 5.88 (d, 1H, J = 3.76 Hz, H-1), 4.64–4.53
(m, 3H, CH2Ph), 4.03 (m, 2H), 3.63 (d, 1H, J = 2.15 Hz, H-6), 3.46–
3.16 (m, 5H, 2NCH2CH3 and H-5), 1.41 and 1.25 (2s, 2 ꢃ 3H,
CMe2), 1.13 and 1.06 (2t, 2 ꢃ 3H, NEt2). 13C NMR (CDCl3,
100 MHz, d ppm): 165.5 (CO), 136.6–127.5 (Ph), 111.5 (CMe2),
104.8 (C-1), 82.0, 81.4 and 79.0 (C-2, C-3 and C-4), 71.9 (CH2Ph),
54.1 and 51.2 (C-5 and C-6), 40.8 and 40.3 (2NCH2CH3), 26.4 and
25.8 (CMe2), 14.2 and 12.6 (2NCH2CH3).
lowing Dhavales procedure.16 The advantages of using our
´
route,17 are that it is totally regioselective and requires a smaller
number of steps from D-glucose aldehyde, in comparison with that
previously described.16 Azepane 23 showed inhibition activity
against b-glucosidase and b-galactosidase in millimolar
concentrations.18
3. Conclusion
4.2.2. N,N-Dibenzyl 2b
Seventy six percent yield, two steps. Rf: 0.7 (1:1 hexanes/ethyl
acetate). ½a 1D7
ꢂ
¼ þ25 (c 0.78, CH2Cl2) 1H NMR (CDCl3, 400 MHz, d
We have demonstrated the utility of D-glucose-derived epoxya-
mides in the synthesis of polyhydroxylated azepane 23 using a reg-
ioselective epoxide opening protocol. The sequence of reduction
with Red-AlÒ, followed by NaBH4, has been shown to be a good
choice to obtain epoxyalcohols from carbohydrate derivative
epoxyamides. However, conversely to the mannose series,6 the
cyclizations of the amino derivatives to carboxamide azepanes 18
and 19 were not effective. More cyclization alternatives are cur-
rently under investigation and will be described in due course.
ppm): 7.33–7.08 (m, 15H, 3Ph), 5.80 (d, 1H, J = 3.22 Hz, H-1),
4.90 (d, 1H, J = 14.51 Hz, CH2Ph), 4.62 (d, 1H, J = 4.39 Hz, H-3),
4.60–4.50 (m, 2H, 2 ꢃ CH2Ph), 4.13–4.08 (m, 3H, CH2Ph and H-4),
4.03 (d, 1H, J = 3.22 Hz, H-2), 3.74 (d, 1H, J = 2.15 Hz, H-6), 3.53
(dd, 1H, J = 2.15, 4.84 Hz, H-5), 1.38 and 1.24 (2s, 2 ꢃ 3H, CMe2).
13C NMR (CDCl3, 50 MHz, d ppm): 167.3 (CO), 136.6–126.6 (3Ph),
111.8 (CMe2), 104.9 (C-1), 82.1, 81.5 and 78.8 (C-2, C-3 and C-4),
72.0 (CH2Ph), 54.8, 51.8, 48.6 and 48.1 (C-5, C-6 and 2NCH2),
26.6 and 26.0 (CMe2). HRMS (FAB): m/z 515.23077 [M+H]+
(C31H33NO6 requires 515.23079).
With regard to the regioselective
a epoxide opening by azides,
the best option was the combination of NaN3/cat. AcOH for
epoxyamides and NaN3/(MeO)3B for the epoxyalcohols. Reduction
of epoxide group in 2a with catalytic transfer hydrogenation was
4.2.3. N,N-Dimethyl 2c
also
a regioselective, giving the C-6 deoxy compound 11.
Eighty nine percent yield, two steps. Rf: 0.2 (1:1 hexanes/ethyl
acetate). ½a 1D7
ꢂ
¼ ꢀ7 (c 5.24, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d
4. Experimental
4.1. General
ppm): 7.30–7.20 (m, 5H, Ph), 5.87 (d, 1H, J1,2 = 3.76 Hz, H-1),
4.64–4.52 (m, 3H, CH2Ph and H-3), 4.06 (d, 1H, J2,1 = 3.76 Hz, H-
2), 4.04 (s, 1H, H-4), 3.67 (d, 1H, J6,5 = 2.15 Hz, H-6), 3.40 (dd, 1H,
J5,6 = 2.15 Hz, J5,4 = 4.30 Hz, H-5), 2.94 and 2.88 (s, 6H, NMe2),
1.41 (s, 3H, CH3) and 1.25 (s, 3H, CH3). 13C NMR (CDCl3, 50 MHz,
d ppm): 166.6 (CO), 136.9–127.9 (Ph), 112.0 [C(CH3)2], 105.2 (C-
1), 82.4, 81.9 and 79.5 (C-2, C-3 and C-4), 72.4 (CH2Ph), 54.3 and
52.0 (C-5 and C-6), 36.2 and 35.5 (NMe2), 26.7 and 26.1 (CMe2).
HRMS (FAB): m/z 364.17600 [M+H]+ (C19H26NO6 requires
364.17601).
Reactions were monitored by thin layer chromatography (TLC)
on E. Merck silica gel plates (0.25 mm) and visualized using UV
light (254 nm) and/or heating with phosphomolybdic acid/cerium
sulfate(IV)/H2SO4 aq solution. Flash chromatography was per-
formed on E. Merck silica gel (60, particle size 0.040–0.063 mm).
NMR spectra were recorded on a Bruker Avance-400 or WP200SY

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N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
4.3. Synthesis of epoxyamides from diol 7: N,N-diethyl-5,6-
anhydro-1,2-O-isopropylidene- -glycero- -gluco-heptofur-
anuronamide 8 and N,N-diethyl-5,6-anhydro-1,2-O-isopro-
pylidene- -glycero- -ido-heptofuranuronamide 9
In an analogous manner, N,N-dimethyl 3c was obtained from 2c
as a white solid in 75% yield. Compound 3c had: Rf 0.7 (1:1 hex-
L
a-D
anes/ethyl acetate). mp: 128–132 °C. ½a D24
¼ ꢀ1 (c 1.09, CH2Cl2).
ꢂ
D
a-L
1H NMR (CDCl3, 200 MHz, d ppm): 7.36–7.24 (m, 5H, Ph), 5.83 (d,
1H, J1,2 = 3.0 Hz, H-1), 4.75–4.61 (m, 2H, CH2Ph), 4.53 (d, 1H,
J6,5 = 3.66 Hz, H-6), 4.41 (dd, 1H, J4,3 = 3.05 Hz, J4,3 = 9.77 Hz, H-5),
4.11 (d, 1H, J3,4 = 3.05 Hz, H-3), 4.07 (d, 1H, H-2), 3.98 (dd, 1H,
J4,3 = 3.05 Hz, J4,5 = 9.15 Hz, H-4), 3.10 and 3.00 (s, 6H, NMe2),
1.40 (s, 3H,CH3) and 1.27 (s, 3H,CH3).13C NMR (CDCl3, 50 MHz, d
ppm): 169.4 (CO), 137.3–127.5 (Ph), 111.7 [C(CH3)2], 104.9 (C-1),
82.2, 81.0 and 80.7 (C-2, C-3 and C-4), 72.6 and 70.9 (C-5 and
CH2Ph), 55.3 (C-6), 37.4 and 35.1 (NMe2), 26.6 and 26.1
[C(CH3)2]. HRMS (FAB): m/z 407.19304 [M+H]+ (C19H27N4O6 re-
quires 407.19306).
The crude aldehyde obtained from diol 7 (6.27 g, 22.58 mmol)
by periodic oxidation,3 was dissolved in dichloromethane
(115 mL) and the sulfonium salt Et2S+CH2CONMe2ꢁCl (5 g,
27.23 mmol) and 40% aq NaOH (28 mL) were added. The reaction
mixture was stirred at room temperature and monitored by TLC.
After 1 h, water was added and the organic phase separated. The
aqueous phase was extracted with dichloromethane (2 ꢃ 5 mL)
and the organic layers were washed with water, dried over
NaSO4 and evaporated in vacuo to obtain an irresoluble mixture
of epoxides 8 and 9 (2:1 by 1H NMR, 7.34 g, 89%, two steps). Rf:
0.2 (1:1 hexanes/ethyl acetate). 1H NMR (CDCl3, 400 MHz, d ppm,
data obtained from the mixture); 8: 5.90 (d, 1H, J1,2 = 3.76 Hz, H-
1), 4.54 (d, 1H, H-2), 4.43 (d, 1H, J3,4 = 2.73 Hz, H-3), 3.95 (dd,
1H, J4,5 = 5.64 Hz, H-4), 3.67 (d, 1H, J6,5 = 2.39 Hz, H-6), 3.50–
3.30 (m, 5H, H-5, 2NCH2), 1.48 and 1.31 (2s, 2 ꢃ 3H, CMe2),
1.25 and 1.13 (2q, 2 ꢃ 3H, CH2Me). 13C NMR (CDCl3, 100 MHz,
4.5. Acetylation of azide 3b and azide 3c
To a solution of azide 3b (380 mg, 0.68 mmol) or 3c (100 mg,
0.25 mmol) in CH2Cl2 were added 3 equiv of acetyl chloride, pyri-
dine and a catalytic amount of DMAP. After stirring for 5 h, an aq
solution of HSO4Na was added and the product extracted with
CH2Cl2. Evaporation of the solvent gave 4b (270 mg, 66%) or 4c
(75 mg, 68%), respectively. Compound 4b had Rf: 0,5 (3:1, hex-
d
ppm): 166.2 (CO), 136.9– and 128.2–127.4 (Ph), 111.0
(CMe2), 104.5 (C-1), 85.1, 80.7 and 73.7 (C-2, C-3 and C-4),
71.9 (CH2Ph), 53.9 and 51.2 (C-5 and C-6), 40.8 and 40.1
(NCH2), 26.3 and 25.6 (CMe2), 13.9 and 12.3 (CH2Me). 9: 5.90
(d, 1H, J1,2 = 2.73 Hz, H-1), 4.51 (d, 1H, H-2), 4.37 (d, 1H,
J2,1 = 2.73 Hz, H-3), 4.26 (dd, 1H, H-4), 3.67 (d, 1H,
J6,5 = 2.39 Hz, H-6), 3.55–3.30 (m, 5H, H-5, 2NCH2), 1.49 and
1.32 (2s, 2 ꢃ 3H, CMe2), 1.27 and 1.15 (2q, 2 ꢃ 3H, Me). 13C
NMR (CDCl3, 100 MHz, d ppm): 165.9 (CO), 111.0 (CMe2), 104.5
(C-1), 84.9, 79.7 and 75.2 (C-2, C-3 and C-4), 71.6 (CH2Ph),
55.2 and 49.4 (C-5 and C-6), 41.1 and 40.3 (2NCH2), 26.3 and
25.7 (CMe2), 14.1 13.6 and 12.3 CH2Me).
anes/ethyl acetate). ½a D20
ꢂ
¼ ꢀ17 (c 0.7, MeOH). 1H NMR (CDCl3,
400 MHz,
d ppm): 7.31–7.10 (m, 15H, 3Ph), 5.80 (d, 1H,
J1,2 = 3.76 Hz, H-1), 5.62 (dd, 1H, J5,4 = 8.60, J5,6 = 4.30, H-5), 4.90
(d, 1H, J = 13.4, CH2Ph), 4.67 (d, 1H, J = 17.19 Hz, CH2Ph), 4.53–
4.30 (m, 6H, 2CH2Ph, H-2, H-4, H-6), 4.19 (d, 1H, J = 14.5, CH2Ph),
3.92 (d, 1H, J3,4 = 3.2, H-3), 1.92 (s, 3H, CH3CO), 1.33 and 1.25 (2s,
2 ꢃ 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d ppm): 169.5 (CONBn2),
166.8 (COO), 136.7–126.6 (3Ph), 112.1 (CMe2), 105.1 (C-1), 81.4 (C-
2), 80.9 (C-3), 78.2 (C-4), 72.0 and 69.8 (C-5 and CH2Ph), 58.5 (C-6),
49.4 and 48.3 (2NCH2), 26.6 and 26.3 (CMe2), 20.7 (CH3CO). Com-
pound 4c had Rf: 0,5 (4:3, hexanes/ethyl acetate). ½a D20
¼ ꢀ35 (c
ꢂ
4.4. Typical procedure for azide epoxide opening: N,N-dibenzyl-
1.2, AcOEt). 1H NMR (CDCl3, 200 MHz, d ppm): 7.32–7.29 (m, 5H,
Ph), 5.85 (d, 1H, J1,2 = 3.7, H-1), 5.61 (dd, 1H, J5,4 = 9.1, J5,6 = 4.3,
H-5), 4.59–4.40 (m, 3H, J6,5 = 5.49, CH2Ph and H-6), 4.35 (d, 1H,
J2,1 = 3.7, H-2), 4.30 (dd, 1H, J4,3 = 3.05 J4,5 = 9.1, H-4), 3.92 (d, 1H,
J3,4 = 3.05, H-3), 3.08 and 2.95 (s, 6H, NMe2), 1.98 (s, 3H, CH3CO),
1.44 and 1.28 (s, 3H, CMe2). 13C NMR (CDCl3, 50 MHz, d ppm):
169.5 (CONMe2), 166.2 (COO), 136.6–128.1 (Ph), 112.1 [C(CH3)2],
105.2 (C-1), 81.3 (C-2), 80.8 (C-3), 77.8 (C-4), 72.1 and 69.4 (C-5
and CH2Ph), 57.9 (C-6), 37.5 and 35.9 (NMe2), 26.7 and 26.3
(CMe2), 20.7 (CH3CO).
6-azido-3-O-benzyl-6-deoxy-1,2-O-isopropylidene-
D-glycero-a-
D-gluco-heptofuranuronamide 3b
To a stirred solution of epoxyamide 2b (4.85 g, 9.39 mmol) in
DMF (15 mL) were added NaN3 (0.92 g, 14.2 mmol) and acetic acid
(0.53 mL, 9.39 mmol). The reaction mixture was refluxed for 2 d,
eluted with AcOEt and washed with water. The combined organic
extracts were dried (anhydrous MgSO4) and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (hexanes/ethyl acetate 5:1), to give 3b (3.69 g, 70%)
as a white foam. Rf: 0.5 (5:1 hexanes/ethyl acetate); mp: 51–
4.6. N,N-Dimethyl-6-benzylamino-3-O-benzyl-6-deoxy-1,2-O-
isopropylidene-D-glycero-a-D-gluco-heptofuranuronamide 5c
59 °C. ½a 2D4
ꢂ
¼ þ28 (c 0.5, CH2Cl2). 1H NMR (CDCl3, 400 MHz, d
ppm): 7.34–7.17 (m, 15H, 3Ph), 5.79 (d, 1H, H-1), 4.69 and (d,
2 ꢃ 1H, CH2Ph) ꢀ4.40 (m, 8H), 4.17–4.10 (m, 3H), 1.29 and 1.25
(2s, 2 ꢃ 3H, 2Me). 13C NMR (CDCl3, 100 MHz, d ppm): 170.0 (CO),
137.4–127.0 (3Ph), 111.8 [C(CH3)2], 105.1 (C-1), 82.4 (C-2), 81.2
(C-3), 80.8 (C-4), 72.6 and 71.4 (C-5 and CH2Ph), 56.2 (C-6), 49.8
and 47.6 (2NCH2), 26.7 and 26.2 [C(CH3)2]. In an analogous man-
ner, N,N-diethyl 3a was obtained from 2a as a white solid; mp
To a stirred solution of 2c (2.2 g, 6.06 mmol) in EtOH (8 mL) was
added BnNH2 (0.99 mL). The reaction mixture was refluxed for 1 d
and then concentrated under reduced pressure. The residue was
purified by flash column chromatography (hexanes/ethyl acetate
1:1), to give 5c (2.13 g, 75%) as a colourless oil. Rf: 0.5 (1:1 hex-
anes/ethyl acetate). ½a D17
ꢂ
¼ ꢀ7 (c 2.12, CH2Cl2). 1H NMR (CDCl3,
102–103 °C; ½a 2D9
ꢂ
¼ ꢀ2:3 (c 1.4, CH2Cl2).
200 MHz, d ppm): 7.40–7.20 (m, 10H, Ph), 5.82 (d, 1H, J1,2 = 3.7,
H-1), 4.64 (at, 2H, J = 12.8, OCH2Ph), 4.51 (d, 1H, J1,2 = 3.7, H-2),
4.25 (dd, 1H, J5,6 = 2.44, J4,5 = 6.1, H-5), 4.05 (d, 1H, J5,6 = 2.4, H-6),
3.87 (d, 1H, J3,4 = 3.1, H-3), 3.79 (dd, 1H, J4,5 = 6.1, J3,4 = 3.1, H-4),
3.73 (at, 2H, J = 12.8, NCH2Ph), 2.93 and 2.88, (2s, 2 ꢃ 3H, NCMe2),
1.37 and 1.26 (2s, 2 ꢃ 3H, CMe2). 13C NMR (CDCl3, 50 MHz, d ppm):
174.2 (CO), 139.1–126.8 (2Ph), 111.3 [C(CH3)2], 104.7 (C-1), 82.2,
81.2 and 80.6 (C-2, C-3 and C-4), 72.3 and 68.6 (C-5 and CH2Ph),
54.8 and 50.9 (C-6 and NCH2), 37.2 and 35.0 (NMe2), 26.5 and
26.1 (CMe2). HRMS (FAB): m/z 471.24960 [M+H]+ (C26H35N2O6 re-
quires 471.24951). In an analogous manner, N,N-dibenzyl 5b was
obtained from 2b as a colourless syrup in 98% yield. Compound
1H NMR (CDCl3, 400 MHz, d ppm): 7.37–7.26 (m, 5H, Ph), 5.84,
(d, 1H, J1,2 = 3.22 Hz, H-1), 4.73 and 4.65 (2d, 2 ꢃ 1H, CH2Ph),
4.53 (d, 1H, H-2), 4.40 (dd, 1H, J4,5 = 9.57, 2.73, H-4), 4.13 and
3.97 (2d, J3,4 = J5,6 = 2.73 Hz, H-6 and H-3), 3.98 (dd, H-5), 3.58,
3.48 and 3.32 (3 m, 4H, CH2Me) 1.40 and 1.30 (2s, 2 ꢃ 3H, 2Me),
1.22 and 1.18 (2t, 2 ꢃ 3H, CH2Me).
13C NMR (CDCl3, 50 MHz, d ppm): 168.9 (CO), 137.5 and 128.3–
127.6 (Ph), 111.7 (CMe2), 105.0 (C-1), 82.4, 81.1 and 80.9 (C-2, C-3
and C-4), 72.7 and 71.2 (C-5 and CH2Ph), 55.2 (C-6), 42.7 and 40.8
(2NCH2), 26.6 and 26.1 (CH2CH3). HRMS (FAB): m/z 435.22430).
[M+H]+ (C21H31N4O6 requires 435.22436).

N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
161
5b had: Rf 0.8 (3:2 hexanes/ethyl acetate). ½a D20
ꢂ
¼ ꢀ31 (c 0.72,
2 ꢃ 1H, CH2Ph), 4.65 (d, 1H, H-2), 4.45 and 4.38 (2dd, J 4,5 = 1.71
and J = 3.76, 9.22 Hz, H-4 and H-5), 4.18 and 4.06 (2d, J = 3.76,
9.22 Hz, H-3 and H-6), 3.43 and 3.26 (2 m, 4H, CH2Me) 1.50 and
1.34 (2s, 2 ꢃ 3H, 2Me), 1.18 and 1.19 (2t, 2 ꢃ 3H, CH2Me). 13C
NMR (CDCl3, 100 MHz, d ppm): 167.6 (CO), 136.1, 128.5–127.7
(Ph), 112.1 (CMe2), 104.7 (C-1), 84.1, 82.3 and 77.4 (C-2, C-3 and
C-4), 72.0 and 70.4 (C-5 and CH2Ph), 57.7 (C-6), 41.9 and 40.9
(2NCH2), 26.8 and 26.3 (CMe2), 14.3 and 12.9 (CH2Me).
CH2Cl2) 1H NMR (CDCl3, 400 MHz, d ppm): 7.30–7.16 (m, 20H,
4Ph), 5.83 (d, 1H, J = 3.76 Hz, H-1), 4.81–4.55 (m, 4H, 2CH2Ph),
4.50 (d, 1H, J = 3.76 Hz, H-2), 4.38–4.33 (m, 3H, CH2Ph and H-5),
4.12 (dd, 1H, J = 3.22, 9.13 Hz, H-4), 4.07 (d, 1H, J = 3.22 Hz, H-3),
3.88 (d, 1H, J = 3.22 Hz, H-6), 3.65 (m, 2H, NCH2Ph), 1.24 and
1.23 (2s, 2 ꢃ 3H, CMe2). 13C NMR (CDCl3, 50 MHz, d ppm): 174.6
(CO), 139.6–126.8 (4Ph), 111.5 (CMe2), 105.0 (C-1), 82.4, 81.9 and
80.6 (C-2, C-3 and C-4), 72.5 and 67.9 (C-5 and CH2Ph), 56.5 (C-
6), 51.1, 49.6 and 47.6 (3NCH2), 26.6 and 26.1 (CMe2). HRMS
(FAB): m/z 623.31208 [M+H]+ (C38H43N2O6 requires 623.31211).
4.9. N,N-Diethyl-6-deoxy-1,2:3,5-di-O-isopropylidene-a-D-glu-
co-heptofuranuronamide 12
4.7. N,N-Dimethyl-6-amino-3-O-benzyl-6-deoxy-1,2-O-isopro-
pylidene-D-glycero-a-D-gluco-heptofuranuronamide 6c
To a solution of 2a (350 mg, 0.89 mmol) in dry MeOH (6 mL)
were added ammonium formate (0.45 g) and 10% Pd/C (75 mg).
The reaction mixture was refluxed for 3 d, then filtered through a
pad of Celite and the filtrates concentrated under reduced pressure
to give a residue. NMR data showed this to be product 11 joined to
debenzylated epoxide 8 (ꢄ3:2), which could not be separated by
column chromatography. The mixture was dissolved in dichloro-
methane (4 mL) after which Amberlyst 15 (250 mg) and dime-
thoxypropane (0.28 mL, 2.3 mmol) were added. After stirring for
6 h, the resin was filtered away and the solution was concentrated
to give a residue which was purified by column chromatography to
give 190 mg of diacetal 12 (62%, two steps) and epoxide 8 (54 mg,
20%). Compound 12 had: 1H NMR (CDCl3, 400 MHz, d ppm): 5.97
(d, 1H, J1,2 = 3.76, H-1), 4.56 (d, 1H, J1,2 = 3.76, H-2), 4.28 (dd, 1H,
J4,3 = 4.30, J4,5 = 7.52, H-4), 4.07 (d, 1H, H-3), 4.07 (ddd, J5,6 = 4.84,
J5,6´ = 12.36, H-5), 3.30 (m, 4H, 2NCH2), 2.58 (m, 2H, H-6,60), 1.46,
1.36, 1.30 and 1.29 (4s, 4 ꢃ 3H, 2CMe2), 1.14 and 1.07 (2t,
2 ꢃ 3H, 2CH2CH3). 13C NMR (CDCl3, 50 MHz, d ppm): 168.8 [CO],
112.0 and 101.1 (CMe2), 106.2 (C-1), 84.2 (C-2), 82.7 (C-3) 75.0
(C-4), 68.9 (C-5), 41.9 and 40.2 (NMe2), 36.7 (CH2CO), 27.2, 26.5
and 23.8 (double) (2CMe2), 14.2 and 12.9 (2CH2CH3). HRMS
(FAB): m/z 344.20725 [M+H]+ (C17H30NO6 requires 344.20731).
In a sealed tube was placed epoxyamide 2c (138 mg, 0,4 mmol)
and treated with aq 28% NH4OH (5 mL). After 2 d with stirring at rt,
TLC (hexanes/ethyl acetate 1:4) showed no starting material and a
new more polar product. The reaction mixture was concentrated to
a colourless syrup and purified by preparative TLC to give pure 6c
(129 mg, 89%). ½a D17
ꢂ
¼ þ1 (c 0.96, AcOEt). 1H NMR (CDCl3, 400 MHz,
d ppm): 7.34–7.24 (m, 5H, Ph), 5.85 (d, 1H, J1,2 = 3.76 Hz, H-1), 4.66
(m, 2H, CH2Ph), 4.53 (d, 1H, J2,1 = 3.76 Hz, H-2), 4.08 (d, 1H,
J = 2.69 Hz), 4.05–4.01 (m, 2H), 3.84 (dd, 1H, J = 2.69 Hz,
J = 9.13 Hz), 3.13 and 2.94 (2s, 2 ꢃ 3H, NMe2), 1.39 and 1.27 (2s,
2 ꢃ 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d ppm): 174.5 (CO),
137.6–127.6 (Ph), 111.6 (CMe2), 105.0 (C-1), 82.3, 81.4 and 81.3
(C-2, C-3 and C-4), 72.6 and 71.5 (CH2Ph, C-5), 50.0 (C-6), 37.6
and 35.3 (NMe2), 26.7 and 26.2 (CMe2). M.S.: 91 (Bn), 72
(M+ꢀ308), 249 (M+ꢀ131). In an analogous manner, was obtained
N,N-dibenzyl 6b as a colourless syrup. Rf: 0.3 (1:1 hexanes/ethyl
acetate) 1H NMR (CDCl3, 400 MHz, d ppm): 7.32–7.15 (m, 15H,
3Ph), 5.81 (d, 1H, J = 3.76 Hz, H-1), 4.71–4.60 (m, 4H, 2CH2Ph and
H-3), 4.50 (d, 1H, J = 3.76 Hz, H-2), 4.46 (d, 1H), 4.32 (d, 1H),
4.09–3.99 (m, 4H), 1.25 and 1.24 (2s, 2 ꢃ 3H, CMe2). 13C NMR
(CDCl3, 100 MHz, d ppm): 175.7 (CO), 137.6–127.0 (3Ph), 111.6
(CMe2), 105.1 (C-1), 82.4, 81.5 and 81.3 (C-2, C-3 and C-4), 72.6
and 72.4 (CH2Ph and C-5), 50.7, 49.8 and 47.8 (2NCH2 and C-6),
4.10. Synthesis of carbamates 14a, 15 and N,N-dimethyl-6-(N-
benzyloxycarbonylamino)-6-deoxy-1,2-O-isopropylidene-
D-gly-
cero- -gluco-heptofuranuronamide 14c
a-D
26.7 and 26.2 (CMe2). ½a D20
¼ ꢀ27:5 (c 0.92, AcOEt). HRMS (FAB):
ꢂ
m/z 533.26510 [M+H]+ (C31H37N2O6 requires 533.26516).
To a solution of azidoamide 3a (304 mg, 0.69 mmol) in dry
MeOH (2.3 mL) were added ammonium formate (257 mg,
4.07 mmol) and 10% Pd/C (46 mg). The reaction mixture was re-
fluxed for 2 d and then filtered through a pad of Celite. The filtrates
were concentrated under reduced pressure to give 243 mg
(0.59 mmol, 86%) of crude amine. The residue was dissolved in
MeOH (10 mL), cooled at 0 °C and then benzyl chloroformate
(0.13 mL, 0.91 mmol) and NaHCO3 (0.14 g) were added with stir-
ring. After 6 h, the reaction mixture was concentrated, the residue
dissolved in AcOEt (75 mL) and the organic solution was washed
with water (2 ꢃ 25 mL), dried (anhydrous MgSO4) and concen-
trated under reduced pressure, to give crude product 14a
(208 mg). Analogously, the reduction of azidoamide 10 (648 mg,
1.58 mmol) gave 565 mg (87%) of the crude amine. Its protection
gave carbamate 15 (459 mg, 61%). Both compounds 14a and 15
could be used in the next reaction without purification. Synthesis
of 14c: To a solution of benzylamine 5c (2.1 g, 4.46 mmol) in dry
MeOH (16 mL) were added ammonium formate (1.78 g) and 10%
Pd/C (0.32 g). The reaction mixture was refluxed for 2 d and then
filtered through a pad of Celite. The filtrates were concentrated un-
der reduced pressure. The crude amine was dissolved in MeOH,
cooled at 0 °C and then benzyl chloroformate (0.94 mL, 6.69 mmol)
and NaHCO3 (1.76 g) were added with stirring. After 2 d, the reac-
tion mixture was neutralized with citric acid and the product ex-
tracted with dichloromethane. The organic solvents were dried
(anhydrous MgSO4) and concentrated under reduced pressure, to
give crude product 14c. Flash chromatography gave pure carba-
4.8. Synthesis of azide 3a and N,N-diethyl-6-azido-3-O-benzyl-6-
deoxy-1,2-O-isopropylidene-L-glycero-a-L-ido-heptofuranuron-
amide 10 from epoxyamides 8 and 9
To a solution of 1.61 g (5.34 mmol) of the mixture of isomers 3a
and 10 in THF (25 mL) at 0 °C were added NaH (280.5 mg, 7 mmol,
60% in mineral oil), TBAI (22 mg, 0.06 mmol) and BnBr (0.68 ml,
5.7 mmol) dropwise, with stirring. After the addition, the reaction
was allowed to return to room temperature. After being left over-
night, the solvent was concentrated and the residue was eluted
with CH2Cl2 (250 mL) and washed with aq 5% NaOH and then with
water. Organic solvent was dried (anhydrous MgSO4) and gave
1.72 g (83%) of the isomeric benzylated epoxyamides with the
same Rf: 0.4 (1:1 hexanes/ethyl acetate). To 1.14 g (2.91 mmol) of
this irresoluble mixture dissolved in DMF (18 mL) were added so-
dium azide (281 mg, 4.36 mmol) and acetic acid (0.18 mL). The
reaction was heated at 95 °C for 48 h. The mixture was then eluted
with AcOEt (100 mL) and washed with water (3 ꢃ 25 mL). The or-
ganic solvent was dried (anhydrous MgSO4) and concentrated. The
residue was purified by column chromatography to give azide 3a
(640 mg, Rf: 0.6, 2:1 hexanes/ethyl acetate) and azide 10
(235 mg, Rf: 0.2, 2:1 hexanes/ethyl acetate), 69% total yield, two
steps. Isomer 3a had the same data as the product obtained from
2a. Isomer 10 had: 1H NMR (CDCl3, 400 MHz, d ppm): 7.38–7.27
(m, 5H, Ph), 6.02 (d, J1,2 = 3.76 Hz, 1H, H-1), 4.71 and 4.55 (2d,

162
N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
mate 14c (1.13 g, 60% two steps). ½a D17
ꢂ
¼ ꢀ15 (c 0.92, CH2Cl2). 1H
2 ꢃ 3H, CMe2). 13C NMR (CDCl3, 100 MHz, d ppm): 136.8–127.9
NMR (CDCl3, 200 MHz, d ppm): 7.29 (m, 5H, Ph), 6.27 (br d, 1H,
OH), 5.86 (d, 1H, J1,2 = 3.6, H-1), 5.03 (m, 4H, OCH2Ph, H-6, OH),
4.45 (d, 1H, H-2), 4.32 (d, 1H, J3,4 = 2.4, H-3), 4.04 (ddd, 1H,
J5,6 = 3.7, J4,5 = 9.2, J5,OH = 9.7, H-5), 3.79 (dd, 1H, H-4), 3.23 and
2.91 (2s, 2 ꢃ 3H, NMe2), 1.37 and 1.25 (2s, 2 ꢃ 3H, CMe2). 13C
NMR (CDCl3, 100 MHz, d ppm): 172.0 (CONMe2), 156.0 (CONH),
136.0, 128.3 and 127.9 (Ph), 111.5 (C-1), 105.1 (CMe2), 84.8 (C-2),
80.4 (C-4), 74.3 (C-3), 70.1 (C-5), 66.9 (CH2Ph), 49.7 (C-6), 37.8
and 35.5 (NMe2), 26.7 and 26.2 (CMe2). HRMS (FAB): m/z
425.19242 [M+H]+ (C20H29N2O8 requires 425.19239).
(Ph), 111.9 (CMe2), 105.0 (C-1), 81.8 and 81.7 (C-2, C-3), 78.9 (C-
4), 72.1 and 69.9 (C-5 and CH2Ph), 64.4 and 62.0 (C-6 and C-7),
26.7 and 26.2 (CMe2).
4.14. 6-(N-Benzyloxycarbonylamino)-6-deoxy-1,2-O-
isopropylidene-D-glycero-a-D-gluco-heptofuranose 22
To a solution of 21 (300 mg, 0.82 mmol) in dry MeOH (5 mL)
were added ammonium formate (0.41 g) and 10% Pd/C (70 mg).
The reaction mixture was refluxed for 1 d and then filtered through
a pad of Celite which was washed with MeOH. The filtrates were
concentrated under reduced pressure to give a more polar com-
pound. The crude product was dissolved in MeOH/H2O (5 mL,
9:1) and treated with benzyl chloroformate (0.14 mL, 1.2 equiv)
and NaHCO3 (0.14 g) at 0 °C. After 2 h, the mixture was concen-
trated, extracted with AcOEt and the solvents evaporated to give
a residue which was purified by column chromatography to give
carbamate 2216 (159 mg, 50%, two steps). Rf: 0.3 (1:3 hexanes/ethyl
acetate). 1H NMR (CDCl3, 400 MHz, d ppm): 7.32 (br s, 5H, Ph), 5.92
(d, 1H, J1,2 = 3.22 Hz, H-1), 5.83 (d, 1H, J = 6.98 Hz, NH), 5.09 (m, 2H,
CH2Ph), 4.50 (d, 1H, J = 3.76 Hz), 4.39 (s, 1H), 4.16 (m, 1H), 4.00–
3.92 (m, 3H), 3.70 (dd, 1H, J = 4.30 Hz, J = 12.36 Hz), 1.43 and
1.28 (2s, 2 ꢃ 3H, 2CH3). 13C NMR (CDCl3, 100 MHz, d ppm): 158.0
(CO), 135.9–128.1 (Ph), 112.1 (CMe2), 105.2 (C-1), 84.6, 79.3 and
75.5 (C-2, C-3 and C-4), 72.6 and 67.4 (CH2Ph and C-5), 61.9 (C-
7), 54.9 (C-6), 26.9 and 26.2 (CMe2).
4.11. Attempts to cyclize carbamates 14a, 14c and 15 to
azepanes
Carbamate 14c (0.5 g, 1.10 mmol) was treated with TFA/water
(5 mL, 3:2) and heated (40–45 °C) for 3 h. Then, the hydrolysed
mixture was concentrated under vacuum and the residue dissolved
in MeOH/HCl 9:1 and hydrogenated with 10% Pd/C for 3 d. After
work-up, the 13C NMR showed a mixture of pyranoses which could
not be purified.
4.12. 5,6-Anhydro-3-O-benzyl-1,2-O-isopropylidene-
-gluco-heptofuranose 20
L-glycero-
a-D
A 70% Red-AlÒ solution in toluene (0.35 mL, 1,24) was added
dropwise to a solution of 2a (300 mg, 0.76 mmol) in THF (9 mL)
at 0 °C. After stirring for 20 min, ethyl acetate was added followed
by a solution of aqueous sodium potassium tartrate and the mix-
ture was stirred for further 15 min. The reaction mixture was ex-
tracted with AcOEt, dried over anhydrous MgSO4, concentrated
under reduced pressure, and then used in the next step without
purification. The aldehyde obtained (Rf: 0.8, 1:2 hexanes/ethyl ace-
tate) was dissolved in dry MeOH (5 mL), cooled at 0 °C and treated
with NaBH4 (16 mg, 0.42 mmol). After stirring for 20 min, the reac-
tion was quenched with several drops of water and concentrated
under reduced pressure. The residue was purified by column chro-
matography to give 20 (180 mg, 74%, two steps). The same com-
pound was obtained from 2b (1.89 g, 3.66 mmol) with a lower
yield (705 mg, 60%, two steps). Epoxyalcohol had Rf: 0.7 (1:2 hex-
Acknowledgments
This research was supported by funds from Dirección General
de Investigación Científica y Técnica of Spain (CTQ2007-66518/
BQU and CTQ2010-16933/BQU and from Consejería de Educación
y Ciencia, Junta de Andalucia (FQM 158 and FQM 03329).
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anes/ethyl acetate). ½a D17
ꢂ
¼ ꢀ28 (c 0.52, CH2Cl2).1H NMR (CDCl3,
400 MHz, d ppm): 7.40–7.26 (m, 5H, Ph), 5.94 (d, 1H, J1,2 = 3.8, H-
1), 4.69 and 4.62 (2d, 2H, J = 11.8, CH2Ph), 4.63 (d, 1H, H-2), 4.07
(d, 1H, J2,3 = 3.2, H-3), 3.95 (m, 2H, H-4, H-7), 3.65 (dd, 1H,
J6,7 = 4.8, J7,7 = 12.9, H-70), 3.32 (dd, 1H, J4,5 = 6.4, J5,6 = 2.1, H-5),
3.25 (ddd, 1H, J6,7 = 6.9, H-6), 1.46 and 1.31 (2s, 2 ꢃ 3H, 2CH3).
0
0
13C NMR (CDCl3, 50 MHz,
d ppm): 139.4–126.7 (Ph), 111.7
4. For other examples of epoxide formation see: (a) Sarabia, F.; Chammaa, S.;
Garcia-Castro, M.; Martin-Galvez, F. Chem. Commun. 2009, 38, 5763–5765; (b)
Illa, O.; Arshad, M.; Ros, A.; McGarrigle, E. M.; Aggarwal, V. K. J. Am. Chem. Soc.
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Chem. Soc. 2005, 127, 2147–2155; (d) Aggarwal, V. K.; Hynd, G.; Picoul, W.;
Vasse, J.-L. J. Am. Chem. Soc. 2002, 124, 9964–9965; (e) Nemoto, T.; Kakei, H.;
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Aparicio, D. M.; Teran, J. L.; Gnecco, D.; Galindo, A.; Juarez, J. R.; Orea, M. L.;
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Ruiz, A.; Chammaa, S. Chem. Eur. J. 2012, 18, 15190–15201; (i) Sarabia, F.; Vivar-
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C.; Oña, N. Tetrahedron: Asymmetry 2008, 19, 932–937.
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(CMe2), 105.0 (C-1), 79.5, 79.2 and 76.5 (C-2, C-3 and C-4), 70.9
(CH2Ph), 61.2 (C-7), 57.4 (C-6), 52.5 (C-5), 25.5 and 25.0 (CMe2).
4.13. 6-Azido-3-O-benzyl-6-deoxy-1,2-O-isopropylidene-
D-
glycero- -gluco-heptofuranose 21
a-D
To a stirred solution of epoxyalcohol 20 (65 mg, 0.20 mmol) in
DMF (2 mL) were added NaN3 (25 mg, 0.40 mmol) and (MeO)3B
(0.04 mL, 0.40 mmol). The reaction mixture was heated at 70 °C
and monitored by TLC. After 2 d, aqueous NaHCO3 was added por-
tionwise at 0 °C and the mixture was stirred for 30 min and then
extracted with AcOEt. The combined organic extracts were dried
(anhydrous MgSO4) and concentrated under reduced pressure.
Purification by flash column chromatography (hexanes/ethyl ace-
tate 2:3), afforded pure 2116a,bas a colourless oil (68 mg, 92%). Rf:
0.7 (1:2 hexanes/ethyl acetate). ½a D17
ꢂ
¼ ꢀ40 (c 0.68, CH2Cl2). 1H
NMR (CDCl3, 200 MHz, d ppm): 7.40–7.26 (m, 5H, Ph), 5.94 (d,
1H, H-1), 4.77–4.50 (m, 3H), 4.26–4.12 (m, 3H, CH2Ph, H-2), 3.90
(d, 2H), 3.60 (q, 1H), 2.46 (br s, 2H, OH), 1.49 and 1.32 (2s,

N. Oña et al. / Tetrahedron: Asymmetry 24 (2013) 156–163
163
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