General synthesis of sugar-derived azepane nitrones: Precursors of azepane iminosugars

Article abstract of DOI:10.1021/jo400130p

A general and efficient method has been developed for the synthesis of sugar-derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones, which are precursors of various azepane iminosugars.

Full text of DOI:10.1021/jo400130p

Article
pubs.acs.org/joc
General Synthesis of Sugar-Derived Azepane Nitrones: Precursors of
Azepane Iminosugars
Wen-Bo Zhao,†,# Shinpei Nakagawa,‡ Atsushi Kato,‡ Isao Adachi,‡ Yue-Mei Jia,† Xiang-Guo Hu,†
George W. J. Fleet,§ Francis X. Wilson,∥ Graeme Horne,∥ Akihide Yoshihara,⊥ Ken Izumori,⊥
and Chu-Yi Yu*,†
†Beijing National Laboratory of Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
§Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, U.K.
∥Summit PLC, 91 Milton Park, Abingdon, Oxon OX14 4RY, U.K.
⊥Rare Sugar Research Center, Kagawa University, 2393 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0795, Japan
#University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A general and efficient method has been
developed for the synthesis of sugar-derived azepane nitrones
starting from aldohexoses, with an intramolecular condensa-
tion of aldehyde and hydroxylamine as the key step. Through
this strategy, each aldohexose produced a pair of azepane
nitrones, which are precursors of various azepane iminosugars.
or azepane nitrones have yet to be reported. On the basis of our
ongoing projects10j−m on the synthesis and application of sugar-
derived cyclic nitrones, herein we report the synthesis of
azepane nitrones.
Intramolecular N-alkylation, the most widely used strategy in
cyclic nitrone synthesis, was not applicable here. As shown in
Scheme 1, D-glucose-derived aldehyde 1 gave oxime 2 when
INTRODUCTION
■
Because of their prominent biological activities, iminosugars
have been extensively investigated for the past 30 years.1
Compared to naturally occurring five- and six-membered
iminosugars, their higher homologues, the polyhydroxylated
azepanes or the azepane iminosugars, have been relatively less
investigated. Azepane iminosugars were first synthesized by
Paulsen in 1967.2 Thirty years later, Wong3 evaluated their
bioactivities and found comparable outcomes with five- and six-
membered iminosugars, which inspired more and more interest
in this field.4−9
Scheme 1. Unsuccessful Intramolecular N-Alkylation
Strategy
New azepane iminosugar family members also appeared.
Seven-membered DNJ homologues5 and 1-N-iminosugars6
both showed good inhibitory activities, while acetylamino
group substituted azepanes were inhibitors of N-acetyl-β-
hexosaminidases.7 Polyhydroxylated perhydroazaazulenes,8 aze-
panes in bicyclic form, were synthesized, though no good
bioactivities have been found yet. Several higher homologues of
calystegine also showed promising inhibitory results.9 However,
few efficient synthetic strategies have been exploited to enable
convenient structure modifications.
As powerful synthons, sugar-derived cyclic nitrones could
greatly facilitate the molecular diversity-oriented iminosugar
synthesis and the study of their structure−activity relation-
ship.10 Five-membered cyclic nitrones have been used widely
for preparing pyrrolidine-based iminosugars,10c−m and six-
membered cyclic nitrones for piperidine-based ones.10m,n To
our knowledge, sugar-derived seven-membered cyclic nitrones
condensed with NH2OH but failed to undergo subsequent
intramolecular alkylation to give nitrone 3 under various
conditions.11 Other leaving groups such as -OTs and -I were
also tried without success; intramolecular nucleophilic sub-
stitution to form seven-membered rings is less favorable than
for five- and six-membered rings.
Received: January 21, 2013
Published: March 4, 2013
© 2013 American Chemical Society
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RESULTS AND DISCUSSION
Scheme 4. Synthesis of Nitrone 3 through Path A
■
Synthesis of Azepane Nitrones. To solve the problem
mentioned above, the azepane ring may be formed first. Diol 4
was obtained from D-mannitol as described (Scheme 2).12 After
Scheme 2. Synthesis of Azepane Nitrone 7 from D-Mannitol
reduction of the resulting oxime with sodium cyanoborohy-
dride gave hydroxylamine 16 in 71% yield over two steps.
Acidic hydrolysis of the dioxolane afforded the desired nitrone
3 in 79% yield. It is necessary to switch the protecting group
dithioacetal to acetal. All attempts to initiate a cascade
hydrolysis of the dithioacetal and subsequent intramolecular
condensation failed to give nitrone 3. Path A introduced a
hydroxylamine at C6 of D-glucose and then formed the nitrone
by condensation on to C1.
double mesylation of the two primary hydroxyl groups, the N-
substituted azepane 5 was given by substitution with allylamine
in 71% yield over two steps. Deallylation of 5 with 1-
chloroethyl chloroformate13 afforded secondary amine 6 in 86%
yield. Using Busque
́
and Figueredo’s protocol,14 6 was finally
oxidized to nitrone 7 in 78% yield as the sole product.
The strategy is efficient only for the oxidation of C2-
symmetric azepanes since only a single nitrone can be
produced; the oxidation of unsymmetrical azepanes, such as
that derived from D-glucitol, showed little regioselectivity,
giving a mixture of two nitrones in 1:3 ratio, which were
difficult to separate. Oxidation of meso-azepanes gave racemic
mixtures.
For path B (Scheme 5), successive oxidation of alcohol 11,
protection of the aldehyde 17 with ethylene glycol and
Scheme 5. Synthesis of Nitrone 21 through Path B
To both increase the ring formation activity and avoid the
regioselectivity problem, we turned to a less used strategy in
cyclic nitrone synthesis: the intramolecular condensation of a
hydroxylamine and an aldehyde.15 D-Glucose with propane-1,3-
dithiol in concentrated hydrogen chloride16 gave the open
chain dithioacetal 8 in 89% yield. Successive tritylation of the
primary hydroxyl group, benzylation of the other secondary
hydroxyl groups in 9 and detritylation, furnished 11 in which
only the C6 alcohol is unprotected (69% yield over three steps)
(Scheme 3).
Scheme 3. Synthesis of Tetrabenzyloxylated Alcohol 11 from
D-Glucose
hydrolysis of the dithioacetal 18 with NBS afforded aldehyde
19 in 68% yield over three steps. Aldehyde 19 was then
transformed to nitrone 21 through similar steps as path A in
51% yield. Path B yielded a nitrone from a hydroxylamine
derived from C1 and an aldehyde derived from C6 of D-glucose.
The two D-glucose-derived nitrones 3 and 21 were thus readily
accessible.
To verify the generality of this condensation strategy, three
other aldohexoses, D-gulose (Scheme 6), D-altrose (Scheme 7)
and L-talose (Scheme 8), were all subjected to the same
sequence described above. Eight azepane nitrones (four pairs of
enantiomers) in all were obtained with yields of 20−44% from
the intermediate tetrabenzyloxylated alcohols (Table 1). The
instability of 40, ent-40, 44 and ent-44 led to lower yields in the
intramolecular condensation step (Table 1, entries 3 and 4),
which need careful workup and especially avoidance of high
temperatures.
Synthesis of 2-C-Alkylated Azepane Iminosugars. The
potential of the nitrones to prepare azepane iminosugars is
illustrated by nucleophilic addition of organometallic reagents
to nitrone 7; diastereoselective addition formed hydroxylamines
54a−f (Scheme 9). Grignard reagents gave good yields and
With alcohol 11 in hand, the subsequent route divided into
two independent paths. For path A (Scheme 4), after
acetylation of the hydroxyl group of 11, the dithioacetal 12
was transformed into acetal 13 with NBS in the presence of
ethylene glycol. Subsequent deacetylation gave alcohol 14 in
73% yield over three steps. Direct change of dithioacetal to
acetal without hydroxyl group protection gave a lower yield.
Swern oxidation of 14 gave aldehyde 15 in 90% yield.
Condensation of aldehyde 15 with NH2OH, followed by
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Scheme 6. Synthesis of D-Gulose-Derived Nitrones ent-3 and ent-21
Scheme 7. Synthesis of D-Altrose-Derived Nitrones 40 and 44
Scheme 8. Synthesis of L-Talose-Derived Nitrones ent-40 and ent-44
excellent d.r. (Scheme 9, entries 1 to 4); MOMOCH2Li17 gave
a relatively lower yield and poorer d.r. (Scheme 9, entry 5);
TMSCF3 gave hydroxylamine 54f along with unreacted nitrone
7 and also in excellent d.r. (Scheme 9, entry 6). After Pd/C
catalyzed hydrogenolysis, 2-C-alkylated azepane iminosugars
55a−f were obtained in high yields. This class of seven-
membered iminosugar C-glycosides has been rarely reported in
the literature.18
The configurations of the new chiral center at C-2 were
1
determined by H NMR spectroscopy. The coupling constants
J2,3 of the hydroxylamine 54a−d were all between 7 to 8 Hz,
which are consistent with 2,3-trans relative configuration. The
fully deprotected 2-C-alkylated azepanes 55a−f also showed
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Table 1. Aldohexose-Derived Azepane Nitrones
CONCLUSIONS
■
In summary, two efficient synthetic approaches toward azepane
nitrones have been developed: (i) C2-symmetric azepane initial
formation of the seven-membered ring, and (ii) for unsym-
metrical azepanes intramolecular condensation of aldehyde and
hydroxylamine as the key step. Several 2-C-alkylated azepane
iminosugars were prepared, and their glycosidase inhibition
activities showed interesting results. Extension of these
strategies to synthesize various azepane nitrones and their
further applications in azepane iminosugar preparation are
under investigation.
EXPERIMENTAL SECTION
■
General Methods. All reagents were used as received from
commercial sources or prepared as described in the literature.
Reactions were stirred using Teflon-coated magnetic stirring bars.
Analytical TLC was performed with 0.20 mm silica gel 60F plates with
254 nm fluorescent indicator. TLC plates were visualized by ultraviolet
light or by treatment with a spray of Pancaldi reagent {(NH4)6MoO4,
Ce(SO4)2, H2SO4, H2O} or a solution of 0.5% ninhydrin in acetone.
Chromatographic purification of products was carried out by flash
column chromatography on silica gel (230−400 mesh). Acidic ion
exchange chromatography was performed on Amberlite IR-120 (H+)
or Dowex 50WX8−400, H+ form. Melting points were determined
using an electrothermal melting point apparatus. Infrared spectra were
recorded on an FT-IR spectrometer. NMR spectra were measured in
CDCl3 (with TMS as internal standard) or D2O on a magnetic
resonance spectrometer (1H at 300 MHz, 13C at 75 MHz). Chemical
shifts (δ) are reported in ppm, and coupling constants (J) are in Hz.
The following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High-
resolution mass spectra (HRMS) were recorded on an LTQ/FT linear
ion trap mass spectrometer. Polarimetry measurements were made at
the sodium D-line with a 0.5 dm path length cell. Concentrations (c)
are given in gram per 100 mL.
a
b
Obtained from aldohexose after four steps. Overall yield from
c
tetrabenzyloxylated alcohol through path A. Overall yield from
tetrabenzyloxylated alcohol through path B.
Scheme 9. Synthesis of 2-C-Alkylated Azepane Iminosugars
55a−f from Nitrone 7
(3R,4R,5R,6R)-1-Allyl-3,4,5,6-tetrakis(benzyloxy)azepane (5).
Methanesulfonyl chloride (460 mg, 4 mmol) was added dropwise to a
solution of diol 4 (543 mg, 1.0 mmol) and triethylamine (606 mg, 6.0
mmol) in CH2Cl2 (5 mL) at 0 °C. The reaction mixture was stirred at
rt for 2 h. CH2Cl2 (20 mL) was added, and the solution was washed
with H2O (2 × 10 mL). The organic layer was dried (Na2SO4) and
concentrated under reduced pressure. The residue was redissolved in
allylamine (5 mL) and heated at reflux for 24 h. The solution was
condensed in vacuo, and the residue was purified by flash
chromatography (silica gel, petroleum ether/EtOAc 5:1) to afford
20
tertiary amine 5 (398 mg, 71% for 2 steps) as a colorless oil: [α]D
=
−16.7 (c 0.6, CHCl3); IR (cm−1) 3063, 3030, 2866, 1642, 1496, 1453,
1367, 1206, 1092, 1068, 1027, 920, 736, 697; H NMR (300 MHz,
1
a
b
1
Determined by H NMR analysis of a crude product. Isolated yield
c
d
CDCl3) δ 7.30−7.23 (m, 20H), 5.93−5.80 (m, 1H), 5.18−5.11 (m,
1H), 4.71 (d, J = 12.3 Hz, 2H), 4.60−4.49 (m, 6H), 3.98 (dd, J = 2.4,
8.4 Hz, 2H), 3.90 (s, 2H), 3.16 (d, J = 6.3 Hz, 2H), 2.99 (dd, J = 5.6,
13.0 Hz, 2H), 2.73 (dd, J = 3.0, 13.0 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 139.0, 138.8, 136.0, 128.6, 128.4, 128.3, 127.8, 127.7,
127.50, 127.48, 117.6, 79.9, 76.4, 73.4, 71.5, 61.5, 52.7; HRMS-ESI
(m/z) calcd for C37H42NO4 [M + H]+ 564.3108, found 564.3104.
(3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)azepane (6). To a
solution of tertiary amine 5 (605 mg, 1.07 mmol) in 1,2-
dichloroethane (5 mL) was added 1-chloroethylchloroformate (307
mg, 2.14 mmol), and the resulting solution was stirred under reflux
overnight. The solvent was removed in vacuo, and the residue was
redissolved in MeOH (5 mL). The resulting solution was again heated
at reflux overnight and then concentrated under reduced pressure. The
residue was purified by flash column chromatography (silica gel,
petroleum ether/EtOAc, 1:1) to give azepane 6 (480 mg, 86%) as a
white solid: mp 76−78 °C; [α]D20 = −34.0 (c 1.0, CHCl3); IR (cm−1)
3444, 3062, 3031, 2919, 1589, 1496, 1454, 1369, 1207, 1095, 1069,
of nucleophilic addition. Yield of catalytic hydrogenation. For 54e,
R= −CH2OMOM; for 55e, R= −CH2OH.
relatively larger J2,3 (5 to 8 Hz) and smaller J3,4 (2 to 3 Hz),
which further proved the same C-2 configurations of 54a−f.
The trans diastereoselective addition is consistent with a
Felkin−Anh transition-state model.19
Glycosidase Inhibition. Azepane iminosugars 55a−f were
assayed as potential glycosidase inhibitors of a range of enzymes
(Table 2). None of 55a,d−f showed any inhibition toward the
tested enzymes. However, compound 55b showed weak
inhibition against β-galactosidase (bovine liver, IC50 = 505
μM), while 55c showed good inhibition against β-galactosidase
(bovine liver, IC50 = 4.5 μM) and β-glucosidase (bovine liver,
IC50 = 12 μM). The alkyl chain length appears to affect the
glycosidase inhibition.
1
1027, 909, 736, 698; H NMR (300 MHz, CDCl3) δ 7.36−7.16 (m,
20H), 4.72 (d, J = 12.0 Hz, 2H), 4.63−4.58 (m, 3H), 4.54−4.49 (m,
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Table 2. Concentration of Iminosugars Giving 50% Inhibition of Various Glycosidases
ab
,
IC50 (μM)
enzyme
55a
55b
55c
55d
55e
55f
α-glucosidase
yeast
NI (13.6%)
NI (14.9%)
NI (10.2%)
NI (5.7%)
NI (5.5%)
NI (21.0%)
539
NI (3.9%)
NI (7.1%)
NI (5.6%)
NI (4.1%)
NI (2.1%)
NI (10.5%)
NI (2.5%)
NI (14.2%)
NI (20.3%)
rice
NI (11.3%)
NI (8.6%)
rat intestinal maltase
β-glucosidase
almond
NI (7.5%)
NI (39.7%)
NI (46.7%)
591
12
NI (9.6%)
NI (6.9%)
NI (0.7%)
NI (9.3%)
bovine liver
NI (27.8%)
NI (15.5%)
NI (27.1%)
α-galactosidase
coffee beans
β-galactosidase
bovine liver
NI (19.4%)
NI (35.5%)
NI (0%)
NI (8.1%)
505
NI (34.2%)
4.5
NI (3.6%)
NI (14.3%)
NI (0.9%)
NI (0.8%)
NI (15.9%)
NI (1.1%)
NI (2.0%)
NI (2.8%)
NI (9.7%)
NI (19.6%)
NI (3.7%)
NI (1.7%)
NI (10.4%)
NI (1.2%)
NI (0%)
NI (2.6%)
NI (6.9%)
NI (5.9%)
NI (2.4%)
NI (6.8%)
NI (0.7%)
NI (1.7%)
NI (2.0%)
α-mannosidase
jack beans
NI (2.2%)
NI (6.7%)
NI (7.7%)
NI (3.4%)
NI (4.0%)
NI (22.1%)
NI (9.8%)
581
β-mannosidase
snail
NI (0.3%)
NI (19.9%)
NI (4.8%)
NI (1.5%)
NI (12.5%)
α-L-fucosidase
bovine kidney
α,α-trehalase
porcine kidney
amyloglucosidase
Aspergillus niger
α-L-rhamnosidase
Penicillium decumbens
NI (1.1%)
NI (8.3%)
NI (0.5%)
NI (5.7%)
NI (0%)
a
b
NI: No inhibition (less than 50% inhibition at 1000 μM). Value in parentheses indicates inhibition % at 1000 μM.
3H), 4.09 (dd, J = 1.2, 8.4 Hz, 2H), 3.72 (s, 2H), 3.50−3.43 (m, 2H),
3.36−3.32 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 138.6, 138.5,
128.42, 128.39, 127.8, 127.71, 127.66, 78.8, 77.8, 73.6, 71.9, 46.2;
HRMS-ESI (m/z) calcd for C34H38NO4 [M + H]+ 524.2795, found
524.2790.
5.5 Hz, 1H), 3.89−3.76 (m, 3H), 3.73−3.65 (m, 1H), 3.06−2.89 (m,
4H), 2.20−2.10 (m, 1H), 1.94−1.80 (m, 1H); 13C NMR (75 MHz,
D2O) δ 73.5, 71.6, 71.1, 69.4, 62.8, 49.2, 29.0, 28.3, 25.3.
6-O-Trityl-D-glucose propane-1,3-diyl dithioacetal (9). The
mixture of dithioacetal 8 (11.3 g, 42.0 mmol), trityl chloride (12.3 g,
44.0 mmol) and 4-dimethylamino-pyridine (51 mg, 0.42 mmol) in
pyridine (150 mL) was stirred at 35 °C for 48 h and then concentrated
in vacuo. H2O (200 mL) was added, and the resulting mixture was
extracted with EtOAc (3 × 100 mL). The combined organic layer was
dried (MgSO4) and condensed under reduced pressure. The residue
was purified by flash chromatography (silica gel, CH2Cl2/MeOH
100:1) to afford compound 9 (18.1 g, 86%) as a white solid: mp 68−
(3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahy-
dro-7H-azepine 1-oxide (7). Oxone (7.38 g, 12.0 mmol) was added
batchwise to the mixture of azepane 6 (5.23 g, 10.0 mmol) and
NaHCO3 (4.20 g, 5.0 mmol) in MeCN (40 mL)/THF (10 mL)/0.01
M Na2EDTA (40 mL) at 0 °C. The resulting mixture was stirred for 3
h. EtOAc (100 mL) was added, and the resulting mixture was washed
with brine (2 × 30 mL). The combined organic layer was dried
(MgSO4) and concentrated under reduced pressure. The residue was
purified by flash chromatography (silica gel, petroleum ether/EtOAc
1:1) to afford nitrone 7 (4.27 g, 78%) as a yellow oil: [α]D20 = −44.0
(c 1.0, CHCl3); IR (cm−1) 3061, 3030, 2869, 1588, 1496, 1453, 1368,
20
71 °C; [α]D = −4.0 (c 1.0, CHCl3); IR (cm−1) 3432, 3058, 3032,
2932, 2900, 1651, 1635, 1597, 1491, 1448, 1422, 1266, 1221, 1076,
1
1032, 910, 766, 737, 706, 633; H NMR (300 MHz, CDCl3) δ 7.45−
7.20 (m, 15H), 4.29 (d, J = 6.6 Hz, 1H), 4.05−3.98 (m, 2H), 3.93−
3.88 (m, 1H), 3.86−3.83 (m, 1H), 3.51 (s, 1H), 3.43 (d, J = 3.0 Hz,
1H), 3.36 (d, J = 5.1 Hz, 2H), 3.08 (d, J = 8.4 Hz, 1H), 2.92−2.81 (m,
3H), 2.64−2.59 (m, 2H), 2.08−1.92 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 143.7, 128.6, 128.0, 127.2, 87.0, 74.2, 73.5, 71.1, 68.1, 64.9,
46.7, 27.1, 26.4, 25.3; HRMS-ESI (m/z) calcd for C28H32NaO5S2 [M +
Na]+ 535.1583, found 535.1585.
1
1237, 1207, 1169, 1094, 912, 820, 738, 698; H NMR (300 MHz,
CDCl3) δ 7.34−7.17 (m, 20H), 7.04 (d, J = 4.7 Hz, 1H), 4.73−4.42
1
(m, 10H), 4.02−3.84 (m, 4H); H NMR (300 MHz, DMSO-d6) δ
7.35−7.21 (m, 20H), 6.92 (s, 1H), 4.71−4.48 (m, 10H), 4.03−3.86
(m, 4H); 13C NMR (75 MHz, CDCl3) δ 138.5, 138.1, 137.9, 137.6,
137.0, 128.7, 128.6, 128.50, 128.47, 128.2, 128.0, 127.9, 127.8, 79.1,
77.4, 74.3, 74.0, 73.3, 73.1, 72.1, 71.7, 62.1; 13C NMR (75 MHz,
DMSO-d6, 333 K) δ 139.5, 139.3, 139.0, 138.8, 135.5, 129.3, 129.23,
129.17, 128.6, 128.5, 79.9, 78.5, 74.8, 73.9, 73.6, 73.5, 72.3, 71.7, 63.4;
HRMS-ESI (m/z) calcd for C34H36NO5 [M + H]+ 538.2588, found
538.2592.
2,3,4,5-Tetra-O-benzyl-6-O-trityl-D-glucose propane-1,3-diyl
dithioacetal (10). To a solution of 9 (380 mg, 0.74 mmol) in DMF
(10 mL) and tetrahydrofuran (10 mL) was added NaH (60% in oil,
163 mg, 4.08 mmol) batchwise. The resulting mixture was stirred at rt
for 30 min. Then tetra-n-butylammonium iodide (5.5 mg, 0.015
mmol) was added. Benzyl bromide (0.44 mL, 3.70 mmol) was added
dropwise at rt, and the resulting mixture was stirred overnight. H2O
(20 mL) was added to quench the reaction, and the resulting mixture
was extracted with EtOAc (3 × 20 mL). The combined organic layer
was dried (MgSO4) and condensed under reduced pressure. The
residue was purified by flash chromatography (silica gel, petroleum
ether/EtOAc 20:1) to afford compound 10 (567 mg, 88%) as a
Typical procedure for the intramolecular condensation strategy to
prepare azepane nitrones is represented by the synthesis of D-glucose-
derived nitrones 3 and 21.
D-Glucose propane-1,3-diyl dithioacetal (8). Propane-1,3-
dithiol (5.6 mL, 0.055 mmol) was added dropwise into the solution
of D-glucose (10.0 g, 0.055 mol) in concentrated HCl (10.0 mL). The
resulting solution was stirred overnight at rt. The product was
precipitated by adding EtOH (100 mL). The white solid was filtered
and washed with EtOH to afford dithioacetal 8 (13.2 g, 89%): mp
134−135 °C; [α]D20 = −8.0 (c 0.5, H2O); 1H NMR (300 MHz, D2O)
δ 4.34 (d, J = 5.8 Hz, 1H), 4.16 (dd, J = 3.3, 5.3 Hz, 1H), 4.00 (t, J =
20
colorless oil: [α]D = −10.0 (c 1.0, CHCl3); IR (cm−1) 3060, 3030,
2929, 2896, 1495, 1450, 1212, 1090, 1065, 1028, 901, 736, 697, 633;
1H NMR (300 MHz, CDCl3) δ 7.48−7.05 (m, 35H), 4.85 (d, J = 11.1
Hz, 1H), 4.77−4.58 (m, 5H), 4.49 (d, J = 11.4 Hz, 1H), 4.41 (d, J =
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12.0 Hz, 1H), 4.21 (d, J = 5.1 Hz, 1H), 4.11 (t, J = 5.4 Hz, 1H), 4.02−
3.94 (m, 2H), 3.87−3.84 (m, 1H), 3.57 (dd, J = 2.4, 10.2 Hz, 1H),
3.39 (dd, J = 5.4, 10.2 Hz, 1H), 2.85−2.77 (m, 1H), 2.75−2.52 (m,
3H), 1.97−1.94 (m, 1H), 1.90−1.75 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 144.2, 138.9, 138.7, 138.49, 138.46, 128.9, 128.34, 128.25,
128.2, 128.1, 128.0, 127.9, 127.6, 127.5, 127.43, 127.36, 127.0, 86.9,
81.9, 79.9, 79.8, 78.4, 75.1, 74.6, 73.8, 72.4, 63.4, 49.5, 30.0, 29.5, 26.2;
HRMS-ESI (m/z) calcd for C56H56NaO5S2 [M + Na]+ 895.3461,
found 895.3467.
2,3,4,5-Tetra-O-benzyl-D-glucose propane-1,3-diyl dithioa-
cetal (11). To a solution of compound 10 (26.2 g, 0.03 mol) in
MeOH (150 mL) and CH2Cl2 (150 mL) was added concentrated
H2SO4 (5 mL) dropwise. The resulting mixture was stirred overnight
at rt. The pH value was adjusted to 8 with NH4OH solution, and the
resulting mixture was extracted with EtOAc (3 × 200 mL). The
combined organic layer was dried (MgSO4) and condensed under
reduced pressure. The residue was purified by flash chromatography
(silica gel, petroleum ether/EtOAc 6:1) to afford tetrabenzyloxylated
alcohol 11 (17.2 g, 91%) as a yellow oil: [α]D20 = −2.4 (c 1.0, CHCl3);
IR (cm−1) 3464, 3062, 3030, 2927, 2897, 1496, 1454, 1209, 1099,
1065, 1028, 909, 736, 697; 1H NMR (300 MHz, CDCl3) δ 7.40−7.23
(m, 20H), 4.90 (d, J = 11.1 Hz, 1H), 4.79 (d, J = 11.4 Hz, 1H), 4.74−
4.66 (m, 4H), 4.51 (d, J = 11.7 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H),
4.18 (d, J = 4.5 Hz, 1H), 4.02 (dd, J = 4.8, 6.0 Hz, 1H), 3.97−3.80 (m,
4H), 3.67 (dd, J = 4.4, 8.9 Hz, 1H), 2.88−2.75 (m, 2H), 2.71−2.61
(m, 2H), 2.20 (t, J = 6.1 Hz, 1H), 2.03−1.98 (m, 1H), 1.91−1.82 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 138.4, 138.3, 138.2, 138.1, 128.5,
128.37, 128.35, 128.3, 128.1, 127.9, 127.81, 127.77, 127.7, 127.6, 81.8,
80.4, 79.8, 78.6, 75.3, 74.4, 74.1, 71.8, 61.1, 49.5, 30.4, 29.8, 26.1;
HRMS-ESI (m/z) calcd for C37H42NaO5S2 [M + Na]+ 653.2366,
found 653.2365.
127.6, 127.5, 104.0, 79.8, 79.5, 78.3, 75.3, 74.7, 74.0, 71.8, 65.3, 64.8,
64.0, 21.0; HRMS-ESI (m/z) calcd for C38H42NaO8 [M + Na]+
649.2772, found 649.2769.
2,3,4,5-Tetra-O-benzyl-D-glucose ethylene acetal (14).
K2CO3 (1.76 g, 12.8 mmol) was added to the solution of acetal 13
(4.00 g, 6.4 mmol) in methanol (50 mL), and the resulting mixture
was stirred at rt for 3 h. After filtration, the filtrate was concentrated in
vacuo, and the residue was purified by flash chromatography (silica gel,
petroleum ether/EtOAc 5:1) to afford alcohol 14 (3.64 g, 98%) as a
light yellow oil: [α]D20 = +20.0 (c 0.5, CHCl3); IR (cm−1) 3465, 3062,
1
3031, 2925, 2884, 1496, 1454, 1210, 1089, 1067, 1028, 735, 697; H
NMR (300 MHz, CDCl3) δ 7.33−7.24 (m, 20H), 5.13 (d, J = 3.9 Hz,
1H), 4.85 (d, J = 11.4 Hz, 1H), 4.80−4.67 (m, 4H), 4.62 (d, J = 14.4
Hz, 1H), 4.48−4.39 (m, 2H), 4.04−3.79 (m, 8H), 3.65−3.61 (m, 2H),
2.30 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 138.8, 138.7, 138.6,
138.5, 128.5, 128.43, 128.36, 128.3, 128.2, 127.7, 127.6, 104.1, 80.2,
79.71, 79.68, 79.6, 75.3, 74.8, 74.2, 71.5, 65.4, 64.9, 61.3; HRMS-ESI
(m/z) calcd for C36H40NaO7 [M + Na]+ 607.2666, found 607.2668.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-D-glucose ethylene
acetal (15). To a solution of oxalyl dichloride (0.34 mL, 4.0 mmol)
in CH2Cl2 (10 mL) was added dropwise DMSO (0.43 mL, 6.0 mmol)
at −70 °C, and the resulting solution was stirred for 20 min. A solution
of alcohol 14 (1.17 g, 2.0 mmol) in CH2Cl2 (10 mL) was added
dropwise at −70 °C, and the resulting solution was stirred for 20 min.
Then triethylamine (1.38 mL, 10.0 mmol) was added, and the
resulting solution was stirred at −70 °C for 15 min and at rt for
another 1 h. The resulting miture was diluted with CH2Cl2 (50 mL)
and washed with H2O (3 × 20 mL). The organic phase was dried
(MgSO4) and concentrated under reduced pressure to afford aldehyde
15 (1.08 g, 90%) as a colorless oil, which was pure enough to use into
20
the next step: [α]D = +6.0 (c 1.0, CHCl3); IR (cm−1) 3087, 3063,
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-D-glucose propane-1,3-
diyl dithioacetal (12). To a solution of tetrabenzyloxylated alcohol
11 (6.31 g, 10.0 mmol) and triethylamine (2.08 mL, 15.0 mmol) in
CH2Cl2 (60 mL) was added acetyl chloride (0.85 mL, 12.0 mmol)
dropwise at 0 °C, and the resulting mixture was stirred at rt for 1h.
The reaction mixture was washed with H2O (2 × 30 mL), and the
organic phase was dried (MgSO4). After concentration under reduced
pressure the residue was purified by flash chromatography (silica gel,
petroleum ether/EtOAc 10:1) to afford ester 12 (5.72 g, 85%) as a
yellow oil: [α]D20 = +4.0 (c 1.5, CHCl3); IR (cm−1) 3062, 3030, 2931,
2898, 1739, 1496, 1454, 1366, 1236, 1092, 1065, 1028, 910, 736, 698;
1H NMR (300 MHz, CDCl3) δ 7.39−7.26 (m, 20H), 4.89 (d, J = 11.1
Hz, 1H), 4.79−4.68 (m, 5H), 4.56−4.51 (m, 2H), 4.42 (d, J = 12.0
Hz, 1H), 4.25 (dd, J = 6.3, 12.0 Hz, 1H), 4.19 (d, J = 5.1 Hz, 1H),
4.04−3.95 (m, 3H), 3.83−3.79 (m, 1H), 2.88−2.75 (m, 2H), 2.69−
2.60 (m, 2H), 2.05−1.99 (m, 4H), 1.92−1.80 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 170.9, 138.6, 138.3, 138.19, 138.15, 128.52, 128.45,
128.40, 128.35, 128.3, 128.2, 128.1, 127.9, 127.8, 127.7, 127.62,
127.59, 81.2, 80.1, 78.7, 78.6, 75.5, 74.1, 73.9, 72.0, 63.9, 48.9, 30.0,
29.5, 26.1, 21.1; HRMS-ESI (m/z) calcd for C39H44NaO6S2 [M +
Na]+ 695.2472, found 695.2467.
3031, 2883, 1733, 1496, 1454, 1397, 1355, 1210, 1122, 1086, 1067,
1028, 945, 736, 697; H NMR (300 MHz, CDCl3) δ 9.67 (d, J = 1.5
1
Hz, 1H), 7.29−7.23 (m, 20H), 5.12 (d, J = 3.6 Hz, 1H), 4.81 (d, J =
11.4 Hz, 1H), 4.75−4.70 (m, 2H), 4.66−4.56 (m, 4H), 4.38 (d, J =
12.0 Hz, 1H), 4.16 (dd, J = 2.7, 6.3 Hz, 1H), 4.02−3.91 (m, 4H),
3.89−3.75 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 202.0, 138.5,
138.4, 138.1, 137.5, 128.4, 128.3, 128.2, 128.11, 128.09, 127.9, 127.8,
127.64, 127.61, 127.57, 103.7, 84.5, 80.8, 79.5, 79.1, 75.2, 74.08, 74.05,
72.5, 65.4, 64.9; HRMS-ESI (m/z) calcd for C36H38NaO7 [M + Na]+
605.2510, found 605.2507.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-hydroxylamino-D-glucose
ethylene acetal (16). General Method to Transform An
Aldehyde to Hydroxylamine. To a solution of aldehyde 15 (1.05
g, 1.8 mmol) in MeOH (10 mL) was added hydroxylamine chloride
(621 mg, 9.0 mmol) and NaHCO3 (1.21 g, 14.4 mmol). The resulting
mixture was stirred at rt overnight and then concentrated in vacuo.
H2O (20 mL) was added, and the resulting mixture was extracted with
EtOAc (3 × 20 mL). The combined organic phase was dried (MgSO4)
and concentrated under reduced pressure. The residue was redissolved
in methanol (20 mL), and sodium cyanoborohydride (227 mg, 3.6
mmol) was added. Two drops of methyl orange was added as the
indicator. The resulting solution was carefully treated with
concentrated HCl/methanol (v/v = 1/10) to maintain the pH value
between 3 and 4 at rt. After the completion of the reaction, the
resulting solution was concentrated in vacuo. The residue was
dissolved in CH2Cl2 (50 mL) and washed with 1 N NaOH (1 × 20
mL) and then brine (2 × 20 mL). After dried (MgSO4) and
condensed under reduced pressure, the crude product was purified by
flash chromatography (silica gel, petroleum ether/EtOAc 3:1 to 1:1)
to afford hydroxylamine 16 (767 mg, 71% for 2 steps) as a colorless
oil: [α]D20 = +32.0 (c 1.0, CHCl3); IR (cm−1) 3268, 3062, 3030, 2925,
2885, 1496, 1454, 1399, 1360, 1210, 1122, 1087, 1066, 1028, 944, 735,
697; 1H NMR (300 MHz, CDCl3) δ 7.36−7.23 (m, 20H), 5.15 (dd, J
= 2.1, 4.5 Hz, 1H), 4.94 (dd, J = 2.4, 11.7 Hz, 1H), 4.83−4.66 (m,
4H), 4.60 (dd, J = 1.5, 11.7 Hz, 1H), 4.49 (d, J = 11.4 Hz, 1H), 4.33
(d, J = 11.7 Hz, 1H), 4.18−4.15 (m, 1H), 3.97−3.73 (m, 6H), 3.58 (d,
J = 2.7 Hz, 1H), 3.17 (d, J = 5.1 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 138.78, 138.76, 138.5 (2C), 128.4, 128.30, 128.26, 128.21,
128.15, 128.1, 127.6, 127.54, 127.49, 127.4, 104.0, 80.1, 79.8, 79.4,
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-D-glucose ethylene acetal
(13). N-Bromo succinimide (3.97 g, 22.3 mmol) was added batchwise
to the solution of ester 12 (5.00 g, 7.4 mmol) in acetonitrile (50 mL)
and ethylene glycol (5 mL), and the resulting solution was stirred at rt
for 1 h. The pH value was adjusted to 8 with saturated NaHCO3
solution, and the resulting mixture was extracted with EtOAc (3 × 50
mL). The combined organic layer was dried (MgSO4) and condensed
under reduced pressure. The residue was purified by flash
chromatography (silica gel, petroleum ether/EtOAc 8:1) to afford
20
acetal 13 (4.21 g, 90%) as a light yellow oil: [α]D = +16.0 (c 1.0,
CHCl3); IR (cm−1) 3063, 3031, 2885, 1739, 1496, 1454, 1367, 1236,
1
1092, 1069, 1028, 737, 698, 605; H NMR (300 MHz, CDCl3) δ
7.33−7.21 (m, 20H), 5.16 (d, J = 4.5 Hz, 1H), 4.87 (d, J = 11.7 Hz,
1H), 4.80−4.64 (m, 4H), 4.57 (d, J = 11.7 Hz, 1H), 4.51−4.39 (m,
3H), 4.23 (dd, J = 6.6, 12.0 Hz, 1H), 4.06 (dd, J = 4.2, 6.6 Hz, 1H),
3.98−3.94 (m, 1H), 3.93−3.85 (m, 3H), 3.81−3.78 (m, 2H), 3.65 (t, J
= 4.5 Hz, 1H), 1.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.0,
138.8, 138.7, 138.5, 138.4, 128.30, 128.25, 128.10, 128.08, 128.0,
3213
dx.doi.org/10.1021/jo400130p | J. Org. Chem. 2013, 78, 3208−3221

The Journal of Organic Chemistry
Article
76.7, 75.3, 74.8, 73.8, 71.7, 65.3, 64.7, 53.8; HRMS-ESI (m/z) calcd
for C36H42NO7 [M + H]+ 600.2956, found 600.2960.
was stirred at rt for 20 min, and then the pH value was adjusted to 8
with aqueous NaHCO3 solution. The resulting mixture was extracted
with EtOAc (3 × 30 mL). The combined organic phase was dried
(MgSO4) and concentrated under reduced pressure. The residue was
then purified by flash chromatography (silica gel, petroleum ether/
EtOAc 10:1) to afford aldehyde 19 (981 mg, 84%) as a colorless oil:
(3S,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahy-
dro-7H-azepine 1-oxide (3). General Method of The Intra-
molecular Condensation. To a solution of hydroxylamine 16 (600
mg, 1.0 mmol) in tetrahydrofuran (5 mL) was added concentrated
HCl (2 mL), and the resulting solution was stirred at room
temperature for 2 h. The solution was diluted with EtOAc (50 mL)
and then washed with H2O (2 × 20 mL) and saturated NaHCO3
solution (1 × 30 mL). The organic phase was dried (MgSO4) and
concentrated under reduced pressure. The residue was purified by
20
[α]D = +4.0 (c 1.0, CHCl3); IR (cm−1) 3089, 3063, 3031, 2883,
1
1729, 1496, 1454, 1397, 1210, 1093, 1069, 1028, 735, 697; H NMR
(300 MHz, CDCl3) δ 9.76 (s, 1H), 7.31−7.16 (m, 20H), 5.26 (d, J =
1.8 Hz, 1H), 4.86 (d, J = 11.7 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H),
4.63−4.44 (m, 6H), 4.16 (dd, J = 3.3, 5.1 Hz, 1H), 4.06−3.85 (m,
7H); 13C NMR (75 MHz, CDCl3) δ 200.8, 138.7, 138.0, 137.8, 137.4,
128.5, 128.44, 128.35, 128.3, 128.2, 128.1, 128.0, 127.9, 127.6, 127.50,
127.47, 104.0, 80.6, 80.0, 77.91, 77.86, 74.3, 73.8, 73.5, 73.0, 65.6, 65.3;
HRMS-ESI (m/z) calcd for C36H38NaO7 [M + Na]+ 605.2510, found
605.2509.
flash chromatography (silica gel, CH2Cl2/MeOH 100:1) to afford
20
nitrone 3 (426 mg, 79%) as a white solid: mp 129−131 °C; [α]D
=
−18.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3031, 2920, 2873, 1608, 1496,
1454, 1393, 1362, 1209, 1119, 1107, 1087, 1029, 909, 859, 735, 696;
1H NMR (300 MHz, CDCl3) δ 7.36−7.20 (m, 20H), 7.14 (d, J = 4.8
Hz, 1H), 4.85 (d, J = 12.3 Hz, 1H), 4.70−4.58 (m, 8H), 4.09 (dd, J =
4.8, 8.1 Hz, 1H), 3.95−3.88 (m, 3H), 3.62 (dd, J = 2.4, 6.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 138.2, 137.9, 137.5, 137.1, 136.3, 128.6,
2,3,4,5-Tetra-O-benzyl-1,6-dideoxy-6,6-(ethylene-1,2-
dioxy)-1-hydroxylamino-D-glucose (20). Following the general
method to transform an aldehyde to hydroxylamine, aldehyde 19 (1.17
g, 2.0 mmol) gave hydroxylamine 20 (875 mg, 73% for 2 steps) as a
128.5, 128.43, 128.39, 128.0, 127.91, 127.89, 127.86, 127.7, 82.0, 77.9,
75.6, 75.0, 73.7, 73.1, 71.9, 71.7, 62.8; HRMS-ESI (m/z) calcd for
C34H36NO5 [M + H]+ 538.2588, found 538.2580.
20
colorless oil: [α]D = −8.0 (c 1.0, CHCl3); IR (cm−1) 3269, 3086,
3062, 2885, 1496, 1454, 1396, 1361, 1209, 1091, 1069, 1028, 736, 697;
1H NMR (300 MHz, CDCl3) δ 7.31−7.23 (m, 20H), 5.27 (d, J = 3.0
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-D-glucose propane-
1,3-diyl dithioacetal (17). To a solution of oxalyl dichloride (254
mg, 2.0 mmol) in CH2Cl2 (10 mL) was added dropwise DMSO (234
mg, 3.0 mmol) at −70 °C, and the resulting solution was stirred for 20
min. A solution of alcohol 11 (631 mg, 1.0 mmol) in CH2Cl2 (10 mL)
was added dropwise at −70 °C, and the resulting solution was stirred
for 20 min. Then triethylamine (0.69 mL, 5.0 mmol) was added
dropwise, and the resulting solution was stirred at −70 °C for 15 min
and at rt for another 1 h. The reaction mixture was diluted with
CH2Cl2 and washed with H2O (3 × 20 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure to afford
aldehyde 17 (553 mg, 88%) as a colorless oil, which was pure enough
to be used directly into the next step: [α]D20 = −6.0 (c 1.0, CHCl3); IR
(cm−1) 3087, 3062, 3031, 2897, 2868, 1732, 1496, 1454, 1397, 1347,
1277, 1210, 1103, 1027, 910, 736, 698; 1H NMR (300 MHz, CDCl3) δ
9.69 (s, 1H), 7.38−7.22 (m, 20H), 4.88 (d, J = 11.1 Hz, 1H), 4.76−
4.58 (m, 6H), 4.39 (d, J = 12.0 Hz, 1H), 4.13−4.05 (m, 3H), 4.02−
4.00 (m, 2H), 2.87−2.77 (m, 2H), 2.68−2.55 (m, 2H), 1.99−1.87 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 201.3, 138.3, 138.0, 137.5, 137.3,
128.6, 128.50, 128.44, 128.40, 128.3, 128.0, 127.9, 127.8, 127.6, 84.8,
82.2, 79.9, 79.7, 75.2, 74.4, 73.2, 72.8, 49.1, 30.2, 29.7, 26.1; HRMS-
ESI (m/z) calcd for C37H40NaO5S2 [M + Na]+ 651.2209, found
651.2203.
Hz, 1H), 4.82−4.75 (m, 2H), 4.73−4.61 (m, 4H), 4.55 (d, J = 11.7
Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.02−3.81 (m, 8H), 3.16 (dd, J =
3.9, 13.5 Hz, 1H), 2.93 (dd, J = 7.5, 13.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 138.8, 138.7, 138.6, 138.53, 128.45, 128.4, 128.3,
128.14, 128.12, 128.0, 127.7, 127.60, 127.58, 127.5, 104.2, 79.3, 78.8,
78.7, 75.7, 74.2, 74.1, 74.0, 73.0, 65.3, 65.2, 54.4; HRMS-ESI (m/z)
calcd for C36H42NO7 [M + H]+ 600.2956, found 600.2967.
(3R,4R,5R,6S)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahy-
dro-7H-azepine 1-oxide (21). Following the general method of
intramolecular condensation, hydroxylamine 20 (200 mg, 0.33 mmol)
gave nitrone 21 (138 mg, 77%) as a yellow oil: [α]D20 = −18.0 (c 1.0,
CHCl3); IR (cm−1) 3087, 3063, 3031, 2868, 1577, 1496, 1455, 1362,
1
1207, 1188, 1095, 1068, 1028, 910, 737, 697; H NMR (300 MHz,
CDCl3) δ 7.34−7.20 (m, 20H), 7.04 (d, J = 5.4 Hz, 1H), 4.79 (d, J =
11.4 Hz, 1H), 4.69−4.57 (m, 7H), 4.53 (d, J = 12.0 Hz, 1H), 4.26 (d, J
= 4.8 Hz, 1H), 4.09 (d, J = 13.5 Hz, 1H), 3.99 (t, J = 7.2 Hz, 1H),
1
3.72−3.67 (m, 1H), 3.62 (d, J = 6.6 Hz, 1H); H NMR (300 MHz,
DMSO-d6) δ 7.36−7.24 (m, 20H), 6.98 (d, J = 5.1 Hz, 1H), 4.77 (d, J
= 11.7 Hz, 1H), 4.68−4.51 (m, 8H), 4.36−4.30 (m, 1H), 4.24−4.20
(m, 1H), 3.94 (t, J = 5.9 Hz, 1H), 3.81−3.73 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 138.2, 137.9, 137.5, 136.9, 134.6, 128.7, 128.53,
128.47, 128.3, 128.01, 127.97, 127.94, 127.92, 127.86, 127.8, 81.1,
79.8, 76.6, 75.1, 73.6, 72.7, 72.2, 63.3; 13C NMR (75 MHz, DMSO-d6,
373 K) δ 138.2, 138.1, 137.9, 137.7, 133.0, 128.0, 127.9, 127.80,
127.79, 127.3, 127.2, 127.1, 127.0, 79.2, 78.8, 75.1, 73.2, 73.1, 72.1,
71.30, 71.25, 62.6; HRMS-ESI (m/z) calcd for C34H36NO5 [M + H]+
538.2588, found 538.2583.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-D-
glucose propane-1,3-diyl dithioacetal (18). The mixture of
aldehyde 17 (3.0 g, 4.77 mmol), ethylene glycol (2 mL) and p-
toluenesulfonic acid (45 mg, 0.26 mmol) in toluene (30 mL) was
stirred under reflux for 1 h, and H2O (50 mL) was added. The
resulting mixture was extracted with EtOAc (3 × 30 mL). The
combined organic layer was dried (MgSO4) and concentrated under
reduced pressure. The residue was then purified by flash
chromatography (silica gel, petroleum ether/EtOAc 10:1) to afford
D-Gulose-derived azepane nitrones ent-3 and ent-21 were
synthesized following the typical procedure except for special
instructions.
D-Gulose propane-1,3-diyl dithioacetal (22). The mixture of D-
gulose diacetonide20 (17.1 g, 0.0658 mol) and propane-1,3-dithiol
(32.3 mL, 0.329 mol) in 6 N HCl (100 mL) was stirred overnight. The
reaction mixture was diluted with H2O (500 mL) and washed with
CH2Cl2 (3 × 100 mL). The aqueous layer was concentrated under
reduced pressure, and the residue was purified by flash chromatog-
raphy (silica gel, CH2Cl2/MeOH 10:1) to afford dithioacetal 22 (15.2
20
compound 18 (2.73 g, 85%) as a colorless oil: [α]D = −8.0 (c 1.0,
CHCl3); IR (cm−1) 3089, 3062, 3030, 2894, 1496, 1454, 1396, 1341,
1210, 1089, 1067, 1028, 909, 736, 697; 1H NMR (300 MHz, CDCl3) δ
7.37−7.21 (m, 20H), 5.30 (d, J = 3.6 Hz, 1H), 4.87 (d, J = 11.1 Hz,
1H), 4.82−4.69 (m, 6H), 4.42 (d, J = 11.7 Hz, 1H), 4.33 (d, J = 5.7
Hz, 1H), 4.25 (t, J = 5.4 Hz, 1H), 4.00−3.83 (m, 6H), 3.77 (t, J = 4.5
Hz, 1H), 2.87−2.61 (m, 4H), 2.06−1.92 (m, 1H), 1.89−1.84 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 139.1, 138.7, 138.6, 138.4, 128.6,
20
g, 86%) as a brown oil: [α]D = +10.0 (c 1.0, MeOH); IR (cm−1)
1
3376, 2932, 2900, 1420, 1278, 1081, 1045, 792; H NMR (300 MHz,
D2O) δ 4.57 (d, J = 2.1 Hz, 1H), 3.94 (dd, J = 2.1, 9.3 Hz, 1H), 3.84−
3.71 (m, 4H), 3.65−3.56 (m, 1H), 3.14−3.04 (m, 1H), 3.02−2.92 (m,
3H), 2.19−2.11 (m, 1H), 1.86−1.71 (m, 1H); 13C NMR (75 MHz,
D2O) δ 73.2, 73.0, 70.2, 69.2, 50.9, 30.2, 29.4, 25.6; HRMS-ESI (m/z)
calcd for C9H18NaO5S2 [M + Na]+ 293.0488, found 293.0487.
6-O-Trityl-D-gulose propane-1,3-diyl dithioacetal (23). Di-
thoacetal 22 (14.5 g, 0.0537 mol) afforded compound 23 (23.5 g,
128.30, 128.27, 128.24, 128.19, 128.1, 127.7, 127.62, 127.55, 127.5,
127.40, 127.35, 127.0, 104.0, 81.0, 80.1, 79.7, 79.5, 75.2, 74.4, 73.9,
73.5, 65.2, 65.1, 49.2, 30.1, 29.7, 26.1; HRMS-ESI (m/z) calcd for
C39H44NaO6S2 [M + Na]+ 695.2472, found 695.2469.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-D-
glucose (19). To the solution of compound 18 (1.35 g, 2.0 mmol) in
acetonitrile (20 mL) and H2O (5 mL) was added N-bromo
succinimide (712 mg, 4.0 mmol) batchwise. The resulting mixture
20
85%) as a white solid: mp 158−160 °C; [α]D = +10.0 (c 1.8,
3214
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Article
CHCl3); IR (cm−1) 3419, 3057, 3030, 2925, 1491, 1448, 1266, 1218,
1077, 1032, 902, 737, 705, 633; 1H NMR (300 MHz, CDCl3) δ 7.45−
7.21 (m, 15H), 4.34 (d, J = 4.8 Hz, 1H), 4.00−3.96 (m, 2H), 3.94−
3.87 (m, 2H), 3.39−3.35 (m, 2H), 3.37 (dd, J = 5.7, 9.9 Hz, 1H), 3.06
(d, J = 5.7 Hz, 1H), 3.01 (d, J = 3.9 Hz, 1H), 2.97−2.70 (m, 5H),
2.14−2.04 (m, 1H), 2.00−1.87 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 143.7, 128.7, 128.0, 127.2, 87.1, 74.1, 73.2, 72.7, 69.6, 64.9, 49.9,
29.6, 28.9, 25.8; HRMS-ESI (m/z) calcd for C28H32NaO5S2 [M +
Na]+ 535.1583, found 535.1582.
light yellow oil: [α]D20 = +4.0 (c 1.0, CHCl3); IR (cm−1) 3479, 3062,
3031, 2884, 1496, 1454, 1395, 1350, 1209, 1092, 1067, 1028, 736, 698;
1H NMR (300 MHz, CDCl3) δ 7.31−7.24 (m, 20H), 5.26 (d, J = 3.6
Hz, 1H), 4.81−4.76 (m, 2H), 4.71−4.55 (m, 5H), 4.48 (d, J = 11.7
Hz, 1H), 4.01−3.80 (m, 7H), 3.76−3.68 (m, 2H), 3.58 (dd, J = 4.8,
11.1 Hz, 1H), 2.07 (t, J = 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
138.7, 138.50, 138.46, 138.4, 128.5, 128.41, 128.36, 128.33, 128.25,
128.1, 128.0, 127.8, 127.71, 127.66, 127.6, 127.5, 104.1, 79.1, 79.03
(2C), 79.00, 74.4, 74.0, 73.9, 72.5, 65.3, 65.2, 62.1; HRMS-ESI (m/z)
calcd for C36H40NaO7 [M + Na]+ 607.2666, found 607.2662.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-D-gulose ethylene
acetal (ent-19). Alcohol 28 (4.20 g, 7.18 mmol) afforded aldehyde
ent-19 (3.98 g, 95%) as a yellow oil: [α]D20 = −2.0 (c 2.0, CHCl3); IR
(cm−1) 3063, 3031, 2885, 1729, 1496, 1455, 1210, 1093, 1072, 1028,
736, 698; 1H NMR (300 MHz, CDCl3) δ 9.76 (s,1H), 7.32−7.16 (m,
20H), 5.26 (d, J = 2.1 Hz, 1H), 4.86 (d, J = 12.0 Hz, 1H), 4.79 (d, J =
12.0 Hz, 1H), 4.63−4.45 (m, 6H), 4.16 (dd, J = 3.6, 5.4 Hz, 1H),
4.05−3.85 (m, 7H); 13C NMR (75 MHz, CDCl3) δ 200.8, 138.8,
138.0, 137.8, 137.4, 128.6, 128.5, 128.4, 128.3, 128.24, 128.17, 128.1,
128.0, 127.60, 127.56, 127.5, 104.1, 80.6, 80.1, 78.0, 77.9, 74.4, 73.9,
73.5, 73.1, 65.6, 65.3; HRMS-ESI (m/z) calcd for C36H38NaO7 [M +
Na]+ 605.2510, found 605.2505.
2,3,4,5-Tetra-O-benzyl-6-O-trityl-D-gulose propane-1,3-diyl
dithioacetal (24). Compound 23 (23.0 g, 0.0448 mol) afforded 24
20
(36.1 g, 92%) as a light yellow oil: [α]D = −8.0 (c 1.0, CHCl3); IR
(cm−1) 3060, 3031, 2932, 2894, 1495, 1450, 1211, 1089, 1072, 1028,
1
901, 735, 698, 646; H NMR (300 MHz, CDCl3) δ 7.39−7.10 (m,
20H), 5.00 (d, J = 11.1 Hz, 1H), 4.69−4.46 (m, 7H), 4.40 (d, J = 11.1
Hz, 1H), 4.04 (dd, J = 4.2, 5.4 Hz, 1H), 3.95−3.87 (m, 3H), 3.41 (dd,
J = 3.3, 9.9 Hz, 1H), 3.24 (dd, J = 5.4, 9.9 Hz, 1H), 2.76−2.54 (m,
4H), 1.99−1.94 (m, 1H), 1.87−1.75 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 144.1, 138.9 (2C), 138.8, 138.3, 128.9, 128.4, 128.33,
128.25, 128.1, 127.9, 127.8, 127.6, 127.5, 127.42, 127.40, 127.0, 86.8,
82.6, 79.7, 79.0, 78.5, 74.6, 74.0, 73.7, 73.2, 63.5, 51.3, 32.3, 30.5, 26.5;
HRMS-ESI (m/z) calcd for C56H57O5S2 [M + H]+ 873.3642, found
873.3632.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-hydroxylamino-D-gulose
ethylene acetal (ent-20). Aldehyde ent-19 (3.80 g, 6.52 mmol)
afforded hydroxylamine ent-20 (2.94 g, 75% for 2 steps) as a light
2,3,4,5-Tetra-O-benzyl-D-gulose propane-1,3-diyl dithioace-
tal (25). Compound 24 (36.0 g, 0.0412 mol) afforded tetrabenzyloxy-
20
20
yellow oil: [α]D = +10.0 (c 1.0, CHCl3); IR (cm−1) 3269, 3062,
lated alcohol 25 (22.6 g, 87%) as a yellow oil: [α]D = −1.5 (c 1.0,
CHCl3); IR (cm−1) 3466, 3062, 3030, 2931, 2895, 1496, 1454, 1395,
3030, 2885, 1496, 1454, 1395, 1359, 1209, 1090, 1067, 1028, 736, 698;
1H NMR (300 MHz, CDCl3) δ 7.34−7.22 (m, 20H), 5.27 (d, J = 3.0
Hz, 1H), 4.82−4.75 (m, 2H), 4.73−4.61 (m, 4H), 4.55 (d, J = 11.7
Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.02−3.82 (m, 8H), 3.16 (dd, J =
4.2, 13.5 Hz, 1H), 2.94 (dd, J = 7.2, 13.5 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 138.8, 138.7, 138.6, 138.5, 128.4, 128.34, 128.32,
128.11, 128.09, 128.0, 127.7, 127.58, 127.55, 127.5, 104.2, 79.3, 78.73,
78.69, 75.7, 74.2, 74.1, 74.0, 73.0, 65.3, 65.2, 54.4; HRMS-ESI (m/z)
calcd for C36H42NO7 [M + H]+ 600.2956, found 600.2964.
1
1351, 1209, 1092, 1028, 908, 735, 697, 606; H NMR (300 MHz,
CDCl3) δ 7.35−7.23 (m, 20H), 5.02 (d, J = 11.1 Hz, 1H), 4.77 (s,
2H), 4.63−4.62 (m, 4H), 4.58 (d, J = 2.4 Hz, 1H), 4.42 (d, J = 11.1
Hz, 1H), 4.00 (dd, J = 3.6, 6.9 Hz, 1H), 3.91 (dd, J = 2.7, 6.9 Hz, 1H),
3.85 (dd, J = 3.9, 5.4 Hz, 1H), 3.76−3.68 (m, 2H), 3.61−3.54 (m,
1H), 2.84−2.62 (m, 4H), 2.09−1.97 (m, 2H), 1.93−1.80 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 138.4 (2C), 138.3, 138.0, 128.9, 128.5,
128.4, 128.3, 128.2, 128.0, 127.79, 127.76, 127.72, 127.68, 82.2, 79.7,
79.1, 77.6, 74.5, 74.0, 73.6, 73.1, 62.1, 51.2, 32.2, 30.4, 26.4; HRMS-
ESI (m/z) calcd for C37H42NaO5S2 [M + Na]+ 653.2366, found
653.2361.
(3S,4S,5S,6R)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahydro-
7H-azepine 1-oxide (ent-21). Hydroxylamine ent-20 (600 mg, 1.0
20
mmol) afforded nitrone ent-21 (440 mg, 82%) as a yellow oil: [α]D
=
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-D-gulose propane-1,3-diyl
+22.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3031, 2867, 1583, 1496, 1454,
1
dithioacetal (26). Tetrabenzyloxylated alcohol 25 (6.31 g, 10.0
1362, 1308, 1238, 1208, 1188, 1099, 1028, 912, 738, 698, 610; H
20
mmol) afforded ester 26 (5.74 g, 85%) as a light yellow oil: [α]D
=
NMR (300 MHz, CDCl3) δ 7.35−7.20 (m, 20H), 7.04 (d, J = 5.1 Hz,
1H), 4.78 (d, J = 11.4 Hz, 1H), 4.69−4.57 (m, 7H), 4.52 (d, J = 12.0
Hz, 1H), 4.27 (d, J = 5.1 Hz, 1H), 4.09 (d, J = 13.5 Hz, 1H), 3.98 (t, J
= 7.2 Hz, 1H), 3.72−3.66 (m, 1H), 3.62 (d, J = 6.6 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 138.2, 137.9, 137.5, 137.0, 134.8, 128.7,
128.5, 128.4, 128.3, 128.03, 127.98, 127.95, 127.93, 127.86, 80.8, 79.7,
76.4, 75.1, 73.6, 72.7, 72.2, 63.2; HRMS-ESI (m/z) calcd for
C34H36NO5 [M + H]+ 538.2588, found 538.2584.
−1.6 (c 3.7, CHCl3); IR (cm−1) 3062, 3030, 2932, 2897, 1740, 1496,
1455, 1366, 1235, 1093, 1028, 909, 736, 698; H NMR (300 MHz,
1
CDCl3) δ 7.37−7.23 (m, 20H), 5.02 (d, J = 11.4 Hz, 1H), 4.81 (d, J =
11.7 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.66−4.58 (m, 4H), 4.54 (d, J
= 2.4 Hz, 1H), 4.40 (d, J = 11.1 Hz, 1H), 4.26 (dd, J = 4.2, 11.7 Hz,
1H), 4.12 (dd, J = 6.0, 11.7 Hz, 1H), 3.99 (dd, J = 4.2, 7.5 Hz, 1H),
3.90−3.83 (m, 2H), 3.81−3.78 (m, 1H), 2.84−2.59 (m, 4H), 2.08−
2.03 (m, 1H), 1.90−1.80 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
170.7, 138.5, 138.4, 138.2, 138.0, 128.9, 128.5, 128.39, 128.35, 128.29,
128.26, 128.2, 127.9, 127.8, 127.7, 127.64, 127.61, 82.5, 78.2, 77.7,
77.6, 74.4, 73.9, 73.8, 73.4, 64.2, 51.2, 32.2, 30.4, 26.5, 20.9; HRMS-
ESI (m/z) calcd for C39H44NaO6S2 [M + Na]+ 695.2472, found
695.2466.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-D-gulose propane-
1,3-diyl dithioacetal (29). Tetrabenzyloxylated alcohol 25 (6.31 g,
10.0 mmol) afforded aldehyde 29 (5.85 g, 93%) as a light yellow oil:
20
[α]D = −8.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3030, 2932, 2896,
2866, 1728, 1496, 1454, 1326, 1210, 1115, 1072, 1028, 909, 735, 697;
1H NMR (300 MHz, CDCl3) δ 9.71 (s,1H), 7.36−7.14 (m, 20H), 5.11
(d, J = 11.1 Hz, 1H), 4.77 (d, J = 12.0 Hz, 1H), 4.71 (d, J = 12.0 Hz,
1H), 4.62 (d, J = 12.0 Hz, 1H), 4.56−4.49 (m, 3H), 4.44−4.39 (m,
2H), 4.08−4.01 (m, 2H), 3.95 (dd, J = 1.5, 7.8 Hz, 1H), 3.89 (d, J =
5.1 Hz, 1H), 2.83−2.56 (m, 4H), 2.08−2.02 (m, 1H), 1.92−1.83 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 201.0, 138.3, 138.1, 137.8, 137.4,
128.6, 128.51, 128.45, 128.4, 128.23, 128.19, 128.1, 128.0, 127.90,
127.72, 127.68, 81.9, 81.0, 80.0, 77.5, 74.2, 74.0, 73.9, 73.3, 51.3, 32.6,
30.4, 26.4; HRMS-ESI (m/z) calcd for C37H40NaO5S2 [M + Na]+
651.2209, found 651.2208.
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-D-gulose ethylene acetal
(27). Compound 26 (5.50 g, 8.17 mmol) afforded 27 (4.66 g, 91%) as
a light yellow oil: [α]D20 = +2.0 (c 1.0, CHCl3); IR (cm−1) 3063, 3031,
1
2885, 1739, 1496, 1454, 1368, 1232, 1090, 1072, 1028, 736, 698; H
NMR (300 MHz, CDCl3) δ 7.34−7.23 (m, 20H), 5.26 (d, J = 3.6 Hz,
1H), 4.77 (d, J = 11.7 Hz, 2H), 4.71−4.61 (m, 4H), 4.56 (d, J = 11.7
Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.28 (dd, J = 4.5, 11.7 Hz, 1H),
4.17 (dd, J = 6.0, 11.7 Hz, 1H), 4.03−3.98 (m, 2H), 3.96−3.82 (m,
5H), 3.75 (dd, J = 3.6, 5.4 Hz, 1H), 1.94 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.8, 138.8, 138.6, 138.5, 138.3, 128.4, 128.33, 128.30,
128.23, 128.15, 128.1, 127.8, 127.60, 127.58, 127.52, 127.45, 104.0,
79.2 (2C), 78.1, 77.0, 74.4, 74.1, 74.0, 72.8, 65.3, 65.2, 64.2, 21.0;
HRMS-ESI (m/z) calcd for C38H42NaO8 [M + Na]+ 649.2772, found
649.2765.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-D-
gulose propane-1,3-diyl dithioacetal (30). Aldehyde 29 (5.50 g,
20
8.74 mmol) afforded 30 (4.93 g, 84%) as a light yellow oil: [α]D
=
−6.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3030, 2936, 2892, 1496, 1454,
1210, 1120, 1089, 1067, 1028, 908, 736, 697; H NMR (300 MHz,
1
2,3,4,5-Tetra-O-benzyl-D-gulose ethylene acetal (28). Com-
pound 27 (4.60 g, 7.34 mmol) afforded alcohol 28 (4.20 g, 98%) as a
CDCl3) δ 7.37−7.26 (m, 20H), 5.16 (d, J = 7.2 Hz, 1H), 5.02 (d, J =
11.1 Hz, 1H), 4.86−4.80 (m, 2H), 4.73−4.63 (m, 4H), 4.53 (d, J = 2.1
3215
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Hz, 1H), 4.41 (d, J = 11.1 Hz, 1H), 4.05−4.01 (m, 1H), 3.97 (t, J = 5.1
Hz, 1H), 3.86−3.81 (m, 3H), 3.77−3.73 (m, 1H), 3.67 (t, J = 5.7 Hz,
1H), 2.83−2.68 (m, 3H), 2.65−2.55 (m, 1H), 2.07−2.02 (m, 1H),
1.91−1.79 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 139.1, 138.9,
138.7, 138.1, 128.44, 128.39, 128.30, 128.25, 128.21, 128.19, 128.0,
127.9, 127.6, 127.5, 127.3, 104.3, 83.2, 80.3, 79.6, 77.8, 75.2, 74.6,
73.94, 73.91, 65.0, 64.8, 51.3, 32.2, 30.4, 26.5; HRMS-ESI (m/z) calcd
for C39H44NaO6S2 [M + Na]+ 695.2472, found 695.2466.
65.4, 46.2, 26.3, 25.8, 25.2; HRMS-ESI (m/z) calcd for C28H32NaO5S2
[M + Na]+ 535.1583, found 535.1577.
2,3,4,5-Tetra-O-benzyl-6-O-trityl-D-altrose propane-1,3-diyl
dithioacetal (33). Compound 32 (11.8 g, 0.023 mol) afforded 33
20
(17.4 g, 87%) as a light yellow oil: [α]D = −6.0 (c 1.0, CHCl3); IR
(cm−1) 3060, 3030, 2932, 2895, 1496, 1449, 1212, 1093, 1067, 1028,
1
908, 736, 697, 633; H NMR (300 MHz, CDCl3) δ 7.48−7.06 (m,
35H), 4.74−4.64 (m, 5H), 4.60 (d, J = 12.0 Hz, 1H), 4.50 (d, J = 11.4
Hz, 1H), 4.36 (d, J = 3.9 Hz, 1H), 4.16 (dd, J = 3.6, 6.3 Hz, 1H),
4.10−4.05 (m, 2H), 4.00−3.96 (m, 1H), 3.54 (dd, J = 2.4, 10.2 Hz,
1H), 3.32 (dd, J = 4.8, 10.2 Hz, 1H), 2.93−2.71 (m, 4H), 2.05−1.90
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 144.2, 139.1, 138.8, 138.5,
138.4, 128.9, 128.3, 128.2, 128.1, 128.0, 127.9, 127.84, 127.78, 127.7,
127.4, 127.3, 127.2, 126.9, 86.7, 83.2, 81.2, 79.1, 78.5, 74.93, 74.85,
72.7, 72.4, 63.2, 50.9, 30.6, 30.1, 26.2; HRMS-ESI (m/z) calcd for
C56H56NaO5S2 [M + Na]+ 895.3461, found 895.3450.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-D-
gulose (ent-15). Compound 30 (4.80 g, 7.13 mmol) afforded
20
aldehyde ent-15 (3.63 g, 87%) as a light yellow oil: [α]D = −4.0 (c
1.0, CHCl3); IR (cm−1) 3063, 3031, 2884, 1731, 1496, 1455, 1210,
1120, 1090, 1069, 1028, 736, 698; 1H NMR (300 MHz, CDCl3) δ 9.67
(d, J = 1.5 Hz, 1H), 7.34−7.22 (m, 20H), 5.12 (d, J = 3.6 Hz, 1H),
4.81 (d, J = 11.4 Hz, 1H), 4.75−4.70 (m, 2H), 4.66−4.56 (m,4H),
4.38 (d, J = 12.0 Hz, 1H), 4.12 (dd, J = 3.0, 6.6 Hz, 1H), 4.01−3.91
(m, 4H), 3.88−3.75 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 202.0,
138.5, 138.4, 138.1, 137.5, 128.5, 128.3, 128.2, 128.13, 128.11, 127.9,
127.8, 127.7, 127.63, 127.59, 103.8, 84.5, 80.8, 79.5, 79.1, 75.2, 74.09,
74.07, 72.5, 65.4, 64.9; HRMS-ESI (m/z) calcd for C36H38NaO7 [M +
Na]+ 605.2510, found 605.2507.
2,3,4,5-Tetra-O-benzyl-D-altrose propane-1,3-diyl dithioace-
tal (34). Compound 33 (17.2 g, 0.0197 mol) afforded tetrabenzyloxy-
20
lated alcohol 34 (10.7 g, 86%) as a light yellow oil: [α]D = +16.0 (c
1.0, CHCl3); IR (cm−1) 3468, 3062, 3030, 2932, 2897, 1496, 1454,
1209, 1094, 1070, 1028, 908, 736, 698; 1H NMR (300 MHz, CDCl3) δ
7.38−7.24 (m, 20H), 4.81−4.78 (m, 3H), 4.70−4.68 (m, 3H), 4.60 (s,
2H), 4.21 (d, J = 3.6 Hz, 1H), 4.16 (dd, J = 3.3, 6.9 Hz, 1H), 3.97 (dd,
J = 3.6, 6.9 Hz, 1H), 3.90−3.83 (m, 2H), 3.78−3.76 (m, 2H), 2.97−
2.78 (m, 2H), 2.74−2.66 (m, 2H), 2.22 (brs, 1H), 2.09−1.87 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 138.7, 138.6, 138.0 (2C), 128.5,
2,3,4,5-Tetra-O-benzyl-1,6-dideoxy-6,6-(ethylene-1,2-
dioxy)-1-hydroxylamino-D-gulose (ent-16). Aldehyde ent-15
(3.50 g, 6.0 mmol) afforded hydroxylamine ent-16 (2.69 g, 75% for
2 steps) as a light yellow oil: [α]D20 = −28.0 (c 1.0, CHCl3); IR (cm−1)
3272, 3063, 3031, 2884, 1496, 1455, 1397, 1360, 1210, 1120, 1086,
1
128.32, 128.26, 128.2, 128.13, 128.05, 128.0, 127.9, 127.6, 127.5, 83.1,
80.6, 79.5, 78.7, 75.1 (2C), 72.9, 72.1, 61.4, 50.5, 30.5, 30.0, 26.1;
HRMS-ESI (m/z) calcd for C37H42NaO5S2 [M + Na]+ 653.2366,
found 653.2366.
1067, 1028, 735, 697; H NMR (300 MHz, CDCl3) δ 7.36−7.22 (m,
20H), 5.14 (d, J = 4.8 Hz, 1H), 4.91 (d, J = 11.7 Hz, 1H), 4.83−4.66
(m, 4H), 4.60 (d, J = 11.7 Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.33 (d,
J = 11.7 Hz, 1H), 4.16 (dd, J = 5.4, 7.2 Hz, 1H), 3.99−3.86 (m, 4H),
3.84−3.75 (m, 2H), 3.57 (t, J = 4.2 Hz, 1H), 3.17 (d, J = 5.7 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 138.99, 138.96, 138.7, 138.6, 128.5,
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-D-altrose propane-1,3-diyl
dithioacetal (35). Tetrabenzyloxylated alcohol 34 (2.52 g, 4.0 mmol)
afforded ester 35 (2.36 g, 88%) as a light yellow oil: [α]D20 = +16.4 (c
1.1, CHCl3); IR (cm−1) 3062, 3031, 2927, 2897, 1739, 1496, 1454,
128.44, 128.37, 128.35, 128.24, 128.20, 128.1, 127.7, 127.64, 127.56,
104.2, 80.4, 79.9, 79.7, 76.8, 75.5, 75.0, 73.9, 71.8, 65.4, 64.8, 54.1;
HRMS-ESI (m/z) calcd for C36H42NO7 [M + H]+ 600.2956, found
600.2955.
1
1366, 1237, 1098, 1067, 1028, 908, 737, 698; H NMR (300 MHz,
CDCl3) δ 7.36−7.23 (m, 20H), 4.82−4.56 (m, 8H), 4.46 (dd, J = 2.4,
12.0 Hz, 1H), 4.25−4.18 (m, 2H), 4.16−4.11 (m, 1H), 4.02−3.97 (m,
2H), 3.85 (t, J = 4.8 Hz, 1H), 2.96−2.81 (m, 2H), 2.75−2.63 (m, 2H),
2.07−1.86 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 170.9, 138.7,
138.6, 138.1, 138.0, 128.4, 128.24, 128.19, 128.13, 128.08, 128.0,
127.9, 127.70, 127.68, 127.4, 83.0, 80.0, 78.9, 77.0, 74.9, 74.8, 72.8,
72.4, 63.9, 50.3, 30.3, 29.9, 26.1, 21.0; HRMS-ESI (m/z) calcd for
C39H44NaO6S2 [M + Na]+ 695.2472, found 695.2470.
(3R,4S,5S,6S)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahydro-
7H-azepine 1-oxide (ent-3). Hydroxylamine ent-16 (600 mg, 1.0
mmol) afforded nitrone ent-3 (406 mg, 75%) as a white solid: mp
20
134−137 °C; [α]D = +18.0 (c 1.0, CHCl3); IR (cm−1) 3061, 3031,
2904, 2871, 1612, 1496, 1454, 1362, 1207, 1107, 1058, 1028, 909, 738,
697; 1H NMR (300 MHz, CDCl3) δ 7.41−7.22 (m, 20H), 7.15 (d, J =
4.8 Hz, 1H), 4.86 (d, J = 12.3 Hz, 1H), 4.71−4.59 (m, 8H), 4.09 (dd, J
= 4.8, 8.1 Hz, 1H), 3.96−3.88 (m, 3H), 3.61 (dd, J = 1.8, 6.6 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 138.1, 137.9, 137.5, 137.1, 136.3, 128.6,
128.5, 128.44, 128.39, 128.1, 127.89, 127.86, 127.7, 82.0, 77.9, 75.7,
75.0, 73.7, 73.1, 71.8, 71.6, 62.8; HRMS-ESI (m/z) calcd for
C34H36NO5 [M + H]+ 538.2588, found 538.2584.
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-D-altrose ethylene acetal
(36). Ester 35 (2.30 g, 3.42 mmol) afforded acetal 36 (1.82 g, 85%) as
20
a light yellow oil: [α]D = +16.0 (c 1.0, CHCl3); IR (cm−1) 3063,
3031, 2886, 1739, 1496, 1455, 1384, 1366, 1236, 1090, 1071, 1028,
1
736, 698; H NMR (300 MHz, CDCl3) δ 7.33−7.23 (m, 20H), 5.16
(d, J = 4.5 Hz, 1H), 4.84 (d, J = 11.4 Hz, 1H), 4.76 (d, J = 11.4 Hz,
1H), 4.69 (d, J = 11.4 Hz, 2H), 4.62 (s, 2H), 4.55 (d, J = 11.4 Hz, 1H),
4.46−4.39 (m, 2H), 4.19 (dd, J = 6.0, 12.0 Hz, 1H), 4.07−4.03 (m,
1H), 4.02−3.83 (m, 6H), 3.79−3.73 (m, 1H), 1.97 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 170.9, 138.9, 138.7, 138.3 (2C), 128.32, 128.30,
128.2, 128.0, 127.93, 127.87, 127.60, 127.58, 127.4, 104.2, 80.0, 79.3,
78.1, 77.4, 74.5, 74.4, 72.9, 72.3, 65.3, 65.0, 64.2, 21.0; HRMS-ESI (m/
z) calcd for C38H42NaO8 [M + Na]+ 649.2772, found 649.2770.
2,3,4,5-Tetra-O-benzyl-D-altrose ethylene acetal (37). Com-
pound 36 (1.73 g, 2.76 mmol) afforded alcohol 37 (1.55 g, 96%) as a
light yellow oil: [α]D20 = +3.0 (c 1.0, CHCl3); IR (cm−1) 3470, 3063,
3031, 2884, 1496, 1454, 1395, 1333, 1210, 1090, 1070, 1028, 736, 698;
1H NMR (300 MHz, CDCl3) δ 7.31−7.21 (m, 20H), 5.08 (d, J = 4.2
D-Altrose-derived azepane nitrones 40 and 44 were synthesized
following the typical procedure except for special instructions.
D-Altrose propane-1,3-diyl dithioacetal (31). Following the
method to prepare 22, D-altrose (5.0 g, 0.0278 mol) and propane-1,3-
dithiol (4.2 mL, 0.0417 mol) afforded dithioacetal 31 (6.95 g, 93%) as
a brown oil: [α]D20 = +0.2 (c 5.0, MeOH); 1H NMR (300 MHz, D2O)
δ 4.21 (d, J = 9.3 Hz, 1H), 4.14−4.08 (m, 2H), 4.00−3.95 (m, 1H),
3.88−3.82 (m, 2H), 3.72 (dd, J = 7.5, 11.7 Hz, 1H), 3.06−2.94 (m,
2H), 2.91−2.82 (m, 2H), 2.16−2.06 (m, 1H), 1.99−1.86 (m, 1H); 13C
NMR (75 MHz, D2O) δ 72.8, 71.6, 70.1, 70.0, 62.0, 47.6, 27.7, 27.3,
25.2.
6-O-Trityl-D-altrose propane-1,3-diyl dithioacetal (32). Di-
thioacetal 31 (6.87 g, 0.0254 mol) afforded compound 32 (11.8 g,
90%) as a white solid: mp 155−158 °C; [α]D20 = −0.6 (c 3.3, CHCl3);
IR (cm−1) 3395, 3059, 3030, 2933, 1491, 1448, 1266, 1225, 1059,
1033, 1001, 903, 737, 705, 633; 1H NMR (300 MHz, CDCl3) δ 7.45−
7.21 (m, 15H), 4.24 (d, J = 9.6 Hz, 1H), 4.13 (brs, 1H), 3.95−3.88 (m,
2H), 3.83−3.77 (m, 1H), 3.51 (dd, J = 3.9, 9.9 Hz, 1H), 3.38 (dd, J =
5.1, 9.9 Hz, 2H), 3.22 (d, J = 6.6 Hz, 1H), 3.14 (brs, 1 H), 3.00−2.85
(m, 3H), 2.63−2.53 (m, 2H), 2.02−1.96 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 143.5, 128.6, 128.0, 127.3, 87.4, 73.6, 71.9, 70.5, 69.2,
Hz, 1H), 4.84 (d, J = 11.4 Hz, 1H), 4.79−4.68 (m, 3H), 4.65−4.55
(m, 3H), 4.51 (d, J = 11.4 Hz, 1H), 4.05−3.90 (m, 4H), 3.88−3.76
(m, 6H), 2.28 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 138.8, 138.6,
138.3, 138.2, 128.5, 128.4, 128.29, 128.26, 128.01, 127.96, 127.9,
127.74, 127.72, 127.6, 127.5, 104.0, 80.1, 79.7, 79.2, 78.8, 74.7, 74.6,
73.0, 72.1, 65.4, 65.1, 61.6; HRMS-ESI (m/z) calcd for C36H40NaO7
[M + Na]+ 607.2666, found 607.2664.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-D-altrose ethylene
acetal (38). Alcohol 37 (2.03 g, 1.94 mmol) afforded aldehyde
3216
dx.doi.org/10.1021/jo400130p | J. Org. Chem. 2013, 78, 3208−3221

The Journal of Organic Chemistry
Article
20
1
38(1.94 g, 96%) as a yellow oil: [α]D = −10.8 (c 1.3, CHCl3); IR
1028, 737, 698; H NMR (300 MHz, CDCl3) δ 9.63 (d, J = 1.5 Hz,
1H), 7.34−7.23 (m, 20H), 5.18 (d, J = 4.5 Hz, 1H), 4.81 (d, J = 11.7
Hz, 1H), 4.67−4.54 (m, 5H), 4.51−4.44 (m, 2H), 4.26 (dd, J = 4.5,
5.7 Hz, 1H), 4.07−4.00 (m, 2H), 3.96−3.79 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 201.5, 138.7, 138.0, 137.8, 137.3, 128.6, 128.5, 128.33,
128.31, 128.30, 128.26, 128.1, 128.00, 127.95, 127.71, 127.66, 127.6,
127.4, 103.9, 84.2, 79.5, 79.2, 79.0, 74.0, 73.44, 73.39, 73.3, 65.1, 65.0;
HRMS-ESI (m/z) calcd for C36H38NaO7 [M + Na]+ 605.2510, found
605.2509.
(cm−1) 3063, 3031, 2883, 1731, 1496, 1455, 1395, 1333, 1210, 1094,
1072, 1028, 736, 698; H NMR (300 MHz, CDCl3) δ 9.45 (s, 1H),
1
7.34−7.17 (m, 20H), 5.13 (d, J = 6.0 Hz, 1H), 4.91 (d, J = 11.7 Hz,
1H), 4.76−4.62 (m, 4H), 4.51−4.44 (m, 2H), 4.22 (d, J = 11.4 Hz,
1H), 4.18−4.06 (m, 3H), 4.01−3.85 (m, 3H), 3.82−3.77 (m, 1H),
3.65 (dd, J = 2.4, 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 201.0,
138.8, 138.4, 137.8, 137.6, 128.5, 128.4, 128.31, 128.27, 128.00,
127.98, 127.9, 127.8, 127.5, 127.4, 104.4, 82.5, 80.8, 79.1, 77.8, 74.0,
73.6, 73.2, 72.2, 65.2, 64.9; HRMS-ESI (m/z) calcd for C36H38NaO7
[M + Na]+ 605.2510, found 605.2506.
(3R,4R,5S,6R)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahy-
dro-7H-azepine 1-oxide (44). Aldehyde 43 (640 mg, 1.10 mmol)
gave a hydroxylamine that was not stable on the silica gel and used into
the next step without further purification to afford nitrone 44 (172 mg,
29% for 3 steps) as a white solid: mp 155−157 °C; [α]D20 = −40.0 (c
1.0, CHCl3); IR (cm−1) 3062, 3031, 2881, 1601, 1496, 1454, 1377,
1227, 1117, 1098, 1027, 839, 742, 696; 1H NMR (300 MHz, CDCl3) δ
7.31−7.21 (m, 20H), 7.09 (d, J = 4.5 Hz, 1H), 4.77−4.67 (m, 5H),
4.59 (d, J = 13.2 Hz, 2H), 4.46 (d, J = 12.0 Hz, 1H), 4.25 (d, J = 13.5
Hz, 1H), 4.14 (d, J = 4.8 Hz, 1H), 4.10−4.04 (m, 2H), 3.89 (dd, J =
10.2, 13.2 Hz, 1H), 3.46 (dd, J = 2.4, 8.4 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 138.11, 138.06, 137.5 (2C), 136.6, 128.7, 128.5,
128.4, 128.24, 128.21, 128.00, 127.99, 127.82, 127.77, 127.7, 127.6,
83.4, 78.8, 76.0, 74.1, 73.7, 73.6, 73.4, 72.1, 64.6; HRMS-ESI (m/z)
calcd for C34H36NO5 [M + H]+ 538.2588, found 538.2591.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-hydroxylamino-D-altrose
ethylene acetal (39). Aldehyde 38 (1.93 g, 3.31 mmol) afforded
20
hydroxylamine 39 (1.61 g, 81% for 2 steps) as a light yellow oil: [α]D
= +16.0 (c 0.5, CHCl3); IR (cm−1) 3268, 3063, 3031, 2886, 1496,
1
1454, 1396, 1330, 1210, 1090, 1070, 1028, 736, 698; H NMR (300
MHz, CDCl3) δ 7.35−7.20 (m, 20H), 5.17 (d, J = 5.4 Hz, 1H), 4.90
(d, J = 11.4 Hz, 1H), 4.79−4.68 (m, 4H), 4.56−4.51 (m, 2H), 4.35 (d,
J = 11.4 Hz, 1H), 4.20−4.16 (m, 1H), 4.08 (dd, J = 2.7, 7.5 Hz, 1H),
4.01−3.98 (m, 1H), 3.95−3.80 (m, 4H), 3.75 (dd, J = 3.6, 5.4 Hz,
1H), 3.25−3.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 139.0, 138.6,
138.50, 138.46, 128.4, 128.33, 128.28, 128.26, 128.1, 128.0, 127.9,
127.8, 127.7, 127.6, 127.5, 127.4, 104.4, 79.8, 79.1, 78.3, 76.2, 74.5,
74.1, 73.1, 72.2, 65.3, 64.9, 54.1; HRMS-ESI (m/z) calcd for
C36H42NO7 [M + H]+ 600.2956, found 600.2953.
L-Talose-derived azepane nitrones ent-40 and ent-44 were
synthesized following the typical procedure except for special
instructions.
(3R,4S,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahy-
dro-7H-azepine 1-oxide (40). Hydroxylamine 39 (300 mg, 0.5
mmol) afforded nitrone 40 (147 mg, 55%) as a light yellow oil: [α]D
20
L-Talose propane-1,3-diyl dithioacetal (45). Following the
method to prepare 22, L-talose (1.80 g, 0.01 mol) and propane-1,3-
dithiol (1.5 mL, 0.015 mol) afforded dithioacetal 45 (2.42 g, 90%) as a
white solid: mp 123−124 °C; [α]D20 = +1.4 (c 2.5, MeOH); IR (cm−1)
3373, 2922, 2898, 1456, 1418, 1122, 1105, 1040, 1013, 983; 1H NMR
(300 MHz, D2O) δ 4.55 (d, J = 3.3 Hz, 1H), 4.01−3.92 (m, 3H), 3.83
(dd, J = 2.1, 6.3 Hz, 1H), 3.71−3.60 (m, 2H), 3.08−2.91 (m, 4H),
2.18−2.08 (m, 1H), 1.87−1.72 (m, 1H); 13C NMR (75 MHz, D2O) δ
74.5, 71.3, 70.7, 70.6, 62.9, 50.1, 29.8, 29.0, 25.5; HRMS-ESI (m/z)
calcd for C9H18NaO5S2 [M + Na]+ 293.0488, found 293.0488.
6-O-Trityl-L-talose propane-1,3-diyl dithioacetal (46). Di-
thioacetal 45 (1.80 g, 0.0067 mol) afforded 46 (2.66 g, 78%) as a
white solid: mp 65−69 °C; [α]D20 = −12.0 (c 0.7, CHCl3); IR (cm−1)
3419, 3057, 2932, 2901, 1491, 1448, 1266, 1220, 1075, 736, 705, 633;
1H NMR (300 MHz, CDCl3) δ 7.44−7.20 (m, 15H), 4.42 (d, J = 3.6
Hz, 1H), 4.08 (dd, J = 4.8, 10.2 Hz, 1H), 4.03−3.98 (m, 1H), 3.91
(dd, J = 6.6, 13.5 Hz, 1H), 3.82 (t, J = 6.0 Hz, 1H), 3.43−3.22 (m,
5H), 3.06 (d, J = 5.7 Hz, 1H), 2.97−2.72 (m, 4H), 2.09−2.01 (m,
1H), 1.97−1.85 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 143.6, 128.6,
128.0, 127.3, 87.3, 75.4, 73.1, 71.8, 69.7, 65.9, 49.6, 29.5, 28.8, 25.8;
HRMS-ESI (m/z) calcd for C28H32NaO5S2 [M + Na]+ 535.1583,
found 535.1583.
2,3,4,5-Tetra-O-benzyl-6-O-trityl-L-talose propane-1,3-diyl
dithioacetal (47). Compound 46 (16.0 g, 0.0312 mol) afforded 47
(24.4 g, 90%) as a light yellow oil: [α]D20 = +22.9 (c 0.7, CHCl3); IR
(cm−1) 3060, 3030, 2895, 1495, 1450, 1214, 1106, 1065, 1028, 735,
697, 633; 1H NMR (300 MHz, CDCl3) δ 7.49−7.18 (m, 35H), 4.94−
4.85 (m, 2H), 4.73 (d, J = 11.1 Hz, 1H), 4.61−4.56 (m, 2H), 4.49−
4.37 (m, 4H), 4.33 (dd, J = 2.7, 6.6 Hz, 1H), 4.02 (dd, J = 3.6, 7.2 Hz,
1H), 3.87 (dd, J = 2.7, 7.2 Hz, 1H), 3.77−3.72 (m, 1H), 3.38 (dd, J =
3.3, 10.2 Hz, 1H), 3.11 (dd, J = 3.9, 10.2 Hz, 1H), 2.82−2.68 (m, 3H),
2.58−2.50 (m, 1H), 2.04−1.98 (m, 1H), 1.90−1.78 (m, 1H);13C
NMR (75 MHz, CDCl3) δ 144.1, 139.2, 138.9, 138.6, 138.3, 128.8,
128.3, 128.2, 128.13, 128.12, 128.06, 127.90, 127.85, 127.6, 127.40,
127.36, 127.33, 127.27, 127.2, 126.9, 86.7, 82.0, 80.3 (2C), 79.2, 75.0,
74.3, 72.9, 72.5, 63.3, 50.6, 31.1, 29.9, 26.3; HRMS-ESI (m/z) calcd
for C56H57O5S2 [M + H]+ 873.3642, found 873.3630.
= +16.7 (c 1.2, CHCl3); IR (cm−1) 3062, 3031, 2870, 1587, 1496,
1454, 1361, 1209, 1098, 1027, 738, 697; 1H NMR (300 MHz, CDCl3)
δ 7.35−7.23 (m, 20H), 7.04 (d, J = 4.5 Hz, 1H), 4.88−4.79 (m, 3H),
4.75−4.58 (m, 6H), 4.53 (d, J = 12.0 Hz, 1H), 4.11 (d, J = 1.2 Hz,
1H), 3.87 (d, J = 13.2 Hz, 1H), 3.67 (d, J = 9.6 Hz, 1H), 3.54 (dd, J =
2.1, 9.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 139.3, 138.5, 138.2,
137.4, 137.2, 128.5, 128.4, 128.2, 128.01, 127.98, 127.93, 127.87,
127.74, 127.69, 127.63, 127.60, 79.8, 79.6, 75.8, 75.2, 74.3, 73.7, 73.4,
71.3, 61.2; HRMS-ESI (m/z) calcd for C34H36NO5 [M + H]+
538.2588, found 538.2584.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-D-altrose propane-
1,3-diyl dithioacetal (41). Tetrabenzyloxylated alcohol 34 (3.16 g,
0.5 mmol) afforded aldehyde 41 (2.85 g, 90%) as a light yellow oil:
20
[α]D = +1.7 (c 1.2, CHCl3); IR (cm−1) 3062, 3031, 2897, 2866,
1
1730, 1496, 1454, 1209, 1107, 1067, 1028, 909, 737, 698; H NMR
(300 MHz, CDCl3) δ 9.46 (s, 1H), 7.36−7.20 (m, 20H), 4.88 (d, J =
11.4 Hz, 1H), 4.79 (d, J = 11.4 Hz, 2H), 4.73−4.63 (m, 2H), 4.61−
4.52 (m, 2H), 4.42 (d, J = 11.5 Hz, 1H), 4.33 (d, J = 6.0 Hz, 1H), 4.21
(dd, J = 4.5, 7.5 Hz, 1H), 4.15 (d, J = 2.1 Hz, 1H), 4.08 (dd, J = 2.7,
7.5 Hz, 1H), 3.91 (dd, J = 4.8, 5.4 Hz, 1H), 2.90−2.78 (m, 2H), 2.75−
2.61 (m, 2H), 2.04−1.98 (m, 1H), 1.94−1.80 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 201.3, 138.4, 138.3, 137.5, 137.4, 128.6, 128.5, 128.30,
128.28, 128.13, 128.06, 128.0, 127.9, 127.7, 127.6, 127.5, 82.2, 81.9,
81.4, 78.0, 74.8, 73.9, 73.3, 72.3, 49.9, 30.3, 29.9, 26.1; HRMS-ESI (m/
z) calcd for C37H40NaO5S2 [M + Na]+ 651.2209, found 651.2206.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-D-
altrose propane-1,3-diyl dithioacetal (42). Aldehyde 41 (2.75 g,
4.37 mmol) afforded compound 42 (2.71 g, 92%) as a light yellow oil:
20
[α]D = −4.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3030, 2893, 1496,
1454, 1210, 1164, 1102, 1067, 1028, 908, 736, 697; H NMR (300
1
MHz, CDCl3) δ 7.32−7.20 (m, 20H), 5.27 (d, J = 3.0 Hz, 1H), 4.87−
4.64 (m, 8H), 4.28−4.24 (m, 2H), 4.03−3.90 (m, 5H), 3.88−3.79 (m,
2H), 2.96−2.80 (m, 2H), 2.77−2.64 (m, 2H), 2.05−1.84 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 139.1, 138.8, 138.6, 138.5, 128.3, 128.20,
128.15, 127.94, 127.92, 127.88, 127.8, 127.5, 127.4, 127.3, 104.3, 83.2,
80.8, 79.9, 78.8, 74.7, 74.4, 72.8, 65.33, 65.25, 50.0, 30.2, 29.8, 26.1;
HRMS-ESI (m/z) calcd for C39H44NaO6S2 [M + Na]+ 695.2472,
found 695.2465.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-D-
altrose (43). Compound 42 (2.55 g, 3.79 mmol) afforded aldehyde
43 (1.83 g, 83%) as a light yellow oil: [α]D20 = −20.0 (c 1.0, CHCl3);
IR (cm−1) 3063, 3031, 2882, 1729, 1496, 1454, 1328, 1210, 1093,
2,3,4,5-Tetra-O-benzyl-L-talose propane-1,3-diyl dithioace-
tal (48). Compound 47 (24.0 g, 0.0275 mol) afforded tetrabenzylox-
20
ylatd alcohol 48 (14.3 g, 82%) as a yellow oil: [α]D = +18.0 (c 1.0,
CHCl3); IR (cm−1) 3447, 3062, 3030, 2931, 2896, 1496, 1454, 1395,
1210, 1104, 1063, 1028, 908, 737, 697; 1H NMR (300 MHz, CDCl3) δ
7.36−7.19 (m, 20H), 5.01 (d, J = 11.1 Hz, 1H), 4.84 (d, J = 11.4 Hz,
3217
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1H), 4.73−4.68 (m, 2H), 4.64−4.60 (m, 2H), 4.57−4.53 (m, 2H),
4.43 (d, J = 11.4 Hz, 1H), 4.05−4.03 (m, 3H), 3.73−3.62 (m, 3H),
2.89−2.76 (m, 3H), 2.67−2.58 (m, 1H), 2.08−2.04 (m, 2H), 1.95−
1.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 138.9, 138.6, 138.2,
138.1, 128.5, 128.42, 128.35, 128.32, 128.28, 128.0, 127.9, 127.8,
127.7, 127.5, 81.7, 81.0, 80.5, 78.9, 74.5 (2C), 73.1, 72.9, 61.6, 51.4,
31.8, 30.3, 26.5; HRMS-ESI (m/z) calcd for C37H42NaO5S2 [M +
Na]+ 653.2366, found 653.2368.
MHz, CDCl3) δ 138.11, 138.06, 137.5 (2C), 136.6, 128.7, 128.5,
128.4, 128.3, 128.2, 128.02, 127.99, 127.84, 127.79, 127.7, 127.6, 83.4,
78.7, 76.0, 74.1, 73.7, 73.6, 73.4, 72.1, 64.6; HRMS-ESI (m/z) calcd
for C34H36NO5 [M + H]+ 538.2588, found 538.2585.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-L-talose propane-1,3-
diyl dithioacetal (52). Tetrabenzyloxylated alcohol 48 (5.50 g, 8.72
20
mmol) afforded aldehyde 52 (5.12 g, 93%) as a yellow oil: [α]D
=
+22.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3031, 2897, 1730, 1496, 1454,
1210, 1097, 1027, 736, 697; H NMR (300 MHz, CDCl3) δ 9.67 (s,
1
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-L-talose propane-1,3-diyl
dithioacetal (49). Tetrabenzyloxylated alcohol 48 (4.70 g, 7.45
mmol) afforded ester 49 (4.36 g, 87%) as a yellow oil: [α]D20 = +14.0
(c 1.0, CHCl3); IR (cm−1) 3062, 3030, 2932, 2897, 1742, 1496, 1454,
1365, 1236, 1104, 1028, 908, 737, 698; 1H NMR (300 MHz, CDCl3) δ
7.37−7.19 (m, 20H), 5.01 (d, J = 11.1 Hz, 1H), 4.83 (d, J = 11.1 Hz,
1H), 4.71−4.55 (m, 5H), 4.51−4.43 (m, 2H), 4.32 (dd, J = 3.6, 12.0
Hz, 1H), 4.15 (dd, J = 5.1, 12.0 Hz, 1H), 4.03−4.01 (m, 3H), 3.82
(dd, J = 4.8, 9.0 Hz, 1H), 2.86−2.78 (m, 3H), 2.67−2.57 (m, 1H),
2.07−1.99 (m, 4H), 1.91−1.85 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 170.8, 138.7, 138.4, 138.2, 138.1, 128.5, 128.32, 128.29, 128.27,
128.2, 128.1, 127.9, 127.7, 127.6, 127.54, 127.52, 81.7, 79.8, 78.9, 78.4,
74.6, 74.5, 73.1, 73.0, 63.9, 51.0, 31.6, 30.2, 26.4, 21.0; HRMS-ESI (m/
z) calcd for C39H44NaO6S2 [M + Na]+ 695.2472, found 695.2468.
6-O-Acetyl-2,3,4,5-tetra-O-benzyl-L-talose ethylene acetal
(50). Ester 49 (3.0 g, 4.46 mmol) afforded acetal 50 (2.47 g, 88%)
1H), 7.36−7.21 (m, 20H), 4.92 (d, J = 11.1 Hz, 1H), 4.65−4.51 (m,
7H), 4.45 (d, J = 12.0 Hz, 1H), 4.22 (t, J = 4.5 Hz, 1H), 4.11 (t, J = 5.1
Hz, 1H), 4.04−4.01 (m, 2H), 2.81−2.68 (m, 3H), 2.61−2.52 (m, 1H),
2.04−1.95 (m, 1H), 1.90−1.78 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 201.5, 138.3, 137.9, 137.7, 137.2, 128.52, 128.46, 128.4, 128.30,
128.27, 128.2, 128.1, 127.8, 127.7, 127.5, 83.8, 81.3, 80.3, 79.0, 74.5,
73.64, 73.55, 73.3, 50.6, 31.3, 30.0, 26.3; HRMS-ESI (m/z) calcd for
C37H40NaO5S2 [M + Na]+651.2209, found 651.2208.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-L-
talose propane-1,3-diyl dithioacetal (53). Aldehyde 52 (5.0 g,
20
7.95 mmol) afforded 53 (4.80 g, 90%) as a light yellow oil: [α]D
=
+16.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3030, 2894, 1496, 1454, 1396,
1210, 1162, 1095, 1070, 1028, 736, 697; 1H NMR (300 MHz, CDCl3)
δ 7.40−7.21 (m, 20H), 5.19 (d, J = 3.3 Hz, 1H), 4.98 (d, J = 11.1 Hz,
1H), 4.83 (d, J = 11.1 Hz, 1H), 4.75−4.66 (m, 3H), 4.57−4.49 (m,
4H), 4.13−3.98 (m, 4H), 3.95−3.77 (m, 4H), 2.85−2.73 (m, 3H),
2.62−2.53 (m, 1H), 2.05−1.95 (m, 1H), 1.91−1.82 (m, 1H); 13C
NMR (75 MHz, CDCl3) δ 139.2, 139.1, 138.4, 138.3, 128.4, 128.3,
128.2, 128.1, 127.9, 127.8, 127.7, 127.5, 127.34, 127.29, 104.0, 81.8,
80.8, 80.6, 78.6, 74.9, 74.8, 74.7, 72.4, 65.5, 65.2, 50.9, 31.4, 30.1, 26.4;
HRMS-ESI (m/z) calcd for C39H44NaO6S2 [M + Na]+ 695.2472,
found 695.2465.
20
as a light yellow oil: [α]D = +16.0 (c 1.0, CHCl3); IR (cm−1) 3063,
3031, 2886, 1741, 1496, 1455, 1367, 1234, 1163, 1099, 1028, 737, 698;
1H NMR (300 MHz, CDCl3) δ 7.32−7.23 (m, 20H), 5.29 (d, J = 3.3
Hz, 1H), 4.87−4.78 (m, 2H), 4.70−4.47 (m, 6H), 4.29 (dd, J = 4.2,
11.7 Hz, 1H), 4.18 (dd, J = 5.4, 11.7 Hz, 1H), 4.02−3.81 (m, 8H),
1.98 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.8, 138.70, 138.67,
138.5, 138.3, 128.4, 128.3, 128.0, 127.92, 127.85, 127.60, 127.57,
127.5, 127.4, 104.2, 79.6, 79.5, 78.8, 78.1, 74.4, 74.3, 73.1, 73.0, 65.4,
65.3, 64.0, 21.0; HRMS-ESI (m/z) calcd for C38H42NaO8 [M + Na]+
649.2772, found 649.2764.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6,6-(ethylene-1,2-dioxy)-L-
talose (ent-38). Compound 53 (4.80 g, 7.13 mmol) afforded
20
aldehyde ent-38 (3.26 g, 78%) as a light yellow oil: [α]D = +14.0 (c
1.0, CHCl3); IR (cm−1) 3063, 3031, 2888, 1731, 1496, 1454, 1332,
1210, 1092, 1072, 1028, 737, 698; 1H NMR (300 MHz, CDCl3) δ 9.44
(s, 1H), 7.35−7.17 (m, 20H), 5.14 (d, J = 6.3 Hz, 1H), 4.91 (d, J =
11.7 Hz, 1H), 4.76−4.63 (m, 4H), 4.51−4.44 (m, 2H), 4.21 (d, J =
11.4 Hz, 1H), 4.17−4.06 (m, 3H), 4.02−3.87 (m, 3H), 3.84−3.80 (m,
1H), 3.65 (dd, J = 2.4, 6.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
201.0, 138.8, 138.4, 137.8, 137.6, 128.6, 128.5, 128.4, 128.30, 128.25,
128.2, 127.98, 127.96, 127.9, 127.7, 127.6, 127.5, 127.4, 127.0, 104.4,
82.5, 80.8, 79.0, 77.8, 74.0, 73.6, 73.2, 72.2, 65.2, 64.8; HRMS-ESI (m/
z) calcd for C36H38NaO7 [M + Na]+ 605.2510, found 605.2507.
2,3,4,5-Tetra-O-benzyl-1,6-dideoxy-6,6-(ethylene-1,2-
dioxy)-1-hydroxylamino-L-talose (ent-39). Aldehyde ent-38 (3.20
g, 5.49 mmol) afforded hydroxylamine ent-39 (2.42 g, 73% for 2 steps)
2,3,4,5-Tetra-O-benzyl-L-talose ethylene acetal (51). Com-
pound 50 (2.47 g, 3.94 mmol) afforded alcohol 51 (2.22 g, 96%) as a
light yellow oil: [α]D20 = +22.0 (c 1.0, CHCl3); IR (cm−1) 3466, 3063,
1
3031, 2884, 1496, 1454, 1395, 1210, 1164, 1100, 1028, 736, 697; H
NMR (300 MHz, CDCl3) δ 7.32−7.20 (m, 20H), 5.31 (s, 1H), 4.86−
4.78 (m, 2H), 4.72−4.64 (m, 4H), 4.58 (d, J = 11.7 Hz, 1H), 4.48 (d, J
= 11.7 Hz, 1H), 4.02−3.81 (m, 7H), 3.74−3.36 (m, 3H), 2.24 (brs,
1H); 13C NMR (75 MHz, CDCl3) δ 138.8, 138.7, 138.6, 138.2,
128.40, 128.38, 128.3, 128.0, 127.93, 127.91, 127.73, 127.67, 127.51,
127.46, 104.3, 80.6, 80.4, 79.7, 78.4, 74.5, 74.2, 73.3, 72.9, 65.5, 65.3,
61.6; HRMS-ESI (m/z) calcd for C36H40NaO7 [M + Na]+ 607.2666,
found 607.2659.
2,3,4,5-Tetra-O-benzyl-6-deoxy-6-oxo-L-talose ethylene ace-
tal (ent-43). Alcohol 51 (2.00 g, 3.42 mmol) afforded aldehyde ent-43
(1.86 g, 93%) as a light yellow oil: [α]D20 = +22.0 (c 1.0, CHCl3); IR
(cm−1) 3438, 3063, 3031, 2882, 1731, 1496, 1455, 1394, 1329, 1210,
1104, 1028, 737, 698; 1H NMR (300 MHz, CDCl3) δ 9.63 (d, J = 1.5
Hz, 1H), 7.29−7.23 (m, 20H), 5.19 (d, J = 4.2 Hz, 1H), 4.82 (d, J =
11.7 Hz, 1H), 4.67−4.53 (m, 5H), 4.51−4.44 (m, 2H), 4.22 (dd, J =
4.5, 6.0 Hz, 1H), 4.07−4.01 (m, 2H), 3.96−3.79 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 201.5, 138.7, 138.0, 137.8, 137.3, 128.5, 128.38,
128.35, 128.3, 128.1, 128.04, 128.01, 127.8, 127.70, 127.66, 127.5,
103.9, 84.2, 79.5, 79.1, 79.0, 74.0, 73.4 (2C), 73.3, 65.14, 65.08;
HRMS-ESI (m/z) calcd for C36H38NaO7 [M + Na]+ 605.2510, found
605.2507.
20
as a light yellow oil: [α]D = −13.0 (c 0.7, CHCl3); IR (cm−1) 3271,
3063, 3031, 2885, 1496, 1454, 1396, 1330, 1210, 1090, 1070, 1028,
1
735, 697; H NMR (300 MHz, CDCl3) δ 7.34−7.22 (m, 20H), 5.17
(d, J = 5.7 Hz, 1H), 4.90 (d, J = 11.7 Hz, 1H), 4.79−4.66 (m, 4H),
4.57−4.52 (m, 2H), 4.35 (d, J = 11.4 Hz, 1H), 4.20−4.15 (m, 1H),
4.08 (dd, J = 2.7, 7.5 Hz, 1H), 4.03−3.99 (m, 1H), 3.97−3.82 (m,
4H), 3.75 (dd, J = 3.6, 5.4 Hz, 1H), 3.25−3.10 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 138.9, 138.6, 138.5, 138.4, 128.4, 128.30, 128.25,
128.2, 128.1, 127.93, 127.87, 127.8, 127.7, 127.53, 127.50, 127.4,
104.4, 79.7, 79.1, 78.2, 76.2, 74.4, 74.1, 73.1, 72.2, 65.2, 64.9, 54.1;
HRMS-ESI (m/z) calcd for C36H42NO7 [M + H]+ 600.2956, found
600.2946.
(3S,4R,5S,6S)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahydro-
(3S,4S,5R,6S)-3,4,5,6-Tetrakis(benzyloxy)-3,4,5,6-tetrahydro-
7H-azepine 1-oxide (ent-44). Aldehyde ent-43 (1.86 g, 3.19 mmol)
gave a hydroxylamine that was not stable on the silica gel and used into
the next step without further purification to afford nitrone ent-44 (687
mg, 40% for 3 steps) as a white solid: mp 150−152 °C; [α]D20 = +44.0
(c 1.0, CHCl3); IR (cm−1) 3063, 3031, 2881, 1602, 1496, 1454, 1377,
7H-azepine 1-oxide (ent-40). Hydroxylamine ent-39 (200 mg, 0.33
20
mmol) afforded nitrone ent-40 (130 mg, 73%) as a yellow oil: [α]D
=
−18.0 (c 1.0, CHCl3); IR (cm−1) 3062, 3031, 2870, 1586, 1496, 1454,
1361, 1209, 1097, 1072, 1028, 910, 737, 697; H NMR (300 MHz,
1
CDCl3) δ 7.36−7.23 (m, 20H), 7.05 (d, J = 4.5 Hz, 1H), 4.89−4.79
(m, 3H), 4.77−4.58 (m, 6H), 4.53 (d, J = 12.0 Hz, 1H), 4.11 (d, J =
0.9 Hz, 1H), 3.87 (d, J = 12.9 Hz, 1H), 3.67 (d, J = 9.6 Hz, 1H), 3.54
(dd, J = 2.1, 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 139.4, 138.5,
138.2, 137.3, 137.2, 128.6, 128.4, 128.3, 128.03, 127.99, 127.94,
127.88, 127.8, 127.69, 127.65, 127.6, 79.7, 79.6, 75.8, 75.3, 74.3, 73.7,
1
1227, 1188, 1116, 1098, 1027, 907, 742, 696; H NMR (300 MHz,
CDCl3) δ 7.32−7.22 (m, 20H), 7.10 (d, J = 4.5 Hz, 1H), 4.78−4.68
(m, 5H), 4.62−4.58 (m, 2H), 4.46 (d, J = 12.0 Hz, 1H), 4.25 (d, J =
13.8 Hz, 1H), 4.14 (d, J = 4.5 Hz, 1H), 4.11−4.05 (m, 2H), 3.90 (dd, J
= 10.5, 13.8 Hz, 1H), 3.46 (dd, J = 2.7, 8.7 Hz, 1H); 13C NMR (75
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73.4, 71.3, 61.2; HRMS-ESI (m/z) calcd for C34H36NO5 [M + H]+
538.2588, found 538.2584.
77.9, 77.5, 73.5, 73.2, 73.0, 72.7, 71.43, 71.35, 55.5; HRMS-ESI (m/z)
calcd for C40H42NO5 [M + H]+ 616.3058, found 616.3053.
(2R,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-2-
((methoxymethoxy)methyl)azepan-1-ol (54e). n-Butyllithium
(2.5 M in hexane, 1.02 mL, 2.55 mmol) was slowly added under Ar
atmosphere to a cooled (−80 °C) solution of the tributyl-
((methoxymethoxy)methyl)stannane (0.930 g, 2.55 mmol) in
anhydrous THF (10 mL). The resulting solution was stirred for 15
min, and then nirone 7 (457 mg, 0.85 mmol) in THF (2 mL) was
added dropwise. After 30 min at −80 °C the reaction was quenched
with sat. NH4Cl, and the reaction mixture was extracted with EtOAc
(3 × 20 mL). The combined organic layer was dried (MgSO4) and
condensed under reduced pressure. The residue was purified by flash
chromatography (silica gel, petroleum ether/EtOAc 3:1) to afford the
major diastereomer hydroxylamine 54e (282 mg, 54%) as a colorless
oil: [α]D20 = −15.0 (c 1.0, CHCl3); IR (cm−1) 3379, 3063, 3030, 2928,
2881, 1496, 1454, 1362, 1208, 1150, 1109, 1060, 1028, 918, 736, 698;
1H NMR (300 MHz, CDCl3) δ 7.35−7.17 (m, 20H), 6.45 (brs, 1H),
4.78−4.49 (m, 8H), 4.39 (s, 2H), 4.10 (d, J = 9.5 Hz, 1H), 3.95 (d, J =
8.6 Hz, 1H), 3.90−3.79 (m, 3H), 3.65 (dd, J = 5.8, 9.7 Hz, 1H), 3.56−
3.44 (m, 2H), 3.35−3.31 (m, 4H); 13C NMR (75 MHz, CDCl3) δ
138.8, 138.7, 138.1, 138.0, 128.54, 128.49, 128.44, 128.38, 127.93,
127.89, 127.85, 127.8, 127.74, 127.72, 127.67, 127.6, 97.0, 77.2, 76.5,
76.2, 73.7, 73.3, 72.7, 72.5, 71.6, 68.8, 66.6, 55.4, 54.5; HRMS-ESI (m/
z) calcd for C37H44NO7 [M + H]+ 614.3112, found 614.3113.
Typical procedure for the addition of Grignard reagent to azepane
nitrone 7 is represented by the synthesis of hydroxylamin 54a.
(2R,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-2-methylaze-
pan-1-ol (54a). To a solution of nitrone 7 (269 mg, 0.50 mmol) in
THF (5 mL) under Ar atmosphere was added MeMgI (3 M in ether,
0.33 mL, 1.0 mmol) dropwise at 0 °C. The resulting mixture was
stirred for 1 h at 0 °C. Saturated NH4Cl (20 mL) was added to quench
the reaction, and the resulting mixture was extracted with EtOAc (3 ×
20 mL). The combined organic layer was dried (MgSO4) and
condensed under reduced pressure. The residue was purified by flash
chromatography (silica gel, petroleum ether/EtOAc 5:1) to afford
hydroxylamine 54a (233 mg, 84%) as a light yellow oil: [α]D20 = −16.0
(c 1.0, CHCl3); IR (cm−1) 3254, 3063, 3030, 2906, 2869, 1496, 1454,
1
1369, 1206, 1092, 1069, 1028, 911, 737, 697; H NMR (300 MHz,
CDCl3) δ 7.32−7.21 (m, 20H), 4.72 (d, J = 12.0 Hz, 1H), 4.68−4.61
(m, 2H), 4.57−4.49 (m, 3H), 4.41 (s, 2H), 4.08 (d, J = 8.4 Hz, 1H),
3.85 (s, 2H), 3.66 (d, J = 7.8 Hz, 1H), 3.49−3.39 (m, 2H), 3.25 (dd, J
= 1.8, 14.4 Hz, 1H), 1.23 (d, J = 6.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 138.7, 138.6, 138.2, 138.1, 128.40, 128.36, 127.92, 127.89,
127.8, 127.71, 127.66, 80.4, 77.2, 73.8, 73.5, 73.3, 72.7, 71.7, 62.5, 54.2,
17.6; HRMS-ESI (m/z) calcd for C35H40NO5 [M + H]+ 554.2907,
found 554.2901.
Hydroxylamines 54b−d were obtained following the typical
procedure.
(2R,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-2-butylazepan-
1-ol (54b). Nitrone 7 (350 mg, 0.65 mmol) and Grignard reagent
nBuMgI (produced by n-butyl iodide and magnisum in ether, 3.25
(2S,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-2-
(trifluoromethyl)azepan-1-ol (54f). To a solution of nitrone 7 (200
mg, 0.37 mmol) and trifluoromethyltrimethylsilane (159 mg, 1.12
mmol) in THF (5 mL) was added tetrabutylammonium floride (582
mg, 2.23 mmol) batchwise at 0 °C. The resulting mixture was stirred at
rt for 1 h. EtOAc (30 mL) was added, and the organic layer was
washed with H2O (3 × 20 mL). After dried (MgSO4) and condensed
under reduced pressure, the residue was purified by flash
chromatography (silica gel, petroleum ether/EtOAc 15:1) to afford
hydroxylamine 54f (157 mg, 70%) as a colorless oil: [α]D20 = −30.0 (c
1.0, CHCl3); IR (cm−1) 3384, 3063, 3031, 2917, 2872, 1496, 1455,
mmol) gave hydroxylamine 54b (334 mg, 86%) as a colorless oil:
20
[α]D = −16.0 (c 1.0, CHCl3); IR (cm−1) 3365, 3063, 3030, 2954,
2927, 2869, 1496, 1454, 1370, 1261, 1206, 1092, 1068, 1028, 911, 803,
1
736, 697; H NMR (300 MHz, CDCl3) δ 7.34−7.16 (m, 20H), 6.57
(brs, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.70−4.62 (m, 2H), 4.59−4.50
(m, 3H), 4.44−4.36 (m, 2H), 4.15 (d, J = 7.5 Hz, 1H), 3.88 (s, 2H),
3.74 (d, J = 7.5 Hz, 1H), 3.37−3.23 (m, 2H), 3.17−3.13 (m, 1H),
1.48−1.26 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 138.7 (2C), 138.2, 137.6, 128.5, 128.40, 128.38, 128.0,
127.8, 127.72, 127.70, 127.6, 127.0, 80.8, 77.2, 76.5, 74.1, 73.5, 72.7,
72.5, 71.8, 68.2, 52.8, 32.4, 28.9, 22.9, 14.1; HRMS-ESI (m/z) calcd
for C38H46NO5 [M + H]+ 596.3371, found 596.3373.
1
1364, 1268, 1207, 1165, 1138, 1091, 1028, 912, 843, 737, 698; H
NMR (300 MHz, CDCl3) δ 7.34−7.12 (m, 20H), 6.26 (s, 1H), 4.76−
4.67 (m, 2H), 4.62 (d, J = 12.0 Hz, 1H), 4.52−4.43 (m, 4H), 4.25 (d, J
= 11.1 Hz, 1H), 4.10−3.92 (m, 3H), 3.83 (d, J = 5.7 Hz, 1H), 3.76 (d,
J = 5.7 Hz, 1H), 3.47 (dd, J = 9.6, 15.5 Hz, 1H), 3.35 (d, J = 15.5 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 138.7, 138.6, 137.7, 137.6, 128.7,
128.62, 128.56, 128.5, 128.2, 128.10, 128.08, 128.0, 127.9, 127.8, 126.5
(q, J = 280.9 Hz), 77.2, 75.6, 75.2, 73.9, 73.7, 73.0, 72.0, 71.6, 68.3 (q, J
= 25.1 Hz), 53.7; HRMS-ESI (m/z) calcd for C35H37F3NO5 [M + H]+
608.2618, found 608.2623.
(2R,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-2-n-nonylaze-
pan-1-ol (54c). Nitrone 7 (269 mg, 0.50 mmol) and Grignard
reagent (produced by n-nonyl bromide and magnisum in THF, 1.50
mmol) gave hydroxylamine 54c (290 mg, 87%) as a colorless oil:
20
[α]D = −10.0 (c 1.0, CHCl3); IR (cm−1) 3365, 3063, 3030, 2924,
Typical procedure for the hydrogenlysis of the hydroxylamines is
represented by the synthesis of azepane iminosugar 55a.
1
2854, 1496, 1456, 1362, 1205, 1094, 1069, 1028, 735, 697; H NMR
(300 MHz, CDCl3) δ 7.35−7.16 (m, 20H), 6.45 (brs, 1H), 4.79 (d, J =
12.0 Hz, 1H), 4.70−4.63 (m, 2H), 4.58−4.51 (m, 3H), 4.44−4.35 (m,
2H), 4.15 (d, J = 9.0 Hz, 1H), 3.88 (s, 2H), 3.74 (d, J = 7.8 Hz, 1H),
3.38−3.22 (m, 2H), 3.17−3.13 (m, 1H), 1.49−1.21 (m, 16H), 0.88 (t,
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 138.7, 138.2, 137.8,
128.5, 128.42, 128.40, 128.00, 127.98, 127.9, 127.8, 127.7, 127.6, 80.7,
77.2, 76.7, 74.1, 73.5, 72.8, 72.5, 71.9, 68.1, 53.2, 32.6, 32.0, 29.9, 29.7
(2C), 29.5, 26.8, 22.8, 14.2; HRMS-ESI (m/z) calcd for C43H56NO5
[M + H]+ 666.4153, found 666.4158.
(2R,3R,4R,5R,6R)-3,4,5,6-Tetrakis(benzyloxy)-2-phenylaze-
pan-1-ol (54d). Nitrone 7 (350 mg, 0.65 mmol) and Grignard
reagent PhMgBr (produced by phenyl bromide and magnisum in
THF, 3.25 mmol) gave hydroxylamine 54d (352 mg, 88%) as a light
yellow oil: [α]D20 = −2.0 (c 1.0, CHCl3); IR (cm−1) 3430, 3062, 3029,
2916, 2868, 1496, 1454, 1359, 1206, 1097, 1069, 1028, 911, 737, 697;
1H NMR (300 MHz, CDCl3) δ 7.43−7.18 (m, 23H), 6.90−6.88 (m,
(2R,3R,4R,5R,6R)-2-Methylazepane-3,4,5,6-tetraol (55a). To a
solution of hydroxylamine 54a (92 mg, 0.166 mmol) in MeOH (5
mL) and 6 N HCl (1 mL) was added 10% Pd/C (15 mg), and the
resulting mixture was stirred under H2 atmosphere overnight. The
catalyst was filtered out, and the filtrate was concentrated at reduced
pressure. The residue was dissolved in MeOH and neutralized with
aqueous ammonium solution, concentrated in vacuo. The above
procedure was repeated for three times to ensure complete
neutralization. The residue was then purified by an acidic ion
exchanger column (Dowex 5WX8−400, H+ form, Aldrich), eluting
with distilled water (50 mL) and then 1 N NH4OH (50 mL), affording
azepane iminosugar 55a (29 mg, 98%) as a yellow oil: [α]D20 = −20.0
1
(c 1.0, MeOH); IR (cm−1) 3364, 2961, 2925, 1457, 1050; H NMR
(300 MHz, D2O) δ 4.06−4.01 (m, 2H), 3.94 (dd, J = 2.7, 8.7 Hz, 1H),
3.80 (dd, J = 2.7, 6.1 Hz, 1H), 3.02 (dd, J = 5.4, 14.7 Hz, 1H), 2.88−
2.77 (m, 2H), 1.21 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, D2O) δ
75.6, 70.7, 69.7, 69.6, 56.2, 48.1, 19.2; HRMS-ESI (m/z) calcd for
C7H16NO4 [M + H]+ 178.1074, found 178.1074.
Azepane iminosugars 55b−f were obtained following the typical
procedure.
(2R,3R,4R,5R,6R)-2-Butylazepane-3,4,5,6-tetraol (55b). Hy-
droxylamine 54b (112 mg, 0.188 mmol) gave azepane iminosugar
2H), 5.41 (brs, 1H), 4.75−4.53 (m, 6H), 4.41 (d, J = 7.2 Hz, 1H), 4.19
(d, J = 11.7 Hz, 1H), 4.12−4.09 (m, 1H), 3.97 (d, J = 6.0 Hz, 1H),
3.92 (dd, J = 2.1, 6.0 Hz, 1H), 3.87 (d, J = 7.2 Hz, 1H), 3.75 (dd, J =
8.4, 15.3 Hz, 1H), 3.37 (d, J = 15.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 142.4, 138.9, 138.8, 138.5, 138.0, 128.4, 128.3, 128.2, 128.1,
127.9, 127.80, 127.77, 127.7, 127.6, 127.54, 127.53, 127.4, 127.0, 79.3,
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Article
55b (38 mg, 92%) as a yellow oil: [α]D20 = −26.0 (c 1.0, MeOH); IR
REFERENCES
■
1
(cm−1) 3365, 2956, 2929, 2871, 1457, 1065; H NMR (300 MHz,
(1) (a) Compain, P.; Martin, O. Iminosugars: From Synthesis to
Therapeutic Applications; Wiley-VCH: Weinheim, 2007. (b) Stutz, A.
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14.4 Hz, 1H), 2.89 (dd, J = 1.8, 14.4 Hz, 1H), 2.73−2.67 (m, 1H),
1.67−1.30 (m, 6H), 0.89 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz,
D2O) δ 74.3, 70.4, 69.13, 69.08, 61.3, 48.4, 32.8, 27.4, 21.9, 13.2;
HRMS-ESI (m/z) calcd for C10H22NO4 [M + H]+ 220.1543, found
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E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-
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(2R,3R,4R,5R,6R)-2-n-Nonylazepane-3,4,5,6-tetraol (55c). Hy-
droxylamine 54c (67 mg, 0.10 mmol) gave azepane iminosugar 55c
20
(27 mg, 93%) as a yellow oil: [α]D = −18.0 (c 1.0, MeOH); IR
1
(cm−1) 3339, 2884, 2853, 1457, 1119, 1065; H NMR (300 MHz,
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Zwanenburg, B.; Chittenden, G. J. F. Tetrahedron 2002, 58, 6907.
CD3OD) δ 3.98−3.90 (m, 3H), 3.83 (dd, J = 2.0, 5.1 Hz, 1H), 3.03
(dd, J = 4.8, 14.1 Hz, 1H), 2.89 (dd, J = 2.1, 14.1 Hz, 1H), 1.66−1.34
(m, 16H), 0.94 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CD3OD) δ
76.4, 72.6, 71.6, 71.3, 63.0, 49.8, 35.6, 33.1, 31.0, 30.8 (2C), 30.5, 27.4,
23.8, 14.5; HRMS-ESI (m/z) calcd for C15H32NO4 [M + H]+
290.2326, found 290.2322.
́
(c) Fuentes, J.; Gasch, C.; Olano, D.; Pradera, M. A.; Repetto, G.;
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(2R,3R,4R,5R,6R)-2-Phenylazepane-3,4,5,6-tetraol (55d). Hy-
droxylamine 54d (125 mg, 0.203 mmol) gave azepane iminosugar 55d
20
(47 mg, 97%) as a yellow oil: [α]D = −24.0 (c 1.0, MeOH); IR
(cm−1) 3357, 2909, 1450, 1068, 1031, 763, 703; 1H NMR (300 MHz,
D2O) δ 7.46−7.34 (m, 5H), 4.27 (dd, J = 3.3, 8.1 Hz, 1H), 4.21 (dd, J
= 3.3, 8.1 Hz, 1H), 4.11−4.08 (m, 1H), 4.05 (dd, J = 2.4, 8.1 Hz, 1H),
3.68 (d, J = 8.1 Hz, 1 H), 3.09 (dd, J = 5.4, 14.4 Hz, 1H), 2.94 (dd, J =
2.7, 8.4 Hz, 1H); 13C NMR (75 MHz, D2O) δ 142.5, 128.9, 127.8,
127.2, 74.2, 71.3, 70.4, 70.0, 64.9, 49.9; HRMS-ESI (m/z) calcd for
C12H18NO4 [M + H]+ 240.1230, found 240.1228.
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Sollogoub, M.; Zhang, Y. M.; Rodríguez-García, E.; Vogel, P.; Jimen
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(2R,3R,4R,5R,6R)-2-(Hydroxymethyl)azepane-3,4,5,6-tetraol
(55e). Hydroxylamine 54e (120 mg, 0.195 mmol) gave azepane
20
iminosugar 55e (35 mg, 93%) as a yellow oil: [α]D = −22.0 (c 1.0,
́
̈
1
MeOH); IR (cm−1) 3366, 2925, 1416, 1106, 1076, 1030; H NMR
Commun. 2007, 183. (c) Jabgunde, A. M.; Kalamkar, N. B.; Chavan, S.
T.; Sabharwal, S. G.; Dhavale, D. D. Bioorg. Med. Chem. 2011, 19,
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Chem. 2009, 17, 5598. (b) Marcelo, F.; He, Y.; Yuzwa, S. A.; Nieto, L.;
Jimenez-Barbero, J.; Sollogoub, M.; Vocadlo, D. J.; Davies, G. D.;
(300 MHz, D2O) δ 4.09−4.05 (m, 2H), 3.98−3.91 (m, 2H), 3.78 (dd,
J = 3.9, 11.4 Hz, 1H), 3.60 (dd, J = 7.5, 11.4 Hz, 1H), 3.15 (dd, J = 5.4,
14.4 Hz, 1H), 2.89−2.76 (m, 2H); 13C NMR (75 MHz, D2O) δ 71.0,
70.5, 69.8, 69.7, 62.9, 62.6, 49.1; HRMS-ESI (m/z) calcd for
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́
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(2S,3R,4R,5R,6R)-2-(Trifluoromethyl)azepane-3,4,5,6-tetraol
́
(55f). Hydroxylamine 54f (112 mg, 0.203 mmol) gave azepane
20
iminosugar 55f (40 mg, 94%) as a yellow oil: [α]D = −20.0 (c 1.0,
́
1
MeOH); IR (cm−1) 3364, 2933, 1387, 1263, 1146, 1068; H NMR
́
Bleriot, Y. J. Am. Chem. Soc. 2009, 131, 5390.
(300 MHz, D2O) δ 4.35 (dd, J = 2.4, 6.6 Hz, 1H), 4.15 (dd, J = 2.1, 8.4
Hz, 1H), 4.04−4.00 (m, 2H), 3.47−3.36 (m, 1H), 3.10 (dd, J = 6.3,
15.0 Hz, 1H), 2.84 (dd, J = 2.1, 15.0 Hz, 1H); 13C NMR (75 MHz,
D2O) δ 126.1 (q, J = 279.8 Hz), 71.0, 70.3, 70.2, 68.5, 61.8 (q, J = 26.3
Hz), 47.6; HRMS-ESI (m/z) calcd for C7H13F3NO4 [M + H]+
232.0791, found 232.0791.
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Garrido, S. Tetrahedron: Asymmetry 2005, 16, 3897.
́
chez, M. I.;
́
́
́
ASSOCIATED CONTENT
Alvarez, M.; Dian
́
́
́
■
S
* Supporting Information
(9) Chagnault, V.; Compain, P.; Lewinski, K.; Ikeda, K.; Asano, N.;
Martin, O. R. J. Org. Chem. 2009, 74, 3179.
1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Goti, A.; Brandi, A. Synthesis 2007, 485. (b) Brandi, A.; Cardona, F.;
Cicchi, S.; Cordero, F. M.; Goti, A. Chem.Eur. J 2009, 15, 7808. For
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AUTHOR INFORMATION
Corresponding Author
*E-mail: yucy@iccas.ac.cn.
■
Notes
́
Vallee, Y. J. Org. Chem. 2005, 70, 1459. (f) Gilles, P.; Py, S. Org. Lett.
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ACKNOWLEDGMENTS
■
This work is supported by The National Basic Research
Program of China (No. 2012CB822101 and No.
2011CB808603), The National Natural Science Foundation
of China (No. 21102149), Grant-in-Aid for Scientific Research
(C) (No: 23590127) (AK) from the Japanese Society for the
Promotion of Science (JSPS) and Summit PLC (UK).
3220
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