Versatile approach for the synthesis of novel seven-membered iminocyclitols via ring-closing metathesis dihydroxylation reaction

Article abstract of DOI:10.1016/j.bmc.2004.03.064

Seven-membered iminocyclitols with diverse diastereomers were prepared starting with D- and L-serines and employing ring-closing olefin metathesis and dihydroxylation reaction sequence. The iminocyclitols were assayed for glycosidase inhibition and compound 20 was found to be a competitive inhibitor for β-glucosidase with K_i 26.3μM.

Full text of DOI:10.1016/j.bmc.2004.03.064

Bioorganic & Medicinal Chemistry 12 (2004) 3259–3267
Versatile approach for the synthesis of novel seven-membered
iminocyclitols via ring-closing metathesis dihydroxylation reaction
a
Chang-Ching Lin, Yi-shin Pan, Laxmikant N. Patkar, Hsiu-Mei Lin,
b
b
b
b
b
Der-Lii M. Tzou, Thangaiah Subramanian and Chun-Cheng Lin
b,
*
a
Department of Chemistry, Tsing Hua University, Hsinchu 300, Taiwan
Institute of Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan
b
Received 17 December 2003; revised 29 March 2004; accepted 30 March 2004
Available online 10 May 2004
Abstract—Seven-membered iminocyclitols with diverse diastereomers were prepared starting with D- and
ring-closing olefin metathesis and dihydroxylation reaction sequence. The iminocyclitols were assayed for glycosidase inhibition and
compound 20 was found to be a competitive inhibitor for b-glucosidase with K 26.3 lM.
2004 Elsevier Ltd. All rights reserved.
L-serines and employing
i
ꢀ
1
. Introduction
from the greater flexibility of seven-membered ring
compared to five- or six-membered ring. Additionally,
azepanes may adopt a quasi-flattened conformation,
improving binding to the active site of the enzyme. This
has stimulated interest in developing strategies for syn-
thesizing new types of polyhydroxyazepanes employing
Glycosidases and glycosyltransferases are involved in
1
the processing and synthesis of complex carbohydrates,
which are essential in various biological recognition
2
;3
processes. Consequently, the design and synthesis of
inhibitors targeting these enzymes recently has attracted
considerable interest.
9–11
12
hemical
and enzymatic methods. Most of these
3
;4
10;12
Iminocyclitols (azasugars),
methods use sugar derivatives as starting compounds
for synthesizing polyhydroxyazepanes, during which
process the stereochemistry of hydroxyl groups at the
carbon backbone was fixed and preserved during syn-
thetic transformation. These approaches result in lim-
ited number of stereoisomers that can be synthesized
simultaneously for SAR (structure–activity relationship)
study. Thus, a synthetic method that provides access to
diverse stereoisomers is extremely desirable. Here, we
describe a new approach for accessing to structurally
versatile stereoisomers of polyhydroxyazepanes and
their glycosidase inhibitory properties.
formed by the replacement of sugar ring oxygen with
nitrogen, are well known for their ability to selectively
inhibit glycosidases, and, hence, are considered as
potentially therapeutic agents for viral, proliferative and
3
–5
metabolic diseases.
Over the last 30 years, most of
works on the design and synthesis of glycosidase
inhibitors have focused on five- and six-membered imi-
nocyclitols, which are considered to mimic the substrate
transition states with oxacarbenium ion character and a
3
;4a;5a;e;6
distorted six-membered ring.
Meanwhile, polyhydroxyazepanes, seven-membered
7
iminocyclitols, received little attention before Wong
and co-workers revealed that polyhydroxyazepanes
exhibited promising glycosidase inhibitory profiles
against a broad range of glycosidases. The enhanced
potency of inhibition has been hypothesized to result
2
. Results and discussion
8
Recently, we delineated a convenient access to func-
tionalized oxazolidinyl azacycles 1 and 2 (Scheme 1)
using ring-closing olefin metathesis (RCM) as a key
step. As outlined in Scheme 1, starting from L-serine 3,
compound 4 was obtained in two steps and subjected to
N-alkenylation using suitable alkenyl bromide in the
13
Keywords: Iminocyclitols; Ring-closing metathesis; Dihydroxylation;
Glycosidase inhibitor.
13;14
*
Corresponding author. Tel.: +886-2-27898648; fax: +886-2-278350-
7; e-mail: cclin@chem.sinica.edu.tw
presence of base. The ester groups of N-alkenyl
intermediates were reduced to give the corresponding
0
0
968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.03.064

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C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
O
attempts to purify aldehyde intermediates resulted in
isolation of the decomposed products. Finally, RCM
O
16
a,b
c, d
OMe
OH
HO
OH
O
O
O
NH
N
of 7 and 8 with Grubb’s catalyst, Cl (PCy ) Ru@
2
3 2
NH2
17
n
CHPh, furnished the required intermediates 1 and 2,
respectively.
O
O
3
4
5
6
: n = 1
: n = 2
Y
X
X
N
Y
The advantage of this approach was that with the
appropriate choice of alkenyl moiety on nitrogen atom
of 4 and nucleophilic addition of alkenyl nucleophiles on
aldehyde intermediates derived from 5 (or 6), six-, seven-
or eight-membered rings could easily be constructed by
placing the olefin double bond at the desired position in
relation to the ring nitrogen. Further functionalization
e
f
h
H
O
O
O
N
N
n
O
O
O
7
7
a X = OH, Y = H
b X = H, Y = OH
2a X = OH, Y = H
2b X = H, Y = OH
g
Y
X
X
Y
h
O
of the ring double bond by epoxidation followed by
11;13;18
O
N
O
N
stereoselective epoxide-ring opening,
11;18e–h;19
or by
results in hydroxylated rings
O
dihydroxylation,
8
8
a X = OH, Y = H
b X = H, Y = OH
1a X = OH, Y = H
leading to a number of stereoisomers, and this approach
has been shown to be successful in the synthesis of
1b X = H,Y = OH
11;13;18;19
Scheme 1. Synthesis of oxazolidinyl azacycles. Reagents and condi-
tions: (a) SOCl , MeOH reflux, overnight; (b) K CO , triphosgene,
pyrrolizidines.
2
2
3
H
2
O/toluene, 87%; (c) 60% NaH, allyl bromide or homoallyl bromide,
As shown in Scheme 2, oxazolidinyl azacycles 1a was
subjected to dihydroxylation using catalytic amount of
osmium tetraoxide (1 mol %) and NMO in acetone/
DMF; (d) NaBH
4
, MeOH; (e) DMSO, (COCl)
2
, CH
2
Cl
2
, Et
3
N; (f)
allylmagnesium bromide; (g) vinylmagnesium bromide; (h) Grubb’s
catalyst (10 mol %), CH
2
Cl
2
, reflux, 12 h.
20
water (8:1) to yield 9. Notably, no reaction occurred
21
when AD mix a or b was used. To simplify the puri-
fication process, 9 was further acetylated to give the
derivatives 10a and 10b. The configurations of these two
stereoisomers were assigned by comparing the proton
coupling constants between the protons on carbons 2
1
3;15
alcohols 5 and 6.
Oxidation of alcohols to yield
aldehydes was followed by the addition of alkenyl
Grignard reagents led to the formations of the corre-
sponding alcohols 7 and 8, respectively. Notably,
J = 3.6Hz
J = 5.2Hz
HO
HO
OH
H
H
H
H
OAc
OAc
AcO
AcO
OAc
OAc
b
a
OH
2 3
two steps
+
O
N
O
N
O
N
O
N
8
3%
O
O
O
O
1a
9
10a
10b
(
5:95)
J = 2.4Hz
J = 7.6Hz
HO
OH
H
H
HO
H
N
H
OAc
OAc
AcO
AcO
OAc
OAc
OH
a
b
O
N
+
O
O
N
N
two steps
O
8
0%
O
O
O
O
1
b
11
13
12a
12b
(
22:78)
HO
N
AcO
AcO
HO
OAc
OAc
OH
OAc
a
b
two steps
+
O
N
O
O
N
O
N
OH
OAc
86%
O
O
O
O
1
4a
14b
2
a
(10:90)
AcO
AcO
HO
HO
OAc
OAc
OH
OAc
a
b
+
O
N
O
N
two steps
3%
O
N
O
O
N
O
OH
OAc
8
O
O
16a
16b
2
b
15
(
50:50)
Scheme 2. Dihydroxylation of oxazolidinyl azacycles. Reagents and conditions: (a) OsO
rt, two steps 80%.
4
, NMO, acetone/H
2
O ¼ 8:1; (b) Ac
2 2 2
O, py, DMAP, CH Cl ,

C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
3261
and 3 as indicated in Scheme 2. The coupling constant of
the syn-isomer is smaller than that of the anti-isomer,
and the proportion of 10a to 10b was determined to be
5
:95. Similar dihydroxylation of other oxazolidinyl
azacycles 1b and 2a/b afforded products 12a and 12b
22:78), 14a and 14b (10:90) and 16a and 16b (50:50),
(
respectively.
The structures for 12a and 12b were easily determined
1
by using H NMR. To determine the stereochemistry of
1
4, 14b was recrystallized and the X-ray crystal was
shown to have a configuration corresponding to com-
pound 14b (Fig. 1). Moreover, the stereochemistry of
compounds 16a/b was determined by comparing their
Figure 2. The molecular models of 1a/b.
1
H NMR with those of their enantiomers. X-ray crys-
from the face opposite the hydroxyl group. As the
orientation of the hydroxyl group changes from S to R
form, the conformation switches from A to B. The
regioselection of dihydroxylation from a face displays
less steric repulsion than that of b face with the ratio
between the two repulsions being 22:78.
tallographic analysis was used to determine the structure
of 16c, an enantiomer of 16a, thus, automatically fixed
the configurations of 16b. Dihydroxylation of allylic
alcohols of cyclic compounds using OsO /NMO system
4
generally results in dihydroxylation with anti-diastereo-
facial selectivity to the existing hydroxyl group (or het-
22
ero atom) on the adjacent carbon atom. The selectivity
is proposed to result from a combination of steric fac-
tors and electrostatic repulsion between the hydroxyl
Once each of the stereoisomers was separated and their
structures determined, compounds 10, 12, 14 and 16
were subjected to oxazolidine ring-opening hydrolysis to
yield corresponding iminocyclitols, as represented in
Scheme 3. Also, epimers of compounds 22–27 (Scheme
23
function and the Os-complex. This study noted similar
anti-diastereofacial selectivities in the formation of
products, 10b and 14b.
3) were synthesized using the established protocol and
starting from D-serine.
These high anti-diastereofacial selectivities probably
result from two heteroatoms, O and N, with a syn-
relationship that reinforces the individual effects. How-
ever, poor diastereofacial selectivities were observed for
dihydroxylation of 1b and 2b, where the two hetero-
atoms have an anti-relationship. Furthermore, as shown
in Figure 2, the molecular models of 1a/b were generated
by energy minimization using the DISCOVER module
from Insight II (Molecular Simulations, Waltham, MA).
The hydroxyl group of compound 1a was found to
significantly influence steric and electrostatic repulsion,
resulting in good regioselectivity of dihydroxylation
The iminocyclitols shown in Scheme 3 were assessed as
inhibitors of different glycosidases, and the results were
listed in Table 1. Compound 20 showed the most
potency inhibition for b-glucosidase. The Lineweaver–
Burk plot (Fig. 3) for inhibiting 4-nitrophenyl b-D-glu-
coside hydrolysis catalyzed by b-glucosidase following
the addition of 20 revealed that this compound binds
AcO
HO
KOH
MeOH/H
O
N
(OAc)2
HO
2
O
HN
17-21
(OH)2
O
1
0, 12, 14, 16
HO
OH
OH
HO
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
HO
HO
HO
HO
HO
N
H
N
H
N
H
N
H
1
7
18
19
20
HO
OH
HO
OH
OH
OH
HO
HO
HO
HO
HO
HO
N
N
H
N
N
HO
HO
H
H
H
2
1
22
23
24
HO
OH
OH
OH
OH
OH
OH HO
HO
HO
HO
HO
HO
HO
HO
N
H
N
H
N
N
H
H
2
5
26
27
28
Figure 1. ORTEP represention of the X-ray crystal structures of 14b
and 16c.
Scheme 3. Preparation of iminocyclitols 17–28.

3262
C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
Table 1. Inhibition of glycosidase with various seven-membered iminocyclitols
Compd no
a-Glucosidase
a-Galatosidase
a-Mannosidase
b-Glucosidase
b-Galatosidase
b-Mannosidase
1
1
1
2
2
2
2
2
2
2
2
2
7
8
9
0
1
2
3
4
5
6
7
8
NI
10
NI
NI
NI
NI
2
21
NI
NI
10
16
42
58
22
30
59
56
47
NI
NI
21
NI
12
7
NI
NI
NI
75
47
6
NI
NI
NI
4
NI
NI
24
37
24
NI
NI
34
32
33
30
10
4
NI
NI
NI
NI
NI
NI
19
28
NI
35
43
27
22
NI
NI
64
66
61
41
NI
NI
NI
NI
1
•
•
•
•
% Inhibition determined at 2 mM concentraction of inhibitor.
NI stands for no inhibition.
Enzyme unit: used 0.05u.
Substrate concentration : ꢀK
m
(mM).
[
I]=0.2 mM
4. Experimental
1
1
2000
0000
All reactions were performed under an argon atmo-
1
13
sphere, unless otherwise mentioned. H and C NMR
spectra were recorded on a Bruker AMX-400 or
8
000
000
000
1
[
I]=0.05 mM
500 MHz. Assignment of H NMR spectra was achieved
using 2D methods (COSY). Chemical shifts are
6
4
2
expressed in ppm using residual CDCl as reference.
3
[I]=0.00125 mM
I]=0 mM
High-resolution mass spectra were obtained with a VG
70-250S mass spectrometer in the FAB mode. Optical
rotation was measured with a Jasco DIP-370 polari-
meter at ꢀ25 ꢁC. Analytical thin-layer chromatogra-
phy (TLC) was performed on precoated plates (silica
gel 60 F-254). Silica gel 60 (E. Merck Co.) was employed
for all flash chromatography. All reactions were carried
out in oven-dried glassware (120 ꢁC) under an
atmosphere of nitrogen unless indicated otherwise. All
solvents were dried and distilled by standard tech-
niques.
[
000
0
0
1
2
-
1
1
/[So] (mM
)
K = 26.3 µM
i
Figure 3. Lineweaver–Burk plot for inhibition of b-glucosidase by 20.
competitively to the active site of the enzyme. The
measured K value of 20 is 26.3 lM. Further, the four
i
iminocyclitols, 20, 25, 26 and 27, which displayed
greater than 50% competitive inhibition for b-glucosi-
dase, all bear a same trans-5,6 configuration (sugar
numbering) found in glucose and have 4-hydroxy miss-
ing. However, one would be surprised that compound
4
.1. 4-(S)-Carbomethoxyl-oxazolidine-2-one (4)
To a reaction mixture containing
5.2 mmol), thionyl chloride (7.78 mL, 106.6 mmol) in
methanol (150 mL) was refluxed for overnight. The
solvent was removed to give -serine methylester
hydrochloride salt in ca. quantitative yield. To a
solution of -serine methylester hydrochloride salt
14.75 g, 94.8 mmol), triphosgene (11 g, 36.97 mmol) and
K CO (20.4 g, 142.2 mmol) in toluene (85 mL) was
L-serine (10 g,
9
2
0 with L-configuration at 6-position displayed the
L
highest percentage inhibition. It is worth to note that the
literature precedence for the seven-membered imino-
cyclitols with the missing hydroxymethyl side arm at the
L
(
8a
6
-position exhibit even higher activity. Our results
reinforces this view.
2
3
added water (85 mL) at room temperature, and then
stirred for 4 h. The solvents were removed and the
resultant residues was triturated with hot ethyl acetate
and then filtered. The filtrate was concentrated to give
the desired compound as oily material (11.97 g, 87%).
3. Conclusion
The oily material was used in next step without further
1
This work has designed a versatile route for preparing
diverse stereoisomers of seven-membered iminocyclitols
in good yields using ring-closing olefin metathesis di-
hydroxylation reaction sequence. The current efforts
involve the synthesis of various seven-membered imi-
nocyclitols. The results will be reported in due course.
purification: H NMR (400 MHz, CDCl
3
): d 3.83 (s,
3H), 4.43 (dd, J ¼ 4:6, 9.4 Hz, 1H), 4.54 (dd, J ¼ 4:6,
1
3
9.0 Hz, 1H), 4.62 (t, J ¼ 9:0 Hz, 1H), 6.25 (br, 1H);
C
NMR (100 MHz, CDCl
170.4; HRMS (FAB) calcd for C
): d 53.1, 53.7, 66.8, 158.9,
3
þ
5
H
8
NO
4
(M+H )
146.0453, found 146.0436.

C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
3263
4
.2. 4(S)-3-Allyl-4-hydroxymethyl-oxazolidine-2-one (5)
to it. After stirring for 1 h, the mixture was treated with
0 mL of H O and 10 mL of saturated aqueous NaCl.
Then it was extracted with CH Cl and dried over
1
2
To a stirred solution of 4 (10 g, 68.9 mmol) in DMF
100 mL) was added NaH (3.3 g, 82.7 mmol, 60%
immersion in mineral oil) at 0 ꢁC. After the evolution of
ceased, allyl bromide (7.1 mL, 82.7 mmol) was
2
2
(
2 4
Na SO . The solvent was removed and the resultant
residues were purified by silica gel flash chromatography
(ethyl acetate/hexane, 1:1, 2.5% MeOH) to give com-
H
2
1
added. The reaction mixture was stirred for overnight at
rt. The solvent (DMF) was evaporated and the resultant
residues were dissolved in EtOAc and washed with
pound 7 as mixtures (900 mg, 72%): H NMR
(400 MHz, CDCl
6H), 4.14–4.37 (m, 6H), 5.15–5.30 (m, 8H), 5.78–5.83
3
): d 2.04–2.28 (m, 6H), 3.82–3.88 (m,
13
water. The organic layer was dried over Na
2
SO
4
, filtered
3
(m, 4H); C NMR (100 MHz, CDCl ) 36.3, 37.1, 44.8,
and concentrated. The resultant residues were purified
by silica gel flash chromatography to obtain the desired
N-allyl oxazolidinone (9.6 g, 75%).
46.4, 58.2, 58.3, 62.2, 64.2, 66.8, 71.0, 118.4, 118.6,
118.8, 119.0, 132.1, 132.4, 133.6, 133.6, 158.8, 159.0;
þ
HRMS (FAB) calcd for C H NO (M+H ) 198.1130,
3
10
16
found 198.1131.
To the stirred solution of above oxazolidinone (9 g,
4
NaBH (2.02 g, 53.5 mmol) in portions and the resultant
8.6 mmol) in methanol (50 mL) at 0 ꢁC was added
4.5. 4(S)-3-But-3-enyl-4-(1-hydroxy-allyl)-oxazolidine-2-
one (8)
4
solution was stirred for 3 h at room temperature. After
the reaction was completed, the reaction was quenched
with water and diluted with dichloromethane and ex-
tracted. The organic extracts were washed with brine
and dried over Na SO . After removing the solvent, the
This compound was synthesized in 53% yield according
1
to the procedure for the synthesis of 7: H NMR
(
3
400 MHz, CDCl
.23–3.31 (m, 2H), 3.54–3.64 (m, 2H), 3.83–3.99 (m,
2H), 4.13–4.26 (m, 4H), 4.31–4.34 (m, 1H), 4.41–4.43
3
): d 2.15 (br, 2H), 2.30–2.47 (m, 4H),
2
4
residues were purified by silica gel flash chromatography
1
to obtain the desired compound 5 (6.9 g, 90%): H NMR
(
(
5
m, 1H), 5.06–5.17 (m, 4H), 5.31–5.37 (m, 2H), 5.40–
.50 (m, 2H), 5.71–5.80 (m, 4H); C NMR (100 MHz,
400 MHz, CDCl
3
3
): d 2.31 (br, 1H), 3.62–3.66 (m, 1H),
.72–3.81 (m, 2H), 3.85–3.90 (m, 1H), 4.09 (ddd,
13
CDCl ): d 32.1, 42.0, 42.8, 58.3, 59.0, 62.5, 63.9, 69.8,
3
J ¼ 1:5, 5.3, 15.7 Hz, 1H), 4.26 (dd, J ¼ 5:9, 8.8 Hz,
69.8, 73.5, 117.5, 117.8, 118.5, 119.4, 134.9, 135.0, 135.1,
135.3, 158.8, 159.2; HRMS (FAB) calcd for C10
1
5
H), 4.37 (dd, J ¼ 8:8, 8.8, Hz, 1H), 5.24–5.31 (m, 2H),
13
H
15NO
3
.82 (dddd, J ¼ 5:3, 7.1, 7.2, 10.1 Hz, 1H); C NMR
þ
(
M+H ) 198.1130, found 198.1128.
(
100 MHz, CDCl
3
): d 45.2, 56.1, 60.8, 64.5, 118.8, 132.4,
þ
1
1
58.6; HRMS (FAB) calcd for C
58.0817, found 158.0832.
7
H
12NO
3
(M+H )
4.6. (9aS)-9,9a-Dihydro-9-hydroxyoxazolo[3,4-a]azepin-
3-one (2a and 2b)
4.3. 4(S)-3-But-3-enyl-4-hydroxymethyl-oxazolidine-2-
one (6)
To the solution of compound 7 (0.9 g, 4.56 mmol) in
dichloromethane (80 mL) was added Grubbs reagent
(
first generation, 375 mg, 0.456 mmol) and the resultant
This compound was synthesized in 57% yield according
1
solution was refluxed for 12 h. After the reaction was
completed, the solution was concentrated and purified
by silica gel flash chromatography (ethyl acetate/hexane,
to the procedure for the synthesis of 5: H NMR
(
3
400 MHz, CDCl ): d 1.89 (br, 1H), 2.31–2.43 (m, 2H),
3
3
3
.19–3.26 (m, 1H), 3.53 (ddd, J ¼ 7:6, 7.6, 14.3 Hz, 1H),
1
:1, 1% MeOH) to give 2a and 2b (1:1, 700 mg, 90%).
1
.63–3.67 (m, 1H), 3.80 (dd, J ¼ 4:0, 11.8 Hz, 1H), 3.86–
.92 (m, 1H), 4.24 (ddd, J ¼ 0:8, 5.7, 8.9 Hz, 1H), 4.34
27
D
For 2a ½aꢁ +38.9 (c 1.10, CHCl
3
); H NMR (400 MHz,
CDCl ): d 1.88 (d, J ¼ 10:6 Hz, 1H), 2.47 (ddd, J ¼ 2:1,
3
(
dd, J ¼ 8:9, 8.9 Hz, 1H), 5.08-5.17 (m, 2H), 5.79 (dddd,
4
1
1
.5, 8.6 Hz, 1H), 2.74 (m, 1H), 3.55 (m, 1H), 3.93 (br,
H), 4.0 (dt, J ¼ 2:3, 8.2 Hz, 1H), 4.34 (br, 1H), 4.36 (br,
13
J ¼ 6:9, 6.9, 10.2, 13.7 Hz, 1H); C NMR (100 MHz,
CDCl
1
3
): d 29.7, 32.0, 41.6, 56.3, 61.0, 64.4, 117.6, 134.8,
13
H), 5.72 (m, 1H), 5.95 (m, 1H); C NMR (100 MHz,
): d 33.1, 42.6, 62.4, 64.0, 67.5, 126.9, 129.6, 158.5;
þ
58.8; HRMS (FAB) calcd for C
72.0974, found 172.0973.
8
H
14NO
3
(M+H )
CDCl
3
1
þ
HRMS (FAB) calcd for C3
8
H
11NO
3
(M+H ) 170.0817,
1
4
found 170.0820; For 2b ½aꢁ )18.41 (c 1.01, CHCl
3
); H
D
NMR (400 MHz, CDCl ): d 2.45–2.60 (m, 2H), 2.86 (br,
3
4.4. 4(S)-3-Allyl-4-(1-hydroxy-but-3-enyl)-oxazolidine-2-
one (7)
1
1
1
1
4
H), 3.53–3.62 (m, 2H), 3.78 (ddd, J ¼ 5:6, 7.3, 8.6 Hz,
H), 4.20 (dd, J ¼ 5:6, 8.9 Hz, 1H), 4.28 (dd, J ¼ 6:8,
13
6.7 Hz, 1H), 4.44 (dd, J ¼ 8:6, 8.9 Hz, 1H), 5.75 (m,
To a stirred solution of oxlalyl chloride (670 lL,
H), 5.94 (m, 1H); C NMR (100 MHz, CDCl ): d 34.7,
3
7
.6 mmol) in CH Cl2 (20 mL) was added DMSO
2
1.7, 64.0, 66.2, 71.1, 127.0, 129.8, 157.9; HRMS (FAB)
þ
(
1.13 mL, 15.9 mmol) at )78 ꢁC. The reaction mixture
was warmed to )60 ꢁC over 20 min and the alcohol 5
1.04g, 6.6 mmol) in CH Cl (5 mL) was added dropwise
calcd for C H NO (M+H ) 170.0817, found 170.0840.
8
11
3
(
2
2
over 15 min. The reaction mixture was allowed to
gradually warm up to )35 ꢁC over 20 min and then
triethylamine (3.7 mL, 26.48 mmol) was added. The
reaction mixture was then brought to )70 ꢁC, and
allylmagnesium bromide (6.6 mL, 6.6 mmol) was added
4.7. (9aS)-5,6,9,9a-Tetrahydro-9-hydroxyoxazolo[3,4-a]-
azepin-3(1H)-one (1)
This compound was synthesized in 86% yield (1a/
1b ¼ 1.13:1) according to the procedure for the synthesis

3264
C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
1
of 2. For 1a H NMR (400 MHz, CDCl
(
1
3
): d 2.25–2.35
(dt, J ¼ 1:9, 10.5 Hz, 1H), 5.32 (dd, J ¼ 1:9, 5.2 Hz,
3
13
m, 2H), 2.48 (1H, br), 2.92 (ddd, J ¼ 3:4, 9.6, 16.8 Hz,
1H); C NMR (100 MHz, CDCl ): d 20.6, 20.8, 20.9,
26.0, 40.4, 52.9, 65.1, 69.5, 69.8, 71.5, 157.9, 168.9,
H), 3.63 (ddd, J ¼ 5:6, 8.5, 14.2), 3.86 (ddd, J ¼ 3:9,
.5, 16.8 Hz, 1H), 4.34 (dd, J ¼ 5:6, 9.1 Hz, 1H), 4.41
8
169.7, 169.7; HRMS (FAB) calcd for C14
þ
H
20NO
8
(
dd, J ¼ 9:1, 8.5 Hz, 1H), 5.77 (ddd, J ¼ 2:04, 4.2,
330.1189 (M+H ), found 330.1181.
13
1
CDCl
3.8 Hz, 1H), 5.91–5.96 (m, 1H); C NMR (100 MHz,
): d 34.7, 41.71, 64.0, 66.2, 71.1, 127.0, 129.8,
3
þ
1
1
57.9; HRMS (FAB) calcd for C
8
H
11NO
3
(M+H )
4.11. (7S,8S,9S,9aS)-7,8-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (12a)
1
70.0817, found 170.0840; For 1b H NMR (400 MHz,
): d 2.24 (br, 1H), 2.38 (m, 1H), 2.46–2.55 (m,
H), 3.30 (ddd, J ¼ 2:9, 8.1, 13.1 Hz, 1H), 3.74 (ddd,
J ¼ 3:1, 8.5, 13.1 Hz, 1H), 4.06 (m, 2H), 4.32–4.40 (m,
CDCl
3
3
D
4
1
1
½aꢁ +16.42 (c 0.96, CHCl
3
); H NMR (400 MHz,
CDCl ): d 1.90 (ddt, J ¼ 3:2, 6.3, 14.3 Hz, 1H), 2.07 (s,
3
13
2
H), 5.94 (m, 1H), 6.03 (m, 1H); C NMR (100 MHz,
3H), 2.11 (s, 3H), 2.14 (s, 3H), 2.36 (dtd, J ¼ 4:2, 10.2,
14.3 Hz, 1H), 3.08 (ddd, J ¼ 3:2, 9.8, 14.3 Hz, 1H), 3.83
(ddd, J ¼ 4:2, 6.3, 14.3 Hz, 1H), 3.96 (dt, J ¼ 4:5,
9.2 Hz, 1H), 4.04 (dd, J ¼ 4:5, 9.2 Hz, 1H), 4.45 (t,
J ¼ 9:2 Hz, 1H), 5.15 (dd, J ¼ 4:5, 7.6 Hz, 1H), 5.27 (dd,
J ¼ 1:7, 7.6 Hz, 1H), 5.34 (ddd, J ¼ 1:7, 3.2, 10.2 Hz,
CDCl ): d 30.9, 42.9, 59.6, 66.1, 73.0, 129.2, 136.4, 158.2;
HRMS (FAB) calcd for C
found 170.0820.
3
þ
8
H
11NO
3
(M+H ) 170.0817,
13
4.8. General procedure for dihydroxylation and
peracetylation
1H); C NMR (100 MHz, CDCl ) 20.7, 20.9, 21.1, 27.2,
3
39.1, 59.1, 66.5, 69.9, 72.7, 73.6, 157.5, 169.6, 169.9,
þ
170.4; HRMS (FAB) calcd for C14
330.1189, found 330.1195.
H
20NO
8
(M+H )
To a solution of alkene (138.1 mg, 0.816 mmol) in ace-
tone/water (2 mL, 8:1) was added N-methyl morpholine
N-oxide (286 mg, 2.44 mmol) and OsO
.04 mmol as a 2.5% wt/wt solution in t-BuOH). The
solution was stirred at room temperature for 4 h and
then aqueous Na SO (saturated, 1 mL) and MeOH
1 mL) were added. The mixture was filtered and filtrate
4
(502 lL,
0
4.12. (7R,8R,9S,9aS)-7,8-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (12b)
2
3
3
4
1
(
½aꢁ +0.46 (c 0.97, CHCl
3
); H NMR (400 MHz,
D
was concentrated in vacuo. The triol was used without
further purification for acetylation.
CDCl ): d 1.99 (m, 1H), 2.03 (s, 3H), 2.04 (s, 3H), 2.19
3
(s, 3H), 2.29 (dtd, J ¼ 5:2, 10.1, 15.1 Hz, 1H), 3.46 (dt,
J ¼ 5:2, 13.5 Hz, 1H), 3.74 (ddd, J ¼ 5:2, 10.1, 13.5 Hz,
1H), 4.02 (dd, J ¼ 5:4, 9.0 Hz, 1H), 4.21 (dt, J ¼ 5:4,
9.6 Hz, 1H), 4.37 (t, J ¼ 9:0 Hz, 1H), 4.93 (dd, J ¼ 2:4,
9.6 Hz), 5.08 (ddd, 1.8, 3.2, 10.1 Hz, 1H), 5.59 (br, 1H);
Acetic anhydride (2.5 mL) was added to the above res-
idues in 5 mL of anhydrous pyridine and stirred at room
temperature for 3 h then concentrated in vacuo. The
isomers were separated by HPLC (ethyl acetate/hexane,
13
C NMR (100 MHz, CDCl ): d 20.7, 20.9, 20.1, 25.0,
3
1
:1, 1% MeOH, ZORBAX column, 3 mL/min).
40.9, 53.2, 65.3, 70.8, 71.3, 73.0, 157.9, 169.5, 169.7,
þ
1
3
70.0; HRMS (FAB) calcd for C14
30.1189, found 330.1185.
H
20NO
8
(M+H )
4
1
.9. (7S,8S,9R,9aS)-7,8-Bis(acetyloxy)-3-oxohexahydro-
H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (10a)
4.13. (6S,7R,9S,9aS)-6,7-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (14a)
3
4
1
½
aꢁ +0.32 (c 1.04, CHCl ); H NMR (400 MHz,
D
CDCl
3
3
): d 1.90 (m, 1H), 2.06 (s, 3H), 2.131 (s, 3H), 2.129
3
4
1
(
s, 3H), 2.30 (dtd, J ¼ 3:3, 10.4, 13.8 Hz, 1H), 3.08 (ddd,
½aꢁ )12.58 (c 0.15, CHCl
3
); H NMR (400 MHz,
D
J ¼ 2:3, 10.4, 14.6 Hz, 1H), 3.86 (ddd, J ¼ 3:3, 6.6,
CDCl ): d 1.82 (d, J ¼ 14:2 Hz, 1H), 2.05 (s, 3H), 2.09
3
1
4.6 Hz, 1H), 4.21 (dd, J ¼ 4:0, 8.3 Hz, 1H), 4.30 (t,
(s, 3H), 2.11 (s, 3H), 2.58 (dt, J ¼ 9:8, 14.2 Hz, 1H), 3.05
(dd, J ¼ 1:2, 14.8 Hz, 1H), 4.13 (dd, J ¼ 5:6, 14.8 Hz,
1H), 4.16 (t, J ¼ 8:5 Hz, 1H), 4.28 (t, J ¼ 8:5 Hz, 1H),
4.33 (td, J ¼ 2:4, 8.5 Hz, 1H), 5.06 (dt, J ¼ 2:5, 9.8 Hz,
J ¼ 8:3, 1H), 4.34 (t, J ¼ 4:0, 8.3 Hz, 1H), 5.20 (ddd,
J ¼ 2:6, 4.2, 10.4 Hz), 5.28 (d, 3.6 Hz, 1H), 5.37 (br, 1H);
1
3
C NMR (100 MHz, CDCl ): d 20.5, 20.6, 20.9, 26.9,
3
13
3
1
(
8.5, 54.5, 63.5, 70.7, 71.4, 73.9, 157.6, 168.1, 169.8,
69.8; HRMS (FAB) calcd for C14
M+H ), found 330.1190.
1H), 5.17 (m, 1H), 5.20 (m, 1H); C NMR (100 MHz,
H20NO
8
330.1189
3
CDCl ): d 20.9, 21.0, 21.0, 29.1, 41.9, 56.2, 63.9, 69.5,
þ
70.2, 71.4, 158.2, 169.9, 170.0, 170.4; HRMS (FAB)
þ
calcd for
3
C
14
H
20NO
8
(M+H ) 330.1189, found
30.1183.
4.10. (7R,8R,9R,9aS)-7,8-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (10b)
4.14. (6R,7S,9S,9aS)-6,7-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (14b)
3
D
4
1
½
aꢁ +0.09 (c 1.04, CHCl ); H NMR (400 MHz,
3
CDCl ): d 1.93 (m, 1H), 2.04 (s, 3H), 2.15 (s, 3H), 2.17
3
3
D
4
1
(
s, 3H), 2.31 (dtd, J ¼ 4:0, 10.5, 14.8 Hz, 1H), 3.45 (dt,
J ¼ 4:0, 13.0, 1H), 3.65 (td, J ¼ 4:0, 13.0 Hz, 1H), 4.10
dd, J ¼ 3:5, 8.9 Hz, 1H), 4.31 (dd, J ¼ 3:5, 8.9 Hz, 1H),
.37 (t, J ¼ 8:9 Hz, 1H), 5.03 (d, J ¼ 5:2 Hz, 1H), 5.11
½aꢁ )14.23 (c 1.02, CHCl
3
); H NMR (400 MHz,
CDCl ): d 2.06 (s, 3H), 2.11 (br, 2H), 2.14 (s, 3H),
3
(
4
2.15 (s, 3H), 3.48 (dd, J ¼ 4:8, 14.6 Hz, 1H),
3.86 (dd, J ¼ 4:8, 14.6 Hz, 1H), 4.08 (dd, J ¼ 5:0,

C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
3265
8
5
.8 Hz, 1H), 4.20 (m, 1H), 4.37 (t, J ¼ 8:8 Hz, 1H),
4.19. (2S,3S,4R,5R)-2-(Hydroxymethyl)azepane-3,4,5-
triol (18)
13
.20 (br, 2H), 5.48 (br, 1H); C NMR (100 MHz,
CDCl ): d 21.1, 21.2, 21.6, 31.7, 44.5, 57.5, 65.5, 68.6,
3
1
7
calcd for
0.6, 71.5, 158.2, 169.4, 170.0, 170.5; HRMS (FAB)
þ
H NMR (400 MHz, CD
3
OD): d 1.81–1.86 (m, 2H),
C
14
H
20NO
8
(M+H ) 330.1189, found
2.81–2.94 (m, 3H), 3.41–3.46 (m, 2H), 3.80 (dd, J ¼ 4:0,
13
3
30.1191.
11.2 Hz, 1H), 3.95–3.99 (m, 2H); C NMR (100 MHz,
CD
3
OD): d 34.5, 43.9, 64.2, 64.5, 73.5, 74.2, 79.7;
þ
HRMS (FAB) calcd for C
Found 178.1082.
7
H
16NO
4
(M+H ), 178.1079
4.15. (6S,7R,9R,9aS)-6,7-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (16a)
3
4
1
½
aꢁ )14.06 (c 1.0, CHCl ); H NMR (400 MHz,
D
3
4.20. (3R,4S,6S,7S)-7-(Hydroxymethyl)azepane-3,4,6-
triol (19)
CDCl ): d 2.07 (s, 3H), 2.09 (s, 3H), 2.15 (s, 3H), 2.21
3
(
(
1
9
t, J ¼ 7:6 Hz, 1H), 2.21 (t, J ¼ 6:5 Hz, 1H), 3.38
dd, J ¼ 5:4, 14.5 Hz, 1H), 3.99 (dd, J ¼ 5:4, 14.5 Hz,
1
H NMR (400 MHz, CD
ddd, J ¼ 3:6, 10.0, 14.0 Hz 1H), 2.76 (dd,
J ¼ 6:0, 14.0 Hz 1H), 2.91 (m, 1H), 3.17 (dd, J ¼
3
OD): d 1.84 (m, 1H), 2.17
H), 4.00 (td, J ¼ 5:0, 9.2 Hz, 1H), 4.11 (dd, J ¼ 5:0,
.2 Hz, 1H), 4.41 (t, J ¼ 9:2 Hz, 1H), 4.86 (ddd,
(
J ¼ 6:5, 7.6, 9.2 Hz, 1H), 5.11 (td, J ¼ 1:5, 7.6 Hz, 1H),
5
(
:6, 14.0 Hz, 1H), 3.48 (dd, J ¼ 7:6, 10.8 Hz, 1H), 3.53
13
5
.36 (td, J ¼ 1:5, 5.4 Hz, 1H); C NMR (100 MHz,
CDCl ): d 20.8, 20.9, 20.9, 31.8, 45.1, 58.5, 66.5, 69.7,
0.2, 72.6, 157.8, 169.2, 169.6, 169.7; HRMS (FAB)
dd, J ¼ 6:4, 10.8 Hz, 1H), 3.95 (m, 2H), 4.14 (dt,
13
3
J ¼ 2:4, 10.0 Hz, 1H); C NMR (100 MHz, CD OD): d
3
7
38.6, 52.0, 64.3, 64.4, 67.9, 70.0, 75.4; HRMS (FAB)
calcd for C H NO (M+H ) 178.1079, Found
þ
calcd for C H NO (M+H ) 330.1189, found
20
3
þ
14
8
7 16 4
30.1185.
178.1072.
4.16. (6R,7S,9R,9aS)-6,7-Bis(acetyloxy)-3-oxohexahy-
dro-1H-[1,3]oxazolo[3,4-a]-azepin-9-yl acetate (16b)
4.21. (3R,4S,6R,7S)-7-(Hydroxymethyl)azepane-3,4,6-
triol (20)
3
4
1
½
aꢁ +12.33 (c 0.96, CHCl ); H NMR (400 MHz,
D
CDCl
3
1
H NMR (400 MHz, CD OD): d 1.90 (br, 1H), 2.30
3
3
): d 1.98 (dd, J ¼ 6:3, 14.6 Hz, 1H), 2.05 (s, 3H),
(
ddd, J ¼ 2:0, 10.8, 14.0 Hz 1H), 3.05 (m, 2H), 3.23
2
(
1
(
2
1
(
.12 (s, 3H), 2.17 (s, 3H), 2.50 (t, J ¼ 14:6 Hz, 1H), 3.03
(
dd, J ¼ 2:0, 14.0 Hz, 1H), 3.70 (m, 2H), 3.84
d, J ¼ 5:2 Hz, 1H), 3.94 (m, 2H), 4.19 (dd, J ¼ 4:0,
(dt, J ¼ 2:8, 10.8 Hz, 1H), 3.90 (dd, J ¼ 3:6, 11.6 Hz,
5.2 Hz, 1H), 4.55 (m, 1H), 4.98 (d, J ¼ 6:3, 1H), 5.27
13
1
3
H), 3.95 (m, 1H); C NMR (100 MHz, CD OD):
13
br, 2H); C NMR (100 MHz, CDCl
3
): d 20.9, 20.9,
0.9, 28.9, 42.9, 61.8, 65.7, 68.6, 69.7, 71.8, 157.7, 169.9,
70.0, 170.4; HRMS (FAB) calcd for C H NO
d 38.9, 47.0, 61.7, 66.1, 67.5, 70.0, 71.8; HRMS
þ
(FAB) calcd for C
7
H
16NO
4
(M+H ) 178.1079, found
14
20
8
178.1082.
þ
M+H ) 330.1189, found 330.1183.
4.22. (3S,4R,6R,7S)-7-(Hydroxymethyl)azepane-3,4,6-
triol (21)
4
.17. General procedure for hydrolysis of oxazolidinones
To a stirred solution of 10 (30 mg, 0.09 mmol) in 50%
aqueous EtOH (3 mL) at 23 ꢁC was added solid KOH
1
H NMR (400 MHz, CD OD): d 1.69 (m, 1H),
3
2
(
1
(
.43 (ddd, J ¼ 3:6, 10.4, 14.0 Hz, 1H), 2.60 (m, 1H), 2.82
dd, J ¼ 2:4, 14.0 Hz, 1H), 3.15 (dd, J ¼ 4:8, 14.0 Hz,
H), 3.44 (dd, J ¼ 8:0, 11.2 Hz, 1H), 3.70 (m, 1H), 3.74
dd, J ¼ 4:0, 11.2 Hz, 1H), 3.85 (m, 1H), 4.03 (dt,
(
51.06 mg, 1.64 mmol), and the mixture was heated at
9
0 ꢁC for 10 h. After this period, the mixture was cooled
to 23 ꢁC and neutralized with dilute HCl. The mixture
was concentrated under reduced pressure. The residues
were subjected to Bio-Gel P2 (fine, 45–90 lm) column
chromatography eluting with water. After removal of
water via lyophilization, the azasugar was obtained
13
J ¼ 2:0, 10.4 Hz, 1H); C NMR (100 MHz, CD
3
OD): d
3
(
1
7.5, 52.5, 64.6, 68.7, 68.8, 69.7, 73.5; HRMS
þ
FAB) calcd for C H16NO (M+H ) 178.1079, found
7 4
78.1072.
(
14.6 mg, ꢀ90%).
4.18. (2S,3R,4R,5R)-2-(Hydroxymethyl)azepane-3,4,5-
triol (17)
4.23. (2R,3S,4S,5S)-2-(Hydroxymethyl)azepane-3,4,5-
triol (22)
1
1
H NMR (400 MHz, CD
3
OD): d 1.58 (m, 1H), 2.22 (m,
3
H NMR (400 MHz, CD OD): d 1.58 (m, 1H), 2.22 (m,
1
3
3
H), 2.81–2.93 (m, 2H), 2.96 (td, J ¼ 1:2, 7.2 Hz, 1H),
1H), 2.81–2.93 (m, 2H), 2.96 (td, J ¼ 1:2, 7.2 Hz, 1H),
13
.48 (d, J ¼ 7:2 Hz, 1H), 3.67 (dd, J ¼ 1:2, 4.4 Hz, 1H),
3.48 (d, J ¼ 7:2 Hz, 1H), 3.67 (dd, J ¼ 1:2, 4.4 Hz, 1H),
13
.88 (m, 1H), 4.04 (dt, J ¼ 2:0, 10.4 Hz, 1H); C NMR
3.88 (m, 1H), 4.04 (dt, J ¼ 2:0, 10.4 Hz, 1H); C NMR
(
100 MHz, CD
3
OD): d 30.9, 44.1, 57.1, 64.4, 70.7, 71.8,
(100 MHz, CD OD): d 30.9, 44.1, 57.0, 64.4, 70.7, 71.8,
3
þ
þ
7
1
7.6; HRMS (FAB) calcd for C H NO (M+H )
78.1079, found 178.1072.
77.6; HRMS (FAB) calcd for C H NO (M+H )
178.1079, found 178.1074.
7
16
4
7
16
4

3266
C.-C. Lin et al. / Bioorg. Med. Chem. 12 (2004) 3259–3267
4.24. (2R,3R,4S,5S)-2-(Hydroxymethyl)azepane-3,4,5-
triol (23)
4.29. (2R,3R,4R,5R)-2-(Hydroxymethyl)azepane-3,4,5-
triol (28)
1
1
H NMR (400 MHz, CD
3
OD): d 1.81–1.86 (m, 2H),
H NMR (400 MHz, CD
3
OD): d 1.73 (ddd, J ¼ 4:0, 9.6,
2
1
.81–2.94 (m, 3H), 3.41–3.46 (m, 2H), 3.80 (dd, J ¼ 4:0,
13.6 Hz, 1H), 2.02 (m, 1H), 2.53 (dt, J ¼ 4:0, 8.0 Hz,
1H), 2.59 (ddd, J ¼ 4:0, 10.8, 13.6 Hz, 1H), 3.15 (ddd,
J ¼ 4:0, 6.0, 13.6 Hz, 1H), 3.39 (dd, J ¼ 8:0, 10.8 Hz,
1H), 3.44 (dd, J ¼ 5:2, 8.0 Hz, 1H), 3.72 (d, J ¼ 5:2 Hz,
1H), 3.79 (dd, J ¼ 4:0, 10.8 Hz, 1H), 4.05 (dd, J ¼ 4:0,
13
1.2 Hz, 1H), 3.95–3.99 (m, 2H); C NMR (100 MHz,
OD): d 34.5, 43.9, 64.2, 64.5, 73.5, 74.2, 79.7;
CD
HRMS (FAB) calcd for C
found 178.1075.
3
þ
7
H
16NO
4
(M+H ) 178.1079,
13
1
6
3
0.0 Hz, 1H); C NMR (100 MHz, CD OD): d 33.1,
3.0, 65.2, 68.4, 71.5, 72.9, 81.2; HRMS (FAB) calcd for
þ
C H NO (M+H ) 178.1079, found 178.1075.
7
16
4
4.25. (3S,4R,6R,7R)-7-(Hydroxymethyl)azepane-3,4,6-
triol (24)
1
H NMR (400 MHz, CD
.17 (ddd, J ¼ 3:6, 10.0, 14.0 Hz, 1H), 2.76 (dd,
J ¼ 6:0, 14.0 Hz 1H), 2.91 (m, 1H), 3.17 (dd, J ¼ 5:6,
4.0 Hz, 1H), 3.48 (dd, J ¼ 7:6, 10.8 Hz, 1H), 3.53
3
OD): d 1.84 (m, 1H),
Acknowledgements
2
We acknowledge financial support from the Academia
Sinica, National Science council in Taiwan (NSC91-
1
(
dd, J ¼ 6:4, 10.8 Hz, 1H), 3.95 (m, 2H), 4.14 (dt,
2
113-M-001-013) and National Tsing-Hua University.
13
J ¼ 2:4, 10.0 Hz, 1H); C NMR (100 MHz, CD OD):
3
d 38.6, 52.0, 64.3, 64.4, 67.9, 70.0, 75.4; HRMS
þ
(
1
FAB) calcd for C
78.1072.
7
H
16NO
4
(M+H ) 178.1079, found
References and notes
1
. (a) Lis, H.; Sharon, N. Eur.J. Biochem. 1993, 218, 1–27;
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(
4
.26. (3R,4S,6S,7R)-7-(Hydroxymethyl)azepane-3,4,6-
triol (25)
T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100,
4683–4696; (d) Ernst, B.; Hart, G. W.; Sina €y . In Carbo-
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. (a) Varki, A. Glycobiology 1993, 3, 97–130; (b) Sears, P.;
Wong, C.-H. Cell. Mol. Life Sci. 1998, 54, 223–252.
. Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38,
1
H NMR (400 MHz, CD OD): d 1.69 (m, 1H), 2.43
3
2
3
4
(
(
1
(
ddd, J ¼ 3:6, 10.4, 14.0 Hz, 1H), 2.60 (m, 1H), 2.82
dd, J ¼ 2:4, 14.0 Hz, 1H), 3.15 (dd, J ¼ 4:8, 14.0 Hz,
H), 3.44 (dd, J ¼ 8:0, 11.2 Hz, 1H), 3.70 (m, 1H), 3.74
2
301–2324.
dd, J ¼ 4:0, 11.2 Hz, 1H), 3.85 (m, 1H), 4.03 (dt,
. (a) Heightman, T. D.; Vasella, A. T. Angew. Chem., Int.
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102, 515–553.
13
J ¼ 2:0, 10.4 Hz, 1H); C NMR (100 MHz, CD OD):
3
d 37.5, 52.5, 64.6, 68.7, 68.8, 69.7, 73.5; HRMS
þ
(
1
FAB) calcd for C
78.1071.
7
H
16NO
4
(M+H ) 178.1079, found
5
. (a) Sinnott, M. L. Chem. Rev. 1990, 90, 1171–1202; (b)
Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199–
2
6
10; (c) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605–
11; (d) St u€ tz, A. E. Iminosugars as Glycosidase Inhibitors:
4
.27. (3S,4R,6S,7R)-7-(Hydroxymethyl)azepane-3,4,6-
triol (26)
Nojirimycin and Beyond; Wiley–VCH: Weinheim, Ger-
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Asano, N.; Molyneux, R. J.; Nash, R. J. Phytochemistry
1
H NMR (400 MHz, CD OD): d 1.90 (br, 1H), 2.30
3
(
(
(
1
ddd, J ¼ 2:0, 10.8, 14.0 Hz 1H), 3.05 (m, 2H), 3.23
2
9
001, 56, 265–295; (g) Asano, N. Glycobiology 2003, 23,
3R–104R.
dd, J ¼ 2:0, 14.0 Hz, 1H), 3.70 (m, 2H), 3.84
dt, J ¼ 2:8, 10.8 Hz, 1H), 3.90 (dd, J ¼ 3:6, 11.6 Hz,
13
6. (a) Varrot, A.; Tarling, C. A.; Macdonald, J. M.; Stick,
R. V.; Zechel, D. L.; Withers, S. G.; Davies, G. J. J. Am.
Chem. Soc. 2003, 125, 7496–7497; (b) Zechel, D. L.;
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3
H), 3.95 (m, 1H); C NMR (100 MHz, CD OD): d
3
8.6, 47.0, 61.7, 66.1, 67.5, 70.0, 71.8; HRMS
þ
(
1
FAB) calcd for C
78.1074.
7
H
16NO
4
(M+H ) 178.1079, found
7
. Previous studies on the the synthesis of azepanes see: (a)
Paulsen, H.; Todt, K. Chem. Ber. 1976, 100, 512–520; (b)
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4.28. (3R,4S,6R,7R)-7-(Hydroxymethyl)azepane-3,4,6-
triol (27)
1
H NMR (400 MHz, CD OD): d 2.10 (m, 2H), 2.63 (td,
3
8
. (a) Moris-Varas, F.; Qian, X.-H.; Wong, C. H. J. Am.
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Wong, C. H. Bioorg. Med. Chem. 1996, 4, 2055–2069.
J ¼ 2:0, 6.8 Hz 1H), 2.78 (dd, J ¼ 2:4, 14.4 Hz, 1H),
3
.06 (dd, J ¼ 4:8, 14.4 Hz, 1H), 3.51 (bd, 2H), 3.87 (m,
1
3
1
NMR (100 MHz, CD
7
H), 3.91 (m, 1H), 3.96 (td, J ¼ 2:0, 5.6 Hz, 1H);
C
3
OD): d 39.3, 52.8, 63.9, 64.3, 67.8,
3.4, 75.8; HRMS (FAB) calcd for C H NO (M+H )
78.1079, found 178.1081.
þ
7
16
4
9. For recent studies on the the synthesis of azepanes from
bis-epoxides see: (a) Damour, D.; Barreau, M.; Blanchard,
1

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2
700.
1
0. For recent studies on the the synthesis of azepanes from
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7
1
1
(
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1
1. For recent studies on the the synthesis of azepanes from
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6. Other approaches to azasugars by ring-closing methatesis:
(
a) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.;