Synthesis of DMJ analogs with seven- and eight-membered iminocyclitols

Article abstract of DOI:10.1016/j.tet.2006.12.002

A straightforward synthesis of new hydroxy azepane and azocane with an additional hydroxymethyl side arm (1-deoxymannojirimycin, DMJ analogs) has been achieved from trans-(2S,4R)-4-hydroxyproline via Grignard addition, ring-closing metathesis, and stereos

Full text of DOI:10.1016/j.tet.2006.12.002

Tetrahedron 63 (2007) 1339–1344
Synthesis of DMJ analogs with seven- and eight-membered
iminocyclitols
a
a
b
Meng-Yang Chang,a, Yung-Hua Kung, Chih-Chong Ma and Shui-Tein Chen
*
aDepartment of Applied Chemistry, National University of Kaohsiung, Kaohsiung 811, Taiwan, ROC
bInstitute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, ROC
Received 30 November 2006; accepted 5 December 2006
Available online 20 December 2006
Abstract—A straightforward synthesis of new hydroxy azepane and azocane with an additional hydroxymethyl side arm (1-deoxymannojiri-
mycin, DMJ analogs) has been achieved from trans-(2S,4R)-4-hydroxyproline via Grignard addition, ring-closing metathesis, and stereo-
selective osmylation as the key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Glycosidases and glycosyltransferases are involved in the
processing and synthesis of complex carbohydrates, which
are essential in various biological recognition processes.3,4
While deoxynojirimycin (DNJ) constitutes a well known
example of a potent naturally occurring glycosidase inhibi-
tor, DMJ has been found as a selective inhibitor of a-manno-
sidase I. Iminocyclitols based on seven- or eight-membered
rings having the same carbon content as the azasugars but en-
dowed with the conformational advantage of a more flexible
azepane or azocane ring that could lead to favorable binding
to the active site of the enzyme have been documented.5–7 In
connection with our studies on trans-(2S,4R)-4-hydroxy-
proline as the chiral material, we are interested in developing
an easy and straightforward approach to two DMJ analogs 1
and 2 via Grignard addition, ring-closing metathesis, and
stereoselective osmylation.
The structural framework of trans-(2S,4R)-4-hydroxyproline
possesses three functional groups that can be easily modi-
fied.1 The skeleton represents the significant feature for
producing a series of different carbon frameworks using an
efficient modification technique. Recently we have intro-
duced a straightforward approach toward anisomycin, epi-
batidine, pancracine, streptorubin B core, statine, and
VigabatrinÒ employing trans-(2S,4R)-4-hydroxyproline as
the starting material.2 To explore a new application, synthetic
studies toward new hydroxy azepane 1 and azocane 2 with an
additional hydroxymethyl side arm were further investigated
as shown in Figure 1. According to the structural framework
of 1-deoxymannojirimycin (DMJ, 3), compounds 1 and 2
have the common configuration of hydroxyl group at the
cyclic ring and their only difference is the extra methylene
group (–CH2–) between C2–C3 and C3–C4 positions.
2. Results and discussion
HO
OH
OH
OH
HO
HO
The straightforward synthesis of compounds 1 and 2 began
from alcohol 4 as illustrated in Scheme 1. The preparation
of alcohol 4 was recently reported from trans-(2S,4R)-4-
hydroxyproline.2 First, compound 5 was synthesized via
one-pot reaction by O-silylation with tert-butyldimethylsilyl
chloride and sodium hydride, followed by N-allylation of
the resultant product with allyl bromide in 80% yield. To
this end, compound 5 was treated with tetra-n-butylammo-
nium fluoride and subsequently oxidized with pyridinium
chlorochromate and Celite to aldehyde 6 under the one-pot
condition in 84% yield. Further, in order to achieve the
synthesis of targets 1 and 2, two dienes 7 and 7a (47% and
50%) or 8 and 8a (45% and 50%) were yielded in nearly
1:1 ratio by Grignard addition of aldehyde 6 with vinyl- or
HO
OH
OH
HO
OH
OH
N
Ts
N
Ts
N
H
DMJ (3)
1
2
Figure 1. Structural characteristics of seven-, eight-, and six-membered
iminocyclitols 1, 2, and DMJ (3).
Keywords: trans-(2S,4R)-4-Hydroxyproline; 1-Deoxymannojirimycin
(DMJ); Azepane; Azocane; Grignard addition; Ring-closing metathesis;
Stereoselective osmylation.
* Corresponding author. Tel.: +886 7 591 9464; fax: +886 7 591 9348;
e-mail: mychang@nuk.edu.tw
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.002

1340
M.-Y. Chang et al. / Tetrahedron 63 (2007) 1339–1344
allylmagnesium bromide. The yields of alcohols 7 and 7a or
8 and 8a were adjusted based on isolated products.
hydrolysis with potassium carbonate in methanol in 89%
and 83% yields. The successful epimerizations of com-
pounds 9a and 10a were determined by comparing their
1H NMR spectra with those of compounds 9 and 10. Stereo-
selective osmylation of allylic or homoallylic alcohols 9 and
10 on the azepane or azocane framework with osmium tetra-
oxide and N-methylmorpholine N-oxide afforded triol 11 or
12 as a single diastereomer.
OH
HO
NaH, TBSCl, THF
ref. 2
OBn
then, allylBr, rt
(one-pot 80%)
HN
Ts
CO2H
OBn
N
H
4
OTBS
O
H
According to the literature reports,4b,6o we envisioned that
the hydroxyl group at C4 position is an important factor
to cause steric hindrance and affects the stereoselective in-
troduction of cis-dihydroxyl groups. Thus, this remarkably
high diastereoselectivity of the hydroxylation would arise
from the steric blocking of the concave face. On examining
the steric hindrance factor of C4 substitutent during the os-
mylation procedure, reaction of compound 9 with acetoxy
group was still afforded the sole product under the same re-
action condition. During the osmylation process, the other
stereoisomers of compounds 11 and 12 were not observed.
The related trans–cis stereochemical structure of triol 11
with contiguous chiral centers at C4, C5, and C6 was deter-
mined by single-crystal X-ray analysis as shown in
Diagram 1.10
TBAF, THF, rt then
PCC, DCM, rt
(one-pot 84%)
OBn
N
N
Ts
Ts
5
6
vinylMgBr,
THF, -78 °C
allylMgBr,
THF, -78 °C
R1
R1
R2
R2
OBn
OBn
N
N
Ts
Ts
7, R1=OH, R2=H (47%)
8, R1=OH, R2=H (45%)
8a, R1=H, R2=OH (50%)
7a, R1=H, R2=OH (50%)
Grubbs 2nd
,
Grubbs 2nd
DCM, reflux
,
DCM, reflux
R1
R1
R2
R2
OBn
OBn
N
Ts
N
Ts
9, R1=OH, R2=H (87%)
9a, R1=H, R2=OH (85%)
10, R1=OH, R2=H (78%)
10a, R1=H, R2=OH (72%)
OsO4, NMO,
OsO4, NMO
THF/t-BuOH (1:3) THF/t-BuOH (1:3)
reflux (for 9)
OH
reflux (for 10)
HO
OH
HO
5
4
4
HO
HO
6
HO
OBn
OBn
N
N
Ts
11 (88%)
Ts
12 (85%)
H2, Pd/C,
H2, Pd/C,
MeOH, rt
MeOH, rt
OH
HO
HO
OH
HO
OH
OH
N
N
Ts
2 (91%)
Ts
1 (93%)
Diagram 1. X-ray crystallography of compound 11.
Scheme 1. Synthesis of DMJ analogs 1 and 2.
The key ring-closing metathesis was examined in the follow-
ing step. Ring-closing metathesis has been established as
a powerful method for the elaboration of medium-sized rings,
including carbohydrates, heterocycles, and alkaloids.4b,8,9 To
build up the azepane and azocane structural skeletons, dienes
7 and 7a or 8 and 8a were subjected to a ring-closing meta-
thesis employing Grubbs’ second generation catalyst and
the expected compounds 9 and 9a or 10 and 10a were gener-
ated, respectively.
According to the corresponding results of osmylated product
11, we think that the similar manner should be also used to
predict the stereochemical structure of triol 12 as a trans–
cis conformation. Finally, synthesis of DMJ analogs 1 and
2 was achieved via hydrogenolysis with hydrogen in the
presence of a catalytic amount of 10% palladium on acti-
vated carbon.
3. Conclusion
In order to increase the total yields of DMJ analogs 1 and 2,
alcohols 9a and 10a were successfully epimerized to the de-
sired alcohols 9 and 10 by Mitsunobu reaction with diethyl
azodicarboxylate, triphenylphosphine, and acetic acid and
In summary, we succeeded in accomplishing the synthesis of
DMJ analogs 1 and 2 in moderate yields via Grignard addi-
tion, ring-closing metathesis, and highly stereoselective

M.-Y. Chang et al. / Tetrahedron 63 (2007) 1339–1344
1341
osmylation as the key steps. The synthesis of desulfonated
DMJ analogs 1 and 2 and their structure–activity studies in
the inhibition of glycosidases will also be investigated in
succeeding works.
388.1588; 1H NMR (500 MHz, CDCl3) d 9.59 (s, 1H), 7.70
(d, J¼8.5 Hz, 2H), 7.34–7.28 (m, 3H), 7.23 (d, J¼8.5 Hz,
2H), 7.18 (d, J¼7.0 Hz, 2H), 5.82–5.74 (m, 1H), 5.16 (d,
J¼17.0 Hz, 1H), 5.11 (d, J¼10.5 Hz, 1H), 4.57–4.52 (m,
1H), 4.39 (d, J¼12.0 Hz, 1H), 4.34 (d, J¼12.0 Hz, 1H),
3.89–3.82 (m, 2H), 3.56 (dd, J¼6.5, 10.0 Hz, 1H), 3.47
(dd, J¼6.5, 10.0 Hz, 1H), 2.78 (ddd, J¼1.0, 7.5, 17.5 Hz,
1H), 2.69 (ddd, J¼1.5, 6.5, 17.0 Hz, 1H), 2.40 (s, 3H); 13C
NMR (125 MHz, CDCl3) d 199.44, 143.35, 137.58, 137.46,
135.38, 129.56 (2ꢀ), 128.37 (2ꢀ), 127.79, 127.66 (2ꢀ),
127.27 (2ꢀ), 117.98, 73.03, 70.62, 52.55, 48.30, 45.31,
21.51. Anal. Calcd for C21H25NO4S: C, 65.09; H, 6.50; N,
3.61. Found: C, 65.45; H, 6.71; N, 3.84.
4. Experimental
4.1. General
Dichloromethane (DCM) and tetrahydrofuran (THF) were
distilled prior to use. All other reagents and solvents were
obtained from commercial sources and used without further
purification. Reactions were routinely carried out under an
atmosphere of dry nitrogen with magnetic stirring. Products
in organic solvents were dried with anhydrous magnesium
sulfate before concentration in vacuo. All reported melting
temperatures are uncorrected.
4.1.3. N-Allyl-N-(1-benzyloxymethyl-3-hydroxypent-4-
enyl)-4-methylbenzenesulfonamide (7 and 7a). A solution
of vinylmagnesium bromide (1.0 M in toluene, 1.5 mmol,
1.5 mL) was added to a stirred solution of compound 6
(500 mg, 1.29 mmol) in THF (20 mL) at ꢁ78 ꢂC. The reac-
tion mixture was stirred at rt for 2 h. Water (1 mL) was added
to the reaction mixture and the solvent was concentrated. The
residue was diluted with water (10 mL) and the mixture was
extracted with AcOEt (3ꢀ20 mL). The combined organic
layers werewashed with brine, dried, filtered, and evaporated
to yield crude product. Purification on silica gel (hexane/
AcOEt¼4/1) afforded compound 7 (252 mg, 47%) and 7a
(268 mg, 50%). For compound 7: [a]3D0 ꢁ19.7 (c 0.1,
CHCl3); HRMS (ESI) m/z calcd for C23H30NO4S (M++1)
4.1.1. N-Allyl-N-[1-benzyloxymethyl-3-(tert-butyldi-
methyl-silanyloxy)propyl]-4-methylbenzenesulfonamide
(5). tert-Butyldimethylsilyl chloride (750 mg, 5.0 mmol)
and sodium hydride (400 mg, 60%, 10.0 mmol) were added
to a stirred solution of compound 4 (1.4 g, 4.0 mmol) in
DMF (5 mL) at rt. The reaction mixture was stirred at rt for
10 h. The procedure was monitored by TLC until the
reaction was complete. Allyl bromide (750 mg, 6.2 mmol)
was added to the reaction mixture at rt for 5 h. The reaction
mixture was concentrated. The residue was diluted with
water (10 mL) and the mixture was extracted with AcOEt
(3ꢀ50 mL). The combined organic layers were washed
with brine, dried, filtered, and evaporated to yield crude prod-
uct. Purification on silica gel (hexane/AcOEt¼5/1) afforded
compound 5 (1.61 g, 80%). [a]3D1 ꢁ25.6 (c 0.025, CHCl3);
HRMS (ESI) m/z calcd for C27H42NO4SSi (M++1)
1
416.1896, found 416.1899; H NMR (500 MHz, CDCl3)
d 7.71 (d, J¼8.0 Hz, 2H), 7.35–7.29 (m, 3H), 7.15 (d,
J¼8.0 Hz, 2H), 7.10–7.08 (m, 2H), 5.89–5.79 (m, 2H),
5.27 (tt, J¼1.5, 17.5 Hz, 1H), 5.13–5.06 (m, 3H), 4.39–
4.29 (m, 2H), 4.27 (d, J¼12.0 Hz, 1H), 4.22 (d, J¼12.0 Hz,
1H), 3.94 (dd, J¼5.0, 16.0 Hz, 1H), 3.75 (dd, J¼8.0,
16.0 Hz, 1H), 3.37 (dd, J¼7.5, 10.0 Hz, 1H), 3.30 (dd,
J¼5.0, 10.0 Hz, 1H), 2.37 (s, 3H), 1.76 (ddd, J¼2.5, 11.5,
14.5 Hz, 1H), 1.56 (br s, 1H), 1.47 (ddd, J¼3.5, 10.5,
14.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 143.07,
139.99, 137.51, 137.43, 135.91, 129.25 (2ꢀ), 128.30 (2ꢀ),
127.75 (2ꢀ), 127.73, 127.49 (2ꢀ), 117.57, 114.18, 72.94,
70.45, 67.85, 54.89, 46.79, 37.93, 21.52. Anal. Calcd for
C23H29NO4S: C, 66.48; H, 7.03; N, 3.37. Found: C, 66.69;
H, 7.32; N, 3.12. For compound 7a: [a]3D0 ꢁ32.1 (c 0.1,
CHCl3); HRMS (ESI) m/z calcd for C23H30NO4S (M++1)
1
504.2604, found 504.2608; H NMR (500 MHz, CDCl3)
d 7.72 (d, J¼8.0 Hz, 2H), 7.34–7.27 (m, 3H), 7.21–7.17
(m, 4H), 5.84–5.76 (m, 1H), 5.13 (dd, J¼1.0, 17.0 Hz, 1H),
5.05 (dd, J¼1.0, 10.0 Hz, 1H), 4.40 (d, J¼12.0 Hz, 1H),
4.34 (d, J¼12.0 Hz, 1H), 4.18–4.13 (m, 1H), 3.86 (d,
J¼6.5 Hz, 2H), 3.56–3.47 (m, 4H), 2.38 (s, 3H), 1.84–1.71
(m, 2H), 0.88 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 142.75, 138.29, 137.96, 136.06,
129.27 (2ꢀ), 128.27 (2ꢀ), 127.60 (2ꢀ), 127.56, 127.42
(2ꢀ), 117.07, 72.86, 71.36, 60.14, 55.09, 47.51, 33.69,
25.90 (3ꢀ), 21.47, 18.22, ꢁ5.38, ꢁ5.44. Anal. Calcd for
C27H41NO4SSi: C, 64.37; H, 8.20; N, 2.78. Found: C,
64.65; H, 8.45; N, 2.56.
1
416.1896, found 416.1895; H NMR (500 MHz, CDCl3)
d 7.72 (d, J¼8.5 Hz, 2H), 7.35–7.28 (m, 3H), 7.20–7.18
(m, 4H), 5.87–5.79 (m, 2H), 5.25 (tt, J¼1.5, 17.5 Hz, 1H),
5.15 (dd, J¼1.5, 17.5 Hz, 1H), 5.12 (tt, J¼1.5, 10.0 Hz,
1H), 5.07 (dd, J¼1.5, 10.0 Hz, 1H), 4.38 (d, J¼12.0 Hz,
1H), 4.33 (d, J¼12.0 Hz, 1H), 4.25–4.17 (m, 2H), 3.87 (d,
J¼6.5 Hz, 2H), 3.50 (dd, J¼6.5, 10.0 Hz, 1H), 3.45 (dd,
J¼6.0, 10.0 Hz, 1H), 2.39 (s, 3H), 1.86 (ddd, J¼5.0, 7.5,
14.5 Hz, 1H), 1.77 (br s, 1H), 1.76 (ddd, J¼6.5, 7.5,
14.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) d 143.01,
140.29, 137.90, 137.53, 135.91, 129.35 (2ꢀ), 128.35 (2ꢀ),
127.74, 127.70 (2ꢀ), 127.46 (2ꢀ), 117.34, 114.99, 72.98,
71.13, 70.19, 54.76, 47.51, 38.47, 21.49. Anal. Calcd for
C23H29NO4S: C, 66.48; H, 7.03; N, 3.37. Found: C, 66.21;
H, 7.15; N, 3.10.
4.1.2. N-Allyl-N-(1-benzyloxymethyl-3-oxopropyl)-4-
methylbenzenesulfonamide (6). A solution of tetra-n-butyl-
ammonium fluoride (1.2 mL, 1.0 M in THF, 1.2 mmol) in
THF (1 mL) was added to a solution of compound 5 (1.0 g,
2.0 mmol) in THF (5 mL) at rt for 1 h. The procedure was
monitored by TLC until the reaction was complete. A mix-
ture of pyridinium chlorochromate (1.0 g, 4.6 mmol), Celite
(3.0 g), and DCM (50 mL) was added to the stirring reaction.
After being stirred at rt for 10 h, the mixture was filtered
through a short silica gel column. The filtrate was dried, fil-
tered, and evaporated to afford crude product. Purification
on silica gel (hexane/AcOEt¼4/1) afforded compound 6
(650 mg, 84%). [a]3D0 ꢁ3.5 (c 0.018, CHCl3); HRMS (ESI)
m/z calcd for C21H26NO4S (M++1) 388.1583, found
4.1.4. N-Allyl-N-(1-benzyloxymethyl-3-hydroxyhex-5-
enyl)-4-methylbenzenesulfonamide (8 and 8a). A solution
of allylmagnesium bromide (1.0 M in toluene, 1.5 mmol,

1342
M.-Y. Chang et al. / Tetrahedron 63 (2007) 1339–1344
1.5 mL) was added to a stirred solution of compound 6
(500 mg, 1.29 mmol) in THF (20 mL) at ꢁ78 ꢂC. The reac-
tion mixture was stirred at rt for 2 h. Water (1 mL) was added
to the reaction mixture and the solvent was concentrated. The
residue was diluted with water (10 mL) and the mixture was
extracted with AcOEt (3ꢀ20 mL). The combined organic
layers werewashed with brine, dried, filtered, and evaporated
to yield crude product. Purification on silica gel (hexane/
AcOEt¼4/1) afforded compound 8 (250 mg, 45%) and 8a
(277 mg, 50%). For compound 8: [a]2D9 ꢁ10.2 (c 0.1,
CHCl3); HRMS (ESI) m/z calcd for C24H32NO4S (M++1)
53.31, 42.19, 38.87, 21.51. Anal. Calcd for C21H25NO4S:
C, 65.09; H, 6.50; N, 3.61. Found: C, 65.30; H, 6.68; N,
3.92. For compound 9a: [a]2D7 ꢁ148.3 (c 0.01, CHCl3);
HRMS (ESI) m/z calcd for C21H26NO4S (M++1) 388.1583,
1
found 388.1582; H NMR (500 MHz, CDCl3) d 7.69 (d,
J¼8.0 Hz, 2H), 7.35–7.28 (m, 3H), 7.26–7.21 (m, 4H),
5.89 (ddd, J¼3.0, 6.5, 10.5 Hz, 1H), 5.79 (ddd, J¼2.5, 6.0,
10.5 Hz, 1H), 4.39 (d, J¼12.5 Hz, 1H), 4.38–4.32 (m, 1H),
4.34 (d, J¼12.5 Hz, 1H), 4.27 (dd, J¼7.0, 18.0 Hz, 1H),
4.23–4.19 (m, 1H), 3.98 (d, J¼18.0 Hz, 1H), 3.33 (d,
J¼4.5 Hz, 2H), 2.39 (s, 3H), 2.27 (ddd, J¼1.5, 11.5,
15.0 Hz, 1H), 2.20 (dt, J¼5.5, 15.0 Hz, 1H), 2.01 (br s,
1H); 13C NMR (125 MHz, CDCl3) d 143.57, 137.96,
137.34, 132.92, 130.95, 129.51 (2ꢀ), 128.33 (2ꢀ), 127.61
(3ꢀ), 127.42 (2ꢀ), 73.16, 72.57, 67.32, 51.67, 42.12,
35.50, 21.51. Anal. Calcd for C21H25NO4S: C, 65.09; H,
6.50; N, 3.61. Found: C, 65.24; H, 6.31; N, 3.49.
1
430.2052, found 430.2057; H NMR (500 MHz, CDCl3)
d 7.70 (d, J¼8.0 Hz, 2H), 7.33–7.29 (m, 3H), 7.14 (d,
J¼8.0 Hz, 2H), 7.09–7.07 (m, 2H), 5.88–5.75 (m, 2H),
5.11–5.04 (m, 4H), 4.34–4.29 (m, 1H), 4.26 (d, J¼12.0 Hz,
1H), 4.21 (d, J¼12.0 Hz, 1H), 3.93–3.87 (m, 2H), 3.72 (dd,
J¼8.0, 16.0 Hz, 1H), 3.35 (dd, J¼8.0, 10.0 Hz, 1H), 3.29
(dd, J¼5.0, 10.0 Hz, 1H), 2.36 (s, 3H), 2.33–2.27 (m, 1H),
2.22–2.17 (m, 1H), 1.71 (ddd, J¼2.0, 11.5, 14.5 Hz, 1H),
1.59 (br s, 1H), 1.37 (ddd, J¼3.5, 10.5, 14.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) d 143.00, 137.57, 137.44, 135.93,
135.04, 129.20 (2ꢀ), 128.29 (2ꢀ), 127.77 (2ꢀ), 127.71,
127.49 (2ꢀ), 117.48, 117.15, 72.91, 70.49, 66.29, 55.02,
46.68, 41.37, 37.36, 21.50. Anal. Calcd for C24H31NO4S:
C, 67.10; H, 7.27; N, 3.26. Found: C, 67.41; H, 7.48; N,
3.39. For compound 8a: [a]2D9 ꢁ56.16 (c 0.1, CHCl3);
HRMS (ESI) m/z calcd for C24H32NO4S (M++1) 430.2052,
4.1.6. 2-Benzyloxymethyl-1-(4-methylphenylsulfonyl)-
1,2,3,4,5,8-hexahydro-azocin-4-ol (10). Grubbs’ second
generation catalyst (30 mg) was added to a solution of
compound 8 (100 mg, 0.23 mmol) in DCM (50 mL) at rt.
The reaction mixture was refluxed for 2 h. The mixture was
concentrated and purified by flash column chromatography
(hexane/AcOEt¼2/1) to yield compound 10 (73 mg, 78%).
[a]2D7 +18.5 (c 0.01, CHCl3); HRMS (ESI) m/z calcd for
1
C22H28NO4S (M++1) 402.1739, found 402.1741; H NMR
1
found 430.2052; H NMR (500 MHz, CDCl3) d 7.72 (d,
(500 MHz, CDCl3) d 7.69 (d, J¼8.5 Hz, 2H), 7.33–7.28
(m, 3H), 7.19 (d, J¼8.5 Hz, 2H), 7.10 (dd, J¼2.0, 8.0 Hz,
2H), 5.64–5.59 (m, 1H), 5.51–5.48 (m, 1H), 4.60–4.55 (m,
1H), 4.40 (d, J¼19.5 Hz, 1H), 4.22 (s, 2H), 4.07–4.02 (m,
1H), 3.82 (dd, J¼2.5, 19.5 Hz, 1H), 3.28 (dd, J¼5.0,
10.0 Hz, 1H), 3.24 (dd, J¼5.5, 10.0 Hz, 1H), 3.11–3.04 (m,
1H), 2.38 (s, 3H), 2.39–2.31 (m, 1H), 2.11 (ddd, J¼2.5,
12.5, 15.0 Hz, 1H), 1.81 (dt, J¼3.5, 15.0 Hz, 1H), 1.68 (br
s, 1H); 13C NMR (125 MHz, CDCl3) d 140.70, 136.34,
135.55, 128.01, 127.16 (2ꢀ), 126.08 (2ꢀ), 125.39, 125.22
(2ꢀ), 124.67 (2ꢀ), 122.79, 70.70, 69.41, 66.85, 49.56,
42.87, 31.34, 29.88, 19.26. Anal. Calcd for C22H27NO4S:
C, 65.81; H, 6.78; N, 3.49. Found: C, 65.38; H, 6.93; N, 3.55.
J¼8.5 Hz, 2H), 7.34–7.29 (m, 3H), 7.20–7.17 (m, 4H),
5.84–5.73 (m, 2H), 5.14 (dd, J¼1.0, 17.0 Hz, 1H), 5.11 (d,
J¼10.5 Hz, 1H), 5.11 (d, J¼17.0 Hz, 1H), 5.07 (dd, J¼1.0,
10.5 Hz, 1H), 4.38 (d, J¼12.0 Hz, 1H), 4.32 (d, J¼12.0 Hz,
1H), 4.26–4.21 (m, 1H), 3.87 (d, J¼6.0 Hz, 2H), 3.72–3.67
(m, 1H), 3.50 (dd, J¼6.5, 10.0 Hz, 1H), 3.44 (dd, J¼5.0,
10.0 Hz, 1H), 2.39 (s, 3H), 2.30–2.25 (m, 1H), 2.16–2.12
(m, 1H), 1.79 (ddd, J¼4.5, 7.5, 14.0 Hz, 1H), 1.67 (ddd,
J¼6.0, 8.0, 14.0 Hz, 1H), 1.58 (br s, 1H); 13C NMR
(125 MHz, CDCl3) d 142.97, 137.92, 137.63, 135.95,
135.48, 129.34 (2ꢀ), 128.34 (2ꢀ), 127.71, 127.69 (2ꢀ),
127.47 (2ꢀ), 118.16, 117.25, 72.97, 71.09, 68.20, 55.16,
47.43, 41.93, 37.89, 21.49. Anal. Calcd for C24H31NO4S:
C, 67.10; H, 7.27; N, 3.26. Found: C, 66.91; H, 7.12; N, 3.63.
4.1.7. 7-Benzyloxymethyl-1-(4-methylphenylsulfonyl)-
azepane-3,4,5-triol (11). A solution of osmium tetraoxide
(5 mL, 2% in THF) in THF was added to a solution of com-
pound 9 (50 mg, 0.13 mmol) in THF (5 mL) and t-BuOH
(5 mL) and N-methylmorpholine-N-oxide (100 mg, 50% in
water, 0.43 mmol) at refluxed temperature for 10 h. Sodium
bisulfite solution (10%, 5 mL) was added to the reaction mix-
ture and the solvent was concentrated. The residue was di-
luted with water (10 mL) and the mixture was extracted
with AcOEt (3ꢀ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to
yield crude compound. Purification on silica gel (hexane/
AcOEt¼1/3) afforded compound 11 (48 mg, 88%). [a]D26
ꢁ60.5 (c 0.01, CHCl3); HRMS (ESI) m/z calcd for
4.1.5. 2-Benzyloxymethyl-1-(4-methylphenylsulfonyl)-
2,3,4,7-tetrahydro-1H-azepin-4-ol (9 and 9a). Grubbs’
second generation catalyst (30 mg) was added to a solu-
tion of compound 7 or 7a (100 mg, 0.24 mmol) in DCM
(50 mL) at rt. The reaction mixture was refluxed for 2 h.
The mixture was concentrated and purified by flash column
chromatography (hexane/AcOEt¼2/1) to yield compound
9 (81 mg, 87%) or 9a (79 mg, 85%). For compound 9:
[a]2D7 ꢁ105.2 (c 0.01, CHCl3); HRMS (ESI) m/z calcd for
1
C21H26NO4S (M++1) 388.1583, found 388.1584; H NMR
(500 MHz, CDCl3) d 7.67 (d, J¼8.0 Hz, 2H), 7.36–7.26
(m, 5H), 7.20 (d, J¼8.0 Hz, 2H), 5.55 (ddt, J¼2.0, 6.5,
11.0 Hz, 1H), 5.48 (d, J¼11.0 Hz, 1H), 4.49 (d, J¼12.0 Hz,
1H), 4.46 (d, J¼12.0 Hz, 1H), 4.29 (dd, J¼6.5, 18.5 Hz,
1H), 4.11–4.06 (m, 1H), 3.92 (ddd, J¼2.0, 5.0, 18.5 Hz,
1H), 3.85 (br s, 1H), 3.59 (dd, J¼4.5, 10.0 Hz, 1H), 3.52
(dd, J¼6.0, 9.5 Hz, 1H), 2.39 (s, 3H), 2.15–2.11 (m, 2H),
1.82 (br s, 1H); 13C NMR (125 MHz, CDCl3) d 143.16,
137.93, 137.54, 136.47, 129.25 (2ꢀ), 128.37 (2ꢀ), 127.66,
127.53 (2ꢀ), 127.39 (2ꢀ), 126.52, 73.29, 72.72, 69.22,
1
C21H28NO6S (M++1) 422.1637, found 422.1639; H NMR
(500 MHz, CDCl3) d 7.70 (d, J¼8.0 Hz, 2H), 7.34–7.27
(m, 3H), 7.20 (d, J¼8.0 Hz, 2H), 7.17 (d, J¼7.0 Hz, 2H),
4.31 (s, 2H), 4.20–4.16 (m, 2H), 4.08 (br t, J¼7.0 Hz, 1H),
3.83 (br s, 1H), 3.53 (dd, J¼3.5, 15.0 Hz, 1H), 3.45 (dd,
J¼9.0, 15.0 Hz, 1H), 3.41 (dd, J¼5.0, 10.0 Hz, 1H), 3.35
(dd, J¼4.0, 10.0 Hz, 1H), 2.39 (s, 3H), 2.32 (dd, J¼9.0,
15.0 Hz, 1H), 2.13 (br s, 3H), 1.97–1.91 (m, 1H); 13C NMR

M.-Y. Chang et al. / Tetrahedron 63 (2007) 1339–1344
1343
(125 MHz, CDCl3) d 143.54, 137.57, 137.11, 129.59 (2ꢀ),
128.38 (2ꢀ), 127.77, 127.61 (2ꢀ), 127.29 (2ꢀ), 74.59,
73.21, 71.30, 69.74, 68.61, 52.29, 45.36, 31.67, 21.54. Sin-
gle-crystal X-ray diagram: crystal of compound 11 was
grown by slow diffusion of AcOEt into a solution of com-
pound 11 in DCM to yield colorless prism. The compound
crystallizes in the monoclinic crystal system. Space group
gel (AcOEt/MeOH¼9/1) afforded compound 2 (22 mg,
91%). HRMS (ESI) m/z calcd for C15H24NO6S (M++1)
346.1324, found 346.1325; 1H NMR (300 MHz, D2O)
d 7.84 (d, J¼8.1 Hz, 2H), 7.44 (d, J¼8.1 Hz, 2H), 4.19–
4.04 (m, 2H), 3.93 (dd, J¼3.3, 16.2 Hz, 1H), 3.82 (br s,
1H), 3.72 (d, J¼7.8 Hz, 1H), 3.52 (d, J¼15.3 Hz, 1H),
3.44 (t, J¼5.4 Hz, 2H), 2.43 (s, 3H), 2.15 (ddd, J¼8.4,
11.4, 14.1 Hz, 1H), 1.92–1.88 (m, 2H), 1.54 (dd, J¼6.9,
14.1 Hz, 1H); 13C NMR (75 MHz, D2O) d 147.79, 138.65,
132.44 (2ꢀ), 130.39 (2ꢀ), 73.67, 71.90, 68.90, 66.04,
56.33, 48.52, 37.94, 35.51, 23.41.
˚
˚
˚
P2(1), a¼5.4539(15) A, b¼9.571(3) A, c¼19.784(5) A,
3
V¼1027.5(5) A , Z¼4, dcalcd¼2.725 mg/m3, F(000)¼896,
˚
absorption coefficient 0.391 mmꢁ1, 2q range (1.03ꢂ–28.36ꢂ).
4.1.8. 8-Benzyloxymethyl-1-(4-methylphenylsulfonyl)-
azocane-3,4,6-triol (12). A solution of osmium tetraoxide
(5 mL, 2% in THF) in THF was added to a solution of com-
pound 10 (50 mg, 0.12 mmol) in THF (5 mL) and t-BuOH
(5 mL) and N-methylmorpholine-N-oxide (100 mg, 50% in
water, 0.43 mmol) at refluxed temperature for 10 h. Sodium
bisulfite solution (10%, 5 mL) was added to the reaction mix-
ture and the solvent was concentrated. The residue was
diluted with water (10 mL) and the mixture was extracted
with AcOEt (3ꢀ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to
yield crude compound. Purification on silica gel (hexane/
AcOEt¼1/3) afforded compound 12 (46 mg, 85%). [a]D26
ꢁ15.2 (c 0.01, CHCl3); HRMS (ESI) m/z calcd for
Acknowledgements
The authors would like to thank the National Science Coun-
cil (NSC-95-2113-M-390-003-MY2) of the Republic of
China for financial support.
Supplementary data
Photocopies of NMR (1H and 13C) spectral data for new
compounds were supported. Supplementary data associated
with this article can be found in the online version, at
doi:10.1016/j.tet.2006.12.002.
1
C22H30NO6S (M++1) 436.1794, found 436.1798; H NMR
(500 MHz, CDCl3) d 7.70 (d, J¼7.0 Hz, 2H), 7.30–7.21
(m, 5H), 7.06 (d, J¼7.0 Hz, 2H), 4.36 (dd, J¼3.0, 12.0 Hz,
1H), 4.27–4.18 (m, 2H), 4.18 (d, J¼12.0 Hz, 1H), 4.10 (d,
J¼12.0 Hz, 1H), 3.87–3.76 (m, 2H), 3.50–3.46 (m, 1H),
3.13 (dd, J¼3.5, 10.0 Hz, 1H), 3.07 (dd, J¼3.5, 10.0 Hz,
1H), 2.54–2.47 (m, 1H), 2.42 (s, 3H), 2.05–1.94 (m, 2H),
1.88–1.86 (m, 1H), 1.83 (br s, 3H); 13C NMR (125 MHz,
CDCl3) d 144.07, 137.40, 136.52, 129.79 (2ꢀ), 128.40
(2ꢀ), 127.81, 127.52 (2ꢀ), 127.47 (2ꢀ), 73.20, 71.52,
70.69, 69.82, 66.76, 51.40, 38.28, 33.23, 30.92, 21.57.
Anal. Calcd for C22H29NO6S: C, 60.67; H, 6.71; N, 3.22.
Found: C, 60.31; H, 6.89; N, 3.38.
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1
C14H22NO6S (M++1) 332.1168, found 332.1174; H NMR
(300 MHz, D2O) d 7.80 (d, J¼8.1 Hz, 2H), 7.45 (d,
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