Synthesis of polyhydroxy 7- and N-alkyl-azepanes as potent glycosidase inhibitors

Article abstract of DOI:10.1016/j.carres.2010.11.014

An effective synthetic method for polyhydroxylated azepanes that contain an alkyl group (Me or Bu) at either the 7- or N-positions is developed. The synthetic routes are accomplished in eight to ten steps from d-(-)-quinic acid. Among the compounds synthe

Full text of DOI:10.1016/j.carres.2010.11.014

Carbohydrate Research 346 (2011) 183–190
Contents lists available at ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of polyhydroxy 7- and N-alkyl-azepanes as potent
glycosidase inhibitors
Tzenge-Lien Shih a, , Ming-Tsung Liang a, Kuen-Da Wu a, Chun-Hung Lin b,
⇑
⇑
,
a Department of Chemistry, Tamkang University, Tamsui 25137, Taipei County, Taiwan
b Institute of Biological Chemistry, Academia Sinica, NanKang 11529, Taipei, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 October 2010
Received in revised form 5 November 2010
Accepted 15 November 2010
Available online 19 November 2010
An effective synthetic method for polyhydroxylated azepanes that contain an alkyl group (Me or Bu) at
either the 7- or N-positions is developed. The synthetic routes are accomplished in eight to ten steps from
D
-(ꢀ)-quinic acid. Among the compounds synthesized, the polyhydroxy 7-butyl azepane (compound 3),
which possessed the R-configuration at C-7 position, is shown to give potent inhibition against b-galac-
tosidase (IC50 = 3 M). Preliminary biological data indicate that the length of alkyl groups along with the
l
proper stereochemistry at the C-7 position is essential for acquiring extra binding affinity. Using similar
synthetic routes, the polyhydroxy N-methyl and N-butyl azepanes are synthesized for the comparison of
their biological activities.
Keywords:
Azepane
D
-(ꢀ)-Quinic acid
Ó 2010 Elsevier Ltd. All rights reserved.
b-Galactosidase
Glycosidase inhibitor
1. Introduction
several important issues are addressed: (1) how to introduce hydro-
xyl groups to various positions of the iminosugar ring for achieving
Polyhydroxypiperidines have attracted immense attention from
the synthetic community owing to their biological importance in
the development of glycosidase inhibitors.1–10 Miglitol™ (N-hydro-
xyethyl-deoxynojirimycin) was developed to target the intestinal
disaccharidase and prescribed for the treatments of type II diabe-
tes1,11 (Fig. 1). N-Butyl-deoxynojimicycin (NB-DNJ, Zavescal) was
used in the treatment of Gaucher disease and also as an anti-HIV
drug.1,12 Introducing an alkyl group to the ring of azasugars can
make drug molecules more hydrophobic for better absorption,
delivery, and enhancement of the uptake by cells.1,13–16 The
seven-member-ring azasugars (iminosugars), so-called azepanes,
have attracted attention due to the activities of glycosidase inhibi-
tors that may be related to their structural flexibility.3,17 A recent
report revealed that the alkyl groups located in the ring or at the
nitrogen site of azepanes can offer potent inhibition against various
enzymes.18 We have studied extensively the discovery of polyhydr-
oxylated azepanes as potential drugs and reported the synthesis of a
series of trihydroxyazepanes.19 We have found several azepanes as
possible candidates for potent glycosidase inhibitors and their
activities were shown to be compatible to the related piperidines.20
To continue our efforts in the synthesis of polyhydroxyazepanes,
the desired stereochemistry, and (2) how to enhance and under-
stand the inhibition potency at the molecular level. In this article,
we describe the expeditious synthesis of polyhydroxylated aze-
panes that contain an extra methyl or butyl group at either the
C7- or N-positions in order to compare with the biological activities
of Miglitol or NB-DNJ. The structures of these azepanes are unique
and have not been reported previously. It is intriguing to study if
the additional alkyl group can contribute to the binding affinity.
2. Results and discussion
Our synthetic strategy to the target molecules 1–4, depicted in
Scheme 1, is straightforward. In order to increase the synthetic
flexibility, alkyl groups (Me or Bu) at the C-7 position were intro-
duced by the corresponding lithiated reagents at an early stage.
Enone 15,21 prepared in four steps from
D-(ꢀ)-quinic acid, was
22
treated with CeCl3 and then a solution of methyllithium was
added dropwise at ꢀ78 °C, to give the separable epimeric mixtures
of 16 (the major isomer, 82% yield) and 17 (the minor isomer, ꢁ8%
yield) mixed with a trace amount of other impurities. The stereo-
chemistry of 16 was elucidated according to the 2D-NOESY spectra
due to the observation of the cross peaks between the methyl
group and the hydrogen at C-1 position. As expected, the nucleo-
phile (Meꢀ) can approach from the less hindered side of 15 to give
16 as the major product.
⇑
Corresponding authors. Tel./fax: +886
27890110; fax: +886 2 26514705 (C.H.L.).
2 86315024 (T.-L.S.); tel.: +886 2
E-mail addresses: tlshih@mail.tku.edu.tw (T.-L. Shih), chunhung@gate.sinica.
edu.tw (C.-H. Lin).
Consecutive rearrangement and allylic oxidation reactions were
carried out to produce enone 20 when tertiary alcohol 16 or 17 was
Biological data shall be addressed to Professor C.H. Lin.
0008-6215/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2010.11.014

184
T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
OH
OH
N
OH
OH
N
HO
OH
OH
OH
HO
OH
OH
HO
OH
OH
HO
HO
N
H
N
H
L-DFJ
NB-DNJ (Zavescal)
Miglitol (Glyset)
(+)-Adenophorine
(Deoxyfuconojirimycin)
Figure 1. The representative polyhydroxylated C- and N-alkyl piperidines.
mixed with pyridinium chlorochromate (PCC) and silica gel23 in
CH2Cl2 under reflux conditions. Interestingly, the reaction rate
was closely related to the stereochemical configuration at C-5 po-
sition. When compound 16 was treated with PCC (3 equiv) and re-
fluxed in CH2Cl2 for 10 h, compound 20 was obtained in 41% yield
(61% yield based on recovery of 16). In contrast, compound 17 was
completely converted into 20 within 1.5 h in 67% yield under the
same conditions. Steric hindrance was realized to play a determin-
ing role in the reactivity because 17 was much more reactive ow-
ing to the less hindered hydroxyl group.
Luche reduction (NaBH4 and CeCl3ꢂ7H2O) of compound 20
generated the sole product 22 with exclusive stereoselectivity.
The allylic alcohol of 22 was protected by using methoxymethyl
chloride (MOMCl) and diisopropylethylamine to give 24. Following
our previous report,19 the double bond of 24 was subjected to
dihydroxylation (with KMnO4, MgSO4, EtOH, H2O), oxidative cleav-
age (with NaIO4), and reductive aminocyclization (with benzyl-
amine and NaCNBH3), leading to the separable epimeric products
26 and 27 in 47% and 7% isolated yields (three steps in total),
respectively. The assignment of the C7-stereochemistry in 26 and
27 was established on the basis of the C7-methyl group and H5
of 26 that possessed the special correlation but not for 27 by
2D-NOESY spectra. The final deprotection of 26 and 27 was carried
out individually by hydrogenation over 10% Pd–C in 2 N HCl to ob-
tain the desired 7(R)-methyl-azepanes-3,4,5-triol 1 (86%) and its
7(S)-epimer 2 (92%), respectively.
The introduction of an alkyl group to the ring nitrogen of aza-
sugars was thought to enhance the uptake by cells.1 Our intention
was to compare the biological activities of N-alkyl azepanes with
the corresponding piperidines (such as Miglitol or NB-DNJ). There-
fore, six N-alkylazepanes 9–14 were also synthesized from com-
pounds 45,19 4619, and 5119 in a similar manner as shown in
Scheme 3. The major differences included the oxidant used in the
19
dihydroxylation, which was replaced with RuCl3–NaIO4 as well
as the amine used in the reductive amination that was substituted
with either methylamine or butylamine. The yields were fairly
comparable to those shown in Schemes 1 and 2.
3. Conclusion
A new family of trihydroxyazepanes 1–14 has been synthesized
that contains a methyl or butyl group at either C7- or N-positions.
These unique molecules were prepared in a facile manner from
D
-(ꢀ)-quinic acid. The reductive aminocyclization in Schemes 1
and 2 led to moderate selectivity at C7 positions in formation of
compounds 26–29 and 41–44. However, their deprotection to yield
the target molecules 1–8 provided us a diverse range to evaluate
their biological activity. Therefore, the preliminary result in the
inhibition activity indicates that the azepane 3 with the butyl sub-
stituent in 7R-configuration has a better inhibition potency against
b-galactosidase (IC50 = 3
lM), as compared to the epimer 4 (no
activity) and the methyl homologs compounds 1 (IC50 = 100
lM)
and 2 (no activity). Also, the stereochemistry at C-7 is essential
and the enhancement of inhibition is most likely due to an extra
binding interaction with the hydrophobic residue in the vicinity
of the enzyme activity site. Detailed biological data of compounds
1–14 are under investigation and will be disclosed in due course.
A similar approach was used to introduce a butyl group at the
C7-position of the azepanes (Scheme 1). Compound 18, with the
same stereochemical configuration as 16, was obtained in a mod-
erate yield (70%), but other epimer 19 was isolated only in a trace
amount. The PCC oxidation of 18 gave 21 in a moderate yield (47%,
69% based on the recovery of 18). The subsequent steps employed
the same conditions described above to efficiently lead to the tar-
get molecules 3 and 4.
4. Experimental
On the other hand, the formation of inseparable diastereomeric
mixtures 31/32 and 33/34 (both pairs in ratio of ꢁ1:1 by NMR anal-
ysis) was observed when compound 3024 was either methylated or
butylated, (Scheme 2). As discussed above, steric effects serve as a
major factor for the successive rearrangement and oxidation of
compounds 16–18, whereas the mixtures 31/32 and 33/34 reacted
relatively faster and were converted to compounds 35 and 36
within 4 h in 85% and 88% yield without recovering the starting
materials. The subsequent reduction provided 37 and 38, and
protection with the MOM group afforded 39 and 40, respectively.
Further dihydroxylation, oxidative cleavage, and reductive amino-
cyclization, and purification by column chromatography produced
pairs of inseparable diastereomers 41/42 and 43/44 in which both
pairs were in ratio of ꢁ10:1 in 43% and 36% total yields. Efforts
were made to separate each diastereomer after final deprotection
by column chromatography, which still led to the isolation of prod-
uct mixtures 5/6 and 7/8 in high yields with almost the same ratios
as those before deprotection. The 2D-NOESY spectra indicated that
compounds 5 and 7 are the major diastereomeric products due to
the close relationship between C-7 alkyl groups and H5.
4.1. General methods
Reactions were conducted under anhydrous solvents and an in-
ert atmosphere of nitrogen unless otherwise noted. Melting points
were uncorrected. 1H (300 or 600 MHz) and 13C (75 or 150 MHz)
NMR spectra were recorded on either Bruker 300 or 600 MHz spec-
trometers. Chemical shifts are reported relative to the residual of
deuterium solvents: CDCl3 d 7.26; CD3OD d 4.89; D2O d 4.6 ppm
for 1H and CDCl3 d 77.0; CD3OD d 49.15 ppm for 13C. Optical rota-
tions were measured with Horbia Sepa-300 polarimeter.
4.1.1. General procedure of alkylation
CeCl3ꢂ7H2O was heated at 110 °C under vacuum (ꢁ0.2 mmHg)
for 4 h to remove water. To the dried CeCl3 was added THF
(ꢁ0.2 M) and the mixture was stirred for 20 min. This mixture was
sonicated for 1 h before being cooled to ꢀ78 °C. Three equivalents
of the corresponding lithiated reagent (MeLi or BuLi) were added
to this mixture. The enone dissolved in THF was added to the above
mixture via cannulation. After the media was stirred for 30 min at
ꢀ78 °C, the reaction was quenched by addition of NH4Cl (saturated)

T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
185
O
O
R
R
O
X
Y
NaBH4
MOMCl
CeCl3 7H2O
PCC/SiO2
iPr2NEt, DMAP
5
2
RLi/CeCl3
1
20 (41% from 16
67% from 17)
21 (47% from 18)
see text
22 (86%)
R = Me
24 (98%)
25 (89%)
OH
O
O
23 (87%) O
O
16 (82%)
17 (8%)
R = nBu
18 (70%)
19 trace
O
O
O
22 R=Me
16 X=Me, Y=OH
17 X=OH, Y=Me
18 X=nBu, Y=OH
19 X=OH, Y=nBu
20 R=Me
21 R=nBu
15
23 R=nBu
OH
R
O
HO
O
O
1. KMnO4/MgSO4
H2, Pd/C
5
4
EtOH/H2O
HO
5
3
MOMO
MeOH, 2N HCl
7
R1
3
2. NaIO4, MeOH
3. BnNH2, NaCNBH3
AcOH (3 steps)
7
OMOM
R1
R2
N
O
1 (86%)
2 (92%)
3 (90%)
4 (91%)
N
R2
H
Bn
26 R1=Me, R2=H
27 R1=H, R2=Me
26 (47%)
1 R1=Me, R2=H
2 R1=H, R2=Me
3 R1=nBu, R2=H
4 R1=H, R2=nBu
27 (7%)
24 R=Me
25 R=nBu
28 (25%)
29 (14%)
28 R1=nBu, R2=H
29 R1=H, R2=nBu
-
H BH2CN (favored)
R
R
O
O
+
BnNH2
AcOH
O
N Bn
O
O
O
NaCNBH3
O
O
MOM
MOM
R=Me or Bu
Scheme 1. Synthesis of 7-methyl- and 7-butyl-azepanes-3,4,5-triols 1–4.
and allowed to warm to ambient temperature. The mixture was ex-
tracted with ether and dried over MgSO4. The resulting crude mix-
ture was purified by flash column chromatography.
solution was stirred for 10 min, and NaCNBH3 (1 equiv) was added
and stirred for 1 h. The reaction was allowed to warm to ambient
temperature and stirred for another 2 h. At the end of reaction
time, the mixture was extracted with EtOAc and washed with NaH-
CO3 (saturated). The organic layer was dried over MgSO4 and puri-
fied by flash column chromatography.
4.1.2. General procedure of PCC oxidation
To a stirred solution of compound 16 in CH2Cl2, for example,
was treated with PCC (3 equiv) and SiO2 (three times the weight
of the amount of PCC). The mixture was heated in CH2Cl2 at reflux
and the reaction was monitored by TLC. At the end of reaction time,
the resulting mixture was filtered through a pad of silica gel,
washed with CH2Cl2 and purified by flash column chromatography.
4.2. (1R,2R)-1,2-O-Cyclohexylidene-5-methyl-3-oxo-4-
cyclohexene (20)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:15?1:4) afforded a white solid in 41% yield. Mp =
4.1.3. General procedure of dihydroxylation, oxidative cleavage,
and reductive aminocyclization
115.0–115.5 °C. ½a D23
ꢃ
ꢀ51.2 (c 1.3, MeOH). 1H NMR (300 MHz,
CDCl3) d 5.92 (s, 1H), 4.59–4.54 (m, 1H), 4.19 (d, J = 5.1 Hz, 1H),
2.71 (d, J = 4.1 Hz, 2H), 1.97 (s, 3H), 1.63–1.30 (m, 10H). 13C NMR
(75 MHz, CDCl3) d 196.0, 158.4, 135.4, 125.1, 109.8, 74.2, 72.4,
37.0, 35.4, 32.6, 24.9, 24.4, 23.7. HRMS (ESI) calcd for C13H18NaO3
[M+Na]+: 245.1154. Found: 245.1144.
This reaction was conducted in a three-step sequence. The ole-
fin in EtOH and H2O (v/v = 9:1, ꢁ0.1–0.2 M) was treated with
KMnO4 (2 equiv) and MgSO4 (2 equiv) at 0 °C. The stirring mixture
was allowed to warm up to ambient temperature and stirred for
another 10 h. At the end of which time, the reaction mixture was
filtered through a pad of Celite and the filtrate was concentrated.
The crude mixture was extracted with EtOAc and washed with
H2O. The organic layer was dried over MgSO4, filtered, and concen-
trated. The mixture was used in the next step without further puri-
fication. The mixture was dissolved in MeOH and NaIO4 (3 equiv)
was added. The reaction was heated at 50 °C for 10 h. The solvent
was removed, extracted with EtOAc, and washed with NaHCO3
(saturated). The organic layer was dried over MgSO4 and concen-
trated. The resulting syrup was dissolved in MeOH and the dried
3 Å molecular sieve (same amount of starting material) was added.
This mixture was cooled to ꢀ78 °C and a mixture solution of
BnNH2–AcOH–MeOH (pH 5–6) was added via cannulation. This
4.3. (1R,2R)-5-Butyl-1,2-O-cyclohexylidene-3-oxo-4-
cyclohexene-1,2-diol (21)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:20?1:6) afforded a colorless syrup in 47% yield. ½a D26
ꢃ
ꢀ32.1 (c 1.0, MeOH). 1H NMR (300 MHz, C6D6) d 5.91 (s, 1H),
4.13 (td, J = 5.1, 1.6 Hz, 1H), 3.97 (d, J = 5.1 Hz, 1H), 2.30 (d,
J = 19.1 Hz, 1H), 1.91 (dd, J = 19.1, 0.8 Hz, 1H), 1.74–1.45 (m,
10H), 1.22–0.95 (m, 6H), 0.74 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, C6D6) d 195.1, 160.7, 125.1, 110.0, 75.4, 73.4, 38.1, 37.7,
36.5, 31.6, 29.2, 25.7, 24.6, 24.5, 22.8, 14.3. HRMS (ESI) calcd for
C
16H24NaO3 ([M+Na]+): 287.1618. Found: 287.1559.

186
T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
R
R
O
NaBH4
CeCl3 7H2O
X
Y
PCC/SiO2
RLi/CeCl3
35 (85%)
36 (88%)
37 (92%)
HO
O
R = Me
O
O
OMe
38 (71%)
O
31+32 (86%)
O
OMe
O
MeO
OMe
OMe
O
MeO
O
MeO
O
MeO
R = Bu
33+34 (86%)
31 X=Me, Y=OH
32 X=OH, Y=Me
33 X=nBu, Y=OH
34 X=OH, Y=nBu
37 R=Me
38 R=nBu
35 R=Me
36 R=nBu
30
R
OH
HO
HO
1. KMnO4/MgSO4
MOMCl
iPr2NEt, DMAP
MeO
OMe
EtOH/H2O
H2, Pd/C
5
O
O
3
7
R1
R2
MOMO
O
MeOH, 2N HCl
39 (89%)
40 (94%)
2. NaIO4, MeOH
3. BnNH2, NaCNBH3
AcOH
41/42 (43%,~10:1)
43/44 (36%,~10:1)
MOMO
5
OMe
N
H
O
MeO
5+6 (~10:1,92%)
7+8 (~10:1,90%)
3
7
R1
R2
N
Bn
39 R=Me
5 R1=Me, R2=H
6 R1=H, R2=Me
7 R1=nBu, R2=H
8 R1=H, R2=nBu
40 R=nBu
41 X=Me, Y=OH
42 X=OH, Y=Me
43 X=nBu, Y=OH
44 X=OH, Y=nBu
-
H BH2CN (favored)
OMe
O
OMe
R
R
O
O
BnNH2
O
+
AcOH
NaCNBH3
O
O
N
O
O
Me
Me
Bn
OMOM
OMOM
R=Me or Bu
Scheme 2. Synthesis of 7-methyl- and 7-butylazepanes-3,4,5-triols from TMB protected enone 30.
X
Y
HO
1. RuCl3, NaIO4
2. NaIO4, MeOH
O
X
Y
H2/Pd/C
2N HCl
X
Y
HO
O
3. RNH2, NaCNBH3
(3 steps)
O
N
R
9 (83%)
O
N
R
10 (69%)
11 (71%)
12 (63%)
47 (48%)
48 (49%)
49 (54%)
50 (59%)
9 X=H, Y=OH, R=Me
10 X=OH, Y=H, R=Me
11 X=H, Y=OH, R=nBu
12 X=OH, Y=H, R=nBu
47 X=H, Y=OBn, R=Me
48 X=OBn, Y=H, R=Me
49 X=H, Y=OBn, R=nBu
50 X=OBn, Y=H, R=nBu
45 X=H, Y=OBn
46 X=OBn, Y=H
1. RuCl3, NaIO4
2. NaIO4, MeOH
OBn
OMe
O
HO
H2/Pd/C
2N HCl
OH
4
HO
3. RNH2, NaCNBH3
(3 steps)
6
3
4
OBn
MeO
O
6
3
O
OMe
O
13 (90%)
N
14 (88%)
N
R
52 (56%)
R
MeO
53 (40%)
13 R=Me
14 R=nBu
52 R=Me
53 R=nBu
51
Scheme 3. Synthesis of polyhydroxylated N-methyl and -butylazepane-3,4,6-triols 9–14.
4.4. (1R,2S)-1,2-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-5-
methyl-3-oxo-4-cyclohexe (35)
194.0, 158.1, 126.3, 100.3, 99.3, 74.3, 67.1, 48.5, 48.1, 36.5, 24.5,
17.8 (ꢄ2). HRMS (ESI) calcd for C13H20NaO5 [M+Na]+: 279.1208.
Found: 279.1200.
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:15?1:6) afforded a white solid in 86% yield. Mp =
4.5. (5R,6S)-5,6-[(2S,3S)-2,3-Dimethoxybutan-2,3-dioxy]-3-
butyl-cyclohex-2-enone (36)
153.3–153.6 °C. ½a D23
ꢃ
+39.9 (c 1.2, MeOH). 1H NMR (300 MHz,
CDCl3) d 5.86 (s, 1H), 4.18 (d, J = 11.3 Hz, 1H), 4.03 (ddd, J = 11.3,
9.9, 6.1 Hz, 1H), 3.26 (s, 3H), 3.21 (s, 3H), 2.60–2.43 (m, 2H), 1.97
(s, 3H), 1.38 (s, 3H), 1.30 (s, 3H). 13C NMR (75 MHz, CDCl3) d
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:15?1:5) afforded a colorless syrup in 88% yield. ½a D25
ꢃ

T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
187
+40.2 (c 2.4, MeOH). 1H NMR (300 MHz, CDCl3) d 5.86 (s, 1H), 4.19
(dt, J = 11.3, 1.1 Hz, 1H), 4.07–3.95 (m, 1H), 3.27 (d, J = 1.2 Hz, 3H),
3.21 (d, J = 1.2 Hz, 3H), 2.62–2.42 (m, 2H), 2.21 (t, J = 7.7 Hz, 2H),
1.50–1.20 (m, 10H), 0.87 (td, J = 7.3, 0.8 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 194.7, 162.5, 125.7, 100.8, 99.8, 75.0, 67.8,
49.0, 48.6, 38.2, 35.7, 29.6, 22.8, 18.3, 18.2, 14.4. HRMS (ESI) calcd
for C16H26NaO5 [M+Na]+: 321.1678. Found: 321.1670.
4.10. (1R,2R,3R)-1,2-[(2S,3S)-2,3-Dimethoxybutan-2,3-dioxy]-5-
methyl-4-cyclohexene-1,2,3-triol (37)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:12?1:6) afforded
a
white solid in 81% yield.
Mp = 67.0–68.0 °C. ½a D25
ꢃ
+160.2 (c 1.4, MeOH). 1H NMR (300 MHz,
C6D6) d 5.30 (s, 1H), 4.35 (t, J = 1.8 Hz, 1H), 3.86 (ddd, J = 16.8,
10.5, 6.0 Hz, 1H), 3.76 (dd, J = 10.5, 7.7 Hz, 1H), 3.18 (s, 3H), 3.09
(s, 3H), 2.25–2.10 (m, 2H), 2.00 (dd, J = 16.8, 6.0 Hz, 1H), 1.41 (s,
3H), 1.37 (s, 3H). 13C NMR (75 MHz, C6D6) d 133.4, 125.0, 99.8,
99.7, 76.0, 70.9, 66.4, 47.9, 35.9, 23.1, 18.5, 18.4. HRMS (ESI) calcd
for C13H22NaO5 [M+Na]+: 281.1365. Found: 281.1375.
4.6. (1R,2R,3R)-1,2-[(2S,3S)-2,3-Dimethoxybutan-2,3-dioxy]-5-
methyl-3-O-methoxymethyl-4-cyclohexene-1,2,3-triol (39)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:35?1:15) afforded a colorless syrup in 89% yield. ½a D24
ꢃ
+147.1 (c 3.0, MeOH). 1H NMR (300 MHz, C6D6) d 5.31 (br s, 1H),
4.90 (d, J = 6.6 Hz, 1H), 4.70 (d, J = 6.6 Hz, 1H), 4.36 (dd, J = 7.1,
1.8 Hz, 1H), 3.94–3.79 (m, 2H), 3.30 (s, 3H), 3.20 (s, 3H), 3.06 (s,
3H), 2.13 (dd, J = 16.0, 9.7 Hz, 1H), 1.99 (dd, J = 16.0, 5.5 Hz, 1H),
1.42 (s, 3H), 1.33 (s, 6H). 13C NMR (75 MHz, C6D6) d 133.8, 123.7,
123.5, 99.7, 99.6, 96.9, 75.7, 74.8, 66.6, 55.3, 47.9, 35.6, 23.2,
18.4. HRMS (ESI) calcd for C15H26NaO6 [M+Na]+: 325.1627. Found:
325.1636.
4.11. (1R,2R,3R)-1,2-[(2S,3S)-2,3-dimethoxybutan-2,3-dioxy]-5-
butyl-4-cyclohexene-1,2,3-triol (38)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:16?1:6) afforded a colorless syrup in 71% yield. ½a D25
ꢃ
+153.0 (c 1.7, MeOH). 1H NMR (300 MHz, C6D6) d 5.39 (br s, 1H),
4.43 (br s, 1H), 3.91 (ddd, J = 16.5, 10.5, 6.0 Hz, 1H), 3.82 (dd,
J = 10.5, 7.6 Hz, 1H), 3.21 (s, 3H), 3.10 (s, 3H), 2.68 (d, J = 3.6 Hz, –
OH), 2.33–2.20 (m, 1H), 2.10 (dd, J = 15.9, 5.8 Hz, 1H), 1.74 (t,
J = 7.7 Hz, 1H), 1.45 (s, 3H), 1.42 (s, 3H), 1.29–1.05 (m, 4H), 0.79
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, C6D6) d 137.4, 124.2, 99.8,
99.7, 76.2, 70.9, 66.6, 48.0, 47.9, 37.1, 34.4, 30.1, 23.0, 18.5, 18.4,
14.5. HRMS (ESI) calcd for C16H28NaO5 [M+Na]+: 323.1834. Found:
323.1843.
4.7. (1R,2R,3R)-1,2-[(2S,3S)-2,3-Dimethoxybutan-2,3-dioxy]-5-
butyl-3-O-methoxymethyl-4-cyclohexene-1,2,3-triol (40)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:25?1:15) afforded a colorless syrup in 94% yield. ½a D24
ꢃ
+88.2 (c 1.9, MeOH). 1H NMR (300 MHz, C6D6) d 5.41 (br s, 1H),
4.97 (d, J = 6.5 Hz, 1H), 4.76 (d, J = 6.5 Hz, 1H), 4.49–4.46 (br m,
1H), 4.01 (dd, J = 10.5, 7.6 Hz, 1H), 3.93 (td, J = 10.5, 5.8 Hz, 1H),
3.33 (s, 3H), 3.22 (s, 3H), 3.11 (s, 3H), 2.30–2.20 (m, 1H), 2.08
(dd, J = 16.3, 5.7 Hz, 1H), 1.78 (dd, J = 7.6, 6.6 Hz, 2H), 1.38 (s,
3H), 1.37 (s, 3H), 1.27–1.09 (m, 4H), 0.79 (t, J = 7.0 Hz, 3H). 13C
NMR (75 MHz, C6D6) d 138.0, 122.7, 99.8, 99.7, 97.0, 75.9, 75.0,
66.8, 55.4, 48.0, 47.9, 37.3, 34.2, 30.2, 23.0, 18.5, 14.5.
HRMS (ESI) calcd for C18H32NaO6 [M+Na]+: 367.2097. Found:
367.2082.
4.12. (3S,4R,5R)-4,5-O-Cyclohexylidene-3,4,5-trihydroxy-3-O-
methoxymethyl-1-methyl-1-cyclohexene (24)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:20?1:8) afforded a colorless syrup in 98% yield. ½a D25
ꢃ
+20.8 (c 1.6, MeOH). 1H NMR (300 MHz, C6D6)
d 5.62 (d,
J = 1.2 Hz, 1H), 4.75 (d, J = 6.8 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H),
4.39 (ddd, J = 7.5, 3.7, 2.5 Hz, 1H), 4.14 (ddd, J = 7.4, 5.3, 2.5 Hz,
1H), 3.86 (dt, J = 5.8, 2.1 Hz, 1H), 3.27 (s, 3H), 2.12 (dd, J = 15.6,
2.0 Hz, 1H), 1.79–1.51 (br m, 12H), 1.27–1.22 (br m, 2H). 13C
NMR (75 MHz, C6D6) d 134.3, 123.7, 109.5, 96.1, 75.8, 73.9, 73.6,
55.5, 36.9, 35.0, 34.1, 26.1, 24.8, 24.6, 23.8. HRMS (ESI) C15H24NaO4
[M+Na]+: 291.1572. Found: 291.1567.
4.8. (1S,2S,3S)-1,2-O-Cyclohexylidene-5-methyl-4-cyclohexene-
1,2,3-triol (22)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
4.13. (1R,2R,3S)-5-Butyl-1,2-O-cyclohexylidene-3-O-
methoxymethyl-4-cyclohexene-1,2,3-triol (25)
hexane 1:16?1:8) afforded
a
white solid in 86% yield.
Mp = 95.0–96.0 °C. ½a D25
ꢃ
+14.2 (c 1.4, MeOH). 1H NMR (300 MHz,
C6D6) d 5.55 (t, J = 1.1 Hz, 1H), 4.20 (ddd, J = 7.5, 4.3, 1.3 Hz, 1H),
4.10 (ddd, J = 7.5, 4.4, 2.5 Hz, 1H), 3.99 (ddd, J = 9.3, 4.3, 2.2 Hz,
1H), 2.88 (d, J = 9.6 Hz, –OH), 2.08 (dd, J = 16.2, 2.6 Hz, 1H), 1.62–
1.51 (m, 12H), 1.24–1.23 (m, 2H). 13C NMR (75 MHz, C6D6) d
134.1, 126.0, 109.5, 76.6, 73.2, 67.7, 36.7, 34.9, 33.4, 26.0, 24.7,
24.4, 23.9. HRMS (ESI) for C13H20NaO3 [M+Na]+: 247.1310. Found:
247.1305.
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:30?1:15) afforded a colorless syrup in 89% yield. ½a D24
ꢃ
+30.8 (c 1.0, MeOH). 1H NMR (300 MHz, C6D6)
d 5.64 (d,
J = 1.0 Hz, 1H), 4.77 (d, J = 6.7 Hz, 1H), 4.68 (d, J = 6.7 Hz, 1H),
4.42 (ddd, J = 7.4, 3.6, 2.0 Hz, 1H), 4.16 (dd, J = 5.3, 2.6 Hz, 1H),
3.89 (t, J = 1.8 Hz, 1H), 3.30 (s, 3H), 2.19 (dd, J = 15.7, 2.2 Hz, 1H),
1.96 (t, J = 7.4 Hz, 2H), 1.76–1.53 (m, 9H), 1.37–1.20 (m, 6H), 0.85
(t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, C6D6) d 138.5, 123.2, 109.5,
96.1, 76.0, 74.1, 73.5, 55.6, 37.6, 36.7, 34.8, 33.0, 30.2, 26.1, 24.8,
24.6, 23.1, 14.5. HRMS (ESI) calcd for C18H30NaO4 [M+Na]+:
333.2042. Found: 333.2037.
4.9. (1S,2R,3R)-5-Butyl-1,2-O-cyclohexylidene-4-cyclohexene-
1,2,3-triol (23)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:25?1:10) afforded a colorless syrup in 87% yield. ½a D25
ꢃ
4.14. (3S,4R,5R,7R)-N-Benzyl-4,5-O-cyclohexylidene-3,4,5-
trihydroxy-3-O-methoxymethyl-7-methylazepane (26)
+14.1 (c 1.4, MeOH). 1H NMR (300 MHz, C6D6)
d 5.56 (t,
J = 1.1 Hz, 1H), 4.21 (ddd, J = 7.6, 4.4, 1.1 Hz, 1H), 4.11 (dt, J = 7.6,
1.7 Hz, 1H), 3.95–3.80 (m, 1H), 2.75 (d, J = 15.8, 2.6 Hz, 1H), 2.14
(dd, J = 15.8, 2.6 Hz, 1H), 1.91 (t, J = 7.0 Hz, 2H), 1.65–1.50 (m,
9H), 1.34–1.20 (m, 6H), 0.86 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
C6D6) d 138.2, 125.5, 109.5, 75.8, 73.2, 67.8, 37.5, 36.6, 34.8, 31.9,
30.1, 26.0, 24.7, 24.5, 23.0, 14.5. HRMS (ESI) calcd for C16H27O3
[M+H]+: 267.1960. Found: 267.1955.
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:60?1:20) afforded a pale yellow syrup in 47% yield.
½
a 2D5
ꢃ
ꢀ16.5 (c 0.9, MeOH). 1H NMR (600 MHz, C6D6) d 7.51 (d,
J = 7.3 Hz, 2H), 7.31 (t, J = 7.5 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 4.61
(d, J = 6.8 Hz, 2H), 4.57 (d, J = 6.8 Hz, 2H), 4.53 (d, J = 7.9 Hz, 1H),
4.00 (dt, J = 8.4, 2.3 Hz, 1H), 3.64 (d, J = 14.1 Hz, 2H), 3.58 (d,

188
T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
J = 14.1 Hz, 2H), 3.38–3.30 (m, 2H), 3.22 (s, 3H), 2.89 (dd, J = 14.5,
1.1 Hz, 1H), 2.10–2.06 (br m, 1H), 1.95 (t, J = 6.0 Hz, 2H), 1.96–
1.64 (m, 7H), 1.38 (dt, J = 11.7, 5.9 Hz, 2H), 1.10 (d, J = 6.9 Hz,
3H). 13C NMR (150 MHz, C6D6) d 141.5, 129.5–127.4 (-Ar+C6D6),
108.6, 95.8, 79.6, 74.1, 72.6, 55.5, 53.4, 53.0, 51.6, 36.8, 36.3,
34.3, 26.1, 24.8, 24.5, 20.6. HRMS (ESI) calcd for C22H34NO4
[M+H]+: 376.2482. Found: 376.2526.
J = 10.5, 4.7, 3.0 Hz, 1H), 2.99 (dq, J = 7.2, 6.6 Hz, 1H), 2.81 (ddd,
J = 13.4, 4.7, 0.9 Hz, 1H), 2.69 (dd, J = 13.4, 10.5 Hz, 1H), 2.00
(ddd, J = 14.4, 9.4, 6.4 Hz, 1H), 1.53–1.47 (m, 1H), 1.00 (d,
J = 6.6 Hz, 3H). 13C NMR (150 MHz, D2O) d 76.8, 71.1, 68.3, 50.0,
47.8, 37.1, 22.3. HRMS (ESI) calcd for C7H16NO3 [M+H]+:
162.1130. Found: 162.1123.
4.19. (3S,4R,5R,7S)-7-Methylazepane-3,4,5-triol (2)
4.15. (3S,4R,5R,7S)-N-Benzyl-4,5-O-cyclohexylidene-3,4,5-
trihydroxy-3-O-methoxymethyl-7-methylazepane (27)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:6:25?1:6:15) afforded a colorless syrup in 92%
Flash column chromatography (230–400 mesh SiO2, EtOAc–
yield. ½a 2D4
ꢃ
+15.6 (c 0.3, MeOH). 1H NMR (600 MHz, D2O) d 4.10
hexane 1:60?1:20) afforded a colorless syrup in 7% yield. ½a D24
ꢃ
(ddd, J = 8.7, 4.6, 1.7 Hz, 1H), 4.03–4.01 (br m, 1H), 3.89 (ddd,
J = 11.0, 4.1, 2.4 Hz, 1H), 3.40–3.33 (m, 1H), 3.27 (dd, J = 13.6,
8.8 Hz, 1H), 3.17 (dd, J = 13.6, 4.7 Hz, 1H), 1.99 (dt, J = 15.0,
11.0 Hz, 1H), 1.84–1.78 (m, 1H), 1.27 (d, J = 6.7 Hz, 3H). 13C NMR
(150 MHz, D2O) d 75.6, 69.5, 65.6, 50.9, 44.5, 34.9, 20.1. HRMS
(ESI) calcd for C7H16NO3 [M+H]+: 162.1130. Found: 162.1141.
ꢀ54.8 (c 0.9, MeOH). 1H NMR (600 MHz, C6D6) d 7.32–7.10 (m,
5H), 4.92 (d, J = 6.6 Hz, 1H), 4.68 (d, J = 6.6 Hz, 1H), 4.64–4.61 (m,
2H), 4.13 (dt, J = 8.2, 2.7 Hz, 1H), 3.51 (d, J = 13.2 Hz, 1H), 3.34 (d,
J = 13.2 Hz, 1H), 3.30 (s, 3H), 2.96–2.90 (m, 2H), 2.77–2.72 (m,
2H), 2.15 (ddd, J = 10.1, 6.4, 2.9 Hz, 1H), 2.00–1.89 (m, 2H), 1.85–
1.70 (m, 6H), 1.46–1.40 (m, 2H), 0.95 (d, J = 6.3 Hz, 3H). 13C NMR
(150 MHz, C6D6) d 140.4, 128.5–127.0 (-Ar+C6D6), 107.6, 97.4,
78.3, 76.0, 75.7, 59.3, 54.8, 52.9, 49.3, 37.3, 36.8, 33.9, 25.7, 24.3,
24.0, 11.1. HRMS (ESI) calcd for C22H34NO4 [M+H]+: 376.2482.
Found: 376.2325.
4.20. (3S,4R,5R,7R)-7-Butylazepane-3,4,5-triol (3)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:6:60?1:6:40) afforded a colorless syrup in 90%
yield. ½a 2D5
ꢃ
ꢀ10.7 (c 0.8, MeOH). 1H NMR (600 MHz, D2O) d 3.98
4.16. (3S,4R,5R,7R)-N-Benzyl-7-butyl-4,5-O-cyclohexylidene-
3,4,5-trihydroxy-3-O-methoxymethylazepane (28)
(dd, J = 8.7, 5.1 Hz, 2H), 3.70 (ddd, J = 10.6, 4.8, 2.9 Hz, 1H), 2.85
(dd, J = 13.3, 4.8 Hz, 1H), 2.81 (dd, J = 13.9, 7.1 Hz, 1H), 2.69 (dd,
J = 13.3, 10.7 Hz, 1H), 1.99 (ddd, J = 14.4, 10.0, 6.5 Hz, 1H), 1.56
(ddd, J = 14.4, 7.4, 5.1 Hz, 1H), 1.36–1.31 (m, 2H), 1.26–1.21 (m,
4H), 0.81 (t, J = 7.0 Hz, 3H). 13C NMR (150 MHz, D2O) d 77.0, 71.3,
68.5, 54.5, 48.3, 36.3, 35.5, 27.5, 22.0, 12.3. HRMS (ESI) calcd for
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:50?1:30) afforded a colorless syrup in 25% yield. ½a D25
ꢃ
ꢀ32.0 (c 0.4, MeOH). 1H NMR (600 MHz, C6D6)
d 7.59 (d,
J = 7.8 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 4.60
(d, J = 8.0 Hz, 1H), 4.56 (d, J = 6.8 Hz, 1H), 4.54 (d, J = 6.8 Hz, 1H),
4.32 (ddd, J = 8.0, 5.2, 2.9 Hz, 1H), 4.04 (dt, J = 9.4, 1.6 Hz, 1H),
3.76 (d, J = 14.1 Hz, 1H), 3.63 (d, J = 14.1 Hz, 1H), 3.56 (dd,
J = 14.3, 9.4 Hz, 1H), 3.26 (dd, J = 15.1, 7.4 Hz, 1H), 3.21 (s, 3H),
2.00–1.85 (br m, 3H), 1.80–1.30 (br m, 15H), 1.00 (t, J = 7.3 Hz,
3H). 13C NMR (150 MHz, C6D6) d 141.4, 129.3, 128.9, 127.5,
108.6, 95.8, 79.8, 74.5, 71.4, 57.0, 55.5, 51.4, 50.8, 36.8, 34.8,
34.2, 33.9, 29.8, 26.1, 24.7, 24.4, 23.3, 14.6. HRMS (ESI) calcd for
C
10H22NO3 [M+H]+: 204.1600. Found: 204.1557.
4.21. (3S,4R,5R,7S)-7-Butylazepane-3,4,5-triol (4)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:6:60?1:6:40) afforded a colorless syrup in 91%
yield. ½a 2D5
ꢃ
+17.9 (c 1.0, MeOH). 1H NMR (600 MHz, D2O) d 3.98
(br s, 1H), 3.85 (dt, J = 11.1, 2.6 Hz, 1H), 3.77 (ddd, J = 9.2, 4.0,
2.9 Hz, 1H), 2.92 (dd, J = 14.0, 9.2 Hz, 1H), 2.76–2.71 (m, 1H), 2.63
(dd, J = 14.0, 4.0 Hz, 1H), 1.83 (dt, J = 14.3, 11.0 Hz, 1H), 1.61
(ddd, J = 14.3, 4.0, 1.1 Hz, 1H), 1.36–1.31 (m, 2H), 1.25–1.19 (m,
4H), 0.80 (t, J = 7.0 Hz, 3H). 13C NMR (150 MHz, D2O) d 75.7, 70.5,
70.3, 52.5, 44.6, 36.3, 34.8, 27.4, 22.0, 13.3. HRMS (ESI) calcd for
C
25H40NO4 [M+H]+: 418.2957. Found: 418.2924.
4.17. (3S,4R,5R,7S)-N-Benzyl-7-butyl-4,5-O-cyclohexylidene-
3,4,5-trihydroxy-3-O-methoxymethylazepane (29)
C
10H22NO3 [M+H]+: 204.1600. Found: 204.1583.
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:50?1:30) afforded a colorless syrup in 14% yield. ½a D25
ꢃ
4.22. (3R,4S,5R,7R)-7-Methylazepane-3,4,5-triol (5)
+30.7 (c 1.4, MeOH). 1H NMR (600 MHz, C6D6)
d 7.35 (d,
J = 7.2 Hz, 2H), 7.35–7.26 (m, 2H), 7.21 (t, J = 7.2 Hz, 1H), 4.90 (d,
J = 6.7 Hz, 1H), 4.68 (d, J = 6.7 Hz, 1H), 4.61 (ddd, J = 13.9, 10.4,
3.7 Hz, 1H), 4.59 (dd, J = 7.5, 3.0 Hz, 1H), 4.12 (dt, J = 7.5, 2.8 Hz,
1H), 3.63 (d, J = 13.6 Hz, 1H), 3.49 (d, J = 13.6 Hz, 1H), 3.31 (s,
3H), 3.08 (dd, J = 14.8, 1.9 Hz, 1H), 2.79–2.73 (dd+m, J = 14.7,
7.6 Hz, 2H), 2.67 (td, J = 13.2, 10.4 Hz, 1H), 2.27 (ddd, J = 13.2, 5.8,
4.0 Hz, 1H), 2.02–1.90 (m, 2H), 1.88–1.70 (m, 6H), 1.62–1.52 (m,
2H), 1.48–1.37 (m, 2H), 1.37–1.27 (m, 3H), 1.17–1.11 (m, 1H),
0.96 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, C6D6) d 141.2, 129.2,
129.0, 128.7, 127.7, 108.2, 97.8, 79.2, 76.6, 76.3, 59.7, 55.4, 50.4,
37.5, 35.6, 34.4, 29.6, 27.9, 26.3, 24.9, 24.7, 23.7, 14.7. HRMS (ESI)
calcd for C25H40NO4 [M+H]+: 418.2957. Found: 418.2924.
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:6:25?1:6:15) afforded a yellow syrup as a mix-
ture in a ratio of 10:1 in 89% total yield (major isomer). 1H NMR
(600 MHz, D2O) d 3.71 (td, J = 9.1, 2.2 Hz, 1H), 3.48 (ddd, J = 10.4,
8.2, 3.7 Hz, 1H), 3.30 (dd, J = 17.5, 9.4 Hz, 1H), 3.09 (dt, J = 17.0,
5.5 Hz, 1H), 2.91 (dd, J = 13.9, 3.7 Hz, 1H), 2.67 (dd, J = 13.9,
10.4 Hz, 1H), 1.96 (ddd, J = 15.2, 9.1, 5.6 Hz, 1H), 1.65 (ddd,
J = 15.2, 4.6, 2.3 Hz, 1H), 1.06 (d, J = 6.7 Hz, 3H). 13C NMR
(150 MHz, D2O) d 80.2, 73.2, 68.2, 48.0, 47.6, 37.5, 21.2.
4.23. (3R,4S,5R,7R)-7-Butylazepane-3,4,5-triol (7)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:6:40?1:6:25) afforded a yellow syrup as a mix-
ture in a ratio of 10:1 in 90% total yield (major isomer). 1H NMR
(600 MHz, D2O) d 3.68 (dd, J = 15.7, 8.8 Hz, 1H), 3.48–3.40 (m,
1H), 3.27 (t, J = 8.4 Hz, 1H), 2.91–2.85 (m, 2H), 2.63 (dd, J = 13.4,
10.8 Hz, 1H), 1.93 (ddd, J = 15.2, 9.1, 6.0 Hz, 1H), 1.69 (dd,
J = 15.2, 2.2 Hz, 1H), 1.40–1.35 (m, 2H), 1.25–1.22 (m, 4H), 0.83
4.18. (3S,4R,5R,7R)-7-Methylazepane-3,4,5-triol (1)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:6:25?1:6:15) afforded a pale yellow syrup in
86% yield. ½a 2D5
ꢃ
ꢀ27.3 (c 0.8, MeOH). 1H NMR (600 MHz, D2O) d
3.97 (dd, J = 4.8, 3.5 Hz, 1H), 3.95 (d, J = 2.6 Hz, 1H), 3.69 (ddd,

T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
189
(t, J = 6.8 Hz, 3H). 13C NMR (150 MHz, D2O) d 80.5, 73.5, 68.3, 52.5,
47.8, 36.0, 35.2, 27.7, 21.9, 23.2.
20.4, 14.0. HRMS(ESI) calcd for C23H36NO3 [M+H]+: 374.2695.
Found: 374.2651.
4.24. (3S,4R,6S)-6-O-Benzyl-3,4-O-cyclohexylidene-1-methylaze-
pane (47)
4.28. (3R,4R,6S)-6-O-Benzyl-3,4-dihydroxy-1-N-methyl-3,4-
[(2S,3S)-2,3-dimethoxybutane-2,3-dioxy] azepane (52)
Flash column chromatography (230–400 mesh SiO2, EtOAc–
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:32?1:4) afforded a pale yellow syrup in 48% yield. ½a D25
ꢃ
hexane 1:16?1:2) afforded a clear syrup in 56% yield. ½a D26
ꢃ
+21.0 (c 0.6, MeOH). 1H NMR (600 MHz, C6D6) d 7.35 (d, J = 7.6 Hz,
2H), 7.29–7.25 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 4.43–4.36 (m, 2H),
4.35–4.28 (m, 2H), 3.38 (tdd, J = 11.2, 4.0, 1.3 Hz, 1H), 3.09 (dt,
J = 11.6, 2.0 Hz, 1H), 2.84 (ddd, J = 13.3, 4.9, 1.5 Hz, 1H), 2.62–2.52
(m, 2H), 2.32 (t, J = 10.1 Hz, 1H), 2.21 (s, 3H), 2.11 (ddd, J = 13.4,
11.2, 2.0 Hz, 1H), 1.90–1.65 (m, 8H), 1.42–1.35 (m, 2H). 13C NMR
(150 MHz, C6D6) d 139.2, 129.0–126.0 (-Ar), 108.6, 76.4, 74.4, 74.2,
70.3, 65.5, 58.6, 48.0, 37.8, 36.7, 34.4, 25.5, 24.3, 24.0. HRMS (ESI)
calcd for C20H30NO3 [M]+: 332.2220. Found: 332.2181.
+117.6 (c 0.7, MeOH). 1H NMR (600 MHz, C6D6) d 7.37 (d,
J = 7.5 Hz, 2H), 7.29–7.25 (m, 2H), 7.19 (t, J = 7.3 Hz, 1H), 4.77 (d,
J = 12.1 Hz, 1H), 4.36 (d, J = 12.1 Hz, 1H), 4.07 (td, J = 8.9, 5.9 Hz,
1H), 3.87 (td, J = 11.1, 1.7 Hz, 1H), 3.57 (ddd, J = 15.4, 10.2, 4.9 Hz,
1H), 3.22 (s, 3H), 3.19 (s, 3H), 2.91 (dd, J = 12.8, 5.8 Hz, 1H), 2.75
(dd, J = 13.9, 4.8 Hz, 1H), 2.57 (ddd, J = 12.8, 8.9, 2.3 Hz, 1H), 2.43
(ddd, J = 13.0, 5.5, 1.4 Hz, 1H), 2.31 (s, 3H), 2.26 (ddd, J = 13.0,
10.9, 2.5 Hz, 1H), 1.49 (s, 3H), 1.47 (s, 3H). 13C NMR (150 MHz,
C6D6) d 139.3, 129.0–126.0 (-Ar), 99.0, 98.6, 75.4, 71.9, 70.1, 68.0,
62.9, 61.4, 47.9, 47.4, 47.3, 35.8, 17.8, 17.7. HRMS (ESI) calcd for
4.25. (3S,4R,6R)-6-O-Benzyl-3,4-O-cyclohexylidene-1-
C
20H32NO3 [M+H]+: 366.2280. Found: 366.2215.
methylazepane (48)
4.29. (3R,4R,6S)-6-O-Benzyl-1-N-butyl-3,4-dihydroxy-3,4-
[(2S,3S)-2,3-dimethoxybutane-2,3-dioxy] azepane (53)
Flash column chromatography (230–400 mesh SiO2, EtOAc–hex-
ane 1:32?1:4) afforded a pale yellow syrup in 49% yield. ½a D26
ꢀ14.9
ꢃ
(c 0.6, MeOH). 1H NMR (600 MHz, C6D6) d 7.39 (d, J = 7.5 Hz, 2H),
7.29–7.25 (m, 2H), 7.19 (t, J = 7.3 Hz, 1H), 4.77 (t, J = 9.8 Hz, 1H),
4.55 (t, J = 10.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.40 (d,
J = 12.0 Hz, 1H), 3.60–3.53 (br s, 1H), 2.80 (td, J = 16.0, 3.5 Hz, 2H),
2.63 (dd, J = 13.4, 9.4 Hz, 1H), 2.40–2.33 (m, 1H), 2.29 (s, 3H), 2.26
(d, J = 12.8 Hz, 1H), 2.02 (dd, J = 14.0, 9.6 Hz, 1H), 1.92 (dd, J = 10.4,
5.2 Hz, 2H), 1.82 (dt, J = 12.2, 6.1 Hz, 2H), 1.73–1.64 (m, 4H), 1.45–
1.35 (m, 2H). 13C NMR (150 MHz, C6D6) d 139.2, 108.2, 76.7, 73.7,
70.2, 63.1, 58.9, 47.7, 38.0, 34.6, 33.6, 25.5, 24.4, 24.0. HRMS (ESI)
calcd for C20H30NO3 [M+]: 332.2220. Found: 332.2205.
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:30?1:8) afforded a pale yellow syrup in 40% yield. ½a D26
ꢃ
+92.8 (c 0.7, MeOH). 1H NMR (600 MHz, C6D6)
d 7.39 (d,
J = 7.2 Hz, 2H), 7.28–7.25 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 4.48 (d,
J = 12.1 Hz, 1H), 4.39 (d, J = 12.1 Hz, 1H), 4.05 (td, J = 9.2, 5.8 Hz,
1H), 3.87 (ddd, J = 11.2, 9.5, 1.9 Hz, 1H), 3.57 (dtd, J = 15.7, 10.3,
4.7 Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H), 3.07 (ddd, J = 13.0, 5.8,
0.8 Hz, 1H), 2.89 (dd, J = 14.1, 4.0 Hz, 1H), 2.65 (td, J = 10.5,
4.7 Hz, 2H), 2.55–2.50 (m, 2H), 2.44 (ddd, J = 13.1, 5.7, 1.9 Hz,
1H), 2.29 (ddd, J = 13.1, 10.7, 8.3 Hz, 1H), 1.50 (s, 3H), 1.49 (s,
3H), 1.48–1.44 (m, 2H), 1.38–1.32 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H).
13C NMR (150 MHz, C6D6) d 139.4, 129.0–126.0 (-Ar), 99.0, 98.6,
75.7, 72.4, 70.1, 68.3, 60.4, 59.5, 58.9, 47.4, 47.3, 35.8, 30.1, 20.4,
4.26. (3S,4R,6S)-6-O-Benzyl-1-butyl-3,4-O-cyclohexylideneaze-
pane (49)
17.8, 17.7, 14.0. HRMS (ESI) calcd for
408.2750. Found: 408.2729.
C
23H38NO3 [M+H]+:
Flash column chromatography (230–400 mesh SiO2, EtOAc–
hexane 1:32?1:16) afforded a clear syrup in 54% yield. ½a D25
ꢀ2.5
ꢃ
(c 0.8, MeOH). 1H NMR (600 MHz, C6D6) d 7.36 (d, J = 7.4 Hz, 2H),
7.30–7.25 (m, 2H), 7.20 (t, J = 7.3 Hz, 2H), 4.46 (d, J = 12.1 Hz,
1H), 4.43–4.33 (m, 3H), 3.39 (tdd, J = 11.2, 4.1, 1.6 Hz, 1H), 3.19
(ddd, J = 11.7, 3.8, 1.6 Hz, 1H), 3.04 (ddd, J = 13.5, 5.0, 1.6 Hz, 1H),
2.65 (dd, J = 13.6, 10.4 Hz, 1H), 2.56 (ddt, J = 12.8, 5.6, 1.5 Hz, 1H),
2.49 (dd, J = 11.6, 9.9 Hz, 1H), 2.45–2.34 (m, 2H), 2.16 (dt,
J = 13.0, 11.2 Hz, 2H), 1.90 (t, J = 5.9 Hz, 2H), 1.82–1.77 (m, 2H),
1.77–1.68 (m, 4H), 1.44–1.33 (m, 4H), 1.30–1.22 (m, 2H), 0.93 (t,
J = 7.4 Hz, 3H). 13C NMR (150 MHz, C6D6) d 139.3, 129.0–126.0 (-
Ar), 108.7, 76.8, 75.0, 74.8, 70.4, 63.8, 59.4, 56.5, 37.9, 37.0, 34.5,
29.7, 25.5, 24.3, 24.0, 20.4, 13.9. HRMS (ESI) calcd for C23H36NO3
[M +H]+: 374.2695. Found: 374.2651.
4.30. (3S,4R,6S)-1-N-Methylazepane-3,4,6-triol (9)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:20:70?1:20:50) afforded a clear syrup in 83%
yield. ½a 2D6
ꢃ
+9.9 (c 0.9, MeOH). 1H NMR (600 MHz, D2O) d 4.00
(dd, J = 9.5, 4.8 Hz, 1H), 3.99–3.95 (m, 1H), 3.89 (ddd, J = 9.5, 4.4,
2.9 Hz, 1H), 3.00 (dd, J = 13.3, 4.1 Hz, 1H), 2.97 (dd, J = 13.8,
3.2 Hz, 1H), 2.88 (dd, J = 12.8, 6.3 Hz, 1H), 2.80 (dd, J = 12.4,
7.9 Hz, 1H), 2.52 (s, 3H), 2.07–1.96 (m, 2H). 13C NMR (150 MHz,
D2O) d 69.8, 69.1, 65.1, 63.1, 59.2, 46.9, 36.8. HRMS (ESI) calcd
for C7H16NO3 [M+H]+: 162.1125. Found: 162.1194.
4.31. (3S,4R,6R)-1-N-Methylazepane-3,4,6-triol (10)
4.27. (3S,4R,6R)-6-O-Benzyl-1-butyl-3,4-O-cyclohexylideneaze-
pane (50)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:20:70?1:20:50) afforded a clear syrup in 69%
Flash column chromatography (230–400 mesh SiO2, EtOAc–
yield. ½a 2D5
ꢃ
+23.6 (c 0.5, MeOH). 1H NMR (600 MHz, D2O) d 4.07–
hexane 1:32?1:8) afforded a pale yellow syrup in 59% yield.
4.01 (m, 2H), 3.90–3.85 (m, 1H), 2.78 (dd, J = 13.7, 5.1 Hz, 1H),
2.66–2.58 (m, 2H), 2.48 (dd, J = 13.7, 6.7 Hz, 1H), 2.27 (s, 3H),
2.23 (dt, J = 9.4, 4.8 Hz, 1H), 1.65 (ddd, J = 14.6, 6.5, 1.8 Hz, 1H).
13C NMR (150 MHz, D2O) d 71.5, 68.3, 65.4, 63.4, 60.3, 47.2, 35.9.
HRMS (ESI) calcd for C7H16NO3 [M]+: 162.1125. Found: 162.1097.
½
a 2D6 +13.2 (c 0.7, MeOH). 1H NMR (600 MHz, C6D6) d 7.41 (d,
ꢃ
J = 7.6 Hz, 2H), 7.30–7.25 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 4.78 (t,
J = 9.5 Hz, 1H), 4.51–4.45 (m, 2H), 4.43 (d, J = 12.0 Hz, 1H), 3.66–
3.60 (br s, 1H), 2.95–2.87 (m, 2H), 2.67 (dd, J = 13.7, 9.5 Hz, 1H),
2.50–2.42 (m, 3H), 2.40–2.32 (m, 1H), 2.09 (dd, J = 14.0, 9.5 Hz,
1H), 1.94 (t, J = 6.6 Hz, 2H), 1.83 (dt, J = 12.1, 5.6 Hz, 2H), 1.76–
1.67 (m, 4H), 1.48–1.30 (m, 6H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(150 MHz, C6D6) d 139.3, 129.0–126.0 (-Ar), 108.2, 77.1, 73.9,
73.8, 70.2, 61.2, 58.9, 56.7, 38.0, 34.7, 33.8, 30.0, 25.5, 24.4, 24.0,
4.32. (3S,4R,6S)-1-N-Butylazepane-3,4,6-triol (11)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:20:70) afforded a clear syrup in 71% yield. ½a D26
ꢃ

190
T.-L. Shih et al. / Carbohydrate Research 346 (2011) 183–190
ꢀ9.4 (c 1.3, MeOH). 1H NMR (600 MHz, D2O) d 3.89–3.82 (m, 3H),
2.81 (dd, J = 13.0, 4.5 Hz, 1H), 2.78 (dd, J = 13.8, 3.8 Hz, 1H), 2.60
(dd, J = 13.8, 6.7 Hz, 1H), 2.50 (dd, J = 13.0, 8.3 Hz, 1H), 2.46 (t,
J = 8.0 Hz, 2H), 1.98–1.88 (m, 2H), 1.42–1.35 (m, 2H), 1.20 (sextet,
J = 7.5 Hz, 2H), 0.82 (t, J = 7.5 Hz, 3H). 13C NMR (150 MHz, D2O) d
70.9, 69.1, 66.9, 61.7, 58.3, 57.5, 37.3, 27.6, 20.1, 13.3. HRMS (ESI)
calcd for C10H22NO3 [M]+: 204.1521. Found: 204.1609.
(t, J = 7.4 Hz, 3H). 13C NMR (150 MHz, D2O) d 72.6, 71.2, 64.9,
60.8, 58.8, 57.2, 38.8, 26.4, 19.6, 13.0. HRMS (ESI) calcd for
C
10H22NO3 [M+H]+: 204.1594. Found: 204.1591.
Acknowledgments
Support provided by the National Science Council(NSC95-2113-
M-032-004-MY3) and Tamkang University are gratefully acknowl-
edged. The authors thank the National Center for High-Performing
Computing and assistance.
4.33. (3S,4R,6R)-1-N-Butylazepane-3,4,6-triol (12)
Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:20:70) afforded a pale yellow syrup in 67% yield.
References
½
a 2D6 +1.8 (c 0.6, MeOH). 1H NMR (600 MHz, D2O) d 4.07–4.01 (m,
ꢃ
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(dd, J = 14.5, 6.8 Hz, 1H), 1.47–1.37 (m, 2H), 1.21 (sextet,
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Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:20:70–1:20:50) afforded a white solid in 90%
yield. Mp = 215.2–220.2 °C. ½a D25
ꢃ
ꢀ5.7 (c 0.7, MeOH). 1H NMR
(600 MHz, D2O) d 4.25–4.21 (m, 1H), 4.03 (ddd, J = 7.3, 7.3,
2.5 Hz, 1H), 3.88 (ddd, J = 7.0, 7.0, 5.3 Hz, 1H), 3.50 (d, J = 13.6 Hz,
1H), 3.38 (dd, J = 13.3, 2.9 Hz, 1H), 3.30–3.21 (m, 2H), 2.28 (ddd,
J = 14.9, 4.7, 3.7 Hz, 1H), 1.93 (ddd, J = 14.9, 8.5, 7.5 Hz, 1H). 13C
NMR (150 MHz, D2O) d 70.5, 70.2, 63.3, 61.9, 58.0, 46.2, 37.9. HRMS
(ESI) calcd for C7H15NO3 [M+H]+: 162.1125. Found: 162.1167.
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Flash column chromatography (230–400 mesh SiO2, NH4OH–
MeOH–CH2Cl2 1:20:60?1:20:40) afforded a pale yellow syrup in
88% yield. ½a 2D5
ꢃ
ꢀ17.2 (c 0.6, MeOH). 1H NMR (600 MHz, D2O) d
4.07 (dddd, J = 13.7, 9.7, 7.9, 4.0 Hz, 1H), 3.77 (td, J = 7.1, 3.4 Hz,
1H), 3.70 (ddd, J = 9.7, 7.7, 3.5 Hz, 1H), 3.13 (dd, J = 14.0, 2.5 Hz,
1H), 3.09 (dd, J = 13.1, 3.8 Hz, 1H), 2.91 (dd, J = 14.0, 6.9 Hz, 1H),
2.86–2.79 (m, 3H), 2.10 (dt, J = 14.0, 3.5 Hz, 1H), 1.84 (dt, J = 14.0,
9.7 Hz, 1H), 1.60–1.47 (m, 2H), 1.27 (sextet, J = 7.4 Hz, 2H), 0.85