Synthesis of branched seven-membered 1-N-iminosugars and their evaluation as glycosidase inhibitors

Article abstract of DOI:10.1016/j.carres.2011.10.039

Four branched tetra- and pentahydroxylated azepanes have been synthesized from a common azepane precursor through dihydroxylation followed by deoxygenation. They have been assayed as glycosidase inhibitors on a panel of 22 glycosidases and one methylated azepane displayed selective, competitive, and moderate inhibition toward bovine kidney α-l-fucosidase.

Full text of DOI:10.1016/j.carres.2011.10.039

Carbohydrate Research 356 (2012) 110–114
Contents lists available at SciVerse ScienceDirect
Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
Synthesis of branched seven-membered 1-N-iminosugars and their
evaluation as glycosidase inhibitors
Hongqing Li a, Yongmin Zhang a, Sylvain Favre b, Pierre Vogel b, Matthieu Sollogoub a, Yves Blériot a,
⇑
,
a UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire (UMR CNRS 7201), FR 2769, C. 181, 4 Place Jussieu, 75005 Paris, France
b Institut des Sciences et Ingéniérie Chimiques, Ecole Polytechnique Fédérale de Lausanne, BCH, CH-1015 Lausanne, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Four branched tetra- and pentahydroxylated azepanes have been synthesized from a common azepane
precursor through dihydroxylation followed by deoxygenation. They have been assayed as glycosidase
inhibitors on a panel of 22 glycosidases and one methylated azepane displayed selective, competitive,
Received 9 September 2011
Received in revised form 22 October 2011
Accepted 25 October 2011
Available online 9 November 2011
and moderate inhibition toward bovine kidney a-L-fucosidase.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Iminosugar
Glycosidase
Inhibitor
Azepane
1. Introduction
2. Synthesis
Interest continues to mount in new applications of natural and
synthetic glycosidase inhibitors to basic research and medicine as
iminosugar-based inhibitors1 have been shown to exhibit potent
activity on diabetes,2 HIV infection,3 viral infections4 or cancer5
leading sometimes to therapeutics.6 In the last two decades, 1-N-
iminosugars have emerged as a major new class of very potent
glycosidase inhibitors by virtue of their resemblance with the carb-
ocationic form of glycosidase transition state. The most famous
molecule of this family, coined isofagomine 1, was reported by
Bols7 and proved to be a strong b-glucosidase inhibitor. As ex-
pected, the potency of isofagomine was further improved by intro-
ducing a hydroxyl group at the C-2 position to afford noeuromycin
2, a nanomolar b-glucosidase inhibitor.8 Meanwhile, many other
sugar analogs with nitrogen at the pseudoanomeric position have
been prepared9 including branched derivatives such as compounds
3–6 (Fig. 1).10 The introduction of an extra tertiary hydroxyl group
was justified in order to hold the sugar hydroxyl groups in the cor-
rect topological orientation and hopefully generate more selective
and potent glycosidase inhibitors. This modification was also ap-
plied to polyhydroxylated pyrrolidine generating compounds such
as 711 and 8 (Fig. 1), this latter displaying promising activity as cor-
rector of del508-CFTR involved in cystic fibrosis.12
In an ongoing program on the design of new glycosidase inhib-
itors, our group has recently reported the synthesis13 and biologi-
cal evaluation14 of ring homologs of noeuromycin. We would like
to report herein our results on branched derivatives of these
compounds. We used a similar strategy as the one developed by
Pandey15 based on the dihydroxylation of the exoalkene present
on the available azacycle 9. Dihydroxylation of 9 using OsO4 and
NMO afforded the separable diols 10 and 11 (93% yield) which
were hydrogenolyzed under mild acidic conditions to afford the
corresponding pentahydroxylated azepanes 12 and 13 as their
hydrochloride salts (Scheme 1).
As tetrahydroxylated azepanes have been proved to be potent
glycosidase inhibitors,16 we were also interested in synthesizing
branched analogs of these compounds and introducing some con-
formational bias with an extra methyl group. Tosylation of the
neopentylic alcohol in diol 10 furnished the crude tosylate in good
yield which was directly reduced with SuperhydrideÒ to yield the
corresponding deoxy derivative 14 (68% yield over two steps). Final
hydrogenolysis furnished the branched tetrahydroxyazepane 15 as
its hydrochloride salt (Scheme 2). The same sequence was applied
to diol 11 to furnish the intermediate 16 (65% yield) and the
branched tetrahydroxyazepane 17.
3. Structure determination
⇑
Corresponding author.
E-mail address: yves.bleriot@univ-poitiers.fr (Y. Blériot).
The configuration of compounds 15 and 17 was confirmed by
NOESY experiments. While the CH3 group in compound 15 showed
Present address: Université de Poitiers, UMR 6514, Laboratoire ‘Synthèse et
Réactivité des Substances Naturelles’, 4, avenue Michel Brunet, 86022 Poitiers, France.
0008-6215/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2011.10.039

H. Li et al. / Carbohydrate Research 356 (2012) 110–114
111
H
N
H
N
H
N
H
N
OH
OH
HO
HO
HO
HO
HO
HO
OH
OH
OH
OH
OH
OH
OH
4
1
2
3
H
H
N
H
N
H
N
N
H
N
HO
HO
HO
C
H
OH
OH
12 25
HO OH
HO OH
HO
OH
OH
HO
5
7
6
8
Figure 1. Structure of isofagomine 1, noeuromycin 2 and branched derivatives 3–8.
Z
H.HCl
N
N
H , 10% Pd/C
2
HO
HO
HO
HO
OBn
OBn
OH
1M HCl, MeOH
quant.
BnO
Z
HO
OH
N
10 (56%)
12
OsO , NMO
4
OBn
OBn
+
acetone/H O
2
BnO
Z
93%
H.HCl
N
9
N
HO
H , 10% Pd/C
2
HO
HO
OBn
HO
OH
1M HCl, MeOH
quant.
BnO
OBn
HO
OH
11 (37%)
13
Scheme 1. Synthesis of pentahydroxylated azepanes 12 and 13.
s
Z
H.HCl
H.HCl
H.HCl
N
Ha
Hb
Ha
Hb
m
m
N
N
1
N
1
s
H , 10% Pd/C
2
1) TsCl, pyridine
6
6
Me
H3C
HO
HO
Me
5
2
5
2
10
11
OBn
HO
OH
OH
OH
OH
1M HCl, MeOH
quant.
4 3
4 3
H3C
HO
2) LiBHEt 1M
3
s
H
H
THF
BnO
OBn
OH
OH
HO
OH
m
OH
OH
14
15
68%
15
17
Figure 2. Main NOE data for tetrahydroxylated azepanes 15 and 17.
Z
H.HCl
N
N
H , 10% Pd/C
2
1) TsCl, pyridine Me
HO
Me
All the branched azepanes were found to be weak glycosidase
inhibitors except for azepane 17 which displayed selective and
moderate competitive L-fucosidase inhibition. This last result can
tentatively be explained by the presence of the methyl group and
the adjacent hydroxyl group which partially display the configura-
OBn
1M HCl, MeOH
quant.
HO
2) LiBHEt 1M
3
THF
BnO
OBn
HO
OH
16
17
65%
Scheme 2. Synthesis of tetrahydroxylated azepanes 15 and 17.
tion of L-fucose. Compared to the noeuromycin ring homologs,
introduction of an extra hydroxyl group on the carbon that bears
the hydroxymethyl group appears detrimental to the inhibition po-
tency of this family of compounds. Compared to tetrahydroxylated
azepanes, introduction of an additional hydroxymethyl group on
the tetrahydroxyazepane scaffold also strongly affects the glycosi-
dase inhibition of these compounds. Such observation has already
been made in the case of polyhydroxylated azepanes mimicking
glyconojirimycins.18 In conclusion, increasing the size and lower-
ing the conformational flexibility of seven-membered iminosugars
by introducing an extra CH3 or CH2OH group mainly abolishes
inhibitory potency and therefore draws the size limits for a glyco-
sidase iminosugar-based inhibitor.
a strong NOE effect with H-4 and H-6a and a medium NOE effect
with H-6b, the CH3 group in compound 17 showed a strong NOE
effect with H-6b and a medium NOE effect with H-4 and H-6a
demonstrating a cis relationship for H-4 and the methyl group in
compound 15 and a trans relationship for H-4 and the methyl
group in compound 17 ( Fig. 2) and enabling the unambiguous
deduction of the configuration of related compounds 12 and 13.
4. Glycosidase inhibition assay
Azepanes 12, 13, 15, and 17 were assayed for their inhibitory
activity toward 22 commercially available glycosidases.17 They
did not inhibit the following enzymes at 1 mM concentration and
5. Experimental section
5.1. General methods
optimal pH: coffee bean
a-galactosidase, b-galactosidases from
Aspergillus oryzae and Escherichia coli, rice
a-glucosidase, amyloglu-
cosidase from Aspergillus niger, snail b-mannosidase, b-N-acetyl-
glucosaminidases from jack bean and bovine kidney. For other
enzymes the results are shown in Table 1.
Melting points (mp) were determined with a Büchi B-535 appa-
ratus and are uncorrected. Optical rotations were measured at

112
H. Li et al. / Carbohydrate Research 356 (2012) 110–114
Table 1
Glycosidase inhibitory activity of compounds 12, 13, 15 and 17
H.HCl
N
H.HCl
N
H.HCl
N
H.HCl
N
Me
Me
HO
HO
HO
HO
OH
OH
OH
OH
OH
HO
Compound/enzyme
HO
HO
OH
HO
HO
OH
HO
OH
17
12
15
13
a-L-Fucosidase
Bovine kidney
b-Galactosidase
Bovine liver
NI
NI
NI
NI
NI
NI
87% (118 lM)
NI
20%
21%
60%
79%
56%
29%
NI
a
-Glucosidase
yeast
b-Glucosidase
Sweet almonds
NI
39%
NI
NI
a
-Mannosidase
Jack bean
b-Xylosidase
Aspergillus niger
30%
NI
NI
NI
NI
% of inhibition at 1 mM concentration, optimal pH, 35 °C, IC50 in brackets, NI = no inhibition at 1 mM concentration of the inhibitor.
20 2 °C with a Perkin Elmer Model 241 digital polarimeter, using
a 10 cm, 1 mL cell. Chemical Ionisation Mass Spectra (CI-MS
ammonia) and Fast Atom Bombardment Mass Spectra (FAB-MS)
were recorded on a JMS-700 spectrometer. 1H NMR and 13C NMR
were performed on a Bruker DRX 400 spectrometer (400 MHz for
1H, 100.6 MHz for 13C). All chemical shifts (d) are given in ppm rel-
ative to the residual deuterated solvent signals. Coupling constants
(J) are reported in Hertz. Reactions were monitored by thin-layer
chromatography (TLC) using Merck silica gel 60 F254 precoated
plates and detection by charring with sulfuric acid. Flash column
chromatography was performed on silica gel Merck 60 (230–
400 mesh).
(C-40), 77.34 (C-50), 72.92, 72.77, 72.72, 71.62 and 71.51
(6 ꢂ CH2Ph), 67.75 and 66.99 (2 ꢂ NCOOCH2Ph), 65.98 and 65.88
(C-70 and C-7), 49.58 and 49.19 (C-60 and C-6), 46.68 and 46.08
(C-10 and C-1); m/z (CI, CH4): 598 (M+H+, 100%); HRMS (CI, CH4):
Calcd for C36H40O7N (M+H+): 598.2805. Found 598.2799.
5.1.1.2. Compound 11.
[
a
]
ꢁ23 (c = 1.0 in CHCl3); 1H NMR
D
(CDCl3, 400 MHz): 7.42–7.18 (m, 40H, 8 ꢂ Ph), 5.26–5.14 (m, 4H,
4 ꢂ NCOOCHPh), 4.90–4.38 (m, 12H, 6 ꢂ CH2Ph), 4.06 (dd, 1H,
J1 a,2 = 2.7 Hz, J1 a,1 b = 13.9 Hz, H-10a), 4.02 (dd, 1H, J3 ,4 = 3.9 Hz,
0
0
0
0
0
0
J2 ,3 = 5.6 Hz, H-30), 3.97–3.93 (m, 2H, H-1a, H-6a), 3.91 (dd, 1H,
0
0
0
0
J3,4 = 4.2 Hz, J2,3 = 5.8 Hz, H-3), 3.82 (ddd, 1H, J2 ,3 = 5.6 Hz,
J1 b,2 = 10.1 Hz, H-20), 3.78 (d, 1H, J6 a,6 b = 14.2 Hz, H-60a), 3.75 (d,
0
0
0
0
Note: For compounds 10, 11, 14, and 16 bearing a benzyloxycar-
bonyl group on the nitrogen, they appear as a mixture of rotamers
by NMR.
1H, J3,4 = 4.2 Hz, H-4), 3.74 (d, 1H, H-40), 3.69 (d, 1H,
J7 a,7 b = 12.2 Hz, H-70a), 3.62 (d, 1H, J7a,7b = 12.7 Hz, H-7a), 3.58
(ddd, 1H, J1a,2 = 3.2 Hz, J2,3 = 5.8 Hz, J1b,2 = 10.7 Hz, H-2), 3.53 (d,
1H, H-7b), 3.50 (dd, 1H, H-10b), 3.48 (app. d, 1H, H-70b), 3.43 (d,
1H, H-60b), 3.37 (dd, 1H, J1a,1b = 14.1 Hz, H-1b), 3.36 (br, 1H, OH),
3.34 (d, 1H, J6a,6b = 14.1 Hz, H-6b), 3.00 (br, 2H, OH, OH0), 2.48
(br, 1H, OH0); 13C NMR (CDCl3, 100 MHz): 156.67 and 155.59
(2 ꢂ C@O), 137.98, 137.93, 137.85, 137.76, 137.51, 137.37, 136.09
and 135.93 (8 ꢂ Cipso), 128.62–127.43 (40 ꢂ aromatic C), 83.30
(C-40), 83.22 (C-3), 82.88 (C-2), 82.12 (C-30), 82.09 (C-4), 81.69
(C-20), 77.21 and 76.51 (C-5 and C-50), 74.34, 73.94, 73.51, 73.32,
71.81 and 71.63 (6 ꢂ CH2Ph), 68.10 and 67.67 (2 ꢂ NCOOCH2Ph),
65.28 and 64.37 (C-70 and C-7), 49.12 and 48.82 (C-60 and C-6),
45.66 and 45.03 (C-1 and C-10); m/z (CI, CH4): 598 (M+H+, 100%);
HRMS (CI, CH4): Calcd for C36H40O7N (M+H+): 598.2805. Found
598.2798.
0
0
5.1.1. (3S,4S,5R,6S)-N-Benzyloxycarbonyl-3-hydroxy-3-
hydroxymethyl-4,5,6-tribenzyloxyazepane 10 and (3R,4S,5R,6S)-
N-benzyloxycarbonyl-3-hydroxy-3-hydroxymethyl-4,5,6-
tribenzyloxyazepane 11
Exoalkene 9 (91 mg, 0.162 mmol) was dissolved in acetone/
water 8:1 (0.7 mL). N-Morpholine oxyde (75 mg, 0.641 mmol)
was added, followed by OsO4 (0.03 mL, 2.5% wt in t-BuOH). The
reaction mixture was stirred at room temperature for 24 h and
then quenched by addition of Na2S2O3ꢀ5H2O (6 mg). The reaction
mixture was stirred for 15 min and then diluted with EtOAc, dried
with MgSO4, filtered, and concentrated. Purification by flash col-
umn chromatography (Cy/EtOAc, 2:1) afforded diol 11 as an oil
(36 mg, 37%, Rf 0.25, Cy/EtOAc, 2:1). Further elution (Cy/EtOAc,
3:2) gave diol 10 as an oil (54 mg, 56% yield, Rf 0.13, Cy/EtOAc, 6:1).
5.1.2. (3S,4S,5R,6S)-3-Hydroxymethyl-3,4,5,6-tetrahydroxyaze
pane 12
Hydrogenolysis of diol 10 (53 mg, 0.089 mmol) with 10% Pd/C
in MeOH and in the presence of 1 M HCl solution furnished quan-
5.1.1.1. Compound 10.
[
a
]
ꢁ14 (c = 1.0 in CHCl3); 1H NMR
D
(CDCl3, 400 MHz): 7.43–7.18 (m, 40H, 8 ꢂ Ph), 5.29–5.16 (m, 4H,
4 ꢂ NCOOCHPh), 4.89–4.40 (m, 12H, 6 ꢂ CH2Ph), 4.24 (dd, 1H,
J1 a,2 = 3.4 Hz, J1 a,1 b = 13.6 Hz, H-10a), 4.17 (dt, 1H, J2 ,3 = 3.9 Hz,
titatively compound 12 (21 mg) as an oil. [
a]
D
+9.2 (c = 1.1 in
0
0
0
0
0
0
J1 b,2 = 10.0 Hz, H-20), 4.11 (t, 1H, J3 ,4 = 3.9 Hz, H-30), 4.05–3.96
(m, 6H, H-1a, H-2, H-3, H-6a, H-60a, OH), 3.94 (d, 1H, H-40), 3.75
(d, 1H, J3,4 = 3.7 Hz, H-4), 3.55–3.40 (m, 5H, H-1b, H-7a, H-70a, H-
CH3OH); 1H NMR (D2O, 400 MHz): 4.27 (ddd, 1H, J1a,2 = 2.3 Hz,
J2,3 = 7.8 Hz, J1b,2 = 10.1 Hz, H-2), 3.89 (d, 1H, J3,4 = 2.8 Hz, H-4),
3.77 (dd, 1H, H-3), 3.64 (dq, 1H, J7a,7b = 12.0 Hz, H-7a), 3.58 (dq,
1H, H-7b), 3.40 (dd, 1H, J1a,1b = 13.5 Hz, H-1a), 3.35 (d, 1H,
J6a,6b = 13.7 Hz, H-6a), 3.29 (dd, 1H, H-1b), 3.17 (d, 1H, H-6b); 13C
NMR (D2O, 100 MHz): 80.02 (C-3), 74.55 (C-4), 74.33 (C-5), 70.21
(C-2), 65.87 (C-7), 47.75 (C-1), 46.37 (C-6); m/z (CI, C4H10): 194
(M+H+, 100%); HRMS (CI, C4H10): Calcd for C7H16O5N (M+H+):
194.1028. Found 194.1028.
0
0
0
0
7b, H-70b), 3.39 (dd, 1H, H-10b), 3.25 (d, 2H, J6a,6b = J6 a,6 b = 14.1 Hz,
H-6b, H-60b), 2.94 (t, 1H, OH), 2.45 (dd, 1H, OH0), 2.04 (br, 1H, OH0);
13C NMR (CDCl3, 100 MHz): 156.76 and 156.44 (2 ꢂ C@O), 138.21,
138.02, 137.43, 137.38, 137.27, 137.07, 136.82 and 136.24
(8 ꢂ Cipso), 128.48–127.45 (40 ꢂ aromatic C), 82.33 (C-3), 82.25
(C-2), 81.80 (C-30), 81.21 (C-20), 78.34 (C-4), 77.53 (C-5), 77.39
0
0

H. Li et al. / Carbohydrate Research 356 (2012) 110–114
113
5.1.3. (3R,4S,5R,6S)-3-Hydroxymethyl-3,4,5,6-tetrahydroxyaze
pane 13
Hydrogenolysis of diol 11 (35 mg, 0.059 mmol) with 10% Pd/C
in MeOH and in the presence of 1 M HCl solution furnished
quantitatively compound 13 (14 mg) as an oil. 2.5
(c = 1.0 in CH3OH); 1H NMR (D2O, 400 MHz): 3.58 (ddd, 1H,
J1a,2 = 3.7 Hz, J1b,2 = J2,3 = 8.3 Hz, H-2), 3.79 (t, 1H, J2,3 = J3,4
8.3 Hz, H-3), 3.69 (d, 1H, J7a,7b = 11.5 Hz, H-7a), 3.66 (d, 1H,
H-7b), 3.59 (d, 1H, H-4), 3.43 (dd, 1H, J1a,1b = 13.6 Hz, H-1a),
3.41 (d, 1H, J6a,6b = 14.3 Hz, H-6a), 3.33 (dd, 1H, H-1b), 3.24 (d,
1H, H-6b), 1.36 (dd, 1H, J = 4.7 Hz, 6.6 Hz, OH); 13C NMR (D2O,
100 MHz): 74.98 (C-3), 74.13 (C-4), 72.62 (C-5), 66.93 (C-2),
65.00 (C-7), 48.09 (C-6), 47.14 (C-1); m/z (CI, C4H10): 194
(M+H+, 100%); HRMS (CI, C4H10): Calcd for C7H16O5N (M+H+):
194.1028. Found 194.1031.
5.1.6. (3S,4S,5R,6S)-N-Benzyloxycarbonyl-3-hydroxy-3-methyl-
4,5,6-tribenzyloxyazepane 16
Regioselective deoxygenation of 11 (55 mg, 0.092 mmol) as de-
scribed above for the preparation of 14 furnished compound 16 as
an oil (35 mg, 65%, Rf 0.41, Cy/EtOAc, 2:1).
[
a]
D
–
[a]
D +4 (c = 1.0 in CHCl3); 1H NMR (CDCl3, 400 MHz): 7.43–7.31
=
(m, 40H, 8 ꢂ Ph), 5.24–5.15 (m, 4H, 4 ꢂ NCOOCHPh), 4.92–4.37 (m,
12H, 6 ꢂ CH2Ph), 4.03 (dd, 1H, J1a,2 = 2.2 Hz, J1a,1b = 14.0 Hz, H-1a),
3.96 (dd, 1H, J3,4 = 3.2 Hz, J2,3 = 6.0 Hz, H-3), 3.94 (dd, 1H,
J3 ,4 = 3.6 Hz, J2 ,3 = 6.2 Hz, H-30), 3.89 (m, 2H, H-10a, H-60a), 3.83
(ddd, 1H, J1b,2 = 9.8 Hz, H-2), 3.74 (d, 1H, J6a,6b = 13.8 Hz, H-6a),
0
0
0
0
3.63 (ddd, 1H, J1 a,2 = 2.3 Hz, J1 b,2 = 9.6 Hz, H-20), 3.59 (d, 1H, H-
40), 3.57 (d, 1H, H-4), 3.41 (dd, 1H, J1a,1b = 14.0 Hz, H-1b), 3.40
0
0
0
0
(dd, 1H, J1 a,1 b = 14.0 Hz, H-10b), 3.37 (d, 1H, H-6b), 3.31 (d, 1H,
0
0
J6 a,6 b = 13.6 Hz, H-60b), 2.68 and 2.58 (2s, 1H, 2 ꢂ OH), 1.36 and
1.28 (2s, 6H, 2 ꢂ Me); 13C NMR (CDCl3, 100 MHz): 155.85 and
155.82 (2 ꢂ C@O), 138.12, 138.09, 138.01, 137.60, 137.55, 136.39
and 136.29 (8 ꢂ Cipso), 128.55–127.47 (40 ꢂ aromatic C), 86.46
and 85.99 (C-4 and C-40), 82.69 and 81.84 (C-20 and C-2), 82.25
and 81.94 (C-30 and C-3), 74.48 and 74.14 (C-50 and C-5), 73.21,
73.02, 72.96, 72.92, 71.77 and 71.75 (6 ꢂ CH2Ph), 67.74 and
67.42 (2 ꢂ NCOOCH2Ph), 53.04 and 52.79 (C-60 and C-6), 45.43
and 45.32 (C-1 and C-10), 22.63 and 22.23 (2 ꢂ Me); m/z (CI,
CH4): 582 (M+H+, 100%); HRMS (CI, CH4): Calcd for C36H40O6N
(M+H+): 582.2856. Found 582.2850.
0
0
5.1.4. (3R,4S,5R,6S)-N-Benzyloxycarbonyl-3-hydroxy-3-methyl-
4,5,6-tribenzyloxyazepane 14
To a stirred solution of compound 10 (78 mg, 0.131 mmol) in
dry pyridine (0.5 mL) under argon was added p-toluenesulfonyl
chloride (30 mg, 0.187 mmol) at 0 °C. The reaction mixture was
kept at room temperature under argon for 24 h by which time
TLC (Cy/EtOAc, 3:2) showed a complete reaction. The mixture
was then diluted with EtOAc, washed with water and brine. The or-
ganic layer was dried over MgSO4, filtered, and concentrated to af-
ford a crude product. To a stirred solution of this crude product in
dry THF (0.5 mL) was added Super-hydrideÒ (0.12 mL, 1 M solution
in THF) at 0 °C. The reaction mixture was kept at 0 °C under argon
for 2 h and then diluted with EtOAc at 0 °C. The organic layer was
washed with 1 M HCl solution, water and brine, dried over MgSO4,
filtered, and concentrated. Purification by flash column chromatog-
raphy (Cy/EtOAc, 5:1) afforded alcohol 14 as an oil (52 mg, 68%, Rf
0.42, Cy/EtOAc, 2:1).
5.1.7. (3S,4S,5R,6S)-3-Methyl-3,4,5,6-tetrahydroxyazepane 17
Hydrogenolysis of alcohol 16 (35 mg, 0.060 mmol) with 10% Pd/
C in MeOH and in the presence of 1 M HCl solution furnished quan-
titatively compound 17 (14 mg) as an oil.
[a
]
D
ꢁ8.8 (c = 0.83 in CH3OH); 1H NMR (D2O, 400 MHz): 3.98
(ddd, 1H, J1a,2 = 3.8 Hz, J1b,2 = J2,3 = 8.1 Hz, H-2), 3.72 (t, 1H, H-3),
3.40 (d, 1H, J3,4 = 8.4 Hz, H-4), 3.39 (dd, 1H, J1a,1b = 13.6 Hz, H-1a),
3.32 (dd, 1H, H-1b), 3.27 (d, 1H, J6a,6b = 14.3 Hz, H-6a), 3.21 (d,
1H, H-6b), 1.36 (s, 3H, Me); 13C NMR (D2O, 100 MHz): 77.64 (C-
4), 75.32 (C-3), 70.74 (C-5), 67.07 (C-2), 51.57 (C-6), 47.01 (C-1),
24.93 (Me); m/z (CI, CH4): 178 (M+H+, 100%); HRMS (CI, CH4): Calcd
for C7H16O4N (M+H+): 178.1079. Found 178.1078.
[
a
]
ꢁ14 (c = 1.0 in CHCl3); 1H NMR (CDCl3, 400 MHz): 7.43–
D
7.30 (m, 40H, 8 ꢂ Ph), 5.29–5.16 (m, 4H, 4 ꢂ NCOOCHPh), 4.86–
4.36 (m, 12H, 6 ꢂ CH2Ph), 4.17–4.12 (m, 2H, H-10a, H-20), 4.05 (t,
1H, J2 ,3 = J3 ,4 = 4.2 Hz, H-30), 4.02–3.92 (m, 4H, H-1a, H-2, H-3,
H-60a), 3.89 (d, 1H, J6a,6b = 14.4 Hz, H-6a), 3.60 (d, 1H, H-40), 3.59
(s, 1H, OH), 3.58 (d, 1H, J3,4 = 3.7 Hz, H-4), 3.42 (dd, 1H,
0
0
0
0
H-10b),
3.37
(dd,
1H,
References
0
0
0
0
J1 b,2 = 10.7 Hz,
J1 a,1 b = 14.5 Hz,
J1b,2 = 10.6 Hz, J1a,1b = 14.9 Hz, H-1b), 3.33 (d, 1H, J6a,6b = 14.4 Hz,
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H-6b), 3.28 (d, 1H, J6 a,6 b = 14.3 Hz, H-60b), 3.19 (s, 1H, OH0), 1.32
and 1.26 (2s, 6H, 2 ꢂ Me); 13C NMR (CDCl3, 100 MHz): 156.66
and 156.43 (2 ꢂ C@O), 138.29, 138.18, 137.63, 137.53, 137.49,
137.35, 136.94 and 136.45 (8 ꢂ Cipso), 128.49–127.49 (40 ꢂ aro-
matic C), 83.94 and 83.45 (C-4 and C-40), 82.52 and 81.21 (C-2
and C-20), 82.35 and 82.03 (C-3 and C-30), 75.29 and 75.19 (C-5
and C-50), 73.11, 73.04, 72.96, 72.82, 71.58 and 71.46 (6 ꢂ CH2Ph),
67.61 and 67.00 (2 ꢂ NCOOCH2Ph), 53.64 and 53.15 (C-6 and C-60),
46.81 and 46.14 (C-10 and C-1), 26.86 and 25.46 (2 ꢂ Me); m/z (CI,
CH4): 582 (M+H+, 100%); HRMS (CI, CH4): Calcd for C36H40O6N
(M+H+): 582.2856. Found 582.2859.
0
0
5.1.5. (3R,4S,5R,6S)-3-Methyl-3,4,5,6-tetrahydroxyazepane 15
Hydrogenolysis of diol 14 (46 mg, 0.079 mmol) with 10% Pd/C
in MeOH and in the presence of 1 M HCl solution furnished quan-
titatively compound 15 (18 mg) as an oil. [
a]
+5.2 (c = 1.0 in
D
CH3OH); 1H NMR (D2O, 400 MHz): 4.22 (ddd, 1H, J1a,2 = 2.3 Hz,
J2,3 = 7.5 Hz, J1b,2 = 9.9 Hz, H-2), 3.75 (d, 1H, J3,4 = 3.3 Hz, H-4),
3.70 (dd, 1H, H-3), 3.35 (d, 1H, J6a,6b = 13.7 Hz, H-6a), 3.34 (dd,
1H, J1a,1b = 13.6 Hz, H-1a), 3.23 (dd, 1H, H-1b), 3.05 (d, 1H, H-6b),
1.37 (s, 3H, Me); 13C NMR (D2O, 100 MHz): 79.71 (C-3), 78.58 (C-
4), 71.98 (C-5), 70.23 (C-2), 50.41 (C-6), 47.55 (C-1), 26.23 (Me);
m/z (CI, CH4): 178 (M+H+, 100%); HRMS (CI, CH4): Calcd for
C7H16O4N (M+H+): 178.1079. Found 178.1081.
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